Document 6wd43g66VmnEY7MNZ3MKBRYzg

onsanto b M ^S A M LOCATI Qft-PHON I I , >Dept, of Medicine & Environmental Health R . C . Dirks, G2WD, 4 -8 8 1 8 ecember 27, 1982 'Ca ~ Toxicology "time lines" Xylene, 2,4,5-trichioro- phenoxyacetic acid TO G.J. Levinskas T .W. Fuhremann F.R. Johannsen ATTORNEY WORK PRODUCT 'ATTCRfiEY-SLIEST PiYIiEE 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. R ic h a r d CZ D ir k s t % \ IN-10M (REV. 2/ 78 ; CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. C l 0 2 8 5 miunaci unii nt-LUi ATTORNEY- CLIEkI 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, but 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 SUBJECT TO PROTECTIVE ORDER. * 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. FI inn,. 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'* 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 8 respiratory tract irritation 3. headache 4. dizziness 6 nausea 5. muscle discomfort 6. liver disorders ATTORNEY WORK PRODUCT All except chloracne gradually disappeared. Report of "150 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 8 hands 4. abdominal pain 8 vomiting 5. jaundice 6. at autopsy acute yellow atrophy CONFIDENTIALMany other reports from 1936-49 cited. SUBJECT TO PROTECTIVE ORDER. C10287 Date 1950 1953 1954 1957 1959 1964 1964 ATTORNEY-CLIENT PRIVILEGE Effects O b s e r v e d / C o m m e n t s_____ ______Reference J Dow Chemical Company initiates acute testing, program with 2,4,S-T, but does not release the information until some of it is published piece meal in '54. Panel on Herbicides, 1970 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) 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 . 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. > Suggested synthetic pathway for dioxin production in the 2,4,5-T process. ' Tomita, M. et a l . Yakugaka ZaTshT"79: 186, 1959 Porphyria Butanea Tarda reported in 2,4-D and 2,4,5-T workers. Bleiberg, J. et a l .: Arch. Derm. 85T793, 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. SUBJECT TO PROTECTIVE ORDER. C10288 a-incnioropnenoxyacetic Acia f\ ;s W i u *-1 J ^ (3) Date 1964 1965 1966 1967 1969 ~1970 Effects Observed/Comments 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. Dow identifies.chloracne problem in 2,4,5,-T workers as TCDD contamination. Standardizes methods of detection and informs other manufacturers. Technology for limiting TCDD contamination to no more than 1 ppm now exists. Dow builds new 2,4,5--T facility designed to limit TCDD contamination. 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. 2,4,5-T production stopped at Nitro, West Virginia plant. 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 i Monsanto World Hdqts. News 24(3), 1980 Panel on Herbicide, 1970 SUBJECT TO PROTECTIVE ORDER, C10289 Date :i970 1970 1972 1974 1975 1975 1976 1976 j . - - , -- , - ,y -------- --- -- - _TJ=. Effects Observed/Comment's >- Y*i f { Ll . i J J - ' ! '* ` ' ' -' * ' * * * _ti 'j UaUiJ*Jh Reference l+J 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 2.4.5- T production stopped at the Krummerich plant; Sauget, Illinois. Monsanto World Hdqts. News 24(3), 1980 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 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 a l .: J. Agr. Foo~Cem. 22:62-65, 1974 (supported by sub sequent studies) 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 Behavioral effects in rodents reported. 1. maze learning inhibited Sjoden, P.O. and Soderberg, V . : Physiol. Psychol. 3:175-178, 1975 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. Hlth. 1:469-484, 1976 Acute dosing in rodents. 1. renal organic acid transport mechanisms affected Koschier, F.J. and Berndt, W . .: Toxicol. Appi. Pharmacol. 37 :169 ; 38:297-306, 1976 CONFIDENTIAL ~C10290 SUBJECT TO PROTECTIVE ORDER. 1979 1980 1982 ---------- ----------------------- H ilU M lM iiu iu v I H -U U JI Effects Observed/CommeATJORHEY* CLIENT P L J Alsea, Oregon epidemiological study on EPA: Environ. Sci. and increased incidence of spontaneous Tech. 13:640-641, 1979 abortion. 1. attributed to periods of h e a v y 2,4,5-T use a) Mortality/carcinogehicity epidemiological study of Nitro plant workers exposed in 1949 accident. lv no excess death or excess cancer death a) Zack, J.A. and Suskind, R.R.: J. Occ. Med. 1:4, 1980 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. 22: 47-50, 1980 Suskind, R.R., et a l ,: in review. j RCD 12/ 21/82 1A L s u i ECTVreOTECriVE ORDER. c 10291 -W-2-e-8-2i-n8-bP--ee-Wor-Mg-u-hyC-tfac-wn-ot-oon-nA-s,-vuD-e-ln.tC-ui-en-2N-g0-W0-G0-,7-Sr-uo-ke-u-3p-0-1-I-n-c-.------------------------- (202) 342-6513 September 29, 1983 PRIAVTILTEOGRENDEAYN'SDWCOORNKFPIDREONDTUIACLT DSMM80tr.ao0.inLlANsoCal.ulnoaLitdsnoi,enTCMdA.boi1FesmSsrogoEpruhadrniByo6u3l1e6v6ard Dear Als IbbpabtwhnyiloarbeedtmipalshtiieslonCaeaiggainnonrssrtdanteepis,feqrfoohyeftuoriosbseenteusisetnasathdo.rse.tafhiIpuneeeowtaxhsMaNcostonheuiairab?ntlylrdlytsoeezbII.paicewonrIaascgfmossshkeuMitoeb.lhdssloieetAfnl,oiaswskfcypaeyoonopborptutrkoouoeisetchhcwshiaoaaaonosuftvurdiflnoevlddtmowehatsaerouilmnJftipaaitsanypicntcdogltyioeuuspWfaraaomlimthfleflaeeoia,arlarptltmIemwlicriaseniailmtxaelhwtlpslhss.iieittttwrhsheatP.rersrhaltieiatwtnbtaurehigsdronoeegwcbwlrsoeiayetpitphlailehermiCcbisteheehasomehutfrhaasoaenevowldnderl As usual, I have a second issue to cover at the same time. ISpoTyeiwcAnnooaffuCortfgunmnTuaDeec"olcCcmlaDdFltutd2Dgaas7,amrtroDieopeyonCeaenpndmtusharoowpe?snmetfeechdpniqaltieaolhalW.o2Dt?)tto.,ete3ehccahnca,aneiTe7dotutdlh,lons8iuiieepstnfC-laTlafiasmoykenretsocnrfrtimkeuoureunanewrliaccectwrcttrnhhniueaooalcrsruoanmeaIetlbrrdlto,homuiRcdoaurc1uaeirevtt9bdclvuesu7eoeeirt6mnemfeedb)wfzrr?yemoiaadcc-nwttiepthhsdnsen-cieddfWs.uiofaniaseofathstuCicxrgaoTtatihthaansnCcnieosneDpoo,rl"swsna(tlDtThuteotityeClhchfoarocDeenrtouuhDnrroeacile)cstnruekrflgdtlaurnehlaeoisdournnoppetewlerranlousallrtctrleschheted(motsaeYsiugrstiegroacetauTnsEhornundCneafsegptDvttl,tpeiuliecDieofrdTnulofsrlihgeltnehuaiecsmmnamlstyksstee(oite.ncohnuoniftnoefrf:,.I I would appreciate your help in both of these areas. Very truly yours, MWyEn^INnBSE,RWGeCinObNerSgU, LPThI.NDG. GROUP Inc. SUBJECT TO PROTECTIVE ORDER. C10292 Monsanto r\itwfv;<ki rKUUUVI ATTORNEY-CUB'iT PRIVILEGE CONFIDENTIAL MONSANTO POLYMER PRODUCTS CO 800 N. Lindbergh Boulevard St. Louis, Missouri 63167 Phone: (314) 694-1000 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.1 a unit of Mo n s ant o C ompany SUBJECT TO PROTECTIVE ORDER. C10293 Dr. Myron Weinberg Ml fUKNEY-CUENT fkiv/LEGI 2 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 SUBJECT TO PROTECTIVE ORDER. C10294