Document KJ37YoJg6QRBJ44ONGXeq6Z0r

A SUMMARY OF TOXICOLOGICAL DATA OF THE PHENOXY HERBICIDES W illiam McBride, M.D. SUBJECT TO PROTECT/VE ORDER. C24720 2 . 4 , 5 - T r ic h l o ro n h o n o x y a c o t It: ac_j(i . Registered in 1948 - phenoxy herbicides - are synthetic plant growth regulators. The phenoxy compounds mimic the properties of a naturaJ.ly occurring plant growth regulator, indoleacetic acid. The military furthered investigation by studying : phenoxy herbicide used as a vegetation control weapon in 1944-1945- Phenoxy herbicides presently in use today in the U.S. s ' include 2,4,D, 2,4,5-T, MCPA, silvex, 24-DB, MCPB, dichlorprop, mecoprop, 2,4-Dep and dichlorprop-methyl. In 1975 the U.S.A. used 59 million pounds of 2,4-D, 6.7 million pounds of 2,4,5-T and two million pounds of si 1vex Stanford Research Institute, Chemical Economics handbook Stanford Research Institute - Menlo Park, California - 1976. AL SUBJECT TO PROTECTIVE ORDER. In 1969> 11,626,000 pounds of 2,4 ,5-1 acid esters and salts were produced in the United States alone. In 197^ the; quantity rose to 12,335jOnf) pounds. Between 1971 and 1974 738,907 pounds of 2,4,5"! wore imported into the U.S. averaging a total of 148,000 pounds per year - E.P.A. - Herbicide report, Document EPA-SAB-74-D01 US EPA, Washington D.C., 1974. The phenoxy herbicide enters the plant in an imperfect and uncontrolled way. It interferes with the regulation of growth processes normally governed by the plants own naturally occurring growth hormones (Ashton, F.M., Craft, A.S. Modi; of action of Herbicides, Wiley Interscience publishers. N .Y . 1973 <. The phenoxy herbicides interfere* with cell division (mitosis) and cell enlargmont, food utilization and various other processes necessary to stabilize life. C 2 4 7^i Scientists do not know the precise mode ol' action of either synthetic or natural plant growth regulators. They know that phono xy herb it:ides are fur more toxic to green plants than to animals. Plant growth regulating compounds act on plant cell compounds such as cellulose and lignocellulose which are not present in animals. 2 )4>5-T Chemistry; 2,4 ,5-Tri.chi orophenoxy acetic acid lias a chemical formula, CgH^CljO^. The pure form occurs as wh:itu crystals and its molecular weight is 2 5.5*49 grams per mole. 2,4>5-T melts at temperatures of 15fi-15^C- It is stable .at its melting point. 2,4,5-T lias a solubility in water of 278 parts per million (-ppm) at 25 C. Further solubility occurs when this herbicide is mixed with acetone, ether, and ethanol. Technical grade 2,4,.5-T manufactured for agricultural application generally contains 90 to 92# of the herbicide and impurities. - detailed composition of the herbicide giver, by one producer*: Dl.O 1.0# 2,4,5 Triehlorophonoxyacetic acid. 0 .5 i 0.1# 2.4.5- Trichl oroanisol e 2.0 - 0.5# 5,metboxy 2,4-dicblorophenoxyacetic acid. 2. 0 t 0.5# 2,methoxy, 4-5 d.ichlorophenoxyacetic acid 0.3 - 0 . I# 24 5-Trichlorophenol. 3.0 t 0.5# hi s 2,4,5-Tr jchl.orophenoxy acetic acid n. 3 - 0.1# 2. 5- di chl.oi'opbeunxyaeef ic aci d 0.2 i 0. 1# S04 o. ? t n.1#s o d i u m s a l t , ol* 2 , 4 , 5-T 0 . 5 - 0 . 7# H.,0 . non 14. ,1 ; i C24722 CONFIDENT!4 L SUBJECT TO PROTECTIVE ORDER. Fisher, J.K. letter, P0T12. In Final EIS, Vol 1. Vifi'l.aUori management with herbicides, U.S. department of Agr icn 11 n r e , Forest*. Service 1977 , - reported that the average Jeve J of d ioxi n .in U.S. product jon ol' 2,4,5"! appears to be about-o.ni m>ra Tliis was supported by Ini.ornal. ional Agency lor Research in Cancer 1977 Chlorinated Diben /.e-d.i ex ins, vol 15 World Health Organ! /.ati on and McQueen et al 2,4,S-! and Human Birth Detects, Division of Public Health, Department oF Health, New Zealand, 1977. Thermal stability - 2,4,5"! is stable at. least to .its melting point ( l5h-I5PC). Biochemical degradation - 2,4,5"! degrades slowly in soil contain jng organic matter under warm moist, cond.i t.ion s , Half life for the herbicide under these optimal conditions approaches several weeks. Metabolic degradation is caused by two concurrent processes. Binding oF the herhj.ci.de molecule to other compounds, mainly glucose to Form a non-tox.ic complex and actual degradation of the molecule. Three months is genera 1ly accepted as the time span For the herbicide to disappear completely From the soil. Disappearance rate is independent of the amount* <>F herbicide present. Even in the presence oF sunlight 2,4,5-T remains relatively nnreactive. Resi dues f A residue is an accumulation oF a product For* a period following initial appJ iration. Reside *s occur when the iniial '* product is not totally degraded. The p>:r*s istenre oF a residue can 0 cause problems. 11 use oF a known toxin leaves sufficient residues in active Ionn, the extend and tineat Lon of that toxicity most he- recognised and appropriate cautions followed. C24723 of the parficu.l ai* chimica I. So tI res iducm Scienti 1'ir stud iils demonstrato ilial pliriioxy herb ir idcs broiik down in soils - Andes, L.J. Murociolo/pe.il breakdown ol' Herbicides in Soils. In Nerbi <ides and the So i I E.K. Woodford et Sugar (cds), Blackwell Sci Tub. Oxford England. 2,4,5-T and 24-D form carbon dioxide, inorganic: chloride mil water as final degradation products. Classified is slightly persisi cut 2,4,5-T takes anywhere from two to six weeks for a fifty percent disappearance rate. Tin* co-operative? studies by Stork et al Soil jnciirppr.'il ion Hindegrat ion of Herbicide Orange Microbial and Hisel ino ecological study ol the U .5. air In ree Logistics command test range Mill AIM Utah l-'imd report, Tocom project No 5Co-21.7-00-01 S U.S. Army Dugway proving ground - Dugway III.ah 1975, Arnold et al. Three years of li e Jd studi es on the soil persistence? and movement of 2,4,-I), 2,4,5-T and TCDD - Weed Science Soc Am. Meet. Abst, 197b - demonstrated the ipp Iic*al.imis of 2,4,5"T *ind 2,4-0 at massivi; rates not only did not sieri 1ise the soil but indeed stimulated the growth of certain microflora, .m<l that fIlis st i.mu 1ition hi i.V have contri hu ted to the degrul.iti on o I Ilie horbi cide. - Norris, L.A. et.; al , The Pursi stcnn: of 2,4, 5-'1' in flu: Pacific Northwest forest., Weed Science, 25(5) 41 7, ll,77 - examined foliage, forest floor and soil for 2,4,S-T residue. The cone Ius ions, summarised in the Journal of Weed S<? Ierne were that willi in six months of appl ica lion, herbicide residues di-c.lincd `.in percent, wi thin one year less than s.i x percent of flu* herbicide remained. They found little leeching of 2,4,5-T from the forest floor to the soil and no residues were found deeper than 15cm. SUBJECT TO PROTECTIVE ORDER. C24724 & 5 II,.1] hi- <;L a l . " C h l o r o d i o x i n s In p e s t i c i d e s , s o i l s Hid I a n t .1 . Knv. Qm.i 1 . , 1 7 1 - 1 7 # , 1 9 7 3 , t'ouml t h a t 2 , 4 , S-T i s r e l i i t i v o J y inohi 1< i n s o i l s . Ho wever, t h a t movcmrnl. docriMM-s as org.in ic coni n i t i ricreases. 2 , 4 , 5-T' t h e r e Core hmiiiics m oderately moli i .11' in c l a y s o i l s and o n l y s l i g h t l y m o b i l e in m u l c h . W;>ier cos jdues : ?,4,5-T acids and esters are soluble in walo.r. In addition 2,4, 5-T rapidly dissipates in streams by di Lu I.ion and photodegradation :in water - see. Crosby & Wong "I'hotodecnmpos ii ion of 2,4,5-T in water J* J, Agr . Food Chem., 2l(6) 1052-J054, 1970. Re st;arch reports i.nvo 1v.irig st ream cent ami nat.ion icoin land spraying in Oregon dunionsLrated that peak concepti at ion oI phenoxy herbicides seldom exceed 0.1 ppm. These residues rarely last for more than a few hours in almost, all the streams, see (Norris, L.A. et a l . The persistence of 2,4,5"!' in a Pacific Northwest Forest" Weed Science, 2 5 (5 ) 417- 1977). The report oC the Advisory Committee on 2,4,5-T to the Administration of the F.P.A. stated that al l ivaClnble diita .indicated that a^small amount of 2,4,5-T is present but does not persist long because clay or the biota absorb the herbicide fcsai CC H koj w i t h i n a matter o f d a y s (F ..P .A . Ilerb:ic*ide Document FI'A-SAIl 5 5 P: 74-001-US F,PA - W a s h i n g t o n Wm Q g^ Animal res idues: D.C., 19 74 ). C24723 ZO ^ CO i=f3} An.inull residues would aceumu 1al.e hee.'tuse ol her,h:icj'de build-up elsewhere. Animals rapidly eliminate about (>Se of ngeslt-d 2,4,5-T unchanged i>n the urine - see (San erltiIt , M.W. el. ;iI. "ihe dose-dope ulent phaemaeitk iMel ic profile of 1',4,5-T Col lowing intravenous administration in rats." Tox. App. Pliann., 3h: 491-501, 197 * 6 Pipe.r el a 1. "Mrlaboli sin oi' 2,4,5-T n Rats." Health Aspects Pesticides, **72, 1973 Piper noted a signi ficant difference in the pi.isma licill H i e el I ieitia.i.ni ng in the dog as compared to the amount seen in the rat. This delayed excretion time tor 2,4,5-T experienced by the dog 1s postulated as the cause lor greater.toxicity oi' the herbicide to rioirs than to rats. Hook et n l , "The renal handling ot 2,4,5-T in the Dog," Pd & Cos Tox, 14: 19-23, 1 9 7 M suggest a tight binding of the herbicide to the animals plasma protein operates as the mechanism for delayed urine clearance in the dog. A study by Cellring et al. "The l'ni.e of 2,4, 5-T J following oral admi ni s1 rat.i on to man'.' Tox. Appl. I'hann., 2b; 152-.UU, 1973, suggests that human ur.i ne cl.ear me* more closely par a 1 1e Is the rate of excretion in the rat than the dog, sec Koc.i ha el al. fIResults of 2 years chronic toxicity study find oncogenic study of rats ingesting diets containing 2,4,5-TV F d . Cosm. Tu x . 17: 205-221, 1979 who support Gehring et n l 's work. Residues do not remain indefinuteJy. ThoLr loss from the environment can be predicted through the chemicalTs lial t Li I'e in various media in the environment and n knowledge oi the ehemi cals physical characteristics. polychlorinated Dioxins Recognised in 19 57 as an impurity jn the manuFactu re of herbicide 2,4,5-T. TCDD is one of the most potent small molecule toxins known to man. Small amounts of the chemical can cause enormous changes in animiil .cells. Currently technical grade 2,4,5-T in tile U.S. routinely contains TCDD levels at or below n.l ppm. C24726' Chemistry 2 , 3,7,8-teirachlorodibenzo-p-dioxin exists as ;i white crystalline solid having a molecular weight or d22 grams prr mole. It melts at temperatures between 3l>3, and 305C. and aecomposes at tempera Lures between 98U - 1U00C. About 9 b .5VJ- ol the* dioxin decomposes at temperatures ol 80uC. 2 ,J*,7,8-TODD arises * during the -hydro 1ysis of totrachlorobonzeno to form 2,4,5- Trichlorophenol, the industrial precursor of 2,4,5-Trichlorophenoxyace acid (2,4,5-T). T.C.D.D. has a low water solubility and a high Cat solubility. Dioxin can accumulate in the environment under some conditions. TCDD however is readily decomposed by uLIra-vioI el light which helps to diminish potential accumulation of the chemical. Crosby and Wong (1977) - "Environmental Degradation of 2,3,7,8-TCDD". Science, 193: 1337-1338 - found that herbicide formulations with TCDD con tarnjnard lose most or all their TCDD within a single day when the leaves, soil or grass of the treated foliage receive natural sunlight. Photochemical dechlorination causes this degradation of TCDD. While the stability of pure TCDD as a persistent residue in the environment is accepted, it is not stable in the presence of its herbicide vehicle. Appearing on the foliage in a thin herbicide film, the contaminent diminishes as it is exposed to sunlight. Crosby and Wong established three requirements for significant dioxin breakdown in the environment. They are (1) dissolution in.a light transmitting Him. (2) The presence o f an organ ir hydrogen-donor - such as a solvonL or pesticide and (3) ultraviolet light. They propose that all three conditions are normally met in applications of 2,4,5-T. Therefore thi-y feel that those data suggest that environmental residues of TCDD often will be considerably less than previously expected. C24727 O & Residue oxpor inents have monitored tho TCDI) levels in land, water and various species oi animals. lor the most part. TCDD residue levels directly compare to the amount ol' initial I(1)1) application and are not- iJofeekab 1r in many instances. Recently the Dow chemical company ol Midland Michigan, released a report demonstrating the production of TCDI) as a by-product of normal combustion processes. Analyzing samples from a number ol combustion products such as re lose incineration emissions, automobile; exhausts, fireplace soot, charcoal grills, cigarette smoke and particulate ,einission from chem i<:a1 plant powerhouses - researchers quantitively measured the amount o f TCDD present - (Dow chemical company - Midland, Michigan, I97l>.) If environmental presence of dioxins from combust ion can be further established and supported, then it will become Auc reusing.! y di fficu.lt i f noc impossible to link environmental residues equ ivocally find solely to horbi ci do spray ing. Toxic i.ty: The way of expressing a chemicals anile toxicity is thron its L D ^ defined us the amount o f chcmica L su fficLent to cause death in 50# of the test animals. An L D ^ value can di ffer' due to such variables as ago or sox of test animals, nutritional, sl.iitc, formulation of toxicant, Lime; of day, route of administration and temperature. Moth; of entrance and chemical form of the. substance can also alter the \ hl)^*. An non observable el`feet loveJ - signifies a toxicological endpoint. Chemicals administered in this concentration cause no observab.l e adverse e ffee Is .* An im a 1s su ffor boxi c oI fects from - ,4,S-T in dosages ' -> ranging from 10 mi IM.grams per kilogram of body weight per day CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. I l e a l.tli a: id h (Mil a t o 1o/a i c v a l u e s a n d c s t , al > I i s h e d o p n t r o 1 p a r a m o t c i -* 3---- 7. 2 2-- ---- 3. IT . 7 7 2-- 7 y-- ** 5 * >--r i * 27 -- 3**. --* * 3* 3 * 2** 3 " -- 3 W*1 r. X 'X l x i + A7 Jr~; 3z* Z! 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The Mnnla-ys also demonstrated a marked iIh t i m m ' in the liacmatopootie pi'i.ress in the hone marrow and hyporr IIn Iar lymphoid tissue (i.r. the hi nod making process). Cellular hy perp 1a.-i appea red on many levels especial ly lii the mucous sc<. r < it iiifi * * ' II s , epithelial lining ol* the hi Liary system and the transitional epithelium of the urinary tract and goblet cells of* the pa Ipe.h rn I conjunct jvao (the conjunctiva of the eyelids). They concluded that the primary target area Cor TCDD in non-human primates (monkeys! is *ho harmetopoe Ljc (blood producing) system'. As exposure longl.liens cellular degeneration involving the lymphoid system, responsible Cor the formation of white blood cells (leukocytes) and hone marrow responsible Cor red blood cells (erythrocyte) format ion, increases in severity. In additional atrophy ol the 1.liyimi.sispleen and lymph nodes also occur. Allen and Van M i\ Ier assert Ihat there i e o n s iderah Ie dill eeences in (lie level ol T(l)l) necessary to prudnre inloxicat ion. T h e LD^f> rang* of 1(-7l>|ig/kg body weight. produces death in S<> ol' the test animals in an acute space of time, a tons iderah I> lower dose of jpg TCDD per kg body weight will a Iso yield the same results when atlmini stored continuously over a nine month period. A 1 Ion and Van Miller also demons!.rate M u d the pathological changes caused by the two dose levels remained quite similar. There Core they he Ieve their data indicate that, exposure to extremely low rone ent.rat. ions of TCDD can produce wi despread de Jetar ious c iTect.s i n pr imat es . ^ Kociba, K.J. et al. Result.s o f a 2 year chronic toxicity and oncogenic! study o 1 *'ja* 7 ,<W-Tet racli Iorod ihen/o-p-d:i ox;i n in rats. CONFIDENT! 4LT o x . and A p p i . Tharm. .-](>: 27*0- .v(lj , IP? 8 SUBJECT TO PROTECTIVE ORDER. C2473 'iw V 'Tlit-y placed male ami female Spraguc -Dawl ey rats aged six to seven weeks into suspended wire' bottom ra/ics. lood and wafer wi!re-available to the animals ad libitum. Cr.oups of I(in rats (50 males, 50 females) ingested a diet that contained 0.1, 0.01, ;0.001 UK TCOD/kg/day for up to t.wo years. The diet, of the control group (^6 males, Pfi female's) 172 rats contained only the carrier, no TCDD. The' TCDD was provided by Dow chemical company and had a purity exceeding 90 percent as determined by electron capture gas chromatography. body Weight and food consumption of 20 males and 2(i- femnl.es at each treatment level, were routinely recorded for- each week of lire first- three months of the study and at monthly nil ri vals thereafter. Eight rats per sex group provided blood sample.-, l o r haemal,ol og ieal invest i gat. i on at three, twe 1ve and tweiil y tlirve months of treatment. Urine samples were' collected from seven to eight rats per sex per group at these same? time levels I<1 determine specific gravity, pH, sugar protein, ketones, bilirubin, ad occult, blood. At terminal, necropsy, investigators collected serum sample's from all survivors or - maximum of IIt rats per sex group for determination. All rats dying or killed during the course o f the study underwent gross pathologic investigiit ion and representati vc S portions of major organs and any lesion suggestive of a signil.i.canl pathologic process or tumour formation were: preserved CONFIDENTIALin 10% formalin. SUBJECT TO PROTECTIVE ORDER. C247-32 - 1J - A Terminal necropsy examination took' place at tin* mil of two years of treatment. Tins weights of the liver, kidney, brain, heart, thymus, spleen, testes and ovaries/uterus were recorded for a maximum of 10 rats per sex per group. Bone marrow smears from most rats were also prepared. They dlso froze portions of fat, liver and kidney from a maximum of five rats per sex p <t group fur possible TCDD analysis. All rats from the control and the high dose level regardless of whether they d:ted dur ing the course of the study o or were killed upon its completion, underwent histologic investigal ion of an extensive listof tissues intended to include a majority of those tissues ^listed above and those collected at. the time of terminal necropsy. All rats from the lower dose levels were subjected to histological exami nation of those selected tissues identlfied as possible targot area organs in addition to gross lesions suggestive of tumor formation. They found at the conclusion of the study (l) continuous ingest, ion of .diets containing approximately 2200 ppt-TCDI) (0. lug/kg.''day) for two year's caused multiple toxic effects, including increased mortality, decreased body weight gain, slight depression -of certain haeniatological parameters, increased urinary of Qexcretion of porphyrins and A-ami no levulinic acid. Increased M oc serum activities of Ap, GOT, and SCPT and morphological changes LU > ^primarily of the hepatic lymphoid respiratory and vascular I issue (J g"H<>f the body. This high dose level seemed to reduce the ineidrne QOJ s d.and severity of chronic renal'disease in aged male rats. IVmalr C24733III* rats given this high dose for two years had 24,000 ppl i'CDI) 0 2O y p r esent in the liver. This .compares with .14,600 ppt TCDD presold u g i n the liver el Irniale rats g.ivein this dose for thirteen weeks, Ihns .jndi Celting. at trininent ol steady state concentration in the early Jn^rfat. i oil *>1` tin* i ill c'l'inrd i a t e d o se l e v e l o f (110 [ pjir TCI)l)A/day ( approx i mat e I y 2 10 ppt i n ( liH .) c a u s r d .1 li's s r r degree o f to x ic i ty . Mere rrsra rch Iuund : I. increascd uri nary tixorrl' i011 o 1 propi 1y r.ius (temu 1os ) 2. liver, toxicity, including an -increased iru:idelicti ol' hepatocellular nndu 1es 3. increased incidence ol' focal alveolar hyperplasia in the lungs. Terminal liver and I'al content of TCDD averaged' $100 and I700 ppt , respect ive Iy . Th is compares with 37oo ppt present in the liver a Iter thirteen weeks at th is dose level. Lifetime ingestion at a dose of 0.00] |ig/kg/day approx. 22 ppt in the diet) caused no effects considered to be ol toxicological s.i.gni ficanee. The Iiver and fat each contained 540 ppt of TCDD at- the end of lifetime ingestion at this low level. Kociba et a I demonstrated a dose related toxic response to TCDD. Al the lowest, levels of TCDD tested, 0. oo( ug/kg/day the authors could find no toxic response at hr ibut ahi e to the* inclusion of TCDD in daily diet gi ven to rats over- a two year period of time. Tox ici1y Summary: CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. TCDD i.nov itahly contaminates 2,4, S-T , no cons ider.it.ion f of toxicity of the herbicide without proper attention to the toxicity of the contaminate TCDD can be considered complete. . Toxic response to 2,4*5-! and TCDI)S vary among and SO within species. LD values for 2,4*5"! range from a single lOOmg/kg alo.se in the dog (acid form) to 500 in the rat (acid form). In the mixed butyl ester form of 2',4*5-1* the mouse exhibits an LD**1* of 4`>0ing/kg sing Ie (lose . C24734 111it i.1V toxic response to 2-,4 ,5-T appears ai dosages oi' 10mg/kg in (lie dog anti escalates to I4*()mg/kg in the mouse. Weight loss, muscle weakness and accompanying tissue changes represi Lin* most common effect.- o l ' 2 , 4 j l - ' t o x i c i t y . In a eh roil i (wo year .-ttidy dotai Iiii/; the c.l'l'oct.s' ol' 7,4, S-i' oil Sprague-Dawley cat.-, Kociha et a I. (I*)7D) ascerta inod a level (.bug/kg! wler*e the animals r\h iIn ked no toxic el Tret s from chronic exposure to 2,4 >t)-l* However t.he herbicide used in this project was puri tied 2,4 *`-`1 containing n. pph TCDD. Cemni'*re a I samples o I' the ehf-niirai nil11 inr Iy contain (>. I p|mi TC 1)1) The thymus and In .i lessor degree, the Lymphoid t issili and bone marrow (including hematological dy sc ras ias derived from damaci' there! arti the primary areas which exhibit a toxic: responsi- i TCDD. Mieti arc least sensitive to T C D D 's toxic HTiicts. Guinea pigs and chicks su (Ter the greatest adverse effects. Initial toxic ri-spouse appears a IT.er single, duses o l` .ipg/kg in the go inon p i* and up to a dose of 1UOpg/kg :in t.he rat . Exposure ol` Rhesus monkey t.o pph TCDI) in the diet reported by Allen and Van Miller ( 1 0 7 7 ). The authors detailed toxic changes leading to death in li v<; oi` tilt* eight monkeys studied, after what they determined to lx; dai Ly doses of 2-.1 Mg/kg TCDD for a chronic period of time. Allen and Van Miller suggesled SUBJECT TO PROTECTIVE ORDER. . C24735 I Kuriha et- al (M>7^) conducted a Iwn year chronic toxirilx study I TCDI) un Sp raglir~Daw Iry rats. Ilirse ex p<r imeni-s demon.-*(.paliti a close related tox ic n:s|mnyc when aciniin isl.errd in daily ditit at doses o 1 0. 1, o .0 I a nel o .00 I Ufi/kg I(-1)1) |>er d .iy The highest dose elicited multiple toxic si^ns, while their- Iowes t dose (0.00]Ug/kg1 caused no effects of to xico Iog ica I s igii ifiranee . Teratogen ic ity : (M;t|forma lions in t In Offspring). The clisc i|>I1ne o I* feralo logy eneornnasses llircr cat.ego rios : Caus'os, mechanisms and iiiani Trs fa 1i mis . A cansis an external element capable of e I.icl t1ng a clei-r imen fa I <hang (teratogeni c agent..). These agents act in specific ways (nn-ehamsm^i .on developing cells. Mechanisms a.I I interact at the ear IIest si iic.s u f development involving many cellular processes and en v irnnmenl a I conditions. Up t.o Day 17 alter conception in humans then* oc* lies a "retractory period11. from day 1^ to day .10 the ernhryo heroines very susceptible to outside j*nter Terence. At this stage the early stages of tissue and organ d:i fterent ia t.ion Lake place (li-um gast.ru Iat.ion to organ cliITerenf iat ion I. Thereaft.er the i-mhryo shows an ine ceasing resistance to teratogenic forces as ocganugi-nes is advances to completion in days ^'l to ho in man Cnun day <>l nuirrpi ion. In a 1.1 species the period of organogenesis remains most, tragi 11* Id on l.side teratogenic influences. Upon comp Iel ion ot organogenesis^ outside influences can general an adverse change, hut these ace usually in the form of growth or fnnet ioual alt.oral ions. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. .fe. $ 17 of the: concept.us ami lhe niamu:ii in which thi s intci nets wi l.h adverse environmental factors. 7 . suscepl. i1)iIity t.o teral ngeties is varies with the developmental st.age at (he t ime of exposure to an adverse in fIvience. . 1 . teratogenic agents ael in specific ways (nicehan isms ) on developing Cells and t issues to initiate sequences of ahnonna 1. development.al events (pat.hosieries is ) . the access of adverse iiffIueure t< de ve Iop inr l issues depends on the nature, of the influence (agent I the loti' manifestat ioiis ol` ahriorni.il development are death, ma Iformat, ions, growth retardation and lunct ion.if del ii it . man i fest itions of abnormal development inereasr .in fre(|uency and degree -is dosage inereases from the no effect level i< Ilie total Jy 1of ha 1 leve l. Almost any e,hom;i e.n I su h st a n ce p o s s e s s e s a t e r a i h'v u m potent ia I when adm iu is l<*red in excess anioiiuls during a sn si <p I iIIe pe of development.. A broad spectrum of compounds 'are respo ns ibl e lor a myriad nl biologieal and chemical of iVcl.s, SUBJECT TO PROTECTIVE ORDER. \ IR - Some types of Drugs and other chemicals that have been shown to-be teratogenic in one or more species of laboratory animal . Drug type salicylates certain alkaloids tranquilizers antihistamines antibiotics hypoglycmies steroid hormones alkylating agents antimalcriais anesthetics antjinetaboli ties solvents pesticide. industrial effeluent miscellaneous Kxanipies asprin, oil ol' wintergreon calT(;inc(nicotine, colchicine meprnh- mate, chlorproinazi no, reserpi no hue Ii/.ine , meclizine, cyclizine chi orainphi:ii ico I, s trep tinyc in tpenri M m , totracycl i< carhutanii do , tolbutamide, hypoglyci ns tr iamci nolonc, cortisone, testosterone busu1fan, chlorombucil, eye]ophosphemide chloroquino, quinacrine, pyrimethamine halothane, urethane, nitrous oxide, pentoharbi* folic acid, purine, and pyrimidine analogs benzene, dimethylsulfoxide, propylene glycol. 2,4 ,5-T, carbaryl, captan, folpet some compounds of Hg, Pb, As, Li, Cd. trypan blue, tryparunol, d i:i:.iox Teratogenic effects won; usually seen only at- doses well above therapeutic levels for the drugs, above or likoJy exposure levels for the environmental chemicals. Source W iJson, J .0 Handbook of teratology Vo. I, General principles and etiology, Janies Wilson, Clarke Priiscr (eds],v Plenum Press, New York and London, H>77. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. G2473S 19 Wilson in his book Knvironment. and hi rib Deleets ( W / l ) opcit, H a t s tli necessary criteria tor rr.coitni s ing a now (rratogrnii agent in man. 1 an abrupt increase in the'incidence of a part in d at- deficit or association of defects ? , coincidence of this increase with a known environmental change, i.e. widespread use of a new drug 3. known exposure to the environmental change early in pregnancies yielding charactoristically defective infants 4. absence of other factors common to all pregnancies yielding infants with the charactoristic defect. Since chemical response varies with dosage; route ol administration and particular agent, Wilson (1977) opcit. has established criteria and categories for classifying chemicals according f to thei r embryofox.i c. (causing damage in early pregnancy) potent ial ^ (assuming exposure to therapeutic or higher dose during 1st trimester) in man. ;|. established as being embryotoxi e (a) iintjUi'st. ionah Iy produces a higher percentage of cl*ve Iupmi'iil a I delects or intrau ter inr death ;in infants of exposed women than otherwise similar nonexposed women. 2. suspected of being rnihryntox ic (a) apparent increase above* background level of dr ve Iopmrnl a 1 defects or iintrauter nr death among infants of exposed women, based on large numbers of accumulated ca.se reports. (b) retrospective surveys iudieate significant increase of delects or death among infants of exposed women, hut "memory bias" ol mot.hers intI'oduees uurertainty G24739 (c) prospective surveys .iudieate significant iiit cease among CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. Numerous studies have been conducted detailing Uie teratogenic embryotexic and letotoxie eiloots generated by 2,4,5-T and its contaminant dioxin. Researchers experimented with a variety of species and have demonstrated both nu effect and lethal levels in many cases. The prime target areas for teratogenic response from 2,4,5-T and dioxin are cleft palate and kidney anomalies. Mutagenicity The ability oi* a substance to induce genetic alterations Because of the similariti os of basic: molecular mechanisms by which chemical mutagens; and'most chemical carcinogens appear to induce genetic effects (i.e. molecular lateral izatton of DNA.) researchers postulate that mutagenic effects can be predictive of carcinogencity - - Scientists rely on short term tests to indicate the mutagenic potential, a chemical possesses. These tests include: 1. tests for mutation in bacteria and eukaryotic microorganisms 2. tests for mutations in somatic mammalian cells 3. tests on chromosomal effects in higher eukaryotes inciuidng nuimiuaj 4. evaluation of DNA repair synthesis. All of the 2,4,5-T mutagenicity studies have drawn either negative or inconclusive results in tests covering primary DNA damage, gene mutations and chromosome effects. The scientific dispute resolution conference on 2,4,5-T> 1979 August, stated that \ reasonably adequate experimental data has been generated regarding 2,4,5-T and that these data are not suggestive of 2,4,5-T induced CONFIDENT* 4Lmutagenic activity. SUBJECT TO PROTECTIVE ORDER. C24740 (& ifl / 4* Tlio scion'll lie dispute resolution conference on 2 ,4,5-T 979 also fel t that results from sever; I inicrob ia J stud ies have determined that TCDD increases the frequency of gene inutal ions. Microbial data suggests that DNA repair processes are involved in lIn mechanism of action since no mutagenic effects ran be elicited in studies using repair defective bacterial strains. The bacteria dala suggests that TCDD acts as a direct initiator of malignant, transformation since most mutagenic carcinogens are of the initiator class. Few promoters or cocarcinogens show mutagenic activity. Carcinogenicity Animal model studi es- have .1ong been used fur prrd ict.i ng carcinogenic potential in man. The species of animals used in these studies must be as carefully considered as the data resulting from the experiment. Rodents meet certain specifications that make them I highly desirable for carcinogenicity experiments. Their lifespan is short - which allows the fullest expression of a positive carcinogenic response. Rodents are small, relatively inexpensive, easily bred, all of which encourage large study samples and confirmation o f test results by other invest!g a L o t s . Yet results obtained using rats or mice cannot hr unequivocally adapted to man .because of certain biological differences O Second the Sprague-Daw ley rat and several mouse sl.raj ns not ed for K O. their high rate of spontaneous tumor incidence are often used in these experiment s so care must lie taken to d i's* r iininaf e bel ween a spontaneous tumors and those caused by carcinogenic mechanisms. Also in carcinogenic response can become apparent long alter the original cancer causing stimulus has hocn removed. Maiii.i festal ious of cellular alterations can take years to develop - By the-time a careinogenic C24741 ^J because Lli.it would not fit with the classic carcinogenic: mechanism. All these factors must bo considered when analyzing a chemical Tor its possible carcinogenic properties. Research conducted on animal models for potential carcinogenic effects of 2,4, 5-T have failed to yield positive results. The E.P.A. Carcinogen Assessment group, report in February l`>79 acknowledged these conclusions. "On the basis of the completed mice and rat studies there js no signi ficant evd donee of carcinogenicity for 2,4j 5"T h 'I'hey added however, that testing had not been done suf fi c im l ly in niic e . TCpD is an ext run* ly potent inducer of hepatic aryl hydrocarbon -(AHH) activity in the rat -(see Poland Glover Comparison of 2,3,1 ,B-tetrachlorobcnzo-p-dioxin - a potent inducer of aryl hydrocarbon hydroxylase with 3-methyl choicutlirenc," Mo.l ec . Pharmacol., 10: 349-359* 1974)- This en/.yine system .is proposed as the promoter of carcinogenic activity. Further, in the presence of known carcinogen DMSO, TCDD is weak tumor initiator in the two stage system of mouse skin tumorgenes is. Investigations of the carcinogenic potential of TCDD have produced dose-dependent results. At relati vely high, long term doses, a diet containing TCDD has been found to cause increased incidence-of liver arid lung tumor as well as nasal turbinate palate tumors in certain rat- species. Two animal studies are important in the analysis of carcinogenesis potential of TCDD. !. a two year chronic study by Kociba et al, 197^. T o x . and Appl. PIiarm., ^6, 279-303, C 24742 2. A 7^ week investigation conducted by Van Miller et a M Increased incidence of neoplasms in rats exposed Ln o\v Ii*Ve I CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER, - -4 - In both studies Spraguo-DawJey fill s wc.tv used. A* (lie hi f;lios L dosage tested their exper imints yielded .siini1ar re.-utll^. A(- highly toxic levels oi* 2200 ppt and <00 iv d y IIn- reports documented an increase in tin; incidence ol liver and lime tumors in Sprnguo-Dawl oy r a ts. At the lower dose levels their results dillered. Kocibas group considered the lower dose ranges negative for carcinogenic eti'cet citing the appearance ot hepatic hyperpl.asI it modules.from a mtxiium dose as the onLy cellular* change observed. Van Miller reported si gni I'dcant carcinogenic potential at doses well below the $00 ppt dose. Tumors, lie claimed, appeared with TCDD levels of 1000 ppt, S00 ppt, 5b ppt and 5 ppt. Only at ] ppt did Van Mi H e r acknowledge no chemical related effects. There have been several criticisms of Van Miller's investigation. The carcinogen assessment group audited the study and found that it had major shortcomings in design and conduct that limited the reliability of data developed at dose 1ovels lower than 100 ppt (EPA 1977). Therefore Its carcinogenic effo cts could only be verified at the two highest, dose levels. In addition the "investigators in the. study reported no tumors in the control animaLs a highly unlikely phenomenon when using Spraguo-DawIey rats" (EPA, 1979). This strain of rats.is particularly susceptible to spontaneous tumor induction and lack of tumors in controls is highly suspect. Also the areas ol' tumor induction at lower dose ranges of TCDD did not currnlatc with the epxectNsd target organs determined from the higher doses - i.c. lung and liver. Also the experiment only involved 10 animals per test group. This small number is below the minimum number recommended by the Nat iunaI Cancer Institute. C 24743 CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. 2S - The Koc.i ha study lias a Iso been cr it i.sed . Km- iha rt a I lound hyperplastic alterations in lhr liver at Mu* 2 10 ppt dose and considered this a negati ve i'iiul iiii*. In an audit- 0 I* the Koejha study by the. Carcinogen assessment group,.a conflict of e Lass iI*ieat ion of hyperplastic nodules became evident. The CAG group re-evaluated the study and concluded that the combined incidence of heprtoceJlular hyperplastic nodules and the hepatocellular carcinomas is statistically significant for both the. 2200 ppt and 210 ppt leveL. Studies by Mi rota and Williams 1979 - Persistence and Growth of Rat Liver Neoplastic Nodules Following Ccosal ion of Carcinogen exposure." J . NCI . 6_/H5)j I257-1265j 1979 - Tii-.y investigated the persistonce and growth of rat neoplasms and concluded-that these nodules represent a different typo of neoplasm than carcinoma possibly a benign neoplasm. They assert that these neoplasci c nodules are not obli gato t*y precursors o f cure jnmnu and may in Iact he at a stage in neoplastic deveLopmont that is less autonomous than carcinoma. Their interpretation of nodule there !'< is an end stage, benign neoplasm that is capable- of continued growth hut. is not. invasive or metastatic and may only :inf rcqiicnt 1y acquire these proper!, ie s . Jn tliei r study , tin: an times, detected no transition of nodules to carcinomas. At intervals after cessat ion of carcinogen exposure., nodules displayed changes suggestive of phenotype reversion or degeneration that were not. present- in carcinomas. : Those who support the Kociha conclusion favour this intorpret at ion o l by per p Ia/>tjc ,,nodu 1es as non-proo I of care inogen.i e.ity . *S lurtlier* support, Ior such rat ionale li es in the Jack of c;trc iilogon ie chat- o) noduJ es to tumors within the two year test period of the Koeiha el. al study. C24744 CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. - 20 - Tho EPA, FIERA Scienti fic Advisory Pane] , Review ol' Fi Ira Sue Lion 6(6) 2 Action mi 2,4* $~1 aliti Sii vox, Sop omhcr 27, l*)71' Also hns rcservations as to whethor hyperplastic noduJos are procursorsj poi1 so ol hepafoccl Iular caccijiunia HUMAN l-XIM-K IKNCK WITH 2,4,5-T and TCDD 1. Dow chemical pLant workers. The; study examines the mortality oP 204 persons exposed to 2,4*5-T during it.s manu facture from 19 5b to 1971 at tho Dow c:homi.eal plant in Midland Michigan. The health status oP 2,4*5~T workccs exposed for a period of over one year.- Investigators concentrated on tho crew directly involved in the 2,4,5-T manufacture process. In general, at exposure concentration of 2,4,5-T (conLai ning 1ess than 1 ppm TCDD) experienced by the workmen in the study, no adverse mortality effects have boon observed al tri but.abi to l,he work environment. Mortality compared well with -that ol' all U.S. while male.-,, and also compares well with the background mortal i.t.y experience in the geographical area see Ott et a l . "a Mortality analysis of employe! engaged in the manufacture of 2,4,5-Trichlorophonoxy aceti c acid." .J. (Ifr , Mod . 2 2( I) 47-59, iyN(). The single observed cancer death occurred as a res; II of respiratory malignancy discovered in a 6 year old retiree who bad I)tin exposed to 2,4 ,5-T I"or eight years. The employee also bad a past history ol" smoking up to two packs ol" cigarettes per d a y . 2. Monsanto plant accident , Nit.ro, West- Virginia A st iicly of the chronic lieaLt h effects of .exposin' to 'ICDD as eel lerleil in Ilie mortal it.y rxperirnee of a group ol mousanko workers who developed symptoms of chloracne following a C24T43 t.r ieh Iorophcnol process accident .in Nitro, West. Virginia^ 1949. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER, CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. acne. 1'rom lesions^ li. pains in niusr Ics of uppnr and lowi* .* 2* TM >*- j: Z. f l- ` L|# 3 c -- 3 J; 3 * 3X C- . ** Si to r r ' << ** * *c Zf *; 3 "i J2 C- 3 X r* "! zz c * X * to < 0 (" t-- r-- to. r * X 3* --3 3T" X 1--* a3 7"* k-- 3 M** 3u . 3 * ^-i3M m* 3 < * ~ 3 r~ 3O M* ,"L V H* X C*" * 7 X vC 5 7 0 3* * p 3 v : ft cr- F-* -- ct rr 3 -r^ c. x; V* 3 3 -- 7* -- c* K N* c . O A X7T M* 3 0. n 0' e 5 m* c r H * H M* X #* X 3 * <t i 3 3 C t* * 3 > 7 Cto to c ,Jcv.- *-; <7 - T* . cr X 1*. 3 - u . << *3 3 x r0 5 < w 3 a t-- y * t--1 *c j3 3 " z * * 3 Ti*tai J i 3 37 r- X kv * *-- 1 3 * a > /*> (-* ** 3 * n /< I--* Si < * z. - ** - ii ^3 X * *"7 H Si 0 3 r; 7T <5 S* -- - C- >-- c* * fS X * <t<o 3 K' 3 3 J5 1 /j X tt~oo ' 7T 0 U- X Xt* c t M. * C* T H* p+* X *3 c u . i; * IS 3 * . -- j, = -- 3 i 7* --* 33 u n c* Si 0 <: 3I 3 O' * - C* o3 c 33 h * J * CO C. ZL JS 3 2 < w j- < 0 L *3 * 3 3 3 l) " 7 C. X z ** X VX -- X set Ch Ior-icm; ad-ion ol' exposed skin. Alter1 these symptoms subsided rh Iuracni' Tin* Journal ol` Occupational Mod ic inr i'('|mrl in January , 1980, carried out a 29 year In H o w - u p <>l 121 members of l.lu- original study cohort - 89 members wn r verified a.^ 1 iv ing and y?. wore verified deceased by death 1 erl. iI*i<at e . The reu II ni standard ised mortality ratio lor al 1 deaths was 0.00 with 12 deaths observed, and 46.41 deaths expected. The report by the American Council on Science and Health 198(1 - lelt this was the only stiitistically significant value determined. There were nine malignant neoplasm with 9.04 expected. > No deaths resulted I'mm stomach nrliver cancer Five iung cancer deaths occurred versus .1.(2 expected. One skin cancer (a fibrous histiocytoma) proved fatal . Mxceod ing Iy m i the expected incidence of its appearance is 0. 1 5* Three drat Its from Lymphatic and heniatopuetie neoplasms resulted with 0.88 expected. There were I7 deaths from d isea sew of the circu 1at ory svs1 ein w ith 25.01 expected. Because the study cohort was smalL and only J2 deatlis wore observed the results from this study cannot be considered conclusive. Nevertheless, this is the best long term study of TCDI) CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. effects to date.^ The analysis of mortality experiences of personnel at this point indicate no apparent excesses of total mortality ' or of draihs due to malignant neoplasms, or c jreu Iat or.v diseases. .1. Arkansas cleft pa Jala* study. 02474 7 j A study to determine what, if any, human ell eels were experienced after exposure to 2,4,5-T. A ret inspect ivi: study on the incidence of cleft palate in areas sprayed with 2,4,5-T. Researchers analyzed fat: ia I cleft rates and concurrent use of 2,4,5-T in Arkansas during Iij4>'-- |07.4 . listjmated levels of exposure In f Ihr hrrhieidr was eat r/pu'i sed as high, medium or low exposure oil the basis of rice acreage during 6 - 7 year intervals beginning Nelson ot al . Rot respect ive study of the relationship between agri cultural uses <>1 ? ,4 ,S- T and cleft palate Occurence in Arkansas ^Trento Iogy . (3l : 377-303, 1979. Nelson found that facial cleft rates presented hy sex> race, time period and exposure group generalLy rose over time. No significant differences were detected in any race or sex group in g . Tlie authors concluded that the Increase .in incidence of this anomaly was due to hotter case assessment rather than actual increase :n incidence. They, cant ioned that "The prese.nl. study does not iiydirate any overt causal relationship bet.ween 2,4,5-T use and facial clefts". Ycl they added "'It. is important to recognise that such an effect, if it were to exist, would not have been detected, if the increase in facial clefts was Ies.s than two fold. A two fold increase in any anomaly would he ext.miic Iv j large. We believe more powerful epidemiological studies of 2,4, S--T are needed to more conclusively resolve tpiest. iorts conei-rn ing its developmental toxicity under conditions of regulated use". 4. Humboldt county CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. The CaJiforuia department, of Ileal Ih tarried mil au epi demi o 1og ica I investigat ion to assess the claims of ah mi rina 1 outcome of pregnancies in the Orleans California area, which inc l.udes a phenoxy herbicide spray ar e a . l i 1 :The rue hods of invest igut on Or leans inc tided O Review of luimho It county vital record for iiiformat ion et.m ern ing all 1 ive births, fetal and infant, deaths, and* congen i(a I ina1format ions occur- ing among in Cants born in- Or leans and nearby area's during the years 1974-197^ 2) Determination ol the dat.es of spraying phenox> herhieides within - live mile radius ol* Orleans C24743 .1) Review of Hon pa Medical Clinic records for live hi rt lis and 41 hih'i-vicws witli affected mothers in Orlrnas t* lairs and details n l pregnancy problems. WiUiin the study period, $7 pregnane ins n n r u m - d . Of 1lies**., eight, 9# ended in spontaneous abort ion, mu* (l percent ) in IVta i death (placenta pfiivial and til; rema in ing 1 8 in live births. I1 - |<eed, D. California dopar tnu;nt of HeaJ Lli Services memorandum, |`urUii:r investigation's into report, of abnormal outcome of pregnancies in Humboldt- and trini ty count ie s , April 27 , 19 79 . " Of the five birtles, six (7.71*) chi Jdron were born with birth dofocts (two hypospadias, two with :incompleto hip socket furmuti on, one cleft lip and palate, one mild talipes cquinovarus) one sudden infant death syndrome at ago seven months. Phonoxy lierhicide spi-iiying has been carried out in the fall of the year since I961 with the exception of J0 2, 1972, and 1973. Spraying ceased in November- 1976. Therefore spraying consistency cannot be estabIished in this rase. When tho 16 abnormal pregnancies were compared to the totai pregnancy outcome for that region, tin* pi cut. re came into perspect jv e ; M The spontaneous abortion rate of 9% is less than the expeeled rate of IS#* ^ 2) Major congenital m al f o rm a t i on s oc c u r at. the rate of 7% of l i v e b i r t h s , w h i le i n c l u s i o n o f minor d e f e c t s b r i n g s tin* p e r c e n t a g e up t o 1 5%. The O r l e n a s r a t e o f o c c u r r e n c e I s 7 . 7 % - s o t h e figures were within the expected boundaries. ' j ) One l e t a l d e a t h and one su d d e n inf an t, d e a t h a l s o r e f l e c t . t h e CONFIDENTIALpattern s estab Iish ed lor th e s t a t e . SUBJECT TO PROTECTIVE ORDER. C-24749 Reed concluded that "it appears unlikely that then; ha* I,con an unusually high rate of pregnancy wastage in Orleans" . 5, St. Louis Missouri, Horse arena, Beale et al, 1977. Long-term effects-ol' dioxin exposure. Letter to editor, Lancet,'j (Hol4 ): 74^. August 197 2, tlie Missouri Division of Health and the Center for Disease Control reported an investigation of a horse arena in Eastern Missouri where 54 of 57 horses exposed to the arena had died of an illness characterised by skin lesions, severe weight loss, and hepatotoxicity. Birds, dogs, cats, insects and rodents were also found dead in and around the arena. A six year old girl who frequented the arena as a playground, developed epistax.is, a gastrointestinal complaint and severe hemorrhagic cystitis characterised by hematuria. Bacterial and viral urine cultures yielded negative results. Throe other persons suffered from milder illnesses with symptoms of headaches and nausea. They aJ so visited the arena though for shorter periods than the young girl. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. Subsequent soil analysis showed that both TCP (trichlorophenol) and TCDD were the probable toxic substance.', causing the adverse health effects. It was found that the arena s o i l contained a TCDD level of 3i.H to 33pg/g(ppm) of soil. The contamination was traced back to waste oil used in the area to -control dust. G 24750 On reoxami nat. ion of the young gi r 1 after a fivi* year interval since exposure, the patient had grown normaLiy. Both height and weight exceeded the 75th percentile. Detailed physical, neurological and chemical examinations revealed n o `ahnorma Ji t Los. Tin* same studies wen; conducted on the patients* sister and mother e x p o s e d simultaneously though less extensively to TCDD and the results were Bua 1e et a 1 concluded "Our experience demons!rates that people exposed to dioxin can recover completely with no apparent sequela from the toxin. It remains to he seen whether ( h e exposure to di oxi n ii* these children will result in abnormal pregnancies or affect their offspring. Scveso, Italy: The Icinesa (Industrie Chimiehu Meda Societa Aruminia) chemical plant did not produce herbicide 2,4,5-T hut made hexachlorophene,.an anti bacterial agent. The herbicide and ri hexachlorophene share a common denominator, 2 ,4 ,S-trichluropheno! In their manufacturing process, . The Icmcsa factory explosion occurred in a reactor that produced 2,4 >5-trichloropheim L by combining tctrach Inmhen/.cnc with sodium hydroxide in an ethyleneglycol solvent. The explosion pro Killed forth a toxic white cloud which when cooled, descended slowly over the surrounding area. Among the chemicals that, contami nated the area during cooldown was the chemical di oxi n (TCDD) Based on determinations made by production officials, an estimated 4 ,h()0 to 5,000 kg of reaction product was lost into the atmosphere (di Domenico, 19771 . Estimates of the TCDD dispersion ranged from 6,50 grams to 1,700 grams - Kearney, P.C. et a l . (TCDD in the environment, sources, fate and decontamination. Environmental Health Perspective, 5 , 273-277, 1973). A sample ol' the escaped product taken from the reactor head for analysis reve Iaed * the presence oT 3.5% 3.5,000 ppm TCDD. C2475 fI Reggiani - The estimation of the TCDD toxic p o t e n t i ai 11 in the light of the seveso fecident. Paper presented at t h e 2 ( ) t h Congress of the European Society of Toxicology, Berlin (V.'e s t ) June 2S-2P, 197H. - Reggiani reported that birds, rabbits a n d CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. with one reading as high as "JO ppm. Children and adults exposed to the descending dust 'complained of nausea and developed .skin lesions accompanied by redness and swellLng. Some experienced the burns and blisters common in exposure to caust ic material. 11 Garattini- 19 77. TCDD poisoning at uveso y Ihi nmed i c i ne , 26: 28-29 . reported the highest TCDD content was deterin inetI in .the' herbivorous animal s . People complained ol* nervous symptoms, mood changes and above al 1 a serious rash-like skin lesion - later- diagnosed as chloracne. The Sr.voso area being divided into two /.ones - Giovanardi, A. (Decontamination progress for the dioxin ronl ,tmj n.it.ctl areas o C Seveso and Modi a , C nulll.u Kesi onaJ e De 1J.1 Lombard ia , Ministero Della Sanita, Milan, Ttaly, August ]8 , 1976 min. p .17 ). described the first zone "A" as a triangular area covering approximately Hit hoc tares (ha 1. Zone A iDeluded land located south, southeast of the Icmosu factory and downwind at t.lu: time ol the accident. Iteggiani (19 78 opc it ) determined that soiL levels registered TCDD levels approximately |0 p|hs. The inliabitents of this area were evacuated in three stages - on July 26, July 28 CONFIDENTIALand August, 2, 1976. SUBJECT TO PROTECTIVE ORDER 024752 34. ' Zone B had doted*able soil levels o 1 T C D D . 4 Reggiani (1978 opcit) later described this area as having residue levels between 0.1 and 10 ppbs for TCDD. This area covered approximated 2 50 ha and was divided between a large* urban center and an extensive rural area with some small residential aggregates. The population of 4,900 was not evacuated. Recommendations were made for the women and children in order to reduce the possibility of exposure. A third Zone, Zone R, covered a total of about 1,430 ha. Occassional residue concentrations, all less than 0.1 ppls TCDD in soil, f characterised this zone. This population of Zone K approximaled 40,000 people. An extensive health surveillance system was set up to determine the mid-term and long-term range effects of TCDD exposure. Medical jsurveillonce included laboratory tests, medical examinations, monitoring of pregnancies and abortions for.any abnormal outcomes, rate of stillbirths, population morbidity and mortality, and cancer registry. The medical surveillonce program was extended to 11 Districts w tli a population of 2 16 ,OOO. Roggi ani, G . (The estimation o f the TODD tuxi ( potential in the l.ight of the Seveso acci dent, Paper present ed at the 20th Congress of the European Society of Toxicology, Berlin (Wcstl June 25-2P, 197^). He concluded "The Seveso accident has not revealed up to now, toxic effects in humans which have not. been observed in other episodes. ChJoracne, the typical skin lesion, has occurred in children with the tendency to spontaneous and rapid healing. Tin*, peripheral nervous system lias perhaps been attacked and reacted with suhclinic.al signs of impairment. Signs of 024*703 involvement of the liver without apparent functional disorders' 1 CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. a n d l o s s , n o g r o s s r i a l f o r r u . i t .1 o i l s , n o g r o w t h i v l - i r f l . i l i n n ;i( 1 <:i,n ,'iiul no c y t b g e n e t i c Jinroiii.i l i t i T i n : i nun f i . u u p . i b i I i t y <! ' I n - population n o t o v e n o f t i n ; f . i u l d r e n w i 1 h <U.! . . r ; n n . * , l i a s n o t h m - i , attain ed . A t U u * d i s p u l o r e - o l u t . o n c o n ; i r : i c c m i 2 , 4 , r. 'I i n 1070 D o c t o r L . S a n c h i o n i a n d Jl . R e n d e r p r c . s c . i u - . ' i d a t a o n a b o r t i o n e x p e r ie n c e s f o l l o w i n g the- e \ p o n : 11 - T w e n t y - e i g h t o l ' t h e 1 -i i n d u c e d a b o r t l u. ' is w e r e r e p r e s e n t e d by p r o d u c t s ot' c o n c e p t i o n Iwd vn-ri. p a r t i a l l y f r a g m e n t e d dui-io*.- c u r r c t t a g e and i ru'.ompJ.rU f o r m o r p h o l o g i c ,, v a l n a l i on No m o r p h o l o g i c m a l f o r m a t i o n s w o re n o t e d i n a n y o f Dios* i h .h 2 ) A s l i g h t i n c r e a s e i n tin;' i n c i d e n c e o f s p o n la n i'u ii.^ a h o r l mi.-, was d e t e r m i n e d i n t i n - M / m u * . T h o s e i n c r e a s e s m i g h t h a v e ie.-n d u e t o i m p r o v e d r e g i s t r a t i o n ' .some o f t h e a b o r t i o n s a l s o m,\ h . - v e b e e n .- 1 1 1 n d 1.11 * ; d ) . i ' o u r l . i ' n i 01 i h e >> c asii-'i o t -pent n r e o u s a b o r t u.-.< e n d u T ' i n a t a l m o r t a l i t.y e x a m i n e d w e r : ; m a l f o r m e d s t r u c t u r a l l y ( 2 4 . 6# ) * T ills i n c i d e n c e was w i t h i n t h e r a n g e t h a t mi*, at be e x p e c t e d g e n e r a l l y , h u t c o u l d n e t h e c o m p a r e d t o t h e r a t e i n t h i s p a r t i c u l a r a r e a p r i o r t o t h e a n : j . d e n i as no d a t a a r e a v a i l a b l e . T h e L y p e s o f m a l f o r m a t i o n s .-a*.on w e n * c o n s i s t e n t w u n t h o s e w h ic h w o u ld be e x p e c t e d s p o n t a n e o u s l y . A l l t h e iM-poi' i eb m al i o r m a t i o n s w e r e i n t h e R an d RT Zones ; w h e r e t h e s o i l concern.rat i oils o f d i o x i n w ere below d e f e c t a b J e l i m i t s . CONFIDENTIAL \ SUBJECT TO PROTECTIVE ORDER. C24754 anti loss, no gross r.ial in rm.it ion- , no growth n -1 nrd.il 1on ul <*-rm ami no cytogenetic -bnrniu.i 111 i Tin: iiai* iHK-upai i1 iiy nl 'de population not oven of llit* ;:iu loron with cU.I>r,u m * , has tn.f h*M'* attained. At tin* dispute resolution con; roare on 1!,4 ,^ T.iu lI/O Doctor L. Sane hioni and II. Kohiler present. cd da* a on .ihort inn experiences following* the rxp 'e:-.on : 1 ^-Twenty-eight of the 1 j ulueed abort :iuns were represented by products of conception !\a< wen. partially li'-amnonted dui in*.currettage and incomplete- lor morphologic w--valn.it ion No morphologic maJ formations were noted in anv c.f these etna*.-. 2 < A slight increase in tin; .incidence of spontaneous abort i>ns 4 was determined in the N Zmic. These incroases m ight have hr.-n clue to improved rogi strati on 'some o.f the abortions also may been .->( 1 1 lnth.u ed 1 . I``ou r-te eo ji \ he -p cases of ~*pont areous abor; and perinatal mort;il ity examined were, iti.ilrorined structurally 124.6%). This incidencre was within the range that mi -at ne expected generally, lml could net. he compared to the rate in ibis [articular area prior to the accident is no data arc available. The types of mul 1ornu L ions .-asen were consistent, w u n those which would be expected spontaneously. All the reported mal iormitions were in the R arid RT Zones; where the soil coat'em. rat ions of diox.in were below detectable limits. CONFIDENTIAL SUBJECT TO PROTECTIVE. ORDER. C24755  A3 sea .I-, . The study duals with a limited number oi` wdhi- n residing in the Alsea Basin Area of Oregon. A number of women living in this 2,4,5-T treated forest area experienced miscarriages, which they said were correlated with the spraying season. .Initially 10 miscarriages were reported by eight women'. Subsequently 13 miscarri.- were reported from nine women. Twelve of the 1.1 miscarriages occurred within the first 20 weeks of gestation. When this data wa."> compared to the 1ive birth rate in Alsea (86 in the six year period studied) a miscarriage rate of 12-13 lies well within the limits of an expected one miscarriage for every seven li ve births. The report noted a seasonal variation in mi scarriage ancidence when the Alsea values wore compared with those from nearby Corvellis,Oregon. However, insufficient evidence precluded any establishment of proof or non-proof for a relation between miscarriages a n d '2,415-T- Mantel, N. (An evaluation of the statistical methods used in EPAS report of assessment of- a field investigation of six years spontaneous abortion rates in three Oregon areas in relation to forest 2,4,5-T spray practices. (Alsea 11 report) George Washington University, March 26, 1979) - commented that "the possibility thus arises that at least some of these miscarriages were experienced by miscarriage-:prone women. He also felt the "publicity about 2 ,4 >5"T spraying and spontaneous abortion could have caused more previoit: spontaneous abortion to bo recalled and reported".Alsea IT C24756 A continuation of the Alsea study, this epidemiologic ~ investigation further analyzed the possible relation between spraying oi herbicide 2,4$ 5-T and reproduction events. Tint results of this study provided the basis:i*or the EPA suspension order in February 28, CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. Tin; Alsea 13 investigators collected data iVniri three areas of* Oregon. The sludy area, which included an area of approximately l60(i square miles of Oregon coast and coastal mount airi range. Tin: "urban" area which is contiguous with t h e si ud> area and included the in Land towns of Corvellis and Albany, and the rura] "control", area which is in sparsely populated eastern Oregon on the Idaho border. The in form ition gathered in the study came from hospital records and included coded diagnoses, age of patient, spontaneous abortion data, gestation period and zip code of patients residence. The investigators limited themselves to spent.am oils abortions of less than 20 weeks gestation. Treated in hospitals in a six year period from 1972-1977. These data were then compared t live births for the respective areas. Conclusions revealed by the EPA study are summarised as follows, 1 1 the spontaneous abortions index (hospitalised miscarriages per 1000 births) for the Alsea study area where 2,4,5-T was used significantly greater than the index for the urban and control areas, where there was no known use of 2 ,4 ,5-T. 2) There was a dramatic increase in the spontaneous abortion index for the study area relative to the urban and control areas in the month oL June and July. This increase followed by approximately two months a period in March and April when 2,4,5-T was used to control vegetal.ion in the study, area. Relative to the urban and control areas in the month of June and JulV* This increase followed by approx imat.e 1y l.wo months a period in March and April when 2,4,5-T was used to control vegetation in the study area. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. C24757 38 - - # r 3) Statistical analysis of these data indicate that there was a ( significant correlation between the amounts of 7,4,S-T used in the study area during spraying season and a subsequent increase in the spontaneous abortion index in the study area> "The Ageway *s systematic survey of the occuranee of spontaneous abortions in an area of ?,4 >5-T use, indicates that there was an unusually high number of spontaneous abortions in the area, and that the incidence of spontaneous abortins may reasonably be related to the use of 2,4*5-1 in that area. Thu data further indicates that the miscarriage experiences which the eight Alsea women reported to the Agency were representative of the experiences of the large population of women living i11 the study area". Numerous critics of the Alsea II study ll Mantal, N, An evaluation of the statistical methods used in EPA report of Assessment of a field investigation of six year spontaneous abortion rates in the three Oregon areas in relation to forest 2,4,5-T spray pesticides (the Alsea II report} George Washington University, March 26, 197V. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. 2) Lamm, 1979. An epidemiologic assessment o f ,the Alsea II report, Tabershaw Associates, August, 1979. 3) Witt, 1979* A discussion of the suspension of 2,4,5-T and the EPA Alsea II study, Oregon State University, 1979. 4) Wagner, S.L. et al. A scientific critique of the EPA Alsea 11 study and report, Environmental Health Sciences Center, Oregon State University, Corvoilis, Oregon, October- 2 5 , 1979. C24753 These cr'it isins^ have revealed fragment, statistical and epidemiological flaws that the majority of the scientific community has accorded little if any weight to the EPA conclusions n Spontaneous ahull ions, of mi scarr iages rrctpieiil l> occur in the first throe mouths ol' pregnancy. Si .il i.-*1 it ciit; a spoil* anrous miscarriage incidence ol 1*1 to US'/. h a 1552 rate most commonly referred to in literature. In the U.S.A. hospitalization rate for spontaneous abortion approaches 3# or 32 per 1O00 maternity aclmi ssions. Wliother a spontaneous abortion will be hospitalised depends on: 1 . whether the women .recognized the event as a miscarriage. ? , Iiow anxious the woman is about abortion and the social support system her life style provides her 3 . whether the woman is financially able to secure treatment. 4 . whether the: treating physieian is a speciali st who deals regu lari y with spontaneous abortion cases. 5 . tile aval lability of treatment in an out-patient clinic. 6 . the standard of health care in the community 7 . the gestational ago of the conceptus and the completeness of the abortion (Lamm, 1979 ) Alsea I I , consi dered only hospi tal iseel spontaneous abortions. Attended abortions in clinics, unattended abortions, and those events lhat took place at area hospita Ls not includod in the study area were not considored. The study numbers, thus don't accurately reflect the miscarriage incidence in either the control or study group. The AJ sea II study stated that obstetricians in the area hospitalised only 10 percent of persons experiencing spontaneous abortion, while general practitioners faced with the same problem CONFIDENTIALhospi tali sell approximately 7bX of these women. SUBJECT TO PROTECTIVE ORDER. C24759 1 . Level of medical practice ? . age! of mother .1 . nutritional state, diet, a variety of mfccUinis agents, anatomic or genetic ahnormal.il.jes, medicine and other drugs, consumption of alcohol or tobacco, soc ie> economic status etc. Thus the effects of the stress agent, 2,4,S-T con Icl not he adequately asessed. Also the towns involvcd in the study Alsou (study I and Corvellis (control) do not maituin constant populations. Alsea a coastal resort, town lias an influx of people during the summer months. CorveJlis a college town, experiences a summer exodus at the end of the school year. Thei bPA cited na dramatic increase in miscarriages whie:h have consistently occurred at an alarming rate. This they attribute to the spraying of herbicide 7,4,5-T* Yet critics say on dotier examination of flu* dal a The* dramatic .June peak was apparent, in oni y one of the six y e . us si.ml ie There was consistency to the abortion pattern and there was no solid esLahlisluuent. of background miscarriage events to clarify a stress related occurrence. In addition there: was no increase? in the nutnbe:r of spontaneous abortions iutlhe latter years of (.he? .study, r veri sprayed in the test. area. Ofhe?r peaks and troughs appearing on the Alsea graphs randomly occur fhoughout the ye:ar and could m d he? attributed to spraying - a strictly seasonal event. SUBJECT TO PROTECTIVE ORDER. C24760 Wagner s t a t e d wlii'ii I In' d a t a wji.s e o r r e c i ed I o .1 romninn hiS|)J ta 1j snti on rate and l lie total number of liosp i ( ,iI iscd spontaneous abortions ;i i t e x p r e s s e d as a percenta^e ul 1 ivc births the values arc: study area - 11.4# urban control- 14 l)% eon trot, area - () . &% At best the Alsoa TD study <'ouid only represent the in hospital spontaneous abort ion index lor its test area. The study has been discredited Id such an extent that it is no 1 onger considered a useful study for analysi s of the alJ eged problem, that is Lhe effects of herbicide ^ ,4 ,S--*1' on human reproduct ion. SUBJECT TO PROTECTIVE ORDER. C24761 St: ic n t i i i c S t u d i e s Tlic first r e p o r t s linking p a s s ih Ie .nlvn-sr h e a l t h effects to Agent Orange appeared in Vietnamese newspaper*. I)-I w m June 26, 1909 and July 5, I9<>9 (Advisory CommiIler mi 2,4 , T). The public response to these reports prompted t.he irl.ni.s|im i ivc studies of Vietnamese hospital records conducted independent ly by Cutting (1970) and Meselson (1 y71)- The President's Advisory Cotiuui Iter on li,4 ^S-- ( 1071 ) evaluated these studies and concluded the till lowing: "Summarizing the Vietnam dat a mi hum.m embryo! **x 1c 1ly , it can be said that (l) the sample of births surveyed was li-om year to year a variable but usually very small liar.lion of Untotal number. (2 ) it was quite unreprusenl.ative of the geographic and ethnic distributions, (3 ) the heavily sprayed and ol herw.i sc exposed areas were greatly under-represented, and (4 1 the hirlli records wore not trustworthy and, therefore, the r.il.es of stillbirth, and especially of congenital malfurmntion, derived from them were equally unrealizable. For example, the overall congenital mu 1.formation rate found in South Vietnam, 4.91 per* 1000 livubirths, Is about half of what was reported in other sLudics in various parts, of Asia, and possibly a quarter of what might ucLually exist, at term. A surther indication that the newborn children were not can.iii LJ y examined is the absence of Down's syndrome in the list of specific malformations compiled by the Army survey (Cutting, e l . , t I. | ( 1 97 0) despite the fact hat some Oriental populations h\ive been reported to have an incidence of this condition not unlike that in W e s t e r n CONFIDENTIALpopulations. SUBJECT TO PROTECTIVE ORDER. C24762 P 'y Finai iy, there is, and can he, nil |h j t isr knowledge .I I1caaenable approxi mati on o 1 the c?xpnsuiT Lo *,4 >'i I (ami ln*iu , I< 1)1)) experienced by pregnant Vietnamese women,.1eluding whet amounts they invested or absorbed and when this may JiuVe occurred during pregnancy. Thus, any attempt to relate birth delects or slilLhirihs to herbicide exposure is predestined to failure. It can only be concluded that the birth records that have been surveyed, and ' probably any that will be surveyed in the future, for SouLh Vietnam for the period 1900-1970 cannot answer* positively tin* *|iu>st ion.-, about possible adverse prenatal effects following human exposure Ui 2,4,S-T. It must be emphasized, however, that the searches that have been made almost certainly would have revealed any marked .increuse in the incidence of birth defects or the jntroducLion of a striking defect such as that produced by thalidomide In spite of considerable effort, no such occurrences were found". A further study on birth defects in South Vietnam was performed by Dr. Ton That Tung, ct al. (iy7l) They reported that out of 9^3 South Vietnamese seeking shelter in the North, in hospitals and lodgings in Hanoi, 19 adult women, including four* mothers and 70 children between the ages of 6 and 14 had experienced direct of UJ a exposure to herbicide sprays while living in the South. Of tln- UJcoc lour mothers, two had given birth to children with Downs syndrome. > 1 Among the 70 children, numerous cases of deformations (ocular l e s i o n s , Ul lumps on forehead, valgus feet (feet that extended outward) and a. chromosomal aberrations became .evident. Tung concluded: (translation in Young, et u l ., 1978) o Ul "Though still limited in number*, our clinical CQ O CO observations donl'irm the results obtained on animals by American researcher's. The massive C2476S and prolonged utilization of deferments bos ides St: i <:nti l'i c Stud i os Tin: f i r s t r e p o r t s linking |)o.s.s 11 I * .h Iv i t s i - h e a l t h effects to Agent Uranic appeared in Vietnamese newspaper*. hrl wren June 26, 1909 and July 5, I9<>9 (Advisory Comm iII< on 2 ,4 ,f, I). The public response to these reports prompted tin- refinspet i ivc studies of Vietnamese hospital rticords conducted i[(dependent Jy by Cutting (1970) and Meselson (l97l). The President1s Advisory Coiiuui I.tee on 2,4,S-T (l97l) evaluated these studies and concluded Lite iol lowing: 11Summari zing the Vietnam data on human embryo! ox 1c 1ly , it can be said that (l) the sample of hirtlis surveyed was I'emn year to year a variable but usually very small fraction of the total number, (2 ) it was quite urirop resent at ive of the geograph ie and ethnic distributions, (3 ) the heavily sprayed and nl herw.i se f exposed areas were greatly under-represented, and (4 ) the birth records were not trustworthy and, therefore, the rat.es of stillbirth, and especially of congenital malformation, derived from them were equally unrealizable. For example, tile overall congenital mal formation rate found in South Vietnam, 4-91 per 1000 iivubirfhs, is about hall* of what was reported in other studies in various parts of Asia, and possibly a quarter of what might acLually exist, at term. A surther indication that the newborn children were not carefully examined is the absence of Down's syndrome in the list, of speeifir malformations compiled by the Army survey (Cutting, H, a I. ) (1970 I despite the fact that some Oriental populations livavc bc.eu ;ep.rted to have an incidence of this condition not unlike that, in Western 1 CONFIDENTIALpopulations, SUBJECT TO PROTECTIVE ORDER. C24764 @ Finally, tluiit is , ami c.m In*, un prei isi* knowledge <>I reasonable- approximation of b1"* l`> ->4>S TiDlM experienced by pregnant Vietnamese women, -including wlial. .iiimimi they ingested or absorbed and when this may haVe occurred dm-inn pregnancy. Thus, any attempt to relate birth drlruLs or stillbirth* to herbicide exposure is predestined to lailure. It can mly In* concluded that the birth records that have been surveyed, and' probably any that will be surveyed in the l'uture, for South Vietnam for the period 1900- 197^ cannot answer positively l.lu* *ji*i*st ion.- about possible adverse prenatal eifects following Iturnan exposure l.o 2,4,5-T. It must be emphasized, however, that Liu; searches that have been made almost certainly would have revealed any marked .1m. rea.-a* in the incidence of birth defects or the introduction of a striking defect such as that produced by thalidomide. in spite of considerable effort, 'no such occurrences were found". A further study on birth defects in South Vietnam was performed by Dr. Ton That Tung, ct a 1. (1971) They reported that out of 903 South Vietnamese seeking shelter in the North, in hospitals and lodgings in Hanoi, 19 adult women, inci uding four mothers and 70 children between the ages of 6 and 14 had experienced dir:cl exposure to herbicide sprays while living in the South. Of the lour mothers, two had given birth to children wiLh Downs syndrom*. Among the 70 children, numerous cases of deformations (ocular* lesions, lumps on forehead, valgus feet (foot that extended outward.) and chromosomal aberrations became .evident. Tung concluded: V (translation in Young, et a l ., 1978) C24*763 "Though still limited In number, our clinical observations Confirm the results obtained on animals by American researchers. The massive and prolonged utilization of defonuants besides CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER, to ancesLral oil and these alterations ran provoke among their progeny congenital tnai forma t ion* tile importance of which remain to be do term in ed. In the abominable- history ai'twarn, have we over seen such an inhuman fate reserved for the survivors except in the case oi atomic wa r ?n A study similar to that of Dr. Tung was performed hy Rose and Rose (1972). The authors reported monstrous births, spontaneous abortions and deaLli among man and animals Toll owing exposure to the defoliants. The linkage of Down's Syndrome and exposure to 2,4,5-T suggested by Tung has been supported by Grumner (-- in a report by Honoroff (1973)). Grumner* s comments after inspection ol' j both North and South Vietnam were: k ''provided that it be understood that Lhi s cist imu U; cannot be anything but a cautious o n e , it may be assumed that there are at least 25,000 children with hereditary delects in Snui.li Vietnam. This does not include all the unborn babies whose mothers were sprayed during the missions that were flown in recent months. It does nut jno Itide those who were stillborn, or. died soon alter hirlli, on account of their serious chromosomatic do fed.s. Even after the war, it will probably be pussihie to arrive at only an approximation of the nil jre M ali- of this crime since one will only be able Lo examine CONFIDENTIALthe survivors when the time comes". SUBJECT TO PROTECTIVE ORDER. C24766 Tung, et .11.j also reported on another advcfM- In*.I(1i effect ho attributed to defoliant exposure. in 19 7.1, Tung reported an increase in the number of persons diagnosed with primary liver cancers in proportion to all cancer patients admitted to Hanoi hospitals during the period 1962-19<lH. He compared the 790 liver case: oul of 7,9 11 totaJ c a m er rases (10#), with those documented in earlier pre-spraying yeais, 1955- 1961. 1^59 liver cases out of total cancer incidence of 5,492 (2.9#). In a 1977 International Agency for Research on Cancer (1 ARC) monograph, (1 97 7 ), the Tung study was criticized for it* limitations in reporting which they considered resulted in an inadequate assessment between herbicide spraying and J iver r.wuer frequency. % - Ford, et al., (197#), offered a 'further factor worthy of consideration, the consumption of aflat ox in-contain inn ted food in parts of the East. Aflatoxin occurs naturally as a cmil.iminanL in cereal grains and has been suggested as. an e x p Iaiwit.i.un lo r the increase in liver cancer incidence. War conditions would he expected to increase aflatoxin risks in available food grains. In 1 9 7 4 , t h e National Academy of* Science (NAS 1 a ni i o i i n e e d results of its study of Vietnam during 1972-1973. The NAS roil Id I*1nd conclusive evidence of association between exposure lo herh 1r 1de.s and birth defects in humans. An analysis of hospital records u< three Vietnamese hospitals showed no consistent pattern of assueiaiion v between mai formations and annual amounts o f h e r b i d dos di ssem m. i l m l . To date then! is sLill a great1 debate about lIn- harmful effects resulting from human exposure to Agent Orange in CONFIDENTIALVi eLnam. Studj.es per funned by Tung have genera 11y hren met SUBJECT T~ PROTECTIVE ORDER. C24767 Dept, of Medicine & Environmental Health - G.J. Levinskas, G2WF (4-8809 March 8, 1982 tutjtct Agent Orange Litigation MemoIMAIHCI. 3/2/82, TMB/GJL TO T.M. Bistline, E2NJ mohTDsebahirevdj.ee.decWldetnioNivolcoleieufaqvmmraueeeravMntsrihetercenewBMllteA.ersoindsfSce,uetmh,tchoemIenastaaprumyiabnrjenotedfocttthT4.5asoutxpIriItceaogirlhseeooasgaw.dicbamwaSlaluiDasncnchawcetaeoedtflholfept.whrtlearhaistetsettdenPontphac.aetuginmoeoInetxenywintsdiHIteahdedrgiwbdionihocniidctdoh,hetesI" by iuwOste"fhufnanaoabrltsiulhtmpkiraaeaesittrsgtlot,sayaefiitsocettthhn2mhhc7eeaeoe,dttonrd.srItoweitxchnicesueotomcttoreaAheirdngneuitisnagnataaerbcqpaltosulperwiaeeanrnseoanctcrreiakstoP.neonatsrforwsmlWiaeabwahrmersieklpbereieeanntccttchhi.ekofaxeimtcatOmopsyrtnloiaeeynetuftoeeeedudm.rh"eiafebnfdnCiecinctfeepuorc1ulrttate9aotyn5ina3tiihbtll.nyo.een,cIgcshAncshedoihsedcoeckebIdkniiunebntohldgloteie,todkeogipdnutMrohtawirapsarhcsyhe 19 MI osunsgagnetost inthatht eDNr.itrMoclBitriigdaet'sionre.view be given to Charlie Love who is defend_ing A J. Levinskas alw CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER, IN-10M (REV. 2/78) C24768