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W E N S AGAINST IOX.C r.H FM irA i I^R K ^O H WASHINGTON 99403 ^ (509; 758 - 5796 CBW {T& W ) ANn The London Conference on CBW held under the auspices of the J. D. Bernal Peace Library LTf l j: l! CBW CHEMICAL AND BIOLOGICAL WARFARE London Conference on CBW edited by STEVEN ROSE GEORGE G. HARRAP & CO. LTD London Toronto Wellington Sydney First published in Great Britain 1968 by G eorge G. H arrap & Co. Ltd 182 High Holbom, London, W.C. 1 J. D. Bernal Peace Library and Steven Rose 1968 Copyright. All rights reserved SBN 245 59485 X Composed in Linotype Times and printed at the St Ann's Press, Altrincham Made in Great Britain Z\01S w, FOREWORD This book is based on the collection of papers presented to the Conference on Chemical and Biological Warfare which was held in the Bonnington Hotel, London, on February 22nd and 23rd, 1968. The aim of the Conference was to provide an authentic assessment of the present level of development of chemical and biological weapons, their manner of use in war, and the possibilities of defence against them; to consider the status of such weapons in international law; and to discuss ethical problems, especially the responsibility of the scientist, in relation to their development and use. The Conference was the first major event to be sponsored by the J. D. Bernal Peace Library, an educational trust set up to collect source material and to provide information of assistance in the struggle for peace and toward ensuring the realization of the fullest potentialities of science in building a world prosperous and without war--aims toward which J. D. Bernal has made a unique contribution. The Conference took place against a background of the use of defoliants and so-called non-toxic chemical weapons in Vietnam and the reported use of more lethal gases in the Yemen. The discussions at the Conference indicated the practicability of the renunciation of CBW by all the major powers at a time when there is still no major investment' of money and personnel in this field. It is in the hope that the spread of factual knowledge about the nature and menace of these weapons will further the campaign for their elimination and for more complete disarmament that these papers are being published. E. H. S. BURHOP London May, 1968 X \O rUo PREFACE The aim of the Conference whose proceedings form this book was a clear one. While we were concerned to amass as substantial a body of information as possible on current developments in chemi cal and biological warfare, our object was primarily to help inform opinion and stimulate discussion on the political, military, legal, and moral implications of the research, and on development, stockpiling, and use of chemical and biological weapons in a period of nuclear stalemate when it appears military strategists are placing increasing weight on the potential of these weapons. We attempted --and I have attempted as editor of this book--to separate the pre sentation of the facts about CBW as a potential and actual war technology, from our assessment of 'its implications. Such a dis tinction is of course at best artificial, and its artificiality will be apparent to the reader. It is not really possible to isolate a weapon or a technology from the political or moral climate in which it is made or used. None the less, in military and legal terms, and in the popular imagination, the chemical and biological weapons, like nuclear weapons, have been so isolated, presenting a separate class of problems. In the Conference, each of these several themes was dealt with in a separate paper, and discussion--often lengthy--followed. In converting the conference texts into book form, I have omitted some few of the papers which seemed to me to be too specialized for a general readership, have slightly edited the individual papers to reduce them in length and to impose a certain uniformity in presentation, and have ruthlessly pruned the discussions which fol lowed the papers, either incorporating points wholesale into the texts, or summarizing the essential themes as they appeared to me at the time or on rereading the transcripts afterwards. All the participants have cheerfully acceded to this procedure, and I must thank them for their participation. I can only hope that the resultant book is readable without losing completely the flavour of a Conference with its implied differences of viewpoint and of personality. 8 CHEMICAL AND BIOLOGICAL WARFARE In the task of both planning the Conference and turning its proceedings into a literate and readable text, the Conference committee, chaired by Professor Eric Burhop and including Mr Bill Carritt, Mr Robin Clarke, Dr John Humphrey and Dr Vic Sidel, has provided consistent support; Mr David Pavett has undertaken the major tasks of checking manuscripts and references; and the services provided by Mr Colin Sweet and the Bernal Library have immeasurably lightened the load. I must particularly thank Mr Bert Ede, who recorded our proceedings, and Mrs Margaret Stern, Mrs Anita Taylor, and Mrs Naomi Wolff, who typed and transcribed against an ever-pressing time limit. Mr. Peter Sommer, of Harrap's, has most efficiently handled the task of getting a book which was being almost continuously updated even as it passed through the printer's hands so rapidly into press. Because of the rapidity with which events have moved even in the few months since the Conference, and the amount of further information that has become available, it has proved possible and necessary to revise some of the papers; statements that were merely guesses in February--particularly about the activities of Porton--can now be documented accurately. This revision has been done where possible without affecting the format of the individual papers by means of editorial insertions. In one or two cases, especially Chapter 9, it has seemed proper to insert substantial additional material. I must take full editorial responsibility for any errors, of fact or interpretation, that these changes may have produced. STEVEN ROSE London August 1968 2-1077 CONTENTS IN T R O D U C T IO N Lord Ritchie-Calder 12 P A R T O N E : THE WEAPONS Chemical Weapons Psychedelics Napalm Biological Weapons Defoliants Starvation as a Weapon J. Perry Robinson 19 C. R. B. Joyce 35 V. W. Sidel 44 I. Mlek 48 A. W. Galston 62 J. Mayer 76 PART TW O: CBW IN USE Vietnam The Yemen M. F. Kahn 87 D.M. Meselson and E. Viney 99 P A R T T H R E E : RESEARCH POLICY United Kingdom United States Soviet Union R. Clarke and J. Perry Robinson 105 Elinor Langer 119 D. E. Viney 130 P A R T F O U R ; LEGAL ASPECTS OF CBW Legal Aspects I. Brownlie 141 10 C H E M I C A L A N D B I O L O G I C A L W A R F A R E PART F IV E : ETHICAL PROBLEMS 13 Preventing CBW J. H. Humphrey and M. Meselson 157 14 Medical Ethics V. W. Sidel 172 15 Scientific Responsibility C. F. Powell 181 16 Some Conclusions S. P. R. Rose 186 BIOGRAPHICAL NOTES 189 REFERENCES 191 GLOSSARY 205 INDEX 207 ILLUSTRATIONS 56 57b e tw e e n p a g e s a n d CBW Research ThMeicmroabsiso-lporgoicdaulctRioenseoafrcahntEhsrataxblibsyhmtheentb, aPtcohrtomneDthoowdn.at the The `8-bair aerosol test sphere. 6F,o00rt0Desthriecekp, Macacriydlaenndta.lly destroyed by nerve gas. Chemical Defence Experimental Establishment, Porton Down. C B W in Use Grenade of CS. Gas-mask The `Mighty Mite' A USAF C-123 P ro v id e r on a defoliation mission. TABLES Page 1. Principal agents of Chemical Warfare 32-33 2. Some properties of selected psychedelic substances 41 3. Identification of BZ by comparison of activity profiles 42 4. Some objectives of reversible CW agents 43 5. Principal agents of Biological Warfare 60-61 6. Plants damaged outside sprayed areas (Vietnam) 65 7. Deaths during the Blockade of the Central Powers (1914-18) 81 8. NLF dossier of deaths caused by toxic gases in Vietnam 94-95 9. British universityinvolvement inCBW research 118 10. U.S. universityinvolvement in CBWresearch(1961-68) 129 INTRODUCTION Lord Ritchie-Calder It is most appropriate that this Conference should be one of the initial activities of the J. D. Bernal Peace Library. In fact I can say: "This is where I came in . . As my MI5 record shows, over thirty years ago, I was involved with Desmond Bernal and a group of scientists who were exposing the near-cynicism of the Air Raid Precautions. We had managed to get hold of one of the gas-masks which were to be issued in the event of war. I was writing about it, but I was also addressing meet ings, tailed by a faithful shadow from the Special Branch. One of the things which I was showing was that the charcoal snout was no protection against arsenical smokes. I stood in front of a screen, had a spotlight thrown on me, and filled my mouth with tobacco smoke and put on the gas-mask. I then breathed out through the canister, and the audience could see the smoke curling up. The then Home Secretary, Sir Samuel Hoare, took a poor view of these activities and he denounced me in the House of Commons. He said arsenical smokes would only make one sick. Whereupon I challenged him to go into a gas-chamber and have the experience of being sick in a gas-mask! But the result was that when the millions of civilian gas-masks were issued on the outbreak of war they all had anti-smoke wafers strapped on to the snouts with sticking-plaster. That was kindergarten stuff compared with the situation today, but security is still as childish. There has been a conspiracy of silence about these activities which are as fraught with mischief and ultimate peril as the development of nuclear armaments. The Doomsday Bug is under wraps! The conspiracy is not confined to military security. Some scien tists themselves shy away from the implications. One knows of distinguished scientists who can be as forthright as the rest in denouncing nuclear weapons but will avoid the subject of chemi INTRODUCTION 13 b i o IT cal and biological warfare, especially biological warfare. It is quite irrational. Although they may not be dealing with official secrets and their own academic thinking is not classified, they can only guess, with uncomfortable perception, at the military applications. It is a psychological inhibition. They simply do not want to believe that their fundamental work can be perverted. Perhaps they are preserving their innocence, like the schoolboy who said he was going to be a biologist: "Physics is bombs. Chemistry's insecticides. Biology is about life." Perhaps they do not want to believe it is about death. This is another crisis of the scientific conscience. Between the Wars Sir Richard Gregory, at the British Association for the Advancement of Science, pointed out that in a chemical dictionary mustard gas and chloroform were on the same page--the malevo lent and the benevolent. But the chemist who discovered mustard gas was just as guiltless as the chemist who discovered chloroform; others took the results of science and perverted them. That was relatively true until the nuclear physicists took the initiative over the bomb. It was they--including Einstein, the lifelong pacifist-- who impressed upon the policy-makers and the generals the possi bilities of turning the laboratory discovery by Hahn and Strassman into a cataclysmic weapon. And the physicists were left with that guilt-sense. But the same sort of thing was also happening in biology during the War. It has been said that agricultural science has produced an innocent weed-killer which has been transformed into a defoliant. But from my wartime experience I recognized the post-war com mercial weed-killer as one of the secret weapons which wartime scientists had dreamed up as anti-crop warfare. Certainly scientists enlisted for war were not overburdened with scruples. Perhaps the Allied scientists did not lend themselves as the Germans did, to putting people into gas-chambers or using concentration-camp victims for trying out nerve gases and new diseases, but they `went along' with biological warfare. One of the principals in Canadian Chemical and Biological Warfare re vealed in 1949 that "one bacteriological weapon developed late in the second World War could wipe out all human life in a given area within six hours and yet leave the area habitable afterwards. . . . While it kills everybody in six hours, it itself is oxidized in twelve hours, leaving the ground perfectly safe to occupy. . . -"1 In fact, it was botulimis toxin that was being described. Botulin became part of a double bluff during the War. Supplies existed 14 C H E M I C A L A N D B I O L O G I C A L W A R F A R E and might have been used, but only if the Germans had first used something of the same--a principle affirmed by both Churchill and Roosevelt in relation to CBW. So we contrived to `serve notice' on the Germans. Certain Canadian servicemen were briefed that if taken prisoner they would, in addition to name, rank, and number, reluctantly disclose that they had been vaccin ated against botulin. A dicey game of poker! It could have meant (as we intended it to) "Don't do anything rash, chum, or else. . . ." Or it might have provoked a pre-emptive strike, and we would have been in a chemical and biological war. By that time, we were nervous about CBW. Hitler's major secret weapons--the VI and V2--had failed, and he was being pushed towards that ultimate culmination in the Berlin bunker. Gas had not been used by either side, but it certainly existed--a fact of which the disaster to the gas-supply ship in Bari was a reminder. Another was when a German shell hit an Allied gasshell dump in the Anzio bridgehead and the gas started drifting towards the German lines. The Allied commander had to use the hot-line technique to his opposite number saying it was an accident and there was no intention to use gas. We may have had to wait until our scientific search parties went into defeated Germany to discover such refinements as the anti-cholinesterases sarin, tabun, and soman, but even allowing for any imprcisions of our espionage system, we knew they had them. Why? Because, of course, we had similar chemical weapons. That is how one works in CBW-- seeing the other side's potential in the mirror of one's own. What we feared was that Hitler, once he had decided that the German people were not worthy of him, would unleash a CBW Gotterdamerung. Then, apart from gas-destruction, we might have had a modem Black Death. Frederic Joliot-Curie suggested `The Secret War' over twenty years ago. He extended the example of nuclear security to biologi cal security. Behind the sky-high walls of secrecy the scientists had produced the Bomb. They had condoned the secrecy, so that it became the physicists' Bigger and Better Bomb, without any account being taken of the biological effects of radiation, without any of the premonitions, safeguards, and interdisciplinary reminders that come from free scientific exchanges--and without any sanctions on its use which proper information exerts. One recalls Attlee's statement, as one who had concurred in the dropping of the bomb on Hiroshima : "We knew nothing whatever at that time about the genetic effects of an atomic explosion. I knew nothing at all INTRODUCTION 15 about fall-out and all the rest that emerged after Hiroshima. As far as I know, President Truman and Winston Churchill knew nothing of these things either, nor did Sir John Anderson who co-ordinated research on our side. Whether the scientists directly concerned knew, or guessed, I do not know. But if they did, then so far as I know they said nothing of it to those who had to make the decision." And in the entire documentation of the British atomic energy effort there was only one brief paper (by the Medical Re search Council) on genetic effects, and that apropos not of the bomb but of the use of radioactive elements as a form of biological warfare.2 What Joliot-Curie did was to extend the lessons to biology. He pointed out that such a war need never be declared. It could go on for years with only the hidden aggressors knowing what was happening. Then, gradually, successive crop failures, devastation of herds by disease, human epidemics (unexplained because the organisms weren't in the books), and a catastrophic fall in the birthrate, through the sterilization of women by tampering with the water supply, would reveal the truth. What Joliot-Curie was arguing for was a full scientific disclosure to alert mankind. But in the `Through-the-looking-glass' world of military expediency the same arguments are used to justify secrecy --Don't put ideas into people's heads! Thus `defence' becomes building up stockpiles of chemical and biological weapons. If the Microbiological Research Establishment at Porton is no more than a means of protecting us against threat ened diseases, why is it not under the Ministry of Health? If we pursue this further, and we must, we shall find, as the Americans found for their own institutions, that there is a whole network of relationships between Porton and the universities and research institutions, contracts and grants ostensibly for academic research with the right to publish--but not if the Ministry of Defence chooses to classify it! (This prophecy has now proved correct. E d) The issues involved are not only the ultimate threat of world war with no holds barred--the ABC war, Atomic, Biological, Chemical--but the corrosion of our attitudes to evil. I return again to the censorship, self-imposed, by the scientists who `just don't want to think about it.' Many of them, unless they are bereft of imagination, must know that their fundamental work, their `pure' science, is being corrupted in this way. They knew the implications of DNA, molecular biology, gene manipulation, of their basic chemistry, and they must know also that intensive work on the 16 C H E M I C A L A N D B I O L O G I C A L W A R F A R E practical applications of such work is going on in `defence' establishments. Even if they are not participating, they are acces sories before the fact, and they must be frank about this. But we cannot be too hard on them when those who are con cerned with peace and war also duck this issue. One may say "Oh, Lord, I've enough to worry about without th at\" but while we are wrestling with non-proliferation and nuclear restraints--very important it is true--no systematic work towards CBW control is proceeding. Pious resolutions, yes, but that is where it stops. It belongs to that tomorrow when we shall get agreements on general and complete disarmament. Meanwhile, as they say in the United States, "C.B.W. ought to have better public relations". What they mean by that is that people should be taught to approve of napalm, defoliation, `police-gas', and so on. This aims to produce the acquiescence of ignorance, which leads to escalation and the legiti mization of the next stage--the point where the military can do what they like. It is an easy progression from justifying the de foliation of jungle so as to deprive guerrillas of cover to `treating' hundreds of thousands of acres of rice-crops to deprive guerrillas-- and the people--of food. And to awarding the highest U.S. civilian medal to a woman scientist who discovered a better riceblast fungus --more effective, that is, than the natural disease which has in the past destroyed Asian rice-crops and killed millions by famine. We get bland terms like `humane' and `anti-bellicose' gases, which include two categories which, in U.S. Army Chemical Corps circles, are jocosely called `off the rocker' and `on the floor'--a homely way of describing psychochemicals and paralysers. And if they won't stay on the floor there are the proper lethal gases too. We have had conventions. At least the Americans are `legal'; they have not signed the Geneva Protocol. But Britain, Australia, and Canada are signatories, although they exercise the reservation on the right of reciprocity. If one is going to reciprocate one must have something to reciprocate with, and thus one justifies peace time research and stockpiling. And Britain, Australia, and Canada have a quadripartite agreement with the United States. But surely~tffe greatest conscience casualty is science itself. While one group of scientists are bending their energies to prevent diseases, another is devising man-made epidemics. While one set is discarding chemicals saying "We dare not use that," another is picking them out of the trash-can and saying "You bet we can!" This is the Jekyll and Hyde of science. 3^l Off PART ONE THEWEAPONS 246351 NSCPBDatshieaopyefrloacovmhllagimiaetcicindaoatelnsllWicaWsseeaaappWoonnessapon J. Perry Robinson C. R. B. Joyce V. W. Sidel I. Mlek A. W. Galston J. Mayer B 1. Chemical W eapons J. Perry Robinson Most of the weapons used today are chemical. The explosion of TNT is a chemical reaction, so is the combustion of napalm. But we are concerned here with those weapons which are based on the toxic properties of chemicals rather than on the energetics of their interaction. In arming ourselves with them we are following the lead of the humble ant or snake. A weapon-system based on toxic chemicals may be looked at as the sum of four parts: (i) a system to deliver the munitions; (ii) munitions to disseminate the chemical agent; (iii) the agent itself; and (iv) the part played by the environment in transporting the disseminated chemical to each target individual. It must be stressed that each target is an individual, and that the weapons we are talking about are purely anti-personnel. Each of the four parts is dependent to a greater or lesser extent on the other parts. If an attacker is relying on the atmosphere to transport the agent to the target individual's lungs, the agent chosen must be one which can be made airborne in a form which will penetrate the lungs. If the chosen agent is one which is sensitive to heat, then the chosen munition must avoid it. This interdepen dence must be kept in mind in what follows. The available chemical agents In 1956, Edgewood Arsenal, the U.S. chemical warfare research centre, published a four-volume Report on Properties of War Gases} This report, which presumably corresponds to the `Red Book' of the British CW station at Porton, is classified secret, but the assumption is that it contains collected data on all chemicals likely to be of any use in chemical warfare. The titles of the volumes are G-agents, Blood and Nettle Gases, Vomiting and Choking Gases, and Lachrymators, and Vesicants. I shall describe two or three of the chemical agents which can be assumed to be in each volume, and also mention known agents 20 C H E M I C A L A N D B I O L O G I C A L W A R F A R E which would now be placed in supplementary volumes, notably the V-agents and the incapacitating agents. vomiting gases and lachrymators. In the training manuals these are classified as riot-control or harassing agents. They are irritants2' '1 and are lethal only in very high concentrations. Some are particularly irritating to the eyes (lachrymators), some to the inner surfaces of the nose and upper breathing tubes (sternutators), some to the skin (orticants), and some, if swallowed, to the upper reaches of the alimentary canal (vomiting agents). The body attempts to counter the irritation either by secreting fluids or by initiating reflex actions, for instance, vomiting, or the desire to scratch. It is the incapacitating nature of these responses which gives the agents concerned their harassing effect and their common names. In general any one irritant will provoke all of these res ponses to a greater or lesser extent. Nowadays, the principal requirements made of these agents are an immediate action, a lack of persistency in the field, and a brief duration of effect. Those agents which can be disseminated as smokes (inevitably non-persistent) are thus preferred. The principal one is ortho-chlorobenzalmalononitrile, known as CS. In order of occurrence its effects are quoted as "extreme burning sensation of the eyes and copious flow of tears; coughing; difficult breathing and chest tightness; involuntary closing of the eyes plus sinus and nasal drip; nausea and vomiting."'1 In the words of the British Government's patent on its use5, "A concentration of between one part in ten million and one part in a million is enough to drive all but the most determined persons out of it within a few seconds". That is to say, it is instantly effective at field concentrations between 1 and 8 thousandths of a gram per cubic metre. CS is more effective than the older agent CN (chloroacetophenone) in that it supplements the latter's lachrymatory action with a more severe skin irritation, and is more stable on storage. Its effects are shorter lived and quicker starting than those of the other preferred agent, DM or adamsite. The agent known as CNS6 is a pre-war formulation of CN which has increased persistency in the field. It contains chloroacetophenone and the vomiting agent chloropicrin dissolved in chloroform.7' 8' 9 A lengthy exposure to these agents is exceedingly unpleasant and painful. Soldiers have been driven mad by the pain. Some have tried to kill themselves to avoid it.10 choking gases. The choking gases are those which act by irrita ting the lower reaches of the breathing apparatus. Far from being 2.(633 THE WEAPONS --CHEMICAL 21 merely harassing, their irritancy is sufficient to destroy the more delicate membranes of the lungs or respiratory passages. On the one hand, this may mean that the body's defences against invading micro-organisms are breached; on the other, it may lead to a total blockage of oxygen uptake and hence death either from pneumonia or bronchitis, or from asphyxia. The symptoms are prolonged and excruciating; the final crisis may be delayed for several hours. The choking gases are the classical agents of chemical warfare. They include chlorine, phosgene, trichloromethyl chlorojormate, and more recently disulphur decafluoride.11 They are unlikely to be used in a modern chemical war, for their initial irritancy or smell immediately warns of their presence, and gas-masks can be donned before a lethal exposure. In addition, their toxicity is nowadays too low. The lethal exposure to phosgene is around 3200 mg-min/m3 12 (a measure of dose and time of exposure combined; e.g., of 1 m g/m 3 for 3200 minutes, or of 3200 mg/m3 for 1 min, or any intermediate combination, see Glossary). nettle gases. The nettle gases are primarily skin irritants, but more painful than those we have already discussed. An exposure to one of them has been compared to being thrown naked into a bed of stinging nettles, hence their name. They were first seriously studied in the 1930's by the Germans, who sometimes referred to them as "Red Cross" agents. A typical nettle gas is dichloroformoxime. The Russians are said to have stockpiled it during World War II.13 At low concentra tions it is a typical skin irritant and lachrymator, but at higher concentrations it blisters the skin and penetrates it to enter the blood circulation. From then on its effects may be lethal; it will reach the lungs and cause pulmonary oedema (swelling due to uptake of water), characteristic of phosgene to which it is chemi cally related. A 1955 report11 from Edgewood Arsenal quotes a lethal toxicity in guinea pigs of 25 mg. per kg. body-weight when placed on the skin.15 Its combination of highly painful skin attack with the possibility of a lingering death by asphyxiation un doubtedly makes it one of the nastiest agents available. There is probably no tactical need at present for the nettle gases. Lethal agents must nowadays be imperceptible and therefore non irritating, while riot-control agents must be non-lethal. blood gases. Dichloroformoxime can act as a circulatory poison if it enters the bloodstream, and this action is a special characteris 22 C H E M I C A L A N D B I O L O G I C A L W A R F A R E tic of the blood gases. These are principally intended for inhalation in the field; once inhaled,.they are rapidly absorbed into the blood circulation where in very small doses they can completely block oxygen circulation around the body. To quote the long-out-of-print British official Medical Manual of Chemical Warfare,16 they "may cause death with dramatic rapidity". The principal blood gases are hydrogen cyanide and cyanogen chloride which replaced phosgene in certain types of munition in the U.S. arsenals during World War II.17 The Russians managed to compound hydrogen cyanide into a form which could be success fully sprayed from aircraft, a considerable achievement.18 The blood gases are not quite as lethal as phosgene, but are far quicker acting and somewhat harder to protect against.12 vesicants. These agents injure every sort of body tissue with which they come into contact. Their principal targets are the skin and the eyes, which they burn and blister. Because they are not very volatile substances they persist in the field for long periods and can be effective for days or weeks after dissemination. If they are used in sufficiently high concentration lethal doses may be absorbed through the skin. If they can be made sufficiently airborne lethal doses may also be absorbed through the lungs. In fact their inhala tion toxicities are generally much higher than those of the other lethal agents which have so far been described. There are two main classes of vesicant--the arsenicals and the mustards. The arsenicals, such as Lewisite and the other dichloroarsines have sharp, irritating odours and cause immediate eye pains.13 In contrast the mustards have practically no smell and cause no initial pain or irritation. None the less, their damage is done within a few minutes of exposure, and after three or four hours the victim may be blinded or so blistered as to be incapable of action. Although the arsenicals give enough warning of their presence for protective clothing to be donned in time, the mustards do not, and it is for this reason that they are still in the arsenals fifty years after their introduction. There are several different mustards, ranging from the compara tively volatile bis(fS-chloroethyl) sulphide or trisifS-chloroethyl) amine to the highly persistent a,u-bis((3-chloroethylthio)alkanes.2<> One of the most dangerous is the agent Q, which will bum or blind at an exposure of less than 50 mg-min/m3, and kill if inhaled (as an aerosol for it is a solid) at dosages of 200 mg-min/m3. Although its tactical use would probably be for skin attack its iusdi THE WEAPONS --CHEMICAL 23 inhalation toxicity approaches that of the older nerve gases. In the words of an Edgewood Arsenal report21 its lung action is "a bonus effect". g-agents. The first nerve gases, or G-agents, were developed in secret by the German chemical industry shortly before and during World War II. They are quick-kill agents of tremendous potency. Some, like tabun, are persistent in the field. Others, like sarin, are non-persistent. They reduced bomb-loads to one-twentieth or less of what was previously necessary. April, 1942, when tabun first went into large-scale production,22 was an even more important date in chemical warfare than July, 1917, when mustard shell were first fired. The very largest targets were now vulnerable to chemical attack. The nerve gases are anti-cholinesterase agents, working by block ing the enzyme which the body uses to destroy one of its chemical nerve signal transmitters after it has done its job. This has two effects. One is that control is lost over the affected part of the ner vous system. The other is that a large concentration of the chemical transmitter rapidly builds up within the body, and that chemical is itself a powerful poison. The body is first incapacitated, and then forced to poison itself. The symptoms of nerve-gas poisoning are diverse and spectacu lar. In a comparatively inactive man an exposure to sarin of 15 mg-min/m3 dims the vision, the eyes hurt and become hard to focus. This may last for a week or more. At 40 mg-min/m3, the chest feels tight, breathing is difficult, there is coughing, drooling at the mouth, nausea, heartburn, and a twitching of the muscles. At 55, there is a strangling tightness and aching of the chest, vomiting, cramps, tremors, and involuntary defaecation and urination. At 70, severe convulsions will set in followed closely by collapse, paraly sis, and death.23 Of the better known G-agents tabun is about half as toxic as sarin, and soman about twice as toxic.24 It is a moot point whether tabun is still considered worth stockpiling. Its toxicity is not as high as the other G-agents, but it has a persistency in the field which may be considered tactically useful, that is to say, midway between sarin and the V-agents, so that it can presumably provide a vapour hazard for some days after dissemination. Again, although it is more quickly destroyed by moisture than are the other G-agents, the resultant hydrolysis product, hydrogen cyanide, is highly poison ous, as is the cyanogen chloride formed when it is treated with 24 C H E M I C A L A N D B I O L O G I C A L W A R F A R E decontaminating solutions. In addition, its casualties are rather less amenable to the use of the oxime-type antidotes than those of sarin,25 but equally there are other G-agents, such as soman25 and cyclohexyl methyl'phosphonofluoridate (GF)20 which are even harder to counter. The Germans stockpiled tabun rather than sarin because they found it easier to make. The final stage in their large-scale process for sarin demanded high fluoride concentrations, and even with elaborate silver-lined apparatus27 they could not get round the corrosion problems. Although they made some hundreds of tons of its intermediates, they could produce no more than half a ton of sarin itself,22 as compared with the 12,000 or so tons of tabun.28 The Americans at least were later able to solve the corrosion prob lems, and have been making sarin ever since. In 1954 the amount of the substance phosphoryl chloride, produced as a by-product, began to prove a severe commercial embarrassment.25 nerve gases. In some circumstances, lethal doses of G-agents can be absorbed speedily by the skin from airborne field concen trations. Since World War II, new nerve gases have been developed which are absorbed through the skin faster and more reliably than the G-agents. The new nerve gases are known to the Americans as V-agents. Although they have not yet officially disclosed the chemical struc tures, it is a reasonable assumption that the V-agents are the S-dialkylaminoethyl alkyl methylphosphonothiolates. If this is so then it is interesting to note that the first openly published30 per cutaneous toxicity figures for them were given by Academician M. M. Dubinin, a staff member of the Karpov Institute in Moscow. The Swedish Ministry of Defence states that between two and ten mg. of F-gas, presumably another name for V-agent, are fatal when placed on a man's skin.24 Such a dose is so small as to be almost invisible.31 Their inhalation toxicity is given as about 5 times that of soman.24 Thus the V-agents are about 2000 times as toxic by skin absorption as mustard gas, and about 300 times as toxic through the lungs. The V-agents are reputedly a British discovery. Certainly it was ICI who in 1955 applied for a patent32 to cover the phosphonothiolates mentioned earlier. They thereby prevented Bayer from getting one on their rather later application.33 One of the inventors named in the Bayer application was the same Gerhard Schrader who was responsible for the nerve gases in the first place.34 THE WEAPONS --CHEMICAL 25 incapacitating agents. Most people have heard of the `psychogases'; some have seen the film of the cat cowering before a mouse under the influence of one--LSD in that particular film. The idea behind such agents is to put the enemy out of action for several hours without permanently harming him, preferably in such a way that he needs no medical attention. Such agents have long been the ideal of chemical warfare theorists; within a few months of the first German chlorine attack in 1915 the specification for a British patent was filed on the idea.30 Parts of it read very much like a Chemical Corps press release of the late 1950's. The pharmaceutical industry has indeed produced a great range of compounds which have such effects.10 But the chemical warfare laboratories demand that they act at very small dosages, exposures of less than 100 mg-min/m3.41 If a drug is as powerful as this it will almost certainly be lethal at higher exposures, and no field commander is going to make any great effort to avoid over-hitting a target. Thus it seems most likely that the purely incapacitating agent is more a weapon of public relations than of war. None the less, the Americans are expending considerable effort in pursuing this particular ideal, both inside the defence labora tories and in those of contractes. Among the earliest of the outside contracts must be that with the Shell Development Company, dating from 1952, which called for an examination of synthetic cannabis derivatives for both incapacitating and lethal properties.42 Incapacitation can be brought about by interference with either the mind or the body. Mental incapacitation, particularly by the hallucinogens, has been more in the public eye, so much so that the terms `incapacitating agent' and `psychogas' are regarded as synonomous. But for the reasons discussed in the next chapter militarily useful incapacitants are more likely to be found among the bodyincapacitating agents--the paralysants, for denying movement, the hypotensives, for causing fainting,>the emetics, the convulsants, the laxatives, and so on, perhaps supplemented by mental derangement. It looks as though the Americans' recently standardized incapacita ting agent BZ, upon whose use there are "critical limitations,"43 falls within this class. Its symptoms include a slowing of mental and physical functions, dizziness, disorientation, and hallucinations, coupled with skin flushing, a speeding up of the heart-beat, urinary retention, and constipation.43 These seem to be very similar to the effects of certain of the anti-cholinergic drugs,14 and it may be that BZ came to light during the search for nerve-gas antidotes related to atropine. It may even be such an antidote. How convenient that 26 C H E M I C A L A N D B I O L O G I C A L W A R F A R E would be. Guesses at its structure should probably include the 3-qninuclidinyl phenyl glycollates. current developments. Before leaving the chemical agents we should indicate one or two lines of research into them which are at present being followed. One is the use of mixtures of chemical agents with either physio logically active ingredients or inert ones. In the former category come those mixtures in which the toxicity of the main component is increased so that the lethal dose of the mixture is lower than the sum of the lethal doses of the components.'16 This is a well-known technique in the formulation of insecticides. Another possibility is a mixture in which one of the components hampers the medical treatment of the poisoning produced by the other component. Thus Russian workers have found that thiourea considerably slows down the reactivation of acetylcholinesterase inhibited by nerve gas.47 A third example is the use of adjuvants to promote the penetration of the skin by chemical agents. Thus Canadian workers have shown that in guinea-pigs the lethal dose through the skin of a 50 per cent solution of soman in dimethyl sulphoxide is six times lower than that of pure soman.48 In the second category, mixtures containing an inert ingredient, comes the very considerable body of work on the encapsulation of toxic agents, that is the coating of minute particles or droplets of the agents with some other component.49 There are several reasons for trying to do this, among them the protection of the agent from thermal decomposition during dissemination, or for the sustained release of the agent within a target area so as to maintain active concentrations within it for a predetermined length of time, or to make capsules designed to rupture when trodden on. Munitions The job of a chemical munition is to create a toxic environment over as much of the target as is compatible with the toxicity of its charge. It must convert its bulk load either into an even distribution of liquid or solid particles of optimal sizes and velocities, or into a cloud of vapour, or into both. It must do this within a certain time. And for economy it must have a high chemical-to-weight ratio. These are severe demands, and they are made more severe by the diversity of chemical agents now in the stockpiles. Each such agent has a combination of physical characteristics and toxic behaviour which is unique. None the less, all munitions work on the same THE WEAPONS --CHEMICAL 27 basic principle. They cause the transfer of energy from a store to the chemical load. Generally the store is either an explosive or pyrotechnic charge or a supply of compressed gas. Its size and mode of transfer depend on the physical characteristics of the chemical agent, its volatility, viscosity, surface tension, as well as the sensitivity of the agent to heat and shock. The simplest chemi cals to disperse are the volatile, non-persistent ones such as phos gene. These require little more than a small explosive charge to break open their container. The hardest ones are probably the heatsensitive solid agents which are intended for lethal effect by inhala tion, which we have not in fact described here at all; they include such things as ricin, a vegetable protein more toxic than the nerve gases and for which the U.S. Army has developed a cluster-bomb system,50 and the bacterial toxins and biological agents discussed in Chapter 4. Here, we describe briefly only three known types of modern munition, varying in role and scale. The nerve-gas artillery shell, such as the American M121 series of 155 mm. projectiles51 have been in production since the middle 1950's. Each shell is about 2 feet long, weighs about 100 lb. and holds about 6 lb. of chemical. Along the axis is a cylindrical, highexplosive burster tube containing about 3 lb. of the explosive Tetrytol. This is a heavy charge; when detonated for an air-burst (by a proximity or time fuse) the nerve gas is atomized into a cloud of small droplets which hang in the air and, in the case of sarin, quickly vapourize. If a non-volatile nerve gas is used, such as VX, part will remain in aerosol form for lung penetration, and part in droplet or spray form for skin effects. Field trials of sarin-filled shell show that for an air-burst 15 feet above the ground a con centration of 3500 mg-min/m3 will be set up in under 10 seconds over an area 20 yards in radius. A couple of breaths of this will kill. In about 25 seconds the concentration 50 yards from the burst is about 100 m g/m 3, to which a less than 10-second exposure is likely to be fatal.24 The 10-lb. mustard-gas thermogenerator cluster bombs are about 18 inches long and perhaps 3 inches wide.52 On impact a pyrotech nic charge is ignited in the nose; this sends a stream of hot exhaust gas at high speed out through coarse nozzles in the tail section. The mustard gas, about 2-3 lb, is sucked into this stream and shattered into small droplets and vapour which on mixing with the surround ing air form an aerosol cloud of exceedingly small and penetrating particle size. Within five minutes of the scattering of a 64-bomb cluster of such munitions under suitable atmospheric conditions, the 28 CHEMI CAL AND BIOLOGICAL WARFARE concentration of mustard gas over 8000 square yards would be enough to cause a week-long temporary blindness following a 5second exposure, or death following the skin absorption of a 2minute exposure/- A B-52 bomber can hold about a hundred such clusters. V-agents can presumably be substituted for the mustard gas if necessary. As a final example, there are chemical warheads for the larger missiles. Chemical warheads are made for, amongst others, the U.S. Sergeant missile, which has a range of about 100 miles, but the actual details of the warheads are classified.'''' What is known is that the Americans have standardized a number of different types of bomblet for clustering within such warheads. Shortly before the missile reaches the target, the warhead breaks open to scatter these bomblets. There may be several hundred per missile. In appearance, the various types of bomblet look alike; they are spherical, and their surface is vaned to impart rotation during descent, the rotation being used both for flight stabilization and to activate the fuses. Various dissemination mechanisms are used; high explosive burst, gas propellant and nozzles on the American's E120 BW bomblet,51 and so on. One type which would be particularly well suited to such labile substances as the botulinal toxins consists of two halves held together by a spring-biassed bellows. As the bomblet falls the bellows expand under the influence of increasing atmospheric pressure until, at a pre-determined height, the two halves fly apart.55 The load of micro-encapsulated powdered agent falls slowly to the ground as a fine cloud. Delivery Systems One of the assets of chemical warfare is that it does not depend on extraordinary delivery systems. Chemical munitions may be adapted for delivery by almost any means--grenade-throwers, artil lery, aircraft, missiles, and so on. Indeed, in some cases the delivery system may be the environment itself--the chlorine cylinders of World War I for instance, or the flow of conditioned air or drinking water in a modern building. An example of one of the few modern delivery systems designed specifically for chemical munitions is the U.S. Army's M55 truck-mounted rocket launcher which launches salvoes of up to 45 small rockets in a space of 30 seconds.56 Missiles are well suited to chemical payloads. A warhead which distributes its load widely tends to counter the inherent inaccuracy. Whether missiles are in fact preferable to artillery or aerial bombing from a cost-effectiveness point of view is another matter. THE WEAPONS --CHEMICAL 29 the meteorological problem. Once a chemical munition has been set off its user has no further control over it. This is of course true for any other munition, but whereas the effects of, say, high explosive, follow within a fraction of a second of detonation, those of a chemical may be delayed for minutes, hours, or even days. In this lies both the strength and the weakness of chemical warfare. On the one hand a toxic atmosphere may be set up which will envelop the whole target area, seeping into tunnels and bunkers, and per meating buildings. On the other hand, the entire load may be blown uselessly away by a sudden wind, or become so diluted by it as to be impotent. A chemical weapon system must take these problems into account. By and large a random scatter of small munitions over the target area will be preferred to the delivery onto it of a single large munition, for not only is the former easier to achieve, it will also tend to be self-compensating in an adverse environment. It must be emphasized that, however well-designed the weapon system is, its effectiveness will still depend critically on the prevailing weather conditions. Thus a 1944 report from the Dugway Proving Ground in America57 indicates that to produce lethal effects in un masked personnel over a third of a square mile with 1000-lb. M79 phosgene bombs between 17 and 192 bombs may be required, depending on conditions. On a calm, clear night, using M79's, about 3 tons of phosgene would be needed, but during a breezy, sunny day, upwards of 35 tons--the difference between of a B-52 bomb load and 2\ such loads. Not that phosgene would be used nowa days, of course, nor that a single bomber could produce the neces sary spread. All this implies that previous knowledge of target conditions is essential to a chemical attack. An unexpected wind profile or tem perature gradient over the target could easily render the whole attack useless. Modern chemical troops are therefore equipped with meteorological apparatus, and a great deal of the research carried out at chemical warfare laboratories is concerned with improving that apparatus and extending its successfulness. Certainly the Chemical Defence Experimental Establishment (CDEE) at Porton maintains close ties with the Meteorological Office. It was not for nothing that the 12th Earl of Dundonald consulted that Office in 1914 before revealing to Lord Kitchener his grandfather's plans for chemical warfare.58 30 C H E M I C A L A N D B I O L O G I C A L W A R F A R E Defence It could be that the introduction of the V-agents and mixed sys tems goes a long way towards restoring chemical weapons to that position of strategic capability which they lost when the first gas masks were supplied to counter chlorine in 1915. We said earlier that with the introduction of tabun the very largest targets became vulnerable to chemical attack. With the introduction of the V-agents those targets can no longer be adequately defended, at any rate not without extraordinary and debilitating effort. One should therefore consider briefly what are the available defences against a chemical attack. Broadly speaking, there are three methods of defence--physical, chemical, and medical. physical. The physical defence is the oldest. It involves putting up physical barriers against the entry of toxic agents into the body. For the individual, it means a gas-mask to protect the eyes and lungs, and chemically impermeable clothing to protect the skin. For collective protection, it means air-conditioned shelters. Over the past fifty years the necessary equipment has in fact been developed to a high degree of efficiency. chemical. In chemical defence, the toxic agent is chemically de composed before it can enter the body. For the individual, this means ointments containing reactive chemicals for smearing over the skin before an attack, or powders for dusting onto contaminated skin after an attack. Or it means clothing impregnated with reactive chemicals. For collective protection, it means the equipment of anti-gas squads with chemicals and spraying apparatus for destroy ing toxic agents deposited on the terrain. Or it means the chemical purification of contaminated food or drinking water. The reactive chemicals used are generally alkalis or chlorine-liberating sub stances,35 as in general the biochemical mechanisms whereby toxic agents exert their effects mean that the toxic agents react with these substances. The chemical purification of contaminated air is less easy, but suitable decontaminants are becoming available, for example aqueous solutions of compounds of iodine monochloride with polyvinyl pyrrolidone36 for spraying into mustard-gassed air. medical. Medical defence (or prophylaxis) involves the destruc tion of the toxic agent within the body before it can exert its toxic effect, or the reversal of its biochemical effect, or the biochemical protection of susceptible sites within the body. All these require the THE WEAPONS --CHEMICAL 31 presence within the body before an attack of the appropriate drug at the appropriate site. With one notable exception, British AntiLewisite,37 this is almost impossible to achieve satisfactorily. But a fourth, less difficult, possibility exists, namely the application of drugs which will poison the body in the reverse direction to the toxic agent. Thus, part of the normal treatment of nerve-gas poisoning which results in an accumulation of the chemical transmitted, acetylcholine, is to block those sites which are attacked by the accumulating chemical transmitter, using as a blocking agent the drug atropine, the active ingredient of deadly nightshade. Obviously the application of antidotes which are themselves poisons poses severe problems, which when coupled with the speed of action of modern chemical warfare agents greatly weakens the potential of medical defences. I think it is true to say that the only reliable defences are the physical ones. But these have the drawback that they are only effective if they can be adopted before an attack takes place. They cannot protect an individual once he is poisoned. And while in the past the smell or initial irritancy of chemicals gave enough warning, chemical agents have now been developed specifically to deny such warning even at lethal concentrations. This means that it is possible for a lethal concentration to be set up over a target without its occupants being aware until too late. If those occupants are to be immune, they must either wear all-enveloping, nerve-gas imper meable clothing and gas-masks, and wear them all the time, or they must be warned by sensitive and automatic chemical alarms to so protect themselves. Alarm systems being studied range from the adap tation of the laser to long-path infra-red spectroscopy to the train ing of animals. Dogs have been taught to bark at sarin concentra tions of about 1 m g /m \ but BZ apparently defeats them.45 There can be no doubt whatever that any man not so protected would be beyond help before medical aid could reach him. Certainly it is true that the necessary impermeable clothing has been developed and indeed supplied to troops as standard equip ment. It is true also that gas alarms are available, but even the best of them give no more than a few seconds warning. During the pre war rearmament period the British Government did of course pro vide everyone in the country with a civilian-type gas-mask. The cost of this ran into tens of millions of pounds.33 In view of today's extra requirements of impermeable clothing and alarms, not to men tion defences against nuclear attack, is it likely that any government, British or otherwise, would still be able to foot the bill? us A rm y C ode T riv ial N am e phosgene CG p russic A C acid d istille d H D m ustard T se sq u i- Q m ustard n itro g e n H N 3 m ustard C h e m ic al S tru c tu re C l\ c= O C l/ HCN 1 N o rm al | P h y sical ! S tate j colo u rless . gas | co lo u rless | liquid S (C H sC H aC l)a colourless to a m b e r oily liq u id 0 (C H iC H aS C H aC H aC I)a C H 2$ C H a C H a C I 1 C H S C H C H jCI N (C H aC H aC I) oily liquid s o lid colourless to a m b e r , oily liq u id S m ell n ew -m ow n hay; im p a rts m etallic caste to to b a cc o sm oke b itter alm o n d s fa in t g a rlic none none fa in t geran iu m sm ell D isse m in a te d F orm S y m p to m s of In to x icatio n gas le th a l co u ghing, I retch in g , fro th in g at m o u th , cyanosis, asp hyxia; p n eu m o n ia vapour i le th a l giddiness, i co n v ulsions, u n co n s| ciou sn ess, asp h y x ia vapour liq u id h a ra ssin g eyes : in flam m ation, photo p h o b ia, u lceratio n , b lindness liq u id aerosol skin : redness, irritatio n , b listers aerosol vapour liq u id aerosol le th a l resem b les C G in its a c tio n o n lungs; o t h e r s y s te m ic effects ; LETHAL AG N ERV E GASES ta b u n GA sarin GB som an GD GE CM PF GF VE VX BBC C am ite CA 0 A (C H a)aN -P-O C H aC H a 1 CN r0 C H a ! C H a-P -O C H 11 F CHa O * C H a-P -O C H 1t F CHa CHa 1 CCH* 1 CHa colourless to dark b ro w n liq u id colo u rless liq u id liq u id liq u id 0 C H aC H a */ C H a-P -O C H \ CH: 1/ F C H aC H a 0 1 C H a-P -S C H aC H aN R i O R (R = alkyl) Br liq u id liq u id liq u id p inkish to b ro w n oily liquid n o n e to fru ity alm o st n o n e vapour liq u id aerosol vapour liq u id slightly fruity to cam p h o r-lik e vapour liq u id aerosol v a p o u r liquid aerosol liq u id vapour aerosol liq u id aerosol so u red fruit liquid a ero so l vapour aerosol h arassin g e y e s: p u p ils constrict, v isio n b lu rs a n d dim s,? ey eballs h u rt resp iratio n : ch est tightness, > d ifficu lty in b r e a th in g t le th a l d ro o lin g , sw eating, nausea, vo m itin g , cram p s, in v o lu n tary defaecatio n o r u rination, tw itc h in g , jerk in g , staggering, headache, confusion, drow siness c o m a, co nvulsions, asp hyxia h a ra s s in g b u rning fe e lin g in m u c o u s m e m b r a n e s , s e v e r e eyt irritation and la c h ry m a tio n , headaci CAP CN ad am site DM OCBM ~S BZ y^ - - - - - C O - C H , C I asci _ OJO i / C1 /C N y-- C H " C \-- / ^C N O Oy----- V O H .- - - N w h ite crystals a p p le b lo sso m can ary yello w to b ro w n ish g re e n crystals alm o st n o n e w h ite crystals p e p p e ry so lid aerosol aerosol aerosol aerosol h a ra s s in g b u rning f e e lin g o n m o is t skin, c o p io u s lach ry m atio n h a ra ssin g headache, sn eezin g , coughing, c h e st pains, nausea, vo m itin g * h a r a s s i n g s t i n g i n g an! b u r n i n g f e e l i n g o n skin, co u g h in g , tears, chest tig h tn ess, nausea s lo w in g o f p h y sic a l an! m e n ta l activity, g id diness, diso rien ta tio n , hallucinations, occasio n al m aniacal b eh av io u r PRINCIPAL PROPERTIES of the major known chemical weapons are outliner' the table above. Smell and normal physical states vary greatly with the j ;y of the agent, and lethal and incapacitating concentrations depend H A R A S S IN G A G E N T S In c a p a c ita tin g A gent T im e of O n set of S y m p to m s g enerally delay ed for several hrs. L D S0 * ; L C t:o * ; L C tso * P e rc u ta n e o u s In h alatio n P e rc u ta n e o u s , A b so rp tio n j (m g - ; A b so rp tio n ( m g p e r m a n ) : m i n / m 3) ) ( m g - m i n / m J) In cap acitatin g D osage ( m g - m i n / m 3) 3200 i F irst U se o r C o u n try of F irst D ev e lo p m e n t G erm ans 1915 im m ed iate d elayed ' (blisters : 1 -48 h o u rs 0.032) 5000 1000 2 0 0 ,0 0 0 1 ,0 0 0 ,0 0 0 > 1 0 ,0 0 0 d elayed d elayed d elayed (blisters : 0 .0 0 4 ) (blisters : 0.0 0 0 3 ) (blisters : a b o u t 0,06) about 400 about 300 ! I 1000 i France, ab o u t I 1865 ; French, 1916 7-d ay blindness: 200 ; 2 -w e e k skin burns : 1000 G erm ans, 1917 UK, USA i pre-W W 2 U K , USA, G erm any, pre-W W 2 I 7-day blin d n ess: ' 200 : 2 -w e e k skin burns : 1000 UK, USA G erm any, pre-W W 2 1500 ( 3 0 'd r o p s ') 150 20 i (unm asked) G erm any, 1937 2000 ( 4 0 'd r o p s ') u p to 1 0 m in follo w in g in halation, o r u p to half a n h r. fol lo w in g p e r cu tan eo u s ab so rp tio n about 250 70 about 70 1 5 ,0 0 0 i >20 | (unm asked) j i ! G erm any, 1938 G erm any, 1944 U K .U S A C anada l a c e 1 9 4 0 's o r early 1 9 5 0 's <5 - R em ark s p ro d u ce d 8 0 % of W W 1 gas fatalities; ex ten siv ely sto c k p ile d in W W 2 sto c k p ile d by U .S .A . from 1942 on m o st w idely stockpiled agent of W W 2 used m ix ed w ith m u stard ; th eir p ro d u ctio n m e th o d s yield su c h m ix tu re s ; th e B ritish sto c k p ile d 6 0 /4 0 H T durin g W W 2 less sm e ll th a n H D , so e v e n m o re insidious sta n d ard G e rm a n tab u n co n tain ed 2 0 % ch lo ro benzene ; to be aerosol d isp e rse d G e rm a n s sto ck p iled large q u a n titie s o f its in te r m ed iates b u t could m a k e only to n hig h ly resistan t to o x im e th erapy h a rd e r to treat than G B sm all im m ed iate sm all 3500 30 French useful as a p e rsisten t 1918 harassing ag en t im m ed iate up to 3 m in u tes im m ed iate 8500 j 3 0 ,0 0 0 | i I v e ry large 80 U SA 1918 20 U K , U SA 1918 10 UK. e arly 1 9 5 0 's U SA , m i d d l e 1 9 5 0 's only sta n d ard iz ed in cap acitating ag en t by 1963 on the rate of breathing and the size of the aerosol particles; figures given are for a breathing rate of 15 litres/min (typical of mild activity). Optii*"'m aerosol size, for maximum lung penetration is 0.5 to 3 microns. * define glossary C 34 C H E M I C A L A N D B I O L O G I C A L W A R F A R E Performance and Evaluation We have quoted figures to illustrate the performance of certain munitions, and also for the same munition under different weather conditions. The great divergence that these show should indicate just how difficult it is to prepare in advance to launch a chemical attack. And the meteorological factor is by no means the only performance variable. Chemical weapons are purely anti-personnel weapons, so a commander must know just how mobile his target is, how wellprotected and disciplined it is, not to mention where it is. He must know the type of ground which it occupies, whether it is open or wooded, dry or damp. Although it is very probable that a Sergeant or a Scud* tactical missile loaded with nerve gas can produce 30 per cent casualties among a fully deployed battle group of 1400 men, and within seconds and under almost any conditions, there is doubt. Perfor mance figures for chemical weapons such as those which suggest 30 per cent casualties over 100 square miles per B-52 bomb-load, are, although often quoted, in fact based on nothing more than an assumption.59 If an adequate prediction of a weapon system's performance under all likely conditions cannot be made, then, however potent that system may be, a commander will be reluctant to employ it, for long term planning will be logistically impossible. It is this fact more than any other which is likely to keep toxic chemicals off future battlefields. One way to evaluate a chemical system is to carry out small-scale field trials and to blow them up to life-size with all the modern techniques of operational research--sensitivity analysis, war gaming, and so on. But this is not enough; there are too many imponder ables, at any rate for today's techniques. The only reasonably cer tain way is by large-scale field trials carried out under all foresee able types of condition. This would be a huge operation. Fortunately the political pressures against it are equally huge. T he Russian equivalent of the Sergeant-- see p. 131. Ed. 3LI 0 ^ 2. Psychedelics C.R.B. Joyce There are at least two conflicting reasons for giving an early place to psychedelic drugs in a catalogue of potential agents of chemical and biological warfare: that they are useless; or that they are nonlethal and therefore in certain circumstances ideal. Here, we will briefly examine both these claims. The first is easy to support or refute at the semantic level. The term `psychedelic' is the result of an attempt to coin a word for what some regard as a characteristic effect of this kind of drug-- its power to "expand consciousness". A psychedelic compound was first defined as "one, like LSD or mescaline, which enriches the mind and enlarges the vision."1 But the word seems always to have been used since as a qualifier or as a collective term (`psychedelics' or `psychedelia') for the chemicals or physical objects that are em ployed to produce the experience. It thus contains a rather sad implication that man cannot attain such a desirable state, an aspect of which is detachment from material preoccupations without material assistance. However, if for the moment we accept this definition for lack of a better, it is clear that any psychedelic drug is one that en larges the vision. A sufficiently enlarged enemy vision will contain all other points of view. Since one of these will be the objective, as far as the enemy is concerned, of any political commander, a psy chedelic drug should be an ideal chemical warfare agent for major strategic use. At a lower strategic level, the techniques of what is inelegantly called brain-washing usually have a similar end in view for an individual or small group. Thus, whatever the possibilities may be for successful widespread use of these substances, it would be sur prising if some have not already been tried out in face-to-face interrogations of prisoners, the obvious test situation before wider use is contemplated at all. Although we have no evidence that psychedelics have been used in this way, hypnotics certainly have. The parallel with psychotherapy is obvious, and LSD has been 36 C H E M I C A L A N D B I O L O G I C A L W A R F A R E extensively used as an aid to psychotherapy. For the most part, the results have been as deeply equivocal as their interpretation has been partisan. On the other hand it can also be maintained, at least for the sake of argument, that psychedelics would be worse than useless in warfare because the possessor of a truly enlarged vision would realize that the standpoints of both sides are equally absurd. The major use in wartime for a true psychedelic would be its impar tial application to both sides by a disinterested third party. If a recent news report has any foundation, cannabis at least is not such a substance: or alternatively, such drugs are not always the pacifiers their civilian users claim. According to this report at least 75 per cent of NLF (Vietcong) and American Forces are regular users. Psychedelics are more commonly known as psychotomimetics or hallucinogens, although in fact drug-induced psychoses can be distinguished from naturally occurring ones by outside observers, although not so easily as by those experiencing them, and even at the height of their experiences most drug-users are aware that these have no external reality, and so are illusory rather than hal lucinatory. The three terms will be used henceforth interchangeably. Mind-enrichment is not experienced by everyone who takes LSD, and it may be that there is no such universal psychedelic. Short of death or of some major toxic effect which untreated would be fatal, there is no drug which is absolutely consistent in the type of its effects from one individual to another, or even reliable from one occasion to another in the same individual. One well-known hallucinogen, trimetiioxyamphetamine (TMA) was found by one group, contrary to the experience of others, to cause "unexpectedly anti-social responses" such that "provocation would have pre cipitated homicidal violence,"2 an unsatisfactory characteristic for a drug intended to reduce the will of the adversary to resist. Not only do people have different thresholds, but these are affected by experience, by expectations, and by previous exposure to the same drug. The development of tolerance to LSD itself, for example, is extraordinarily rapid--a highly significant degree is induced by a single dose. The subsequent loss of tolerance also occurs rapidly, and is complete in two to four days. Together, these phenomena mean that LSD cannot be taken effectively more frequently than once every three days or so : within that time a second attack with the substance after a first had failed would itself be bound to fail. In discussions of this problem it often seems to be assumed, at least by those not privy to official secrets, that an effective `psy- THE WEAPONS --PSYCHEDELICS 37 chochemical' must be of the lysergic acid diethylamide (LSD) type. This is not necessarily true. There are many other candidates for the job. A recent dictionary of psychotropic drugs'1 contains the formulae of "all compounds which have been reported to have any psychotropic activity", of three specified kinds: tranquillizing, energizing, and hallucinogenic. It excludes only certain large but well-established categories, such as the opiates and barbiturates, that have by now rather well-defined properties. Of 690 compounds in this collection no fewer than 90, or 13 per cent, are reported to have hallucinogenic activity. The name of at least one manufac turer is given for about half of these; the proprietors of the others are anonymous, but one or two manufacturers' names, such as Sandoz, Lakeside, Penick and Dow (who are also large-scale manu facturers of napalm1and of at least one chemical--which- .has found use among American `hippies/the notorious DOM, qr STP) appear relatively frequently among those which are named. Some 15 of the 370 companies listed as supplying at least one psychotropic drug are responsible for at least one hallucinogen each. Although certain chemical groupings, such as the indoles, are closely associated with hallucinogenic activity, there is no single structural feature that is common to all reported hallucinogens: even nitrogen is not essential, as the cannabis derivatives demon strate. On the contrary, of the major groups of psychotropic drugs there is not one that lacks a hallucinogenic member. Of 140 relatives of phenothiazine, for example, two are said to be hallucinogenic; of 66 phenylethylamines, 13, while 11 out of 17 LSD derivates are hallucinogenic. Hallucinogenic properties are therefore widespread. Even the anti-depressive imipramine is said to have caused hal lucinations at doses of over 300 mg,5 an amount not infrequently given to depressed psychiatric patients. Just as there often appears to be a dose of any so-called sedative that is excitatory, it may be that a further increase in dosage of most drugs active on the central nervous system will produce the kind of disruption known as psychedelic. If this is so the effect of changes in chemical structure will be shown upon such features as potency, or the ease with which the agent reaches its site of action, rather than upon the behaviour elicited. Several well-known examples are shown in Table 2. It is very important that many of them are known to be lethal. If the claim often made for riot-control or disabling substances--that their effects are entirely reversible--is to be taken seriously, the organic fluorophosphonates are not eligible as `off the rocker' agents-- those under discussion. On the other hand, their effects resemble 0- O ^ 38 C H U M 1C A L A N D B I O L O G I C A L W A R F A R E those reported for the American gas BZ7' 8 more closely than do those of most other contenders (Table 3), (See also Chapter 1). One additional comment may also be made about BZ. When the drug known as STP, originally a Dow product, began to circulate among the .`hippie' communities in California there was some suggestion that it might be, at least tentatively, identified with BZ. But this perhaps is no more than an indication of the difficulty of this area --for instance at one point the U.S. Food and Drug Administration also identified BZ as the herb drill, an innocuous enough substance. But it is very difficult to be sure how many substances, or synonyms for the same substance are used; it may be that the real BZ is a mixture of a number of the compounds described in Chapter 1. Even those indoles previously thought to be virtually non-lethal are now believed to be responsible, albeit indirectly, not only for deaths by suicide or under psychotic delusion, but to have delayed effects extending through the machinery of chromosomal damage to the offspring of those e x p o s e d .1,1This may prove to be a general effect of psychedelics; work is in hand at the moment to examine the possibility. It cannot be too often repeated that there is, in any case, no such thing as a safe chemical. Even water can kill. Table 2 also makes it clear that the range of doses of different substances which may be given for their hallucinogenic effects is about a million. This is a thousand times larger than that for their duration. The two aspects are not correlated. There is a wide range of extremely potent substances available--at least one is more potent than LSD11--some short- and some relatively long-acting. Potency alone is unlikely to be a major consideration in the develop ment of new psychedelic agents. One bomber or rocket with a tenton payload can deliver thirty-three effective doses of LSD, or one effective dose of atropine, for every present inhabitant of the earth. However, such a delivery would only effectively saturate a much smaller area: perhaps some 400 square miles, which is enough for many purposes. On the other hand, more potent agents do have the advantage that they take up less storage space and hence are also less easily discovered, whether at their site of manufacture or in transit. The other properties listed in Table 2 for the relatively non-lethal substances--their speed of onset and the time for which their actions last--are of more interest in determining the circumstances under which they could be used. In general, these factors are directly related: the faster the onset, the faster the recovery. The route by which the drugs are administered is also relevant, as in most phar macological situations, but substances with powerful effects on the THE WEAPONS --PSYCHEDELICS 39 brain are in general readily absorbed, whether given by mouth or by injection, and they are of course particularly well absorbed from gases or aerosols. Only the skin unmarked by lesions may be an effective barrier, and then not to all--not, for example, to the mustards and the phosphonales. Some ingenuity is probably being shown, and not only by the writers of thrillers, in developing selective delivery systems for drugs with psychedelic properties. Contamination of a major water supply has often been discussed, and dismissed as too crude, too un predictable in its effects because of the variable affinity for water of different human beings--especially, perhaps, the decision-makers who are the major targets. Air-conditioning systems, pepper-pots, a prepared cigarette are progressively more selective and hence more suitable for use in small groups, particularly when these contain certain members of both the attacking and the attacked com munities. A microphone prepared to deliver an aerosol could help to discredit a politician in the eyes of his own community without any of his adversaries being present. At times one is inclined to imagine that some technique of this kind has already reached a considerable degree of sophistication. But if so it is disappointing that the method does not seem to work better. However, according to the U.S. Field Training Manual' the information available about BZ shows that the means for delivering and dispensing it are intended for non-selective use on a medium but indiscriminate scale. The psychological objectives of theoretically reversible chemical warfare agents are summarized in Table 4. In the absence of hard scientific evidence it can be no more than a personal opinion, but it seems that the objectives, which may be worthwhile and easily attainable by pharmacological means, are not to be achieved with psychedelic drugs. They seem at the moment to be a side issue if not a side-effect, more attractive for propaganda purposes because of the fantasies about mind-control that they may arouse in the minds of the opposition, than for the military or political useful ness of the actual experiences the engender. Since, however, it is relatively easy to produce new compounds with activity on the central nervous system and it is not very difficult to synthesize many of them in quantities that would make their large-scale employment feasible, a measure of effective political support or of successful `selling' by scientists involved in their production may well be enough to guarantee their continued research and development. This chapter has been obliged to concentrate upon the little that is known about American experience with military psy- 40 C H E M I C A L A N D B I O L O G I C A L W A R F A R E chedelics. Next to nothing is known about experience in other countries. An important review of the properties of psychotomi metic compounds by a former member of the CDEE at Porton, subsequently on the staff of the DRS at the British Embassy in Washington, contained no reference to the uses of such substances for defence or attack.12 Such silence, at the time as well as sub sequently, can be constructed in any way one wishes. It is impos sible, therefore, to be sure how chemicals with these actions are seen militarily and politically. To discuss the other major problems of protection, treatment, detection of use, detection of manufacture, and international con trol of manufacture would be to pile fantasy upon a foundation that is already far too speculative. A form of protection might be chronic medication with the agent expected to be used, or one similar to it, in order to achieve a degree of tolerance or cross-tolerance, but the consequences might be dangerous. The best treatment of non-fatal poisoning is inactivity. No drug can restore uncomplicated normal function faster than healthy in activation and excretion. To attempt to hurry it on with analeptics, even after an overdose of morphine or of barbiturate, is often mis guided. There is some suggestion that to treat methoxyamphetamine poisoning with a tranquillizer--the approved way to abort a `bad trip' on LSD--may deepen the intoxication. To detect in use such drugs as these, which have their charac teristic effects upon behaviour, is particularly difficult. For the most part they are tasteless, odourless, and colourless, and active in minute quantities. Sensitive animal indicators (the analogue of the miner's canary and fire-damp), such as the Siamese fighting-fish which responds characteristically to LSD, do exist. It is said that dogs have already been trained to detect the smell of cannabis. But a general detector based on physical techniques, for the presence of bacteria and vesicants as well as psychedelics seems more useful. The question of international control is a depressing one: at least some of the substances discussed are still prepared, when re quired on an appreciable scale, from natural sources--cactus, mush room, tree-bark, or fungus. But they are synthesizable; most have been synthesized; and the syntheses are continually becoming simpler. Although illicit LSD manufacture can sometimes be de tected, prohibition of manufacture is another matter. Meanwhile there are additional risks: supplies of psychedelics, like poison gases, can leak. Whether they leak or not, they have an equally disastrous history, present, and future. TABLE 2 Some Properties of Selected Psychedelic Substances tr o Co 03 DQ. QO. O c OC D <D Q. OLO c o oo t0t) (1) CoO * TABLE 3 Identification of BZ by Comparison of Activity Profiles SIGN S HItlailoullnsuiscoinnosar Paralysis thHeyrpmoia SMloewnitnagl Vertigo teHnyspioon Headache SmSwLataaeiolctaiivnortaiinn-g DVioamrrhitoinega BZ 7'8'17 LSD1316 Anticholinergics 13' 16 Anticholinesterases1113 Cyanogens 8' 13 Arsenicals 13 Benzothiazoles 11 + + + + ? + ? + ++ -- ?+ --+ ? + ++ ? ?-- ---- ? + ?? ++ ?? ?-- ++ ++ ++ ?? + ?? -- ---- -- ---- + ++ + +? + ++ ? ?? TABLE 4 Some Objectives of Reversible CW Agents Tim e-Scale Technique Agent ! O b je ctiv e j Behaviourtype disorders 1. LO N G T ER M CBpsroayncinvhe-owrtsahiosehnrainpgy, Scytatorvtoaxtiiocna, ncohxrioanic 2. IN T E R M E D IA T E `ePxspyecriheendceelic' Intoxication PCsoyncfhlicotlorgeiscoalluWtioanr-f-a-r-e------ ---->y- AEcncliegphttaenncmeent "] Motivational Defoliants- AApgainthgy, mutations Somatic Indoles Anticholinesterases Piperidyl benzilates ,, (idaDlhlmeuiasrsneleliueaonsclngiiizasana,)gateitoimonn,esn,t Cognitive 3. B R IE F SpAakuretaolelnytsooi-msmicotocrrisis NHLaeyxprvaoettivegenasssiveess -* Immobilization Motor 3. Napalm V. W. Sidei There are two reasons for a brief discussion of napalm. First, cir cumstances in Vietnam have led to an association of napalm with chemical weapons. But it is important in developing control measures that the issues in dealing with incendiary weapons, such as napalm, be separated from the problem of dealing with chemical weapons, for different issues are involved in the control of the devel opment, production, or use of the two different types of weapons, and confusion of the two may lead only to weakening controls against either. Second, one of the major issues in the development of chemical and biological weapons is the role of secret weapons re search in universities. The development of napalm is a fascinating case study of applied weapons research by a university chemist on a well-known university campus.* The Weapon Napalm is gelled petrol or, in the American terminology, gelled gasoline. Originally, the term `napalm' denoted the thickener that produced a gel when added to petrol; later it was broadened by usage to denote the incendiary gel itself. The name is derived from the first syllables of naphthenate and palmitate, two fatty acids first thought to be the active principles of the thickener. However, the material used in the original synthesis was mislabelled, and actually contained the soaps of all the fatty acids of coconut oil. These other acids, especially lauric acid, were found to be essential to the gel. Although literally a misnomer, the name napalm has been retained as a generic one for weapons of this type.2' 3 Recently the term has also been applied to a gel consisting of petrol, benzene, and poly styrene which is also called `incenderjell' or Napalm-B.11 When mixed with thickener petrol changes from a thin volatile * M uch of this m aterial has been gathered in co-operation with D r Peter Reich; some of it has previously appeared in the New England Journal of Medicine. THE WEAPONS --NAPALM 45 liquid into a tough, stable, sticky gel. Raw petrol is useless as an incendiary weapon; napalm is ideally suited for this purpose. In contrast to many modern weapons, napalm is produced from cheap common ingredients and can be delivered in simple devices.5 Incendiary techniques and the development of napalm Incendiary' weapons have a long history in warfare, references to the use of fire in war going back to 2400 b.c. Although the intro duction of explosives in the fourteenth century temporarily eclipsed the use of incendiaries, the advantages of fire over blast were well known to military strategists. Blast is self-limiting; incendiary agents are self-propagating, have a prolonged duration of action, and are capable of producing far more disruption and terror than an equal weight of explosives. But it was not until the advent of aerial warfare and the development of efficient incendiary sub stances, notably napalm, that fire reclaimed its role in war. Incendiary agents were used in World War I, and an attempt was made by both the German and the Allied Forces to use petrol in flame-throwers.6 This was hazardous and unsuccessful, but it led to a recognition of the potential danger of incendiary warfare. The treaties of Saint-Germain-en-Laye in 1919 and Trianon in 1920 prohibited the use and manufacture of the flame-throwers along with that of chemical agents. Several provisions against the use and manufacture of flame-throwers and chemical weapons were in cluded in the separate peace treaties negotiated by the United States with the Central Powers. However, it is of interest that the Geneva Protocol of 1925 which prohibited the use of poison gases and bacteriological warfare did not deal with the use of incendiary weapons.7 At the time of the outbreak of World War II, the United States Army Chemical Warfare Service was interested in developing an improved incendiary mixture. They enlisted the aid of Professor Louis Fieser of Harvard University, a distinguished organic chemist. aHe first supplied the Chemical Warfare Service with formula for a petrol gel using raw rubber as a thickener. This was a moderately effective agent, but the Japanese invasion of the East Indies cut off the supplies of natural rubber and necessitated the development of a synthetic thickener. The research programme that followed, con ducted at Harvard University, was presented subsequently in great detail in Fieser's book, The Scientific Method,3 and Fieser has never expressed concern for his part in its development. The first success ful napalm detonations were conducted on a Harvard University O ri 46 C H E M I C A L A N D B I O L O G I C A L W A R F A R E games field and behind the football stadium. It is thus an excellent example of applied weapons research in the universities. The napalm gel proved far superior to the original rubber-based gel, and napalm was used extensively by the United States in incen diary raids on Japan during World War II.8 Napalm was also used in Korea, where it was called the United States' "best all around weapon,"8 and it has been used extensively in Vietnam.10 Effect of napalm Napalm casualties are caused primarily by heat and by carbon monoxide poisoning.11 The adhesiveness, prolonged burning time and high burning temperature of napalm favour third-degree burns, and such bums are likely to be deep and extensive, often resulting in severe scarring and deformities, especially when they occur under conditions making early skin-grafting difficult. Kidney failure may be another serious complication. The igniting agent in napalm weapons, white phosphorus, may become embedded in the tissues and continue smouldering and re-igniting long after the initial trauma. It was reported in Korea that panic is more likely to be observed among napalm victims than among those wounded by other agents.5 The weapon caused far more deaths in Japan than were caused by the atomic attacks on Hiroshima and Nagasaki.8 Conclusion Although certain incendiary weapons such as flame-throwers were coupled with chemical weapons when mentioned in peace treaties after World War I and although napalm has, due to circumstances in Vietnam, been coupled with chemical weapons in recent years, the most important control document on chemical and biological weapons, the Geneva Protocol of 1925, does not link the two. Control would be strengthened by clearly maintaining the separation of the two types of weapons--that is, chemical and biological on the one hand and incendiary on the other--in measures for control and disarmament. Although explosives are also chemicals there has been no attempt to link them with `chemi cal weapons' in arms control documents (see Chapter 1). Perhaps control would be most facilitated by recognizing both the nature of the weapon and the modality by which it has its effect. Thus ex plosives and incendiaries are `physical' weapons, producing their effects by blast and heat. Chemical weapons and biological weapons have special toxic modes of action which are not mediated through such `physical' effects. Although the distinction is a scientifically THE WEAPONS--NAPALM 47 inexact one, it may be useful in developing controls: the special quality of nuclear weapons--their radiation effects--has proved useful in control efforts. I believe the special toxic quality of chemi cal and biological weapons which may permit their definition and control should not be blurred by coupling them with incendiaries. 4. Biological Weapons I. Malek In this chapter I wish to deal with the most important and most dangerous types of biological weapons--those that use micro organisms (e.g., bacteria, bacilli, viruses, rickettsias, and fungi). This should be more accurately termed microbiological than biological warfare, as some biological agents can doubtless be devised that do not fall into these categories. I will indicate the scope of the potential weapons and the possible defences against them. Lastly, I will consider possible means of controlling the use of such weapons. The extent of the threat There are two extreme points of view on biological weapons. One view underestimates them and regards them as weapons whose effects and potential danger to humanity cannot be compared with those of nuclear weapons. The other stresses not only their danger, but their relative ease of production and use (compared to nuclear weapons), especially in local wars. Such a view also stresses the difficulty of controlling the production and use of biological weapons, thus enhancing their potential danger. This second view is strengthened by the knowledge that some countries are spending enormous sums on the research and develop ment of biological weapons with huge research institutes, often with better facilities than microbiological institutes, studying the peaceful utilization of micro-organisms. As Elinor Langer points out in Chapter 10, even if these sums seem small in comparison with annual expenditure on research and development of nuclear weapons and rockets, when one examines the scale to which biolo gists are accustomed in conducting their research they are substan tial. The reality of the threat is sharpened by the persistent memory of the terrible plagues which in the course of history have taken a far greater toll of human lives than war itself. The Spanish influ- 3ud' '?7 THE WEAPONS --BIOLOGICAL 49 enza epidemic after World War I is still relatively recent, and people are regularly reminded of it by the after-effects of similar epidemics which, though less dangerous, occur even today. In addition, con temporary techniques make it relatively easy to produce infectious aerosols and to disperse them over wide areas. Much research effort has been devoted to a study of exactly how such an aerosol cloud spreads, how long it remains in the atmosphere in an active state, and what is its most effective means of dispersal. Certainly, much of the work at Porton and Detrick is directed to this end. Without overdramatically raising apocalyptic visions of the effec tiveness of biological weapons, it must be apparent that I, as a microbiologist, believe that there is a greater danger from under estimating biological weapons than from overestimating them. After all, these are potential weapons which can easily affect the balance of forces in any conflict, especially in those cases where the control of epidemics is difficult, whether in territories with poorly devel oped health services or a terrain that has not yet been sufficiently investigated epidemiologically, or when the normal life and physical resistance of the people have been severely damaged by nuclear attack. I do not wish at this point to go into the technical details of the conditions under which biological weapons can be used. We can be sure however that in the research on biological weapons, on which the military spend such enormous sums, attention is being paid to these questions of strategy. That is why I cannot side with the fatalistic view that in a situation where the effective restriction of the use of biological weapons is difficult we must be content to rely on effects of public opinion and the fact that as yet the agents may not be sufficiently controllable to make them as reliable as chemical weapons. The scope of the weapons The idea of using microbiological weapons goes back to the ex perience with infections and epidemics, which have been a serious military problem throughout the history of wars. Despite the devel opment of vaccines, sera, and antibiotics, they remain, even without artificial introduction and dispersion, an important and difficult military problem. There are in fact several examples of the use, or alleged use, of micro-organisms against populations even in the pre-microbiological era; for example, the introduction of smallpox to the American Indians by the early settlers who gave or sold them infected blankets or trinkets. Allegations of `the poisoning of wells' form a similar class. D 50 C H E M I C A L A N D B I O L O G I C A L W A R F A R E advantages and disadvantages of biological weapons. The most powerful argument in favour of the use of microbiological techniques in warfare aimed at population destruction is the rela tively great variety of possible agents, often with completely differ ent routes of infection, ways of spreading, incubation periods, and very limited possibilities of prevention, defence, and cure. Some of the infectious agents enter the human body most effectively by way of the respiratory tract, and these can be either bacteria (e.g., plague, tularaemia), spores of bacilli (e.g., anthrax), rickettsiae Q-fever, viruses (e.g., influenza, psittacosis, dif ferent types of encephalitis), or even fungi (e.g., coccidiomycosis, histoplasmosis). Naturally each of these infections needs a completely different diagnostic approach and demands a different cure. Specific prevention, where this is possible, varies from case to case. Such infections can, in principle, be very easily spread under favourable meteorological conditions over vast areas by the use of aerosols. Other infective or toxic agents can penetrate the human body directly through mucous membranes, such as the eye or nose. Among these are several viruses and some bacteria (e.g., those causing tularaemia, brucellosis, rickettsias, and botulism). Some others are most effectively absorbed orally with food or contamin ated water (e.g., salmonellosis, dysentery, and cholera). And to make the situation still more complicated, these agents can be used in mixtures, thus causing extremely complex diagnostic problems for those attempting to identify and combat the disease. All this, together with the minute dimensions of the organisms-- of the order of one micron in diameter (a micron is 0 001 mm)-- and the often complicated and slow methods of detection and identification, means that a population subjected to a microbio logical attack would probably not be able to identify its cause before the infection had become widespread. The second important quality of these microbiological agents is that they are alive and can reproduce. Thus a chain of infection from one infected person to others can easily occur. This is especi ally dangerous with respiratory infections, where the time of greatest infectivity often begins in the incubation period when the symptoms are very slight and non-specific, and when infection spreads through minute exhaled droplets to all persons in the vicinity of the infected persons. Even in communities not unbalanced by war conditions such spreading of infection can be very hard to control. Experiences with the recent foot-and-mouth disease in cattle in Great Britain, with smallpox epidemics introduced from countries where it is not THE WEAPONS --BIOLOGICAL 51 adequately controlled, or with myxomatosis--originally introduced artificially to limit the rabbit population and afterwards spreading uncontrollably--are examples of this problem even in highly organized societies. All these problems can be still more severe in countries with insufficiently developed medical and public health services or, of course, under war conditions. A further advantage of the biological agents as weapons is that some are very resistant to external conditions and can remain latent but potentially infective for many years. An example is the anthrax bacillus, whose spores may remain infective for a hundred years or more--as evidenced by the case of the Scottish island, Gruinard, discussed by Robin Clarke in Chapter 9. With other organisms, conditions can be created to make them sufficiently resistant to survive in the form of aerosols for long periods of time. Because of the minute dimensions of micro-organisms, they can be easily dispersed in the form of aerosol clouds of great dimen sions which can move for very long distances. Field tests have been carried out in the United States, using either fluorescent particles or non-pathogenic bacterial spores of bacilli, showing that such aerosol clouds generated by spraying from a ship along a 150-mile stretch of coast, spread out over 55,000 square miles of land, over which a minimum dose of 15 particles and a maximum dose of 15,000 particles were inhaled by members of the affected popu lation. In spite of the rather unfavourable conditions during this experiment, the cloud could be followed about twenty-three miles in the direction of the wind with viable cell densities corresponding to sufficiently high infective doses, even inside buildings. To achieve this it was sufficient to spray some 500 litres of a suspension of a harmless bacteria (bacillus subtilis).1 The infectious effectiveness of such aerosols depends greatly on the size of the dispersed particles or droplets: the smaller the particles, the more effective they are. With the techniques available today it is easy to produce highly effective aerosols with relatively small devices--perhaps small enough to make possible individual sabotage without real danger for the saboteur, particularly as the incubation period for the disease would give him time to disappear from the scene before the first symptoms were noticed. Similarly it would be much easier to carry massive amounts of such infective agents in aeroplanes than, say, bombs. It can be objected that these are mostly hypotheses made on the basis of experiments with animals and with experience gained in the laboratory. But even these results show that the danger caused by infectious aerosols, especially with some micro- 52 C H E M I C A L A N D B I O L O G I C A L W A R F A R E organisms where the inhalation route is not the natural one, could be greater than supposed. The infectious or toxic dose of some micro-organisms or their toxin (i.e., the poison they produce) can be very small, so a very small amount of dispersed material could infect or intoxicate large numbers of people. Thus the aerosol doses of Pasteurella tularaemis on humans was experimentally evaluated at about 25 to 50 cells; in the case of Q-fever, only one micro-organism (Coxiella burneti) might be sufficient to cause infection, so that in one gram of dis persed material many million infectious doses can be present. Drinking 100 ml. of water from a reservoir of some 5 million litres capacity would cause serious infection or intoxication if as little as half a kilogram of Salmonella, 5 kg. of botulinum toxin, or 7 kg. of staphylococcal enterotoxin had been introduced.1 Of course, these are only illustrative data upon which it would be possible to enlarge further by considering other infections and other conditions of dispersal. There is also the possibility of the spread of infection by use of living vectors, such as insects, ticks, or lice, thus forming persistent foci of infection under favourable conditions. Very much is now known about the ecology of such vectors and the way in which they participate in the dissemination of infection. Allegations about the use of germ warfare by the United States in Korea claimed that animal carriers had been used in this way.3 A minor but important potential advantage of biological agents is that they do not require large, expensive, and complicated equip ment for their use, especially in comparison with equipment neces sary for nuclear weapons. Any well-equipped microbiological laboratory with normally skilled technical personnel can readily produce large quantities of the agents if infectious strains of micro-organisms are available. In the case of intended microbiological attack it is possible to prepare one's own personnel, for instance by vaccination against selected micro-organisms, so that they would not be seriously en dangered when entering the infected area. The possibility of clandestine use of the agents must also be raised, for identification of the artificially introduced infection is often not easy and can take a long time, while allegations of their use are not easily proved or disproved--witness the allegations about Korea5--especially where the epidemiological background of the country is not sufficiently known and its medical services are not fully competent. I H \i W HAl' ONS K I O L O C I C A I , 53 And one final advantage: biological weapons are directed against a population (human or animal). They cannot cause any material damage; they lead only to great human losses and produce profound effects on morale, and cause panic. This alone could make the microbiological weapons attractive to a potential aggressor. These then are the main reasons which make the weapons ex tremely dangerous and could make them attractive to an attacking force under some special conditions. Bearing these in mind why then have biological weapons not been already used, since nuclear and even chemical ones have been? The answer lies in the fact that these weapons also have their disadvantages, particularly, perhaps, in comparison with chemical weapons. The most important of these is that their effectiveness depends on not only the agent itself, but also on ecological and meteorological conditions, over which the aggressor has no control. In addition the relatively slow develop ment of most infections diminishes their short-term tactical value to a commander concerned with immediate advantage. The effect of biological agents lies in the strategic dimension only. But I believe that it is not merely because of these disadvan tages nor of insufficient knowledge that the weapons have not been used. I am convinced that those huge installations and organiza tions which study their potential with such efficiency have been able to togather sufficient technological experience to be able use these weapons on a large scale, fully corresponding to the level of highly sophisticated contemporary military techniques. Defence against biological warfare Over the past hundred years a number of techniques for con trolling the spread of infectious diseases have been evolved. Among the major achievements have been the ability to isolate and identify a great many infectious agents, the discovery of how these agents behave, how they are able to enter the human body, and the mechanism of their pathogenic activity. This knowledge has created the possibility of a variety of epidemiological measures, notably isolation, disinfection and sterilization, and most important, im munization and vaccination. These last depend on the introduction either of mitigated or dead infectious agents or of specific anti microbial agents such as chemotherapeutics or antibiotics. All these possibilities are naturally also at our disposal for use against micro organisms disseminated as weapons. But there are difficulties which 54 CHI . M CAL A N D B I O L O G I C A L W A R F A R E make all this highly elaborate system less effective in the case of massive artificial infection with microbial weapons. Firstly, despite the great success in controlling infectious diseases, there still exist dangerous infections where control is not yet very efficient, either because of the difficulty of diagnosis, as is the case with some virus diseases, or because we do not have sufficiently efficient preventive vaccination or therapeutic measures of chemo therapy or antibiotics. It must be assumed that precisely these microbial agents will find favour in a potential attack. Secondly, even where epidemiological knowledge is sufficient, in the case of massive dispersion of agents, any counter measures will inevitably lag behind the speed of the outbreak. It will be possible to identify the infection only after the appearance of clear clinical symptoms, and this is usually too late, as the greatest infectivity often occurs during the later stages of the incubation period and before the clinical symptoms have become clear. If one adds the time necessary for exact laboratory identification it is obvious how difficult it will prove to cope sufficiently with the speed of an induced epidemic. This is still more true of any attempt at preventive immuniza tion. It is hard to imagine that all the population at risk by expo sure to microbial attack could be vaccinated against all possible agents. And if the vaccination is begun after attack with an identi fied agent it would take days or even weeks before sufficient im munity could be achieved. Another difficulty is connected with the fact that nearly all the dangerous micro-organisms likely to be used as biological weapons can exist in mutant forms for which further preventive measures would be necessary. Mutant forms can develop naturally, as in the ominous case of penicillin-resistant organisms, but it is also possible to create them artificially by means of exposure to radiation or toxic chemicals. And the last difficulty results from the fact that immunity-- be it natural or artificially induced by vaccination--can readily be destroyed by exposure to radiation. Thus all the advantages of prior vaccination would be lost and all the induced infection would occur in much more dangerous forms in the case of nuclear attack. Thus the greatest danger of the possible use of microbial weapons is in conjunction with the dropping of nuclear bombs. That is why, in spite of the fact that suitable strains are available for use as vaccines or in the production of antigens, which could be used for immunization against many potential biological agents, a THE WEAPONS --BIOLOGICAL 55 full immunization programme will probably never become a general prophylactic measure.1 Thus it becomes necessary when thinking about defence to seek ways which would enable us to make it more efficient and which would diminish these gaps. The most important would be the development of methods to make the detection of possible microbial attack more efficient. Heden' subdivides detection into three stages, those of warning, sampling, and identification. All of these must be accomplished so as to shorten the time necessary for active defen sive steps. Modern microbiological methods and knowledge offer several possibilities which have probably already been explored in the existing special military institutes. An important step towards international confidence in this area would be to distribute this in formation as widely as possible. There are available, for instance, devices for sampling of air probes with a very high capacity, which can gather some 10 cubic metres of air per minute into a liquid flow of 10 ml., making rapid warning of the presence of infective aerosol clouds possible and effective.1 Or a method using fluorescent labelled anti-bodies (substances which would bind onto specific microbiological strains) could be used for rapid identification of the agents present in such a cloud. Other possible protective systems are of the mechanical variety--efficient, positive pressure shelters, or disinfection procedures and, in the case of suspected insect vector attack, repellents and so forth. But these must inevitably have a limited role in any protection of the population at large.. Thus biological weapons provide, by comparison with chemical ones, a much greater diversity of agents and methods of induction, they can only be identified with much greater delay, and in spite of considerable knowledge about the agents and the possible defence against them in principle, in practice they are much more difficult to control. They could probably cause much greater disaster among people for a smaller expenditure of effort. On the other hand the chemical weapons are much better defined, more easily manageable, and their effect more immediate. Thus they have a potential tactical significance which the biological weapons lack. One of the characteristic features of biological weapons is that it is difficult to distinguish work done purely for defensive ends from that which is mainly offensive. Furthermore, if defence is to be effective and prepared in time it must be based on knowledge that can easily be transferred to offensive uses. That is why military establishments working on the development of these weapons do 5f C H E M I C A I . A N D B I O L O G I C A L W A R I A R H it mostly under the label of defence. Biological weapons, therefore, can be used as an excuse for not reaching agreement on general disarmament, especially in the absence of an early and thorough study of the problems involved, to enable the arguments on the impossibilities of disarmament and inspection to be refuted (see Chapter 13).7, 7 Such considerations have led to the establishment of a study group attached to the international scientists' Pugwash Movement, with the objects of (a) identifying the questions that had to be solved; (b) contributing to their solution on a contemporary scienti fic level; (c) helping spread knowledge of the actual danger of biological weapons and the struggle against the secrecy of their preparation and production; and, (d) seeking ways and means of speeding the banning of biological weapons and disarm am en t.6-7 The work of the Pugwash study group was directed also towards three questions : new methods for the quick detection of any bio logical weapon attack; the possibility of control and inspection of institutes in countries voluntarily giving up any activity which could be misused for the development of biological weapons; and, finally, the general tactics of a campaign leading to complete biological disarmament. Interesting experimental results were obtained on the second question. By trial inspections of four microbiological institutes in different countries that volunteered (Sweden, Denmark, Czecho slovakia, Austria), relatively effective methods of inspection were worked out. The conditions were also defined under which such a voluntary ban on work on biological weapons and control of such a ban would be effective, while insuring protection against their use by another party. At the same time, it was estimated to what extent the experience of the Internationa! Atomic Energy Agency in Vienna, in the control of the peaceful uses of nuclear energy, could be used for a similar system of control of means of biological war fare and the use of micro-organisms for peaceful purposes. Finally, a significant contribution was made when the Stockholm Peace Research Institute (SIPRI), founded and financed by the Swedish Government, chose as one of its research projects the prob lem of biological weapons.* It has started work on the legal impli cations of biological weapons and their ban. Rapid detection * Representatives of SIPRI were present at the Conference, includ ing Dr Bjornerstedt and Dr Nemec, and were able to give a preliminary account of this study, which, however, has not been included as such in this text. Ed. o O <D CC 2 -c o 2 o to<ooa 3 (0 O~ a - (D o. "2 u^j C0 >> CTOO -XP .2 ^ 2 Sr- 5 ? S c C l) _C u H TO TO o <* CBW Research `y vTahset adeisropseorslatlesctasppahbeilrietiensickonfabmoemdb`ltehtes 8a-rbealtle1sted inside this e> CBW Research agnDrdeuarjarvvieecneghngotarlesdctsoe6n1020tth00t0eessphtrDseeuegogpnfwaawanytenreeewpwreaosncvcoinizdgzelengtafroollryunthdde.esdtTriohsysiseedmcionomnatmiolanunndaoslf CBW Research A portion of Fort Detrick, Maryland Headquarters Building, ChPeomrtoicnalDDoewfne,ncWeilEtsx.perimental Establishment C B W in Use AgVGabiresoetvnnaeaasdmeusoefdCinS aiRGnpiagpVshri-otemvtneaadsmkfor use U .S . .Arrny 0(O D c 1co 0C)J o u_ < CO 13 < Qj O5^. CL C0M0 i O ce C3) O fC 5 o co Cl 3 0) co c_o/ oc ce c3O E c ~coe o ce 5 rz cce <D > ~CC C0o) c o ccoo C- c o "ce ~ 'TS)3 _T__ TH li Wi: A P O N S -- D I S C U S S I O N 57 methods and the possibilities and forms of inspection have also been studied, but the findings are so far only in a preliminary stage. These are the main tactics of real defence against biological war fare. In my comments on the limitations of conventional defence against these weapons, I tried to make clear that a consistent and co-ordinated international effort leading towards the complete ban of these weapons is the only truly efficient way of defence of man kind against a disaster which will bring it back to medieval times where pestilence can decimate populations. DISCUSSION The major issues of the discussion were whether the state of bio logical weapons research had indeed reached the point where the weapons were technically feasible, and whether inspection tech niques of the sort outlined by Academician Malek were likely to prove effective. Dr Humphrey, while not denying that biological weapons could be developed to a stage where they could be useful strategically or tactically on a large scale, queried whether the difficulties which face their use had been solved for the simple reason that it is extremely difficult to try them out on man. All biologists are aware that one cannot argue from another species like guineapig or pig to man. In the case of chemical weapons, we have fairly precise data on their properties and behaviour, but biological weapons are considerably less predictable. From the point of view of the field commander biological weapons fall into two categories: the first are those which carry a high rate of infectivity but which would not then normally develop, passing from person to person; and the second, those which rely for their effect on spreading, plague-like, through the population. An example of the former is the incapacitating Dengue fever which produces severe symptoms two or three days after infection, knocking out the fighting poten tial of the victims. Dengue fever would not, however, spread from person to person as it is a systemic disease, does not produce sputum, and is normally carried by an insect, the sandfly. In the absence of sandflies, therefore, the effects of the use of the weapon die out within a few days. This is one sort of weapon that has achieved a degree of popularity in certain circles on the grounds that it is a humane, non-killing weapon, but it is hard to put this theory to the test without involving a large number of people. 58 C H L M 1C A L A N D B I O L O G I C A L W A R F A R K The other sort of biological weapon, analagous to the plague, is even more difficult to test. It is clear, however, that such weapons would have no military value until they had achieved epidemic proportions. In addition it would be necessary for the military commander to ensure that his own troops were specifically im munized. Professor Meselson pointed out that if biological weapons do become militarily significant one would see it developing because the tests required would have to be under combat conditions. The chance of having an effective biological weapon developed secretly is very remote. The only way one can do the kinds of tests that would develop a predictable weapon would be under wartime conditions, and if that went on one would surely know it. Even development is a fairly conspicuous process, whereas simple manufacture of an already perfected weapon might be more easily concealable (the very conspicuousness of the process made it amenable to inspection techniques such as that pioneered by SIPRI). But as both Dr Humphrey and Professor M. Pollock pointed out, one still knows very little about the real problems involved in dissemination, in maintenance of biological agents (other than anthrax spores) in a stable form, and so on. The problems are similar, but still more complex than those, outlined by Mr Perry Robinson, for chemical weapons, with the additional complica tion that the biological systems are self-reproducing ones. To Professor Pollock this lack of knowledge that anyone had of the possible spread and mutation of such infective agents would be enough to make any country think twice about their use, in case they rebounded. Dr Viney, by contrast, raised the spectre of the potential use of biological warfare agents against comparatively isolated targets--garrison islands or ships at sea--which could presumably be attacked with a fair degree of optimism that the attack would not rebound onto the attacking side. A second point raised by Professor Pollock was whether it was really possible to distinguish between offensive and defensive research on biological weapons. Such a distinction seemed tenuous to him. It does not, for instance, seem possible to devise a maxi mally efficient defence against bacteriological agents without study ing in detail the particular agents a potential aggressor might use. But, as Dr Viney pointed out, offensive research does not neces sarily imply an offensive capacity; this might still not be necessary and provide a point at which control could be exercised. The final issue concerned the feasibility of actually detecting the use of biological weapons. Professor Pollock thought the problem a greater one than Academician Malek had perhaps allowed. With the case of Korea in mind, unless one actually has the opportunity of finding evidence, for instance an aeroplane shot down filled with infected flies or a bacterial bomb clearly marked with its label of origin, would it not be extremely difficult to know definitely whether in fact biological weapons had been used? THE WEAPONS--DISCUSSION 59 But, as Dr Viney said, despite the difficulties of such an inter national inspectorate, it must not be dismissed even by the sceptics and hard-headed, because the real function of such a body would be quite as much to disprove allegations as to prove them. From the point of view of persuading politicians who are not likely to believe that a committee, in actual war circumstances, could do scientific work on the spot fast enough for it to matter (especially as it is quite likely that biological attack would come after a nuclear attack or after a conventional attack, so that the questions might have rapidly become irrelevant), it would still be very useful for such a body to exist for the purpose of disproving panic allegations or even malicious allegations. Hence the value of the SIPRI studies. o D ISE A SE O RG AN ISM IN F E C T IV IT Y EFFECTS SU RVIVAL TRAN SM ISSIO N B A C T E R IA L D IS E A S E S an th rax u c e llo s is ch o lera glan d ers m elio id o sis p la g u e tu laraem ia B acillus a n c h ra c is 1u2 0 , 0 0 0 o r g a n i s m s o f inhaled B rucella m eliten sis h ig h 1 300 organism s ? V ibrio c h o le ra e M alleo m y ces m allei W h icm o rella p seu d o m allei lo w by in gestion h ig h 3200 o rg an ism s in h a le d h ig h P a sc e u re lla p e stis P asceurella tu la re n sis h ig h 3000 o rg an ism s v e ry high < 5 0 o rg an ism s inh aled ? resp irato ry form n o r m a l l y f a t a l if u n treated . lo n g lasting ; recurrent severe : f e v e r; ra re ly fata! : se v e re intestinal ; infeccion; s o m e tim e s fatal ! in a c u te fo rm , ` se v ere fev er often fatal i n o r m a lly fata! | fever, p ro d u cin g I m ania and d eliriu m very se v ere ; : o fte n fatal i severe fever; ; 5 -8 % fatal j sp o re fo rm in g ! hig h ly sta b le in h a la tio n (also fro m an im als) skin infection stabilized w ith in h a la tio n d ex trin and in gestion p ro te in p ro d u c ts (also fro m a n im als) in gestion (also fro m a n im als) un stab le in h a la tio n in gestion (also fro m an im a ls) in h a la tio n in gestion (also fro m an im als) in h a la tio n in gestion in je c tio n b y fleas in h a la tio n in gestion in jectio n by insects R A L D IS E A S E S o rea k b o n e fever dengue v iru se s m um ps p o lio m y elitis j p sittacosis high m o s t in cap acitatin g single m o sq u ito bite : fev er k n o w n ; 2 o rg a n is m s in h a le d ? i v e ry ra re ly fatal h ig h ! in cap acitatin g I but not severe | severe, perm an en t lo w d isability; so m e - I tim e s lethal | m ild to se v ere high j fe v e r; s o m e tim e s ' facal h ig h injectio n by m osquito in h a la tio n i inhalation 8 5 % survive 23h at 21 -24C as aerosol j in gestion inhalation of j m o is t air ; inhalation I in gestion in jectio n by insects n allpox y ello w fever P o x v iru s v ariolae i h ig h a `f e w ' o r g a n i s m s h ig h single m o sq u ito b ite se v ere; often , fatal Jau ndice ty p e fever; 30% m ortality in h a la tio n , ing estio n injection by m o sq u ito < inhalation R IC K E T T S IA L D IS E A S E S Q -fever C oxiella b u rn etii ep id em ic ty p h u s R ickectsia prow azeki v e ry high I o rg an ism in h aled ? 1 0 * 6g in fe c te d tissu e h ig h F U N G A L D IS E A S E co ccid io id o m ycosis C o ccid io id es im m icis 1350 spores 'X IN fever for 1 w ee k ; 1 % m o rtality se v ere; often fatal m ild to se v ere fever; rarely facal sc a b le poor i inhalatio n ; ingestio n , in je c tio n b y ticks i n j e c t i o n b y l o u s e I inhalation I ing estio n ? sp o re fo rm in g hig h ly stab le j ' inhalation b o tu lism C lo strid iu m bo tu lin u m 0`12ug1t o x i c d o s e sev ere poisoning; 60-70% m ortality d e c o m p o s e s in j in h a la tio n 1 2 h in a ir j ingestio n CHARACTERISTIC PROPERTIES of some biological agents are shown in the table above. The properties are those of the naturally occurring strains which can, of course, be altered; a highly infective strain of poliomyelitis, for instance, has been produced. Relatively few of the properties of the orgr ms causing diseases such as tularaemia and yellow fever, for instance, wou ,iave to be changed whereas those of epidemic typhus are almost WlO' VACCINES THERAPY STORAGE EIMXMTEUNNTITOY F EPIDEMICITY REMARKS a v a ila b le antibiotics as sp o res a v a ila b le in U SSR a n tib io tic s vaccine red u c es sev erity and in cid en ce d iffic u lt several m o n th s u n satisfacto ry antibiotics u n sa tisfa c to ry difficult a v a ila b le a n tib io tic s a v a ila b le a n tib io tic s lim ited ? ) ' p rese n t to u n k n o w n ex ten t lim ited ! p re se n t to u n k n o w n ex ten t present lo w lo w h ig h lo w lo w h ig h none a v a ila b le d iffic u lt m a ss p ro d u c e d difficult l scable eig h t y e ars at 4 1 F present w id esp read lo w h ig h m a ss p ro d u c e d difficult w id esp read lo w u n s a tis fa c to ry a n tib io tic s m a ss p r o d u c e d difficult scable w h e n freeze dried p rese n t to u n k n o w n ex ten t w id esp read -- on d e c lin e in E u r o p e and N . A m erica ? m a ss p ro d u c e d difficult i Ii s c a b l e a t 0 - 4 C p r e s e n t h ig h h ig h none o n e of th e m o st stable ag en ts affects b o th m a n and d o m e stic anim als u n lik e ly to b e effectiv e via w ater sy stem s affects b o c h m a n a n d d o m e stic anim als v e ry rare a n d little k n o w n d ise a s e only p n e u m o n ic (re sp irato ry ) p la g u e likely to b e of B W u se g o o d B W ag en ts ap art fro m d o u b ts c o n ce rn in g stability m ig h t b e useful as an incapacitatin g a g e n t little u se as B W a g e n t b e ca u se of w id esp read im m u n ity lim ited by lo w infectivity an d w id esp read im m u n ity birds act as rese rv o ir of d isease; im m u n ity m a y b e fairly w id e spread generally im m u n ity to o w id esp read n atu rally a su b -tro p ica l disease a s tra in w h ic h c o u ld s u r v iv e in te m p e ra te clim ate m ig h t be dangerous a v a ila b le m ass produced a n tib io tic s a n tib io tic s | stable i j difficult present present none v e ry h ig h in fectivity high b u t c an n o t spread m an-to m an u nlikely B W a g en t ; p o o r s ta b ility u n satisfacto ry an tibiotics ? as sp o res present lo w hig h ly stab le ; su itab le a g en t if a v a c c i n e w e r e p r o d u c e d available as to x o id d iffic u lt j bacteria as j sp o res o r to x in ( in a irtig h t I co n tain er none none acts m o re q u ick ly th a n a n y o th e r B W a g en t ; tro o p s could in v ad e a fte r 24 h entirely unsuitable. Agents against which vaccines are in mass production are not likely to be used in B W ; on the other hand, an agent would not be used in BW unless a vaccine were available . The psittacosis organism is no longer technically classed as a virus, but is included under that heading for convenience. Mumps is unlikely to be used in BW but is : -luded for comparison. 5. Defoliants* A. W. Galston The programme Chemicals are being used against forested and agricultural lands in Vietnam as part of United States military strategy and tactics. This is the first time that chemicals designed to damage or kill plants have been used in war. To damage or kill a plant may appear so small a thing in comparison to the human slaughter every war entails as to be of little concern. But when we intervene in the ecology of a region on a massive scale we may set in motion an irreversible chain of events which could continue to affect both the agriculture and the wildlife of the area--and therefore the people--long after the war is over. The purpose of using herbicides, as stated by a U.S. Government spokesman, is twofold: Chemical herbicides are being used in Vietnam to clear jungle growth and to reduce the hazards of ambush by Viet Cong forces. . . . Destruction of food is undertaken only in remote and thinly populated areas under Viet Cong control and where significant denial of food supplies can be effected by such destruction. . . .' f A precedent is being set which is important for two reasons: In the first place once chemicals become accepted weapons in the arsenals of nations, it may be difficult to draw the line between one chemical and another; between one use of chemicals and another. Secondly, the widespread aerial spraying of herbicides can affect the land, water, and living things which must support the people in peace or in war, in independence or under foreign domination, and whatever their form of government. It is this aspect of herbicide use which concerns us here. Assistant Secretary of State Dixon Donnelly, the U.S. Government *The basic data in this chapter first appeared in Scientist and Citizen, August-September, 1967. Used by permission, t But see pp. 152-53. 3-UoK THE WEAPONS --DEFOLIANTS 63 spokesman quoted above, also said that the chemicals in use in Vietnam are "used extensively in most countries of both the Free World and the Communist Bloc for selective control of undesirable vegetation. They are not harmful to people, animals, soil or water." The implication of the word `selective' is that these herbicides are also not harmful to plants other than the target species. Less reassuring were the words of the twelve plant physiologists who wrote to President Johnson that the massive use of chemical herbicides could upset the ecology of an entire region. In the absence of more definite information than we now have about the effects of such use, they suggested that such an upset could be catastrophic.- With two such diametrically opposite interpretations before us, an examination of what is known and what is unknown about these chemicals is in order. American biologists who visited Vietnam in 1966 observed damage to a variety of plants.'1 This ranged from serious damage to fruit trees and other commercial plants in rural areas not deliberately sprayed to effects on various species in and around Saigon. Without a controlled study it is difficult to relate plant damage to source; in some cases other agents, such as jet-plane exhausts, may be partly responsible for the effects. There has also been some spraying with malathion for mosquito control. Species affected are listed in Table 6. It is important to note that spraying is being done quite close to Saigon, and that plants are being affected within a range of about thirty miles from the target areas. The information contained in the Table comes from informal observations by scientists who have been in Vietnam. There appears to be no formal study of the effects of the spray programme on the many interconnected plant and animal species of Vietnam. The fact is that even in limited and controlled conditions we do not fully understand the basis for the altered behaviour of a plant when we apply various chemicals from outside the plant. To add to the uncertainty, only a few species have been investigated inten sively, and as we shall see shortly, species differ greatly in their response to synthetic growth regulators. As a result, when we spray a synthetic chemical from an aeroplane over a mixed population of exotic plants growing under uninvestigated climatic conditions--as in Vietnam--we are performing the most empirical of operations. We learn what the effects are only after we perform the experiment, and if these effects are larger, more complex, or otherwise different 64 C H E M I C A L A N D B I O L O G I C A L W A R F A R E from what we expected there is no way of restoring the original conditions. The scale The. 12th Air Commando Squadron, in the first nine months of 1966 alone, defoliated a Vietnamese area of 1000 square miles, equivalent to the size of the entire State of Rhode Island in the United States, Derbyshire in Great Britain, or the entire state of Luxembourg.1 Included in this area were about 70,000 acres of crops, mostly rice. The acreage of cropland rendered unproductive by sprays had risen to more than 150,000' by the beginning of 1967. In the early part of 1967 the special Spray Flight of the 309th Aerial Commando Squadron expanded operations to include the so-called demilitarized zone separating North and South Vietnam, as well as war zones C and D and areas adjacent to Laos and Cambodia, and during 1967 a total area of 965,000 acres was sprayed. This is expected to rise to 2 million acres in 1968. The spraying programme, named `Operation Ranch Hand', started in 1961 with two C123 transport planes, and has gradually grown to this much larger programme. The chemical most used is a mix ture of esters of 2, 4-D and 2, 4, 5-T6 released from high pressure nozzles beneath the wings and just under the upswept tail of the planes. Each plane carries about 1000 gallons of spray and approx imately 3 gallons are released per acre, usually in the early morning, when the air is calmest and the danger of drifting is least. Within twenty-four hours the foliage begins to wither and turn brown. By the end of six weeks the leaves fall off the trees. For defoliation, reapplication is usually necessary at the beginning of each new growing season.7 In 1961 sixty spray sorties were flown; 1962 saw the number increased to 107, which included defoliation along canals and rivers in a large part of the heavily populated Mekong delta and a mountain pass near Qui Nhon, the port city north of Saigon. In 1966 combined defoliation and crop-spraying operations had in creased to the point where approximately 1,324,430 gallons of her bicides were sprayed over more than half a million acres of land, and plans were to triple the programme.6 During 1967, 965,000 acres of land were affected, perhaps 450,000 acres of this being cropland. This would be about five per cent of South Vietnam's eight million acres under cultivation, and the programme has continued unabated into 1968. The amount of herbicides being used is suggested by a Business ^Lli TABLE 6 Plants Damaged Outside Sprayed Areas (Vietnam) FOOD CROPS AND COMMERCIAL PLANTS Common Name Genus (and Species when known) Rubber-trees Cassava Breadfruit Papaya Starapple Figs Sweet Potato Beefwood, or South Sea Ironwood, cultivated for lumber Mango Ficus elastica Manihot esculenta Artocarpus integrifolius Carica papaya Chrysophyllum cainito Ficus ipomoea batatas Casuarina Limnanthes mangifera PLANTS IN THE VICINITY OF SAIGON (perhaps thirty miles from the nearest sprayed area) Common name Family Genus (and Species when known) Sweet cassava Cassava Starapple Plney tree W illow Beefwood Papaya Hibiscus Flowering maple Tropical or Indian almond Petarboom Royal Poinciana (peacock flower) Silk Cotton Tree Dogbane Sweet potato Breadfruit Figs Euphorbiaceae Euphorbiaceae Sapotaceae Guttiferae Salicaceae Casuarinaceae Caricaceae Malvaceae Malvaceae Combretaceae Leguminosae Leguminosae Bombacaceae Apocynaceae Convolvulaceae Moraceae Moraceae Jatropha Manihot esculenta Chrysophyllum cainito Calophyllum Salix Casuarina equisetifolia Carica papaya Hibiscus Abutilon indicum Terminalia catappa Peltrophorum ferrugineum Poinciana regia Eriodendrum anfractuosum Ipomoea Artocarpus integrifolius Ficus E 66 C H E M I C A L A N D B I O L O G I C A L W A R F A R E Week item announcing the disappearance from the U.S. domestic market (except in small packages for home owners) of 2, 4-D and 2, 4, 5-T. The military demand is said to be four times present U.S. capacity.8Total production in 1965 of 2, 4-D and 2, 4, 5-T was close to seventy-seven million pounds.5 It was announced on July 11th, 1967, that contracts for 557.690.000 worth of chemicals for defoliation and crop destruction have been awarded by the Defense Supply Agency. The quantity of chemicals being purchased was not announced, but even allow ing for some price increase the amount in dollars suggests a pur chase of between six and seven million gallons. (The Air Force budget for the fiscal year that ended June 30th, 1967, provided 539.500.000 for about five million gallons. If prices remained the same the new contracts would be for more than seven million gallons,10 according to official Pentagon figures.) Meanwhile the value of British exports of herbicides and associated substances to the United States has risen from S730.986 in 1964 to 52,739,949 in 1967. Targets are selected by U.S. or Vietnamese officers and must be approved by a province chief, the Vietnamese Army general staff, the U.S. Military Assistance Command, and finally the American Ambassador. Effects of defoliation There are reports0'11 that cacodylic acid, an organic arseniccontaining compound, is being used against elephant grass and rice; both of these are the narrow-leaved type of plant which would be expected to be fairly resistant to the usual formulations of the 2, 4-D type of herbicide. Of the three herbicides mentioned above cacodylic acid is probably the most toxic to man. According to the authoritative Merck index12 it is dimethylarsenic acid, contains 54.29 per cent arsenic, and is extremely poisonous. The lethal subcutaneous dose in dogs is one gram per kilogram body-weight. (Other sources suggest that cacody lic acid may be even more poisonous, with an LD5,, of 184 mg/kg --E d.)11* If the same toxicity held for man about seventy grams, or slightly over two ounces, would kill the average 150-pound man if administered subcutaneously. Smaller doses could result in nausea, diarrhoea, headache, mus cular pains, weak pulse, and coma. All these symptoms flow from *See glossary. TH 11 W E A P O N S -- D E F O L I A N T S 67 the paralysis of capillaries and degeneration of the lining of the intestinal tract known to be induced by arsenic. In view of the persistence of this material and the cumulative nature of arsenic toxicity, its wide use certainly may pose dangers for the civilian population of Vietnam. And indeed, eye-witness reports from in dividuals in the sprayed areas have apparently described such symptoms (see Chapter 1). The additional danger that arsenic may be accumulated by plants which would be eaten by man must also be investigated, since such an effect would greatly magnify pos sible toxity. It has already been reported1,1 that injection of cacodvlic acid into trees can kill the bark beetle, Dendroctonus, infect ing the trees. Official statements have referred usually only to the less toxic 2, 4-D and 2, 4, 5-T, but Assistant Secretary of Defense, Cyrus Vance, when asked in 1965 whether arsenic and cyanide compounds were being sprayed over the rice fields of South Vietnam, replied, "We are making limited use of them in the southern part of Vietnam but not yet in the north."11 It is hard to escape the conclusion that aerial spraying of cacodylic acid produces some harm to the human and animal life below. The basic formulation for 2,4-D and related herbicides varies with the region, the climate, and the target plant. For example, the Dow Chemical Company product called Esteron R 245 O.S. de signed "for the control of trees, bush, and broadleaved weeds" contains 67-7 per cent of 2 ,4 ,5-T. This material is usually mixed with either diesel oil. No. 1 or No. 2 fuel oil, or kerosene before spray application, although water sprays are sometimes recom mended. About one gallon of Esteron per one hundred gallons of water is a usual mixture. If applied by aeroplane, the practice in Vietnam, about one to four pints of Esteron per acre is the recom mended amount. The label on this Dow preparation carries a "WARNING" on which the following statements are found: Do not contaminate irrigation ditches or water used for domes tic purposes. Caution. May cause skin irritation. Avoid contact with eyes, skin, and clothing. Keep out of reach of children. Another Dow product, called Formula 40 R, which contains alkanolanrine salts of 2,4-D and is designed "for the selective control of many broad-leaved weeds in noncrop areas and in certain crops" carries a more definitive statement: fis C H E M I C A L A N D B I O L O G I C A L W A R F A R E Causes irritation of skin and eyes . . . In case of contact, flush eyes with plenty of water for at least 15 minutes and get medical attention; wash skin with soap and plenty of water. Remove and wash contaminated clothing before re-use. Do not wear con taminated shoes. Herbicides have not been successfully designed to act against only a single plant or group of plants. If carried by wind, drift, or even vaporization they can destroy neighbouring plots of useful plants. The warning on Esteron states: Do not apply Esteron 245 O.S. directly to, or otherwise permit it to come into direct contact with . . . desirable plants which are sensitive to 2, 4, 5-T, and do not permit spray mists to drift onto them, since even minute quantities of the spray may cause severe injury during both growing and dormant periods. . . . Applications by airplane, ground rigs and hand dispensers should be carried out only when there is no hazard from drift. Do not apply by airplane in the vicinity of cotton, grapes or other 2, 4, 5-T susceptible vegetation. At higher temperatures, vaporization may cause injury to susceptible plants growing nearby. Do not graze to dairy animals within seven days after treatment (to avoid contamination of milk). Effects on birds and animals were noted in a Reuter dispatch from Saigon which said that "Chemical sprays have played havoc with bird life, destroying vegetation and the insects on which birds feed. Monkeys and deer have also been affected."15 The extent of the damage that may be caused by the widespread and indiscriminate use of herbicides can only be approximated because of the paucity of direct experimental data. The reassuring statements about the innocuous nature of the herbicides in use in Vietnam are based on laboratory and field tests in the U.S.A. These have shown the selective nature of these chemicals--their effectiveness against one kind of plant, while leaving some other kinds unharmed. (Although, as noted above, there are limitations to this selectivity.) These tests have also demonstrated that 2,4-D and 2 ,4 ,5-T do not persist for a long time in the soil. A serious ecological upset is nevertheless possible. The main points of concern are as follows: The mechanism of action of the defoliants is imperfectly under stood. We are therefore setting in motion on a large scale a bio logical process whose action and consequences we cannot altogether foresee or control. THE WEAPONS --DEFOLIANTS 69 Most experience with these herbicides has been in environments very different from that in which they are now being used. Their effect on individual plants indigenous to that part of the world has not been studied nor have we information about their movement through the food chains in that area. While experiments performed in Great Britain and the United States indicate that numerous species and strains of common soil micro-organisms are effective in breaking down these compounds, in this process they are transformed into new compounds which may, under some circumstances, have deleterious consequences. Let us look at each of these problems in more detail. Mechanism of action Defoliation with herbicides mimics the natural seasonal defolia tion. Leaves of deciduous plants are attached to the stem by a nar row stalk called the petiole. Through this petiole runs vascular tissue which conducts water and nutritive materials into the leaf and organic matter out of the leaf. As long as the leaf-blade pro duces the hormone auxin in moderate concentrations the leaf remains on the plant. In normal concentrations auxin plays a useful role in various aspects of plant growth. If, for natural reasons, such as the shortening days of autumn, or for artificial reasons, such as injury to the leaf blade, the production of auxin in the leaf-blade ceases or slows down measurably, then a layer of large, weak, thinwalled cells which are easily ruptured is formed at the petiole and results in leaf fall. (This is called the abscission layer.) The knowledge that lowered auxin levels in the leaf-blade result in leaf fall suggested to chemical plant physiologists that the de liberate application of auxin `antagonists' or compounds which lowered auxin levels in the leaf could furnish a means of control ling leaf fall. This suggestion was put to work in agricultural practice many years ago when defoliants were applied to cotton plants several days in advance of harvest of the bolls, so that the mechanical cotton-picker would not be clogged by the undesirable leaves. The reverse practice, that of prolonging the retention of leaves and fruits on trees to promote better growth and ripening, can be accomplished by spraying with carefully controlled con centrations of substances with auxin activity. The concentration must be carefully controlled, because if it becomes too high un desirable side effects are produced which may even kill the plant. We will deal with these later. There are still many gaps in our knowledge of the control of leaf 70 C H E M I C A L A N D B I O L O G I C A L W A R F A R E fall. (For example, there are three other classes of hormones (abscissins, gibberdlins, and cylokinins) in addition to the auxins, which play a role-- as yet u n k no w n-- in leaf fall. Recent investigations10 have revealed that high, toxic levels of auxins, which kill some plants and alter growth patterns in others, probably work through the control of the synthesis of still another plant hormone, ethylene. This substance, which can cause leaf fall, abnormal flowering, and altered growth patterns in various plants, has long been used to ripen fruits artificially by causing the sharp increase in respiration (the climacteric) which normally precedes ripening. Ethylene is normally absent, or present in very small quantities, in growing plants. The application of abnormally high auxin levels or some appropriate stimulus from the outside world can cause its production in the plant. Application of chemicals with high auxin activity, such as 2,4-D and 2,4,5-T, might have this result. Ethylene is volatile and effective in several parts per thousand million of air; it can readily migrate from plant to plant and cause growth aberrations. The old observation that one rotten apple in a barrel causes them all to spoil is based on the fact that ethylene is produced in greater quantities in infected and injured fruit tissues; once produced it can induce adjacent fruits to ripen and spoil pre maturely. Thus, however carefully a herbicide might be applied to a restricted area, if it gave rise to significant quantities of ethylene the results in neighbouring crops could be catastrophic. Effect in the South-east Asian environment 2, 4-D and 2, 4, 5-T are especially effective against broad-leaved plants. In fact, this selectivity is so marked that 2,4-D is sold for application to grass lawns, where appropriate concentrations will kill dandelions, plantains, and other common lawn weeds with out affecting the growth of the grass. Of course, as many home gardeners have discovered to their sorrow, raising the 2,4-D con centration somewhat can result in greatly inhibited grass growth. Thus, the same 2,4-D and 2,4,5-T which are being used exten sively as tree defoliants may be used, with somewhat different, stronger formulation, for the purpose of killing or rendering unproductive various food crops, including rice. Unless carefully controlled, both as to area and concentrations sprayed, the jungle defoliation aspect of the herbicide programme in Vietnam can kill crops in areas where such an outcome is not intended. In addition to the observations cited earlier, there is other >1 THF. W E A P O N S -- D E F O L I A N T S 71 evidence that aerial sprays have done considerable unwanted damage as a result of drifting and volafization of sprayed materials. For example, it is widely known that rubber-trees at a Michelin plantation were inadvertently killed by drifting spray. The United States has compensated the French owners at about S87 per tree.17 On December 13th. 1965, three aircraft flew over Thoi An Dong, a village of the Phong Phu district, spraying defoliant extensively. Watermelon only 20 days from full maturity were seriously damaged, as were rice, vegetables, and fruits. Crops in the adjacent villages of Phuce Thoi and Tong Tuyen were also heavily damaged. Fhe entire area was supposed to be `secure' from the United States point of view, and thus should not have been sprayed at all. Con Son, an island half a kilometer from Can Tho, was subjected to defoliation treatment six times between June and December, 1965. Papaya, jack fruit, milk fruit, coconut, watermelon, mustard cab bage, and beans were adversely affected. At An Nghiep hamlet, beans, cabbage, and tomato were adversely affected. The damage ranged from 40 to 100 per cent, rendering the crops unprofitable for harvest. Some farmers also decided not to replant, thus amplify ing the economic loss.18 Another problem is that herbicides may affect a susceptible link in an important food chain. For example, fish are an important element in the Vietnamese diet and are frequently bred in rice paddies.19 Herbicides may not be directly toxic to fish, yet may affect them indirectly if they prove toxic to the micro-organisms on which the fish feed. The appearance of chlorophenols (derived from 2,4-D and 2,4,5-T) in a water supply, at concentrations as low as one part per thousand million renders the water unpalatable, and possibly harmful.20 The toxic levels of sixteen aquatic herbicides for the micro crustacean Daphnia, which is a fish food and thus an important elementary link in the food chain of streams, lakes, ponds, and rivers, have recently been measured.21 Among the more important conclusions are the following: (i) While herbicides are in general less toxic than insecticides, the high concentrations required for effective action suggest that several (not including 2,4-D) could be dangerous to Daphnia under field conditions, (ii) Lethal action may be delayed until long after the test compound has been removed. This suggests that previously determined inhibitory levels may be seriously in error, (iii) Mammals (such as laboratory rodents) can not be used to estimate damage on Daphnia, and vice versa, (iv) ". . . even brief exposure of Daphnia to certain compounds II 74 C H F M I C A L A N D B I O L O G I C A L W A R F A R F. Environmental Alteration, under the chairmanship of David R. Goddard, was set up to examine both the MRI report and an analysis of it to be prepared by the National Academy of Sciences. Before either document could be examined the Pentagon released its own summary of the report, and through its director of plant science research at Fort Detrick, Dr C. E. Minarik, minimized the ecological impact of herbicides and defoliants used in Vietnam. Two articles quoting extensively from Dr Minarik appeared in articles written by Walter Sullivan in the New York Times of January 4th and 7th; Dr Minarik was also heard over CBS news, repeating the same message. Clearly, the Pentagon felt some need to respond to the challenge. The Pentagon's Summary Digest of the M R I Report did reveal that relevant scientific studies in the ecological area are very scanty and that practically no scientific reports dealing with the Vietnamese area's response to applied herbicides are available. They also admitted to the use of another compound, picloram, a derivative of picolinic acid, which the Dow Chemical Company's own house organ Down to Earth reveals is remarkably long-lived in the soil. In one study, less than 5 per cent of the picolinic acid derivatives had disappeared from soil in well over a year. The D.O.D.'s comment on this is "Picloram . . . is persistent in soils but will tend to leach to depths of two to four feet under average rainfall and soil conditions." In commenting on the danger that humus removal from tropical soils may reduce the soil to an im pervious rock (an almost irreversible process known as laterization, and a risk of the defoliation campaign which had been expressed by several scientists), the summary says: "No evidence has been obtained that such irreversible changes have resulted in areas in Vietnam subject to defoliation. Observers in Vietnam have indicated that the vegetational succession following defoliation in tropical forests is one in which grasses rapidly cover the ground in dense stands followed by rank growth of weeds and vines which are effective in minimizing soil change." If this is true, soil laterization is probably not a danger . . . but, then, the entire purpose of the defoliation operation is vitiated by an even denser ground cover than existed before. The National Academy of Sciences assigned the report to Dr A. Geoffrey Norman, head of the Division of Agriculture of its affiliate, the National Research Council. Dr Norman, himself former head of plant research at Fort Detrick, in turn appointed a com mittee composed of four academic people, one U.S. Department of THE WEAPONS --DEFOLIANTS 75 Agriculture researcher, and the director of plant science research at Dow Chemical Company to advise him. Their report, forwarded to the D.O.D. on January 31st. 1968, was called "only a first step in investigating further the ecological effects of intensive use of her bicides" by Frederick Seitz, president of the National Academy of Sciences, in the New York Times of February 13th, 1968, Walter Sullivan again wrote an article under the headline "Defoliation Study Casts Doubt on Long-Term Damage in Vietnam" indicating that: "There are no clear indications that widespread aerial spray ing to strip Vietnamese war zones of foliage will do long-term damage." He admitted that too little is known to have confidence in these conclusions and that all data were gathered from literature review and interviews, rather than on-the-spot experience. Quite a different picture was painted by Thomas O'Toole of the Washing ton Post who wrote on February 20th, 1968, under the headline "Report paints grim picture of Defoliation in Vietnam" : "The chemical defoliation of Vietnam's jungles and forests may be doing permanent damage to its wildlife, soils and streams, a Pentagon-commissioned report acknowledges. At a minimum, two rare species of monkeys and four other animals are in danger of extinction because of the spray programme. The danger of soil laterization is present, and damage to water resources cannot be excluded." These contrary views of the same report summary in dicate the need for continued study of this complex situation. As of now, we await the AAAS evaluation of the full report. But whatever the outcome, the decision, it is clear, will be based on insufficient data. To quote the report, "The extent and pattern of herbicide treatment in Vietnam have no precedent. Therefore, it is difficult to predict the effects with any accuracy." 6. Starvation as a Weapon* Jean Mayer A United States Government spokesman explains that food is as important to the Viet Cong as weapons, and that herbicides are used "where significant denial of food supplies can be effected by such destruction."1' 2 There is as yet little direct evidence from Vietnam of the effects of crop destruction on the NLF, no data on starvation of persons who can be categorically defined as `Viet Cong', no reports that NLF prisoners have been found to be physically incapacitated by malnutrition, no clear evidence of a lessening of the NLF's will to fight. Yet it is clear that malnutrition is common among Vietnamese civilians, whether due to diet deficiences unrelated to the war, to food problems resulting from other war conditions, military and economic, to the conscious efforts of denying food to the NLF, or to a combination of all three. Information justifying the programme has never been released by military or other U.S. Government sources. In the absence of such data we must turn to other, less direct information and to historical inferences. In spite of the paucity of information from Vietnam, the effects of food denial as a weapon are no mystery. We can turn to well-documented sources for answers to the questions: How does a food shortage affect a population? Which elements of the population are most affected? Is starvation an effective strategic weapon? The answers to these questions can then be related to the situation in Vietnam. The effects of starvation on the human body are well known and were described in detail in a number of populations immediately following World War II. Famine affects different elements of the population in different ways and to different degrees; this has been observed in famines occurring in peace-time as well as in war. The author has personally observed famines on three continents, one of them Asia. * The basic data in this chapter first appeared in Scientist and Citizen, August-September, 1967. Used by permission. THE WEAPONS --STARVATION 77 Finally, although herbicides have not been used in previous wars, the creation of famine through blockade has been frequently used, and there is historical evidence of its effects. Effects of Starvation The first and most obvious effect of starvation on the human body is the wasting of its fat deposits. A nutrition survey of South Vietnam in 1959 found that the average weight of civilian males was 105 pounds,'1 suggesting that such body-fat deposits would generally be meagre in Vietnamese to start with. The stomach and intestines, heart and lungs are affected next; the size of the liver is drastically diminished. The intestinal lining becomes thin and smooth, thereby losing some of its absorptive capacity, and diarrhoea results. Thus starvation is a self-accelerating process, particularly in children; because of intestinal damage, the food that is available is poorly absorbed, undernourishment increases correspondingly. The damaged lining of the stomach fails to secrete hydrochloric acid, which is important for digestion. Both blood pressure and pulse rate fall. Early effects of starvation are cessation of menstruation in women and impotence and loss of libido in men. Hair is dull and bristling, and in children abnormal hair grows on the forearms and back. The skin acquires the consistency of paper and not infre quently shows the irreversible dusty brown splotches which are permanent marks of starvation. In extreme cases, particularly among children, the lips and parts of the cheeks are destroyed. The body becomes susceptible to infection and disease. The psychologic state deteriorates rapidly; the individual becomes obsessed with food, mentally restless, apathetic, and self-centred. A recent paper prepared by U.S. Physicians for Social Responsi bility, for Senate hearings on the refugee problem, summarized the medical problems in South Vietnam.5 It pointed out that malnutri tion is widespread among South Vietnamese civilians; beri-beri, night blindness, and anaemia are found frequently; Kwashiorkor, a form of protein malnutrition, occurs and is a major component of the problems of wound-healing and resistance to infections; infant and child mortality is high. Kwashiorkor is a deadly disease affecting children after weaning. It causes degeneration of the liver, pancreas, and intestines, oedema, and eventually death. Diseases associated with malnutrition, such as tuberculosis, are rampant. Although it is impossible to know to what extent these problems stem from the 78 C H E M I C A L A N D B I O L O G I C A L W A R I-A K L crop-destruction programme, there can be no doubt that if the programme is continued these problems will grow. in many parts of South-east Asia, there are food shortages in the best of times, and any strain on the food supply, whether from political factors or natural disasters, may result in famine. A general consequence of famine is the social disruption, including panic, which accompanies it. Starving people attempt to journey to other areas where they hope to find food, and chaos increases. Weakened by lack of food they are susceptible to disease, and these factors interact with one another; disease adds to social disorganization which in turn makes disease more difficult to combat. In Vietnam, migration has been set in motion by military attacks, or fear of such attacks, on villages or towns, and by the destruction of agricultural lands. At Senate hearings on refugee problems in South Vietnam and Laos, Frank H. Weitzel, Acting Comptroller General of the United States, gave the numbei of refugees in South Vietnam in the fiscal year 1965 as 600,000 six times what had been expected.9 In November an additional statement from Mr Weitzel gave a total of 719,000, but said 258,000 were classified as resettled. At the end of 1966, the New York Times put the figure at a million, growing at a rate of about 70,000 a month.10 A news item on July 3rd, 1967, states that almost two million refugees were now in government resettlement camps--one in every seven South Vietnamese.11* These recently uprooted people are a different population from the 1955 refugees from North Vietnam who, ac cording to the South Vietnamese Government, are now resettled. In 1965 refugees were almost 100 per cent women, children, and older men.12 Twenty-six years of almost uninterrupted war have placed strains on the food supply, especially severe in the last two years. South Vietnam, which exported 49,000 metric tons of rice in 1964,13 must now import it. Figures for 1966 are not yet available, but 240,000 tons were imported in 1965.14 At the time of writing infant mortality is estimated at 25 to 30 per cent, more than ten times that of the United States or Britain. Maternal death rate is twenty-five times that of the United States. Life expectancy at birth is about thirtyfive years. In an environment where sanitation is primitive and medical facilities are in short supply, a great additional hazard is the risk of epidemics which can grow like wildfire in a weakened, starving, and migrating population. * More recent figures do not appear to be available; but the aftermath of the Tet offensive must have greatly increased them. THE WEAPONS--STARVATION 79 Bubonic plague is endemic, and although only eight cases were reported in 1961, the number is said to have risen to 4500 in 1965.5 Malaria is also endemic, and the appearance of a form of the disease which does not respond to traditionally effective drugs is a matter of grave concern. Cholera and smallpox have been habitual fellowtravellers of Asian famine with influenza and relapsing fever also frequent. In 1965 the number of cases of cholera in Vietnam increased by 25,000 according to the World Health Organization.15 In that same year Dr Howard Rusk reported that among refugees "tuberculosis is highly prevalent, as are skin infections, intestinal parasites, trachoma, and other diseases of the eyes, typhoid, and leprosy."10 A study of three examples from wars fought within the past hundred years goes a long way towards indicating the effect of food denial as a weapon. the siege of Paris. Paris was under siege by the Germans for 129 days in 1870-71, during the Franco-Prussian War. One of the reasons given by the Government for surrender was the lack of food within the city. However there was a desperate military situa tion in the rest of the country. Prior to the siege one of the main French forces was defeated at Sedan; during the siege the other was defeated at Metz. Thirty-six new divisions were organized and equipped from Tours, but a number of them were driven into Switzerland, where they were disarmed and interned. According to Baldick,17 the total number of deaths in Paris rose from 3680 in the first week to 4465 in the third--and presumably rose higher as the siege dragged on for eighteen weeks. The winter was severe and people suffered from cold as well as hunger; epi demics swept the city, with smallpox the biggest killer. Melvin Kranzberg describes the effect of the food shortage on the people of Paris: "With the exception of the dent made in their pocket-books the rich did not suffer from famine during the siege. . . . As for the poor, the men were not badly off, but the women and children suffered. The men could get enough to eat and perhaps too much to drink merely by enlisting in the National Guard."18 blockade of the central powers. In the early days of World War I, the Western Allies were optimistic that the hunger engen dered by the blockade of the Central Powers--Germany, AustriaHungary, and the smaller countries allied with them--would help win the War quickly. After the War, the importance of the Blockade may have been exaggerated by German historians in order so C H E M I C A L A N D B I O L O G I C A L W A R F A R E to play down military defeats; it may have been underestimated by British, French, and American historians. The fact remains that it took four years of the combination of blockade and military action to defeat the Central Powers. Famine oedema, a relative increase in the water content of the body, was observed in civilians in Hamburg in the winter of 1916-17, in Berlin in January, 1917, and in Vienna and the Rhine land later the same year. In 1918 it became common throughout Central Europe. Tuberculosis, which is closely related to malnutri tion, began to rise in 1914 and continued to rise throughout the War. In Vienna, the mortality rate from tuberculosis rose almost 100 per cent; in Germany, 44 per cent.19 The excess of deaths in the civilian population during each of the War years over the number of deaths for the year 1913 totalled 762,796 (see Table 7). These figures represent the number of deaths which under `normal circumstances' presumably would not have happened. They were probably due to a combination of food shortage with other factors. Medical care of civilians suffered because of the army's drain on medical personnel and facilities. There was a shortage of fuel be cause importation of coal was reduced by the Blockade and internal distribution was disrupted by the War. Although most of the War was fought on French and Russian soil, the Austro-Hungarian Empire was invaded, with some if its villages and countryside be coming a battleground. If the figures below are compared with deaths in the army it can be seen that civilian deaths in excess of normal may have been about half as great as the army losses. However, it must also be said that the very war conditions which cause excess civilian deaths make reliable statistics difficult to assemble. George A. Schreiner, an Associated Press correspondent, spent the first three years of the War in Germany and the nations allied with it, including considerable time with the armies on both East ern and Western fronts. He states that many men in the army received better food than they had as pre-war civilians. He says that the army "came first in all things", and that when it became necessary to reduce the bread ration, this was made good by in creasing the meat and fat ration.20 Schreiner quotes a "food dicta tor" as saying that thousands of the poor aged were going to a premature death. THE siege OF Leningrad. The most recent, the most lethal, and yet the most completely ineffective use of starvation as a strategic THE WEAPONS --STARVATION 81 TABLE T ` Deaths during Blockade of the Central Powers (1914- 18) Deaths in the Army ExiPncoetpshsueladCteioiavntilhs anbwdaOottntuhlenrtfohdieueslgdh Tsihcrkonuegshs (pDrBeulsoeuctmkoaadtbheley) 4231PtrnsohdtdtostWWWW-twhaeaaaarrrrrwYYYYdaeeeeuraaaaerrrr 343215397104,,,,953750344623 62,417 33238004,,,,131362997904 10,902 22159829831,,,,621723767540* Total 1,456,952 133,982 762,796 * To end of 1918. weapon of war was the siege of Leningrad by the Nazis in World War II. It closed around the three million people of the city on September 8th, 1941. For four months only 45,000 tons of food were brought in by water, air, and finally by the road across the ice of Lake Ladoga, and this was expected to sustain the military as well as the civilian population. Late in January, 1942, a corridor was opened which permitted both the importation of food and the evacuation of large numbers of people, but the siege was not com pletely lifted until two years later. By this time almost a million people--about a third of the city's population--were dead from hunger, cold, and their attendant diseases, and from the bombing and shelling of the city. As in the previous cases, the soldiers defending the city had better rations than the civilians, although their rations, too, had to be cut in November, 1941, when things were at their worst.21 Hospital records for the starvation period show some of the effects on infants and pregnant mothers: an increase in stillbirth and premature birth and a rise in neo-natal mortality.22 The early and worst parts of the siege were accompanied by German victories elsewhere in the nation; German armies came within a few miles of Leningrad homes and factories where people F 82 C H E M I C A L A N D B I O L O G I C AL W A R I A R L continued to live and work. Nevertheless, the troops, besieged along with the city, defended it successfully and eventually broke the blockade. While historians differ in assigning significance to these blockades as effective military techniques, it is clear from all three of these examples that food denial in war affects the fighting man least and last, if at all, and is therefore unsuccessful unless accompanied by military victories by the blockaders. ft is hardest on civilians, parti cularly children and the elderly; where economic class divisions are sharp, it is particularly hard on the poor. Destroying food in Vietnam The increasing use of herbicides in Vietnam referred to in the previous chapter suggests that the U.S. Military plans to enlarge the area where food crops will be destroyed. News stories have reported other methods being used in the food-denial campaign. In areas under the political control of the NLF, U.S. and South Vietnamese troops may establish temporary military control long enough for a `harvest protection' operation. This is carried out by entering the area at harvest time, holding off NLF rice-collectors, while peasants are required to sell their sur pluses to the government or to the commercial market, and then withdrawing.23 The agricultural area in the demilitarized zone and just to the south of it has been rendered completely unproductive, as have special areas in the immediate proximity of Saigon (Operations Junction City and Cedar Falls in the `iron triangle'). As many as 600,000 Vietnamese have been removed from agricultural produc tive labour and at the time of writing are residing in camps.24 Rice that has already been harvested may be destroyed. Some times it is dumped into large pits and covered with shark repellent or other obnoxious compounds; attempts have been made to burn or scatter it. Captured rice has been dumped into the Rachbenggo River by U.S. troops. According to General William W. Berg, U.S. Air Force Deputy Assistant Secretary of Defense, "Our combat units are well aware of the food shortages in South Vietnam and are not wantonly destroying captured rice whenever it can be salvaged and put to local use. However, in a fluid combat situation, available time, manpower, and transportation will not always permit removal of captured goods to a safe area."2' Charles Mohr has reported in the New York Times that the THE WEAPONS --STARVATION S3 troops have found rice to be "one of the most maddeningly indes tructible substances on earth. Even with thermite molten-metal grenades, it virtually will not burn. The scattering of rice does not prevent its collection by patient men."2' These practical difficulties suggest one reason for the use of chemical sprays. Another, and perhaps the most important reason, is that it entails a more efficient use of personnel. "What's the difference between denying the Viet Cong rice by destroying it from the air or by sending in large numbers of ground forces to prevent the enemy from getting it?" a Pentagon spokes man asked. "The end result's the same; only the first method takes far less men.-'26 Whatever method is used, the examination of past wars and famines makes it clear that the food shortage will strike first and hardest at children, the elderly, and pregnant and lactating women; last and least at adult males, and least of all at soldiers. That these conclusions have applied to Vietnam as well is sug gested by the Vietnamese nutrition study, carried out in 1959 by Americans and South Vietnamese under the latter's Committee on Nutrition for National Defence, in which an equal number of army and civilian Vietnamese were compared.27 "In the general sense, the nutritional status of the military is superior to that of the civilian population, without appreciable differences between Army, Navy, and Air Force," says the study. While the average civilian male weighs 104-3 pounds, his counter part in the military weighs 113 0 pounds. And, for those who might suppose the difference results from military selection procedures favouring bigger men from the general population, the study reports: Inductees (Quang Trung) weighed 107 pounds on the average, the lowest weight among any of the military. A group of similar men completing their basic training (Quang Trung) has an average weight of 114 pounds, suggesting that the change from a civilian to a military diet resulted in a prompt weight gain, in spite of the strenuous activity of basic training. Considering the combined military services, continuation of such weight gain during the first year of military life was further evidenced by the weight gain from an average 107 pounds for those in the service less than three months to an average of 118 pounds for those with six months to one year of service. South Vietnamese army medical care was also superior to that available to civilians, as Dr John Reed of the U.S. Public Health Service testified on his return from working with Vietnam refugees: 84 C H E M I C A L A N D B I O L O G I C A L W A R F A R E . . there are only about 800 qualified physicians in the Republic of South Vietnam. Of this 800, 500 are in the military service. Of the remaining 300, approximately half, or 150, are in private practice in Saigon, so this leaves only about 150 doctors for the entire rural population in South Vietnam.""8 This refers to the South Vietnamese government side, but on the other side, NLF soldiers were likewise expected to get the fighter's share of whatever food there was. Whether extra rations were en forced by an organized government structure or confiscated by armed bands of guerillas, the end result was the same. Unless direct evidence to the contrary from U.S. observations in Vietnam is forth coming, this conclusion seems unavoidable: from a military view point, the attempt to starve an enemy can be expected to have little or no effect. What it can be expected to do is to add to the flow of refugees already far beyond the capacity of the programme designed to care for them. The history of modern war has been one of increasing involve ment of civilians. Starvation as a weapon is an aspect of such in volvement, one which has the peculiar property of inflicting suffering on civilians while doing little damage to the military. To destroy crops--with herbicides or in any other way--is therefore to employ a weapon whose target is the weakest element of the civilian population. I would strongly suggest that the proscription of famine as a weapon, whether by chemicals, through food destruction, fire, or mechanical methods, or through food denial by blockade, seizure of foodstuffs, or imposed excessive rationing, be the subject of a separate international convention. The manner in which food is destroyed or denied is less important than the final result. Abandon ment of this method of waging war should be all the easier in that it is cruel while at the same time of no definite military value. DISCUSSION In the discussion to this Session, Dr Lindop suggested that inter national scientific pressure, such as through a group of scientific assessors, from the International Confederation of Scientific Unions (ICSU), the major international scientific body, could report on the bin-e THE WEAPONS--DISCUSSION R5 defoliated areas and predict the possible damage produced. Dr Gal- slon agreed that this would be desirable, and that the more pressure that was put on the Pentagon in particular, the more the chances that some teams of inspectors would be sent out there. There had been a few visiting scientists sponsored by the Department of Defense to survey the effects of drifting chemicals and to take a look at possible upsets in the ecology and disappearance of certain rare species. The argument that was used by the Department of Defense against the journey to Vietnam of experts who might like to take a look for themselves is that a great many of these operations had been carried out in areas controlled by the NLF, and that the U.S. Army could not then in good conscience release a group of people into an area over which they had no control militarily. Dr Lindop pointed out, however, that International Red Cross inspection teams were sent into combatant areas without guarantee of safety. The influence of an international team would be immense. PART TWO CBW IN USE 78 VThieetnYaemmen M. M. Meselson & D. E. Viney F. Kah I r t" '* 7. Vietnam M. F. Kahn Sources In this report I shall deal mostly with practical aspects of the use of CBW in Vietnam. I will also report on my personal experi ence as an investigator for the International War Crimes Tribunal (IWCT) set up by Bertrand Russell, and also as a member of the Scientific Commission of the Tribunal. I would like first to describe the methods used by the Tribunal investigators and also the sources of the information made available to us. Our sources were as follows: (i) Reprints or photostats of the main U.S. reports and papers, appearing in both the general and technical American press, dealing with CBW in Vietnam, (ii) Texts of all the dispatches issued by American war correspondents in Vietnam, including those which were not (for whatever reason) pub lished by the news agencies, (iii) Official reports of the Commission of Enquiry on the American War Crimes in Vietnam, a body set up by the Democratic Republic of Vietnam (DRV) (North Vietnam) with a technical appendix of material evidence and numerous pic tures. (iv) Official reports of the Committee for the Denunciation of War Crimes Perpetrated by the U.S. Imperialists and their Puppets in South Vietnam, an organ of the NLF of South Vietnam with technical appendix of material evidence and pictures, (v) Reports of the investigation teams, sent by the IWCT to both the DRVand NLF-controlled areas of South Vietnam, (vi) Reports of the members of the Scientific Commission of the IWCT, including a technical appendix and results of chemical analyses and of animal experiments. I shall add to this documentation data collected through my personal experience as a member of both investigation teams in the DRV and South Vietnam (NLF-controlled areas) and as a member of the scientific commission. SS CHF. M1CAL AND B I O L O G I C A L W A R F A R E Comment on the use of Napalm and Phosphorus Although napalm and phosphorus are not in the strict sense chemical or biological weapons (see chapter 3) since they are mainly incendiary weapons, it is worth pointing out that this classification is-somewhat arbitrary. As far as napalm is concerned, numerous reports show that this compound, when burning, gives rise to large amounts of carbon monoxide. This happens mostly when napalm is burning indoors, when its combustion is incomplete. Thus there are reports of Japanese soldiers killed during World War II by napalm without any visible burns. While in South Vietnam, I had the opportunity to observe the following case: M. Nguyen Van Ba, male, 36 years old, had received a small amount of napalm while trying to protect himself in a shelter during a U.S. Air Force attack over the village of Ta-Bang (Province of Tay-Ninh) in 1966. He had felt a burning on his hand, and then became comatose for several hours. When he awoke, according to the people who discovered him, he was in a bad state of complete disorientation and had hallucinations. Since then he had had a tremor with hypertonia, exaggeration of postural reflexes, and complained of significant loss of vision. On examina tion I found a very large concentric narrowing of his eye field on both sides; these symptoms are suggestive of the results of intoxica tion, similar to domestic gas poisoning. The burning scar was very tiny, and the effects induced by this burning were obviously not sufficient to explain his state; other people with him in the shelter were found dead. It is worth pointing out that carbon monoxide intoxication greatly increases the lethality of napalm since it prevents the victim from escaping the fire. As far as phosphorus is concerned, as well as horrible burning this compound causes a severe intoxication and hepato-nephritis (liver and kidney poisoning), which in most cases is fatal, even when the burning appears superficial. In fact, phosphorus penetrates deeply into the skin and the subcutaneous tissues, since it produces phosphoric acids which are very acidic, and spreads all over the body. In addition to these toxic effects on man one has to consider the effects on cattle, poultry, and fish. Fish forms the bulk of the pro tein intake of the Vietnamese peasant, and poisoning results when a phosphorus bomb or shell falls into any lake or area of water used for breeding fish. CRW IN USF -- VIETNAM Defoliants and Herbicides S9 Chapters 5 and 6 have already discussed these compounds and their use in Vietnam. I shall mention only some particular aspects of their use which I noted during my investigations in South Vietnam. targets. The province of Tay-Ninh, where I stayed mostly, had been heavily attacked by defoliants. I saw large areas of rice fields and of jungle which had previously received amounts of defoliant. Over the jungle the results of the attack were hardly noticeable. I never saw the cover provided by the leaves completely destroyed. However I did see in some places an abnormal amount of freshly fallen leaves on the earth and occasionally some more heavily damaged trees, proving that the defoliants had been used. Most of the places attacked in the jungle areas were in fact on the edge of the jungle close to the rice fields. On the other hand, I saw heavy damage caused by defoliant on plantations including trees and papayas. Dessicated leaves, swollen, cracked, and fissured stems, and stunted fruits unfit for eating were evident. The witnesses who testified to our Commission were unanimous in their accounts of the spraying of chemicals and the resultant damage to crops. As far as the rice fields were concerned, our evaluation was less precise as the results of the chemical spraying were mixed with the results of neglect caused by the non-stop land and air bombardment in the `free-killing zones', but here, too, the testimony of the Vietnamese peasants was unanimous concerning the damage caused to the rice by the chemicals. Thus, for the investigation team on the spot it was beyond doubt that concentrated attacks on the food supplies of the Vietnamese people was the main target of the so-called defoliants in Vietnam. The obvious ineffectiveness of the chemicals on the declared target --the jungle--contrasts sharply with the relative efficiency against crops and food and trees. TOXICITY OF THE DEFOLIANTS FOR HUMANS AND ANIMALS. Assistant Secretary of State, Dixon Donelly, quoted by Galston in Chapter 5, said that the chemicals in use in Vietnam . . are not harmful for people, animals, soil or water". Despite this, several dozen witnesses heard by our Commission in South Vietnam told us of the physiological troubles they underwent following the spraying of chemicals. In most of the cases it is true that these troubles were relatively mild or transitory in adults. But we were told about lethal 90 C H F M I C A L A N D B I O L O G I C A L W A R L A R L cases occurring among children. In fact adults take care, being informed by the medical services of the NLF, to avoid eating fruits and herbs after chemical spraying. But children do, on occasion, eat fruit coated with chemicals. Miss Thuy-Ba, M.D., chief of the medical staff of a provincial NLF hospital, described to us a lethal case she observed. A five-year-old boy was brought to the hospital after he had eaten contaminated fruit. He had severe abdominal pain, vomiting, then diaorrhea with blood in his stools, followed by collapse and death. On pathological examination, the post mortem revealed disseminated necrosis of the intestinal mucosa. We collected numerous reports of the heavy losses inflicted on cattle and poultry by the chemicals. Buffaloes, pigs, hens, and ducks died by the dozen after spraying. These animals--like the children --were not reluctant to eat foodstuffs, even heavily coated by chemicals. The Commission of Inquiry of the DRV has carried out experi ments to test the animal toxicity of these compounds, and in a first set of experiments the animal tested was the duck. The chemical was DNOC (Dinitro-ortho-cresol). Each animal weighing 075 to TO kg. received either 20 or 100 mg. of the substance. Death subsequently occurred from 5 minutes (120 mg.) to 14 minutes (20 mg.). Pathological findings in these animals revealed extensive damage to the digestive tract with haemorrhages. One has to bear in mind that an amount of 20 to 100 mg. may easily* be ingested by animals feeding in a chemical-coated area. Thus localized vitamin deficiencies were sometimes associated with these symptoms, and one has also to consider the possible, yet unpredictable, delayed consequences not only for the exposed people, but also for their descendants. Gases in use in Vietnam THEIR NATURE AND DISSEMINATION METHODS IN USE. Despite the first official denials concerning the use of gases in Vietnam, the use of CN (chloroacetophenone); DM (adamsite), an arsenical com pound; and CS (ortho-chlorobenzalmalononitrile) has now been admitted by the Americans, and there is a persistent report that the * Some of the conference participants were less certain that it would be easy to build up an intake of quite so large a dose as this. However there now exists, in the French literature, a case of the near fatality of a small French girl and the death of her dog following the use of 2, 4,-D as a herbicide near Lille, France.11Erf. 341X3 CBW IN USE --VIETNAM 91 hallucinogen, BZ, was used on at least one occasion, in Bong-san, in March 1966, The method of dissemination of these gases calls for further comment. It has been reported that the chemicals are used mostly in the form of aerosols.11 In fact, at least for CS on which I was able to collect precise data and material evidence, the methods of dissem ination involve the dispersion of solid particles which undergo direct sublimation from solid to gas. They are not dispensed as droplets, or true solution dispersed with an aqueous phase, which is the definition of a true aerosol. In the projectiles, such as hand grenades of either cylindrical or spherical form, CS is present as a powder which is disseminated in small particles by the explosion of a standard detonator. This detonator is the same as the detonator of the explosive hand grenade. The heat caused by the explosion helps the sublimation of the solid compound. This factor is impor tant when attempting to calculate the concentration obtained by the use of these projectiles in an enclosed space. Another way of dissemination which is especially adapted to a closed area is the dispersion of the powder by means of a high velocity wind machine, nicknamed `Mighty Mite' by the Americans. This machine provides a very powerful air stream, and can very easily build up high concentrations of gases in caves and shelters. In some cases gases are used in the open air, thrown in cluster canisters for example, or in numerous small projectiles dispersed by a special type of multi-barrelled portable mortar. One of these was shown to the IWCT in Roskilde by the North Vietnamese dele gation. But reports from the American side acknowledge the fact that this kind of use was rather ineffective because of the quick dispersion of the gas in the atmosphere and the fact that Vietnamese troops were able to protect themselves with gas-masks. But it is the alternative use of the gases which is more disturbing --their injection into shelters and caves to force out people from their safe underground protection. In fact, as many reports have confirmed, virtually the whole population (both soldiers and civil ians) is obliged to take protection in caves or underground shelters to escape shells, bombs, and the less conventional weapons such as cluster-bomb units, napalm, and phosphorus. When gases are thrown into such shelters a condition is obtained which differs completely from that following use in the open air. All the data available for CN, DM, and CS are calculated for low concentrations obtained by dispersion in the open air. But it must be emphasized that when powder is thrown into a closed area 92 C H E M I C A L A N D B I O L O G I C A L W A R F A R E much higher concentrations build up. In fact, these concentrations cannot actually be calculated by the users of the gas. For a given dose the concentration of gas in the air depends on temperature, humidity, and above all, the volume of air into which the gas is dispersed, and it is obvious that this volume cannot be either cal culated or even estimated by troops using the gas. When applying the gases soldiers inevitably pump in the maxi mum amount they feel possible. Such machines as `Mighty Mite' provide the possibility of blowing in more than 22 lb. of CS into one shelter. A very high concentration of this compound within the shelter can easily build up. are the gases `harassing' or lethal? This point has been dis cussed, particularly by the Americans themselves, in the context of the fact that `riot-control' and tear gases are not prohibited by the Geneva Convention. However, some semi-official U.S. sources acknowledge that even if a gas is formally labelled as `harassing', death may sometimes result from their use. Thus in his book Tomorrow's Weapons1 Rothschild states that CS has a low lethal ity potential. For CN, DM, and CS, toxicity figures indicate a lethal concentration of 100 to 300 m g/m 3 of air.* For DM, which has been reported in use over the South Vietnam town of Hue in February, 1968, it is stated that this compound . . . "is not approved for use in . . . any operation where deaths are not acceptable" (e.g., riot control). However the field manual of the U.S. Army reports that it may be used combined with CN in munitions and in "military or paramilitary operations, in counter insurgency operations, or in limited or general war . . . where possible deaths are acceptable" [my italics]. One has to remember that the gases used in World War I, in 1915, and now prohibited by international law were not, by far, 100 per cent lethal gases; mort ality was only about 10 per cent of those affected.2 the factual reports. The first information appeared in March, 1965 in the New York Times3 when George Reedy of the Presiden tial Press Office stated, "The gases are rather standard types of riotcontrol agent". On the same day Secretary of State Robert McNamara stated that these gases "could be obtained through commercial channels." He * Mr Robinson has also pointed out that toxicity data on CS is also to be found in the open literature1 13. The use of DM as a harass ing agent by British forces has been ruled out on the legal grounds that its use contravenes the General Protocol, 1925, according to Porton Technical Paper No. 651, declassified in June 1968. Ed. CBW IN USL -- V1KTNAM 93 displayed an illustrated catalogue issued by one manufacturer, and it was stated that "Mr McNamara is understood to have tried the effectiveness of CS gas personally to compare it with types used in World War II."3 He added that; "Rather than use firepower, there by jeopardising the lives of non-combatants, to drive the Vietcong out of the area the South Vietnamese troops dispensed riot-control agent". Dean Rusk, quoted by the New York Times, stated that, "It wasn't very effective. When the wind blew it away, it was dissi pated, it did not achieve the purpose", and he concluded, "the anticipation is, of course, that these weapons be used only in those situations involving riot control or situations analogous' to riot con trol". As it can be seen from these declarations, the use of these gases in shelters or caves was not under consideration, officially at least, in March 1965. The following month, Time magazine stated: "Compared with napalm bombs that incinerate whole villages, or a white phosphorus shell that burns a man to the bone, the temporarily disabling gases used in Vietnam seem more humane than horrible".4 There fol lowed many reports from Trung Lap5'6 describing how the gases were injected into tunnels and shelters, including those where civil ians were hiding. Then came the story about Robert Bowtell, given as follows in the New York Times: "Non toxic (sic) gas and smoke being used against Vietcong guerillas, in tunnels north-west of Saigon, have killed one Australian soldier and sent six others to hospital, officials said today. Cpl. Robert Bowtell, 21, of Sydney, died of asphyxiation although he was wearing a gas mask".7 This information was con firmed from different sources.* It was the first official admission of the possible lethality of the so-called tear gases. As a matter of fact, dispatches from Vietnamese sources alleged that in Han Nghia (Long Hu province) troops belonging to the 173rd U.S. Brigade together with Australian and New Zealand troops had used gases extensively against the civilian population hidden in shelters. From January 8th to 15th, 1966, more than one hundred people were killed by the gases in the shelters. It can be seen that the two reports fit completely, and provide * Since the conference my attention has been drawn to a rather more detailed account in the Courier M ail (Australia), January 13th, 1966. The report suggests that a build-up of carbon monoxide in the tunnel may have been a contributory factor in Bowtell's death. The involvement of CS, though, is not disputed. Ed. 94 C H E M I C A L A N D B I O L O G I C A L W A R F A R E TABLE 8 C B W I N U.SI:; -- V I E T N A M 95 ci -' a G 96 C H E M I C A L A N D B I O L O G I C A L W A R I A k L official evidence of the lethality of the gases used in the tunnels and shelters. From Vietnamese sources, more data was obtained which indicated an extensive use of gases, and numerous deaths. The NLF in South Vietnam prepared a detailed report, parts of which are reproduced on pp. 94-95. In fact, the NLF claim that there have been a minimum of thirty well-authenticated cases of the lethal use of gas prior to December, 1967. Deaths must run into several hundreds and those less affected into many thousands. These are inevitably minimum figures. One may recall that the mortality rate from gas in World War I was only about one in ten, yet the post war records of those in France and Britain who did not die from gas at the time made it clear that the after-effects may persist, and many deaths attributable to the gas may occur years after the gas attack itself. For instance, any kind of bronchial irritation may increase the rate of lung cancer incidence in the affected population. During our inquiry in Vietnam in Tay Ninh Province, peasants told us that they found big barrels that the local officers had identi fied as probable gases. We went to see these barrels and found a large, heavy container, easily identified, since the contents were clearly labelled. Each barrel was said to contain eighty lb. of CS. It is noteworthy that the label put on these barrels read "RIOT CONTROL". I remember our thoughts when looking at these words; they were obviously misleading, since it is difficult to imagine how the average policeman could handle an 80-lb barrel in an attempt to control any kind of riot. It is possible that this barrel was intended to feed a `Mighty Mite'--which is not intended for use against riots. We made a small hole in the barrel and took away a sample of grey powder. Very soon we became severely ill with tearing coughs, agonizing abdominal pains, vomit ing, and headaches. This happened despite the fact that we were in the open air, had protected our faces with a kind of mask made of plastic, and were well aware of the toxicity of the compound. We were sick for several hours. The samples we took back to France were formally identified by Professor Lederer's laboratory in Paris and were used for the experiments described in the following section. VExieptenraimme8nts done with the gases used by the United States in As has been said, it appears that the gases used by the United States in Vietnam were not simple harassing agents, owing to the way in which they were used in confined and closed areas where CBW IN USE -- VIETNAM 97 the concentration becomes high. The potential lethality of these gases is, as we have shown, recognized by the United States (reluc tantly and indirectly) and by the Vietnamese. To further elucidate this point, experiments were carried out on animals. The first set of experiments were carried out at Hanoi, by the members of the Vietnamese Commission on the U.S. War Crimes. Dr Vigier of France attended the experiments.9All these experiments were filmed and the film was shown in Copenhagen for the Tribunal. The experiments were as follows: DM was tested on a monkey at a concentration of 15,000 mg/nr1. The monkey showed severe respiratory seizures within 20 minutes and died within 45 minutes. Pathological findings included severe liver damage. CS was tested first on a cat, at 15,000 m g/m 3. The animal died within 30 minutes. Pathological findings included severe lesions, mainly of liver, brain, and kidneys. The same compound was tested on a monkey at a concentration of only 5000 m g/m 3. Death occurred in 25 minutes, with severe lesions similar to those seen in cats. The second set of experiments were carried out in France by Professor Roussel in his laboratory devoted to industrial and en vironmental toxicology. He made a precise study of the toxicity of CS on mice, and found that at a concentration of CS powder of 200 to 2,500 mg/nr1 of air, two-thirds of the exposed mice died in 10 hours. The pathological findings included severe lesions in kidney, liver, and respiratory tract. Conclusions It is not possible at the time of writing to assess whether other gases or toxic agents have been used by the United States in Viet nam. Many reports have referred to the possibility of use of com pounds such as LSD as a weapon in Vietnam, and it must be emphasized that if any such experiment has been carried out by the United States in Vietnam it would be difficult to collect suffi ciently precise data to present reliable evidence here. Moreover, American statements on the use of these weapons have been consistent only in their evasiveness. Thus even when they were trying to make the world believe that they were using only "tear gas" in Vietnam, it was revealed that DM was pro hibited even in the open air for riot control, because it was known that fatal casualties could result from its use. In the New England Journal of Medicine, Sidel and Goldwyn have stated: 98 C H li M 1C. A L A N D B 10 L O G IC A L W A K 1 A R E Even if a "humane weapon'' is developed, its humanity will require the delivery, as in the laboratory, of a precisely measured dose to a standard victim. Both these requisites have thus far been impossible to obtain in the field. Chemical and biological weapons are notoriously uneven in their dispersal and therefore in the amount absorbed by each recipient; to ensure that every person receives an incapacitating dose, some will have to receive an overdose. Furthermore, the young, the elderly and the infirm will be the particularly susceptible victims.10 There is little to change in this statement. Only a word. Instead of "will be", we have to put "are". ADDENDUM The following information has since come to my notice. M.F.K. Recent scientific reports have shown that defoliants like 2, 4-D do not need to be ingested in order to be toxic; they are able to penetrate the skin so that mere contact is sufficient. (LACOMBE, A., Revue Franaise de pdiatrie, 1967, III, 207. See also NEILSEN, K., Fatal poisoning in man by 2, 4-D. Acta Pharmacol., 1965. 22. 224234.) A first-hand testimony of the lethality of the so-called riot-control gases was made available to me by Dr Alje Vennema. While serv ing in Quang Ngai Provincial Hospital he saw many cases of fatalities following exposure to the gases. The principal cause of death was respiratory. See New York Review of Books, May 9th 1968. 8. The Yemen M. Meselson The History Since 1963 there have been sporadic reports of the use of poison gas in the Yemeni civil war. It has been alleged that the gas was being used by the Egyptians on behalf of their allies, the Yemeni Republicans. The charges have come from the Yemeni Royalists, their supporters the Saudi Arabians, from various journalists, and, most authoritatively, from the International Red Cross. So far as the outside world is concerned suggestions, of the use of gas in the Yemen began on July 8th, 1963, with an article in the London Daily Telegraph by Richard Beeston stating that there had been a gas attack on the village of A1 Kanma. Following this story, U Thant initiated an inquiry "to determine whether poison gas has been used in the fighting in the Yemen." A United Nations observation team in the Yemen produced a preliminary report stating they had no evidence that gas had been used but that inquiries were continuing. No definite conclusion was ever an nounced by the U.N. I find no further reference in the press to the use of gas in the Yemen until November, 1966, when Wilfred Thesiger, a British archeologist and explorer who had spent some time with the Royalists, stated that he had come into a village shortly after a gas attack. Thesiger reported seeing twenty victims of what he termed "blinding gas" and said that he treated a boy suffering from "blister gas" that might have been a form of mustard. The first alleged use of nerve gas took place on January 5th, 1967, on the village of Kitaf, the military headquarters of the Yemeni Royalists. This would be the first use in any war of nerve gas, a class of compounds far more deadly than any other known war gases. Judith Listowel, writing in the Statist, reports an inter view with the survivors and states that 155 persons were killed and 200 more severely poisoned. There happened to be a Red Cross team in the vicinity of Kitaf at the time, and they are alleged to have 100 C H E M I C A L A N D B I O L O G I C A L W A R F A R E sent a cable to their superiors reporting the gas attack and requesting gas-masks. The Red Cross did not officially acknowledge the tele gram, but the Red Cross Director in Geneva stated that all parties had been appealed to not to use illegal weapons. On January 24th, Jordan threatened to withdraw recognition of the Yemeni Republi can government unless the use of gas was stopped. On January 31st, the United Arab Republic Minister of National Guidance, Mohammed Fayek, denied that the U.A.R. had ever used gas and furthermore said that Egypt would welcome a United Nations fact-finding commission to investigate the charges. Over the next three months, the Saudi Arabian ambassador to the U.N. urged U Thant to speak out against the use of gas in the Yemen apparently not wishing to place the matter before the U.N. himself. The Saudi Arabians did however produce several pages of medical and chemical evidence purporting to show that nerve gas had been used at Kitaf. The evidence includes measurements of the phosphate content of the blood of human and animal casualties, supposedly an indication of the use of nerve gas. However, some of the figures seemed far too high to be reasonable. On May 10th, 1967, according to a report published in the New York Times and attributed to the International Red Cross, there was an attack using gas on two Yemeni villages, Gadafa and Gahar. On the following day the International Red Cross team in Jidda, Saudi Arabia, received an urgent request for help. They arrived in Gahar on May 15th after being attacked on the road by military aircraft. The team conducted an autopsy and examined several survivors. Their report claims that 75 people were killed by the attack and 273 more by attacks on other villages later in May. The autopsy results were sent to the Faculty of Forensic Medicine at the University of Berne for evaluation, where it was concluded that the victims described had indeed been killed by poison gas, the most likely agent being mustard. Although these details have never been officially acknowledged by the Red Cross, on June 2nd. 1967, it issued a statement saying: The International Committee of the Red Cross has again received, from delegates in the Yemen, reports of bombing by toxic gas. A medical team led by the head of the R.C. Mission in the Yemen went on May 15 and 16 to a village in the northern part of the country to attempt to give aid to the victims of bombing which had taken place some days previously and as a result of which, according to the survivors, many inhabitants had died of asphyxiation. Delayed by air raids to which the convoy was victim, I.C.R.C, doctors on arrival at the site immediately 04 i o2-3 c n w IN DSP -- THE YEMEN mi gave treatment to some of the wounded and collected various indications pointing to the use of poison gas. Extremely disturbed and concerned by these methods of warfare, which are absolutely forbidden by codified international and customary law, the Inter national Committee of the Red Cross at once communicated its delegates' reports to all authorities concerned in the Yemen con flict requesting them to undertake a solemn engagement not to resort in any circumstances whatever to the use of asphyxiating gases or any other similar toxic substances. The salient points in this record are that poison gas has been used in violation of the Geneva Protocol, that it has been used against civilians, and that nerve gas may have been employed in some of the attacks. The evidence indicates that Egypt is respon sible, but Egyptian officials have denied the charge and have asked for an international investigation. There have been no reports of gas warfare in the Yemen since the Arab-Israeli war of last year. However, it was not until about that time, with the first official Red Cross confirmation that gas had been used, that world reaction began to assume serious propor tions. This, together with a variety of political reasons, may explain the failure of the world community to take more decisive steps to enforce the 1925 Geneva prohibition against gas warfare. The Yemeni events and the United Kingdom D. E. Viney The first official British comment on the accumulating evidence of the use of toxic gas in the Yemen came on January 31st, 1967, when the Prime Minister agreed in the House that "such evidence as I have suggests pretty strongly that poison gas may have been used". It was immediately after this that Egyptian papers invited the U.N. to investigate, and the U.A.R. National Assembly was told by its Arab Affairs Committee (February 6th) that the allegations were a defamatory invention put out by Jordan and Saudi Arabia. After unauthorized versions of the International Red Cross team's report had reached the press, and interest in the subject had been enhanced by Israeli apprehensions during the Middle East conflict in June, the Government was again pressed for comment. Minister of State, George Thompson, stated on July 3rd: "We have received well substantiated reports that gas was used several times. Both a mustard type and a choking type have been used on different occa sions." When the possibility of a British initiative was raised Foreign Secretary, George Brown, reiterated that "we condemn the use of gas in the Yemen," but argued that it would be most appropriate 102 CHP . MI CAl . A N D B I O L O G I C A L WAR F ARF . for some Arab country, such as Saudi Arabia, to take action in the first place. That was on July 6th. Later in the month over two hundred Members of Parliament nevertheless signed a letter request ing that the Government should do something, and Mr Brown told an all-party delegation of three that the United Kingdom would consult with other powers as to "the best means of putting, a stop to this clear breach of generally accepted rules of conduct". Immediately after this Parliament went into recess. When it met again the Egyptians were pulling out of the Yemen; the British Government made it clear that none of the other powers consulted was interested in initiating further action and that it considered in any case that such an initiative might now exacerbate the situation in the Yemen rather than assist a settlement. It was of course wide'v assumed that a desire to avoid further unpopularity with the Arab world in the wake of the Middle East war played a major role in setting this attitude, and the West would no doubt have found itself isolated if it had impugned Egypt. The Soviet Union, Czecho slovakia, and other countries who had taken up a strongly proArab line could not have been expected to lend any diplomatic aid for such a purpose, even though they were better placed to exert persuasion on Arab countries than the British were. If they made private representations in Cairo on the undesirability of flouting the Geneva Protocol--and it cannot be excluded that they did so-- they evidently had little success. Since the expert evidence of the use of lethal gases in the Yemen was not made public, no-one without special access to the facts can point the finger dogmatically at Egypt. However, the evidence was apparently found persuasive by British Ministers who had every political reason not to inflate the issue. The reasons why no international action was in the end taken are understandable enough. But the net result is that the Geneva Protocol, that lone achievement in the history of attempts to proscribe particular classes of weapons, is seen to have been flouted with impunity in the very kind of military confrontation where, because of the extreme in equality of strength and the impossibility of deterrence or reprisal in kind, respect for law is almost the only motive for restraint; and indeed to have been flouted (it seems) by a state which signed the original Protocol in 1925, reaffirmed its adhesion on becoming a Republic in 1953, and joined in the general acclamation of the ban on lethal chemical weapons during the United Nations debate in 1966. PART THREE RESEARCHPOLICY 9 10 11 SUUonnviittieeeddt USKntianiotgendsom R. Clarke and J. Perry Robinson Elinor Langer D. E. Viney (' 9. United Kingdom Robin Clarke and J. Perry Robinson The organizers of this conference felt it important that representa tives from the Ministry of Defence or its chemical and biological research centres at Porton Down, Wiltshire, should be asked to attend the conference and give papers on official United Kingdom policy. In consequence, representatives of both the Chemical Defence Experimental Establishment and the Microbiological Defence Establishment at Porton, as well as the Director of Chemical and Biological Defence, were invited to deliver papers on research policy and on matters of defence. Unhappily, all three were unable to get permission to do so, although there have been television appearances both before and since.1 What follows, therefore, is an attempt by two outsiders interested in the problem to summarize the results of some fairly extensive detective work and present what little is known about the British Chemical and Biological Warfare effort and the policies that lie behind it. Later, we shall indulge in a little speculation, but first we shall list what little is already public knowledge. The research establishments CHEMICAL DEFENCE EXPERIMENTAL ESTABLISHMENT. Much the oldest is the Chemical Defence Experimental Establishment (CDEE), as it is now called, which began on its present site in Wiltshire in 19162--shortly after the first chemical weapons were used in World War I. As its name implies, it was from the first designed to be a defensive organization for all three military services. It now comes within the compass of the Ministry of Defence. Its budget is not publicly known and nor is the size of its staff. According to a press release2 which was prepared in 1964 on the occasion of a press visit to Porton, much of its work is devoted to the solving of peace-time problems in civilian life; for example, it gives advice on the design of respirators for protection against industrial dusts and poisonous 106 c h e m i c a l a n d b i o l o g i c a l w a r f a r e vapours and gives assistance in the treatment of poisoning from accidents in the use of agricultural chemicals. However, undoubtedly one of the main contributions of the CDEE has been the improvements made by it in the respirator. From the respirators used in the last war, the CDEE developed a number of new models, of which the Light Respirator Mark 7 was in service in the early 1960's and which has now been replaced by the S6. A third type was developed at the CDEE for civilian use, and others have been developed for special service requirements, such as those of air crew. But the respirator is likely to be insufficient protection in time of chemical attack. The CDEE has also produced air filtration units for use where respirators may not be practicable, and these units are already installed in certain buildings and ships. One of these units, built entirely from non-magnetic material, has been designed for use on mine-sweepers. The CB suit, which is said to be impervious to radioactive dust and to all chemical and biological weapons, was also developed at the CDEE. It is a remarkable advance on other protective CB suits in that it is very light and porous to allow passage of both air and moisture. Various other types of protective overclothing have also been developed there, sometimes as a result of close collaboration with the American, Canadian, and Australian establishments.'1 Alarm equipment to go with these protective devices has also been produced. It includes alarms said to give virtually instantaneous warning of the presence of nerve gases in either liquid or vapour form, another device for indicating when it is safe to remove the respirator, as well as detective pads which will indicate the presence of liquid chemicals by changing colour. The CDEE has also been at the forefront in the therapy of nerve-gas poisoning.1 Like the Swedish and the American establish ments, it has developed devices5 for the automatic injection of a standard dose of atropine into the bloodstream through the thigh. The injector is claimed to be superior to either of the other two models available in that the needle is pressure-sensitive. One of the first drawbacks of such injectors was the danger of the needle striking the bone with consequent medical complications. The British injector is designed so that pressure on the needle of the kind likely to be caused by contact with the bone causes the needle to halt its advance. A pill to be taken at the same time as the injection has also been developed. It contains the oxime known as P2S and has also found uses in treating cases of agricultural poison ing from phosphorus-containing insecticides.2 R E S E A R C H POLI CY -- U N I T E D K I N G D O M 107 This side of the CDEE's activities, at least, is publicly known and is, indeed, described extensively in its scientific literature. Development work of this kind is also backed up by a pure research programme into the classical subjects of chemical and biological research centres--the physics of aerosols and sprays, micromcteorology. measurement of the size of particles and their con centration in the atmosphere, etc. Perhaps the only other publicly known fact--and certainly the only publicly known fact of offensive relevance--is that the riot-control agent CS was developed in the 1950's at the CDEE.6 [The information that has become available about CS since the conference is quite extensive and is summarized in an addendum to this paper. Ed] MICROBIOLOGICAL RESEARCH ESTABLISHMENT. The Other main unit at Porton, the Microbiological Research Establishment (MRE), is much more recent in date and probably better known if not to the public then at least to civilian scientists. In 1945, some forty-five people7 were employed there, of whom fifteen were scientists, but the laboratory facilities were at that time far from ideal. The laboratories were therefore expanded, a job which was completed in June 1951,8 and which was apparently carried out so that micro biologists, which the defence effort needed, could be attracted. This move was clearly successful, and the scientific work of the establish ment gained rapid recognition. Clearly the MRE also grew in size, and though its exact complement of scientific staff is not publicly known, we know that in 1964, for instance, forty-one people authored openly published scientific papers from the establishment.9 [In 1966, forty scientific papers were published by staff of the MRE, accord ing to a Parliamentary Answer.54] The MRE has a reputation for scientific excellence, and this could not have been gained behind closed doors. On the contrary, access to the M RE is relatively easy, and it opens its doors--or at least some of them--to around 2000 visitors every year.1 Its policy is equally liberal towards the publica tion of research results. According to the Director--and a glance at the microbiological literature tends to confirm what he says-- about 80 per cent of the work that goes on at the MRE is published in the open literature. Perhaps, in case there is any confusion about it, something should be said about the scientific nature of this unclassified work. Perhaps the best known concerns the continuous cultivation of bacteria,8 a technique if not actually pioneered at Porton then certainly followed up very quickly by workers there. The net result 108 C H E MI C A L . A N D B I O L O G I C A L W A R F A R E of this--and similar work, of course, in Czechoslovakia and the United States--was the ability to grow bacteria indefinitely at a constant rate under standard conditions and with constant com position. This technique has proved particularly valuable in industry for the preparation of vaccine material and for growing the fungi used in the production of antibiotics. Another field of important work has concerned the pathogenicity of disease-causing organisms. Scientists at the MRE, for instance, identified a specific toxin liberated by the anthrax bacillus and later proved their ability to produce it in vitro. They also resolved it into three components.10 Similarly, in work first reported in 1961, they found that the bacterium Brucella abortus which causes brucellosis, or Malta fever, has a predeliction for foetal tissue.11 The MRE workers found that this was because such tissue contained erythritol which stimulated the bacterial growth. A substantial number of papers have also been published by workers at the M RE on the subject of the survival of bacterial species, particularly in aerosol form. In 1966 a single issue of the Journal of General Microbiology carried four articles by MRE scientists.12' 12a One dealt with the nutritional requirements of the plague bacillus and related species, two were on the survival of bacterial aerosols and the factors affecting it, and the last was on the survival of bacteria in suspension. Though the very fact that these papers were published at all virtually proves they are not representative of the growth, storage, and dispersal of British biological plague bombs, they do show that there is more than one way of interpreting the nature of the research effort at Porton. Officially, of course, all work there is either concerned with defence or is so basic that it has no military implications at all. Equally, and several workers at the MRE have admitted this, there is no clear dividing-line between offence and defence in these matters. Even to study defence requires that scientists learn how to produce samples of various weapons so that different defensive measures can be evaluated. The production of these samples may provide informa tion useful to a nation which wishes to produce sample weapons on a larger scale--and perhaps one should recall that Porton has very few secrets, if any, from similar establishments in Australia, Canada, and the United States. Is there, then, any concrete evidence that any of the work carried out at Porton, other than that done during World War II, has been done for offensive purposes? Early in World War II Defence officials sprayed anthrax on the island of Gruinard off the north-west coast RESEARCH POLICY --UNITED KINGDOM 109 of Scotland.' " 19 This was clearly a field trial of a biological weapon and one of the few that has ever been openly recorded. But the aim of the exercise, according to the present Director of the MRE,1 was to establish whether or not biological warfare was at that time feasible. Dr Gordon Smith, Director of MRE, has said that it was then that several officials really began to believe that biological warfare was practically possible.1 The experiment, incidentally, also demonstrated one of the great drawbacks of biological warfare in that the island that was sprayed in the 1940's is still contaminated and, according to Dr Gordon Smith, is likely to remain so for another hundred years. There is no evidence that this experiment, however, was the first step in the production of biological agents for use in war. We know of no other fields trials until the 1950's, when inanimate particles were sprayed from aircraft in the Bahamas area in 1954.16- 17 However, for chemical weapons, which do not necessarily require field testing over large areas, we are aware of several field trials. Thus Porton Technical Paper No 239 of 1951 is entitled "The Lethality to Rats of GB and GE from HE/Chem. Weapons in the Field",18 while No 424 of 1954 is entitled "The Production of Casualties in Monkeys with GB Vapour".19 These two papers are not openly published. But again it could be easily argued that the trials were to test various defensive measures. Detailed discussion of the exact balance of offence and defence in exercises of this kind is somewhat futile until such time as the officials concerned can be persuaded to reveal more about them. The overwhelming evidence at the present time is that both units are concerned primarily with defence and that a relatively small proportion of their work, possibly inevitably, may also have offensive implications. Neither is there any evidence of the manufacture of any weapons at Porton. We know, of course, that the equipment for the manufacture of the raw material for biological warheads is available at the MRE at Porton. Indeed, during the Asian 'flu epidemic of 1957, the MRE produced more than 600,000 doses of 'flu vaccine.8 This means they could equally well produce 600,000 doses of a biological warfare agent. In that sense, the existence of the MRE must be reassuring to officials concerned with BW policy. For although Britain has both signed and ratified the Geneva Protocol-0 forbidding the use of chemical and biological weapons in war, the Protocol does not preclude retaliation in kind. While Britain has never shown any indication that she intends to break the Geneva Protocol, officials must have considered the possibility 110 C H E M I C A L A N D B I O L O G I C A L W A R F A R E that a potential enemy might do so first. If they did, and it was decided to retaliate in kind, the MRE at Porton would probably provide the necessary biological material. Chemical Weapons If this seems obvious the situation with regard to chemical weapons is much less so. We do know that Britain possessed chemical weapons, but never used them, throughout World War II. After the War they were mostly disposed of, about 100,000 tons in all, some off the west coast of Ireland21 and some in the Bay of Biscay.22 The last load was sunk in September 1948,21 under the direction of the Ministry of Transport. Captured German stocks were for the most part also sunk, tens of thousands of tabun shells, for instance, were sunk in the Baltic.23 Captured German gas bombs were still being sunk in 1957, by then in the Atlantic.21 Have any chemical weapons been manufactured since then? Except for various riot-control agents, there is no evidence of this. There was a pilot plant built for the manufacture of DFP, Britain's rather weaker version of the German nerve gases, at Sutton Oak, in Lancashire,25 which began operating in 1945, but has since been resited at Nancekuke, Cornwall. In fact, we know of next to no evidence of the manufacture of chemical weapons nor of any arrange ments with industry for such manufacture if it should be required.* Such arrangements existed before the last War and indeed were widely proclaimed. However, in view of th similarity of the nerve gases to some of the modern insecticides, there is no doubt that the chemical industry could go over to nerve gas manufacture without much difficulty. Optimistically, one is tempted to conclude that Britain has no operational stocks of chemical weapons, but the psychology of the situation is obviously so delicate that no officiai is ever going to confirm or deny such a suggestion, whichever way the truth lies. Britain's Defence^Potential On the other hand, there is absolutely no doubt of Britain's determination to defend herself against chemical and biological attack. We are not only carrying out an expensive research and development programme into the best ways of achieving this, but we have, for instance, some several million post-World War II gas masks already stocked for civilian use.28 Furthermore, chemical * But see p. 114. Ed. 3LH3. r l s l a r c h p o l i c y -- umtkd kingdom in defence equipment is now standard for troops in specific areas, particularly the British Army of the Rhine. Every soldier in areas where chemical warfare is thought likely is now issued with the S6 respirator and with three auto-injectors loaded with atropine for the treatment of nerve gas poisoning. In addition, British soldiers involved in chemical warfare would have chemically sensitive pads sewn on their battlcdresses, which would respond by colour changes if liquid chemical became splashed on to them. Soldiers are also issued with specially impregnated pads with which to wipe off any chemical that comes into contact with skin. The chemical and biological suit that was developed at Porton is now being made available to soldiers in special areas, and a residual vapour detector --a device to tell when the atmosphere is free from contamination-- is being made available to section leaders, i.e. the leaders of every ten men. Much of this equipment will also double as protection against biological weapons, but a pack of broad spectrum antibiotics would also be issued to soldiers for use as a `blanket cure' should they become involved in a biological attack.26 One can only hope that the scientists who recommended this particular policy have since looked closely at recent figures on infective drug resistance. From information such as this, and from some knowledge of the research activities at Porton, it would be tempting to conclude that Britain is genuinely concerned only with defence against chemical and biological weapons. Future policy There is, however, one area in which there is still room for doubt. That area concerns the exploitation of discoveries made at Porton during the various research programmes. The normal way of exploiting inventions and discoveries is through the medium of patents, but when one examines those in which the British Defence authorities have had a hand, a number of dubious points emerge. Most of the Ministry of Defence patents which have been published have an obvious usefulness in industry, sometimes of great significance. These patents are justifiably exploited to their full commercial worth. They include those for British Anti-Lewisite2S for the treatment of metal poisoning, artificial breathing-machines,29 cascade impactors30' 31 for studying air pollution, the spinning-top atomizer32 for producing accurately dimensioned particulate sprays, an improved process for making dialkyl phosphorohalidates,33 (essentia] raw materials in the production of many insecticides), and H 112 C H E M I C A L A N D B I O L O G I C A L W A R F A R E plague vaccines/''1 Most of these have been exploited through the conventional channel for doing so, the National Research Develop ment Corporation (NRDC). Indeed, one of the purposes of the NRDC is just that, to exploit commercially discoveries made in Government laboratories. The decision as to whether the Ministry or the NRDC should handle a Government patent application rests with the Ministry, although the NRDC's advice is being increasingly sought. In general, the Ministry will retain those patent applications in a field in which it can operate better than the NRDC, for example a field in which only its contractes are likely to need patent protection. Thus, the Ministry has retained the title in the patent6 on the riot-control agent CS and in that on a novel process for making the nerve gas sarin.-6 Occasions do arise when a patent application is assigned to the NRDC who then finds that there is no normal commercial outlet for it, in which case it may well be assigned back to the Ministry, perhaps for future use. But there are occasions when this process of assignment and re-assignment looks odd, particularly if it is so timed that the patent is published in the name of the NRDC. It might almost be said that this process was intended solely to conceal the Ministry's connection with the patent, particularly if the patent goes on to live its full life. There are two particularly pertinent instances of this. One such patent'16 discloses a method of forming carbon-phosphorus bonds by way of what is now called the `Perrin-Kinnear complex' after its discoverers at Porton. This patent was subject to security measures during its early years, and was kept in force for its full term. It describes an extremely simple method of making nerve-gas intermediates. The second patent67 discloses a continuous process for making methylphosphonothionate esters, compounds which are possible intermediates in V-agent manufacture. In view of the continued payment of annual taxes on these patents, and of the convoluted history of their proprietorship, it is reasonable to assume that the Ministry thinks them important. It is not in the least improbable that the Ministry is licensing their inventions, profitably, to other nations or to industry. But there is little further evidence to support this, apart from the existence of overseas equivalents to some of the patents concerned."s- The position over the exploitation of Porton discoveries under international exchange agreements is much clearer. In 1960 the Ministry of Defence confirmed"'-41 a newspaper report42 that information had been supplied to the United States under such an \ 31113 4 R E S E A R C H P O L I C Y -- U N I T E D K I N G D O M 113 arrangement, and that that information formed the basis of a process for making a nerve gas which was about to go into largescale production, at the Newport nerve-gas plant. It was not dis closed which nerve gas it was, but since the Americans had then a very satisfactory process of their own for mauufacturing sarin or GB, the assumption is that it was their other now-standardized nerve gas, the V-agent VK. If this is so it may be that the informa tion passed included that disclosed in the last patent referred to.31 Conclusions There appears to be no evidence directly available that the United Kingdom is producing lethal offensive chemical weapons or even that she has stockpiles of them. The patent literature, however, leaves room for doubt about a number of connected issues. There is very little doubt that the United Kingdom has in the recent past supplied know-how to the United States of direct relevance to the manufacture of at least one nerve gas which is being stockpiled there. And, finally, the presence of a number of patents in the literature suggests that the United Kingdom is in a position to sell toxic weapons, or at least components of them, to other countries. We know this is done for some of the lachry matory agents; it is also possible that it could be done for some of the lethal agents. It is interesting to compare the British Government's security classification of chemical defence work with that of the Americans. Until recently the British attitude was almost invariably to keep it secret. Even the official history of the World War II weapons development programme makes practically no mention of chemical warfare equipment, beyond admitting that "it absorbed a great deal of energy and many notable developments occurred." 13 The Americans on the other hand follow a very erratic course. There are times when it has seemed that their classification system has broken down. On several occasions the Department of Commerce have published in one of their information journals abstracts of still classified reports.44 On another occasion they published through unclassified channels an index45 to an entire range of classified reports published over a period of a year. During General Creasy's great public relations campaign42' 46 to get both the public and Congress to accept the idea of toxic warfare, a great quantity of material was declassified, some of it describing still classified British work. As the campaign backfired, the declassification programme slowed down until the present time, 114 C H E M 1C AL A N D B I O L O G I C A L WA R ! A R E when the U.S. Department of Defense is possibly more cagey than our own Ministry, In several instances, declassified reports'17,'1S which had been iiiade available in our scientific libraries were recalled to the United States, never to be seen again. The same sort of thing happened immediately after World War II. Thus in 1946, reports of the interrogation of German chemical warfare workers were published,'1'-1 only to be quickly recalled. Similar Jaapanese reports remained published however. On the British side, tjhe German reports remain classified, but the Japanese ones werp released a short time ago.50 The final point that should be made concerns the reason why the two units at P3orton have remained steadfastly classified since World War II. The hope that they might become civilian establishments has been ralised several times31, 32, 43 since then, and indeed a number of scientists have left Porton simply because they were under the impression that the units would be declassified and they then realized that this was not going to happen. Why not? From what has been described of the work there very little if any would be out of place in any major civilian chemical or microbiological research centre. Why, then, does such a move not take place? Our guess is that the Ministry of Defence wishes to continue having its cake and eating it. Under the present arrangement it can maintain a front of having only defence interests with an immediate option of diverting its efforts, via Porton, into totally different channels. It is difficult to see what other reason there could be for not declassifying the establishments and thus allaying the largely unnecessary suspict<on which still lingers round them. ADDENDUM Since the Conference, further inform ation about the activities at Porton D ow n has becom e available, partly as a result o f the publicity follow ing the C onference itself, partly as a result o f the publication o f the evidence o f the H ouse of C o m m o n s Select C om m ittee on Science and Technology, which has been exam ining the role o f Britain's D efence Research Establish m e n t s . T h e S e l e c t C o m m i t t e e v i s i t e d P o r t o n o n M a y 6 t h 1968 a n d h e a r d evidence fro m M r C . N . G adsby and D r C. E. G ordon Sm ith, Directors respectively o f the C D E E a n d the M R E . Part o f the inform ation given in t h e s e h e a r i n g s w a s p u b l i s h e d in "T h e O b s e r v e r " , M a y 26th 1968, a n d w a s subsequently judged to be a breach o f Parliamentary Privilege. T h e full report of the C om m ittee was, however, eventually published on July 8th 1968, a l t h o u g h c e r t a i n s e c t i o n s o f t h e e v i d e n c e w e r e o m i t t e d , a p p a r e n t l y R F. S F. A RC H P O L I C Y - A D D E N D U M 115 o n s e c u r i t y g r o u n d s . A c c o r d i n g t o " T h e O b s e r v e r ", J u l y 28lh 1968. t h e M inistry oj D efence originally wanted to leave out rather m ore o f the evidence, but chan g ed its m in d both in view o f the prior "O bserver" leak a n d the adverse publicity which P orton was receiving. W h a t fo llo w s is a su m m a ry draw n fro m this evidence, the replies to a num ber o f Parliamentary Q u e s t i o n s a n d r e l a t e d n e w s s t o r i e s (se e, e.g. " T h e T i m e s " , J u n e Is/ 1968). --Editor. Cost, facilities and policy Of the two Establishments at Porton, the CDEE costs 1,600,000 annually and employs some seventy scientists and engineers (including medical doctors). The MRE costs 900,000 a year and houses forty-eight scientific officers and seventy-six experimental officers (an item, presumably relating to medical doctors, was censored from the Minutes here). Some of this cost, to both Establishments, is recovered in sales to other government Departments, and also commercially, by way of patents let through the National Research Development Corporation. Porton is advised by a group of external scientists, drawn partly from the universities; the current list of twenty-two (1968) includes: Professors N. K. Adam, F.R.S., F. Bergel, F.R.S., E. Boyland, J. I. G. Cadogan, N. B. Chapman, R. C. Cookson. D. H. Everett. R. B. Fisher, D. J. E. Ingram. C. A. Keele, P. L. Krohn. F.R.S., G. J. Kynch, W. V. Mayneord. F.R.S.. M. D. Milne, P. R. Owen. A. E. Ritchie. H. N. Rydon. J. B. Speakman. R. H. S. Thompson. S. Tolansky, F.R.S., M. Weatherall, A. Wilson, and Dr R. D. Keynes. F.R.S. As well as these external advisers, Porton has attached to it a number of Service officers-- thirteen altogether on the establishment of the CDEE. from Army. Navy, and Air Force, whose function is to specify Service requirements in detail: amongst these officers are medical doctors. There is also a member of the U.S. Standardisation Office, U.K., permanently located at Porton, a standing reminder of the existence of the Quadripartite Agree ment between the U.S.. U.K.. Australia, and Canada on information-sharing. Another reminder was. incidentally, provided recently when a paper jointly authored by two workers at the MRE and one at Fort Detrick on gene transfer between two strains of P a ste u r e lla P s e u d o t u b e r c u l o s i s (a relative of the plague bacillus) appeared in the J o u r n a l o f G e n e r a l M i c r o b i o l o g y . Other versions of this Quadripartite Agreement, both tripartite and bilateral, exist with other NATO countries. Despite these links, the Directors of both CDEE and MRE have categorically stated that the work of their Establishments is entirely defensive, and that stockpiles and retaliatory capacity, should Britain be attacked, are both lacking. Porton's responsibility, according to the Director of CDEE. is confined to providing defensive techniques for the Forces; D r Gordon Smith extends his definition of the defensive role of MRE to the civilian population as well. So far as secrecy is concerned, MRE publishes, according to its Director, some 80 to 90 per cent of the work done, but "it is an extremely difficult figure to calculate with any degree of accuracy." To a question as to whether the actual output from MRE, if what was published amounted to some 80 to 90 per cent was not somewhat meagre, the Director replied : "I think our publication record is quite good. I think it could be improved if some members of staff who are rather slow at writing papers would hurry up with them . . . it is our practice to try and offer a substantial piece of work before we publish it." No figures are available for the propor tion of C D E E 's work which is published, but it was generally agreed to be considerably less than that of MRE. Nonetheless, secrecy at Porton has become a matter of considerable public concern. The Select Committee asked whether Porton held `open days' and 116 C H E M I C A L A N D B I O L O G I C A L W A R F A R E was told that its directors had asked to hold them but that permission had not been granted. Even before the Minutes had been published, though, it was announced in Parliament that open days at Porton would be instituted. A later amplification by Mr John Morris, Minister of Defence for Equip ment, made it clear that the first open day was to be for MRE only and that attendance would be by invitation to "representatives of universities, learned societies, research associations, local authorities, industry, the press" and "a number of organisations likely to be interested in the work of the establishment." There appears to be no intention of extending the open day to the work of CDEE as well. Porton and the Universities In addition to its external advisers, Porton has another type of link with the universities. This consists of a series of collaborative projects with individual members of university staffs and of specific research contracts. An example of the type of collaborative project is that which resulted in a joint publication by two workers at St Thomas's Hospital and the Director of M RE in T h e B r i t i s h M e d i c a l J o u r n a l (J a n u a r y 29t h 1966) which contains a description of research in which a series of patients suffering from terminal cancers were experimentally infected with live Langat virus--which causes encephalitis, though is normally not infective in humans--and which for various reasons the authors hoped might serve to alleviate some of the effects of the cancers (which were mainly leukaemic); the research findings were negative, however; all the patients subsequently died. So far as the research contracts go, the CDEE has twenty-seven, including those with Birbeck College, London, University College of Wales, Oxford, Oxford College of Technology, Birmingham, King's College, London, Welsh College of Advanced Technology, Institute of Neurology, Middlesex Hospital Medical School, University of Liverpool, Chelsea College of Advanced Technology, Queen's University, Belfast, Portsmouth College of Technology, University of Edinburgh, University of Southampton, University of Sheffield, St Mary's Hospital Medical School, University of Exeter, University of Kent, and University of St Andrews. Exact details of many of these contracts are not available, but a summary is provided in the Table. Examples include a contract to Professor Henry Rydon, Exeter, (who is also on the Advisory Board and previously worked at Porton) to study the isolation, purification, and structure of the plant toxin ricin--rather analogous to botulinus and tetanus toxins, though much less powerful; to Dr Mary Whittaker, Kings College London, for work on acetylcholinesterase enzymes (those whose activity is blocked by the nerve gases); to D r B. Jacques, Portsmouth College of Technology, on the synthesis of 4-hydroxyl, 1, 2, 3, 4 tetra-hydroisoquinolines (substances with related structures are known to be hallucinogens); and to Professor Harry Smith, Birmingham, on the fractionation of compounds of microbial origin impor tant in the pathogenesis of infectious diseases. None of these contracts appears to be for a very large amount of money, and most appear to be administered so as to allow a fair degree of freedom to the recipients; that is, they are not specifically classified. Indeed Professor Rydon has laid down as the criteria under which he would accept any external contracts coming into his department (at a Teach-In on CBW held at Exeter University on June 11th 1968) that the work must be of relevance to the interests of the Department and must have no restrictions on the right to publish. Such criteria are certainly wholly admirable; nonetheless it must be noted that what the Ministry of Defence means by unclassified is given in a Parliamentary answer by the then Under-Secretary of State for Defence on February 26th 1968: When arranging a research contract the Ministry of Defence agrees with the university who is to supervise the work, but the Ministry does -3 112>b Rr SRMi C H POLI CY-ADDENDUM 117 not normally have a voice in deciding who should carry it out. The results of research for defence are, in accordance with general scientific practice, published freely p r o v id e d th e re are n o o v e r rid in g co n s id e ra tio n s o j n a t i o n a l in tere st, in clu d in i; se c u r ity . Universities undertake to consult the Department before publication. Over the past two years, no universitylias declined to undertake a research contract offered to it. [Our italics]. One must also assume, that however the recipients of the Porton contracts read the significance of their work, those who awarded them the contracts in the first instance must have felt that the work was in some way related to Porton's prime mission; it certainly has no brief to function as a charitable foundation, awarding money for projects irrelevant to its interests. Nancekuke and the CS controversy Apart from Porton. other `in-house' developmental work on chemical warfare is carried out at the Porton outstation of Nancekuke (Portreath) in Cornwall, where pilot-plant facilities for the manufacture of chemical agents exist. Two substances at least are known to be manufactured there, the nerve gas VX, currently made in test quantities only, and the harassing agent CS (see Chapter 1). CS is manufactured in quantities of around four to six tons a year. Some at least of this is transported to the factory of Schermuly Ltd. (a subsidiary of the Charterhouse group), near Dorking in Surrey; here the CS canisters are made and filled, CS is exported to about sixty foreign countries at a price of 35 shillings per pound. In addition, it is supplied to thirty-six of the eighty police forces in England and Wales, as well as to some in Scotland. Police instructions as to the use of the CS is that it is "only to deal with armed criminals or violently insane persons in buildings from which they cannot be dislodged without danger of loss of life, or as a means of self-defence in a desperate situation, and that in no circumstances should they be used to assist in the control of disturbances". (Mr Buchan, Under-Secretary of State for Scotland.) If the evidence of Dr Kahn (Chapter 7) is taken into account, though, it is clear that the use of CS in the type of confined space envisaged in this instruction to police might not be without its hazards. Taking the figure quoted by Porton for the L Ct,,,, of CS, one might expect that the explosion of one Porton CS grenade in the average-sized suburban living room would result in the build-up of a dose lethal to half the exposed population within twentyminutes--(assuming the CS powder remained dispersed in the air) doubtless less if those exposed were at all unhealthy, or included young children (see also the discussion of the toxicity of CS in S c i e n c e J o u r n a l , August 1968). It is certain, though, that the CS used in Vietnam is not of British manufacture. N o r is the gas used during May 1968 by the Paris police, which, code-named CB, the French version of CS, is apparently produced in that country. British-made CS is apparently not exported either to France or the USA. It may be noted in passing that the French CB grenade, according to an analysis made in May 1968 by Dr Kahn, holds a charge of no more than 1-2 grams of CS. The Porton-patented canister described in the preceding chapter contains 30-40 grams, whilst the Mighty Mite used in Vietnam may contain 80 pounds (that is, 35,500 grams). Nonetheless, even though in Paris the gas was used on the open streets, several casualties from the use of CN and CS have been reported from Paris, including allega tions of partial or total blindness and at least one death. It is likely that most of these were CN casualties, but it must be emphasized that a proper medical evaluation of this data is not currently available in England. But additional evidence as to the potential hazards of these agents, and also the American combined agent, containing mainly CN, and known as Mace has come from a study made at the University of Michigan, and reported in the N e w S c i e n t i s t (June 20th 1968), has made clear that the spread of their use should not go unquestioned. Table 9 CBW Research Contracts let to British Universities* C hemical D f j-pa 'c h E x p r.K iM i.N rA L E stablishment Nature of Research Location Research on Fluorohydrocarbons ... University of Birmingham The isolation purification and structure determination of physiologically active peptides University of Exeter The Development of Ultra Microbiochemical Techniques to explore the mode of action of drugs ............... University of Liverpool Synthesis of Components of Pharmacological or Thera University of Manchester peutic interest I. of S. and T. A study of the processes concerned with the metabolism St Mary's Hospital of drugs and toxic substances Medical School Determination of the Structure of Pharmacologically Active compounds ... University of Sheffield Studies in the chemistry of organo-phosphorous com pounds University of St Andrews Synthesis of 4 Hydroxy 1, 2, 3, 4 Tetrahydriosoquinolines Portsmouth College of Technology Histopathological Studies in Neurotoxicity Institute of Neurology ............................................................................... London University Research on the optical properties of Aerosols ... University College of South Wales The Absorption and Removal of Hydrocyanic Acid Gas by Solids University of Bristol Metabolism and Toxicity of Highly Fluorinated Cyclo- hexames University of Birmingham Effect of prolonged inhibition of Cholinesterase in Middlesex Hospital Animals Medical School A combined behavioural electro-physiological and bio chemical investigation of the central action of certain drugs University of Birmingham Investigation of the preparation and properties of fibrous absorptive carbons ... University of Bristol A Physico-chemical investigation of the reaction of Nucleophiles with unsaturated gases King's College, London An investigation of the ability of some biological systems to inactivate acetyl chlorine and of the mechanism of Chelsea College of Science such inactivation and Technology Genetica Factosa and the effect of infantile stimulation on the activity of the acetycholine--cholinesterase and other systems in the brain of the rat ... University of Southampton Nucleophilic Catalysis in Relation to the treatment of Organophosphate poisoning ......................................... University of Kent Some aspects of the Biochemistry of the skin ... Queen's University, Belfast Factors influencing the gelation of liquids with special reference to organic liquids and gels without chemical Welsh College of cross-links Advanced Technology The effect of drugs on neuro-muscular transmissions and contractile force of mammalian skeletal muscle University of Bristol Studies relevant to the reactivation of Organo-phosphorus inhibited enzymes ... University of St Andrews M icrobiological R esearch Establishment Nature of Research Investigation of Fluorocarbohydrates Diffusion controlled electrodes for use in biological systems Investigation of the use of Hydrated Calcium phosphate and related materials for the purification and fractiona tion of viruses and viral compounds Fractionation of Compounds of Microbial Origin impor tant in the pathogenesis of infectious diseases ... Electrophoretic Behaviour of Bacteria ............................ Location University of Oxford Birkbeck College, London University Oxford College of Technology University of Birmingham University of Liverpool * Source Hansard, May 20th 1968 10. United States Elinor Langer Recently research on the chemical and biological weapons establish ment in the United States has made considerable progress. Research within the establishment has undoubtedly made progress as well, but that is beyond the control of the concerned scientists, campus acti vists, and reporters who are responsible for the upsurge in public attention to the CBW question. As a result of these labours we can begin our discussion on a somewhat more sophisticated level, and specifically by clearing the air of a number of points of official propaganda concerning CBW that, while not necessarily technically untrue, have a cumulatively misleading effect. Briefly, these official contentions are that the CBW programme is marginal; that it is inexpensive; that it is unsuccessful; and that it is defensive in nature. The terms "marginal" and "inexpensive" are relative ones, appli cable to the CBW programme only when compared with the nuclear weapons programme, the military space programme, or any of the other multi-billion-dollar American defense activities that involve the substantial acquisition of hardware. Because chemical and biological weapons development is by its nature less costly, com parative expenditures reveal nothing of the scope of the programme, the intent of its sponsors, or their degree of commitment to it. The scientific resources of the United States are so great that commit ment of even a fraction of its energy holds promise of significant results. In other words, the CBW programme can be both marginal and capable of vast destruction.s, f Second, "unsuccessful". For many years certain sections of the U.S. Defense Department have made an effort to communicate the sense that the difficulties in developing CBW weapons, particularly biological weapons, were insurmountable. (The CBW enthusiasts, housed chiefly in the Chemical Corps, have always resented this and have tried to put their contrary view across, but have been somewhat restrained by security precautions in doing so.) The origins of this contention lie in part in public relations and in part 120 C H E M I C A L A N D B I O L O G I C A L W A R F A R E in the genuine dilemmas encountered by the research programme in its early years, particularly during and after World War II. To be usable as weapons systems, biological organisms must possess a number of complex characteristics simultaneously. In the early post-war years it was not clear that the necessary combina tions could be achieved, and there was honest debate over feasi bility. There is still debate and much of it is still honest; however there is also an obvious tendency on the part of Government officials and researchers to use the earlier difficulties as a smoke-screen for the substantial progress that has been made. Men of enormous ability have been working prodigiously on these problems for a number of years. References in the open literature and interviews with those close to military developments leave little doubt that these workers have met with much success, particularly in under standing techniques of aerosol dissemination. In addition, references in military manuals strongly suggest that at least some biological weapons systems have become available. In the United States the answers to two key questions that would help establish the truth ("What is the current view of the feasibility of biological weapons?" and "Which biological agents have gone into the production stage?") are classified. Granted that classification can conceal failure as well as success and is frequently used in that fashion, the point is that we have no reason to assume failure.) /'Third, "defensive". With a few exceptions, such as development of detection and protective equipment, little CBW research can be accurately described as defensive--a word that may conceivably apply to the intentions of the policy-makers (/.<?., we are doing it because others are doing it) or to the occasion of CBW's use (i.e., we don't mean to use it first)TBecause of the nature of chemical and biological weapons, research even in seemingly `pure> areas, such as the development of vaccines, has at least equal implications for offensive and defensive use.^This central point has in fact played a key role in early_(and continuing) internecine fighting about the CBW programme. /When the biological warfare programme was expanded around 1942 the Army Surgeon-General took the position that only the defensive aspects should be studied. The Chemical Corps argued successfully that offensive and defensive aspects could not be separated, and was awarded control of the entire pro gramme. For years the disapproval of the Army Medical Corps of the CBW programme was so intense that they refused to station a medical team at Fort Detrick, the BW research centre.Jln recent years, however, opposition has waned, and the Army doctors have XU3 $ RESEARCH POLIC Y--UN ITED STATES 121 been represented at Detrick:, though the medical unit appears to centre its attention on medical aspects of CBW research such as immunization and therapy. As one of the military's CBW manuals points out "CB defence is a prerequisite to an attack capability."1 Development of chemical and biological research The current healthy state of the U.S. CBW research programme is intimately related to a larger trend in U.S. weapons policy, the swing away from the `massive retaliation' doctrine that began in the late 1950's and reached its fruition under Kennedy in the New Frontier. Before that time the Army Chemical Corps was something of an orphan, a victim of the uproar against gas warfare that set in after World War I. The Corps believed in itself and went about touting statistics demonstrating that gas casualties in the War suffered less than other types of casualties (the statistics are still frequently recited), building up its constant theme that chemical and biological weapons are more "humane" than other forms of warfare. But the audience was small and made up mostly of the already committed. The Corps was given only crumbs of the military budget, usually around $35 million a year. There was another peak, during the build-up of Detrick at the time of World War II, but that concentration dissipated too in the demobilization after 1945. In 1959 the Corps invented and carried out an expan sionist mission "Operation Blue Skies", designed to win public sup port for its latest enthusiasm, "incapacitating" weapons, particularly psychochemicals. It was_that., campaign, endorsed by potent interest groups such as the American Chemical Society, that doyetailed with the decision of the Kennedy administration to acquire a weapons arsenal more versatile than the nuclear stockpile. CBW budgets began to rise, along with the budgets for a variety of other non-nuclear armaments which seemed to offer more flexibility in fighting limited wars. ("Between 1961 and 1964 the CBW budget (Research and Development) nearly tripled, rising from $57 million to about $158 million. The bulk of R & D money is spent by the Army, although the Navy and Air Force in recent years have also undertaken CBW research.)ln 1961 about another $136 million was spent (by the three services) for procurement; procurement figures for more recent years are not availableOn addition to the funds for R & D and procurement, there is a large standing capital in vestment in CBW. How large it is impossible to say as the figures are tucked away under various camouflaged titles in the military budget. However, according to its own advertisement, Fort Detrick 122 C H F . MI C A L A N D B I O L O G I C A L W A R F A R E alone, the centre of U.S. biological warfare research, occupies 1300 acres of land (near Frederick, Maryland), has a building complex valued at S75,000,000, "one of the world's largest animal farms", and "facilities for conducting research with pathogenic organisms that are among the best in the world". Civil involvement For a variety of reasons the military has found it necessary and desirable to contract out a substantial portion (perhaps as much as half, or more) of its CBW research and development to universities, research corporations, and private industry. The reasons are inter esting and reveal something about the climate in which work in CBW is performed. The Chemical Corps has a public relations problem even within the Pentagon. Defense Department employ ees, who have attended high-level Pentagon briefings on a whole range of U.S. weapons systems, report that seasoned generals and admirals who can calmly devote whole mornings (or whole careers) to the business of nuclear destruction become queasy and indignant when it is the Chemical Corps' turn at the blackboards. The reluc tance of competent researchers to submit to the conditions of work on military-controlled bases has posed considerable problems of recruitment for `in-house' research. In addition, there has been considerable interest on the part of industry in getting a share of the work. Reluctance to work on a military base is not the same thing as scruples about the substance of the research, and the con tracting-out operation until recently ran into scant opposition. In a sense it has permitted university and other private researchers to have what they might well consider the best of two worlds: military money and private prerogatives. An item-by-item count of who is doing what has been built up over the last few years, and part is shown in Table 10. But the con clusion may be briefly summarized: virtually any topic we could think of that would facilitate the development of usable weapons systems is under study in the United States. Labour is rationally divided, with basic scientific research being performed chiefly at universities; research on the means of delivery by industry, particu larly the aero-space industry; and a variety of functions of both sorts by the non-profit organizations. (It appears that at least fifty universities, perhaps twenty-five companies, and about a dozen research institutes are now holding or have recently held CBW contracts^he work ranges in scope from the million-dollar research on weapons-dissemination at the University of Pennsylvania to R E S E AR CH PO LIC Y--UNI TED STATES 12) individual medical research contracts of perhaps S10,000 a year; it ranges in apparent lethality from the study of the "supersonic delivery of dry biological agents" (Litton Industries) to investiga tion of the "chemical and physical principles applicable to BW detection" (The University of Buffalo). The list of co-operators includes not only universities, non-profit organizations, and in dustry, but some of the most prestigious organizations of American science, including the National Academy of Sciences, which runs a fellowship programme, and the American Society for Micro biology which has for years provided Fort Detrick with advisory services. The U.S. Public Heath Service maintains close liaison with Fort Detrick, and receives a few hundred thousand dollars a year for its efforts. A number of foreign university researchers have also accepted contracts and grants stemming from the CBW research programme. Defense establishment Notwithstanding all the outside assistance, the internal capacity of the Government remains substantial. Fort Detrick, with a staff of 120 Ph.D.'s, 110 M.S.'s,* 320 B.S.'s,* 34 veterinarians, and 14 physicians, is the principal CBW station with a major research function. Only about 15 per cent of the research findings are pub lished through conventional scientific channels. Detrick is particu larly proud of the three or four occasions when, in co-operation with other scientific societies, it organized research symposia (the principal topic: airborne infection). Another of these occasions--a joint symposium with the American Institute of Biological Sciences in celebration of Detrick's 25th birthday--has recently taken place and--a symptom of changing tempers--was boycotted by a large percentage of the intended participants. But most of the research done at Detrick becomes part of a secret literature managed by the Defense Department and available to other Government agencies or contractors only on a `need to know' basis. Fort Detrick, in addition to its research activities, is involved in process development, small scale production, and design and operation of pilot plants. Closely related to Detrick is the Dugway Proving Ground which employs about 900 people (and occupies an area in Utah almost as large as the county of Hampshire). Dug way is the principal station for field assessment and testing of *The American M.S. and B.S. degrees are similar to the British M.Sc. and B.Sc. Ed. 124 C H E M I C A L A N D B I O L O G I C A L W A R F A R E chemical and biological munitions. According to Pentagon officials there are no large-scale trials of chemical and biological agents on human subjects. (Limited testing is done at Detrick using volun teers--Seventh Day Adventists who serve in the Armed Forces only as non-combatants--and experiments have from time to time been performed on prisoners. But the military evidently believes that the value of testing is outweighed by the dangers of contamina tion and limits its trials to animals or to non-pathogenic simulants of active biological warfare agentsLSometimes testing on animals is inadvertent, as with the accidental slaughter of 6000 sheep during recent tests of a new nozzle for dissemination of nerve gas at Dugway (the sheep were grazing on ranch lands 30 miles away). It is worth noting that the Pentagon insists--contrary to opinions voiced by some in the conference--that these trials would form an ade quate basis on which to test deployment of chemical and biological weapons. ^Biological munitions are produced at Pine Bluff Arsenal, a 15,000 acre installation outside Pine Bluff, Arkansas, which employs about 1400 people. Pine Bluff also produces toxic chemical munitions and riot-control munitions. Its activities range from manufacturing the agents to filling and assembling the weapons. Research and develop ment on chemical weapons and some production and assembly take place in a number of components of the Edgewood Arsenal, in Edgewood, Maryland. A variety of chemical munitions, including nerve gas, mustard gas, `incapacitants', and anti-crop weapons are produced at the Rocky Mountain arsenal in Denver. The U.S. also operates a major manufacturing plant--at an estimated annual cost of $3-5 million--in Newport, Indiana, where the nerve gas, sarin (see Chapter 1) is produced and loaded into rockets, land mines, and artillery shells. The plant is managed by the Food Machinery Corporation, has 300 employees, and is reported to have been operating twenty-four hours daily since 1960. Additional chemicals were manufactured during the middle 1950's at a plant in Muscle Shoals, Alabama, now closed. Training of officers and troops in the use of chemical and biological weapons takes place at the U.S. Army Chemical Centre and School at Fort McClellan, Alabama; related activities in the Air Force occur at Eglin Air Force Base, in Florida. Most of the procurement of the chemical defoliants and herbi cides in use in Vietnam is done on a commercial basis. In the summer of 1967 the Pentagon announced the award of $577 million to the following chemical companies to purchase oLU*/6 R E S E A R C H POL IC Y--U N ITED STATES 125 defoliants for Vietnam: Dow, Diamond Alkali, Uniroyal, Thomp son Chemical, Hercules, Monsanto, Ansul, and Thomas Hayward. About another dozen companies also sell chemicals, including various tear gases, to the Government. Chemical weapons are produced in forms fit for the requirements of all military services. They are available in a variety of mani festations from artillery shells to the Sergeant missile, which has a range of 100 miles, the Honest John and Little John rockets, and chemical land mines. They are also available as bombs for delivery by conventional military aircraft. Detailed information on delivery systems for biological agents is classified, but the unclassified manuals suggest that they are available as warheads for missile systems (for large area attacks), as cluster bombs, and as spray tanks and dispensers mounted on aircraft. The justification--the protesters Recent protests in the United States have called forth a variety of defences from those in CBW and related research and development. Some representative samples: "We are an electric utility and our contract with the Federal Government covers the supplying of electric services for the Dugway Proving Ground. That is as far as our relationship with the Dugway Proving Ground goes and what the power is used for is beyond our knowledge." E. A. Hunter, Vice-President, Utah Power and Light Company.2 ( "Government contracts represent a big part of our research efforts--it's a way of life." H. Ridgely Warfield, director of John Hopkins Institute for Co-operative Research, recipient of over $1 million in contracts for "studies of actual or potential injuries or illnesses, studies on diseases of potential BW significance, and evaluation of certain clinical and immunological responses to cer tain toxoids and vaccines."2) "In no way do we feel that our firm is being `morally com promised' by handling CBW work for the Pentagon. We feel we have an obligation to respond to Pentagon requests for assistance." R. L. Carnahan, vice-president, Travelers Research Center, a major recipient of contracts involving study of factors affecting dissemina tion of chemical and biological weapons, and author of a study of public reaction to CBW use.'1 A similar response was made by Dow Chemical Company following protests over its manufacture of napalm. Dow issued a statement which read in p a rt: "Dow accepted this contract because we feel that simple good citizenship required that we supply our Government and our military with those goods 126 C H E M I C A L A N D B I O L O G I C A L WAR KARL. they need when we have the technology and capability and have been chosen by the Government as a supplier." "No war was ever fought with the intent to be kind. Each weapon as it is used to kill makes man quite as dead, his family quite as bereaved. As a weapon is effective, so it will be used, and the resources of the entire nation will be utilized by the Government on request, or by requisition, to produce those weapons deemed by the Military to be most effective in concluding the war . . ... Scientists make their peculiar contribution to man's welfare. At times it is used well. At times, inventions for survival in one time of history become agents for genuine human betterment and even become powerful agents to impress on man his need to abrogate force. But other men than scientists also direct the course of civili zation. If you spend your powers assaulting one aspect of a problem which cannot be solved by that aspect, you waste your powers. By your reasoning, nearly every facet of American life should be halted, from the production of breakfast food to air transport, since almost all contribute to the prosecution of this war which no one wants. Stop the war with adequate international action or accept the reality that man is still primitive, and that a man or a woman or a child is as dead from mortar fire or shrapnel or a simple rifle." Melvin Calvin, Nobel prize winner, professor of chemistry and molecular biology, University of California, Berkeley, member, Board of Directors, Dow Chemical, manufacturers of napalm. (Calvin's letter appeared in the campus paper, Daily Californian, after a graduate student had challenged him to state his views on the manufacture of napalm and its use in Vietnam.) "I submit that there is almost no major corporation that is not contributing in some way to the Vietnam war regardless of the points of view of its executive". Thomas Watson, President, IBM. (Letter to Brown University campus paper criticizing students there who attacked Dow Chemical.) In general, university protesters over CBW and related war re search have divided into three groups--a `left' or radical minority willing directly to confront the issues of the moral use of research results for war; a `rightist' or conservative minority (usually in the engineering sections) fearful of the damaging consequences to them selves of ending military contracts on any grounds; and a liberal `centre' willing to oust the research but chiefly on the libertarian or educational grounds that faculty members must not interfere with one another's interests. The Dow argument (the Government needs us) is also heard with regard to university and CBW, though less frequently. )b 1 RESEARCH POLICY--UNITED STATES 127 A number of universities have attempted, in the wake of un favourable publicity, to divest themselves of their CBW research projects (the University of Pennsylvania) or of all universitysponsored military or secret research (Cornell, the University of Michigan). In each case, divestiture has provoked considerable tumult, and efforts have been made to find grounds for cancellation not involving moral censure. Instead, dialogue has focussed on the issues of `publishability' and `relevance of the research to the university's teaching mission'.(The contrary argument, made by-- among others--University of Pennsylvania President, Gaylord Harnwell, is that by tradition American universities guarantee their faculties `academic freedom' to research whatever questions they choose; the administration's job is to insulate the faculty from changing political windsY) Policy U.S. policy regarding CBW see-saws between two poles--the declaration of no first use by President Roosevelt in 1943 and the refusal of the Pentagon and State Department to endorse a similarly worded declaration in 1960. What about Vietnam? So far, known U.S. operations have been confined to spraying the jungle and NLF food crops, and to the use of theoretically non-lethal gases, albeit not necessarily in a non-lethal fashion. (The use of BZ has been alleged, but to my knowledge not proven. The same is true of alleged experimental use of other chemicals in underground tunnels, etc.) [But see Chapter 7.] According to a recent report by the Mid west Research Institute (commissioned by the Pentagon in response to scientists' protests), enough herbicide was used in 1967 to `treat' 965,000 acres, although because many areas were treated more than once, the total acreage defoliated was less. Its conclusion, briefly, is that the possibilities of long-term adverse effects are minimal and that the spraying may even be beneficial in some instances. Is this chemical and biological warfare? U.S. officials repeatedly say it is not: others insist that it is. But perhaps the importance of the question is overrated. Surely the important thing is not to name these activities, but to understand what they, along with the other barbarities, are doing to that country. The question in the use of herbicides, as Jean Mayer has pointed out (Chapter 6) is the ethics of starvation, not the ethics of the means of destroying crops. The issue in Vietnam is not the vehicle of destruction but the destruc tion itself. I think that this raises an important question: Why are we spend- i 128 C H E M I C A L A N D B I O L O G I C A L W A R F A R E ing so much time on CBW? I have had to think about this a great deal myself in the course of my own work and have come to reject most of the conventional answers. [ do not believe that CBW is less moral than other means of war, or even that it is necessarily a more unpleasant way to die. 1 do not accept the argument that the tenuous restraints on CBW which have been followed up until now indicate that man is capable of `civilizing' warfare; I believe that the United States--as well as other countries--would use any means of war that they believed, overall, would advance their interests^) I believe that CBW is a violation of international law, but I believe that `resettlement' of villagers in Vietnam is a violation of equal proportion, and that law is as unlikely to restrain one as the other. 1 agree with those who say that CBW is a perversion of science, but I believe that with Hiroshima and other developments science had already demonstrated sufficient perversion and CBW does not appear unique. C I think those who argue that CBW should be watched because it is of special utility in the counter-revolutionary wars the United States and other imperial powers will undoubtedly be fighting have so far done no more than assert their point. Finally, I think that to confine talk about the risks of `escalation' in Vietnam or else where to chemical and biological weapons at a time when escalation is taking other equally dangerous paths is academic.) Why then bother about CBW? I think there are a few main reasons, although perhaps they will seem rather ethnocentric ones. First, I think that many people believe that some or all of the argu ments above are true, including people who, for a variety of reasons, are unwilling to engage in direct anti-war activity or to oppose the government's policies overtly. This is true, for instance, of the scientists' coalition in the United States as well as of a number of university-based protesters. As a result CBW has become a good tactic for dissidents; it is a vulnerable point in the military-industrial complex.(a related reason is that it exposes how some of America's structural and civil liberties, such as `academic freedom', are in adequate to guarantee an ethical scholarly climatey Concern about CBW may, in consequence, help to promote serious university reform. The same may be true in Britain and in a number of continental countries that co-operate with the U.S. defense-research effort. A final reason is that CBW is small enough and manageable enough for outsiders to come to grips with the problem as a whole, and reform seems possible; it weighs less RESEARCH PO LIC V--U N IT ED STATES 129 heavily than the tangled mass of the Vietnam war, on the one hand, or the arcane mysteries of nuclear defense, on the other. Progress in opposing CBW seems possibIe.(J3ut the fact is that we could abolish CBW altogether without making the world much safer or our universities more wholesome^yAt the risk of sounding trite, -4CBW is only a symptom. Perhaps tfrese are not good words for a CBW conference. But it is important to remember that CBW is only a battle; it is not the war. y TABLE 10 U.S. university involvement in CBW research, 1961-68* SELECTED EXCERPTS University Department Researcher Project Boston Chemistry California (Berkeley) Chemistry California (Los Angeles) C o n n e cticu t Pharmacology Dr. Mason Dr. Rapoport Dr. Taylor Illinois (Urbana) Illinois Institute of Technology Indiana Dr. Finger Dr. Ehrlich Dr. Rudsell Johns Hopkins Maryland Massachusetts Dr. Woodward Dr. Kunsberger Oklahoma Pennsylvania Drs. DuBois, Koelle, Haugoard Virginia Medical College W ashington State Dr. Hoff Dr. Hendrix CW agents Lethal and incapacitating agents Medical aspects of CW Synthetic products of psychedelics Crop and food destruction agents Improved biological aerosols More effective toxic compounds Disease of potential BW significants Vulnerability of man to BW Emetics as possible incapacitating agents BW in remote conflict areas Applied research on CBW systems including evaluation of defoliants in Vietnam New lethal and incapacitating agents Anti-crop warfare This list is selected from a directory of 57 universities, institutes ail having U.S> Department of Defense contracts: the total of all D.o.D. contracts to U.S. universities amounted to $ 380 million in 1966. Other colleges etc. include:--Brooklyn, Buffalo, California Medical Schools, Chicago, Clarkson, Columbia, Cornell, Delaware, George Peabody, George W ashington, Georgia, Hahneman, Iowa, Kansas, Maryland, MIT, Michigan, Minnesota, New York, N. Carolina, Ohio, Oregon, Pittsburgh, Rutgers, St. Louis, Stanford, Tennessee, Texas, Utah, W ashington, Western Reserve, W illiam and Mary, W isconsin, Yale. * Data compiled from details published by Michael Klare, V ie l R e p o rt, January, 1968. 11. Soviet Union D. E. Viney This chapter seeks only to assemble a few salient facts publicly known about the potential for chemical and biological warfare of the Soviet Union and the Government's apparent attitude towards it; and to add a minimum of what seems to the author reasonable speculation. Potential Soviet spokesmen have, since World War II, repeatedly forecast that future world conflicts are bound to involve the use of both chemical and biological weapons (if only because the `aggressor' would initiate it), and as the Soviet Union is patently capable of producing many kinds, it would be surprising if she had not pro ceeded from intensive research to the stockpiling of whatever agents she had decided to rely upon. This further step would of course not necessarily follow if the Soviet Union came to regard a conflict be tween CBW-capable powers as unlikely, or if she abandoned faith in the efficiency of deterrence, or the legitimacy of retaliation, in the CBW field; there is no sign of her adopting these positions. There is no reason to think she would stockpile newly discovered agents of dubious value; one can be less sure that she would destroy old stocks of agents which, for her, had been outdated by more sophisti cated ones, but might again prove useful in special circumstances or be made available to friendly nations with different military re quirements. It is well known that the Russians acquired a headstart in the business of nerve gases at the end of World War II by overrunning a German plant manufacturing the least toxic of the nerve gases then known, tabun, and seizing a stock of some 12,000 tons of it. In view of their subsequent interest in organo-phosphorus com pounds generally, it would be surprising if they had not kept at least level with the West in perfecting the manufacture of more toxic ones, and of both more and less volatile agents than tabun. Perry RESEARCH POLICY --SOVIET UNION 131 Robinson (Chapter 1)' mentions that the Russians were, surpris ingly, the first (in 1960) to publish percutaneous toxicity figures for the V-agents. Among the less advanced agents, the same chapter mentions evidence that the Russians stockpiled what might be called the `lethal-irritant' dichloroformoxime, in World War II, as well as adapting for field use hydrogen cyanide (which in the West has often been dismissed as a possible weapon because of its volatility). Around 1960 U.S. sources, in the course of a campaign to make CBW more acceptable, published statements claiming that some 15 per cent of all ballistic warheads on the Warsaw Pact front were chemical ones--an estimate neither confirmed nor denied by official quarters in any other country (nor, incidentally, attacked as provo cative by Soviet spokesmen). Some Warsaw Pact exercises have certainly been conducted on the assumption that chemical weapons would be employed, alone or in conjunction with nuclear attack. The use of chemical warheads with tactical ballistic systems such as the SCUD missile (range up to 150 miles) or the FROG free-flight rocket (range of later versions up to 30 miles) would represent a formidable capability, each missile, assuming a warhead filled with nerve gas, being able to produce a high proportion of fatalities over an area of 1 sq.km, or more among target personnel, unless they were provided with the most advanced protective clothing and were wearing it at the time of attack. American writers have spoken of Soviet preparedness for delivery of chemical agents by such other means as normal artillery shells and aircraft bombs. They have also mentioned spray-tanks for dissemination from aircraft,2 and though it might be thought un likely that much faith would be placed on aircraft flying at vulner ably low altitudes and speeds in a European theatre of conflict, their military utility could be higher elsewhere; it is in any case known (see Chapter 1) that the Russians adapted hydrogen cyanide for dispersal by just such means. Nothing is known, on the other hand, of any Soviet success in developing feasible incapacitating agents. As for biological agents, intensive research can be assumed if only for the same reason as with other advanced countries, i.e., the need to produce vaccines. It is widely reported that the Soviets have field-tested mild patho gens, and they obviously have ample territory for the purpose. Soviet research into the possibilities of mass vaccination from the air must have suggested military applications. However, the crucial facts require no detailed evidence; the Soviets are clearly in a posi- 13: CHF . M1 CAL A N D B I O L O G I C A L W A R F A R L tion to embark on large-scale manufacture of biological agents if ever the}' decide to; and equally, there is no reason to assume that they have formulated a military requirement of this kind, or ever will. The felt need for a deterrent, /.<?., retaliatory, capability does not mean a felt need for the means of replying to every agent with the same agent, or even to every whole class of agents with the same class. As for Soviet defensive equipment against chemical or biological weapon attack, it was said in 19642 to include a very advanced gas-mask, adequate qualities of protective clothing against chemi cal agents, detection and identification equipment similar to the West's, but no automatic warning systems. Civil defence prepared ness is actively promoted by paramilitary and youth organizations through which perhaps half the population have at some time received thorough classroom training in defensive techniques. Underground shelters with air-filtration exist in major population centres, though their capacity is no doubt just as inadequate in terms of general war contingencies as in any other country. Military doctrine Doctrine can best be inferred from deployment, so that the fol lowing remarks apply only to the Soviet Warsaw Pact front, and only to chemical weapons. Until a few years ago it may well be that chemical warheads were seen by Russians partly as a substitute for tactical nuclear war heads, which were harder to develop than the more powerful nuclear warheads used on long-range missiles, and so were not available in sufficient quantities to counter the known American capabilities. Assuming however that there is now some balance on the tactical nuclear level, a lethal chemical weapon capability would still make sense in these roles: (i) tactically, to destroy personnel without destroying installations and communications to one's own detriment, and without rendering large areas inaccessible to one's own side for such long periods as would nuclear weapons; (ii) to furnish a military option above the conventional level, but still short of nuclear escalation; and (iii) to deter chemical weapon attack by an opponent. Of these three roles, the first two only remain attractive as be tween nuclear opponents on the assumption (by no means certain) that the use of advanced chemical weapons would avert nuclear escalation and not simply precipitate it. But the third, deterrent, role would still remain valid, and even the existence of large, deployed 2 -in f RESEARCH POLICY-SOVIET UNION 133 stockpiles on the Soviet side would be consistent with a Soviet view that deterrence was their primary role, but that the capability must remain a large one in case deterrence failed. Although a dis tinction can be made of course between use of a chemical weapon capability to deter any attack and to deter a chemical weapon attack, this does not invalidate the foregoing argument. Exaggerated inferences can be drawn from the statements of Soviet military men. who are after all just as liable--sometimes more--to inject political and empire-making considerations into their analyses as those of other nations. Marshall Zhukov's 1956 obiter dictum before a Party Congress that "a future war, should it be unleashed, will be characterized by the massive use of . . . means of mass destruction such as atomic, thermo-nuclear, chemical, and bacteriological weapons" cannot seriously be used in 1968 to argue an active Soviet interest in possessing an offensive capability in all parts of the spectrum. Marshall Sokolovsky says more soberly in the 1963 edition of Soviet Military Strategy that in a future war "one must expect the aggressor to use chemical and bacteriological weapons in conjunction with nuclear ones". A prefatory note by the publishers of Bacteriological Weapons and How to Defend Against Them 1even more cagily says that "future war is considered by the aggressive circles of the USA to be a total war in which means of mass destruction will be widely used". This booklet is recom mended for use by "agitators, propagandists, lecturers and teachers" and is largely devoted to a description of epidemic diseases and means of controlling them. It is possible, then, that instruction based on such books is seen primarily as a means of inculcating general hygienic practices and knowledge, with the anti-Western implica tions as a propaganda bonus. It is interesting, however, that this particular book does not repeat the charges lavishly made by Rus sians and Chinese alike at the time of the Korean War, that the Americans had actually used biological weapons--in particular insect-borne agents--at that time. Its historical review jumps from alleged Japanese activities during World War II to the use of defoliants and anti-crop compounds in Vietnam. Arms-controi doctrine The USSR is one of the fifty or so countries which have signed the Geneva Protocol of 1925 binding them not to use "asphyxiating poisonous or other gases", nor "analogous liquids, materials or devices", nor "bacteriological methods of warfare" against fellowsignatories. Like Britain and many others, the Soviets put in a 134 C H E M I C A L A N D B I O L O G I C A L W A R F A R E reservation releasing them from these restrictions if they found themselves at enmity with a country "whose forces, or the forces of whose allies" failed to respect the Protocol. Strictly, then, the USSR is not inhibited by the Protocol vis--vis the U.S. (as a non-signatory), nor would she be against British forces allied to U.S. forces in a conflict in which the United States was not respect ing the Protocol. Of course, the United States may be held to have a virtual `no first use' policy regarding CBW; and some jurists argue that the Geneva Protocol, though contractual in form, has entered into the body of international customary law (see Chapter 12) through long (if not universal) observances, so that it is binding among non-signatories as much as signatories. Possibly some Soviet jurists would take this view, and the tendency in Soviet legal writing is certainly to take the Protocol seriously and grant it some efficacy as a factor which, alongside mutual deterrence, prevented chemical agents from being used in World War II. These considerations do however draw attention to the greatest East-West bone of contention in regard to CBW, i.e., whether nonlethal chemical agents are in fact banned under the Geneva Proto col. It is outside the scope of this chapter to mention the many arguments that have been adduced on each side. Suffice it to point out that though the Soviet authorities have used tear gas for riotcontrol just as Western states have done, it by no means follows that they, or we, must logically condone the use of the same agents in wartime against enemy forces. The last major international debate on CBW was that in the U.N. at the end of 1966, where the Hun garians and various African delegates made most of the antiAmerican running; the Soviet delegates do not appear to have spoken at all. (The debate ended with a general appeal for all countries to adhere strictly to the Protocol, but cast little light on the points at issue.) The Soviet Union is meanwhile on record with its 1962 plan for General and Comprehensive Disarmament (GCD) which proposes complete abolition of both chemical and biological weapons, during the second of three 3-year disarmament stages; against this, the corresponding Western blueprint advocates study of the special difficulties of chemical and biological arms-control in Stage I, a halving of stockpiles in Stage II, and elimination of the rest and of manufacturing facilities in Stage III. The Soviet plan makes no mention of inspection difficulties, nor of discrimination problems, and by analogy with the Soviet stand over inspection in other fields one must assume that at present they would not con template giving alien inspectors the right to do anything but observe RESEARCH POL]CY--DISCUSSION 135 the actual destruction of agreed quantities of agents. It seems a long time, too. since those inter-war disarmament negotiations when the Soviets proposed that factory committees in each country should ensure the non-production of prohibited weapons. It must be feared in any case that implementation of the GCD plans is not a thought uppermost in the minds of negotiators of any major power today, so doggedly do the obstacles seem to have grown instead of shrinking. Meanwhile the Soviets are probably happy to stand pat on the Protocol as they see it, plus their known capability in those CBW fields which they consider effective. In regard to the contentious non-lethal agents, they may feel them selves to be in somewhat of a public relations quandary. As occa sional users of riot-control agents they could not approve of any statements appearing to condemn these as intrinsically inhumane. On the other hand they probably do not foresee any great military need for these or other non-lethal agents on their own side (expect ing to be on the guerrilla, not counter-guerrilla, side of limited wars) and can hardly oppose any criticism of the Americans in Vietnam. It is therefore not likely at present that the Russians will be eager partners in any efforts to secure a redefinition of terms as a means of strengthening the Protocol. And even where lethal agents are used in clear violation of the Protocol, as in the Yemen, political con siderations will put a severe brake on Soviet reactions. It is not suggested that those seeking ways of constraining CBW, and especially of constraining the spread of CBW capabilities, should give up: simply that they should bear the political background in mind. V DISCUSSION Two major issues were raised in this discussion. First, the nature of the quadripartite and tri-partite agreements between Britain Canada, Australia and the United States were 'questioned by Pro fessor Wall, who quoted an interview given by Dr Pennie, Deputy Chairman of the Canadian Defence Research Council to a Canadian magazine.1This interview gave two important items of information. One was a fairly detailed description of the Suffield Proving Ground north of Medicine Hat in Alberta, Canada. It consists of a set of closed laboratories and also a thousand square mile tract of 136 C H E M I C A L A N D B I O L O G I C A L W A R F A R E land which is used specifically, according to Dr Pennie, for studying the spread of organisms. Equipment from all parties to the agree ment was tested there. Asked how the pact works, Dr Pennie re plied : "There are regular meetings of scientific staff engaged in this particular line of work in all three countries, and there is free dis closure of information in all these areas. We also attempt to divide the work between laboratories whether they be in Britain, the United States or here (Canada) wherever the work suits. You can understand that you need specialized facilities for this type of work. There are facilities in Canada which don't exist in Britain; there are some in Britain which do not exist in the United States so it makes good sense and sound logic to try and divide up the work." Professor Wall went on to point out that the existence of an agreement of this kind places equal responsibility on all four mem bers of this quadripartite pact. The second major theme concerned the issue of secrecy: should work at Porton continue to be secret? If it was exclusively defensive in character, why could it not be declassified? The general arguments in favour of secrecy were indicated by Dr Viney and Professor Meselson who pointed out that there were two sorts of secrecy: conspicuous and clandestine. The former variety could lead to opinions in other defence establishments that there was something worth investigating. The very knowledge of the existence of secret research is a powerful deterrent to one's enemies. But the clandestine sort also has considerable advantages --there is less danger of spying and political control is easier. Countering the move to declassify secret research at Porton, Dr Viney pointed out that if one disclosed all the facts about a genuinely defensive capability, then the research becomes under mined because the potential enemy knows what one is equipped to defend oneself against. Further, revealing all that is known about CBW would amount to a proliferation of dangerous knowledge. Whilst this does not mean that secrecy must be eternal in a world of sovereign states, there are sound, peace-loving reasons for maintaining secrecy until such time as it can be assumed that all countries have given up offensive intentions. Finally, Professor Meselson showed that, from the point of view of a British Minister of Defence, Porton probably offered an ex tremely high return on investment. In exchange for a small expen diture at Porton and the maintenance of the quadripartite agree ments, he had access to the results of the much larger programme of the United States. For this reason alone, the Ministry would probably fight quite hard to maintain secrecy. After some theorizing as to the actual percentage of secret work carried out at Porton, the Conference heard the arguments in favour of declassification. Mr T. Dalyell (Member of Parliament for W. Lothian) suggested that many of the scientists at Porton might prefer to work in the open in order to achieve healthier relations with university scientists. Dr Sidel felt that the chances of the development of offensive weapons by any power would be oai4fc> RESEARCH POLICY --DISCUSSION 137 much reduced in a world where a policy of complete openness was pursued. Dr Rose pointed out that throughout the history of science, secrecy or no secrecy, there are many instances of simultaneous discovery. For example, it is now abundantly clear that the Soviet Union would have developed its own atomic weapons within a very short space of time irrespective of the leakage of secrets that oc curred in the 1940s and early 1950s. An exactly comparable situa tion applies today to CBW--the South Africans are surely capable of making many of the weapons, whilst one can be reasonably con fident of the ability of the universities and chemical industry' in Western Germany to be sure that they require very little help from Porton's publications. In fact, one could say that the synthesis of the chemical agents described by Perry Robinson are within the scope of any reasonably competent organic chemist. As far as biological agents are concerned, the central problem is that of mass production and this should be within the capabilities of any drug house with a pilot plant. Mrs Galston attempted to deal with Dr Viney's concern that scientific information should not fall into the wrong hands by pointing out that in our present world every hand at this point and for this type of weapon is the `wrong hand'. <1 J I T4V V N IH b VJ -HU. X > h a V * , PART FOUR LEGAL ASPECTS OF CBW 12 Legal Aspects I. Brownlie 12. Legal Aspects I. Brownlie General features of the law The first and major characteristic of the law of war is its para doxical nature. The United Kingdom Manual of Military Law1 states that the development of the law has been determined by three principles: First, the principle that a belligerent is justified in applying compulsion and force of any kind, to the extent necessary for the realisation of the purpose of war, that is, the complete submis sion of the enemy at the earliest possible moment with the least possible expenditure of men, resources and money; secondly, the principle of humanity, according to which kinds and degrees of violence which are not necessary for the purpose of war are not permitted to a belligerent; and thirdly, the principle of chivalry, which demands a certain amount of fairness in offence and de fence, and a certain amount of mutual respect between the opposing forces. In spite of the element of paradox, the law has produced certain factors of discrimination in the means of carrying on war. The prin cipal factors are, first, the prohibition of weapons which cause unnecessary suffering in proportion to their destructive effect, and, secondly, a distinction between combatants, whether regular or irregular, and non-combatants. The law and the statesmen who influence its development utilize categories which may not seem very sophisticated or up to date. In many ways legal categories are bound to have rough edges partly because they set standards for a great variety of people most of whom are neither scientists nor lawyers. However, the legal categ ories have in general maintained a sufficiently close relationship with technical developments. The law has employed the category of chemical warfare since at least 1919, though the legal reference is usually the formula which prohibits "the use in war of asphyxi ating, poisonous or other gases, and of all analogous liquids, 142 C H E M I C A L A N D B I O L O G I C A L W A R F A R E materials or devices." The Dictionary of US. Army Terms, pub lished in 1953, defines chemical warfare as "the tactics and tech nique of conducting warfare by use of toxic chemical agents." The weapons may be thought to include incendiary fuels2 and smoke gases, but this is a matter of doubt. The indisputable content of the category is the list of anti-personnel gases; incapacitants, for example, hallucinatory drugs; choking gases, such as chlorine and phosgene; nerve gases, including sarin and tabun; gases which affect the oxygen supply in the blood; and blister gases including mustard gas and lewisite. Since 1925 the legal materials have contained the category of "bacteriological methods of warfare". The modern technical con cept of biological warfare includes bacteriological methods, but extends to a wider range of agents. The Dictionary of US. Army Terms defines biological warfare as "the employment of living organisms, toxic biological products, and chemical plant growth regulators to produce death or casualties in man, animals or plants; or defence against such action." The US. Army Manual, published in 1956, describes biological warfare as "the military use of living organisms or their toxic products to cause death, disability, or damage to man, his domestic animals or crops" and continues: "It includes the employment not only of bacteria but also of other micro-organisms and higher forms of life, such as insects and other pests . . . While certain chemical anti-crop compounds are not truly biological warfare agents, they are so considered as a matter of convenience." It seems to be a matter of historical accident that the use of gases has been regarded as chemical warfare while the use of bacteria and `toxic biological products' is classified separately. Other features of the law require brief notice. Much of the law consists of treaties, and in some connections states are concerned to point out that they are not a party to this or that treaty. Never theless, international law may develop rules of customary law which are evidenced by state practice in the form of protests, official warnings, manuals of military law, and various diplomatic mater ials. A treaty may by its terms provide evidence of the state of general international law in two ways: by containing statements purporting to be declaratory of existing law; and independently of the first method, by being accepted as a statement of the law even by non-parties. Finally,\the modern principle is that the law of land warfare applies to international conflicts whether or not the parties characterize an armed conflict as a `state of war'. An insur gency may constitute an armed conflict, and, although it will not be o a ih <\ LEGAL ASPECTS OF CBW 143 of an international character unless there is substantial foreign inter vention against the lawful government, it is now generally accepted that the general principles of the humanitarian law of war apply to internal conflicts./ Tinhteernparotihoinbaitliolanwof chemical warfare in customary There is a great deal of evidence in support of the view that chemical warfare as a genus is prohibited by customary inter national law./The peace treaties of World War I and the Treaty of Berlin of August 25th, 1921, between the United States and Germany, contain provisions which prohibit the importation or manufacture by Germany of certain gases and other liquids and devices, and in doing so treat as already prohibited "the use of asphyxiating, poisonous and other gases and all analogous liquids and devices." In 1922 the Washington Treaty was concluded.3 This contains a provision the substance of which was to be repeated in the Geneva Protocol of 1925. Article V prohibits "the use in war of asphyxiating, poisonous or other gases, and all analogous liquids materials or devices." The United States ratified the Treaty on June 9th, 1925,1 but it failed to come into force because of the absence of French ratification. The French failure to ratify, it may be noticed, had nothing to do with the reference to chemical warfare, but flowed from the limitations on submarines in the Treaty. The Geneva Protocol signed on June 17th, 1925 'The Protocol is the most important instrument concerning pro hibited weapons.It provides as follows: . . . the undersigned Plenipotentiaries, in the name of their respective Governments: Whereas the use in war of asphyxiating, poisonous or other gases, and all analogous liquids, materials or devices, has been justly condemned by the general opinion of the civilised world; and Whereas the prohibition of such use has been declared in Treaties to which the majority of the Powers of the World are Parties; and To the end that this prohibition shall be universally accepted as a part of International Law, binding alike the conscience and the practice of nations; Declare: That the High Contracting Parties, so far as they are not already Parties to Treaties prohibiting such use, accept this K 144 C H E M I C A L A N D B I O L O G I C A L W A R F A R E prohibition, agree to extend this prohibition to the use of bacteriological methods of warfare and agree to be bound as between themselves according to the terms of this declaration. International lawyers of great authority have held that insofar as the instrument relates to chemical weapons it is declaratory and affirmative of the customary law at the time.5 Forty-nine states signed the Protocol, which came into force in 1928. In 1944 there were forty-four parties by ratification or accession. Since then another fourteen states have become parties, including India, Paki stan, Cuba, and a number of African States. China's accession of 1929 has been recognized by the People's Republic of China. The United Kingdom, France, the USSR, and a number of other states are parties subject to a condition of reciprocity.6 The United States did not become a party to the Protocol, but the Protocol has ac quired considerable prestige and is referred to as evidence of the general law.7 Thus in the Shiinoda case8 a Japanese court con cerned, inter alia, with the legality of the atomic attacks on Hiroshima and Nagasaki, referred to the Protocol as a source of relevant rules although neither the United States nor Japan were parties to it. The United States and CBW The position of the United States obviously calls for further examination since its non-participation in the Geneva Protocol is a companion to that country's scientific and military resources and proven readiness to prepare and resort to chemical warfare and related techniques. The failure to ratify the Protocol did not stem from any decisive negative stand on its subject matter but from a desire to avoid an omnibus prohibition. However, since World War II the United States policy has been more equivocal. The US. Army Field Manual9 expressly states that "the United States is not a party to any treaty, now in force, that prohibits or restricts the use in war fare of toxic or non-toxic gases . . . or of bacteriological warfare". American official sources have in fact adopted a fairly clear view on these matters on a number of occasions in the past. In 1932, on the basis of proposals by President Hoover, the General Com mission of the Disarmament Conference adopted a resolution which condemned the use of gas, bacteriological, and incendiary warfare as methods of warfare. A study by the U.S. Naval War College in 193510 concluded that "the use of poisonous gases and these that qsTire LEGAL ASPECTS OF CBW 145 cause unnecessary suffering is in general prohibited; the use of smoke-screens and of tear gas has not been included in the category of prohibited acts, but the use of bacteriological warfare has been prohibited''. Of interest is the robust statement of President Roose velt which is printed in the Department of State Bulletin dated June 12th, 1943.11 This statement includes the following passages: From time to time since the present war began there have been reports that one or more of the Axis powers were seriously con templating use of poisonous or noxious gases or other inhumane devices of warfare. I have been loath to believe that any nation, even our present enemies, could or would be willing to loose upon mankind such terrible and inhumane weapons. However, evidence that the Axis powers are making significant preparations indicative of such an intention is being reported. . . /U se of such weapons has been outlawed by the general opinion of civilised mankind. This country has not used them, and I hope that we never will be compelled to use them. I state categorically that we shall under no circumstances resort to the use of such weapons unless they are first used by our enemies. / In a debate in the United Nations General Assembly on October 16th, 1952, Dean Acheson, then United States Secretary of State, declared:12 "We will not commit aggression with chemical weapons or bacteriological weapons, which we have been falsely and slander ously accused of using." The American position would seem to be far from consistent, and in the case of chemical weapons the U.S. Army Field Manual ignores the evidence for the existence of a customary rule prohibit ing use. In any case the American position, in so far as it appears to deny the existence of prohibitions, relates to non-prohibition of chemical and biological weapons as a class, tout court. Thus it is subject to various specific rules as to methods of conducting war in general. I shall enlarge on this aspect of the matter later on. The 1966 Resolution of the United Nations General Assembly On December 5th, 1966, the General Assembly of the United Nations adopted the following resolution: 13 The General Assembly Guided by the principles of the Charter of the United Nations and of international law : Considering that weapons of mass destruction constitute a 146 C H E M I C A L A N D B I O L O G I C A L W A R F A R E danger to all mankind and are incompatible with the accepted norms of civilisation. Affirming that the strict observance of the rules of inter national law on the conduct of warfare is in the interest of maintaining these standards for civilisation; Recalling that the Geneva Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous or Other Gases, and of Bacteriological Methods of Warfare, of 17 June 1925, has been signed and adopted and is recognised by many States. Noting that the Conference of the Eighteen-Nation Committee on Disarmament has the task of seeking an agreement on the cessation of the development and production of chemical and bacteriological weapons and other weapons of mass destruction, and on the elimination of all such weapons from national arsenals, as called for in the draft proposals on general and com plete disarmament now before the Conference. 1. Calls for strict observance by all States of the principles and objectives of the Protocol . . . signed at Geneva on 17 June 1925, and condemns all action contrary to those objectives; 2. Invites all States to accede to the Geneva Protocol of 17 June 1925. / The resolutions of the General Assembly are normally not bind ing as such on member states, but resolutions on legal questions provide clear evidence of the state of the law, since the resolutions represent the deliberate and collective view of those states giving affirmative votes. This resolution is expressly concerned with legal issues and was adopted by 101 votes/ No state voted against, but three--Cuba, France, and Gabon--abstained. /The significant features of the resolution are as follows. First, it assumes that the Geneva Protocol today constitutes general inter national law and no longer a mere contract for actual parties to it. Secondly, this assumption extends both to chemical and bacterio logical warfare. Thirdly, the prohibition seems to be of these types of warfare tout court because the weapons concerned are weapons of mass destruction/ On this third point it might be argued that the reference to weapons of mass destruction cuts down the effect of the resolution because not all chemical or bacteriological weapons are necessarily of this type. However, the intention of the resolution is clearly to deal with these weapons as types; hence the focus on, and emphatic reference to, the Geneva Protocol. In general the resolution clearly militates against the former apparent reservations in the position of the United Stales. The United States took part in the process of amending the original proposal and voted for the resulting text. LEGAL ASPECTS OF CBW The question of conditional legality 147 The materials examined so far relate primarily to the issue of prohibition unconditionally of the classes of chemical and bacterio logical weapons. It is important to tackle the problems from a different point of view for a number of reasons: the United States might renew its stand against prohibition tout court; the observer, and especially the non-lawyer, may feel that the alternative to categorical prohibition is that CBW is lawful without qualification. This cannot be so on any view of the legal position. Insofar as particular chemical and biological weapons have in discriminate effects, or cause unnecessary suffering, they can only have conditional legality. The V.S. Army Manual necessarily adopts the principle of conditional legality, since any more permissive principle would be utterly untenable. Paragraph 36 of the Manual thus provides: The use of weapons which employ fire, such as tracer ammuni tion, flame throwers, or napalm, and other incendiary agents, against targets requiring their use is not violative of international law. They should not, however, be employed in such a way as to cause unnecessary suffering to individuals.^ Although the U.S. Army Manual is equivocal in dealing with both chemical and bacteriological weapons, the general implication is that in its regime a conditional legality exists as in the case of fire weapons. The position of conditional legality must be given some elabora t io n .^ is an uncontestable principle of customary law that it is forbidden to use arms, projectiles, or material calculated to cause unnecessary suffering. 14/Moreover, numerous rules of customary law, repeated and developed in the Geneva Conventions of 1949, would be inevitably broken if weapons are used which produce extensive, indiscriminate, and possibly unknown and uncontrollable results. Two Conventions in particular are involved here: the Geneva Convention for the Amelioration of the Condition of the Wounded and Sick in Armed Forces in the Field,15 and the Geneva Convention Relative to the Protection of Civilian Persons in Time of War.16 The indiscriminate character of certain types, at least, of chemical and biological techniques needs stressing. Moreover, the elements of persistence and consequential action may aggravate the problem. 148 C H E M I C A L A N D B I O L O G I C A L W A R F A R E Assessment of the legal position It is not very useful to examine the various forms of special pleading to be found in some of the literature in favour of freedom of action and choice of weapons.Arhe fact is that the vast majority of writers in various languages take the firm view that both chemical and bacteriological weapons are prohibited and that the Geneva Protocol now represents general or customary international law.'yThe current United Kingdom Manual of Military Law con tains a careful codification of The Law of War on Land prepared with the assistance of Sir Hersch Lauterpacht, later the Briti^i judge on the International Court of Justice. Paragraph 111 of The Law of War on Land provides that "the use of poison and poisoned weapons, asphyxiating, poisonous or other gases, and of all analo gous liquids, materials or devices, and bacteriological methods of warfare are forbidden." This view of the law receives recent and very substantial reinforcement from the General Assembly reso lution of 1966. In the debate on that resolution the United States reacted to charges relating to the conduct of the war in Vietnam by saying that the only gases it had used were irritant gas, tear gas of the type normally used in riot control. The United States' position is interesting because it does not lay stress on permissiveness, but pleads that an exception exists to the overall prohibition. The exception does create some difficulty. In all probability the definition in the Protocol was intended to be com prehensive for the genus of substances with which it dealt. In November 1930, the United Kingdom presented a memorandum to the Preparatory Committee of the Disarmament Conference which stated that the Protocol definition included non-toxic gases and notably irritant gases.18 On the other hand, if the genus con cerned is confined to those weapons which cause unnecessary suffering tear gas may not be included as such, and everything will depend on the type and the way it is used. It may be noticed that the U.S. Naval War College Study of 1935 states that the prohibi tion does not include smoke-screens and tear gas. A more serious threat to the legal regime comes from the doc trine of reprisal. Several parties to the Geneva Protocol, including the United Kingdom and the USSR, made a reservation of recipro city, and/the customary law contains the principle that reprisals may be employed in reaction to a prior violation of the law committed by the enemy/However, the doctrine of reprisals is limited in that a reprisal must not be in excess of the degree of violation com- LEGAL ASPECTS OF CBW 149 mitted by the enemy and reprisals directed against wounded and sick prisoners-of-war and civilians, protected under the Geneva Convention of 1949, are unlawful and constitute war crimes] A further consideration is the possible effect of the strong terms of the General Assembly resolution : the consequences may be that the rules in the Protocol are now jus cogens and not subject to the doctrine of reprisals and also that reservations on the same theme are void.19 Some other relevant legal principles The use on a substantial scale of weapons which cause indiscrim inate harm to combatants and non-combatants and which in any case cause unnecessary suffering will involve the commission of crimes against humanity. Crimes against humanity were declared to be crimes under international law in the Agreement on Military Trials of 1945,20 which provided for the establishment of an Inter national Military Tribunal at Nuremberg. /The definition contained therein refers, inter alia, to "murder, extermination, enslavement, deportation or other inhumane acts committed against any civilian population.''/T he Agreement on Military Trials had twenty-three parties, and a unanimous resolution of the United Nations General Assembly affirmed "the principles of international law recognized by the Charter of the Nuremberg Tribunal and the Judgment of the Tribunal."21 ' Depending on the effects of the particular weapon and the con ditions in which it is used, to resort to chemical and, more especi ally, biological warfare might constitute a breach of the Genocide Convention.22' However, the intention in such a case must be "to destroy, in whole or in part, a national, ethnic, racial, or religious group, as such . . ,"23/Finally, if large scale and reckless use of weapons and techniques produced effects which spread over fron tiers the state using weapons in this way would be in breach of the duties toward neutral states which the customary law imposes on belligerents. Article 1 of the Hague Convention of 1907, concerning the rights and duties of neutrality, provides that "the territory of neutral Powers is inviolable." Defoliation and crop destruction The practice of aerial spraying for purposes of defoliation and crop destruction was clearly not foreseen by the various legal con trols relating to the conduct of war. Moreover, the rationale behind SU l I 150 C H E M I C A L A N D B I O L O G I C A L W A R F A R E the existing rules is the causing of indiscriminate and unnecessary suffering to people by direct means. Nevertheless, practices which must result in depriving peasant communities permanently of their food resources constitute a crime against humanity and if persisted in, when large-scale distress is manifest, would amount to genocide. Large-scale destruction of the fertility of a countryside is an opera tion which is probably more strikingly indiscriminate as between combatants and non-combatants than any technique other than resort to nuclear weapons. A `scorched-earth' policy which is carried out in circumstances in which specific material resources are kept out of enemy hands and which is accompanied by a taking of res ponsibility for the subsistence of civilians from the area concerned is not necessarily illegal. Of course, the normal scorched-earth technique is not aimed at the ecology of a region in any case. A further point is that pillage of captured places and unnecessary destruction of property are forbidden by rules of undisputed authority. Large-scale crop destruction must fall foul of these rules, more especially when it is carried out from the air. Incendiary weapons The classification of weapons has been a matter of conventional and historical association. Neither the legal definition nor, it seems fairly clear, the scientists include fuels and incendiary weapons in the category of chemical weapons. As Dr Sidel points out in his paper on napalm,21 explosives and incendiary weapons are `physi cal' weapons, producing their effects by blast and heat. As a class it is doubtful if such weapons are prohibited since they do not appear to fall within the terms of the Geneva Protocol.25 Neverthe less, the normal rules of the law apply: /napalm and similar weapons can be used lawfully only against military targets and "their use against personnel is contrary to the law in so far as it is calculated to cause unnecessary suffering."26 / Control of armaments and disarmament It is well known that, in spite of adherence to rules limiting or prohibiting the use of certain types of weapons, states may manu facture and/or, possess the weapons concerned. Disarmament is the better form of insurance therefore. Recent proposals for dis armament have shown particular concern for the prohibition of the production, possession and use of chemical and bacteriological weapons. This concern is perhaps an index of the growing role of LEGAL ASPECTS OF CBW 151 such weapons in military preparations. In this connection it is worth recalling an existing treaty provision in Protocol III of 1954 to the Brussels Treaty of 1948.27 Article One of the Protocol stipu lates that the Federal Republic of Germany shall not manufacture in its territory atomic, biological, and chemical weapons. In Annex II the following definitions occur. A chemical weapon is defined as "any equipment or apparatus expressly designed to use, for military purposes, the asphyxiating, toxic, irritant, paralysant, growth-regulating, anti-lubricating or catalysing properties of any chemical substance." A'biological weapon is defined as "any equip ment or apparatus expressly designed for use, for military purposes, harmful insects or other living or dead organisms, or their toxic products." Concluding remarks It will suffice to make certain general points.1 / (i) If the Geneva Protocol is regarded as declaratory of the cus tomary law only in respect of chemical warfare/then the distinction between chemical and bacteriological warfare may matter since the prohibition of the latter type may be less firm. The chemicalbiological distinction is difficult to maintain in some ways at least. Thus the existence of non-biological poisons, the low molecular weight toxins, blurs the line with chemical warfare. However, the general practice of states and the evidence provided by the United Nations resolution of 1966 justifies the conclusion that both chemi cal and biological warfare are prohibited by general, i.e., customary, international law. / (ii) The prohibition existing on the basis of the Geneva Protocol and the United Nations resolution is clearly not restricted to lethal gases. It almost certainly includes all anti-personnel gases. (iii) Even if the Geneva Protocol was regarded as in some way defective, and even if it were to be denounced by'some of the parties to it, it cannot be emphasized too strongly that the ordinary laws of warfare still apply. The layman, who knows about the Protocol but is ignorant of the law of war in general, is ready to. assume that everything turns on the Protocol. The overriding principle, which applies to all weapons, is that weapons should not be used which are calculated to cause unnecessary suffering or are inevitably in discriminate as between combatants and others. These principles may be found in any statement of the law of land warfare, includ ing the British Manual of Military Law, Part II. is: CHEMICAL AND BIOLOGICAL WARFARE DISCUSSION Discussion of Dr Brownlie's paper ranged extensively over many of the issues he raised; two particular topics may perhaps be singled out, the legality of the U.S. use of chemical weapons and defoliants in Vietnam, and the general question of whether the activities of international lawyers, in building a legal framework in which war could be conducted, helped reduce its risk. On the first point, the use of the weapons in Vietnam, Dr Brownlie reiterated that attempts to discriminate between lethal and non-lethal weapons failed; the definition of chemical weapons was concerned not so much with lethality but with the concept of "asphyxiating, noxious or causing unnecessary suffering". Dr Galston asked what the position was regarding the use of food deprivation as a weapon, and if the deliberate destruction of food, either by the dumping of captured bags of rice or by the destruction of rice plants in the field, were challenged and the United States asked to supply a basis for its actions, what likely legal basis would be used. In reply Dr Brownlie pointed out that there is no legal provision on scorched earth policy as such. The British Manual, for example, which is quite detailed, not only in its actual provisions but in the comments on provisions, where it suggests examples of the scope of particular provisions, says that the poisoning of wells is illegal bpt the diversion of watercourses is allowed. It comes back to the general principle that one cannot use means of conducting a war which cause unnecessary and indiscriminate harm to the civilian population/ It thus becomes a question of how this general principle is applied to the particular facts.,And this is a problem no matter what area of war is discussed. If a war zone is declared and treated without the slightest attempt to sort things out, then it would be very difficult to find a legal basis to say that this behaviour came within the accepted rules. On the other hand if a given war zone, before declaring it a war zone, is claimed to be occupied by foreign forces and the civilians were behind the lines somewhere (where one has lines), then there are no legal risks at all: one just treats everything as an open target. ' Mr M. Leitenberg pointed out that the U.S. Field Manual (USFM 27.10.1949 para. 24 and 1956 para. 40, 41) was very precise on this point. Thus it states that destruction of food crops and food supplies is prohibited unless it can be shown that these are for the use of enemy combatant personnel. \The United States has said repeatedly (i) that intended victims of'this campaign are male Viet L E G A L A S P E C T S O F CBW -- D I S C U S S I O N 153 Cong combatant personnel who are in isolation from the com munity and (ii) that to make sure that there is no unnecessary suffering caused to civilians they are warned in advance and told where they can go. Now, while this may not be the case in practice, there remains a very interesting connection between the U.S. law of warfare and what the U.S. Government claims to be doing. But according to Donald Hornig, President Johnson's Science Advisor, the real purpose of the anti-crop programme has been directed at moving the population out of NLF-controlled areas into those controlled by the Saigon regime. This puts quite a different perspec tive on the programme and is borne out by a survey of defoliated areas. Crop destruction has been most marked not in the sparselyoccupied areas where the effect would be largely confined to the NLF guerillas but to the densely-populated, fertile Mekong Delta --the `Rice Bowl of South East Asia'. Thus, as Dr Brownlie concluded, it all depends on the evidence on the particular case concerned. In the Vietnamese case, the U.S. policy of declaring war zones and then treating everything in the zone as a free target might be quite good evidence on this particular point. The second theme was raised by Professor Arnott, who asked whether Dr Brownlie felt that the body of international law relating to warfare produces any inhibitory effect at all on the behaviour of governments when it suits them otherwise. Those who were engaged in the early battles to contain nuclear weapons, claimed Professor Arnott, do not believe that the fact that they haven't been used is in any way due to any international agreements, test bans, or what ever, but because so much is known about these weapons that they are politically impossible; this is the sanction which prevents their use. The same would be true for CBW as well. Dr Brownlie replied to this challenge that his answer could not be his opinion as a lawyer, because this was a matter of politics and sociology. There was a difference between talking about rules and their efficacy. If one brought a criminal lawyer into the discussion, he would talk about criminal law, but he would not have said the law is probably not worth talking about because only ten per cent of warehouse break-ins in London ever come to conviction. Rules of themselves could not dictate in matters of high policy, but could have some sort of moral imperative which affect governments in this sphere. The problem of enforcement is a complicated one-- the rules themselves are never self-enforced--they cannot be, and the rules of warfare present more of a problem than there would be in some other areas of law. But one of the ways out is to remind governments publicly that they have in fact said these things and signed these treaties. One of the problems is the sociological question of why law is observed at all. Governments are not individuals--they are like rather vast and complex corporations. Within a government one can have different views on crucial matters of international law. In times past the Admiralty has had one view and another sector 154 C H E M I C A L A N D B I O L O G I C A L W A R F A R E has another view. In the United States, on some leading ques tions of international law the State Department has a different view from the Department of Justice--on sovereign immunity, for in stance, immunity of foreign states and their agencies. So if one is talking about states, one must remember they are not individual be ings. The problems are different from those of making internal laws. On the world scene there is a newer type of community, a definite sort of community consisting of 130 large corporations which can behave as very complex units. Thus despite its inadequacies, the codification of international law remains a powerful tool. PART FIVE ETHICALPROBLEMS 13 Preventing CBW 111654 SSMocemideeinctaiCfliocEntRchleiucssspioonnssibility J. H. Humphrey and M. Meselson V. W. Sidel C. F. Powell Steven Rose 13. Preventing CBW (a) J. H. H um phrey In discussing what might be done about the danger that chemical and biological weapons may become accepted as part of the normal armoury of nations, it will be more useful if we consider them from the point of view of those who regard it as their business to pre pare for wars as well as from that of those who regard resort to war as an unnecessary and unacceptable way of settling differences between nations. So long as national governments, and those who maintain them in office, continue to prepare for war rather than repudiate it, arguments about whether one way of killing people or of putting them out of action is more beastly than another are liable to appear academic and to be ineffective. While I accept that to take part in the development and use of chemical and biological weapons poses ethical problems for the scientists involved and that to take part in `public health in reverse' is indeed directly contrary to a physician's role, the ethical prob lems seems to me to be personal and not essentially different from those which face a physicist or engineer working on ballistic missiles or a bomb sight. Further, I doubt whether to those at the receiving end an attack with chemical or biological weapons could be much more unpleasant than one with napalm or saturation bombing with anti-personnel missiles. Once the weapons are such that the person who uses them is not made aware of the direct consequences of his actions, and especially if he has been taught to regard his enemies as creatures whose lives are incomparably less important than his own, he can escape such emotions as pity, disgust, or horror which might make him hesitate to use the weapons except perhaps in the heat of battle. To me and, I suspect, to military planners it seems illogical to set chemical and biological weapons in a category apart from other modern weapons on grounds of beastliness alone. The question is, are there other grounds on which these weapons can be distinguished? I think there are. The first and most important, as explained by Dr Brownlie, is that the people in all countries and the politicians in their public 158 C H E M I C A L AND BI OLOGI CAL. WA R F A R E pronouncements recognize such a distinction--even though it may be illogical and based on an accident of propaganda and history. The terms of the Geneva Protocol, publicly supported at the United Nations in December 1966, by the representatives of all the major powers including the United States and Japan, forbid the first use of chemical and biological weapons in warfare, although they do not forbid research on or possession of such weapons. Despite its obscurities and the tenuousness of any guarantees of observance the Geneva Protocol provides a statement of good intentions which it has not been possible to achieve in respect of any other weapons. The second is that investment in CBW, although by no means inconsiderable, is still small compared with investment in conven tional and nuclear weapons. At present, so far as one can tell, CBW is regarded rather as a useful adjunct to the existing armoury, although the situation might change if both wars and the nuclear stalemate continue. Some of the advantages claimed for weapons of this kind have been set out in General Rothschild's book Tomorrow's Weapons, and include cheapness, minimal destruction of property and fixed installations, flexibility (including the capacity to reach persons protected against all but very powerful conven tional weapons), and, in a strange way, humaneness, since the nonlethal weapons may incapacitate the enemy sufficiently to destroy his fighting power temporarily. Although lethal chemical and bio logical weapons could conceivably be used against more or less specific targets, they are nevertheless essentially indiscriminate in their action and are classified as weapons of mass destruction. The status of non-lethal chemical and non-lethal biological weapons (if the latter are under serious consideration) has been left blurred, and it is arguable whether they should be defined as weapons of mass destruction. These are the weapons which are put forward by their protagonists as being humane. Since few people--at least in peace time--relish the idea of killing, the humaneness claimed for CBW could lead to its being regarded as acceptable, despite the Geneva Protocol. I find it hard to understand--and this doubt is confirmed by the example of the use of non-lethal chemical weapons in Vietnam--how non-lethal weapons can deter or defeat a determined enemy, except when used as a means of making conventional weapons more effective. This is a matter which requires careful discussion and hard thinking. The third difference is that much of the research which goes into the development of chemical and biological weapons, or into defence against them, is of a very similar nature to research which E T H I C A L P R O B L E M S -- P R E V E N T I N G CBW 159 would legitimately be pursued without any consideration of CBW. For example, the toxic properties of the organo-phosphorus insecti cides need to be studied for the sake of the persons who make and use them; similarly important is work aimed to discover antidotes and to devise adequate protective clothing. The defoliants used in Vietnam are standard agricultural chemicals, and spraying them from aeroplanes to defoliate trees--rash though this may appear to ecologists--has already been done in Africa in attempts to clear the tsetse fly, vector of trypanosomiasis, from parts of the`tsetse belt.' What sets apart work on chemical weapons is the deliberate and secret investigation of properties which increase their toxicity for man, the preparation and manufacture of devices for use in war, and the stockpiling of chemicals for this purpose. Similarly the development of biological weapons requires research into factors controlling the pathogenicity of microbes and their mode of dis semination; study of techniques for rapid detection and identifi cation; large-scale culture methods; preparation of protective vac cines; and so on. Nearly all the research required could quite properly be undertaken as non-military projects in universities, medical research institutes, or enterprises engaged in the manu facture of vaccines. Even intensive investigations on uncommon and exotic highly virulent microbes could be entirely justifiable in a wholly peaceful world, both on scientific grounds-and because of the possibility that some time, somewhere, such microbes might become disseminated and give rise to serious epidemics such as have repeatedly ravaged man and other animals in the past. As with chemical weapons, microbiological research and development be come biological weapon research only insofar as techniques are devised for deliberately spreading pathogenic infective agents in war. A fourth feature of chemical and biological weapons is that their manufacture does not require elaborate or highly specialized instal lations which would be difficult to conceal. Indeed the potential activity per unit weight of these weapons, especially of biological weapons, is so great that quite small factories or parts of factories could suffice to supply the military requirements. Apart from the need for precautions essential for the handling of highly danger ous materials nothing obvious need distinguish such factories from others making ordinary fine chemicals or, say, antibiotics or bac terial vaccines. Consequently, inspection and verification to ascer tain whether the ingredients of such weapons were being made would present much greater difficulty than in the case, for example, of fissile material for nuclear weapons. L IM) c: H li M 1C A L A N D B IO L O Ci 11 A L W A R I- A R 11 With these four general points in mind, it seems to me that there are a number of ways in which the further development of chemical and biological weapons might be halted and the danger of their further use in war diminished.* The first is by ensuring that the support publicly given to the Geneva Protocol by almost all the national delegations at the General Assembly of the United Nations in December, 1966, is strengthened and not eroded. This means that the issues involved must be clearly discussed and widely enough understood to put political pressure on the governments of those countries which have not ratified the Protocol to do so. Without minimizing the unpleasantness of CBW or the ethical ob jections to weapons of this kind, I think that the most valid reason for doing this is that the Geneva Protocol, if not a giant confidence trick, is a real beginning in that limitation of weapons which all countries in the United Nations have declared they wish to seek. Until the difficulties presented by inspection and verification have been got round it may be difficult to extend the Protocol to forbid research on or possession of chemical and biological weapons, although states could be encouraged to renounce these for them selves, as Austria has done. But even if all countries had adhered to the Geneva Protocol allegations of infringement in times of tension or war might still be made, and would require rapid investigation, since the right of retaliation in kind would remain. There is need for a recognized organization prepared to do this. It might be the International Red Cross Organization, or perhaps the World Health Organization because of its accepted expertise in epidemiology and its non partisan reputation. All this would minimize the danger of the future use of CBW, but it would not prevent countries from researching on and pre paring such weapons as a precautionary measure to permit retalia tion. The next and more important goal is for all countries to renounce the use of CBW altogether. This would imply that no secret research, by government or industry, could be done on potential weapon agents, and that open research on them in scale and content must have a clearly non-military aim. Renunciation of CBW could be made soon--indeed it might become much more difficult later--because no country has yet made such a major in- * M any of the issues mentioned here have been raised under the stimulus of discussions held under the auspices of the Pugwash Movement. gaib^ E T H I C A L P R O B L E M S -- P R E V E N T I N G CBW 161 vestment in these weapons as to feel its security threatened by renouncing them as part of a general agreement. It would be a gesture of mutual confidence which could lead to other and more important steps towards disarmament in more sensitive areas. Finally, what should be the future of the establishments which have been built up to study and prepare for national defence (and, to a greater or lesser degree, offence) in relation to CBW? It is important to consider this question, since on the one hand they are likely to have a powerful vested interest in their own continued existence, with the possibility of arguing for this at the top level, and on the other hand they represent a sword which could be changed, with a minimum of beating, into a magnificent ploughshare. I will consider our own establishments, the MRE and the CDEE at Porton Down. I will start with the assumption that their own public image of themselves is broadly correct. That is, that their function is to study potential offensive agents only in relation to devising means of defence against them; that the great bulk of the original scientific work done there is published; and that most of the scientists take jobs there not only to earn a reasonable salary, but because they are given excellent facilities to study scientifically interesting problems and because they have a genuine belief that their work is important for the military defence of the country. Furthermore, I know that they are willing toQielp other civilian institutions with advice and the provision of materials and facilities. Nevertheless, in accepting this image I think it necessary to make two reservations. The first is that the study of defensive measures may not be so innocent as it might appear if studies of offensive measures and discoveries relating to these are left to our American allies on a reciprocal basis. In the absence of other information it may be wiser to assume that the collaboration which began during World War II has not ended. The existence of an agreement between Britain, Canada, Australia, and the United States, and of shared proving grounds for CBW research at Suffield, Alberta, and Innisfail, Queensland, are examples. It is important to know what are the general terms and duration of this quadripartite agreement. The second reservation is that the out put of published work from Porton would appear somewhat meagre if it represented the total useful output from an ordinary research institute with a comparable staff and facilities, and this is bound to give the impression that more goes on there than is revealed. Despite these reservations, the fact remains that at Porton are collected teams much of whose work has a direct relation to the problems of 162 C H L M 1 C A L A N D B I O L O G I C A L WA R I A R L civilian life, but has much less impact on these than it might do if the primary object of the establishments were not to undertake partly classified work for the Ministry of Defence. I do not of course, know, what classified work goes on at Porton nor what is the purpose of keeping it secret. Let us suppose, hypo thetically, that significant defensive advances have been made, such as the development of a very effective general purpose gas-mask or of a rapid and extremely sensitive method for detecting airborne microbes. Would the revelation of such developments diminish their defensive value? Or might not this actually be increased, by show ing that it would be difficult for one country to steal a march on another in this field? The answers do not seem to me to be obvi ously `yes' and `no' respectively. It would be unrealistic to expect that the Ministry of Defence could abolish its establishments at Porton out of hand, or even declassify all the past work which has been done there, unless other countries known to be interested in CBW such as the United States and the USSR were prepared to do likewise. However this does not mean that no initiative can be taken. Provided that our Government were not contemplating becoming engaged in a war within the next few years involving CBW--despite the Geneva Protocol--and especially if it were meanwhile prepared to make a real effort at the international level to reach agreement to renounce these weapons, I suggest that for a trial period of not less than five years all the future work carried out at Porton should be declared declassified. Because, I suspect, biological weapons are presently less important than chemical weapons it might be easier to declassify the MRE first. The CDEE might follow suit later, after allowing time to observe whether there was a favourable international reaction to the first initiative, and time to sort out possible complications about chemical weapons shared with our allies. Work on the defence of man and animals against highly virulent and pathogenic organisms or work on toxic chemicals could proceed much as at present and might well be more effective because collaboration with other workers would be easier and more natural. Of course the results would not be the exclusive property of the Ministry of Defence, but there would be nothing to prevent the armed forces from obtaining advice and making use of them as they wished. Even during the trial period I would like to see at least a part of MRE positively devoted to international col laboration, for example with the World Health Organization over problems of mutual interest (of which there are many) or with the SLll^ E T H I C A L P R O B L E M S -- P R E V E N T I N G CBW 163 Food and Agriculture Organization over such projects as the large-scale production of micro-organisms as food additives for regions where dietary protein is inadequate. Similarly part of the Chemical Defence section might act as a Research Association for the by no means economically insignificant protective clothing in dustry (which at present has none). Collaboration of this sort would not only have the advantage of promoting goodwill but could help towards defraying the cost of keeping Porton going. To make such a gesture would carry some risk, but it would be an act of leadership by this country which could produce quite disproportionate gains by helping to break the deadlock over dis armament. Furthermore, by making the gesture for an initial trial period, without disbanding the teams which have been built up. even the risk would be minimized. (b) M. Meselson Half a century has passed since the world's only major outbreak of poison gas warfare. Large-scale germ warfare has never been attempted. Gas and germ warfare are explicitly prohibited by inter national law in the Geneva Protocol of 1925. Considering the enor mous scale of gas warfare in World War I, it is remarkable how well the Protocol has been respected. There have been only two instances of verified poison gas warfare since 1925--in Ethiopa, and in the Yemen. In Vietnam the United States has been employing a powerful but generally non-lethal anti-riot agent, maintaining that the Protocol does not forbid it. When compared with the recent history of other forms of warfare the record shows that the governments and peoples of the world have come to practise and expect a degree of restraint against the use of chemical and biological weapons not found for any other class of weapons, except nuclear ones. The chief factor justifying that res traint is the same for both nuclear and CB warfare--apprehension that, once begun, it would open up an unfamiliar and highly un predictable dimension of warfare that might lead to the extermina tion of very large numbers of troops and civilians, especially one's own. D estructiveness of CBW There is no doubt that existing nuclear weapons could destroy entire populations. Although the performance of chemical and biological weapons in any particular attack would be less predic 164 C H E M I C A L A N D B I O L O G I C A L W A R F A R E table than that of nuclear weapons, they too have very great poten tial for mass killing. The most effective method of strategic CBW attack would presumably entail the production by bombers or missiles of a cloud of toxic or infectious material over or upwind from a target, to be inhaled or absorbed through the skin by persons in the attacked population. Although masks, protective suits, and special shelters can provide effective protection against known chemical and biological agents, the cloud would readily penetrate dwellings and other ordinary structures. An attack by a single bomber, dispensing one of the more deadly nerve gases, could kill most unprotected persons within an area of at least five square miles, this being the size of the zone of high mortality caused by the Hiroshima and Nagasaki atomic bombs. Although nerve gases are among the most poisonous substances known to be suitable for military use, it may well be possible to devise weapons containing far more poisonous materials, perhaps toxins or related substances. Weapons based on such super-poisons might become as destructive to unprotected populations as thermo nuclear weapons of equal size. Poisonous as nerve gases are, virulent micro-organisms and viruses can be a million or more times more so, in terms of the amount that can cause incapacitation or death. Although many in fectious agents are rapidly inactivated or lose their virulence when dispersed in the atmosphere, this obstacle to the development of biological weapons can probably be circumvented or overcome with sufficient research effort. If so, biological weapons could sur pass thermo-nuclear bombs in terms of the area coverage possible for a weapon of specified size. However, even after very extensive research, the performance of biological weapons is likely to remain subject to great uncertainty. Their effects would depend in large measure on poorly understood and highly variable factors that determine man's resistance to infection. A biological attack intended to be highly lethal might actually kill very few persons, and, con versely, an attack expected only to cause temporary incapacitation could cause high mortality. Although biological warfare agents might be chosen from among those that are not highly contagious under natural circumstances, this would not preclude the unexpected initiation of a widespread epidemic under the very unnatural conditions inherent in military use. Indeed, it is possible that bacteria or viruses disseminated in an aerosol cloud could subsequently emerge from the exposed popu lation of humans, insects, birds, rodents, or other animals with in E T H I C A L P R O B L E M S -- P R E V E N T I N G CBW 165 creased persistence, contagiousness, and virulence to man. Largescale operations in regions populated by many persons or animals would be more risky than small operations in desolate places, and viruses might be more hazardous than bacteria. How ever, we cannot evaluate the risks with any confidence in any of these situations. Therefore, the field testing of live biological weapons and especially the outbreak of actual biological warfare would constitute a menace to the entire human species. The uncontrollability of CBW A major uncertainty in predicting or controlling the course of CBW, once it is begun, would arise from the great variety of pos sible weapons and targets, from the incapacitating to the highly lethal and from the local battlefield to entire continents. Once begun at any level in earnest it would be very difficult to predict how far CBW might go. Distinctions and stopping places would be very difficult to define and to keep. The preparations and training re quired for one form of CBW would facilitate and therefore tempt escalation to larger scale and more deadly CBW operations. The breakdown of barriers to weapons once regarded as illegal and peculiarly uncivilized can inspire and encourage methods of war fare even more savage than those underway at the time. The vulnerability of troops or civilians to CBW attack depends very much on the availability and effectiveness of protective facili ties, the rigour of defensive training and discipline, and the perform ance of early-warning systems. All of this may act to place an unusually high premium on surprise or clandestine attack and on the use of novel or unexpected agents or means of dissemination. Once the effect of surprise has worn off and defensive precautions have been instituted, CB warfare might continue on a large scale but with relatively inconclusive effects until new weapons are intro duced or until conventions against the attack of previously invio late targets are transgressed. The myth of humane CBW ft is well known that some chemicals such as tear gas are able to incapacitate a man for a short time with little risk of killing. Some people have concluded from this that the introduction of non-lethal chemicals and even of biological weapons thought to be non-lethal might actually make war more humane. The argument has shown considerable appeal both for thoughtless zealots who 166 C H F. M IC A 1.. A N D B I O L O G I C A L W A R F A R H wish to advance the practice of CBW in any form and also for persons who genuinely hope to make war less savage. Although it is true that some chemical warfare agents are relatively non-lethal in themselves, it seems to me almost certain that their use would definitely not make wars on the whole less savage and would in fact risk making them much more so. It is nave to expect that in a real war non-lethal agents would be used by themselves. Once introduced into a combat area, the pressure would be very great to utilize them in any manner that " ^increased the overall effectiveness of general military operations. Non-lethal chemical weapons would be used to increase the effect iveness of lethal ones. Tear gas can reduce the accuracy of enemy rifle fire, allowing one's own forces to approach more closely, in creasing the accuracy and intensity of their counterfire. It can be used to force men out of protective cover and into the line of fire or the path of bomb and shell fragments. Under the desperate pressures of a war fought with artillery, bombs, napalm, and other lethal weapons, it is only reasonable to expect that "non-lethal" weapons once introduced will come to be used in order to kill. This has happened in Vietnam where the U.S. forces have spread riot gas over large areas to force persons from protective cover to face attack by fragmentation bombs. It happened in World War I when both sides used tear gas and other non-lethal chemicals in grenades and artillery shells to facilitate conventional infantry and artillery operations. This is not to say that non-lethal weapons would necessarily make war any more savage than it already is. "H ow ever, it seems unrealistic to expect that they would make it any less so. In any case, if tear gas or similar agents should prove at all effective when first used both sides would introduce protective devices and tactics, making subsequent use of such agents much less effective. Thus, except perhaps when they are first introduced, non-lethal chemical weapons are unlikely to have much effect except to set the stage for more deadly CBW operations. The conduct of non-lethal CBW can greatly facilitate prepara tions and training for the use of lethal chemical and biological agents. When combatants learn to protect themselves against the effects of mild or `conventional' agents the temptation will be strong and the means will be at hand to experiment with more deadly ones. During the first year of World War I both sides used tear gas and other harassing agents until the Germans introduced lethal chlorine gas. Following that, both sides tested a large number of E T H I C A L P R O B L E M S -- P R E V E N T I N G CBW 1fi7 poison gases seeking to find ones that would be decisive in battle. The first attack with poison gas had a devastating effect. The Allied front was broken, and 5000 of the 15,000 gas casualties died. How ever, even though more effective gases were introduced in great quantity by both sides, advances in defensive preparations prevented gas from being a decisive weapon in World War I. Advocates of "humane" gas warfare often point out that, at least toward the end of World War I, gas produced casualties with proportionately less mortality than did high-explosive weapons. However, this was not because commanders on both sides wished to fight without killing, Nbut rather because the most effective gases then known caused more wounds than deaths. Modern nerve gases are vastly more lethal than the old World War I gases. Can anyone have much confidence that skin-penetrating nerve gas would not have been used in World War I had it become available in 1917? The difficulty of allowing the limited employment of gas without running the risk of bringing the whole chemical and biological arsenal into use has been con cisely stated by T. C. Shelling in his book Arms and Influence (Yale University Press, 1966). `Some gas' raises complicated questions of how much, where, under what circumstances; `no gas' is simple and unambiguous. Gas only on military personnel; gas used only by defending forces; gas only when carried by projectile; no gas without warn ing--a variety of limits is conceivable . . . But there is a sim plicity to `noa gas' that makes it almost uniquely a focus for agreement when each side can only conjecture at what alternative rules the other side would propose and when failure at co ordination on the first try may spoil the chances for acquiescence in any limits at all. These principles appear to have been understood by the leaders of both sides in World War II, during which neither lethal nor non-Iethal gases were employed. At the outbreak of the War, both sides exchanged assurances that they would observe the Geneva Protocol of 1925. Later, in 1943, President Roosevelt declared: Use of such weapons has been outlawed by the general opinion of civilized mankind. This country has not used them and I hope that we never will be compelled to use them. I state categorically that we shall under no circumstances resort to the use of such weapons unless they are first used by our enemies. Although many rules of war were violated in that conflict, it is fortunate for all sides that the rule against gas was observed. Ger IfM C H E M I C A L A N D B I O L O G I C A L W A R F A R E many had secretly developed and produced a large quantity of nerve gas. Although the Allies had no weapon of comparable dead liness, they could have produced vast quantities rather soon after becoming aware of its existence. Since the previous restraints against anti-city warfare had already broken down, the introduction of nerve gas in the midst of World War II would almost certainly have caused a death toll vastly greater than it was. Chemical and biological weapons by their very nature are suited to the attack of large areas; their natural targets are people rather than military equipment; important military personnel can be equipped and trained to use protective devices far more easily than can civilians. For all of these reasons, civilians are the most natural and most vulnerable targets for CBW attack. If the barriers against CBW are broken down, civilians are likely to become its main victims. Chemical and biological weapons and minor powers The development and initial production of a new weapon usually requires much greater sophistication and effort than is needed to reproduce a weapon already possessed by another. The accessibility of chemical and biological weapons to smaller powers will depend very much on the CBW programmes of great powers and, for a limited time, on measures to keep the results of those programmes secret. With chemical and biological weapons as with other weapons, great powers will probably lead the way unless they deliberately refrain from doing so. The chemical compositions of several nerve gases are published in the open literature, and detailed manufacturing procedures could be specified by competent chemists and chemical engineers. Although no thorough cost-analysis has been published, it would appear that a considerable number of smaller nations could pro duce and integrate nerve gas weapons into their artillery and air forces without great economic strain. Commercial transport aircraft could be modified without great difficulty to drop or spray the gas. No small power is definitely known to produce nerve gas or to have been supplied with it by another, although there have been news paper reports that Egypt has used a nerve gas on a small scale in the Yemen conflict. The acquisition of nerve-gas weapons would greatly increase the destructive potential of a small nation's military forces, but it might also greatly reduce its overall security by provoking its neighbours to arm themselves similarly. This they might do by producing the E T H I C A L P R O B L E M S -- P R E V E N T I N G CBW 169 gas themselves or by demanding it from their great power allies. If nerve gas warfare should ever break out between two small states, the population of one or both could be largely annihilated within a short space of time, and the intense feelings provoked around the world might well ignite a much larger conflict. The attempt to develop biological weapons of reasonably assured characteristics would require a costly and technically sophisticated effort and an elaborate testing programme. Indeed, only use in war itself would provide the kind of information that responsible military men would require before placing much reliance on a radi cally new type of weapon. It seems unlikely that a small power would attempt the development of biological weapons except per haps as a deterrent threat. However, this would be an extremely risky posture for a small power unless large powers had already legitimized the possession and threatening display or use of bio logical weapons. Why single out CBW for special prohibitions? ^ As long as wars continue to be fought with high explosive weapons and napalm, what sense does it make to maintain special constraints on CBW? The question is understandable, but it seems to me that some substantial answers are contained in the remarks above. We realize that special rules are required for nuclear weapons. The distinction between conventional weapons and nuclear ones of any size is a real one, and the importance of main taining it is generally understood. Chemical and biological weapons share with nuclear ones the attribute of potentially overwhelming destructiveness. Biological weapons could pose a threat to the entire human species. Both chemical and biological weapons place a high premium on clandestine and surprise attack, thus lessening stability. Once developed, chemical and biological weapons can be exceed ingly cheap, relatively easy to produce, and quick to proliferate. They would threaten civilians especially. Their use would violate the oldest major arms control treaty still in force. Finally, there are moral arguments, although each person must evaluate them for himself. Tt is widely held that the use of chemical and biological weapons would be cowardly and inhuman. Perhaps this is because their use could make mass killing and subjugation technically easier than it already is. Some have said that poison-gas warfare would be more humane than other forms of lethal combat. Perhaps so. But it may also be more acceptable to the onlooker and to those who might consider themselves responsible. Is it not partly 170 C H E M I C A L A N D B I O L O G I C A L W A R F A R E in order to relieve the conscience of society that many civilized countries perform legal executions by means that are considered humane? Indeed, it may be that men inwardly dread the eventual consequences to civilization of introducing methods for the killing or subjugation of large numbers of their fellows easily and `humanely'. Preventing the use of chemical and biological weapons It is important for nations to understand that it is in their long term interest to prevent the use of chemical and biological weapons. This principle could be understood better and more widely than it is today. Discussions and publications by private persons can help. Studies by competent national and international organizations could command wide attention and respect. The United Nations might consider forming contingency plans for the investigation of allegations concerning the use of chemical and biological weapons. Some of the political difficulties standing in the way of such investigation might be eased if the machinery were partly set up in advance and if its purpose were to establish whether or not chemical and biological weapons had been used rather than to identify the user. It might be agreed that the request of the alleged victim would be sufficient to initiate an investigation. If this were not acceptable it might be required, instead, that all combatants in a given conflict agree to the holding of any inspec tion. At least this would place the aggressor in the position of having to oppose an investigation. Some nations or areas might declare themselves to be free of chemical and biological weapons. The Austrian State Treaty pro hibits that country from developing or possessing such weapons. West Germany has given assurances to its allies in the Western European Union that it will not produce chemical and biological weapons, and the Union's Arms Control Agency conducts periodic inspections throughout its European territory to provide assurance that no member is producing these weapons. Obviously, there would be many problems and choices involved in setting up CBWfree areas. However, the possibility should be carefully investigated. A start in this direction has been made by the Pugwash Biological Warfare Study Group which has conducted experimental inspec tions for the non-production of biological weapons in NATO, War saw Pact, and unaligned countries. As in most arms-control matters, the decisions lie mainly with the super powers, although the initiative may be taken in part by J I'E E T H I C A L P R O B L E M S -- P R E V E N T I N G CBVV 171 other nations. Nevertheless, it is vital that the super-powers under stand that the use of chemical and biological weapons anywhere in the world would constitute a threat to their interests. Possessing nuclear weapons, they do not need chemical and biological weapons as a major deterrent. There may be a certain symmetry in the view that biological weapons are needed to deter the possible use of such weapons by an enemy. However, in the nuclear environment, the proposition is devoid of logic. The super-powers have no need for biological weapons, and by producing and displaying them they would only make trouble for themselves in the future. The Geneva Protocol provides a relatively clear and unique standard to guide both the practice and the expectations of mem ber nations. The Protocol has been ratified by all major powers except Japan and, ironically, the nation which proposed it at Geneva --the United States. Many of the states organized since World War li, including the People's Republic of China and both Republics of Germany, have ratified the Protocol or have agreed to be bound by the ratification of their predecessors. Less than two years ago, in December, 1966, the General Assembly of the United Nations passed without opposition a resolution calling for strict observance of the Geneva Protocol and appealing for universal accession to it. The United States and Japan voted in support of the General Assembly resolution along with 99 other states. It is important to secure the actual ratification of Japan, the United States, and other nations that have not yet ratified the Protocol. Means should be found to make clear that viruses as well as bacteria and non-lethal as well as lethal chemical and biological weapons are meant to be included under its prohibition. But great care must be exercised to make sure that attempts to further clarify the scope of the Protocol do not result in weakening its universal authority. 14. Medical Ethics V. W. Sidel Discussion of the role of the physician in relation to biological war fare is complex and difficult. One must consider not only the ethical implications of the various roles which the physician may be called upon to play directly in relation to such weapons, but one must also be concerned in more general terms with the roles of the military and civilian physician.* It is first of all important to make clear that it is not simply a straw man that is being attacked--that is, it must be made explicit that biological weapons are being developed and produced4 and that physicians are being asked to contribute to their development. Examples of physician participation are clear. Professor Rosebury wrote of his experiences: "At Detrick a certain delicacy concen trated most of the physicians into principally or primarily defensive operations; the modifiers principally or primarily [italics in the original] are needed because military operations can never be ex clusively defensive."1 An editorial in Military Surgeon, apparently commenting on nations other than the United States, says: "In certain positions, a military surgeon or civilian doctor might be assigned to jobs other than healing. He is perhaps required to per form or to participate in scientific investigations, the purposes of which are not new remedies for the sick, but more and more power * I am indebted to many people in the development of these ideas. Dr Theodor Rosebury, a microbiologist who directed research at Camp Detrick during World War II, has since repeatedly warned of the dangers of biological weapons and has discussed their ethical implications.1 My colleagues in Physicians for Social Res ponsibility in Boston, especally Drs Robert Goldwyn, Bernard Lown, Peter Reich, and David Savitz, have contributed greatly to the discussions of these problems. Many of the ideas presented here have been drawn from papers written in collaboration with Dr Goldwyn: one was published in 1966 in the New England Journal of Medicine2 and one will be included in a book on medical ethics to be published later in 1968 in the United States by Little, Brown, & Co.3 ETHICAL PROBLEMS --MEDICAL 173 ful atomic, bacterial and chemical weapons of aggression.',;i At Fort Detrick, the major biological warfare research establishment in the United States, there are currently employed 14 M.D.'s, 120 Ph.D.'s, and hundreds of other scientists and technicians.'1 It is very likely that other physicians are associated with the many secret research projects in academic institutions which are listed in Chapter 10. Before turning to the specific roles of the military and the civilian physician, the argument that it is unethical for a physician to parti cipate in the development, production, or use of biological weapons must be briefly reviewed. (1) The dangers to both civilian and military population of biological weapons have already been discussed. In summary, the dangers that have relevance to medical ethics a re : (a) They are likely to be used against non-combatants. Major General Thomas J. Hartford stated in a signed editorial in Military Medicine: It appears that . . . (biological weapons) would be used prim arily for strategic rather than tactical purposes. It would be an excellent means of producing non-effectiveness without causing damage to material things. Thus it is possible that the civilian and not the military population might be the prime target. If an enemy were attacking the New York-New Jersey coastal area he would be more interested in producing disability in the millions of industrial workers than in the few thousand military personnel stationed in the target area. . . (b) They are unpredictable. Beyond the immediate consequences there may be ecological, medical, and social results impossible to foresee. A biological agent introduced into a susceptible population may cause disease or mortality on a scale not visualized by the attacker. An example is the measles virus which, although usually relatively benign, can cause a large number of deaths under certain conditions--for example, in an unprotected population such as the Fiji Islanders, of whom 20 to 25 per cent died from measles or its consequences in 1875, or in a population weakened by war such as the women and children in Boer concentration camps in 1900.: In contrast to other weapons, biological agents may make the human being not only a victim but also a propagator. An example in another species occurred in May, 1952, in the Department of Eure et Loire in France. One or two rabbits were inoculated with myxo matosis virus; by the end of 1953 the disease had spread through 26 departments in France, and through Holland, Belgium, Ger many, and Switzerland, killing between 60 and 90 per cent of the rabbit population.8 174 C H E M I C A L A N D B I O L O G I C A L W A R F A R E (c) They are truly `public health in reverse'.5 They are designed to undo much of the work that physicians and other medical wor kers have done to eliminate and control infectious disease. They are, therefore, clearly genocidal, and furthermore may be genocidal in the sense of damaging vast groups of the human race rather than a single people. (2) There are specific passages in widely respected medical oaths which appear to argue against participation by medical doctors in such research. For example, the Hippocratic oath states: . . I will use treatment to help the sick according to my ability and judgment, but never with a view to injury and wrong-doing. Neither will I administer a poison to anybody when asked to do so, nor will I suggest such a course. . . ,"10 The Oath of Geneva, a moderniza tion of the Hippocratic Oath, formulated by the World Medical Association in 1948, states: . . I will not permit considerations of religion, nationality, race, party, politics, or social standing to in tervene between my duty and my patient; . . . even under threat I will not use my medical knowledge contrary to the laws of human ity."11 Even more specifically, the Code of Ethics in Wartime of the World Medical Association states: ". . . It is deemed unethical for doctors to weaken the physical and mental strength of a human being without therapeutic justification and to employ scientific knowledge to imperil health or destroy life."12 (3) These professional oaths codify a body of professional con duct which has served through the centuries to make the physician better able to perform his healing role. Any member of the profes sion who weakens the ethical standards of the profession by taking part in activities which contribute to disease, disability, or untimely death only weaken the professional status, and therefore the healing potential, of all physicians. Turning first to the role of the military physician, the entire role of the physician in the armed forces is an ambiguous one. One role for the military physician was eloquently stated in 1965 by Sir Theodore Fox, former editor of The Lancet: "A nation's lawyers must execute its laws even when this means the execution of a human being; a nation's soldiers must kill whomsoever their leader commands; but the doctor--perhaps because of his religious origins --is excused such destruction. Even in war, he may be permitted to believe in human brotherhood--to treat all men without political or racial or religious distinction."1,1 And many physicians have in deed distinguished themselves in war by devoted and sometimes heroic service to both friend and foe. ETHICAL PROBLEMS --MEDICAL 175 But there is another side to the physician's participation in war or in the preparation for war. Field Manual 8-10 of the U.S. Army states clearly that "the Army Medical service is a supporting service of the combat elements of the Army primarily concerned with the maintenance of the health and fighting efficiency of the troops." Its mission, the Manual continues, is to "conserve manpower . . . (for) early return to duty" and to "contribute directly to the military effort by providing adequate medical treatment and rapid orderly evacuation for the sick and wounded".14 Dr Morris Fishbein, the former Executive Secretary of the American Medical Association, presents this side of the military physician's role even more strongly: "Military philosophers say there could never be wars if there were no doctors. No doubt they are right. The anguish and destruction of the human body in war with modem weapons would be impossible to contemplate without the healing ministrations . . . that modern medicine provides."15 Within this overall conflict of the healing and the combatpromoting roles of the military physician, there are a number of individual conflicts. Attempts have been made to resolve some of these dilemmas by formal codes of conduct. The best known of these are the Geneva Conventions of 1949 which stipulate that medical personnel are to be considered non-combatants; they are, if captured, to be returned to their own forces as soon as possible; and, in return for this special status, they are forbidden to use arms except to defend themselves and their patients.16 It is clear that these Conventions perform a useful military function; the special non-combatant status of medical personnel enables them better to carry out their healing role. It would appear to be in the self-interest of the combatants to preserve the clear non-combatant role of the physician. An example, not directly related to CBW, of the types of ethical problem which can arise is provided by the recent court-martial of Howard W. Levy, M.D., Captain in the Army of the United States. Although other issues were involved, one of the major charges on which Levy was convicted and sentenced to three years hard labour was his refusal to obey an order to train Special Forces troops in specialized techniques. This refusal was based in part on Levy's belief that such men, functioning in the dual capacities of combat soldiers and "medical personnel", would break down the distinction between combatant and non-combatant necessary to effective appli cation of the Geneva Conventions; in training them, he felt, he would produce a net increase in disease, disability, and death. He M A 176 C H E M I C A L A N D B I O L O G I C A L W A R F A R E also believed that such poorly-trained, unsupervised men might do more medical harm than good and that, since their primary duty was as combat soldiers rather than medical personnel, they might be required to abandon sick and wounded patients or otherwise behave in a manner contrary to medical ethics and/or the Geneva Conventions. Whether Levy was right or wrong in these views is not relevant to our discussion here; what is relevant is that as a military physician he was ordered to do something he felt he could not ethically do as a physician and, upon refusing to do so, he was court-martialled and convicted. The defence that the order was contrary to Levy's view of his medical ethical responsibilities was held irrelevant and was not permitted as a defence at his trial.17' 15 The result of the Levy trial forces a re-evaluation of the role of the military physician. Until his conviction it may have been possible for the military physician to hold the view that he was still the arbiter of his own medical ethics; that he might do those things which contributed to health and were therefore ethical, and that he might refuse to do those things which he felt to be professionally unethical. Since the result of the Levy trial, if allowed to stand, suggests that the American military physician is no longer free to make such ethical decisions once he has entered the military service, the American physician may have no choice at all except to refuse to enter military service. This line of reasoning forces us to return to a paragraph written in 1938 by Professor John Ryle, Regius Professor of Physics at the University of Cambridge: It is an arresting, if at present a fantastic thought, that the medical profession which is more international than any other, could, if well co-ordinated, of its own initiative put a stop to war, or at least increase its uncertainties, and hamper its aims considerably so as to give pause to the most bellicose of Govern ments. It is everywhere a recognized and humane principle that prevention should be preferred to cure. By withholding service from the armed forces before and during war, by declining to examine and inoculate recruits, by refusing sanitary advice and the training and command of ambulances, clearing-stations, medical transport, and hospitals, the doctors could so cripple the efficiency of the staff and aggravate the difficulties of campaign and so damage the morale of the troops that war would become almost unthinkable. Action of this kind would also produce a profound effect on the popular imagination. In such refusal of service (if such refusal were decided upon in the last resort) there would be no inhumanity comparable with the inhumanity which medicine at present sanctions and prolongs. But let the dream pass and fantasy make room for facts.18 ETHICAL PROBLEMS --MEDICAL 177 It would be ironic indeed if the court-martial of Captain Levy should be one of the events which would turn Professor Ryle's fantasy into fact. The problem of the civilian physician, whose need to be guided by medical ethics is uncomplicated by a concurrent need to obey military orders, is quite different. Again a model may be found in circumstances which were not directly related to CBW, the conduct of German physicians during World War II. Although only a rela tively small number of German physicians actually took part in the infamous medical crimes for which the Nazi physicians were con victed at Nuremberg, hundreds of others knew of them. As a 1946 editorial in the journal of the American Medical Association put it: Perhaps most serious of all is the failure of German medical organizations and societies to express in any manner their dis approval of these widely known experiments. Physicians have a right to expect that men trained in the traditions of medicine would refuse to participate in any way in such acts of inhumanity and brutality. In some instances the defence has been offered that these experiments were conducted under the highest authority of the German state. That cannot possibly be considered in the slightest an extenuation of the failure of these physicians to act in accordance with the principles and traditions of their profes sion.20 Thus the responsibility of the physician is visualized as far broader than simply refusing to take part in an activity which he finds unethical. He must not only refuse himself to participate but he must actively "express his disapproval". Failure to do so represents complicity. One of the greatest dangers in regard to CBW may simply be the apathy toward this problem of most of the medical profession. What guidelines should the physician use with regard to his or another physician's, participation in research, development, pro duction, or use of CBW? There seems no doubt of the unethical nature of the physician's participation in development, production, or use of offensive weapons of any type; the fact that chemical or biological weapons are the ones with which the physicians may become engaged and the ones about which he has specialized know ledge gives him a special responsibility not only to refuse to work on but also actively to protest against the development, production, or use of such weapons. But what about research and development of defensive measures 78 C H E M I C A L A N D B I O L O G I C A L W A R F A R E against chemical or biological agents? `Defence' has often been given as justification for the work being done by physicians and scientists on such weapons. We have already noted that Dr Rosebury, who has participated in such research, feels that the distinction between offensive and defensive research is ethically and technically blurred. What guide-line should be used by the physician who wishes to work on defence against such or, a much more common problem, wishes to conduct research in fields which might in some unforesee able way contribute to the development of weapons? It seems to me that the least ambiguous guide-line is that of free access of infor mation. If the physician engages in research which is freely pub lished, whether it be on micro-organisms in general or in defence against biological warfare in particular, he cannot be ethically faulted. It is when he engages in `defensive' or `pure' research in secret that he cannot be distinguished ethically from those who work on the development or production of weapons. In summary, it seems to me that the ethical physician must con tinually ask himself whether what he is doing will lead to a net increase or decrease in disease, disability, and untimely death. For the military physician, it may at one time have been possible to consider his activities as producing a net benefit; I believe that, in the United States at least, recent events have made this view unten able, and the ethical physician may have to refuse to participate at all. Finally, there appears to me to be no question that for the civilian physician ethical principles can best be protected by a refusal to participate in, and an active protest against, secret re search in general and work on biological weapons in particular. As Rosebury has suggested: "Ethical principles are not a luxury; the essence of ethics--concern for the value of man--is indispen sable for the survival of medicine as a profession and doubtless also for the survival of mankind as a species."1 DISCUSSION Dr Sidel's paper on medical ethics raised isues that were discussed at length by the Conference. Professor Mayer raised the point that he, like Dr Sidel, was a SU l 6 7 ETHICAL PROBLEMS --DISCUSSION 179 witness, in fact the opening defence witness, at the Levy trial. A feature of the court-martial was that the United States Army was abiding by the ordinary legal rules of having Captain Levy tried by a jury of his peers, but it considered that his peers were officers of similar rank, and the twelve officers who were sitting on the court-martial were, in fact, infantry officers. There was not a single medical officer on the jury. This is extremely significant because it means that the quality of a medical officer as a physician was not something which was considered relevant in his trial. The testimony on medical ethics, the history of the Geneva Conventions and their significance was, in effect, already discounted by the very choice of the court-martial. The American Medical Association and other medical bodies were extraordinarily indifferent to the fact that a physician could be tried on a question of medical ethics by people who were not themselves physicians and where physicians were not even represented. This suggests an abdication by the medical pro fession of its responsibility to look into possibilities of medical ethics being involved in a conflict with a civil power. A second, still broader question raised by Dr Sidel is the need for a better definition of who in fact is a physician. Perhaps the definition of a physician is out of date if it implies that a physician is anybody who is a doctor of medicine or has an equivalent degree. Obviously the Hippocratic oath should apply to them in all situa tions including those in which they are in effect working on chemi cal warfare. If on the other hand the definition of a physician is one which involves only those people who are actively engaged in therapy a number of people who are doctors of medicine will not be covered, but at least in the United States many people who are in professions not usually considered as specifically medical, such as clinical psychologists, might well come under that classification. But many researchers on CBW would then be excluded from this ethical debate. Mr M. Birnstingl was doubtful whether the moral responsibilities of the doctor could be restricted in this way. There is surely a danger of medicine allowing itself to become a tool of the current political ideology, when seen only in terms of the Hippocratic ethical tradition, without considering the wider issues. The Hippo cratic tradition is concerned with the doctor's ethical and humani tarian role in relation to a single individual, his patient, and gives him no guidance as to his position regarding, for instance, the war in Vietnam. Modem warfare would be impossible without the co operation of doctors, and they are able to take part without any violation of their ethics. They withdraw and wait while their fight ing friends drop toxic gas or napalm, after which they may help the victims who survive. To a physician trained to prevent suffering, such a role may appear irrational, but it is sanctioned by medical ethics, through its apparent humanitarian function. But the wider situation has been well described by Dr Howard Levy as "Kill, Kill. Cure, Cure." and this is the situation which the doctor's presence supports. A doctor may need to do this kind of thing, but he cannot ISO C H E M I C A L A N D B I O L O G I C A L W A R F A R E shelter behind his humanitarian role. He is always an accomplice to the wider act, and it is his relation to this which he must consider. When civilian populations are being annihilated and other norms of human conduct disregarded a doctor must decide whether he can continue to subjugate medicine to such a policy. Professor Mayer has pointed out elsewhere that Howard Levy's stand was not solely a matter of medical ethics, although the circumstances of his trial may have forced him into making his defence on these narrow grounds. But Levy was also concerned with moral questions extending far outside his professional code, namely the submission that no doctor has a right to allow himself to be used in what he believes to be a genocidal war. And its corollary, an attempt to prevent medicine from being subjugated to a political purpose and becoming just a cog in a wheel of bad and degraded ideology. Finally, that the doctor's dilemma was also the scientist's was stressed by Professor Burhop, who pointed out that in practice questions of the social responsibility of scientists could not be separated from assessments of political and moral factors. It was difficult to adopt simple-minded criteria applicable in all circum stances. During World War II he, like other scientific colleagues who had earlier been active in the movement against war and fascism, saw no contradiction in working on the development of the first nuclear weapon. It seemed clear that the development of a nuclear weapon by German scientists was entirely feasible and that, possessing such a weapon, Hitler would have had no compunction about holding the whole world to ransom in order to achieve his aims. Similarly, today, it should not be difficult for an American scien tist, mindful of his social responsibilities, to decide that to give freely of his knowledge and talents to assist his Government to subjugate the people of Vietnam, whether by the development of CBW or by the improvement of napalm or anti-personnel weapons, was evil and reprehensible. Unfortunately, the situations one usually has to face are less clear-cut. For example, what attitude should a university adopt toward the question of accepting funds from defence agencies for open peace-time research in basic science? Perhaps the question of whether the research is open or secret could provide a useful criteria. Scientists should not participate in secret work, whether in university or government institutions. Secrecy is far more impor tant for the development of new offensive than defensive weapons. 15. Scientific Responsibility C. F. Powell By vvay of an introduction to this theme, I want to comment in general terms on the place and responsibility of scientists in our pre sent situation. I have no technical competence in CBW but I believe that this issue and the problems raised in the earlier chapters should be seen as only a part of the general problem of avoiding a catas trophe for our whole civilization. What is involved here is not only the future of humanity but also matters of great importance for the future of science itself--for its moral standing and effectiveness. It is possible, even if we avoid a general war, for scientific research to decline, and this research is our indispensable instrument for overcoming the grim prospect of widespread hunger in the next twenty years to which Bernal has quite recently again directed our urgent attention. We were brought up in a situation in which science enjoyed im mense respect and prestige. I believe this derived from the aims and methods which characterized the development of science under the stimulus of the Baconian philosophy and the work of those in Europe who thought like him--Leonardo, Galileo, Descartes. The new method was to replace the appeal to ancient authorities by reliance upon the observation of nature and by acting upon it, by experiment. And the new aim was to be the improvement of the human condition. It was Bacon's passionate conviction that the discovery of printing, the compass needle, and gunpowder gave only a faint intimation of what was becoming possible for mankind if the search for fruitful knowledge were pursued in a systematic and organized way. Contrary to those who sometimes assert that Bacon was naively optimistic about the advantages which would follow from the pro gress of discovery, he well understood that the advancement of knowledge could be put to good or evil purpose: speaking of the fruits of mechanical invention he said: "Out of that same fountain come instruments of lust and instruments of death. For, not to speak of the arts of procurers, the most subtle poisons, as well as 1S2 C H E M I C A L A N D B I O L O G I C A L W A R F A R E cannon and other instruments of deslruction are the fruits of mechanical invention, and well we know how far in cruelty they do exceed the Minotaur himself". There could hardly be a better pas sage with which to illustrate the theme of this book. Bacon was also clear about a point that is of great contemporary importance; that the advancement of knowledge was not to be judged only on the basis of its immediate utility. In the fable of Atalanta he makes the point very clearly. Atalanta lost the race because she stooped down to pick up the golden apple. She is typical of that short-sighted mechanical ingenuity which fails to see that the true aim is the widening of our basic understanding, so that useful applications may flow "not singly, but in knots and clusters". It is unnecessary for me to stress the immense success of the developments which Bacon foreshadowed. The whole material basis of our civilization has been transformed, and surely it is a process to which there is no limit. This is not always firmly under stood. It is easy to acknowledge that our whole society has been transformed by the advancement of science without really under standing that, if we don't destroy ourselves, the whole world in a hundred years' time will be as different from the present as our own times are from the world of 1800. Of course material prosperity is not the only thing for securing a happy life. But it certainly shouldn't be underrated. At least in the developed countries, tech nology has immensely improved the human condition; the most severe critics would hardly deny that the three-fold increase in the expectation of life in the United Kingdom is a good thing. What could be more important than an increase in good health or of the life-span? But our powers have now reached the point where we are pre sented with the familiar dilemma where we have on the one hand the possibility of an indefinite extension of human well-being and, on the other, the growing danger of a fearful catastrophe. A num ber of clear responsibilities rest upon scientists in this situation, and one of the bright features of our time is the growing disposition of scientists to assume them. The first is that they should take an active part, in public affairs, especially in fields where they have special technical competence. At least in some scientific circles this idea has not, in the past, always been welcome. I can remember eminent colleagues of mine, less than twenty years ago, most vigorously asserting, and taking some pleasure in doing so, that their work had no relevance to prac <$u t 1 ETHICAL PROBLEMS--SCIENTIFIC RESPONSIBILITY 183 tical affairs. Of course, we have to make a clear distinction between the manifold aims which animate scientists in their work and why great public resources should be applied to their support. It is very dangerous to take too narrow a view here in formulating public policy. It is possible for a scientist to be passionately interested in his work and to be quite indifferent to the practical consequences which flow from it. But his indifference is not a reason for not sup porting him if his work contributes to the advancement of science, or to the intellectual quality of the work and teaching of the in stitute in which he is employed, or to practical benefits in the short or the long term, or to all of these ends. But the idea still persists in some circles that fundamental science merely provides a pleasant diversion, an agreeable life, for scientists, without any real advantage to society. An engineer from one of our great steel companies recently asserted to me, for example, that fundamental science had never contributed anything substantial to the advancement of industry. He was somewhat taken aback when I asked him if he attached any importance for industry to the dis covery of electricity. Of course this was rather an extreme example, but we can find undercurrents in the same direction in many places. Even among scientists scholastic attitudes still linger on, in the sense that there is an indifference to the practical advantages flow ing from scientific discovery, and this indifference ought to be cor rected by the close involvement of scientists in everything touching the consequences of their work. But the advantage of their involve ment in public affairs does not depend only on their technical com petence. They are the representatives of severe disciplines. They are used to challenging the basic premises of their subject, and it is not only in science that this process is of fundamental importance for the formulation of wise policies leading to successful action. It is easy for us to laugh at the flat-earth theories of the Middle Ages and to fall into the same kind of error in relation to the imaginative leap required to resolve the profound problems which we face in our sciences and our societies. It is in the nature of the human condition that we find it difficult to escape from the limitation of our commonly accepted premises. We establish principles which are valid for the particular range of experience with which we are familiar in our local situation in history, in time, and in environment. And their success in allowing us to take successful action in our particular circumstances en courages us to assume for them a universal, eternal validity, until painful experience overthrows our pride. This process of rejecting 1S4 C H F M I C A L A N D B I O L O G I C A L W A R F A R F cherished assumptions in the face of a wider experience, although often painful, is familiar to scientists, and they can help with the resolution of some of the great problems of public affairs to which, with their expertise, they seriously apply themselves, through the critical and creative approach to problems which science encourages. It is in such issues that it seems to me scientists have the respon sibility to speak out, not least in order to ensure the continuing prestige of their calling. I remember a discussion with Joliot* in which he pointed out that it is an illusion to think that in order to influence people and opinion it is sufficient for a man to tell the truth as he sees it. An element of art is involved here. One can be so far ahead of one's audience as to be out of sight, so that one be comes isolated and ineffective. But to give any kind of leadership in the formation of opinion one has to be ahead and not dragging behind the march of events. And surely our standing is increased when through the march of events the soundness of the position we have taken early is demonstrated. I have said that the public involvement of scientists is essential for the maintenance of the morale of science. Scientists too would be flat-earthists if they thought that they could count automatically upon the continuing esteem they have enjoyed in the past while doing nothing in the face of the fearful possibilities which have arisen as the result of their work. In this connection they ought to be deeply concerned with the attitudes of young people, for ex ample, in Western countries. What do they see? They may know of the aspirations of the founders of modem science, but what is the present reality? They see not only the fearful perversions of modern science that we have been discussing, but they may reason ably be anxious that the balance between the good and the evil seems to be rapidly changing. Of all our resources on a world scale, about 70 parts in 1000 are devoted to armaments--and much of it today to scientifically based armaments; and 3 parts in 1000 to fundamental science. They see that, by contrast with the immense resources going into armaments, relatively little is going into the developing countries, most of it ill-considered and therefore ineffective--and quite in sufficient in the prevailing political situations in these states to enable them to take any serious steps to ensure the economic and social emancipation of their people. In thic situation, the appraisal of science by the young people is such that they begin to prefer what they tend to regard as more innocent and less exacting occupations. s: The French physicist; one of the fathers of atomic science. Ed. SW 7 0 ETHI CAL PROBLEMS--SCIENTIFIC RESPONSIBILITY IS5 The sciences in our time are exacting disciplines and make great demands on young people. With our increasing penetration into nature, the language of science and its basic conceptions and ideas become more and more remote from those of our ordinary lives. Young people welcome challenges to their creative powers; they are prepared to submit to severe disciplines if they believe in their validity and moral standing, but they are not prepared to meet the personal sacrifices involved if they suspect the ends to which their work leads, or if they regard them as evil. I am anxious in that these considerations seems to me to have a bearing on the fact that in the United Kingdom the number of young people entering science is, in a growing population, beginning to decline; and this is at a time when science and its even wider applications is our indispensable resource for the resolution of the profound problems with which we are faced. Of course, scientists have other responsibilities too, but I have tried to indicate some of the crucial ones. I may add perhaps the important battle for the recognition of the proper role of science, for the increase in its standing. The fact is that it is still true that science in our country is almost outside the common culture. In the organs of government there are many people who are entirely inno cent of any acquaintance with science. In a scientific age it is almost impossible to understand fully the role and significance of funda mental science, its potentialities and the problems involved in its proper sustenance and application if one has acquaintance with it only at second-hand. It is for this reason that scientists must become more involved in government, must contribute more effectively to the popularization of science, must help to ensure that our whole culture becomes more and more infused with all that is best in science. In conclusion, let me add, that throughout his working life, in all these issues Bernal, in whose honour this conference has been held, has been one of our great champions. Without him, not only would this meeting never have taken place, but the whole level of our discussions would have been much poorer, and our possibilities of solving our problems much less. We are all deeply in his debt. 16. Some Conclusions Steven Rose The implications of CBW spread far beyond the issues of lethality versus non-lethality, or even legality versus non-legality. Firstly, any examination of CBW inevitably involves one in a study of its use in what has become the greatest political issue of our day--the war in Vietnam. Most of those who attended the Conference--as indeed most people throughout the world--had strong, though often divergent, views on this issue. That chemical weapons have been used in Vietnam is unquestioned. The scale of this use is outlined by Dr Kahn and Professor Galston in Chapters 5 and 7, and the profound effects on the population by Professor Mayer in Chapter 6. It is perhaps now doubtful whether the use of the wea pons has or will alter the course of this war. If it is the case that chemical and biological weapons are seen by the military as in some sense ideally suited to anti-revolutionary, anti-guerilla warfare, in that they are primarily directed against the population as a whole, events in Vietnam are far from demonstrating the success of this strategy. And in terms of scale, conventional weapons, such as napalm, fragmentation bombs, etc., have certainly done more damage to the civilian population than has the--still relatively limited--use of CS or the defoliants. None the less the two issues, CBW and Vietnam, have, for better or worse, become inextricably intertwined. But CBW research will continue even when the American ex peditionary force finally leaves Vietnam to reconstruct itself. The research and development of these weapons has achieved a power ful, perhaps irreversible, momentum. And in this onward course, many hitherto untouched institutions of scientific research have been swept along. Attempts, as Elinor Langer describes, to assess the extent of CBW research in the United States revealed that substantial areas of American university life have become per meated by secret research on CBW and related defence topics. This classified research is now proceeding on an unprecedented scale; a considerable proportion of America's scientific talent is becoming SOME CONCLUSIONS 187 locked up in activities directly or indirectly of service to the U.S. Department of Defense. Until recently it had been possible to regard this as a uniquely American problem, but at the beginning of 1968 a series of Parlia mentary Questions revealed that in Britain, too, universities were undertaking a significant amount of classified research. No less than thirty-seven classified research projects were let to British universities by way of the Ministry of Technology in the latter half of 1967, and two directly by the Ministry of Defence. The exact fields of these research projects are not known at present, although most probably they are concerned with many topics other than CBW as well. But these revelations, which have sprung directly out of concern by the scientific community about the extent of CBW research, also change, at least in part, the emphasis of the issues raised. Classified research in the universities presents a new class of problems; the traditionally open teaching and researching activities of the university are seen to be in danger of becoming undermined, so that various fields of scientific research, ostensibly without military significance, are supported by military funds and shackled by the demands of secrecy and security. The need for secret research may be argued; the case against it being performed in the universi ties in peace-time, so distorting and warping their educative role, is overwhelming. Here is another theme with which, inevitably, an investigation into CBW becomes interlocked. The problem of the potentially military significance of basic scien tific research raises other issues, too, that need a more thorough in vestigation. At least since World War II, a substantial proportion of scientific research, in fields as diverse as linguistics and high-energy physics, has been supported by money from a variety of Defence budgets, both in Britain and the United States--and probably many other countries too. This research, unlike the classified research we have so far discussed, has been open and often without any appar ent military significance. Yet the chapters by Dr Sidel and Professor Powell inevitably raise the question of how far one should continue to regard this money as manna from heaven. Does the source of such funds--and the fact that the donors perceive a military ad vantage in obtaining this knowledge, even if its military significance is obscure to the scientist actually performing the experiments-- mean that, to adopt Dr Sidel's phrase, "the ethical scientist or physician should have no truck with them" ? Such questions begin to open out from the confines of CBW itself to the very heart of suni .j IMS C H E M I C A L A N D B I O L O G I C A L W A R F A R E any exploration of the role of scientific research in contemporary society. To return to CBW again, the third major issue raised is that exemplified in Chapter 13 by Dr Humphrey and Professor Meselson, and expanded in the discussion of the work of Pugwash and SIPRI which have not been included in this published text, of how far it is possible, by techniques of agreed international inspec tion and control, to limit the development of new weapons systems and the arms race that these imply. The endeavours of the arms controllers have so far met with some partial success in the field of nuclear weapons--the test ban treaty and the non-proliferation agreement are examples. CBW presents unique problems in that the relatively low-grade technologies required for the fabrication of the weapons are within the capacity of many countries, not merely the handful with nuclear capability, but it also presents unique possi bilities for the achievement of control, because of both the legal position on the use of the weapons, discussed by Dr Brownlie, and the relatively cautious attitude to their development so far taken by most of the important powers with the possible exception of the United States. And, as Professor Meselson pointed out, the time to control a weapon is before it has been developed and put into the military arsenals. Here perhaps lies our hope. The enormous repugnance that CBW arouses in most people and its present limited--though future enormous and enormously dangerous--potential, would seem to make both the possibility of and the need for some action impera tive. This, certainly, was the message of our conference. We believe that this presentation of the record of our proceedings, by alerting as many as possible to the issues involved, will help in this aim. Biographical Notes Martin Birstingel, w.s., r.R.c.s. is a surgeon at St. Bartholomew's Hospital and visited Vietnam for the International W ar Crimes Tribunal. Ian Brownlie, m.a., d .phil. is Fellow of W adham College, Oxford, University Lecturer in International Law, and a barrister of G ray's Inn. He is the author of In te r n a tio n a l L a w a n d th e U se o f F o rc e b y S t a t e s (O.U.P., 1966) and T h e L a w R e la tin g to P u b lic O r d e r (Butterworth, 1968), and editor o f the B r itis h Y e a r B ook o f International Law . Eric Burhop, f.r.s., m.sc., ph.d. is Professor of Physics at the University of London. H e is the a u th o r o f T h e C h a lle n g e o f A to m ic E n e r g y (Lawrence & W ishart, 1951) and numerous publications on atom ic and nuclear physics. Robin Clarke is the editor of S c ie n c e J o u r n a l (London) and the author of W e A l l F a ll D o w n : th e P r o s p e c t o f C h e m ic a l a n d B io lo g ic a l W a r fa r e (Allen Lane, the Penguin Press, 1968). Arthur Galston, ph .d ., m.s., b.s. is Professor of Biology at Yale University, President of the Botanical Society o f America, and National Science Foundation, Science Faculty Fellow at K ing's College, London, D epartm ent o f Biophysics. He is the author o f P rin c ip le s o f P la n t P h y s io lo g y (Freeman, 1952) and L i f e o f th e G re e n P la n t (Prentice-Hall, 1964). John Humphrey, f.r.s., m.d ., b.a. has spent alm ost his entire career in medical research, mainly immunology. His interest in chemical and biological warfare dates from his association with the Cambridge Scientists' Anti-War Group before W orld W ar II. C. R. B. Joyce, m.a., b.sc., ph.d. is Reader in Psychopharmacology in the University of London and Head of Pharmacology at the London Hospital Medical College. M. F. Kahn is Professeur Agrg de Mdecine in the Facult de Mdecine de Paris and a Consultant Physician to the Paris Hospitals. He was a member of the Scientific Commission o f the International Tribunal for W ar Crimes in Vietnam, and a member o f the Diversification team o f the Tribunal in the DRV and the N LF held areas of South Vietnam. Elinor Langer, b.a. is a former staff member o f S c ie n c e magazine (Washington D . C.) and did graduate work at the Johns Hopkins University School for Advanced International Studies. ^Patricia Lindop, b.sc., m.b., b.s., ph .d . is Reader in the D epartm ent o f Radiobiology at the Medical College of St Bartholomew's Hospital, London. She is medically qualified and is doing research on the long-term effects o f radiation. 190 C H E M I C A L A N D B I O L O G I C A L W A R L A R L Ivan Malek, m.u.dr., dr.sc. is a member of the Czechoslovak Academy of Science and Director of the Czech Biological Institute where he conducts research into antibiotics and the continuous cultivation of micro-organisms. He has been associated with peace movements for many years including Pugwash and the World Federation of Scientific W orkers and was awarded the Lenin Peace Prize in 1967. Jean Mayer, ph.d., d .sc., m.a. is Professor of N utrition and lecturer on the History of Public Health at Harvard University and a Fellow of the American Academy of Arts and Science. He is the author o f some 400 research papers, 20 popular papers, and two books. M. Meselson, m.s., ph.d. is Professor of Biology at H arvard and a Fellow of the American Academy o f A rts and Science. He is winner of the U.S. National Academy of Science Prize for Molecular Biology. Martin Pollock, m.a., m.b., b.chir., f.r.s. is Professor of Biology at Edinburgh University in the D epartm ent o f Molecular Biology. He is medically qualified and is especially concerned with public health, bacteriology, and epidiomology. C. F . Powell, m.a., ph.d ., f.r.s. is Melville Wills Professor o f Physics in the University of Bristol. He was awarded the Nobel Prize for Physics in 1950 and the Lomonsov medal o f the Soviet Academy o f Science in 1968. He is President of the World Federation o f Scientific Workers. Lord Ritchie-Calder was D irector o f Plans of Political Warfare in the Foreign Office during W orld War II, was Science Editor of the London N e w s C h ro n icle from 1945 to 1967 and was Professor of International Relations at Edinburgh University from 1961 to 1967. He is author o f 28 books including M a n A g a in s t th e D e s e rt (Allen & Unwin, 1958), M a n A g a in s t th e J u n g le (Alien & Unwin, 1954), and C o m m o n s e n s e a b o u t a S ta r v in g W o r ld (Gollancz, 1962). J. Perry Robinson, b.a.(oxon) read Chemistry at Oxford University and wrote his thesis on certain aspects of chemical warfare. He is training to be a patent agent and has recently worked at the Stockholm International Peace Research Institute. Steven P. R. Rose, b.a., ph.d. is a research biochemist. He graduated at Cambridge, read a ph.d. in London and was previously Research Fellow at New College, Oxford before returning to London to work on problems connected with the biochemistry o f memory and learning. He is the author o f T h e C h e m is tr y o f L i f e (Penguin, 1966) as well as general science articles and research papers. Victor Sidel, m .d . is Associate in Medicine at H arvard Medical School and Chief of the Community Medicine Unit at Massachussets General Hospital. He is a member o f the Executive Com m ittee o f the U.S. Physicians for Social Responsibility and editor with Frank Ervin and Saul Aronon of T he F allen S k y (Hill and Wong, 1963). Derik E. Viney, b.a., ph.d. was previously a member o f the Arms Control and D isarmament Research U nit of the Foreign Office and currently researches and broadcasts on international affairs. Patrick Wall, m.d . is a neurophysiologist and novelist. He is Professor of Anatomy at University College, London. at (73 References INTRODUCTION 1. Q u o te d by M . L e iten b erg in S c i e n t i s t a n d C i t i z e n A u g u st, 1967. 2. See M . G o w rin g , B r ita in a n d A t o m i c E n e r g y 1939-45, (M acm illan, 1964). CHAPTER 1 1. US A r m y C h e m i c a l C o r p s B o a r d , ASTIA Documents Nos. 108456--108459, 23 July, 1956. 2 . K e e l e , C. A.; A r m s t r o n g , D. : Substances producing pain arid itch (Arnold, London, 1964). 3. M o n c r i e f f , R. W. : The chem ical senses, (Leonard Hill, London, 3rd edn, 1967). 4. P e n n , W. E. : "Riot control chemicals" Ordnance 50, 192-4, 1965. 5. H e r M a j e s t y 's P r i n c i p a l S e c r e t a r y o f S t a t e f o r t h e W a r D e p a r t m e n t : "Improvements in apparatus for controlling riots" British Patent No. 967660, dated 14 Nov. 1960. J. P.;6 . G u i g n a r d , M u h l e t h a l e r , M .; O t r a m a r e , M .; F o r e l , A .: Vietnam : docum ents on chemical and bacteriological warfare (Dr Philip Harvey, London, 1967). 7 . P r e n t i s s , A. M . : Chem icals in W ar : a treatise on chem ical warfare New York (McGraw-Hill, 1937), p 144. 8. J a c o b s , M. B. : W ar gases : their identification and decon tamination New York (Interscience, 1942), p 24. 9 . B r o p h y , L. P.; M i l e s , W. D.; C o c h r a n e , R. C. : T he C hem ical W arfare Service; from laboratory to field (Department of the Army, Washington, D.C., 1959), p 133. 10. Haldane, J. B. S. : "Callinicus; a defence of chemical warfare" (Kegan Paul, London, 1925), p 10. "A note1 1 . C h e m i c a l D e f e n c e E x p e r i m e n t a l S t a t i o n , P o r t o n : on the toxicity of Z" Porton Report No. 2351, 15 April, 1942. 1 2 . E d g e w o o d A r s e n a l : "Status summary on t h e relative values of AC, CK and CG as bomb fillings" Project Co-ordination Staff Report No. 1, 10 July, 1944. 13. GHQ, AFP AC:O f f i c e o f t h e C h i e f C h e m i c a l O f f i c e r , "Intelligence 'report on Japanese Chemical Warfare", Vol. II, BIOS/JAP/PR/393, 1 March 1946, p 61. N 190 C H E M I C A L A N D B I O L O G I C A L W A R F A R E Ivan Malek, m.u .dr., dr.sc. is a member of the Czechoslovak Academy of Science and Director o f the Czech Biological Institute where he conducts research into antibiotics and the continuous cultivation of micro-organisms. He has been associated with peace movements for many years including Pugwash and the World Federation of Scientific Workers and was awarded the Lenin Peace Prize in 1967. Jean Mayer, ph.d., d.sc., m.a. is Professor of Nutrition and lecturer on the History of Public Health at Harvard University and a Fellow of the American Academy of Arts and Science. He is the author of some 400 research papers, 20 popular papers, and two books. M. Meselson, m.s., ph.d. is Professor of Biology at Harvard and a Fellow of the American Academy of A rts and Science. He is winner of the U.S. National Academy of Science Prize for Molecular Biology. Martin Pollock, m.a., m.b., b.chir., p.r.s. is Professor of Biology at Edinburgh University in the D epartm ent o f Molecular Biology. He is medically qualified and is especially concerned with public health, bacteriology, and epidiomology. C. F. Powell, m . a ., p h .d ., f . r .s . is Melville Wills Professor o f Physics in the University of Bristol. He was awarded the Nobel Prize for Physics in 1950 and the Lomonsov medal o f the Soviet Academy of Science in 1968. He is President o f the World Federation o f Scientific Workers. Lord Ritchie-Cald er was Director o f Plans of Political Warfare in the Foreign Office during W orld War II, was Science Editor of the London N e w s C h ro n icle from 1945 to 1967 and was Professor of International Relations at Edinburgh University from 1961 to 1967. He is author of 28 books including M a n A g a in s t th e D e s e rt (Allen & Unwin, 1958), M a n A g a in s t th e J u n g le (Allen & Unwin, 1954), and C o m m o n s e n s e a b o u t a S ta r v in g W o r ld (Gollancz, 1962). J. Perry Robinson, b .a .(o x o n ) read Chemistry at Oxford University and wrote his thesis on certain aspects o f chemical warfare. He is training to be a patent agent and has recently worked at the Stockholm International Peace Research Institute. Steven P. R. Rose, b .a ., p h . d . is a research biochemist. He graduated a t Cambridge, r e a d a p h .d . in London and was previously Research Fellow at New College, Oxford before returning to London to work on problems connected with the biochemistry o f memory and learning. He is the author of T h e C h e m is tr y o f L i f e (Penguin, 1966) as well as general science articles and research papers. Victor Side), m .d . is Associate in Medicine at H arvard Medical School and Chief of the Community Medicine Unit at Massachussets General Hospital. He is a member of the Executive Comm ittee o f the U.S. Physicians for Social Responsibility and editor with Frank Ervin and Saul Aronon of T he F allen S k y (Hill and Wong, 1963). Derik E. Viney, b .a ., p h . d . was previously a member o f the Arms C ontrol and Disarm am ent Research U nit o f the Foreign Office and currently researches and broadcasts on international affairs. Patrick Wall, m.d . is a neurophysiologist and novelist. He is Professor of Anatomy at University College, London. References INTRODUCTION 1. Q uoted by M. Leitenberg in Scientist and Citizen A ugust, 196". 2. See M. Gow ring, Britain and A to m ic Energy 1939-45, (M acm illan, 1964). CHAPTER 1 1. US A r m y C h e m i c a l C o r p s B o a r d , ASTIA Documents Nos 108456--108459, 23 July, 1956. 2. C. A.; D. :K e e l e , A rm stro ng, S u b sta n c e s p ro d u c in g p a in a -.d itc h (Arnold, London, 1964). 3. M o n c r i e f f , R. W. : T h e c h e m i c a l s e n s e s , (Leonard Hill, Loncoc . 3rd edn, 1967). 4. P e n n , W. E .: "Riot control chemicals" Ordnance 50, 1965. 5. H e r M a j e s t y ' s P r i n c i p a l S e c r e t a r y o f S t a t e f o r t h e D e p a r t m e n t : "Improvements in apparatus for controlling r.c z= ~ British Patent No. 967660, dated 14 Nov. 1960. J. P.;6 . G u i g n a r d , M u h l e t h a l e r , M .; O t r a m a r e , M .; F o r e l . a . V ie tn a m : d o c u m e n ts on ch em ica l a n d b a cterio lo g ica l w a:-- ~ t (Dr Philip Harvey, London, 1967). 7. P r e n t i s s , A. M. : C h e m i c a l s i n W a r : a t r e a t i s e o n c h e ; ~ : w a r fa r e New York (McGraw-Hill, 1937), p 144. 8. B. : :J a c o b s , M . W a r gases th eir id en tifica tio n a n d d .c ::-- t a m in a tio n New York (Interscience, 1942), p 24. 9. 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L.; Y e v i c h , P. P.; et al: "The inhalation toxicity of sequimustard (Q) aerosol............." MLRR 403 (Sept ember, 1955). 22. G a t e s , M.; R e n s h a w , B.: "Fluorophosphates and other phos phorus-containing compounds" Summary Technical Report, Division 9 NRDC, (1946), Vol. 1, Ch. 9. 23. C. H.; M. K.; P.;T r a s k , C h r is t e n s e n , C resth u ll, O berst, F. W.; M c N a m a r a , B.: "An estimation of the percent military effectiveness of soldiers with various degrees of incapacitation from GB vapour in various tactical situations" CWLR 2294, (August 1959). 24. F o r s v a r e t s :F o r s k n i n g s a n s t a l t "BC-stridsmedel" FOA orien- terar OM No. 2, 1964 (revised June 1967). 25. E.;H e i l b r o n n , T olagen, B.: "Toxogonin in sarin, soman and tabun poisoning" B io c h e m . P h a r m a c o l. 14, pp 73-77. 26. B e r r y , W. K.; D a v i e s , D. 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"New basic estersI m p e r i a l C h e m i c a l I n d u s t r i e s L i m i t e d : of thiophosphonic acids and salts thereof" British Patent No. 797603, dated 4 June 1956. 33. F a r b e n f a b r i k e n B a y e r AG: "Phosphonic acid esters" British Patent No. 847550, dated 23 June 1958. 2, / / 1 5 REFERENCES 193 34. F a r b e n f a b r i k e n B a y e r A G : " V erfah ren zu r H erstellung von N -substituierten Am inocyanphosphinsaure-bzw . -- thiophosphinsau reestern " G erm an P aten t N o. 767511, filed 22 July 1937. 35. U S S e c r e t a r y o f t h e A r m y : " D econtam inating so lution" U nited States P a te n t N o. 3079346, issued 26 F e b ru a ry 1963. 36. G e n e r a l A n i l i n e a n d F i l m C o r p o r a t i o n : " In terh alo g en p ro ducts of polyvinyl pvrrolidone" U nited States Patent No. 2754245, issued 10 July 1956. 37. P e t e r s , R. 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H . : "A nticholinergic psychotom im etic agents" Internat. Rev. Neurobiol. 4, (1963). pp 217-273. 45. K -9 T r a in in g A g e n c y : "T rain in g and use o f dogs fo r CW detection" Final report on C ontract No. D A 18-108-CM L-6607. 46. F l e i s h e r , J. H .; F a y t o l , A. B .: "Effects o f . . . . E PN on the toxicity of . . . . G B " Fed. Proc. 20, (1961), p 434. 47. V .R o z e n g a r t , I.; E.B a l a s h o v a , K . : " M e c h a n ism o f `a g in g ' of cholinesterase inhibited by organophosphorus com pounds" D okl. Acad. N auk. SSR. 164, (1965), pp 937-40. 48. M c D e r m o t , H . L.; F i n k b e i n e r , A. J.; W i l l s , W. J.; H e g g i e , R. M .: "The enhancem ent of penetration of an organophos phorus anticholinesterase through guinea-pig skin by dim ethylsulphoxide" Canadian Journal of Physiology and Pharmacology 45, (1967), pp 299-303. 49. S t a n f o r d R e s e a r c h I n s t i t u t e : " M ethod of encapsulation o f aerosols by in situ polym erization" U nited States Patent No. 3219476, issued 23 N o v e m b e r, 1965. 5 0 . U S S e c r e t a r y o f the A r m y : "L ight high explosive b o m b f o r dispersing toxic and insecticidal aerosols" U nited States Patent N o . 3207071, issued 21 S ep tem b er, 1965. 51. S h i r k , W . F .; M i r s h a k , W . G . : " Im p ro v e m e n ts in th e 155 m m chem ical shell, M 121E1" D R -T R :2 -6 1 , Picatinny A rsenal, (July 1961). 52. C o m i n g s , E. W- ' "T h e rm a l g e n e ra to r m u n itio n s" S u m m ary T ech n ical R e p o rt, D ivisio n 10 N R D C , (1946), V ol. 1, C h. 30. N* 194 C H E M I C A L A N D B I O L O G I C A L W A R F A R E 53. "Study, design, fabrication and test of Sergeant chem ical w arhead" A m erican Service Technical Inform ation Agency D ocum ent No. 427855. 54. 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Sci., Vol. 6 6 (1957), p 418. 2. S h u l g i n , A. T.; B u n n e l l , S.; S a r g e n t , T .: Nature, Vol. 189, (1961), p. 1011. 3. U r d i n , E.; E f r o n , D. H . : "Psychotropic Drugs and Related Compounds," Washington, D.C.: Superintendent of Documents (1967). 4 . S a m u l e n s o n , R. J . : Science, Vol. 1 5 8 , ( 1 9 6 7 ) p 1 0 3 1 . 5. K l e i n , D. F .: Amer. J. Psychiat, Vol. 121, (1965) p 911. 6 . J o y c e , C. R. B.: "Prediction from Man to Animals" in Animal Behaviour and Drug Action edited by S t e i n b e r g , H. et at. (Churchill, London, 1964). 7. US : "EmployD e p a r t m e n t o f t h e A r m y , N a v y a n d A i r F o r c e ment of Chemical and Biological Agents" Field Training Manual FM 3-10 (1966) Washington, D.C. 8. G u i g n a r d , J. P. et a t: Vietnam: Documents on Chemical and Bacteriological Warfare. (Dr P. Harvey, London, 1967). 9. G eher, W. F .: Science Vol. 158, (1967), p 265. J . : Science Vol.S.1 0 . I r w i n , and E gozene, 157, (1 9 6 7 ), p 313. 11. R o b i n s o n , J. P .: "Chemical Warfare" Science Journal Vol. 3 pp 33-40 (April 1967). 12. D o w n i n g , D. W .: "Psychometric compounds" in Psychopharma- cological Agents, ed. G o r d o n , M . , Vol. 1 (Academic Press, Lon don, 1964). 13. L.G o o d m a n , S. and G i l m a n , A.: Pharmacological Basis of Therapeutics" (Macmillan, New York, 1965). 14. J o c o b s e n , E .: "Hallucinogens" in Psychopharmacology: Dimen sions and Perspectives, ed. J o y c e , C. R. B. (Tavistock, London, 1968). 15. W e i s s , A. J. et al: Science Vol. 136 (1962), p . 151. &)L 1ns REFERENCES 195 16. H olter, A.; Osmond, H. : The Hallucinogens (Academic Press, New York 1967). 17. Sidel, V. W.; G oldwvn, R. M.: "Chemical Weapons: what they are and what they do" Scientist and Citizen, Voi. 9 (1967), pp 141-48. CHAPTER 3 1. R eich, Peter; Sidel, V ictor W .: " N a p a lm " New England Journal of Medicine 277, (July 13, 1967), pp 86-88. 2. 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L a n g e r , E l i n o r : " C h e m ic a l a n d B iological W a rfa re (I I): T h e W eapons and the Policies" Science, 155:303. These num bers were supplied to Science in January 1967, by the Pentagon. 4. " R epublic of V ietnam , N utrition Survey, O ctober-D ecem ber, 1959." A R eport by the Inter-departm ental C om m ittee on N u tri tion fo r N atio n al D efense, July, 1960. 5. C o l l in s , J. L .; E r v in , F r a n k ; L e v i, V ic k i; S a v it z , D a v id : " M edical Problem s of South V ietnam " Physicians for Social R esponsibility, B oston, Jan u ary , 1967. 6. U n it e d N a t io n s C o m m is s io n f o r A s ia a n d t h e F a r E a s t : " M ulti-P urpose R iver Basin D evelopm ent, P a rt 2B W ater R e sources D evelopm ent in B urm a, India, and P akistan" (Bangkok, D ecem b er 1956). 7 . P a k i s t a n M i n i s t r y o f H e a l t h (in collaboration w ith the U n i versity o f D acca and the U.S. N utrition Section, Office o f In ter n a tio n a l R esearch , N a tio n a l In stitu tes of H ealth ). " N u tritio n Survey of E ast P akistan, M arch, 1962-- Jan u ary , 1964" (U.S. D e p a rtm e n t of H e a lth , E d u c a tio n a n d W elfare, M ay 1966). 8. Pakistan 1955-56 (P ak istan P u b licatio n s, K a ra c h i, 1956). 9. W e i t z e l , F r a n k H . : "T estim ony b efo re H earin g s o f the S ub com m ittee to Investigate Problem s C onnected w ith Refugees and Escapees of the C om m ittee on the Judiciary, U nited States Senate, E ig h ty -N in th C ongress, July 13-Septem ber 30, 1965." (U.S. G o v e rn m e n t P rinting Office, 1965). 10. N e w Y o rk Times, O c to b er 9, 1966. 11. A r n e t t , P e t e r ; F a a s , H o r s t : " A m e ric a n C la im s o f P ro g re ss in V ietnam D isputed" St. Louis Post-Dispatch (AP), July 3, 1967. 12. Rusk, Howard: " R efugee C risis in V ie tn a m ," N e w Y o rk Times, S ep tem b er 12, 1965. 13. Statistical Yearbook, 1966, (U .N ., 18th Issue, N ew Y o rk , 1967), p 277. 14. Faltermayer, Edmund K .: "S o u th V ie tn a m 's E c o n o m y " Fortune M arch 1966, p 22S. 15. " R efu g ee P ro b lem s in South V ie tn a m ," op. cit., p 137. 16. I b i d . , p 366. 17. B a l d i c k , R o b e r t : The Siege o f Paris (B a tsfo rd , L o n d o n , 1964). 198 C H E M I C A L A N D B I O L O G I C A L W A R F A R E 18. Kranzberg, Melvin: The Siege o f Paris, 1870-1, A Political and Social History (Cornell University Press, Ithaca, New York, 1962). 19. Keyes, Ancel, et a l : The Biology o f H um an Starvation V ol. 1 an d 2 (U n iv ersity o f M in n eso ta Press, M inn eap o lis, 1950). 20. Schreiner, G eorge A .: The Iron R ation (H a rp e r an d Bros., N .Y ., 1918). 21. Werth, Alexander: Russia at W ar (E. P. D u tto n an d C o., N .Y ., 1 9 6 4 ). 2 2 . A n t o n o v , A. N . : "C hildren B orn D uring the Siege o f L enin g ra d ," J. Pediatrics, 3 0 : 2 5 0 - 5 9 , 1 9 4 7 , q u o te d by K eyes. 23. Mohr, Charles: " U .S. S p ray P lan es D estro y R ice in V iet C ong T e rrito ry " N ew Y ork Times, D ecem ber 21, 1965. 24. A BC B roadcast, July 2, 1967. 25. Berg, Gen. William W . : L e tte r to S en ato r Ja c o b K . Javits, M ay 18, 1966. 26. Welles, Benjamin: "P e n ta g o n B acks U se o f C h em icals," N ew Y o rk Tim es, S ep tem b er 21, 1966. 27. " R ep u b lic o f V ie tn a m N u tritio n S tu d y ," pp. 1, 62, 85. 28. " R efugee P ro b lem s in S outh V ietnam and L ao s," p. 134. [This refers, of course, to only the rural areas under Saigon control.] 29. Q uoted in Blockade and Sea Power M. Parm alee (T.Y. Crowell C o., N ew Y o rk , 1924). CHAPTER 7 1. Rothschild, J. H . : T om orrow 's W eapons, (M cG raw -H ill, New Y ork, 1964). 2. Prentiss, A . M . : Chem icals in W ar (M cG raw -H ill, N ew Y ork 1937). 3. N ew Y ork Times, M arch 25, 1965. 4. Tim e, A p ril 2, 1965. 5. Faas, H orst; White, Edw in: A sso ciated P ress, 10th Jan u ary , 1966. 6. Amett, Peter: A sso ciated P ress, 12 Ja n u a ry , 1966. 7. N e w Y o rk Tim es, J a n u a ry 13th 1966. 8. T h e p a th o lo g ic a l re p o rt based o n studies o f CS, p e rfo rm e d in P ro fesso r R o u sse l's la b o ra to ry o f in d u stria l a n d en v iro n m en tal toxicity in Paris, was m ade available to conference participants, b u t is tech n ical in n a tu re a n d is n o t in clu d ed in this text. It describes th e leth al effects of D r K a h n 's sam p le on lab o rato ry m ice. 9. D r J. P. V igier, Senior Investigator, C N R S , m em ber o f IW CT. 10. Sidel, V . an d Goldwyn, R . : N e w England Journal o f Medicine, Vol. 277. (1967). 11. Rothschild. J. H . : " C h em ical a n d B iological W a rfa re in Viet n a m " Science, 167 (A pril 1967). 12. Punte, C. L. et al: Toxicology and A pplied Pharmacology 4 (1962 pp 656-662. 13. ------ A rchives o f E nvironm ental Health 6 (1963), pp 366-374. sui 1 7 REFERENCES 199 14. Lacombe, A . ; Farriaux, J. P .; Fontaine, B .; Muller, P . M . : Revue de Pcdiatrie I I I (4) ( 1 9 6 7 ) , p p 2 0 7 - 1 3 . CHAPTER 9 1. BBC T V P ro g ram m e, B B C -2, 25 A pril, 1967, H orizon; "T he shape of war to com e". 2. M inistry of D efence P ress release, P tn / A T 3 0 0 1 /2 8 6 8 /6 4 . "T h e Chem ical Defence Experim ental Establishm ent, M inistry of Defence, Porton." 3. " N ew d e v elo p m en ts: CB p ro tectiv e g a rm e n t" Ordnance, V ol. 51 (1966) p 304. 4. D a v i e s , D . R .; G r e e n , A. L . : "T he ch em o th erap y o f p o iso n ing by o rg a n o p h o sp h a te an tich o lin esterases." Brit. J. Indust. M ed, V ol. 16 (1959), pp 128-34. 5 . W a r O f f i c e "Im provem ents in or relating to hypoderm ic inject- tion a p p a ra tu s" B ritish P aten t N o. 915262, dated 29 Jan u ary 1959. 6. ------ "Im p ro v em e n ts in a p p a ra tu s fo r co n tro llin g rio ts" B ritish P a te n t N o. 967660, d a te d 14 N o v e m b e r 1962. L. P.; :7. B r o p h y , M i l e s , W. D .; C o c h r a n e , R. C . "T he Chem ical W arfare Service: from laboratory to field" (D epartm ent o f the A rm y , W ash in g to n , D .C . 1959). 8. S m i t h , G o r d o n C. E . : "T he M icrobiological R esearch E stab lish m ent, P o rto n ," Chemistry & Industry (1967), pp 33-46. 9. T h e M i c r o b i o l o g i c a l R e s e a r c h E s t a b l i s h m e n t : " A b stra c ts o f Published W ork, 1964." 10. S t a n l e y , J. L .; S m i t h , H . : "T h e th re e fo rm s o f a n th r a x toxin: their im m unogenicity and lack o f dem onstrable enzymic a ctiv ity " J. gen. M icrobiol. V ol. 31 (1963), pp 329-37. 11. S m i t h , H .; K e p p i e , J.; P e a r c e , J. H .; F u l l e r , R .; W i l l i a m s , A. E .: "C hem ical basis of virulence of Br. abortus. I. Isolation of Br abortus from borine foetal tissue." Brit. J. exp. Path. Vol. 42 (1961), pp 631-37. 12. D i x o n , B. "W h a t are they up to at P o rto n D o w n ? " N ew Scientist Vol. 32 (1966), pp 558-59. 13. J. gen. M icrobiol. V ol. 45 (1966), p 2. 14. C l a r k e , R : "T h e secret arm s ra c e " , W eekend Telegraph 22 M arch, 1967. 15. T im es 23 M arch , 1954, p 3 (P arliam en t, C o m m o n s, 22 M arch , 1954). 16. Tim es, 12 M a rc h , 1954, p 8 " G e rm W a rfa re d efen ce." 17. Tim es, 23 Ju n e, 1954, p 8. "G e rm W arfa re tests" . 18. Snyder, F . M .; Chadwick, L . E . : " L eth ality o f G .F . an d G.B. vapour to fruitflies, etc . . . M L R R 201, Edgew ood A rsen al (July 1957). 19. C r e s t h u l l , P ., C h r i s t e n s e n , M . K . a n d O b e r s t , F . W . : "E s ti m ated speed of action of GB vapour for death and various degrees of incapacitation in m an" C R D L R 3050, Edgewood A rsen al (Ja n u a ry 1961). 200 CHEMICAL AND BIOLOGICAL WARFARE 20. "Protocol fo r the prohibition o f the use in w ar of asphyxiating poisonous or other gases, and of bacteriological methods of w a rfa re : G en ev a, Ju n e 17, 1925." C n d 3604 (T reaty series No. 24, 1930). 21. T im es 7 S eptem ber, 1945, p 2 "P oison-gas d u m p ed in the sea." 22. T im es 17 S ep tem b er 1948, p 2 " D isposal o f C hem ical am m u n i tion." 23. T im es 10 M a rc h , 1960, p 4 " D an g ero u s C a rg o ." 24. H a n sa rd V ol. 620, C o lu m n 164 (31 M a rc h , 1960) (W ritten answ er to questions). 25. J.R o b i n s o n , P . : "C h em ical W a rfa re " Science Journal, V ol. 3, (A pril, 1967), pp 33-40. 26. Clarke, R .: W e A ll Fall D o w n : the Prospect o f Chemical and Biological W arfare (A llen L an e, T h e P en g u in Press, 1968). 2 7 . Anderson, E . S . : "T ra n sfe ra b le d ru g resistan ce" Science Journal Vol. 4 (A pril 1968), pp 71-76. 2 8 . M i n i s t r y o f S u p p l y : "Im provem ents in or relating t o the pre paration o f dithiol com pounds" British Patent N o . 579971, dated 15 A p ril, 1943. 29. N a t i o n a l R e s e a r c h a n d D e v e l o p m e n t C o u n c i l : "A rtificial breathing m achine," British Patent N o. 828731, dated 5 June, 1958. 30. ------ " Im p ro v e m e n ts in a p p a ra tu s fo r sam p lin g p o rtic u la te c lo u d s," B ritish P a te n t N o. 580705, d a te d 13 S ep tem b er, 1945. 31. ------ " Im p ro v e m e n ts in o r relatin g to a ir sam p lin g a p p a ra tu s" , B ritish P a te n t N o . 1081881, d a te d 14 A p ril, 1966. 3 2 . M i n i s t r y o f S u p p l y : "Im provem ents in o r relating to spray- producing and atom izing m eans" British Patent N o. 629686, dated 31 July, 1948. 33. ------ "A process fo r th e p re p a ra tio n o f esters o f fluoro p h o sp h o n ic acids and chlorophosphonic esters," British P aten t N o. 601210, d a te d 12 F e b ru a ry , 1948. 34. N a t i o n a l R e s e a r c h a n d D ev elo pm en t C o u n c il : "Im prove m ents in plague vaccines" British Patent N o. 1020531, dated 2 M arch, 1962. 35. M i n i s t r y o f S u R p l y : " Im p ro v e d p ro cess fo r th e m a n u fa c tu re of organic phosphorus com pounds" B ritish P atent N o. 810930, dated 4 M arch, 1955. 36. ------ "Im p ro v e m e n ts in o r relatin g to th e p ro d u c tio n o f organic p h o sp h o ru s c o m p o u n d s" B ritish P a te n t N o. 707961, d a te d 20 M ay, 1949. 3 7 . War Office: " Im p ro v e m e n ts in th e m a n u fa c tu re o f dialkyl alkylphosphonothionates," British Patent N o. 897698, dated 9 Septem ber, 1959. 38. M i n i s t r y o f S u p p l y : " M an u factu re of m onoalkyl alkylphos- p h o ro -flu o rid ite " U n ite d S tates P a te n t N o . 2957017, issued 18 O ctober, 1960. 39. N a t i o n a l R e s e a r c h a n d D e v e l o p m e n t C o u n c i l : "Process for preparing dialkyl alkylphosphonothionates" U nited States Patent N o. 3035081, issued 15 M ay 1962. REFERENCES 201 40. Times, 14 and 24 M arch, 1962, (p a rlia m e n ta ry papers). 41. H an sard Vol. 620, C olum ns 1322-3 (30 M arch, 1960), (oral ans wers to questions). 42. Times, 8 M arch, 1960, p 12 "P ressure in U.S. fo r chem ical w eapons" 43. P o s t a n , M. M ., H a y , D ., and S c o t t , J. D .: Design and D evelop m ent o f W eapons (H .M .S.O . 1964). 44. e.g., J a c k s o n , J. B . : " D e v elo p m e n t o f d e c o n ta m in a tin g solution D S-2" C W LR 2368. 45. Technical A bstracts Bulletin (A S T IA ): C um ulative Index, Ja n u a ry -- D ecem b er, 1961. 46. S c h n e i r , W.: "T he C am paign to m ake chem ical w arfare respect able" The Reporter 1 O ctober, 1959, pp 24-8. 47. e.g., B o o z e - A l l e n A p p l i e d R e s e a r c h I n c . : Q u a r te r ly In te rim R e p o rt N o. 16, 31 Ju ly , 1961 on C o n tra c t N o. D A 18H )64-C m l206. 48. e.g., A r m o u r R e s e a r c h F o u n d a t i o n : " A e ro so l stu d ie s w ith bacteriophage." R eport fo r 25 Jan u ary -- 8 F ebruary, 1960 on. C ontract N o. D A 18-064-404-Cml-353. 49. e.g., G o r d o n , K . : " In fo rm a tio n on p o iso n gas m a n u fa c tu re in G e rm a n y ." Office o f th e P u b lic a tio n B o ard , PB re p o rt N o . 12. 50. e.g., " Intelligence re p o rt on Jap an ese chem ical w a rfa re , V ol. I l l " B .I.O .S ./J .A .P ./P .R ./3 9 5 (1 M a rc h , 1946). 51. B u t l i n , K . R .: " P ro sp ectin g in in d u s tria l m ic ro b io lo g y " N ew Scientist V ol. 13 (1962), pp. 804-6. 52. "T h e p o sitio n o f the P o rto n la b o ra to ry " N e w Scientist, 16 A ugust, 1962. 53. H a n sa rd V ol. 530, C o lu m n 19-20, 12 Ju ly , 1954, (o ral answ ers to questions). 54. H an sard , C ol 1026, 8 N ovem ber, 1967, (oral answ ers to questions). CHAPTER 10 1. U.S. Field M a n u a l: 101-40, (1962), p 10. 2. L a n g e r , E .: Science, 155, 174-179 (1967). 3. Q u o ted by S. H ersch in Chem ical & Biological Warfare. (B obbs- M errill, N ew Y o rk , 1968). M a c G ib b o n & K ee, L o n d o n , 1968. 4. L a n g e r , E. Science, 155, 299-305, (1967). CHAPTER 11 1. R o b i n s o n , J. P. : "C h em ical W a rfa re " Science Journal (A pril 1967). p 33-400. 2. R o t h s c h i l d , J. H . : T o m o rro w 's W eapons (M c G ra w -H ill, N ew Y o rk , 1964). 3 . A r k h a n g e l s k y et al. Bacteriological W eapons and how to defend against them (M oscow M ilitary P ublishing H ouse, 1967). 202 CHEMICAL AND BIOLOGICAL WARFARE C H A P T E R 12 1. T h e L a w o f W a r o n L a n d (H.M.S.O. 1958 edn, Part III). 2. See below--"Incendiary Weapons". 3. H udson, M. O .: I n t e r n a t i o n a l L e g i s l a t i o n Vol. II (New York, 1931), p 794. 4. The date of ratification has some significance since it is close to the date of signature of the Geneva Protocol (see below). See also the resolution, supported by the United States, .3 May 1923, J. B. Scott, T h e I n t e r n a t i o n a l C o n f e r e n c e s o f A m e r i c a n S t a t e s (New York, 1931), p 290. This resolution made express reference to the provision of the Treaty of Washington. 5. See L . :O p p e n h e i m , International Law, Vol. II, 7 t h edition, (London 1952), p 344; S c h w a r z e n b e r g e r , G .; T h e L e g a l i t y o f N u c l e a r W e a p o n s (London 1952), p 38. Note also the Hague Declaration Respecting Asphyxiating Gases, signed 29th July, 1899; United Kingdom, M a n u a l o f M i l i t a r y L a w , Part III (1958), p 199. 6. United Kingdom, M a n u a l o f M i l i t a r y L a w , Part III (1958), p 216. 7 . For other condemnations of chemical warfare see the Resolution of the General Commission of the Disarmament Conference, 23 July, 1932; Resolution of the League Council, 14 May, 1938; Resolution of the League Assembly, 30 September, 1938; Final Act of the Consultative Meeting of American Foreign Ministers of the American Republics, 23 September--3 October, 1939, item vi. See also Convention on the Limitation of Armaments of Central American States, 1923, article 5, M. O. Hudson, I n t e r n a t i o n a l L e g i s l a t i o n , Vol. II, p 942. ^>-8. International Law Reports, Vol. 32, p 626. 9. 1956 edition. *10. I n t e r n a t i o n a l L a w S i t u a t i o n s , U.S. Naval War College, 1935, p 106. See further H y d e C. C .: I n t e r n a t i o n a l L a w , 2nd edn, Vol. Ill (Boston, 1945), paragraph 662A. 11. The statement is also printed in I n t e r n a t i o n a l L a w D o c u m e n t s , U.S. Naval War College, 1942, p 85. 12. See U . S . D e p a r t m e n t o f S t a t e B u l l e t i n , Vol. 27 (1952) p 641. 13. U . N . M o n t h l y C h r o n i c l e , December 1966, p 32; U.N. General Assembly, Off. Rees., 21st session, supplement No. 16 (A/6316), p 11. 14. For a standard account of the law see the United Kingdom M a n u a l o f M i l i t a r y L a w , Part III, Chapters I and V. 15. I b i d . , p 224. 16. I b i d . , p 272. 17. For recent surveys of the law and literature see M e y r o w i t z : A n n u a i r e f r a n c a i s d e d r o i t i n t e r n a t i o n a l , 1964, p 81; O 'B r i e n : in G e o r g e t o w n L a w J o u r n a l , Vol. 5 (1962) p 1; M o r r i s G r e e n s p a n : T h e M o d e r n L a w o f L a n d W a r f a r e (University of Cali fornia Press, 1959). 18. Parliamentary Paper, Misc. No. 17 (1930) Cmd. 3747. REFERENCES 203 19. O n j u s c o g e n s s e e Brownlie, I . : P r i n c i p l e s o f P u b l i c I n t e r n a t i o n a l L a w (O .U .P . 1966). 20. D e p a r tm e n t o f S ta te B ulletin , V o l. 12, p 222. 2 1 . R e s o l u t i o n 9 5 . S e e f u r t h e r Schwelb : B r i t i s h Y e a r B o o k o f I n t e r national L a w (O .U .P . 1946), p 178. 22. See U nited K in gd om M a n u a l o f M ilita ry W arfare, P art III, p 217 and in form ation in a m en d m en ts to the M a n u a l. 23. W riter's italics. 24. Cross-reference. 25. T h ou gh effects overlap, explosives and incendiary w eapons are not classified together with N u clear w eapons. O n nuclear w eapons s e e Brownlie, i n I n t e r n a t i o n a l a n d C o m p a r a t i v e L a w Q u a r t e r l y , V o l. 14 (1965), p 437. 26. U n ite d K in g d o m M a n u a l o f M ilita r y W a r fa r e part IJI, paragraph 1 0 0 , n o t e 1. S e e a l s o t h e U . S . A r m y F i e l d M a n u a l , p a r a g r a p h 3 6 , quoted above. 27. P rotocol III on the C ontrol o f A rm am ents. Parties are Belgium , France, the Federal R epublic o f G erm any, Italy, L uxem bourg, the N etherlands, and the U nited K ingdom . CHAPTER 14 1. Rosebury, Theodor: "M edical Ethics and Biological W a rfa re" Perspectives in B iology and M edicine 6: 512-523, Summer, 1963. 2. Sidel, Victor W- and Goldwyn, Robert M . : "Chem ical and Biologic W eapons-- A Prim er" N ew England lournal of Medicine 274: 21-27 (6 January, 1966). 3. Goldwyn, Robert M. and Sidel, V ictor W .: "T he Physician and W ar" in Torray, E. Fuller, ed. E thical Issues in M ed ic in e: The Role o f the Physician in Today's Society Little, Brown & Co. Boston. 4. Langer, Elinor: "Chem ical and Biological W arfare" in Science 155: 174-79, 299-305, 1967. 5. Mayer, C. F. (E d ito rial): "The H ippocratic O ath, T he Pledge of G eneva, and ABC W arfare" in M ilitary S u rg e o n : 369, (1952). 6. Hartford, J. T . : "M edical D efense A gainst Biological W eapons" in M ilitary M edicine 128: 145, (1963). 7. Brincker, J. A. H . : "H istorical, Epidem iological and Aetiological Study of M easles" Proc. R oy. Soc. M ed. 31: 807-828, 1938. 8. Clarke, R . : " Biological W arfare" in Science Journal (Novem ber, 1966) . 9. U.S. D epartment of H ealth, Education and Welfare: Effects o f Biological W arfare Agents. (U.S. G overnm ent Printing Office, W ashington, D.C.,) July, 1959. 10. N opar, Robert E. "Plagues on O ur C h ild re n : T he T h reat of Biological W arfare" in Clinical Pediatrics 6; 63-73 (February, 1967) . 11. Irish, D. P. and McMurray, D. W .: "Professional O aths and A m erican M edical Colleges" J. Chron. Dis. 18: 275-289 (1965). 204 C H E M I C A L A N D B I O L O G I C A L W A R F A R E 12. World Medical A ssociation: Code o f Ethics in Wartime (W orld M edical Association, New Y ork, 1956). 13. Fox, Theodore: "Purposes of M edicine" Lancet II: 801 (1965). 14. U nited States Army: Medical Service Theater o f Operations, Field Manual FM 8-I0. (Department of the Army, Washington, D.C., N ovem ber, 1959). p 17. 15. F ishbein, M .: Doctors at War (E. P. D alton, New Y ork, 1945), P 3. 16. U nited States Army: Lectures o f the Geneva Convention of 1949, 20-151. (D epartm ent of T he Arm y, W ashington, D.C., A pril, 1958). 17. Langer, Elinor: "The C ourt-M artial of C aptain Levy: Medical Ethics v. M ilitary L aw " in Science 156: 1346-50, 1967. 18. Glasser, Ira: "Judgm ent at F o rt Jackson: The Court-M artial of C aptain H ow ard B. Levy" in L aw in Transition Quarterly I I I : (Septem ber 1967), pp 123-56. 19. Ryle, John A., Forew ord in Joules, H., ed. : The Doctor's View of War (G eorge Allen and U nw in Ltd., 1939), pp 7-10. 20. E d ito rial: "Brutalities of Nazi Physicians" 1. A m . Med. Ass., 714, (1946). Glossary This short glossary defines those technical words and phrases that appear in the text but which are not defined there. Formulae of chemicals, or names of microbial organisms, which are referred to only p a ss im are also not included. Adamsite. Yellow irritating smoke containing arsenic. Aerosol. Dispersion of fine droplets of a liquid in the atmosphere. Anthrax. M alignant fever of sheep or cattle, or of humans infected by them; often fatal. Antibody. Molecule produced as part of the body's natural defence against infection; it has the property of binding onto the surface of foreign particles or cells. Asphyxia. Extreme condition resulting from oxygen lack and excess carbon dioxide in the bloodstream. Atropine. Poisonous crystalline alkaloid which interferes with certain types of nervous stimulation. U nder some conditions, in low concentrations, it can serve as an a n tid o te to the anticholinesterase nerve gases. Au xins. Plant horm ones responsible for growth and leaf retention. Avitaminosis. Debilitated condition caused by insufficient vitamin intake-- often results from prolonged starvation or undernutrition. Beri-Beri. Disease o f the peripheral nerves due to lack of Vitamin common in tropical countries. The symptoms are body swelling and pain in the extremities. Botulism, botulinus toxin. Fatal poisoning of the nervous system caused by the toxic product of a bacteria, clostidium botulinum. Brucellosis. Bacterial infection which can cause abortion in animals and remittent fever in man. Ecology. Study of the relationship between organisms and their environment. e d 5,,. Dose of an agent (generally non-lethal) which is effective against half the population exposed. Emetic. An agent which induces vomiting. Enzyme. A biochemical substance (protein) which acts as a catalyst, changing the speed of a chemical reaction without itself being used up in the process. In vitro. Biological term implying an experiment conducted in an artificial environment ("in glass" , i.e., a test tube). Lachrymator. Substance which causes shedding o f tears. Laterization. An almost irreversible process whereby tropical soil exposed to the sun becomes converted to a hard, brick-like rock. Lethal Dose. Dose o f an agent sufficient to kill. Lethal Dose(60) or LD(50). Dose o f an agent which is lethal against half the population exposed. Lewisite. Chemical warfare agent with blistering action. Mg/metre3. M easurement of the concentration o f an agent as milligrams (thousandths of a gram) per cubic metre. 206 C H E M I C A L A N D B I O L O G I C A L W A R F A R E Mg/metre3/min. Measurement of the exposure to an agent; as exposure of a given number of minutes to a given concentration. Necrosis. D eath of a piece of tissue or an organ. Neuritis. Inflammation of the nerve causing pain. Non-pathogenic (of a micro-organism). N ot causing disease. Pathogenic (of a micro-organism). Causing disease or death. Percutaneous. Effected through the skin. Prophylaxis. Prevention of disease. Psychotomimetic. Substance whose effects are similar to those of mental illness, e.g., schizophrenia. Psychotropic. Substance which acts upon the central nervous system causing effects on behaviour. Pulmonary oedema. Swelling of the tissue of the lungs with results usually associated with bad circulation. Pyrotechnic charge. A munition containing smoke-producing chemicals. Sequellae. Abnormal condition resulting from previous disease. Subcutaneous. Introduced below skin. Tol erance. Phenomenon whereby with repetitive doses of a drug increasingly large concentrations are required to produce the same result. Cross-tolerance. When doses of one drug produce tolerance to another. Toxic. Acting as or having the effects of a poison. Toxicity. Measure of the dose of a toxic agent required to produce a toxic effect. Ugr. M icrogram, i.e., millionth o f a gram. Vector. An animal, insect, or other organism that carries and transmits a virus or other micro-organism. Index o, a,-b i s ( - c h l o r o e t h y t h i o ) a l k a n e s , 22 A d a m s i i e (D M ). 20,, 90-2, 97 A erosols, 27, 39, 49, 51, 52, 91, 107, 164 Am erican Association for the A d vancem ent of Science (AAAS), 73, 75 A nthrax, 50, 51, 58, 108-9 A nti-cholinergic drugs, 25 A n !i- c h o lin e s te r a s e (see Nerve-gas) A n t i g e n s , 54 Arsenicals (see Vesicants) A sphyxiation, 20-1 A t r o p i n e , 25, 31, 38, 106 A ttlee, C ., 15 A u stralia, 17, 93 A ustria, 56, 170 A u x i n , 69-70 b i s ( - c h l o r o e t h y l ) s u l p h i d e , 22 Blood gases, 21, 22 B o t u l i n u s t o x i n , 14, 28, 52 B ow tell, C pl. R o b e rt, 93 B r i t i s h A n t i - L e w i s i t e , 31, 111 Brown, G eorge (Foreign M inister), 101, 102 BZ, 25, 31, 38, 39, 91, 127 C a c o d y l i c A c i d , 66 C a n a d a , 17, 26, 106, 108, 135, 161 C a r b o n m o n o x i d e , 88 Chemical Defence Experim ental E stablishm ent (see P orton D own Research Establish m ent) C hem ical w eapons (see D efoliants), 19-32, 39, 109 C h in a, 144 C h l o r i n e , 21, 166 C h l o r o a c e t o p h e n o n e (C N ), 90, 91, 92 C h o k in g gas, 20-21, 101, 142 C lassification, 16, 19, 120 CNS, 20 C rop destruction (see Defoliants), 76, 78, 82-3, 152-153 CS (see O rtho-chlorobenzalm al- onitrile) C y a n o g e n c h l o r i d e , 22, 23 C yclohexyl m ethylphosphono- f l u o r i d a t e (G F ), 24 C zech o slo v ak ia, 56, 108 D eclassification, 113-14 D efence, 30-31, 53-7, 106, 110-11, 120, 132, 164 D efin itio n o f BW , 142, 151 D efin itio n o f C W , 19, 46, 142, 151 D efo lian ts, 14, 16, 62-75, 89, 127, 149-50 D elivery system s, 26, 27, 28-9, 51, 52, 90-92, 131, 168 D engue fever, 57 D ep artm en t o f D efense, 73-5, 114. 119, 123 D etection, 40, 50, 52, 54, 55, 56, 58-59, 106, 110 D i c h l o r o f o r m o x i m e , 21 D i m e t h y l a r s e n i c a c i d , 66 D isarm am ent, 56, 134-5, 150-1, 159, 162-3 D issem ination (see Delivery sys tem s, A erosols), 26, 38, 51 D i s u l p h u r d e c a f l u o r i d e , 21 D onnelly, D ixon, 62, 73, 89 208 C H E M I C A L A N D B I O L O G I C A L W A R F A R E D ow Chem ical C om pany, 37, 38, 67, 74, 75. 124 D ugw ay P rovin g G ro u n d , 123 E dgew ood A rsen al, 19, 21, 23 Egypt (see Yemen) E pidem ics, 49, 50-51, 109, 159, 173 E x p en d itu re, 4S, 66 K o re a , 46, 52, 58 L a u r i e a c id , 44 Levy, C ap t. H o w a rd , 175-77, 179-- 80 L e w i s i t e , 22 Lysergic acid diethylam ide (LSD), 25, 35, 36, 37, 38, 40 F o rt D etrick, 49, 74, 120-2, 123-4, 172-3 M cN am ara, R o b ert, 72, 73, 92, 93, 173 M edical ethics, 120-1, 172-80 G asm asks, 13, 21, 31, 91, 93, 132 G as w arfare (see W orld W ar I), 13, 14, 15, 90-7 G en ev a P ro to c o l (1925), 17, 45, 46, 101, 102, 109, 133-4, 143-44, 146, 151, 158, 160, 163, 166, 171 G erm an y , 14, 15, 21, 24, 25, 110, ,, 114, 151, 167-8, 170, 171 G re a t B ritain, 17, 24, 25, 31, 105-- 118 (s e e P o rto n D ow n) M eteo ro lo g ical facto rs, 29, 53 M icrobiological Research Estab lishm ent (see Porton Down) M id-W est R esearch Institute, 73, 74 M ilita ry L aw ( s e e L evy), 141, 147, 148, 175 M ilitary secu rity , 13, 14, 44-45, 112, 113 M inistry of D efen ce, 16, 111, 112, 114, 136, 162, 187 M unitions, 26-8 H allucinogens (see Psychedelics), 25, 37 H arassin g agents, 92-7, 142, 166 H erb icid es (see D efo lian ts), 127 if. M ustard gas ( s e e V esicants), 22, 27, 28, 30, 99, 100, 101, 124, 142 M y x o m ato sis, 51, 173 H o o v er, P resid en t, 144 H y d r o g e n c y a n i d e , 22, 23, 131 N a p a lm , 17, 44-47, 88, 91, 93, 150 N ational A cadem y of Science (U .S.), 74, 123 Im m u n iz a tio n , 55, 58, 131 (s e e N erv e gas, 14, 15, 23^1, 25, 26, 27, V accin atio n ) 31, 99, 100, 112, 113, 124, Im perial C hem ical Industries, 24 130, 164, 168, 169 In ca p a c ita tin g agents, 20, 25-6, 57 N ettle gas, 21 Infectious agents, 50 N on-lethal gas (see T ear gas, Inspection, 52, 56-7, 134-5, 159, H arassing agents, Incapacita 160 ting agents) In te rn a tio n a l ag reem en ts (s e e In N u c le a r w arfare, 15-16, 49, 54, 59, ternational Law, Geneva P ro 132, 169, 170 tocol) N u re m b e rg T rib u n a l, 149 International Control (see Inspec tion), 40, 46 -7 , 55, 56, 57, 5S In tern atio n al L aw , 127, 128, 141-- 51 I o d i n e m o n o c h l o r i d e , 30 O rtho-chlorbcnzalm alononitrile (CS), 20, 90, 91, 92, 93, 97, 107, 186 J a p a n , 46, 114, 158, 171 Jo lio t-C u rie, F., 15, 16 P a s t e u r e l l a t u i a r e m i s , 52 P e n tag o n , 74, 123-124, 125, 127 P h o s g e n e , 21, 22, 27, 29 t?1ns IN D E X 209 P i c o l i n i c a c i d , 74 Pine Bluff A rsenal, 124 Plague, 48, 50, 57, 78, 108, 112 Poison gas (s e e G as w arfare, Nettle gas) P o l y v i n y l p y r r o l i d o n e , 30 Porton Down Research Establish ments, 15, 16, 19, 29, 40, 49, 136, 161-63 Production of CBW, 52, 110, 124, 131, 168 Psychedelics, 35-40 Pugwash M ovem ent, 56, 160, 170 Toxicity of BW, 14, 52, 164 Toxicity of CW , 19-28, 66, 71, 88- 90 T richlorom ethyl chlorophorm ate, 21 T r i m e t h o x y a m p h e t a m i n e , 36 Tri-partite agreement on CBW {see Q uadripartite agreement) T r i s { P - c h l o r o e t h y l ) a m i n e , 22 2 , 4 - D , 64, 66, 67 ff, 90 { se e D efoli ants) 2, 4 , 5 - T , 64, 66, 67 ff (see D efoli ants) Quadripartite agreement on CBW, 16, 106, 108, 113, 135-6, 161 3-Q uinuclidinyl p h en yl glycollates, 26 Red Cross, 99-101, 160 R esearch, 55, 58, 105-137 (s e e University Research) R i c i n , 27 Riot control, 21, 37, 93, 96, 135, 166 Roosevelt, President, 127, 145, 167 Rosebury, Professor, 172, 178 Rothschild, G eneral J. H., 92, 158 Rusk, D ean, 93 Schrader, G erhard, 24 Secrecy. 134-5, 136-7, 161, 186-7 Shell D evelopm ent Com pany, 25 Siege of Leningrad, 80-82 Siege of Paris, 79 Sokolovsky, M arshall, 133 Soviet U nion, 21, 22, 24, 26, 130- 135 S t a p h y l o c o c c a l e n t e r o t o x i n , 52 Starvation (as a m ilitary tactic), 76, 152 State D epartm ent (US), 127 Stockholm Peace Research Insti tute (SIPRI), 56, 58, 59 SufReld Proving G round, 135, 161 Sweden, 24, 56 United N ations, 100, 102, 145-6, 148-9, 151, 158, 160, 170 U nited States {see V ietnam, U.S. expenditure, and Geneva Protocol), 24, 25, 27-9, 51, 62-63, 76, 78, 82-84, 119-29, 144-5, 146, 148, 149, 151, 152-3, 158, 161 University research, 44, 45, 122-3, 1 2 6 ,7 ,8 ,9 , 186-7 U.S. expenditure, 66, 119, 121-2, 124 V accination, 15, 49, 52, 53, 54, 108, 109, 112, 120, 159 {se e Im m unization) Vance, Cyrus (Assistant Secretary of D efense), 67 V e s i c a n t s , 22, 23 V ietnam , 44, 62, 68, 70-5, 76, 77, 78, 82-4, 87-98, 127, 152-3, 158, 166, 180 Vomiting gases and lachrimators, 20, 21 W orld H ealth O rganization, 160, 161, 162, 174 W orld W ar I, 23, 25, 45, 46, 49, 79-80-96, 121, 163, 166-7 II, 14, 15, 16, 21, 22, 23, 45, 46, 76, 80-2, 88, 108, 110, 114, 130, 167, 168 T ear gas, 125, 134, 166 Yem en, 99-102, 168 Thompson, George, (Minister of State), 101 Zhukov, M arshall, 133 J& sH & lTrS - 2,4,5-T & Silvx Cancellation r '1*. i f. *V > *."* *; v , . . : v-v .-.ENVIRONMENTAL PROTECTION AGEN.CY EXHIBITS ... -- . DATE DESCRIPTION STATUS 1 3-15-80 2 3-15-80 3 3-15-80 4 3-15-80 5 3-15-80 6 3-15-180 7 3-15-80 8 3-15-80 9 3-15-80 10 3-15-80 n 3-15-80 D irec t Testimony o f Mr. Ronald Thomas Survey o f Polychlorodibenzo-p-dioxin Content In Selected P e s tic id e s - Woolson, E .A ., Thomas, R.F. and Ensor, P .D .J. 1972 Monalvo, J .G ., Ryan, J .F . and Flagg, R. - A nalysis o f Technical Grade P e s tic id e s f o r TCDD a t th e ppb Level. EPA P ro je c t No. 68-01-3981. Physical Engineering Sciences D iv., Gulf South Research I n s t i t u t e , New O rleans, LA B user, H. and B osshardt, H. 1974. D eterm ination o f 2,3,7,8-TCDD a t ppb Levels in Technical Grade 2 ,4 ,5 -T in 2,4,5-T Alkyl e s t e r and 2 ,4 ,5 -T Amine S a lt H erbicide Form ulations by Quadrapole Massfragementography. J . Crom. 90: 71-77. Tore-Ramstad, Mahle, N.H. and Matalon, R. 1977. Automated Cleanup o f H erbicides by A dsorption Chromatography fo r Determ ination o f o f 2,3,7,8-TCDD. An. Chem. 49: Dow Chemical Company. Method ML-AM-75-34. D eterm ination o f TCDD in 2 ,4 ,5 -T , Silvex and C hlorinated Phenols (unpublished) Documents which Dow Claims co n tain c o n fid e n tia l Data on Dow's A nalysis o f TCDD co n ten t in commercial 2,4,5-T produced between 1975 and 1979 (CONFIDENTIAL) D irect Testimony o f Ms. Anne Barton Snedecor, George W. and Cochran, W illiam G ., S t a t i s t i c a l Methods 6th E d itio n , Iowa S ta te U n iv e rsity P re ss , pp. 10-16 W alter, Hellen M. and Lev, Joseph, S t a t i s t i c a l In fe re n c e , H olt R inehart and Winston, 195, pp. 1-17, and 60-76 F le is s , Joseph L. S t a t i s t i c a l Methods fo r Pates and P o rtio n s, Wiley 1973 Chapters 2 & 3 pp. 14-33 and Table 3, pp. 176-194 In II tl 11 It II II II II II II 12 3-17-80 D irect Testimony o f Dr. Dawn G. Goodman II 13 3-17-80 Kociba, R .J. Keys, D.G., Carreon, R.M., Wade, C .E ., D itte n b e r, D. II K alnins, R ., Frauson, L ., Park, C.N ., Hummel, R ., and Humiston, C.G. 1978a. R esults of the Two-year Chronic T oxicity and Oncogenicity Study o f 2,3,7,8-T etrachlorodibenzo-p-dioxin in R ats, T oxicol. Appl. Pharmacol. 46: 279-303 14 3-17-80 Kociba, R .J. 1979a. L e tte r and th re e ta b le s se n t to H. Warnick, II Special P e s tic id e Review D iv isio n , U.S. Environmental P ro te ctio n Agency, from R .J. Kociba, Toxicology Research L aboratroy, Health and Environmental S cien ces, Dow Chemical U .S.A ., Midland, Michigan February 20, 1979 4W 13 NO. DATE 15 3-17-80 ! 16 17 l\ ! 18 / t.:. 19 20 II ir 21 22 23 ? r i i "KA U U U t NU. 4 I S cu a i . 2,4,5-T & Silvex Cancellati on - ^H?CWMNrAL- P'RTCTtoii- GENtY' EXHIBITS -v-' T/'H' -2- DESCRIPTION STATUS Kociba, R .J ,, Keys, D .G .,. C arreon, R.M,, Wade, C .E ,, D itte n b e r, D ., K alnins, R ., Frauson, L ., Park, C.N ,, Hummel, R ., and Humiston, C.G. 1977. R esults of a Twe-year Chronic T o x ic ity and O ncogenicity Study o f 2,3^7,8-iT etrachlorodibenzo-p-dioxin (TCDD) in Rats. Unpublished study. Toxicology Research Laboratory, Health and Environmental Research. Dow Chemical, U .S.A ., Midland, Michigan September 28, 1977 In S q u ire, R.A., and L e v itt, M.H. 1975. Report o f a workshop on c la s s ific a tio n of SDecific heoatocelluar lesions in ra ts . Cancer Res. 35:3214-3215 " I n s t i t u t e o f Laboratory Animal Resources (ILAR), N ational Research C ouncil, N ational Academy o f S ciences, 1980. H isto lo g ic typing o f Liver tumors o f the r a t. J . National Cancer I n s titu te . 64:178-206 " H iro ta , N ., and W illiam s, G.M. 1979. P e rsiste n c e and growth o f a r a t liv e r n e ip la stic nodules following cessation of carcinogen exposure. J . N atl. Cancer I n s titu te 63:1257-1265 " Van M ille r, J . P . , L a lic h , J . J . , and A llen , J .R ., 1977. Increased incidence o f neoplasms in r a ts exposed to low le v e ls o f 2 ,3 ,7 ,8 -te tra c h lo ro d ib e n x o -p -d io x in . Chemosphere 6:537-544 " Toth, K ., Som fai-R elle, S ., Sugar, J . , and Bence, J . 1979. carcinogenicity testin g of herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and of pure dioxin in Swiss mice. Nature 278:548-549 " Kociba, R .J.,K ey es, D.G., Lisowe, R. W., K alnins, R .P ., D itten b er D.D., Wade, C .E ., G orzinski, S . J . , Mahle, N.H., and Schwetz, B.A. 1979b. R esults o f a two-year chronic to x ic ity and ocogenic study of rats ingesting d iets containing 2,4,5-trichloroohenoxyacetic acid (2 ,4 ,5 -T ). Food Cosmet. T oxicol. 17:205-221 " Kociba, R .J. e t a l. 1978b. R esults o f a two-year Chronic T oxicity " and Oncogenesis Study o f Rats Ingesting D iets Containing 2 ,4 ,5 - T richlorophenoxyacetic Acid (2 ,4 ,5 -T ). Unpublished stu d y . Sept. 27, 1978 Leuschner, F ., Leuschner, A ., Hubscher, F ., Dontenwill,W ., and R ogulja, P.V. 1979. Chronic Oral T o x ic ity o f 2 ,4 ,5 -T , Batch No. 503 Control No. 153574 b--c a lle d fo r Short `2 ,4 ,5 -T ' -- in Sprague-Dawley (SIV 50) r a t s . Unpublished Study. Laboratorium fo r Pharmakologie and T oxikologie, Hamburg. A pril 9, 1979. pp 1-29, 39-41 " B ionetics Research Labs, Inc. 1968. Evaluation of C arcinogenic, T eratogenic, and Mutagenic A c tiv itie s o f S elected P e stic id e s and In d u s tria l Chemicals. Vol. 1. pp 1-53, 57,67,75,97-110, 225-228 " 17714 >r ' ' f t - /** ` 1j NO. DATE 37 9-23-80 38 39 40 41 4-3-80 42 II 43 . II 1 II 45 II 46 II 47 II 48 II 49 II 50 II 51 II C9 II FIFRA DOCKET NO. 415, e t a l. 2 ,4 ,5 -T & Si 1vex C ancellatio n *: . ' / ;i/'>.it(V;IRONMENIAU:RROTECTI^`A G E N C Y v A:.--.';'X-*vr ' EXHIBITS - 4- DESCRIPTION STATl F arb er, E. 1976. P u ta tiv e P recu rso r le s io n s : Sumary and some a n a ly tic a l considerations. Cancer Research 36:2703-2705 In Memorandum from C. Hirem ath, EPA to R. A lb e rt, EPA on February 22, 1980 II telephone co n v ersatio n w ith Ward, N ational Cancdr I n s t i t u t e . February 29, 1980 L e tte r from T. F i s c h e tt i , N ational Cancer I n s t i t u t e , To E. Anderson CAG, EPA, January 24, 1979. Attachment: NCI C arcinogenesis Bioassay Experimental Designed S tatus Report, p .l. ~II Wogan, G. e t a l . 1974. Carcinogenic e ff e c ts o f low d ie ta ry le v e ls o f a fla to x in B] in r a t s . Food Cosmet. T oxicol. 12:681-685 D irect Testimony o f Dr. K. Diane Courtney w/Curriculurn V ite II Report o f th e S e c re ta ry 's Commission on P e stic id e s and T heir R elatio n sh ip to Environmental Health ppg. 665 - 675 II T eratogenic E valuation o f 2 ,4 ,5 -T , Science 108:864-866, 1970 II T eratology S tudies with 2 ,4 ,5 -T rich lo ro p h en o x y acetic Acid and II 2 ,3 ,7 ,8 -T etra c h lo ro d ib e n z o -P -d io x in , K. Diane Courtney and John A. Moore Studies o f the T eratogenic E ffe c t of 2 ,4 ,5 -T in Mice, R. R o ll, Federal In s titu te of Health II Embryotoxic E ffe cts in Mice T reated with 2,4,5-T rich lo ro p h en o x y acetic Acid and 2,3,7,8-T etrachlorodibenzo-p-D ioxin II S t a tis tic a l A nalysis o f T erato lo g ic Data: Problems and Advancements . Cornelius J . Nelson and Joseph F. Holson II T eratogenic P o te n tia l o f Methadone and 1-Alpha-Acetylmethadol (LAAM) in Rats and R abbits, G. L. Kennedy, e t a l . II P renatal E ffe cts o f H erbicides: Evaluation by the P renatal Development 11 Index, K. Diane Courtney Retarded Development o f F etal Renal A lkaline Phosphatase in Mice Given 11 2,4,5 -T rich lo ro p h en o x y acetic Acid, B. Highman "Apparent Hydronephrosis" as a Normal Aspect o f Renal Development in Late G estation o f Rats: The E ffe ct o f Methyl S a lic y la te , David C. Woo and Richard M. Hoar T eratogenic Studies on 2 ,4 ,5 -T rich lo ro p h en o x y acetic Acid in the Rat and R abbit, J . L. Emerson, D .J. Thompson, R. J . S tre b in g , C.G. Gerbig and V.B. Robinson II II 17715 2 .1 ' ^ f * I: . NO:_______ DATE 25 3-17-80 25 27 28 29 2 31 32 32A 9-23-80 33 33A 9-23-80 34 :1 " 36 2,4,5-T & Sii vex Cancellation ENVIRONMENTAL'PROTECTION AGENCY EXHIBITS -3- DESCRIPTION STATUS Innes, J.R .M ., U lland, B.M., V alerio , M.G., P e tr u c e lli, L ., F isb ein , L ., H art, E .R ., P a llo tta , A .J ., B ates, R.R., P e te rs, J . 1969. Bioassay of P esticid es and in d u stria l chemicals fo r tum origenicity in m ice.: A p relim in ary n o te. J . N a tl. Cancer I n s t. 42:1 TO!-1114 In Muranyi-Kovacs, I . , R udali, G ., and Im bert, J . 1976. Bioassay o f " 2 .4 .5 - trichlorophenoxyacetic acid fo r C arcinogenicity in mice. Br. J. Cancer 33:626-633 Muranyi-Kovacs, I . , e t a l. 1977. Study o f the C arcinogenicity of 2 .4 .5 - T in Mice. Paper presented to the Fourth Meeting o f the European A ssociation f o r Cancer Research. September 13-15, 1977 " Dow Chemical Company. 1965. R esults o f Two-Year D ietary Feeding Study in Rats o f Kurosal SL (Potassium S a lt o f S ilv ex ) Unpublished Study, pp 1-14, 38, 43-46, 73-95. " Gehring, P . J . , and B etso, J .E . 1978. Phenoxy a c id s: E ffe cts and f a te in mammals. In Ramel, C ., ed. C hlorinated phenoxy acid s and t h e i r dioxins. Ecol. B ull. (Stockholm) 27:122-133 " M ullison, W.R. 1966. Some to x ic o lo g ic a l a sp ects o f s ilv e x . P re se n t- " ion a t th e Southern Weed Conference, Ja c k s o n v ille , F l a ., Jan. 18, 1966 Dow Chemical Company. 1965. R esults o f a Two Year D ietary Feeding Study in Dogs o f Kurosal SL (Potassium S a lt o f S ilv ex ) Unpublished study, pp 1-5 " D irect Testimony o f Dr. Roy E. A lb ert Revised D irect Testimony Qr, Roy E, A lb e rt. Carcinogen Assessment Group. EPA. Risk Assessments on 2,4,5 -T S ilv e x , and TCDD. P a rt I . February 28, 1980 C orrections to CAG's Risk Assessment On 2 ,4 ,5 -T , S ilvex & TCDD 9/12/8C U.S. Environmnetal P ro te c tio n Agency. Interim procedures and g u id elin es fo r h ealth r is k and economic impact assessm ents o f suspected carcinogens. 41 F.R. 21402-21405 (May 25, 1976). " w " " r' A lb e rt. R .E ., R.E. T ra in , and E. Anderson 1977. R ationale Developed by th e Environmental P ro te ctio n Agency ^or th e Assessment o f Carcinogenic Risk. J . N a tl. Cancer I n s t. 58(5) 1537-1541 " Work Group on Risk Assessment o f the Interagency R egulatory L iaison " Group (IRLG). 1979. S c ie n tif ic Bases fo r I d e n tif ic a tio n o f P o te n tia l Carcinogens and E stim ations o f R isks. 44 F.R. 39858-39879 (Ju ly 6, 1979) 17716 ..3_lVSi f -X it EPA EXHIBITS 2,4,5-T & Silvex Cancellation NO. DATE 53 4-3-80 54 55 56 57 58 r~- 59 60 61 62 63 64 65 66 67 DESCRIPTION STATU Short Papers, Study o f the E ffe c ts o f High Levels o f 2 ,4 ,5 T richlorophenoxyacetic Acid on Foetal Development in th e Rat In Action De L 'H erbicide 2 ,4 ,5 -T (Acide T richlorophenoxyacetique) Sur Des Rats B lancs, Pendant La Periode De La G estation " Pre- and P o stn atal S tudies on 2 ,4 ,5 -T rich lo ro p h en o x y acetic Acid, 2,4-D ichlorophenoxyacetic Acid and T heir D erivatives in R ats, K. S. Khera and W.P. McKinley " T esting of the Substance 2,4,5-T fo r T eratogenicity in Rats C.H. Boehring Sohn Ingelheim Am Rhein " T esting o f the Substance 2,4,5-T fo r T eratogenicity in Rats (Technical Lot No. 70 200/371) " The N on-T eratogenicity o f 2 ,4 ,5 -T rich lo ro p h en o x y acetic a cid in th e " Rhesus Monkey (Macaca m u la tta ), by William J . Dougherty The E valuation o f the T eratogenic E ffe c ts o f 2,4,5 -T rich lo ro p h en o - " o x yacetic Acid in the Rhesus Monkey, By. W.J. Doughtery, F .C oulston, L. Golberg A bnorm alities of I n tra u te rin e Development in Non-Human Prim ates by James G. Wilson " T eratogenic Studies w ith 2 ,4 ,5 -T and 2,4-D in th e Hamster, by T.F.X. C o llin s and C.H. Williams " (1 Page) T eratology 4 (2) : 236 (1971) Teratology and P ostnatal Studies in Rats Treated O rally with 2-(2,4,5-T richlorophenoxy) propionic Acid (Silvex) and 2 -(2 ,4 ,5 Trichlorophenoxy) propionic Acid, Propylene Glycol Butyl Ether E sters (Silvex-PGBE). Dow Chemical Company, U .S.A ., 1973. (EPA P e s tic id e P e titio n No. 8F0675). Mouse T eratology S tudies with C hlorodibenzo-P-D ioxins, K. Diane Courtney I T era to g e n ic ity o f 2,3 ,7 ,8 -T etrach lo ro d ib en zo -p -D io x in in CF-1 Mice F.A. Smith, B.A. Schwetz, and K.D. N itschke Study of the T eratogenicity of 2,3,7,8-T etrachlorodibenzo-pdioxin in th e R at, G.L. Sparschu, F.L. Dunn and V.K, Rowe P o lychlorodibenzo-p-dioxins: P e rin a ta l E ffe cts and th e Dominant Lethal T est in W istar Rats 17717 AH'? 7 FIFRA DOCKET No. 415, et a l . 2,4,5-T and Si 1vex Cancellation EPA EXHIBITS NO. DATE DESCRIPTION STATUS 68 4-3-80 L tr dtd Ju ly 27, 1978 to Federal R e g ister Section In 69 ,r Three-G eneration Reproduction Study o f Rats In g estin g 2 ,4 ,5 -T rich lo ro p h en o x y acetic Acid in th e D ie t, by F.A. Smith, et al. 69a 10-27-80 Table 3 - 2 ,4 ,5 -T : T hree-G eneration Reproduction Study 70 4-3-80 Chronic Oral T o x icity o f 2 ,4 ,5 -T Batch No. 503, Control No. 153574 B - Short 2 ,4 ,5 -T in a Reproduction Study Covering Three Generations of Sprague-Dawley Rats 71 " T etrachlorodibenzodioxin: An A ccidental Poisoning Episode in Horse Arenas 72 Morphological Changes in Monkeys Consuming a D iet Containing " Low Levels of 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -D io x in , J.R . A llen , et a l. 73 (1 Page) A sb stra c t: S ix teen th Annual M eeting, Tox. Appl. Pharm. " 41 : 177 (1977) 74 (1 Page) T oxicological E ffe cts Produced in NonHuman Prim ates " C hronically Exposed to F ifty P a rts Per T r illio n 2 ,3 ,7 ,8 -T e tra - chlorodibenzo-p-D ioxin (TCDD), S. L. Schantz, e t a l . 75 P e rin a ta l N ephropathies, by James E. Gibson " 76 " P o stn atal E ffe cts of Maternal Exposure to 2 ,3 ,7 ,8 -T e tra c h lo ro - " dibenzo-p-dioxin (TCDD), by J.A . Moore, e t a l . 77 " T hree-G eneration Reproduction Study o f Rats In g estin g 2 ,3 ,7 ,8 - " T etrachlorodibenzo-p-D ioxin (TCDD), by F .J . Murray, e t a l . 77a ^ i Z 30 Table 4 - TCDD T hree-T eneration Reproduction Study " 78 A b stra c ts: S ixteenth Annual M eeting, Tox. Appl. Pharm. 41 : 200 " 1977 79 Epidemiology and Pathology o f a T etrachlorodibenzodioxin Poisoning Episode, by Renate D. Kimbrough, e t a l . I 80 A Survey of the Embryotoxic E ffe c ts o f TCDD in Mammalian S p ecies, by D. N eubert, P. Zens, A. Rothenw allner & H .J. Merker 81 The E ffe cts o f Various Doses o f 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p Dioxin Administered with 2,4,5-T richlorophenoxyacetic Acid on Rat F etal Development, by G. L. Sparschu, F.L. Dunn, R.W. Lisowe, and V.K, Rowe 17718 0 -1(3 3 2,4,5-T/Silvex Cancellation EPA EXHIIBTS NO. DATE______________________________DESCRIPTION______________________________________STA 82 D irect Testimony o f Mary Burr Paxton, w/Curriculum V itae I 83 S t a t i s t i c a l Methods fo r Research Workers, by S ir Ronald A. F ish er " 84 Suppression o f C e llu la r Immunity in Rats and Mice by Maternal " Treatm ent with 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -D io x in , by Joseph G. Vos and John A. Moore 85 Evaluation of Carcinogenic, Teratogenic, and Mutagenic A c tiv itie s " o f S elected P e s tic id e s and In d u s tria l Chemicals, August 1968 86 The Use o f th e Ja ck k n ife to E stim ate P roportions from T oxicological " Data in th e Presence o f L i t t e r E ffe c ts , by Beth Gladen 87 Exact Sample S izes f o r Use with th e F ish er-Irw in T est fo r 2x2 Tables " . by J.K . Haseman 88 (2 Pages) A b stracts 11 89 Hormonal A lte ra tio n s in Female Rhesus Monkeys Fed a D iet Containing ,r 2 ,3 ,7 ,8 -T e tra c h lo ro d ib e n z o -p -d io x in , by D.A. B a r s o tti, L .J. Abrahamson, and J.R . Allen 90 A nalysis o f Dichotomous Response Data from C ertain T oxicological E xperi- " m ents, by J.K . Haseman, L.L. Kupper 91 D irec t Testimony o f Dr. Gary D. Hodgen, w/Curriculum V itae " 92 S p e c ific Radioimmunoassay o f Chorionic Gonadotropin During Im plantation " in Rhesus Monkeys, by Gary D. Hodgen, e t a l . 93 E ffe cts o f Fetectomy on Plasma Estrogens and Progesterone In Monkeys " (Macaca m u la tta ), William W. T u lln er and Gary D. Hodgen 94 Plasma E strogens, Progesterone and Chorionic Gonadotropin in Pregnant " Rhesus Monkeys {Macaca m u latta) A fte r Ovariectomy, Gary D. Hodgen and W illiam W. T u lln er 95 Role o f th e Prim ate Placaenta In C o rtiso l S ecretion by th e Maternal " A drenals, Gary D. Hodgen, Bela J . Gulyas and W illiam W. T u lln er 96 A New Radioimmunoassay fo r F o llic le rS tim u la tin g Hormone in Macaques: " O vulatory Menstrual C ycles, Gary D. Hodgen, e t a l . 97 Luteal Phase Defects in the Rhesus Monkey: The S ig n ific an c e o f Serum " FSH:LII R atio n s, John W. W ilks, Gary D. Hodgen and G riff T. Ross 98 A lpha-F etoprotein in Subhuman Prim ates: Factors A ffecting Serum Levels " During Pregnancy, W. T u lln e r, e t a l . 17719 2,4,5-T/Silvex Cancellation - EPA EXHIBITS- NO. DATE 99 100 101 102 103 104 I \ 105 106 107 108 109 110 111 112 113 114 115 DESCRIPTION STATUS R egulation of F o llic y lo g e n e s is .in the Cycling Rhesus Monkey: S e le c tio n o f the Dominant F o l l i c l e , Arnold Goodman, e t a l. Menopause in rhesus monkeys: Model fo r study o f d iso rd e rs in the human c lim a c te ric , by Gary D. Hodgen Ir Composite P a tte rn o f C irc u la tin g LH, FSH, E s tra d io l, and Progesterone during th e M enstrural Cycle in Cynomolgus Monkeys (39834), Arnold L. Goodman, e t a l . F etal o r Maternal Hypophysectomy in Rhesus Monkeys (Macaca m u la tta ): E ffe c ts on the Development o f T estes and Other Endocrine Organs, Bela J . Gulyas, W illiam W. T u lln e r and Gary D. Hodgen Human O vulation "Endocrine c h a r a c te r is tic s o f o v u lato ry and anovulatory m enstrual cycles in th e rhesus monkey, J.W. W ilks, G.D. Hodgen and G.T. Ross II Post Partum P a tte rn s o f C irc u la tin g FSH, LH, P ro la c tin , E s tra d io l, and Progesterone in Nonsuckling Cynomolgus Monkeys, by Arnold L. Goodman and Gary D. Hodgen Corpus Luteum--Conceptus--F o llic le R elatio n sh ip s During th e F e r t il e Cycle in Rhesus Monkeys" Pregnancy Maintenance D espite E arly Luteal Removal, Arnold L. Goodman and Gary D. Hodgen D irect Testimony o f Dr. Wilbur P. McNulty, w/Curriculum V itae T o x ic ity o f 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n x o -p -d io x in in Rhesus Monkeys (Macaca m ulatta) Following a Single Oral Dose, E.E. McConnell, J.A . Moore and D.W. Dalgard T o x icity of 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -d io x in fo r Rhesus Monkeys: B rie f R eport, Wilbur P. McNulty McNulty: Protocol Inform ation and Unpublished Data D irect Testimony o f Dr. Michael I . L u ster, w/Curriculum V itae C r itic a l Reviews in Toxicology , Edited by Leon Goldberg E ffe c t o f 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -d io x in on th e Immune System o f Laboratory Animals, by J.G . Vos, J.A . Moore, and J.G . Zink! Toxicologi Immunotoxicity Assessment o f D ioxins, by RonaldH in s d ill, e t a l . Impairment o f Thymus-Dependent Immune Functions by Exposure o f the Developing Immune System to 2 ,3 ,7 ,8 -T e trac h lo ro d ib e n zo -p -d io x in (TCDD) 17720 oL ( t <?> FIFRA Docket No. 415, et al. 2,4,5-T/Silvex Cancellation 'X EPA EXHIBITS NO. DATE 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 DESCRIPTION STfil Laboratory S tu d ies on th e Immune E ffe c ts o f Halogenated Aromatics By Michael L. L u ste r, Robert E. F aith and George Clark Ir The E ffe c t o f P e rin a ta l Exposure to T etrachlorodibenzo-p-D ioxin on th e " Immune Response o f Young Mice, by P e te r T. Thomas and Ronald D. H in sd ill Increased S u s c e p tib ility to B acterial In fectio n as a Sequela of Exposure " to 2,3,7,8-T etrachlorodibenzo-p-D ioxin, J.E . Thigpen, e t a l. Studies on 2 ,3 ,7 ,8 -T etrach lo ro d ib en zo -p -D io x in Induced Immune Suppression " and Decreased R sistance to In fe c tio n : Endotoxin H y p e rse n sitiv ity , Serum Zinc C oncentrations and E ffe c t o f Thymosin Treatm ent, by J.G . Vos, e t a l . Examination o f Bone Marrow Immunologic Param eters and Host S u sp ec tib i l i t y Following Pre- and P ostnatal Exposure to 2 ,3 ,7 ,8 -T e tra c h lo ro dibenzo-p-dioxin (TCDD) " Tissue D istribution o f the Receptor fo r 2,3,7,8-T etrachlorodibenzo-pdioxin in th e R at, by Jan M.B. C arlstedt-D uke " E ffects of B rief in V itro Exposure to 2,3,7,8-T etrachlorodibenzo-pDioxin (TCDD) on Mouse Lymphocytes, by Michael I. L u ste r, e t a l . " Medical Problems Raised by the TCDD Contamination in Seveso, I t a l y G. Reggiani " D irect Testimony o f Dr. Renate D. Kimbrough, w/Cirrculum V itae " Map MISSOURI / ILLINOIS Memorandum to D ire c to r, Center fo r D isease C o n tro l, from B a cterial Disease Branch, Epidemiology Program, S ubject: Toxic I lln e s s , Lincoln County, Missouri " Memorandum to C hief, B a cterial D iseases Branch, from Renate D. Kimbrough Subject: Rabbit Ear Test fo r the Presence of 2,3,7,8-T etrachlorodibenzo d io x in , dtd Ju ly 30, 1974 " T etrachlorodibenzodioxin: An A ccidental Poisoning Episode in Horse Arenas, Coleman D. C a rte r, e t a l . , " Epidemiology and Pathology of a T etrachlorodibenzodioxin Poisoning Episode " by Renate D. Kimbrough, M.D., e t a l . Memorandum to D ire c to r, Center fo r D isease C o n tro l, from Cancer and B irth Defects D iv., Bureau o f Epidemiology, and C lin ical Chemistry D iv., Bureau of L aboratories Subject: 2,3,7,8-T etrachlorodibenzodioxin Contamination o f Salvage Motor Oil Used in Dust Control Spraying in M issouri 17721 t 2,4,5-T & Silvex Cancellation EPA EXHIBITS NO. DATE 131 4-22-80 132 4-22-80 133 tl 134 II 135 If 136 II 137 tl 138 It DESCRIPTION STATUS D irect Testimony o f F rederick W. Kutz A Method For D eterm ination o f Low Levls o f Exposure To 2,4-D and 2 ,4 ,5-T Comparative Metabolism o f Phenoxy H erbicides In Animals Residual P ro p e rtie s o f 2 ,4 ,5-T and Picloram in Sandy Rangeland S o ils C .J. S c if r e s , H.G. McCall, R. Maxey, and H. Tai Memorandum to Robert Brown, SPR dtd March 22, 1979 in re Summary o f Federal M onitoring Program Data On 2 ,4 ,5 -T ,S ilvex and TCDD Human and Environmental M onitoring f o r H erbicides Used In F o re stry M uTtiresidue Procedure fo r Halo-and N itrophenols. Measurement o f Exposure to Biodegradable P e s tic id e s Y ielding th ese Compounds as M etabolites National P e stic id e Monitoring Programs In In h h M h h h 17722 3111^ 2 - s 71 P .7 ' EPA EXHIBITS rirKM uuuuii d u . 410, et ai. 2,4,5-T & Silvex Cancellation 10. DATE 139 4-16-80 140 141 4-17-80 142 143 144 145 146 147 148 " 148 (A) 9-25-80 148 (b) '> -5-81 149 " 150 " 150-1 151 152 " " " 153 " ,54 " DESCRIPTION STATU D irec t Testimony o f Dr. W illiam M. Upholt IN Dioxin Implementation Plan D irec t Testimony o f Dr. Morton Beroza " n Exposure, T o x ic ity , and Risk Assessment o f 2,4,5-T/TCDD (This Report Contains Inform ation of P ro p rie ta ry Nature and Should Be Disseminated A ccordingly) " Table 1 - Summary o f Environmental Chemistry Data Requirements By Intended Use P a tte rn (FR R eprint) " P e rsiste n c e o f 2 ,4 ,-D , 2 ,4 ,5 -T , and Dicamba in Range Forage Grasses The Fate o f 2,4,5 -T rich lo ro p h o n o x y acetic Acid (2 ,4 ,5 -T ) Following Oral A dm inistration to Man - P. J . Gehring, CG. Kramer, B.A. Schwetz, J.Q . Rose, and V.K. Rowe " Environmental Degradation of 2,3,7,8-T etrachlorodibenzo-p-dioxin (TCDD) " Response o f Dow Chemical U.S.A. To N otice o f R ebuttable Presumption " A gainst R e g istra tio n and Continued R e g istratio n o f P e stic id e Products Containing 2,4,5-T Environmental D istrib u tio n o f 2,3,7,8-TetrachlorodibenzO -p-D ioxin " (TCDD) Applied With S ilvex To T urf In M icroagpecpsuste C orrections - A Comparison o f Trace Element Contents of FL.&Brazil Orange t P ersisten ce and Metabolism o f Chlorodioxins In S o ils " Report OEHL TR-78-92 USAF OEHL TECHNICAL REPORT The Toxicology, Environmetal F a te, and Human Risk o f H erbicide Orange and I t s A ssociated Dioxin The Toxicology, Environmental F a te , and Human Risk o f H erbicide Orange and I t s A ssociated Dioxin " D istrib u tio n o f 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -d io x in (TCDD) In Aquatic Model Ecosystem " Chlorodioxins in P e stic id e s , S o ils , and Plants - C.S. H elling, " A. R. Ise n se e, E.A. Woolson, P.D .J. Ensor, G.E. Jo n es, J.R . Plimmer, and P. C. Kearney P h o to ly sis o f highly C hlorinated D ibenzo-p-dioxins by S unlig h t " Absorption and T ranslocation o f Root and Foilage A polied, 2,4 D ichlorophenol, 2,7-D ichlorodibenzO -p-D ioxin, and 2 ,3 ,7 ,8 -T etrac h lo - rodibenzo-p-dioxin - Allan R. Isense and Gerald E. Jones 17723 2.11*?.3  NO. DATE 155 4-17-80 156 157 158 159 160 161 62 163 164 165 4-18-80 166 167 168 169 170 171 172 173 FIFRA DOCKET NO. 415, et al. 2,4,5-T & Si 1vex Cancellation EPA EXHIBITS DESCRIPTION STATUS R etention and Excretion o f 2,3,7,8-T etrachlorodibenzo-pdioxin by Rats - George F. F rie s and George S. Marrow In TCDD A nalysis in Environmental Samples " L e tte r to EPA Document Control O ffic e r dated June 28, 1980 from Dow Chemical Company, Environmental S ervices signed by John R. C led h ill " A Search fo r 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -d io x in (TCDD) in an Environment Exposed A n-ually to 2,4,5-T richlorophenoxyacetic Acid Ester (2,4,5-T)H erbicides " A Residue Study o f Beef C a ttle Consuming 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo - " p-Dioxin (TCDD) A Residue Study On Sheep Consuming 2 ,3 ,7 ,8 -T e tra c h lo ro d ib e n z o -p Dioxin (TCDD) S e c re tio n o f TCDD In Milk and Cream Folowing The Feeding o f TCDD To L actatin g Dairy Cows A Search fo r the Presense of 2,3,7,8-Tetrachlorodibenzo-p-D ioxin Beef F at - C.W. Kocher, N.H. Mahle, R.A. Hummel & L.A. Shadoff A nalysis For TCDD Residues In Rice Grain From R e ta il S to res and From F ie ld s T reated w ith 2 ,4 ,5 -T C hlorinated In s e c tic id e s : Fate In Aqueous Suspension Containing Mosquito Larvae D irect Testimony of Mr. Robert A. Maxey Phenoxy Acid H erbicides In Water Water Tables Memorandum in re Summary o f Water Supply Performance E valuation Study from John A. W inter to Dwight G. B a llin g er D ire c t Testimony o f Mr. Thomas E. Dixon Interagency Agreement Between The U.S. Geological Survey and The U.S. Environmental P ro te c tio n Agency National Surface Water Monitoring Program Routine A nalytical L ist MASQUAN S ta tio n s to be included in a n 'In te n s iv e Survey of U.S. Cotton Culture Pesticides 17724 <2.1 ( 9 4 '< a 2,4,5-T & Sii vex Cancellation EPA EXHIBITS 3. DATE 174 4-18-80 175 II 176 176-1 II II 177 It 178 II 179 180 II II 81 II DESCRIPTION STATU L e tte r to R .J. P ic k e rin g , U.S. Geological Survey dated Jan . 29, 1979 In Memorandum to Mike D e lla rco , EPA, SPR dated Ju ly 24, 1979 from Tom Dixon, L ife S c ie n tis t Survey and A nalysis Div. " Maps " L e tte r to John Zackrison, Esq. of Kirkland & E llis dated April 17, 1980 w /attachm ent " Memorandum to F o re st S u p e rv iso r, W illiam ette NF and D ire c to r Watershed dated Dec. 28, 1978 from Paul E. Buffam " L e tte r to Mr. Tuck Vath, North Coast tia te r Q uality Control Board dated August 18, 1977 in re to Six River F a lls 1975 H erbicide Spray M onitoring Program signed by Richard D. LaVEN " L e tte r to Mr. Tuck Vath dated Nov. 26, 1975 signed by W.D. Harlan " Memorandum dated Aug. 30, 1976 to Howard S teeley from John B ernhardt in re Aquatic M onitoring R esults o f ITT Rayonier 1976 A erial Spray P ro ject In Western Washington " L e tte r to Mr. Tim Backstrom dated Sept. 24, 1979 from John B ernhardt " 182 183 II . II 184 4-22-80 185 It 186 187 188 189 II II II II 2 ,4 ,5 -T P e rsiste n c e In A West V irg in ia Watershed F o rests and Rangelands As Sources o f Chemical P o llu ta n ts , 1976 L.A. N orris and D.G. Moore D irect Testimony o f Robert W. Baughman T etrachlorodibenzo-P -D ioxins In The Environment High R esolution Mass Spectrom etry At The Picogram Level - A th e s is by Robert W. Baughman An Improved A nalysis For T etrachlorodibenzo-p-D ioxins An A n alytical Method f o r D etecting TCDD (D ioxin): Levels o f TCDD In Samples From Vietnam I T etrachlorodibenzodioxin In The Environment: Sources, F a te , and Decontamination N e u tra l Cleanup Procedure fo r 2,3,7,8-T etrachlorodibenzo-p-dioxin Residues in Bovine Fat and Milk " " " " " " " " .90 191 II II Symposium On The Use o f H erbicides In F o restry TCDD A nalysis In Environmental Samples (Final Report) i x i r\n u u w im - 1 HKj t i j j c u a i 2 ,4 ,5 -T & Si 1vex C an cellatio n "t m t ftbfiMEfiTAL PRCfECTIBn AGENCY*' EXHIBITS J. DATE 192 4-22-80 193 194 195 196 197 198 99 -JO 4-23-80 201 202 203 204 205 206 207 208 __________________ DESCRIPTION________________________________________ STATUS L e tte r to Ms. Carolyn K. O ffu tt, O ffice o f Special P e stic id e In Review, EPA signed by Matthew Meselson, Harvard U n iv ersity Memorandum to A ssociate D ire c to r, RRP dated Feb. 13, 1979 from C h ief, ECB in re TCDD In Human Milk Study " Memorandum to Mr. Karl E. Bremer, Toxic Substances C oordinator EPA, Region V dated Dec. 20, 1978 from Dr. Edward 0. Olswald in re Summary o f R esu lts f o r Analyses o f Samples o f Fish From Michigan " Memorandum dated A pril 9, 1979 to Mr. Karl E. Bremer, TS,EPA Region, V signed by Edward 0. Olswald, Ph.D. " Memo to A. Dupy. , H arless,?.M eselson, Berosa, Baughman, Upholt & " Gross dated March 20, 1980 signed by Donald G. Barnes, H ealth E ffe c ts & Science Policy, O ffice of A ssistant A dm inistrator for P esticides & Toxic Substances Tables (Beef Fat) " V irg in ia Right o f Way Study " DMP Deer and Elk Study " D irect Testimony o f Dr. `Au6ry E. Dupuy, J r . " Sample P rep aratio n and Gas Chromatography-Mass Spectrom etry Determination of 2,3,7,8-Tetrachlorodibenzo-P-D ioxin " D irect Testimony o f Gunter Zweig " Essays In Toxicology by Frank R. Blood " Wiley Award Address - The Vanishing Zero--Ten Years L ater. A S ta tu s Report on Recent Advances in P e s tic id e A nalysis, by Gunter Zweig " E stim ation o f Small Amounts o f 0,0 -D ieth y l - O ,p-N itrophenyl Thiophosphate by P. R. A verell and M.V. N orris " C olorim etrick D eterm ination o f DDT Color T est For R elated Compounds 1 DDT Residues In Milk from Dairy Cows Fed Low Levels o f DDT In T heir Daily Rations " " Separation and I d e n tif ic a tio n o f C hlorinated Organic P e stic id e s by Paper Chromatography. XI. A Study o f 114 P e stic id e Chemicals; Technical Grades Produced in 1957 and Reference Standards by Lloyd C. M itc h e ll, HEW 17726 FIFRA DOCKET NO. 415, et al. 2,4,5-T & Silvex Cancellation .o ENVIRONMENTAL' PROTECTION AGENCY EXHIBITS <0. DATE DESCRIPTION ~ ..... STATU 209 4-23-80 S p e c ific D etection o f Halogens and Phosphorus by Flame Io n iz a tio n by A rthur Karmen, John Hopkins U n iv e rsity School of Medicine In 210 " Chromatographic Techniques fo r P e sticid e Residue A nalysis, Gunter Zweig " 211 " Residue A nalysis A pplications o f Mass Spectrom etry by James F. Ryan " 212 4-24-80 D irect Testimony o f Mr. Robert L. H arless " 213 Dioxin T oxicological and Chemical A spects, Edited by Flamingo C attabeni " , and Aldo C avallaro and Giovanni G alli 214 26th Annual Conference On Mass Spectrom etry and A llie d Topics dated May 28-June2, 1978, S t. L ouis, Mo. 215 25th Annual Conference on Mass Spectrom etry and A llie d Topics dated May 29 - June 3, 1977, W ashington, D.C. 216 A nalysis o f Environmental Samples f o r TCDD Residues 217 4-25-80 Gas Chromatography/Mass S pectrom etric Methods o f A nalysis For 2,3,7,8 -T etrach lo ro d ib en zo -P -D io x in (TCDD) Residues 218 Memorandum to Mike D ellarco , SPR, from Robert H arless dated Feb. 26, 1980 in re R esults o f C a p illa ry Column GC/HRMS A nalysis Performed On E x tra c ts of Human Adipose T issue fo r 2,3,7,8-TCDD Residues (Neele Biopsy F e a s ib ility Study) 219 220 " Chart Memorandum dated Feb. 11, 1980 to Mike D ellarco , SPR Div. from Robert H arless in re R esults o f C a p illa ry Colum GC7HRMS A nalysis Performed On E x tra c ts o f Sediment, S o il, and Fish fo r 2,3,7,8-TCDD Residues 221 " Memorandum to Ms. Carolyn K. O f f u tt, SPR from Edward 0. Oswald, Ph.D. dated April 4 , 1979 in re R esults o f C a p illary Column GC/HRMS Analyses Performed on E x tract o f Water and Sediment fo r 2 ,3 ,7 ,8 -T etrach lo ro d ib en zo pardoxih. (TCDD) 222 " D irect Testimony o f Dr. Thomas 0. Tiprnan 223 4-30-80 223A 6-25-80 224 " 25 It D irect Testimony of Dr. Michael L. Gross w/Cirrculum V itae D irect Testimony o f Dr. Michael L. Gross (SUPPLEMENT) Final Report A nalysis o f S elected Environmental Samples fo r TCDD by GLC-MS Techniques Memo dtd Feb 20, 79 Ms. Carolyn O ffu tt, Dioxin P ro je c t Manaaer, EPA w /attachm ents Data Report #1 17727 ^u<?7 FIFRA DOCKET NO. 415, et a l . 2,4,5-T & Sil vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS NO. DATE DESCRIPTION 226 4-30-80 H erbicide Orange S ite Treatm ent and Environmental M onitoring Summary Report and Recommendations fo r Naval C onstruction B a tta lio n Center G ulfp o rt M ississip p i November 1979 227 " Final Report U ltratrace Analysis of Tetrachlorodibenzo-p-dioxin in Samples o f Deer T issue by Gas Chromatography/High R esolution Mass Spectrom etry Ju ly 10, 1979 228 " L tr dtd Ju ly 13, 79 to Dr. Hugh Black, U.S. F orest Service San F rancisco, CA, w /attachm ent Final Report U ltra tra c e A nalysis o f T etrachlorodibenzo-p-dioxin in Samples o f Deer T issue by Gas Chromatography/High R esolution Mass Spectrom etry, from Dr. Michael L. Gross STATUS In 229 5-1-80 230 231 232 233 234 5-6-80 235 236 237 238 D ire c t Testimony o f Mr. James J . Boland P e stic id e In c id e n t M onitoring System (PIMS) P e stic id e In cid e n t R eport-#16228 Summary o f Reported P e stic id e In cid en ts Involving 2 ,4,5-T P e stic id e In cid e n t M onitoring System Report No. 245 (I Summary o f Report In cid e n ts Involving 2,4,5-TP P e stic id e In cid e n t M onitoring System Report No. 242 D irect Testimony o f Mr. Michael J . D ellarco FR dated AdH I 21 , 1978 - P e s tic id e Programs - R ebuttable Presumptions Agains R e g istra tio n and Continued R e g istra tio n o f P e stic id e Products Containing 2,4,5-T FR dtd March 15, 1979 Decision and Emergency Order Suspending R egist a tio n s fo r C ertain Uses - Suspension Order - N otice o f In te n t To Cancel Suspended Uses (30 Days to Request Hearing) on 2, 4,5-T & S il vex (FRL-1275-1 0PP-30000/26D) P relim inary D eterm ination Concering the R ebuttable Presumption A gainst R e g istra tio n o f C ertain Uses o f P e stic id e Products Containing 2,4,5-T richlorophenoxyacetic Acid (2 ,4 ,5 -T ); Hearing A v a ilib ity o f P o sitio n Document ' Final Determination Concering the Rebuttable Presumption Against R e g istra tio n fo r C ertain Uses of P e stic id e Products Containing 2,4,5-T - Notice o f In te n t to Hold a Hearing To Determine Whether o r Not C ertain Uses o f 2,4 ,5 -T Should Be Cancelled - P u b lica tio n o f Final P o sitio n Document Concering a ll Non-Suspended Uses o f 2 ,4,5-T 17728 3-1 FIFRA DOCKET NO. 415, et a l . 2,4.,5-T & Si 1vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS NO. DATE_______________________ DESCRIPTION__________________________________________ STATUS 239 5-6-80 (FRL-1275-2-0PP-30000/3T) Prelim inary Determination Concering In A Rebuttable Presumption Against R egistration of P esticid e Products Containing 2-(2,4,5-T richlorophenoxy Propionic Acid (S ilv e x ); Hearing: A v a ila ib ility o f P o sitio n Document 240 " Final D eterm ination Concerning The R ebuttable PresiimDtion A gainst " R e g istra tio n For C ertain Uses o f P e s tic id e Products Containing S ilv ex N otice o f In te n t to Hold a Hearing To Determine Whether Or Not C ertain Uses of Silvex Should be C ancelled- P u b lica tio n o f F inal P o sitio n Document Concerning All Non-Suspended Uses o f Silvex 241 ; 242 " 5-9-80 L e tte rs to EPA, A dm inistrator commenting on th e Suspension & C an cellatio n of 2,4,5-T & Silvex D ire c t Testimony o f M r.Emil Regelman " " 243 " Report o f A nalysis - Tobacco f o r 2,4-D & 2 ,4 ,5 -T Check " 244 ( " R esults o f Arkansas Dept o f H ealth re s u ls from Samples o f A lfa lf a , watermelon, pond w ater and well w ater c o lle c te d Ju ly 21, 1978 and analyzed " 45 " Laboratory A nalysis Reprot - S ta te of Oregon Department of F o restry dated March 16, 1977 - Water Sample " 246 " Report o f Loss A rising Out o f Use o f P e s tic id e s In v iste g a tio n Report " 247 " Laboratory S ervice Sample Report - West V irg in ia Department o f A g ricu ltru e 17729 NO. DATE 248 5-Z--80 249 250 251 252 253 253a 253b 254 255 '36 .57 258 258a 258b 258c 258d 258e 258f 258g 258h 2581 258j ^8k rxrr\n i i>iu . eu a i . 2,4,5-T & Silvex Cancellation * ,-v W-y--x. r V ;; ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION D ire c t Testimony o f Mr. C harles Lewis Map - Location o f Houston and Dickerson C ounties, Tennessee Map - Location o f Treatm ent Area in R elation to Houston and Dickerson Counties, Tennessee A ffid a v it o f Mr. L. P. Denevan Dickson Municipal A irp o rt in R elation to Treatment Area Report on A nalysis Report of Analysis Report of Analysis DED - WEED LV-4T Label DED-WEED LV-4D Label P e s tic id e Episode Report Form dated May 1, 1979 P e s tic id e Episode Report Form dated May 1, 1979 Dickson-Houston County H erbicide Incident A ffid a v it o f W illiam D. Parchman A ffid a v it o f Douglas Adams A ffid a v it o f W illie Ray Pate A ffid a v it o f Mrs. John Spicer A ffid a v it o f Mr. E. N. S ta n f ill A ffid a v it o f Mr. Bob D illa rd A ffid a v it o f Mr. Pat W hitaker A ffid a v it o f Mrs. Earlene Whitaker A ffid a v it o f Mr. L este r Baker A ffid a v it o f W. G. Vann A ffid a v it o f Mrs. Dorothy Parchment STATl In II 17730 2.13-0 V- - rtZ1 t'VV j g '.Vi^ti--^ "-^ FIFRA DOCKET NO. 415, e t a l. 2,4,5.-T & Silvex Cancellation 'ENVIRONMENTAL PROTECTION AGENCY EXHIBITS NO. DATE DESCRIPTION STATI 258L 5-7-80 A ffid a v it o f Mr. J . L. S ta n f il l In 258m II A ffid a v it o f Mr. C harles Adkins II 258n II A ffid a v it o f Mr. Douglas Adams II 258o 259 260 II II II A ffid a v it o f Mr. J . R. Anderson S elected Damage S ite s In R elation To Trenchmann P ro p erty , TN S elected Damage S ite s in R elation to Trenchman Property in Houston Co. TN !l II II 261 II Photo It 262 263 264 >5 06 267 II II II II II II Photo Photo Photo Map (L e ste r Baker Dwelling Area) Photo L e tte r to Mr. Frank D aviti in re A erial a p p lic a tio n o f d e fo ila n t over 3000 acre t r a c t of tim ber in houston County, Tennessee from Joseph H. Rossman II II II II II II 268 II L e tte r to Vernon R. Knight in re A erial H erbicide a p p lic a tio n s and p o ssib le groundwater contam ination in Houston County, Tennessee II 269 270 271 II II II Photo Photo L e tte r to Mr. E. H. Trenchmann dated Ju ly 25, 1978 in re A erial A pplicationof d e fo ila n t in Houston County II II II 272 II Photo - A eiral view looking e a s t showing Mr. P a te 's farm II 273 II Report o f A nalysis (tobacco fo r 2,4-Q & 2 ,4,5-T Check II 274 II Report o f A nalysis (Dark Fired Tobacco Leaves) II ?75 II Photo - Color photograph taken , showing ty p ic a l in ju ry to tobacco It damaged from h erb ic id e s applied to property owned by Mr. E.H. Trenckmann c / 6 II Color photo taken Ju ly 20, 1978, showing ty p ic a l in ju ry to tobacco II damaged from h erb ic id e s aplied to prooerty owned by Mr. E.H. Trenckmann 1 7 7 3 ^,^1 t* i` , FIFRA DOCKET NO. 415, e t a l . 2 ,4 ,5-T & Silvex C ancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS NO. DATE 276a 5- 7-80 276b II 277 278 279 280 II II II II 281 It 282 II 283 II 284 284a It II 284b II 284c II 284d II DESCRIPTION STATU Color Photograph taken Ju ly 20, 1978 showing ty p ic a l In ju ry to tobacco damaged from h e rb ic id e s a p p lied to p ro p erty owned by Mr. E.H. Trenckmann In Color photograph taken Ju ly 20, 1978 showing ty p ic a l in ju ry to tobacco damaged grom h e rb ic id e s ap p lied to p ro p erty owned by Mr. E.H. Trenckmann Report o f A nalysis (Tobacco fo r 2,4-D & 2 ,4 ,5-T check) II II Report o f Analysis (Tobacco Leaves) II A erial view looking n o rth , showing lo c a tio n o f Mr. Vann's Tobacco field II View looking e a s t (c o lo r photograph taken Sept. 27, 1979) showing II home o f Mr. Pate (c e n te r) and walnut tr e e (c e n te r r ig h t) damaged from h erb ic id e s being ap p lied to a s i t e approxim ately 4000 f e e t to th e south on p ro p erty owned by Mr. E.H. Trenckmann View looking north (c o lo r photo taken Sept. 27, 1979) showing walnut II tre e s damaged on Mr. P a te 's farm from h erb ic id e s applied approxim ately 4000 f e e t to th e south on property owned by Mr. E.H. Trenckmann View looking north (c o lo r photo taken S ept.' 27, 1979) showing fiv e o f s ix walnut tr e e s damaged on Mr. P a te 's farm from h erb icid es a p p lied approxim ately 4000 f e e t to th e south o f Property owned by Mr. E.H. Trenckmann II A erial view looking south (co lo r in frared photograph taken S e p t.26, 1979) o f Mr. P a te 's farm II Map - W.R. Pate Dwelling Area II View looking north(photo taken Ju ly 20, 1978) showing walnut tr e e s bordering Mr. P a te 's farm damaged by h erb ic id e s ap p lied apporxim ately 4000 f e e t to th e south on pro p erty owned by Mr. E.H. Trenckmann II View looking North (photo taken Ju ly 20, 1978) sh o w in g 'trees bordering II Mr. P a te 's farm. The yellow ing in th ese tre e s was ty p ic a l o f th e more s u s c e p tib le sp ecies in th e area (w alnut, lo c u s t, and s a s s a fra s s ) Rose bushes (photo taken Ju ly 20, 1978) on Mr. P a te 's farm showing damage from h e rb ic id e s applied approxim ately 4000 f e e t to th e south on pro p erty owned by Mr. E.H. Trenckmann II Tomato p la n t (Photo taken Ju ly 20, 1978) on Mr. P a te 's farm showing II damage from h erb icid es applied approxim ately 4000 f e e t to the south on pro p erty owned by Mr. E.H. Trenckmann 1773 2  i. * I x i r\n U v w i\L I m j t I 5 c u a I . 2,4,5-T & S ii vex C ancellatio n 'ENVIRONMENTAL PROTECTION 'AGENCY EXHIBITS NO. DATE 285 5- 7-80 286 286a " 287 288 289 290 291 292 " 293 " 294 " 295 " 296 5-9-80 297 II 298 II 299 II 300 II 301 II 302 II 303 " DESCRIPTION STAT A erial photo looking e a s t taken Ju ly 24 1978, o f Mr. W illiam 's farm showing ty p ic a l damage to tr e e s in th e v ic in ity of th e area receiv in g the h e rb ic id e a p p lic a tio n . Spray area is approxim ately 4000 f e e t to the southw est. In Color photograph o f r e l i e f model showing th e Trenckmann p ro p erty and fiv e (5) se le c te d damage s i t e s . " R e lie f Model - la rg e map approxim ately 36"x24" (Not in th e Folder) " Location of Topographic P ro file " P ro file (Graph) " Tennessee Valley A uthority M eteorological Data " County Maps o f Dickerson and Houston Counties " Color in fra re d photograDh taken Sept. 26, 1979 showing a p o rtio n o f th e " treated area L e tte r to th e property owners dated Ju ly 26, 1978 in re damage crops from Jack M ilton, A ssista n t Extension A gent.U niversity of Tenn. D irec t Testimony o f Mr. Michael E. Cooper D irec t Testimony o f Mr. L e ste r Baker D irect Testimony o f Mr. W illiam Edgar Matthews D irect Testimony o f Richard P e trie Map - Pumphrey Farm Location Perry County, Arkansas Map - Pumphrey Farm Location Perry County Map - Pumphrey Farm and A djacent Owners A erial Spray Agreement Record o f Custom-Application w ith 2 ,4-D ,2,4,5-T Or Other HormoneType H erbicide ED-WEED Label Answers o f Richard Black and Om niflight H e lic o p te r, Inc. To In te rro g a to rie s o f P l a i n t i f f - Civ 78-47 - In The C irc u it Court of Perry County, Arkansas II II 17733 3 3 ,^ 3 NO. DATE 304 5-9-80 305 306 307 308 309 310 311 312 313 314 315 316a 316b 317 318 " " 319 320 321 5-9-80 321a " FIFRA DOCKET NO. 415, e t a l . =' . \ -.-`i . -24,5-T. &. Si 1v ex .Caji$ellatlon- ; ..u ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION STAT.I Answers To I n te rro g a to rie s - No. Civ 78-47 - In the C irc u it Court of Perry County, Arkansas In A irc ra ft In sp ectio n fo r C e r tif ic a te To Apply 2 ,4 ,-D , 2,4,5-T Or Other Hormone-Type H erbicide " Color In fra re d A erial Photograph o f Pumphrey Farm and Sprayed Area taken On October 1, 1979 " Pumphrey Farm and Sprayed Areas - F lig h t Path o f 6-15-78 - Arkansas K raft Co. Sprayed Area " Arkansas R egulations o f 2,4-D , 2,4 ,5 -T and Other Hormone-Type H erbicides, " Graphic Sc: " Pumphrey Farm Topographic Map " Color photograph o f 2 'x 2 ' r e l i e f model showing 160 acre Arkansas K raft owned tim b erlan d , 80 a cre In te rn a tio n a l Paper Company Timberland and 240 a cre Pumphrey Farm. . t: " Longitudinal P ro file - Cross Section B " Local C lim atological Data " Color In fra re d A erial Photograph o f Pumphrey Farm and Arkansas K raft Company Taken on Oct. 1, 1979 " Color low A ltitu d e A erial Photo o f 160 acre Arkansas K raft Company treatm en t area and a d jacen t Pumphrey farm lookin toward the Southwest " Blowup o f E x h ib it 314 " Blowup o f E xhibit 314 " Report o f In sp ectio n on 2,4-D , E tc. Complaint " L e tte r to Om niflight H elico p ters, Inc and Arkansas K raft Corp. dated " Ju ly 25, 1978 sighed by Ralph Pay, Dept, o f Commerce Arkansas S ta te P lan t Board , - Pumphrey Farm Topographic Map - Health Department Sample P oints Pumphrey Farm Topographic Map - Health Department Sample Points " " 17734 FIFRA DOCKET NO. 415, et al. 2,4,5-T & Silyex Cancellation NO. DATE 322 5-9-80 323 324 325 326 327 328 329 330 331 5-9-80 332 ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION STATE Local C lim atological Data In L e tte r to Mr. Allen Pumphrey dated Ju ly 21, 1978 from James T. Green, J r . , U n iv ersity o f Arkansas Cooperative Extension Ser. Plant Analysis Information Sheet - A gricultural Diagnostic Service Laj)ora.tory U niversity o f Arkansas A gricultural D iagnostic Service Laboratory , U niversity o f Arkansas Soil Diagnosis and P lan t A nalysis Report L e tte r to Mr. A llen Pumphrey dated Ju ly 31, 1978 from James T. Green A gricultural Diagnostic Service Laboratory - U niversity of Arkansas D iagnostic Soil Sample Inform ation Sheet Soil T esting and Research Laboratory A gricu ltu re Experiment S ta tio n and Extension S ervice Cooperating Agronomy Department F a y e tte v ille and Marianna, Arkansas - T est R esults D ire c t Testimony o f Mr. Wibur D. Wise R e jected 333 5-13-8334 335 336 337 338 339:1 339.2 340.1 340.2 340.3 .. D irect Testimony o f Dr. George W. K e itt WEEDONE 2,4,5-T Label - Reg. No. 264-9 Monongahela Power Company C ontract S p e c ific a tio n f o r V egetation Management A erial Right-of-Way Maintenance In sp ecto r A erial SDray Check L is t Appalachian Power Company's Accumulation 12-Point Dismissal System H elico p ter Spray Claim - 45H Release In Full of All Claims V ic in ity Map, Annamoriah Area, Calhoun County, WV. Location Map, Annamoriah Area D etail Map, Annamoriah Area 17 ll  , . : . ... .. . FIFRA DOCKET NO. 415, et al. 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PROTECTION'AGENCY EXHIBITS NO. DATE DESCRIPTION 340.4 5-13-80 A erial Color Photograph, S ite 2 , Annamoria Area STATUS In 340.5 A erial Color Photograph, S ite 3, Annamoria Area 340.6 A erial Color Photograph, S ite 4 , Annamoria Area 340.7 340.8 A erial Color Photograph, S ite 5, Annamoria Area A erial Color Photograph, S ite 6, Annamoria Area tl 340.9 A erial Color Photograph, S ite 7, Annamoria Area 340.10 A erial Color Photograph, S ite 8 , Annamoria Area 340.11 L e tte r to Warningsfrom R.E. Frame to W.R. J e f f r e y , Asplundh 340.12 L e tte r from John Perdue and Thomas Mason to Deward O ffu tt 340.13 An A erial Spraying In v e s tig a tio n on the P roperty o f Beward L. O ffu tt 341. EPA Study In West V irg in ia - D etail Map-Calhoun County 342.1 V ic in ity Map Showing M illstone Area in r e la tio n to WestV irg in ia . 342.2 Location Map showing M illsto n e s i t e in r e la tio n to Calhoun County 342.3 D etail Map w ith Contours, showing Power Line and Oil and Gas Wells on P arsons' Property 342.4 D etail Map showing same fe a tu re s as 342.3 and With U.S. Geological Survey 20 f t . Contours added 342.5 Aerial Color Photograph of Parsons' Property and V icinity 342.6 A erial Color Photograph o f Pasture Field showing w ater h o le, under power lin e , w ithin th e right-of-w ay 342.7 342.8 Color Photograph o f Topographic R e lie f Model Showing P arso n 's pro p erty and v i c i n i ty , Power l i n e s , b u ild in g s , ro ad s, o il and gas w e lls , and vegetatio n l L e tte r from John Perdue and Thomas Mason to Paul A. Parson dated Oct. 10, 1978 343 " Model, M illstone Case ( approxim ately 3 'x 3 ') It 344 " Film M illstone - Annamoriah Cases (No D u p lic a te )(F ile d in Expando) 17736 1 NO. . DATE 345 5-13-80 346.1 346.2 346.3 346.4 346.5 346.6 346.7 346.8 346.9 346.10 II II II 346a. 2 346a.3 " 346a.4 346a. 5 346.6 " 347.1 347.2 347.3 II II FIFRA DOCKET NO. 415, et al. J 2'i4:,5.-T.:A Silyex Cancellation -. .. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION________________________________________ STATU L e tte r from Robert Fram, Program le a d e r, P e s tic id e Use and A pplication P la n t P est Control Div. West V irg in ia Department o f A g ricu ltu re to W. R. J e f f r e y , Chemical S u p e rv iso r, Asplundh Tree Expert Company, dated August 4, 1978. In Asplundh A ccident Report " L e tte r from Harold Kahn to Mr. B ailey , Kentucky U t i l i t i e s Company " L e tte r from John K irch, Amchem, to Harold Kahn " Memo from Gaston Rose to Don B u rre ll, Asplundh " Memo from Bob J e ffre y to Don B u r r e ll, Asplundh " L ia b ility Accident N otice, Asplundh, describing nature of spray a c itiv ity " Handwritten Note " Memo from Gaston Rose to Don B u rrell dated 8/1/76 L etter-from Lindsey Ingram to Herschel Taylor L e tte r from Herschel T aylor to Harold Kahn WEEDONE ? ,4 ,5 -T Label - EPA Reg. No. 264-9-AA Case Review by A rthur D. Baker, I I I II II C ivil Peanlty Warning C ita tio n from Robert A. Poss to King County Road D i s t r i c t L e tte r from Mary Toohey to Vance Hitchcock covering N otice of V iolation from WSDA L e tte r Of Warning from Mary Toohey to Dewey E aster Map o f V ic in ity w here-the in c id e n t occured L e tte r from James Seidel to EPA Federal R e g iste r Section in response to the RPAR Notice (FR#843/30,000/26) I L e tte r from T. Saylor to Asplundh L e tte r from Donald B u rre ll, Asplundh, to T. S ay lo r, dated Ju ly 2, 1979 L e tte r from Donald B u rre ll, Asplundh, To T. S ay lo r, dated Aug. 11, 1979 17737 NO. DATE 348.1 5-13-80 348.2 348.3 348.4 348.5 348.6 348.7 349.1 349.2 349.3 349.4 350.1 350.2 350.3 350.4 350.5 350.6 351.1 351.2 351.3 351.4 351.5 " " " 351.6 FIFRA DOCKET NO. 415, et a l . 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PROTECTION AGENCY ' ' EXHIBITS '* DESCRIPTION ~ ~ STAT1 Memo, P ublic S erv ice In d ian a, A erial Spray Claim re B i ll i e F a ith , by S. E. Brandt in Map o f lo c a tio n " Memo from J . McQueen to K. Weigand and L. N e id iffe r dated S ept. 14, " 1978, containing lab analysis data Not Used Asplundh Daily H e lic o p te r Spray re p o rt fo r Aug. 1,1978 " Asplundh D aily H e lico p terSpray Report fo r August 8, 1978 " Asplundh D aily H e lic o p te r Spray Report fo r August 2, 1978 11 H e lic o p te r Spray Claim re Thomas Young " L e tte r from W. R. J e f f r e y , Asplundh, to Dr. J . B aniecki, WVU, req u estin g a n a ly sis o f a p la n t sample " WVU Lab re p o r t, p e st Specimen re c o rd , 9/4/74 " Release in fu ll of a ll Claims " H elico p ter Spray Claim re W illie B. G re en leif " Monongahela Power R/W Maintenance In q u irie s ," L e tte r from E. Haines to R. Frame, WV DA, req u estin g sample A nalysis " Release in fu ll of a ll Claims " L e tte r from W. R. J e f f r e y , Asplundh, to G re en leif acknowledging damage due to spraying " Daily H e lic o p te r Spray Reports fo r Ju ly 6-8, 1978 " H e lico p ter Spray Claim, re : W. C o ttre ll " Monongahela Power R/W Maintenance Inquiry re : W. C o ttre ll I L e tte r from E. Haines to R. Frame req u estin g Sample A nalysis " " Release In Full of All Claims " L e tte r from W. R. J e f f r e y , Asplundh, to W. C o ttre ll acknowledging damages from spray and enclosing check " Copy o f Check from Asplundh to Clarence W. C o ttre ll " . 17733 NO. DATE 352.1 5-13-80 352.2 352.3 352.4 352.5 352.6 352.7 352.8 353.1 353.2 353.3 353.4 353.5 353.6 353.7 354.1 354.2 354.3 354.4 II II 354.5 355.1 355.2 355.3 355.4 II II FIFRA DOCKET NO. 415, et al. 2,4,5-T & Silvex Cancellation '* ' ENVIRONMENTAL PROTECtiON AGENCY EXHIBITS '~ DESCRIPTION STATUS H e lico p ter Spray Claim re ; Martyn Lee Krupa In H elic o p te r Spray Claim re : Wilma Krupa " Memo on th e Krupa Claim by Ed H aines, Asplundh " Memo by Bob J e ffre y on Krupa Claim " Ohio Department o f A g ric u ltu re Laboratory Report " Memo on P la n t Damages " L e tte r from W. R. J e ffre y to R. W ulfhorst, Ohio Department o f A griculture " Release In Full o f AH Claims " P ublic S ervice Indiana Claim memo re M eredith Lee, by S. E. Brandt " Location Map, a ttach ed to Claim Memo " H elic o p te r D aily Spray Report f o r August 24, 1978 " H elico p ter D aily Spray Report fo r August 25, 1978 L e tte r from W.R. J e f f r e y , Asplundh, to Meredith Lee acknowledging damages " Release In Full o f All Claims " H e lic o p te r Daily Spray Report f o r August 23,1978 " A erial Spray Claim re : Cecil R ow lett, by S.E.Brandt " D aily H elic o p te r Spray Report f o r August 1, 1975 A.M. D aily H elic o p te r Spray Report f o r August 1, 1975 P.M. L e tte r to Cecil Rowlett from W.R. J e f f r e y , Asplundh, acknowledging damage Release In Full o f All Claims 1 A erial Spray Claim re : Howard M allory, by S.E. Brandt D aily H elic o p te r Spray Report fo r 8 /1 /7 5 , A.M. Daily H e lico p ter Spray Report fo r 8 /1 /7 5 , P.M. INA Report o f Claim S e ttle m e n t, from R. C h ristia n 17739 v r I ' ' . * NO. DATE 356.1 5--13-80 356.2 II 356.3 II 356.4 II 356.5 II 356.6 II 357.1 II 357.2 II 357.3 II 357.4 II 357.5 II 357.7 II 357.8 II 357.9 II 357.10 II 358.1 II 358.2 II 358.3 II 359.1 Il . 359.2 Il 359.3 II 359,4 II 359.5 II 359.6 II 359.7 II FIFRA DOCKET NO. 415, e t a l. 2,4,5-T & Silvex Cancellation , *4 environmental' protection Agency ' EXHIBITS ; DESCRIPTION STATI H elico p ter Spray Claim re : J e rry Elkins D aily H elico p ter Spray Report f o r May 25, 1976 D aily H e lic o p te r Spray Report f o r May 26, 1976, A.M. In II D aily H elic o p te r Spray Report fo r May 26, 1976, P.M. II D aily H elic o p te r Spray Report f o r June 11, 1976 II Release In Full o f All Claims It Spray Claim Report re : Raymond King II Asplundh Spray Claim Report re : Raymond King II D aily H elico p ter Spray Report f o r Ju ly 27, 1976 It Memo from W. R. J e ffre y to Bob C h ristia n It Handwri tte n Note II Release In Full of All Claims II D aily H e lico p ter Spray Report fo r Ju ly 26, 1976 If D aily H elic o p te r Spray Report fo r Ju ly 26, 1976 II D aily H e lico p ter Spray Report fo r Ju ly 28, 1976 II H elico p ter Spray Claim re : Anthony Stevens Daily H e lico p ter Spray Report fo r Ju ly 27, 1976 i II II Copy o f a Check to Anthony Stephens from Asplundh II L e tte r from Simon Herold to SWEPCO II L e tte r from L. Bango to S. Herold II H e lic o p te r Spray Claim re : Simon Herold II D aily H elico p ter Spray Report f o r May 22, 1976 II Memo from H. Daniel to Bob J e ffre y II F ile Note in d ic a tin g May ww was l a s t spray d ate on th a t u t i l i t y It Release In Full o f All Claims II 17740 - a i 34 o NO. DATE 360.1 5-13-80 360.2 360.3 360.4 360.5 360.6 360.7 360.8 360.9 360.10 " 360.11 " 360.12 " 360.13 " 361.1 361.2 361.3 361.4 361.5 362.1 362.2 362.3 362.4 362.5 362.6 FIFRA DOCKET NO. 415, et al. . . 2,4,5-T.& Silvex Cancellation. ENVIRONMENTAL PROTECTION AGENCY' EXHIBITS -' DESCRIPTION STAT H elicopter Spray Claim re : Theodore Karpinski in H elicopter Spray Claim re: Alexander Karpinski " R/W Maintenance in q u iry re : TheodoreKarpinski " R/W Maintenance in q u iry re : Alexander Karpinski " L e tte r from Ed Haines to Bob Frame Requesting Lab Analyses " West V irg in ia Department o f A g ricu ltu re Lab S ervice sample Report " D aily H elico p ter Spray Report o f June 23, 1977 " D aily H elico p ter Spray Report o f June 23, 1977 " D aily H elico p ter Spray Report o f June 23, 1977 " L e tte r to Mr. Theodore K arpinski dated Ju ly 18, 1978 from W.R. Je ffre y " Release In Full o f All Claims " L e tte r to Alexander Karpinski dtd Ju ly 18, 1978 from W.R. J e f f r e y " Release In Full o f All Claims " H elic o p te r Spray Claim r e : Thomas S lau g h ter " D aily H e lico p ter Spray Report f o r May 19, 1977 " D aily H e lico p ter Spray Report fo r May 23, 1977 " L e tte r from K. Lawrence to R. Bates " Release In Full of All Claims " A erial Spray Claim Report and Map re : C.H. E ck ert, by S.E. Brandt " H elic o p te r Spray Claim re : C. H. E ckert " Daily H elico p ter Spray Report f o r Aug. 1, 1978 " Memo from W.R. J e ffre y to C.H. E ckert " L e tte r from W.R. J e ffre y to C. H. E ckert " Release In Full o f All Claims " 17741 NO. DATE 363.1 5-13-80 363.2 363.3 363.4 363.5 II II II II 363.6 363.7 363.8 363.9 363.10 II II II II II 364 II 365 II 366 II 367 II 368 II 369 II 370 II 371 ft 372 1 373 II FIFRA DOCKET NO. 415, et al. 2,4,5-T & Sil vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION STAT L e tte r from Mabel Stephens to Jim M artin d ale, in cluding t a l l y of destroyed timber IN L e tte r from John Gaughan II to Jim M artindale, w ith map II L e tte r from David Hunter to Steve Bodie II L e tte r from John Gaughan II to David Hunter II L e tte r and ta b le o f damaged tre e s from Jim Neil to John Gaughan, in cluding invoice to Marvin Morgan E sta te II L e tte r from David Hunter to Bob J e ffre y II L e tte r from W.R. J e ffre y to David Hunter II Release o f All Claim s, E ls ie Morgan II Release o f All Claim s, Mabel Stephens II L e tte r to Mr. Bob J e ffre y in re Claim o f E ls ie C. Morgan dated Ju ly 9, 1976 from David E. Hunter Arkansas Power & L ight Company II Report e n title d "Chemical Control o f Brush and Environmental II S afety o f Roadside V egetation Management Chem icals," by D. James Moore, Purdue U n iv e rsity , 1976. (J o in t Highway Research P ro je c t JHRP- 76-32), pp. 86-90 D irect Testimony o f Dr. William Loy II EPA Study Areas in Oregon - Map II Benton County - A!sea Study Area - Map II North H alf Lincoln County - Rose Lodge Study Area - Map it Alsea V egetation D istrib u tio n - Map II A!sea S ettlem en t D istrib u tio n - Map II Alsea Hydrology - Map t it Alsea Land Ownership - Map II A lsea, Three Dimensional Contour Model (only 1) A * p' It 374 Rose Lodge, Three Dimensional Contour Model (only 1) / oh v 17742 NO. DATE 375 5-13-80 376 377 378 379 380 381b 382b 383b 384a 384b 385a 385b 386a 386b M r R A DOCKET NO. 415, et al . 2,4,5-T & Si 1vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION__________________________ STATI Alsea Area a ll H erbicide A p p licatio n s - Maps In Rose-Lodge, H erbicide A p p licatio n s - Maps " Rose Losge, V egetation D is trib u tio n - Map " Rose Lodge, S ettlem ent D is trib u tio n -Map " Rose Lodge, Hydrology - Map " Rose Lodge, Land Ownership - Map " Rose Lodge #1 - Low o blique a e r ia l view facing South. Showing th e Salmon River in th e backgroundw ith Bear Creek Road on the r ig h ts Houses and proxim ate cle ar-.c u ts shown " Rose Lodge #2 - Low oblique A erial view facing North. Showing th e Salmon River in th e backgroundw ith Bear Creek Road in the c e n te r ground. R elatio n sh ip between c le a r cu ts and proxim ity o f settlem ent " Rose Lodge #3 - Low oblique a e r ia l view facing South looking a t Bear Creek Road a re a . R elatio n sh ip o f se ttle m e n t and proxim ity o f clear cut operations " A lsea#!- Photograph o f low oblique a e r ia l view o f Honey Grove V alley area facing w est. Showing se ttle m e n t p a tte rn s and r e l a ti o n ships o f roads and creeks " A lsea#!- Tracing o f Low oblique a e r ia l view o f Honey Grove Creek V alley area facing w est. Showing se ttle m e n t p a tte rn s and re la tio n sh ip of roads and creeks " Alsea #2 - Photograph o f low oblique a e ria l view o f Honey Grove Creek Valley facing north e a s t, showing surrounding h i l l s and past logging operations " Alsea #2 - Tracing o f low oblique a e ria l view facin g N.E. Showing Honey Grove Creek V alley and surrounding h i l l s and p a s t logging operations < Alsea #3 - Photograph o f high oblique a e ria l view looking e a s t showing general re la tio n s h ip s o f se ttlem e n t p a tte rn s , roads and creeks in a fo re s t m ilieu " " Alsea #3 - Tracing of high oblique a e ria l view looking e a s t. General re la tio n sh ip s o f settlem e n t p a tte rn s , ro ad s, and creeks in fo rest m ilieu 17743 NO. DATE 387 5-14-80 388 389 390a 390b 390c 390d 391 392 393a 393b 394 H r RA DOCKET NO. 415, et al. 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION D irect Testimony o f Mr. John Anderson R esults o f the Stream M onitoring Program Conducted during FY 1977 H erbicide Spray P ro je c t by John J . Cameron and John W. Anderson Memorandum to D i s t r i c t Manager from A s s is ta n t D i s t r i c t F is h e rie s B io lo g is t dated June 24, 1978 in re Follow-up on the R esults o f the Stream Monitoring Program Conducted During the FY1977 A erial A pplication o f H erbicides to the Bud-break Stage o f V egetation Growth High e le v a tio n photo o f w ater m onitoring study area - Class II stream with buffer H elicopter a p p lic a tio n o f H erbicide spray a t Upper Smith River Unit Typical watercourse monitored in study White p a in t s t r i p marking buffered zone fo r a e ria l a p p lic a tio n D irect Testimony o f Mrs. C h ristin a Hutchison Oregon Department o f F o restry Map showing lo c a tio n o f spray u n it and m onitoring p oints L e tte r from Susan Page to Logan A. N o rris, dated A pril7, 1977 L e tte r from Logan A. N orris to Susan Page, dated A pril 26, 1977 L e tte r from C l if f Mann, Oregon Department o f F o re stry , to Mr. E rnest H utchison, dated May 2, 1977 STAT In II " " " 11 1 " " ' NO. DATE 395 5-14-80 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 FIFRA DOCKET NO. 415, et al. 2,4,5-T.& Silvex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION STATU D ire c t Testimony o f Dr. Bernard Smale In USDA F o re st Service map o f P a c ific Northwest Region " A erial in fra re d c o lo r p o in t o f P u b lish e rs' Paper Company F o re st spray u n it a f te r broadcast bum (looking e a s t) . McMillin Creek and tr e e b u ffe r se p e ra te th e two sp ra ted s i t e s . The broadcast burn (black in photo) o f the h erbicide d essicated tre e s and brush in d ir e c tly d e fin es th e s iz e and lo c a tio n o f sprayed a re a s . Manual o r mechanical tr e e and brush removal was applied to s e n s itiv e areas such as canyon w alls o f McMillin Creek " Rose Lodge S ettlem en t and Land Ownership Map. Combination o f 378 and 380 " Rose Lodge Land Ownership and Hydrology Map " A erial in fra re d c o lo r p r i n t o f th e Bear Creek Road se c tio n o f Rose Lodge, Oregon and p o rtio n o f a jo in in g P u b lish e rs' Paper Company fo re s t c le a r c u t. Photo taken due e a st a f te r broad c a st burn of Ju ly 31, 1978. Green o f tr e e s , g rass appears red , sunlighted areas yellow and black recorded unchanged in in frared photographs " A erial in frared color p rin t o f McMillin Property and adjoining P ublishers' land " Oregon F o rest P ra c tic e s Act Chemical Rules and G u id elin es, 1978 S ta te o f Oregon, Department of Forestry " N o tific a tio n o f O perations f i l e d by P u b lish er Paper Company o f in te n t to apply h e rb ic id e s (Feb. 4 , 1977) " P ilo t applicator record of spray operation " WEED0NE 170 Product Label D0WP0N (M) Grass K ille r Label P ortlan d S ta te U n iv e rs ity , Oct. 3, 1978 Newspaper account o f Rose Lodge In cid e n t " S ta te o f Oregon, Department o f A g ricu ltu re Memorandum by T. H arrison " summarizing Rose Lodge In c id e n t, 1978 Color Pring o f malformed leaves o f artichoke p la n t from M cM illin's garden " Color pring o f malformed leaves (form ative e ff e c ts ) on a rtich o k e p la n t from M cM illin's garden " Report o f Loss A rising out o f Use o f P e stic id e s In v e s tig a tio n Report " dated Sept. 19 & Oct. 6 1978, claim ant Norma McMillin 17745 i ; *' i * NO. DATE 412 5-14-80 413 II 414 II 415 tl 416 417 It 418 419 420 421 II II II II 422 423 II II 424 th ru 430 431 5-15-80 432 II 433 434 II 435 II 436 II 437 II FIFRA DOCKET NO. 415, et al. 2,4,5-T & Silvex Cancellation M ' * ENVIRONMENTAL' PROTECTION AGENCY ' EXHIBITS DESCRIPTION STATl Request fo r Analysis - P esticide residue In Color p r in t o f damaged squash p la n t from McMillin vegetable garden II Color p r i n t o f o f branch o f damaged ro se o f McMillin property II Color p r i n t o f Phenoxy symptoms on grape in McMillin garden II Not Used Map - R elatio n sh ip o f P u b lish ers Spray S ite To Major Streams w ater Sampleing Locations on Streams and Following Rose Lodge Dwellings II NOAA Weather records from P a c ific C ity , Salem and Depoe Bay Oregon f o r June 21 through Ju ly 20, 1978 II Memorandum dated Nov.17, 1978 to J e f f Handy, Oregon S ta te Dept, o f F o re stry from Kent A. Sm ith, OSDA Dept o f A g ric u ltu re , Oregon If Request f o r A nalysis - P e s tic id e Residue by Oregon S ta te F o restry II Oregon S ta te Dept, o f F o re s try 's Memo dated Dec. 5, 1978 to M. Templeton signed by J . Handy in re spray contam ination a t Rose Lodge, Oregon II Common Sense Steps to Take In Avoiding D rift If Reducing A irborne D r if t Losses w ith Nalco-Trol by Norman B. Akesson, It and Wesley E. Yates Not Used D irect Testimony o f Mr. Thomas H arrison fl Summary Sheets on P e s tic id e In v e s tig a tio n s made by the Oregon S ta te II Department o f A g ric u ltu re in 1976, 1977 and 1978 D irect Testimony o f Mr. William H. Kosean II D irec t Testimony o f Dr. Thomas Ellwanger II H erbicide P ro je c t 1976, Performance Summary, from: Matthew Kowalewski (Alsea area S i l v i c u l t u r i s t ) , to F ile : -YA 514-CT6-132 II Bureau o f Land Management (BLM) P ro je c t Map fo r P ro je c t No. S-A-HT-76-ld II Location o f Alsea Area w ithin Benton County, Oregon II 17746 NO. DATE 438 5-15-80 439:. 440 441 442 443 444 445 446 447 448 448b 449 450 451 452 453 FIFRA DOCKET NO. 415, et al. 2,4,5-T & Si 1vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBIT DESCRIPTION STAT Topographic Map o f Alsea Area In Log book o f Mr. Charles H. McKeen (Evergreen p ilo t) in d ic a tin g a c t i v i t i e s from April 1 thu A pril 6, 1976 " O bservation o f Mr. Mel! Kiliman (BLM) dated A pril 3, 1976 " A erial black and w hite photo showing th e Greens' property viewed from d ire c tly overhead. Property lin e s are ind icated along w ith lo c a tio n s o f p ic tu re s and sampling p o in ts o f April 7, 1976 BLM in sp e c tio n " D eposition o f Mr. Charles H. McKeen, dated January 21, 1977 " Statem ent o f Mr. Gary Green to Bruce L. Engel (Counsel fo r th e Greens) " Statem ent o f Mrs. G isela Green to Bruce L. Engel " Statem ent o f Mr. M errill Maloney to Bruce L. Engel " Overlay of Alsea settlem ents over BLM-treated portions o f Sections 33, 3, 27, and 5 " L e tte r dated May 25, 1979 from Mr. Neil S k i l l , O ffice o f S ta te F o re s te r, to Mr. Tom Ellw anger, EPA " Overlay of Alsea land ownership over Alsea settlem ents " Same as e x h ib it 448 w ith markings " BLM Report Number 1 (Form 9100-la) by Mr. Matthew Kowalewski, dated April 3, 1976 " L e tte r dated May 29, 1979, from Mr. Robert Thompson o f Evergreen H e lico p ters to Mr. Tom Ellwanger o f EPA " Memorandum dated April 9, 1976, from Mr. Joe Patton o f BLM to D i s t r i c t Manager and F ile s , su b je c t: In v e s tig a tio n o f p o ssib le H erbicide Spray Damage - Honeygrove Road Area " P lo t map in d ic a tin g lo c a tio n of'sam p les taken on April 7, 1976 by BLM personnel " Memorandum dated April 19, 1976, from Mr. Joe Patton o f BLM to " D i s t r i c t Manager and F ile s , in re P o ssib le H erbicide Spray Damage - Gary Green Property 17747 3- 13^1 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBIT NO. DATE 454 5-15-80 455 II 456 II 457 5-16-80 458 It 459 II 460a II 460b II 461a II 461b II DESCRIPTION STAT E d ito ria l on Spray damage from C o rv a llis G azette Times, dated August 12, 1976, by Beverly anc C harles Chance In L e tte r dated June 29, 1977, from Mr. Lloyd B. E ricsson (A ttorney rep re se n tin g Evergreen H e lico p ters) to Bruce L. Engel (Counsel fo r the Greens) II D irect Testimony o f G isela Green II D irect Testimony o f Daniel Elam II L e tte r to Daniel Elam dated August 24, 1979 from M artin Thingvold II L e tte r to Mr. Daniel W. Elam dated January 31, 1977 from Arnold P. Appleby, P ro fe sso r o f Crop S cience, Oregon S ta te U n iv ersity II L e tte r to Daniel Elam dated September 16, 1976 from M artin Thingvold II Extension Agent, Oregon S ta te U n iv ersity L e tte r to Mr. Martin Thingvold dated September 13, 1976 from:Homer M. Hepworth, Extension Agronomist -- Weed C ontrol, Oregon S ta te U n iv ersity II L e tte r to James W akefield, C hief M etero lo g ist Weather Forecasing N ational Weather S e rv ice , P ortland Oregon dated September 20, 1976 from Daniel W. Elam II L e tte r to Daniel W. Elam dated September 22, 1976 from James D. W akefield, M eteorologist U.S. Department of Commerce, N ational Oceanic and Atmospheric A dm inistration II 462 6-5-80 D irect Testimony o f Mr. Neil T. S k ill II 463 II F ield Guide to Oregon F o rest P ra c tic e Rules - S ta te o f Oregon Department of Forestry II 17748 3. ^ 1 NO. DATE 464 5-20-80 465 " 466 " 467 " 468 5-22-80 469 470 471 472 473 474 475 476 477 478 479 480 481 482 a 482b 2,4,5-T & Sil vex Cancellation " ENVIRONMENTAL *PROTECTION 'AGENCY ': EXHIBITS DESCRIPTION STATU D irect Testimony o f Mr. Ugo F. Pezzi In Map o f Siuslaw N ational F o rest Laboratory A nalysis R eport, dated June 14, 1971 from Oregon Department o f A g ric u ltu re , Purchase O rder, U.S.D.A, dated May 25, 1971, Sample an aly ses and ta g s . Laboratory A nalysis R eport, dated September 19, 1972 from Oregon Department o f A g ric u ltu re , and l e t t e r from Perske to H ia tt, dated August 22, 1972 D irect Testimony o f Dr. Jack D. G r if f ith t e t t e r from Bonnie H ill o f A lsea, Oregon dated A pril 11, 1978 to EPA " " Report o f the C o n su ltativ e Council on Congential A bnorm altities in Yarram D i s t r i c t , by J . E. A lfred March, 1978 & 2 ,4 ,5 -T and Human B irth D efects, Department o f Health June 1977 " F ie ld , Barbara and K err, C harles. 1979. H erbicide Use and Incidence " o f Neural-Tube D efects. L ancet, June 23, 1979, p. 1341 Report of Assessment of A Field Investigation of six -y ear Spontaneous " Abortion Rates In Three Oregon Areas in R elation To F o re st 2,4,5-T Spray P ra c tic e s , EPA 1979 D irect Testimony o f Dr. Thomas J . Keefe Protocol fo r Second Phase o f Spontaneous Abortion Study Colorado Epidemiologic P e sticid e Studeis Center Colorado S tate U n iv e rsity , F ort C o llin s , Coloracdo, October 1978 In v estig atio n of Six-Year Spontaneous Abortion Rates in Three Oregon Areas In R elation to 2,4,5-T Spray Areas - Colorado Epidemiologic P e stic id e Studies Center - January 1979 D irect Testimony o f Dr. Robert C. Duncan L e tte r from Thomas J . Keefe, Ph.D. to Dr. Robert Duncan dated June 27, 1979 Computer f i l e - Spontaneous a b o rtio n s in Study Area and Control Areas by h o s p ita l, zip code, d a te , and g e sta tio n a l age (Feb. 14, 1980) D irect Testimony o f Dr. Renee Stringham In (By Ord R esolution No. 16- Oregon Medical A ssociation House o f Delegates April 22-24, 1977 Notice - Physicians Reaffirm c a ll fo r H erbicide Moratorium, Oregon " B a llo t T itle - Lincoln County Watershed P ro tectio n Ordinance file d " 4/10/80 B a llo t T itle - Lincoln County Roadside Spraying Ordinance f ile d " ....- ........... - - NO. DATE 483 5-30-80 484 485 486 487 488 488b 489 490a 490b 491 492a 492b(1) " 492b(2) " 493a(l) " 493a(2) " 493a(3) " 493a(4) " 493a(5) " 93a(6) " n r r v i u u u n l j m u * `t i a j e u a i . 2,4,5-T & Si 1vex Cancellation ENVIRONMENTAL'PROTECTION AGENCY EXHIBITS DESCRIPTION ST/ D irect Testimony o f Mrs. Bonnie H ill In The P ro te c tio n and P u rific a tio n of Rural Water Supplies Div. Of S a n ita tio n Oregon S ta te Borard o f Health - 1971 L e tte r to Federal R e g iste r Section dated Ju ly 27, 1980 from Wilbur P. McNulty, M.D., Oregon Regional Prim ate Research Center Oregon Blue Book 1979-1980 Index to C itie s and Towns w ith 1975 P opulations - From Oregon O ffic ia l Highway Map, prepared by Oregon S ta te T ran sp o rtatio n Commission L e tte r to Ms. Bonnie H ill dated Ju ly 12, 1977 tra n s m ittin g copies o f Alsea Area a e r ia l h e rb ic id e spraying in 1975 and 1976 Bureau o f Land Management Use o f 2 ,4 ,5 -T , S ilvex and 2,4-D (c h a rt) Map - W illam ette In d u s trie s L e tte r to Mr. Jay G iles EPA dated Oct. 1, 1979 from Neil T. S k ill F orest P ra c tic e s D ire c to r, F o restry Dept. Oregon tra n s m ittin g copy o f Computer P rin to u t Computer P rin t Out L e tte r to Bonnie H ill dated March 31, 1980 in re to data requested from Laurence R. F o s te r, M.D., Oregon Department o f Human Resources Health Division fo r Informal Map - Salem Map - Alsea Map - Alsea Map - Alsea Map - Alsea Map - Alsea Map - Alsea Map - Alsea 17750 rii-KA uuLNti n u . "h d , ex; ai. 2,4,5-T & Si 1vex Cancellation NO. DATE 493a(6) 5-30-80 493b II 493c 1 493d 493e(l) II II 493e(2) II 494 5-29-80 495 6-6-80 496 II 497 197a 497b 497c 497d 498a 498b 498c 499 II 11 II II II II II II ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION ST Map - A!sea Oregon I L e tte r to Mrs. Bonnie H ill dated March 10, 1980 from Ned H. Davis D i s t r i c t Ranger, U.S. Department o f A g ric u ltu re II C hart (showing Year, T ri Number, A cres, Form ulation o f 2 ,4 ,5 -T Sprayed) Bureau o f Land Management Spray Data Map - Alsea 1 II II Map - Salem D i s t r i c t T ran sp o rtatio n Plan D irect Testimony o f Dr. Ian C.T. Nisbet It II D irec t Testimony Of Mr. James R. Yowell II 20"x20" enlargement of a e ria l photo taken April 19, 1980, with overlay in d icatin g the locations o f the ap p licatio n s i t e , soybean damage, and ad jacen t crops II Photo re p o rt prepared fo r EPA by th e Remote Sensing L aboratory, LockheedEngineering and Management S ervices Comoany II Photo taken A pril 19, 1980, w ith overlay in d ic a tin g property and crop II Ownership Photo taken April 19, 1980, with overlay in d icatin g areas o f herbicide II a p p lic a tio n and crop damage Photo taken April 19, 1980, with overlay in d icatin g selected physical and C ultural fea tu res Photo taken April 19, 1980, with overlay in d icatin g ric e fie ld ir r ig a tio n and drainage flow II ll Photo taken March 10, 1980 looking e a s t across Casey r ic e f i e l d II Photo taken March 10, 1980 looking n o rth e a st from Beasley soybean field II Photo taken March 10, 1980 lookipg west across Beasley soybean field II Record o f Custom A pplication with 2,4-D , 2 ,4 ,5 -T , o r o th er Hormone-type h e rb ic id e , Don Spurlock, Heth Flying S e rv ice , August 7, 1979 JM NO. 500a DATE 6-6-80 500b 500c " 501a 501b 501c 501 d iOle 501 f II 502 503 504 505 506 FIFRA DOCKET NO. 415, et al. 2,4,5-T & Si 1vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION STATU Record o f Communication Memoranda Prepared by Jim Yowell dated A pril 10, 1980 I Record o f Conmunication Memoranda prepared b y 'Jim Yowell A pril 24, 1980 " Record o f Communication Memoranda prepared by Jim Yowell dated May 15, 1980 " Transvaal Brush-Rhap A-4T L abel, EPA Reg. No. 11687-13, accepted Feb. 14, 1972 " L e tte r from A. E. S id w e ll, D irecto r o f Research, T ran sv aal, In c. " to EPA Fungicide-H erbicide Branch, and attachm ent, November 20, 1972 Memo from T. E. Adamczyk, Acting C hief, Fungicide-H erbicide Branch to f i l e s , Dec. 20, 1972 " L e tte r from James L. Skaptason, C hief, Products Control Branch to Vertac, In c ., concerning tra n sfe r of P esticide R egisterations from T ran sv aal, I n c ., to V ertac, I n c ., Dec. 8 , 1976 " Vertac Brush-Rhap A-4T L abel, EPA Reg. No. 39511-17, accepted Sept. 27, 1979 " A pplication fo r Supplemental R e g istra tio n o f D is trib u to r No. i ' 39511-17-1386, subm itted by Universal C ooperatives, In c. approved Sept. 26, 1978 " Dow DMA 4 H erbicide L abel, EPA Reg. No. 464-196, accepted May 16, 1979 " Regulations o f 2,4-D, 2 ,4 ,5 -T , and o th er hormone-type h erbicides adopted under Acts 389 and 410 o f 1975 by th e Arkansas S ta te P lan t Board on Dec. 5, 1975 and amended Dec. 9, 1977, C irc u la r 9-A, Arkansas S ta te P lan t Board " A irc ra ft Inspection fo r C e rtific a te to Apply 2,4-D , 2 ,4 ,5 -T , o r o th e r hormone-type H erbicide, Mr. E rnest H i l l, March 23, 1979 " Form 1004, Arkansas S ta te P lan t Board, 2,4-D , e t c . , Complaint subm itted by Mr. Thomas B easley, August 27, 1979 " Report o f In sp ectio n on 2,4-D , e t c . , Com plaint, f i le d by Mr. E rnest H i l l , August 27, 1979 " 17752 ni-KA DUCKET NO. 415, et al. 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PR'OTEcW U N A G E N C Y EXHIBITS NO. DATE_____________ DESCRIPTION STATU 507 6-6-80 Soybean D iseases A tla s , Published by th e Cooperative Extension S e rv ic e , U n iv ersity o f A rkansas, copy o f page 18 concerning "Phenoxy H erbicide Injury" (The e n tir e Soybean Disease A tlas is l i s t e d as Reference 1) In 508 L e tte r from Ralph Pay, Arkansas S ta te P la n t Board, to Heth FTying S e rv ic e , September 7 , 1979 509 Photo taken March 10, 1980 o f access ro ad , ric e f i e l d , and soybean fie ld 510a Photo taken March 10, 1980 o f soybean stu b b le showing ad v en tito u s root formation 510b Photo taken March 10, 1980 o f soybean stu b b le showing adventnetious root formation 511a Close-up photo o f sample o f soybean stu b b le taken March 10, 1980 511b Close-up photo o f sample o f soybean stu b b le taken March 10, 1980 12 Samples o f Soybean stu b b le c o lle c te d by Jim Yowell from Beasley soybean f i e l d on March 10, 1980. (brown Box f i le d in Expando) 513 6-12-80 514 515 516 517a 517b D irect Testimony o f Dr. Connie J . Stone Lavy, T. L. P ro je c t Completion Report to National F o rest Products A ssociation. Measurement o f 2,4,5-T Exposure o f F orest Workers. August 30 to Oct. 3, 1978 Ramsey, J .C ., Lavy. T. L ., and Braun, W.H. Exposure o f F o rest Workers to 2 ,4 ,5 -T : C alculated Dose Levels. Simpson, G .R ., H iggins, V ., Chapman, J . , and Bermingerham, S. 1978. Exposure o f Council and F o restry Workers to 2 ,4 ,5 -T . Med. J . Aust 2: 536-537 Kolmodin-Hedman, B ., Erne, K ., Hakansson, M., and E g q v ist, A. 1979. Control o f Occupational ExDOSure to Phenoxy Acids (2,4-D and 2 ,4 ,5 -T ) I Vetenskaplig S k rifts e rie 1979:17 Kontroll av yrkesmassig exponering fo r Fenoxisyror (2,4,-D och 2 ,4 ,5 -T - B ir g itta Kolmodin-hedman, Kurt Erne, Marianne Hakansson och Anita Engqvist 17753 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PROTECTION AGENCY. . EXHIBITS !0. DATE_________________________DESCRIPTION_______________________________________________ S] 518 6-12-80 D irect Testimony o f Mr. Frank P. Beck J r . Ir 519 " General Highway Map, Washington County, M is s is s ip p i, marked to Indicate location of the site 520 " M ississippi Dept, o f A griculture and Conferee, Div. o f P lant In d u stry , A p p lic a to r's Report o f th e A pplication o f HormoneType H erbicides by A irplane (2,4-D , 2 ,4 ,5-T, e t c .) Ju ly 17, 1979 521a " L e tte r from P h ilip D. Lewis, Lewis Bros. Flying S e rv ic e , dtd May 19, 1980 521b " L e tte r from W. G. Boykin, T rip le B. Farms, to Frank Beck, dtd May 20, 1980 522 " Label fo r Amchem Amine 2 ,4 ,5-T fo r R ice, EPA Reg. No. 264-86 523 " T est o f M ississippi Code, Sections 69-21-1 to 69-21-27, concerning Regulation o f Crop Spraying by A irc ra ft 524 " M ississip p i Department o f A g ricu ltu re and Commerce, Div. o f P la n t In d u stry , R egulations Governing the A pplication o f Hormone-Type H erbicides by A ir c r a f t, as amended, Dec. 12, 1974 525 " M ississip p i Department o f A g ricu ltu re and Commerce, D ivision o f Plant Industry, Requirements fo r A erial A pplicators to Obtain a License to Apply Hormone-Type H erbicides 526 " M ississip p i Department o f A g ricu ltu re and Commerce, D ivision o f P la n t In d u stry , A erial A pplication o f Hormone H e rb icid es: Study Guide. 527 " M ississip p i Department o f A g ricu ltu re and Commerce, D ivision of Plant Industry, C ertificate of A ircraft Inspection for Lewis Bros. Flying S e rv ice , April 6, 1979 528 " L e tte r from Roy Reid, Area P est Management S p e c ia lis t, M ississip p i Cooperative Extension S e rv ice , S to n e v ille , M iss is s ip p i, to Mike Peeples, D ivision o f P lant Industry, M ississippi Department of A g ric u ltu re , May 19, 1980 529 " Magazine a r t i c e e n ti t le d "Drop boom" boosts accuracy and improves Coverage," in Custom A p p lic a to rs, F ebrurary, 1980, p. 111-115 529b-l th ru b5 5 Photos o f Lewis Bros. Flying S ervice A irc ra ft 17754 4 V - ' \ - NO. DATE 530 6-12-80 531 532 533a-c " 533d-f " 534 535 6-17-80 36a 536b 537 538 539a 539b 540a 540b n r K M UUUML1 NU. `H D , et a l . 2,4,5-T & Silvex Cancellation *ENVIRONMENTAL PROTECTION AGENCY ' ' " ` EXHIBITS " DESCRIPTION Sketch o f a p p lic a tio n S ite and damaged crops by Mike P eep les, D ivision of P lant Industry M ississippi Department of A g ric u ltu re and Commerce, A pril 16, 1980 ST I M ississip p i Department o f A g ricu ltu re and Conmerce, D ivision o f P lan t In d u stry , Report o f the Inspection of Crops fo r the presence o f in ju ry re s u ltin g from A erial A pplication o f Hormone-Type H erb icid es, August 1, 1979 " Color Photograph taken August 1, 1979 looking south across Mr. Wood's " soybean and cotton f ie ld s . Color photographs taken August 1, 1979 o f 2 ,4,5-T damage in Mr. Wood's soybean f i e l d " Color photographs taken August 1, 1979 o f Mr. Woods' co tto n f i e l d and damaged c o tto n . " Color photograph taken August 1, 1979 looking north a cro ss Mr. Woods' co tto n and soybean f i e l d s . D irect Testimony o f Dr. Rainer Frentzel-Beyme " " P ro fesso r A lfred M. Thiess & Dr. R. Fretzel-Beym e, Department of Occupational Medicine & Health P ro te c tio n , BASF A k tie n g e se llsc h a ft, Ludwigshafen AM Rhein, West Germany. M o rta lity Study of Persons Exposed to Dioxin Following an Accident Which Occurred in the BASF on 13 November 1953 Table - Cancer deaths o f the BASF Dioxin stu d y , by s i t e and morphology of malignancy M o rtality of Persons Exposed to Dioxin during an A ccident which Occurred in th e BASF AG on November 17, 1953' T ables: A dditional Data from follow -up of BASF dioxin study Schwerste akute Chloracne, eine M assenintoxikation durch 2 ,3 ,6 ,7 -T e tra c h lo rd ib e n z o d io x in , by Paul J . Goldmann Severe Acute Chloracne. A Mass In to x ic a tio n by 2 ,3 ,6 ,7 T etrachlorobenzodioxin, by Paul J . Goldmann 1 Follow-up Report uber das Trichlorphenol-D ioxin-Unfallgeschehen in der BASF AG vom 13. November 1953 Follow-up Report on th e T richlorophenol-D ioxin Accident a t BASF AG on 13 November 1953, by A.M. T hiess and P. Goldmann * 17755 Z,4,b-i & Silvex cancellation ENviRONMEMTAL- ''PROTECTION AGENCY-' EXHIBITS NO. DATE DESCRIPTION STA 541 6-18-80 D irect Testimony o f Dr. Kirk T. K itchin I 542 " Induction o f M ultiple Forms o f Mouse L iver Cytochrome P-450 " 543 " 2,3,7,8-T etrachlorodibenzo-p-D ioxin Induction o f Aryl Hydrocarbon " Hydroxylase in Femlae Rat L iver. Evidence f o r De Novo Synthesis o f Cytochrome P-448, by Kirk T. K itchin and James S. Woods 544 " Induction and Suppression o f Hepatic and E x trah ep atic Microsomal " Foreign-Compound-Metabolizing Enzyme Systems by 2 ,3 ,7 ,8 -T e tra chlorodibenzo-p-D ioxin, by G.F.R. Hook, J.K , Haseman and G.W. Lucier 545 Induction o f Aryl Hydrocarbon Hydroxylase A ctiv ity in Various " Cell C ultures by 2 ,3 ,7 ,8 -T etrac h lo ro d ib e n zo -p -d io x in 546 Comparison o f 2 ,3 ,7 ,8 -T etrach lo ro d ib en zo -p -d io x in , a Potent " Inducer o f Aryl Hudrocarbon Hydroxylase, with 3-M ethylcholanthrene 547 T ransplacental Induction o f Mixed-Function Oxygenases in Extra- " H epatic T issues by 2,3,7,8 -T etrach o ro rd ib en zo -p -D io x in 548 2 .3 .7 .8 - T etrachlorodibenxo-p-D ioxin (TCDD) E ffe cts on Hepatic " Microsomal Cytochrome P-448-Mediated Enzyme A c tiv itie s ' 2 549 TCDD- Induced Changes in Rat L iver Microsomal Enzymes, by G.W. " Lucier, e t a l . 550 Sex-Dependent Regulation o f Benzo[a]Pyrene and Zoxazolamine " Metabolism in Rat T issu e s, Hira L. Gurtoo and N a ta lie Bejba Parker 551 T ransplacental Inducution o f Carcinogen-Hydroxylating Systems with " 2 .3 .7 .8 - T etrachlorodibenxo-p-dioxin ' 2 , by David L. B erry, e t a l . 552 Organ S p e c ific Induction of Drug M etabolizing Enzymes by 2 ,3 ,7 ,8 - " T etrachlorodibenzo-p-dioxin in the Rat 553 Q u a n tita tiv e and Q u altativ e Changes in the Metabolism o f Benzo(a) " pyrene in Rat T issues a f t e r I n tr a g a s tr ie A dm inistration o f TCDD 554 P o stn atal S tim u latio n o f H epatic Microsomal Enzymes Following " A dm inistration o f TCDD to Pregnant Rats 555 Studies on th e Mechanism o f T o x icity o f the C hlorinated Dibenzo-p- " d io x in s, by Alan Poland and Edward Glover 556 " S e lec tio n o f Inducers: An Im portant F actor in C h aracterizin g " Genetic D ifferences to Induction o f Aryl Hyrdocarbon Hydroxylase in S tra in s of Mice, Rajendra S. Chhabra, e t a l . 17756 i 1 1 r\n u u u i \ c i n u . *ti j j c u o i . 2,4,5-T & Silvex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS W! DAT 557 6-18-80 558 " 559 6-24-80 560 " 561 " 562 6-25-80 563 " 564 6-27-80 564A " 565 566 567 568 569 570 571 572 DESCRIPTION STATI Chlorinated Dibenzo-p-dioxins: Potent Inducers of o-Aminolevulinic Acid S ynthetase and ARyl Hydrocarbon Hydroxylase I I . A Study of th e S tru c tu re -A c tiv ity R e la tio n sh ip , Alan Poland & Edward Glover In E ffe c ts o f Microsomal Enzyme Inducers IN VIVO and In h ib ito rs IN VITRO " on th e Covalent Binding of Benzo[a]Pyrene M etabolites to DNA Catalyzed by L iver Microsomes from G e n e tic a lly Responsive and Nonresponsive Mice, Alan R. Boobis, e t a l . D irect Testimony o f Dr. Joseph F ranklin Holson U tility o f Pharmacokinetics in Designing Toxicological Protocols and Improving In te rsp e c ie s E x tra p o la tio n , John F. Young and Joseph F. Holson Data Tables from NCTR T eratology Study o f Technical and P u rifie d Grades o f 2,4,5-T Report to Veterans A dm inistration c/o Lawrence B. Hobson, M.D. Ph.D ., Trace A nalysis of T etrachlorodibenzo-p-dioxin (TCDD) in Human Adipose by Michael L. G ross, P ro fesso r and D irecto r 2-13-80 TCDD (2 ,3 ,7 ,8 -T e tra c h lo rd ib e n z o -p -d io x in ) in Body Fat of Vietnam Veteran and Others D irect Testimony o f Dr. George S tre is in g e r D irect Testimony o f Dr. George S tre is in g e r (ADDENDUM) L tr dtd 17 Oct 1977 to Mr. J e rry MacLeod, B io lo g is t from Michael Watson, Ph.D. L tr dtd 6/4/79 to Mr. David Graham, USDA, F o rest Service from Aubry E. Dupuy, J r . , Ph.D ., Chemist Memo to Hugh Black, U.S. F orest S e rv ice , from Dave Z einer dtd December 8,1978 w/Deer Tissue-Phenoxy H erbicide Study Animal H istory L tr dtd January 28, 1974 Sioxin'M eeting - December 13, 1973 L tr dtd March 13, 74 Mr. C arroll W. C o llie r "Dioxin Meeting, Washington, D.C. December 13, 1973, Beef Fat Phase II Three-G eneration Reproduction Study of Rats Given 2 ,3 ,7 ,8 -T e tra chlorodibenzo-p-D ioxin (TCDD) in the D ie t, F .J . Murray, e t a l . 17757 NO. DATE 573 6-27-80 574 9-23-80 575 579 7-1-80 580 " 581 582 583 584 7-3-80 585 586 587 7-7-80 2,4,5-T & Si!vex Cancellation ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION 2 ,3 ,7 ,8 -T etrach lo ro d ib en zo -p -D io x in (TCDD): R esults o f a 13-Week Oral T o x ic ity Study in R a ts ', R .J. K ocira, e t a l. ST L tr to Dr. C.B. Hiremath tra n sm ittin g a copy o f Promoting Action o f TCDD In H epatocarcinogenesis 2',;3 ,7,8-T etrachlorodibenzo-p-dioxin as Cocarcinogen Causing 3M e ty ch o la n th re n e -in itia te d Subcutaneous Tumors in Mice G en etically "Nonresponsive" a t Ah Locus' H isto ric a l Control Data - Study No. 4 Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-D ioxin fo r Possible C arcinogenicity (Gavage Study) Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-D ioxin for Possible C arcin o g en icity (Dermal Study) D irect Testimony o f Dr. A rthur W. Galston Photodecomposition of 2,4,5-T richlorophenoxyacetic Acid 2,4,5-T in Water Residues o f Chlorophenoxy Acid H erbicides and T heir Phenolic M etabolites in T issues of Sheep and C a ttle Degradation o f 2 ,4 ,5 -T rich lo ro p h en o x y acetic Acid in Woody P lan ts by Charles H. F itz g e ra ld , e t a l . Ecological C onsiderations Regarding Massive Environmental Contamination with 2,3,7,8-T etrachlorodibenzo-para-D ioxin D irect Testimony o f Dr. Matthew Meselson Memorandum o f Telephone Conversation between Dr. P a tric k O'Keefe Department of Chem istry, Harvard U n iv ersity and Dr. David F ire sto n e, A nalytical Chemistry and Physics Branch in re Analysis o f Low Levels (p a rts per t r i l l i o n and sub p a rts per t r i l l i o n ) o f TCDD (2 ,3 ,7 ,8 -te tra c h lo ro d ib e n z o -p -d io x in ) in Human Milk Light and E lectron M icroscopic O bservations in Macaca M ulatta Monkeys fed Toxic F a t, J r . R. A llen , D.V.M., Ph.D ., and L.A. C arstens, B.S. D irect Testimony o f Dr. 01av Axel son It 17758 Q_\ NO. DATE 588 7-7-80 589 590a 590b 591a 591b 592 593a 593b 593c 593d 593e 594 595a 595b 596a 596b 597a 597b " 598 " II DESCRIPTION STATUS H erbicide Exposure, M o rta lity and Tumor Incidence. An Epidem iological In In v e s tig a tio n On Swedish R ailroad Workers Aspects On Confounding In Occupational Health Epidemiology " Fenoxisyror Och Cancer " Phenoxy Acids and Cancer " H erbicide Exposure and Tumor M o rta lity " H erbicide Exposure and Tumor M o rta lity ; an Updated Epidem iological In v e s tig a tio n On Swedish R ailroad Workers " A nalysis o f Some Older Scandinavian Form ulations o f 2,4-Dichlorophenoxy " A cetic Acid and 2,4,5-T richlorophenoxy A cetic Acid For Contents of Chlorinated Dibenzo-p-dioxins and Dibenzofurans Epidemiologisk metodik och bekampningsmedelsstudier " S ta tu s : MSG: 202 (L is tin g from 1 to 173) Epidemiologic Methodology And P e s tic id e S tudies " Epidem iologisk Metodik - Synpunkter PA K ritik Over Bekampni ngsm edelsstudi e r " Epidemiologic Methodology - Views On C ritic ism Of P e s tic id e S tu d ies " Case-Control Study: S oft-T issue Sarcomas and Exposure to Phenoxyacetic " Acids Or Chlorophenols C ase-C ontrol-studie Over maligna mesenkymala mjukdelstumorer och ex p o sitio n fo r kemiska su b stan ser " Case-Control Study on M alignant Mesenchymal Tumors o f th e S o ft T issue and Exposure To Chemical Substances " Maligna lymfom och ex p o sitio n f o r kemiska su b sta n se r, s a r s k i l t organiska losnigsm edel, k lo rfen o ler och fenoxisyror M alignant Lymphoma and Exposure To Chemical Substances, E sp e cially Organic S o lv e n ts, Chlorophenols and Phenoxy Acids < A Note on O bservational Bias In Case R eferent Studies In Occupational Health Epidemiology " " A Note on O bservational Bias In C ase-R eferent S tudies In Occupational " Health Epidemiology Symptomatology, M orbidity and M o rtality Experience o f C hlorinated " Phenoxyacid Herbicide (2,4-D; 2,4,5-T ) sprayers in Finland. A C linical and epidem iological Study 17759 2,4,5-T & Silvex Cancellation NO. DATE 617 7-9-80 618 619 620 621 622 7-10-80 623 624 625 626 627 628 629 630 631 632 633 634 635 DESCRIPTION STA' L e tte r to Stevens Van Strum concerning lack o f spray records f o r Lane County f o r ro ad sid e sp ray in g , 1974 th ru 1976 In U n iv ersity o f Oregon Medical School records o f Irene D urbin's d eliv ery of youngest son " U niversity o f Oregon Medical Records concerning her youngest son surrounding h is b irth (Lyle George Durbin) " Resume o f O ffice V is its o f Lyle George Durbin, Dr. Reed McNeal, M.D. " Medical Records Concerning James P a tric k and Kim K erstin Durbin, 1974 and 1975, Dr. Reed McNeal, M.D. " D irect Testimony o f Gail S lentz " B1M, Coos Bay D i s t r i c t , Smith-Umpqua Resource Area Map " U.S. Geological Survey Topographical Map o f re le v a n t p o rtio n o f Roman Nose Quadrangle " Spray Data from Bureau o f Land Management f o r 2 2-acre t r a c t in q u e stio n , f o r 1975 and 1977 " Medical Records fo r Gail S le n tz , Sacred Heart H o sp ital, Feb. 13, 1978 " Medical Records f o r Gail S le n tz , Dr. Alan Cohn, Feb. 16, 1978 L aboratory A nalysis R eport, GHT L ab o rato ries o f Im perial V alley , C a lifo rn ia D-10831 Laboratory A nalysis R eport, GHT L aboratories o f Im perial V alley, C a lifo rn ia 000169-E Medical Records o f Gail S le n tz , Dr. Sarah Hendriskson, A pr.5, 1978 L tr to NCAP dtd A pril 11, 1980 in re to I t r dated A pril 8 , 1980 from Robert W. B rig h t, U.S. Department o f I n te r io r D irect Testimony o f P h issis Cribby T ra n sc rip t o f BLM spray o p eratio n by Chetco ranger d i s t r i c t inspector, 4-9-75 ' Contractor Performance Rating Sheet fo r Forest Service Contract 11-10428-8 Report to F ile s , In sp e cto r Robert T urner, 3-14-75, Gold Beach Ranger D is tric t 17760 n r r w uu^Nci NU. `H O , et ai. 2,4,5-T & Si 1vex Cancellation NO. 599a DATE 7-7-80 599b 600 7-9-80 601 602 603 604 605 606 " 607 " 608 609 610 611 612 613 614 615 616 DESCRIPTION STATUS XXXVI L ak a resa llsk ap e ts Riksstamma anordnad av Svenska L a k a re sa ll- In skapet pa Stockholmsmassa, A lv sjo , Stockholm 5-8-dec 1979 XXXVI N ational Conference Of The Medical Society Sponsored By The Swedish Medical Society At Stockholmsmassan, A lvsjo, Stockholm, 5-8 December 1979 " D irect Testimony o f Pat Clary '* Bureau o f Land Management, Roseburg D i s t r i c t Map (S to u ts Creek watershed area) " U.S. G eological Survey topographical map o f S touts Creek w atershed area " Spray data from BLM, S to u ts Creek, A p ril, 1976 " A ffid a v it from Ju d ith Kahle concerning response o f Roseburg Lumber " to request fo r spray information Medical Records fo r P a tric ia C lary, spring o f 1976, 4-4-76, Dr. Monson " Medical Records fo r P a tr ic ia Clary 5-12-76 and 5-28-76 Dr. Grosso Oregon Department o f A g ricu ltu re Laboratory A nalysis R eport, Lab. Number 10653 Medical Records fo r Aisha C andrian, November, 1977, Douglas Comm. H ospital " Medical Records fo r P a tr ic ia C lary, June o f 1978, Dr. Falk " D irect Testimony of Irene Durbin " See Map, (E x h ib it No. 616) " L e tte r o f March, 1979, from David W hite, Lane County Health Department to Irene Durbin " EPA E x h ib it No. 223, p. 16,17,18, S ite #9 Sample analyzed by Research T riangl Park, and U niversity of Nebraska L aboratories l Responses by th e U.S. F o rest S e rv ice , Alsea D i s t r i c t to In te rro g a to ry #25, C..A.T.S. v. Berg!and (D.Or. 1977) 428 F;S. 908 " A erial Maps " Alsea D i s t r i c t map with overlays of roadside and a re a l spray s i t e s " 1974 through 1976 2,4,5-T & Sil vex Cancellation NO. DATE 636 7-10-80 637 " 638 639 640 641 642 643 644 645 646 647 648 649 DESCRIPTION Contract Daily Diary, 8-30-75, 3-31-75, 9-10-75 Handwritten re p o rt on C ontract 11-10466-S by Suskiyou C ontracting O fficer Report on H erbicide S p i l l , Gold Beach D i s t r i c t 4-28-76 by F o re st P e s tic id e Use C oordinator Handwritten re p o rt o f s p i l l describ ed in PHC-7 C ontract D aily D iary, A pril 2 0 - 2 7 , 1976 on C ontract 11-10485-S Determ ination o f N on-R esponsibility, 1977, U.S. F o rest S erv ice, Region 6 O ffice L e tte r from Siskiyou C ontracting O ffic e r, 4-19-76 fin d C o rv allis Aero Service Non-Responsible C ontract 53-0401-9-12 Chetco Ranger D i s t r i c t and C o rv a llis Aero Services, Inc. Payment Invoice f o r C ontract in PHC-12 Incident Report, Contract 53-101-8-6, Siskiyou National F orest, 4-27-78 C ontract D aily D iary, 4-29-78 on C ontract 11-1-485-S D irec t Testimony o f Norma G rier U.S. Geological Survey Topographical Map o f French Creek watershed area Oregon Department o f A g ric u ltu re Water Sample Laboratory A nalysis Report #05427 through 05430, PARC 3 STA In " II IV II NO. DATE 650 7-15-80 651 652 653 654 7-17-80 654A 655 656 657 658 659 660 661 662 663 664 7/21/80 665 666 667 " 668 7-24-80 668-1 668-2 669 670 DESCRIPTION STA D ire c t Testimony o f Mr. J e re C h ristn e r In Map (w ater sampling s i t e ) Lowell Ranger D is tr ic t W illam ette N ational " F o re st Oregon Water Sample A nalysis R esults " Samples A fte r Spraying On Day o f Spraying " D ire c t Testimony o f Dr. Logan N orris Corrections or C larificatio n s The B iologic and Economic Assessment o f 2 ,4 ,5-T- A Report o f the USDA-States-EPA 2 ,4 ,5-T RPAR Assessment Team, Feb. 15, 1979 (Expando) It H erbicide Residues in A ir, A!sea Basin - 1977 II Impact o f 2 ,4 ,5-T on B lodgett F o re st - D escription o f an Experimental " A erial A pplication o f 2 ,4 ,5-T The P e rsiste n ce o f 2 ,4 ,5-T in a P a c ific Northwest F orest II P ersiste n ce o f 2,4-D and 2 ,4 ,5-T in Chaparral Soil and Vegetation Update on Data From 2 ,4 ,5-T Study In A West V irg in ia Watershed dated June 16, 1980 TCDD P e rsiste n c e In Low L ight I n te n s itie s - O ffice R ep o rt'7 /1 /8 0 " TCDD In Fish From Oregon F o re st Streams - O ffice Report 7/1/80 " The Response o f Coho Salmon and Guppies to 2 ,3 ,7 ,8 -te tra c h lo ro d ib e n z o - " p-d io x in (TCDD) in Water D irec t Testimony o f Mr. Lavell 0. S tran g er " Siskiyou N ational F o rest - H erbicide A pplicators Handbook " H erbicide Methods " D ivision 100 - General S p e c ific a tio n s - C ontractor fu rn ish ed Property and Services D irect Testimony o f Alvin L. Young, Major, USAF P o rtio n s o f D irect Testimony and E xhibits o f Major Alvin Young S ubject to Motion To Exclude P rin ts of 41 s lid e s shown by Dr. Young Ju ly 22, 1980 P e rs is te n c e , Bioaccumulation and Toxicology of TCDD In an Ecosystem T reated With Massive Q uanities o f 2 ,4 ,5-T H erbicide Ecological Studies On A Herbicide-Equipment T est Area (TA C-52A) Eglin AFB R eservation, F lo rid a , Jan. 1974 17763 NO. DATE 671 7-24-80 672 673 674 675 676 7/25/80 678 679 680 681 682 683 684 685 686 687 688 689 690 " 691 9/4/80 692 " n r r s r t u u l m i I NU. < f l 3 , et ai. 2,4,5-T & Silvex Cancellation DESCRIPTION ST/ F ield S tudies o f W ild life Exposed to TCDD Contaminated S o ils IN Studies o f the Ecological Impact of R epetitive Aerial Applications " Of H erbicides On The Ecosystem o f T e s t Area C-52A, E lgin AFB, F lo rid a Fate o f 2 ,3 ,7 ,8 -T etrach lo ro d ib en so -p -D io x in (TCDD) In th e Environment " Summary and Decontamination Recommendations Residual Levels o f 2 ,3 ,7 ,8 -T etrach lo ro d ib en zo -p -D io x in (TCDD) Near H erbicide Storage and Loading Areas a t E lgin AFB, F lo rid a " H isto p ath o lo g ical and U ltra s tru e tu a l S tudies o f L iver T issue From TCDD " Exposed Beach Mice (Peromyscus Polionotus) D irect Testimony o f Dr. Rodney w. Bovey " Control o f Live Oak by H erbicides Applied a t Various Rates and Dates Control o f Huisache and A ssociated Woody Species In South Texas H erbicide Combinations f o r Woody P la n t Control The Use o f A Woody P la n t Nursery In H erbicide Research Hormone-like H erbicides In Weed Control Control o f Yaupon and A ssociated Species D aily and Seasonal Response o f Huisache and Macartney Rose to H erbicides Response o f S elected Woody P la n ts In The United S ta te s to H erbicides In E ffe c t o f Paraquat and 2 ,4 ,5 -T on the Uptake and T ransport o f Picloram " in Woody P lan ts P ersistence o f 2,4,5-T in Grasslands of Texas " Occurrence o f 2,4,5-T and Picloram in Surface Runoff Water In the Black!ands of Texas Occrrence o f 2,4 ,5-T and Picloram in Subsurface Water In the Blacklands " of Texas Chemical Control o f Mesquite . D irect Testimony o f Mr. David A. Graham Memorandum o f Understanding between the U.S. Department o f A g ricu ltu re " and th e U.S. Environmental P ro te c tio n Agency dtd Dec. 2, 1976, and Supplement dated Oct 14/18, 1977 17764 NO. DATE 693 9/4/80 694 695 696 697 698 698a 10-9-80 699 699-A 699B 700 701 702 703 704 FIFRA DOCKET NO. 415, et al. 2, 4, 5-T & Sil vex Cancellation U.S. Environmental P ro te c tio n Agency E x h ib its DESCRIPTION statu: USDA-Forest S e rv ice , June 11, 1980, l e t t e r to th e Record "2,4,5_T Use on N ational F o re st System Lands." In Report o f the F o rest S e rv ic e , F isca l Year 1977, USDA, Feb. 15, 1978, P a rt I I I E. P e s tic id e Use. " Summary o f Phenoxy H erbicides in Water. F o rest S ervice I t e r from Region 6 to C hief, June 23, 1980 " Progress Report - B iological Assessment of Herbicide Treatment on a Pine-hardwood Ecosystem, James R. Dickson, USDA-Forest S e rv ic e , 1978 " Feeding Preferences o f Deer fo r Selected H erbicide Treated V egetation, Campbell, Dan L. e t . a l . , 1980, USDA-Fish and W ild life S e rv ice , Forest-Animal Damage Control Research P ro je c t, Olympia, Washington USDA-Forest S e rv ice , l e t t e r to the Record, "1978 ^ e Management y lum from Edwin L. Johnson to th e Dioxin Im plementation Task Force with attach ed Dioxin: P o sitio n Document, D raft April 26, 1977, Dioxin Working Group, U.S. Environmental P ro te c tio n Agency S ta te o f C a lifo rn ia , Department o f H ealth, Memorandum to th e Record from Dwayne Reed, MD e t al on "Epidemiologic In v e s tig a tio n o f Reports o f Abnormal Outcome o f Pregnancies in Denny, CA," March 21, 1979 U n iv ersity o f Iowa, College o f M edicine, l e t t e r from D.P. Morgan to Lee L eiserso n , Feb. 20, 1979, w ith attach ed re p o rt e n title d "Report on In v e s tig a tio n o f Alleged Phenoxy H erbicide E ffe c ts On Persons Residing in Six Rivers and T rin ity F orest Areas o f C a lif." Environmental P ro te c tio n Agency N ational Interim Primary Drinking Water R egulations 40 CFR 141; 40 CFR 59565, 12/24/75; Amended by 41 FR 28402, Ju ly 9, 1976; 44 FR 68641, Nov. 29, 1979 Department o f A g ricu ltu re Federal Agency Plan: C e rtif ic a tio n o f A pp licato rs o f R estricted-U se P e s tic id e s . 45 FR 21703, Apr. 2 , 1980 F o re st Service Manual, Chapters 2140 and 2150, Oct. 1979 F orest P est Management-Washington O ffic e , P e stic id e Incidents Report-" ed F iscal Year 1980, USDA-Forest S ervice F orest Service l e t t e r to C hief from Region 5, "P e sticid es Incidents" " w ith e n clo su re , March 14, 1980 17765 NO. DATE 705 9-4-80 706 707 708 709 710 711 712 713 714 715 716 717 718 2,4,5-T & Silvex Cancellation ...U. S.. ENVIRONMENTAL PROTECTION AGENCYEXHIBITS DESCRIPTION F o rest S ervice l e t t e r from Zane Sm ith, Regional F o re ste r to C hief, January 18, 1980, r e la tin g to Tordon 101R in c id e n t on th e Six Rivers N ational F o rest (2) Claim o f Richard C. O verholt a g a in s t Humbolt County, C a lifo rn ia w ith appended 12/5/79 re p o rt by Jon Resenberg, M.D. f i le d by Harland and Gromala, a tto rn e y s . Recieved by County C lerk on Jan. 11, 1980. (3) F o rest S ervice I t r from Zane Smith to C h ief, June 9, 1980, fowarding re p o rt on the Six Rivers N ational F o re st Tordon 101R in c id e n t STATl In " F o rest S ervice Nov. 13, 1978, l e t t e r to Douglas M. C o stle , EPA EPA's Nov. 29, 1978 response to John R. McGuire, C h ief, F o rest S ervice signed by A. E. Conroy I I . F o rest S ervice Jan . 12, 1979 l e t t e r to Douglas M. C o stle , EPA. " F o re st S ervice Health and S afety Code (FSH 6709.11) USDA F o rest Service, June 1979, pp. 339-343. " F o re st S ervice Manual, Chapter 1950, Feb. 1980 " F o re st S ervice Handbood 1909.15, "The NEPA Process Handbook " F orest S ervice Advisory Memorandum No. 206 Summary o f correspondence " received on 2 ,4 ,5-T is s u e , Oct. 24, 1978 Example l e t t e r , P riv a te in d iv id u al - H.S. Lovestead to USDA S e c re t- " ary Bob Berg!and, May 24, 1978 Example l e t t e r , non-Forest in d u stry - Richard A. McDougal, P re sid e n t " N ational C attlem en's A sso c ia tio n , to USDA S e c re ta ry Bob B ergland, May 18, 1978 Example l e t t e r , F o rest In d u stry - P h illip D. Chadsey fo r the In d u s tria l F o re stry A ssociation to USDA S e c re tary Bob Bergland, Apr. 27, 1978 " Example l e t t e r , lo cal governments - Board o f County Coranissioners, " Douglas County, Oregon, to Rupert C u tle r, a s s is ta n t D irecto r (Sec.) of Agriculture F o rest S ervice l e t t e r to th e rec o rd , D.R. Hamel, June 9, 1980Summarizes correspondence received as a r e s u l t o f CATH and NCAP campaign " N ational C o a litio n f o r A lte rn a tiv e s to P e s tic id e s (NCAP) News, Fall 1979, page 9 " C itiz en s A gainst Toxic H erbicides (CATH), Issu e A le rt (undated) " CATH l e t t e r to B ill B its a s , NCAP, Oct. 10, 1979 17766 NO. DATE 719 9-4-80 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 II z,4,b-T & Sil vex Cancellation U; .5,-ENVIRONMENTAL PROTECTION-AGENCYEXHIBITS DESCRIPTION STTT Example l e t t e r from CATH and NCAP campaign, Jim Davis to S tu a r t E iz e n s ta t, Dec. 26, 1979 " Example re p ly , F o rest S ervice I t r to Jim Davis, Feb. 7, 1980 " Example I t r to CATH and NCAR campaign, Gary Reiss to Mr. E iz e n s ta t " receiv ed Nov. 29, 1979 Example re p ly , F o rest S ervice l e t t e r to Gary R eiss, Dec. 13, 1979 " P u b lic a tio n o f fin a l Rule, F e d e ra l,:Vol. 43, NO. 175 Sept. 8 , 1978" " "R eservations in A u thority to Apporve H erb icid es." (43 FR 39953) "Apply P e stic id e s C orrectly - A guide fo r commercial a p p lic a to rs ," " USDA and EPA (undated) F o re st S ervice Manual, Chapter 2140, March 1978 " F o rest S ervice Manual, Interim D ire c tiv e No. I , 2140 - P e s tic id e Use Management, 4/27/78 " F o rest S ervice Manual, Interim D irec tiv e NO. I I , 2140 - P e s tic id e Use Management, 5/4/78 " F o rest Service Manual, Interim D ire c tiv e No. I l l , 2140- P e stic id e Use Management, 6/29/78 " F o re st Service Manual, In terim D irec tiv e No. IV, 2 140-P esticid e Use Management, 9/14/78 " F o rest S ervice Manual, Chapter 2140, Feb. 1979 " F o re st S ervice P olicy on P esticid e-U se and C r ite r ia fo r Use o f 2 ,4 ,5 -T and 2,4-D , 45 FR 1650, Ja n . 8 , 1980, and c o rre c tio n , 45 FR 10824, Feb. 18, 1980 " Forest Service l e t t e r to Regional F o re ste rs, S tatio n D irec to rs, and Area D ire c to rs, Aug. 21, 1978 2 ,4,5-T and R elated Compound Risk Inform ation - EPA's RPAR P o sitio n Document No. I " F orest Service I t r to Regional F o re ste rs, S tatio n D irec to rs, and " Area D ire c to rs, Advisory Memorandum No. 196, Ju ly 24, 1978, 2,4,5-T and r e la te d Compound Risk Inform ation - assessm ent o f Hazards by Dr. Frank Dost P esticide-U se Management A c tiv ity Review, P a c ific Northwest Region " USDA-Forest S e rv ice , 1978 F o rest Service Manual Chapter 1410, Ju ly 1978 17767 fT 7X& i ,**,0-1 a iiivex cancellation U,S, ENVIRONMENTAL PROTECTION...AGENCY EXHIBITS NO. DATE____________ DESCRIPTION ___________ ____________________STATU 736 9-5-80 D irec t Testimony o f Dr. Roy J . Sm ith, J r . In 736-1 " 737 Pay, R. L e tte r dated J u ly 23 1980, to Roy J . Sm ith, J r . , USDA, " S t u t t g a r t , A rkansas. In re Use o f 2 ,4 ,5 -T fo r weed control in r ic e in Arkansas 738 Rice M ille r's A ssociation, Rice Acreage in the United S tates (5-Page " re p o rt p re sen tin g r ic e acreage s t a t i s t i c s f o r 1979, published by th e Rice- M ille rs ' A sso c ia tio n , A rlin g to n , V irg in ia ). 1979 739 McCarty, R. l e t t e r dated Ju ly 23, 1980, to Roy J . Smith, J r . , USDA " S tuttgart,A rkansas. Personal conmunication regarding use of 2,4,5-T f o r weed c o n tro l in r ic e in M ississip p i 740 Coley, J.D . l e t t e r dated August 7, 1979, to Document Control O ffic e r " EPA, W ashington, D.C. Use o f 2 ,4 ,5 tT fo r weed co n tro l in r ic e in M ississippi 741 Coley, J.D . l e t t e r dated January 10, 1980, to Hearing C lerk, EPA " Washington, D.C. Use o f 2 ,4,5-T on r ic e in M ississip p i . *2 Coley, J.D . l e t t e r dated January 28, 1980 to Hearing C lerk, EPA " Washington, D.C. Use o f 2 ,4,5-T on r ic e in M ississip p i 743 Ross, J.B . l e t t e r dated August 10, 1979 to Document Control O ffic e r " EPA, Washington, D.C. in re Use o f 2 ,4 ,5 -T fo r weed co n tro l in r ic e in M ississippi 744 Baldwin, F .L ., l e t t e r dated Ju ly 23, 1980, to R .J. Smith, J r . , USDA " S t u t t g a r t , A rkansas, in re Use o f 2 ,4 ,5 -T fo r weed control in r ic e in Arkansas 745 Houston, D.W., l e t t e r dated Ju ly 28, 1980, to Roy J . Smith, J r . , " USDA, S t u t t g a r t , Arkansas. 746 Huey, B .A ., l e t t e r dated Ju ly 21, 1980, to Roy J . Smith, J r . , USDA " S t u t t g a r t , A rkansas, in re Use o f 2 ,4 ,5 -T fo r weed co n tro l in Arkansas I 747 Smith, J.E . l e t t e r dated Ju ly 25, 1980, to Roy J . Sm ith, J r . , USDA " S t u t t g a r t , Arkansas in re Use o f 2 ,4 ,5 -T fo r weed control in r ic e 748 Sm ith, R .J ., J r . , W.T. Flinchum and D.E. Seaman in re Weed Control " in U.S. Rice P roduction, USDA A g ric u ltu re Handbook 497 (R epository No. 442) 1977, pages 14-15, 36-42, and 45-48. ,.9 Arkansas Cooperative Extension S erv ice. Recommended Chemicals fo r " Weed and Brush C ontrol. MP-44. A rkansas, 1980, pages 42-46. 1i n7n7nbno r NO. DATE 750- 9-5-80 751 9-10-80 752 1 753 II 754 II 755 II 756 II 757 U. S. ENVIRONMENTAL PROTECTION AGENCY ' ' EXHIBIT DESCRIPTION '' ' -- -------- STATI October 17, 1978 Memo to C harles Lewis, EPA from Roy J . Sm ith, J r . Subject: Size o f ric e farms in 2,4,5-T use area D irect Testimony o f Dr. Louis F. Bouse Inform ation f o r 2,4 ,5 -T Assessment Team, 1978, L.F. Bouse A erial-Spray P enetration Through Foliage Canopies, Trans, o f the ASAE 1 2 (1 ): 86-89, 1969, L.F. Bouse- D rift Comparisons o f Low-Expansion Foams and Conventional Sprays. Weed Science 21(5): 405-409, 1973, L. F. Bouse and R. E. Leerskov. In II II II II Comparison o f Recoveries from a Tower-Mounted Dual Spray. T rans, o f th e " ASAE 18(3): 467-470, 1975, L.F. Bouse and M. G. Merkle. Spray Recovery From Nozzels Designed to Reduce D r if t. Weed Science 24(4): 361-365, 1976 L. F. Bouse, J.B . C arlton and M.G. Merkle. (R epository USDA No. 70) II D irec t Testimony o f Dr. P h ilip C. Kearney 758 759 9-15-80 760 II 761 II 762 9-30-80 763a II 763b II 764 II 765a II 765b II P e sticid e M obility In S o ils I I . A pplications o f Soil Thin-Layer Chromatography by Charles S. H elling D irect Testimony o f Dr. Robert A lfred Squire II Dow TCDD Chronic T o x ic ity Study In Rats Tumor Incidence Summary Table II H isto lo g ic Typing o f L iver Tumors o f th e Rat D irect Testimony o f Dr. Lennart H arden II II S o ft-T issu e Sarcomas and Exposure To Chemical Substances: A Case Referent Study II Table: Type and d u ratio n o f exposure fo r cases and re fe re n ts exposed to Phenoxyacetic acid s in Eriksson e t a l . 1980 II M alignant lymphoma and exposure to chemical su b sta n c es, e s p e c ia lly organic so lv en ts, chlorophenols and.phenoxy acid s. A case-control study II (In Swedish) Maligna mesenkymala tumorer och ex p o sitio n f o r fen o x isy ro r II - en k lin is k o b se rv a tio n , Lakartidningen 74: 2753-4. S o ft-T issu e Sarcomas and Exposure to Phenoxy Acids: A C lin ic al O bservation by L. H ardell (E nglish tr a n s la tio n o f 765a) II 17769 1C DATE 766 9-30-80 l 767 /68a , 768b ~n 769 -I y 770 I 4 , 771 77? 0 , 773 10-1-80 774 775 776 10-7/80 777 10-8-80 r ir rvA u u u i\t i nu t i v j c u u 2 ,4,5-T & Si 1vex C ancellation U. S. ENVIRONMENTAL PROTECTION AGENCY ' " EXHIBITS -r'* ' ' DESCRIPTION STATUS M alignant lymphoma o f h i s t io c y t ic type and exposure to phenoxyacetic acids or chlorophenols, Lancet 1 (8106): 55-56 In "Case-Control S tu d ie s ,: Chapter XII in Epidemiology: P rin c ip le s and Methods, L i t t l e Brown and C o., a t 256-265. " Questionnaire fo r living subjects in Eriksson, e t a l. " EPA tr a n s la tio n o f E riksson e t a l . q u e stio n n a ire " The Use o f phenoxy h e rb ic id e s in Swedish F o re stry : Amounts, types and modes o f a p p lic a tio n . In Ramel, C. ( e d .) , C hlorinated Phenoxy Acids and T heir D ioxins, Ecol. B ull. (Stockholm) 27:219-230 " Granstrom, B. 1978. The Use o f phenoxy acid h e rb ic id e s In Swedish a g ric u ltu r e . In Ramel, C. ( e d .) , C hlorinated Phenoxy Acids and T heir D ioxins, Ecol. B ull. (Stockholm) 27:231-234 Zack, J.A . and R.R. Suskind 1980. The m o rta lity Experience o f workers exposed to Tetrachiorodibenzodioxin in a trichlorophenol process a c c id e n t. J . Occup. Med. 22: 11. Cook, R .R ., J.C . Townsend, M.G. O tt, and L.G. S ilv e r s te in 1980. M ortality experience o f employees exposed to 2 ,3 ,7 ,8 -T etrach lo ro dibenzo-p-dioxin (TCDD). 0. Occup. Med. (in p re s s ). " " " D irec t Testimony o f Dr. Richard R. Monson A M o rtality A nalysis of Employees Engaged In The Manufacture of 2 ,4 ,5-Tri chiorophenoxyaceti c Aci d In.. Camera Memo dtd Sept. 12, 1980 to E lizabeth Anderson, CAG from A cting, C hief Environmental Fate Branch, HED in re Exposure Assessment fo r 2 ,4 ,5 -T , S ilvex and TCDD CV o f W illiam D. S chutte I 17770 . - i<J DATE f DO 10-9-80 801 II 802 II 803 II 804 II 805 It 805a II 805b II 806 10-10-80 806A 807 II 00C,0- 209 II II 810 10-14-80 811 II 812 II 813 10-15-80 814 II 815 816 217 \ II II It '-.ENVIRONMENTAL-PROTECTION.AGENCY EXHIBITS * "* DESCRIPTION STATUi D irec t Testimony o f Kenneth V. Thimann In M olecular Model o f Methane (Photo) II M olecular Model o f Benzene (Photo) II M olecular Model o f A cetic Acid (Photo) II M olecular Model o f In d o le-3 -A cetic Acid (Auxin) (Photo) II M olecular Model o f 2 ,4 ,5 -T (M odifiable to D epict S ilvex and 2,4,-D ) II M olecular Model o f S ilv ex (Photo) It M olecular Model o f 2,4-D (Photo) II D irec t Testimony o f Dr. Robert R. Bumb Townsend R atios "E valuation o f th e A n aly tical Chemical Procedures o f The Dow Chemical Company f o r D eterm ination o f P o ly ch lo rin ated D ibenzo-p-dioxins" (June 1979) II II It M olecular Model o f 2,3 ,7 ,8 -T etrach lo ro d ib en zo -p -D io x in (Photo) II "The Trace C hem istries o f F ire -- A Source o f th e Routes f o r th e Entry o f C hlorinated Dioxins in to th e Environment" by the C hlorinated Dioxin Task Force (With Appendices) (1978) II D ire c t Testimony o f David T. B u zzelli II Memorandum from P. E. McGrath To D ire c to r, SPRD, in re I d e n tif ic a tio n o f P e stic id e s P o ssib ly Contaminated With C hlorodioxins, dated Feb. 22, 1980 II Dow 2 ,4 ,5 -T & Silvex Labels II D irect Testimony o f P ro fe sso r Robert K ilp a tric k , Cbe, Md, FRCP II "Review o f th e S afety f o r Use In The U.K. o f th e H erbicide 2,4,5-T " Advisory Committe on P e s tic id e s , subm itted to M inistry o f A g ric u ltu re , F is h e rie s and Food (March 1979) II H erbicide 2 ,4 ,5 -T , House o f Commons O ffic ia l Report 971 (48) a t 434-35 II (Ju ly 26, 1979) Composition o f the Advisory Committee on P e stic id e s (Jan. 1, 1980) II Government Departm ents, e tc . Represented on the Advisory Committee on II Pesticides 17771 ENVIRONMENTAL PROTECTION AGENCY EXHIBITS' NO. DATE 818 10-15-80 DESCRIPTION "The Control Scheme: The P e s tic id e s S afety Precautions Scheme (PSPS)," e x tr a c t from the Royal Commission on Environmental P o ll u tio n Report a t 61 (S ept. 1979) STAT II 819 United Kingdom O ffic ia l Recommendations fo r Sale o f 2 ,4 ,5 -T and Fenoprop (S i!vex): 819a 819b M inistry o f A g ricu ltu re, F ish eries and Food, P e sticid es Branch, Chemical Compounds Used In A g ric u ltu re and Food Storage: Recommendations fo r Safe Use In G reat B r ita in , 2,4,5-T " Sheet 168 (Jan. 24, 1967) M inistry o f A g ricu ltu re, F ish eries and Food, P e sticid es Branch "Chemical Compounds Used as P e s tic id e s : Recommendations fo r Safe Use In th e U.K., 2,4,5-T " Sheet 1430 (March 14, 1980) II 819c " M inistry of A g ricu ltu re, F ish eries and Food, P esticid es Branch, "Chemical Compounds Used As P e s tic id e s (Use In F o re stry ): Recommendations f o r Safe Use In th e U .K ., 2 ,4 ,5 -T ," Sheet 1443 March 14, 1980 819d " M inistry o f A g ric u ltu re , F is h e rie s and Food, P e stic id e s Branch, "Chemical Compounds Used In A g ricu ltu re and Food Storage (Home Garden Use)" Recommendations fo r Safe Use In th e U.K, Fenoprop," Sheet 804 (June 1, 1971) 819e " M inistry o f A g ricu ltu re, F ish eries and Food, P e sticid es Branch " "Chemical Compounds Used in A g ric u ltu re and Food Storage (A g ric u ltu ra l and H o rtic u ltu ra l U se): Recommendations f o r Safe Use in th e U .K ., Fenoprop," Sheet 972 (Dec. 1, 1972) 820 " Anonymous, "2,4,5-T-W here Next? The Lancet a t 1114-15 (Nov. 24, 1979) " 821 The S afety o f H erbicides 2,4-D and 2 ,4 ,5 -T , T urner, D .J ., F o restry Commission B u lle tin 57 (1977) 822 10-16-80 D irect Testimony of Dr. Richard J . Kociba 823 H isto ric a l Control Data II 824 " L e tte r to Mr. J . Guy Gwenne dtd Jan. 17, 1980 from P ro fesso r Dr. F. Leuschner , 825 " 2,3,7 ,8 -T etrach lo ro d ib en zo -p -D io x in (TCDD): R esults o f a 13-week Oral T oxicity Study in Rats 826 " E valuation o f C arcinogenic, T eragenic, and Mutagenic A c tiv itie s of S elected P e sticid es and In d u stria l Chemicals, Vol. 1, Carcinogenic Study, B ionetic Research L abs., I n c ., Prepared fo r NCI - Aug. 1968 17772 3- 13- 49- NO. DATE 827a 10-16-80 827b 827c 828 829 10-17-80 830 " 831 " 832 833 834 835 836 837 838 " 839 " 840 U.S. ENVIRONMENTAL PROTECTION AGENCY . EXHIBITS ' DESCRIPTION STATI Chronic Oral T o x ic ity o f 2 ,4 ,5 -T , Batch No. 503, Control No. 15374 b - C alled f o r S hort '2 ,4 ,5 -T ' - In Sprague-Dawley (Siv 50) Rats - Repeated dosage over 130 weeks) (With Special a tte n tio n to Carcinogenic P ro p e rtie s) Apr. 9, 1979(Expando) In Chronic Oral T o x ic ity o f 2,4,5-T * Batch No. 503, Control No. 15374 b - C alled f o r s h o rt '2 ,4 ,5 -T - In Sprague-Dawley (Siv 50) Rats - Repeated dosage over 130 weeks)(With sp e cia l a tte n tio n to carcin o g en ic p ro p e rtie s ) Apr. 9, 1979 (Expando) Chronic Oral T o x ic ity o f 2 ,4 ,5 -T , Batch No. 503, Control No. 153574 b - C alled fo r s h o rt *2,4,5-T - In Sprague-Dawley (Siv 50) Rats - Repeated dosage over 130 weeks - (With sp ecial a tte n tio n to carcin o g en ic p ro p e rtie s ) Apr. 9, 1979 (Expando) R esults o f Two Year D ietary Feeding Study In Rats o f Kurosal SI (Potassium S a lt of Silvex) D irect Testimony o f Dr. F rancis J.C . Roe II S tra te g y fo r d e te c tio n o f cancer hazards to Man , S ir Richard Doll Mutagenic P rin c ip le (s ) in Tryptophan and Phenylalanine P yrolysis Products Mutagen-carcinogens in Food, with Special Reference to Highly Mutagenic P y ro ly tic Products In B roiled Foods Iso la tio n and S tru ctu re Determination o f Mutagenic Substances in L. Glutamic Acid P yrolysate Cancer and Environment: Higginson Speaks Out Recent Developments In th e Design o f C arcin o g en icity T ests on Laboratory Animals E ffe c t o f Q uality and Quanity o f D iet On Survival and Tumour Incidence in Outbred Swiss Mice The E ffe c t o f Long-Term Food R e stric tio n On Tumors In Rodents A etiology o f B reast Cancer: A B rie f Review Food and Cancer Are N u tr itio n is t w orries about th e epidemic of Tumours In Laboratory " Animals? F .J.C . Roe 17773 3^3 U.S. ENVIRONMENTAL PROTECTION AGENCY c EXHIBITS. NO. DATE I DESCRIPTION -- ---------------- STATU 841 10-17-80 E ffe c ts o f P retreatm en t with 2,3 ,7 ,8 -T etrach lo ro d ib en zo -p -D io x in on th e C apacity o f H epatic and E x trah ep atic Mouse T issues to Convert Procarcinogens to Mutagens f o r Salm onella Typhimurium Auxotrops In 842 10-22-80 D irec t Testimony o f Dr. James G. Wilson II 842a 843 844 845 846 847 848 II Chart (Response). 1 Report o f the Advisory Committe on 2 ,4 ,5-T to The A dm inistrato r o f th e Environmental P ro te ctio n Agency, subm itted May 7, 1971 II Report on th e Treatm ent o f Pregnant Rhesus Monkeys with 2 ,4 ,5-T Acid 10-28-80 II D irec t Testimony o f Di\ Bernard A. Schwetz Toxicol. Appl. Pharmocol. 22:317 (A bstract) 2 ,4 ,5-T in Mice Teratogenic E ffects of II In v e s tig a tio n s on th e Embryotic E ffe c t o f 2 ,4 ,5-T In NMRI-Miice II N onteratogenic E ffe c ts o f 2 , 4 , 5 -T richlorophenoxyacetic Acid and 2,4,50T propylene glycol butal e ste rs herbicides in sheep 349 II 850 II A Q uality Assurance Review o f Dr. A lle n 's 500 PPT TCDD Monkey Study dated May 8 , 1980 Evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D ), 2,4,5T richlorophenoxyacetic acid ( 2 ,4 ,5-T ), and 2 , 3 , 7 ,8 -tetrachlorodibenzop-dioxin (TCDD) tb x ic ity in C57BL/6 mice 851 10-30-80 852 II D ire c t Testimony o f Dr. Colin N. Park D irect Testimony o f Dr. E. Marshall Johnson 853 11-26-80 D irect Testimony o f Dr. Steven H, Lamm II il It II II II II II It II II II 854 10-29-80 855 10-31-80 856 II 857 11-4-80 D irec t Testimony o f Dr. E. G. McQueen D irect Testimony of Dr. Sheldon L. Wagner 1 D irect Testimony o f Dr. Alan A gresti D irec t Testimony o f Michel A. Ibrahim , M.D., Ph.D. II 11 o58 II The Case-Control Study Consensus and Controversy II 17774 ** > Q NO: DATE 859 11-5-80 860 11-7-80 860a & b 861 11-10-80 861a II 861b II 861c II FIFRA DOCKET NO. 41b, ex ai. 2,4,5-T & Silvex Cancellation U.S. Environmental P ro te c tio n Agency Exhibits ' "" ' DESCRIPTION D irec t Testimony o f Dr. Ralph R. Cook D irect Testimony o f Dr. P h ilip Cole Chart D ire c t Testimony o f Dr. G. Reggiani Review A rtic le - Medical Problems Raised by th e TCDD Contamination in Seveso, I t a l y , G. Reggiani V alutazione Q u a n tita tiv a D ella Esposizione Umana D ella TCDD N elle Zone Di Seveso Map - Location o f Contaminated Area Sl/i I II 11 II 11 II 862 L e tte r to The Health O ffic e r o f Seveso and Meda II 863 Acute Human Exposure To TCDD In Seveso, I t a l y , by G. Reggiani II 864 11-13-80 864a 864b 865 II II II 866 II 867 11-17-80 867a " It 868 II 869 II 870 11-18-80 871 II 872 873 . 874 11-19-80 II II D irect Testimony o f Dr. H. Tuchmann-Duplessis Frequency o f A bortions Broken Down by Degree o f Contamination Hand drawn document (diagram) D irec t Testimony o f Dr. V.K. Rowe Research on Chemical Acnegens Using Human S ubjects D irect Testimony o f Dr. Kenneth D. Crow L tr to K.D. Crow, FRCP dtd June 21, 1978 from P .J . Gehring Chloraoe: The Chemical Disease Chloracne from the accid en tal production o f tetrachloridebenzodioxin D irect Testiomony o f Dr. Otto H utzinger Workshop - Impact o f C hlorinated Dioxins and R elated Compounds On The Environment, Oct. 22-24, 1980 1 D irect Testimony o f Dr. Ralph T. Ross Prelim inary Dioxin Implementation Plan C ritiq u e o f Segments o f L e tte rs Whick R elate To The Adequacy of A n alytical Methods fo r TCDD In Environmental Samples II II If 1 II II II II II II II II II II 17775  9 0 . DATE 875 n -20-80 876a It 876b 876c It H 876d II 876e 877f 876g 76h It % It It It 76i II 876j 876k 876L 876m 876n 876o 876p 876q 876r 876s 76t It It It II II It It It It It II 2,4,5-T & Silvex Cancellation U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION D irect Testimony o f Dr. Ford L. Baldwin Photo - View o f Flooded Rice F ield and Levees a t th e E arly T ille r in g Stage Photo- View o f Rice F ie ld w ith E arly Season Weed Problem Photo- Draining o f Rice Fie! in Preparation fo r Early Season Application of 2,4,5-T Photo- View o f Rice F ie ld Following E arly Season A pplication o f 2,4,5-T Photo - View o f Rice F ie ld a t Midseason, J u s t P rio r to Time o f Midseason A pplication o f 2,4,5-T . Photo - Typical B roadleaf Weed Problem--Curly Indigo Photo - Typical B roadleaf Weed Problem -- Morning Glory Photo - Base o f Rice Stems Showing P anicle I n i ti a t i o n and Internode Elongation Photo - Typical Computer P rin t-O u t Showing A ppropriate 2,4,5-T Midseason A pplication Dates 2,4,5-T Treatment o f Levees. View o f Levee Following A pplication o f 2,4,5-T Photo - A erial A pplication of 2,4,5-T Photo - View o f Rice P la n t Showing Phenoxy H erbicide Damage Photo - View o f Rice F ield Showing "Heading" Stage Photo - Rice F ield Containing Mature Rice Photo - Rice Panicle Containing Rice Hulls Photo - Rough Rice , Photo - Rice E lev ato r, and P art o f Rice Drying and Storage F a c ility Photo - Dumping Harvested Rice a t th e Drying and Storage F a c ility Photo - F in a l, Polished White Rice Kernals STA' In II II II tl It It tt It II It It II It II II II II II II II 17776 a u n t? . . DATE 877 11-21-80 878 It 879 It 880 II 881 II 882 II 883 II 884 II 8S5a 85b f'S c 885d 885e 885f 885g 885h 885 i 885j 885k 885L 885m 885n II II II II II II II II II II II II II II U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION D irect Testimony o f John L. M e rrill L ivestock and Meat S itu a tio n - Aug. 1980 Bovine Growth and Composition by H.B. Hedrick Technical Standard and S p ecificatio n s fo r Deferred Grazing L ivestock S la u g h te r Annual Summary 1979 Meat Animals Production D isp o sitio n , Income 1978-1979 Money Value o f Food Used By Households In The United S ta te s , Spring 1977 In creasin g Forage on Ozark Wooded Range, John H. Ehrenreich & Robert F. B u tte r Photo- Cow w ith Newborn C alf Photo- Cows w ith Calves Near Weaning Time Photo - Weaned Calves on Wheat P asture Photo - Y earlings in Feedlot Photo - C a ttle On Dormant Range Receiving Supplemental Feed Photo - C a ttle Receiving Hay When Snow Covers Grass Photo - N u trie n t Uses o f C a ttle Photo - Body Composition o f C a ttle Photo - Brush Root Growth Photo - Brush Use o f M oisture Photo - Brush Competition With Grass Photo - Mesquite In fe s ta tio n in Texas Photo - U ntreated Mesquite in W illacy County, Texas Photo - U ntreated Mesquite in DeWitt-Gonzales County Area, Texas STAT In II II II II II II II II It II II II II II II H II II II II II 17777 s u a 4*7 j $ NO. od5o' 885p 885q 885r 885s 885t 885u 885v DATE 11-21-80 11 II II II II II II 885w 885x II II -35y 5z II II 886 11-23-80 887 II 888 It 889 12-3-80 890 12-4-80 II 891 892 12-8-80 893 II 894 II 895 11 U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION STA1 Photo -T reated Mesquite in Oldham County, Texas II T reated Running Mesquite In McMullen County, Texas II U ntreated Mesquite In th e r o llin g P la in s o f Texas II Regrowth M esquite in Knox County, Texas II U ntreated Running M esquite in McMullen County, Texas II N on-infested Rangeland in Wheeler County, Texas II P o st and Blackjack Oak In fe s ta tio n in Texas II U ntreated ( l e f t and T reated (R ight) Post Oak and B lackjack Oak I n fe s ta tio n Near Bryan, Texas tl Sand Shinnery Oak I n f e s ta tio n in Texas II U ntreated Sand Shinnery Oak I n fe s ta tio n in the E astern Panhandle o f Texas II Cactus In fe s ta tio n in Texas II Cactus and Mesquite Competition with Grass on Texas Range Di r e c t Testimony o f Dr. Lewis A. Shadoff In II II II 11 II II II II II It II II In te rla b o ra to ry Method V alid atio n Study fo r D ioxin.an in terim Report Environmental Samples of S elected Methods Development D irec t Testimony o f Dr. Henry F re is e r D irect Testimony o f Hyland R. Johns Asplundh Chemical Foreman's Manual D irect Testimony o f Dr. John C. Ramsey It II II II II II The Fate o f 2 ,4 ,5 -T rich lo ro p h en o x y acetic Acid (2,4 ,5 -T ) Following Oral A dm inistration to Rats and Dogs ll Pharam acokinetics o f 2,4 ,5 -T PGBE E ste r Applied Dermally to Rats II Determ ination o f 2,4,-D Exposure Received by F o restry A pplicato rs Spring 1980 ll 17778 2,4,5-T & Silvex Cancellation U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS NO. DATE DESCRIPTION STATUS 896 12-9-80 D irec t Testimony o f Dr. Richard Wilson In 896a 897 12-11-80 898 In te rs p e c ie s Comparison o f Carcinogenic Potency, Edmund Crouch, & Richard Wilson D irec t Testimony o f Dr. Michael Newton r The Phenoxy H erbicides (Second E d itio n ) Aug. 1978 " " " 899 P olution Control In The F o re st Products In d u stry " 900 It 901 S02a 902 12-12-80 L e tte r to Arvid C. Ell son, Portland,O regon dtd Nov. 17, 1978 from W illiam D. C lo th ie r Exposure o f Forest Herbivores to 2,3,7,8-T etrachlorodibenzo-p-dioxin (TCDD) In Areas Sprayed w ith 2 ,4 ,5 -T Chart D ire c t Testimony 6 f Werner H. Braun " " 903a Photograph o f 2 ,4 ,5 -T A p p lica to r Study - Backpack Crew 903b " - Backpack Loading " 903c " - Backpack S p ray er's Truck " 903d " - Backpack Sprayer " 903e 903f " - Backpack Sprayer '* '* - Tractor Sprayer " 903g 903h. " " " - Mixing fo r T racto rs - Loading the T ractor " " 903 i 903g 903k " - Flagmen " " - Loading the H elicopter " " - Flagman's View " 904a Photographs o f 2,4-D A p p lic a to r Study - 2,4-D A pplication Area 904b " - A erial Crew " 904c " - Batchman Loader " 904d " - P i l o t 's Boot 904e " - Leather Flying Gloves " 904f " - Protective Clothing " 17779 ............... ...................................................... ............ ...................... .0^4*3 U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS NO. DATE 905 905a 905b 906 12-16-80 907 908 909 910 911 912 12-17-80 913 " 914 " 915 916 917 918 DESCRIPTION STA D ire c t Testimony o f P h ilip G. Watanabe Chart Chart (reversible) "The A pplication o f Fundamentals In Risk A ssessm ent", Paper d e liv ere d a t American Chemical S o ciety Symposium o f P e stic id e Chemist and Modern Toxicology, (June, 1980) In " C o rn fie ld , J . , "C arcinogenic Risk Assessm ent," S cience, 198 a t 693-699 " (Nov. 18, 1977). G ehring, P .J . and B lau, G .E ., "Mechanisms o f C arcinogenesis: Dose Response," J . Environ. P a th o l. T o x ic o l., 1_ a t 163-179 (1977) " S q u ire , Robert A ., "Human Risk Assessment from Animal D ata," Paper D elivered a t American Chemical S ociety Symposium on P e s tic id e Chemist and Modern Toxicology, (June, 1980) " P i t o t , H .C ., e t a l . , "Q u a n tita tiv e E valuation o f th e Promotion by 2 ,3 ,7 ,8 -T etrach lo ro d ib en zo -p -d io x in o f H epatocarcinogenesis from D iethylnitrosam ine,"C ancer R esearch, 40 a t 3613-3620 (O c t., 1980) " Poland, A. and G lover, C ., "An Estim ate o f the Maximum in Vivo Covalent Binding of 2,3,7,8-T etrachloro-dibenzo-p-dioxin to Rat L iver P ro te in , Ribosomal RNA, and DNA," Cancer Research, 39_at 33413344 (S ept. 1979) " D irect Testimony o f Dr. Perry J . Gehring General E le c tric Comments on IRLG Report FDA, 21 C.F.R. 170.22 FDA, "C a ffe in e/ D eletion o f Gras S ta tu s , Proposed D eclaratio n That No P rio r Sanction E x is ts , and Use on an Interim B asis Pending A dditional Study," 45 Fed. Reg. 69817-38 (Oct. 21, 1980) " C o llin s, T .F .X ., e t a l . , " A Comprehensive Study of the Teratogenic FDA, "Selenium in Animal Feed," 38 Fed. Reg. 10458-60 (Apr. 27, 1973) " " S auerhoff, M.W., e t a l . , "Dose-Dependent Pharm acokinetic P ro file o f Silvex Following Intravenous A dm inistration in R ats," J . Toxicol. Environ. Health 2:605-618 (1977) " 17780 . NO. DATE 920 ,<*,0 - 1 & aiivex cancellation U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS DESCRIPTION ........ 921 922 923 924 925 2-11-81 926 " Testimony o f th e American Council on Science & Health American Council on Science and H ealth P relim inary Report on 2,4,5-T STATUS In " 17781 *-" NO. DATE 930 1-27-81 931 II 932 II 933 In re 2,4,5-T & Silvex Cancellation U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS - DESCRIPTION D irect Testimony o f Dr. Michael L. Gross L e tte r to Mr. Michael D ellarco dated Oct. 2, 1980 from Michael L. Gross en clo sin g Data Report XIII Memo to Mike D ellarco dated S ept. 18, 1980 from Robert H arless in re R esults o f C a p illa ry Colum GC-HRMS Analyses Performed on E x tra cts o f Human Adipose f o r 2,3,7,8-TCDD Residues statu: In II II 934 934a 935 1-30-81 ** D irect Testimony o f Dr. Renate D. Kimbrough ** Centers For D isease C o n tro l's Human Health Assessment Approach Involving Im properly Disposed Chemical Wastes D irect Testimony of Joseph S. Carra II II II 936 2-4-81 D irect Testimony o f Dr. John C. B a ila r, I I I II II 937 938 2-3-81 939 ir . 940 ii 941 it 942 ti 943 ii Memo to Diana R eisa, Ph.D. dated Jan. 26, 1979 from H.W. Spencer, Ph.D in re Report o f TDA review o f TCDD 2, y e a r r a t feeding study by Dow Chemical Company D irec t Testimony o f Mr. Robert G. Heath Edwin L. Johnson, L e tte r to Blue Ball C onstruction Company, dated November 27, 1979 (w /responses) Lincoln County Road Department, Maintenance D iv isio n , D aily Spray Report dtd 1974 Lincoln County Road Department, Maintenance D iv isio n , D aily Spray Reports (1975) Amchem P roducts, I n c ., Label fo r Weedon 2 ,4 ,5-T Township and Range Map o f Lincoln County, Oregon (w ith Zip Code Zones) II II n it ii n ii 944 Direct Testimony o f Mr. Gerald Hall 945a Annual P re c ip ita tio n Summary - 1963-1979, Source: Department of Commerce, N.O.A.A. N ational C lim atic C enter, A sh e v ille , N.C. ii 945b Daily P r e c ip ita tio n Summary - T idew ater, Oregon (L incoln) Ju ly 1, 1979 ii to June 30, 1980 945c Isohvetal maD o f Lincoln Countv - Source: Frank and Laenen; Water ii Resources of Lincoln County Coastal Area, Oregon, U.S.G.S. 1977 - /Admitted by Order Admitting E xhibits dated Feb. 26, 1981 17 78 2 i in re 2,4,5-T & S U vex Cancellation U.S. ENVIRONMENTAL PROTECTION AGENCY EXHIBITS 0. ! 15d 945 945f 946a 946b 946c 947a 947b 947c 948 950 951 952a 952b 952c 952d 952e DATE DESCRIPTION STATI ** Mean monthly d ischarge o f S ile tz and Alsea R ivers. Source: IBID In ** R elatio n sh ip between p r e c ip ita tio n and w ater well le v e ls,S o u rc e . Ibid ** S elected USGS gaging s ta tio n s and average monthly flow s, Source Ibid ** Lincoln County, Oregon - base map 1"= 1 m ile - problem area * Appendix- Index o f R iver Basins and Sub B asin s, Lincoln County, 1979 ** Goal 6 - A ir, Water and Land Resources Q uality - Inventory Maps ** Lincoln County, Oregon - two Cross S ections from a e r ia l Photo s o ils mapping * USDA Soil C onservation Service o r S o ils - 1 Index o f S o ils from Cross Sections ** I d e n tif ic a tio n Legend - Mapping symbols fo r mapping u n its ** High A ltitu d e (U-2) a e ria l photo o f Alsea Bay, southern p o rtio n o f Lincoln County and Northwesternmost Lane County,Oregon 1:32,500 ** Photo enlarged and sp lic e d U.S.G.S. quadrangle Map o f so u th e aste rn Lincoln County, Oregon 4" - 1 Mi 1e^T^copy-Tn th e O riginal F ile ) irk A ir Photo o f unincorporated Lincoln County, Oregon, south o f Lincoln C ity and S i l e t z Bay 1" = 400 m iles (1 Copy in the O riginal f i l e ) ** Location map f o r map e x h ib its , Lincoln County, Oregon 2-3-81 Map o f p rin c ip a l domestic w ater rig h ts by approximate p o in t d iv e rs io n . Lincoln County A p p lic a tio n s(la rg e copy hot in fo'Tclers) ** Appendix to w ater rig h ts map number 952 above Water rig h ts f ilin g s fo r a ll Lincoln County A pplications * Township and Range mapping o f approxim ate poin ts o f d iv ersio n fo r a ll Lincoln County w ater rig h ts ap p lica tio n s irte Index o f v a lid w ater r ig h ts by Township, range and S ection fo r a ll Lincoln County w ater rig h ts II **/ Admitted by Order Admitting E x h ib its dated Feb. 26, 1981 17783 EX.H'Z RESULTS OF A TWO-YEAR CHRONIC TOXICITY AND ONCOGENIC STUDY OF RATS INGESTING DIETS CONTAINING 2,4,5-TRICELOROPHZNOXYACETIC ACID (2,4,5-T) N6V 3 0 1373 3y r 1 R. J. Xociba, D. G. Kayes, R. W. Lisowe, R. ?. Ralnins, D. D. Qittenfaer, | C. E. Wade, 5. J. Gorzinski, i-- N. S. Mahle* and 3. A. Schwatz Reviewed 3y: K. S. Rao September 27, 1973 Toxicology Research Laboratory (and Midland Analytical Laboratory*) Health and Environmental Research Dow Chemical U .5.A . ga?'i>Lf TABLE OF CONTENTS Page SUMMARY ..................................................... 1 INTRODUCTION . . ........................................... 3 MATERIALS AND M E T H O D S ...................................... 7 Experimental Design .................................. 7 Test M a t e r i a l ........................................ 7 Diet P' reparation . . . . . . ........................... Clinical Observations .............................. 8 3- Necropsy Examination '.................................... 11 Histologic Examinationof Tissues . . . . . . . . . . . 12 Statistical Evaluationof. D a t a ........................... 13 R E S U L T S ....................................................... 15 Dietary Content of 2 , 4 , 5 - T .............................. 15 Body Weight D a t a ........................................ 15 Food Consumption D a t a .................................. 16 Mortality ................. 16 Palpable Masses and Animal Observations ............ 16 H e m a t o l o g y ...............................................17 U r i n a l y s i s ............ IS Urinary Volume, Creatinine, Porphyrins and d e l t a - A L A ........................................ IS Clinical C h e m i s t r y .................................... 19 Organ W e i g h t s ............ . ......................... 19 Gross and Histopathologic Obse r v a t i o n s.......... '. . 20 Tumor I n c i d e n c e ........................................ 24 DISCUSSION ........... . ................ '.................. , 26 SIGNATURE P A G E ............................. '. : ..........29 R E F E R E N C E S ................................................... 30 3-PAC-E SUMMARY TABLE . . . . ............................... 33 FIGURES I AND 2 ...............................................36 TABLES 1-41 ............................................. 33 APPENDICES 1 - ^ 2 ..............................................221 2A -1 - SUMMARY Groups of Sprague-Dawley rats were maintained on diats supplying 30, 10 or 3 mg of 2,4,5-T/kg body weight/day for up to 2 years, with an interim nacropsy attar 118-119 days. The highest dose level of 30 tag of 2,4,5-T/kg/day was associated with some degraa of toxicity. This included a decreased body weight gain, increased relative kidney weights increased urinary excretion of total urine volume, coproporphyrin and uroporphyrin plus slight morphologic alterations of the kidney, liver and lungs. In the kidney, this involved primarily the presence of mineralized deposits in the renal pelvis. Liver effects associated with the highest dose level of 30 mg of 2,4,5-T/kg/day included an increased incidence of focal biliary hyperplasia and inflammatory changes plus de creased incidence of hepatocellular degenerative changes. The incidence of focal pulmonary inflammatory changes, primarily accumulation of alveolar macrophages, was also increased at this highest dose level. Parameters unaffected by treatment with this highest dose level of 30 mg 2,4,5-T/kg/day included the rata of mortality, food consumption, pal pable masses, hematology (red blood cell count, hemoglobin, packed cell volume, total and differential white blood cell count, thrombocytes and reticulocytes), routine urinalyses, urinary excretion of creatinine or delta-aminolevulinic acid, serum clinical chemistry (urea nitrogen, glutamic pyruvic transaminase and alkaline phosphatase activities, bilirubin, total protein, albumin and globulin), organ weights (except -2 - or kidneys as described above), tumor incidence as veil as gross and microscopic morphology of all organ systems of the body (except as described above). At the intermediate dose level of 10 mg of 2,4,5-T/kg/day, there vers only minimal effects, limited primarily to an increased incidence of mineralized deposits in the renal pelvis; an increase in urinary excre tion of coproporphyria was noted in males only during the early phase of the study. At the lower dose level of 3 mg of 2,4,5-T/kg/day, there were no alterations in any parameter considered related to treatment over the course of this 2-year study. Thus, the results of this study revealed no oncogenic response in rats, even when administered a sufficiently high dosage of 2,4,5-T to induce toxicity. INTRODUCTION 2.4.5-- Trichlorophenoxyacecic acid (or 2,4,5-T) has bean used as a selec tive herbicide for weed control on certain crops, pastures, grazelands and forests. In the production of 2,4,5-T, the starting material for the aromatic portion of the compound is' tetrachlorobenzene. Tetrachloro'oenzene is hydrolyzed to 2,4,5-trichloroph^nol, which is subse quently reacted with chloroacetic acid to form 2,4,5-T. In the pro duction of the trichlorophenoi, several impurities.may be formed under certain unfavorable conditions. One of these impurities is 2,3,7,3tetrachlorodibenzo-p-dioxin (TCDD) which may be found at low levels in the trichlorophenoi. In 1966 The Dow Chemical Company imposed upon itself a manufacturing specification of less than 1 ppm TCDD in 2,4,5-T. This has been subsequently lowered to 0.1 ppm maximum level of TCDD in 2,4,5-T. Various toxicologic studies have been conducted with 2,4,5-T over the past 25 years. The single oral dose LD50 of 2,4,5-T has been reported to be 389 mg/kg in mice, 381 mg/kg in guinea pigs, 500 mg/kg in rats and 310 mg/kg in chicks (Rowe and liymas, 1954). In dogs, the single oral LD50 of 100 mg/kg reported by Drill and Hiratzka (1953) is probably due to the slower race of urinary elimination of organic acids such as 2.4.5- T in dogs (Piper et al., 1973). The compound 2,4,5-T is readily absorbed and rapidly excreted by animals, including man. The half-life values for the clearance of carbon-14 accivicv from the olasma of rats aiven single oral coses of labeled -4 2,4,5-T at doses of 4, 50, 100 and 200 mg/kg were 4.7, 4.2, 19.4 and 25.2 hours, respectively (Piper _et_ al. , 1573) . The half-lives for elim ination from the body of those rats were 13.6, 13.1, 19.3 and 23.9 nours, respectively. In dogs given C" labeled 2,4,5-T at 5 mg/kg, half-life values for clearance from the plasma and clearance from the body ware 77.0 and 36.6 hours, respectively. This lower rate of clear ance may explain-the greater toxicity of 2,4,5-T in dogs than in rats. Five human volunteers ingested 5 mg/kg of 2,4,5-T containing lass than 0.05 ppm TCDD (Gehring et al., 1973). Essentially all the 2,4,5-T was absorbed and excreted unchanged in urine, with a half-life of 23.1 hours. This rate of excretion more closely resembles that observed in the rat than the dog. In a previous unpublished subchronic toxicity study of 2,4,5-T in rats conducted by this laboratory, no evidence of adverse effects was ob served in rats fed dose levels of 3 or 10 mg/kg/day for 90 days. It higher dose levels of 30 or 100 mg/kg/day, there were increases in liver and kidney weights, elevations in serum enzymes, and other indications of slight toxicity. Drill and Hiratzka (1953) found no adverse effects in dogs given 2.5 or 10 mg/kg of 2,4,5-T for 5 days/veek for 3 months; four dogs could not tolerate a higher dose level of 20 mg/kg and died during the experiment. Highmar. a , (1976) repor tad results of short-tar o x i c i r y 3 t u d i a s in nice using samples of 2, 4,5- I wish varying c o m e o f T C D D . T h e s e GO -5 - stuaies, which wera in conjunccion wich teratology studies, reported multiple toxicologic effaces due to treatment with high doses of 120 or 60 mg of 2,4,5-T/kg; lower dose levels were not studied. Smith at al. (.1978) recently have reported on a 3-generation repro duction study of rats ingesting 2,4,5-T. No adverse effects were seen at a dose level of 3 mg/kg/day. Dose levels of 2',4,5-T which were sufficiently high to cause signs of toxicity had no affect on repro ductive capacity of rats except for a tendency toward a reduction in neonatal survival at dose levels of 10 and 30 mg/kg/day. There have been.several studies conducted over the past 10 years in mice to assess the potential oncogenicity of 2,4,5-T. Innes et al. (1969) reported no increase in the incidence of tumors in 2 strains of mice given the maximum tolerated dose (21.5 mg/kg/day) of 2,4,5-T (containing approximately 30 ppm of TCDD) via stomach tube from day 7 to day 28 of age. After weaning at 28 days of age, 60 ppm of 2,4,5-T was mixed directly in the diet for approximately 18 months. In a National Cancer Institute study conducted at 3ionetics Research Laboratories (1968) but never published, weanling mice (2 strains) ware given by single subcu taneous injection a dose of 215 mg/kg, wich subsequent observation for 18 months. The authors concluded there was no increase in the incidence of tumors due to 2,4,5-T. in 1976, Muranyi-SLovacs a l . published the result studies of 2,4,5-T in 2 strains of nice. This m i t t . a m o u o i i c a t i o n -O-- reported results of their study of 2 inbred strains of nice (C3E and XVIIG) given 2,4,5--T (100 ng/1) in their drinking water for 2 months beginning at 6 weeks of age. The nice were subsequently fed diets containing 30 ppm (approximately 12 mg/kg/day) of 2,4,5-T for the duration of the lifetime study. 3ased on their method of combining tumor types, the authors reported a statistically significant increase in tumor incidence of C3H mice. No significant differences in tumor incidence were found in the mice of the XVIIG strain. In a subsequent communication, Muranyi-Xovacs et al. (1977) reported on the other studies they had conducted in which the same 2 strains of mice as used in their diet study were given a series of neonatal subcutaneous injections of 2,4,5-T with no resultant increase in tumors. In order to evaluate the long-term toxicity and oncogenic potential of 2,4,5-T in rats, the study reported herein was conducted. This study involved the dietary administration of 30, 10 or 3 mg of 2,4,5-T/kg/day to rats, for up to 2 years. -? ' , -) J --) c X 0) ? -- -7 - MATSRIALS AND METHODS Experimental Pasin. Two groups of mala and famale Sprague-Dawlay rats, Spartan substrain''", 7-8 weeks old, were randomly placed (2/cage) in sus pended wire-bottomed cages to be used for a 118-119 day and a 2-year chronic toxicity study. Animals were randomized using a table of random numbers. Individual rats were identified by metal ear tags; rats of each 2 dose level were also identified by toe-clipping. Food and water wera available ad libitum. On March 5, 1975, the rats were placed on diets providing 2,4,5-T according to the following: 2,4,5-T mg/kg/day 0 30 10 3 118-119 Day Study Initial No. of Rats Mala Female 10 10 10 10 10 10 10 10 2-Year Study Initial Mo. of Rats Mala Female 86 86 50 50 50 50 50 50 Test Material. The purified sample of 2,4,5-T used for this two-year study was supplied by M. Getzandanar of The Dow Chemical Company and was designated as Sample AGR133711. The identity of the 2,4,5-T acid material was verified prior to study initiation by elemental analysis, gas chromato graphy, solid probe mass spectrometry, gas chromatography-mass spectrometry nuclear magnetic resonance spectrometry and infrared spectrometry, within the limits of precision of each of these techniques, the natarlal--was-essen tiallv that of 2.4.5-trichloroohenoxvacatic acid. Assay via titration '"Spartan Research Animals, Maslatt, MI. ? Purina Laboratory Chow, Raiston-?urma Co., St. Louis, MO. -8 - indicated approximately 99% 2,4,5-- trichlorophenoxyacetic acid. Other phenoxy acid impurities amounted to 1.3 weight percent as determined by gas chromatography, using gas chromatography-mass spectrometry, 2,3,7,3tetracnlorodibenzo-p-dioxin, hexachlorodibenzo-p-dioxin, heptachlorodibenzo-p-dioxin and occachlorodibeazo-p-dioxin were not detected at limits of detection of 0.33 ppb, 0.12 ppb,.0.40 pp'o and 0.40 ppb, respec tively. The recrystallization solvent, tatrachloroethyle'ne, was present at 0.22%. Table 1 lists the specific analytical data. Diet Preparation. This sample was used to prepare the premixes and test diets according to the following general procedure: A 1% premix was prepared by dissolving an appropriate amount of 2.4.5- T in reagent grade acetone and thoroughly mixing it with ground laboratory chow. This premix, after drying, was mixed with rat chow to prepare the diets that supplied 30, 10 and 3 mg 2,4,5-T/kg body weight/day. The body weights and food consumption of 20 rats/sex/group were used as the basis for preparing these diets. Control rats were supplied with ground laboratory chow treated with an equivalent amount of acetone. Portions of each prepared diet from each dose level collected during months 5, 7, 12, 19 and 23 were submitted for 2.4.5- T analysis. Clinical Observations. Rats were observed for general health status and possible toxicologic response during the study, with observations n -9 - recorded at the tine of each monthly weighing of the rats. Beginning ac 6 months, observations were also recorded at the tine of each monthly palpation for the detection of palpable masses. 3ody weights were recorded at approximate weekly intervals for all 10 rats/sex/group killed after 118-119 days and also for 20 rats/sex/group during the first 3 months of the two-year portion of the study. There after, body weights of rats used in the 2-year study were recorded at approximate monthly intervals. Food consumption was recorded at approximate semi-weekly intervals for all 10 rats/sex/group scheduled for the interim kill after 118-119 days and also for 20 rats/sex/group during the first 4 months of the two-year portion of the study. Thereafter, food consumption was recorded for up to 20 rats/sex/group for 1 week/month during the rest of the two-year study. 31ood samples for hematological determinations were collected from the tail veins of 8 rats/sex/group after 82-33 days of treatment from the group scheduled for the interim kill after 113-119 cays. From the rats on the two-year study, blood samples were also collected from 8 rats/sex/ group after 89-90, 364-365, and. 726-727 days of treatment. The total erythrocyte count (X3C), total and differential leukocyte counts ("730), thrombocyte and reticulocyte counts, packed cell volume (PCV), and hemo- 3 glo'oin (Hgb) concentration were determined using automated'' or manual procedures. 3 Coulter Counter Model Z3I, Coulter Electronics, hiaaan, Fioraca. -1 0 - Urine samples were collected from 8 rats/sex/group after 32-33 cays of treatment of the group scheduled for the interim kill at 113-119 days. The same number of rats from the two-year study were sampled after 3990, 364-365, and 726-727 days of treatment (when group sires permitted). Urine specific gravity, pH, and the presence or absence of glucose, pro- 4 Cain, ketones, bilirubin and occult blood were determined at each of 4 these times, and urinary urobilinogen was also evaluated on days 364- 365 and 726-727 of treatment. Urinary levels of creatinine, coproporphyria, uroporphyrin with or with out delta-aminolevulinic acid (celta-ALA) ware determined by a consulting laboratory'3. Rats were housed individually in metabolism cages for col lection of 24 or 48 hour urine samples in glass jars wrapped in aluminum foil and packed in dry ice. Urine samples of 5 rats/sex/group were col lected from Che group scheduled for the interim kill at 118-119 cays on three occasions before day 106 of treatment and once just prior to the interim kill. Urine samples of 4-5 rats/sex/group ware also collected after 95-97, 183-190, 361-363, 564-566, and 693-700 days of the two-year period of treatment. Urine volumes were recorded for each individual rat. At both the interim necropsy after 118-119 days and the terminal necropsy after 2 years, serum samples were collected from a maximum of 10 rats/sex/ group for the determination of blood urea nitrogen (BUN), serum glutamic 4 Ames Bililabstix or Multistix, Ames Co., A.0 Optical, Buffalo, NY. ^Bio-Science Laboratories, Van Nuys, CA. :, IN, and IS Meter, -1 1 - pyruvic transaminase (SGPT) , alkaline phosphatase (A?) , total direct and indirect bilirubin, total protein, albumin, and globulin. Automated procedures were used for these determinations0 . Necronsy Examination. An interim necropsy anamination was conducted after 118-119 days of treatment of 10 rats/sex/group that had been predesignatad for this purpose. All rats were deprived of food overnight prior to killing by decapitation. The ayes of all rats were examined by gently pressing a glass slide against the cornea under bright fluorescent illumination. Any observations on the eyes were recorded as part of the gross necropsy observation records. The eyes for a maximum of 5 rats/sex/ group were preserved in Zenker's fixative. Eyes from the remaining rats were fixed in 10% buffered formalin. A complete gross pathologic examination was performed by a veterinary pathologist. Representative sections of all major organs and tissues were preserved in formalin fixative. These tissues included liver, kidneys, heart, pancreas, spleen, brain (cerebrum, cerebellum and brain stem), spinal cord, peripheral (sciatic) nerve, pituitary gland, stomach, small intestine, large intestine, mesenteric lymph node(s), skeletal (thigh) muscle, salivary gland, testes, epididymides, accessory male sex glands, urinary bladder, uterus, ovary, trachea, esophagus, aorta, thoracic lymph node(s), thymus, lungs, bronchi, integument, thyroid gland, parathyroid glands, adipose tissue, eyes, adrenal gland(s), and any other grossly observed lesion. The weights of the liver, kidneys, brain, heart, thymus, spleen, testes and ovaries/uterus (as a unit) were recorded on ail 10 rats/sex/group. ^ T e c h n ic o n A u to A n a iv z e r , T e c h n ic o n C o r p o r a tio n , R ye, NY. 5 -1 dJo'] -1 2 - All rats dying or called during the course of the 2-year study were also subjected to a gross pathologic examination. Representative portions of ail major organs and tissues as listed above, plus tongue, mandible, skull (including nasal turbinates, ear canal, etc.) along with any gross lesions suggestive of a significant pathologic process or tumor formation were collected from each rat and preserved in formalin fixative. Terminal necropsy examination was conducted on all survivors at the end of 2 years of treatment, (March 8-11, 1977) using procedures similar to chat described for the interim necropsy to weigh and preserve in fixative all those organs and tissues listed above, including those tissues preserved from rats dying or culled during the study. At the time of terminal ne cropsy, a peripheral blood ana femoral bone marrow smear was prepared from most rats, and filed for future reference, if indicated. Portions of fat, liver and kidney from a maximum of 5 rats/sex/group were frozen for possible 2,4,5-T analysis at the time of both the interim and terminal necropsy- examinations. Histologic Examination of Tissues. Histologic examination was conducted on paraffin embedded sections of tissues which were stained with hema toxylin and eosin (H&E). All rats from the control and high dose groups killed after 118-119 days were subjected to histologic examination of an extensive list of tissues listed in Table 39. Additional sections of liver and kidney from most control and top dose rats killed afcer 118119 days were stained for lipid content using Oil Red 0 Stain. Tissues -1 3 - collected at the interim kill (after 118-119 days) from the lower dose groups were not examined due to the absence of any definite treatmentrelated effects in the high dose group. Rats from all treatment and control groups of the 2-year study, regardless of whether they died, or were culled during the study, or were killed at the termination, were subjected to histologic examination of H&E stained sections of an ex tensive list of tissues from organ systems of the body. These tissues are listed in Tables 40 and 41. Additional sections of kidneys from 5-7 female rats from the control and high dose groups of the terminal kill were stained with Oil Red 0, Mallory's reaction for iron, Ziehl--Meelson stain for acid fastness, Dahl's Method for Calcium and the periodicacid-Schiff reaction (Luna, 1968). Statistical Evaluation of Data. Hematology, urinary and clinical chem istry parameters, body weights, organ weights, and organ/body weight ratio data were statistically analyzed by a one-way analysis of variance followed by Dunnett's Test, p<0.05, (Steel and Torrie, 1960). Data on mortality, palpable masses, gross pathology, histopathology and tumor incidences of the rats of the 2-year study were analyzed using Fisher's Exact Probability Test, p<0.05, one sided test (Siegel, 1956). The statistical evaluation of the gross and histopathologic data from the 2-year study was conducted on the following basis: a) Gross Pathology Observations: Statistical evaluation of the cumulative data for the entire study comoared the data of eacn -1 4 - of the treatment groups against the data of the concrol group of that sex. The data were visually inspected, and those cases suggestive of a statistical difference iron control were analyzed. b) Histopacholbgy Observations and Tumor Incidences: This statistical evaluation compared the cumulative data of each dose group against the data of the control group of that sex. The exact number of tissues examined was used as the total group size in each analysis performed. The data were visually inspected and those cases suggestive of a statistical difference from control were analyzed. ~ --, i ~j j --1 -1 5 - RESULTS Dietary Concent of 2,4,5-T. Analyses of feed samples indicated the dosage levels of 30, 10 and 3 tig 2,4,5-T/kg/day equated with approxi mately 677 ppm, 230 ppm and 35 ppm of 2,4,5-T in the diet (Table 2 and Appendix 1). Repeated analyses of the feed samples indicated generally good agreement between the intended content of 2,4,5-T and the results of analysis for 2,4,5-T content. On one occasion, analysis of the diet for the group of rats given 3 mg 2,4,5-T/kg/day indicated a somewhat higher than expected content of 2,4,5-T, but this was considered to have minimal impact on the study. Sody Weight Data. Body weight data are included in Table 3 and Appen dices 2 and 3 (118-119 day study), and Table 4 and Appendices 4 and 5 (two-year study). Mean body weights of all treated male and female rats in the 118-119 day study showed no statistically significant differences from control means. Mean body weights of females given 30 mg 2,4,5T/kg/day were statistically decreased at four time periods during the course of the two-year study. The mean body weights of males given 30 mg 2,4,5-T/kg/day had a trend towards slightly lower values during most of the two-year study. Males and females-given 10 or 3 mg 2,4,5-T/kg/day had no statistical differences from control values, except for 1 time period whan the mean body weights of males given 10 mg 2,4,5-T/kg/day were statistically increased. This isolated observation was considered of no toxicologic significance. 5U3-1/ -1 6 - Food Consumption Data. Food consumption data are listed in Table 5 and Appendices 6 and 7 (113-119 day study) and Table 6 and Appendices 3 and 9 (2-year study). There were no consistent deviations in the food con sumption of males or females at any of the 3 dose levels during the course of the 113-119 day-study or the 2-year study. The few sporadic cases in which there was a statistical increase or decrease between the control and various treatment groups followed no consistent trend,.and were considered of no toxicological significance. Mortality. Cumulative mortality data from the two-year study are in cluded in Tables 7 and 8 and Figures 1 and 2. The group of mala rats given 30 mg 2,4,5-T/kg/day had a statistically significant decreased rata of mortality during the latter portion of the study, possibly secondary to a lesser degree of chronic renal disease noted in these male rats. Females at this dose level showed no difference from the control mortality rata. Males and females given 10 mg 2,4,5-T/kg/day had statistical increases in mortality rate during 4-5 time periods. Males given 3 mg 2,4,5-T/kg/day had statistically decreased mortality rates during 4 time periods. Females at this low dose level showed no differences from control values. These differences in mortality races in rats given 10 or 3 mg 2,4,5-T/kg/day shewed no dose-related effects and were considered of no toxicological significance. P a lp a b le M a sse s a n d A n im a l O b s e r v a t i o n s : T he c u m u la tiv e num b ers o f r a ts o f th e tw o -y e a r stu d y w ith p a lp a b le m a sses d e te c te d a t m o n th ly in te r v a ls -1 7 - ara given in Table 9. The first palpable mass was noted in a sale rat of the control group. Thera ware no statistically significant differences between control and treated male rats except during nonchs 13 and 14, when male rats given 10 mg 2,4,5-T/kg/day had an increased incidence of pal pable masses. This was considered of no toxicological significance due to its isolated occurrence and lack of a dose or temporal response. There were no differences in the number of treated female rats with palpable masses except for a statistically increased number of rats with palpable masses in the group receiving 30 mg of 2,4,5-T/kg/day during months 9 and 10 only; the female group receiving 10 mg 2,4,5-T/kg/day showed a statistically significantly increased incidence of palpable masses during month 14 only. These observations were considered of no toxicological significance due to these isolated occurrences and absence during the latter phases of the study. Examination of the rats during the course of the 2-year study revealed no clinical evidence of toxicity attributable to these levels of traacment with 2,4,5-T. Hematology. The hematology data from the 113-119 day study are listed in Table 10 and Appendices 10 and 11. The hematology data from the 2-year study are listed in Tables 11-13 and Appendices 12-17. Thera ware no statistically significant differences from control values at any dose Lav&I. ac any cirne during tne course or the suocmroTiic or cnxonic por~ cions of the study. Xld-13 I -1 3 - Urinalvsis. Urinalysis data for cha 113-119 day study ara listed in Table 14 and Appendices 13-19. Examination of urinary specific gravity, pH, glucose, protein, ketones, bilirubin and occult blood showed no changes considered related to treatment. Urinalysis data from the twoyear study are listed in Tables 15-17 and Appendices 20-25. Repeated examination of the above listed parameters plus urobilinogen at the last two time periods revealed no changes considered related to treatment. On one occasion there was a statistical decrease in the specific gravity of mala rats given 10 mg 2,4,5-T/kg/day; however, this was considered of no toxicological significance due to its isolated occurrence and lack of dose response. Urinary Volume, Creatinine, Porphyrins and delta-ALA. These data for the 118-119 day study are summarized in Tables IS and 19 and individually listed in Appendices 26-29. The data from rats used in the two-year study are summarized in Tables 20-24 and listed individually in Appendices 30-34 ") In males receiving 30 mg 2,4,5-T/kg/day, there were statistically signi ficant increases in total urine volume and excretion of ccproporpnyrin and uroporphyrin. In males receiving 10 mg 2,4,5-T/kg/day, there was a statistically significant increase in copropcrphyrin excretion in the early phase of the study only. In females receiving 30 mg 2,4,5-T/kg/day, there was increased excretion of coproporphyrin at most of the sampling times during the study; the excretion of uroporphyrin was statistonally decreased after 119 days and statistically increased after 566 days. -1 9 - In mala rats receiving 3 mg of 2,4,5-T/kg/day and in faaala rats receiv ing 10 or 3 ag 2,4,5-T/kg/day there were no statistically significant changes in total urinary volume, or excretion of creatinine, coproporphyrin, uroporphyrin, or delta-ALA at any time during the study. Clinical Chemistry. The data from rats killed at the .interim necropsy after 118-119 days on study are listed in Table 25 and Appendices 35-36. The. data from rats killed at the termination of the two-year study are listed in Table 26 and Appendices 37-38. Analyses of serum samples collected by decapitation showed no alterations considered related to treatment with any of the dose levels in regard to 3UN, SGPT, A?, bilirubin (total, direct, indirect), total protein, albumin, and globu lin. SGPT was statistically increased in females given 10 mg 2,4,5T/kg/day for 118-119 days; however, this was considered of no toxico--logical significance due to its isolated nature, lack of dose response and absence at time of the terminal necropsy. Organ Weights. The data from rats killed at the interim necropsy after 118-119 days are listed in Table 27 and Appendices 39-40. A statisti cally significant increase in relative weight of the kidneys of mala rat. given 30 mg 2,4,5-T/kg/day was considered to be related to treatment. The data from rats killed at the termination of the two-year study are listed in Tables 23 and 29 and Aooendicas 41-42. The only statistical -2 0 - differance was a decrease in che absolute heart weight of males given 30 mg 2,4,5-T/kg/day; this was considered to be of highly questionable toxicological significance due to the absence of any discernible aross or histopathologic changes in these hearts. There were no alterations in weights of brain, liver, testes, spleen, thymus or uterus/ovaries at any of the dose levels which were considered related to treatment. Gross and Histopathologic Observations. The gross necropsy and his topathologic observations for rats killed after 118-119 days are tabulated in Tables 30 and 31, respectively. There were no gross or histopatho logic observations that were considered to be the result of treatment with any of these dose levels for 118-119 days. The gross necropsy and histopathologic observations for rats from the two-year study are included in Tables 32-33 and 34-35, respectively. This includes data on all rats that died, were culled or survived to the terminal kill after 2 years. In view of the voluminous nature of che pathology data included in Tables 30-35, examples of the major treatment-related observations have been selected for the attached Summary Table. These pathology results are discussed below. The kidneys of female rats receiving 30 mg 2,4,-5-T/kg/day had gross and microscopic evidence of an increased incidence or mineralized deposits in the renal pelvis; these mineralized deposits were sometimes accompa nied by a localized inflammatory reaction of the adjacent renal pelvis ; --i .) -q j --i "1 _) -2 1 - epithelium. Ocher renal effects attributed to ingestion of 30 mg 2,4,5T/kg/aay included an increased content of pigment within the cytoplasm of proximal convoluted tubular epithelial cells (females), and a decrease in the severity of the chronic nephropathy that normally occurs as a spon taneous entity, especially in the males of this^strain of rat. The special stains applied to sections of kidneys of the control and high dose group indicated similar staining reactions for both groups, except that the increased pigment noted in the high dose group gave an increased positive reaction with Mallory's stain for iron. The 3 cases of petechial hemorrhage of the urinary bladder noted in the group of male rats given this high dose level were not considered'to be related to treatment cue to the fact these cases of hemorrhage occurred secondarily to geriatric inflammatory processes originating in adjacent structures. At the in termediate dose level of 10 mg 2,4,5-T/kg/day, there was an increased incidence of mineralized deposits in the renal pelvis of female rats. Statistical increases in the incidence of focal renal tubular atrophy and renal aggregations of lymphoid cells noted in this group of female rats were considered to be a secondary result or an cveralc decrease m the severity of the geriatric chronic renal disease noted in this group. A statistical decrease in the incidence of mineralized depostts rn tne renal pelvis of kidneys of male rats given 10 mg 2,4,5-T/kg/day may or may not have been the result of treatment. At the lower dose level of 3 mg 2,4,5-T/kg/day there were no renal lesions of any type in either males or females that were considered related to treatment. -2 2 - The decreased sever!cy of the spontaneous chronic nephropathy noted in male rats receiving 30 mg 2,4,5-T/kg/day, was accompanied by a secondary decrease in the incidence of mineralization of pulmonary alveoli, myo cardium, myocardial blood vessels and gastric mucosa and muscularis. Although the kidney was the primary target organ, the liver was also affected slightly by lifetime treatment with 30 mg 2,4,5-T/kg/day. The group of male rats given 30 mg 2,4,5-T/kg/day had a decreased incidence of liver enlargement and an increased incidence of focal biliary hyper plasia and periportal inflammation. Livers of females at this high dose level had an increased incidence of focal aggregation of reticuloendothel ial calls adjacent to degenerate or necrotic hepatocytes and a decreased incidence of multiple foci of hepatocellular alteration (swollen hepato cytes). The incidence of focal hepatocellular cytoplasmic vacuolization was decreased in livers of males given 30 or 10 mg 2,4,5-T/kg/day. Al though the incidence of grossly visible liver nodules was higher in che control group of females than in the treatment groups, this was assumed to be due to a somewhat higher incidence race of this observation in this control group as compared to our historical experience (t6%). Livers of rats given 3 mg 2,4,5-T/kg/day had no observations attributed to the lifetime ingestion of ,this dose level. The lungs of rats given 30 mg 2,4,5-T/kg/day had some observations that di directly or indirectly may have been the result of this level of treatment The grouo of males given this high dose level had an increased incid sncs -23- o focal pulmonary interstitial inflammation, focal accumulacions of alveolar macrophages and cholescerol clefcs. A few females given chis high dose level had increased incidence of focal accumulacions of secre tory material in Che alveoli. At the intermediate or lower dose levels of 10 or 3 mg 2,4,5-T/ kg/day there ware no pulmonary changes attributed to treatment, with the possible exception of an increased incidence of focal interstitial fibrosis in lungs of females of the intermediate dose level. However, as this observation was not seen at the higher dosage level, it is of highly questionable toxicologic significance. Examination of the tissues of the cardiovascular system revealed no lesions that could be definitely attributed to the ingestion of any of these dose levels of 2,4,5-T. In the group of rats given 30 mg 2,4,5T/kg/day, the females had a statistical increase in the incidence of hearts with a dilated, flaccid ventricle; however, the opposite trend occurred in the heart of males given chis same high level. In males given eipher 30 or 10 mg of 2,4,5-T/kg/day, there was an apparent trend toward decreased incidence of both periarteritis and left atrial thrombosis; however, these observations may not have been the result of treatment with these dose levels of 2,4,5-T. There were no other gross or histopathologic observations on the various organs that were considered to be the result of ingesting 30, 10 or 3 mg of 2,4,5-T/kg/day for up to 2 years. The other observations not discussed above but listed in Tables 32-35 which were statistically different from -2 4 - the controls were not considered to be the result of treatment usually due to (1) lack of a dose response or (2) abnormal incidence in the control group when compared to historical control data. Tumor incidence. Tumor incidence rates for mala and female rats are tabulated in Tables 36 and 37, respectively. These data are listed for each of the sequential 6-month periods as well as the terminal kill: the cumulative results for each category of tumor type are also included. The spectrum of tumors that have been historically observed in rats of this strain were noted in the liver, nasal turbinates/hard palate, lungs, pancreas, kidney, urinary bladder, testes, ovary, uterus, musculoskeletal tissue, oral cavity, tongue, salivary glands, stomach, small intestine, large intestine, subcutaneous tissues, integument, mammary gland, ear canal, brain, peripheral nerves, pituitary gland, cranial cavity, adrenal glands, eye, lymph nodes, thymus, spleen, mesentery, thyroid and para thyroid glands. Upon statistical analyses of these tumor data, the incidence rates for all categories of tumor types occurring in any of the groups given 30, 10 or 3 mg 2,4,5-T/kg/day were comparable to the control group, with the exception that the incidence rate of ir.reriollicular C-cell adenoma of the thyroid was statistically increased in females given the low dose level of 3 mg 2,4,5-T/kg/day. This observation was considered not related to treatment based on the lack of a dose response and an unusually lower incidence of thyroid adenomas in this con group of females when compared to h.iscoricai control data (up to Thus, none of the tumors listed in Tables 36 and 37 were conscie' ] -2 5 - relaced to treatment with any of these dose levels of 2,4,5-T. Table 38 summarizes the total numbers of tumors per group, the average number of tumors per rat, and the time interval listing of rats with. tumors for each group. Hone of these parameters were affected by any of these dose levels of 2,4,5-T with these data comparable to the control groups. ." /a s i -2 6 - DISCUSSION During che course of chis two-year scudy, paramecers found to be unaf fected by treatment with any of these dose levels of 30, 10 or 3 rg of 2,4,o-T/kg/day included the rate of mortality, food consumption, palpable masses, hematology (K3C count, Hgb, PCV, total and differential W3C, thrombocytes and reticulocytes), routine urinalysis, urinary excretion of creatinine or delta-ALA., serum clinical chemistry (BUN, SG?T, AP, bilirubin, total protein, albumin and globulin), organ weights (except kidney at highest dose level), tumor incidence as well as gross and microscopic morphology of all organ systems of the body (except for kidney, liver and possibly lung lesions described below. The highest dose level of 30 mg of 2,4,5-T/kg/day predictably caused some degree of toxicity. This included a decrease in body weight gain, an in creased urinary excretion of total urine volume, coproporphyrin and uropor phyrin, increased relative kidney weights as well as morphologic alterations of the kidney, liver and possibly lung. In the kidney, this involved pri marily the presence of mineralized deposits in the renal pelvis, sometimes accompanied by a resultant localized reaction of the adjacent renal pelvis epithelium. The chronic nephropathy normally encountered as a geriatric occurrence in aged rats was decreased in rats given 30 mg of 2,4,5-Tkg/day. Morphologic alterations in the liver considered to be the result of treat ment with this high dose level of 30 mg 2,4,5-T/kg/day included an isad incidence of periportal inflammation, focal biliary hyperplasia and -27- inflammatory cell aggregations adjacent to degenerate hepatocytes; this was accompanied by a decreased incidence of multiple foci of swollen hapatocytes and focal cytoplasmic vacuolization, lungs of rats given 30 mg 2,4,5-T/kg/day had indications of focal pulmonary inflammation, including focal accumulations of alveolar macrophages and cholesterol clefts. At the. intermediate dose level of 10 mg of 2,4,.5-T/kg/day there was only minimal toxicity, limited 'primarily to an increased incidence of miner alized deposits in the renal pelvis; an increase in urinary excretion of coproporphyria was noted in males of this dose level only during the early phase of the study. -At the lower dose level of 3 mg of 2,4,5-T/kg/day there were no alterations in any parameter considered related to treat ment over the course of this two-year study. In this study, there were no tumors considered to be the result of treatment with, any of the dose levels, including the maximum tolerated dose of 30 mg 2,4,5-T/kg/day given for 2 years. The absence of any oncogenic response noted in this study concurs with the results of most of the previous oncogenic studies on 2,4,5-T that have been reported. The 1969 report of lanes et al. found no oncogenic response in either of 2 strains of mice given the maximum tolerated dose of 21.5 mg 2,4,5T/kg/day. The 1963 study by the Bionetics Research Laboratory noted no increase in tumors in mice of 2 strains given a single subcutaneous injection of 215 mg 2,4,5-T/kg. t U 2 l 1T 3 -23- The only published oncogenic study which reports an increase in Cursors allegedly due to treatment with 2,4,5-T is one of the four studies con ducted by Muranyi-Kovacs _et a l . and published in 1976 and 1977. In these studies, mica of the C3Hf strain that were given a single dose level of 80 ppm (approximately 12 mg/kg/day) of 2,4,5-T had a statistical increase in the so-called "non-incidental'' types of cursors. Mice of the XVIIG strain that were given the identical regimen of treatment with 2,4,5-T did not have any increase in tumor incidence. When Muranyi-sCovacs ejt al. (1977) gave neonatal mice of these same 2 strains (C3Ef and XVIIG) a series of sub cutaneous injections of 2,4,5-T there was no resultant increase in tumor incidence in either strain of mouse. In the one oncogenic study.out of four conducted by Muranyi-Kovacs e^_ al. in which there was reported to be an oncogenic response due to 2,4,5-T, it is interesting to note that there was no specific "target tissue" that was showing the alleged onco genic response. This is contrary to the vast majority of cases wherein a true positive oncogenic response typically affects specific target tissue(s)., with the resultant increase in tumors originating from the target tissue(s). Overall, the results of this study concur with the results of all but one of the previous oncogenic studies which have been reported on 2,4,5-T. In the study reported herein, rats given 30 or 10 mg of 2,4,5-T/kg/day tor 2 years had some cosa-related toxicity (primarily renal) but no oncogenic response; rats given 3 mg of 2,4,5-T/kg/day had no adverse effects re lated to treatment. 2 / 2- -29- This report was prepared end submitted by the following Staff Members: S^/j. Kociba, D.V.M., ?h.D. Diplomate, American College of Veterinary Pathologists Associate Scientist Toxicology Research Laboratory September 27, 1978 1 ) is- 'Jj-fo -3-7-7%________________ D. G. Keys's, 3.S. Medical Technologist American Society of Clinical Pathologists Research Medical Technologist Toxicology Research Laboratory September 27, 1978 R. W. Lisowe, His to technologist American Society of Clinical Pathologists Senior Research Histologist Toxicology Research Laboratory September 27, 1978 tf/U SiS 9 -J R . P . Kalnins, 3.S . Medical Technologist American Society of Clinical Pathologists Research Medical Technologist Toxicology Research Laboratory September 27, 1973 /O03AJq 7 9-J7-7# D. D. Dittenber, 3.S. Medical Technologist American Society of Clinical Pathologists Research Medical Technologist Toxicology Research Laboratory September 27, 1978 Senior Research Toxicologist Toxicology Research Laboratory September 27, 1973 (?, UJ<x*3> 9 a 7 - 7 r ~ C. E. Wade Research Biologist Toxicology Research Laboratory September 27, 1978 /3 ASSm j Z i 2. Cct7 3 3. A. Schwecz, "D.V.M., Ph.D. Director Toxicology Research Laboratory September 27, 1978 REVIEWED 3 Y : Research Specialist Analytical Laboratories Midland Division September 27, 1973 .S '^ -0 1 \ qjg K. S. Rao, D.V.M., Ph.D. Research Specialist - Toxicology Toxicology Research Laboratory September 27, 1978 1 22 -3 0 - REFERENCES Bionetics Research Laboratories (1968). Evaluation of Carcinogenic, Teratogenic and Mutagenic Activities of Selected Pesticides and Industrial Chemicals. Report No. NCI-DCCP-CG-1973-1-1 issued August 1968. Drill, V. A. and Hiratzka (1953). Toxicity of 2,4-Dichlorophenoxyacetic Acid and 2,4,5-Trichlorophenoxyacetic Acid. A report on their acute and chronic toxicity in dogs. Ind. Hyg. and Occup-. Med. 7, 61-67. Gehring, ?. J.,. Kramer, C. G. , Schwetz, 3. A., Rose, J. Q. and Rowe, V. K. (1973). The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Following Oral Administration to Man. Toxical. Appl. Pharmacol. 26, 352-361. Highman, 3-, Gaines, T. 3. and Schumacher, H. G. (1976). Sequential Histopathologic, Hematologic, and Blood Chemistry Changes Induced by a Technological and a Purified Preparation of 2,4,5-Trichloro phenoxyacetic Acid. J. Toxicol. Environ. Health 1, 469-484. -3 1 - Iimes, J. R. H., lland, 3. M. , Valerio, M. G., Petrucelli, L. , Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk, H. L., Gart, J. J., Klein, M . , Mitchell, I., and Peters, J. (1969) . Bioassay of pesticides and industrial chemicals for tumorigenicity in nice: A preliminary note. J. Hat. Cancer Inst. 42, 1101-1114. Luna, L. G. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, 3rd Edition, 1968. McGraw-Hill Book Company, Hew York, New York Muranyi-Kovacs, I., Rudali, G . , and Imbert, J. (1976). Bioassay of 2,4,5-Trichlorophenoxyacetic Acid for Carcinogenicicy in Mice. Brit. J. Cancer 33, 626-633. Muranyi-Kovacs, I., Rudali, G . , and Imbert, J. (1977). Study on the Carcinogenicity of 2,4,5-T in Mice. Abstract of presentation at Fourth Meeting of the European Assoc. Cancer Res., University of Lyon, September 13-15, 1977. Piper, W. N., Rose, J. Q . , Leng, M. L. and Gehring, ?. J. (1973). The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Following Oral Administration to Rats aha Dogs. Toxicol. Appl. Pharmacol. 26, 339-351. i 2 .' S 7 -3 2 - Rove, V. K., Hyman, I. A- (1954). Summary of Toxicologic Information on 2,4-D and 2,4,5-T Type Herbicides and an Evaluation of the Hazards to Livestock Associated with Their Use. Am. J. vat. Res. 15, 622-629. Siegel, S. (1956). Mon-parametric statistics for the behavioral sciences. McGraw-Hill 3ook Company, Inc., Mew York. Smith, F. A., Scnwecz, 3. A., Murray, F. J . , Crawford, A. A., John, J. A., Kociba, R. J . , Humiston, C. G. (1978). Three-Generation Reproductive Study of Rats Ingesting 2,4,5-Trichlorophenoxyacetic Acid in the Diet. Abstract presented at 17th Annual Meeting or Society of Toxicology, March 12-16, 1978. Steel, R. G. and Torria, H. H. (1960). Principles and procedures of statistics. McGraw-Hill 3ook Company, Inc., Mew York. SUMMARY T A B L E S U M M A U Y 01*' M A J O l t O B S E R V A T I O N S IN HATS M AINTA INED ON D IE T S C O N TA IN ING 2 , 4 , 5 - T 2F O R U P T O YEAUS ( In c lu d in g S e le c te d D ata E x tr a c te d from T o ll D ata b ase fo r P u rp o se of D e p ic tin g E f f e c ts C o n s id e re d R e la te d to T re a tm e n t) Sex D ose (m g /k g /d a y ) N um ber o f R a ts in G roup (2-Y ear + 118-D ay S tu d ie s ) PARAMETER U o d y N e l glu. ( g r a n t s ) ( M c a u i S . D . ) Food Consum ili Ion N o ila | i i y P a lp a b le M usses and C l in ic a l O b s e rv a tio n s Il.-IN.Ito 1 O ^ v ( H H C , I'CV, llB b , U l t e , d i f f e r e n t i a l H O C , p 1 a i c J e l s , r e (. 1 c u 1 u c y l e s ) U i i n a j y s l s ( s p e c i f i c g r a v i t y , pii, p r o t e i n , g l u c o s e , K eto n es, o c c u lt blo o d , b il i r u b i n , u ro b ilin o g e n ) Hi i n . t t y E x c r e t i o n - ( i l U - i i y D a y S t u d y ) T o l a ) u r i n e v o lu m e (4 8 b r . volutile i n m l) ( M e a n i S . D . ) C.'o p r o p o r p b y r I n ( j t g / 4 8 b r . ) ( M e a n i S . 0 . ) II r o | m r p h y r i t i ( | t g / 4 b b r . ) ( M e a n i S . 1) . ) C rea lin i m: De 11 a - a m i nil 1e v u 1 1nJ c a c id Ut i n a r y E x c r e t i o n - ( T e r m i n a t i o n o f T w o - Y e a r S l n d y ) Copri/jioi pityri.n (p g /'i8 h r . ) U r o p o r phy r l n (|ig/4U b r . ) C l i n i c a l C h e m i s t r y (SO FT , BUN, A P, b i l i r u b i n , a l b u m i n . g lo b u li n , LoLal p ro le ltt) O r^ u i U e i r M s ( b r a i n , l i v e r , t e s t e s , b o a ri th y m u s, )s p l e e n , o v a r c s / u l . c r u s ) - ( l l . M - 1 1 9 D a y a n d 2 - Y e a r S L u d i c:i K i d n e y s - (1 I l l - D a y S t u d y o n l y ) ( g m / 1 0 0 gm 11.W .) (M ean !S . U .) C r o s s an il II1 l o j s i i lui 1o g y E x a m i n a t i o n ( A i l o r g a n s y s t e m s ) : K idney - M in e ra liz e d d e p o s its in p e lv is L o c a liz e d r e a d , ion a d j a c e n t to m in e r a l Ized d e p o s i t s M u d e r a i o l.p s e v e r e e l i c o n i e r e n a l d i s e a s e I n c r e a s e d pigm ent in r e n a l L o b u la r c y to p la s m M i ite t a 1 i z a L i o n s e c o n d a r y t o r e n a l d i s e a s e S e e n I n - pit 1m o n a t y a 1v.:o L i m y o c a i d i uni m y t i c a i d i 1 1 b l o o d v essels g u s t i l e m u c o s a /imi m u s c u l a r l s 0 06+10 M ales 30 10 50 + 10 50-1-10 3 50+10 3115m 375123 306*25 3U5125 ---- -- ---- 3o*o 1 7 .5 * 4 .9 4 .m .o 49211 4 3 . 6 * 9 . 3a 7 .7 * 4 .7d 36*14 2 4 .6 * 9 .6 " 5 .0 1 3 .1 4 0 2 L0 2 3 .1 2 4 .2 4 .5 2 2 .0 1 4 .6 1 6 .0 4 .7 1 1 .0 2 2 .8 * 1 3 .0 4 .O il.5 -- 9 .7 1 4 .4 3 .0 il.3 -- 1 5 .2 2 3 .6 3 .0 2 0 .9 -- 0. 7010.09 """ ____ 0 .7 9 * 0 .0 6 " 0 .7 3 1 0 .0 5 0 .7 2 2 0 .0 5 5 6 /0 6 1 1 /0 6 5 /06 1 2 /0 6 2 5 /0 5 -- -- 2 2 /5 0 d -- 0 /5 0 " 0 /5 0 0 /5 0 d 1/5 0 " -- -- 30 /5 0 -- 4/5 0 2/5 0 5/5 0 9 /49 -- -- 20 /5 0 -- 0 /5 0 3/5 0 6/5 0 1 3 /4 9 0 86+10 Fem ales '3 0 10 50+10 50+10 3 50+10 253214 244112" 253H 5 2 5 4 1 1.2 9 .6 2 1 .9 -- -- -- 1 6 .4 i7 .o" -- -- -- -- 9 .2 1 0 .(5 -- -- -- -- 1 0 .3 * 3 .5 -- 5 .8 2 1 .9 0 .0 * 9 .0 -- -- 9 .0 1 2 .3 -- -- 6 .5 1 2 .3 -- -- ____ -- -- -- -- 1/0 6 25 /8 6 6 /0 6 0 /0 6 B /5o" 3 Z /5 0 " 1/5 0 11 /5 0 " -- -- -- -- 5 /50 22 /5 0 2/5 0 0 /5 0 -- -- -- -- 1 /5 0 1 9 /5 0 6 /5 0 0 /5 0 -- -- -- -- i Si ill i :i L t e a I I y pCO.O'i. ------ I n d i c a t e s Ftif pat anici ef:i d l t l e r e n i from c o n t r o l v a lu e ( s ) when a n a ly z e d u s in g a n a l y s i s o f v a r ia n c e and D unnei l ' s T e s t, p < 0 .0 5 p a ra m eL e r was c o n s id e r e d u n a f f e c te d a t any le v e l o f t r e a tm e n t. w i L l i v o 1urn 1n o u s o r m u i l i p l e o b s e r v a t i o n s , o n l y s e l e c t e d r e p r e s e n t a t i v e v alu es a re lis ted in sum m ary or F is h e r 's ta b le . E xact P ro b a b ility Test, SUMMARY TABLE (Continued) SUMMARY O F M A JO R O B S E R V A T I O N S I N R A T S M A I N T A I N E D ON D I E T S C O N T A I N I N G 2 , 4 . 5 - T FOR UF T O 2 Y E A R S D a t a b a s e f o r P u r p o s e o f D e p l e t i n g E f fliCLS C o n s i d e r e d R e l a c e d t o T r e a t m e n t ) D o s e .(j!*g/|<gAjay) C iNil(illIel." lL LilS ii oujj ( 2 - Y e a r T 1 I B - P a y S t u d i e s ) ivkanetek ( c o n i *d) C r o s s a m i li i s L o p a l h o l o g y E x a m ! n a t i o n ( c u n t * d ) I . I V C L* - Eii i a r g c m e n t I'ucul b i l i a r y h y p e r p l a s i a I'oi I p o i l a l I n 1 i n m m a L i o n Focal a g g re g a te s of re tic u lo e n d o th e lia l c e lls a d jac eu L to d e g e n e ra te o r n e c r o tic h e p a to c y te a M u ltip le lo ci of liuj>a L o c y t e s ) h e p ato c ellu lar a lte ra tio n (sw o llen E m .i ] h e p a l o c o 1 l u i a r c y t o p l a s m i e v a c u o 1 i z a c l o u i . u n K ii la ic a l i lit e i si. i 1 1a 1 i n f l a m m a t i o n Eoiaii J a m m u I u t i u n s o f a l v e o l a r m a c r o p h a g e s i n a l v e o l i E m a 1 r h o I c s l c r n I c I e i: t s t-'ui a i a e n n u i 1 a t i o n e o t s e c r e t o r y m a t e r i a l , i n a l v e o l i C u i'll i o v a s c o l a r - D i Iat e<l/t Iiia: Id v e n t r i c l e IV r iai't.er 1Li s la lt a t r i a l L hrom busis T . . MI DI a (Sc c ( a ll org an sy stem s) a t t a c h m i t.upp Ic m e n ta 1 tum or d ata) 0 86110 11 /8 6 9/8 6 29 /8 6 3 6 /8 6 21 /8 6 28 /8 6 6/U 6 28 /8 6 20 /8 6 1 2 /8 6 30 50110 Ma le a 10 50110 3 50110 l/5 0 u 16/50** 28/50** -- -- 8/50** 27/50** 29/50** 9/50** -- 9/5 0 8/5 0 3 /50 7/5 0 8 /5 0 9/5 0 -- -- 12 /5 0 " 5/50** 13 /5 0 5/5 0 -- 7 /50 8 /5 0 6 /5 0 3 /50 6/5 0 7 /5 0 " -- _____ 2 0 /5 0 5/50** 1 6 /5 0 6 /5 0 -- 1 5 /5 0 1 2 /5 0 6 /5 0 0 86+10 E em ales 30 10 50(10 5 0 (1 0 36 /8 6 15 /8 6 0 /8 6 0 /8 6 -- -- 36/50** 3/50** -- ____ -- -- 6 /5 0 " 3/50** -- -- -- -- 21 /5 0 6 /5 0 -- ____ -- -- 2/5 0 2/5 0 -- -- 3 5 0 (1 0 -- -- 17 /5 0 6 /5 0 -- ____ -- -- .2 /5 0 1 /50 -- -- S l a i: I s t i c a 1 l y d i t f e r e n l P<0. lit*. f ro m c o n t r o l v a i u c ( s ) w h e n a n a l y z e d u s i n g a n a l y s i s o t v a r i a n c e aiul D u n n c t t ' s T e s t , p < 0 .0 5 o r F i s h e r 's ------------ I n d i c a t e s p a r a i H u L e r w a s c o n s i d e r e d u n u t t e c t e d a t a n y l e v e l o t t r e a t m e n t . t o r p a i a m e l . u r s v i l l i v o l u m 1n u n s n r m u l t i p l e o b s e r v a t i o n s , o n l y s e l e c t e d r e p r e s e n t a t i v e v a l u e s a r e l i s t e d i n s u m m a r y t a b l e . E xact F ro b a b ilily 'te s t, Z i___ i .1 SUMMARY TABLE (Continued) SUPPLEMENTAL TUMOR INCIDENCE DATA IN RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T Sex. Dose (nip,/kj'/day) Number of Rats in Group Males 0 30 10 06 50 50 Total Number of Tumors in Group 172 97 71 Average Number of Tumors per Rat 2.0 1.9 1.4 N_umbe_ oi Tumor-bearing Rats/Number of Rata in Group These Da La Liu ted in Time Intervals in Months: L-6 7-12 .13-10 19-24 Terminal Kill .Totali 1/1 1/2 8/14 60/63 6/6 76/06 (80%) 0/0 0/0 6/9 24/25 14/16 44/50 (oo%) 0/0 1/1 15/22 20/23 4/4 40/50 (00"/) 3 50 89 1.0 0/0 0/1 9/12 26/28 9/9 44/50 (00%) 0 86 ' 308 3.6 Females 30 10 50 50 150 147 3.0 2.9 3 50 140 2.8 S 0/0 1/2 16/17 30/31 36/36 03/06 (97%) 0/0 2/2 9/9 ` 18/10 21/21 50/50 (100%) 0/1 1/2 11/11 25/25 11/11 40/50 (96%) 1/1 0/1 10/11 10/10 19/19 40/50 (96%) aNo sta List ini.l differences from control data when a islyxed using Fisher1s Exact Probability Test, p<0.05. IV; r e m i t Mortality 00 figure 1 CUMULATIVE MORTALITY OF MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR TWO YEARS Control 30 iug/kg/day 10 uig/kg/day 3 mg/kg/day waaMedOB t I7 Months on Test I'K.'lJUli 2 b G IT L ___j ___ ..... J J -3 8 - TABLS 1 ANALYSIS OF SAMPLE OF 2,4,5-T USED- IN TWO-YEAR DIETARY STUDY 2,4,5-Trichlorophanoxyacetic Acid by deration - 99.1% Other Phanoxy Consonants___________________ GLC Condition No. 2.6- dichlorophenol 2,4-dichlorophanol 2.3.6- trichlorophenol 2.4.6- trichlorophenol' 2.4.5- trichlorophanol 2-chlorop'nenoxyacetic acid 4-chlorophenoxyacetic acid 2.5- dichlorohydroquinone mono methyl ether 4.6- dichlororasorcinol mono-methyl ether 4.5- dichlorocatechol mono methyl ether 2.6- dichlorophenoxyacetic acid ,5-dichlorophenoxyacetic acid ,4-dichlorophenoxyacatic acid 3.4- dichlorophenoxyacetic acid 2.4.6- trichlorophenoxyacetic acid 2.3.6- trichlorophenoxyacetic acid 4.5- dichloro-2-methoxyphenoxyacetic acid 2.5- dichloro-4-methoxyphenoxyacetic acid 2,4-dichloro-5-methoxyphenoxyacetic acid bis(2,4,5-trichlorophenoxy)acetic acid Unknown A , Unknown B 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1,3 1 1 il :} -- - 2 3 3 Weigi Parcs N.D .* N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.12 0.02 N.D. N.D. N.D. 0.34 0.67 N.D. 0.03 0.06 JxJ The following gas-liquid chromatography conditions were used to determine the impurities: Flame ionization detectors were used in all cases. GLC Conditions Column: 3' x 1/3" 25% LAC 2R44, 2% H^PO^ on 30/100 mesh Chrom W Column Tamp. 215C, Injector Tamp. 235C, Detector Temp. 230C GLC Conditions 2 Column: (glass) 10' x 1/3" 5% OV-1Q1 on 30/100 mesh Chrom 0 Column Tamp. 280C, Injector Temp. 305C, Detector Temp. 325C GLC Conditions ?3 Column: (glass) 101 x 1/3" 5% OV-101 on 30/100 mesh Chrom Q Column Temp. 235C, Injector Temp. 23QC, Detector Tamp. 2153C N.D. is not detect ad- ..The limit of etaction is estimated as c,, . ^ jnxnown A r.as tne proposed structure of bromodichloropheno:cya '"Unknown 3 has the crcocsed structure of tetrach1cro?henoxyace Data from Dow reoor ts ML-aL 37-561 an AL 33-607. -3 9 - TABLE L (Continued) ANALYSIS OF SAMPLE OF 2,4,5-T USED IN TWO-YEAR DIETARY STUDY Dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin Bexachlorobenzo-p-dioxin Heptachlorodibenzo-p-dioxin Octachlorodibenzo-p-dioxin N.D. = None Detected Data from Dow Report A1-7S-70077. Found ppb N.D. N.D. N.D. N .D ._ Limit of Detection ppb 0.33 0.12 0.40 0.40 -4 0 - TA3LE 2 MEAN ANALYTICAL CONTENT OF 2,4,5-T IN DIETS OF RATS USED IN A TVO-YEAR TOXICITY STUDY Time Interval, Months 5 7 12 19 (.males) 19 (females) 23 (males) 23 (females) Mean dietary content of 2,4,5-T Anticipated Dose Level of 2,4,5-T (ns/k^/dav) 30 10 3 580 ppm 660 ppm 750 ppm 760 ppm 630 ppm 700 ppm 660 oom 180 ppm 240 ppm 250 ppm 250 ppm 200 ppm 250 ppm 240 ocm 63 ppm 63 ppm 93 ppm 65 ppm 64 ppm 150 ppm 94 pom 677 ppm 230 ppm 85 ppm SUP. 90 TAULE 3 MEAN UOD UElGIITS"* OF MALE AND EEMAl.E UATS MAI NTA INED ON DJ ETS CONl'AINNG 2,4.5-T FOU 118 AND 119 DAYS Du c 0 :io 10 ) >l : X N M M N Dava on T e s t ----------------------------------------------- -- --------------------------------------------------------------------------------------------- * - -------------------- 2b6 1 3 20 32 39 46 53 60 21,719 24 3 ilO 337H 5 32911.8 2 4 H a 10. 3 3 4 1 1 9 243112 336119 367118 357122 364126 366122 384119 377124 386131 385126 401*22 391138 40 2 i3 5 402128 412135 408127 41913U 421130 437129 426130 437143 436 t3 4 450130 440131 451146 45 136 4 6 2 i3 0 447131 46H 51 462140 68 454131 462136 46 5 t5 6 458146 81 88 481*35 494134 474134 480135 49 5 1 6 1 # 500163 486*42 494142 95 499132 484142 510166 502142 102 5 0 /1 3 3 492136 517165 500*45 117 v j iiy 494142 512*66 50U144 0 1` 20017 240110 25118 25 9 ill 270112 274112 2 8 2 il3 288U 4 289112 299114 3 0 2 15 306115 31.0115 516 `J U 318118 2 i: t o 1- 20517 24218 255H O 265111 274110 2 7 7112 282H 1 209115 290113 296H 3 302H 5' 306116 311116 5 1 15 jih ju 10 l- I9 9 i6 240114 254115 26H 16 269120 277H 8 2 8 3 20 2U8 12 1 2 9 4 i 24 303122 306123 310124 313126 316*22 326127 i V 2 0 114 24017 256110 263*12 261 2 7311 3 284113 290H 2 290114 299*13 305114 307114 312114 314*13 318*24 `\ \ l wl` o l n g i 7 . n n t > uii stan d ard d ev iac i n . 2( 1 0 r a t s / g r - u t i j * J j o n s e d rats /c a g e ). N o s L . 1 1 i : H i c a l 1 y t i g n i L: L e a n l d i f f e r e n c e s f r o m c o n t r o l i i i c a n s u s l n g a n a l y s l s o l : v a r i a u c c a n d D u n n e t C s t e s t , < 0 .0 5 . [ L. i ..J ) 1 b -42- 7A3LE 4 MEAN BODY WEIGHTS* ?OR MALZ AND ZZ2ALZ -UTS MAINTAINED ON DIETS CONTAINING 2 , 4 ,5 - T 70S. 2 YEARS Days on Tes c 0 6 13 20 26 32 39 4 53 50 63 75 31 38 95 123 152 175 130 203 232 253 291 314 349 377 405 433 463 501 531 559 587 622 550 635 714 732 M ales 0 30 ici 244I2 290cl3 33417 36221 38521 39626 414+30 430 i 33 444*30 45536 472i38 479*39 48839 49343 498i36 521 536*42 560ri9 56157 567C4 586r50 596*49 61752 627*53 , 622*54 635*55 641r58 65650 654r6l 647 61 63259 620;62 617*65 591C64 57872 562*61 54350 538;51 243 riO 290I0 329*12 356*16 375*21 393*20 40320 42422 437 30 45223 46727 4722S 47727 43729 49233 508*32 527*42 55034 55735 55445 57846 53547 60647 616*50 60953 62062 62660 64355 63960 641+6 63666 623*70 63 S06 6 il 3 5 607 77 533*99 573110 580C5 247*11 297 15 337 19 36724 336*25 40630 42332 43935 44936 4o4r4Q 43140 43548 4 9 74 5 51047 50S43 52653 54650 57260 57760 575*54 598*56 60957 62555 63559 62359 64162 639*63 649*31 65130 647 30 54093 64931 65079 64339b 530106 564+30 516I25 539 72 Dose L e v a i n g /'k g /'day 30 24413 237 14 33119 36123 38525 39723 411-30 42830 44734 45433 47237 47937 48436 49337 503-41 517+40 546*43 556*42 56044 57051 59354 60555 623*56 63159 625*57 63364 64361 6 6 0 to 4 654 72 55465 65062 63958 61965 62i56 61255 59664 53979 537 102 19 5 7 217i0 234 9 2414 253I4 26115 26612 27215 273*16 231*16 23 9 15 290I6 293I3 299I6 30117 310 19 31521 33022 33025 323 26 j 4 0 23 345+26 35433 36128 364*31 37235 373 3 6 39342 40050 4347 40651 41353 42163 42067 42079 42569 4 5i92 453U2 Zeaal es 30 10 194 9 214*11 23012 24012, 244 +12^ 254+12 25913 26412 26615 271*14 27915 23016 2S214 23715 23317b 303 17 30713 319-19 320*13 322 22 33I23 33526 34726b 34727 354+29 3 59 3 3 36039 38142 33945 399-55 39545 41i50 42061 43271 433C69 45196 447 33 19710 21710 235*10 249*11 25315 261*14 26613 27014 27315 231*14 23816 29015 29415 29916 299I7 305 23 31322 32624 330 17 333 20 340-21 34625 35325 . 36523 37033 37938 382+44 39650 41765 40849 40543 42052 43462 44938 4 2 7 79 43999 19110 41359 3 197 9 2 2 0 il 23711 24913 25412 263*13 27214 2731S 279.15 284 15 29315 29417 297 18 303+17 30617 317 20 320*17 33S24 33924 33 6 21 34720 353*23 35926 363=26 367 23 373 3 5 3S040 407 5 3 41i56 -1C53 4225 7 42456 427 61 4 2 5 59 427 65 436-59 433*75 43210I a gram s. b S eaciscicaily sig n ific a re d e v ia c i n :ro a cancro! aean u sin g araly sis o*' v a r i a n c a ard D unna'+ 's Z-sz o<0.05. CUXW TABLE 5. MEAN FOOD CONSUMPTION3 01' MACS AND FEMALE ItATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR 118 AND Hi) DAYS Uu.se 0 JO 10 J 0 JO 10 J SoK 0-J M 25i2 M 25 +1 M 25i l H 20*1 8-10 20+2 26il 261 27il 11-1 J 14-17 18-20 2812 27il 27ll 27*1 2912 26 +1b 26llb 27il 2812 27 +J 2611 26il 21-24 26i2 26l2 24l4 26+1 Days on T est: 25-27 28-31 32-34 23 +3 25H 2613 2611 2611 25il 26i2 27il 2612 2611 26 +2 26+1 35-38 39-41 27 +2 26*1 26l2 26*1 28+2 2611 25l2 26+1 42-45 28ll 2713 2613 28ll 46-48 49-52 2712 2612 26 +2 26ll 2612 2713 26l3 2 711 53-55 26+2 26i2 26+3 27il i- 20 +3 '!* 1.9+0 1- 20*1 1' 20t L 19tl 19i2 19*2 19*1 20tl 19*1 201-1 19*2 21 +3 20*1 20*2 20*2 191) 2012 23 +7 2l)l2 2611 25l J 26 +1 25 +2 2011 18ll 1911 1911 20l 1 19+1 20+1 21)13 19l2 19il 22i 3 19*1 20l2 18 +1 20il 19ll 2012. 19+1 2012 J 9ll 2012 lOtl 2315 21H 19 +1 18i2 2013 19l2 20 +1 18 +1 2011 1.912 19l2 18 +1 2012 18 +2 A 11 .lain In plains as mean one standard deviationi (1.0 rats/yroup housed 2 rats/cuge). 'Sl.il isi ic ui ly lilynl fJcuiic difference from control me<ui, us lug analysis of variance and Dunuec t*s test, i><0.05. 3-1 2 .9 ! i 1 L_.. - j j a i 3 o TAULE 5 (Continued) MEAN FOOD CONSUMPTION" OF HAl.li AND FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,6,5-T FOR H R AND 119 DAYS Done 0 30 JO 3 0 30 10 3 ------------------------------------------------ -----------------D--axy-s---o-n---T-e--a-t SeK 5 6 -3 9 6 0 -6 2 6 3 -6 6 6 7 -6 9 70 -7 3 77-RO a i - 8 3 8 6 -8 7 M 2612 272 M 222 25i2 M 25t6 26i2 M 25l2 2 6 ii 2512 26i2 25t2 26H 2611. 25i2 25t3 25H 2 6 ll 26t2 25i2 2 5 il 2712 2712 2611 2711 2512 2612 25l2 2611 2611 2 5 il 2612 2610 88-90 25l2 2512 2512 27l5 91-96 26i6 26U 26:t2 2711 95-97 102-105 106-108 109-111 2512 2613 2613 26 ll 25l2 ' 2511 2711 2 6 il 2612 28i5 2612 26i6 23l2 26 l l 2613 2612 F 2011 22i3 19H 1* i m b 1 8 i 2 b 1 8 i l 1' 1911 1 9 1 1 I 9 i l F 3710b 1 9 li 1912 20t6 1712 1712 17i 2 1 9 il 1 7 il 1 7 il IRi 2 20l0 I9 l2 20l2 2 6 l2 b 2013 1811 1911 19H 2 0 ll 20l 1 2011 2 0 il 20l3 1812 1 9 il 1912 2011 18 l l 2011 20i2 1 9tl 18 l l 1 9 li 18l2 2011 2010 1 9ll 2011 19l5 20i3 2H 6 213 1911 22l8 18l2 2112 A1 l di La i n plains an mean 1 one s t a n d a r d d e v i a t i o n (10 r a t a / g r o u p L oused 2 r a u s / c a g o ) . L>L, ini. t n t j < illy s i g n i 1 i c a n t J i t f e r e n c o tro n i c o n t r o l mean u s in g a n a l y s i s o f va r la n c e and O u u n e t t 's t e a t . > < 0 .0 5 . Ci ' o TA3LE 6 MEAN .-COD CONSUMPTION2 FOR. MALI AND FEMALE 3AT3 MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 -T FOR 2 FEARS Days on Tese 0-3 4- vj o-1* 11-13 14-17 13-20 21-24 25-27 28-31 32-34 35-38 39-41 42-45 46-43 49-52 53-55 56-59 50-62 63-66 67-69 70-73 77-30 31-83 34-37 88-90 91-94 119-122 123-125 147-150 151-153 130-131 182-185 203-206 207-209 231-234 235-237 259-262 263-263 287-290 291-293 315-318 319-321 350-353 373-381 406-409 434-437 469-472 497-500 532-535 560-563 533-591 623-625 551-654 6 ' 5- -6--:6 35 -/ 0 24:1 2 7 :1 25:2 2 7 :1 23:2 26:2 2 5 :1 27:2 25:1 26:2 27:2 2 6 :1 27:1 2 6 :1 26:2 26:2 2 6 :1 25:2 26:2 23:2 26:2 26:1 25:1 25:1 25:2 25:1 24:5 26:2 25:2 24:3 29:5 25:3 26:3 25:4 26:2 25:2 25:1 26:2 25:2 26:2 24:1 27:3 25:3 25:4 25:2 25:5 20:5 25:2 24:2 25:4 23:3 25:3 21:6 7 O- 9 2' Dose Laval na/ka/dav M ales_____________________ __________________ F e a a le s r30 LO '_3 0 30 10 24:1 2 4 :1 27:1 27:1 25:1 26:2 26:2 26:2 2 6 :1 27:2 25:1 26:1 24:1 2 5 :1 25:1 27:2 25:1 25:1 24:1 25:1 25:1 25:2 25:1 25:1 27:2 27:1 26:1 26:2 27:3 26:1 25:1 25:1 25:1 25:3 24-1 24:2 25:1 25:1 23:1 25:2 25:1 26:2 2 4 :1 26:1 24:2 26:1 25:1 25:1 2 5 :i 25:1 2 5 :1 25:1 26:1 26:2 2 5 :1 25:2 . 25:1 25:1 23:1 24:1 2 6 :1 27:1 25:1 24:3 25:4 24:1 25:4 27:1 27:3 25:2 26:1 26:1 26:2 26:1 26:2 ' 25:1 25:1 * 25:1 2 6 :2 26:2 25:1 25:1 27:1 27:1 26:3 28:3 26:4 27:5 25:2 24:2 25:2 23:4 24:6 22:5 24:4 26:3 25:3 24:1 27:5 29:6 -2i2i:24 b 23:3 24:1 23:3 21:5 2105z:'7 22:3 21:5 24:1 25:2 26:2 25:2 27:2 26:2 2 6 :2 25:2 25:2 25:2 25:2 25:2 28:3 26:3 26:2 24:2 2 5 :2 24:2 25:2 24:3 26:4 26:2 25:2 26:2 25:2 2 5 :2 24:2 25:2 25:2 24:2 25:2 25:4 24:3 26:5 23:2 26:2 25:2 26:2 25:2 26:2 25:2 26:3 24:4 26:3 25:2 24:4 24:3 25:1 24:3 25:2 24;2 22:5 23:6. 22:3 13:2 19:2 18:2 19:1 21:2 21:3 20:3 20:2 18:2 19:2 19:1 19:1 21:3 19:2 19:2 18:1 13:1 13:1 79*2 18:2 19:3 13:1 13:2 19:2 18:3 13:1 19:1 20:2 19:2 17:2 20:1 13:1 17:1 20:2 20:2 19:2 13:2 19:2 20:5 19:2 13:2 . 21:2 19:3 13:6 19:3 19:2 13:3 20:2 20:3 24:5 21:3 21:3 20:4 20:3 21:5 19:1 20:2 18:2 18:1 13:1 20:5 17 :lb 19:1 20:3 19:2 13:1 13:1 19:2 13:2 17:1 17:1 16:1 13:1 13:1 15:1 13:3 18:1 17:1 13:1 17:2 17:1 19:2 19:2 18:1 17:2 19:3 13:1 20:3 23:4 21:3 20:3 19:2 19:3 19:2 19:2 19:2 20:2 ' 21:3 21:4 19:2 19:1 19:5 21:5 13:2 2 4 ii 1o-2 20:2 Z1Z9z:3 ' -D 20:2 20:2 1 9 :l 19:1 2 i:3 20:2 13:1. 13:1 22:4 21:3 18:1 21:5 19:4 18:3 20:4 18:1 13:3 17:1 20:1 13:2 20:3 19:1 19:2 20:3 19:3 13:1 19:4 19:4 19:2 13:2 21:5 19:2 19:2 20:2 22:4 22:5 20:3 21:2 19:2 19:2 20:2 21:4 20:2 21:3 19:2 13:1 16:6 i3 rS 19:3 25 T*! :_4 21:2 - r c2 3 20:2 20:1 19:1 191 19:2 19:2 1133t:1i ", 20:1 19:1 19:1 19:2 20:2 13:1 19:3 13:3 19:2 17:1 13:1 17:2 20:3 19:1 13:1 19:1 . 13:1 13:2 19:2 19:1 13:2 17:2 20:2 19:1 19:2 22:3 20:2 20:2 19:2 20:2 19:2 20:2 19:2 21:2 20:2 19:2 20:2 21:2 17:4 20:2 19:3 22 4' :5 -' 23:4 21:4 20:2 *_I- a g r a n s // r a n //ca y . 3 3 : a : i s : i c a l i y s g r . i d i c a n e d i r f e r e n e e : r o : c e n e r ! r.aan u s in g a n a l y s i s o : v a r ia n c e and T e n n e c : r 3 ZSZ , p <0.05 . 15 l -46-- TABLE 7 CUMULATIVE MORTALITY DATA OF MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR TWO YEARS Original No. in Group Days on Test 0 No. Dead (Z Dead) 86 o 0-30 31-60 61-90 91-120 121-150 151-180 181-210 211-240 241-270 271-300 301-330 331-360 361-390 391-420 421-450 451-480 481-510 511-540 541-570 571-600 601-630 631-660 661-690 691-720 721-728 0 0 1(1.2) 1(1.2) 1(1.2) 1(1.2) 1(1.2) 1(1.2) 1(1.2) 2(2.3) 2(2.3) 2(2.3) 2(2.3) 5(5.8) 6(7.0) 9(10.5) 10(11.6) 16(13.6) 23(25.7) 32(37.2) 47(54.6) 67(77.9) 74(86.0) 77(89.5) 79(91.7) Total No. of Rat3 on Study 36 Dose Level 30 N o . Dead (% Dead) (ns/kg/day) 10 N o . Dead (% Dead) 50 50 0 0 0 0 0 0 0 0 0 0 0 0 2(4.0) '2(4.0) 2(4.0) 4(8.0) 6(12.0) 8(16.0) 11(22.6) 16(32.0) 19(38.0) 24(48.0)a 27(54.0)a 32(64.0)a 39(78.0)a 50 0 0 0 0 0 0 0 0 1(2.0) 1(2.0) 1(2.0) 1(2.0). 2(4.0) 2(4.0) 4(3.0) 9(18.0) ,12(24.0)a 22(44.0)a 24(48.0)a 29(58.0)a 37(74.0)a 38(76.0) 42(84.0) 45(90.0) 46(92.0) 50 3 N o . Dead (% Dead) 50 0 0 0 0 0 0 0 0 0 0 0 1(2.0) 2(4.0) 3(6.0) 4(8.0) 6(12.0) 10(20.0) 12(24.0) 14(28.0) 23(46.0) 30(60.0) 32(64.0)a 34(68.0)a 38(76.0)a 40(80.0)3 50 aStatistically signific:ant difference fron control values by Fishi Exact Probab ility last p<0.05. 1 (3 0 ? - -4 7 - TABLE 8 CUMULATIVE MORTALITY DATA OF FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR r.70 YEARS Original No. in Grouo 0 N o . Dead (% Dead) '86 Days on Test 0-30 31-60 51-90 91-120 121-150 151-130 IS1-210 211-240 241-270 271-300 301-330 331-360 361-390 391-420 421-450 451-430 481-510 511-540 541-570 571-600 601-630 631-660 661-690 691-720 721-732 0 0 0 0 0 0 1(1.2) 1(1.2) 1(1.2) 1(1.2) 2(2.3) 2(2.3) 2(2.3) 4(4.6) 5(5.8) 9(10.5) 12(14.0) 18(21.0) 20(23.2) 25(29.1) 29(33.7) 34(39.5) 41(47.7) 46(53.5) 46(53.5) Total No, of Rats on Study 86 Dose Level 30 No. Dead (% Dead) (rg/kg/dav) 10 No . Dead (% Dead) 50 50 0 0 0 0 0 0 0 0 0 1(2.0) 1(2.0) 2(4.0) 3(6.0) 3(6.0) 3(6.0) 7(14.0) 9(18.0) . 11(22.6) 12(24.0) 15(30.0) 13(36.0) 24(43.0) 25(52.0) 27(54.0) 28(56.0) 50 0 0 0 0 0 1(2.0) 1(2.0) 1(2.0) 1(2.0) 1(2.0) 3(6.0) 3(6.0) 3(6.0) 4(3.0) 5(10.0) 3(16.0) 13(26.0)a 14(23.0) 15(30.0) 16(32.0) 21(42.0) 25(50.0) 33(66.0)a 35(70.0)a 38(76.0)" 50 3 N o . Dead (% Dead) 50 0 0 0 1(2.0) 1(2.0) 1(2.0) 1(2.0) 1(2.0) 1(2.0) 1(2.0) 2(4.0) 2(4.0) 3(6.0) 3(6.0) 3(6.0) 5(10.0) 7(14.0) 10(20.0) 12(24.0) 16(32.0) 20(40.0) 23(46.0) 26(52.0) 29(58.0) 29(53.0) 50 a "Statistically significant Ettact Probability Test, ?<0.05. rota control vai (ies by Fisi -48- TABLE 9 HATS WITH PALPABLE MASSES MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR TWO YEARS Oi lg1ual Dose Number of tltiy > Animalu Males 0 U 30 50 ' 10 50 3 50 Fuma l i s 0 oo It) 3 lib 50 50 50 Month of Stu d y and C u m u la tiv i; Number o f Kata u l c l i P a l p a b l e Maa S C S 1 2 3 4 5 6 7 8 9 10 n 12 13 14 15 16 17 18 19 20 21 22 23 24 0 0 1 l 1 1 2 1 0 1 i 1 1 2 5 a a 12 13 14 15 15 15 15 000000011000 122244597788 0 0 0 0 0 0 1 1 1 1 3 3 6 a 6 ? 6 7 9 10 11 12 13 13 13 13 0 0 0 0 0 0 0 0 0 0 0 . 0 1 2 3 8 9 11 11 12 12 14 14 14 0 0 0 0 0 0 0 0 1 ' 2 6 9 14 18 27 37 *45 53 55 59 60 67 69 69 o ' 0 0 0 0 0 1 1 6 a 6 a 6 7 7 12 14 16 U23 28 31 35 38 41 4 2 44 0 0 0 0 0 0 0 2 2 2 4 6 14 19a 25 27 29 31 32 38 39 40 42 42 0 0 0 0 0 0 0 0 1 1 4 7 10 12 17 23 29 31 33 36 37 40 40 41 P a l p a b l e m a s s e s may I n c l u d e t u m o r s , p r e p u t i a l g l a n d a b s c e s s e s , e t c . w h ic h s o m e tim e s u n d e r g o d r a i n a g e and s u b s e q u e n t r e g r e s s i o n , `^ t u t ( s i ( r a l l y s i g n i f i c a n t d i f f e r e n c e from c o n t r o l v a l u e s by F i s h e r ' s E x a c t P r o b a b i l i t y T e a t , p < 0 .0 5 . o Dose mg /k>;/day 0 30 JO 3 TABLE 1 0 MEAN HEMATOLOGIC VALUES OE MALE AND FEMALE RATS ON DAYS 82 AND 83 OF A 118-119 DAY DIETARY STUDY OF 2,9,5-T 8 KUC Ugb FCV WBC SCK Percent: x 10^/iiuii^ g/100 ml x 10^/min^ M Mean 59.2 1S.D. 11.3 9.21 10.39 17.0 10.7 13.7 12.2 M Me in 59.0 iS .D . 11.9 9.22 10.20 17.1 10.5 19.1 11.8 M Meim 53.2 IS .1). 1.1.8 9.18 10. 52 17.3 10.5 15.3 12.0 M Mean 52.5 IS .D. 12.2 8.91 10. 35 17.3 10.8 19.5 12.3 WBC Differential Count (%) Neut Lymph Mono Eos in Baso 12 89 3 1 0 10 88 2 0 0 11 86 2 1 0 11 87 1 1 0 Throm bocytes xlO^/mm^ Reticulo cytes % 1.393 1.265 1.2 1.298 1. 128 1.2 1.202 1.182 1.295 1.278 1.2 41S vO i 0.6 0 F Mean 50.1 8. 19 16.2 12.9 iS .1). 11.8 10.93 10.6 1 .6 30 1' Me;ill 52.5 8.56 16.9 12.0 IS .1). i5.9 10.63 11.2 12.8 10 1' Mean 50.6 8.12 15.9 11.5 IS .1). 12.3 10.28 10.9 12.3 3 F Mean 50.1 8.15 16.0 J.1.9 tS.D. 12.9 10.95 10. 9 12.2 10 88 1 1 11 87 1 1 7 91 1 1 8 91 0 1 0 1.175 i .195 0 1.183 1.203 0 0.978 1.088 0 1.199 1.187 No statist ica1ly aigni1leant differences from conirol mean using analy iilti of variance arid Dunnett's tes t, p<0.05. 1.6 1.3 1.9 1.1 L __i ii_ J .) I V ^0 TABLE 11 lKj.se mjj/kji/di'X SX 1 of Anim als/ C r o n |) MEAN 1IEMAT0L0U1C VALUES L'OR MALE ANI) IEMALE KATS ON DAYS a u AND 9 0 OE A TOO - Y E A R DI E TARY STUDY OE 2 . 4 , 5 - ' : r l ' CV KI1C Nr U IJliC w n c D1 f f e i e n t i a l C o u n t ( X ) Throm bocytes P e i c e n t " X 1 0 6 / mi u 3 r / 1 0 0 m l x 1 0 ^ / u i m ^ N e u t l . y mp l i M o n o E o s I n U u a o k ! 0 ^ / iiihi^ lie ti cu Vocytes X uM a MEAN 55.7 9. 22 17.4 12.3 i i 87 2 0 0 1. 204 1.1 iS .D . i 1.. A 1.41 1.8 12.9 1.194 JO M 8 MEAN 54.8 9. 29 17.5 12.8 i i 87 1 1 0 1. 276 .9 i S . l>. . 8 i . 3 2 1.3 12.4 1.169 JO M a MEAN 9.41 17.7 12.9 12 86 1 1 0 1. 292 1.1 IS .O . 13.1 t . J6 il.O il.3 1.287 JM a MEAN 55. A 9 . A4 17.8 12.7 11 87 1 1 0 1.084 1 .1 lS.1). i2.4 i . 39 l.U 13. 2 1. 131 0 i` a MEAN AS. J a . 17 15.a 9.4 9 90 1 0 0 1.268 1.4 iS .D . ll.l i . 38 1.6 n . a 1.241 JO r* a Mi: AN 48.8 8.24 16. 2 12.0 9 89 1 1 0 1.07 3 1.7 I S . IK 12.9 1.39 1.7 i 2 . 4 1.134 10 i- a MEAN 50. J a. r/ 16. 2 n. 5 12 86 1 1 0 1.253 1.1 tS.I). i2 .2 i . S2 1.9 13.5 1. 121 J a MEAN 50. 7 a . 11 16.3 11.3 a 90 1 1 0 1.171 1.4 IS.l). i 2 .0 i . 46 1.7 n . a l . 125 Nu s t a t i s t i c a l 1y s i g n ! I c . i n t d l l l e r e n c n s l: r o m c o n t r o l m e n u s u s i n a m i l y s i s o f v a r i a n c e a m i D e n n e t t ' s t e s t , | 5 < 0 . 0 5 . JU\JZ1Z TABLE 12 H ose iiij'/kg/tJ a y Sex 11 o f A n i m a l s / O r o u |> MEAN HEMATOLOGIC VALUES LOR MALE AND FEMALE RATS 164 165 2 4 5-1O N D A Y S AND OF A TW O -Y EA R D IETA RY STUDY O F .. r FCV Fore: o u t K il C 0X ] ^ / i n m ^ he a r /100 m l WUC x lO 'V m iu ^ UDC D lf f e r e n t l a l C o u n t (X ) T hrom b o c y te s N eut Lym ph M ono E o sln B a s o xlO ^/m iu^ R e tlc u lo cy te s X 0M a MEAN 4S O . a . 34 16.4 12.4 17 79 3 1 0 1.121 1.4 1S . D . 14.2 1.71 11.3 15.2 l . 206 10 N a MEAN 49.9 a . 24 16.4 13.5 15 a i 22 0 1.161 .9 iS .l). 12.2 1.24 1.7 12.3 1.299 10 M a MEAN 49.9 a. io 16.2 12.5 17 79 2 2 0 1.101 1.1 iS .l). 5l l . 1.68 1.8 11.0 1.195 3M 0F a MEAN 49.6 a. io 16.4 14.3 i a 78 2 2 0 1.028 1.2 is.n . 15.2 1.92 6l l . 13.9 1. 156 a MEAN 47. 1 7. 5a 15.2 10.7 16 81 1 2 0 . 938 1. 1 iS .l). U .4 1.14 t .4 i 3. 5 1. 098 10 1- a M E A N 47.6 7.72 15. 7 11.3 13 84 1 2 0 . 903 1.2 0I S . . 12.2 1.49 1. 9 i 2.a 1. 125 10 F a M E A N 46.4 7.79 15.3 a .6 17 a o 12 0 1.052 1.1 i s .u . 12 . 1 1.4 5 1. 7 12. 2 1.170 1F a MEAN 46.1 7.79 15.3 9a . 15 a o 2 3 0 .951 1.0 iS .l). 12. 7 1.51 11. 0 12.9 1.089 N o a l a i iti t i c u U y s ig n ific a n t d iffe re n c e s from c o n tr o l m eans u s in g a n a l y s i s of v a r ia n c e mul D unne L i' s t e s t . l ><0. 05. \P l ; L. I 1 a i - -! TAULE 13 Dose 0 30 10 :j 0 30 10 3 of Anim ais/ Sex Croup MEAN HEMATOLOGIC VALUES FOR MALE ANO FEMALE RATS ON DAYS 7 2 6 AND 7 2 7 O P A T U O - YKAR DI UTAUY STUDY OP 2 , 6 . 5 - 1 r l` CV Perenne KIJC X h / V iHII!'* Hg r / 1 0 0 ml U UC x lU'Vuuii^ U UC I U C f e r u n c i a l C a n n e (%) Neut Lymph Mono C a n in Unno Throm bocytes Re t l e u l o cy tes % M U MPAN 66.J 6.79 16.8 16.8 62 69 8 1 0 1.066 1.7 iS . 0. *5.6 i l . 01 11.7 . 1 6 .5 1 . 262 M MEAN 6 7.7 7.62 15.6 16.6 33 59 7 1 0 .878 2 .1 iS. 0. 13.6 l . 55 il. 16. 8 *.107 M 6 MPA N 67.3 7.50 15.6 17.6 6 2 68 8 2 0 .860 1.8 iS .U . i 3 .A 1.63 1.9 15. 2 1.055 M 8 MEAN 66. 2 7.05 16.9 12.9 31 61 7 1 0 .932 1.1 + S . . 16.3 1 . 66 il. 2 *6 .2 1.193 F 8 MEAN 67.3 6.91 16.9 8 .0 25 66 7 2 0 1 . 200 1.6 iS.i). 13.8 1 . 55 *1.1 l l .8 i. 156 E 8 MEAN 66.6 6 .06 16.3 8 . 1 27 66 6 1 0 1. 136 3 . 7 iS .0. 15. 6 U . 20 11.9 11.8 1.279 F MEAN 66. 7 6.60 16.9 8 .2 26 65 7 2 0 . 991 2.3 * 8 . 1). 4. 2 11.03 *1 .8 i 2 . `J 1.105 F 8 MEAN 6 5. 2 6 . j :i 15.1 9. 3 32 60 7 1 0 1 . 222 1.3 iS.l). i5. 0 1.66 1 1.a 12.0 1.218 No j 1 a L i L l e n l l y b l y i i i i i t - u n i : d i i L e r e n e e s L r o m c o n t r o l . m e a n s u s i n g a n a l y s i s o f v a r i a n c e a n d D u n n e c t ' s r e s t , p < 0 . 0 5 . 8 9 Dose mg/kg/day 0 30 10 3 Stix M M M M TABLE 14 SUMMARY OF URINALYSES OF MALE AND FEMALE RATS ON DAYS 82 AND 83 OF A 118-119 DAY DIETARY STUDY OF 2,4,5-T Specific Cravi t:y 1.03010.006 1.027+0.007 1.035+0.005 1.03810.010 pll . 6.5-7.0 6.5-7.0 6.0-7.0 6.0-7.0 Sugar neg.(8) neg.(8) neg.(8) neg.(8) Protein 1+(1) 2-1(3) 3l(3),4-i(l) 11(1),21(4) 3T(3),41(0) l+(2),2-1-(1.) 3+(5),4-1(0) 1-1(1), 21(2) 3-1(4), 4-1(1) Ketones neg.(8) Occult Blood neg.(7),mod.(1) Bilirubin neg.(8) neg.(8) neg.(8) neg.(8) neg.(8) neg.(8) n e g . (6),small(l) mo d .(1) neg.(7),small(l) ueg.(8) i neg.(8) V 0 F 1.04310.006 6.5-7.0 neg.(8) trace(3) ,1-1(3) neg.(8) n e g . (8) 2-1(1), 3 1(1) neg.(8) 30 F 1.04210.008 6.0-7.0 neg.(8) trace(6) ,1-1(1) neg.(8) neg.(8) 21(1) neg.(8) C* 01 U3 10 F 1.044+0.013 neg.(8) 1-1(5), 2-1(2) 3+(l) neg.(8) n e g . (8) neg.(8) 3 F 1.05010.010 6.0-8.0 neg.(8) trace(l),1-1(2) neg.(8) neg.(8) 2-1(2), 3-1(3) neg.(8) pll ilSLcd 1 iail|;e of values, Protein content (juantltated oil basis of trace to 4+. "'no statist! ca.l.iy significant: differences from control means using analysis of variance and Dunnett's test, p<0 .05. j i1i ..J L....J L.. J j ;___ j L._.) l.. j j i TABLE 15 SUMMARY OE URINALYSES 01? MALE AND FEMALE RATS ON DAY 09 AND 90 OE A TWO-YEAR DIETARY STUDY OE 2,4,5-T Dose II of Animals/ mg/kg/day Sex Croup Specific Gravity pll 0M a 1.0441.006 (6.0-7.5) 10 M 8 1.044.008 (6.5-7.0) JO M 8 1.0411.009 (6.0-6.5) 3M 8 1.042+.007 (6.0-7.5) Glucose N e g (8) Neg(8) Neg(8) Neg(8) Protein H-(l)2+(6) 31(1) U(2)2+(3) 31(3) 11(2)21(3) 31 (3) 11(4)21(2) 3+(2) Ketones Neg(8) Neg(8) Neg(8) Neg(0) Occult Blood Neg(8) ]11 1 1 r u l ) l n N e g (8) Neg(8) Neg(8) Neg(8) Neg(8) Neg(0) Neg(8) 0E 10 E 10 E 1 i' 8 8 8 8 1.0301.008 (6.0-7.0) 1.0261.004 (6.0-7.0) 1.0251.007 (6.0-7.0) 1.0291.006 (6.0-7.5) Neg(8) N e g (8) Neg(8) Neg(8) Trace(6) 31(2) Neg(8) Trace(7) 2+ (1) N e g (8) Trace(3) J1(3) 2l-(l) 31(1) Neg(8) 'Jrace (3) 11(2)21(2) 31(1) Neg(8) Neg(8) Neg(8) N e g (8) Neg(8) Neg(7) N e g (8) Small(1) N e g (8) Neg(8) l No s t a t i s t i c a l l y sig n ll: L ea n t 1)11 . 1 1 a L u i l a s range o f v a lu e s . d iffe r e n c e s fro m c o n tr o l 1` r o t e i n c o n t e n t < | u a n 11 1a t e d o n b a s i s o f t r a c e t o 4 1 - . m eans u s in g a n a ly s is o f v a r ia n c e and D unne r e ' s te st, p < 0 .0 5 . q k re t a h u ; i SUMMARY 01- URINALYSES VALUES OR MALE AND EEMAI.E RATS ON DAY 364 AND 365 OR A TWO-YEAR DIETARY STUDY OR 2 , 4 , 5 - T (Jouit (1 o f A n i m a i s / uig/Ug/day Sex C r o u |> Speciflc Oravlty pll C l u c o s e Protein 0M a 1 . 0 4 1 t . 008 ( 5 .5 - 6 . 0 ) Neg(8) 3+(8) 30 M 8 1 . 0 3 9 t . 0 0 `J ( 6 . 0 - 7 . 0 ) N e g ( 8) 31(8) Ketones Neg(8) Neg(8) Occult Ulood B iliru b in Neg(7) Sum 1 1 ( 1 ) Neg(B) Neg(O) Neg(8) Urobilinogen E h r l i c h Unl t s / d l 0. 1( 8) 0. 1( 8) JO M 3M 8 1 . 0 3 1 ^ .0 0 9 (5 .5 -6 .5 ) Neg(8) ,, 3+(8) Neg(8) Neg(7) Neg(8) 0.1(8) Small(l) 0 1 88 1 . 0 4 1 t . 007 ( 6 . 0 - 6 . 5 ) Neg(8) 3-1(7)41(1) Neg(8) Neg(8) Neg(8) . () 0 l1' 30 R 10 R 3R a 1.0251.009 (5 .5 -6 .5 ) Neg(8) 11(1)21(4) Neg(8) Neg(8) Neg(8) 0 . 0 ( 1) 0 . 1( 7) 31-(3) 8 1.0221.006 (5 .5 -7 .0 ) Neg(8) 11(3)21(2) Neg(8) Neg(8) Neg(8) 0.0(1)0.1(7) 3-1(3) a 1.0291.009 (6 .0 -6 .5 ) Neg(8) 21(3)31(5) Neg(8) Neg(7) Neg(8) 0. 1( 8) Sum 1 1 ( 1 ) a 1.0311.010 (5 .5 -6 .0 ) Neg(8) 1+ ( 1) 2-1(1) N e g (8) Neg(8) Neg(8) 0.1(8) 31(6) "S i ,i i i i i ,i I I y s i g n i f i c a n t d i f f e r e n c e f r o m c o n t r o l mean u s i n g a n a l y s i s o f v a r i a n c e a n d D e n n e t t ' s f e a t , p < 0 . 0 5 . pll I i n i oil a n r a n g e o f v a l u e s . i'r o i i i n e m i t o u t i odq u a n t L a 1 o n b a s i s o f t r a c e t o 4 l . I L__ i 1___I !... J ; i L__J TAUUi 17 SUMMAHY OK UlUNALYttliS UT MALI- AND m i A L E UATS ON DAYS 726 AND 727 Gl- A TWO-YliAR D1UTARY STUDY Ol' 2,4,5-T Dos l ol7 A n i m a l a / mg/Ug/day Sex Group Spec i f li' Gravicy Pii Giucose I*r o t e 1a 0M 1.0231.oca7 (6 .0 -7 .0 ) Neg(7) 3+(7) Ke t o n e s Neg(7) Occult iliood U l l i r u h 1a Neg(5) Neg(7) Sma 1 1 ( 1 ) Moderace(i) U m ilili nugeu Ulir lic.li Un i t s / d l 0.1(6)1.0(1) 30 M IO M J M 8 1.0271.009 (6 .0 -6 .5 ) Neg(8) 3l(8) Neg(8) Neg(8) Neg(8) 0.1(7)1.0(1) 16 1.0221.003 (6.0) Neg(6) 3 ( A) Neg(6) Neg(6) Neg(6) 0.1(6) a 1.022,1.007 (6 .0 -6 .5 ) Neg(8) 31(7)21(1) Neg(8) Neg(8) Neg(8) 0. I (8) 0V IO !' IO !' 1f U' o o a (6 .0 -7 .0 ) Neg(8) 21(2)3-1(6) Neg(8) Neg(6) Neg(8) 0.1(8) T r a c e (1) Smull(l) a 1.0251.007 (6. 0-7.0) Neg(8) ) 1 ( l ) 2 i (1) Neg(8) Neg(5) Neg(8) 0. 1(8) 31(6) T r u c e ( 1) Sma 1 1 ( 1 ) l.arge(l) 7 1 .0 3 0 i.0 l6 (6. 0 -7.0) Ne(7) 21(3)31(3) Neg(7) Neg(5) Neg(7 ) 0.1(7) 6-1(1) T ra c e (1) l-arge(l) a (81 . 0 3 2 1 . 0 1 0 ( 6 . 0 - 7 . 0 ) N e g ( 8 ) 2 l ( l ) 3 l (7) Neg(8) Nt-'fi ( 6 ) Neg ) 0.1(8) Snui 1 1 ( 2 ) No s i a l i s l. i c ii 1 1y a i j*n I i i CunL d i t tuirtMicos t r oni c o n t r o l memitt u u l n g a n u l y s i s o f v a r i a n c e a n d D u n i i e t t ' s t n s t , |><0.0!). I>ll l i m e ] ni i a l i n e ol v a l i i e s . l'xoli-.iii c o n l o n i . i|u;iu( 1t i i l o d o n b a a i s o l t r a c e Lo A) . P p! Y! !. (" lu U> h-* lo O OO *0 ,3 Mj n. [5 u '- is " i; " i: ... (inli tVnu 1 ` Hao ` ;o (0 h 1 O O O fl HOrt y (t) n> 3 VCA H* UyQ fu P Ut O H* k~* h-* t-* Ui Ut Ut Oi H t. C<O HH* O cr O H M 4> 00 It H* 4>l-o O L1+o I-* 00 LO CT' iM+ |Nj O '-O LO I-4 l i ^4 H* Ni Li+O IO O I-* O , H 00 00 LO H K> V> io H* It Ni 00 O' cr It IO "O O ""4 1 OO I-* 4> 4>* CT 1+ O O h-* M 4> Ut II OO LMo <l>o H OO M L0 vO II I-* IO Co O 1+ M H1 i-o MO It OM "O -o It O H* v> 00 It OO OM --4 H 1+ O O C5 H* 00 O It OO OM Ln O II OO OO cr M3 il04 Ov Li O It N^4i 00 CT It Ut 00 On 00 It LO -*4 o\ 4> H I-* Lo CT\ M It H P- 4> Lo 1+ to 4^ LO O If H CO 4> o- 4.5 0.15 . 113 0.7 23.1 30.5 40 LO K L 1+ H Lo H* iie- L -* Lo oO o Dose 2,4,5-' mg/kg/day K Sex 1- j--* Number fr-* Ui Ut Ui Samples ih~+* LO 4> Ov 1+ MM vOo Total Urine Vol. 10+0 L0O0 48 hr. (ml) Jb Creatinine mg/48 hr. 29.4 5.4 23.8 3.2 29.1 7.6 V1+O -KP*>* 1* 4> vo to 1+ H P- ^ Coproporphyrin O' O' LO On pg/48 hr. VO U fb fu H oo NO M N> 00 Lo -!> 1-0 O 0O ib fb 0.60 0.16 pg Coproporphyrin mg Creatinine b1+O Ul MO 14+N -O "O ''1 fu 4.1 1.8 Uroporphyrin pg/48 hr. II- 1+ O O o o pg Uroporphyrin 1--*1-0 *^4 00 OVO MUt mg Creatinine P> 1L+o vo LO -p- 116 22 delta-ALA pg/48 hr. H1+4to H 1-*to 1+ t-* 4* pg delta-ALA vO ~-4 LO LO I--*M mg Creatinine ,1 ij oPd sampi tssg-ii. life HO f 13 O aH Io-4 on pi fM* I H qsi < o1J k P 2> isH0MI0 rO* p-Si P ppij roil O vo a 2hOif 3H|i- rw* I-* -UIIlI 5 a N uMn> H ^fhi4 00 p h5 o11 Hc/i S pN fc O*1 *-i| I-1 dr -!> UHIt M iOd H\c\/>> a *x 0.19 0.16 102 36 1.9 I___ J J . J ] ti a Oj pn 11 tu H- n nI H(/j fi j (0 H - O P tu U t~* P . t~* Lo O OO n G U i U i U i lo Ul 14.9 u p Ui a 1* I p O 0) p n H- n r ti It It M I t ro II I-* - H- CO -O !>> U i v> H 4>- O Ui i i tu LO O O MM U i 4> np (U f t i/ n PV H- hl 'U 1 II (li O I (U OP Ui O nI-* O LO r o It O "-1 M II h-4 4> LO II O 00 VO U fl> 10.5 12.6 1.15 ih H O p O O P 11 1 G I-* p D P P Uai UHUO* PP tu 1+ O ON LO It O Ul U i 1--* H en 00 Ui It O P'- 1+ OO O Ul - 0 LO 11 OO - en O 4* H OO LO o o \ vG H OO I-1 Ui I- LO lO-t O M l> 1O+ O M K> l-l OO MM (U _ IOI O t-* IN 0.8 0.08 u\ 1-* i Il II H II OO OO OO OO G i-i, OO OO OO OO [O J> M LO M t-O h-* U i fijare 0. 07 0.05 0 .9 0.5 1.47 0.50 Dose 2,4,5-T M O to 0 0 mg/kg/day K r < K Sex L n U U Number Samples 12.8 2. 2 1+ M CJ\ * 0 M3 0 0 1+ M t/i H 4> U) Total Urine Vol 24 hr. (ml) 1+ M to to IO LO I J-- 1 O t o O'* 1 + t --* J-* l o cr\ 0 Creatinine mg/24 hr. !-# H* 4> 00 M3 0 0 1-+0 IO 0 IO -J> 1+ M to to CT\ O Coproporphyrin pg/24 hr. 1.13 0. 21 1+ OM IO VO to IO V |ig Coproporphyr: mg Creatinine It OM Ui to i1 OO JO VO Uroporphyrin pg/24 hr. H- 00 O H* t/ IO It OO OO IO -o tig Uroporphyrin mg Creatinine 3H I lun43 RH O HO% w CMUT1l Jo > M r| fi-J " {2 n U.J1 tu !.H i1*CJ {H(7i>1 H M W W - J S H H^ mo *) r<qJ O'^1 s^H*i ^I 5oo3 R 3 I- 1 TA3LZ 19 r O t/j tl. rr <1 f t 0) p . -( (A n fU p . rd o O ii> (l> t - 4 l~* tb J a . (/) j.i. u uo r. ^ H HM-i InnD Hniu- -n 0> n rr H- <u D 1/1 O ri (D 'U y\ IUi)) (l O Ml o Ul o 0 o o n t o M P ft id t: 01 ,i. jj UQ 11 id iu 01 J.I. 01 M OJ O Lo Oo *Lj v i U l U l Ui Ul MEAN S. D If g CO m a HK ui m a^ ,+ s ui R it H* 4> M vD It I-* JN VI M It i " 4 LO Lo M It I D -IN LO U l if M lo v> U l -fN If Lo V> "-0 -D It Ul o If f-1 M O CO If oO Ul V) I t I-* Ui Ul Ul It LO 00 Ul Lo It M JN l o "O It OM 00 IN It CD O 4> (JO 1 J H-* M -IN ~-o VO If I-4 ON CD -"-J If I D VO M V It l o ON o ON It l J ON |n Ut fu It O I-* |D 1-- It o u> 00 " 0 It oM h- Ui It Oo i d 00 It o I-* Ui o It M to |N I-* O II ID I-4 IN If M Id U i VI to It Ul vo V I ON I f t-* ON t~* ON ON II 4> 'V ON VO I t I- U) Ui t o ON It | n 00 o LO U) K u> l+ K wh It Ul IN ON I t ID I D *~-4 t o IN I f ID U l ID 00 |N It M 00 N4 M It O ID IN U l It oo ID vO I f H* ON ON O ON It I D ON I D H-* q \^ Tt A M to OOO 'X Vj X Ul Ul Ul it+/i gp k ko It X Ui CJ m cn h iM+ t> 4^ v1+O to Ul 1+ H NO OO IOtN NO II H Ino vO It P- N^1O U M ON M Ul Ul 1+0 to M -u O m uM oM f 1+ o NO 00 Ul It 4-^ to VO ON pi It M IvO to No *-4 Pi It O ISO VO VO It IvO 4N O VO o II N'-OJ -"-0 Ul It 1- InO I--* vO 1+ It oto ovO op- M O It O I-* ON M 11 M O n " 0 \ NO MM UH l> O n 8 'I? Ul I--1+1to 1-0 M v o II M l-o U i O i NJ OII Ui O U i Dose 2,4,5-T mg/kg/ay Sex II of Animals/ Croup Total Urine Vol. 48 hr. (ml) Crea tlnine mg/48 hr. Coproporphyrin' pg/48 hr. pg Coproporphyrin/ mg Creatinine Uroporphyrin |ig/48 hr. |ig Uroporphyrin/ mg Creatinine Delta-ALA pg/48 hr. |ig Delta-AI.A/ mg Creatinine [i M >U H td to O Ht"* It- Kl 2S I a H nP >K a to ^ u VO M H OH Ui t-* IH VO \i> -~l I <4 o Ka I>I M in ^?O a oi s c<-Ji oid M Mr fP'>l > Ci Ui H n 1-3 1U-J4 H M Ji- Mn Hif.dNtA wum nj t/i o oi O o *idd Hr i 0 ofd do K |rF-1 fra OM t P tu hr. i-i -d 4> - AL Ui m cr; 1 X do hd Mo is p t1d4 Hfc r* M |vO O | Ul vO 1 t 1 - .J 1 fU o C/i rtj rr (U < i t fu H* M U H- r t fu HPO o fu (l> f- H fu f u UJ O (M c 0 H* u Ih <D H* rt O r r (u - fi U r t rt iX (U M. CO i i ) rt iti - ( M a I y \ J OO (l> o U tn 1 O FJ o o 1--1 rt M o rf0D3u (W(HrAj- 0f u `<fHu* l(H/Aj- h-1 U> LO O oO -rj n j ix j Ul U Ui u II- U RK k IL|--tO1Ut"4 1*0 4> LIIo I- LO Ut ON Lrot jO-i u Lo ir l~o* U a\ It I-* IO IO 1+ oo ovo OfsN HLOOVOO II o f> 00 CO Hl/l a 5FpK2>I! hQNIO 00 IO IIOt t-o* ho oo II VO COIO H O"O UIO H- 1-' Lo Ut II OIO o"O o ON It-t-* 0 oo II o l> LO II in m: Ok 1+ in sR Vk Li+OU4> l>>IO iH+o M vO O IUtt M vO oO I-it> IO o 1--J o 1"O1- M ON o fu H IOONU00fiu Il~I* vO VOO' II Mt~4v4O> 1+ 1-* II- I- IO -o IO Ul H oMvO CoO vO 11 UOMi O--oo lOIOi 00 o 1U1t o VOO MO> li o 4> IO IO 0o 4> TA3 AL S .D . LO ot--1 LO o o X pc: L/l Ln L a L/l 1+ s It l/l pS O I t rA 1L/5 a it K L/i og It H* LO o 00 O - CO 1+ LO 4> O Ln |o 1+ r o LO Ln M on It I-* 0 0 lo "0 It O N) ON LO 1+ oO H* -O a \ L/l 1+ M IO I-* CT\ O it O LO 1+ 4> 00 ro Mo i t LO 4>* M LO IO i t ro 4 ^ LO 0 0 CO H --* vO *0 "O It 1 - IO M 4> It Oo to L/i L/l it m Lo ro !> o it H* LO i t LO LO LO LO Cjx It H LO o LO Lo Ln 1+ LO O L/i OL It H ' 4> O "O LO 4> fti it M LO L/I ON L/I I t LO 4> O Ln IO It M a x LO 4> IO It -* O n -P- LO it 1 - LO L/i 4-' It O IO o IO It o H* 4^ 0 0 H-* It oo M o ro ro I t t~* !' I-* on O it O LO it IO 00 4> 4> iot IO Dose 2,4,5-T m g /lc g /d a y Sex // o f A n i m a l s / C roup T o t a l U r in e V o l. 48 hr. (ml) Creatinine mg/48 hr. Co prope rphy r1n pg/48 hr. |ig Coproporphyrln/ mg Creatinine Uroporphyrin |.ig/48 hr. |ig UroporphyrI n/ mg Creatinine Delta-ALA Ug/48 hr. |jg Delta-ALA/ k 3Vhin* 2o j CP*I lK/ to-* 00 1-1 oL O o p' tHPm->* 1 r /^amS tHPl*IOHP-i<>*- 1 M eo ti hHMO2^i HPcnc<:>5/Jii o li 1 b MaM pfHaj LH/J Su< Ol-rj IO Mn HcHtf<1iiii uoIPH" o w ii Lh'ii ^pd' Ti fi HlH.>i >jNH^ noi-cj oOn j s tU3/nJ4 l-'' L/i H1 *l g H c; OPordO rMH 10 0O1x 00 Ox t - vO ON a x ON 0 0 mg GreatinInc s IPHI O LA h i Pr>t OH< H(r/r)- IvO<f-uui'- fn0lj-i).` I- f;:u1 ^ n . 01 H- a 0*1 C J : J W nrri>i H hO n fu - }.J Ul r r (U jj 01 O rt s. 0) 01 'U 0) / \ a> o 1-1, o Ln o 0 o o n M O H-* u 0 pi fj 01 yO<" ni XViCn->/i*l H</i- MO LOO i+ l/i M u fe i+ K CA M o fes 1+ g LA R a fe Pi t- LA i? O fe H H on Ul ON tu 4N i+ lu IU LO vo o \ H I--* Lo Lo a\ 00 i+ o LO MD 0 0 II- I-* IU Ul H* OO1-^ OO4>N* 1HO+* -Ou HO- IU 4> vO 1+ M ON IU 0 0 Mo H- |U tu LO vo o 1+ - H* Ui u p- 1+ O ON -u " J 1+ IU 0 0 IU 1+ O LO LO OMuO 1hO+- 0O0 1O+ Lo LO 11 H 1--* u O vO CO H ru ON ON o o co H IU LO 0 0 IU i+ IU *U Lo i-* 1+ M LO MO ON 00 fu i+ I-4 -P- LO IU Ul H M co 4>* on n> i io Ul - 0 ON II- l--1 gn 4^ 1i O IlU> OOo \ 11 Lo O oo o i1! Ul IU 4> 075 11- 1--* "U U 1+ , OM Lo iJO Ol'O ^ 1 HO Ul LO O KK LO oO KX Ln Ln Ln j s 1+ K [/i g a fed It CO P a fed It K Ui al si t Pi /j }i> aa It La M 4> CO 1+ CO La ON Oo 1+ r o La 4> no LO It M -O Lo M It H* r o O 4N it Oo N ) ON Lo NO II M I--1 Oo It O u> LA o It to Ln 4> CO ON O I t LO Lo ON LA -!> It h-* IO o O CO it P- t-* M .^ O I t LO lo ON 0 0 I t 4> OO 4 ^ LO O |U i t LO - o NO NO LA I t Lo 4>- ON O La I t I-* IO LO ON LO It IO ON ON "O 11 M lo IO l- J H 1--* 1--* IO ON ON & I t IO 00 M it o Ln Lo LO It H (O M JO It Oo LO 0 3 M LO It oO IO LA r o NO It OO U> ON M r--* it- I-* Lo I-* oo nl--* 0 0 oO I t t-* IO H OO jf o LO '-a I - 4 it o ro 4> lo It O IO LO 0 0 D ose 2 ,4 ,5 - T m g /k g /d ay Sex E II of Animals/ Croup `focal Urine Vol. 48 -hr. (ml) Creatinine mg/48 hr. Coproporphyrin pg/48 hr. |ig Coproporphyria/ mg Creatinine Uroporphyrin pg/48 hr. pg Uroporphyrin/ mg Creatinine Delta-AIA pg/48 hr. pg Delta-ALA/ mg Creatinine po >Hco 3 Utn M OEd !> i-1 H>II j~' -< PJ o I 'S LO LO on CraJ HMO hI- CO H--1 }l> 2* < ON LO 0rfl I Mtki> O EcM; ia E ri y 3iI1<d5HM3 H fi> h i H o O *4 o m j? oMU ^ H *hi o o 3 o pdt-li *"ti HLO di l l pa J i>i . *opoda -< *0t| hto kp- fhWip<adii IO t i X |> u. u\ g u h1 IW-* ot-a t*i o ft pM3j i. j l___ - i ..j s J i-- -J j X [3 l3 tu O C/l I'll r i (U < rr fu H1 LO I-U f t fu HpO O f (U I--' 1 - P> P f.L l/i LJ in ' PP p Np *u a> i j. rr o NP -P Uj n il !- il* P U O fl M (D fu 'U l/) / s il* O N ON Ln O FJ O O n H O h-* (b fu P KU<* P* P P 1--* U) 'I H* LO U) O o- O H j >rj hrj U l u i LU L a rII K 1/4 > a II O O IO IO !> 1+ K ) O r I-* 1-* IO 1+ 1--* I-* ON L/l LO 1 1IO O M H CT* U0 C O liM U I - 4 4> H CO R Ob * H en on Ln O 0O H 10 t o I-* o \ IO II l--J Lo on 00 4> 1+ IO - 1 'O v H ro "4 LH C O 1+ M LO -o 00 II- .< en og il- K en 13 O HLO ^ 1 IO V.O vO O H- M l> -O CO r o Hl o L*i M lo U i ON H- H 4 e n co o IO 11- i--* U VJD --4 L O P i r I-* Lo O '-O 'O M- M IO I-* LO 4> f IILO 0 0 ro v II 1 - ON -o o II I--1 U ON LO ir M Ui IO fu H O lo Ln O J--` tO to o O o \X K Ul Ui Ul -P\ ii+n KP O 1+ K h" P o 1+ "P a 3 it to V o 5i l+ r o ON U) "4 00 o n i+ I'O On M N) 1+ h-* LO Ui 40 to It tO "O OM '- I 4> M to to O to O 1+ t - to i> ro U l 00 1+ 4>~ 43 O to 1--* 00 (U I<to ro -o 43 Co it I-* t o ON ON o -*- it to 00 t o I'O It to ON O O it ro ON 00 -!> U l i t i-* Ul I'O - 4 it H t o I'O 4> Ul 1+ M 1-* O N It M -1-^ O Ul 43 1t M IO IO 40 00 1+ o 00 to I t t-* -4 Pto It H ON 00 it M to U -* it to 43 VO 00 I-* i t H* ON o It o to ON 00 D ose 2 , 4 ,5 -T m g /k g /d ay Sex II of Animals/ Group 33 OH i-d O ! o Wrfl hi n h o >o*1 H 1-4 1O Total Urine Vol. 48 hr. (ml) Creatinine mg/48 hr. Coproporphyrin pg/48 hr. |ig Coproporphyrin/ mg Creatinine Uroporphyrin pg/48 hr. pg Uroporphyrin/ mg Creatinine <4 k h - o pi h* CJ M rM L'1 H Lt1o" 3 ui U) o i *"N n Ul p Hh m S t*j k H >k J H O a H to to o ul V.l> a Oo U l 1-0 1 l-i *4 Ul o r cJ U l CD ON f11> Ph j *1U l On pJ On n H {*> bJ rH to I'O to i On ro 1 P Vjo d ii tes (u O o> rh ri Pi <n Pi Hi-| i H* r ru HpO O (u P P - J HO UQ c ri M p Iu rt) h nO r pi -a in n rt u . V, (l) M ' VJ D /\ P on ID U l I- fl * r< O 0 O O P ri ii O M D (U P O' Pl P Pl M ui UJ h-* LO LO O OO J -'1 t-ij U -P- U t U1 14 s l/i P O S1+ K LD O 1+ \x Wj P Ot 14 L/) P OS H In ) - o H |N> O 1+ H-* |NJ 0 0 cO on 1+ N> cri L O U 1+ J--* CT* 4^ O In) 00 II I-* 00 O U Hh o MO LO 0 ir l'O U i i - 1 -O -O 0 0 I I h-* 4> o \ fo O H <o 00 00 O H ut Ln -1 ON ON 14 M |v) vO Ut O II H Ut vO 00 i 1H U) |N) O' II H LO U t 4^ n O *-* ^1 00 II IN) U t Ln vo HH IN) O Ut 1+ OM "4 Ln 1+ LO U t LO O 14 M IO oo Ui II 4-* l~* LO ON It O c> O 14 M CJN " 4 II OO 4> v> H- l~ l o --1 OO 1+ I-* h o 4> OO 1h M Ut Lo OO II h-* I-* LO OO H l'O lO CX) 4 > 1+ IN <40 Ut 11L*) 0 0 cr\ 4>* 14 h-* NJ MO LO s U 14 K oi P Ok 14 In ) v O N) U t * v> t o 14 IN ) P> V) r o 14 i-* Lo U t ON In ) 14 hO ON 4> ON II LO co O 14 . O I- U t LO 14 r-* CJN o n Oo H l o -*-j 4^ 00 HO-* OLi O 3: K u: Ln Ul Ln CIfO sR 1 iint hi a iCtO s R a1 If L i er vO CP* 4n 1+ IO 4 > IN Ln 00 It 4N VO -P' '-J 11 oIN VO vO VO o n 11 H * VO VO VO ON 1f I--* Li hi o 00 1+ l-o v o '-J O IN |N> II- h i U i IN 4> 0O If M ON IN o ON II M Li ON CO If M u> Li O If OM Ln h> I f f-* H* ^-4 LM 1f f~* IN Ho If oIO h i 00 It I O ON 4> o HI t 4N 0 0 ^4 if oM h i O If o|v i Ioo-* If o1i fu->* o II 1--* IO f o oo It O 4> oo O l0f0 X) S | o^ 1I--t* ui Li M D ose 2 ,4 ,5 - T m g /k g /d ay Sex //of Animals/ Group Total Urine Vol. 48 hr. (ml) Creatinine mg/48 hr. Coproporphyrin Ug/48 "hr. jjg Coproporphyrin/ mg Creatinine Uroporphyrin pg/48 hr. pg Uroporphyrin mg Creatinine Delta-AI,A |ig/48 hr. |ig Delta-AI.A/ mg Creatinine I 3 PH* o H4 cM M I 50S H|pi I-<S pi a> >h Uo ki/i p w|*i a> M vmo pM 2O -1< t!"p* <q O I ip o u- r' 0TJ n HUi p ro1* `o*1 H1 Pd<ii nw >1<! tl-i1 p|p PJ H rp OH i HIH o ;p q m n pi P i h HO f< 0 K O ta c-/3i pd *C q i< c o hJ M 3 ltpHiciij [ i4> rj UHi, rL n3o) PI o s 3pHj i. - j L.-.J : ..J l....j TABLE 25 MOAN C L I N 1C A L C H EM ISTR Y V A L U E S OR A 1 1 a - 1 1 9 DAY OF MALE D IE T A R Y AND FEM ALE RATS AT STUDY OF 2 , 4 , 5 - T TER M IN A T IO N * D ose m g /k g /d a y 30 10 3 Sm BON in g /1 0 0 m l H M ean . S D . M M ean i d . 1). M M ean S . 1). H M ean S . D. 21 5 19 i2 20 i2 20 i3 SC PT m tl/m l 54 9 57 10 53 10 50 5 AP m U /m l 111 25 117 36 100 18 114 24 lili i r u b i n T o ta l m g /100 m l .1 0 .1 0 .1 0 .1 0 B ilir u b in D ir e c t m g /1 0 0 m l 0 0 0 0 0 0 0 0 B ilir u b in In d ir e c t m g /lO O m l .1 0 :1 0 .1 0 .1 0 P r o te in To ta 1 gm/1 0 0 m l 6.4 0.2 . 6.2 0.2 6.2 0.3 6.2 0.3 A lb u m in gin /1 0 0 m l 2 .2 0. 2 2 .2 0 .2 2 .2 0 .3 2 .2 0. 2 G lo b u lin g m /1 0 0 ml 4 .2 0. 2 .4 .0 0 .3 4 .1 0 .3 4 .1 0 .3 O 30 .10 3 F M ean S . D. F M ean i S . D. F M ean S . D. F M ean S . D. 19 2 21 3 22 3 . 20 3 44 3 46 5 56a 12 52 4 102 21 115 18 111 35 90 16 .1 0 .1 0 .1 0 .1 0 .1 0 0 0 .1 0 .1 0 0 6 .6 0 0 .3 .1 6 .8 0 0 .4 0 6 .8 0 0 .3 0 6 .8 0 0 .3 2 .6 0 .2 2 .8 0 .1 2 .6 0 .3 2 .8 0 .2 S t a l l s i ica 1J y s g n i 1 le a n t in c r e a se from c o n t r o l m ean u s in g a n a l y s i s o f v a r ia n c e and D u n n e tt's le s t, p < 0 .0 5 . 4 .0 0. 2 4 .1 0 .3 4 .2 0 .3 4 .0 0. 3 TABLE 26 MEAN CLINICAL CHEMISTRY VALUES EOU MALE AND FEMALE RATS AT TERMINATION OE A TWO-YEAR DIETARY STUDY OF 2 , 4 , 5 - T \ y jkO&oii/oday Sux II of A n i m a l s / Group UUN hik/'IOO mi sen* mil/mi AP iiiU/mi Total Mil J r u b i n m g / 100 ml D irect 811 Iru liin m g /100 ml Indirect B ilirubin m g/100 ml Total P ro te in Albumin gin /100 in1 gm /100 ml G lo b u lin Bin/100 ml 0M 6 MEAN 56 40 90 .2 .1 .1 5.7 1.6 4.0 iS.l). 58 8 17 0 0 0 0.4 0.2 0. 2 so M 10 MUAN 40 48 108 .2 .I .1 6.0 1.9 4. 1 I S . I). 47 11 61 0 0 0 0.3 0.3 0.4 10 M 4 mi-:AN 36 35 96 .2 .1 .1 5.6 1.6 4.0 iS.D. 24 66 0 0 0 0.1 0.0 . 0.6 3M 9 MEAN 25 38 74 .2 .1 .1 6 .0 1.9 4. J iS.D. 20 5 24 0 0 0 0.4 0.2 0. 5 0 10 NKAN 1? 42 68 .2 .1 . 2 6.5 2. 6 3 .9 iS.D. 6 10 47 .J 0 .1 0 .6 0.4 0.4 30 F 10 MKAN 19 37 59 .2 .1 .1 6.3 2 .6 3. 7 iS.li. 6 6 19 .1 0 .1 0. 2 0. 5 0. 5 JO t' 9 MliAN 16 40 56 .2 .1 .1 6 .4 2 . 6 3. 7 I S . IK 3 9 18 .1 .1 .1 0.3 0. 5 0. 7 3 ! 10 MEAN 56 4 2 63 .2 .1 .2 6. 2 2. 2 4 .0 iS.D. 10J 20 28 .1 0 .1 0. 5 0. 7 0. 7 Nu s i n L i s l l e a l ly s J g n i f l e a n t d i f f e r e n c e s f r u n c o n t r o l means u s i n g a n a l y s i s o f v a r i a n c e and D u n n e d 1a t e s t , |j < 0 .0 5 . )n2 r L.....- : L.... L.. I .J j . .............. J L_.... ) i ....... j .. I ........j ! 0&* TABLE 27 Doso 0 JO 1u MEAN BODY WEIGHTS, ORGAN WEIGHTS, AND OKCAN/llODY WEIGHT RATIOS OE MALE AND TEMALE RATS AT TERMINATION OE A 1 18-119 DAY DI ETARY STUDY OE 2, A, S-T l''tl ti l 0(1 Hody ____________________________ ______________ __Ort*(ii> W o l f i t s (g am i g / JOO g Hotly H e i g h t s ) Ut: 1gill lieu 111 Heart 1, i v e t Kiilueya Tee lies Sox ..._ B____ _ J S . _ b / lQQr e/100k 8 / 100 a _ B/lOOfi. bAQPb M Moan H i A ). A6 6 i27 1.IIS 10.00 0 . AO 10.02 1. AO 0 . JO io. n 10.02 12.55 2.60 11.87 lO. 30 3.28 lO.AA 0.70 10.00 A. 05 10.31 0.87 10.06 M Mini it i t ; , l). A/A t J6 1.(16 10.0B 0.13 10.02 1. A1 0. JO 10.15 lO.OJ IJ.A5 2.83 li.OA 10.26 3.7A l O . A2 0 . 7 O'* 10.06 A. 01 10.33 0.85 10.09 N Hl.'.l LI Hi A ). Aii y lb 1 1 .115 1 0 . OB 0.3U lO.OS 1.39 0.20 10. 12 10. 02 13.25 2.60 *2.32 10.17 3.57 1 0 . A6 0.73 10.05 A. 00 10.32 0.83 lO .U M Mc a n H i . 1J. A 111 j A:i 1.115 10. 07 0 . S3 1 0 . OA 1.3B 0 . 20 10.07 10.02 13.57 2.B1 11.05 10.23 3.A2 10.37 0.72 10.05 A.1A 10.31 0.B7 10.10 Spleen -- B- kAOOk 0.85 iO. 12 0.18 10. 03 0.89 lO.lA 0.19 10.03 0.92 10.07 0.19 10. 02 0.87 iO . 10 0.18 10.02 Thymus _._a_ b/ loor 0 . 3 5 0. OB 10. 08 *0.02 0 . 3 7 0. 08 lO. 06 10.01 0 . 4 0 0. OB 1 0 . 11 lO. 02 0 . 38 0. OB 10. JO *0.02 GvarJea/U terus 0 V Moan 2011 1 .1)1 0.61 0 . OJ 0 . J1 7 . BA 2 . 6 3 1 . OA 0.65 0.7B 0.27 0.75 0. Vj 0 . 32 0 . 11 i S . 1). i l A lO . OB 10. OJ 10.12 10.0A 10.55 iO .ll 10.30 10.11 10.25 lO. 09 1 0 . 1 0 1 0 . OA 10.07 *0.03 10 { Moan 200 1. BO 0 . 6 2 0 .8 5 0 . 20 7.72 2.66 1. OB 0 . 6 II 0.78 0.27 0.6A 0.22 0. 32 0 .1 1 S. 1). l i 7 lO . 03 lO . OJ 10. IB 10. 00 10. 70 lO . 17 1 0 .1 7 10. 03 10.22 lo .o a 1 0 .1 5 10. 05 10. JO iO. 04 10 1* Mon it 202 1 .7B 0 . 61 0 . OA 0 . J2 7.72 2.6A 1 . BO 0.65 0.68 0.2A 0.67 0 . 23 0.3.1 0. 11 AS. li. 12A *0. 06 10. 06 10.06 lO. 02 ill. 01 1 0 .1 7 tO. 1.0 1 0 . 0 5 1 0 . 19 1 0 . 0 8 lO .JB 10. 06 10.07 *0.03 1 1' (loan 202 1. BO 0. 62 1.02 0. 35 B . I 3 2 . 7B 2.06 0.70 0.07 0.30 0.7 2 0 . 25 0 . 3 3 0. 11 S . 1). 112 lO. 05 lO.OJ 10.07 lO. 02 10.7 A 10.10 10. 20 1 0 .0 6 iO. 25 1 0 .0 9 10.06 10.02 10.09 *0.03 41S L a t 1ii l i c il I 1y a l k a l i 1(:auL il i c i ' c a s o f itomi mean u s i n g a n a l y u i u o f va r i a n c e a n d Dunne lit s t e a t , | i < 0 . 0 5 . TABI.K 28 M E A N O R G A N W E I G H T S A N D O R G A N T B O D Y W E I G H T R A T I O S F O R M A K E H A T S A T T E R M I N A T I O N O F A `I V O - Y E A R D I E T A R Y S T U D Y O F 2 , 4 , 5 - T N ose o mean S .1). JU MEAN J S .1). 10 MEAN S . 1). J m i :A N 5.1). FaaLeil Bud y We IgliC ____ i L - 508 154 __________________________________ ______________________________________________O r b a t i W e i g h t s B rain r / iooh H eart fi/IO I.lv e r ____ H . k/ iook (g am i g/lO Q K Body W eig h ts^ K idneys ____6 . _ nZifi T estea ____ a _ r/ iook 2 .0 0 to . 06 0 .4 0 0.04 2 .0 7 1 .2B 0 . 1 1 0 .0 7 1 7 .7 2 1 2.27 3 .4 9 1 0 .3 5 5 .8 6 1(1.49 1 .1 4 1 0 .1 1 3^93 1 0 .6 5 0 .7 7 1 0.11 534 i9 2 532 in 2 .0 1 lO .lO 0 .3 9 1 0 .0 7 2 .0 1 0.01 0 .3 U 1 0 .0 5 1 .0 2 u 0.15 0 .3 5 1 0 .0 7 2 .0 8 1 .19 0 . 0 1 0 .0 8 1 5 .5 2 1 1 .8 1 2 .9 6 1 0 .6 1 1 8 .0 9 1 0 .3 6 3 .4 5 1 0 .4 9 5 .0 3 1.05 5 .7 2 1. 68 0 .9 7 0.28 1 .1 0 1 0 .24 3 .7 8 1 0 .9 9 4.18 1 0 .0 5 0 .7 0 1 0.1 5 0 .8 0 * 10.12= 554 UOO 2 .0 0.09 0 .3 0 1 0.05 1 .8 7 1 0.12 0 . 35 0.05 1 7.59 1 2 .7 4 3 .1 2 1 0.31 5 .4 2 1 1 .2 3 1 .02 1 0 .3 3 3 .6 2 1 1 .0 3 0.6 6 1 0.20 S p lee n /lO Q a 1 .29 1 0 .1 9 0 .2 5 1 0.02 1.2 0 1 .30 0 .2 3 1 0.0 5 1.3 8 1 .21 0.2 7 1 0.0 8 1 .2 4 1 0.1 8 0.2 3 Gl 0 . 0 4 T hym us ____B _ k/JOOk 0.1 0 1U . 3 0 .0 2 1 0 .0 1 0 .11 0.03 0 .0 2 1 0.01 0 .1 ) 1 0 .0 4 0 .0 2 1 0.01 0 .13 1 .05 0 .0 2 iO .O l -4 .a L l s L i c u 11 y u i y n t f i c a n i d i f f e r e n c e f r o m c o n t r o l m e a n u s i n g a n u l y a i a o f v a r i a n c e a m i D u n n c t t ' u t e a t , , p < 0 . 0 5 . 1 ; J i___J L I i J !) e TABLE 29 MEAN ORGAN W E I G H T S AND O RGAN T O BODY W E IG H T R A T I O S EOR FE M A L E R A T S A T T E R M I N A T I O N O F A T W O -Y E A R D I E T A R Y ST U D Y O F 2 , 4 , 5 - T D ose in 0 HKAN i.b.1). JU m-AH iS .l). 1 0 MliAN JLli . U . 3 MliAN ili.O. f a s l i:d . body W>! I j j l l t _ _ _ E _____ A 19 in b rain K /100& 1.U 2 1 0.07 0 .4 6 io .n A il lU O 1 .0 1 t o . 06 0 .4 5 tO . 09 3H9 50 1.U 4 i0 .0 4 0 .4 0 t O . 07 4i.91'41 1 .0 6 tO .05 0 .4 7 1 0 .0 9 H eart __E_ r / io o r 1 .2 0 tO . 20 0. J2 1 0 .0 7 1 .2 6 tO . 10 0 .1 2 1 0 .0 7 1 .2 7 tO . 10 0 .3 3 tO . 04 l . JO t O . 15 0 .3 2 1 0 .0 6 O rgan L iv er W eig h ts ( g im i d k / 1 0 0 r b o d y W e i g h t s ) K idneya O varJ.ee/L Jteru3 JL __________ n Z io o n r / io o r 1 3 .0 7 1 3 .92 3 .1 2 iO .64 3.00 10 .4 7 0 .7 5 tO . 20 0 .9 9 1 0 .4 0 0 .2 5 1 0.14 1 2 .5 5 1 2 .4 7 3 .1 0 1 0.57 3 . 00 t o . 35 0 .7 5 1 0 .19 l.ll tO . 51 0 .2 9 1 0.16 1 1.07 tl.7 3 2 .0 6 1 0.30 2 .9 6 10 . 39 0 .7 0 1 0 .1 5 1 .0 9 10.31. 0 .2 9 1 0.11 1 3 .02 1 4 .40 3 .3 1 t O . 62 3 .1 2 1 0 .5 0 0 . 79 1 0 .2 2 0 .2 5 1 0 .42 0 .2 A io .n S p ieo n oZ io o r 0 .0 6 t0 .3 6 0 .2 1 1 0.00 0 .0 5 10.1 0 0 .2 1 1 0.06 0.0 5 1 0 .1 3 0 .22 1 0.03 O .O U t O . 43 0 .2 2 1 0.12 Thym us ____ r/1 0 0 r 0.0 9 1 0 .0 4 0 .0 2 lO .U l 0 .0 9 1 0 .0 4 0 .0 2 1 0 .0 1 0 .1 1 1 0.03 0 .0 3 1 0.01 0.0 9 iO .O A 0 .0 2 0.0 1 N o a t a l i i j L 1 c a L l.y s i g u l f i c a n t d i f f e r e n c e f r o m c o n t r o l m e a n u t s i n g a n a l y s i s o f v a r i a n c e a n d D u n n e i t ' s t e a t , p < 0 . 0 5 . TABLE 30 GROSS OBSERVATIONS OF MALE ANT FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR 113-119 DAYS Observations _________________Dose Laval fag/kg/day) Male Female 0 30 10 3 0 30 10 3 Congestion ox thymus (secondary to decap itation) 0 /1 0 Dilatation of renal pelvis with miner alized deposits 0/10- Hemorrhage within medi astinum (secondary to decapitation) 1/10 Circumscribed red foci in lung, ^1 mm diameter) 1/10 Mineralized deposits in renal pelvis 0/10 Organized plug within lumen of urinary bladder 4/10 Organized plug within lumen of urethral orifice 0/10 Congenital anomaly of pectoral limb 0/10 Distended uterus due to estrus cycle - Focal corneal cloudiness unilateral 0/10 - bilateral 0/10 Diffuse corneal cloudi ness - unilateral 0/10 1 /1 0 1/10 0/10 0/10 1/10 2/10 1/10 0/10 - 0/10 0/10 0/10 0/10 0/10 0/10 0/10 1/10 0/10 1/10 1/10 - 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 4/10 0/10 0/10 - 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 ' o / i o 2/10 0/10 1/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 1/10 2/10 1/10 1/10 1/10 0/10 0/10 1/10 0/10 1/10 1/10 0/10 0/10 0/10 1/10 0/10 D-S. Za. . 1 3 td 3LS 3 U Z H C 6 T O l IT E C 3 w i t h observant.on/number of ra t3 in gr' O u p . -70- TABLE 31 MICROSCOPIC OBSERVATIONS ON TISSUES OF EATS MAINTAINED ON DIETS CONTAINING 2,4,5-1 FOR 113-119 DAYS Observations 0 Increased hematogenous pigment in thoracic lymph node 0/6 Focal tracheitis 2/10 Peribronchiolar lymphoid aggre gates in lung - slight slight to moderate 7/10 3/10- Perivascular lymphoid aggre gates in lung -- slight moderate 2/10 1/10 Focal accumulation of inflamma tory exudate within bronchiole 1/10 Focal interstitial pneumonia 1/10 Alveolar histiocytosis 0/10 Focal alveolar epithelialization 0/10 Focal congestion of thymus 0/10 Renal tubular-cast formation slight or ungraded moderate 6/10 1/10 Aggregates of brown pigmant in kidney 3/10 Focal renal tubular atrophy 4/10 Renal glomerular adhesions 1/10 Dilatation of renal tubules 2/10 Proteinaceous plug in lumen of bladder 4/10 Lymphoid aggregates in incer5 titiuxn of kidney 1/10 Dose (mg/ks/dav) 1? arn .a ^ 30 0 30 0/8 2/10 0/10 0/10 1/8 1/10 9/10 1/10 "8/10 2/10 9/10 1/10 1/10 0/10 1/10 1/10 0/10 0/10 _0/10 3/10 0/10 0/10 3/10 1/10 2/10 1/10 0/10 0/10 0/10 0/10 1/10 1/10 1/10 2/10 6/10 0/10 2/10 1/10 0/10 0/10 0/7 0/10 1/10 0/10 0/10 1/10 0/10 0/10 1/10 3/10 1/10 0/10 1/10 0/10 0/10 0/10 0/10 Data listed as number of rats with oo3ertrpr,-o n /!__ bar. 0- tz.3sues a*.*~r-> ar< 2~l -71- TABLE 31 (Continued) MICROSCOPIC OBSERVATIONS ON TISSUES OF RATS MAINTAINED ON DIETS CONTA.INING 2,4,5--T FOR 118-119 DAYS Observations Dose (mg/kg/day) Male '7123.1.2 0 30 0 30 Mineralized deposits within kidney 1/10 Dilated renal pelvis 0/10 Kidney - rat content (oil red 0) - absent absent to very slight - absent to slight 6/10 3/10 1/10 Focal pancreatic acinar atrophy and fibrosis 2/9 Increase in size of single islet in pancreas 1/10 Sialoadenitis, sometimes with involvemenc of submandibular lymph node 2/8 Focal myocarditis 1/10 Intestinal nematodiasis 1/10 Focal edema of gastric wall 0/10 Focal aggregation of mononuclear cells in skeletal muscle 0/10 Slight increase in hematogenous pigment in spleen 0/10 Aggregations of inflammatory cells in lumen of uterus - Keratinized eoithelial whorl(s) in thyroid 0/10 Focal periportal aggregation of reticuloendothelial cells in liver 0/10 2/10 1/10 8/10 2/10 0/10 0/10 0/10 2/10 1/10 3/10 1/10 1/10 0/10 0/9 0/10 3/10 1/10 6/10 2/10 2/10 1/8 0/10 2/10 0/10 '8/10 1/10 1/10 1/10 0/10 4/10 0/10 3/10 0/10 0/10 5/10 1/10 1/9 2/9 0/10 4/10 0/10 0/10 4/10 . 0/10 1/10 1/10 0/10 Data listed as number of rats wit h observati on/number of cissues '3Tr!rr*^c. <s J 1! j i j ! ; j .. -- 2_(3 7^1 -72- TASLS 31 (Continued) MICROSCOPIC OBSERVATIONS ON TISSUES OF RATS MAINTAINED ON DIETS CONTAINING 2,i,5-T FOR 113-119 DATS Observations _________ _______ Dose (mz/kg/dav)_______ Mala Female __0 30 0 30 Focal aggregation of reticulo endothelial cells sometimes adjacent to degenerate-- appearing hepatocytes 3/10 Cytoplasmic vacuolation of isolated hepatocytes -2/10- Liver - fat content (oil red 0) absent absent to vary slight absent to slight 2/9 4/9 3/9 8/10 1/10 5/9 1/9 2/9 10/10 1/10 8/10 1/10 1/10 8/10 0/10 6/9 3/9 0/9 Data listed as number of rats with observation/uumber of tissues examined. 2.133.8s 73- TASLZ 32 GROSS OBSERVATIONS OS MALE RATS AUilAISES OS 3IETS CONTAlifING 2,4,j-r 70S j? TO TA0 TEARS Diagnosis Coda Xuabet of ra ts r.ecropsied during Cha cime p e r io d indicated 1-6 Months 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g / d a y 3 ag/kg/day 1 0 3 0 Months 2 0 ]_ X 12-13 Moachs 14 9 ?2 12 A-L A-2 A-3 A-a A-7 A-9 a- ig A -11 >-1 ADRENAL GLANDS Enlarged adrenaKs) Hoccied adranal(s) Rinpoinc d a rk f o c i on a d r e n a l( a ) Pinpoint pale fo c i on a d re n a i(s ) 0 ag/kg/day 30 a g/kg/day 10.ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g / d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g / d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 flig/kg/day 3 mg/kg/day Darkened and/or aongescad appearance of adrenals Decreased size of adranaK s) Hecorrhagic aooearance of adrenal Cysc(s) vichir. adrar.al Gray aooearance or a d ren a ls Kectorrhszic - a t 3r i a l associated v ith adrar.al 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g / d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g / d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g / d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 ag/.kg/day 3 ag/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g / d a y 3 ag/kg/day cardiovascular system C ag/kg/day 30 n g /k g /d a y 13 a g /k g / d a y 3 ag/kg/day 0 *0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 3 "1 3 1 '0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 '0 0 0 0 0 0 0 0 o o 0 0 0 3 3 3 1 0 1 0 1 1 2 0- 3 0 1 3 3 0 0 2 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 3 0 0 0 0 } 2 19-24 Mancha 53 25 23 23 Tersanal Cuaulaciv Kill Results 6 36 16 50 i 50 9 50 IS 3 6 5 6 3 5 2 7 3 1 2 1 2 1 2 1 1 0 1 1 0 0. 0 1 0 0 2 0 0 0 0 1 0 0 0 0 A 1 0 7 2 > 5 4 6 1 4 0 0 0 1 2 5 1 3 0 0 0 0 a 1 1 1 0 0 0 0 1 1 0 2 0 X 0 0 3 1 0 n 0 3 0 3 0 7 1 V 24 14 u 9 7 4 7 3 13 9 3 3 11 2 1" 3 1 2 2 2 x 0i-J\ 0 2 1 0 ; 0 x 0 0 /. L 0 0 3 0 1 0 : 2 2 5." ._ s r s d n.5 r.u.rber of r a t s f o r vhdch ode l i s t e d o b s e r v a t : .on V2 5 p r e s e n t . 5 . 2 : i s t i c a l l y d i f f e r e n t f r o n c o n t r o l d a t a v hen a n aly se d us:=5 -- e r ' s I aScc P r o b a b i l i t y T e s t, p<0.05. -- 04 3 - I V ; t (U t. to o o o a . H to vO't <Tt 3 O) 'O 'O s O fO W M r l f > v-t 'O co ^ n in oi --t o o r -l M O O 00vOvOO'r 'O rS s t O r l rvl vn r I v o n r l ;A3LZ 32 (Continued) Z O to ww M *i; o t^ *!i i -<1 mi qt? - i 7 s,t m n M N O . I r-( o MR H >! i t o n't Z oo MZ HM >3 O <Q JO H to z eo O O G >. >. d crl >, d X) T) d s,x> ^ xt ^,i ,,ov*r h r - -h,r M bn bo-M, W H fl M d o fo* ro-4 ri n b0 n rl d to Vt o u d rl d Tj ti 0) U d 0) o. O H fl n utTj do .O M rf fj _ tu d d) ri rj Z C3 1. f t O l Ql dd ft o fi m f tooo OOOO OOOO O O O O OOOO OOOO o o o o >v d d >, d x ) "U d X) '- X.* ^ W) bP ^ N) ,,/ M NI M bn w*--, bo 0 N> d Fl O Oo OH n d ;d>nl%x>d)s -oV0Wd!0>SorbbdoPn .Mbn odn o*--i X>d)> _ovn bdn m >ds 13 -Vbn bdf) o bdt)s nn tRn om dd bn bdn o-i >dt>j hP .'S. bdn m sctejl -Vbn bnn o dd Of) s odn oo Td) bil bn 6 o-4 T>d)s bf) b6O n It d u T U H to VH W Of d to -I tn Of tv 3> 01 d t*n 9 i -I S -d u9 d ud dM Hn -ri O 5 cu tj to d , tl fl II r| tI d M V-* 01 n. o it M fll O Si -I r l J-> O M to tu u ud * t o to tu .ci a t<nuf.t od y i ^ J HdItMj u (if 1 U --I O O OO O r-l r-l r-l O O O <nr-~ ' -.1 c * ! O r o O oooo oooo --I o o --i o o o o o O O ' oooo oooo o o --i r-i o o o o O O O r-l o o o o o o o o oooo o o o oooo oooo o o o o o o o o ooo oooo oooo oooo oooo oooo oooo oonn XttIs y6.P br n o Tn)l rV6?P M > oo TbtJs -6v:0 w> o TtJ _bVP, bHP o t^yT>npJ.nj. bn o o -Xntl yp.n rbP oo >rNWt) Mi Or - l TnJ) yb.P bnP o TaMtOUrjl ti ' MO ttOuH "<aVU>Iu)) >0FoP1uataHJ))i OM MI t t-Hrl t>P4tH1!) ..l.HdnO-tVHi- tdvj yo.n bt P o t>t yo.n nr o or o t>ni yh.P -t^oXtn. bnP or - l bt P O r.-OonMt ttuVatPmtrili *Ou ttn Pttt -tWVm1>I yotmbtt.P>yotoXtbbt.Pn t>tN yM bt P Or - l t{tIS yM) bt P o tt8Pto>tOt> rrlt taPtmi PO UOHu HPt141 tt ybP 6t 0 o t>n>i y6.0 bt P Oo tbts bP bt P or - l 'T>t Js ybP boO r-t ' OM tttoubtdnPi ttt ytybtt(orU.P,f tuMt8d n?;)| y6P 6nP o tt -V6p. bP Oo -.n-Vt6tbrV-K!!0Pj. or - l t>t v6{P 611P n -<a1Vmt0n) tr.oOo--1 P1Mur1l Vtt(r11)l MoJ t1nEt.1}i t 11i i>n _/ Mr i brln trI t 6t 0 r>lr 6t 0 6r l0 n r-> r - l o:> (1;1111 >ot .MHr tOtr:tj1 tt,iHSn/ i/ tn O yit i, trtl -rt il1 o. Ir po niitOnii;. li t-1 i t j )tii1 pO. rDn1u1. 1 \p rIn rmIo O' r OI o 1r-l m o 'O r -l r-l mI mI f.) tn toInrIil tlnt o. o TtJ IJ in Po t o t1i) n. o tr <vti "1 I I -- t n.1i O ei -75- TA3L2 32 (Continuad) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T "OS. u? TO r-.'0 TEARS D iagnosis Coda Mumber o f ra e s necroosied during cha cine period in d ic a te d 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 a g /k g /d a y 3 mg/kg/day I 0 0 0 7-12 Months 13-13 Months 2 0 1 I 14 9 22 12 CENTRAL NERVOUS 3TSTEM (C onc'd) C-2 Com pression on b ra in w ith or w ithout m alacia from p itu ita r y 0 ag/kg/day 0 - *0 mass 30 m g/kg/day 0 0 10 m g/kg/day 0 0 3 mg/kg/day 0 0 0 0 0 0 C-4 Focal hemorrhage in region of 0 mg/kg/day 0 0 0 p in eal gland 30 m g/kg/day 0 0 0 10 m g/kg/day 0 0 0 3 mg/kg/day 0 0 0 C-5 C ra n ia l mass in v o lv in g b ra in 0 mg/kg/day 0 0 0 30 m g/kg/day 0 A 0 10 a g /k g /d a y 0 0 0 3 ag/kg/day 0 0 0 C-6 Area o f ra a ia c ia i n b r a in 0 ag/kg/day 0 0 0 30 a g /k g /d a y 0 0 0 10 m g/kg/day 0 0 0 3 mg/kg/day 0 0 0 C-8 C ra n ia l mass in v o lv in g c r a n ia l 0 mg/kg/day 0 0 0 nerve w ith com orassion on b ra in 30 m g/kg/day 0 0 0 10 a g /k g /d ay 0 0 0 3 ag/kg/day 0 0 0 ZYFS D-l C loudiness of cornea(3) w ith or 0 ag/kg/day 0 1 2 w ithout dryness 30 m g/kg/day 0 0 AV 10 m g/kg/day 0 0 7 3 mg/kg/day 0 0 3 0-2 C loudiness of Ians (lea s a s ) 0 mg/kg/day 30 m g/kg/day .10 m g/kg/day -3 m g/kg/day 0 0 0 0 00 0 .0 02 01 0-3 Hemorrhage an d /o r fo ld in g of 0 mg/kg/day 0 0 0 re tin a in one eye 30 a g /k g /d a y 0 0 0 10 m g/kg/day 0 0 1 3 mg/kg/day 0 0 0 0-4 E rosion of cornea 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 A 0 0 0 0 D-5 Mass in v o lv in g aye v ic h o r w ith o u t 0 m g/kg/day 0 0 0 a so ohc ha I .t .u s 30 m g/kg/day 0 0 0 10 m g/kg/day 0 AV 0 3 mg/kg/day 0 0 0 3-6 C in era ci n and o ro c ru sio n of ave from o r b it 0 mg/kg/day 30 n g /k g /d e y A 0 3 *> J 0 0 10 m g/kg/day 0 J `J 3 ng/hg/dey 0 a 0 19-24 Mouths o3 25 23 23 1 2 0 1 0 1 0 0 0 1 A 2 0 0 1 1 0 0 1 0 25 12 3 9 i 4 0 1 1 0 0 0 1 0'0Aj 0 i 1 Aj 0 2 1 0 Ca" = l i s t a d as number o f r a t s fo r w hich th e 1:.seed o b s e rv a tio n ves p r e s e n t . K ill 6 16 4 9 C um ulative R esults 36 50 50 50 0 0 12 00 02 00 02 00 00 0 /U*v 01 02 02 0n 0a 01 01 00 0 0 01 00 4 33 13 25 46 19 13 1 21 5 6 3 35 01 00 0x 00 01 00 00 00 00 01 91 0G 0G 0. 3 1A J 0- i 0 .-. _ .!1I "--1 j 1 . _i -- 2^f331 -76- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS D iagnosis Code Number o f r a t s necropsied during th e tim e p erio d in d ic a te d i--6 Mnchs 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 1 0 0 0 D-7 D-8 E -l E-2 E-3 E-5 E-6 E-7 E-8 E-9 E-10 EYES (C o n t'd ) P ro tru sio n of eye w ith or w ithout p u ru len t n e c ro tic d e b ris extending from the o ra l c a v ity 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 Shrunken appearance of one eye 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 GENERAL D ecreased amount of adipose tis s u e in abdominal c a v ity 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 Postm ortem a u to ly s is 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 .0 Loss o f body c o n d itio n (unkempt appearance, roughness of h a irc o at and/or decrease in size) 0 m g/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 m g/kg/day 0 0 0 0 Exudate accum ulation l a t e r a l to e x te rn a l nares and eyes (bloody m aterial) 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 Excess adipose tis su e 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 P e rin ea l s o ilin g or m atting 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 D iffuse paleness of tissu e s (anemia) - o th e r cau ses than subcutaneous mass fo rm atio n 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 1 0. 0 0 Hemorrhage in abdom inal c a v ity 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 1 0 0 0 Em aciated appearance (in a n itio n ) - 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 0 4 3 5 6 6 0 5 1 3 1 11 6 2 0 0 1 2 0 3 0 2 1 1 0 2 1 3 1 1 0 0 0 0 1 0 0 19-24 Months 63 25 23 28 Term inal Cum ulative K ill R esults 6 86 16 50 4 50 9 50 000 000 0 0 0 101 000 000 000 101 31 0 36 10 2 15 7 1 13a 11 0 17 5 0 11 404 5 0 10 204 27 0 31 11 0 12 7 0 18 9 0 15 8 0 11 404 202 203 406 000 104 202 507 405 102 505 306 405 205 102 305 0 00 101 000 6 1 0 0 6t 000 303 Data l is te d as number of r a ts fo r which the l i seed o b se rv a tio n was p re s e n t. S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a ta when a n a ly z e d u s in g F i s h e r 1s E x act P r o b a b i l i t y T e s e , p<0 .0 5 . 0 -133? - -77- TABLE 32 (Continued) GROSS OBSERVATIONS OH MALE RATS MAINTAINED ON DIETS CONTAINING 2 ,4 ,5 -T FOR UP TO TWO YEARS D iag n o sis Code Number of r a t s necropsied during the time period in d ic a te d 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day i 0 0 0 7-12 Months 2 0 1 1 E -ll E-12 E-14 E-15 E-16 E-17 E-18 E-19 E-22 E-2S E-26 GENERAL (C ont'd) D iffuse paleness of tissu e s (anemia) - secondary to subcutaneous oass(es) form ation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day C an n ib alism 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Reddened appearance of f e e t, pinna, 0 mg/kg/day scrotum, and abdominal muscle 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day S tra n g u la ted omental f a t (fo c a l f a t 0 mg/kg/day necrbsis) 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Excess* f l u id i n abdomen 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Edematous and/or a tro p h ic appearance of omental fa t or mesentery 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day M alocclusion of d en tal arches 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hemorrhage of mouth, tongue, hard p a la te , and n a sa l passages (unknown cause) 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Module of ad ip o se ty p e t i s s u e in abdomen 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Focal thinning of the haircoat 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Accumulation of exudate around genital o rifice 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 0 '0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 '0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 2 1 1 0 1 0 0 0 0 0 0 0 o' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 19-24 Terminal Cumulative Months K ill R e su lts 63 6 86 25 16 50 23 4 50 28 9 50 20 2 000 001 00 0 20 4 30 4 001 000 00 1 000 000 000 011 000 000 20 2 20 01 10 2 .0 2 1 1 2 314 000 10 i 20 2 10 1 00 0 00 0 000 000 10 1 00 0 000 011 000 000 000 000 001 000 000 000 10 1 000 000 Data l i s t e d as number of r a t s fo r which th e l i s t e d o b se rv a tio n was p re s e n t. 2 .1 3 .3 3 -78TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO TEARS D iagnosis Code Number o f r a t s necropsied during th e cime p e rio d in d ic a c e d i-6 Months 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 1 0 0 0 7-12 Months 2 0 1 1 13-18 Months 14 9 22 12 E-27 E-30 E-31 E-32 ' F-2 F-3 F-4 F-5 F-6 F-7 F-9 GENERAL (C o n c 'd ) Abdominal d isc en c io n 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Uremic odor 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Blood along v e n tr a l a sp e c t o f body 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Darkened e x te rn a l nares 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day GASTROINTESTINAL SYSTEM U lceration or erosion of gascric mucosa 0 m g/kg/day 30 m g/kg/day ' 10 m g/kg/day 3 m g/kg/day M in eralizatio n of g a stric w all (pale lin e a r sc ria tio n s) 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day In te s tin a l m ass(es) or nodule(s) 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Hemorrhage in to g a s tr o in te s tin a l tra c t 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day T hickening, edema, an d /o r hemorrh ag e in w a ll of cecum som etim es due to uremia 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Dark m a te ria l in g a s tr o in te s tin a l tr a c t (or darkened ingesca or feces) 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day P e te c h ia l hem orrhage on g a s tr ic mucosa w ith o r w ith o u t a s s o c ia te d hemolyzed blood 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o' 0 0 0 0 0 0 0 0 o- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 '0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 2 4 1 6 7 0 1 0 0 1 0 1 0 0 0 2 2 2 i 4 2 4 0 2 2 19-24 Months 63 25 23 28 Term inal Cum ulative R ill R esults 6 86 16 50 4 50 9 50 10 00 00 o 0 00 10 00 00 00 00 00 10 00 00 00 10 1 0 0 0 0 1 0 0 0 0 0 1 0 0 0 1 909 214 202 305 20 1 25 4 1b 2 08 6 0 13 4 15 113 101 112 2 14 112 102 202 404 1 o 1 103 507 406 102 206 103 408 101 103 20 D ata l i s t e d a s number o f r a t s f o r w hich th e l i s t e d o b s e r v a tio n was p r e s e n t . a5 c a t i s c i c a l l y d i f f e r e n t from c o n tr o l d a ta when a n aly zed u sin g F is h e r ' s Exact P r o b a b ility T e s t , p< 0.0 5 . TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS D iagnosis Code Number o f r a t s necropsied during the tim e period in d ic a te d 1-6 Months 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 1 0 0 0 F-10 F -ll F-12 F-13 F-14 F-15 F-16 F-17 F-18 F-19 F-20 GASTROINTESTINAL SYSTEM (C o n t'd ) D ecrease of norm al in g e sta in g a stro in testin al tra c t 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day T hickening an d /o r edem atous appear- 0 m g/kg/day ance of mucosa of stomach 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Firm w hite focus in stomach 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day N onglandular mucosa o f stomach showing roughening a n d /o r p o ss ib le focal p ro liferatio n 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day D ila ta tio n of stomach or g a s tro in te s tin a l tra c t w ith gas (cause o th e r th an mouth b re a th in g ) 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Focal g a s tric hemorrhage or hemolyzed blood 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Hem orrhagic e n te r it i s 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day Nodule o r polyp on stom ach mucosa 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day D iste n tio n of stomach and g a stro i n t e s t i n a l t r a c t due to mouth b re a th in g 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Edematous appearance of m esentery 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day D iverticulum of sm all in te s tin e 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 3 1 3 1 2 1 1 4 0 0 0 0 0 0 0 0 1 1 1 0 0 1 7 1 1 0 0 0 1 0 0 0 1 0 0 0 0 0 1 0 0 0 1 0 19-24 Months 63 25 23 28 Term inal Cum ulative R ill R esults 6 86 16 50 4 50 9 50 9 0 12 20 3 205 405 619 416 304 6 1 11 001 000 000 000 00 01 00 1 .0 0 1 0 1 001 001 001 000 18 1 19 8 3 12 7 0 14 629 102 000 000 000 012 000 011 000 001 000 000 10 1 000 000 00 1 000 101 000 001 000 Daca lis c e d a s number o f r a t s fo r w hich th e l i s t e d o b s e rv a tio n was p r e s e n t. 1 -- i --J --r ! .. J 1 i 1 .J 1 1 1 -80- TABLE 32 (Continued) i-- GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 F-21 F-22 F-23 F-24 F-25 F-26 F-27 F-28 F-29 F-30 F-32 GASTROINTESTINAL SYSTEM ( C o n t ' d) Roughened appearance of nonglandul a r mucosa 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hyperemic appearance of g a s tric mucosa 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Ulceration of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Intussusception of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Necrotic e n te ritis of small in te stine extending into a p e rito n itis in v o lv in g l i v e r and omentum 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal th ic k e n in g of cecum 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day In fa rc tio n of small in te s t i n e due to v a s c u litis and thrombosis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hyperemia of sm all in te s tin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Nodule in mesentery 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Enlarged Peyer's Patch along small intestine 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Yellow b i le - s t a in i n g m ate ria l in gastrointestinal cract 0 mg/kg/day 30 mg/kg/day. 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 1' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 36 16 50 4 30 9 50 10 1 00 0 00 1 00 0 1 0 0 0 X 0 00 0 00 0 10 1 000 00 0 000 1 0 -L 00 0 00 0 00 0 10 1 00 0 00 0 000 000 10 1 00 c 000 00 0 000 10 X 00 0 00 0 000 10 1 00 0 000 000 000 10 1 011 02 2 000 000 20 3 00 0 10 x 000 Data l i s t ed as number of r a t s f o r which the l i s t e d o b s e r v a t i o n was p r e s e n t . QJ33t> -81- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO TEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 F-33 F--34 F-35 F-37 F-41 F-42 F-43 F-44 . F-45 F-46 F-47 GASTROINTESTINAL SYSTEM ( C o n t 'd ) Mucoid, loose, and/or w a te ry -lik e m aterial in g astro in testin al trac t 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Change in t e x tu r e of s t o o l softened, moistened 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hemolyzed blood in g a s t r o i n t e s t i n a l tra c t due to s e lf-in g e stio n 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Reddish mucoid flu id in i n te s tin e 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day White film over stomach su rface 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day White granular appearance of small intestine 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Increased ingesta in gastroincestinal tract 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Gaseous d is te n tio n of p o rtio n s of intestinal tract 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day O verdistention of in te stin e with . ingesta secondary to in te s tin a l mass 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day E rosions of cecum 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Edema of s m a l l i n t e s t i n e 0 mg/kg/day 30 mg/k g/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 1 0 1 0 0 0 2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 102 101 10 2 000 000 101 1 0 3a 000 000 101 00 1 101 000 000 000 101 000 000 000 101 101 000 000 000 101 000 000 000 101 000 101 000 101 10 1 000 000 000 10 1 000 000 000 10 1 000 000 Data liscad as number of rats for which the listed observation was present. Statistically different from control data when analysed using Fisher's Exact Probability Test, p<0.05. 2J337 -82- TABLE 32 (Continued) GROSS OBSERVATION'S ON MALE RATS MAINTAINED OH DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated F-48 GASTROINTESTINAL SYSTEM ( C o n t 'd ) D ila ta tio n of stomach with in gesta F-49 Friable gastrointestinal tract F-50 C a ta r r h a l ex u d ate in cecum LIVER G-I Enlarged liv e r G-2 Darkened o r c o n g e s te d l i v e r G-3 G-13 G-4 Paleness of liv e r - (anemia) probably re la te d to subcutaneous mass (es) form ation Paleness of l iv e r - (anemia) other causes Atrophied liv e r G-5 Sm all p a l e f o c i i n l i v e r G-6 Red o r d a r k e n e d f o c i i n l i v e r G-7 N o d u l e ( s ) i n l i v e r 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 ,,0 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/d3y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 0 0 0 0 0 3 1 5 1 4 2 7 1 0 0 0 0 4 1 3 4 1 0 0 0 2 3 0 0 0 0 a 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 36 16 50 4 50 9 50 000 000 10 1 000 000 000 1 0. 1 000 000 000 000 10 1 7 0 11 0 0 la 20 7 20 3 8 0 12 215 3 0 10 30 20 2 000 0 0 1 000 12 1 1 7 416 00 j 30 7 00 i 00 0 000 10 1 10 5 n 11 5 235 54 9 11 5 16 459 5i 6 45 50 01 00 01 5 i 0 X. D ata l i s t ed a s c u m b e r .o f r a t s f o r which th e l i s t e d o b s e r v a t i o n was p r e s e n t . s t a t i s t ! c a l i y d i f f e r e n t from c o n t r o l d a t a when a n a l y s e d us:Lng F i s h e r ' s Exact P r o b a b i l i t y T e s t , p<0 .05. -83- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE BATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day , 10 mg/kg/day 3 mg/kg/day 1 0 0 0 G-9 G-10 G--11 G-12 G-14 G-15 G-16 G-26 G-17 G-18 G-19 LIVER ( C o n t 'd ) Accentuated lobular pattern of liver 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Biliary cysts in liver 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Nodular mass(es) in liv e r (prob ably m etastatic) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Decreased size of liv e r (atrophy) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Linear, fib ro tic reaction or capsular chickening on l iv e r due to d is t o r ti o n with or wichouc necrosis 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Pale area(s) in liver 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Strangulation of small portion of liver 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day F ib ro tic adhesions becween l iv e r and kidney 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cyst in liv e r containing blood 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day ' 3 mg/kg/day L i n e a r p a l e a r e a s (3 / 4 cm) i n liver 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Icterus 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 2 0 2 1 0 0 0 0 0 0 0 0 1 0 1 0 1 0 1 0 1 0 .0 0 0 0 1 0 0 0 0 0 0 0 .1 0 0 0 0 1 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative Kill Kabults 6 86 16 50 <4 50 9 50 406 202 002 102 707 112 202 101 001 000 000 000 506 3 14 102 303 124 156 012 112 10 2 112 000 000 000 000 001 000 0 11 000 000 000 000 0 00 001 000 000 000 000 001 10 1 10 1 000 000 Data l i s t e d as number or r a t s f o r w hic h che l i s t e d o b s e r v a t i o n was p r e s e n t . i i I3 3 ? -84- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR CP TO TVJO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 G-21 G-22 G-23 H-l H-2 H-3 H-4 H-5 H-6 H-7 H-8 LIVER (C o n c 'd ) Focal darkened area(s) in liv e r 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Friable texture of liver 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Mottled appearance of liv e r 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day LYMPHORETTCULAR SYSTEM E nlarged c e r v i c a l lymph nodes 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day E nlarged t h o r a c ic lymph nodes 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day E nlarged m e s e n te ric lymph nodes 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Moist, edematous and/or hyperemic a p p ea ran c e o f m e s e n t e r i c lymph nodes 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Edema a n d /o r h yperem ia o f t h o r a c i c lymph nodes a n d /o r c o n g estio n 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day. E nlarged thymus 0 mg/kg/day 30 m g/kg/da y 10 mg/kg/day 3 mg/kg/day Mass i n v o lv in g thymus 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Enlarged and/or moist appearance of 0 mg/kg/day h e m o rrh a g ic a x i l l a r y lymph n o d e (s) 30 x g /k g /d a y 10 m e/k g /ca y 3 mg/kg/day 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1' 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 c 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 1 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 404 000 000 101 10 1 101 000 000 000 000 000 101 101 000 000 000 10 1 000 0 0 -> 000 528 012 3 0 3 101 11 2 123 224 30 3 21A 011 001 404 001 000 000 000 000 000 000 10 10 1 20 3 000 000 Data l i s t e d a s number of r a t s fo r v h ic h th e l i s t e d o b s e r v a t i o n was p r e s e n t . -85- TABLE 32 (Continued) GROSS OBSERVATIONS' ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO YEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1 -6 Months 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 1 0 0 0 H-9 H -ll H-12 H-14 H-15 H-16 H-17 H-18 H-19 ' H-20 a-21 LYMPHORETICULAR SYSTEM ( C o n t 'd ) Darkened, hemorrhagic appearance of 0 mg/kg/day m e s e n te r ic lymph node a n d /o r hema- 30 m g/kg/day togenous pigment 1 0 mg/kg/day 3 mg/kg/day 0 0 0 0 Mass i n v o l v i n g m e s e n t e r i c lymph nodes, thymus, re n al lymph node, and m esenteric tis su e s 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 C ongestion of m e s e n te ric lymph nodes 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 0 0 0 Darkened and/or congestion of th o r a c ic lymph nodes 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 0 0 0 Edema w i t h o r w i t h o u t h e m o r r h a g ic pigment in sublumbar lymph nodes 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 0 0 0 Hematogenous pigment in m esenteric lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 H y p e rp la s tic appearance of lymph nodule in small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 E nla rged r e tr o p h a r y n g e a l lymph node w ith edema and p u r u le n t exudate 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day . 0 0 0 0 Darkened, hemorrhagic appearance of th o r a c ic lymph nodes 0 mg/kg/day 30 mg/kg/day 1 0 . mg/kg/day 3 mg/kg/day 0 0 0 0 Darkened appearance of submandibul a r lymph nodes 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 0 0 0 Enlarged and/or darkened peria o r t a l lymph nodes 0 mg/kg/day 30 m g/kg/day 10 mg/kc/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 0 1 l 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 1 0 0 0 1 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 3 0 1 2 0 0 0 0 1 0 0 1 0 0 0 2 1 1 0 0 0 0 0 0 1 0 0 0 1 0 0 0' '1 0 0 0 1 0 0 0 1 0 1 ff 1 5 2 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 5 3 2 0 0 0 1 1 0 0 2 1 0 1 2 1 1 0 0 0 0 1 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 9 0 1 - 0 Data listed as number of racs for which the listed observation was present. d M Hi - 86TABLE 32 (Continued) GR O SS O B SE R V A T IO N S ON MALE RATS C O N T A IN IN G 2 , 4 , 5 - T EOR UP 70 TWO YRAa S Diagnosis Codec Number of rats necropsied during the tine period indicated 1-6 Months 0 og/kg/day 30 og/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 H-22 H-23 H-24 H-2S H-29 H-30 I-1 1-3 1-4 1-5 J-l LYMPHORETICULAR SYSTEM (Cont'd) Decreased s i z e of m e s e n t e r i c lymph nodes 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day Enlarged subm andibular lymph nodes 0 .mg/kg/day 30 og/kg/d ay 1 0 mg/kg/day 3 mg/kg/day Congestion of i l i a c lymph nodes Hematogenous pigment in th o rac ic lymph Qode Gelatinous appearance of mesent e r i c lymph node Mottled appearance of mesenteric lymph node 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day MUSCULOSKELETAL SYSTEM Dem ineralization of bones Atrophy of hind limb musculature 0 og/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 1 0 mg/kg/day 3 mg/kg/day Mass or nodule in v o lv i n g r i b 0 mg/kg/day 30 og/kg/day 1 0 mg/kg/day 3 mg/kg/day Generalized atrophy of musculature 0 og/kg/day 30 og/kg/day 1 0 mg/kg/day 3 mg/kg/day PANCREAS Nodule(s) in region of pancreas 0 3g/kg/day 30 og/kg/day 10 og/kg/day 3 og/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 7 -1 2 M o n th s : 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 00 0 1J-3 M o n th s I; 9 'Z u 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 6 1 3 - \ *- * 4 y*-.r :h * 0j < ;3 :s T i! r " . i " .- i i C- i n u l a , t i v e 1 - 'e s u l ts - 36 16 50 50 > 50" 000 l i2 000 000 000 000 000 1 0 1 000 000 000 10 1 000 0 11 000 000 10 00 30 00 1 0 0 0 00 30 i0 00 0 0 1 30 51 10 0 56 * 3 10 1 000 000 000 10 0 00 10 00 1 0 1 0 3 0 00 0 *0 i. 3 ** * .w li Data listed as number of rats for which the listed observation was present. a * ?'-'3 - -87- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TOO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 J-4 J-5 K-l K-2 K-3 K-5 K-6 L-0 L-l L-2 L-2A PANCREAS ( C o n t 'd ) Edematous appearance of pancreas 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Pale appearance of pancreas 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 PITUITARY GLAND Enlarged p itu ita ry 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Dark red fo c u s(fo ci) on p i tu i t a r y 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Hemorrhagic or darkened p itu ita ry 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Mass I n v o l v in g p i t u i t a r y w ith e x tension into brain 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Cyst w ithin p itu ita ry 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 REPRODUCTIVE SYSTEM Decreased size of te s tis (unila te ra l) (atfophy) 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0" 0 Decreased size of te ste s (b ila te r al) (atrophy) 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 '0 Flaccid te s tis (unilateral) 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day . 0 0 0 0 Flaccid testes (bilaceral) 0 mg/kg/day 30 m g /kg/da y 10 m g/kg/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 1 0 0 1 1 1 0 0 0 1 1 0 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 2 4 3 1 0 O' 1 0, 4 1 1 1 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 10 1 \0 0 0 10 1 00 0 00 0 00 1 000 000 70 8 214 50 6 213 022 033 304 124 50 5 20 2 20 2 20 2 00 0 00 0 00 1 000 10 1 000 000 000 8 1 10 213 203 01i 22 0 24 12 1 17 7 . 0 10 10 1 12 21 3 123 10 2 01i 14 0 18 517 6 13 315 Data 11s :ed a s number o f r a t s t o r which the l i s t e d o b s e r v a t i o n was p r e s e n t . S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a c a when a n a l y z e d u s i n g F i s h e r ' s E xact P r o b a b i l i t y T e s t , p < 0 .05. "1 i s .. 1 ! - ...j -8 8 TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR U? TO TVO YEARS Diagnosis Code Number of r a t s necropsied during the time period Indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 L-3 L-4 L-5 L-6 L-7 L-8 L-9 L-10 L-ll L-12 L-13 REPRODUCTIVE SYSTEM (Cont'd) Decreased size of accessory sex glands (atrophy) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day .0 0 0 0 Flaccid accessory sex glands 0 mg/kg/day 3 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 .0 Accessory sex glands impacted with secretory material 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal pale appearance of sem inifer- 0 mg/kg/day ous tubules 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Mass i n v o lv in g p r o s t a t e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Enlarged and/or edematous accessory 0 mg/kg/day sex g la n d ( s ) w ith or w ithout exu- 30 mg/kg/day dative material 10 mg/kg/dav 3 mg/kg/day 0 0 0 0 Decreased size of eoididyraides 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 00 0 Edematous appearance of t e s te s 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Yellow d isc o lo ra tio n of epididymis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Flaccid appearance of epididymis 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Friable texture of testes 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 0 1 1 1 0 0 0 0 0 0 0 Q 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 3 3 3 0 3 1 1 0 0 1 0 0 0 '0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 23 23 28 Terminal Cumulative Kill Results 6 86 16 50 4 50 9 50 16 1 21 10 1 14 50 8 9 1 10 8 0 11 20 3 2 1 0 1 13 10 1 00 1 000 10 1 30 3 112 102 000 000 10 1 000 00 1 10 1 20 2 000 20 2 61 0 0 0? 0 0 oa 00G 10 i 01i 000 011 10 1 000 000 000 202 000 000 000 000 000 10 1 000 Data l i s t e d as number of r a t s fo r which the l i ste d o b s e r v a t i.on was p r e s e n t . "S t a t i s t i c a l l y d i f f e r e n t from c o n tr o l d a ta when analyzed using Fish e r ' s Exact P r o b a b i l i t y n e s t , ?<0 .05. ^ 3^ -89- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO W O YEARS Diagnosis Code Number of r a t s necropsied during Che tim e p e r i o d indicated 1-6 7-12 Months Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 2 0 1 1 L-I4 L-15 L-16 L-17 L-18 L-19 L-20 M-12 M-16 M-10 M-10A REPRODUCTIVE SYSTEM (C onc'd) Inf lamination and protru sio n of penis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Area of d isc o lo ra tio n adjacent to pale area in cesces 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Hem orrhagic a r e a on t e s t i s (50%) 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Yellowish m aterial in o rific e of penis (probably agonal) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Tan c o lo r of t e s t i s ( e s ) 0 mg/kg/day 30 m g/kg/day 10 mg/kg/dav 3 mg/kg/day Dark d is c o lo r a tio n of prepuce and penis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Congenital absence of one t e s t i s 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day RESPIRATORY SYSTEM Clear liquid in nasal passages 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Mass w i t h in d o r s a l n a s a l p assa g es 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day keratinized abscess-like lesion located above the hard p a ia te in the v e n tra l portion of the nasal tu rb in a te s, blocking airway 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day K eratinized debris in nasal turbin- 0 mg/kg/day ates 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Tidrr.mal Cumulative Kill Sosultj 6 cb 16u 50 50 9 50 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 1 0 0 0 0 0 1 o 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 1 0 0 1 0 - 0 1 1 0l 0 0 0 0 0 1 0 2 0 -> 0 20 0000 0 303 0 10 1 0 0 00 0 0 0 0 0 3 100 i 0 030 O' 1 0 * 0 000 0 10 * 0 00 0 0 00 000J Data listed as number of rats for which the listed observation was presenc. 2-4 -90TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of ra cs necropsied during Che time pe riod indicated i--6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 M-l M-2 M-3 M-m M-5 y.- M-a :!~5 M-I3 M-14 M-17 RESPIRATORY SYSTEM (Cont'd) Pulmonary congestion, consolidac io n , a nd/or edema ,, 0 mg/kg/day 30 mg/kg/day 10. mg/kg/day 3 mg/kg/day Pleural effusion (hydrothorax) - 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Suooleural pale foci in lungs (suggestive of alveolar h istio cytosis) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Red or dark f o c i in lungs 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Darkened and/or congested color in lung tissue 0 mg/kg/day 30 mg/kg/day -10 mg/kg/day 3 mg/kg/day Pulmonary aceieccasi*s 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Resistance to collaose or subpleural ae^rseaces suggestive or mineralization 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hematogenous oigment in lungs 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pale and/or dark areas in lungs (mottled) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Frothy fluid in bronchioles 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Nodule(s) in lung 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative. Kill Results 6 86 16 50 4 50 9 50 2 0 00 0 9 2 2 4 1 1 0 0 2 18 13 22 18 1 1 0 0 160 023 130 001 28 0 '2 21 14 0 3 0 1 370 1 .3 ' 0 500 15 0 1 13 0 13 07 1 2 1 0 15 0 000 010 110 12 01 20 0 '1 1 0 0 0 050 010 1 2 0. 030 000 000 00 0 10 0 011 010 0 0 .0 020 14 3 2a ` 4 23 10 4a 9 7 5 4 1 10 5 3 6 10 4 3 15 3a 5 7 0 1 ., 2 4 1 2 1 3 1 3 3 0 0 0 i 2 I 0 2 Daca l i s t e d as number of r a t s f o r which che l i s t e d o b s e r v a t i o n was p r e s e n t . a_s t a t i s t i c a l i y d i f f e r e n t from c o n t r o l data when analyzed using F i s h e r ' s Exact P r o b a b i l i t y t e s t , p<0 .05. ^63^(9 -91- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Coda. Number of r a t s necropsied during the time period indicated > 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 7-12 Months 2 0 1 1 M--11 ' M--12 N-l N-2 N-5 N-6 0-1 0-2 P-1 ?-2 RESPIRATORY SYSTEM ( C o n t 'd ) Nodule(s) in lung (possible m etastasis) -0 m g/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 Respiratory distress 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 SPLEEN Enlarged spleen 0 mg/kg/day 30 m g/kg/day 10 m s/ka/day 3 mg/kg/day 0 0 0 0 0 0 1 0 Mass(es) involving spleen 0 mg/kg/day 1 0 30 mg/kg/day 0 0 10 m g/kg/day 0 0 3 mg/kg/day 0 ,0 Decreased size of spleen 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 Cyst on sp le en 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 THYROID AND PARATHYROID GLANDS Enlarged thyroid or parathyroid 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 Enlarged parathyroid(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 URINARY SYSTEM Moderate to severe chronic re n al disease (moderate to severely mottled, enlarged, oale, and/or roughened kidneys) 0 me/kg/dav 30 tne/ke/dav 10 mg/kg/day 3 mg/kg/day 0 0 0 0 1 0 0 0 Slight chronic renal disease (slig h t enlarged, pale, mottled. and/or roughened kidneys) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 1 0 0 0 13-18 Months 14 9 22 12 0 0 1 0 0 0 1 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 4 2 3 3 7 >4 17 10 3 3 0 19-24 Months 63 25 23 28 Terminal Cumulative R ill Results 6 86 16 50 4 50 9 50 10 1 000 00 1 000 000 000 00 1 000 40 7 000 10 0 101 10 2 000 000 000 101 011 000 000 000 000 000 011 40 5 10 1 203 000 19 1 24 9 0 11 6 1 10 60 9 47 17 26 13 - 32 15 - - ; 6 1 13 - i: Data l i s t ed as number of r a t s or which th e l i s t e d c b s e rv a c i on was prc:senc . S t a t i s t i c a l l y d i f f e r e n t from c o n tr o L d a t a ;hen a n a l y z e d u s i ng F i s h e r ' s F x a c t \?rebab 1it y Test* p<0 .05. na -92- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 P-3 P-4 P-5 P-6 P-7& P-20 P-10 P-12 P-136 P-16 P-14 P-15 P-17 URINARY SYSTEM (Conc'd) M ineralization of renal cortex or pelvis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Dilated renal pelvis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cyst(s) in kidney 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Subcaosuiar white foci in kidney 0 me/kg/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mass or nodule in kidney 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day Reddened color of urine in u rinary bladder 0 ng/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Organized plug w i t h in lumen of urinary bladder 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/day 3 mg/kg/day Dark and congested appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day Several c a lc u li in urinary bladder 0 mg/kg/day with distension of bladder with 30 mg/kg/day u r i n e with o r w ithout e p i t h e l i a l 10 mg/kg/day congestion or hemorrhagic appear- * 3 mg/kg/day ance Renal c a lc u li 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/dav 3 mg/kg/day Slight pale appearance of kidneys 0 mg/kg/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 1 1 2 2 2 1 4 1 4 4 9 4 1 0 0 0 1 0 0 0 0 0 0 0 1 0 2 0 1 1 3 0 1 0 0 0 1 0 0 0 0 1 0 0 19-24 Months 63 25 23 28 Terminal Cumulative Kill Results 6 86 16 50 4 50 9 50 51 20 2 0 22 51 30 30 20 27 4 10 4 72 11 2 10 00 00 00 10 10 00 00 00 20 00 00 21 I0 10 10 20 00 10 10 10 10 00 00 00 00 00 00 00 00 00 00 7 3 4 6 8 4 7 3 35 18 18 17 2 0 0 0 2 1 0 0 1 2 0 0 u 2 3 1 3 1 4 1 2 1 0 0 1 0 0 0 0 1 0 0 Daca l i s t ed as number of r a t s for which the l i seed o b s e r v t ! on was p r e s e n t . 3S c a c i s t l c n l l y d i f f e r e n t from c oncroi daca when analyzed using F ish e r '1s Exact P r o b a b i l i t y T e s t, p<0 .05. 2,<*>3 ^ - 93- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day . 10 m g/kg/day 3 mg/kg/day 1 0 0 0 P-18 ' P-19 P-21 P-22 P-23 P-24 P-25 P-26 P-27 P-28 P-33 URINARY SYSTEM ( C o n t 'd ) Slight roughened appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day U ro lith iasis with distension of urinary bladder 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Thickening and/or hyperemia of urinary bladder 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Ascending urinary tra c t in fectio n 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day P e te c h ia l hemorrhages on u r in a r y bladder mucosa 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Friable texture of kidneys 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day C ystic mass extending o ff both kidneys 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Pale focal area in kidney 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day U rethral plug causing d isten sio n of 0 mg/kg/day urinary bladder 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Mass w i t h i n u r i n a r y b l a d d e r 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Overdistension of urinary bladder 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 1 0, 1 000 20 2 000 10 000 000 000 20 2 20 2 000 000 10 1 000 000 000 000 3 0 3a 000 10 1 10 1 10 1 000 10 1 000 000 101 000 000 000 000 10 1 000 000 000 10 1 011 000 000 000 20 2 000 000 000 Data l i s t ed as number of r a t s f o r which the l i s c e d o b s e r v a tio n was pre s e n t . a S t a t l s c i c a l l y d i r t ' e r e n t from c o n t r o l d a t a when a n a l y z e d u s i n g Fi s h e r 1s Exact P r o b a b i l t i y T e s t , pCO.05. 1 i 9 3^ - ^ -94- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the tine period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 1 0 0 0 7-12 Months 2 0 1 1 P-34 P-35 P-36 ' P-37 P-38 P-39 Q-l Q-l Q-2 Q-3 Q-3 URINARY SYSTEM ( C o n t ' d) Enlarged Sidneys 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Edema o f k i d n e y s 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Pale to greenish color of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Granular appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Darkened focus in wall of urinary bladder 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Hemorrhagic m aterial in "oelvis 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day INTEGUMENT AND SUBCUTANEOUS S u b c u t a n e o u s mass - mammary and m idcervical region Number of masses per an im ai: i 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day S u b c u t a n e o u s mass - mammary and m idcervical region Number o f masses p e r a n im a l: 2 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Subcutaneous mass - eye, e a r, region Number o f masses p e r a n im a l: 1 head 0 mg/kg/day 3Q m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Subcutaneous mass - body or limb region Number of masses p e r a n im a l: i Subcutaneous mass - body or limb region Number of masses per a n im a l: 2 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 me/kc/dav 30 m g /k g /d a y 10 m ^/kg/dav 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 0 0 0, 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 1 0 0 0 1 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 6 2 0 4 0 0 0 0 5 0 0 1 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 1 0 0 0 1 0 1 0 0 1 1 0 0 0l 0 0 1 1 0 0 0 1 0 0 0 1 0 0 0 0 0 1 0 0 0 1 l 0 0 0 - 31 6 0 0 0 1 5 1 0 - I - : 1 Data listed as number of rats for which cho listed observation was present. -95- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during Che cime p e r i o d indicated i--6 Months 0 mg/kg/day 30 mg/kg/day `10 m g /k g /d a y 3 mg/kg/day i 0 0 0 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-12 Q-13 Q-14 INTEGUMENT AND SUBCUTANEOUS ( C o n t 'd ) Subcutaneous mass - body o r limb region Number o f masses p e r a n im a l: 3 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day H y p e r p l a s i a of mammary t i s s u e 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Mammary g l a n d galaccocele formation 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Subcutaneous abscess 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Cutaneous nodule or mass form ation Number of m asse s o r n o d u l e s p e r rat : i 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Abscess of Zymbal giand and causing o titis 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Cystic stru c tu re adjacent to salivary glands 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Epidermal inclusion cyst 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Subcutaneous edema 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day Abscess of p rep u tial gland 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Necrotic debris in ear canal 0 mg/kg/day 30 mg/kg/day 10 :ng/k g/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-13 Months 14 9 22 12 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 l 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 00 0 .0 00 01 10 00 00 00 10 00 00 00 10 00 00 10 21 1 2 1 0l 0 00 00 00 00 00 00 00 00 00 00 10 10 10 10 00 00 61 24 20 40 00 0 10 10 0 0 0 1 1 1 0 0 1 0 0 0 2 0 0 1 3 1 4 1 1 0 0 0 0 1 0 0 0 0 3a 1 1 1 0 0 7 6 2 4 0 0 3^ Daca l i s c e i as numuer of r a e s t o r '.hich the l i s t e d o b s e r v a t i o n vas pra s e n c . a S t a C i o C i t a l l y u i i r ' t r e n c from c o n t r o l d a t a vhen a n a l y z e d u s i n g F i s h e r 1s E xact ? r o b a b i i i t y l o s e , p<0 .05. -96- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 1 0 0 0 Q-7 Q-15 R-l R-2 S-l S-2 T-l T-2 T-3 T-4 INTEGUMENT AND SUBCUTANEOUS ( C o n t 'd) Cutaneous nodule or mass form ation Number o f n o d u le s p e r r a t : 2 0 mg/kg/day 30 ig /k g /d a y 10 m g /k g /d a y 3 mg/kg/day Cyst form atio n on l a t e r a l a sp e c t of 0 mg/kg/day thorax 30 m g/kg/day 10 m g /k g /d a y 3 rag/kg/day SALIVARY GLANDS Edematous appearance of sa liv a ry glands 0 mg/kg/day 30 rag/kg/day 10 m g /k g /d a y 3 mg/kg/day Enlarged and firm appearance of salivary glands 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day TONGUE R o s tr a l le s io n on tongue (apparent tearing) possibly agonal 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Mass o r nodule in v o lv in g tongue with or without adjacent aoscessation 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day ORAL CAVITY S o f t e n i n g and n e c r o s i s o f gums 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day N ecrotic and inflammatory process in oral cavity 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3' m g /kg/da y Mass w ith in o r a l c a v i t y in v o lv in g hard palate 0 mg/kg/day 30 m g/kg/dav 10 m g /k g /d ay 3 rag/kg/day Accumulation of keraciniced debris on hard p a la t e 0 mg/kg/day 30 mg/kg/day 10 m g / k g/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill R e su lts 6 86 16 50 4 50 9 50 10 1 000 000 000 000 0 11 000 0 00 000 000 00 1 0 00 101 000 000 000 000 0A 0 0 (J 1 00 0 1 G1 34 000 0 00 1c 1 0 Q0 00 0 020 0 0 * C 0 0 00 11 01 0j 0 0 30 0 30 0 20 01 0 3 O' 00 Daca listed as number ot raes for which che lisced observacin was present. | -97- TABLE 32 (Continued) GROSS OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during che time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 1 0 0 0 THORACIC CAVITY U-l C ystic mass w ith in th o rac ic c av ity 0 mg/kg/day 0 30 mg/kg/day 0 10 m g /k g /d ay 0 3 mg/kg/day 0 7-12 Months 2 0 1 1 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 19-24 Mnchs 63 25 23 28 Terminal Cumulative Kill R esu lts 6 86 16 50 4 50 9 50 1 0, 0 0 0 0 0 0 1 0 0 Data l i s t e d as number o f r a t s fo r which the l i s t e d o b s e rv a tio n was p r e s e n t. 34>3 -98- TABLE 33 GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 0 1 1 A-1 ' A-2 A-3 A-4 A-5 A-6 A-7 A-o A-9 A - 10 3-3 ADRENAL GLANDS Enlarged adrenal(s) Mottled adrenal(s) Pinpoint dark foci of adrenal(s) P inpoint pale fo c i on ad ren a l(s) Darkened and/or congested appear- ance of adrenals ......... - ........ Decreased size of adrenal(s) Hemorrhagic appearance of adrenal(s) Brown d i s c o l o r a t i o n o f a d r e n a l ( s ) Cyst(s) within adrenal Gray appearance of a d ren a ls 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/k g /d ay 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day 0 me/ke/dav 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 ma/ka/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 mg/kg/day . 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 CARDIOVASCULAR SYSTEM Mesenteric p e r ia r te r itis with or without thrombosis (d ilated , tortuous, sclero tic, e tc ...) 0 mg/kg/day 30 m g / k g / d a y 10 mg/kg/day 3 mg/kg/dav 0 '0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 19-24 Monchs 31 18 25 13 Terminal Cumulative K ill R e su lts 36 86 21 50 11 50 19 50 4 7 13 24 04 9 0 60 6 0 1 2 3a 2507 2518 180 9 0303 4 3 23 30 2 0 2 3 15 5 198aa 3 6 11 20 2 3 18 23 1 2 12 0 2 2 4a 1 5 8 15 115 7 014 5 1113 0000 0 213 0000 0000 0000 0156 012 3 0000 00 22 0- 1 0 1 0000 0000 0000 0011 0000 00 00 00 00 00 3 3 00 11 010i 0101 00 11 0011 010 1 0011 Data l i s t ed a s number o f r a t s f o r which th e l i s t e d o b s e r v a t i o n was p r e s e n t . a S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a ta when a n a ly s e d u s in g F i s h e r ' s Exact P r o b a b i l i t y T e s t, p < 0.05. -99- TABLE 33 (Continued) CROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING' 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated i--6 Months 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay * 3 mg/kg/day 0 0 1 1 B-4 B-5 B-7 B-10 3-11 B-14 C-2 C-3 C-7 C-8 CARDIOVASCULAR SYSTEM ( C o n t 'd ) Thrombosis of l e f t atrium 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Dilated and/or flaccid v en tricu lar myocardium. 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day D ilatation of p ericardial sac with hemorrhage and apparent in filtra tio n of neoplastic cells (th o rac ic mass) 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Abdominal mass w ith c y s t i c sp aces (possible vascular origin) 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Hematoma ac b a se of t a i l 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day A xillary vessels enlarged (adja c e n t to subcutaneous mass) 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day CENTRAL NERVOUS SYSTEM Compression on b r a in w ith or w ithout m alacia from p i tu ita r y mass 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Paravertebral mass causing lordosis 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Focal hemorrhage in brain 0 mg/kg/day 30 mg/kg/day 10' mg/kg/day 3 mg/kg/day C ra n ia l mass involving c r a n i a l nerve w ith compression on b r a in 0 mg/kg/day 30 mg/k g/day 10 mg/k g/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 19-24 Months 31 18 25 18 Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 0 0 0 0 0 2 0 0 0 0 0 0 0 0 1 0 0 00 1 0 0 0 0 0 0 2 2 0 0 2 1 0 0 0 0 0 0 0 0 0. b 0 0 0 0 0 0 14 04 01 05 00 10 00 00 00 01 00 00 00 00 01 00 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 2 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 3a 2 1 0 0 0 1 0 0 1 0 0 0 0 1 0 1 0 0 7 4 1 6 0 1 0 0 0 1 0 0 0 0 1 0 Data l i s t e d as number of r a t s fo r which the l i s t e d o b s e rv a tio n vas p r e s e n t . a .b t a t i s t i c a l l y d i f f e r e n t from c o n t r o l dacn when a n a l y z e d u s i n g F ish . e r 1s Exact P r o b a b i l i t y T e s t , p<0 .0 5 . -100- TAHLE 33 (Continued) CROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR L'P TO W O YEARS Diagnosis Code Number o f raC3 necropsied during the time period indicated 1-6 Mnchs 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 0 1 1 EiES D-l Cloudiness of com ea(s) with or 0 mg/kg/day 0 without dryness 30 mg/kg/day 0 10 m g /k g /d a y 0 3 mg/kg/day 0 D-2 C l o u d i n e s s o f l e n s ( l e n s e s ) 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 GENERAL E-l Decreased amount of adipose tis s u e 0 mg/kg/day 0 in abdominal cavity 30 m g/kg/day 0 10 m g/k g /d ay 1 3 mg/kg/day 0 E-2 Postmortem a u t o l y s i s 0 mg/kg/day 30 m g/kg/day 10 m g/k g /d ay 3 mg/kg/day 0 0 0 0 E-3 Loss of body c o n d itio n (unkempt 0 mg/kg/day 0 a p p e a ra n c e , roughness of h a i r c o a t 30 m g/kg/day 0 and/or decrease in size) 10 m g /k g /d ay 1 3 mg/kg/day 0 E-4 Overgrowth of in c iso r tee th (with 0 mg/kg/day 0 o r w ith o u t u l c e r a c i o n or in fla m n a - 30 mg/kg/day 0 t i o n o f h a r d p a l a c e o r gum l i n e ) o r 10 m g /k g /d ay 1 other dencal abnorm alities (tee th 3 mg/kg/day 0 broken off, e tc.) E-5 Exudate accumulation la te ra l to 0 mg/kg/day 0 e x te rn a l nares and eyes (bloody 30 mg/kg/day 0 m acerial) 10 m g /k g /d ay 1 3 mg/kg/day 0 E-6 Excess ad ipose tis s u e 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 E-7 P e r i n e a l s o i l i n g o r m acting 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 0 0 0 E-8 D iffuse paleness of tis su e s (ane- 0 mg/kg/day 0 mia) - ocher causes than sub- 30 m g/kg/day 0 cutaneous mass form ation 10 m g /k g /d a y 0 3 mg/kg/day 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 1 1 0 0 1 1 .0 1 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 1 1 0 0 1 0 0 1 2 1 2 1 0 0 1 1 3 1 0 2 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 1 0 0 0 19-24 Mnchs 31 18 25 18 Terminal Cumulative K ill PwSultS 36 36 21 50 11 50 19 50 10 20 31 5 14 20 10 7 17 5 11 16 3 15 19 156 0 3 3a 0 10 11 11 2 16 7 2 il 13 0 16 236 4 05 102 0 01 24 6 0 10 5 07 9 0 10 3 16 034 000 0 12 000 4 15 000 304 0 11 204 0 00 1 01 0 00 202 0 2 0o 0 2 101 001 0 00 0 0 101 Data listed as number of rats for which the listed observation was present, Statistically different from control data when analyzed using Fisher's Exact Probability Test p<0.05. -101- TABLE 33 (Continued) GROSS OBSERVATION'S ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO TEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day , 0 0 1 1 E-10 E-Ll E-12 E-13 E-15 E-16 ,, E-17 E-19 E-20 E-21 E-23 GENERAL ( C o n t 'd ) Emaciated appearance (in an itio n ) 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Diffuse paleness of tissues (anemia).- secondary to subcutaneous tnass(es) formation 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Cannibalism 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Abdominal organs decreased in s iz e due to s ta rv a tio n 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Strangulated omental fa t (fo cal fa t 0 mg/kg/day necrosis) 30 m g/kg/dy 10 mg/kg/day 3 mg/kg/day Excess f l u i d in abdomen 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Edematous and/or a tro p h ic appearance of omental fat or mesentery 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Hemorrhage of mouth, tongue, hard p a la te , and na sa l passages (unknown c au se) - Abdominal mass w ith adhesions to m ultiple organs 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Inflammation or necro sis of mesente r ic fa t sometimes with yellow coloration 0 ms/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Nodule involving m esenteric fa t 0 mg/kg/day 30 mg/kg/day 10 m g/kc/day 3 mg/kg/day 0 0 1 0 0 0 0 0 0 0 0 a 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 1 1 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 0 0 0 1 1 1 0 2 0 0 0 0 0 0 0 0 0 1 0 0 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 00 20 20 00 41 10 10 21 10 10 00 00 00 00 00 00 01 00 00 11 20 00 00 0 0 00 00 00 00 10 00 00 00 1 .0 00 00 00 10 00 00 10 01 00 00 00 0 2 3a 0 6 3 2 4 2 3 0 0 1 0 0 0 1 c 0 3 2 0 1 0 1 0 0 0 1 0 0 0 1 0 1 0 1 0 0 1 1 0 0 0 Data l i s t e d a s number o f r a t s f o r which th e l i s t e d o b s e r v a t i o n was p r e s e n t . ^ t a t i s t i c a l i y d i f f e r e n t from c o n t r o l d a t a whei a n a l y z e d u s i n g F i s h e r ' s E xact P r o b a b i l i t y T e s t , p<0 . 0 5 . iL#>3 -102- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during Che tim e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 1 7-12 Months 2 2 2 1 E-24 E-26 E-27 E-2S E-29 F-2 F-3 F-4 F-5 F-6 F-7 GENERAL ( C o n t ' d) Thickened gingiya surrounding molar teeth Accumulation of exudate around genital orifice Abdominal d is te n tio n Firm and granular appearance of mesenteric fat Hemorrhage from t a i l GASTROINTESTINAL SYSTEM Ulceration or erosion of gastric mucosa M ineralization of g astric wall (pale lin ear striatio n s) In te stin a l mass(es) or nodule(s) Hemorrhage into g a s tr o in t e s t in a l tract Thickening, edema, and/or hemorrhage in w a ll of cecum someciaes due Co u re m ia Dark m a te ria l in g a s t r o i n t e s t i n a l tra c t (or darkened ingesta or feces) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30. m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day .0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0,, 0 1 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 0 0 1 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 1 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 1 19-24 Months 31 18 25 18 Terminal Cumulative K ill R esu lts 36 86 21 50 11 50 19 50 00 01 00 00 o 0 00 01 00 00 00 00 00 10 00 00 00 00 01 00 00 0 1 0 0 1 0 1 0 0 0 2 0 1 0 0 0 0 1 0 0 326 214 405 304 001 0 0. 0 101 112 112 123 101 0 11 0 00 011 000 000 0 11 000 000 000 31u 101 0 11 0 23 Data listed as number of racs for which the lisced observation was present. -103- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP OH $ O Diagnosis Coda Number of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day * ' 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 F-9 F-10 F -ll F-13 F-14 F-15 F-17 F-18 F-20 F-30 F-31 GENERAL ( C o n t 'd ) Pecechial hemorrhage on g a s tr ic mucosa w ith or w ithout a sso c ia te d hemolyzed blood 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Decrease of normal ingesta in gastrointestinal tract 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 0 Thickening and/or edematous appear- 0 mg/kg/day ance of mucosa of stomach 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Nonglandular mucosa of stomach showing roughening and/or p o ssib le focal proliferation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 D ilata tio n of stomach or g astro in te s tin a l tra c t with gas (cause o th e r than mouth b re ath in g ) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal g a stric hemorrhage or hemolyzed blood 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Nodule or polyp on stomach mucosa 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 D iste n tio n of stomach and g a stro i n t e s t i n a l t r a c t due to mouth breathing 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Diverticulum of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 m<x/ks/dav 3 mg/kg/day 0 0 0 0 .Enlarged Peyer's Patch along small intestine 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Thickened wall and overdistended appearance of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 2 2 1 1 0 0 0 1 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 1 0 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill R e su lts 36 86 21 50 11 50 19 50 102 000 000 10 1 30 4 20 3 7 0 9a 10 2 10 1 000 10 1 112 000 001 000 10 1 000 001 000 001 3 6 10 314 517 527 011 01i 000 101 10 1 000 10 1 000 000 10 1 000 000 1 1 -> 011 000 000 02 000 000 00 0 Data listed as number of rats for which the listed observation was present. aScatis ticallv different from control data when analyzed using Fisher's Exact Probability Test, p < 0 . 0 5 . -104- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 F-32, F-33 F-34 F-35 F-36 F-37 F-38 F-39 F-40 F-41 GENERAL ( C o n t 'd ) Yellow b ile -s ta in in g m ate ria l in gastrointestinal tract 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mucoid, loose, and/or w a te ry -lik e m aterial in gastrointestinal tract 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Change in te x tu r e of s to o l softened, moistened 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Hemolyzed blood in g a s t r o in t e s t in a l 0 mg/kg/day t r a c t due to s e lf - in g e s tio n 30 m g/kg/da y 10 mg/kg/day 3 mg/kg/day I n te s tin a l nematodes 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Reddish mucoid flu id in in te s t i n e 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Decreased flu id in g a s tro in te s tin a l 0 mg/kg/day tract 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day O verdistention of esophagus with ingesta 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Implants from i n t e s t i n a l neoplasm throughout abdominal v isc era 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day White film over stomach su rface 0 mg/kg/day 30 mg/k g/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 13-18 Months 17 9 11 11 00 00 01 00 00 00 0- 0 00 00 01 00 00 01 00 00 01 01 00 00 00 00 00 01 00 00 00 00 0. 0 00 00 00 00 00 00 00 00 00 00 00 00 19-24 Months 31 18 25 18 Terminal Cumulative R ill R e su lts 36 86 21 50 11 50 19 50 1 12 101 2 0. 3 I 01 0 11 000 000 0 00 000 001 0 00 101 001 101 000 0 12 001 000 0 00 0 00 000 0 00 001 000 101 000 000 0 00 101 000 000 0 00 101 0 .0 0 0 00 000 0 00 101 000 000 Daca l i s c e d as number of r a t s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . 2. 360 -10S- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO YEARS Diagnosis Code Number o f r a t s necropsied during the tine period indicated i--6 Months 0 mg/kg/day 3Q m g/kg/da y 10 mg/kg/day 3 mg/kg/day 0 0 1 1 G-l G-2 G-3 G-13 G-5 G-6 G-7 G--9 G-10 G-12 G-14 LIVER Enlarged liv e r Darkened or congested liv e r Paleness of liv e r - (anemia) probably related to subcutaneous mass(as) formation Paleness of liv e r - (anemia) other causes Small pale fo c i in l iv e r Red o r d a rk e n e d f o c i i n ' l i v e r Module(s) in liv e r Accentuaced lobular p attern of liv e r B iliary cysts in liver Decreased size of liv e r (atrophy) Linear, fib ro tic reaction or c a c s u la r th ic k e n in g on Liver due to d is to rtio n with or without necrosis 0 mg/kg/day 30 mg/kg/day 10 mg/kd/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/k g/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 1 0 0 0 0 0 0 0 2 3 1 2 3 0 2 1 0 0 1 0 6 1 0 1 1 0 0 0 1 0 0 1 1 0 0 1 0 0 0 0 1 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill R e su lts 36 86 21 50 11 50 19 50 24 7 000 00 0 213 000 000 000 20 2 428 20 6 304 114 036 022 013 113 4 13 17 044 1 1 3a 134 8 30 44 1 17 20 3 6 9a . 0 13 14 1 0 11 1 13l aa 0 0 oa 101 001 000 000 00 1 157 213 10 1 03 336 13 0 * 01 00 10 00 0 1- Data l i s t e d as number o f c a t s f o r which th e l i s t e d o b s e r v a t i o n was p r e s e n t . ^ S t a t i s t i . c u l l y d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d u s i n g F i s h e r ' s Exact P r o b a b i l i t y T e s t , p< 0 . 0 5 . -106- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS 1-6 Months D i a g n o s i s Number o f r a t s . Code necropsied during che t in e period , - indicated 0 rag/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 LIVER ( C o n t 'd ) G-15 Pale area(s) in liv er r* I 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 G-25 Diaphragmatic herniation of liv e r 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 G-28 Yellow appearance of liv e r 1 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 i G-29 White d isc o lo ra tio n of one lobe of 0 mg/kg/day 0 1 liver 30 mg/kg/day 0 10 mg/kg/day 0 3 mg/kg/day 0. G-19 -- -........................ Icterus 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 G-20 Subcansular depressed foci in 0 mg/kg/day 0 liver 30 mg/kg/day 0 10 mg/kg/day 0 1 3 mg/kg/day 0 G-21 Focal darkened area(s) in liv e r 0 mg/kg/day 0 30 mg/kg/day 0 10 mg/kg/day 0 3 mg/kg/day 0 G-22 Friable texture of liv e r G-23 Mottled appearance of liv e r 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 G-24 D isc o lo ratio n and d iffu se in f i lt r a ti v e enlargement of liv e r 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 LYMPKORETICULAR SYSTEM H-0 G e n e r a l i z e d e n la r g e m e n t of many 0 mg/kg/day 0 lymphoid t i s s u e s (iymphadenopathy) 30 mg/kg/day o' sometimes with a reddish appear- 10 mg/kg/day 0 ance) 3 mg/kg/day 1 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 101 1 0 .1 0 00 101 000 000 000 101 101 000 000 0 00 000 000 101 0 00 102 0 00 001 000 0 00 000 001 0 0 0 0 22 0 00 1 23 0 44 101 0 00 0 00 0 00 101 000 0 00 101 0 00 0 00 0 00 101 20n 0 00 0 00 00 Data lisced as number of rats for which the iisted Observacin was present. aStatiscicaHy different from control data when analyzed using Fisher's Exact Probability Test, p<0.05. -107TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code dumber of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day 0 0 1 1_ H-2 H-3 H-4 H-6 H-7 H-8 H-9 H-12 H-13 H-14 11-21 LYMPHORETICULAR SYSTEM ( C o n t 'd ) E nlarged th o r a c ic lymph nodes m 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Enlarged m esen teric lymph nodes 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Moist, edematous and/or hyperemic a p pearance of m e s e n te r ic lymph nodes 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day Enlarged thymus 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Mass i n v o l v i n g thymus 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day Enlarged and/or moist abearan ce of hem orrhagic a x i l l a r y lymph noae(s) 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Darkened, hemorrhagic appearance of 0 mg/kg/day m e s e n te ric lymph node a n d /o r hema- 30 mg/kg/day togenous pigment 10 m g/k g /d ay 3 mg/kg/day C ongestion of m e s e n te ric lymph nodes 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Enlarged and congested or hemorrh a g ic i l i a c lymph nodes 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Darkened and/or congestion of th o r a c ic lymph nodes 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Enlarged and/or darkened o eria o r t a l lymph nodes 0 mg/kg/dav 30 m g/kg/day 10 mg/k g/day 3 mg/kg/day 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 1 0 0 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 000 0 0 0' 00 1 000 123 000 000 00 1 000 000 000 001 001 000 000 000 000 10 1 000 001 10 1 20 2 10 1 113 1 19 20 0 11 11 088 4 12 16 000 000 001 000 001 101 000 000 000 000 00 1 000 000 10 1 000 000 Daca l i s t ed as number o f r a t s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . ) 9A30>3 -108- TABLE 33 (Continued) CROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T' FOR UP TO TWO YEARS Diagnosis Code Humber o f r a t s necropsied during the time oeriod indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 H-25 H-26 H-27 1-1 J-l J-3 K-l K-2 K-3 K-7 LYMPHORETICULAR SYSTEM ( C o n t 'd ) Mass i n v o l v i n g m e s e n t e r i c lymph node Mass(es) involving thoracic or c e r v ic a l lymph nodes (probable m etastasis from thyroid) E n larg ed i l i a c and r e n a l lymph node MUSCULOSKELETAL SYSTEM Dem ineralization of bones PANCREAS Nodule(s) in region in pancreas I n t e r l o b u l a r edema PITUITARY GLAND Enlarged p itu ita ry Dark red fo c u s(fo ci) on p i tu ita r y Hemorrhagic or darkened p itu ita ry Irreg u lar shape 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/k g/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 .0 4 2 0 1 5 0 0 0 1 1 0 1 1 1 0 0 19-24 Months 31 18 25 18 Terminal Cuuuiativi: K ill Results 36 S6 21 50 11 50 19 50 00 10 00 00 0 1 0 0 011 00 0 10 1 00 0 00 00 10 00 0 0 1 0 022 000 00 0 011 088 123 10 1 314 00 i 00 0 00 0 000 12 15 31 9 6 17 11 2 13 13 3 4 8 17 448 3 > 5 437 5 7 13 539 5 1 a 6 3 lo 00 1 00 1 00 000 Data l i s t e d a s number o f r a t s f o r which t h e I. i s t e d o b s e r v t ; .on v a s pr s s e n t . `^ S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d u s i r.g F i s h e r 1 S E.XC t P r o b a b i l i t y T e s t , ?<0 . 0 5 . -109- TABLE 33 (Continued) GROS'S OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR CP TO TOO TEARS Diagnosis Code Number o r a t s necropsied during Che tim e o e r i o d indicated i--6 Months 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 0 1 1 K-8 K-9 LL-1 LL-2 LL-4 LL-5 LL-6 LL-8 LL-9 LL-10 LL-L1 PITUITARY GLAND (C o n c 'd ) Mottled 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Pale area in p itu ita ry 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day REPRODUCTIVE SYSTEM Mass o r n o d u le i n v o l v i n g ov ary and/or oviduct 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day Cyst in ovary 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Endometrial polyp(s) 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Endometrial hyperplasia (chickened) 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Cystic endometrial hyperplasia (thickened, cystic) 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day Distension of ucerus with dark flu id (a lte re d blood and so ft debris) 0 mg/kg/day 30 m g/kg/day 10 m g/k g /d ay 3 mg/kg/day S light roughened appearance of u te rin e endometrium 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Hemorrhagic c y s t-lik e stru c tu re a d ja ce n t to ovary and nodules w ithin mesometriun attached to uterus 0 mg/kg/day 30 ^ g / h g / d a y 10 m g/kg/day 3 mg/kg/day Nodule or mass involving u teru s 0 mg/kg/day 30 ma/kg/dny 10 " g/kg/dav 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 13-18 Months 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 0 2 1 1 0 0 1 0 1 5 3 0 1 1 0 1 0 1 0 1 0 1 0 0. 0 0 0l 1 19-24 Months 31 18 25 18 Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 1 .0 00 00 10 00 00 10 00 04 00 10 01 16 12 21 03 38 06 32 21 23 03 23 03 0 13 36 12 23 01 00 00 00 00 00 00 00 00 00 00 00 23 01 11 10 1 0 0 1 0 0 1 0 4 0 1 1 9 3 4 3 13 7 7 3 5 4 5 4 18 12 3a 6 2 0 1 0 1 0 1 0 1 0 0 0 5 1 -3) Data list ad as number o f r a t s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . M u t t s t e a l l y d i f f e r e n t f r o m c o n t r o l d a t a wheu n n a l y r e d u s i n g i s h e r 13 E xa ct P r o b a b i l i t y T e s t p < 0 .05. - 110- TABLE 33 ( C o n tin u e d ) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during che time period indicated 1-6 Months 0 mg/kg/day 30 rag/k g/day 10 m g /k g /d ay 3 mg/kg/day 0 0 1 1 LL-12 LL-13 LL-14 LL-1S LL-16 LL-17 LL-13 LL-19 LL-20 M-12 M-15 REPRODUCTIVE SYSTEM ( C o n t 'd ) Distention of uterus 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Hyperemia of uterus 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Decreased size of ovaries with a brown d isc o lo ra tio n 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Clear fluid in uterus 0 mg/kg/day 30 rag/kg/day 10 m g/k g /d ay 3 mg/kg/day Red f o c u s ir. u t e r u s .............. .0 m g /k g /d ay 30 m g/kg/day 10 m g/k g /d ay 3 mg/kg/day Mass i n v o l v i n g v a g in a 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Decreased size of uterus 0 mg/kg/dav 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day- Hemorrhagic m aterial in uterus 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Thickened area in uterus 0 mg/kg/day 30 m a/kg/dav 10 m g/kg/day 3 .mg/kg/day RESPIRATORY SYSTEM Clear liquid in nasal passages 0 mg/kg/day 30 dav 10 Ais/ke/dav 3 mg/kg/day Mucoid m a t e r i a l i n n a s a l t u r b i n a t e s 0 mg/kg/day 30 mg/kg/day 10 mg/kg/uav 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 19-24 Months 31 18 25 18 Terminal Cumulative K ill R e su lts 36 86 21 50 11 50 19 50 0 213 0000 0 000 0000 0 101 0 000 0 0 00 0000 0 101 0 0 00 0 101 0 101 0- 1 1 2 0 0 00 0 0 00 0000 0000 0 101 0000 0 0 00 00 11 0 0 00 0000 0 0 00 0 0 -) 2 0000 0 0 0 o 0000 0 0 00 1001 0 0 11 0 0 00 0 0 11 0 000 0 0o0 0 0 00 0 0 00 0 0 0 0 0 10 1 0000 0 00 0 0030 100 i 0000 Data listed as number of rats for which the listed observation was present. -111- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the tis e period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 M--1 M--3 M-4 M-5 M-6 M--9 M--13 M--17 M--11 S--1 RESPIRATORY SYSTEM ( C o n t 'd ) Pulmonary congestion, consolidat i o n , a n d /o r edema 0. mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day Subpleural pale foci in lungs (suggestive of alveolar h istio cytosis) 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Red o r d a rk f o c i i n lungs 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day Darkened and/or congested color in lung tissue 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day Pulmonary a te le c ta s is 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Hematogenous pigment in lungs 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day Pale and/or dark areas in lungs (mottled) 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Nodule(s) in lung 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day Nodule(s) in lung (possible metastasis) 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day SPLEEN Enlarged spleen 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 7-12 Months 2 2 2 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 o. 0 0 0 0 0 0 0 0 0 0 0 0 13-13 Months 17 9 11 11 0 1 0 0 0 1 1 1 0 1 1 1 0 0 1 1 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 2 0 1 2 4 3' 3 19-24 Months 31 13 25 13 Terminal Cumulative S ill Results 36 86 21 50 11 50 19 50 1 e0 0l 30 0l 7 12 24 62 14 49 15 0i 32 00 00 00 10 10 00 20 00 01 00 00 01 00 00 00 00 00 00 00 10 20 00 00 00 422 2 0 0 61 1 2 4 1 19 7 9 6 13 7 2a 6 0 0 1 2 1 0 3 1 2 0 0 1 1 0 0 0 0 0 0 1 2 2 0 1 8 6 5 ii D ata l i s t ed ns number of r a t s f o r i.-hich th e l i s t e d o b s e r v a t .on was p r e s e n t . a s. t a t i. s t_i. c a i l y d i f f e r e n t from c o n t r o l d a t a -h e n a n a l y z e d us ing Fisl e r ' s E xact P r o b a b i l i t y T e s t , p<0 . 05 . i i -n ! 1 ... ... 04^1 -112- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the tine period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 SPLEEN ( C o n t 'd ) N-3 Congested appearance of spleen 0 mg/kg/day 0 30 mg/kg/day 0 10 m g/kg/day 0 3 mg/kg/day 0 N-4 P ale focus i n s p le e n 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day 0 0 0 0 THYROID Aim PARATHYROID GLANDS 0-1 Enlarged thyroid or parathyroid 0 mg/kg/day 0 30 mg/kg/day 0 10 mg/k g/day 3 mg/kg/day 00 0-2 E n la r g e d p a r a t h y r o i d ( s ) 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 00 0 0 URINARY SYSTEM P-1 Moderate to severe chronic renal 0 mg/kg/day 0 disease (moderate to severely 30 mg/kg/day 0 mottled, enlarged, pale, and/or roughened kidneys) 10 m g/kg/day 3 mg/kg/day 0 0 P-2 Slight chronic renal disease 0 mg/kg/day 0 (slight enlarged, pale, mottled, and/or roughened kidneys) 30 m g/kg/day 10 m g/kg/day 00 3 mg/kg/day 0 P-3 M ineralization of renal oelvis 0 mg/kg/day 30 m g/kg/day 00 10 m g/kg/day 3 mg/kg/day 00 P-4 D ilated re n a l p e lv is 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 P-5 Cyst(s) in kidney 0 r.g/ks/dav 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 P-6 Suocapsular white fo c i in kidney 0 mg/kg/day 0 30 mg/kg/day 0 10 m g/k g/day 0 3 mg/kg/day 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 00 0 0 00 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 1 0 0 0 1 0 0 0 0 0 0 00 0 3 0 0 1 1 0 01 0 0 3 0 1 1 1 1 1 0 0l 1 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill R e su lts 36 86 21 50 11 50 19 50 00 00 00 00 00 00 00 10 0 0 1 0 0 0 1 1 03 3 022 01 0 2 1 2 00 1 1 1 1 00 0 10 1 03 6 1 2 1 0L0 1 2 6 3 ii 15 088 225 24 6 011 2 6 8a 2 0 5a 011 337 00 1 02 1 1 4 2 14 6 10 1 0 1 1 14 6 10 2 000 000 000 Data i xs cd as number of r a t s f o r which Che l i s t e d o b s e r v a t i on was p r e s e n t . 3Statistically different iron; control data when analyzed using Fisher's Exact Probability Test, p<0.05. -113- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS .'MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TSiO YEARS Diagnosis Code Number o f r a t s necropsied during che time period indicaced 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 P-7 &P-20 P-8 P-9 P-13 &P.-16 P-15 P-17 P-18 P-19 P-22 P-24 P-26 URINARY .SYSTEM (C o n t 'd) Mass o r n o d u l e i n k i d n e y 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Atrophy of kidney(s) (decreased size) 0 -mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Small in te s t i n e adherent to capsu- 0 mg/kg/day l a r s u r f a c e of e n la r g e d k id n e y , and 30 mg/kg/day the c o rte x showing m u ltip le pale 10 m g /k g /d a y focal areas 3 mg/kg/day Dark and congested appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Renal c a lc u li 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Slight pale appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day S light roughened appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day U ro lith ia s is with d iste n tio n of urinary bladder 0 mg/kg/day 30 mg/kg/day 10 m g/k g/day 3 mg/kg/day Ascending urinary tra c t in fectio n 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day F riable texture of kidneys 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day Pale focal area in kidney 0 mg/kg/day 30 m g/kg/day 10 ms/kc/dav3 mg/kg/day 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 1 0 1 3 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 0 00 101 0 00 0 00 0 00 000 102 0 00 000 000 0 01 0 00 000 0 00 0 01 0 00 0 00 0 00 0 00 0 01 10 1 001 000 0 01 104 10 1 3 03 101 000 001 0 00 000 0 00 0 00 0 00 0 11 10 1 000 0 00 000 011 00c 000 000 Data listed as number of rats for which che listed observation was present. -- -114- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TO0 YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 P-29 P-30 P-31 P-32 Q-l Q-l Q-l Q-l Q-l Q-2 URINARY SYSTEM ( C o a t 'd ) S lig h t enlargement and fla c c id k id - 0 mg/kg/day ney secondary to d ila te d p e lv is 30 mg/kg/day 10 m g /k g /d ay 3 mg/kg/day Pale, anemic appearance of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d ay 3 mg/kg/day D ila ta tio n of u rin ary bladder and compression of u re te r secondary to u t e r i n e mass 0 ag/kg/day 30 m g/kg/day 10 m g/k g /d ay 3 mg/kg/day Dark greenish d is c o lo ra tio n of kidneys 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day INTEGUMENT AND SUBCUTANEOUS S u b c u ta n e o u s mass - mammary and midcervical region Number o f m asses p e r a n im a l: i 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day S u b c u ta n e o u s mass - mammary and midcervical region Number o f m asses p a r a n im a l: 2 S u b c u ta n e o u s mass - mammary and midcervical region Number o f masses p e r a n im a l: 3 S u b c u ta n e o u s mass - mammary and midcervical region Number of masses p e r a n im a l: 4 0 mg/kg/day 30 mg/kg/dav 10 mg/k g/day 3 mg/kg/day 0 m2 / k z / d a v 30 m g/kg/day 10 m g/k g/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/k g/day 3 mg/kg/day S u b c u ta n e o u s mass - mammary and midcervical region Number of masses p e r anim al: 5 0 mg/kg/day 30 m g/kg/day 10 mg/k g/day 3 mg/kg/day Subcutaneous mass - eye, e a r , region Number o f masses p e r a n im a l: i head 0 mg/kg/day 30 m g/kg/day 10 mg/k g/day 3 rag/kg/dav 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 2 2 i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 19-24 Months 31 18 25 18 Terminal Cumulative K ill R e su lts 36 86 21 50 11 50 19 50 000 0 100 1 000 0 000 0 010 1 000 0 0000 000 0 010 1 0000 000 0 00 0 0 0000 0000 010 1 00 0 0 5 -- 11 46 7 10 6. 8 8 25 7 18 3 21 8 22 1 8 9 18 1 7 7 15 1 7 5 13 0 4 6 10 3 4 10 17 314 8 1 1 1 33 . 213 6 224 8 2011 020 2 020 2 l' 1 0 2 000 0 0213 000 0 020 2 000 0 0000 1 1 0 * Data l i s t e d as number o f r a t s f o r v h i c n t h e l i s t e d o b s e r v a t i ; >n was p r e s e n t . a S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a t a './hen a n a ly z e d u s i r ;g F i s h e r ' s Exact P r o b a b i l i t y T e s t , p<0 .0 5 . -115- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day , 10 m g/kg/day 3 mg/kg/day 0 0 1 1 Q-3 Q-3 Q-3 Q-4 Q-5 Q-7 Q-ll Q-12 R-3 S-l S-2 INTEGUMENT AND SUBCUTANEOUS ( C o a t 'd ) Subcutaneous mass - body o r limb region Number o f masses p e r a n im a l 1 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Subcutaneous mass - body or limb region Number o f masses p e r a n im a l: 2 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Subcutaneous mass - body or limb region Number o f m asses p e r a n im a l: 3 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day H y p e r p l a s i a of mammary t i s s u e 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Mammary g l a n d galactocele formation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cutaneous nodule or mass form ation Number o f n o d u le s p e r r a t : i 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Abscess of c lito r a l gland 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Subcutaneous edema 0 mg/kg/dy 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day SALIVARY GLANDS Cystic gland structure involving salivary 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day TONGUE R o stra l l e s io n on tongue (apparent tearing) possibly agonal 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mass o r n o d u le i n v o l v i n g tongue with or without adjacont abscessatiou 0 mg/kg/day 30 mg/kg/day 10 n g / k t / d a y 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 7-12 Months 2 2 2 1 0 1 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 3 0 0 0 0 0 0 0 0 0 0 0 3 2 1 2 2 1 0 1 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0or 0 1 0 0 0 0 19-24 Months 31 18 25 18 Terminal Cumulative K ill R esu lts 36 86 21 50 11 50 19 50 53 13 3 " 0* 32 21 20 10 00 11 10 00 00 6 12 29 33 35 36 25 42 23 02 01 00 0 ,0 20 00 00 00 10 00 00 10 01 0 00 00 00 00 00 00 0 c1 00 0 00 11 5 3 5 3 2 1 0 2 1 0 0 21 13 7 10 11 8 6 6 2 ]_ 0 0 3 0 0 0 1 1 0 1 1 0 0 0 0 0 0 1 0 00 Data li s c e d ns number of r a t s for which the l i s t e d o b se rv a tio n vas p re s e n t. VSbZ'Ii -116- TABLE 33 (Continued) GROSS OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the time period indicated THORACIC CAVITY U-2 F l u i d i n t h o r a c i c c a v i t y 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg^day 0 0 1 1 7-12 Months 2 2 2 1 13-18 Months 17 9 11 11 19-24 Months 31 18 25 IS Terminal Cumulative K ill Results 36 86 21 50 11 50 19 50 0 mg/kg/day 0 0 0 2 0 2 30 mg/kg/day 0 0 0 0 0 0 10 m g/kg/day 0 0 0 3 0 3 3 mg/kg/day 0 0 0 2 0 ? Data l i s t e d as number of r a t s f o r which the l i s t e d o b s e r v a t i o n was p r e s e n t . -117- TABLE 34 MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during che time period indicated i--6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 7-12 Months 2 0 1 1 H-01 H-02 H-03 H-04 H-05 H-06 H-07 H-08 H - 10 H - 11 LIVER Number o f t i s s u e s exam ined 0 m g/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day H eD atocellular Changes Necrosis with accompanying inflam matory re ac tio n - sin g le focus 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Necrosis with accompanying inflam matory reactio n - focal 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Necrosis with accompanying inflam matory re ac tio n - m ultifocal 0 mg/kg/day 30 mg/kg/day ' 10 mg/kg/day 3 mg/kg/day Necrosis with accompanying inflam matory re ac tio n - dissem inated 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cytoplasmic vacuolization single focus 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cytoplasmic v acuolization - focal 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cytoplasmic v acuolization - m ultifocal 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Cytoplasmic vacuolization - d isseminated 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day A c c e n tu a te d l o b u l a r o a t t e r n due co cen trilo b u lar atrophy 0 mg/kg/dav 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day H epatocellular a lte ra tio n (swollen heoatocytes) - single focus 0 mg/kg/day 30 m g/kg/dav 10 mg/k g/day 3 mg/kg/day 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2` 0 1 1 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 0 0 13-18 Months 14 9 22 12 14 9 22 12 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 2 i 2 i 4 0 2 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 1 1 19-24 Months 63 25 23 28 Terminal Cumulative till Rsulta 6 86 16 50 4 50 9 50 63 25 23 28 0 0 0 0 0 2 0 2 i i 0 1 0 0 1 0 2 3 0 1 24 3 3 14 1 0 0 1 5 1 2 0 0 1 0 0 8 2 3 3 6 16 4 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 5 5 2 6 0 1 0 0 0 0 0 0 0 0 0 0 1 2 0 1 86 50 50 50 0 0 2 0 0 2 0 2 1 1 0 2 0 0 1 0 4 7 2 2 34 3 12 20 1 1 '0 1 6 1 L 1 0 1 1 0 11 H 4 3 Daca l i s e ed as number of r a t s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . a $ c a t i $ t i c u l l y d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d u s i n g F ish c r 1s Exact P r o b a b i l i t y T e s t , p / \o o t_n 34)3 -- .jj.igncsr^ n - 17 1l u .a > ' ^' ' X\, J * Ft . F'` . -> t c*d a ---- ' .__ _ - -118- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAIL.O V; CONTAINING 2,4,5-T FOR C? TO TVO EARi -- i s Number o f r a e s necropsied during the time period _-- indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 H ep ato cellu lar Changes (Cont'd) H epatocellular a lte ra tio n (swollen 0 mg/kg/day . 0 hepatocytes) - focal (2-3) 30 mg/kg/day 0 10 mg/kg/day 0 3 mg/kg/day 0 .H epatocellular a lte ra tio n (swollen h e p ato cy te s) - s e v e ra l f o c i (>2) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 H epatocellular a lte ra tio n (swollen hepatocytes) - single area 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 H epatocellular a lte ra tio n (swollen hepatocytes) - several areas 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 H epatocellular carcinoma(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal vacuole formation with or without mineralized debris 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal confluent vacuole formation with or without mineralized debris 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day. 0 0 0 0 Inflammatory C ell Changes Focal accumulation of inflammatory c e lls , prim arily mononuclear c ells within liv e r 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal aggregates of retcu lo endothelial cells frequently adJacent to degenerate or necrotic hepatocytes 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 F ibrosis w ithin heDacic tissu e focal 0 m/tez/dav 30 mg/kg/day 10 m s/k c/d a v 3 mg/kg/day 0 0 0 0 Fibrosis - subcapsular - focal 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 i as number of r a t s foe "which che l i s t e d o b servacin vas i l l y d i f f e r e n t from c o n t r o l d a c a when a n a l y z e d u s i n g :i.-~ 7-12 Montns 2 0 1 1u ;Men-. : ? i: - 10 00 00 01 0n 0 0 z 00 00 0I 01 00 00 00 00 0. 00 00 00 00 r0 0o 00 Q0 3 1 0o 03 0 3 ** T 3" 13 -* :- o - *' - 3 - Ml -119- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code dumber of r a t s necropsied during che cime perio d indicated l - 6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 H-48 H-49 H-50 H-70 H-71 H-72 a-74 H-75 H-85 H-86 H-S9 Inflammatory C ell Changes (Cont'd) Fibrosis - subcapsular - m ultifocal 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Increased pigment aggregates in liver 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Inflammatory adhesions to capsule 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day B ile Ducts and Vascular Channels B iliary hyperplasia - focal 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day B iliary hyperplasia - m ultifocal 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day B iliary cyst formation 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day P erip o rtal inflammation 0 mg/kg/day 30 m g/kg/day 10 rag/kg/day 3 mg/kg/day Focal periportal fibrosis 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day E ctasia of vascular channels 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Congestion of hepatic sinusoids 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Perivasculitis - focal 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 .0 0 0 0 00 22 0000 0000 0101 1 0 1 2. 00 00 0000 0101 0000 0000 0000 16o9 1 7 6 14 .0 7 1 8 04 26 0000 10 0 1 0000 0 10 1 0 70 7 0 3 14 1214 03 14 2 23 3 29 5 11 12 28 44 19 0347 1 14 29 11 08 4 20 7 18 13 3 11 0718 0123 1203 141 6 14 18 0 3 14 10 0 1 0112 3' o 0 5 0 1 L 11 0 0 0 0 I 2 Deca l i s t cd a s number of r a t s f o r which Che l i s t e d o b s e r v a t i o n was pro; s e n t . S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a t a uhe n a n a l y z e d u s i n $ 7i s h e r ' s Exact P r o b a b i l i t y T e s t , p<0 .0 5 . -120- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO YEARS Diagnosis Code Number o f r a t s necropsied during th e cime perio d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 H-91 H-92 R-04 R-05 R-06 R-07 R-08 R-20 B ile Ducts and Vascular Channels (Cone.) Focal extramedullary hematopoiesis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Retention cyst formation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day RESPIRATORY SYSTEM Nasal Turbinates/Hard Palate Number o f t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Keratoacanchoma of nasal tu rb in a tes 0 mg/kg/day /hard palate 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Squamous c e l l carcinoma of hard palate 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Acute hemorrhage (trauma) and area or inflammation of nasal tu rb in a te s 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Mixed adenoma o f hard p a l a t e 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Squamous m ecap la sia of n a s a l tu rb in a te epithelium and glands of hard palace 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Trachea Number o f t i s s u e s examined 0 mg/kg/day 3 0 'mg/kg/day 10 mg/kg/day 3 tag/kg/dav Focal trac h eitis 0 mg/kg/dav 30 mg/kg/day 10 jns/kc/dav 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 0 0 0 13-18 Months 14 9 22 12 2 2 5 3 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 14 9 22 12 2 2. 2 2 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 608 406 107 205 101 000 000 000 2 14 101 101 202 0 01 0 00 000 000 101 0 00 101 101 0 00 101 0 00 0 00 0 11 000 0 00 0 00 101 0 00 0 00 000 62 6 35 24 16 49 '23 4 50 28 9 50 16 3 21 4 7 13 4 4 10 6 2 10 Daca l i s t ed as number of r a t s f o r which t h e l i s e e d o b s e r v t : ion was p r e s e n t . 3Jfc3*7fo -121- TABLE 34 (Continued) MICROSCOPIC OBSERVATION'S ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Mumber o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 7-12 Months 2 0 1 1 R-21 R-23 R-24 R-25 R-30 R-31 R-32 R-33 R-34 R-35 Trachea (Cont'd) Diffuse trac h eitis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal e p ith e lia l hyperplasia of tra c h e itis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Diffuse e p ith e lia l hyperplasia of trachea 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Secretory m aterial in trachea 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Lungs Number o f t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Focal peribronchiolar aggregates of lymphocytes 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal i n t e r s t i t i a l inflammation 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Focal accumulation of inflammatory cells in alveoli 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal accumulation of alveolar macrophages in alv e o li 0 mg/kg/day 30 mg/kg/dav 10 m g/kg/day 3 mg/kg/day Alveolar proteinosis 0 mg/kg/day 30 r.g /k g /d a y 10 mg/kg/day 3 mg/kg/day C holesterol c le fts in lung 0 nn,/ks/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0` 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 1 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 13-18 Months 14 9 22 12 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 14 9 22 12 9 7 17 7 0 3 3 1 0 0 0 0 2 5 4 5 0 0 0 0 o' 1 0 1 19-24 Months 63 25 23 28 Terminal Cumulative R ill Results 6 86 16 50 4 50 9 50 0 0 o 000 001 202 505 20 3 101 10 1 001 000 000 202 404 000 000 000 63 6 86 25 16 50 23 4 50 28 9 50 57 5 72 21 14 42 13 4 35 17 8 32 18 3 21 16 8 27a 2 0 5a 3 1 5a 101 2 13 000 000 24 1 28 14 10 29a 3 1 13 7 4 16 101 2 13 000 022 5 0 6,, 5 3 9" 505 1 24 Daca l i s t e d a s number of r a c s f o r which the 11 se e d o b s e r v t : Lon was p r e s e n t . a b, e a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a t a when a n a l y s e d u s i n g Flab e r ' s e x a c t P r o b a b i l i t y T e s t , p<0 .0 5 . U .M '/ \i f j i 4i i i j ( i I i !1 -122- TABLE 34 (C ontinued) MICROSCOPIC OBSERVATIONS ON MALE RAIS MAINTAIN--'? CONTAINING 2 , 4 , 5 - T FOR CP TO K O VlAy-;"' Diagnosis Code Number or r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day 1 0 0 0 7-12 Months 2 0 1 1 R-36 R-64 R-37 R-38 R-39 R-40 K-41 R-42 R-43 R-44 R-45 Lungs (Cont'd) Pulmonary edema, c o n g es tio n , c e l lu la r exudation, wich or without focal fib ro sis secondary to heart fa ilu re, renal disease and/or .vascular disease C ellular exfoliation secondary to renal failure or heart failure Focal alveolar fib ro sis secondary to heart failure or renal failure Pulmonary a te le c ta s is Alveolar m ineralization Focal pulmonary aggregates of hematogenous pigment Focal alveolar hyperplasia Pulmonary edema Focal in te r s titia l fibrosis Focal granulomacous inflammation w ith o r w ith o u t fo re ig n body present Focal pulmonary hemorrhage 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 30 3 0 J 0 0 0 0 0 0 0 0 0 1. 0 0 0 0 0 0 0 0 0 0 0 0 0 a 0 X 0J 0 0 0 3 : - 0 - - - 2 0 2 - Q 0 2 0 0 0 2 0 0 0 0 0 2 0 X 5 <\ 0 0 0 0 o 0 0 0 0 o 7 Data l i s t e d a s number of r a t s f o r which the l i s t e d o b s e r v a t i o n V3S pro Statistically dificrent iron control data when analyzed using Ft~r.or s 2.)3 *7s' -123- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO TEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 R-48 R-49 R-51 R-52 R-53 R-54 R-55 R-56 R-59 R-oO R-61 Lungs (C ont'd) Focal hyperplasia of bronchiolar epithelium 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Aspirated p articu late matter 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day M u ltifo c a l exudative pneumonia 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Pulmonary congestion 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Increased perivascular aggregates of lymphocytes 0 mg/kg/day 30 m g/kg/day 10 m g/kg/da y 3 mg/kg/day Secretory m aterial in bronchus or bronchiole 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Focal inflammation of bronchus 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Focal area of in te r s t i ti a l inflamnation 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day In f l a i m a t o r v - c e l l s w ith in lumen and/or around bronchiole(s) 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Focal secretory m aterial in a lv e o li 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M ultifocal alveolar hyperplasia, squamous m e ta p la sia and fo c a l necrosis 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 1 0 0 0 0 1 0 0 0 0 0 1 1 0 0 1 0 1 0 0 1 -0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 o 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative R ill Results 6 86 16 50 4 50 9 50 819 10 2 0 0 oa 202 000 000 001 000 001 000 000 000 10 2 001 000 000 00 1 011 001 10 1 808 304 101 0 0 oa 101 102 000 0 00 000 112 000 000 1 0 '1 303 000 000 505 i 0i 202 001 101 000 000 000 Data Lise e-J a s number o f r a t s f o r which th e l i s t e d o b s e r v t ! .on was p r e s e n t . J S t a t i s t i c a i l y d i t e u r e n t from c o n t r o l d a ta when a n a ly z e d u s i n g F ish e r ' s Exact P r o b a b i l i t y T e s t , p<0 .05. a * 5 7? -124- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 R-62 R-63 R-70 R-65 R-90 R-92 R-94 C-01 C-02 Lungs (Cont'd) M ultifocal alveolar hyperplasia 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Area of adenomatous a lv e o la r hyper- 0 mg/kg/day p la s ia and i n t e r s t i t i a l inflam - 30 mg/kg/day mation 10 mg/kg/day 3 mg/kg/day Pulmonary adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Area of necrosis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pleura Focal p leu ritis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal fib ro tic p leu ritis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal fibrosis of pleura 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day CARDIOVASCULAR SYSTEM Heart Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day Focal myocardial degeneration and inflammation with or without fibrosis - slight 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Focal ravocardial d e g e n e ra tio n and inflammation with or without fib ro sis - moderate 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 1 0 1 1 i 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 1 14 9 22 12 7 5 15 9 0 4 i 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 86 16 50 4 50 9 50 10 1 000 000 000 000 000 000 10 1 000 000 000 001 011 000 000 000 20 3 000 10 1 10 1 0 11 000 000 000 00 1 000 000 001 63 6 36 25 16 50 23 4 50 23 9 50 37 i ^9 15 12 32 13 2 33 18 5 33 15 j. 349 419 6 4u Data l i s t e d a s number o r a t s fo r which the l i s t e d o b s e r v a t i o n vas p r e s e n t . Sl4>3^6 -125TABLE 34 ( C o n tin u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO TEARS Diagnosis Code Number of r a t s necropsied during the tine period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 C-03 C-04 C-05 C-06 C-07 C-08 C-09 C-10 C -ll C-20 Heart (Cont'd) Focal myocardial degeneration and inflammation with or without fib ro sis - pronounced 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Myocardial m ineralization 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 A trial thrombosis 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Subendocardial fib ro e la sto sis of myocardium 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Area of myocardial necrosis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Congestion of heart 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal hemorrhage 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Focal myocarditis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal p e ric ard itis ' 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 A orta an d /o r Larse A n te rio r Medic s t i n a l A r t e r v ( i e s ) Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 Focal mural m ineralisation 0 mg/kg/day 30 mg/kg/day 10 m g/kg/dav 3 mg/kg/day 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 10 0 0 13-18 Months 14 9 22 12 0 1 0 1 0 0 0 2 0 0 0 0 0 1 1 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 14 9 22 11 6 3 6 7 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 6 17 203 112 001 4 15 000 202 10 3 10 1 12 314 123 606 101 001 10 2 10 1 011 000 000 000 000 001 000 10 1 000 001 000 a 00 i 01 000 000 000 i 01 000 000 000 60 6 33 25 16 50 21 4 43 /n *i t. 9 48 34 2 43 10 i i 24 o 2 17 14 3 24 Data l i s t ad jis number o f r a t s f o r which th e l i s t e d o b s e r v a t i o n was p r e s e n t . -126- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Coda Number of r a t s necropsied during Che c i n e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 7-12 Monchs 2 0 1 1 C-21 C-22 C-23 C-24 C-30 C-31 C-32 C-33 C-34 C-35 A orta and/or Large A n te r io r M e d ia s tin a l A r te r v ( ia s ) ( C o n e ' d) Focal thickening of endothelial lining 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Thrombosis of th o rac ic a r te r ie s 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Inflammatory reaction around thoracic artery 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Aortic plaque formation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 31ood Vessels - Degeneration of myocardial blood vessels 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 M ineralization of myocardial blood vessels 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 P e r i a r t e r i t i s and s c l e r o s is of mesenteric' and/or other blood vessels - very slig h t 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 P e r i a r t e r i t i s and s c l e r o s i s of mesenteric and/or other blood vessels - slight 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 P e r i a r t e r i t i s and s c le r o s is of m esenteric and/or other blood vessels - moderate 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 P e r i a r t e r i t i s and s c le r o s is of m esenteric and/or ocher blood v essels - pronounced 0 mg/kg/day 30 mg/k g/day 10 mg/k g/day 3 mg/kg/day 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 1 0 0 0 0 \ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 2 3 1 0 0 0 0 0 0 0 0 0 0 0 0 0 11 6 16 11 1 0 3 3 2. 1 7 3 2 1 4 4 1 0 1 1 2 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative Kill Resilles 6 16 4 .9 86 50 50 50 25 5 339 14 26 8 2 11 6 5 11 000 000 0 00 0 11 000 000 000 01 10 1 000 000 000 48 4 65 19 12 37 14 3 33 15 9 36 11 0 12 0 0 o3 205 30 6 16 5 31 22 7 9 2 18 4 5 12 h 0 15 5 39 307 1 19 11 0 12 404 102 70 3 70 9 1 34 303 10 Data l i s t e d a s number of r a c s f o r which Che l i s t e d o b s e r v a t i o n was p r e s e n e . a 5 t a t i s c i c a l l y d i f f e r e n t from c o n t r o l d a t a hen a n a l y z e d u s i n g Pis! 1e r ' s e x a c t ?rcl a b i l i t y T e s t , p<0. 0 5 . -127- TABLE 34 (Continued) MICROSCOPIC NERVATIONS ON MA12 RATS MAINTAINED ON DIETS CONT---INIMG 2 , 4 , 5 - f Fl P. UP TO TWO YEARS Diagnosis Code Number o f r a t s necroosied during Che cime p e r i o d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 7-12 Months 2 0 1 1 13-18 Months 14 9 22 12 C-36 C-37 C-38 C-39 P-01 P-02 P-03 ?-04 P-10 P-11 Blood Vessels (Conc'd) Thrombosis secondary to p e r i a r t e r i t i s and s c le ro s is 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M ineralization of vascular - isolated or focal channels 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M ineralizacion of vascular - disseminated channels 3 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hemorrhagic rupture of m esenteric vessel with severe p e ria rte ritis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day PANCREAS Acinar Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/day 3 mg/kg/day Focal atrophy of pancreatic acinar tissue 3 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal fib ro sis of atrophic pancreatic acinar tissue 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal inflammation of pancreas 3 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day Hyperplastic focus (fo c i), of pancreatic acini r.odulufw ! mg/kg/day 33 mg/kg/day 13 mg/kg/day 3 mg/kg/day P a n c r e a ti c a c i n a r adenoma 3 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreatic acinar adenocarcinoma 3 mg/ks/dav 0 m g/kg/dav ID mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 \ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 : 0 0 0 0 0 0 Q 0 0. c 0 O' 0 0 ; 1 0 0 0 1 0 1 2 1 0 1 0 0 0 0 0 14 9 22 12 6 3 7 2 0 0 1 0 5 0 3 1 1 0 2 2 2 3 O -> 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 9 0 10 123 303 303 809 101 001 103 506 000 10 2 20 2 20 2 000 000 000 63 6 86 25 16 50 23 4 50 28 9 50 28 2 38 12 13 28 7 1 15 14 5 21 303 0 22 001 0 33 5 1 11 3 53 003 023 14 0 15 213 4 1 7^ 00 19 4 26 9 8 20 4 39 12 3 17 : 02 000 0 00 0 00 Data l i s t e d as number o t r a t s t o r which tin* -L s i e d o b s e r v t : on was pc.' s e n : . " ^ S ta tis tic a lly d i f f e r e n t from c o n tro l data r. a n a l y z e d u s i n g F i s h e r 1> 0\.' .ibubilicy T e s t , p<0 .0 5 . ^k>2>%3 i |' l ! ... I i ; - .. ; ) 1 i ! | i i : i t i \i ] t ! ' ! j j -128- TABLE 34 (Continued) Mi c r o s c o p i c ob servations on male rats maintained on d i e t s CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Code Number o f r a c s necropsied during the cime p e rio d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 P-12 P-13 P-14 P-20 P-25 P-26 U-01 U-04 U-OS U-09 Acinar (Cont'd) M ultifocal atrophy of acinar tissue 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Vacuole formation in acinar tis su e 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Focal necrosis of pancreas 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day I s le ts of Langerhans Enlarged pancreatic is le t 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day P a n c re a tic i s l e t c e l l adenoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Pancreatic is le t c ell adenocarcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day URINARY SYSTEM Number o f t i s s u e s exam ined 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Kidr.ev D ilated renal tubules with eosino-p h ilic cast formation - slig h t 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Focal atrophy of renal tubules 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Mineralized deposits in renal oarenchyma M ineralized denosits in renal pelvis 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 2 0 1 1 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 2 0 0 0 0 0 0 1 0 1 0 0 1 2 1 0 0 0 14 9 22 12 1 0 0 0 0 0 0 0 3 0 0 5 5 1 1 4 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 86 16 50 4 50 9 50 00 0 1 00 00 00 00 00 00 20 00 00 00 0 1 0 0 0 0 2 0 2 0 0 0 102 1 13 2 0 01 2 2 10 2 13 2 57 5i 7 5 3 10 0 01 0 00 101 0 00 63 86 25 16 50 23 4 50 28 9 50 0 01 0 00 001 000 0 00 0 00 001 0 00 14 0 17 101 1 07 5 0 10 16 1 22 5 28 O0 3 74 Data H a t e d as number o f r a t s f o r which th e l i s t e d o b s e r v a t i o n was p re s e n t . " t a t i s t i c a l i v d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d us in; F i s h e r ' s Sxacc P r o b a b i l i t y T e s t , p < 0 . 0 5 . %4 >3 5 '{ -129- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during Che tim e p e r i o d indicated 1-6 . Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 U- 1 0 U -ll U-12 U-13 U-14 U-15 ' U-16 U-18 U-19 U-22 U-23 Kidney (Cont'd) Hematocyst in renal pelvis 0 rag/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Cyst form ation in kidney not due to 0 mg/kg/day chronic nephropathy 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Inf laminacin of re n a l p e lv is 0 rag/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Progressive chronic nephropathy very slig h t 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Progressive chronic nephropathy slight 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 rag/kg/day Progressive chronic nephropathy moderate 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Progressive chronic nephropathy pronounced 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal tubular hyperplasia 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Dilated renal pelvis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Increased hematogenous pigment associated with chronic renal disease 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Nodular p ro life ra tio n of renal pelvis epithelium 0 mg//kg/day 30 mg/kg/day 10 rag/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 1 0 0 2 0 0 0 0 0 0 2 1 0 2 3 1 2 0 1 3 4 2 7 4 16 8 0 0 0 0 1 1 1 0 0 0 0 0 3 1 3 6 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 0 0 0 0 2 1 2 1 1 2 0 0 2 1 0 0 4 2 5 3 11 5 7 .46 16 13 13 00 1 0 0 1 0 1 0 0 0 0 32 14 9 3 0 0 0 0 0 0 0 X 1 1 0 0 0 4 0 1 1 5 0 3 2 3 3 3 3 2 1 2 0 ,0 0 0 1 0 0 0 0 2 0 0 7 1 6 0 0 1 0 2 3 2 2 2 3 0 0 4 6 0 3 9 8 7 6 15 14 12 12 56 22a 30 23 0 0 1 0 2 2 1 0 1 0 0 41 22 133 20 Daca l i s t e d a s number of r a e s f o r which che l i s t e d o b s e r v a t i o n was p r e s e n t . 3S t a t i s t i c a l l y d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d u s i n g F i s h e r ' s Exact P r o b a b i l i t y T e s t , p<0 .05. -130- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the cime p e rio d indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 U-24 U-25 U-26 U-27 U-28 U-29 U-5l U-33 U-55 U-37 0-38 Kidney (Cont'd) Focal hyperplasia of renal pelvis epithelium 0 ng/kg/day 30 m g/kg/day 10 rffe/kg/day 3 mg/kg/day Multifocal suppurative n ephritis, hyperplasia of renal peivis epitheliuip, with in f lanmatiori and a fibrocic area in renal pelvis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal purulent nephritis not associaced wich nephropachy 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day EosinoDhilic m aterial wichin epithelium of renal tubules 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Area of i n t e r s t i t i a l fib ro s is and hyperplasia of renal tubules 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Anomalous focus of columnar mucosal 0 mg/kg/dav epithelium in cortex of kidney 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Renal p elvis tr a n s itio n a l c e ll adenoma 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Renal t u b u la r adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day P a p illa r y adenoma of re n a l p e lv is (unilateral) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Perirenal s te a c itis (inflammation) 0 ne/kc/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day L ipidosis (fa tty change) 0 mg/kg/day 30 mg/kg/dav 10 m a/ka/dav 3 mg/kg/dav 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 3 4 2 4 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 86 16 50 4 50 9 50 15 1 51 4 0 40 19 10 6 8 00 1 000 000 000 202 0 22 000 10 1 10 1 000 000 10 1 000 000 10 1 0 00 000 0 N \J 0 000 1 J 1 000 0 00 1o1 0 00 0 00 101 0 00 0 00 0 11 0 00 000 0 30 0J1 0 30 0 30 0 ,> 0 0 00 0 31 0 30 0 -0 Data l i s c e d a s number of r a t s or w hich t h e Li se e d o b s e r v t ion vas p r e s e n c , -131- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS Oil MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR CP TO TOO YEARS Diagnosis Code Number of r a t s necropsied daring Che c in e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 U-39 U-40 U-41 U-42 U-43 U-58 U-70 U-71 U-72 U-73 Kidney (Cont'd) Thrombosed re n a l v e s s e l 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal granulomatous inflammation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day F ibrosis, lip id o sis, heraatocyst, o rg a n iz ed hematoma w ith secondary fibrosis, lipidosis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Accumulation of lip id laden macroohages 0 mg/kg/day 30 n g / k g /d a y 10 mg/kg/day 3 mg/kg/day Single subcapsular focus of fibros is and inflammation 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Renal carcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day U rogenital Trace Number of u r i n a r y b l a d d e r s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Diffuse u rocystitis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal urocysticis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal hyperplasia of urinary bladder mucosa 0 mg/kg/day 30 n g /k g /d a v 10 mg/kg/day 3 mg/kg/day Diffuse hyperplasia of urinary b lad d e r mucosa 0 mg/kg/day 30 rng/kg/dav 10 r?_g/kg/day 3 mg/kg/dav 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0, 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 13-18 Monchs 2 0 1 1 14 9 22 12 10 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 2 14 08 1 20 1 12 01 00 00 01 00 00 00 01 00 00 00 00 01 00 00 01 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 00 1 0 00 00 00 00 10 00 00 00 10 00 00 00 00 10 00 00 00 10 10 00 00 00 62 6 25 16 22 4 28 9 31 21 00 00 10 10 00 11 00 00 00 11 31 31 00 o0 1 1 0 0 0 0 1 0 0 0 1 0 0 0 0 1 0 0 0 1 1 0 0 0 85 49 47 50 5 3 0 ]_ 1 1 0 3 0 0 0 5 4 0 - Data listed as number of rats for which the listed observation was present. -132- TABLE 34 (C o n tin u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR. UP TO TWO YEARS Diagnosis Code Number o f r a e s necropsied during Che c in e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 U-74 U-78 U-79 U-80 U-Sl U-83 U-84 U-85 U- 8 6 X- 0 1 U rogenital Tract (Cont'd) ' Organized lu g w ithin lumen of urinary bladder 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day T ra n sitio n al c e ll carcinoma of urinary bladder with m etastasis to kidney 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Diffuse e p ith e lia l hyperplasia of ure te r secondary to c a lc u li 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Organized plug of secretory m aterial in urethra 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal hemorrhage of bladder second- 0 mg/kg/day ary to in f laminacin of accessory 30 mg/kg/day sex glands 10 mg/kg/day 3 mg/kg/day M ineralized d e o o s its in lumen of urinary bladder 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Diffuse inflammation of urethra 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day S ingle submucosal lymphoid aggregate 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Inflammation of accessory sex 0 mg/kg/day g lan d s w ith e x te n s i o n i n t o m uscular 30 mg/kg/day layer of urinary bladder 10 mg/kg/day 3 mg/kg/day REPRODUCTIVE SYSTEM Testes Number of t i s s u e s examined 0 mc/kit/dav 30 m e/k s/d a v 10 mg/kg/day 3 mg/kg/day U nilateral s lig h t decrease in soerm acogen e s is 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 c 0 7-12 Months 2 .0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 0 0 0 13-18 Months 14 9 22 12 3 2 2 1 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 0 0 0 0 0 14 9 22 12 1 1 2 1 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 30 6 215 0 13 0 12 0 11 000 0 0 0 000 001 000 0 00 0 00 0 00 0 00 0 01 0 00 0 00 101 000 000 101 0 00 0 00 0 00 .0 0 0 0 00 0 00 101 0 00 0 00 0 00 101 0 00 101 0 00 0 00 63 0 36 25 1 50 23 4 50 28 9 50 1 02 0 12 0 0 0 0 Tl Data list cd as number of rats for which the lis e e d o b s e rv ae : ion was p r e s e n t . -133- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS . CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a t s necropsiad during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 7-12 Months 2 0 1 1 X-02 X-03 X-04 X-05 X-06 X-07 X-08 X-09 X-20 X-10 X-21 . X-22 Testes (Cont'd) B ilateral slight decrease in spermatogenesis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day U n ilateral moderate to pronounced decrease in spermatogenesis (atrophy) - focal 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day U n ilateral moderate to pronounced decrease in spermatogenesis (atrophy) - diffuse 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day B ila te ra l moderate to pronounced decrease in spermatogenesis (atrophy) - focal 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day B ila te ra l moderate to pronounced decrease in spermatogenesis (atrophy) - d i f f u s e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M ineralization of atrophic sem inif- 0 ms/ks/dav erous tubules 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day I n t e r s t i t i a l edema 0 mg/kg/day 30 mg/kg/day 10 ne/kg/dav 3 mg/kg/day Focal hyperplasia of i n te r s t i ti a l cells 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day In te rs titia l cell adenoma of testis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Sperm granuloma 0 mg/kg/day 30 m s/ks/day 10 mg/kg/day 3 mg/kg/day Mesothelioma 0 rae/ke/dav 30 mg/kg/dav 10 ng/kg/day 3 mg/kg/day S e r t o l i c e l l tumor 0 mg/kg/dav 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 0 0 0 0 0 0 0 0 o0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Terminal Cumulative Months K ill Results 63 25 23 23 * 6 16 4 9 86 50 50 50 1438 20 13 2 ' 1 0 3 020 2 140 5 141 6 421 7 4 4 3 IIa 1719 0213 120 3 0224 2 18 03 17 07 0 20 2 5a 2 10 07 150 6 1 8 1 10 110 2 0011 2 9 0 11 020 2 1 2, 0 3 1135 100 i 000 0 000 0 000 0 030 3 0000 0000 0011 0314 10 23 0 2 0 2 001 1 010 1 0000 0000 000 0 0 10 1 00 0 0 0000 000 0 100 1 000 0 0000 0000 Data liscod as number of rats for which the listed observation was present. JScatistically different from control data when analyced us ins Fisher's Enact Probability Test, p<0.05. -134- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4',5-T FOR U? TO W O TEARS Diagnosis Code Number o f r a t s necropsied during the tine period indicated i--6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 X-30 X-31 X-32 X-33 X-40 X-41 X-42 X-43 Accessory Sex Glands Number o f a c c e s s o r y s e x g la n d s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Number o f e p id id y m a l t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Slight decrease in secretory conten t of accessory sex glands 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Moderate to pronounced decrease in secretory content of accessory sex glands (atrophy) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Inflammation of accessory sex glands w ith o r w ith o u t edema 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal p rostatic e p ith e lia l hyperplasia 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Decreased (and/or degenerace appearing) spem atogenic elements in epididymis 0 mg/kg/day 30 mg/k g/day 10 mg/kg/day 3 mg/kg/day Focal i n te r s titia l inflammation, edema a n d /o r atro p h y of epididym is 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Cystic d ila ta tio n of seminal vesicle 0 rag/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Corpora amylacea in accessory sex glands 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day MUSCULOSKELETAL SYSTEM Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day 1 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 00 0 7-12 Months 2 0 1 1 2 0 1 1 2 0 1 1 0 0 1 0 2 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 1 13-18 Months 14 9 22 12 14 8 22 12 14 9 22 12 7 3 9 6 4 4 6 1 1 0 1 1 0 1 0 0 5 4 4 1. 1 2 2 0 0 0 0 0 0 0 0 0 14 3 20 11 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 62 6 85 25 16 49 23 4 50 28 9 50 63 6 86 25 16 50 23 4 50 27 9 49 31 2 40 10 7 20 17 3 30 19 4 29 10 1 18 3 6 13 208 3 16 7 19 4 15 00i 304 5 06 0 23 0 00 101 25 0 30 15 1 20 7 0 11 7 3 11 16 0 17 8 1 11 204 3 0 3a O' 0 0 101 0 00 0 00 1c 1 0 00 0 00 0 00 62 25 "D9 25 6 15-0 34O - Data l i s t ed as number of r a t s f o r which t h e 1i s t e d o b s e r v a t i o n was p r e s e n t . a S t a t i s t i c u l l y d i f f e r e n t from c o n t r o l d a t a when a n aly ze d u sin g F ish e r f s Exact P r o b a b i l i t y T e s t , ? < 0 . 0 5 . 9b 3 -135- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number of r a e s necropsied during Che time p e r i o d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 M-01 M-04 M-06 M-07 G-06 G-08 G-10 G -ll MUSCULOSKELETAL SYSTEM (Conn' d) Focal degeneration and inflam mation 0 mg/kg/day- of s k e le ta l muscle > 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day .Multifocal degeneration, inflamaation, with or without atrophy of s k e le ta l muscle 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Chondrosarcoma of rib 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day V ertebral h e aling re a c tio n to fracture 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day GASTROINTESTINAL SYSTEM Oral Cavity Number of gingival tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Oral papilloma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal inflammation and k e ra tin iz a tion of epithelium 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Tongue Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day V a sc u litis and v ascu lar degeneration 0 mg/kg/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Inflammation and/or hyperplasia of submucosal giands 0 mg/kg/day 30 m g/kg/day 10 m g/kg/d3y 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 J. 13-18 Months 14 9 22 12 10 02 04 01 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 1 0 0 1 0 0 0 0 1 0 0 0 13 8 19 12 3 1 5 - 7 6 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 23 5 29 10 5 17 6 2 12 9 5 15 10 1 011 000 000 10 1 00 0 000 000 000 00 0 1 o- 1 000 10 1 011 000 000 10l 00o 000 000 000 01 000 000 63 6 S3 25 16 49 23 4 -.0 2S 9 50 l1 2 3 -0 ** 3 4- 3 : 3 1 -* 3 * - * Daca listed as number of rats for which the listed observation was present. Statistically different from control data when analyzed using Fisher's ifxuct ;'rob.ibi11c r: Mb3 ^ -1 3 6 - TAHI.i: J.'t ( C o n t i n u e d ) MICROSCOPIC OBSERVATION:! hn MALE RATS MAIMTA . \ 0Ix DIETS CONTAINING 2 , for UP TO TWO 1 1 ^ 1 Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/dav 10 m g /k g /11.i v 3 mg/kg/il.iy 1 0 0 0 G-13 G-15 G-16 G-17 G- 2 0 G-30 G-31 G-33 G-35 G-36 Tongue (Conc'd) Degeneration and inflaimnacion of muscles 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Squamous m e ta p la sia of tongue 0 mg/kg/d.iv 30 m g/kg/dav 10 mg/kg/day 3 mg/kg/day Hyperplasia and/or hyperkeratosis of squamous epithelium 0 mg/kg/d.iy 30 m g/kg/,|..y 10 mg/kg/Jay 3 mg/kg/d.iy Focal hemorrhage 0 mg/kg/d.iv 30 mg/kg/,|.iv 10 mg/kg/tiny 3 mg/kg/day S t r a t i f i e d squamous c e l l carcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/d.iy 3 rag/kg/day S aliv arv Glands Number o f c i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day I n t e r s t i t i a l edema of s a l i v a r y gland 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Sialoadenitis 0 mg/kg/day 30 mg/kg/day 10 rag/kg/day 3 mg/kg/day Hypertrophy of g landular components 0 mg/kg/day of sa liv a ry gland 30 mg/k g/day 10 mg/kg/day 3 mg/kg/day I n t e r s t i t i a l in f lamination 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Atrophv of acinar tissue 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/ k g / a a y 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Month 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Data l i s t e d as number o f r a t s f o r which the l i s t e d , o b s e r v a t i o n was p r e s e n c . 13-18 Months 14 9 22 12 o o X 0 o o 2 0 o Q o 0 o o o 0 o 1 o 0 12 7 17 10 o o o 0 o X o 0 0 o 0 0 o o 1 1 o o 1 0 19-24 Months 63 25 23 28- Terminal Cumulative K ill R e su lts 5 86 16 50 4 50 9 50 xo1 ooo oox 000 59 202 x14 0 1i ooo xox oo0 000 ooo ooo ooo 101 1o1 2 x4 ooo i 01 59 6 80 23 15 23 4 45 25 8 44 ooo 1o1 0 00 000 3o 3 oo1 oo0 000 1oX oo0 000 0 00 3o3 -3 '1t ? 0 1 i 4 ) o 203 1x7 -1 3 7 TABLE 34 ( C o n t i n u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during che time p e rio d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 ng/kg/day 1 0 0 0 G-37 G-38 G-39 G-45 G-46 G-47 G-48 G-49 G-50 G-51 S alivary Glands (Conn'd) Cystic d ila ta tio n of ductular structures Adenoma Increased numbers of mast c e lls Stomach Number o f t i s s u e s examined Focal g astric ulceration D ilatation of gastric pits M in e raliza tio n of g a s tr ic muscul a r i s a n d /o r g a s t r ic mucosa Submucosal edema of stomach Hyperplasia of nonglandular mucosal epithelium Focal area of inflammation of stomach wall Hyperkeratosis or nonglandular mucosa of stomach 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 ais/kg/dav 30 m s/k g /d ay 10 m g/kg/dav 3 mg/kg/day 0 ng/kg/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 1 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 .0 1 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 00 00 0 0 11 0000 00 00 0101 00 00 0000 00 0 00 11 0000 00 00 0000 14 62 6 85 9 25 ' 16 50 22 22 4 49 12 27 9 49 00 00 0101 0000 1001 4 28 59 10 8 59 3 36 4 18 1 19 4 18 6 19 01 63 76 0 25 0 la 09 0 13 1405 0 0 00 0303 00 11 2407 0 101 1102 13 15 0203 0 101 11 13 0 0 00 03 00 01 1. 3 03 00 01 1 Data l i s t ed as number or r a t s f o r which th e l i s t e d o b s e r v t ; Lon was Pr` s e n t . ^Statisti tally d i f f e r e n t from c o n t r o l d a t a wnen a n a l y z e d us 1113 F i s h e r 1s E x ac t ?: o b a b i l i t y T e s t , p < 0 . 0 5 . Ld) c ct3 -1 3 8 - TABLE 34 ( C o n t i n u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON D IETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Code Number o r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 G-52 C-53 G-55 G-59 G-61 G-71 G-74 G-76 G-77 G-78 Stomach (Cont'd) Focal ero sio n of g a s t r ic mucosa 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day D iffuse inflammation of stomach 'w a ll 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day K eratinized cysc formation - wall of stomach 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day S t r a t i f i e d squamous papillom a of g a s t r i c mucosa 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Anomalous e p i t h e l i a l in g astric wall cyst formation 0 rag/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Small In te s tin e Number of t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal u lc e ra tio n and/or infiammation of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day R eactive lymphoid hyperplasia of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Mucocystadenocarcinoraa of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Adenocarcinoma of small in te s tin e 0 mg/kg/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Fibrosarcoma of small in te stin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 0 00 0 0000 0 10 1 0000 0 20 2 0000 0 101 1012 0001 0 10 1 0011 0000 0213 0000 0000 0 10 1 0000 0000 0000 0011 14 62 6 35 9 25 16 50 22 23 4 50 12 25 9 47 1304 0000 0000 0000 0 20 2 0123 1203 0*1 2 3 0102 0000 0000 0000 010 2 0000 0000 011 0000 00 31 0000 0000 Data list ed a s number o f r a t s f o r which th e 11 se e d o b s e r v a t : on was p r e s e n t . i 1 i i f l tl1 f E f 1 p lt ! rt k F Yti k il i' l. j V J ; S4>3C?`/ -1 3 9 TABLE 34 ( C o n t i n u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON D IETS CONTAINING 2 , 4 , 5 - T FOR uP TO TWO YEARS Diagnosis Code Number o r a t s necropsied during Che tim e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 G-79 G-80 G-31 G-87 G-88 G-89 G-89A G-89B G-89C C-90 Small I n te s tin e (Conc'd) Lymphosarcoma of sm a ll i n t e s t i n e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M ulcifocal hemorrhage in small intestine 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hvreremia of small in te s tin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Necrotic e n te ritis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day U ndifferentiaced sarcoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Lymphosarcoma of sm all i n t e s t i n e 0 mg/kg/day w ith m e t a s t a s i s to m e s e n t e r i c lymph 30 mg/kg/day node 10 mg/kg/day 3 mg/kg/day Mucocystadenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Segmental necro sis due to incussusception 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day P a p i l l a r y adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Larce In testin e Number o f t i s s u e s examined 0 mg/kg/day 30 cna/ka/dav 10 mg/kg/dav 3 mg/kg/day Incescinal nematodiasis 0 mg/kg/day 30 ms/ka/dav 10 mg/kg/day 3 mg/kg/dav 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 2 0 1 ]_ 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 01 0 .o 10 00 01 00 00 00 0 :0 00 01 00 10 00 00 00 00 10 00 00 01 00 00 00 01 00 00 00 01 00 00 00 00 00 00 01 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 1 0 0 0 0 0 1 0 1 0 0 0 0 1 0 0 1 0 0 0 1" 0 0 0 1 0 0 0 :0 0 0 1 14 63 6 36 9 25 .16 50 21 23 4 49 12 27 8 43 1 -4 1 134 3 20 13 0A 3 Daca listed as number of rats for which the listed observation vas present. Q -1 4 0 - TABLE 34 ( C o n tin u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINEDi ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TV.'O YEARS Diagnosis Code dumber o r a ts necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 7-12 Months 2 0 1 1 G-9X G-92 G-93 G-94 G-95 G-99 G-100 G-110 S-01 large In testin e (Cont'd) Diffuse inflammation of large intestine 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Focal inflammation of large in 'testin e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Edema a n d / o r i n f l a m m a t i o n o f w a l l of la r g e i n t e s t i n e an d /o r cecum 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Edema a n d / o r u l c e r a t i o n w i t h o r w ith o u t inflam m ation of cecum due to uremia 0 r^a/ka/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Reactive lymphoid hyperplasia of large intestine 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0, 0 0 R eactive lymphoid h y p e rp la sia of cecum 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Lymphosarcoma of la r g e i n t e s t i n e with m etastasis to mesenteric lymph node 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 P eritoneal Cavity P e r ito n itis secondary to perforated 0 mg/kg/day ulcer 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 .0 SUBCUTANEOUS-TISSUES, INTEGUMENT. AND MAMMARY GLAND Subcutaneous (nontumorous) Subcutaneous abscess i-, Subcutaneous ( tumorous) 0 ns/ka/dav 30 mg/k g/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 T o ta l number of subcutaneous cumors/humber of ra ts bearing subcutaneous tumors 0 mg/kg/day 30 mg/k g/day 10 m g /k g /d a v 3 mg/kg/day 0 /0 0 /0 0 /0 0 /0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 /0 0 /0 1 /1 0 /0 13-18 Months 14 9 22 12 0 0 1 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 /1 i/i 1 /1 1 /1 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 000 011 001 000 000 101 000 000 101 000 10 1 40b 000 101 001 0 00 606 415 314 10 1 000 202 0 00 000 00 0 10 1 0 00 00 0 10 1 0 00 0 00 0 00 00 10 i0 20 i 1 1 3/3 0 / 0 9/9 3/3 3/3 / / / 3/31 / 1 0 /0 6/6 5/ 3 11/ 10 Data l i s t e d as number of r a t s for which the l i s t e d o b s e r v a d on was ore s e n t . AS c a c i s c i c a l l y d i f f e r e n t from c o n t r o l d a t a vh e n a n a l y z e d u s i E i s n e r 1s E xact ? r o b a b i i i c y T e s t , Data l i s t od as t o t a l number o f t h i s ty p e ne o p l a sm /n u c h e r of r a t s b e a r i n s t h i s t ype neopl..:sm. p<.0 . 0 5 . N. -1 4 1 - TABLE 34 ( C o n t i n u e d ) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 rag/kg/day 1 0 0 0 S-12S-17 S-20 S-22 S-23 S-24 S-24A S-25 S--26 Subcutaneous (tumorous)3 (Cont'd) Subcutaneous fibroma 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Subcutaneous adenocarcinoma without 0 mg/kg/day metastasis 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Malignant fibrous histiocytoma with m ecastasis to abdominal cavity 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Malignant fibrous histiocytoma without m etastasis 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Subcutaneous liposarcoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day S u b c u ta n e o u s myxoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Subcutaneous carcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mammary Gland (noncumorous) Number of t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 rag/kg/day 3 rag/kg/day Mammary g l a n d h y p e r p l a s i a 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Mammary g l a n d galactocele formation 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 rag/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 c/o 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0 0 0 .0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 1/1 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0 1 8 4 0 1 1 2 0 0 J1. 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 3/3 . 1/1 1/1 4/4 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 4 0 3 6. 1 0 0 1 1 0 0 0 0/0 2/2 0/0 3/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 1 0 2 0 0 0 0 0 0 0 0 4/4 3/3 2/2 8/6 0/0 1/1 0/0 C /0 0/0 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 5 3 11 12 1 V i 3 1 0 1 0 Data l i s t ed as number of r a t s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . "'Data l i s t e d as t o t a l number of t h i s type neoplasm /num ber of r a t s be ar in g t h i s t;vpe n e o p la ST. 24 -142- TABLE 34 ( C o n tin u e d ) MICROSCOPIC OBSERVATION'S ON MALE RATS MAINTAINEDON DIETS CONTAINING 2,4,5-T FOR 0? TO TWO YEARS Diagnosis Code Number of r a t s necropsied during the time period indicated 1-6 Months 0 ng/kg/day 30 mg/kg/day 10 ng/kg/day 3 mg/kg/day i 0 0 0 7-12 Months 2 0 1 1 S-30 3-32 S-33 S-3S S-60 3-61 S-63 S-64 3-68 S-69 Mammary (tumorous)3 - T o ta l number of subcutaneous tumors 0 ag/k g/day /number of r a t s b e a r in g su b c u tan e - 30 mg/kg/day ous tumors 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary gland fibroadenoma/ adenofibroma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary gland adenocarcinoma w ith out metastasis 0 mg/kg/day 30 ag/k g/day 10 ag/k g/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary gland adenocarcinoma with metastasis 0 mg/kg/day 30 ng/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary gland carcin osarcom a 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Integument (nontumorous) Number of t i s s u e s examined 0 ag/kg/day 30 mg/ke/dav 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Epidermal inclusion cyst(s) with or without inflammation/rats bearing epidermal cysts 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Abscess of p re p u tial gland 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day .3 mg/kg/day 0 0 0 0 S u p e r f ic ia l n e c ro tic and inflam matory de b ris on integument 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Epidermal hyperplasia and d iffu s e inflammation of debris adjacent to subcutaneous mass or abscess 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 rag/kg/day 0 0 0 0 Keratinizing hyperkeratosis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day 0 0 0 0 Area of in f lamination of subcutaneous adnexa 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1 0 0 0 1/1 0/0 0/0 0/0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 1/1 1/1 1/1 1/1 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 9 5 16 7 0/0 0/0 2/2 0/0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative Kill Results 6 86 16 50 4 50 9 50 8/8 0/0 9/9 3/3 3/3 7/7 1/1 0/0 3/3 6/6 5/3 12/10 1/1 0/0 1/1 1/1 0/0 1/1 0/0 0/0 1/1 0/0 2/2 2/2 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 59 6 75 23 16 44 19 4 39 27 9 43 3/3 3/2 7/6 0/0 1/1 1/1 3/3 0/0 5/5 1/1 1/1 2/2 112 134 000 101 000 001 000 000 10 1 20 2 000 101 101 000 000 000 00 00 0. 0 10 0 0 o 1 Data listed ns number of rats for which the listed observation was present. `\)ata listed as total number of this type neoplasm/'number of rats bearing this type neoplasm. a.42 -143- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 S-72 S-75A S-76A S-7 6C' S-76 S-79 N-01 Incegumenc (tumorous)'1 Tot a l number of cutaneous tumors/ number o f r a t s b e a rin g cutaneous tumors 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day .Squamous p a p illo m a o f in te g u m en t 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Adnexal carcinoma with m eta stasis to lungs 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Fibrosarcoma adjacent to ear tag 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Adnexal cystadenoma Ear Canala T o ta l number of e ar car.al tumors/ number of r a t s b e a rin g e a r c an al tumors 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Zymbal gland carcinom a of e a r c an a l 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 .mg/kg/day Subauricul3r undifferentiated sarcoma w i t h m e c a s t a s i s t o l u n g s NERVOUS SYSTEM Brain Number o f t i s s u e s e x ^ z in e d 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30' mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal malacia in b rain 0 mg/kg/day 30 mg/kg/day 10 m g /k t/d a v 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 -0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0/0 . 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 2 0 1l 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 S6 16 50 4 50 9 50 0/0 2/2 0/0 2/2 0/0 1/1 0/0 1/1 2/2 0/0 1/1 3/3 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 1/1 0/0 1/1 0/0 . 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0 /0 0 /0 Q/0 0/0 0/0 0/0 0/0 0/0 1/1 4/4 0/0 3/5 0/0 0/0 1/1 1/1 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 1/1 3/3 0/0 4/4 0/0 0/0 1/1 1/1 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 14 63 6 36 9 25 1 50 ?2 23 4 50 12 28 9 50 0 0 2 1 0 0 : l 0 0 0 '/ 100 L Duca listed as number of rats tor which the listed observation was present. Data listed as total number o; this type neoplnsn/number of rats bearing this type neoolasm. 3 e?*-? -144- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied daring the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day ` 10 m g/kg/day 3 mg/kg/day 1 0 0 0 N-02 N-03 N-04 N-05 N-06 N-08 N-12 N-22 N-23 N-25 N-19 NERVOUS SYSTEM ( C o n t 'd ) Focal g lio sis of brain 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal inflammation in brain 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Vacuolizacion of white m atter of b r a i n which may o r may n o t be artifact 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mineralized deposits in brain 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Compression'malada or hemorrhage, and/or hematogenous pigment in brain adjacent to picuicary adenocarcinoma 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Hemorrhage in brain 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Hemorrhage surrounding p ineal gland 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Astrocytoma w ithin cerebrum 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Astrocytoma w ithin cerebellum 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Granular c e l l myoblastoma of b ra in 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Astrocytoma or mixed g l i a l neo plasm of cerebellum 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 0 0 0 1 0 0 0 0 0 0 2 8 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 36 16 50 4 50 9 50 2 1 0 0 1 0 0 0 18 6 4 4 0 0 0 0 2 0 0 0 3 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 1 1 1 1 0 0 0 02 01 00 01 01 00 00 00 0 19 06 17 0 12 0 00 00 00 02 00 0 00 03 0' 0 0 .0 00 00 01 00 00 00 01 01 00 00 00 00 0 0o 0. 1 01 0: 0L 0G 0J 0J Data l i s t e d a s number of r a t s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . -b 'i -145- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TOO TEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated i'-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 N-40 N-41 N-42 N-60 N-62 N-64 N-66 N-67 N-63 S p in a l Cord Number of t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day V a c u o l i z a t i o n of. s p i n a l co rd which may or may noc be a r t i f a c t 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day In c re a se d number of g l i a l c e l l s 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal hemorrhage in sp in a l cord 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day P e rip h era l Nerves Number of t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Vacuolization of p e rip h e ral nerves 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M e d ia s tin a l m alignant schwannoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Schwannoma of c r a n i a l ne rv e 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal inflammation of peripheral nerve 0 mg/kg/day 30 mg/kg/day 1 0 .mg/kg/day 3 mg/kg/day M ineralization of peripheral nerve 0 mg/kg/.day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M alignant schwannoma of c r a n i a l nerve with involvement of cerebrum and n asal tu r b in a te s 0 mg/kg/day 30 mg/kg/dav 10 mg/kg/day 3 mg/kg/day 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 1 0 1 1 0 0 1 1 0 0 0 c 0 0 0 0 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 14 9 21 12 0 0 5 8 0 0 0 1 1 0 0 1 13 9 20 11 6 0 2 4 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 63 6 85 25 16 50 23 4 49 27 9 49 11 0 11 404 8 2 16a 4 0 13a 10 1 000 000 001 20 3 000 00 0 00 1 61 6 82 . 25 16 50 23 4 48 24 9 45 38 6 50 14 13 27 4 23 29 12 7 23 10 1 000 000 000 000 000 10 1 000 011 000 000 000 00 1 000 000 000 000 000 000 10 1 Data i i s c ed as number o f r a t s f o r which th e l i s t e d o b s e r v a t i o n was p r e s e n t . ^ S t a t i s t i c a l i y d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d u s i n g F i s h e r 1s Exact P r o b a b i l i t y T e s t , p<0 .0 5 . d (t>tPA t -146- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR UP TO TWO TEARS Diacnosis Code Number of r a t s necropsied during the time period indicaced 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 N-80 N-81 N--82 N-83 N-85 NT-8 6 N-87 N-88 N-89 N-92 P itu ita ry Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 Retention cyst(s) in p itu itary 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 P itu ita ry hematocyst 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Increased hematogenous pigment in p itu ita ry 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Hemangiectasis of p itu ita ry 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Hyperplastic focus in p itu ita ry 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 P i t u i t a r y adenoma fo rm atio n (s ) 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 P itu ita ry adenocarcinoma without extension or invasion of brain 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 P itu ita ry adenocarcinoma with invasion of brain 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Mineralized debris in p itu itary 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day 0 0 0 0 Hemorrhage adjacent to p i tu ita r y 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 0 1 1 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O' 13-18 Months 14 9 22 12 13 9 21 11 3 0 1 0 0 0 0 0 0 0 0 0 2 0 0 0 4 0 3 3 2 0 3 1 0 0 1 0 0 1 0 0 0 1 q d 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 59 6 82 24 16 49 22 4 48 26 9 47... 3i 7 156 1 0 q* 4 15 404 000 101 1 1O 101 000 0 00 0 00 417 0 44 202 0 33 10 0 17 42 1 0 5 5 i 06 17 3 22 5 5 10 9 2 13 4 5 10 40 21 2 1 0 0 A 3 2 2 101 001 0 00 0 00 0 ,) 0 01 o ) 0 00 0 0 1 - ) Data l i s t ed ns number of r a ts to r which the l i s t e d o b se rv a tio n vas p r e s e n t . X?if X f : 1 -147i TABLE! 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS .CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a t s necropsied during Che t im e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day i 0 0 0 N--71 A-01 A-02 A-03 A-05 A-20 A-21 A - 22 A-23 A-26 Cranial Cavity Neurofibroma adjacent to c ra n ia l nerve 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day . 0 0 0 0 ADRENAL GLAND Number o f t i s s u e s exam ined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 General Adrenal gland hematocyst formation 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Hemangiectasis of adrenal gland(s) 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Isolated focus of purulent inriammaticn in adrenal glands 0 mg/kg/day 30 mg/kg/day 10 m g/kg/da y 3 mg/kg/day 0 0 0 0 Congestion 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Cortex Adrenal c o rtic a l necrosis with or without hemorrhage and/or purulent inflammation 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Vacuolization of adrenal c o rtic a l cells 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 M ineralization of adrenal cortex 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Atrophy of adrenal cortex 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Aggregates or hematogenous pigment in adrenal cortex 0 mg/kg/day 30 mg/kg/day 10 m g/k^/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 0 1 1 13-18 Months 14 9 22 12 00 00 00 00 2 12 09 0 22 1 12 1' 0 00 02 00 0 o00 00 00 00 00 01 00 11 00 03 00 00 00 01 00 19 05 0 13 05 00 00 00 00 00 00 0 00 00 00 00 00 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 10 1 0 b . 0 000 000 63 6 84 25 15 50 23 4 49 28 9 50 15 1 17 639 7 2 11 628 0 0 .0 011 000 000 202 1 0 a1 . 001 000 0 0 0 0 n 0 0 1 0 0 13 5 0 3 202 10 10i 48 4 62 17 14 36 20 4 37 25 5 35 202 000 0 0 0 0 0i; 0 0 j 00 00 - 00 : 0-00 0L Data l i s t e d a s number of r a t s t o r which th e l i s c e d o b s e r v a t i o n was p r e s e n t . 3d>Ho3 -148- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 1 30 m g/kg/day 0 10 mg/kg/day 0 3 mg/kg/day 0 A -30 A-31 A-32 A-40 A-41 r A-42 A-44 A-45 A-46 A-4 7 Cortex (Cont'd) Hyperplastic focus (fo ci), of adrenal cortex nodule(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Adenoma of a d r e n a l c o r t e x 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Adenocarcinoma of adrenal cortex 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Medulla H yperplastic nodule of adrenal medulla(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Adrenal pheochromocytoma, unilateral 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Adrenal pheochromocytoma, b ila te ra l 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Adrenal pheochromocytoma, malign a n t, no m e t a s t a s i s - u n i l a t e r a l 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Adrenal pheochromocytoma, m alignant - u n ilateral 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Adrenal ganglioneuroma 0 mg/kg/day 30 mg/kg/day 10 n g / k g /d a v 3 mg/kg/day Adrenal pheochromocytoma, malign ant - no m e t a s t a s i s - b i l a t e r a l 0 mg/kg/day 30 mg/kg/day 10 mg/k g/day 3 mg/kg/day EYE Number of t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/k g/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 13-18 Months 14 9 22 12 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0, 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 2 0 1 1 3 3 6 4 0 0 1 0 0 0 0 0 3 3 7 4 2 1 4 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13 9 20 il 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 16 0 19 5 2 . 10 4 2 12 9 4 18 0 11 213 102 303 101 0 00 0 00 0 11 17 2 22 5 2 10 7 1 15 6 4 14 29 i 32 9 4 14 8 3 15 5 4 11 2 14 4 26 2i 3 101 5 16 0 11 0 11 2 13 101 000 000 000 0 00 1 01 00 000 001 000 0 00 10 c15L 6 oi r-0 23 - -o 23 - i D-ica l i s t e d as number o f r a t s Cor which thu l i se e d o b s o r v n e i.on was p r e s e n t . 24 4o 4 -149- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO TEARS Diagnosis Code Number o f r a t s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 E-01 E-02 E-03 E-07 E-08 E-09 -10 E -ll E-12 Z-02 Z-03 EYE ( C o n t 'd ) Focal k e r a t i t i s of eye 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day . D iffuse k e r a t i t i s of eye 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Focal or diffuse hyperplasia of corneal epithelium 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Focal m in e ra liz a tio n of eye 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day R ecrobulbar k e r a t in i z in g squamous c e ll carcinoma vich extension into cranium 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Intraorbical undifferentiated sarcoma w i t h i n v a s i o n of c r a n i a l cavity 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Phchisis bulbi with chronic inflammation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Focal inflam m ation of c i l i a r y body 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day B i la t e r a l r e t i n a l atrophy and degeneration 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day MISCELLANEOUS Postmortem a u to ly tic changes in a ll organs 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Inflammation or m esenteric fat 0 mg/kg/day 30 mg/k g/day 10 mg/kg/dav 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13-18 Months 14 9 22 12 1 2 0 1 0 .0 4 2 0 1 3 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 1 0 1 0 1 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 71 53 5 1 41 24 0 35 11 51 18 1 25 22 31 30 10 10 20 00 10 00 00 C0 00 10 00 00 00 00 10 00 10 00 00 00 00 00 01 00 00 00 0 5o 00 1 9 10 6 6 25 8 6 8 20 8 7 5 4 1 1 3 0 1 0 0 0 0 1 0 0 0 0 1 0 1 0 0 0 0 0 L \ 0l *.) 0 - Data l i a c e d as nim ber o f r a c s f o r which t h e l i s t e d o b s e r v a t i o n was p r e s e n t . -150TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON HALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a c s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 rag/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 Z-04 Z-07 Z-08 Z -ll Z-12 Z-13 L-01 L-03 L-20 MISCELLANEOUS ( C o n t 'd) Focal mesenteric s t e a t i ti s and/or necrosis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day .Mediascinal fa t inflammation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day G eneralized in c re a s e d number of mast c e lls 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day M esenteric lipoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Purulent abscessacion of mesentery 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Granulomatous m ediascinal inflam ration 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day LYMPHORETIC'JLAR Lymph Modes - G e n e r a l G eneralized lymphosarcoma with widespread m etastasis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Generalized lymphosarcoma ( r e tic u la r c e ll type) with widespread m etastasis 0 tag/kg/dav 30 mg/k g/day 10 mg/kg/day 3 mg/kg/day T horacic Lvooh Node(s) Number o f t i s s u e s exam ined 0 mg/ka/dav 30- mg/kg/day 10 mg/kg/day 3 mg/kg/day Pooling of edema, pigment, an d /o r red blood c e lls in sinusoids of t h o r a c ic lymph node 0 mc/k^/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 2 0 1 1 1 0 0 0 13-18 Months 14 9 22 12 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 13 7 22 11 3 3 9 6 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 86 16 50 4 50 9 50 00 0 000 00 0 20 2 60 6 000 001 001 000 022 000 000 011 000 000 000 011 000 000 000 000 000 000 001 011 000 000 00 1 001 000 000 000 59 6 81 21 16 44 22 3 48 27 7 4 48 4 57 15 8 26 18 3 30 17 5 23 Data l i s t ed as number of r a t s cor which th e l i .seed o b s e r v e r : Lon was p r e s e n t - -151- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO YEARS Diagnosis Code Number o f r a c s necropsied during the time period indicated 1-6 Months 0 mg/kg/day 30 rag/kg/day 10 a g /k g /d a y 3 mg/kg/day 1 0 0 0 L-22 L-23 L-24 L-25 L-30 L-31 L-32 L-33 L-34 L-35 L-36 T h o r a c ic LymDh Mode(s) ( C o n t 'd ) Reactive lymphoid h yperplasia of th o ra c ic lymph node(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day .Congestion of t h o r a c ic lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cyscic d ila ta tio n of lymphatics of th o r a c ic lymph node(s) 0 mg/kg/day 30 a g /k g /d a y 10 mg/kg/day 3 mg/kg/day Reticuloendothelial c e ll hyperplasia 0 ag/kg/day 30 mg/kg/day 10 m a/k s/d a v 3 mg/kg/day M e s e n t e r i c Lvmoh Node(s) Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 m g/kg/cay 3 mg/kg/day Pooling of edema, pigment, an d /o r red blood c e ils in sinusoids of m e s e n te ric lymph node 0 mg/kg/day 30 a g /k g / d a y 10 a g /k g /d a y 3 ag/kg/day Inflammatory process in mesenteric lymph node 0 stg/kg/dav 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Reactive lymphoid h y p erp lasia of m es en teric lymph node 0 ag/kg/day 30 a g /k g / d a y 10 a g / k g / d a y 3 ag/kg/day Cystic d isten tio n of lymphatics of m e s e n te ric lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day Fibrotic tissue in mesenteric lymph node 0 ag/kg/day 30 mg/k g/day 10 mg/k g/day 3 mg/kg/day Increased numbers of h is tio c y te s in m es en teric lymph node 0 mg/kg/day 30 m p /k j/d a v 10 a g /k g / d a y 3 ag/kg/day C on g estio n of m e s e n te r ic lymph node 0 mg/kg/day 30 a g / k g / d a v 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 _0 0 0 0 0 0 0 13-18 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 86 16 50 4 50 9 50 0 00 0 0101 0000 010 1 010 1 0303 0000 0 10 1 0000 0000 0000 0 10 1 0000 0000 100 1 0000 12 60 6 81 9 23 16 48 19 20 4 44 9 25 8 42 7 39 4 51 6 16 12 34 9 9 3 21 1 15 4 20 100 1 0011 000 0 0000 0213 0 10 1 0000 021 3 0 20 2 0000 0 00 0 0 00 0 000 0 0011 0000 0000 1. 1 0 3 0000 0000 100 1 120 3 0000 0000 0 10 1 Data l i s t . .'d a s number of r a t s f o r which t h e 1.i s t e d observed:ion v a s pre:s e n t : . -152- TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS OM MALI RATS MAINTAINED ON DIETS CON[TAILING 2 , 4 , 5 - T ?0R ? 10 WO YEARS -- Diagnosis Coda Number o f r a t s necropsied during the cine period indicacad 1-6 Monchs 0 ag/kg/day 30 m g/kg/day 10 a g / k g / d a y 3 ag/kg/day 0 0 AJ L-42 1-46 L-90 L-95 1-52 .-56 1 1-39 S u b c u t a n e o u s Lyrash Modes Number o r t i s s u e s examined 0 ag/kg/day 30 m g/kg/day * 10 m g/kg/day 3 mg/kg/day Reactive hyperplasia os subcu-- caneous Lynch node 0 mg/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 mg/kg/day rib ro tic tissu e la subcucaneous Lymph node 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day P e r i a o r t a i Ivmnh Mode dumber or tis s u e s examined 0 ag/kg/day 30 a g /k g /d a y 10 a g / k g / d a y 3 ag/kg/day S lig h t re a c tiv e lymphoid hyperp ia s ia , edema, and pooling oc red blood c e lls 0 mg/kg/day 30 a g /k g /d a y 10 m g/kg/day 3 ag/kg/day Lvmoh Modes (unknown l o c a t i o n ) Number o r t i s s u e s examined 0 mg/kg/day 30 -ag/kg/day 10 a g / k g / d a y 3 mg/kg/day Edema, t o o l i n g of rad blood c a l l s , , and c y s tic d iia ta c io n 0 mg/kg/day 30 m g /k g /d a y 10 a g / k g / d a y 3 ag/kg/day Thyraxis Number o r t i s s u e s examined 0 ag/kg/day 30 a g /k g / d a y 10 a g / k g / d a y 3 ag/kg/day Z o ic h a iia i h y p e ro la s ia of thymus 0 ag/kg/day 30' ag/kg/day 10 a g /k g / d a y 3 ag/kg/day Thymic L'r m r h o s a rc o a a 0 mg/kg/day 30 a g / k g / c a y 10 a g / k g / d a y j mg/'5/ lay F o c a l hetiorrr.sge y o r c c a o l y agor.ai;) 0 mg/kg/rev 30 ag/kg/day 10 a g / k g / d a y 3 ag/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0_ 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 n 3 0'J 0 3 o 0 0 7-12 Months 2 0 1 1 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 1 2 0 0 0 0 0 0 0 D 3 0 0 0 13-13 Months 14 229 1n 0 i 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 12 4 14 10 0 0 0 0 0 .h 0 0 0 0 19-24 Terminal Cumulative Monchs K ill R e su lts S3 25 23 23 * 6 16 4 9 36 50 50 50 3I 4 3 4 .a 3. i 4 4i 6 1 01 101 000 000 000 001 000 000 00 0l 0 0 0. 0 00 00 10 00 0 0 1 0 0 01 0 101 000 000 001 10 1 000 000 000 43 l 59 22 12 38 17 3 35 19 7 37 0 0 'j 000 1 0 0n'j 1 o 3j 0 02 'J 3 3 j - `J - 'J 0 00 30 00 3 .j Q DDaacca u s e e d as cumber of rats f o r vhich the .l i s t a d o b s e r v a d or vas o r e s e n t . -153 TABLE 34 (Continued) MICROSCOPIC OBSERVATIONS ON MALE PATS MAINTAINED ON DIETS CONTAINING 2,4,5-T ;OR uP TO W O TEARS Diagnosis Coda Munber o f r a t s necropsied during the cine period indicacad 1-6 Mone Lis 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day i 0 0 0 L-60 L-61 1-62 ,-63 L-70 L-64 L-58 T-01 T-03 SPLEEN Number o f t i s s u e s examined Splenic acrophy with or without incraased hemosiderin pigment Incraasad hematogenous pigment in spleen Increased extramedullary deratepoiesis in spleen R e tic u lo e n d o th e lia l or lymphoid hyperplasia of spleen Lymphosarcoma o f s o la e n Congestion of spleen Capsular cyst formation THYROID AND PARATHYROID Thyroid Number o f t i s s u e s examined Thyroid interfoilicuiar C-cell adenoma Thy-aid i->-a>--o' ` `c-' 1" '--= ' adenocarcinoma vith uetastasis 0 mg/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/da y 10 m g/kg/da y 3 mg/kg/day 0 mg/kg/day 30 m g /k g /d a y 10' m g /k g /d a y 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/da y 3 mg/kg/day 0 mg/kg/day 30 m g /kg/da y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10. m g/kg/da y 3 mg/kg/cay 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/cay O --^ ^r3/ --- : 3C mg/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .-*1 J 0 0 7-12 Months 2 0 1 2 0 1 1 0 0 0 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 2 0 0 0 0 o0 0 2 0 i 1 0 0 .*\ 0 : 0 0 0 Caca listed as number of rats for vhicLn the listed observation. vas present. 13-18 Months 14 229 12 14 9 22 12 5 0 1 2 5 6 18 9 5 3 14 9 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 13 .3 22 12 0 1 'j 0 J 0 J 0 19-24 Months 53 25 23 23 Terminai Cumulativa K ill Jesuits 6 36 16 50 A 50 9 50 63 6 25 16 23 4 23 9 40 30 30 20 42 3 18 13 22 13l 0 45 5 16 ` 9 13 4 22 8 30 00 00 00 10 00 00 00 00 00 1 0 0l 00 00 0 0 0l 36 50 50 50 9 3 4 5 51 37 32 37 55 28 32 39 3 0 0 1 1 0 0 0 2 0 1 1 0 0 02 63 6 i 24 16 43 23 3 49 23 3 49 336 24 202 213 i 0i 00 nJ 0 1A _; 1\ --, j --' 1 - -1 5 4 - TA3LZ 34 ( C o n tin u e d ) MICROSCOPIC OBSERVATIONS ON MALI RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T :OR up TO TNO TZARS Diagnosis Code Number o f r a t s necrcpsied during "he cine period indicated 1-6 Honchs 0 mg/kg/day 30 m g/kg/day 10 mg/'kg/day 3 mg/kg/day i 0 0 0 T-04 T-05 T-06 T-iO T-Ii T-20 T-22 T-23 -_24 Thyroid (Cant'd) H yperplastic focus of in c a rfo llic u la r C c a lls w ithin chyroid Thyroid hyperplasia (fo llic u la r) Retention cyst in thyroid Mineralized deposits in thyroid Focal fo llic u la r overdistantion Parathyroid Number a t t i s s u e s examined Secondary parathyroid hyperplasia (renal) H yperplastic focus in parathyroid I n te r s titia l fib ro sis of parathyroid iecacocysw if. o s ra c h v ro id 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day :3 m g/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Q 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .3 V 7-12 Months 2 0 i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1_ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 J 13-18 Mnchs 14 9 22 12 i 0 0 2 0 0 1 0 1 1 2 0 0 0 0 0 0 0 0 I 12 7 19 10 3 A 14 3 0 0 0 0 0 0 0 0 0 r, 0 0 19-24 Months 63 25 23 23 13 5 4 7 2 1 0 0 0 0 1 0 0 0 0 1 0 0 0 0 60 24 22 25 38 17 14 12 0 1, 1 0 1 0 0 0 0 0 1 0 ad as r.unbar o : recs for vhizh rha 1i s red aoservs.cz oreseoz. S ill 6 16 4 9 Cumiiaciva RasuJ.cs 36 50 50 50 1 15 6 11 04 ? 11 02 01 0 00 01 01 03 2? 00 00 00 01 00 00 00 01 6 79 12 43 3 44 5 42 4 50 4 25 i 29 3 23 00 0i 01 00 0l 00 00 00 00 0 J 01 0: a (HlO -155- TA3L2 35 MICROSCOPIC OBSERVATIONS CM FEMALE RAIS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - 1 POP. 'J? TO TWO TEARS Diagnosis Cods Number o f r a c s necropsied during cha cime p eriod indicacsd 1-6 Monchs 0 mg/kg/day 30 m g/kg/day 10 mg/kg/'day 3 ng/hg/day 0 0 1 H- 0 1 H-0 2 H-0 3 H-0 5 H-06 H-0 7 a-o a H-09 H-1 0 : i_ LIVER Number o f " i s s u e s examined 0 ag/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day 0 0 1 1 H eoacocellular Changes Necrosis wish accompanying inflam macory raaccion - sin g le focus 0 ag/kg/day 30 m g/kg/da y 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Necrosis wich accompanying inflam macorv raaccion - focal 0 mg/kg/day 30 a g /k g /d a y 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Necrosis wich accompanying inilam macory reaccion - m ulcifocal -- - Cycoola-smic v a cuoiizacion single focus 0 ag/kg/day 30 a g /k g /d a y 10 mg/kg/day 3 mg/kg/day 0 ag/kg/day . 30 a g / k g / d a y 10 m g/kg/day 3 ag/kg/day 0 0 0 0 .0 0 0 0 Cycooiasmic vacuoiizacion - focal 0 mg/kg/day 30 a g /k g /d a y 10 ag/kg/day 3 ag/kg/day 0 0 0 0 Cytoplasmic vacuoiizacion - n u lc ifocal 0 ag/kg/day 30 mg/kg/day 10 m g/kg/day 3 ag/kg/day n !J 0 0 0 Cycoolasmic vacuoiizacion - d is seminacad 0 ag/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Cycoolasmic vacuoiizacion - suggescive of ra tty tnecatsorphosis 0 mg/kg/day 30 m g/kg/dav 10. mg/kg/day 3 mg/kg/day 0 0 0 0 Az acnczernitluoaot ed ul a l r o b a u c la ro rp ohy a t t e r n cue co 0 mg/kg/day 30 m g/kg/day 10 n g / '<g/day 3 ag/kg/day 0 0 0 0 Heoacocellular ilceracion (swollen heoatccytes) - sir.cie focus 0 -g/kr/dsv 2C mg/kg,- day 10 m g/kg/day 3 mg/kg/dav J 3 0 7-12 Monchs ? 2 2 1 2 2 2 i 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0- 0 0 0 0 0 1 0 0 1 0 0 0 0 J 3 13-18 Monchs 17 9 11 11 17 9 11 11 0 1 0 1 2 1 2 i i 0 2 0 1 0 0 0 4 0 1 0 0 0 0 0 1 0 1 1 0 0 o 0 0 0 2 1 1 y 19-24 Monchs 31 13 25 IS Terminal Cumulative S ill Resulcs 36 36 21 50 11 50 19 50 31 36 IS 21 25 11 13 ' 19 11 10 10 03 10 01 10 10 30 00 00 20 i1 02 21 00 7 12 25 52 2 2i i0 iy i 00 00 00 20 10 00 00 y 0 y 0y 3 3 : 79 3c 33 1 -V 36 50 50 50 2 2 1. 4 3 2 3 2 5 0 2 2 3 2 3 0 23 7 7 6 6 1 3 3 2 0 J. 3 2 1 0 2 ; 5 3 o r> -J 6 -- 3 a : a i i s c a d a s n u a b e r o f r a c s for- w hich che l i s c e c o b s e r v a t i o n was p r e s e n t . SL<t>HU -155- TA3LE 35 (Concinued) MICROSCOPIC OBSERVATIONS ON jEMALE 3ATS MAIMTAINcD ON DIETS CONTAINING 2,4,5-1 FOR UP TO Ti'O TEARS Diagnosis Code dumber or racs necropsied during che cime oeriod indicaced 1-6 Monchs 0 ag/kg/day 30 ag/kg/day IQ a g / k g / d a y 3 ag/kg/day 0 0 1 1 3 -1 2 3 -1 7 3 -1 3 3 -1 4 3 -1 5 H-lo H-13 3 -1 9 3 -2 0 12_ 9 T 2 Heoacocellular Changes (Conc'd) Heoacocellular alceracion (swollen h e p a c o c y c e s ) - l o c a l (2 - 3 ) - 0 ag/kg/day 3 0 mg/kg/day 10 ag/kg/day 3 ag/kg/day Hepacocalluiar alceracion (swollen hepacocyces) - several foci (>3 ) 0 ag/kg/day 3 0 ag/kg/day 10 m g / k g / d a y 3 mg/kg/day Heoacocellular alceracion (swollen hepacocyces) - single area 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Heoacocellular alceracion (swollen heoacocyces) - several areas 0 ag/kg/day 30 ag/kg/day 10 a g / k g/day 3 ag/kg/day H y oemiascic nodule(s) 0 ag/kg/day 3 0 mg/kg/day 10 ag/kg/day 3 ag/kg/day Heoacocellular carcincnia(s) 0 ag/kg/day 30 ag/kg/day 10 a g / k g / d a y 3 ag/kg/day focal vacuole f o m a c i o n vich or vichouc mineralized debris 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day focal confluenc vacuole formacion wich or wichouc aineralized debris 0 ag/kg/day 30 ag/kg/day 10 a g / k g / d a y 3 ag/kg/day Muiciole aulsinucieaced cells in liver (megakarvocyces) 0 ag/kg/day 3 0 ag/kg/day 10 a g / k g / d a y 3 ag/kg/day Swelling of individual hepacocyces 0 ag/kg/cay 30 ag/kg/day 10 a g / k g / d a v 3 ag/kg/day Oiscorcion of lobular oaccern 0 ag/kg/day 3 0 m.g/kg/cay 13 ag/kg/day 3 / <5/lev 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 0 0 o 3 3 7 -1 2 Mnchs 2 7 2 i. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o o0 0 0 0 0 0 0 0 0 0 0 0 0 'J 1 3 -1 3 Mnchs iy 9 11 11 0 0 1 1 3 1 0 0 4 1 0 0 1 0 0 0 1 0 1 0 0 0 0 2 2 5 0 0 0 1 0 0 0 0 0 0 0 0 0 0 3 O3' 1 9 -2 4 Mnchs 31 18 25 13 Terminal Cuaulacive Kill Rssulcs 36 36 21 5 0 11 5 0 19 50 3 2 2. * 2 4 0 0 1 3 2 5 0 3 0 1 0 0 0 1 0 0 0 0 0 1 2 i 4 0 1 s 5 0 0 0 0 0 7 0 1 .3 0 0 - 11 3 5 i 3 2 0 3 3 6 2 5 7 2 1 3 3. 2 2 2 1 0 0 0 0 0 0 0 27 15 9 15 0 0 0 0 0 0 0 0 0 0 3 0 14 10 3 4 15 3a 5 4 15 10 7 5 ii i 2 3 4i 3 2 2 0 0 0 3 4^ 9" + 27 IS 13 20 0 0 0 0 2 0 1 3 3 * Ds C3 UUS c ec as n u m b e r or racs for w h i c h the 1 i s c e d o b s e r v e r : .on was o r e s a n c . J^ 0 'll!CIS Cl c a l l y d i f f e r e n c from c o n c r o l d a c a wh e n e n a l v c e d us:.ng :is:"ler's :<acc P r o c a o i l i c y 7 esc, p<0 . 0 5 . [--43 F i b r o s i s w i t h i n h e p a t i c t i s s u e - 0 n g / k g / d a y l 1 SU ru ,'i; P 1i 11 oi *In 1- o l" Ok i j (0 1 i . i i |u In < i. ; j i * (.: [1 O' IU lU 11 rt tu O [, n > li 1 ll i i >1 l` o i1 1 0) 11( > , uo 1 '{ n <1 o ;.r K` a <i f 1. j j ' r> ,, P ; j' ft) *; (D ; ; ;) 0i Hi (ll V a P i1- ' o O' tJ UJ (B ft) (1. CJ <; tu i/i 11 o :i P l/J 01 (il u ' 1Ill M (l> (A ft) l.1.' n i<> o 'U u p O' 1 l- i i- h - f t P - ' * p* P 1 - P A AA H ' ti < r> O H ft) M JS' h (b U ' 01 O ' rt Ul \ O (V o ft) (U (A a (/) P (A A a A o o<0 lb Uk 3 U o. n a tu 1n n 1 lb A P H- l/l A n 'CJ (W C 3 ' cn lu pJ O' 1*- C A rt> 0 P A :x 3 P (l) it n 'U P* (A (A p Ap 3 o O UQ A P P 0Q fu n (A >< t-i A o ip o n UQ I |U i'i ft A o O Vj IU (A o (A u P c (A A 1 - 0 c3 t-- 1 ft> oU- u> o o Uy uQ U Hi UQ uq^ UQ^ s* IN' UQ l*." is" UQ 0 q UQ ptu. A v . a. (U ` <1 P P '< oU l 1--* U l op a ti 0Q ii u 0Q UQ UQ ?r /t* UQ 7T V? UQ I f ) UQ A. P n. P. (tuX ' < p (U *<{ '< ou> t-k UJ oo El y UQ 0 a UQ ^v. (IQ UQ IN' (V UQ IS" / T UQ UQ UQ t(uX v< CfuU atu. p. (U o; ou > I-* L~) oo y3 OQ p p UQ UQ UQ JT V . is- 0Q s. 7? UQ IN* Ut UQ fuA A A . P - p) NQ P P U> I- * UJ t_> OO a ii UQ a Vi UQ OQ UQ IS- UQ 7T IN* UQ UQ UQ AA PA AP *-Q P P '< 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day oo O O O ooo Oooo oO O O OOOO oooo Ooo oo o oooo O o oO OOOo o oo o Oooo oooo oooo oooO O O O H-* oooo focal O O o o o o o -* O O O I-1 O ro I--*O o o o o O O O t-1 Ul o o o t-* o o a o o o o o o o o o o o o o o o o t-- o O O "' O O I-- h" O O O I-- O ro OOOM O O O l'J L 0 ag/kg/day 30 a g /k g /d a y 10 a g / k g / d a y 3 ag/kg/day ru W FU i fO O wi IG La in>l lju*j ibross vishin hapacic "issue ingle locus ;V U i. (h ' i (b A p 13 O p n CU <0 O A f p O i--* O n ir O P (U n UQ n O - Q m P t (A P . -- (U n UQ UQ O ta a> (0 n p I--* IV ro I - Ui 1 J (U O n i, iv ( io r t O .p n> rf P rr (P H - P pn (P r t p O - H r< G OI f l U) p a. o u> i - La O OO y UQ y U (A (M7T*yQ**r.UQ '<fU ^(uL vrA<u- stu C O J H - (0 G n -- n P ` 1 - tu p Ui H P (U r 1 'U O p i O <p p bM n (U p 11 -- P fu 1- n h*' O yP O pG O hi p p HnP p P, n> M (u (U ri n g O tu n> n 1- O H ri to 3 l-t P H, P fu n O n <i o 10 p p n p* (U p JQ (V M L-J p * c a O OO aB UQ B 0jQe UQ jv UU?QruUQ;Q*--r ` "-.U Q UQ p. *'*>s cl fu ( S{U L (X fU v<j si; 0 t-i tu p D Oa *1 0 tu r i (U O (A O (0 ro P- p p gp pp r fu G ri n PO O P* fu ru il H JQ UQ (V P Ui n ID Ui O O p n -- P La P LJ O OO BB 0Q g g UQ y?v- - UQ UQ ?r ^ UQ JS" } C 0 Q p ^ ^ u g (H p p p Pfu. ^ *P<'-P4 *< i-*- n P P P- P* n> ro n hn P m f i n G il fu P O n ng (V a P UI pG 10 r i i o IX a> n i P - |U P P r> O r i Ui PP P UQ U I i-- L-J o OO B fci UQ H f i uQ UQ UQ ^ p. Pp . pP `-fui OOOO OOOO OOOO OOOO O O O O O O O O |--* O |--* OOOO h* A A N ;a Ht n j*J o en n o ra M nO o Zo j-3 U* eu in t-i ta f` t~i <5 za Cl io 11O--34 HI 2: s| S 111 .O-lirls/jl l5-i f* 'H O O O O 1-0 4> <o ou I-- I-- I-- '-> OOOO O Li PI O O O O ai o u i IO H U A O O t->O W U Oj H O O O I- O' A M4-N O O O O kMJI Ui H O O fr- 4 o h - io u 3 v0p pHn*trPui L__J L__ J i i ..........] , 1 'A3L 35 (Concinued) i -L53- TA31.3 35 (Continued) microscopic OBSERVATIONS ON FEMALE RATS .MAINTAINED OS OUT'3 CONTAINING 2 , i , 5 - T FOR tf? TO TVQ YEARS Diagnosis Coda Number of rails necroosied during the time oeriod indicated L-o Months 0 ag/kg/day 30 ng/kg/day 10 n g /k g /d a y 3 ag/kg/day 0 0 1 1 7-12 Months ? 2 2 i a- 70 3 i l a Ouccs and V a sc ular Channels S illa ry dyoeralasia - focal 0 mg/kg/day 30 tag/kg/day 10 a g /k g /d a y 3 mg/kg/day ' 00 00 00 00 a - 71 3-72 3iliar7 hyperplasia - multifocal 3iiiary cyst formation 0 ng/kg/day 30 a g /k g /d a y 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 a g /kg/da y 3 ag/kg/day 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 H-74 Pariooreal inflammation 0 ag/kg/day 30 a g /kg/da y 10 a g /kg/da y 3 ag/kg/day 0 0 0 0 0 0 0 0 3-75 Focal oerioortal fibrosis 0 ag/kg/day 30 a g /kg/da y 10 a g /k g /d a y 3 ag/kg/day 0 0 0 0 0 0 0 0 3-35 H-36 Fctasia of vascular channels Congestion of heoacic sinusoids 0 ag/kg/day 30 a g /kg/da y 10 a g/kg/da y 3 ag/kg/day 0 ag/kg/day 30 ag /k g /d a y 10 a g/kg/da y 3 ag/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 3-39 Perivasculitis - focal 0 ag/kg/day 30 ag /k g /d a y 10 ag /k g /d a v 3 ag/kg/day 00 0 J 3 0 0 0 H-91 Focal extram edullary hemacoooias i s 0 ag/kg/day 30 a g /kg/da y 10 tag/kg/day 3 ag/kg/day 0 0 0 0 0 0 0 0 2SSPI3AT0RY SYSTEM Trachea Number of t i s s u e s examined r- : o Focal tra c h e itis 0 ag/kg/day 30 a g /k g /d a y 10 a g /kg/da y 3 ag/kg/day 3 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 .eg/ kg/cay 0 0 L 0 n 3 0 n l 2 1 Q 0 1 13-13 Months 17 9 11 11 1 0 0 0 2 0 0 0 2 0 0 L 3 a I 0 2 0 2 0 i 0 1 1 0 1 0 0 0 0 0 0 6 5 3 7 17 7 Li 11 i j T 19-24 Months 31 13 25 13 Terminal Cumulative Xil 1 Results 36 36 21 50 U 50 19 50 1 3 10 13 4 20 2 ,0 ? 2 10 ? 01t 000 000 2 7 11 2 L3 i 22 020 0n 7 10 35 T_ 0 2 i02 213 011 00 i 012 5 9 13 155 325 3 5 10 a 00 022 00 20 i 2 0 0 02 i 0 000 000 15 13 35 12 3 20 105 1 29 1 13 31 35 36 13 22 50 25 i l 30 13 13 50 3 0 13 12r 51? Oaca l i s a sc ss number of r a t s for vh ich the l i s t e d t o s e r v a c i .on -as p r e s e n t . ai_C i c i s : : c a l l v c i i i a r e n c from c o n t r o l data vher. analyzed u s 2.ng Fisci s r 1s Txac t ? r o b a b i l i t y T est, ?<0 Q-bHl'l TABLE 35 (Continued) MICROSCOPIC OBSERVATION'S ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR LT? TO TWO FEARS Diagtios i s Coda Number o f r a t s cecroosied during the cine period indicated 1-6 Months 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g /d a y 3 ag/kg/day 0 0 1 1 R-23 R-24 3.-30 3-31 R-32 R-33 R.-34 R-35 R-36 Trachea (Conc'd) Focal e o ic h e lia l hyperplasia or crachea 0 ag/kg/day 30 a g /k g /d a y 10 a g / k g / d a y 3 ag/kg/day Diffuse e p ith e lia l hyperplasia of crachea 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Lur.g s Number of t i s s u e s examined 0 mg/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Focal peribronchiolar aggregates of 0 ag/kg/day lymphocytes 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Focal i n te r s t i ti a l inflaaaacion 0 ag/kg/day 30 a g /k g /d a y 10 a g / k g / d a y 3 ag/kg/day focal accumulation of inflammatory ceils in alveoli 0 ag/kg/day 30 a g /k g /d a y 10 a g / k g / d 3 y 3 ag/kg/day focal accumulation of alveolar nacroohages in a lv eo li 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 mg/kg/day Alveolar oroteinosis 0 mg/kg/day 30 m g/kg/day 10 a g /k g /d a y 3 mg/kg/day C holesterol c le f ts in lung 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Pulmonary edema, c o n g estio n , c a l ic ie r exudation, v ith or virhouc focal f ib r o s is secondary to heart fa ilu re , renal disease and/or vascular disease 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg;day 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 :0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 7-12 Months 2 2 2 1 0 0 0 0 0 0 0 0 2 2 2 1 7 0 1 1 0 0 1 0 0 0 0 0 2 0 0 0 0 0 0 1 0 0 0 0 0V 0 13-13 Months 17 9 11 11 1 0 0 0 0 1 0 0 17 9 il 21 15 8 11 10 6 5 2 4 0 1 0 0 9 7 5 5 0 l 2 0 3 A 1 0 0 0 19-24 Months 31 13 25 18 Terminal Cumulative R ill Results 36 36 21 50 11 50 19 50 001 000 000 000 000 001 000 000 31 36 36 13 21 50 25 11 50 13 19 50 0/ 30 70 16 20 41 13 9 39 12 15 33 i i 16 33 9 11 - 25 5 3 ila 4 3 lia 000 00 1 000 10 1 21 21 53 13 10 30 11 3 23 8 10 23 7 9 20 549 427 1 7 10 6 6 13 6 4 13 213 1 13 000 000 1 V 1 11 'ace 14a; ec a s aur.ber o: r a t s f o r which th e l i s t e c o b s e r v e s : on was pr a s e n c . iz z is z L c a l l ; - d i f f e r e n t frort c o n t r o l d a ta vhen a n a l y z e d u s i n g F i s h e r ' s I x a c t P r o b a b i l i t y T e s t , ?<3 35. ' j L ... 1 - -- ; j --J -160- TABLE 35 (Continued) microscopic OBSERVATIONS ON ;PENALI RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T TOR 0? TO TOO TEARS Diagnosis Cede Number oc r a t s necropsied during the cine period indicated 1-6 Months 0 mg/kg/day 30 a g / k g / d a y 10 m g/kg/day 3 ag/kg/day 0 0 2 1_ a - 3a 8.-39 R-40 S.-41 R- 4 2 R-43 a-Ai 3.-4 5 3.-43 ?.-4 9 3.;? Lungs (Coat'd) Pulmonary a te le c ta s is 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Alveolar niaeralizacion 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Focal pulmonary aggregates of hematogenous pigment 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Pocal alveolar hynarplasia 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Pulmonary edema 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 ag/kg/day Focal in te rs titia l fibrosis 0 mg/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Pocal granulomatous inflammation v ie d o r w ithout f o re ig n body present 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 mg/kg/day Focal pulmonary hemorrhage * 0 mg/kg/day 30 m g/kg/day 10 a g /k g / d a y 3 mg/kg/day Pocal hyperplasia of bronchiolar eoithelium ' 0 mg/kg/day 30 m g/kg/day 10 a g / k g / d a y 3 ag/kg/day Asolratad particulate natter 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day Pudrcnarv congestion 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 '3 3 0 7-12 Months 2 2 2 2 i 0 1 0 0 0 0 0 0 0 0 0 0 I 0 0 0 0 0 0 0 0 2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 o J 1 j 13-13 Months 17 9 11 11 0 0 0 0 2 0 0 0 0 0 0 0 2 L 0 0 0 0 0 0 0 0 I 0 0 2 0 0 0 0 1 0 0 2 0 0 0 1 3 0 3 0 0 0 19-24 Months 31 13 25 13 Terminal Cumulative K ill Resuits 36 36 2 i 50 2i 50 19 50 01 01 10 "0- 0 2 i 3l 001 0 1 0 0 0l 0 L4 000 000 2 0 2 000 34 9 5 1 21 20 7 224 0 0` 0 00 10 0 0 1. 000 0 2d d 2 4" 000 0 22 024 1 0 0 2 2-> 3I 4 123 002 000 000 007 207 000 020 00d n 0 0J 3 0 >J 0 c 003 0d -J Csce 2.i 5 t ed a s numoer o l p a t s c o r w hich -ns d i s c e d o b s e r v e d .on vas p r e s e n t . c a l l / d i f f e r e n t f r m c o n t r o l d a t a when a n a l y z e d u s i **5 * 1i e r ' s ELcact ? r obab i d i .ty C a s t , ?<0 .03. a i> 4 -1 6 1 TA3LZ 35 ( C o n tin u e d ) MICROSCOPIC OBSERVATIONS ON P 2 A L 2 RATS MAINTAINED ON D IIT S CONTAINING 2 , 4 , 5 - T FOR. C? TO W O TZARS 1-6 Months 7-12 Months Diagnosis Code Number o f r a t s necropsied during the tine oeriod indicated 0 ng/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ng/kg/day R-53 Lungs (Conc'd) Increased perivascular aggregates of lymphocytes 0 ag/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 01 1 * 0 0 0 0 2 2 2 1 0 0 0 0 R-54 Secretory m aterial in bronchus or bronchiole 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 ng/kg/day 0 0 0 0 0 0 0 0 R-59 Inflam m atory c a l l s w ith in lumen and/or around bronchiole(s) 0 mg/kg/day 30 n g / k g /d a y 10 n g / k g / d a y 3 ng/kg/day 0 0 0 0 0 0 0 0 P-60 Focal secretorv m aterial In alveoli 0 ng/kg/day 30 n g / k g / d a y 10 ng/kg/d'ay 3 ng/kg/day 0 0 0 0 0 0 1 0 3.-62 M ultifocal alveolar hyperplasia 0 ng/kg/day 30 n g /k g /d a y 10 n g / k g / d a y 3 ng/kg/day 0 0 0 0 0 0 0 0 3.-64 C e llu la r e x foL iation secindary to renal failure or heart failure 0 ag/kg/day 30 a g / k g / d a y 10 n g / k g /d a y 3 ng/kg/day 0 0 0 0 0 0 0 0 13-18 Months 17 9 11 11 . 0 0 0 1 0 1 ? 0 02 1 0 0 2 ]_ 0 0 0 0 0 0 0 G 0 19-24 Months 31 18 25 13 T erm inal Cumula ci</e R ill R esu lts 36 36 21 50 11 50 19 50 112 033 000 001 134 124 103 10 1 101 204 012 000 0c 0 ? 0 l3 002 202 0 0, 0 000 0l 0 0 0 1 000 000 1l 0 0 i 1 C-01 C-02 -.-05 CARDIOVASCULAR SYSTEM Heart Number o f t i s s u e s examined Focal m vocardial d e g en e ratio n and inflammation with or without f ibrosis - slight Focal m yocardial degeneration and inflammation with or without fibrosis - noderace A trial thrombosis 0 ng/kg/day 30 n g /k g /d a y 10 n g /k g /d a y 3 ng/kg/day 0 ng/kg/day 30 n g /k g /d a y 10 m g/k g /d ay 3 mg/kg/day 0 mg/kg/day 30' n g /k g /d a y 10 a g / k g / d a y 3 ng/kg/day 0 ag/kg/tay 50 n g / k g / d a y 10 a g / k g / t a y 3 ag/kg/tay 0 0 1 1 0 0 0 0 0 0 0 0 0 0 .3 3 ? 17 31 36 2 9 18 21 2 11 ' 25' 11 1 11 18 19 0 9 3 17 0 1 5 13 0 2 10 6 0 4 9 13 00? 1 0o 0 0 0 3 0 1 1 0 01. rh 0C On Q o 0 2 J 3 w i. JS.Z3. l i s t ed as number o f r a t s f o r which th e l i s t a d o b s e r v a t i on vs.s or e s s e : . a_5 ca c i s : : c a l l / d i f f e r e n t from c o n t r o l d a t a when a n a l y z e d use ng F i s h e r ' s e x ac t P r o b a b i l i t y T e s t , ?<Q . 0 5 . 36 50 50 50 31 19 13 26 3 0 2 2 0 o - .j J ; - --J ..... i ; -- 5UWi'7 -152- TABLE 35 (Continued) MICROSCOPIC OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,i,5-T FOR CEP TO TVO TEARS Diagnosis Coda Number o r r a c s aecroosiad during she cine period indicacad 1-6 Months 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 7-12 Months 2 2 i 13-13 Months 17 9 11 H 19-24 Months 31 13 25 13 Terminal Cumulative K ill Results 35 36 2 i 50 i i 50 19 50 Heart (Coat'd) C-06 Subendocardial fib r o e la s to s is of 0 mg/kg/day 0 0 0 0 0 myocardium 30 m g/kg/day 0 0 0 1 0 10 m g/kg/day 0 0 0 0 0 3 mg/kg/day 0 0 1 2 0 C-IO C-L2 C-20 C-21 C-24 Focal myocarditis 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 V entricular thrombosis 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 Aorta and/or Larsa Ancarlor Mediasc in e i A rtarv (ie s) Number o f t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 1 0 Focal mural m ineralization 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 Focal chickening of endochelial lin in g 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 Aortic plaque formation 0 mg/kg/day 30 m g /k g /d a y 10 m g /kg/da y 3 mg/kg/day 0 0 0 0 0 0 0 0 0l 0 0 0000 0000 0000 0000 0000 0010 1 15 30 36 2 7 16 21 2 10 23 i i 1 11 16 19 000 2 0 00 3 00 20 0222 0 32 7 0 13 7 0 15 0 122 0 10 0 00 00 00 00 00 00 31ood V assals C-30 Degeneration of myocardial blood 0 mg/kg/day 0 0 9 10 13 vessels 30 m g/kg/day 0 10 7 5 10 m g/kg/day 0 1 5 3 3 mg/kg/day 0 0 4 5 6 C-31 M in eralizatio n of m yocardial blood 0 mg/kg/day 0 0 2 i. 0 vessels 30 m g /k g /d a y 0 00 0 0 10 m g /k g /d a y 0 0 0 0 0 3 mg/kg/day 0 0 0 0 1 C-32 ? e r i a r r a r i t i s and s c l e r o s i s oc nese n ta ric and/or other blood 0 mg/kg/day 30 m g/kg/da y 0 0 0 0 0 0 0 0 4 - vessels - very slig h t 10 " y/ji1? / 3 v o 3 .3 2 1 3 mg/kg/day 0 -0 r>.r3 ' ' S ' ad as number o : r a t s t o r v h i c h th e l i .seed o b s e r v e d .or vas p r e s e n t . 'Statistically different from control data vn.dr. enaiyred using Eisner's 3:'.sc: Probability Test, p<0.C5. 0 1 0 3a 0 1 0 0 0 0 0 1 33 16 47 17 2 3 2 b 12 11 7 5 2 0 0 0 32 13 13 15 2 0 0 1 4 i3 163 TABLE 35 ( C o n t i n u e d ) M I C R O S C O P I C OBSERVATIONS ON RATS MAINTAINED ON DIETS CONTAINING 2,4,5-7 FOR OP TO TN0 TEARS Diagnosis Coda .Vuaber of rat3 necroosied during che cine oeriod indicated 1-6 Monchs 3 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day 0 U i i C-33 C-34 C-35 C-36 -37 ?-0i ?-02 ?-03 3iood Vessels (Conc'd) Periartericis and sclerosis of nesenceric and/or ocher blood vessels - slighc 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Periartericis and sclerosis of nesenceric and/or ocher blood vessels - moderate 0 ag/kg/day 30 mg/kg/day 10 ag/kg/day 3 ag/kg/day Periarteritis and sclerosis of mesenteric and/or other blood vassals - oronouncad 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day thrombosis secondary to oariarze cis and sclerosis 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Mineralization of vascular channels - isoiaced or focal 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day PANCREAS Number of tissues examined 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Acinar Focal aoroohy or pancreatic acir.ar tissue 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Focal fibrosis of acroohic pancreacic acinar tissue 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Focal inflanmation of oancraas 0 ag/kg/day 30' ag/kg/day 10 ag/kg/dav 3 ag/kg/day Hyperplastic focus (foci), noduie(s) of oancraatic acini 0 ag/kg/day 30 ag/kg/day 10ag/kg/cay 3 ag/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 9 9 2 i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 9 0 0. 1 0 0 0 0 0 0 0 0 0 0 0 0 0 13-13 Months 17 9 11 11 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 17 9 11 11 1 u 0 0 0 0 0 0 o 0 0 0 0 0 59-24 Months 31 13 25 13 Iarainal Cuaulacive Till Results 36 36 21 50 11 50 19 50 1 35 0 44 1 01 \ 01 0 11 0 00 000 000 0 00 000 0 00 0 1I 00 0 000 00 0 0l l 000 0 00 0 00 112 31 36 36 17 T 1 49 25 11 50 IS 19 50 6 15 IS 4 3 13 3 7 12 4 7 15 044 0 1_ i 0 00 i0 1 1 l9 000 000 0 00 l0 T_ 0 0 <j 000 "1 0 ja z z 1is-;ad as r.urosr sf rats for vhich the Lis tec observed zn vas p r e s e n t. SZ2 . Z S d call'-' dffersrz from control data vhen analyzed usi 5 . i.3- er !s Exact ?rooeb ili t> _as t, "d0 Lz . i 1 i i ; J n -J j -1 t -- ": - adwt1? -1 6 4 TA3L2 35 (C o n c in u e d ) MICROSCOPIC OBS ERVATIOMS 0M TEMALE RAIS MAI2T.-.IMEO ON DIETS CONTAIMIMG 2,4.5-X POR U? TO T/O IE.a s Diagnosis Code Munbar or rats necroosiad during the tine oariod *'-*r. 'r*apH 1-6 Monchs 0 mg/kg /'day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day 0 0 L 1 7-12 Monchs 2 2 2 1 13-13 Monchs 17 9 IX 11 19-34 Monchs 31 13 25 13 Terminal Cumulative Hull Resulcs 36 36 21 50 u 50 19 50 ?-!0 P-13 ?-20 ?-2i ?-25 U--31 3-02 0-03 :J-0i .Acinar (Conc'd) Paucraacic acinar adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Vacuole fornacion in acinar cisaue 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Is lacs or Langerhar.s Enlarged oancreacic islec 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreatic islet rail adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreacic islec call adenocar- -cinema - 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day iRIMAEE 3ESTEM Xidnev Humber oc tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 zg/kg/day Dilated renal tubules with eosinoohilic case formation - slight 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Diiaced renal" cubules vied eosinoohilic case formacion - noderace 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Dilated renal tubules - rrenounced 0 mg/kg/day 30 -zg/kg/day 10 mg/kg/day 3 mg/kg/day :ocal etroohv or renal tubules 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 ng/ks/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 3 0 1 0 0 0 0 0 0 3 3 \J J 0 1 00000 00000 00 10 1 00000 0 1 2 10 13 000 77 0 0 2 0 2a 01 57 00n ix 300 ix 0010 3 00X l 2 01163 00 1 12 002x3 00i0 1 00000 000 11 00000 03000 2 1.7 31 36 36 2 9 13 21 50 2 11 25 11 50 - L- 13 19 50 1. 4 9 4 13 0 5 7 5 17 2 6 7 2 17 0 7 7 2 17 00 10 0 0 1 0 u 00033 0010 " 00 31 000J3 00300 0 0 0 nJ 0 039 35 277 0- - 3 - 16 --1 2 i Saca .iscad as number :: raes for vhimh cha llscac observacin vas oresanc. a5caciscically diffarar.c from moncrol daca vhen snalyrec using reader's I:cscr Probabi-icy Tase, TA3LS 35 ( C o n tin u e d ) i MICROSCOPIC OBSERVATIONS ON FEMALE EATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T EOS. 0 ? TO TWO TEARS 1-6 Months Diagnosis Coda Number of rats r.ecropsiad during che time period indicacad Sidney (Cont'd) U-05 Focal glomerular adhesions ^ 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 1 0 mg'/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 'J-06 U-0 7' Focal interstitial fibrosis Focal interstitial aggragacas of lymphoid calls 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 -.-.0 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 Q 17-08. Mineralized deposits in renal parenchyma - 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 09 Mineralized denosits in ranal pelvis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 U-l-I Cyst formation in Sidney not due to 0 mg/kg/day chronic neohrooachv 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 Ur 12 . Inflamnacior* of ranal oelvis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 C-I3 Progressiva chronic nephrooathy very slight 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 U-rl4 Progressiva chronic nephropathy slight 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 V- 13 Prosressive chronic neohrooachv moderate 0 mg/kg/day 30 mg/kg/cav 10 mg/kg/day 3 mg/kg/day 0 0 0 Q ^ Progressiva chronic nerhromazhy _ O " o ' V j / m s v 0 crenounced 30 mg/kg/day n 10 mg/kg/day 0 c mg,- ::g/cay 'J 7-12 Moachs 2 2 2 j. 13-13 Months 17 9 11 11 0 0 0 0 1 1 1 2 00 00 12 o0 01 02 15 04 04 02 00 02 2 1 -1 1 0 0 0 0 4 3 7 '' 4 1 0 1 1 00 00 0c 00 06 0 2 02 03 02 00 00 00 02 00 00 00 o 0 3 2 0 0 - 19-24 Months 31 13 25 13 6 5 3 3 3 1 0 1 3 3 4 2 7 1 6 3 16 11 11 9 1 1 0 1 '1 2 0 0 13 6 3 6 4 0 2 1 3 0 3 2 1 L 4 ~ Terminal Cumulative Cili P.esulcs 36 36 21 50 u 50 19 50 1 2 1 1 2 2 0 0 1' 3 0 1 10 3 2 7 22 17 7 7 3 0 0 1 0 0 0 2 16 10 7 9 10 4 i 4 6 0 1 2 0 1 - 3 8 5 6 5 3 3 1 5 8 ioa 7 21 6 3 12 44 OH 26 21 5 i 1 3 1 2 0 2 35 is 17 IS 16 1 33 5 11 0* - 3 2 4 - 3a:a list ad =s number of race for vhich che listed obsarvatc.or. vas or as ant. a, ..cally different from control data vhen analyzed us:.r.g Fisher 1s ;,;-;acz Probability Test, p O .05. _ --: 1 ~] -- --1 i -- 160- TABLE 35 ( C o n c in u a d ) MICROSCOPIC OBSERVATIONS ON ISOLALE RATS MAINTAINED ON D IETS CONTAINING 2 , 4 , 5 - T FOR T? TO TVO TEARS --4 Ii-- |o Diagnosis Coda Number at raes necroosiad during cha time period indicar ad 1-6 Mnchs 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 ag/kg/day 0 0 1 1 0-17 0-18 0-19 0-20 U-22 0-23 U-24 0-25 U- 25 j_27 " -? 9 Kidnav (Cont'd) Conges cion of kidney 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day' 3 ag/kg/4ay Focal tubular hyperplasia 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Dilacad ranal oaivis 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Focal cibrocic area In correx or oelvis 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Increased hematogenous pigment associated wich chronic canal disaase 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Nodular oroliferation of renal oelvis eoichelium 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Focal hyoerplasia o: ranal pelvis aDithelium 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 ag/kg/day Hulcifocai suoouracive nephricis, hyperplasia of renal oelvis apichelium, with inf lamination and a fibrocic area in renal pelvis 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Focal ourulanc naohritis noe associaced wich neohrooachv 0 mg/kg/dav 30 ag/kg/day 10 ag/kg/day 3 ng/kg/day Fosinophilic nacerla! vichin eoicheiium of renal cu bules 0 ag/kg/day 30 mg/kg/day 10 mg/kg/day o mg/ jcg/cay Anomalous focus cf columnar mucosa 1 0 mg/kg/day eoicheiiun in corcex of icr.ev 30 .mg/ kg/ day 10 mg/kg/day 3 ag/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 fl 0 0 0 0 0 0 0 0 0 0 0 o 0 0 0 J Mnchs } 2 2 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Q J 0 0 13-18 Months 17 9 u 21 0 1 0 0 0 0 0 0 1 l 1 0 0 0 0 0 0 0 0 2 5 6 4 o 0 3 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 29-2 i Mnchs 31 18 25 13 Terminal Cumulariva Kill Results 36 36 21 50 il 50 19 50 0 0 0. 0 0 0 0 0 2 0 2 0 0 1 0 0 0 1 1 0 10 o 3 5 2 i 1 0 0 0 0 0 0 0 0 n 0 0 ;-l L 0 A J 0 0 0 0 0 2 0 0 2 0 0 2 0 0 0 0 0 0 0 0 0 14 18 7 7 i 0 0 2 0 0 0 1 1 0 0 0 0 0 0 0 0 0 J 0 1 1 0 2 0 0 1 3 J. 4 1 0 2 0 0 0 1 2 0 25 J/ 22 19 .L 4 3 0 0 0 1 1 0 fl 0 0 J U 0 -- C a i a . I s C ad as number of raes for which che 1isced osservai .on vas presene. cecia cirally different frota concroi caca when analysed us _ng 7usr er 1s Fxac c. Probabili:;/ Tesi, p<0 .05. 9-$) L/<?'c -1 0 7 TAB L 2 35 ( C o n t i n u e d ) MICROSCOPIC OBSERVATIONS ON 7EMAI.Z EATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - t EOS 0 ? 10 TWO TEARS >1under or rare necropsied during che cime period indioaced 1-6 Moncha Q mg/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Q 0 1 1 C-30 Kidney (Conn'd) Diffusa suppurative nephritis with necrosis and congestion in one kidney 0 ag/kg/day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day U-- 31 Increased vacuolizacion of tubular epithelium 0 ag/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day li-32. and Epithelial hyperplasia of renal II-34 pelvis secondary co urolichiasis 0 mg/kg/day 30 ag/kg/day 10 mg/kg/day 3 mg/kg/day -33 Perirenal inf lasmacion 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 ag/kg/day 35 Area of lipomacosis, fibrosis 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day U-36 Increased pigment within renal tubular cytooiasa 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day U-57 Renal hemangioma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Urosenical Trace Urinary 31add-sr Nuaoer of cissues exaained ' 0 ag/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day I-70 Diffuse urocyscicis 0 ag/kg/day 30 ag/kg/day 10 mg/kg/day 3 ag/kg/day **-71 Focal urocyscicis 0 ag/kg/day 30 ng/kg/dav 1C mg/kz/day 3 mg/kg/day 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 T_ 0 0 0 0 0 0 `j 7-12 Moh chs T 2 2 I 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o. 0 0 0 0 0 2 2 2 1 0 0 0 0 0 0 0 0 13-13 Moncha 17 9 11 n 0 0 0 0 0 0 0 0 0 1 1 0 i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 17 9 10 10 0 0 0 0 0 2 aJ 0 19-2 4 Months 31 13 25 18 Terminal Cumula z .sill Rasul 3o 36 21 50 ii 50 19 50 00 0 00 0 00 1 00 0 00 0 00 0 00 1 10 1 00 0 012 00 1 0l i 00 00 0 000 00 0 10 1 00 0 000 000 00 0 i 10 IIa 000 000 000 10 1 00 0 00 0 30 32 31 17 21 49 24 10 47 13 17 47 0 o' 0 ll2 0 Q AV 0 ? O 00 0 00 j 0 AJ 0 0 laca listed as number o: rats far which the 1is red observacin --S3 presen:. Sea cii cica.11'/ oiffarani from oor.rrol iaca vh en analyzed using ;LS'r.er's T:>:acr Prooaoil.icy Teso, ?<C..35 . 1 ! --) -- -- -- --' Q,ibH^3 -1 5 3 TA3LE 35 ( C o n tin u e d ) MICROSCOPIC OBSERVATIONS ON FEMALE SAT5 MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOE -J? TO TWO TEARS Diagnosis Coda Number of rats aacropsied during the cine period, indicated l-o Months 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day 0 0 L 7-12 Months 2 T I I3-L3 Months 17 9 11 19-24 Months 31 13 25 13 Terminai Cumulative Kill Rasults 36 3o 21 50 11 50 19 50 U-72 Urinary Sladdar (Cont'd) Focal hyperplasia of urinary biad- 0 ag/kg/day der mucosa o 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day u-73 Diffusa hyperplasia of urinary bladder mucosa 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day C-82 Diffuse epithelial hyperplasia of urinary bladder secondary to urolithiasis 0 mg/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day REPRODUCTIVE SYSTEM Ovarv Number or cissues examined 0 ag/kg/dav 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day X-50 X-51 Eluid-fiiiad ovarian cysc > Atrophy of ovary 0 ag/kg/day 30 ag/kg/dav 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day X-52 pocai inflaamacion. of ovary 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day X-53 Increased hemaccgenous pigmenc in ovary 0 ag/kg/day 30 ag/kg/day 10 ag/ka/day 3 ag/kg/day X-54 Focal fibrosis in ovary 0 mg/kg/day 30 ag/kg/dav 10 ag/kg/day 3 ag/kg/day 55 P.eirarocvsu in ovary k - 56 : ibrosis or ovicucrs 0 ag/kg/day 30 ag/kg/dav 10 ng/kg/cay 3 ng/Cg/nay 0 rr.g/.*;g;cay 30 ag/ka/day 0 mg/kg/dav 3 ag/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o IJ J 0 000 1 1 00000 00000 00 0 1 1 0. 0 0 1 1 00 10 1 00 10 1 000 2 2 00000 010 12 00000 00000 2 13 29 33 77 2 9 .17 20 43 2 3 20 11 42 1 3 17 15 42 0 3 4 14 21 005 9 14 025 2Q 0 1i 5 005 30 005 i 7 00 12 0030 3 000 1i 00000 0 o- 0 0 0. 0000a 00000 00 000 00011 00000 00000 0010 1 q 0000 00Q 00 00 0 J 0 n 1 1 03 13 1 0 0 J 0 0; 3 11 0 3 0 0 J 0a 33 0 00- 3a cs u.S - h e l i s t e d ^ o s e r v a n o n - a s o r s s e r . r . -1 6 9 TA3L2 35 (Cancinued) MICROSCOPIC OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR U? TO W O ''EARS l-o Months 7-12 Monchs 13-13 Months Diagnosis Coda Number of rats necropsied during che cime period indicated 0 mg/kg/day 30 ag/kg/day iO mg/kg/day 3 ag/kg/day 0 0 1 1 2 17 29 2 11 L l1 X-57 Ovary (Cont'd) Cyscic diiacacion of oviduct 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day 0 0 0 0 0 0 a. ,, 0 .0 0 0 0 :<-58 Diffuse purulenc and granuloma cous 0 ag/kg/day 0 0 0 inflammation 3Q ag/kg/day 0 0 0 10 ag/kg/day .0 0 0 3 mg/kg/day 0 0 0 X-59 tnilanmacory adhesions 0 mg/kg/day 0 0 0 30 mg/kg/day 0 0 0 10 mg/kg/day 0 0 0 3 mg/kg/day 0 0 0 X-60 hyperplasia of incerscicial cells 0 mg/kg/day 30 ag/kg/day 10 mg/kg/day 3 mg/kg/day 0 0. 0 0 0 0 0 0 0 0 0 0 67 Granulosal cell neoolasm of ovary 0 ag/kg/dav 0 0 0 30 mg/kg/day 0 0 0 10 mg/kg/day 0 0 0 3 mg/kg/day 0 0 0 X-70 X-72 X-74 Uterus Number of uterine tissues examined 0 ag/kg/day 30 mg/kg/day 10 cg/ks/dav 3 ag/kg/day Area(s) of cyscic endometrial hvoerriasia 0 ag/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day Sauamous cnecaolasia vich or vichouc 0 ag/kg/day karatinizacion of endometrium 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day Uterine inflammation 0 ag/kg/day 30 ag/kg/dav 10 ag/kg/day 3 mg/kg/day 0 0 1 1 0 0 .0 0 0 0 0 0 0 0 0 0 -> 2 t_ 0 AJ 0 .0 0 0 1 0 0 0 ri 0 17 9 11 11 7 5 3 3 4 i 3 1 l l 0 0 X-75 'C- 7~ hvdrometra of uterus 0 mg/kg/day 30 ag/kg/day 10 mg/kg/dav 3 mg/kg/day a ocro-T.ai :o;v2 rorr.acion in ucerus C mg/kg/day 30 mg/kg/day 10 ns/kz/dev 3 mg/kg/day 0 0 0 'J> 0 3 01 00 00 r> 0 0 1/1 j 1/1 1/ 1 2/1 00 19-24 Months 31 13 25 18 Iermina1 Cumulative Sill Results 36 36 21 50 11 50 19 50 01 00 00 0 '0 00 00 10 00 10 00 00 00 20 00 20 00 04 00 10 01 1 0 0 0 0 0 1 0 1 0 0 0 2 0 1 0 i 0 1 1 31 36 36 17 21 49 24 11 49 13 19 50 9 16 32 5 10 20 n 5' 10 5 5 13 2 ? 3 23 5 i2 7 ?i 0i2 00 1 303 000 00 1 00 0 000 03 3 3/3 13/13 i-/ 1- 3/3 '37 11 ' 11 5/4 3/3 11; ? 1 ' 1 OA,/' A-v ->' - Data lisa ed 3 r.ucioer o: racs for vhich ;he iisted observt!on vas preser.c. "Daza iis r=d as rccai nunber of "his cype r.eopLasn/r.unber z z rats beari ng this z y p e r.ecplaser. 170- TABL 35 ( C o n t i n u e d ) MICROSCOPIC OBSERVATIONS ON 7RMAL RAIS MAINTAINED ON DIRTS CONTAINING. 2,4,i-T 70S. 0? TO TWO TSARS Diagnosis Code Number o f ra c e necropsied during the cime period indioaced 1-6 Months 0 ag/kg/day 30 a g / k g / d a y 10 m g/kg/day 3 mg/kg/day 0 0 1 1 7-12 Months 2 2 2 1 x-ai X-35 X-37 X-93 X-95 X-96 X-97 X-98 X-99 . X-IOO V_ : r' ~ Uterus (Conc'd) Number o f v a g i n a l " i s s u e s examined 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 M alignant schwannoma of th e vagina 0 a g /k g /d a y 0 30 a g /k g /d a y 0 . ... . ___ . 10 m g /k g / d a y - ... 0 3 ag/kg/day 0 M alignant schwannoma or uearns with m etastasis 0 ag/kg/day 30 a g /k g / d a y 10 a g / k g / d a y 3 ag/kg/day 0 0 0 0 Adenocarcinoma of uterus without m etastasis G mg/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day 0 0 0 0 Area(s) of endometrial hyperplasia 0 ag/kg/day 30 m g /k g /d a y 10 a g / k g / d a y 3 ag/kg/day 0 0 0 0 large evst formation in uterus 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g /d a y 3 ag/kg/day 0 0 0 0 Myosarcoma of uterus 0 mz/kz/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day 0 0 0 0 Schwannoma of u t e r u s 0 ag/ks/dav 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 0 0 0 Leiomyosarcoma of u teru s with m e ta s ta s is to lytaoh node 0 ag/kg/day 30 a g / k g / d a y 10 m g/kg/day 3 ag/kg/day 0 0 0 0 Fibroma of uterus 0 ag/kg/day 30 a g /k g /d a y LC a g / k g / d a y 3 ag/kg/day 0 0 0 0 Ti 2 ^ r a "7' 2, 3 ag/kg/day 30 a g / k g / d a y 10 n s / k s / d a v 3 ag/kg/day 0 0 0 0 S c u e rc s ns or u t e r i n e v e s s e l s 0 ag/kg/day 30 m g/kg/day 10 m g /k g /d a v 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 o 0 0 J J 0 0 0 Daca l i s t ac a s number oz r a t s f o r which t h e 1i s t e d o b s e r v e r ; .on was pr e s e n - t . 13-13 Months 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 l 1 0 0 0 0 0 0 0 I 0 0 0 0 1 0 0 0 0 0 0 0 3 0 J 0 T ] 0 0 .l J l9-2i Months 31 13 25 13 Terminal Cumulative Jesuits 36 36 21 50 i i 50 19 50 0i 1 0i 1 0 0 o 000 000 0 11 000 000 10 1 000 000 000 13i 000 011 000 3 3 14 214 513 325 J 4 6 2 0 /. 1 0 2 1 l 000 00 00i 000 000 000 01 001 000 000 101 000 000 o 0l 0 0 "3 0'J ' - 0 L- 30 J 3 003 30 J 100 0 24 ^3-6 171- TAB L2 35 (Concinued) MICROSCOPIC OBSERVATION'S ON FEHAL RATS MAINTAINED ON DIETS CONTAINING 2,4',5-T FOR UP TO TWO YEARS Diagnosis Coda Camber o f r a e s necropsiad during she cine period ir.dicaced 1-6 Nonens 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 M--01 M-04 M--05 G-07 G--10 - Lj MUSCULOSKELETAL SYSTEM Number o f e i s s u e s examined 0 mg/kg/day 30- m g /k g /d a y 10 m g/kg/day 3 mg/kg/day Focal degeneracin and inflammacion 0 mg/kg/day of ak alecal muscle 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day M ulcifocal degeneracin, inflammacion, wish or vichout atrophy of skelacal muscle 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day Rhabdomyosarcoma surrounding v e rte b ra i column vich m e ta sta s is to lungs and subcutaneous tis su e s < 0 mg/kg/cay 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day GASTROINTESTINAL SYSTEM Oral Cavicy Number o f gingival tissues examined 0 mz/kz/dav 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Fibroma of gingiva 0 mg/kg/day 3.0 m g /k g /d a y 10 m g/k g /d a y 3 mg/kg/day Tonsue Number o f c i s s u e s ' exam ined 0 mz/kz/dav 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day v a s c u litis and vascu lar degeneracion 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Inflammation and/or hyperplasia of submucosal glands 0 mg/kg/day 30 m g/kg/day 10 m g /k z /d a y 3 mg/kg/day D e g e n e ra tio n and infla m m atio n of muscles 1 mg/kg/cay 30 reg/k g/dav 1C t i g / k g / d a y 3 ng/ks/fay 0 0 1 1 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0."JV 0 0 o c J 7-12 Monchs 2 22 i l2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 3 0 J 13-13 Months 17 9 11 11 17 9 . 11 11 3 1 2 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 17 9 11 11 2 0 0 0 12 7 4 4 3 Q 0 - 19-24 Monchs 31 IS 25 13 31 15 24 is 4 1 9 3 0 1 0 0 0 0 0. 0 T e r m i n a l Cumula :iv K ill Resul C5 36 36 21 50 11 50 19 50 ' 36 86 21 46 10 48 18 48 16 23 57 2 1369 00 02 00 00 00 01 00 00 000 0 11 000 000 000 0 0 0 1 0 0 1 00 30 35 33 13 21 49 25 IT 43 IS 19 43 158 022 1 0 0l 1 1 23 21 513 10 30 7 7 13 6 10 3' 0 00 00J J Caca l i s t e d as number of r a t s for vh ich the l i seed o b s rv a te on vas or a s e n t . __, ; \ j -j --i --\ j -172TASLE 35 (Continued) MICROSCOPIC 08SSR7AXIOMS ON ? 2 i A U SAXS MAIMXAISZD ON DIETS CONTAINING 2,i,5-T tCR if? TO TVC 'fEAHS Diagnosis Code Number of r a t s nacroosiad during th e cime period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 7-12 Months 2 2 2 1 G-15 G-20 G-13 G-46 G-47 C--13 G-49 G-50 C--51 2-52 Tongue (Gonc'd) Squamous m ec ap la sia o f congue 0 mg/kg/day 30 m g/kg/day 10 m g/k g /d a y 3 mg/kg/day 0 0 0* 0 'o c ra c ifia d squamous c a l l carcinoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Adenoma o f congue glandular comooneacs of 0 mg/kg/day 30 m g/kg/da y 10 m g/kg/day -0 mg/kg/day 0 0 0 0 3 comach Number o f c i s s u e s e x a a in e d 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 D ilatation of gascric pics 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Mir.eraiizacion of gascric nuscul a r i s and/or g a sc ric mucosa Submucosal edema of s comach 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 Eyoerolasia of nonglandular mucosal eoitheiium 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 coca! area of inflammation of scomach v a il 0 mg/kg/day 30 m g/kg/day 10 m g/kg/da y 3 mg/kg/day 0' 0 0 0 nyoerkeracosis of nonglandular mucosa of scomach 0 mg/kg/day 30 m g/kg/day 10 m g/kg/da y 3 mg/kg/day 0 0 0 0 7oc.il erosion of g a sc ric mucosa 0 mg/kg/day 30 m g /k g /d a y 10 ma/ka/cav 3 mg/ kg/ day c J 3 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 13-13 Monchs 17 9 11 11 5 2 2 1 0 0 0 0 0 0 0 0 17 9 11 11 5 2 3 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 J 0 0 0 3 19-24 Monchs 31 13 25 13 Terminal Cumulative K ill R esu lts 36 36 21 50 11 50 19 30 45 52 3 1 02 00 10 00 00 10 00 00 00 14 9 6 3 0 1 0 9 1. 0 0 0 31 36 . 36 IS 21 50 25 11 50 17 19 49 3 9 17 5 9 16 4 1. 3 359 07 0 0 <3 000 22 1 000 0 11 000 000 T_ 1 lr i0 00 3 2 2 0 225 i 01 000 000 001 00 0 J 0 n r\ 3 2 I l -- 90 023 Data Disc ed as nuncer of racs for .'h.ich che 1:Lscec o b s e r v e d .or. vas prasenc. -173- TABLE 35 (Continued) MICROSCOPIC OBSERVATION'S ON FEMALE RAIS MAINT.AIMED ON DIE'IS CONTAINING 2 , 4 , 5 - T FOR L'p 10 TWO TEARS Diagnosis Code Number o f r a c e necropsiad during che cin e pe rio d indicated 1-0 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day nU 0 1 1 7- ? Months 2 2 21 G-55 C-57 G-59 G-7L C--7'- G-76 G-77 G-79 C -32 C--S3 . Stomach (Conc'd) Keratinized cysc formation - wall of stomach Squamous poly?- of stomach mucosa S t r a t i f i e d squamous papillom a of g a s t r i c mucosa Small In te s tin e Number o f t i s s u e s exam ined Pocal ulceration and/or ir.rlaimacion of small in te stin e R e a c t i v e Lvmiohoid h y p e r p l a s i a of smali in te s tin e Mucocyscadenocarcinoma of small Intestine Adenocarcinoma of sm all i n te s t i n e Lymphosarcoma of sm all i n t e s t i n e Diffuse inflammation of small intes tine r ^ e r s t s t t n g y ^ 3 o i ' / e r t t w U ^ **-- 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day C mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 ms/ks/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 ms/kz/cav 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 n e /k g /c a y 3 mg/kg/day 0 .mg/kg/day 30 n s / k g / d a y 10 rag/kg/day 3 mg/kg/day 0 n s/,< g /cay j-o _ g / -eg; c a y 1 j n g / .<2 / c a y 3 .tg; .<5/ cay 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .*j> J 2 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 j j Da t a S C 3 ^ =3 -a-3 l i s t e d o b s e r v t ! on vas p r e s e n t . 13-13 Months 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 17 9 11 11 0 0 0 0 0 0 0 0 0 0 Q 0 0 0 0 0 0 0 0 0 0 0 r, 0 0 r\ 19-24 Months 31 13 25 18 Xer a i n a 1 C u m u la tiv e R ill Results 36 3o 21 50 11 50 19 50 011 000 000 000 000 000 000 10 1 123 000 000 000 29 36 84 18 21 50 25 11 50 IS IS 50 000 000 10 2 001 0 11 2 s -> 0 1 347 000 10 1 00 0 000 000 000 000 011 0 0 0 1 01 000 000 0 2 -) 00 0 011 2 00 0 3J -J J0 3 MH-Xe! TABLE 35 (Continued) MICROSCOPIC OBSERVATIONS ON FEMALE PuiXS MAINT.AiNED ON 3 ISIIS CONTAINING 2 , i , 5 - T FOR it? TO TWO fZ.AAS Diagnosis Coda Number oc r a c s necroosiad during the time parted indicated 1-6 Months 0 mg/kg/day 30 n g / k g / d a y 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 G-34 G-35 G-36 C--90 G-92 C--93 G-95 s-o: Small In ta s tin a (Cant'd) Leiomyoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Leiomyosarcoma 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 Focal mucosal hyperplasia 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 G Lar?e In testin e Number o f t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 1 Ir.cascinai neaatodiasis 0 ag/kg/dav 30 m g/kg/da y 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 - o c a l i n f l a m m a t i o n o r Large intestine 0 mg/kg/day 30 a g / k g / d a v 10 a g / k g / d a v 3 mg/kg/day 0 0 0 0 Edema a n d / o r i n f l a a n a t i o n o f v a l j L or la r g e in c a s c in a an d /o r cecum 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 R aactiva lymphoid hyperplasia or large intastine 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 SUBCUTANEOUS TISSU IS. INTEGUMENT , ACfD MA-OtART GuAND Subcutaneous (nor.cumcrcua) Number o f in c e g u a e n t a r v t i s s u e s examined 0 mg/kg/day 30 m a / k g / d a y 10 n s / l c s / d a v 3 mg/kg/day 0 a 0 0 5uocucar.ecus aoseass 0 ng/kg/dav 30 r.g / k a /d a v 10 r.g/ k g / d a y j , j g / .^5 / --a . 0 0 0 0 7-: o Months 2 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 2 2 ? 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 13-13 Months 17 9 2i 17 0 0 0 0 0 Q 0 0 0 0 0 0 16 9 11 11 i -l 2 2 0 0 0 1 0 0 0 0 0 1 1 3 8 6 7 L0 1 Q 2 -0 -9-24 Months 31 18 25 13 Terminal Cumulative K ill Results 36 36 2 i 50 11 50 19 50 0 0. 1 0 0 0 0 0 0 0 0 0 31 16 25 13 1 0, 1 1 0 0 0 .0 0 0 0 0 1 1 0 0 0 0 0 0 1 0 0 0 0 1 0 0 36 2i 11 19 4 1 1 0 0 0 0 0 1 0 0 0 3 3 2 2 0 0 1 0 1 0 0 0 0 1 0 0 85 43 50 50 12 4 3 0 0 0 1 1 0 0 0 4 5 2 5 27 36 t n 16 2- 43 25 11 O 13 19 10 1 030 11 0 0- Tate l i s t e d as r.'jsbe: of ra ts for hich the l is te d re se rv a tio n vas r e s e n t . -175- TA3LE 35 (Concinued) MICROSCOPIC OBSERVATIONS OS FEMALE RATS MAINTAINED OS DIETS CONTAINING 2,4,5-T FOR uP TO TWO TEARS Diagnosis Coda Number of r a e s necropsie! during che cime p e rio d indicated 1-6 Monchs 0 mg/kg/day 30 m g/kg/da y 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 3-04 S-05 3-11 S-12 S--I l 3-15 S-21 3-25 Subcucaneous (noncunorous) (Conc'd) Subcucaneous trauma. secondary co subcutaneous mass # 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Subcucaneous ourulenc iaflaaaac:ion 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Subc uc ane ous ( t u m o r o u s ) 3. l o c a l number o f subcutaneous tumors/number of racs bearing subcutaneous tumors 0 mg/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day Subcutaneous liDoma 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Subcucaneous fibroma 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 mg/kg/day Fibrosarcoma 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day Subcutaneous carcinosarcoma 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day Subcutaneous nyteosarcoma 0 mg/kg/day 30 m g/k g /d ay 10 m g/kg/day 3 mg/kg/day Mammarv Gland ( n o n t :a t c r o u s ) Number o f t i s s u e s examined 0 mg/kg/dav 30.mg/kg/day 10 n g / h g / d a y 3 mg/kg/day Mamma" -' glar.d h v o e r o l a s i a 0 mg/kg/dav 30 m g /k g /d a v 10 m g /k g /d a y 3 mg; k g / d a y 0 0 0 0 0 0 0 0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Q/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0 0 0 0 0 0 0 0 7-12 Moneas 2 2 2 1 13-13 Moneas 17 9 U II 19-24 Monchs 31 18 25 13 G em inai Cumulative K ill Results 36 36 21 50 11 50 19 50 0 0 0 0 0 0 0, 0 0 0 1 0 00 o. 0 01 00 00000 00 0 00 00000 00 10 1 1/1 32/14 69/30 79/31 131/75 2/2 15/7 30/16 41/19 33/44 1/1 12/9 50/23 22/10 35/43 0/0 12/3 31/15 33/17 76/40 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 . 0/0 0/0 0/0 0/0 0/0 0/0 1/1 ' 1/1 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0'/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0 7 16 25 49 0 1 3 13 22 a0 i 20 3 32 9 10 11 30 0 5 15 30 -tl 0 3 17 -I 0 'J 13 7 3 5 ' in Cats l i s t e d as number o: r a c s f o r which :h s l i s t e d o b s e r v a t i o n was pr a s e n c . '`Caca l i s c e d as c o c a l number of t h i s -type n e o p ia s r t / n u ti b e r t : r a cs b e a r i n g t h i s ty p e of n a o ? L a s n . ^Scac i s t i c a l l y d i f f e r e n t from c o n t r o l daca when s n a l y c e c u s i n g F i s h e r '3 1x3. CZ ? r o b a b i l i cy T e s t , p<0 .0 5 . V i ;- - -L7S- TA3LE 35 (Concinued) MICROSCOPIC OBSERVATIONS ON "EMALE r a t s m a i n t a i n e d o n d i e t s CONTAINING 2,1,5-T 70S. C? TO 1VO TEARS Oiagnos is Code Number oc r a c s necropsied during che cime perio d indiosced 1-4 Mnchs 0 mg/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 mg/kg/day 0 0 1 1 S-26 3-27 S-30 S-31 3-3 2 5-33 5-34 3-36 5-3? 51 Msaarv Gland ( n o n tu sio ro u s) ( C o n t 'd ) Mammary g l a n d galactocaie form ation 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Mammary g l a n d g r a n u lo m a t o u s r e action 0 mg/kg/day 30 m g/kg/day 10 m g/k /d ay 3 mg/kg/day Mammarv (c um orous)3 T o ta l number or subcutaneous tumors 0 mg/kg/day /number of ra ts bearing subcu- 30 m g /k g /d a y taneous tumors 10 m g /k g /d a y 3 mg/kg/day Mammary g l a n d f i b r o a d e n o m a / adanofibroma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Mammary g la n d adenoma 0 mg/kg/day 30 m g/kg/dav 10 m g/kg/day 3 mg/kg/day Mammary g la n d a d e n o c a r c in o m a w i t h ouc m ecascasis 0 mg/kg/day 30 m g/kg/day 10 s a / x s / d a v 3 mg/kg/day Mammary glan d a d e n o c a r c i n o m a v i t h mecas c asis 0 mg/kg/day 30 m g/kg/da y 10 m g/kg/day 3 mg/kg/day Mammary g l a n d cy stad e n o m a 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Mammary g l a n d f ib r o m a 0 mg/kg/day 30 m g/kg/day 10 m g /kg/da y 3 mg/kg/day Mammary g l a n d e v s t f i b r o a d e n o m a / evstadenofibroma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Mama--- eland u n c la s s ifie d m align ant r.so c l a s s 'carcinom a v ic h accomsanvina fibrous p ro life ra tio n ) 0 mg: kg / da/-' 30 mg/ kg. day 10 m g /k g /d a y 3 mg/kg,- day 0 0 0 0 0 0 0 0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 c/o 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 3/0 0/0 0/0 0/0 0/0 0/0 c/o 0/0 J/ J 0/0 7--L2 Mnchs 2 7 2 0 0 0 0 0 0 0 0 1/1 2/2 1/1 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 c/0 1/1 0/0 5/ C 0/0 13 --13 Mnchs 17 9 11 11 5 1 0 2 0 0 0 0 32/14 15/7 12/9 12/3 25/13 11/7 12/9 9/7 3/2 1/1 0/0 1/1 3/2 L/l 0/0 0/0 0/0 i/i 0/0 i/1 0/0 0/0 0/0 i/i 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/ 0 :0/0 00 0/0 19-24 Terminai Cumuiscive Mnchs K ill Essuies 31 36 36 13 21 50 25 11 50 13 19 50 - 9 16 26 14 5 66 30 9 19 14 358 0 11 0 0 0a 01i 69/30 30/16 50/23 31/15 51/25 15/10 35/18 14/9 10/6 3/2 3/2 4/4 i/i 2/ 2 0/0 2/2 ii n7 0/0 1/1 2/2 0i n/ 0 1/1 0/0 3/2 3/3 1/1 4/4 i/i 7/6 b/ d O/'O <J j/: 0; 0 79/31 41/19 22/10 33/17 62/27 23/15 14/10 24/15 2/2 5/5 1/1 2/1 3/3 3/3 i/1 2/2 0/0 0/0 0/0 0/0 0/0 3/3 4/2 0/0 3/3 0/0 0/0 0/0 9/7 i/ i 2/1 4/3 9/0 00 0. 0 1/ 131/76 33/41 35/43 76/40 133/65 55/53 62/33 47/31 15/10 9/3 4/3 7/6 7/6 6/6 i/i 4/4 i/ 1 4/4. 0/ 7/ 01 in 3/3 6/4 7/7 4/4 3/2 3/3 i/1 13/11 5/5 9/7 10/4 1; 1 0/0 Daca l i s e ed as number of r a t s fo r v h ic h the li=;ced o b s s r v s c io n vas p r e s e n t . T a r a lis - r a d as c o t a i r.ur.ber of t h i s t y p e nso? Las--/ enrober o : r a t s : ea r i ng ch i s cype of n e o n i a s r a . ~6^30 -177- TA3LE 35 (Continued) MICROSCOPIC OBSERVATIONS ON FEMALE SAIS MAINTAINED ON DUETS CONTAINING 2,4,5-T FOR U? TO TVO TEARS Diagnosis Coda Number of r a e s necropsied during cha cime p e rio d indi-naced 1-6 Months 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day 0 0 I 1 7-12 Months 2 2 2 1 5-4 2 S-60 5-62 S-65 S-66 5-6 7 5-72 5-7 c3 Mammary ( t u m o r o u s ) 3 ( C o n c 'd ) Mammary g l a n d c y s c a d a n o c a r c ir .o m a without m etastasis 0 mg/kg/day 30 m g /k g /c ay 10 a g /k g /d a y 3 mg/kg/day Incsgunenc (noncumorous) Number o f t i s s u e s examined 0 mg/kg/day 30 ag/kg/day 10 mg/kg/day 3 mg/kg/day Epidermal in clusion cyst with or without inflammation 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 ag/kg/day Abscess of c li t o r a l gland 0 ag/kg/day 30 a g /k g /d a y 10 a g / k g / d a y 3 mg/kg/day Focal epiderm al thickening and in flammation or dermis 0 ag/kg/day 30 ag /k g /d ay 10 mg/kg/day 3 ag/kg/day Focal Inf lamination of dermis 0 ag/kg/day 30 m g/kg/day 10 a g / k g / d a y 3 mg/kg/day Chronic inflezraarior. secondary co tumor 0 rng/kg/dsy 30 m g/kg/day 10 m g /k g /d a v 3 mg/kg/day Integument ( tumorous)a l o c a l number of cu taneous tumors/ number of r a t s b e arin g cutaneous tumors 0 ag/kg/day 30 m g /kg/da y 10 a g /k g /d a y 3 mg/kg/day Squamous pap'iiaoma of integum ent 0 ag/kg/day 30 a g / k g / d a y 10 m g/kg/c ay 3 ag/kg/day Seracoacanthoma 0 ag/kg/day 30 m g/kg/day 10 m g /kg/da v 3 ag/kg/day 0/0 0/0 0/0 0/0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 c/o 13-13 Monchs 17 9 11 11 0/0 0/0 0/0 0/0 3 6 7 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 19-24 Monchs 31 13 25 13 Te m i n a ! Commise i v a R ill Results 36 36 21 50 U 50 19 50 0/0 1/1 0/0 0/0 27 IS 25 13 0 0 0 0 1 0 0 0 1 2 0 0 0 1 0 0 u 0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 3/0 0/0 . 0/0 0/0 1 /1 0/0 0/0 0/0 0/0 36 72 21 43 22 4 3 19 4 7 00 I1 00 00 01 00 0 0 00 01 02 00 00 00 01 00 00 00 c1 00 00 2/ 2 0/0 0/0 0/0 1/1 0/0 0/0 0/0 1/1 0/0 0/0 0/0 2/2 0/0 0/0 0/0 1/1 0/0 0/0 0/0 1/1 0/0 0/0 07 0 Daca b i s t e c as number o: ra e s cor vhicn cha l i s t a d o b s e r v a tio n vas p r e s e n t . "Daca las ca d as co cal number or c h is type rece la s a , number oc raes re a r in g caes cype c: recpiasm . ! -; n -_J{1 -- 11 - 1\ ! - --' -- 3-&H33 -1.78- TABLE 35 (Continued) MICROSCOPIC OBSERVATIONS ON FEMALE TATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR O'? TO TV) TEARS Diagnosis Code Number o f ra c s necropsied during che rime period indicated 1-6 Mnchs 0 mg/kg/day 30 m g/kg/day 10 m g/k g /d a y 3 mg/kg/day 0 0 2l S-76 5-78 N-01 N--3 2 M-03 N-04 N--06 V- 11 'L car Canal3 To c a l number o f e a r c a n a l r u m o rs/ number of. c ars b e arin g e a r c a n a l CUEt0r3 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 2ymbal gland carcinoma of ear canal 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Adenoma ( s e b a c e o u s ) o f Zymbai gland 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 NERVOUS SYSTEM 3rain Number o f r i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 1 Focal aalacia in brain 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 Focal g lio sis of brain 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/dav 0 0 0 0 Focal inflammation in brain 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 0 0 0 Vacuolizacion of ohice maccer of b r a i n v h ic h sa y o r -say n o t be artitacc 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 ng/kg/d3y 0 0 0 1 Conoression naiacia and/or henorrhage, and/or henacogenous oig^snr in b r a i n a d ja c a n c co p i c u i c a r y adenocarcinoma 3 mg/kg/day 30 n g / x g /d a y 3 mg/kg/day 0 c 0 0 N e ovascularization secondary :o c r a n i a l neODlssm r*j*s . a Q ? " i 7 5 ; s 0 " 'onc^uc' ^ =r C ;_ ii 0 mg/kg/day 30 m g /kg/da v 10 .mg/kg/day 3 mg/kg/day j ---g/ y 2/ d a '-r 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 0 o 0 y c 3 0 7-12 Mnchs 2 2 2 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 o 0 0 0 13-13 Mnchs 17 9 11 li 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 17 9 11 11 0 0 0 1 0 0 0 0 1 0 0 0 3 1 1 4 0 0 0 0 3 A 3 0 A 0 0 0 19-11 Mnchs 31 13 25 13 T e r m i n a l ;l u n u l a c i v a Resuirs 36 36 21 50 11 50 19 50 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 31 36 36 13 21 50 25 11 50 13 19 50 00 0 000 A0 0 0 0 ]_ 01i 30 1 000 000 001 .0 0 0 000 000 5 12 1 6 10 3 66 A0 ? 0 00 00 20 9 15 17 i 3 0 0 0 0 0 0 0'J 1A 1 0 o 3 1 J 1J 1 30 Decs L is : ac as nunber o: ra re fo r vhich :he Li seed o b s e rv e r! on -a s ?rsi s e n : . 3 "Decs I t s cad is coca! nunber o: this type r.aop Lasm/number o : r a zs 3aa:r i n g cbls :ypa 3: r.eop l a so.. dsAH3<J TABLE 35 ( C o n t in u e d ) MICROSCOPIC OBSERVATIONS ON ; EMALE PATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T EOR ? TO TWO TEARS Diagnosis Coda Mumbar o f r a c s necropsied during Che cime p e r i o d indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/'day 3 mg/kg/day 0 0 1 1 7-12 Months 2 2J 7 13-13 Months 1.7 9 xx Xi 19-24 Months 31 13 25 13 Terminai Cumulative K ill R esu lts 36 36 21 50 11 50 19 50 N-40 N-60 N-oo N-30 N-31 >i-83 N--35 Soinai Cord Number o f c i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day V acuolization of s o in a i cord which may o r may n o t be a r t i f a c t 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Peripheral Serves Number o f C i s s u e s examined 0 mg/kg/day 30 m g/kg/cay 10 .tng/fca/dav 3 mg/kg/day Vacuolization of peripheral nerves 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Focal inflammation of peripheral nerve 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day P itu ita ry 'lumber o f t i s s u e s examined 0 mg/kg/day 30 m g /k g /d a y 10 a g / k a / d a y 3 mg/kg/day Retention cyscCs) in p itu ita ry . P icuicary hemacocysc Hamangiactasis of p itu ita ry 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g /k g /d a y 10 n a / k s / d a v 3 mg/kg/day Evnerolascic focus in oituicarv 0 ag/kz/day 30 mg/kg/day 15 m g /k g /c a y 3 mg/kg/cay 0 0 1 1 0 0 0 1, 0 0 1 1 0 0 x 0 0 0 0 0 A 0i. Q 0 0 0 0 0 0 0 0 0 3 0 0 J 0 j 2 17 31 . 36 86 2 9 13 21 50 2 11 25 11 50 0 11 18 ' . 19 49 0 0 6 17 13 0 0 A 6 10 2 0 4 7 9 7 4 3 1293aa . 2 16 30 35 33 j. 3 17 21 47 2 10 23 10 y6 0 11 15 13 45 0 5 9 24 33 x 3 5 15 24 2 2 5 16 0 5 0 10 2 i 00000 00003 00000 0 0- x 0 X 1 16 29 36 82 2 9 17 ' 21 49 1 9 24 9 ii 0 70 17 13 45 . 00 10 1 0l 001 00000 00000 00 10 i 00000 00 000 0 0 1 0 ^ 01 0i 0 "1 0x 6 12 19 4 7 12 30 56 o 0 7 3 15 o 2 3 3_ 0 00 - Z3.Z3. l i s : ed S3 number of r o c s f o r which che 1i s c e d o b s e r v a c i on was t r es en t . ' S t a t i S t i t a l l y d i f f e r e n t from t o n c r o i d a t a vh en a n a l y s e d u s i ng P ish. e r ' s Fxact P r o b a b i l i t y T e s t , p<0 .05 . ; --; | J . ; --> $ J > ^ 3 p -- 130-- TABLR 35 ( C o n c i n u e d ) MICROSCOPIC OBSERVATION'S ON 7RMALR RATS MAZMTAINRD ON DIRTS CONTAINING 2 . 4 , 5 - 1 TOR U? TO TOO TEARS Diagnosis Code Number o f r a e s necropsied during Che c in e p e r i o d indicaced 1- Monchs 0 mg/kg/day 30 m g /k g /d a y L0 n g / k g / d a y 3 ag/kg/day 0 0 13 N-36 N-37 N-38 N-90 N-9I M-70 A-Oi _,70 3 A -05 Picuicarv (Conc'd) P ic u ic a ry adenoma form acion(s) C mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Picuicary adenocarcinoma wichouc extension or invasion of brain 0 ma/ka/dav 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day Picuicary adenocarcinoma vich invasion or brain 9 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day P ic u ic a ry adenoma a r i s i n g from oars ir.cermedia 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Hyperplasia o f'picuicary 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day C ranial Cavicy Neurof ibrosarc'Oma 0 mg/k2/dav 30 n g / k g /d a y 10 m g/kg/day 3 mg/kg/day ADP.HAAL GLAND Number o f c i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 m g/k g /d a y 3 mg/kg/day General Adrenal gland henacocysc formacin 0 ns/kz/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day r.emangieccasis of a drenal glar.d 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day "solaced focus cf ru ru lsn c inf'ammacion in a ir e a : c ^ n d s 3 mg/kg/day ju mg/kg/cav 13 m g/kg/day 3 rig/ kg; cay Ccr.aas "ion 0 ng/kg;cay 30 mg/kg; day 10 m g /kg/da y 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 3 0 c3 : 0c 'J 7-12 Monchs 2 2 2 1 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 1 0 0 0 0 0 3 3 3 0 0 3 3 3 13-13 Monchs 17 9 11 11 3 3 1 3 2 0 0 0 1 0 0 0 0 0 0 0 0 2 0 0 0 0Q 0 17 9 11 11 3 2 i 0 0 0 0 0"l nA 3 J ~\ - 19-21 Monchs 31 13 25 IS Terminal Cuauiacive R ill Rasulcs 36 36 21 50 11 50 19 50 10 8 13 9 1 2 3 i 3 2 2 0 1 0 0 0 0 0 0 0 0 0 2 0 30 13 25 18 20 3 19 9 0 1 0 0 1 3 0c J 1 1 0 24 3 6 11 3 3 0 2 i 0 0 2 0 0 0 0 2 1 0 0 0 0 0 0 36 21 11 19 20 12 7 12 0 0 0 0 3 3 0 0 3 0 0 0 42 19 20 23 6 5 3 6 5 2 2 2 1 0 0 0 1 2 0 0 0 0 1 0 35 50 50 50 47 2U 23 22 0 0 1 J - 3aca Idscad as number of ra es fo r v h ich cha l i s c a c o b s e rv a c i n *as p ra san c . 94H3&> -131TA3LE 35 (Continued) MICROSCOPIC OBSERVATIONS ON FEMALE SAIS MAINTAINED ON 3IETS CONTAINING 2,4,5-T FOR UP TO TVO TEARS Diagnosis Coda .'lumber o f r a t s aacropsiad during the cine period indicated L-o Moncas 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 1 1 A-20 A -21 A -22 A - 23 A-24 A-23 A - 30 A - 31 A - 40 A--4 i a Corzax Adrenal c o r tic a l necrosis wich or wichouc hemorrhage aad/or purulent inflammation 0 mg/kg/day 30 m g/kg/day 10' m g /kg/da y 3 mg/kg/day Vacuolization of adranal c o rtic a l calls 0 mg/kg/day 30 mg/kg/day 10 m g /k g /d a y 3 mg/kg/day M ineralization of adrenal cortax 0 mg/kg/day 30 m g/kg/day 10 m g /kg/da y 3 mg/kg/cay Atrophy of adrenal cortex 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Focal areas of axcrameduilary hematopoiesis in adrenal glands 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Focal fib ro tic reaction within adrenal cortax 0 mg/kg/day 30 m g/kg/cav 10 m g /k s /d a y 3 mg/kg/day Hyperplastic focus(foci), of adrenal cortex nodule(s) 0 ms/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Adenoma o f a d r e n a l c o r t e x 0 oiz/kz/dav 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Medulla H yoernlastic nodule of adrenal medulla(s) 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day . Adrenal oneochrcmccytoma, unilateral 0 tig /3/ day 30 m g/kg/da y 10 m g/kg/day 3 mg/kg/day Adrenal cneochronccvtoca, n a lig c e n t , co m e t a s t a s i s - u n i l a t e r a l 0 mg/kg/day 50 rr.g/kg/day 10 mg/kg/day 3 r.g/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 A`J 0 0 0 0 0 0 0 0 0 0 0 0 -J1 3 > 0 0 7-12 Months 2 2 2 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 A 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 \ A 0 13-13 Months 17 9 11 11 0 0 1 1 11 5 5 4 0 0 1 0 1 0 0 0 1 0 1 1 1 0 0 0 1 3 2 4 2 2 0 0 2 1 1 0 1 0 0 0 0 0 0 19-24 Months 31 13 25 13 Terminal Cumulative K ill Resuits 33 36 21 50 11 50 19 50 112 2 13 10 2 01 2 23 26 61 14 16 35 14 3 27 13 14 31 000 00 0 10 2 0L 11 3 022 00 00 0 0 3. 2 000 00 1 00 1 00 1 00 0 000 000 11 15 10 a3 6 11 31 19 15 21 046 10 3 294 022 926 24 30 -A 353 1 46 0 39 11- :3 01 Aj 5J 00 : 2 Oaca l i s t e d as number or r a t s :n r v h i th the l i s t e d o b s e r v a tio n as p r e s e n t. -132- IA3LE 35 (Continued) MICROSCOPIC OBSERVATIONS ON FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T 70S. I? 10 ~ C TEARS Diagnosis Cods Number oc r a t s necropsiad during che cine period indicaced 1-6 Mnchs 0 mg/kg/day 30 m g/kg/day 10 n g / k g / d a y 3 mg/kg/day 0 0 1. E-OI E-02 E-03 E-07 S-10 2-02 Z-03 Z-04 Z-07 EYE Number or t i s s u e s examined Focal k a ra e ic is of eye D iffuse k e r a c it i s of eye Focal or d iffu s e h y p e rp la sia of corneal epithelium Focal a iiia ra liz a c io n of aye P hthisis buibi with chronic inflammacion MISCELLANEOUS Postmortem aucolycic changes in a il organs Inflammation of aesenceric fac Focal m esenteric sta a c ic is and/or necrosis M ediastinal fac inflammation 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 n g /k g /d a v 3 mg/kg/day 0 mg/kg/day 30 m g/kg/da y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/cav 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 1 0 'm g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/da y 10 m g/kg/da y 3 mg/kg/day 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 n u 0 0 0 0 0 0 0 nv 0 0 0 0 n 0 7-12 Months 2 2 2 1 1 2 2 i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ]_ 0 0 0 0 0 0 0 0 0 0 0 0 13-13 Months 17 9 11 11 17 9 10 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 1 0 19-24 Months 31 13 35 13 term inal Cusulasiva K ill lesclzs 36 36 21 50 11 50 19 50 31 13 25 18 0 0 0 0 1_ 0 0 fh u 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 01 0 c 0 0 : 0 0 2 0 36 21 ii 19 1 0 2 i 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 1 0 0 2 0 0 - 0 0 0 'J 35 50 49 50 1 0 2 i j. 0 0 0 1 0 0: 0 0 0 0 2 0 0 L 0 0 1 0 1 2 l1 0 0 0 * 0 0_ 2- J 3 Data l i s : ad as number of r a t s f o r w hich th e 1SC2C o b s a i " / a c i or. v a s p r a s e r . c . Q &H3* -133 TABLE 33 (Continued) MICROSCOPIC OBSERVATIONS ON IEMALE SAIS MAINTAINED ON DIETS CONTAINING 2,1,5-T TOR U? TO INO TEARS Diagnosis Coda Number o f r a c s necropsied during the cine period indicated 1-6 Months 0 mg/kg/day 30 a g / k g / d a y 10 mg/kg/day 3 ag/kg/day 0 0 1 X O1-- Z -ll 2-14 Z-Lj -16 2-3.7 Z-13 L- 0 1 L- 0 2 MISCELLANEOUS (C o n n 'd ) M uicifocai m esenteric granulomacous 0 ag/kg/day in fla m m a tio n w ith in flam m atory a d - 30 mg/kg/day hesions w ith in cha abdominal 10 mg/kg/day cavity 3 mg/kg/day M esenteric lipoma 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day Hemorrhage in to a e s e n te ric tis s u e 0 ag/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Abdominal heaangiosarcoma 0 ag/kg/day 30 a g / k g / d a y 10 ms/kg/day 3 mg/kg/day Granulocytic laukamia 0 ag/kg/day 30 mg/kg/day 10 ag/kg/day 3 ag/kg/day G eneralized leu k o c y tic response due 0 ag/kg/day to purulent inflammation of sub- 30 a g / k g / d a y cutaneous mass 10 n s/k s/d a v 3 mg/kg/day G eneralized monocytic leukemia 0 ag/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day LYMPHORETIC DEAR Lymoh Nodes - G e n e r a l G eneralized lymphosarcoma with widespread m etastasis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day Intraabdom inal lymohosarcoma or carcinosarcoma of unspecified o rig in with widesoraad m etastasis 0 ag/kg/day 30 m g /kg/da y 10 rz/V.z/dav 3 ag/kg/day T h o ra c ic Ivmon Nods(s) Number of t i s s u e s examined 0 mg/kg/dav 30 rcz.'kg/dsv 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 0 0 0 0 1 0 0 0 0 0 7 1 1 7-12 . 13-13 Months Months 2 17 29 2 LI 11 00 00 00 00 00 00 00 00 01 00 00 00 00 00 04 00 00 00 00 00 00 00 00 00 00 00 00 0V - 01 00 01 00 00 00 00 00 14 3 29 1 10 19-21 Months 31 13 25 13 Terminal Cumulative K ill Results 36 36 21 50 11 50 19 50 101 000 000 000 0 41 000 000 000 001 000 000 000 000 000 001 000 000 000 10 1 000 000 000 000 10 4 000 000 0 Q0 :01 10 0 10 1 0 0 4 00 1 40 1 000 0o0 0 Q0 25 33 71 13 0 ' ? 41 44 cl 17 -6 a t a l i c ec as number o: r a t s t o r which the l i seed o s s e r v a c i on vas pr e s e r . t , a ,, __ _ _ _ tally different trcr. control data vhs n analysed u s i ng fisher 's exact P ro b a b ili ry Test, ?<0 .05. ' -- ...J --1 1 1 i TMi *'7 T- * --1 -- -184TASLE 35 (Continued) MICROSCOPIC OBSERVATIONS ON EEMA1E EATS MAINTAINED ON DIETS CONTAINING 2.4,5-T EOR CP TO IVO TEARS Diagnosis Coda Number or racs aecroosied during the rime period rndicaced " 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 I L-20 L-22 1-23 L-30 1-31 1-32 L-33 1-35 i.-3~ Thoracic Lyaoh Noaa(s) (Conc'd) Pooling of edema, pigment, and/or rad blood cells in sinusoids of thoracic lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Reactive lymphoid hyperplasia of choracic lymph node(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Congestion of rhoracic lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mesenceric Ivrr.oh Noce(s) Number of tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pooling of a d ^ a , oigsenc, and/or red blood cells in sinusoids of mesenteric Lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Zr.flacaacorv orocass in .tesenceric lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Reactive Lyrr.ohoid hyperplasia of r.esanteric lymoh node 0 ng/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Cystic distencion of lymphatics of mesenteric lymph node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Increased numbers of histiocytes in mesenteric Ivnoh node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day lynohangioma of nesar.teric lymna node 0 mg/kg/day 30 ma/'kg/.dav 10 mg/kg/day 3 ng/kg/ day 0 0 1 0 0 0 0 0 0 0 0 0 0 0 l 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 J 7-12 Months 2 l -) 1 13-13 Months 17 9 u 19-24 Months 31 13 25 13 Cumulative Sill Results 36 36 21 50 n_ 50 19 50 0 0. 1 0 0 0 2 0 0 0 0 0 3 3. 4 6 0 0 0 0 0 0 0 0 16 7 3' 1 3 1 0 0 0 1 0 9 5 5 9 0 a 0 0 0 0 0 0 2 16 30 36 1 9 17 -M 1 9 25 11 0 3 16 L5 0 10 ' 17 16 0 6 13 10 0 2 12 7 0 2 9 *6 0 0 I0 0000 0000 0 0 .0 1 124 0 1i 2 0 1 1 1 07 31 0001 0000 0000 0000 0000 0000 0 n i.- 0 3 0 0 h ."l J 0 10 J 00 3 *1 2 h J 30 h 3 33 15 19 22 3 1 3 `0 0 0 x 0 34 43 47 39 43 29 L5 17 1 0 0 1 11 7 3 6 i 0 0 0 0 0 1 0 1 J 3-~= ' ^ ns number a- -sts for which the 1iscac obser.'atr or. ws s c-es ^"r -135TABLZ 35 (Continued) MICROSCOPIC OBSERVATIONS ON I^MAIE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-1 f o r a? 10 n o 'EARS Diagnosis Coda Number of racs necropsied during -ha cine period ir.dicacad Suboucaneous Lvmnh Nodes Number of Tissues examined L-40 L-41 L-42 1-45 Inflammacion of subcutaneous lymph node(s) Pooling or red blood cells and serum vichin subcutaneous lymoh node Reactive hyoerpiasia oc suocucaneous lynch node Cvstic dilatation of lymphatics L-46 Pibrocic tissue in subcutaneous lyaoh node Thvrr.us Number of tissues examined L-50 Lymohoid hyperplasia of thymus L-56 Thymic Irmohosarcoma 1-57 Congestion of thymus "ibrctic area in thvnus 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 1 7-12 Months 2 2 2 I 13-13 Months 17 9 11 11 19-24 Months Termina1 Cuaulacive Kill Pesulcs 31 36 36 18 21 50 25 11 50 13 19 50 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/cay 3 mg/kg/day 0 mg/ki-'day 30 mg/kg/iav 10 mg/kg/day 3 mg/kg/day 0 0 1 O' 0 0 0 0 0 0 0 0 0 0 0 w 0 3 o 3 1 7 2 1 0 0 0 0 0 o 0 0 0 0 0 0 0 3 0 -1 23 12 29 56 00 10 00 00 01 00 00 00 21 01 01 00 00 00 00 00 00 00 00 00 9 '4 6 15 s 22 3 16 01 00 00 00 00 0i 00 00 01 0Q 00 -0 0. 0 00 00 00 6 11 4X , 7 1 12 3 14 00 01 00 00 01 00 00 00 25 01 01 00 11 00 00 11 11 00 00 00 36 70 20 43 10 43 13 43 01 00 00 00 00 01 00 00 0 0Q 00 0 i1 1 0 j J2 Data List ed as number or rats for -hich the listed observaci.on vas present. j J --A i J ! --` -- > J -- Q4HHI -.86- TA3LE 35 (Continued) MICROSCOPIC o b s e r v a t i o n s o n PENALE r a t s m a i n t a i n 'ED ON DIETSCONTAINING 2,4,5-1 POR 0? 10 TWO TEARS Diagnosis Coda N'umbar of raes necrcpsled during ene cine period indicaren l- Mnchs 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day 0 0 2 1 L-60 L-l L-62 L-63 L-65 L- 1-67 --o: SPLEEN Number of tissues examinad 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Splenic atrophy with or without increased hemosiderin piapnenc 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Increased hematogenous pigment in spleen 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Ir.craased extraaedullary hamacoooiesis in soleen 0 ag/kg/day 30 n2/ka/dav 10 ag/kg/day 3 ag/kg/day Reciculoendocheiial or lyraohoid hyperplasia of soleen 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day "ocal araa of necrosis and hemor* 0 ag/kg/day 3C ag/kg/day 10 ag/kg/day 3 ag/kg/day Toca! acsiiuiar eoosics 0 ag/kg/day 30 ag/kg/day 10 ag/kg/day 3 ag/kg/day Generalizad myeioid leukenia aoDaranciv oriar.acing ir. soleen ' 0 ag/kg/day 30 mg/kg/day 1C ag/kg/dy 3 mg/kg/day THXXOID AND PARATSYRCID Ihvroid Number of cissues examinen 0 ag/kg/day 30 ag/kg/day 10 'ag/kg/day 3 ag/kg/day ThvTOid inzarfoIlirular C-os11 ad anona 0 ag/kg/day 3C ng/kg/day 10 ng/ .sg/ cay 3 ag/kg/day 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 nu n 0 0 0 0 0 0 0 n 0 0 0 0 .* 0 1 i 3 0 7-12 Mnchs 2 2 2 2 " 13-13 Months 17 9 22 11 2 17 29 2U 1 11 L0 00 00 10 19 16 2s 03 1 14 27 2 10 09 01 00 00 00 00 Q0 01 00 00 01 00 00 00 00 00 00 2 17 29 2 11 l 11 .3 01 00 0- L9-2! Months 31 13 25 13 Terminal Cumuiaziva kill iUsuizs 36 C 21 50 11 50 19 30 30 17 25 13 2 0 2 3 15 9 S 4 22 12 13 22 0 1 0 0 0 0 0 0 0 0 0 0 Q 0 0 1 36 21 11 19 0 0 0 1 16 14 7 9 23 15 7 22 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 35 49 50 50 3 0 3 5 41 30 23 21 60 36 37 32 2 1 0 0 0 0 1 0 0 2 0 0 0 0 0 1 30 36 35 13 20 -9 23 11 -0 13 19 50 1 23 23b 1 2 23 - -'w' lis ec as nunber or raes zcr vn aor. m e liszed observar!.en -vas prasenz . rally differenz fren ronero! daza vhen analyzed usi*5 *-S*aj r= "xac z ?*obabili * .es r , d j .05. S ct^ a . -137- TA3LE 35 (Continued) MICROSCOPIC OSSERVAIIONS ON FHMAL1 PATS MAINTAIN ED ON DIET3 CONTAINING 2,4,5-T POP CP TO TWO TEARS Diasr-l o s is Code 'lumber oc rats necropsied during the time period indicated 1-02 Thyroid (Conc'd) Thyroid intertollicular C-cell adenocarcinoma vichouc metastasis * 1-6 Monchs 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 1 - 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 7-12 Months 2 2 ? 1 0 0 0 0 T-03 Thyroid intertollicular C-cell adenocarcinoma with aecastasis ' - ~ .. 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 T-04 Hvoerolastic focus of ir.terfoiiicu- 0 mg/kg/day iar C cells within chyroid 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 c 0 T-06 Retention cyst in Chyroid 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 7-09 Focal or diffusa inflammation thyroiditis 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 00 00 0 o00 T-20 Parathyroid Number of tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/cav 3 mg/kg/day Secondary parathyroid hyperplasia (renal) 0 ns/c?/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day f) 0 1 0 0 0 0 0 2 2 p 1 0 0 0 0 T-21 Parathyroid adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 T-23 Interstitial fibrosis of parachvroid 0 mg/kg/day 30 mg/kg/day 10 mg/kg/dav 3 mg/kg/day 0 0 J 0 0 0 0 0 13-13 Months 17 9 H 11 0 0 0 0 0 0 0 0 2 1 1 2 0 1 0 0 0 0 0 0 17 9 10 9 2 0 1 2 0 0 0 0 0 0 0 19-21 Months 31 13 25 13 Terminal Cumulative Kill Results 36 36 21 50 ii 50 19 50 i2 3 011 000 022 01i 000 10 2 0 0 0 9 13 24 A 8 13 s 4 13 34 3 044 00 i 000 30 3 00 0 000 011 000 39 27 17 13 12 5 20 14 20 10 10 12 01 0l 00 00 00 20 00 10 0 75 41 30 34 4 1 3 5 2 2 0 0 0 ? 0 0 Data listed as number of rats tor which the li scad observed.on vas present. -188- IA3LE 36 TUMOR INCIDENCE IN' MALE RATS MAINTAINED OH DIRTS CONTAINING 2,4,5-X POR UP TO TVO STARS Diagnosis Code Number of racs r.ecropsied during che cine period indicated 1-6 Mor.rhs 0 mg/kg/day 30 mg/kg/day L0 mg/kg/day 3 mg/kg/day 1 0 0 0 S-16 R-04 3.-05 S-07 LIVES. Humber or tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day deoacocellular Changes Hepacocaliular carcinoma(s) 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day RESPIRATORY SYSTEM Hasai Turbinates/Hard Palace Number of cissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Keracoacanchoma or nasal curbinaces 0 mg/kg/day /hard palate 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Squamous ceil carcinoma of hard palace 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Mixed adenoma of hard oaiace 0 tp.a/kz/dav 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 c 0 0 0 0 0 0 7-12 Moachs 2 0 2 ! 2 0 1 1 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 13-13 Mnchs 1 9 22 1? 19-24 Mnchs 63 25 23 23 Terreinal Cumulaciva lesulcs 6 36 16 50 4 50 9 50 14 9 22 12 0 0 0 0 63 25 23 2S 3 0 0 0 6 36 16 50 4 50 9 50 03 1 .1 00 21 1 2 2A 0 10 1 0 10 1 0? 0? 10 0 i 0000 0000 0000 0 l 0I 0000 0 10 1 0 01 00 2 0 000 00Q 0 0000 Number of cissues examined R-70 -Pulmonary adenoma PANCREAS Acinar Number of cissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30. mg/kg/day 10 mg/kg/day 3 eg/kg/day 1 0 0 0 0 0 n 0 0 mg/kg/day 3G mg/kg/day 10 mg/kg/day 3 ng/kg/cay L 0 1 0 2 14 63 6 36 0 9 25 16 50 1 22 23 4 50 2 12 23 9 50 00 000 00 000 00 000 0 10 0 1 2 2i 63 o 3 T -, T n 23 3 12 23 6 36 30 , 30 9 30 S k ciW ^ -189- TABLE 36 (Continued) tumor incidence in male rats maintained on dirts CONTAINING 2,4,5-T TOR 'I? TO UNO TEARS Diagnosis Code Nuaber of rats necropsiad during che cine period indicarad 1-6 tfonchs 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day i 0 0 0 ?-10 P-11 P-25 P-26 L'-51 0-53 U-55 T-58 PANCREAS (Coat'd) Acinar (Coat'd) Pancreatic acinar adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreatic acinar adenocarcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day islets of lan2erhans Pancreatic islet call adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreatic islet cell adenocarcinotna 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day URINARY SYSTEM Number of tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Kidney Renal pelvis transitional cell adenoma 0 mg/kg/day 30 mg/kg/day 10 ag/kg/day 3 mg/kg/day Renal cubuiar adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Paoillary adenoma of renal pelvis (unilateral) 0 mg/kg/day 30. mg/kg/day 10 mg/kg/day 3 mg/kg/day Renal carcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Months y 0 i. l 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 rV\ 0 Q 0 13-13 Months 14 9 22 12 2 3 2 2 0 0 0 0 0 0 1 ? 1 0 0 0 14 9 22 12 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-- ?i Months 63 25 23 28 Terminal Cumulaciva Sill Results 6 36 16 50 4 50 9 50 19 4 26 9 8 20 4 39 12 3 17 20? 0 00 000 000 10 2 13 ?57 5 T_ 7 5 3 10 001 000 101 000 63 6 86 25 16 50 23 50 2S 9 50 0 00 0 00 101 0 00 0 00 101 0 00 0 00 0 11 0 00 0 00 0 00 l0 0 00 0 00 Q 0n Data listed as number or rats for vhich the 1istad observation vas orasene. ! < i t ...i 1 _l *1 i ! -- --< l a c a r s c i c i a l c e l i adaaoma of ca sc ia 0 ng/kg/day 30 ag /k g /d a y 10 rag/kg/day 0 3 1 .1 1 r"i ' i o (vi O IO CJ> ON iO M O i/i d (V X. O I X Ui n 11 O on d H* ; r O -* (D C/J -* O H- Mp O !' K ` P My j i - J > r r< f- U i/ j O r1 l/i H Aa- 11 c > - * O i o 1 " C< o 10 CJ CJ OO n . |J [1 ; i 1 i.j 00 y J oo uo 00 00 H J ijg *- . o o 0 0 <;r V? A* V u< 0-1 Y- U'l U'J 0 0 u Uo O'l .0 0 uo ( O- 1 . r. o. P f. p P i. p p P lu w n LO H* OO il a 00 a a oo UQ 0 0 '--s ? ' `K 0 0 y ? <; (jo uo 00 p . fi. IU p . P . p ru U * < *< *w* o - C i o oo a (JO a a 0 0 00 00 Y? 00 ? r Y ` 00 V , 0 0 (JO p. \ p. (U p - o . fu pp '< i O O O h-* C J i-* C i o oO aa 00 y a 00 uo 00 Y-` * N VK* Oo Y>` Y ? O-: UO 0 0 p. PP P . p . (U p ''X '< C J h-J C J o OO aa Q y 0 0 00 00 P` U'J JS" x r 0 0 00 00 P* v -. P* P P. p P PP '< o a (JO y? 00 PP -i O OO O oooo oooo O OO O oooo oooo oooo oooo o o o o (-*O 00 4> oooo O O J-1 o oooo O lv) O CJ o O O I- V 4 > u ON o ooo o ooo O O O (-- o o o -* (-* fO c j }-hb<re Zi H p il u (/t Q` ri AA fi A o rii n 01 P a> A a> X fu . fi 0 (U A- w fo 0 va o o rj ri } IH il l/l <? U1 H H LO i~* u j o Oo 00 00 P | i (IO UQ 00 'K -V . 'v . `f \ 00 7* 00 00 uo A. -- A. A A- A A A A '< o$ o ; n AH O n ri i J- (U pr p A H - fu (A A 1 HA '4 n IO Hoi o* O h- A fu fu A h- A |U n na f- l; f-- h- r o P ` fu H 0n (D I * nA fu O (A n 0 fu fu (A o H- -> Oi O 1-- u t o oo B0 <10 0 0 (10 ^ 0 0 00 ?? fs" 00 j v x * no --.0 0 00 p . ^ (X AAAA A A^ '1 o jo n> P n fu H H- 1 n fu fu O r O O A r fu AA A il* H fc X fu Ht (f> A o r - LJ O oO P0 00 0 0 00 *"-UQ U0 7? fi* 00 s*.- '/ ? & ) '^ .0 0 00 v-A -** ^ A AAAA vcj tu A O O O I- OOOO OOOM P - fu P(DUO O A Uj r-- n p P P ` (b r A rt n 0 H- t \ a On o A fu H- a *1 n 0 (fi <u A !- o A- fl> 11 `O A. A 1 1 A- A H- C r a *1 io A. 0 U UJ I - 1 u j O OO 00 uo 0 0 00 'v 00 00 v~ ***. X * uo X* ^ 00 00 <10 A *-K. ^ A A A- A A ^ A A -< S<J O O O 1-** ;OAnAj- 1O-i' m o io OOOO |-- |-- O t o O ro :oPc AnP` h*1-4 IO H ro J-1 IO i o v> -!> o o o p io O 00 1-- 1-0 f IO r o vo 4> 1-- O U> Pl n P ' CO A o s*> ss n HH U r-3l Pn M o iM >tj {l> Oi p (A fc E 36 (C o n c in u s d ) on r* ! ! 2 l/>i l/l IO io IO 0> OO Lo Ln Lo oooo IO N io O' co io oi ro vO4>OnO'OOOO'u t u u ou O O O I-* io c r O ' O O O 1--* OU-iO4>vOUi*t i o i o i o a '* co Lo Ln u -* O A Pi n IO P ' 4> A <04>O\ O' U l U t U t co 0 0 0 0' fi A / 3 J-* f 1p A 1-- n va g AA A A (U 1- n n l J0j A -191- TA3LE 36 (Concinued) TUMOR INCIDENCE IN MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T FOR U? TO TVO TEARS Diagnosis Coda Number o r a c s necropsiad during Che c in e p e r i o d indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day IQ m g /k g /d a y 3 ng/kg/day i 0 0 0 7-12 Months 2 0l - G-20 G-38 G-59 g- ; 6 C--7 7 GASTROINTESTINAL 3T5TE-M ( C c n c 'd ) Tongue .Number or C issu a s examined 0 mg/kg/day 30 m g/kg/da y 10 mg/kg/day 3 mg/kg/day S c ra c irie d squamous c e l l carcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Saiivarv Glands Number o f t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Adenoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Stomach Number of c i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day S t r a t i f i e d squamous oaoillom a of g a s tr ic mucosa 0 ng/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Small Incascir.e Number or c i s s u e s exam ined 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Mucocystadenocarcinoma of small in te stin e 0 mg/kg/day 30m g / k g / d a y 10 mg/kg/day 3 mg/kg/day Adenocarcinoma of sm all in te s tin e 0 mg/kg/day 30 m g/kg/day 10 n g /k g /d a y 3 ng/kg/day 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 T. 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 2 0 i 1 0 0 0 0 7 0 1 0 0 0 0 2 0 1 1 0 0 0 0 0 0 0 9 ' i s t e d i s " umber o~ -= - = ' t r u.-" * - - ' b e 1 :' - - 2^ V-. - m>-->-m- ^ vas ' r e s e n t 13-13 Monchs 14 9 22 12 19-24 Monchs 63 25 23 23 Terminal Cumuiacive R ill Rasulcs 6 36 16 50 4 50 9 50 13 63 6 3 25 16 19 23 4 12 28 9 0 1 0 l 2 0 01 0 0 0 83 49 46 50 1 4 0 1 12 59 6 ao 7 23 15 45 17 23 4 45 10 25 3 44 0 10 i 0. 0 0 0 0000 0 00 0 14 62 6 85 9 25 , 16 50 22 22 12 27 4 49 9 49 0 ? l .3 0 00 0 0 00 0 0-01 14 52 6 35 9 25 16 50 22 23 4 50 12 25 9 47 0 10 1 000 0 0 0 Q0 000 0 00 0. 0 0 0 0000 0 11 7 1-39A Muaocyscadsaoaa ft i 1 u Pi ft 11 in (0 , . 1ft- Oi ft ri ID 11. o. ii> 11 ft (/I j'. o I it u ' 1 il' i i :.i O i: M u' ll' ft i Ol <, rii in o i i 1( \ *; ft 1 ' fi J (1 ; j (U ft Ot o i - u P> n Ul 11 ffui. ;U I O' 1 J fti y (U Jt >( s* lu (. 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P- pi ^ P (u r '< ViJ I,, oo o o O O O H- OJ )-* O OJ o o ri 0 00 a 0 00 UO oo JS- * - jrr U1) JS* j>r f t ) o. 00 00 P. ft p. p. ft f t p) '< O J i-- O U 00 0 "- - 0 0 7? u o jr ai P - -V. f t f.o *< ft -V CD C l o o Oo o 1 O 0 oCD 1 4 o oo o o H * f-* o l-J oO o o oo 0 ag/kg/day 30 s g / k g / c a y h- )-* I- -J O' t- U O) o>j- uj cc. OOOO O O H*O OOOO o o o o - o o o o o O t"* VI K..J L.J O i.-J O V O I I j - i VO Ol - J 'O o o o o 00 )>OvO' oooo oooo O O t- CD )- c.j O O O O O h~* h b fS 0 OO ?1 4 Oj on I vO O v oo P T' o fL Hn- 'S P P P 'O p` Ho P en nP P p rni no P3 U) P H- (fl O r*i n O Ul rl PP P 1-- Ul 4 P Pn -* P P r MP \*- P o ri H- -* P P P P" OJ 4o-* Oj O O UPQ P n P UQ ^ o o UQ '/ f i JV UQ '/fi UQ UQ un PL Ss PI P CL p . PI P P `N* ' < V< c_: p PL Hrit ii (U ri p p n 4-*P n p a UI p o>( o P P OJ r-* o j o oo il p UQ P B UQ UQ UQ v r -V- '/fi OQ '/fi un un UQ a P. p a. a P p p> ^ s do P' O Ul p oo El P O i-t. Ul El P 4-- 4- ' y n p 0) n HP P Oj 4 - OJ o oO a (J UQ 13 B UQ UQ Q ?fi ?r JS" ?' un UQ un CL --. V A . P PL fL P X PP 'll Lit C l H- B cr P Ul ot H H 4-* Ui O p i-t t-i n P o n 1-3 o p 4*1 a Ui U l p n i-l 4-*- IH oP rit P P* F Ut El O .P O 4-- p U r< Ui 4-* o r | - 4JP PW li ri pO Ui o np l J- n p(V CL OJ 4-* O Oo j o OBQ U El El UQ ^ U Q UQ ?T '/fi Q '/fi ? r UQ -" -u n 0Q PL P - P PL P . P p P -"< s< X Oo oO o oo o oo Oo o oOO OO U H- P- P p u1n1 ion HO- M- n p MJ yypp p. p n 1- H O' o II o p Pn u> 4-J- 'O El Ui p H- 1 o p . P Mi u P- p ri n P - P H- P n O ri 01 P- 4L y UQ OJ I-* OJ o Oo U UQ |3 y li UQ UQ UQ '/ f i '/ f i un '/fi '/fi un un un PL P - p p . PL P P P n-4 nc; *< o o O 4- O 4- Pn 1 O' y in oooo o oo o oOOo oooO i -- 4-- o IO c O -i p1 f l 4-* y |vj Ui Oooo o O h- o o 4-* O o oooo O O O 4-- o o o o o o o * - * o o o o i-- I-) J-- In) IO VO 4> ; i " O OJ yi n -* y ut Ui y i- o nP I ivj -i or ?o Oo ` *-< KO t-1 41 {*-i m t Ui 4-H n 4 M O ti Ni 14 4> \C PU . tn -i MJ fo OH pi Ui id ii 4-1 i L O i- U J 4-1 om 'S 1*1 O - Si fe u M4-1 H Ui H &r* t*i OOJ' oO p nI* PP(V P. 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P- P (1 P v j CU (U fu (U ' < p p "< s< p p '< P P ^ < '<( '-i) '< X P o Oo o o 0 o oooo o o C) L'J o CJ o o Ut o O t-J Li o o o o o o o o o o o o o o o o o o o o ili Pl i O O t.J o o o o o o o o o o - o o O O O O o o o o o o o o oV. *>>-*. -ow o oooo oooo oooo o o o o u <t> O o *~J O O Lj O k- O O -- *--* L~* oooo oooo f(ooU- o o o o C> O O !* O O (--1 fr--1 l- i O o o o' o o o o P Ut I.J o o o * o o cj r- O O I o i i-* u > o o o o o o 1o o o O CJ O i- O O O I" O O f O't h*u l o o o o `o o o ooo ooo o o o l-i o o o o. o l-j o o o o l o o o LOO U> O O O|-o o o o o O o ( o -os \o Vo oV 0/0 0/0 0/0 0/0 0/0 3 ag/kg/day 0/0 0/0 0/0 0/0 0/0 10 a g / k g / d a y 1/1 0/0 0/0 0/0 0/0 30 a g /k g /d a y 0/0 0/0 0/0 0/0 0/0 0 ag/kg/day i-23 ' Sucucaneous liposarcom a t/1 O O ._> O O O l- Of O L i u.) - IO - l-i h-i IO h-* -' (-* IJ W 'I ^ l-t u "O vO O O I-* o f o o o o o - o ^O \O ^h- o \ MO O O O O (" o M ifS L TUMOR INCIDENCE IN MALE RATS MAINTAINED ON D I ( /i U1 Lrt 1 IO JO o s o |s> X 0 0* A Ci c 'S 0c 0 0) A 0 n o x-J rt o 11 |U Lo 0 (IQ n ol o o ft FI N UQ ?C ? e <|Q UQ jg a p. 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Ptu P . p* (U P fu O O o l' o rPI n O' U (A t-- l' o i o \C o "O pI n I-- P ' IO Uj o o oo oo oo o IO o o o IO o o oooQ o O ($ o I-- i o r-` l o IO LO 4> Lo PI n I-* li' U) ui ri o ?a o i-t o 55 n Hn 'y u l i PI * IH n M o i-i lo I' Ut 1 la r-i o JJ *i ?o Ul c i- i-J O r-i vi li r*i LJ r<3 I-l o C/l u 1-1 ta ri ul TV m&r* LO o\ nop 0nHPo> p. 30 n g /k g /d a y 0/0 0/0 10 ng/kg/day 0/0 0/0 1/1 0/0 0/0 3-ng/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 , o o I-* h o o 1-* I-* o o I - io o o r - IO o o o h-1 V. X o O O 1- 0/0 o k-- o o -- o 1-- o o o I- o o o I-* o o oooO oooo O r-*O O O - o l o I- * IO O t-*O O n o V, r * o LO h-* IO o o -- o f-* o o o J-- IO i o IO O' c o L O G l LJ 1o io P1 n l'J {y t> (A 1O' Ut o Ut O Ut Ci a O' ) a> 'i 1 I- I-* H- I - ti fu H* n po B np iA p (f-u* I- n Ol < a> -195- TABLE 36 ( C o n t in u e d ) TUMOS. INC I2ENCE IN MALE PATS Mill TA.INE3 ON 0IETS CONTAINING 2 , 4 , 5-T FOR If? I 0 TWO YEARS Diagnosis Code Number o r r a t s necropsiad during che cine period indicaced L- Moneas 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 1 0 0 0 7--*? Monehs 2 0 1 1 N-22 N-23 N'-25 N-19 S-62 S-64 Nr--53 NERVOUS SYSTEM Brain Number o f t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Ascrocycoma w ith in cerebrum 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Astrocytoma w ithin cerebellum 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Granular c e ll ar/oolascoaa of brain 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Ascrocycoma or mixed g l i a l neoplasm of cerebellum 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Peripheral Serves 'umber of t i s s u e s examined 0 mg/kg/day 30 mg/kg/day 10 a z / k s / d a v 3 mg/kg/day M e d ia s tin a l - lig n a n c schwannoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Schwannoma of c r a n i a l c a rv e 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day M alignant schwannoma o f c r a n i a l nerve with involvement of cerebrum and na sa l curbinaces' 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/cay Picuicarv Mumber of t i s s u e s examinee 3 mg/kg/day 30 n s / k g / d a y 10 ng/kg/day 3 mg/kg/day 1 0 0 0 0 0 0 0 0 0 0 0 O' 0 0 0 0 0 0 0 1_ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 .* .) 0 2 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 2 J 1 - ` ' s - ec as numbe- o-` ~a=3 : : r -^ s 1iscec observad on was or - s e n t . 13-13 Months 11 9 22 12 14 9 22 12 0 0 1 0 0 0 0 2 0 0 0 0 0 0 0 0 13 9 20 11 0 0 0 0 0 0 0 0 0 0 0 0 13 9 21 19-24 Months 63 25 23 23 Terminal Cumulative S ill Results 6 36 16 50 4 50 9 50 63 6 25 . `16 23 4 28 9 00 10 00 00 00 00 00 0c 00 10 10 10 10 00 00 00 61 6 25 16 23 2 24 9 20 00 00 00 00 00 10 00 00 00 00 0 5? 6 16 nn 25 ' 86 . 50 50 50 0 1 0 0 0 0 l 0 1 l 1 1 b 0 0 32 50 48 45 i 0 0 0 0 0 1 0 0 0 32 43 -3 _. ; --i ' . .u i ! _ a<W 5Y a la rio iVKT Offnuu y h1-*- p- (il r(ui |o l -` > |U PL h> p. 0) rt M a l) ;i r- ru tu p Pi Pfu i-- M p o r h f-* I - fu P O- H n* 'O O i p ` ll> oo lh n ;.r 1 1 |0 il oti !-* J Oti P O i-i. Ui o o ! p p- O rl *1 Oti P 11 u> p lu n I-* j - op pp o o H- rl fi * n u A -' O p. O a> n ph fol CU ru Mi (U r*. H p( fu r> o r1 It (U A P e; i O' Iti t o M (1 Hlii U) p fu Ui ff> fu 0 lP rt> p. ! j- 1/| LO I--* Lo O (U O O p. El J 44 ;) U (JO o --. 04 00 u ` . -- A' Ut 04 A' A* 04 f> 00 UU n (X ri P P- (X fu fu fu tu n 'S o p ; U O O O o Lfl u ll> (i) ill P n O OOo LO 1- LO o Oo yy 04 0 0 04 04 04 A* --(14 Y> /S" 04 04 04 X P (X p. fu `4 vP*i SPc5 LO H* LO o OO yy 04 y J 04 UQ 00 \ Y " -- A" 04 A* a * 04 04 04 A* .L (U P. P. P P fu '< '-1 '< O O Oo O O Oo o o LO 1- LO o oO y El 04 y y UQ 0Q 04 A* -- A" 04 A* 04 U4 04 n. P. p P- (X P P *< mp- co O O I-* 1--1o O IJ 00 00 00 to i - I ro oooo o - o o I-* I'J l' io IO vo IO IO Ui Ol o o O O O -* Lo i -- I J o (y i o i o cr> CO J Ol U I - 1 .0 ( - t - i-* o o o o o - - VO C' O O' 1 - I J |- ` LO i - u i i ' ro i-> o o *-* lo io ioovj>ovoii co 7?S f f c | -j Oj o o ai 4--1 0 0 --j a\ P P fp` P <! n po rii * o` 1 O 0 P P P- Pn p p n rr O O H P P h*P -* O 1-4 P P l JP H* O P < Hci < < P H(/) n H- rO HPn P OM l-ll ' U* P ri P . PP lJ- P PO O p ri P HP O P P ** n y hp i <1 r X Hri r PP P H* (A n P- P On 0 OP n P* P H* P P O. <P PP U) n *-* o O H0P o O0 n* P cr ri H* P rr H- P* PO P r xt r o Hr* f PP H* Hn r PP *\ i '< < P P* n Po Po 0 n B P A- rit O *1 H Pn HO P /s (A LO K-* Lo O OO U0 OQ y y (10 UQ <10 ?" V , V ?" IM V? ?~ (ro 4M 4M P- cl P P- P. P P P s< '< X oLO I-* LO OO 0y uo y y 00 Q 4M ?4M JK* ? i` 4J0 (10 4M V . CL P p . P- P '< p P '< -< '< U 1- U o Oo 00 o o H y (10 ' - u o uo IL" 4M V ?" (10 4M 00 CL Cl P P - CL P ^ PP '< *< O h-* Lo O OO BB 0Q ( i a 4M -- - UQ 410 -- JC ?" OQ Pi* ? r OQ (10 00 fL -v . CL p P . CL p ^ P P "<* OOOO OOOO OOOO OOOO OOOO OOOO oooo oooo OOOO 0 0 f - * 0 O 1-* O Q H W O N O O O h- O O O h -1 10 t- * W l U I v j UQp. p <l 0 P- (D P- O fl tlP *4. (A p(U. (D Uni Hf(Pi-- Un. ri M P- in OaH hPlnu UpO u HO UO O ui'Pi?-oq-rU^O?Ur(^fJQj aU^17c34ji` s -.(H Jg fr c(ul ppiTsp bP i H fOi xj OOs r*n-4 >13- tHJ n U0m MnP-<I IO U u1.RPi Ofo (H/l y a r% ii s*VH>' II.J- ^O rh'i H{pppj.- U i4-0* Pri i'IJ OOOO oooo o o i-* o u i - 0 1 ( O O O 1--* <0 *>O' O' RR w^ Bp (A H ` fr-RH -3.97- TA3LE 36 ( C o n t in u e d ) TUMOR INCIDENCE IN ALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , 5 - T SOS. U? 10 WO TEARS Diagnosis Coda lusher of rats necroosiad during the cine period indicated 1-6 Months 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/dav 0 0 0 A--42 A--44 A-45 -46 A-47 ADRENAL GLAND ( C o a t ' d) Medulla (Conn'd) Adrenal pheochromocytoma, b i la t e r a l 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day Adrenal pneochromocytoraa, maiign a n t, no m e t a s t a s i s - u n i l a t e r a l 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g / d a y 3 mg/kg/day Adrenal ohsochrotnocvcoaa, a a llg nant, m etastasis, u n ila tera l 0 mg/kg/day 30 a g /k g / d a y 10 m g/kg/day 3 mg/kg/day Adrenal ganglioneuroma 0 ag/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Adrenal oheochromocytoma, m aiign ant - no m e t a s t a s i s - b i l a t e r a l 0 mg/kg/day 30 m g/kg/day 10 a g / k g / d a y 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 2 2 0 0 0 0 0 0 0 0 a r 0 0 0 0 0 0 1 0 . 0' 0 13-18 Months 14 9 22 12 1 0 0 0 0 0 0 0 0 0 0 0 c 0 0 0 0 0 0 0 19-24 Months 63 25 23 23 Terminal Cumulative K ill Results 6 36 16 50 4 50 9 50 21 4 -2 21 10 51 01 01 2i 10 00 00 00 00 20 00 00 00 00 00 20 4 6 3 X 6 1 2 3 2 0 0 0 0 1 0 0 1 0 0 1 E-08 E-09 2-11 T- - j ' Mum'oer o f t i s s u e s examined 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day R etro b u lb ar k e r a t in i z in g squamous cell carcinoaa with extension Into cranium 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day In trao tb ital unditferer.tiated sarcoma w i t h i n v a s i o n o r c r a n i a l cavity 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day MISCELLANEOUS M esenteric liooma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1*fM?K0 R1'TIC1'1_--R '-.-.-ijc; , ' . j n o - - : Oer.srslicad Ivmohcsarccna with vidasoread m etastasis 3 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .*) 0 3 J 2 13 61 5 32 0 9 25 16 50 1 20 23 4 48 2 11 23 9 49 00000 0020X 00000 00 000 00000 000p0 00 10 2 00000 000 21 00000 00000 0000c 0 ~0 3 0 0'J 0 j 0 0 0 <*N .J 310 Data l i s t e d as number of r a t s dor w hich t h e 1.i s t e d o b s e r v a t i o n was p r e s e n t . } J 1 --1 i1l ...j , --* A rt'S 3 'oOn ion om mo u ~tl n r-1 ll1 :V.!? f1-' >n vd - o ' r-l U t t tHo M1*1 S F n n o n r-. HO M ?i S in D r o1 ?to: rT--i1 f -1 sutotoi .--1 o o o y " M vJ 3 tF-ii ri HO IO Fi UM ui M n ;|J MH uiF-J uoa oo ? sO_SnootsO^ynni, "sCoMTsO0tt,0lPi sso*.TOttbty-s,,,PlPi "'.rTsv-snnbos!)nfn r-l O O O oooo oooo 'O VO <1 O ' oooo n< t nr-l *h-*l o-->I oooo C'l si O O O O O N (T>MM oooo r-l o ^ --I o o o o -i O O O -TAOV>no0ts*!nl0s,, so'ardo>Nnr,>injIsoat-o&tW*.i)ns) td A00 0t0 r> t d *r<1Jt1TtJ -I O O O o o o o 'sOTAsttO0t>.I0P, ''yomTssMott,ni l s^roATMott-s.Iln) TNti A00 0t0 r> *Ftd A00 0t0 o to 'AS0otn0. om -'.otSOt00ty-sdis,00''-Jmssotod,no. d Otf r-l o O O s,,o-V>n00tU.00.i>'sTAOts>tO0nt.I>0.P'orTAs0Otot--I0n1s T>tI* -0y.0 0t0 CO InJl tidlJ '.uiOaHiii -ooWO1r1fi' **for-|jltHUtMrJfj 6 <V Tl nr!i U.n a h a u M H 9 o a! ei w rt owt otrni ~nOxif OU p. R , <u t(1.1 I&J UI HitNrl! 'r--QU->fI*r(u1nlf0jl d (1) tJ u u ni nf ill O --I t .t P R -i o o o OOOO <J-00<7>0> co <i <t \0 N N n r-IO O 'H vo vo m cr> -t o -- o o o o -I o o o ro s t t l c O .o c -i r'-i r -1 c i rn c i C'l --I O O --I OOOO nforiN rH C.I -o o -io o oooo o OOo o Oo o Os >, >s n| o) n XI cd X) 00 on t oo _V. _v? on y, y. on Ol 00 n t on B oo O r-i p--1 o --ao'ai0ti. ou onBj Mno &>*Hr:* S0v5lj oou V) o xo:- e QOr> g. V a & o 'S . Cvt o - i rH o o O O O o o o o o o O o o o O Oo o o t>S >, Tl o tN d Tv. T Rl TJ <*> t>n f>n y y. t>o y --S. y 00 bn 00 B on I! d oO O o r--1 o >S >S o cd >s cd T T /Vd. td Ti do on bn y. y y. 's . ' S 00 J,' bo on on n a ti 00 (1 oo o CO r-H r r >. >, o-. rl ni >v o t u ni u s. vs vi hO on (>0.y. y 00 y. (0 or 00 n f 00 Fl r o o -I oT--1 c r -i -( ai o vi i a) o ri 4 ri id ni rH y. ,*i ai CJ tfi al rH| --1 1d0 O V co -rl 0l ti urt '1-1 rl o x l ol ri E 01 O o .o u d fl >n a 0 .c -d pr. H d r--H1 frfll ai 0 u ni iu u 10 1 uu td 11 -i n d o >i .r. >i r | rl --t i O '11 m u ai i.i ti o r r.2 rt >i o Ir T nj rH O OO > c ti)OI .r-f< Ti rH e n OO 11 H f-i o i: 'II w o) i U) fli ri O U O h ni W) ,n (i xl a11i D l.l .ct: .r i> n i i 10 u n11) ot o M <U .n II ri <nn) u nu1.(0i ti u 0 o -199- TA3LE 37 TUMOR in c ide nc e in pemal X RATS MAIDTAINZD ON DIETS CONTAINING 2 , 4 , 5 - 1 FOR UP TO TWO TZARS Diagnosis Cjda Number or r a c s necroosied during the rise oeriod indicated 1-6 Months 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d a y 3 mg/kg/day 0 0 1 i H-15 H-IS 9-10 ?-25 ?-25 -j_57 LIVER Number oc t i s s u e s examined 0 0 mg/kg/day 30 mg/kg/day 10 m g/k g /d a y 3 mg/kg/day Hyperplastic nodula(s) 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day Heoacocallular carcinoma(s) 0 mg/kg/day 30 m g/kg/day 10 a g /k g /d a y 3 mg/kg/day PANCREAS Number oc "issues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreatic acinar adenoma . 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Pancreatic islet cell adenoma - 0 mg/kg/day 30 mg/kg/day 10 ng/kg/day 3 mg/kg/day Pancreatic islet ceil ader.ocarcinona 0 mg/kg/day 30 mg/kg/cay 10 mg/kg/day 3 mg/kg/day ORINARE SYSTEM Kidney Number oc tissues examined 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day Penal hemangioma 0 mg/kg/day 30 mg/kg/cav 10 mg/kg/day 3 mg/kg/day PIPi-ODL'CTIVl 3'iSTPM Dvarv Number of tissues examined 0 mg/.eg/nay 30 na/kg/dav 10 mg/kg/day 3 mg/kg/day 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 no 0 0 0 1 1 7-12 Months ? 2 2 i 2 2 2 1 0 0 0 0 0 0 0 0 2 2 2 i 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 1 0 0 0 0 2 n " 13-13 Months 17 9 11 21 17 9 11 11 1 0 2 0 2 0 0 0 17 9 22 22 0 0 0 0 1 0 0 0 0 0 0 0 17 9 11 11 0 0 0 0 13 3 3 3 29-? Months 31 13 25 13 31 13 25 IS 0 0 1 0 0 0 0 0 Terminal Cumulative K i l l PeSUUCS 3 6 36 21 50 11 50 19 50 36 21 11 ' 19 3 1 1 2 i 0 0 0 36 50 50 50 4 1 3 2 2 0 0 0 31 36 36 17 21 49 25 11 50 IS 29 50 000 000 10X 000 16 8 222 213 20 1 000 0 21 000 000 31 36 36 13 21 50 25 22 50 18 19 50 QQC I 01 'J 0 0 00Q 29 33 -7 17 20 -0 Tfi 11 -? 15 Data listed as number of rats for vhich the -isted observation ves oresent. 1 __ , j 1 .i i t>u *o r| U ntU . . | t -tI nV>) u t ;-J <f o o <- o o - o '- <--1 --1 0 0 o to n n n M <t N ' N . -s. n r o m cm oooo HPI n{.d M>J 't O ri fi 1 frii} cOrJ o o i ? ! 'O tMi . 3H r'l O W U i-l f ". 7. *t n t} DO rri oo oo f - . <r i- i <-l oooo rt r-i rt i oooo oooo O O -- i *-1 o o oo O O O OO O t rt oooo >> fc'' n| nj >> P} T T t i T -' T pp bP (rfi w .vi ,,r bn w> btn t H bt0 Oo o n -I m c<n (J rl T) 10 Vi O u :J -H ni -r) Vi t i o) T n- MJ T T O -.4 01 01 in r i u U O- H nj <11 O i tJ .O 1 -t (3 J U di . Dr t Tt V . ti 1-1 -t rl to O nbf*flJ rt) Ot J n rj a H l/i to w H H u o a o Cti Oc L,i >> ^ nJ p >% nj T T ni T T X N) N v . W) -V? J*J bO A ^ b0 W) t tbit t t bO OO O n Mn U ni > o 'U o t V) ti r1 O. o a> tel -t (l o t ti tVoI d a ti u O >> bs >> ti ni ni 't T ni T T bt bO -^. bO y. W> t t60 b P ^ Mi t t bO O o rn O<--t n >S bs f*. nj nj t>N ni -t -t ni T ^ T Mi bO ho y. M) .V ^ ^ bfl NI t tbn El t bfl oo O M - I en >N >> n) nj f s n -el t ni T 'v. T \ t>n t>n --^ Mi A r' bP ,,vi -v . y, *-> bo on*--. on t bO t t oo o tn fH m O O ti t r l id >1 (U V) O d (0 /i rl IJ tli t r-l U (1) u n `M O V) VI 4) tr. XI o u3 ti tto >i O itj t .i t O rl U ti LF o i-i t- ^i o n. -H tti o n jj to T 0t trl ti X OI VI o t V) to t 1.1 t ti t rl bfi nJ > tj O Vi 01 .O t 7. M! I dJ) H'z'b O*-1OO *HOOO -.1 o --IO OO--I O OO OC? O O --I O O OOOO riOr-O OOOO 0 0-40 OOO1 o o o o f-4 o o o - 4 0 0 0 OOOO OOOO OOOO OOOO OOOO O O -IO 0 0 0 --4 OOOO OOOO OOOO OOOO OOOO o o o o OOOO OOOO OOOO O O O O OOOO OOOO 0 mg/kg/day 30 a g / k g / d a y 10 n g / k g / d a y 3 ng/kg/day Malignane senz'annona o ehe vagina >. >- nl ill J 3 'fl nl 3 *fl bn hfl _y '__y ,,y _hyf 00 Ml Mi fl 0 00 fl ns Oo O m -1 o Si tJ H 3 i nJ aJ 7l M O n] 0 O ri fl ni .fl u 0 L n rl fl <n cd nl fl u hfl in r | ni -1 ki n} D fl >> >> fl fl nl x i ;G fl fl Tl m> on Mt .y ^ Ml 'v, V , .y M) Ml Ml fl fl OP fl fl OO O O i--1 rO U 3 O Si u H w n Vt ni u fl o fl e o a rj fl U fl M fl fl fl U ofl U ffll fl 1.1 cl 11 s. fl >s ^ >y fl fl fl Tl G fl O --- XI bn Oil Ml ^ IV) .y OP 00 00 fl 0 00 fl fl OO o o --l o fl 3 M fl u 3 4-1 o' g o o M fl fl O y. * i*- > >> fl n > fl 3 -3 fl 3 u mi on on _y .y. f\f> .V? .y 00 on OP Fl fl 00 fl ri OO o r ? --1 ro fl 3 f. fl U 3 'M O fl fl O G Gfl S G U tO > . >fl fl X fl T '3 fl tj f'O Mi--. Ml .y .y. no .... .y Mi 0 0 ''on fl ri on fl fl oo o fl m jj M rl \ fl n) fl3 3 PO r! i.l ri .G M sno s. r- fl il o oIJ 3 li fl fl H fl fl O fl fl U M fl o .1 u fl d! rl X-31 n r - vO r-~- CO no CO CT <T n1 111 1 M XM .fffillI mroi. A n. '0 \i Mt a r; trfntl i.II fl n , f\i .11 f0l m fl oc: i , I <11 uo m M 11 fl -y n a 11 .o ;J n fl fluu 1j fli ni .-1 -1 o . r1 o a 11 r: .r! n p.r! d -.1 Ai n \>. H Si 1c 11 O 'i '1J fl o i) II fl fl 11 Xi 1i fi :! O r* 1.1 .1 fl n) -nO o : j 11 t: fl rn (Il ni 3 Tl (l) fl i.t U fl -frl1 1 .-1 fl fl i 1 fl fl O !f l -201- TA3LS 37 (C onc inue d) x TUMOR INCIDENCE III FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T "OR UP TO TVO YEARS Diagnosis Code Number or r a c s nacropsisd during he ciae period 1-6 Mnchs 0 mg/kg/day 30 m g/kg/day 10 a g /k g /d a y 3 ag/kg/day 0 0 2 1 7-1 2 Months 2 21 1 13-13 Mnchs 9 11 11 X-99 X-100 M-05 G-07 G-20 G-13 REPRODUCTIVE SYSTEM ( C o n c 'd ) Ucerus (Conc'd) Fibroma of ucarua 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day Fibroma of vagina MUSCULOSKELETAL SYSTEM Number o f c i s s u e s exam ined 0 mg/kg/dav 30 a g /k g /d a y 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/da y 3 ag/kg/day Rhabdomyosarcoma surrounding v e rc e b r a l column w i s h a e c a s c a s i s co lungs and subcutaneous tis su e s 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day GASTROINTESTINAL SYSTEM Oral Cavicv Number o f gingival cissues examined 0 mg/kg/day 30 m g/kg/day 10 a g /k g / d a y 3 ag/kg/day Fibroma or gingiva 0 mg/kg/day 30 m g/kg/day 10 a g /k g / d a y 3 mg/kg/day Tongue Number o f c i s s u e s examined 0 ag/kg/day 30 a g / k g / d a y 10 mg/kg/day 3 ag/kg/day S c ra c ifia d souamous c e l l carcinoma 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 ag/kg/day .Adenoma of g l a n d u l a r c o ao o n e n cs or - --13---- 0 mg/kg/day 30 m g/kg/dav 10 mg/kg/day 0 ng/kg/day 0 0 0 0 0 0 0 0 0 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 o 2 00 00 00 00 00 00 00 00 2 2 2 0 0 0 0. 0 17 9 11 11 0 1 0 0 00 00 00 00 0 0 0r\ 00 00 1 17 19 1 11 0 11 00 00 00 00 00 00 Q0 0J ` i s ^ a c a s nu-ib-3- o r - = r S w 'r--'i -re : seed o b se rv a tio n vas a ra s e n t. 19-24 Mnchs 31 13 25 13 T em inal Cumulative S ill Results 36 36 21 50 11 50 19 50 00 0 0 00 10 01 00 00 00 31 36 15 22 24 10 18 13 00 00 00 00 0 0 0 1 1 0 0 0 36 - 43 43 0 1 0 0 00 02 00 00 0 0 02 00 00 30 18 25 . 13 0 2 0 0 2 0 0 0 35 21 il 19 0 0 0 0 o 0 0 0 0 2 0 0 0 1 0 0 33 49 43 43 0 1 ,-v 0 0 0 J -7 du t> 202- TA3LE 37 (Concinued) TUMOR IMCEJENCS d ? 2 1 Z RATS MAIM7AIME) ON' DIETS CONTAIHIMG 2,4,3-T 70S. u? TO T0 'iZ A S S Qiagnos is Coda Number o r cacs necroosiad during cde cine period indicaced 1-6 Mcnchs 0 ag/kg/day 30 mg/kg/day 10 m g/kg/day 3 ag/kg/day 0 0 1 1 G-57 G-59 GASTROINTESTINAL SYSTEM (C o n c ' d) S eomach Number o r c i s s u e s examined Squamous polyp o f scomach mucosa S c ra c iiie d sauamous paoillom a of g a s tr ic mucosa 0 ag/kg/day 30 mg/kg/day 10 a g /k g /d a y 3 ag/kg/day 0 mg/kg/day 30 a g /k g / d a y 10 m g/kg/day 3 mg/kg/day 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 ag/kg/day 0 0" 1 2 0 0 0 0 0 0 0 0 G-76 G-77 G-79 G-34 G-35 Small Incascine Number o f c i s s u e s examined Mucocyscadenocarciaoma of small incescine Adenocarcinoma of sm all incescine Lymphosarcoma of sm all in cescin e Leiomyoma Leiomyosarcoma 0 ms/kg/day 30 a g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g /k g /d a y 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 ag/kg/day 30 a g /k g / d a y 10 a g / k g / d a y 3 ng/kg/dav 0 0 L 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .3 0 7-L2 Mor.chs 3 2 7 i 2 2 2 i 0 0 0 0 0 0 0 c 2 2 2 1 0 0 0 0 0 0 0 0 Q 0 0 0 0 0 0 0 0 0 0 0 13-13 Months 17 9 11 T' 17 9 11 11 0 0 0 0 0 0 0 0 17 9 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 31 13 25 18 Terminal Cumulative m i Jesuits 36 36 22 50 i i 50 19 50 31 36 86 18 21 50 25 11 50 17 19 49 000 00 0 000 10 1. 1 0 2 0 3 0 00 0 00 0 29 36 34 13 21 50 25 11 50 18 19 50 0. 0 10 00 00 0 J. 0 0 00n 000 00 o 011 00 0 011 000 00 0 000 000 10 1 00 0 0 L 1. 00 Q o 0 0 0 '0J D ata l i s t ad as number o f r a c s f o r v h i c h che 1i s c e d o b s e r v a c i or. v a s or25 e r. 0 . -203TA3LE 37 (Continued) TUMOR INCIDENCE IN FEMALE 'RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T "OR U? TO W O TEARS Diagnosis Cods Number o f r a t s necroosied during the time period indicated 1-6 Months 0 ng/kg/day 30 mg/kg/day 10 m g /k g /cay 3 ng/kg/day 0 0 1 1 5-11 S--12 S r 14 S-I 5r21 5-30 3-431 3-32 SU3CUTANE0US TISSUES, INTEGUMENT, .AND MAMMARI GLAND a^u o. c u c a n e o u s , c u a o r o u s )v l .Total number of subcucaneous tumors/number of r a ts bearing subcucaneous cuaor3 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 . 0/0 0/0 0/0 Subcutaneous lipoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Subcucaneous fibroma 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Fibrosarcoma ............... .... Subcutaneous carcinosarcoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Subcucaneous myxosarcoma 0 ng/kg/day 30 m g/kg/day 10 a g /k g /c a y 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammari ( n u m e r o u s ) a lo c a l number of /number of racs caneous cumors s u b c u c a n e o u s cucio r s bearing subcu- 0 ng/kg/day 30 ng/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary g l e n a f i b r o a d e n o m a / adenofibroma 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary g l a n d adenoma 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 Mammary g l a n d . cue m etastasis 0 ng/kg/day 30 mg/kg/day 10 mg/kg/tav 3 mg/kg/day 0/0 0/0 0/0 3/0 7-12 Monchs 2 2 2 1/1 2/2 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 2/2 1/1 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 13-13 Months 17 9 11 -1 32/14 15/7 12/9 12/8 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 32/14 15/7 12/9 12/3 25/13 11/7 12/9 9/7 3/2 1/1 0/0 1/ 1 3/2' 4/1 0/0 0/0 19-24 Monchs 31 13 25 13 Terminal Cumulative 'Cl 11 Results 36 36 21 50 11 50 19 50 \ 69/30 30/16 50/23 31/15 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 . 0/0 1/1 0/0 0/0 0/0 1/1 79/31 '41/19 22/10 33/17 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 131/76 38/44 35/43 76/40 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 1/1 69/30 30/16 50/23 31/15 51/25 15/10 35/13 14/9 10/6 3/2 3/2 4/4 1/1 } /r 3/0 2/2 79/31 41/19 22/10 33/17 131/76 33/44 85/43 76/40 62/27 2S/15 14/10 24/15 138/65 55/33 62/38 47/31 2/2 5/5 1/1 2/1 15/10 9/3 i/3 7/6 3/3 3/3 1/1 i ,*> 7/6 5 /5 i 4/4 'Data l i s t e d as to ca i number of th is type neoplasn/number of ra ts bearing ' "1! J __, | --i --; --iI -, 204 TA3LE 37 (Continued) TUMOR IMCIODCZ 221 H i A i SAIS MAINTAINED ON' DIETS CONTAINING 2 , 4 , 5 - T FOR ? TO TNO TZARS Oiagnos:is Code dumber o z raes necroosied daring che cine period indicated L- Months. 0 mg/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 mg/kg/day 0 0 ]_ i 7-12 Monchs o 7 2 2 S-33 3-34 3-3 5-37 S-41 3-42 5-72 5-763 3U3CuTANHOUS TISSUES. INTEGUMENT, AND MAMMARY GLAND (Coat ' d) Marxiarv (T um orous)3, (Cacic'd) Mammary g l a n d a d e n o c a r c i n o m a w i t h ecascasis 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 Mammary g l a n d cyscadenom a 0 mg/kg/day 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Mammary g l a n d f ib r o m a 0 mg/kg/day 30 m g/kg/day 10 m s/kg/dav 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Mammary g l a n d c y s t f i b r o a d e n o m a / cys tad en o f i b roma 0 mg/kg/day 30 mg/kg/day 10 m g /kg/da y 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Mammary g l a n d u n c l a s s i f i e d m a l i g nanc neoolasm (carcinoma with accomoanying fibrous p ro life rac i n ) 0 mg/kg/day 30 m g/kg/day 10 3 2 /k z /d a v 3 mg/kg/day 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 Mammary g la n d c y s c a d a n e c a r c i n o n a wichouc mecascasis 0 mg/kg/day 30 a z / k z / d a v 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Inteeument (tumorous)'" l o c a l number of cucaneous cumors/ number cf raes bearing cucaneous cumors'" 0 mg/kg/day 30 n^ /rc ^ /d ay 10 m g/k g /d a y 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Sauamous oaoillom a of integument 0 mg/kg/dav 30 mg/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Keratoacanthoma 0 az/kz/dav 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 13-13 Months 17 9 11 11 0/0 1/1 0/0 1/1 0/0 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 070 3/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 Q/C 19-24 Months 31 13 25 13 Terminai CucuLacivs K ill Resales 36 36 21 50 i i 50 19 50 1/1 0/0 1/1 2/2 0/0 4/4 0/0 0/0 0/0 1/1 0/0 2/2 2/2 0/0 i n 0/0 3/3 3/3 2/2 4/2 6/4 1/1 0/0 ' 2/2 0/0 3/3 4/4 3/2 0/0 3/2 3/3 0/0 3/3 1/1 0/0 1/1 4/4 9/7 13/11 4/4 1/1 5/5 7/6 2/1 9/7 6/4 4/3 10/7 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 2/2 2/2 0/0 0/0 0/0 0/0 0/0 o/c 0/0 0/0 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0 /0 3/0 j /Q Tocai number of ear canal cursors/ 0 mg/kg/iay 0/0 0/0 0/0 ; 1 o / c 1 '1 number of raes b e a rin a ear car.al 30 m g/kg/day 3/ 3 3/0 3/0 0/o 0.' 0 cumo rs 10 T.Z: k.2, CSV 3/ 0 c /0 3/ 3 0/0 3' 3 o/o 1 mg/kg/day 0/0 0/0 3/ 3 1/ - J / 'J - i s c e d as c o c a l number of c h i s cyme neoc lasm /num ber of r a e s ce a r ir . g c h i s : 0r neoplasm. aivfco 205 TABLE 37 (Continued) - D iagnosis Code Musber of r a ts nacropsiad during che e lse period in d ic a te d TUMOR INCIDENCE CONTAINING IM 2 , 4FE, 5M-ATL.EFORRATSUPMA10INTVAAQINEYDEAORNS 0IETS 1-6 Months 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 0 1 1 7-12 Months l 2 2 L 13-13 Months 17 9 11 19-24 Months 31 13 25 13 T erm inal Cum ulacive k ill R esults 3o 86 21 50 i i 50 19 50 SUBCUTANEOUS TISSUES, INTEGUMENT, AND MAMMARY GLAND (Cone ' d) Ear C anaia (C onc'd) 3-76 Zymbal g la n d c a rc in o m a o f e a r c a n a l 0. a g /k g /d a v 0/0 0/0 0 /0 1/1 . 30 m g/kg/day 0 /0 0 /0 0 /0 0 /0 10 a g /k g /d a y 0/0 0/0 0/0 0/0 3 m g/kg/day 0/0 0/0 0/0 0/0 3-73 Adenoma (se b a c e o u s) o f Zymbal 0 m g/kg/day 0/0 0/0 0/0 0/0 gland 30 a g /k g /d a y 0/0 0/0 0/0 0/0 10 a g /k g /d a y 0/0 0/0 0/0 0/0 3 ag/kg/day 0/0 0/0 0/0 1/1 NERVOUS SYSTEM N--36 '.7--37 \I-38 :r-70 Munber oc r is s u a s exam ined R ic u ic a ry adenoma corm acion(s) R icu ic ary adenocarcinom a'w ichauc ex pansion o r in v a s io n oc b ra in P itu ita ry adenocarcinom a w ith invasion of b rain P ir u ir a r y adenoma a r is in g from oars interm edia C ran ial C avity N eurofibrosarcom a 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 0 1 0 0. a g /k g /d a y 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day _ 0 0 0 0. 0 ag/kg/day 30 m g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10-a g /k g /d a y 3 ag/kg/day 0 .3 0 0 r\ J 0 0 0 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 m g/kg/day 0 0 0 0 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 ag/kg/day 0 0 0 0 l 16 2 Jm 9 9 0 10 0a 03 01 03 02 00 00 00 01 00 00 00 00 00 00 00 00 00 00 00 29 17 24 17 10 3 13 9 1 2 3 3 2 2 0 1 '0 0 0 0 0 1 0 ADRZNAL G1AXD Number o f -tis s u e s exam ined 0 m g/kg/day 30 m g/kg/day 10 a g /k g /d a y 3 ag/kg/day n 3 1 - 9 i_7 30 9 9 13 9 11 25 - 11 *3 ] j ,;2 LLSZ d as r.u ab er of r a r s fo r v d ia n " fie l i s r e d o b s a r v a r i on vas r r e s a n : . re d es o o c a l number o f : i i s -*/?- n a o p l a s r / n u n r a r or r a r s be r i n g r h i s v ,-pe of n e o p la s m . 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 1/1 0/0 0/0 0/0 0/0 0/0 0/0 1/1- 36 91 9 13 24 3 6 11 3 3 0 1 L 0 0 2 0 o 0" 0 32 49 44 45 42 19 20 23 6 5 3 6 5 9 2 9 I 0 0 0 00 00 01 00 36 35 91 50 11 50 50 IU `io1J (o f TA2LE 37 (Continued) TUMOR INCIDENCE IN FEMALE RAIS MAINTAINED ON DIETS CONTAINING 2 , 4 ,5 - 1 FOR U? TO TWO IEARS D iagnosis Coda Number o r ra c s necropsied during she lin e period in d ic a te d A -31 ADRENAL GLAND ( C a n t'd ) C ortex Adenoma of a d re n a l c o rta x A--41 A--44 M edulla A drenal oheochromocytoma, u n ilatera l A drenal oheochronocyrotna, n a iig n a n t, no m e t a s t a s is - u n i l a t e r a l Z -ll MISCELLANEOUS (C o n c 'd ) M e se n te ric liDoma 2-15 Abdominal bemangiosarcoraa Z-16 G ran u lo cy tic leukem ia 2-13 G en eralized m onocytic leukem ia 1-01 1-02 1YMPH0RETICULAR Lvnrah Modes - G e n e ra l G en eralized lymphosarcoma w ith videsorsad re ca sra sis In rraa b d o m ir.al V.monosarcocia or carcinosarcom a or a n so e c iiie d o rig in virr. vicesoraac c erescssis L-6 Motic ha 0 m g/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 m g/kg/day 0 0 1 - 7-12 MoncMs ? 2 ? 0 m g/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 m g/kg/day 0 - 0 00 00 00 0 m g/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 m g/kg/day 0 ag/kg/day 30 m g /k g /d a y 10 m g /k g /d a y 3 m g/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 m g/kg/day 0 -m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 C m g/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 m g/kg/day 0 m g/kg/day 30 m g /k g /d ay 0 ~*? ?/ d a v 3 ag/ g/ ay 0 0 0 1 0 0 2 0 0 ,00 0 0 0 O 1 3 - L8 Months 17 9 ii 2 2 0 -o 1 0 0 0 0 0 0 0 0 0 0 0 0 0 L 0 0 0 0 ,0 0 0 0 0 1 0 1 0 0 J J 19-24 Monchs 31 13 25 13 Term inal C iisuiacive R esales 36 36 21 50 50 19 50 o- 4 10 22 02 14 02 11 12 02 00 00 00 01 00 00 00 00 00 00 00 00 00 10 00 00 00 00 10 6 3 4 2 6 2 2 3 2 0 0 0 1 0 0 0 0 0 T, 0 0 0 1 0 0 0 0 1 i 02 l a .0 1 0 J01 1a L 0J 000 0 Dara l i i i e d as - u - b e - o- -o -s - 3 - w r ' c i -he V^53 p r s s a n c . o U (o~ L^ -207- TA3LE 37 (Conciaued) TUMOR INCIDENCE IN FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR UP TO TWO TEARS D iagnosis Code Number or r a t s necroosiad during Che tim e p e r io d ia d ic a c e d 1-6 Months 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 m g/kg/day 0 0 1 1 7-12 Mnchs 22 2 2 L-37 '-5 6 L-67 T-01 T-02 1-03 LTMPHORETICULAR (C o n n 'd ) M esen teric Lvaoh Node(s) Number o f t i s s u e s exam ined Lymphangioma o f m e s e n te ric lymph node Thvmus Number o f t i s s u e s exam ined Thymic lymphosarcom a SPLEEN Nuaber of tis s u e s examined * G eneralized m yeloid leukem ia apparently o rig in a tin g in spleen THTROID AND PARATHYROID T h y ro id Number o f t is s u e s exam ined Thyroid ia t e r f o l l ic u l a r C -c e ll adenoma Thyroid ia t e r f o l l ic u l a r C -c e ll adenocarcinom a w ithout necas c asis acenocarcnncma v im zietascasts 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 1 1 0 0 0 0. 0 0 0 Q 0 0 0 0 2 1 1 0 0 0 0 0 1 2 2 i 0 0 0 0 2 2 2 1 0 0 0 0 2 2. 2 1 0 0 0 0 0 0 0 0 0 0 0 0 13-13 Months 17 9 11 11 16 9 9 3 0 0 0 0 9 6 3 8 0 0 0 0 17 9 11 11 0 0 0 0 17 9 11 11 0l 0l 0 0 0 0 0 0 0 0 19-21 Mnchs 31 18 25 18 T erm inal Cum ulative K ill R esu lcs 36 36 21 50 11 50 19 50 30 36 17 21 25 11 16 15 10 00 00 00 24 36 15 20 22 10 16 18 00 10 00 00 30 36 17 21 25 11 18 19 00 00 00 10 84 48. 47 39 1 0 0 0 70 43 43 43 0 1 0 0 85 49 50 50 0 0. 0 1 30 36 85 18 20 49 23 11 48 13 19 50 123 236 022 2 11 10a i 23 0ii 000 0: 2 0I 000 1 01 000 D ata l i s t ec as number of r a t s fo r w hich th e l i s t e d o b s e rv a n t.on was pr s s e n c . 3 " S t a t i s c i c a l l y d i f f e r e n t from c o n t r o l d a ta '-h e n a n a ly z e d u s i .ng F is h e r ' s Exacc P r o b a b i l i t y T e s t , ?<0 .0 5 . -208- TABLE 37 (Conciauad) TUMOR INCIDENCE IN FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,i,5-T FOR U? TO TO TEARS D iagnosis Code Number o f ra e s necroosied during che cine period in d icated l-o Months 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 ng/'kg/day 0 0l - 7-12 Monchs p 2 2 1 THYROID AND ? ARATHYROID Farafty.roid Number o f zis s u e s exam ined 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 1_ 0 2 2 2 1 T-21 P a ra rh y ro id adenoma 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 0 0 0 0 0 0 0 Daca iis c e d as number oc ra e s f o r b ie n che .scad o b s e rv a tio n vas p re sa n e . 13-13 Months 17 9 11 11 17 9 10 9 0 0 0 0 19-21 Months 31 13 25 13 Term inal Cum ulative S ill lesu ics 3 36 21 50 11 50 19 30 29. 27 17 15 12 5 10 14 01 0i 00 00 75 il 30 34 1 1 0 0 TABLE 38 SUPPLEMENTAL TUMOR INCIDENCE DATA IN RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T Sex Dose (mg/kg/day) Number of Rats in Group Males 0 30 10 3 86 50 50 50 / Total Number of Tumors in Group 172 97 71 89 / Average Number of Tumors per Rat 2.0 1.9 1.4 1.8 Nuniber ol: T umor-bearing Rats/Number of Rats In Group Theye DaLa Listed in Time Intervals in Months: 1-6 7-12 .13-18 19-24 Terminal Kill 1/1 1/2 8/14 60/63 6/6 0/0 0/0 6/9 24/25 14/16 0/0 1/1 15/22 20/23 4/4 0/0 0/1 9/12 26/28 9/9 TotaLa 76/86 (88%) 44/50 (88%) 40/50 (80%) 44/50 (88%) Females 0 30 10 3 86 50 50 50 308 150 147 140 3.6 3.0 2.9 2.8 0/0 1/2 16/17 30/31 36/36 0/0 2/2 9/9 18/18 21/21 83/86 . 50/50 (97%) (100%) 0/1 1/2 11/11 25/25 11/11 48/50 (96%) 1/1 0/1 10/11 18/18 19/19 48/50 (96%) aNo statistical differences from control data when analyzed using Fisher' s Exact Probability Test, p<0.05. 0Ni> 1 5^ L I____ i 1 I____1 l------ J : j L - . - J . i ....... J ...... I ........j -210- TASLE 39 TISSUES EXAMINED MICROSCOPICALLY PROM MALE AND FEMALE PATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR 113-119 DAYS Tissues Liver Liver (oil rad 0) Kidneys Kidneys (oil red 0) Heart Pancreas Spleen Brain Spinal cord Peripheral nerve Pituitary Stomach Small intestine Large intestine Mesenteric lymph node(s) Skeletal muscle Salivary gland Testes Epididymis Accessory sax glands Urinary bladder Uterus Ovary Vagina Trachea Esophagus Aorta Thoracic lymph node(s) Thymus Lungs Integument Thyroid giand Parathyroid gland(s) Adipose tissue Eyas Adrenal(s) Payer's patch Submandibular lymph noda(s) Subcutaneous lymph n c d e (s ) U n i d e n t i f i e d lymph n c d e (s ) N i c t i t a t i n g membrane Male 0 Dose (mg/kg/day) Female 30 0 30 109 10 10 10 9 10 . 10 10 10 9 10 10 10 10 10 8 10 10 10 10 -- -- -- 10 8 9 6 10 10 7 10 5 8 5 10 4 J 3 0 0 10 9 10 10 10 10 10 10 10 9 10 10 10 10 9 10 10 10 10 10 10 -- -- 10 10 10 8 10 10 7 9 6 10 5 10 4 2 1 J 0 10 10 . 10 10 10 8 10 10 9 7 5 10 10 10 7 10 10 -- -- -- 7 10 10 0 10 10 Q 10 10 1099 7 10 5 9 2 ]_ L/k 0 - 109 10 10 10 10 10 10 10 8 9 10 10 10 10 10 9 -- -- -- 10 10 10 3 10 10 9 8- 10 10 10 10 8 10 5 10 4 9 9 D a t a l i s t e d a s number o f r a t s f o r v h i c h t h e l i s t e d w l S S U S W .3 :d2 X 3 2 1 2 .^ 1 5 : microscopically. -2 1 1 - TABLE. 40 TISSUES EXAMINED MICROSCOPICALLY PROM MALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , ,5 -T POR UP TO TWO YEARS Number o f ra c s n e c ro p s ia d d u r in g Che tim e p e r io d in d ic a c e d L iver K idneys A drenals H eart P a n c rea s S o le e n P e rip h e ra l Nerve S p in a l Cord P itu ita ry B rain M e se n te ric lymoh Node 0 m g/kg/day 30 a g /k g /d a y L0 m g /k g /d a y 3 ag/kg/day 1-6 Mnchs 1 0. 0 0 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g /k g /d ay 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 a g /k g /d a y 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 m g/kg/day 0 m g/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g /k g /d ay 3 m g/kg/day 0 m g/kg/day 30 m g/kg/day 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g /k g /d a y 10 m g/kg/day 3 m g/kg/day 0 m g/kg/day 30 m g /k g /d ay L0 m g /k g /d a y 3 m g/kg/day 0 m g/kg/day 30 m g /k g /d a y 10 m g/kg /d ay 3 m g/kg/day 1 0 0 0 1 0 0 0 1 0 0 0 L 0 0 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 i 0 0 0 : 0 rJ\ 7-12 M onths ? 0 i l 2 0 1 1 2 0 1 1 2 0 0 1 2 0 1 1 2 0 1 1 2 0 1 1 1 0 1 1 1 0 1 1 2 0 1 1 2 0 I 1 2 0 1 0 13-L8 Mnchs 14 9 22 12 14 9 22 12 14 9 22 12 12 9 22 12 14 9 22 12 14 9 22 12 14 9 22 12 13 9 20 11 14 9 21 12 13 9 21 il 14 9 22 12 i? a 19 9 19-24 Mnchs 63 25 23 - 28 T erm inal C um ulative K ill R esults 6 86 15 50 4 50 9 50 63 6 25 16 23 4 28 ' 9 86 50 50 50 63 6 86 25 16 50 23 4 _ _ 5 0 _____ 28 9 50 63 6 84 25 15 so 23 4 49 23 9 50 63 6 86 25 16 50 23 4 50 28 9 50 63 6 86 25 16 50 23 4 50 28 9 50 63 6 86 25 16 50 23 4 50 28 9 50 61 6 82 25 15 50 23 4 48 24 9 45 63 6 85 25 16 50 23 4 49 27 9 49 39 6 32 2 i 16 49 22 4 48 26 9 47 63 6 36 25 16 50 23 4 50 23 9 50 60 6 31 23 16 43 20 2 44 25 3 42 2U 212- TASLS 0 ( C o n tin u e d ) TISSUES EXAMINED MICROSCOPICALL* FROM MAI, RAIS MAINTAINED ON DIETS CCNTAINI MG 2 , 4 , 3 - r FOR u? 10 TUO TEARS Number oc r a c s a e c r o o s i e d during the time period indicaced Small Incas pine Large Incescine Scomach Tescas epididymis Urinary Bladder Accessory Sax Glands Lungs S k e le ta l Muscle S aliv ary Gland Aortra o r L arge M a c i a s r i n a i Arcarv 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1-6 Monchs 1_ 0 0 0 0 mg/kg/day 30 m g/k g /d a y 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 a g /k g / d a v 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g /k g /d a y 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 mg/kg/day 30 mg/kg/'day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 20 T.2 / s ? / d a y 10 .T.5 / r'/ CSV 3 mg/kg/day 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1_ 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 7-12 Monchs 2 0 11 13-13 Monchs 14 9 22 12 2 14 09 1 22 1 ' -12 2 14 09 1 21 1 . 12 2 0 14 9 1 22 1 12 2 14 09 1 1 12 2 L4 09 1 22 1 12 2 14 03 1 20 1 12 2 14 03 1 22 1 12 2 i /. 09 1 22 i 12 1 14 03 20 1 11 2 12 0 1 7 10 2 14 0c 1 *>o 1 11 19-24 Monchs 63 25 23 23 Terminal Cumulative R ill Results 6 36 15 50 4 50 9 50 52 25 23 25 63 25 23 27 62 25 22 27 63 25 23 28 63 25 23 27 62 25 22 23 62 25 23 23 63 25 23 23 62 25 22 25 59 13 23 25 50 25 2^ 27 6 16 4 9 6 16 4 3 6 16 /. 9 5 16 4 9 6 16 4 9 6 16 4 9 6 16 4 9 6 15 4 9 6 15 4 9 6 15 3 5 i5 4 9 35 50 50 47 86 50 49 48 35 50 49 49 86 50 50 50 36 50 50 49 35 49 47 50 35 49 50 50 S6 50 50 50 34 48 47 <*6 so -5 43 44 33 50 -3 -3 -2 1 3 - TA3LS 40 (C o n tin u e d ) T ISSU ES EXAMINED MICROSCOPICALLY PROM MALE RATS MAINTAINED ON D IETS CONTAINING 2 , 4 , 3 - T -OR UP TO TNO TEARS Number of r a t s n e c ro p sie d during the time period indicated 0 mg/kg/day 30 a g /k g /d a y 10 mg/kg/day 3 ag/kg/day 1-5 Monchs 1 0 0 0 7-12 Months 2 0 1 1 13-13 Months 14 9 22 12 19-24 Months 63 25 23 28 Terminal Cumulative K ill Results 6 36 16 50 4 50 9 50 Thyroid 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 2 13 63 6 34 0 3 24 16 43 1 22 23 3 49 1 12 23 3 49 Parathyroid 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 1 12 60 6 79 0 7 24 12 43 0 19 22 3 44 1 10 25 6 42 Esophagus 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 1 14 62 6 84 0 9 25 16 50 1 21 21 4 47 0 12 28 9 49 Trachea 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 2 14 62 6 85 0 9 24 16 49 1 22 23 4 50 1 12 28 9 50 T h o r a c i c Lymph Node 0 mg/kg/day 30 mg/kg/day 10 mg/kg/day 3 mg/kg/day 1 0 0 0 2 13 59 6 81 0 7 21 16 44 1 22 23 3 43 1 11 27 7 46 Thymus 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 ag/kg/day 1 0 0 0 2 12 43 1 59 01 4 14 22 17 12 3 38 35 1 10 19 7 37 Integument 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 1 9 59 6 75 0 5 23 16 44 0 16 19 4 39 0 7 27 9 43 Tongue 0 ag/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 1 13 63 6 33 0 8 25 16 49 0 19 23 4 46 1 12 28 9 50 Eyes 0 mg/kg/day 30 m g/kg/day 10 mg/kg/day 3 mg/kg/day 0 0 0 0 2 13 61 6 32 0 9 25 16 50 1 20 23 4 48 1 11 28 9 49 Remarkable Mesenteric 3Iood Vessels Mammary Gland 0 mg/kg/day 0 1 6 35 3 45 30 m g/kg/day 0 0 1 11 5 27 10 mg/kg/day 0 0 3 10 2 20 3 mg/kg/day 0 0 7 12 5 24 0 mg/kg/day 0 0 0 4 1 5 30 a g / k g / d a y 10 m g/kz/dav 0 0 0 0 I0 S 3 2 q 3 2i 3 ag/kg/cay 0 0 6 2 12 In a d d itio n to the standard l i s t cc 'i s s u e s presented above, c e r t s in o che r tessu e s were exani ned n ic r o s c o o i c a i i v , nose ocean due to a g r o s s iy - r e c c gnicad les io n . Ihese t is s u e s a re l i s t ed below. S u b c u t a n e o u s Lymph Mode 0 ag/kg/day 0 0 0 3 L4 30 a g / k g / c a y 0 0 1 3 4 3 10 a g /k g /d a y 0 0 0 3 I 4 3 ag/kg/day 0 0 i A 16 i ___ ._|}\ --) ! --i --- i : --* RWC."? TABLE 40 ( C o n t i n u e d ) T IS S U E S EXAMINED M IC R O S C O P IC A L !? PROM MALE EATS MAINTAINED ON DIETS CONTAINING 2', 4,, 5 - T POR UP TO TNO TEARS Number o f r a t s n e c r o p s i e d during the time period indicated 0 ag/kg/day 30 n g /k g /d a y 10 a g /k g / d a y 3 ag/kg/day 1-6 Months : J 0 0 P in eal Gland 0 mg/kg/day 30- m g /k g /d a y 10 m g/kg/day 3 mg/kg/day Remarkable T horacic 3iood Vessels 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day S u b a u ric u la r Mass 0 ag/kg/day 30 m g/kg/day 10 a g /k g / d a y 3 ag/kg/day Urecar/Urechra 0 ag/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day C e r v i c a l Lymph Node 0 mg/kg/day 30 m g/kg/day i0 mg/kg/day 3 ag/kg/day Hard P a la te /N a sa l T urb in ates 0 mg/kg/day 30 a g / k g / d a y 10 m g/kg/day 3 mg/kg/day Mesentery 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g /d a y 3 ag/kg/day Remarkable M ed iastin al Tissue 0 mg/kg/day 30 m g/kg/day 10 m g /kg/day 3 mg/kg/day P re p u tia l Gland 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g /d a y 3 mg/kg/day Cecum Oral Cavitv 0 mg/kg/day 30 a g / k g / d a y 10 n g / k g / d a v j ms / -=> 0 r.s/V;s/csv 30 a g / k g / d a y 10 n g / k g / d a y 3 mg/kg/day 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7-12 Months 2 0 1 13-13 Months 14 9 22 12 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 -0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 >J J 0 0 i 0 0 0 1 0 0 0 1 0 1 0 1 j. 1 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 2 ? 0 0 0 0 0 0 j 0 0 j r\ r\ 19-24 Months 63 25 23 23 Terminal Cumulative S ill P.asuics 6 36 15 50 4 50 9 50 2 0 0 0 0 2 0 1 4 0 2 0 0 0 0 1 0 0 0 0 2' 1 1 2 6 0 1 3 7 0 0 0 3 1 1 0 1 0 0 - 1 n 0 i J 2 0 0 0 0 2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 c 0 1 0 0 0 0 0 2 J 0 0 0 1 0 0 1 0 0 5 0 0 0 1 4 0 1 5 1 2 0 1 1 0 1 0 1 0 0 4 1 1 2 6 0 n 4 7 0 2 2 - 1 0 1 r\ 1 1 1 0 0 X \^ 7 b TABLE 4 0 ( C o n tin u e d ) T IS S U E S EXAMINED M ICR O SCO PICA LLY FROM HALE RATS MAINTAINED ON DIETS CONTAINING 2 , 4 , , 3 - T "OR UP TO TNO TEARS Number of r a t s n e c r o p s i e d d u rin g che tim e p e rio d in d ic a te d 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 1-0 Months 0 0 0 7-12 Months 2 01 ' 13-18 Months u 9 22 12 LymDh Nodes (unknown o r i g i n ) Rib C ran ial Nerve or C ran ial Cavicy R e t r o p h a r y n g e a l Lymph Node R e tro b u lb a r Mass Lip P e r i a o r t a l Lymoh Node 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g /kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day - 0 mg/kg/day 30 m g/kg/day 10 m g/kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g /kg/day 3 mg/kg/day 0 mg/kg/day 30 m g/kg/day 10 m g /k g /d a y 3 .mg/kg/day 0 0 0 o' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19-24 Months 63 25 23 28 Terminal Cumulative K ill R esu lts 6 36 16 30 4 30 9 50 101 000 000 0 0 1 L0 1 000 101 000 10 2 000 101 000 0l 000 000 000 000 1 0. 1 000 000 000 000 101 000 000 000 101 0 0 0 D ata oa Cumorous aad nontum orous g r o s s ly - r e c o g n i 2 ed su b c u tan e o u s aad cu tan eo u s n o d u les o r m asses a re lis te d in Table 34. 216- TABL2 1 1 1 TISSucS 33LUC2IZD .'GCSCSCOPICALL? .TPflii TZiALZ 2ATS ON DIZTS COSTAZOTISG 2 ,4 , 5-T 702. G? to rro 72A2S Nuaber c i r a ts n ecrn rsied cu ria ; the r is e period in d ic a te d L iv er Sidneys Adrenals learn Pancreas Spleen P eripheral Nerve S p in al Cord P ituitary 3raia 0 ag/kg/day 30 a ;/k g /d a y 10 = g /k g /d a y 3 a;/kg/day 1 -6 Months 0 0 x 1 7-12 Months 2 2 2 i 13-13 Months 17 9 22. u 0 ag/kg/day 30 mg/kg/day 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ag/k g/d ay 10 ag/k g/d ay 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 ag/k g/d ay 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 ag/k g/d ay 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ng/kg/day 10 a g /k g /d a y 3 ag/kg/day 0 mg/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day ' 0 mg/kg/day 30 ag/kg/day 10 ag/k g/d ay 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 ag/kg/day 3 ng/kg/day 0 ag/kg/day 30 n g /k g /d a y 10 n g /k g /d a y 3 ng/kg/day 0 -- day 30 a g /k g /d a y 10 a g /k g /d a y 3 ng/kg/day . 0 0 1 1 0 0 1 1 0 0 1 1 0 0 1 0 0 1 1 0 0 1 7 0 0 2 1 0 0 1 0 0 1 0 0 0 n 1 'jI 2 17 29 2 11 i 11 2 17 29 2 11 1U 2 17 29 2 11 2 11 2 17 29 2 11 i 11 2 17 29 2 11 1 11 2 17 29 2 11 2 22 2 IS 23 2 10 0 11 2 17 29 2 11 0 22 1 16 29 i9 0 10 2 17 29 2 11 1 17 2 16 19 19 03 19-24 Months 51 IS 23 13 Terminal Cumulative K ill Sesulrs 36 86 21 50 u 50 19 50 31 36 36 IS 21 50 2S U 50 IS 19 50 31 36 36 18 21 50 23 11 50 IS 19 50 30 36 35 18 21 50 25 22 50 13 19 50 31 36 36 13 21 50 25 11 50 IS 19 50 31 36 36 17 49 25 11 50 13 19 50 30 36 85 17 22 49 25 7i 50 is. 19 50 30 35 33 17 27 47 23 10 46 15 13 . 45 22 36 36 IS 22 50 25 u 50 13 19 49 29 36 32 17 21 49 24 9 44 17 18 45 32 36 35 13 7*7 50 25 21 50 13 19 50 30 36 34 17 22 4S 2w - * *7 26 25 39 -217- TA3I.2 41 (Concinued) TISSOSS -2I2IHJ MiaOSCOEICALL? 77.011 notALZ SAIS M A H m i H S D ON DXZTS C O N T A I S a G 2,4,5-T ~0R 03 10 TVQ T2.US Number o z raes n ecrop sied duriag sha s is a parlad iadicacsd Smail Incas cine larga lacascine 3Cama.cn O vary(ias) Gvxduces'} tlriaary 31addar Ucarus Langa S k eleca l Mnscia . S a liv a r j Gland Aorta or lar^a Msclastinal Arceoy 0. ag/k g /d a y 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ag/k g /d a y 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ag/k g/d ay 10 ag/k g /d a y 3 ag/kg/day 0 ag/kg/day 30 ag/kg/day 10 ag/k g/d ay 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ag/k g/d ay 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 ag/kg/day 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 ag/k g/d ay 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 ag/kg/day 3 ag/kg/day 0 ag/kg/day 30 ag/kg/day 10 ag/k g /d a y 3 ag/kg/day 0 ag/kg/day 30 ag/k g/d ay 10 ag/kg/day 3 ag/kg/day 1-6 Moneas 0 0 1 1 0 0 1 1 0 0 1 1 0 0 1 1 0 0 1 1 0 0 1 L 0 0 1 0 0 1 2. 0 0 1 1 0 0 1 1 0 0 J. i 0 0 L 0 7-12 Moneas 2 2. i 13-13 Moneas 17 9 11. U 19-24 Moncha 31 13 23 13 Terminal C uaulscive X111 R esa les 36 36 21 30 i_i_ 30 19 50 2 17 29 36 34 2 9 13 21 50 2U 25 n 50 i u. 13 19 50 2 16 9 31 16 36 n 35 43 2 11 25 U 50 2 11 13 19 50 2 17' 31 36 86 2 9 13 21 50 2 11 25 ij. 50 11 17 19 49 2 15 31 36 35 2 9 17 21 49 2 11 24 11 49 2U 13 19 50 2 lo 29 33 77 2 9 17 20 48 2 3 20 11 42 i 8 . 17 15 42 2 17 30 32 31 2 9 17 21 49 2 10 24 10 47 L 10 13. 17 47 2 17 31 36 36 2 9 17 21 49 ? 11 24 H 49 1 11 13 19 50 2 17 31 36 36 2 9 18 21 30 2 11 25 50 1 11 13 19 50 2 17 31 36 36 - 1 9 15 21 46 2U 24 10 48 0 U 13 13 43 2 13 29 36 32 O 9 15 20 45 2 9 21 11 44 2 11 17 13 43 3 L 30 36 33 2* y 10 15 23 'O1 11 4 47 i 11 15 19 4; -2 1 3 TA3LE 41 ( C c n tin u e d ) TISSU ES ElCAMIirED M IC R O SCO PICA L!? HICM TEMALE RaXS MAINTAINED ON D IETS CONTAINING 2 , 4 , 3 - T TOE UP TO TVO TEARS Number or r a t s n e c r o o s i e d during the time period indicated 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day 1-6 Months 0 0 1 1 7-12 Months 2 2 2 i 13-1S Months 17 9 H u Thyroid Parathyroid Esophagus Trachea T h o r a c i c Lymph Node Thymus Incegutaen c Tongue Eye(s) Remarkable M esenteric Blood Vassals Mammar v Cland 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 m g/kg/day 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g / k g / d a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 a g /k g /d a y 10 a g /k g /d a y 3 ag/kg/day 0 mg/kg/day 30 a g / k g / d a v 10 a g / k g / d a y 3 ag/kg/day 0 mg/kg/day 30 m g/kg/day 10 a g / k g / d a y 3 ag/kg/day 0 mg/kg/day 30 a g / k g / c a y 10 a g /k g /d a y 3 ag/kg/day 0 ag/kg/day 30 m g/kg/day 10 a g / k g / d a y 3 mg/kg/day 0 ag/kg/iav 3C m g /k g /c a y 10 a g /k g / d a y 3 mg/kg/day 0 ag/kg/day 30 a g / k g / d a y 10 a g / k g / d a y 3 ag/kg/day 02 02 1 ? 1i 02 02 I2 01 02 oT 2 li 02 02 1? 1i 0i 02 12 1i 0i 02 12 0 0i 00 00 00 01 0 L 02 00 01 02 12 11 00 00 00 0 'j 00 q3 vj 0 o-J\ 17 9 11 11 17 9 10 9 17 9 3 11 17 9 11 11 14 3 9 10 9 6 3 8 3 6 7 10 IJ Q 11 11 17 9 10 11 2 0 1 1 7 i 4 9 19-24 Months 31 13 25 IS Terminal Cumulative k ill Results 36 36 21 50 i i 50 19 50 30 36 35 IS 20 49 23 11 43 13 19 50 29 27 75 17 13 41 12 5 30 10 14 34 31 33 36 17 21 49 25 11 47 13 19 50 31 36 36 13 21 50 25 21 50 13 19 50 26 33 74 13 19 42 21 11 44 17 17 46 Z4 36 70 15 20 43 22 10- -J 16 13 43 27 36 72 16 21 43 25 l i 43 IS 19 47 30 35 33 13 2 i 49 25 i i 43 13 19 43 31 36 35 13 21 50 25 11 49 13 19 50 2 9 11 0 60 315 ? 53 16 2 6 4 9 3 13 20 L2'-0j 3 -- 22 30 -219- TABLE 41 (Continued) TISSUES EXAMINED MICROSCOPICAL!? PROM S l U i RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T 70S. CP TO TWO TEARS Number or r a t s a e c ro p sie d d u rin g che cin e p e rio d in d ic a c a d 0 mg/'kg/day 30 m g/kg/day 10 m g /k g /d ay 3 m g/kg/day 1-6 Months 0 0 2 7-12 Months 2 2 2 i 13-13 Months 17 9 11 11 19-24 Months 31 18 23 13 T erm inal Cum ulative R ill R esults 36 36 21 30 11 30 19 30 la a d d itio n to th e sta n d ard l i s t or tis s u e s pr e se n te d above, a d d itio n a l tis s u e s were examined a ic r o s c o p ic a lly , m ost o fte n r e s u ltin g from g r o s s ly - reco g n ized le s io n s , and th e se c is su e s a re lisce < below. S u b c u ta n e o u s Lymph Node 0 m g/kg/day 0 0 2 3 5 11 30 m g/kg/day 0 0 1 2 4 7 10 m g /k g /d a y 0 029 1 12 3 m g/kg/day 0 0 5 6 3 14 P in e a l Gland 0 m g/kg/day 0 6 0 0 0 6 30 m g /k g /d ay 0 00 0 0 0. 10 m g /k g /d a y 0 0 0 0 0 0 3 m g/kg/day 0 0 1 0 0 1 A bdom inal Mass 0 m g/kg/day 0 0 0 1 0 1 30 m g/k g /d ay 10 m g /k g /d a y 0 0 0 0 0 1 0 0 0 0 0l 3 m g/kg/day 0 0 0 0 0 0 C e r v ic a l Lymph Node 0 m g/kg/day 0 0 0 0 1 l 30 m g/kg/day 0 0 0 0 0 0 10 m g/kg/day 0 0 0 1 0 1_ 3 m g/kg/day 0 0 0 0 0 0 P a r a v e r te b r a l Mass 0 m g/kg/day 0 0 0 0 0 0 30 m g/k g /d ay 0 1 0 0 0 1 10 m g/k g /d ay 0 0 0 0 0 0 3 m g/kg/day 0 0 0 0 0 0 Remarkable M esenteric T issue 0 m g/kg/day 0 0 0 3 2 5 30 m g/kg/day 0 0 0 0 1 1 10 m g/kg/day 0 0 0 1 0 1 3 m g/kg/day 0 0 1 3 1 5 Remarkable M e d ia stin a l T issue 0 ag /k z /d ay 0 l 00 0 l 30 m g/kg/day 0 0 0 0 0 0 10 m g/kg/day 0 0 1 2 0 3 3 m g/kg/day 0 0 0 1 0 1- C l it o r a l Gland 0 m g/kg/day 0 1 2 0 0' 3 30 m g/kg/day 0 0 0 0 0 0 10 m g/kg/day 0 0 0 0 i. 1 3 m g/kg/day 0 0 0 0 0 0 V a g in a /V a g in a l Mass 0 m g/kg/day 0 00 0 1 1 30 m g/kg/day 0 0 0 0 1 1 10 m g/kg/day 0 0 0 0 0 0 3 m g/kg/day A J 0 0 0 0 0 G ingiva 0 m g/kg/day 0 0 0 0 0 0 30 m g /k g /d a y 0 0 0 0 1 1 10 m g /k g /d a y 0 0 0 0A 'J 0 3 m g/kg/day 0 3 0 0 0 0 1 } I 1 1 --' --, j ----i -- -- -- .. 1 Q .l^ 7 .I(O-'4u4 IP CJ LA D ata on g r o s s i y --r e c o g n iz a d su b c u c a n a o u s and c u c a n e o u s a a s s a s and n o d u le s a r e l i s cad i n iU h rt IkSLE 41 (C o n cin u ed ) 3one Marro r* ft. 55 c: e ft o M 1-*- 0O ' ft ft& P OQ 1 n ft JT ri n> c n ft n p 0 u> it sSo' u CD fPftt H 1 o O o ft- en H- fftt. 0 ag/kg/day 30 a g /k g /d a y 10 ag /k g /d a y 3 ag/kg/day U Ho Wo O O(^f0?jQqtNr..u\9?qrO(^\MTHQTUUf0jQQtcS3 (u |u S'ju f t . - f t . f t 4-4 ^ OW0q Hot uo t o t 00 o'f*VJqN'-t--.*0.U--QJQ*Kv-**. UO^^?QQrI^JfNtT- ^ tu tu ^fu ft. ft. ft oj t Ol">uO O t CM u t UQ JK- ^v~~- oQ oq OQ 7-r OQ '" -.(N OQ f t . ***. ft. *(<Uj f|1t]. |fut. ^(U '< ^ oooo oooo oooo oooo i~* t-- o O Oa n t--t Xr ftd (A ooo o oooo oooo o o o o oooo oooo oooo t -- ro to IO K o 'J p1 rt t fj' lo (n I---* yi---. fr b o P1 fl 1-- P' UJ V 3 1-1 Ul-t' HL/t g 55 l'i ot-i 0*x 1t*o11MH c*i a no m55 oCO hn 55 O hi - P I-- Ui 1 l-J O ?o d r-J O d Yw o O l-1o o --o o o --o o o o o o oooo oooo oooo oooo o O )- o o t--o o 0 1--0 0 O O o h-* SD r: !; I W0 <U c Cfl I(U- - n ri H- -221- APPENDIX 1 Month of Study When Sample Collected 5 5 5 5 5 7 7 7 7 7 12 12 12 12 12 ' 19 19 19 19 19 19 19 19 23 23 23 23 23 23 23 23 ANALYTICAL CONTENT OF 2,4,5-T IN DIET USED IN A TWO-YEAR TOXICITY STUDY IN RATS Content of 2,4, 5-T in Diet Samnles Intended Analytical Results 10,000 ppm 591 ppm 199 ppm 57.4 ppm 00.0 ppm 10,000 ppm 660 ppm 219 ppm 65.4 ppm 00.0 ppm 9000 opm 19Qa 530 ppm 180 ppm 63 ppm 2 ppm 9500 ppm 660 ppm 170a 240 ppm 63, ppm N.D. 10,000 ppm 698 ppm 223 ppm 77.7 ppm 00.0 ppm 10,700 ppm 740-760 ppm 250 ppm 89-97 `pom N.D. 10,000 ppm 760 ppm 276 ppm 81 ppm 654 ppm 192 ppm 66.8 ppm 00.0 ppm 10,000 ppm 714 ppm 253 ppm 76.7 ppm 650 ppm 212 ppm 60.4 ppm 00.0 ppm 10,000 ppm 760 ppm 250 ppm 62-67 ppm 590-670 ppm 200 ppm 64, DDm N. 0.b*' 9300 ppm 700 ppm 250 -ppm 150 ppm 660 ppm 240 ppm 94 ppm 15 ppm Dietary Dose Level me/kg/day Premix 30 10 3 0 Premix 30 10 3 0 Premix 30 10 3 0 Premix 30 Males 10 males 3 Males 30 Females 10 Females 3 Females 0' Premix 30 Males 10 Males 3 Males 30 Females 10 Females 3 Females 0 "Lover value excluded from calculation of average dietary content. bNone Detected. -222A??ENDIS 2 Dose n s /k s /d a v 0 30 iO 3 INDIVIDUAL AND MEAN 3QDY !-EIGHTS FOR, MALE RATS MAINTAINED ON DIETS CONTAINING : , 4 , ,5 -T "OR L13 DAYS Nuaber j 23 2 0 Davs en Tase 26 32 39 46 53 60 53 31 38 95 L0 2 116 75-594 238 323 361 366 339 36L 4 LO 417 425 434 457 463 465 463 431 75-595 233 333 365 330 396 363 414 433 443 440 469 471 474 435 464 73-596 252 320 342 367 374 394 414 432 449 402 46o 433 438 497 501 75-597 248 347 373 389 406 427 444 463 467 443 472 437 498 498 477 75-598 243 336 370 391 407 432 457 466 432 439 506 525 534 535 494 75-599 251 342 365 389 399 421 441 450 464 460 434 498 498 315 510 75-600 270 374 409 427 455 432 506 521 536 518 570 573 574 586 540 75-601 244 330 355 373 391 406 424 437 443 453 467 485 495 501 508 75-602 243 341 373 394 414 423 440 452 459 442 464 432 438 496 491 75-603 242 326 357 366 332 402 415 427 447 453 455 473 474 490 436 MEAN 247 337 367 334 401 412 437 450 462 454 431 94 499 507 490 iS .O . =9 =15 =13 =19 = 2 2 =35 =29 =30 130 =31 =35 i i 4 =32 =33 =29 75-624 253 327 359 330 388 405 420 436 443 445 462 470 47 6 455 477 75-623 235 314 347 369 379 396 416 425 423 425 451 446 454 471 437 75-626 250 346 363 395 4 U 427 443 463 470 494 506- 508 516. 526 537 75-627 245 325 348 350 365 378 396 408 424 442 451 462 471 434 491 75-628 248 362 399 .422 447 457 434 493 502 529 531 462 530 543 558 75-629 237 316 339 363 373 392 421 422 425 439 457 541 464 471 463 75-630 256 353 389 407 423 44 470 433 492 508 525 531 543 552 561 75-631 234 316 340 359 369 387 420 414 421 434 439 442 416 455 456 75-632 223 308 332 351 366 386 395 409 414 437 446 451 454 465 458 75-633 245 327 352 371 338 402 423 446 454 471 476 436 498 501 433 MEAN 243 329 357 377 391 408 426 440 447 462 474 430 484 492 494 S S .3 . CIO =18 = 2 2 =24 =23 =27 =30 =31 =31 =36 =34 =35 =42 =36 =42 75-614 247 324 352 371 330 395 406 421 429 436 459 458 391 473 473 75-613 229 297 311 325 336 347 357 361 372 356 336 339 476 405 409 73-616 233 313 340 357 369 383 4Q0 417 415 417 443 453 456 465 435 73-617 250 341 375 401 4L3 441 455 476 490 502 530 546 552 543 553 75-613 249 345 388 413 441 460 434 509 523 534 563 570 537 592 595 75-619 261 353 337 410 434 451 470 434 502 439 533 543 347 553 563 75-620 252 330 357 379 395 409 431 443 457 459 496 497 503 513 439 73-621 254 349 373 411 424 433 456 476 434 490 520 522 542 546 547 75-622 255 352 392 419 442 464 492 503 527 527 578 534 593 612 531 75-623 252 329 356 366 333 398 414 423 432 424 443 44L 450 457 460 KEAN 248 334 364 336 iQZ 419 437 451 463 463 495 500 510 517 512 rS .D . rlO =19 =26 =31 =35 =38 =43 =46 =31 =56 =61 =63 = 6 6 =65 =6 o 75-604 256 353 387 407 419 444 46L 475 493 490 510 515 524 521 529 75-605 237 325 357 383 392 415 430 445 457 456 471 476 474 476 477 75-606 244 339 330 399 423 453 473 496 512 497 460 552 564 569 569 73-607 242 333 351 370 335 400 408 419 433 436- 547 463 472 475 432 75-608 in 302 323 334 345 358 365 378 377 346 397 405 420 421 429 75-609 262 370 403 426 44 o 462 430 496 509 513 533 540 536 569 576 75-610 241 325 355 379 402 413 431 437 451 452 433 439 499 501 495 75-611 254 350 383 405 420 436 451 463 473 476 491 504 499 512 514 75-612 243 336 364 381 398 416 439 455 463 469 496 513 523 534 522 75-613 234 326 355 367 337 409 424 436 446 443 475 433 490 501 439 MEAN 243 336 366 335 402 421 436 450 462 453 436 494 502 508 508 =S.D. Cl 2 =19 = 2 2 =26 =23 =30 =33 =56 =40 =46 =42 =42 =42 =45 =44 Ko s c a c i s c i c a l l y s i g n i f i c a n e d i f f e r e n c e s from c o n c r o i m eaos u s in g Du n e c e ' 3 c e s e , ? < 0 .0 5 . ! --* ; i .- j -i --j --! __j -> ! __1 HA H *tfi 223APFZXDIX 3 IZTDIVIDUAL A*MD 300? VEICHTS "OR 721A.2 XATS AiyTA22f&D OS OIZIS CONTAINING 2 , 4 , 5 - t "OR, 119 3A?S Oose a z /fc z /d a v 0 30 10 3 Nusoer 6 Davs Otl T se 13 2 0 26 32 39 46 53 50 63 31 33 95 1 0 2 116 75-634 196 227 244 245 266 260 265 274 270 232 233 236 290 291 298 75-635 201 239 247 252 250 256 274 231 290 294 239 297 300 304 315 75-636 209 251 260 258 279 281 292 297 298 309 311 320 313 330 321 75-637 191 225 243 243 260 258 273 271 275 234 292 297 300 305 233 75-638 197 235 243 254 262 279 277 232 233 291 295 290 298 299 3L 75-o39 202 247 234 259 269 256 2S1 239 239 102 299 312 309 316 326 75-640 206 . 241 264 268 235 232 238 299 299 308 314 315 320 332 327 75-641 188 237 243 250 255 266 273 279 273 284 292 295 299 304 312 75-642 205 245 251 266 275 234 291 299 310 308 314 316 328 331 337 7 5 -6 4 3 ' 208 255 258 278 293 295 309 313 295 326 333 334 335 345 350 SA# = S .D . ZOO 240 7 2 1 0 251 259 270 274 232 238 =9 = 1 1 = 1 2 = 1 2 =13 =13 289 299 302 306 310 316 313 = 1 2 =14 =15 =15 =15 =18 =18 75-664 208 246 252 263 269 231 276 235 290 294 292 303 309 312 320 75-665 200 237 245 252 260 262 262 271 272 230 233 234 291 290 291 75-666 195 233 248 255 266 265 279 283 282 234 294 291 295 297 306 75-667 204 240 256 264 272 278 236 289 298 298 302 300 307 309 311 75-668 208 247 ,261 270 275 234 231 230 234 286 294 295 307 301 312 75-669 194 237 251 269 234 232 291 297 299 307 323 329 326 331 338 75-670 206 235 247 258 273 265 273 276 282 290 301 301 300 311 319 75-671 215 243 255 268 271 279 233 295 290 302 303 310 314 313 323 75-672 212 261 27S 292 298 301 307 324 318 325 332 335 345 341 357 75-673 208 242 253 261 270 270 234 236 233 294 298 311 315 314 308 MZAN iS.O . 205 242 255 255 ' 74 277 232 239 290 296 302 306 311 312 319 =7 ; 3 = 1 0 = 1 1 = 1 0 = 1 2 - 1 1 =15 =13 =13 =15 =16 : i 6 =15 =13 75-654 192 223 239 243 252 263 25 274 272 236 237 293 298 295 305 75-655 199 249 252 269 279 237 295 295 300 311 310 314 314 312 343 75-656 205 258 270 236 310 309 319 329 343 339 343 343 260 351 365 75-657 195 229 242 248 256 258 265 268 272 230 232 233 238 290 298 75-658 L96 237 254 ' 262 27.0 273 276 287 299 313 310 313 320 325 309 75-659 202 237 252 259 260 276 285 236 293 296 310 324 315 323 331 75-660 210 263 233 290 298 305 313 321 327 335 347 344 349 352 367 7 5 - i 194 229 236 246 252 256 262 266 270 279 231 278 276 292 301 75-662 197 246 254 261 260 270 277 231 238 297 302 299 312 313 338 75-663 197 230 246 250 258 266 272 275 277 237 292 . 300 301 308 299 MEAH 199 240 254 261 269 277 233 238 294 303 306 310 313 316 326 iS.D . =6 =14 =15 =16 = 2 0 =18 =2 0 =21 =24 =2 2 =23 =24 =26 =2 2 ' =27 75-644 194 231 245 253 263 266 233 236 293 293 295 297 299 303 303 75-645 206 243 265 275 282 298 309 309 313 317 323 331 333 330 3-3 75-646 199 233 252 253 265 2 b 274 233 231 292 296 293 307 320 316 75-647 203 239 243 252 260 257 271 277 272 2SS 238 291 303 299 312 75-643 199 237 257 264 272 264 278 236 235 29L 303 306 312 316 334 75-649 196 233 252 265 263 266 275 273 2 S1 290 294 294 302 307 334 75-650 198 239 243 253 257 271 271 230 274 235 296 296 294 308 299 75-651 204 242 261 256 273 279 292 298 294 304 310 313 316 264 75-652 203 250 256 260 253 271 233 295 296 308 313 312 316 322 331 75-633 204 253 276 290 273 290 297 308 320 321 327 324 333 337 342 JEAN 2 0 1 Z40 256 253 268 273 234 290 290 2 9 9 305 307 312 314 313 SS.O. :: =7 =1 0 =12 =3 =13 =13 = 1 2 =14 =13 =14 =14 =14 =13 =24 Mo s t a c s c i c a i l y s i g n i f i c a n e d i f e r e n c e s ire c o o c ro l a e a o s u s ic g O u n n a c c 's c a s e , ? < 0 .0 5 . SU -224- AFPEHDIX 4 INDIVIDUAL AND MEAN 30DY SIGHTS OF mal2 -UTS MAINTAINED ON DIETS CONTAINING 2 ,4 ,5 - T rOR 2 A S Oose r.g/kz/uay 0 >unoer 574 575 676 677 6 73 679 530 : L 632 533 634 635 536 637 638 639 690 691 692 693 594 695 696 597 698 699 TOO 701 "02 703 704 705 706 707 703 709 710 711 712 713 *1 /, 715 715 ' 17 713 719 720 721 VLL 723 724 725 726 727 723 729 730 731 732 733 734 735 736 737 733 739 74Q 741 742 743 744 7*5 *40 "4* ' -3 *49 730 *52 75] 754 755 7 56 73" 758 7 59 223 223 246 345 111 236 5 34 9 255 225 225 231 251 230 243 238 242 233 216 243 251 224 249 266 259 252 257 277 254 123 247 239 245 247 252 240 254 236 24 5 232 250 255 253 247 232 245 253 253 39 243 25 223 237 243 241 241 241 224 234 237 252 254 225 243 256 249 2*3 241 250 259 240 24 251 2*2 225 262 220 1- 233 229 2;4 250 251 232 233 257 239 340 134 331 303 343 310 354 272 308 230 319 297 343 233 330 304 352 273 325 293 333 293 33L 308 363 300 352 301 344 296 341 235 ' 325 271 303 262 304 294 336 MEAN23 290:13 33- 20__ 365 357 372 596 330 345 377 353 379 354 364 365 395 381 376 375 347 320 326 358 Days 3 c Study anti 3ody e i g n e s la : 15 22 39 ____4 333 397 4 LI 424 *33 337 *06 -23 444 *59 395 400 -25 *43 *36 412 -34 Lo 472 497 351 362 333 392 403 366 379 401 417 430 396 406 435 443 *70 369 381 399 4L" 444 392 409 430 *46 459 379 395 415 439 449 337 407 418 439 456 386 401 416 43<* 444 405 424 442 461 432 411 425 443 461 469 395 416 436 454 475 405 430 443 470 434 360 374 394 410 423 362 340 347 357 363 342 344 343 355 366 375 391 403 422 434 432 506 362 *15 392 455 42 455 431 514 384 443 412 435 427 495 394 414 352 43 393 377 4 392 442 392 452 336 459 393 457 331 426 360 412 365 433 411 413 383 433 400 465 388 437 385 4 54 346 336 397 460 394 4O 401 -69 363 413 412 4 416 4 58 401 *55 355 404 374 429 371 422 375 427 364 425 371 431 386 440 364 412 386 455 381 441 323 375 409 473 411 476 332 440 392 433 397 452 377 435 415 *7 5 373 423 334 -47 *07 43 L 33 4 '.9 34 L 398 296 -43 335 -51 369 - 20 36 2 415 343 595 379 *20 379 423 4j4 06 393 443 as ' -4L *11 4 83 335:21 396:36 10 *30:3 3 -4- :20 60 4 51 471 40 303 422 439 473 44 5 47 *56 47 454 495 439 437 500 435 373 369 443 53 *62 493 -74 521 435 457 498 *60 *92 475 475 470 522 506 506 516 ' 443 385 392 458 75 49 504 *rs 327 -40 43 -97 42 498 432 433 430 524 527 513 525 434 389 40L 467 31 *76 312 436 537 *43 472 5L3 -72 513 439 439 436 527 534 524 535 *64 396 410 479 J H 3 479:59 -33:39 LH &0 -225- APPSUDCX i (C oncim i ) INDIVIDUAL ANO MEAN 300Y 4cICKT3 OF MALI UTS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR 2 YEARS Dos-i TsAg.'day 0 Aniza1 :iuobr 75- 674 675 676 77 673 679 530 531 682 633 634 635 686 637 638 689 690 691 692 693 694 695 696 697 693 599 700 701 702 703 704 705 706 707 70S 709 . 710 711 7L2 713 714 715 716 717 713 719 720 721 722 723 724 *2: 726 727 72S 729 730 731 732 733 734 735 736 737 733 739 740 741 742 743 745 74 747 '-3 749 750 '5 1 752 '5 3 7 54 755 7 56 757 753 759 MEANrSD 38 430 520 494 547 453 435 520 427 510 497 502 496 545 332 543 542 470 402 415 434 493=43 )5 437 524 497 556 463 432 524 432 316 509 507 502 544 538 549 551 470 402 526 434 534 466 520 495 579 439 553 559 321 454 435 495 491 5 LO 513 513 43L 44,0 547 42 474 525 470 513 537 527 513 454 523 522 515 467 477 467 461 461 463 492 453 498 490 427 534 534 493 499 491 479 520 430 493 526 472 425 501 5 21 -30 -51 lii 477 64 574 512 37 513 493=36 ::3 509 559 432 590 479 516 535 503 539 536 525 507 595 562 366 564 434 419 44 L 512 521:46 : 2 5L3 531 539 591 4 90 525 553 514 565 549 530 532 635 576 606 534 509 429 473 526 657 501 555 507 43 524 591 594 56L 488 504 551 542 543 555 558 516 464 538 487 437 587 504 549 587 575 529 474 554 571 570 513 511 506 507 514 504 525 432 541 523 469 550 573 5 23 537 517 525 572 521 535 572 3C 465 543 579 312 -73 -56 -93 497 609 540 523 557 536:42 3avs o : ic u d y - nd Body W tUhcs Ln Gratas L75 -50 503 133 -B 5 3 530 545 540 552 531 591 600 609 636 652 561 559 571 554 605 603 620 615 523 630 506 515 519 532 529 550 555 567 579 538 539 577 6G7 617 619 530 54 543 561 567 574 536 600 612 537 567 530 576 589 610 553 543 566 571 . 580 553 549 564 538 60S 643 655 653 . 638 686 593 599 600 613 ,, 3 623 633 649 695 684 623 iO 605 637 657 520 432 530 552 562 436 4G4 452 476 430 501 503 519 531 549 550 550 5 580 709 722 734 530 544 554 607 631 644 553 562 574 634 709 725 553 580 570 64 5 671 677 644 657 672 533 601 508 511 535 5-2 540 546 556 577 585 503 577 592 606 569 588 533 530 396 6 L2 595 621 623 559 575 590 491 500 516 627 646 653 5L7 535 546 524 536 549 L 633 64 7 533 556 553 570 537 606 620 64 L 560 516 643 545 542 347 543 500 515 522 536 603 614 510 624 632 599 627 635 543 569 557 545 562 579 540 553 569 533 43 571 550 563 536 523 341 546 557 567 597 508 531 529 574 605 597 564 333 598 491 513 507 577 597 503 602 631 643 550 377 502 575 594 513 551 571 571 545 564 575 534 602 607 539 362 57 4 563 578 380 601 631 5 34 533 54 557 -99 510 22 560 :59 523 626 a63 5::- 537 3:4 360 305 51- 5-4 503 532 5 50 522 3-2 557 520 333 5-3 564 535 700 568 394 603 5-5 564 273 572 53C 515 560:49 361:57 2= 7 ;- 336:50 39:9 L 339 570 630 652 552 606 5 54 590 651 621 605 6L7 705 647 71C 674 530 491 563 598 749 575 630 395 743 594 833 700 834 572 570 618 633 805 639 66 5 606 532 672 566 566 6 33 533 618 .835 894 344 n50 656 7*> 593 602 53534 606 5 812 543 619 6L1 537 620 83.3 615 634 232 585 620 602 60 7 66 ; 332 639 - ;: 56 7 : 53" : a 362 '23 6 34 53n 618 ; :- -;t 3U 605 537 644 659 355 619 57' 536 655 630 616 627 673 654 732 636 539 507 567 513 763 571 705 500 755 511 704 713 650 571 530 633 636 509 643 573 620 534. 635 572 534 8 73 595 627 692 699. 560 655 553 587 613 607 595 533 603 376 625 563 623 622 543 519 569 519 64 33 539 6j 3 619 514 633 295 : -0 6 70 =50 : 55 229 57? 263 569 '3 3 6-7 513 5 21 527=52 34 9 602 632 847 630 351 516 663 233 653 625 626 634 701 663 715 676 595 500 569 508 774 573 716 593 755 592 697 714 530 554 563 612 626 622 2S 673 610 532 673 562 573 663 593 20 895 6.7 5 551 645 627 666 594 614 591 537 599 537 614 546 634 519 553 614 665 610 a2S 572 336 63: 600 6.07 676 535 253 653 6 '5 27535-51 56 L 562 . 745 644 605 60 5 3:2:54 377 600 639 653 633 561 522 671 599 31 630 642 641 720 630 7 3.3 679 601 508 575 614 733 539 740 615 761 817 705 '2 9 554 553 573 626 657 625 642 631 625 545 685 577 537 574 601 635 717 707 560 665 652 704 610 54 5 605 500 50 C1 629 363 553 620 550 632 S3 626 535 569 59o 64 7 611 619 597 2-5 3z3 7C5 553 5"7 : 250 579 *-4 651 622 13 615:55 oil W- & 1 -226- AP?NDIX i ( C o n c ia u e d ) Oose .:g /k g /d a y 0 Animal Mumoer 75- -05 674 515 75 538 576 574 577 521 578 569 679 653 630 690 631 616 632 536 583 540 584 685 654 6 8 6 743 687 693 588 589 695 690 6 2 3 691 . SU 592 572 593 625 694 300 695 593 696 743 697 613 598 7< 599 533 700 703 701 702 574352 :7q03l 580 580 705 524 706 571 707 534 708 654 709 691 710 532 711 712- 5oG 594. 713 536 714 ' 598 715 593 716 2 1 717 643 713 "19 595 720 703 566 573 543 725 729 523 555 723 608 729 505 730 U 731 615 732 542 773334 55149 735 637 736 551 737 544 733 572 739 539 635 53 742 599 743 64 7 744 533 745 529 74 703 *4 7 504 743 330 50 51 32 53 757 753 759 * :i 597 ; "9 500 530 336 33 7 s2 3 42 :5 3 [ND[VIDUAL AND JSAN 30DY WSIGHT3 OF iALS SAIS MAliTACNED Off OIETS CCNTAlNI.NC 2,4,5-T :0R I 1EARS 641 701 599 561 657 708 613 703 559 663 669 760 704 762 704 627 537 5S4 647 325 602 734 643 659 709 748 658 598 590 673 581 656 670 714 586 . 704 590 617 595 529 660 702 737 533 593 747 569 633 649 611 617 532 324 652 537 557 647 573 572* 702 544 544 493 505 566 552 543 ;-v* 524 333 7 14 5 Lu 615 5 20 535 732 5 35 622 5 5 6 :6 0 552 593 563 651 712 631 709 653 675 663 773 723 775 699 646 545 577 649 320 535 750 540 675 698 744 659 576 534 676 590 639 559 695 533 700 538 615 698 537 650 570 719 579 590 478 753 642 639 633 61 6L5 64 7 656 535 650 665 575 671 691 657 660 512 3a i 633 650 715 62 4 599 713 i 593 5 29 3 50 773 599 650 519 65 4 :6 1 Oays ac 5cudy ar.d 3ody ''ei-zr.ca la G raaa 546 691 559 646 713 632 598 559 663 637 753 695 770 877 642 535 564 643 323 577 726 541 563 oo 756 567 554 452 570 871 5i3 576 534 575 696 336 697 59 627 650 579 639 777 612 638 504 634 610 64 2 652 573 644 664 539 666 673 642 513 605 642 630 542 636 620 595 57.3 515 506 319 537 6 57 515 54 7 :6 1 540 -29 532 659 7U 635 536 534 676 578 711 690 . 634 640 533 543 542 784 572 677 534 644 560 754 53L 532 545 5L4 --D ea- 546 569 704 619 587 539 590 637 693 544 44Q 529 780 546 535 520 653 515 738 524 300 533 635 676 569 595 597 535 559 6 Z 530 519 5 59 576 635 595 573 533 823 833 2/ O 662 ;ai 690 563 619 600 556 640 559 636 663 646 505 565 521 636 511 627 629 610 393 553 51-3 559 52 5 390 523 373 5 3 2 :5 9 659 504 6L9 594 525 632 525 624 547 647 653 613 573 517 512 520 575 513 610 5 31 505 5 22 525 351 760 64 2 576 6 2 0 :6 2 550 506 534 511 510 -92 477 550 534 624 615 536 696 64 5 656 616 611 538 536 576 547 559 -O ead -- 513 501 565 550 520 602 570 531 553 431 -O ead- 643 579 549 708 591 536 551 610 -O ead533 500 757 364 622 --Oead-- 724 507 526 591 54 9 -Oead-- 579 634 535 571 631 620 509 613 513 533 553 Oe a d 1 ' 711 546 -O ead--Oeac-- 533 534 517 554 63 L 590 570 575 516 602 560 535 376 463 -Oead-- 50/ 643 --1 779 556 --Oead^ 733 622 535 639 595 619 634 601 493 573 533 G4 504 653 302 502 525 - - 'i 6 21 303 617 :65 453 546 :.7o 595 535 596 5 9 1 :6 . 57 L -Oead-- 596. 537 Oead 523 415 -Oead- -O eac- \'0 -Oead- 548:0 454 323 515 329 Oead 503 513r;1 3U 4 $ 2 - -227- APPENDIX (Coacinued) INDIVIDUAL ANO MAN 200Y VSICHTS OF SAL 2ATS .'AINTAINED ON OUTS CONTAINING 2,4,5*"T FOX 2 'iZAS Josa 30 Nuxoar 75- 0 ; 360 361 362 363 364 365 366 367 363 369 870 371 872 873 374 375 376 877 373 379 330 381 382 333 384 385 386 S87 338 339 390 391 892 393 396 393 396 397 398 399 900 901 902 903 906 905 906 907 908 909 MEAvNrSD ^44 233 237 233 244 243 240 230 -243 240 -263 252 246 242 244 261 231 226 225 235 257 233 231 232 49 234 238 242 25 i 240 244 254 262 264 230 253 249 265 244 239 256 244 243 257 239 243 24 247 - 236' 243=10 296 332 234 317 231 3X2 299 365 :04 33 291 318 288 326 232 325 - 287 329 276 \ 315 318 ' 353 297 339 296 329 238 331 290 324 237. 319 290 325 280 325 273 329 233 323 290=10 329=12 :a 370 339 333 369 378 339 347 344 346 334 395 366 353 361 355 343 360 356 36L 360 356=16 Oavs oc S cu d '/ and 3odv Ve. id e s in C ra s s 26 32 39 3 53 335 13 429 3 62 353 371 390 400 413 361 381 393 07 2 1 387 06 25 4 1 60 401 427 43 59 -75 359- 369 383 398 19 363 389 402 416 433 370 384 604 410 26 365 374 386 404 412 347 359 373 387 396 414 442 453 473 490 334 401 416 437 447 372 394 403 419 429 385 412 424 439 457 372 389 406 416 431 361 377 388 406 26 331 396 411 424 642 379 397 405 29 42 382 396 416 438 52 373 392 412 427 452 405 482 359 408 358 42S 381 449 364 413 359 429 353 419 327 373 408 475 347 391 402 439 379 440 404 465 376 427 360 423 377 425 370 426 4 LO 486 370 426 364 423 431 513 359 4t2 373 27 407 473 357 595 338 459 398 463 371 344 38 343 417 375=21 393:20 50 73 432 34 4 71 92 .24 447 44 L 626 06 99 75 444 73 5 39 56 51 64 74 452=23 -.0 98 45 44 5 83 503 3 60 446 43 413 525 464 49 484 460 652 6 493 489 5 503 47 54 94 511 47 469 437 449 4L7 533 476 455 636 464 459 475 474 -39 492 3L 512 452 61 99 513 50 71 450 453 429 542 473 467 432 469 64 477 83 38 92 SU 4 2 3 -223- APPENDIX 4 (Cocicinued) INDIVIDUAL AMD MEAN 30DY EIGHTS OF MALE RATS MAINTAINED ON DCSTS CONTAINING 2,*,i-T -OR. 2 TZARS Dose ng/kg/day :o A iiiaai Uuade? 73- 360 3oL 362 363 364 36 5 366 367 366 369 370 371 372 373 374 375 376 377 373 379 380 381 382 383 384 385 386 387 338 389 390 391 392 393 394 395 396 397 398 399 900 901 902 903 904 905 906 907 908 909 33 522 453 476 5io 525 453 430 457 460 423 551 437 434 495 480 479 483 495 502 511 SANrSD 437=29 95 530 459 475 ' 513 463 541 436 464 466 435 559 489 433 510 436 437 497 501 520 523 543 460 435 506 450 490 443 413 548 437 552 96 514 435 431 433 479 555 477 467 530 *61 434 525 440 323 536 431 425 452 492=33 123 510 473 495 5L4 553 482 510 467 473 449 570 503 502 550 501 503 501 524 536 547 508=32 152 564 497 3T5 533 564 503 537 433 499 465 612 514 530 554 530 523 517 ' 535 552 579 539 489 527 547 470 517 439 4 54 573 459 592 532 551 524 516 504 526 597 507 493 27 506 520 571 462 552 563 522 444 439 527:4 2 Davs oc Cudy and 3ocv yJei^hes In Grass 175 130 203 232 253 579 537 597 619 631 519 527 523 540 543 530 536 535 JOJ 576 559 567 572 599 14 601 508 611 644 637 522 525 527 532 5oo 54'6 553 546 367 534 511 513 504 532 511 525 526 525 567 563 484 492 436 504 514 523 635 545 6 6 8 679 537 545 550 564 577 333 568 557 531 594 573 538 575 595 565 539 539 557 574 583 530 536 545 570 580 515 539 538 594 574 556 568 563 567 599 564 573 592 607 607 590 597 598 519 6 14 617 667 661 512 532 547 570 599 607 573 536 593 486 505 518 556 563 532 509 564 547 474 504 503 625 569 72 482 503 5 12 632 669 673 565 593 05 595 617 629 538 544 553 533 549 563 563 569 576 561 576 592 625 623 641 532 562 570 506 527 535 525 543 544 631 37 43 506 576 J !3 552 617 t*3 499 5 L7 517 531 09 622 539 635 623 564 568 615 459 491 469 523 34 7 564 550:34 557:35 554:45 3:46 535=4 7 -91 669 568 601 633 557 592 610 562 582 536 695 603 597 607 591 595 539 622 4 7 644 637 562 640 6 L0 524 607 562 527 638 523 704 624 653 575 574 334 613 544 533 5T5 5 2 574 600 JJJ 54 1. 64 L 633 635 506 57? 606:47 3 U 349 631 533 507 44 531 05 514 559 594 545 724 612 615 , 601 599 617 537 35 55 52 538 565 55 09 523 23 571 533 725 554 717 632 654 576 536 599 26 606 609 557 652 577 23 j 34 545 553 639 5 54 512 596 632 530 510 522 697 507 597 532 600 549 712 622 609 500 579 594 602 35 544 473 37 563 662 531 539 13 571 54* 731 349 711 39 662 560 579 601 36 625 597 555 16 377 01 72 545 42 43 51 510 583 616=50 609=53 377 725 589 19 634 709 5 13 597 596 611 553 717 639 631 603 534 15 08 59 567 Dead 700 567 73 574 552 23 593 549 753 564 753 543 673 560 534 07 656 645 20 560 413 539 535 532 564 49 53 36 521 504 e ' 620=62 J ! J n __i - . --1 ! W H 1/ Dose '3/'day JO Aaiaai Nuaoe r 360 361 362 363 364 365 366 367 363 369 370 871 372 373 374 375 376 377 373 379 330 331 332 383 384 383 386 337 388 339 390 391 392 393 S94 395 396 397 398 399 900 901 902 903 904 905 9G6 907 908 909 MEANrSD 715 333 624 640 722 531 606 603 605 556 706 639 639 531 567 621 616 661 656 703 561 670 573 553443 52-2 552 732 56 5 725 679 572 592 591 624 671 654 633 560 592 538 711 536 643 666 538 311 601 6 2 6 :6 0 -229- aPPENT)IX 4 (Cjacinued) INDIVIDUAL AND MEAN 300Y -SIGHTS of MALZ 2ATS MAINTAINED ON DIETS CONTAINING 2,4,5-T :C& 2 YEARS 735 599 533 546 754 643 612 525 634 575 726 662 659 613 572 627 640 673 637 672 575 692 533 570 660 503 592 736 573 723 572 700 577 520 644 562 641 671 533 620 598 717 573 659 692 713 533 5T3 43;55 740 608 542 633 761 533 597 535 646 530 721 670 645 * 504 576 626 543 671 635 592 565 705 561 563 657 507 592 792 577 719 631 678 531 609 621 535 633 632 565 627 534 710 535 653 695 730 533 623 639:60 743 601 633 522 761 631 594 539 642 578 674 572 661 ' 607 612 534 672 677 632 553 715 517 577 543 637 593 792 571 711 673 679 503 624 507 623 673 557 642 710 592 653 632 745 575 624 541:61 3 c Scudy and 3ody V eijh s 531 559 537 741 733 303 595 590 541 542 536 620 538 574 763 760 754 603 577 543 577 556 561 636 537 635 652 639 531 552 599 666 667 678 657 656 543 565 533 622 624 613 631 635 632 634 633 633 677 676 54Q 529 524 713 723 723 583 5S1 531 543 524 625 602 539 600 601 608 798 770 757 530 533 532 539 632 570 576 691 664 663 677 508 606 614 621 598 all 483 444 593 694 632 691 567 544 542 642 O' OU 699 594 573 579 577 523 599 577 533 67? 536 749 751 751 514 500 520 629 626 531 636:66 623:70 636:66 693 574 a-53 536 750 621 560 593 570 -O ead- 560 653 628 362 726 576 608 613 703 566 677 662 -D ead593 617 511 643 -Oead- 566 498 569 611:55 o25 533 -O eaq---- 543 5L5 438 Dead 617 623 632 Dead 492 441 381 Dead 732 732 707 Dead 506 524 -O ead--D ead- 701 -- Dead-- 562 516 Dead 404 ---- Dead-- -- 704 695 11 -"Dead" --1 -D ead- 542 688 575 534 593 535 538 563 513 484 619 655 739 Deac 661 453 402 Dead 530 527 512 500 671 671 033 636 639 434 Dead 577 -Dead- v e43a9o - 433 559 576 554 753 620 607:77 556 64Q 753 Oead539 533:99 -D ead540 629 666 570 573*110 533 526 650 555 580:55 - 230- APPENDIX 4 (CoQcinued) INDIVIDUAL AND MEAN 300Y '-cICETS OF MALE RATS MAINTAINED ON OIETS CONTAINING 2 , 4 , 5-T FOR I YEARS POS ag /'< 2 /d ay LO ANunmiabaelr 3- 310 311 312 313 3LL 313 315 317 313 319 320 321 322 323 324 325 323 327 323 329 330 331 . 332 333 334 335 336 337 333 339 340 341 342 343 344 345 34o 347 343 349 350 351 352 353 354 355 356 357 358 359 257 247 237 237 272 240 234 253 250 259 212 232 247 239 252 253 249 242 238 252 238 259 259 254 245 234 254 242 24 253 223 260 247 256 246 243 250 263 252 253 233 240 252 243 250 230 253 24 245 244 MEAN SO 247 :1 1 5 309 297 230 232 329 308 234 303 298 305 274 300 301 231 302 324 303 235 239 237 297:15 L3 354 333 312 313 375 353 313 345 332 338 330 352 346 308 347 . 374 337 325 325 322 20 333 367 343 347 412 333 350 377 360 359 370 390 , 375 326 384 419 358 343 352 348 337:19 367:24 Pays 3 c Scudy and 3ody W eighrs La Grams 2s 32 9 -o 53 414 433 453 479 437 335 409 416 431 443 362 376 331 399 410 368 387 397 414 432 432 454 463 439 504 412 427 443 453 465 363 376 392 414 425 390 403 413 435 44 7 377 395 409 430 443 375 395 415 430 451 383 414 421 437 453 410 432 452 481 495 399 423 442 449 461 345 356 372 373 336 414 436 447 462 476 449 474 504 526 543 375 397 419 429 442 363 377 398 408 417 366 380 409 4 LI 423 365 387 ... 4~09... _ 419 433 335 - 363 " 393 459 394 443 363 430 404 479 366 422 413 474 396 473 331 426 403 463 316 353 401 437 373 432 416 430 381 444 388 462 407 497 412. 439 416 454 393 437 361 413 369 427 390 439 372 423 373 429 366 414 427 516 391 451 362 425 336 456 386:25 406:30 423:32 439:35 449:36 50 505 456 417 438 519 479 433 453 456 461 460 512 464 393 493 567 453 427 4 37 442 53 525 *76 436 459 521 496 452 439 4 75 476 476 530 437 398 514 * 535 471 449 454 457 r3 534 479 444 462 524 504 4 56 433 434 479 484 541 495 396 530 539 470 446 457 456 464 ;4Q 431:40 435:43 31 547 439 451 472 551 511 466 502 433 491 496 533 501 402 533 609 433 465 467 466 497:45 \ J n ! __ } i ! --1 _ i , APPENDIX 4 (Conclaued) INDIVIDUAL AND MEAN BOOT ^SIGHTS OF MALS RATS MAINTAINED ON DIETS CONTAINING 2,4,5"? "OR 2 TZARS >?sa a%i'<-2,Jd av Animai S'urahar 75- 10 lO ill 312 SU SIA 315 3 !>n 317 318 319 320 321 322 823 324 825 326 827 828 329 330 331 332 333 334 835 336 3.37 338 339 340 341 342 343 344 345 346 347 348 849 $50 $51 352 853 $54 853 356 357 353 559 NEANlSD 33 5 503 4 53 433 570 531 476 512 494 500 305 577 515 416 545 625 491 477 475 431 510:47 95 570 511 467 490 580 532 483 511 495 499 504 572 511 418 552 634 497 477 479 435 413 527 438 490 529 479 551 532 479 529 391 490 526 503 534 545 552 523 556 436 469 435 473 432 435 562 499 438 507 508:43 123 533 519 477 499 573 543 496 535 5LI 524 519 595 509 430 562 672 432 500 495 431 525:53 152 617 543 499 521 611 370 519 555 543 544 526 624 544 442 599 706 514 505 506 521 452 576 539 530 547 520 578 533 312 564 415 599 538 571 544 571 589 603 562 606 507 525 ui 503 515 527 611 545 511 544 543:50 Days oc Scudy aed 3cdv 'Jeizazs la Orara. 175 130 203 232 253 64 5 644 *47 570 6 71 562 53 572 533 506 524 529 529 544 561 534 545 545 5L 573 637 647 646 668 630 606 608 610 642 567 543 543 554 564 573 5cS 533 576 596 613 566 573 568 591 505 5 5 7 563 570 598 509 JJO 565 560 572 589 642 640 645 665 531 573 578 570 599 593 458 455 451 462 439 622 629 639 658 671 732 734 749 733 300 530 537 541 561 573 527 536 535 361 572 525 534 539 554 567 542 539 340 555 577 468 437 498 619 646 563 555 569 531 561 583 597 579 617 829 549 566 590 612 643 643 597 622 620 558 576 533 594 506 515 444 462 470 649 672 585 581 598 527 610 623 643 573 533 603 599 623 637 627 645 651 646 669 678 595 517 .625 627 546 563 539 539 571 563 592 536 506 536 525 539 539 533 563 550 560 530 592 632 669 571 372 539 605 537 530 559 580 595 5 0 4 572:60 577:60 575:54 593:56 509:57 291 314 349 596 7 *20 634 531 571 596 599 701 710 672 666 591 809 523 618 620 624 614 519 583 601 682 . 700 593 602 300 ' 3X3 637 705 737 330 531 592 575 531 534 593 533 530 522 534 63 5 700. 605 604 623 636 542 653 601 5L2 662 631 537 532 533 609 529 635 494 503 70S 711 540 662 643 670 626 633 637 69 679 634 635 698 5 33 645 635 693 590 598 521 625 -- Oeac---- 563 575 562 37 623 35 677 577 6?4 631 534 ^9 6LO 6L3 702 536 552 597 719 705 614 577 612 532 57 7 703 575 507 693 801 606 533 539 56 530 . - 702 596 630 655 593 674 623 5T5 591 508 598 673 639 642 662 633 4 54 697 607 633 575 537 643 631 636 559 601 625:55 635:59 628:59 37 7 71$ 54j 54^ 621 733 7-^6 1 26 577 629 653 593 712 579 515 706 324 610 592 596 547 Dead 733613 652 677 596 . ? 609 62S 591 532 714 694 S3 660 634 697 674 653 7C6 620 3J4 569 590 653 roo O-4 562 590 541:6 Dose ng/ '<g/ a 10 A n im a l Number *3- 310 311 312 313 314 315 316 317 313 319 320 321 322 323 324 325 326 327 323 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 343 349 350 351 352 353 354 355 356 357 353 359 72ft 543 545 62 L 735 7! 1 590 6a 9 563 725 564 516 711 324 610 593 501 530 756 620 653 630 603 744 593 519 590 527 703 593 544 553 532 599 663 542 702 517 665 560 572 66 7 691 654 565 590 -r* AiV'ENlKX 4 (C o tlC irtu e d ) INDIVIDUAL AND MEAN dOU* -.'glCHTS OF MALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-7 "OR Z YEARS Days 3 c S tu d y and 3ody ^ e ig n c s in C rac s 559 537 749 723 730 696 535 5 5 0 669 664 663 662 5 6 4 698 325 575 -D ead- 640 641 677 54 L 632 535 602 520 -D ead- 767 779 773 763 755 752 720 645 673 643 633 747 743 733 741 729 734 721 529 637 636 Dead 622 625 606 537 530 4j 2 353 556 o52 549 546 554 530 >49 527 338 Dead 557 6n 1 553 670 663 533 6 L7 56 7 553 51J 472 474 734 726 731 710 533 667 620 - o ; jouJ 573 542 . 543 552 539 529 541 517 451 446 309 Dead 727 701 711 639 649 596 842 346 332 325 314 730 756 625 527 551 431 501 590 533 570 575 550 521 621 317 532 520 438 494 410 573 521 --D ead- 764 749 -- -- Dead-- 539 640 536 629 Dead 571 557 536 Dead 674 -Deau 540 736 732 716 750 753 767 720 538 541 537 TLJ 501 595 543 " 7 Di-ad Dt-id Dea." Dead 708 Deau 723 715 739 732 745 712 64 3 _-ad 665 645 527 630 690 535 572 582 531 671 54m 536 534 600 700 690 672 - j / 547 613 Dead 720 735 759 Dead 673 646 500 675 661 534 705 639 525 Dead 535 _ D-ad 540 538 645 ' 530 513 512 567 532 355 556 531 564 676 577 670 660 541 507 497 433 447 Dead Dca,. 530 553. "01 591 531 560 - 11 5I9 696 694 593 eau ,, 'ad Dead 713 722 670 530 590 593 a77 e **a Deaa 565 604 395 573 Dead 51=30 647=30 640=93 549=3 1 550=79 643=39 a 550=10 6 >64 =30 516=125 559 =7! 3 c a c is c i c a l l y s l ^ n i i i c a a c i y d ix ie c e n c from che concroi. mean by Q uactecx'a =es =, =<0.05.. n CU -223- AP?SNDCX 4 (C o n tin u a d ) INDIVIDUAL AND MEAN 20DY WEIGHTS 0? MAX.2 .UTS MAINTAINED OM 01X23 CONTAINING 2,4,5-T ?OR 2 YEARS Oose Nusiber Days a t S tudy and 3odv - iz h c a ln Craa s Ttsg/l<g/d a v 75- 0 5 13 : q 15 32 29 46 5 3 50 53 75 31 760 227 7TL 256 762 238 7^3 219 754 248 735 227 756 251 767 243 768 260 769 233 770 246 275 303 276 258 299 255 292 291 307 301 236 324 359 3 77 395 417 431 443 59 435 492 4 97 24 386 406 414 436 444 4G 465 479 *22 -88 313 342 356 364 376 394 405 409 422 431 425 300 325 339 343 359 374 398 407 412 434 36 352 381 405 423 443 455 471 -34 502 506 511 299 320 339* 349 349 330 392 399 4 L5 -1? 330 354 372 230 400 417 429 -3 8 451 453 465 329 361 334 407 422 439 452 462 484 436 4 94 354. 392 408 421 438 459 476 439 513 518 522 361 402 434 454 460 487 503 522 541 546 552 325 349 375 394 410 420 429 440 452 461 467 77.1. 227 270 311 342 365 391 398 416 425 433 459 472 472 772 257 300 345 381 397 410 427 443 473 477 99 499 507 773 233 274 317 341 260 376 390 405 425 430 444 452 460 774 235 271 310 333 363 368 373 337 399 408 428 423 437 775 252 290 343 368 338 399 409 430 451 456 473 479 490 776 230 278 321 352 371 383 404 422 454 450 471 474 475 777 229 276 329 360 391 411 431 451 474 4 3 4 505 515 523 773 256 309 362 389 412 429 437 456 467 432 498 503 511 779 247 299 344 374 404 410 433 460 472 439 313 525 527 730 257 345 399 731 236 420 502 732 269 415 473 733 251 403 470 734 225 342 381 735 250 395 458 736 264 437 516 737 259 415 *75 738 258 388 452 739 239 383 433 790 223 343 334 791 253 404 472 792 268 413 486 793 255 390 439 794 235 339 381 795 223 358 403 796 230 797 253 365 420 394 2*64 798 225 382 450 799 222 346 392 300 24 384 432 301 237 393 63 302 256 384 432 303 243 383 450 304 257 414 81 305 240 392 453 306 247 331 307 241 390 449 30fi 254 OC 233 412 435 4CS 433 3 3 1 tI9 361r23 9 ,1 < 9 ^ 9 A??SIDIX 4 (Conciaued) INDIVIDUA!. AMD MEAN 30DY '.'EIGHTS OF MALI SAIS MAINTAINED ON 0ET3 CONTAINING 2,4,5-1 FOR 2 TSARS A n im a l Number 75- S3 760 504 75 L 502 752 433 763 440 764 523 / 0 0 437 756 471 757 504 768 533 759 563 770 471 771 433 772 520 773 464 774 446 775 492 776 437 777 523 773 779 535 730 731 732 733 734 735 735 737 733 739 790 791 791 793 794 795 796 797 799 799 300 SOI 302 303 304 305 306 307 S03 309 MEANsSD 493 :3 7 95 515 512 437 452 524 44 5 474 504 538 52 435 490 523 471 450 508 493 534 5L7 537 454 574 547 534 431 529 583 549 5 LI 487 426 522 560 496 413 458 479 529 506 453 471 523 477 509 508 499 500 544 563 503*41 123 534 545 443 473 532 457 473 524 557 535 516 512 550 482 453 513 521 572 526 53 5174Q .2 2 561 561 469 515 544 473 512 547 604 612 526 524 569 501 484 533 539 537 552 530 435 642 596 573 463 532 45 597 563 533 462 549 623 545 462 492 516 598 549 435 490 557 505 575 531 553 543 548 534 6L5 546:48 Davs ac Scudv and 3ody ` 'e i^ n c s '.a Crams 1 / 2 130 203 232 253 532 590 593 625 630 537 538 534 609 614 434 431 432 503 503 534 537 541 330 562 53 561 560 533 596 439 " 90 497 510 523 524 534 533 546 553 552 554 550 576 592 624 622. 639 704 676 633 543 545 663 673 559 567 569 536 602 538 541 545 557 566 534 539 . 606 632 621 512 517 520 533 550 497 501 512 529 541 560 553 567 585 530 549 546 553 566 586 501 619 607 620 629 564 S 571 600 523 503 603 613 619 645 509 527 538 630 725 736 622 6 6 554 519 611 623 439 525 524 522 543 575 672 690 712 622 639 653 597 613 623 552 572 539 434 509 519 530 604 618 639 667 707 557 533 595 431 503 514 510 538 551 539 562 573 637 653 679 574 538 606 508 517 532 527 547 574 536 615 534 526 543 553 608 527 54 2 533 599 593 530 599 625 564 597 390 530 507 617 622 533 6 6 L 633 561 553 556:42 560:44 570:51 593:54 605:53 :n 662 623 523 537 521 542 32 612 697 676 627 571 651 * 574 578 597 510 544 622 664 553 754 632 556 541 634 7n7 673 563 596 531 623 717 5L2 524 560 593 695 613 554 575 643 570 572 533 632 603 666 60S 636 623:56 314 673 636 527 504 625 546 535 536 724 703 535 531 646 331 399 501 519 642 535 663 562 778 696 564 544 701 752 632 665 622 538 546 722 504 531 563 602 710 W 564 599 46 579 636 574 639 520 543 632 696 631:59 549 577 599 525 500 524 547 573 510 706 646 534 531 653 532 612 574 6 LI 516 635 569 556 771 534 659 544 579 74 5 573 663 618 536 633 704 507 533 563 631 724 556 599 508 35 573 675 542 6" 3 606 4 669 595 525:57 377 530 593 532 512 540 556 538 519 731 679 650 533 551 500 535 591 Dead 625 639 572 575 309 639 572 561 703 771 1 663 637 539 549 622 732 529 553 534 616 731 595 561 527 55 536 597 -96 567 613 679 595 709 ' 638:64 ; -- .. . * ---1 --- - 3 .1 4 9 o Dose ag/kg'dav Aaina> Number "50 76L "52 753 76^ 765 766 767 768 769 770 771 772 773 778 779 730 731 782 783 734 735 736 737 733 739 790 791 792 793 794 795 796 797 799 300 301 302 503 304 305 3G6 307 508 309 EAN:SD 675 570 550 536 663 594 754 663 595 673 503 650 535 0 1 .4 639 576 534 314 577 575 566 717 777 565 590 652 552 625 695 627 555 579 619 741 560 630 546 530 639 576 30 591 709 673 543:61 -235- APPSJTOIX * (C o a c in u e d ) 2NDIVtDUAL AND SAW 300Y EIG H TS 3? ALS RATS AlN'TAIilZD ON DIZT3 CONTAINING 2 , 4 , j - T TOR 2 'fCARS 690 569 553 697 534 590 644 732 637 632 693 618 631 584 616 653 564 553 339 590 700 539 733 734 632 530 534 702 632 530 609 547 740 552 577 658 660 601 708 703 634 709 735 729 660:6^ 531 423 575 607 536 534 633 709 690 625 686 622 709 522 a/1 655 536 579 333 571 695 579 712 676980 "15 5 70 307 594 704 650 583 593 660 749 592 667 647 501 593 724. 639 714 736 742 654:72 Oavs oc Scudy ar.d 3ody Welgnc3 53 7 550 boo o43 633 513 563 525 Dead 565 569 574 560 566 553 556 522 577 531 692 63L 679 632 532 662 533 533 0/ 0 0 . . 634 597 704 594 630 542 -- -- Dead-- - 688 667 672 621 615 607 586 555 617 623 630 630 613 613 608 597 677 656 570 -- -- -- Dead-- 608 610 614 618 605 531 570 561 721 728 745 723 721 708 678 519 ------ Dead-- 5C8 Dead Dead 593 544 468 620 654 564 343 562 669 576 635 780 619 705 65 L 569 502 663 552 573 606 653 735 591 571 639 532 596 726 625 713 7? C 7 25 654:65 622 503 547 672 641 611 583 571 536 323 733 633 573 541 530 590 653 532 793 705 713 673 640 529 594 569 567 570 583 641 547 639 532 539 535 6 IS 607 605 653 543 632 714 713 590 599 603 523 673 531 691 620 573 590 593 578 533 536 673 --------------- Oeaa- 596 666 693 614 537 433 715 699 716 "16 599 593 730 716 715 .6 5 0 :6 2 539:53 619:65 597 599 5L7 610 647 640 553 429 Daad 511 Dw-i543 CJJ ------ De=3c-----o i l 605 572 572 576 564 601 590 536 615 506 321 -- Dead- -iD e a d 554 547 581 565 " Dead 652 576 751 OO/ 694 6 71 691 621:56 635 639 660 635 12:55 609 -- Dead-- 690 451 596:64 542 Dead 663 625 "'Dead 1 Dead 59:79 5.37:10 9.1 HU 236- aP?2N D IX 3 INDIVIDUAL AND MEAN 30DY -EIGHTS 3? "IMALZ RATS MAINTAINED ON DIETS CONTAINING 2,4,5-: TOR 2 YEARS Dos Nuabar ?g;>g/diy -5- 0 0 910 203 911 209 912 195 913 192 914 201 915 202 516 200 917 204 918 192 919 194 920 202 921 L37 922 198 923 199 924 139 925 138 926 137 927 195 923 L90 929 200 930 217 93 L 197 932 192 933 195 934 201 935 201 936 197 937 190 933 190 939 139 940 197 94 L 195 94 193 943 209 944 L98 945 193 94 ISO 947 135 943 L91 949 193 9 5 0 203 951 138 952 199 953 192 954 195 955 L2Q 956 193 957 191 958 197 959 190 960 137 961 190 962 134 963 296 964 204 965 194 966 200 967 192 963 197 99 203 970 195 971 191 972 198 973 133 974 197 975 207 975 195 977 139 973 201 379 192 930 206 93 L 201 352 211 933 135 96- 133 955 183 936 202 200 938 2OC 9 39 200 990 192 991 133 992 135 993 ^ 194 994 190 995 132 MEANSD 195: 5 239 239 213 204 214 213 223 225 214 216 224 203 219 208 212 210 206 213 205 233 :10 -3 246 247 234 222 232 235 239 253 232 232 232 219 238 230 224 231 220 235 231 246 23-4:9 263 259 250 232 243 244 259 274 241 249 252 229 253 242 238 221 226 259 241 244 245:x4 CczasDays oi sc-ady ana 3 od/ v i* h e s i s -5 32 39 -* ii 233 270 249 233 244 252 259 272 243 259 254 229 250 240 237 235 229 250 244 255 270 253 249 244 257 .249 254 250 242 235 237 249 270 256 253 249 223 240 250 253 273 221 262 250 252 229 24 L 253 244 249 241 252 230 253 296 262 260 270 253 264 257 255 244 230 257 272 249 250 270 240 236 255 253 233 252 243 232 275 25 L 245 249 2 50 250 243 232 230 266 243 257 260 232 236 257 276 265 . 238 260 250 247 243 236 253 252 252 273 273 272 255 253269 232 238 257 273 270 246 269 253 252 259 249 272 256 273 232 239 231 251 253 273 301 297 273 230 255 274 271 255 259 257 273 246 230 230 233 293 232 253 277 232 295 209 277 275 300 254 298 263 260 266 258 273 233 298 303 273 273 270 231 269 279 273 272 249 275 275 270 233 277 263 243 269 272 299 233 229 296 257 273 257 265 257 260 275 235 273 245 297 304 279 291 236 273 234 3C0 234 251 253 273 296 27 5 233 293 253 317 273 292 252 Ml 264 2 96 520 297 270 25 273 263 255 256 259 .53:14 251:15 256 272:15 .73:16 90 239 297 291 259 277 233 211 309 276 279 233 260 298 255 267 266 260 233 233 294 231:15 63 300 304 299 262 234 293 315 320 237 292 294 266 299 273 274 272 266 290 294 300 239:16 75 306 300 296 272 236 292 320 322 236 293 290 255 295 275 111 274 263238 300 298 290:15 3: 304 310 301 254 233 292 323 324 236 302 291 267 304 279 277 277 267 292 306 308 293:13 : ) i i f J1 -- 1 237- APPEMOtX 5 (C o n cittu ed ) INDIVIDUAL AND MEAN 1QQX WEIGHTS OF :E-MALI 3AI3 MAINTAINED ON OtSTS CONTAINING 2,4,5-T FOR 2 TEARS Doss a g /k a /d a v A nim al 'lu m b a r 73- 8 0 910 305 911 313 912 99 913 70 914 92 915 303 916 321 917 329 91S 96 919 289 920 305 921 275 922 316 923 ' 290 924 33 925 239 926 277 927 303 928 309 929 310 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 943 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 375 976 977 973 379 380 331 932 333 2`34 53: 336 537 93-3 939 990 99: 392 993 394 995 MEAN-50 :9 4 ? Lo *5 . 23 3L0 306 303 266 298 299 323 331 295 311 302 Z7Z 304 282 236 235 278 297 312 313 325 301 295 297 304 292 >13 306 297 256 279 302 299 308 300 292 265 239 295 322 316 255 311 297 299 297 293 294 293 304 294 322 263 313 319 307 313 318 313 313 315 3L0 290 235 301 322 300 315 333 290 346 303 217 : 79 3C7 237 32? 32 4 317 233 294 205 236 309 333 299 321 322 316 230 308 305 337 342 292 324 314 291 334- 293 291 237 285 306 311 333 30 La 17 310:1? L32 331 329 320 233 312 311 347 377 307 322 313 288 330 298 296 301 273 309 319 331 342 310 317 307 313 306 320 314 310 265 301 316 324 342 314 301 277" 302 314 352 310 270 329 312 311 300 308 310 300 315 343 309 279 326 346 325 319 333 337 327 341 324 303 296 3L7 341 312 333 343 305 353 312 33 2 97 317 96 333 347 334 306 311 323 93 353 321 517 315=21 Davs o f S tu d y and 3odv V a lin e s l a S ru n a______ -75 130 303 532 i s a 191 w 343 350 360 353 372 334 404 402 413 345 343 339 355 360 335 333 364 334 342 343 351 359 353 367 369 300 295 302 310 320 321 326 333 333 336 338 353 367 369 367 362 323 321 321 332 332 346 350 351 360 360 346 361 367 374 377 380 370 373 388 336 406 441 444 449 311 312 310 322 326 326 329 332 345 340 358 358 379 393 390 386 332 333 323 340 345 354 349 349 300 297 308 307 301 313 321 323 361 363 361 382 338 397. 407 ' }9S 311 310 305 321 317 328 337 322 314 307 309 320 314 322 323 324 311 311 305 324 324 336 369 380 289 236 303 305 300 309 312 325 324 327 323 337 342 346 350 340 337 333 333 344 339 354 356 352 345 349 34 L ' 355 333 376 367 393 324 376 369 334 397 385 369 346 336 36L 358 357 330 345 346 358 366 365 328 342 336 346 365 355 327 338 343 363 369 373 293 313 321 330 337 331 340 337 347 359 361 363 333 353 344 360 353 371 327 339 330 347 348 351 236 300 308 3L9 - 326 326 314 332 346 344 348 361 323 334 341 201 ---- Dead-- 324 340 343 393 396 390 340 377 373 384 381 402 322 340 344 348 349 354 308 3L7 312 323 326 325 290 297 297 307 313 3L6 313 324 323 335 331 327 335 345 354 362 370 381 377 403 387 398 400 412 340 338 350 36L 368 385 279 239 292 315 319 321 345 349 350 361 362 375 331 323 322 342 337 342 325 323 333 341 340 345 309 327 314 326 320 322 316 313 313 329 333 335 317 323 322 337 34L 337 305 320 323 323 337 323 322 333 335 347 363 386 329 371 333 370 372 377 366 335 343 381 387 388 291 305 310 314 317. 320 361 335 397 416 430 434 -- Dead------ 343 355 351 363 362 364 336 340 359 375 360 362 344 354 355 366 362 364 360 371 392 393 409 398 341 352 356 368 330 369 352 373 384 399 394 408 332 342 34 5 382 330 387 299 314 331 335 343 335 305 311 315 324 325 326 327 327 333 355 334 367 350 366 370 331 330 334 315 324 333 323 339 325 354 368 363 339 392 402 346 364 350 56 3 371 ] 63 314 325 334 333 347 340 374 330 333 33 7 356 339 324 325 229 40 339 ]4o 365 333 3 71 3 5 334 37? 305 317 314 ' 24 325 321 323 3 :1 353 357 36 7 3; 3 301 312 321 32? : : : 33o 321 335 390 392 -16 -33 37 77 531 39 3 392 392 350 253 353 331 330 .0 1 321 327 327 340 347 352 94 330 332 34 5 349 372 325 359 362 375 396 -0 5 38 305 316 3L7 312 330 232 204 325 34 343 346 311 350 369 373 57 4 10 317 255 360 373 377 382 577 416 366 378 339 e 376 364 392 459 338 399 353 334 405 338 323 395 321 358 361 395 407 362 367 357 388 334 368 375 353 342 331 398 434. 354 333 322 327 393 45 387 327 286 342 350 323 336 346 334 4 22 239 398326 4 54 366 371 , 360 430 370 435 397 336 323 3 70 393 333 413 377 43 36 34 5 3.5 5 313 355 :-3 -54 -01 -09 365 35 392 323 362 415 397 330=22 333=25 323=25 340=23 545=26 354-33 351:13 354=31 372:35 Dosa T .g /'& g /ciay 0 A nim al Number ?7 "3i--- 9 LO 9 LI 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 923 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 94S 949 950 951 952 953 954 955 95 958 959 960 961 962 983 964 965 966 967 968 969 970 971 972 973 974 975 976 977 973 979 9S0 931 932 983 934 935 936 93 7 959 990 991 992 ' 993 994 995 EANtsD 05 *22 359 376 371 382 364 334 335 403 342 354 413 340 327 406 311 377 364 397 417 358 359 377 408 349 368 385 347 341 372 405 426 356 337 316 330 397 409 336 383 345 J4 341 336 333 463 388 396 327 462 365 379 364 416 436 391 325 325 355 388 335 425 360 340 390 346 332 367 J-; -`01 403 362 390 325 382 292 373:3 -233- APPENDIX 5 (Continued) LNDIVIDUAL AND MEAN 300Y WEIGHTS OF FEMALE RAIS MAINTAINED ON DIETS CONTAINING 2,4,5-T -OR 2 YEARS 4, -3!-3i 476 377 392 351 395 383 408 4 33 347 423 353 376 126 352 341 418 331 415 368 419 132 376 402 410 44 5 360 338 399 367 359 405 416 446 366 352 336 338 426 431 355 394 359 355 346 371 512 410 408 353 499 374 400 383 452 491 4Q9 347 351 338 460 352 -05 363 393 333 90 30 406 *:o 379 o l 412 336 334 415 393:42 T46 8j 479 379 414 360 392 388 409 494 350 447 361 420 444 359 353 429 339 423 351 425 440 372 413 409 355 391 390 391 385 369 424 441 332 388 351 333 443 444 362 393 367 364 382 392 383 453 412 360 513 374 416 380 440 395 545 422 343 348 s5r0t 1i 520 366 420 370 390 397 516 353 453 357 473 356 360 453 319 422 349 439 437 371 403 413 356 365 392 449 334 405 450 457 397 427 350 340 463 463 370 425 371 376 373 357 407 422 372 516 375 413 367 450 '*** 423 356 350 322 454 335 352 406 366 413 372 416 4 L7 332 424 344 255 432 400:50 315 339 - 401 373 391 397 370 405 15 -30 339 453 359 351 493 26 403:47 Days oc S tu d y and 3ody '.Veignca l a C r a m a ______________________________________ I t5u31 5: 5a9' ?57347~ ~ 5 22 650~ i --635_ 714, _7_3_2. 567 373 392 385 378 331 _ 407 413 419 17 418 413 406 398 371 392 380 373 399 397 392 385 393 407 399 397 413 136 454 431 412 446 463 477 467 461 442 382 JCUU 523 567 601 357 357* 349 352 356 360 367 362 482 515 569 352 361 355 354 374 404 423 430 484 541 _ D-ud 36 3 375 374 359 327 29L 463 485 513 586 695 322 323 327 326 318 317 307 292 432 323 448 450 443 .. 438 426 408 387 446 445 440 426 430 433 425 412 440 369 439 384 472 396 475 405 503 426 542 506 683 --11 1 738 405 423 433 467 489 532 610 563 436 446 455 457 444 458 476 Dead 343 363 363 363 373 420 433 490 391 425 406 415 453 416 419 413 m 422 431 497 389 405 409 398 04 436 475' 455 414 439 435 425 429 454 469 455 447 459 432 399 457 475 460 37 483 515 539 563 371 381 389 392 395 409 4 0 1 Dead . 356 375 333 379 385 415 446 473 339 349 343 339 334 325 340 323 464 437 495 488 504 499 596 537 -Dead 531 - 381 381 381 401 394 395 407 403 438 420 439 435 407 407 460 462 389 391 395 429 398 417 27 449 51 97 577 619 386 470 587 350 _ 398 399 25 425 0 417 414 350 363 507 515 378 378 418 436 455 -w / 422 420 352 349 344 335 341 410 364 331 393 573 292 4 14 61 391 431 346 357 27 406:51 92 347 -21 368 394 329 05 333 357 290 01 4-3 352 342 3: 413:58 23 365 523 386 437 447 437 424 334 427 352 45 373 390 333 06 373 384 07 536 01 33 363 350 45 21:63 425 51 561 367 362 320 375 443 438 433 398 316 390 _ 512 _ 347 69 377 536 30 337 339 03 633 -13 _ 42 341 303 65 20:67 372 441 426 jcuu 427 401 306 297 373 454 420 39 398 300 356 526 376 363 349 .09 05 335 -l- 15 32 356 305 59 20:79 377 567 359 331 312 72 388 5L *3j. 36 333 299 93 25:59 629 567 - 1 Dead--------- 371 524 - 362 578 439 413 297 Dead 442 443 297 23 Dead 563 j 74 350 352 -- Dead--------550 331 433 4-5 50 -61 89 5 J 4 39 304 305 291 238 237 520 541 51:92 53:112 ;/ -- J l 1 _] j _/ --' -239* APPEMDIX 5 (Coacinued) INDIVIDUAL AMD USA 30DY WSICHTS OF T&ALZ 2ArS NAXNTAINED ON DtTS CQNTANINC 2,i,i-I TQR 2 'tSABS Dose sg/kg/day 20 Animal .'tumber o- 0 3 1096 1097 1098 1099 1100 110 L 1102 1103 1104 LIOS. 1106 1107 . 1108 1109 1110 lili 1112 1113 1114 1115 L ila 1117 1113 1119 1120 1121 1122 1123 1121 1125 1125 1127 1128 1129 1130 1131* 1132 1133 2134 1135 1136 1137 1138 1139' 1140 1141 1142 1143 114-4 1145 178 199 192 204 204 206 192 136 135 191 200 . L9.7 .132 191 197 137 200 204 U3 135 188 190 213 190 123082 200 193 ` 200 196 195 139 193 207 207 196 136 193 184 176 196 134 134 195 134 2Q0 136 190 214 139 194:9 200 222 210 224 227 216 213 206 197 213 216 . -214 199 210 2X6 204 221 230 238 201 214:11 13 217 236 229 242 240 236 232 211 216 232 223 225 217 236 233 219 241 251 248 214 230:11 20 232 249 226 248 247 248 244 232 223 243 233 240 235 247 242 227 233 254 261 213 240:12 Pays oc SCugy and 3ody -e lg h c s in Grana 26 22 39 i 53 233 253 245 251 255 256 247 232 229 250 236 243 US' 250 248 230 264 ' 255 262 231 241 236 267 241 230 245 245 226 248 249 234 231 244 261 26L 236 231 260 231 222 242 232 228 242 235 258 241 238 265 239 244:12* 240 263 249 265 257 263 257 239 241 259 248 253 233 267' 257 237 266 265 276 237 - 241 263 259 269 - 265 275 261 243 242 264 254 263 239 272 260 243 273 271 275 245 254:12 259:13 248 271 264 273 264 277 271 250 243 265 249 273 . 250 279 270 244 231 270 275 257 264:12 249 232 255 234 271 235 275 25 i 251 267 255 275 253 284 269 243 292 272 284 255 239 265 500 257 253 270 250 257 270 233 250 247 263 282 291 249 251 236: 274 238 255 253 246 268 261 230 253 265 238 258 50 3 253 279 257 233 279 236 279 252 249 271 257 275 257 291 275 251 295 276 234 256 " 259 235 272 298 238 302 237 254 251 233 265 231 263 296 . 234 260 303 231 291 264 271:1 : c a c ia c lc a lly s ig n if i c a n : d e v ia c i n f-roo c o n e ro l oean u sin g D u aaec c'j c e se , ?<0.Q5. 75 261 235 ??? 298 231 294 233 253 252 289 265 234 266 301 235 257 307 293 239 261 31 253 235 276 298 235 290 237 25 253 237 278 235 267 300 264 233 306 295 296 270 232:14 -240- aPPSNOLX 5 (Continued) INDIVIDUAL AND MEAN 30DT -EIGHTS OF FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR. 2 TSARS Animal Dose Number z/kg/day 75- 33 L096 1097 L098 1099 1100 1101 1102 1103 1104 1105 L106 1107 1108 1109 1110 1111. 1112 1113 1114 1113 1116 1117 1113 1119 1120 1121 ' 253 293 231 302 290 300 294 275 268 290 282 237 271 304 290 264 313 302 302 275 1123 112LI25 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1133 1139 1140 1141 114 2 1143 1144 1143 MSANlSD 287*15 95 253 294 275 309 239 305 302 270 265 290 273 287 276 315 291 265 316 302 300 270 277 289 333 277 270 292 231 279 292 306 271 269 237 303 311 276 277 320 304 250 281 230 265 292 231 312 282 293 306 259 288=17 a 123 279 316 293 313 296 315 314. 234 238 301 287 303 238 313 302 273 323 321 326 322 303117 152 279 320 303 331 307 323 315 237 235 312 291 306 308 328 309 233 332 317 329 290 296 311 355 299 299 305 238 297 306 330 289 291 302 324 330 296 239 341 310 270 295 307 270 312 301 334 296 315 331 292 307=13 L75 130 203 232 253 296 297 293 300 323 342 333 342 357 362 314 323 323 327 341 344 354 355 378 365 322 312 320 329 320 334 333 327 344 339 324 330 327 335 330 302 304 294 312 J l4 294 294 293 237 233 323 323 315 343 327 307 304 314 330 332 312 319 318 329 333 310 306 314 343 332 332 341 347 347 357 319 314 323 327 327 295 294 298 311 317 354 350 345 363 372 325 331 323 336 338 345- ..... 3ui------- - 3 3 2 ------- 343 - - - 394 291 306 313 308 319 301 311 313 323 332 344 384 400 425 316 321 323 301 314 305 330 344 344 304 307 319 303 320 323 321 324 331 335 342 355 297 312 314 308 314 322 321 325 341 353 343 344 341 377 380 312 326 344 349 311 314 302 372 369 325 328 334 282 286 237 333 313 308 322 322 322 301 311 326 326 343 363 327 336 329 371 364 354 299 309 304 365 334 342 341 349 347 304 307 317 319=19 320=13 322=22 331=23 335=26 291 332 337 375 339 353 338 319 297 355 332 344 346 365 335 325 335 352 381 320 313 345 434 341 320 36 L 321 34i 339 384 334 324 350 366 373 352 331 395 343 303 3L9 344 352 377 329 374 322 347 365 320 347=26 314 349 377 379 333 376 339 359 333 337 298 334 333 342 341 * 366 327 333 384 344 389 319 324 350 436 347 295 362 323 350 333 337 323 331 333 357 378 359 324 391 345 299 313 352 350 373 339 338 325 350 373 317 347=27 a 352 408 344 342 382 379 347 336 360 367 339 342 335 358 232 299 331 342 345 351 131 346 364 366 367 375 333 322 334 336 394 410 354 360 398 402 330 331. 340 333 357 356 455 430 352 353 330 324 373 397 313 310 356 367 344 341 392 397 334 Dead 339 334 345 358 359 . 361 395 393 376 389 335 330 389 396 344 359 304 308 322 317 355 352 331 333 1 Dead 363 381 395 338 326 33- 359 359 394 333 333 335 35iz>? 359=33 c a l l / s ig n ir ic ao c. d e v ia tio n from c o n tr o l mean u sin g D u n n e tt'a t e s t . p<0 .0 5 . -- j } H *--i j ! 1__1 1 .--. --> 1 ._j 9 J M- APPENDIX 5 (ConciRued) INDIVIDUAL AND MEAN 30DY -cICHTS OF FEMALE RATS MAINTAINED ON DIETS CONTAINING ',,5-7 FOR Z YEARS Dose g g /'s g /d a y A tiiaaZ Nisaoer 75- 30 1096 1097 L098 1099 1100 103. 1102 1103 1104 1105 1106 1107 1108 1109 LUO 1U1 1112 1113 1U 4 L lii 1U6 1117 U 13 1119 1120 1121 1122 1123 1124 1125 1127 1123 L129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 U40 '.141 1142 1143 1144 1145 MEANiSO 415 361 385 336 370 342 339 299 334 333 343 375 379 332 336 410 351 399 333 335 336 493 336 326 393 292 368 340 412 . 133 361 107 343 103 357 364 311 349 353 373 400 399 343 354 412 357 435 365 375 373 525 374 335 112 340 389 358 441 336 359 361 389 306 2S9 399 409 428 443 341 357 399 412 355 361 310 315 336 331 315 376 398 429 -------------------------405 4 57 384 398 344 372 335 389 333 406 526 350 360=39 381=42 ->6d 443 358 111 345 364 371 324 355 . 362 399 401 394 346 373 432 355 429 359 375 372 348 373 311 411 399 382 354 448 360. 421 429 443 362 423 381 313 326 381 425 427 394 389 407 352 389=45 Days oc Scuay and 3ody e iz h c a in Ocaas 331 559 587 156 87 374 360 424 11 344 352 374 366 380 399 341 326 347 350 356 384 442 403 - 396 397 404 348 300 378 393 454 438 356 366 367 445 435 373 107 397 373 374 631 363 364 385 356 453 366 400 423 470 365 428 350 325 339 415 440 432 456 398 410 342 399*55 396 365 463 366 408 428 486 375 439 371 329 329 487 459 43 408 4 L3 415 346 395=45 71 353 399 345 370 434 327 366 407 414 4L5 355 393 454 373 458 384 386 380 452 414 351 477 367 426 423 497 382 450 368 348 440 39 422 422 349 04=44 74 490 353 348 343 350 343 -D ead336 338 511 353 351 338 340 361 389 375 443 534 ' 634 -Dead-- 42* 421 121 437 486 365 358 367 364 464 153 378 468 376 390 377 386 415 396 412 333 387 336 373 374 --D ead- 459 457 -D ead137 359 357 36 195 366 143 502 356 460 380 371 333 438 469 190 436 434 448 550 577 576 381 381 382 450 454 158 369 362 362 333 415 432 -Dead* 43 493 -Dead* -O eaa493 423. 427 370 11=50 27 454 357 420:61 37 67 364 32=71 529 349 -D ead370 5 Li 353 382 533 420 129 397 363 --D ead- 155 465 --Deao-- --Dead1 405 441 431 *1 394 399 363 372 463 580 827 35 L 350 449 738 473 510 363 355 458 96 351 346 --Dead-- -- 51 65 359 433=69 66 509 371 451=96 536 359 395 431 457 471 440 415 364 357 329 512 362 494 339 54 56 L 365 4.7=33 a t W c? /7 42 APPENDIX 5 (Coticiaued) INDIVIDUAL AND MEAN 30DY WEIGHTS OF FEMALE UTS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR 2 TSARS Doe 10 Animal .Number v 75 1046 1047 L043 1049 1050 L051 1052 1053 1054 .1053. 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 L076 1077 1078 1079 1080 L081 1082 1083 1084 1085 1086 1C37 1038 1089 1090 1091 1092 1093 1094 1095 JANsSD 0 216 132 203 198 203 200 197 198 216 179 192 199 198 209 215 200 204 191 191 191 203 186 219 201 208 191 197 197 204 205 197 193 199 L83 137 193 134 194 222 178 134 186 189 201 193 201 204 136 201 195 197:10 5 232 208 219 226 2'* 216 211 219 233 19A .. 205 213. . 217 227 226 212 226 216 207 213 13 __20 247 258 223 238 234 247 251 266 242 255 238 253 237 253 232 250 252 268 216 234 223 235 239 252 236 243 241 251 246 254 228 239 242 261 230 245 217 221 230 255 217*10 235:10 249:1. Days oc Seudy and 3oay We.l i n e s in Grams 26 32 39 46 53 253 241 256 273 260 254 251 257 278 243 241 250 258 253 266 238 265 252 228 257 269 244 272 249 268 238 229 254 253 273 258 257 267 239 233 267 232 249 282 230 240 225 257 261 234 243 263 247 279 249 253si5 270 245 264 235 265 253 263 266 236 252 247 258 261 260 273 239 268 256 231 265 261:14 275 256 264 239 263 257 269 263 296 266 248 267 264 265 273 249 271 263 239 267 266:13 231 255 276 296 273 268 262 270 299 267 259 272 275 272 277 250 273 263 240 274 270:14 232 252 275 300 273 270 273 266 303 272 270 281 279 273 286 253 275 266 251 275 232 265 291 267 284 266 243 230 279 236 275 276 288 253 266 292 253 263 299 241 257 246 282 278 255 267 298 270 305 267 273:15 50 237 259 273 308 230 273 238 274 317 276 274 235 283 279 237 260 290 275 260 235 28L :li 68 >99 252 237 315 290 289 299 272 323 284 278 290 291 287 * 293 263 296 284 262 295 75 299 269 239 320 236 239 297 231 322 285 273 294 289 287 299 272 300 231 269 304 233:16 290:13 31 299 272 292 323 293 295 314 230 330 297 285 296 295 233 303 273 299 288 274 301 294:13 1 -- - --* j i --1 j --i 1 -243- APPENDIX 3 (Continued) INDIVIDUAL AMD MEAN 300Y WEIGHTS OP PEALS 2ATS MAINTAINED ON DIETS CONTAINING 2,4,3-7 "OR 2 'EARS Oose -g/kg/day A nim al Number 73- 20 1046 1047 1043 L049 1050 1051 m57 1053 L054 1053 1056 1057 1058 L059 1960 L061 1062 1063 1064 1065 1066 1067 1063 1069 1070 LQ71 1072 L073 1074 1075 1076 L077 1073 1079 1080 1081 1082 1083 1084 1085 1086 1037 1088 1089 1090 1091 1092 1093 1094 1095 MSANrSD 33 306 277 295 326 292 301 236 333 299 290 303 302 293 306 273 305 296 268 303 2 9 9 -i 95 3C8 230 303 331 296 301 239 335 297 239 301 300 29L 314 277 307 291 270 310 301 293 312 290 312 294 266 313 308 313 301 301 318 269 391 321 2S2 292 314 276 291 270 307 312 236 290 320 293 336 292 299=17 o Ut li IO co Days oc Study and 3ody W eights in Crams 123 152 175 ' 30 203 232 258 291 314 349 377 324 327 338 334 345 353 360 365 376 372 373 235 297 299 352 305 310 320 323 323 349 362 303 316 322 316 331 332 347 353 362 351 362 343 359 366 354 364 379 379 379 391 386 336 312 322 323 346 338 342 358 356 380 332 373 317 319 335 323 336 359 35 330 330 393 400 312 305 313 320 327 339 337 336 345 333 339 325 358 368 340 363 365 368 377 379 374 379 309 324 32S 349 332 332 343 343 365 358 367 300 308 310 313 308 312 330 325 330 327 333 312 U 3 332 333 336 350 355 368 393 369 403 308 313 344 339 330 343 346 354 365 374 376 277 233 268 296 313 306 309 321 324 325 323 317 331 344 343 351 363 364. 377 331 389 402 233 300 304 302 308 319 313 324 339 347 360 315 324 329 337 337 339 338 361 367 390 422 311 317 320 331 330 336 332 342 348- 34 7 336 235 295 299 300 294 305 312 322 322 331 335 319 330 343 344 364 362 367 406 409 429 441 322 334 338 336 349 353 352 365 314 325 325 320 338 347 349 353 321 345 351 353 369 377 381 396 305 315 323 335 336 352 343 358 329 347 360 371 380 339 408 408 313 339 360 369 416 430 459 514 237 393 298 305 312 311 312 317 327 335 347 34 353 357 360 365 325 333 34 5 350 371 377 338 403 322 338 339 352 352 354 359 372 327 337 350 350 386 ----Dead 322 333 333 340 }44 356 351 356 384 358 365 377 385 419 431 432 310 322 336 296 332 339 342 343 316 337 334 333 343 351 354 372 340 365 ` 373 333 392 402 425 436 302 314 320 344 342 344 362 377 305 312 315 319 362 404 Dead -- 337 374 366 388 397 404 4L7 426 299 308 314 324 337 339 324 336 317 325 336 346 34 356 365 3 233 295 304 305 315 313 324 324 330 347 350 360 336 33L 408 -06 327 357 367 383 332 388 400 06 239 316 316 336 350 373 377 339 303 313 324 333 336 341 338 340 349 341 354 367 555 364 379 374 310 331 346 374 379 373 420 432 359 379 382 4U 408 409 393 402 310 324 331 338 346 349 356 318-22 326-24 330-17 333 20 340=21 346=25 358=25 365=23 370-33 379=38 s-W *? APPENDIX 5 ( C o n tin u e d ) M r - i - i - h i - i - i-1 i-1 -r H i - r r 4 r i - r - h (- i - i i - Io o o o o o o o o o o o o o o o o o o o o o o o o o oo oo oo oo oo oo oo oo o o o o o o o o o o o o o o o o ' ' ` ' `C ' ) > C O O O ) O B C O O D O O D C l ' j v j v j ' . j v j - . | ^ v j v i vC) T( J\ i0('TC ' T( >' 30 ''00 ''00 ''00 ''33 '' a ' 0 ' C A C / > l / i O U i k - i O ' i J i C n L n f ' > ( ' f ' | P U J J % l - 0 ' > C O - 4 0 ' L / l > L J p J r 0 ' C O - > 4 ' Ul ( U l>> H O v i a i - v l 0 ' W f ' U M - O 1 3 - ^ 0 i U l ' U I ' J I " O ' l l J ' J 0 ' *g le- ii OP- u4>su^U>* Uoi'O' l>Nu>au>l UuJ rf> lv |{ '- U lf ''I O O 'l- i CrtvC>>'U' UJ p U U Ul U U P W U P U U P' Ul p u t o U U U t O 'tO U I H U tO u iQ O 'O tU p U 'iU O N S O O N O '' Oj O 'P O 'O 'C O 'O 'J i- ' I - O ' P O' 0 3 p -v O Q v N > * ^O 'C I t i |> l> U U U (V l - p - H U > P i p- m ov qi ut u> p> u uui oUo1Uot U"i oOt I Ii 'OUi |P- 'U' i CP U Pr 'UJ u Pl LLOA UP ` O tO 'H O O H H 'O U lO O U0t U'HPP ttt "oO l'o4O 0PPPP wU'4IOOl lWU- OWJ i ' U U H *> *- w f > u P- ON' ivOO'OU' UlUuiiUClOPf'vOlU-J 'fO* SO' i> p U Ol Ul u r-- UI vD <> O CO hJ OI OI P t/1 LA U (MO to Ol p |P LO O' COUl o O O l*Ms) S U O) P Ut tu p i o l o P 0 >0 "4 Ul ! O' vj vj Ln W P U L O U U P IO IO Wp sUoC tBMU tOuUaiuO HC D"tA! *P p- uo pM U C Ul COH Is) fft P U (P CU I-' +' Ul *' +> W f ' U f ' uifl ON UOI "t-! UO >Uo f<o sP ' Ot UN> N UOli ftJ-44>> l ' Oi O' ^ `O *'op i IPOP LsO UHl O i- P O 'I H ^ OvjO.- uPl'l- to (A LO to H O00 O' 0 Ui np wt O tpO wH Ot oO iuO wf f wi i Ot too wo t p p U P p o u i Ui Cu toUM(DHat P*(ul Ul Ul P to lo PIO P t 00 La lO O' U to U a>Ul h ^ * U00l UULl HP f fPi ULlL uOi Ni>O Ui it oPt ptoC Uu GOGO - O t N t A P O i H O H (D i/> P- ui P- ui a o> oi -o o Lm lO Ul O lO ' O' W U (I P* 1' U P' r-_ _ Wu p fl` pT-> 0(t)- O-i CPo pAi P' 0O0' I LI io p U U U 1' SCOU vl tOOO o t--LJ I--1 U --J Ul p O' o 0o P H n MPoi l |o M .f`<l H K" Hi 3 P AU U Au l- 0) U P o *> M O. Ot P (L M Q 9PS L- i .... L Jl iJ ] ...J -245- aPPSNDCC 5 (Conciaued) INDIVIDUAL AND MEAN 30DY WEIGHTS OF FEMALE RATS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR. I TEARS Dose ag/Wday Aniaai. Nuaoec 73- 996 997 998 999 1000 to o l :o c2 LOO 3 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1013 1019 1020 1021 1022 1023 1024 1025 1026 1027 1023 L029 1030 1031 1032 1033 : 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 104 5 MEANSD 0 ZOO 173 202 206 197 137 '3 9 L92 zoo 219 195 20.1 213 198 216 197 137 206 136 200 139 208 196 192 131 L97 191 133 199 201 L97 193 196 197 138 195 138 196 206 213 205 ' 201 195 198 190 195 133 138 193 204 1 9 7 :9 5 13 220 237 197 212 223 245 225 247 224 249 m205 2 3 0 208 > 17 230 213 231 235 250 219 237 226 247 238 247 213 223 233 249 219 235 210 213 237 251 211 235 217 241 2 2 0:11 2 3 7 :1 1 Days oc S tudy and Soqy W elches in Crams ZO 25 32 39 4 53 240 255 252 269 276 276 226 237 244 256 244 249 263 260 269 279 231 239 259 259 276 233 238 294 253 272 230 236 303 303 227 229 240 255 256 257 231 237 241 248 253 261 243 256 253 271 277 237 236 243 252 258 263 270 259 256 267 2 S Q 299 294 257 253 275 238 294 302 257 265 276 237 309 302 266 267 373 235 292 237 242 249 333 255 261 260 257 266 273 232 238 294 245 252 264 270 273 234 242 243 249 254 265 270 269 272 285 295 293 305 249 257 255 233 264 259 249 253 257 274 274 230 .. .. 2 3 6 268 251 269 252 270 250 284 248 253 234 314 259 233 240 253 266 292 250 273 252 273 256 29 L 249 264 276 300 261 235 255 273 249 274 250 274 261. 232 275 299 262 233 260 236 245 233 257 231 230 247 249 267 249 271 236 253 244 267 269 296 2 4 9 :1 3 2 5 4 :1 2 2 6 3 :1 3 2 7 2 :1 4 2 7 3 :1 3 2 7 9 :1 5 50 279 255 297 222709288 252 291 257 291 296 298 292 265 297 239 267 303 274 235 58 292 267 301 311 275316 271 297 273 296 306 305 300 269 299 300 233 317 233 291 75 290 265 304 311 323 267 271 305 274 301 308 299 302 275 306 303 284 321 235 295 2 3 4 :1 5 293:13 2 9 4 :1 7 297 274 304 219 329 273 253 300 231 298 313 310 301 277 311 301 232 323 235 294 297 ;!! 3 -1 5 0 .APPENDIX 5 (C o n ciau ed J INDIVIDUAL AND MEAN 30DY WEIGHTS OF -MALI 3ATS MAINTAINED ON DIETS CONTAINING 2 , 4 , j - T "Oft 2 YEARS A ni.nal Dose Number ag/icg/aav / V- 996 997 998 999 LQOO 1001 1002 L003 1004 1005 L006 1007 1008 1009 1010 1011 1012 1013 L014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1023 1029 1030 1031 1032 1033 1034 1035 1036 1037 1039 1040 1041 1042 1043 1044 1045 MSANsSD 38 304 292 305 321 329 273 273 310 236 311 314 320 302 233 324 304 237 333 285 299 303=17 93 310 279 312 325 333 282 273 311 235 319 333 325 305 236 323 311 291 333 296 309 235 291 301 301 285 344 316 284 317 300 310 315 292 325 312 290 320 296 315 317 315 309 307 273 298 300 233 298 324 306=17 123 322 237 327 336 336 287 234 316 300 330 350 328 318 303 339 324 299 347 300 314 317=20 152 327 293 326 350 342 324 296 326 312 339 345 338 320 286 339 330 310 350 309 313 310 305 317 312 304 349 332 299 335 3Q9 315 335 296 340 338 314 313 314 320 332 326 325 327 312 292 306 230 315 334 320=1' Days oc Seedy and 3odv W elches la Gcan s 173 130 203 232 253 332 330 333 370 349 317 321 313 326 350 340 343 346 353 361 360 363 354 368 376 351 344 j s i .. 358 364 314 313 315 347 349 302 308 310 313 314 352 348 344 359 363 313 315 314 366 327 365 363 361 359 384 360 374 370 332 392 371 381 350 364 373 340 338 351 345 341 296 296 ' 298 313 303 372 362 382 38S 409 340 343 337 340 351 317 309 325 354 338 368 371 373 381 385 325 321 338 330 360 329 332 329 333 363 327 346 351 316 323 326 318 341 343 336 346 364 304 310 310 377 385 398 346 365 362 309 332 333 343 360 355 333 337 337 335 341 338 366 360 361 332 324 343 349 365 370 364 369 374 319 326 323 319 342 352 321 323 337 342 357 346 344 357 360 339 349 346 334 345 345 338=24 339=24 343 298 327 321 303 329 358 336=21 360 310 325 332 311 337 365 347=20 375 312 338 354 321 355 392 353=23 291 349 339 375 377 362 361 331 368 328 395 406 390 358 305 420 365 336 401 351 361 345 341 346 357 316 397 370 337 369 354 353 377 339 337 374 335 339 347 360 * 388 357 348 335 319 344 355 316 375 398 359=25 314 349 377 361 353 360 374 373 334 381 375 373 369 368 373 336 334 372 374 336 344 403 384 408 423 406 404 328 362 307 308 429 427 364 364 332 323 398 404 353 379 367 361 1 --Dead 1 342 349 352 355 365 378 313 319 4Q4 410 365 373 343 341 363 359 350 352 353 351 385 397 341 335 333 385 398 404 353 335 340 341 342 344 357 374 379 399 359 364 ' 343 352 362 331 395 17* 378 414 344 370 343 439 457 433 371 311 454 372 346 420 367 386 341 364 386 316 420 375 346 358 354 362 419 Dead 391 415 342 352 343 397 399 371 349 388 402 417 327 324 333 352 349 363 356 364 365 327 333 336 357 396 396 406 398 '416 363=25 367:23 373=35 ; 1 .) \ I --i --) 1 J ! 1 i i _i iI INDIVIDUAL AND MEAN 30DY WEIGHTS OF FEMALE. RATS MAINTAINED ON DIETS CONTAINING 2 , * , i - r FOR 2 TEAAS O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 'O 'U 'u v o I 0> Ul f 1 U N ' ('O'OUt'UNN)|S V' u u u u t> h'I- O^ to NO)' O' fw troj CJ ^ Urf Oi W Lkl 4-' Ul ( D H 'O 'O U ttf'U S NttiUmMO'OUtA^r'HiJi r/o' Ou -uJ Ou 'fu' JiO C O fltlw 'O O i N U O 'O 'O O 'N U i i f i U t 1 I wt ' u|si | Ut* O U>JvU4 i uv il pt>v Ktvi iu o io ttO ''O r o 'o fv Ul U LJ ui Ui P Ul 4S Ui Ui rj Co O' w co 03 u to r - 00 O' L/lf'>OUiuOCT'0'a'~'4ttJ iO 'r-, ' 'l --O o - P t > 0 `0 1I ! ---O>i--fl t4-> Ot- II I Co t - l / l O ' vO a o o i i> f w u u t> , UOM'UO'OO Li riui 'Ot O'Oo Nu iUu Il l U t' u P t 03U O ' N J lO H I- W l> 4' w (. w f 4' U l lO O ' I-* O ' U U i o to O 03 ' j l/l Ul ' U U F VOU F Ul I ^ Oi v| 03F F- O' 00 VI N 00 vt U F t ' U 4-v P u F F i I'tv O o ro o a iu o N i i Co O J O J> --1 u i "-J fl I I O ' O ' N 00 F t ' ' Co p ui ' 4 <0 t" WS O' Ul H P Ui Ui !- -- CO UJ V f U F u u Jvi ' U H MO' O' tv f r- Ul J' P u t ' f- Ul 0 >0 '|x |-O N F v J H N V * Ui tv f. i oo 1.' o > u i 03 u. "0 h* O >0 Ui (' Ci>O O>oo t ' p Ul P Ui p 0l O' u 00u 00 oi Ol >o m j u u o Ui u u O 00 00 u o ' U U U P F' UI O O' 00|>Ju - M vj to O WO' MW P t ' t ' U U UI U *S tv 0>I* O' O' ifl I" Ci M to l>U|s>'4)St''j-| UiA v tv p PO GO *->LA Ui i J 1| 1 . 1. Ui Ui p* Ui 00 sj O' O>4Ul F- oi -4 v-i p O >-UI t-- *vi O F '4 '4 U I|-, F N O -a F w ~44-- O' O O|s O' F<Ciu'O'OiK>vjlfl00 t-i O O' o CM4 Ui * [i P Ui JP - ISf> P Ul fvj CD v-4 J Ul Ul u>1 u Oi O' '1 1 00 H CnN 1 . O' WU l> ' u i--4 h-3P r* vj U) COu u o t ' t' ' u w 4 u 4' Ui M43VJ0I)V|UNN O 'P'N H^'O I'JIAU' J3 00 11 X. sj t. 1. t' p 0 O' P 01 o c a O SO o< O 00 I -vi Vj 1 p ul o O' UJ P tv ..J u u r OJ PMP M Lll UI T ' fo UI F UI U P Ui 1 Vj M |UU F ui J UI F F N Ul Oi 1 0 A r. A . UI Vj L1 1 . J.. o } Oi > 1> 11 1. j. L1 n P 1* O' O H-- . F -V t> /I A L p 1* 1 S. 1 O' o I1 f^s* WJ Ui O' O' Ui Oi L J1 A . UOvJi' w'PO UOi' Li ^ IS Ui <J 1- <1 u> t t' c. Ui t' <S Ui ui F O O' H f- f> Ol ft1.) n AC. vpO UCUOiI Out-i 0Op3 CLSOi Ol Ui OtP-' Ui ^f UJt--v HOLJi U. Ul ui Ui tv 4' ui t ' O' Oi Li Ul P O' o O' a iu o u i o (. > 1 03* 1 UFi Wtv Upi UUi v4>j tO-' H1 O' ui a a ui o o 1 s i ta|vol UNP OOtvl uFi uOtvi' OFF' L nft P Ar . r-- Ul p lj (1 UI ui p UI P- oO' Q i'e 243A P S fO U o INDIVIDUAL AND MEAN "OOD CONSUMPTION1 OF MALE SATS MAINTAINED ON DIETS CONTAINING 2 , 4 , j- T "OR I I S DAYS A niaal a a /k z /'d a v Number -------------------------------------------------------------------- -------------------- Dayg on T e s t___________________________________________________ 0-3 3-10 11-13 14-17 13-20 21-24 25-27 23-31 32-34 35-38 39-41 42-^5 46-43 49-52 0 So ,, 30 75-594 75-595 75-596 75-597 75-598 75-599 7-OO 75-601 75-602 75-603 MEANiS.D. 24 24 25 29 26 25=2 75-624 75-625 75-626 75-627 75-623 75-629 75-630 75-631 75-632 75-633 MEANiS.D. 25 24 27 25 26 25=1 23 25 25 29 26=2 25 26 23 26 26 26=1 29 26 26 29 31 23=2 25 26 29 27 27 27=1 29 27 23 31 30 29=2 29 27 26 24 26 25 29 23 30 23=2 26=2 25 26 25 26 25 24 26 32 23 27 26 . 25 27 26=1* -- 27=3 26 26=2 25 25 25 13 Z3i3 O 25 25 27 24 2b 25=1 25 25 25 28 27 26=1 24 24 27 24 27 25=1 25 24 25 23 23 26=2 24 25 27 26 23 26=1 26 2631 27 2712 26 25 27 26 27 26sl 31 27 26 29 27 23=2 25 25 27 25 27 26=1 27 27 26 29 23 23=1 26 25 31 26 23 27=3 25 27 24 30 27 27=2 24 25 25 29 27 26=2 25 ' 26 25 26 23 29 26 25 23 26=2 31 27=3 24 24 24 23 23 Z62 25 25 28 25 27 26=2 10 75-614 75-613 24 24 25 25 25 17 22 24 24 23 22 23 22 22 21 75-616 75-617 25 16 26 24 26 25 25 25 24 25 25 26 26 25 25 75-613 75-619 26 27 23 28 27 25 2b 27 27 27 26 23 29 29 23 75-620 75-621 25 26 26 27 27 27 26 26. 25 26 26 27 26 26 26 75-622 75-623 25 27 23 23 26 23 31 27 27 27 27 29 27 23 23 MEAN=3.0. 25=1 26=1 27=1 26=1* 26=1 24=4 26=3 26=2 26=2 26=2 - 25=2 26=3 26=2 26=3 26=3 3 75-604 75-605 26 75-606 75-607 25 75-608 75-609 27 75-610 75-611 26 75-612 75-613 25 MEANsS.D. 26=1 27 27 27 29 25 27=1 27 29 27 23 26 27=1 27 27 27 23 26 27=1 27 26 2b 27 26 26=1 26 26 26 IT 25 26=1 23 27 26 27 24 26=1 27 27 2b 23 26 27=1 27 26 25 27 26 26=1 28 27 26 2b 26 26=1 27 . 23 27 26 30 23 25 26 25 2b 23 26 26 26=1 28 23=1' 26 26=1 27 23 25 27 26 27=1 27 27 25 27 27 27=1 Each v a lu e r e p r e s e n ts th e mean d a l ly food co n su m p tio n f o r 2 r a t s housed in th e same: c a g e . aA li w eights a re la grams w ith aean. = one s candard d e v ia tio n cor each dose L evel. ^ S ta tis ti c a l ly d if f sreac from conci o l asan u sin g Dunnec=' s te s t . p<0.05. - i J _. i n i 1 J J 1 -- 249A??SJIDIX 6 (Continued) INDIVIDUAL AND MEM FOOD CDMSL'MPTTQN'1 OF MALE 3AT3 MAINTAINED ON OIETS CONTAINING 2,-,5-T ?OR 113 DAIS Dose A nim al a z /k z /d av dumber 56-59 0 75-594 75-595 24 75-596 75-597 24 75-598 75-599 n *5-600 75-601 23 75-602 75-603 27 H E A N iS .D . 26:2 60--62 23 24 27 29 27 27:2 63-66 23 24 25 23 26 25:2 67-69 23 23 24 26 25 24:1 70-72 26 24 26 23 27 26:1 77-30 24 26 29 23 26 2 7 :2 Oavs 30 T e st 31-33 34-37 3 8 - 9Q 91-94 95-97 102-105 106-108 109-111 23 24 22 21 23 24 7-? 20 25 26 25 - 25 23 23 22 26 25 25 26 25 24 24 24 26 28 27 29 37 23 27 .22 26 35:2 26 26:1 26 25:2 23 27 2 6 :4 .. 2 5 :2 27 35:2 26 24:2 25 23:2 30 75-624 75-625 19 23 24 23 22 25 23 25 23 24 24 25 24 23 75-626 75-627 21 25 25 26 24 27 25 24 24 25 30 24 24 25 75-628 75-629 23 23 30 23 27 30 26 27 27 23 27 27 29 24 75-630 75-631 25 24 25 23 23 26 23 25 23 25 24 24 24 25 75-632 75-633 24 26 27 26 26 23 27 27 26 27 27 2b 37 22 M E A N tS .D . 22:2 25:2 26:2 25:2 24:2- 27:2 24:2 25:1 25:2 26:1 26:3 25:1 23:5 24 r l 10 75-614 75-615 19 22 22 21 21 24 23 22 22 23 22 27 22 23 75-616 75-617 25 25 25 27 24 26 25 25 24 27 24 25 - 23 75-613 75-619 27 27 27 27 27 25 26 27 27 27 29 27 26 23 75-620 75-621 26 27 27 25 25 26 25 26 25 27 25 27 24 21 ` 75-622 75-623 23 23 27 27 27 27 27 27 27 ' 28 28 23 23 22 h S A N r S .D . 25:4 26:2 25:2 25:3 25:2 26:1 25:2 26:2 25:2 26:2 26:3 27:1 24:2 24:3 3 75-604 75-605 27 26 27 25 75-606 75-607 27 27 27 26 75-608 75-609 21 23 24 23 75-610 75-611 27 25 27 25 75-612 75-613 26 26 26 25 M E A N tS .D . 25:2 26*1 26:1 25t i 24 25 23 25 25 25:1 27 23 26 27 26 27:1 26 28 24 25 25 2 6 il 26 27 26 26 27 26:0 35 25 24 25 24 27:5 27 23 27 26 26 27:1 26 27 26 25 26 26:1 26 27 26 26 26:1 25 . 23 33 26 25 24 26 24 24 2b:4. 21 24r2 ach v a lu e r e p r e s e n ts th e oean d a i ly food consum ption f o r 2 ra c s housed l a th e same c a g e. 3A11 w e ig h ts a r e l a gram s w ith s e a n : o a e s ta n d a r d d e v i a t i o n f o r e a c h d o s e l e v e l . ^ S t a t i s t i c a l l y s ig n if ic a n tly d iffe re n c e from c o n tro l nean u sin g O unnecc's cesc, ?< 0.05. Rl 250APPENDIX 7 INDIVIDUAL AND MEAN FOOD CONSUMPTION4 OF FEMALE SAIS MAINTAINED ON DIETS CONTAINING 2,4,5-T FOR L19 0AS a ? / kg/ d av S'umhe r 0-3 0 75-634 75-635 17 75-036 75-637 19 75-638 75-639 20 75-640 75-641 21 75-642 75-643 24 MEANS.D. 20*3 3-10 19 L1 - 1 3 19 14-17 19 13-20 21 21-24 27 Davs on T e st 15-27 23-31 32-34 L9 20 20 35-33 13 39-41 19 42-45 L3 46--43 4 9 -5 2 13 20 53-55 13 L9 19 20 13 26 21 21 17 19 13 13 19 IS 17 20 21 21 13 25 19 17 19 20 20 20 19 19 13 20 20 22 21 26 19 20 21 19 25 20 13 21 21 20 19*1 22 20*1 25 213 19 191 27 26=1 22 20*1 20 20=1 20 19=2 22 20=2 21 20=2 22 20=2 22 19=1 21 20=1 19 19=2 30 '75-664 75-665 75-666 75-667 , 75-668 75-669 75-670 75-671 75-672 75-873 MEANaS.D. 19 13 19 19 19 19=0 18 13 20 13 21 19=2 19 20 20 19 18 19=1 13 19 20 19 21 22 19 19 20 20=1 22 20=2. 24 25 23 24 29 25*3 18 13 19 13 20 13=1 13 19 2013 19 19=1 13 19 19 ia 20 19=1 13 13 13 17 20 18*1 IS 19 19 19 20 L9*l 17 20 18 17 20 13=1 17 21 13 16 19 13=2 17 19 17 17 19 13*1 IS 19 13 13 19 18=1 10 75-654 75-655 21 19 19 19 19 25 19 19 20 20 18 19 18 13 13 75-656 75-657 20 20 20 21 19 26 19 20 20 13 19 19 16 21 20 75-658 75-659 18 17 22 13 20 25 13 19 22 21 21 23 21 22 21 75-660 75-661 22 21 20 23 20 27 21 21 20 20 19 21 19 19 19 75-662 75-663 20 19 19 22 36 23 2Q 22 27 20 23 31 23 20 23 NSASS.D. 20*1 19*2 20=1 20*2 23=7 26=1 19*1 20=1 22*3 20=1 20=2 23=5 20=3 20*1 20*2 3 75-644 75-645 19 19 75-646 75-647 20 17 75-648 75-649 20 18 -75-650 75-651 19 19 75-652 75-653 21 . 20 hSANiS.D. 20=1 19*1 IS 19 13 13 22 19=2 13 20 21 13 22 20=2 19 19 21 20 23 20*2 24 24 25 24 23 25=2 20 19 19 17 13 19=1 19 27 19 18 19 20*3 19 19 19 20 21 19*1 19 13 18 13 21 19=1 20 L3 19 L7 20 19=1 20 22 20 19 22 21=1 17 13 18 13 23 19=2 19 17 19 13 22 19=2 13 la 13 13 21 13=2 Each v a lu e r e p r e s e n t s th e a e a a d a l l y food c o n su m p tio n f o r 2 r a t s h o u sed i n th e 3ame c a g e . l l w eig h ts a re In g ran s w ith mean = one sta n d a rd d e v ia tio n fo r each d o se l e v e l. --i -- -- .j - 9 S ? 0<o -251APPENDIS ; (C o n cin u ed ) DJDIVI3UAL AMD ISAM FOOD CONSUMPTION1 OP F2AJLS FATS MAINTAINED ON DIETS CONTAINING 2 , ! > , j - r FOR 129 DAIS m e/tca/da v Number 56-59 a 75-634 75-635 21 75-636 75-37 17 75-638 75-639 19 75-640 75-641 19 75-642 75-643 21 MEANrS.D. 20*1 50-62 20 20 22 23 21 I2i2 63-66 13 13 19 13 21 19sl *7-69 19 17 20 13 27 20*4 70-73 19 17 13 19 21 19 1 77-30 20 20 20 20 20 20*0 31-33 17 13 20 25 20 20*3 34-37 22 20 19 L9 21 20*1 38-90 20 13 13 13 24 20*3 91-94 19 20 20 19 20 20*1 95-97 L02-105 L06-L08 1 0 9 - 111 19 21 19 21 13 21 27 20 13 19 13 18 13 20 12 L3 20 M tl 20 2 0 il 20 19*5 13 1 9 tl 30 75-664 75-665 17 16 17 16 16 21 17 13 17 17 13 . 19 , 16 16 75-666 75-667 16 17 13 17 13 17 IS 20 19 19 19 20 19 20 75-668 75-669 16 17 13 16 17 21 20 20 17 18 16 20 20 19 75-670 75-671 16 13 13 16 17 13 17 13 16 18 20 20 24 37 75-672 75-673 MEAffiS.O. 19 1711" 20 18*2b 20 13*1 20 17r2 13 1 7 ;l 19 19*2 19 13*1 21 20*1 20 182 20 13*1 13 13*1 20 20*0 19 20s3 20 22i8 10 75-654 75-655 13 75-656 75-657 20 75-658 75-659 19 . 75-660 75-661 19 75-662 75-663 19 MEAitiS.D. 1 9 ;1 13 13 19 13 21 19 18 20 18 19rl 13 19*1 16 15 17 20 19 17*2 17 17 17 19 13 1 7 il 19 20 20 19 23 20*2 13 19 20 17 19 19rl 19 20 21 21 21 20*1 17 21 13 18 19 19*1 20 21 19 19 20 20*1 19 19 19 20 IS 19*1 19 IS 20 13 20 19cl 17 16 19 30 21 21-6 19 15 17 20 18 18*2 3 75-644 75-645 17 19 75-646 75-647 17 19 75-648 75-649 13 19 75-650 75-651 - 19 75-652 75-653 17 22 MEANS.D. 1 7 i0 b 1 9 * 1 21 17 18 21 19S2 15 lb 13 17 20 17i2 20 . 16 13 13 21 15*2 -- 13 27 19 24 IS 24 13 28 26s2h 21 19*1 20 20 21 18 22 20*1 13 13 20 16 20 19*2 18 13 20 20 23 20*2 L7 17 21 17 20 18*2 19 20 19 22 201 22 20 13 23 17 20t3 13 21 23 19 23 ^ 2lc2 Each v a l u e r e p r e s e n t s th e mean d a l l y food co n su m p tio n f o r 2 r a c s h o u sed La th e same c a g e . aA ll w eig h ts a r e la grams w ith mean z one s ta n d a rd d e v ia tio n f o r each dose L evel. ^ S ig n if ic a n tly d i f f e r e n t from c o n tr o l mean by D unnecc'a t e s t , ?< 0 .0 5 . a .i5 'o 7 .VPPSNDIX a INDIVIDUAI. AND MEAM :0 0 0 COlSUMPTION OF yjVLS 3AIS HAINTAaNED OF DCSTS CCNTAINING 2 , i , 5 - T rOR 2 ISA85 Cose .Tig/kg/dav Nuaac 75- 6 74 75 676 677 678 679 530 581 582 633 634 635 686 687 638 689 690 691 692 593 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 0- 1 47 24 27 26 29 23 26 24 26 26 29 23 26 25 29 24 26 23 27 23 26 7- M 25 27 24 24 29 24 28 25 25 25 3ays oa Tese and Gcama/Rac/Dav l i - 14- 13- 21- 25- 23- 32- 35- 39- 4 2 - 46- 4 9 - 53- 56- 0- 53- 7- '0 - 77- 14 13 25 23 32 35 39 42 46 49 >3 50 50 53 r 70 *4 31 SO 2527 31 28 25 25 25 25 26 27 25 25 27 25 so 24 27 : : 27 SO 2723 29 27 27 29 23 23 23 23 23 23 27 27 w 25 23 27 2726 27 j 25 26 24 24 25 25 24 24 25 25 23 . 24 21 24 26 27 26 25 26 24 27 27 25 26 26 25 26 26 25 26 22 26 NO 23 23 27 26 23 26 51 23 23 28 26 27 26 27 25 27 24 27 27 26 27 24 25 29 24 25 26 25 26 ' 24 25 25 25 23 25 22 1 4 24 29 29 29 26 23- 26 27 29 27 27 27 23 29 23 23 29 25 23 27 27 27 26 26 23 26 23 za 23 23 28 23 23 27 26 23 25 27 26 26 26 24 23 24 23 23 24 26 23 24 23 25 26 22 24 21 23 24 26 27 26 23 27 24 24 25 26 27 26 25 25 25 25 26 26 27 723 724 725 726 727 723 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 745 746 745 '49 750 .7'5521 753 753 ' 59 MZAS2S0 24 =1 27=1 2$=: :Q * No d aca a v a l l a s i . 23=2 26:2 25:1 27:2 25:1 26:1 6:2 23:2 ; ! --, -; .1 j ! su ^ o t -253- APPSNQIX 3 (Conclnued) INDIVIDUAI. AND XSAU :O0D C0NSUPTI0N OF MALS 2ATS MAliltAINED ON Q[TS CONTAlNIJiC 2 . 4 , 5 - r :OR 2 YSAAS 3os mg/kg/dav 0 Animai Nuraoer 75- 674 675 676 77 678 679 680 w 581 682 683 684 685 636 637 688 639 690 691 692 693 669945 696 697 693 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 713 719 720 721 722 723 724 725 726 727 723 729 730 731 732 733 734 735 736 737 738 739 740 741 Oavs on Tese and Oran s /9 a c /0 a v 3 i64 3438 Sd ii 9195 119- 123126 147131 151134 130132 132136 203207 207210 231235 235238 259263 25326 237291 25 25 24 26 25 25 24 23 26 25 24 26 25 25 25 17 : s 27 26 25 27 27 27 26 27 27 29 19 27 27 25 27 25 23 24 22 23 23 25 23 22 18a 16 24 25 23 23 MD 24 23 25 25 25 25 25 25 24 26 25 - 26 25 23 .'0 24 25 27 27 28 27 27 28 26 29 23 27 31 27 27 23 HO 23 26 24 23 25 25 24 24 23 ZI 39* 23 24 26 24 24 24 24 24 23 27 27 27 26 29 27 26 27 27 27 28 28 29 26 27 23 26 26 26 26 L4 27 27 23 27 26 26 23 23 17 27 28 28 24 24 23 23 18 24 . 22 21 ND 23 23 27 23 23 11 25 22 26 26 27 27 28 29 23 24 23 24 32 13 25 25 24 25 24 7'443? ' 50 'o d ac j .ivai rii rXC\^Z*C 53 759 25:1 24:5 26:2 25 z2 24:3 29:5 25:3 26:3 >> a : a L ar.aiysia cai i m a c i a n s . 2 5 :i 28:2 25:2 pLLb cff -254- APPENOIX 3 (Concinued) INDIVIDUAI. AND MEAN FOOD CONSUMPTION OF SALE RATS MAllTAINED N 0ITS CONTAINZNG 2 ,4 ,3 - T "OR 2 YAES Dose 3is / W d a v 0 Mumer 73- 574 575 576 677 678 679 530 631 582 683 584 685 686 637 638 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703, 704 705 706 707 708 709 no- 7U 712 713 714 715 716 717 713 719 720 721 722 723 724 725 726 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 774456 747 743 749 730 752 291294 25 23 26 23 25 31 24 26 315319 24 23 23 25 23 25 26 23 25 319322 26 26 36 26 23 25 29 28 24 26 350354 25 23 26 27 23 23 26 23 22 373332 25 23 21 28 21 21 31 23 29 Pays oa Teac and O ra a g /R a c /Day 40- 34- 69- 497- 532410 438 473 501 536 23 25 24 24 23 560564 23 14 22 MD 21 24 23 23 25 35 23 24 24 25 27 27 24 27 26 27 23 25 13 23 21 23 26 25 26 23 27 24 25 27 17 26 SD23 23 27 27 24 24 37 30 27 15 25 20 29 *24 24 23 588- 523- 551- TOO- 7l i 592 627 555 590 na 22 12 23 21 19 25 26 23 23 25 25 -- Oead------------ 21 22 U 21 Oead *^" ^>ead-- 26 26 23 -- HJead-- MD Dead ------------------------ Dead--------------------------- 29 31 DauJ 20 24 NO -- 3ead-- 26 23 25 Dead 30 28 -- Oead-- -- Oead-- 21 Dead -Oead MD Dead -- Oead-- 733 759 MEA.V=3 -5=2 24:1 27:3 NO No daca a v a i i a i a . :5s4 25r2 25; 20=5 25*2 .3=4 13=3 25=3 oU5l o 2S5- APP5NDIX 3 (C ontinuad) ODIVIDUAL AND .'EA-N rooo consujption of mals .u t s maotaiued oh qcsts COTZAIXZXG 2 . 4 , 5 - ? "03 2 TLKRS Ooaa ca /x a /d a v A alaal Nuaer o- 3- 417 30 360 361 21 26 362 363 25 27 364 365 25 27 366 367 25 27 368 869 23 25 870 871 24 27 372 373 23 23 874 375 23 27 376 377 24 27 373 879 24 27 330 381 382 383 334 338838 387 338 389 890 891 392 393 894 395 396 397 398 399 900 901 902 903 904 905 906 907 908 909 XEiUllSD 21:1 27:1 "aya oa Taat and O raas/R ac/C av 7- LI- 14- 15- 2' - 25- 28- 32- 35-- j 9-- 12- l o - 49- 53- 56- 60- 63- 67- 70- - 7. l i 14 13 21 25 23 32 35 39 42 lo 49 53 56 50 5] 57 ;o 74 31 25 25 25 24 26 25 24 25 25 26 24 25 25 25 23 26 24 25 25 26 77 26 24 n 25 26 25 26 27 29 25 26 25 25 24 26 24 25 25 25 25 25 25 24 25 25 25 25 25 27 26 26 26 2S 24 25 23 25 24 26 28 26 24 23 24 25 23 26 25 27 25 29 24 24 24 23 25 23 25 25 26 24 24 24 24 23 25 24 26 26 34 25 25 24 24 24 24 25 25 30 26 29 25 25 23 . 24 25 24 27. 25 27 26 25 24 25 23 25 24 24 25 23 24 24 25 25 24 24 23 25 24 25 24 24 22 23 21 23 24 24 24 25 24 24 24 23 24 24 24 25 24 23 25 24 IV 25 23 25 W 26 26 26 26 25 25 26 26 24 25 25 28 23 27 25 24 25 23 24 25 26 27 27 27 26 27 26 26 27 27 29 27 23 23 27 27 27 26 27 NO 25:1 26:2 26:1 25:1 21:1 25:1 25:1 21:1 25:1 25:1 27:2 2S:1 2 7 :J 25:1 25:1 21:1 25:L 23:1 25:1 21:1* HD * No daca a v a tla b la . a3 c a c 3 C ic a ll7 s ig n if ic a n e d iife ra Q c e from co n c ro i nean uaing Duxmact's c a se , p<0.QS. cX\.S l 156* APPENDIX 3 (Continued) INDIVIDUAL AND MEAN "OOD CONSUMPTION Of MAI* RATS MAINTAINED ON DIETS CONTAINING 1 , 4 , 3-T -OR .2 TEARS losa ay 30 Animal Number 75 360 361 Pays on Tase nd Ccama/Rac/Qav 31- 34- 33- 91- 119- 123- U 7 - 151- 180- 132- 203- 207- 131- 135- 59- 263- 287- 34 38 n 95 123 i n i l i l L34 132 136 207 110 235 238 263 256 291 25 25 24 24 27 27 26 23 27 26 24 28 23 23 27 23 26 362 363 24 26 25 24 26 23 26 24 27 26 24 27 27 26 25 26 24 364 365 24 24 25 25 26 26 26 25 23 26 32 20 27 26 26 27 . 27 366 367 23 24 24 24 23 23 26 25 25 23 26 26 26 23 27 25 868 369 24 25 25 24 25 25 26 22 24 23 23 26 27 26 23 22 26 870 871 23 25 24 24 23 ' 25 23 21 26 24 23 26 26 25 26 27 24 872 873 23 24 26 25 27 25 25 24 25 24 23 27 26 26 26 26 24 374 375 25 25 25 25 25 26 24 24 27 25 33 17 27 25 25 25 26 376 377 24 25 25 25 25 25 24 23 27 26 24 27 26 25 25 24 24 378 379 30 23 23 23 29 23 26 24 27 NO 25 23 35 27 30 28 26 380 381 332 383 384 385 386 387 388 389 390 391 392 893 394 395 396 897 398 399 ?QO 901 902 903 904 903 906 907 908 909 MEANSD 24:2 25=1 25:1 25:1 26:1 26:1 25:1 23 :1 25:1 25:1 25:4 25:4 27:3 26:1 26:2 26:2 25:1 D Do daca available.