Document DYRy3angLGpDRD9NjDN1d3on

Monsanto M O V -SA.MI L O C A T I O N PH O N | Dept, of Medicine & Environmental H e a l t h R . C . Dirks, G2WD, 4 - 8 8 1 8 C*ATf. December 27, 1982 SUftJlCT Toxicology ''time lines1' Xylene, 2,4,5-trichlorophenoxyacetic acid TO G.J. Levinskas T.W. Fuhremann F.R. Johannsen ATTORNEY WORK PRODUCT ATI iS i Y -C L E aT P m 3 Attached are the toxicology "time lines" for the two referenced materials. The dates and references are, according to my literature review, the first substantive studies to indicate that the mentioned effects may be caused by each material. The dates should not be considered to be the point at which the effects were proven to be a result of exposure. Many of the effects cited (i.e. the teratogenicity of 2,4,5,-T) have not yet been generally accepted as fact. Negative findings have not been generally included in the time lines. Thus, if certain organs, tissues or organ systems have not been mentioned, it is either because they were not examined or, more probably, because they were not affected in the particular studies discussed. Apart from the above explanations, the information included in the time lines should be fairly self-explanatory. Please let me know if these are acceptable. /cld enc. Richard C* Dirks * IN-10M (R E V . 2/78J CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. C l0285 ATTORNEY-CLIENT PRIVILEGE 2,4,5-trichlorophenoxyacetic acid 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) is a herbicide which was manufactured by Monsanto from 1946 until 1970. Until the late 1960s and early 1970s there was very little toxicologic information available. Effects attributed to acute exposure to 2,4,5-T include eye and respiratory tract irritation, headaches, dizziness and nausea, muscle discomfort and, most frequently,. chloracne. Chronic effects in humans attributed to 2,4,5-T include all of the previously mentioned signs and liver disorders, jaundice, edema of the face and hands, loss of appetite, weight loss, bleeding of the gums and hematologic (blood) effects. Chronic studies in rodents have reported thymic and splenic atrophy, hypocellularity of bone marrow and lymph nodes, renal effects and negative behavioral (learning) ability. Several reports of positive mutagenic activity are published, b u t 1 the weight of evidence shows 2,4,5-T to be both non-mutagenic and non-carcinogenic. Many of these studies (and others) are compromised by significant levels of TCDD in the 2,4,5-T sample. The most oft-cited effect of 2,4,5-T besides chloracne is teratogenicity. The effects appear to be very species-specific and again are confounded by TCDD contamination. This issue remains controversial. C10286 Date 1899 1918 1936 1936 1946 1948 1948 1949 1949 2,4,5-Trichlorophenoxyacetic Acid Effects Observed/Comments Reference Chloracne described, believed to be caused: by free chlorine. Herxheimer, K.: Munch Med. Wschr. 46:278, 1899 Chloracne attributed to certain chlorinated hydrocarbons. Wauer, H . : Zbl. Gew. Hyg. .6:100, 1918 One of the first reports of chloracne in chlorinated biphenyl plant worker. Also reported lassitude, loss of appetite, loss of libido. Jones, J.W. and Alden, H.W.: Arch. Derm. Syph. 33:1022-1034, 1936 Liver effects ("acute yellow atrophy") from certain chlorinated naphthalenes. Flinn,. F.B. and Jarvik,. N.E.: Proc. Soc. Exp. Biol. Med. 35:118-120, 1936 Initiation of 2,4,5-T process at Krummerich Plant, Sauget, 111. Monsanto World Hdqts. News 24(3), 1980 First registration of 2,4,5-T on March 2 by Am. Chem. Prod. Co., Ambler, PA. "Report on 2,4,5-T,r Panel on Herbicides, Presidents Science Advisory Comm., 1970 Initiation of 2,4,5-T production at Monsanto*s Nitro, West Virginia plant. Monsanto World Hdqts. News 24(3), 1980 Accident at Nitro plant. Approxi mately 121 people involved. Complaints included: Monsanto World Hdqts. News 24(3), 1980 1. chloracne 2. eye 5 respiratory tract irritation 3. headache 4. dizziness 6 nausea 5. muscle discomfort 6. liver disorders ATTORNEY WORK PRODUCT AT1M-&1M POHSE All except chloracne gradually disappeared. Report of "ISO to 280" workers in four different factories with chloacne. Also: Teleky, L.: Klin. Wschr. 27:249-257, 1949 1. loss of appetite 2. nausea 3. edema of face 6 hands 4. abdominal pain 6 vomiting 5. jaundice 6. at autopsy -* acute yellow atrophy Many other reports from 1936-49 cited. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. G10287 2,,-4.5-Trichlorophenoxyacetic Acid f t l l U f t f t t l I1URIV mUUUii.l ATTD1M Y - CL1EI PRIVILEGE Date _______ Effects Observed/Comments_______ ___ R e f e r e n c e (2) 1950 Dow Chemical Company initiates acute testing program with 2,4,5-T, but does not release the information until some of it is published piece meal in 154. Panel on Herbicides, 1970 1953 Published toxicology information: 1. inferred LD50 (dog) = 100 mg/kg 2. 20 mg/kg/day killed 4 dogs in 11-75 days 3. 10 mg/kg/day - no deaths in 90 days (dogs) Drill, V.A. and Hiratzka, T.: AMA Arch. Indus. Hyg. Occ. Med. 7:61, 1953 a. weight loss b. leg stiffness c. weakness d. gum bleeding/slight hema tologic effects (+ lymphocytes) e. liver - focal necrosis (not thought to be treatment related) 1954 Some Dow acute toxicity (LD50) information published: rats - 500 mg/kg, mice - 389, guinea pigs - 381, chicks - 310. 1000 mg/kg fatal to a steer in 3 days 500 mg/kg signs of acute tox. in 3 days (steer). Rowe, V.K. and Hymas, T.A.: Amer. J. Vet. Res. 15:622, 1954 1957 1. Report that chloracne caused by TCDD - definitive. 2. First report of chloracne in 2,4,5-T workers specifically, (non-accident situation). Suggestion that it may be due to dioxin impurity. Kimmig, J. and Schulz, K.: Dermatologica . 115:540, 1957. > 1959 Suggested synthetic pathway for dioxin production in the 2,4,5-T process. Tomita, M. et al. Yakugaka Za'sshi 79: 186, 1959 1964 Porphyria Butanea Tarda reported in 2,4-D arid 2,4,5-T workers. Bleiberg, J. et*al.: Arch. Derm. 5771)3, 1964. 1964 Toxicity to domestic animals a) liver degeneration in cattle Palmer, J.S. and Radeleff, R.D., Ann. N.Y. Acad. Sci. 111:729-736, 1964. CONFIDENTIAL " c10288 SUBJECT TO PROTECTIVE ORDER. 2y 4,5-Trichlorophenoxyacetic Acid 0 m Date Effects Observed/Comments 1964 With an increase in the demand for 2,4,5-T, Dow Chemical changes its production techniques to increase yield- Result was an outbreak (60 workers) of chloracne. 1965 Dow identifies.chloracne problem in 2,4,5,-T workers as TCDD con tamination. Standardizes methods of detection and informs other manufacturers. Technology for limiting TCDD contamination to no more than 1 ppm now exists. 1966 Dow builds new 2,4,5-T facility designed to limit TCDD contamina tion. 1967 National Cancer Institute (NCI) study from Bionetics Research Laboratory evaluated the carcinogenic and teratogenic potential of 2,4,5-T which was later shown to contain 27 ppm TCDD. Reported 2,4,5-T to be teratogenic in mice, embryotoxic in rats at relatively high doses. These studies were questioned because of: . 1. abnormal variations in procedure 2. small numbers of animals used 3. teratogenicity and embryolethality in controls 4. animal strains used were inappropriate 5. no common skeletal malforma tions were found in controls 6. known teratogens did not cause significant teratogenic responses. 1969 2,4,5-T production stopped at Nitro, West Virginia plant. -1970 Dow teratology study with 2,4,5-T (with low TCDD contamination) showed 2,4,5-T to be non-teratogenic in rats at doses of 1,3,6,12 and 24 mg/kg/day. Reference Panel on Herbicides, 1970 Panel on Herbicides, 1970 Panel on Herbicides, 1970 Panel on Herbicides, 1970 ; Monsanto World Hdqts. News 24(3), 1980 Panel on Herbicide, 1970 SUBJECT TO PROTECTIVE ORDER. C10289 2j4,5-T-Trichlorophenoxyacetic Acid ,i Date 3Vi Effects Ob served/Comment's J: -r 1 Iy;ij',*4i? '!= J :r 1\. jll']m* J y ij *,J J ^ JJ Li O l] ` Reference (4 ) ri970 National Institute of Environmental Health Sciences produced studies with 2.4.5-T containing varying amounts of dioxin.. Concluded 2,4,5-T to be teratogenic in mice regardless of dioxin content, but rats showed a teratogenic response more related to the dioxin levels of the samples used. Panel on Herbicides, 1970 1970 2.4.5- T production stopped at the Krummerich plant; Sauget, Illinois. Monsanto World Hdqts. News 24(3), 1980 1972 Human neural tube defects reported in offspring of New Zealand 2,4,5-T workers. Sare, W.M. and Forbes, P.I.: New Zealand Med. J. 75:37-38, 1972 1974 Subchronic and chronic studies in rodents with 2,4,5-T. 1. Increased liver weight 2. Increased liver glycogen 3. No enzyme effects 4. positive effects completely reversible Chang, H., et al.: J. Agr. Foo'iT'ClIem. 22:62-65, 1974 (supported by sub sequent studies) 1975 Suggestion of possible mutagenic activity - human chromosome effects. 1. single chromatid breaks 2. sample had significant TCDD contamination Fujita, K., et a l . J. Jpn. Assoc. Rural Med. 24:77-79, 1975 1975 Behavioral effects in rodents reported. 1. maze learning inhibited Sjoden, P.O. and Soderberg, V . : Physiol. Psychol. 3:175-178, 1975 1976 Chronic studies in rodents: 1. thymus atrophy 2. splenic atrophy 3. hypocellularity of bone marrow and lymph nodes Highman, B., et a l .: J. Toxicol. Environ. " H l t h . .1:469-484, 1976 1976 Acute dosing in rodents. 1. renal organic acid transport mechanisms affected Koschier, F.J. and Berndt, W.O.: Toxicol. Appl. Pharmacol. 37:169 ; 38:297-306, 1976 SUBJECT TO PROTECTIVE ORDER. C0290 2,4,5-Trichlorophenoxyacetic Acid MTORriEY WORK F R - b d i UIMH-CUQS ppttt.Date Effects Observed/Comme 1979 Alsea, Oregon epidemiological study on increased incidence of spontaneous abortion. EPA: Environ. Sei. and Tech. 13:640-641, 1979 1. attributed to periods of heavy 2,4,5-T use 1980 a) Mortality/carcinogenicity epidem iological study of Nitro plant workers exposed in 1949 accident. 1. no excess death or excess cancer death a) Zack, J.A. and Suskind, R.R.: J. Occ. Med. 1:4, 1980 1982 b) Study on Dow 2,4,5-T workers. 1. no excess death or excess cancer death. Completion of morbidity study of Nitro plant workers exposed to 2,4,5-T process (including accident exposed persons). b) Ott, M.G., et al.: J. Occ. Med. Z T t 47-50, 1980 Suskind, R.R., et al, in review. RCD 12/21/82 T1AL c 10291 W einberg Consulting Group Inc. 2828 FenmyivtnkAvenue NW,Suite 301 W uh*ttn. D.C 20007 (202) 342-6513 September 29, 1983 ATTORNEY'S WORK PRODUCT PRIVILEGED AND CONFIDENTIAL Dr. Allan T. Ford Mail Code A1SE Monsanto Company 800 N. Lindbergh Boulevard St. Louis, Missouri 63166 Dear Al: I am interested in analyzing the works and writings of all experts who will be used" by plaintiffs in the Nitro case. As you would anticipate, I am starting with Camow and Coneybear. May I ask if you could supply me with the biographies and bibliographies of each? I would like to have a list of materials written by either or both and, to the extent possible, copies of the actual articles. Please let me have these as soon as possible. If Monsanto has not made a formal literature search then please request author searches of both from Jan Williams with hard copies of aU writings for us. I would be most appreciative of your help in this. As usual, I have a second issue to cover at the same time. In "Fate of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in the Environment: Summary and Decontamination Recommendations," the authors (Young, Thalken, Arnold, Cupello and Cockerham, 1976) discuss hepatic ultrastructure studies (cf. page 27 et seq.). The inference made by the authors of this report is that ingestion of TCDD do not cause structural or steric effects on the endoplasmic reticulum. I would appreciate it if you would review this against your knowledge of effects of TCDD on hepatocellular ultrastructure and intracellular organelles and tell me if you agree with the inference I have drawn. Can we conclude that TCDD has no effect on the endoplasmic reticulum? What other references support your conclusions? What is known about effects of TCDD on cellular organelles in the intact mammal? I would appreciate your help in both of these areas. Very truly yours, W \ CONSULTING GROUP Inc, M einberg, Ph.D. SUBJECT TO PROTECTIVE ORDER. C10292 Monsanto ATTORNEY v/o r k product ATTORNEY-CU&4T PRIVILEGE CONFIDENTIAL MONSANTO POLYMER PRODUCTS CO. BOO N. Lindbergh Boulevard St. Louis, M isso u ri B3167 Phone: (314) 6 9 4 - 1 0 0 0 October 13, 1983 Dr. Myron Weinberg Weinberg Consulting Group. Inc. Suite 301 2828 Pennsylvania Avenue, N.W. Washington, DC 20007 Dear Myron: In answer to your September 29 letter, I have completed literature searches on most but not all of the expert witnesses who are to testify for the plaintiffs in the Nitro litigation. I will xerox and send the ' 8" stack to you late this week or early next week, but I need to organize and find out what is missing first. I have run a few of the "experts" through LEXIS/NEXIS with poor results. I believe that there is more in the media domain than I am seeing. Do you know of an alternate source for covering the media area? Perhaps our lawyers can do more with the legal data base. In terms of getting hard copy of the abstracted papers, do you think that I should give these papers priority over the TCDD literature? I seem to be taxing both the DMEH and R&D libraries at the moment, and the expert witness literature looks to contain hundreds of articles. How ever, I can stop and move in this direction if necessary. On your second question: "can we conclude that TCDD has no effect on the endoplasmic reticulum?", I do not think that the Young inference is real as there are indications to the contrary in the literature. I discussed the matter with Dr. Knutson of Poland's staff this week, and she indicat ed that with acute or chronic exposure, there is a progressive thicken ing or swelling of the endoplasmic reticulum - the end result of which I am not sure about but will do some looking. It is interesting that Knutson indicated that she did not know of any study of the long-term effects or the ramifications in terms of toxicity. 7.509/RNG.l a unit of M o nsanto Com pany SUBJECT TO PROTECTIVE ORDER. C10293 Dr. Myron Weinberg -2- attorney-client privilege CONFIDENTIAL October 13, 1983 I have enclosed the articles from the last batch of abstracts you sent us. We are still finding less than 20% of the toxicological papers which indicates the inherent weakness in our data base. We have begun enter ing new papers as fast as we can get folders made up, key words assigned, and computer input completed. We expect to have another 250 papers this week and possibly 400 next week. I have sent you a computer printout of the data base as it existed early last week. I am looking forward to seeing you next Monday. I will be staying at the Guest Quarters just down the street from your office. Sincerely, A. M. Ford, PhD. Enclosures cc: T. Bistline C . Love G. Griffin F. E. Kearney W. McCarville P.S. - I have enclosed a book of the process chemistry involved in the various Nitro processes. This book is considered very confidential to Monsanto Company, and we would like it returned at the end of the litigation. 7.509/RNG.2 CONFIPE'NTIAL SU BJECT TO PROTECTIVE ORDER. C10294