Toxic Effects of Paraquat

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DOI 10.1378/chest.65.4_Supplement.65S1974;65;65S-67SChest

Renate D. KimbroughToxic Effects of the Herbicide Paraquat

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* From the Env ironm en ta l P ro tec tion A gency , C ham blee, C a .

CHEST 65 : 4 , A PR IL , 197 4 SU PPLEM ENT 16TH ASPEN LUNG CONFERENCE 65 5

D ISCUSS IOND r. W eibe l: I have a comm ent w ith respec t to thecovering of d iv id ing ce lls b y typ e 1 ce lls . It w ou ld ben ice to con ceive of these ce lls h id ing b eneath th e typ ece ll lin in g w hile th ey d iv ide , bu t I don t th in k you canrea lly m ake th is po in t. Y ou w ill o ften find ty pe 2 ce llspa rtia lly co vered by flap s of type 1 cells . A ssum ing th a tabo u t one-th ird of the ty pe 2 ce lls a re covered by ty pece ll flap s, then ab ou t 15 percen t o f th e type 2 ce llp ro file s occurring on ran dom sec tions shou ld app ear tobe com ple te ly covered ; th is oin t sh ou ld be loo ked a tca re fu l ly .Dr. E vans: The po in t w e are m ak ing resu lts from ou rin te rp reta tion o f the da ta w e h av e co llec ted . T hese da tacons ist o f ex am p les o f ce lls during m ito sis and labe ledtyp e 2 ce lls obse rved in the e lec tronm icro scope at th etim e in te rv als o f 1 , 4 , 5 , 8 , and 1 2 hou rs a fter in jection oftritia ted thym id in e. A t one hour, w e observed tha t 13p ercen t o f the labe led type 2 ce lls w ere covered by m o re

Tox ic E ffec ts o f th e H e rb ic id e P a raq ua t*Rena te D . K im brough , M .D .

Paraqua t is a gen era l w eed k ille r o f th e b ip yridy lfam ily of h erb ic id es (1 , 1 -d im ethy l 4 ,4 b ip yri-

d y lium ). P araq ua t is ava ilab le e ithe r as the d ich lo ride ord im eth y l su lfate sa lt, bo th com pounds are w ate r so lub le .In the U n ited S ta tes the fo llow ing fo rm ula tio ns a reava ilab le : O rtho paraqua t, a 29 .1 p ercen t so lu tio n , O rthod ua lparaqua t, a 42 percen t so lu tio n , and O rtho Spo t,w eed and grass k ille r, a 0 .44 p ercen t so lu tion . Paraqua tw as d ev e lo ped in the 1 950s , an d cam e on to the m arke tin C rea t B rita in in 1 962 . It w as reg iste red fo r use in theU nited S tates in 19 64 . R eg istra tion a lso perm its ae ria lsp ray ing o f d ilu ted fo rm ula tio ns.

A cco rd ing to a recen t ed ito ria l inance t ,1 the to talnum ber o f h um an d ea ths kn ow n to the m anufac tu re rf rom paraq ua t po ison ing is now 124 w orldw ide . In ad-d ition , 6 0 persons w ho have reco vered from paraqua tp o ison in g are a lso kn ow n. T he fa ta l d ose in adu lts isthough t to be abou t 15 m l of a 20 percen t so lu tion , o r am outh fu l as it is desc ribed in m ost case h is to ries.F orm ula tio ns w h ich co n ta in 5 percen t o f p araq ua t ifacc id en ta lly sw allow ed are u sua lly no t fa ta l. F a talpo ison ing in a lm ost a ll cases h as been due to in gestion ofthe m ate ria l. T he in itia l sym p tom s of po ison ing cons ist o fbu rn ing of the m outh an d th roa t, fo llow ed by nauseaand vom iting . A fte r a la ten t period of u p to sev eral days ,inc reasing resp irato ry d istress deve lops , a trans ien t e ffec tis a lso o bserved o n k idn ey , live r and hear t func tion andtrans ien t neuro log ic s ig ns a re seen , bu t dea th is usua llythe resu lt o f a p rog ress iv e fib ros is and ep ith elia l p ro life ra -tion tha t o ccu rs in the lungs .

D erm al exposure to th e paraqua t concen tra te m ayresu lt in severe sk in ir rita tion . D ilu ted spray so lu tionsm ay prod uce s ligh t to m odera te irrita tion . P araq ua t isab sorbed th ro ugh the sk in . In tox ic ity s tu d ies co nduc tedin our labora to ry w e found tha t the acu te derm al LD ,0

than ha lf o f the ir free su rface by the ad jacen t typece lls . A t th is tim e , the labe led ce lls have no t d iv ided , andour v alue of 13 percen t is s im ila r to you r re fe rence to 1 5percen t as the n um ber of ty pe 2 ce lls covered by th ead jacen t typ e 1 ce lls seen in sec tion s under n orm alcond itions . A s cell d iv ision pro gressed , w e no ted anin crease in the p ercen tage o f labe led type 2 ce lls coveredby th e ad jacen t type 1 ce lls. A t five hours, th e va lue w as36 percen t, and a t 1 2 hours 45 p ercen t w ere covered .F rom ou r observa tio ns w ith the elec tronm icroscope of 31typ e 2 ce lls during m itosis , w e fo und tha t a ll w ere ly ingon the basem ent m em brane and tha t 1 4 w ere partia llycov ered by th e ad jacen t ty pe 1 ce lls. W e in terp re t theseda ta to ind ica te th at as type 2 ce lls u ndergo d iv is io n ,they m ove apart ov er the basem ent m em brane and be-nea th the ad jacen t ty pe 1 ce lls so tha t one or b o th s is te rce lls are partia lly co vered by type 1 ce lls .

in ra ts w as 80 m g p araqua t/k g body w eig h t in m alesand 90 m g/kg in fem ales , w h ile the acu te o ra l LD ,, inm ale ra ts w as 10 0 m g/kg and in fem ales 1 10 m g /k g .2T hese find ing s in d icate th a t the re do es no t seem to b e agrea t d iffe rence be tw een th e ora l an d derm al tox ic ity inrats.

M cD onagh and M artin repo rted fou r cases o fparaqua t po iso n ing in ch ild ren . O ne of th e pa tien ts , ath ree -y ear -o ld boy , w as adm itted to the hosp ita l w ithsu perfic ia l burns on h is righ t th igh and hands 2 4 hoursa fte r he h ad sp illed a 20 percen t paraqua t concen tra te(C ram oxone) on h is clo thes . H e h ad a lso been seenp lay in g near a p oo l o f the liqu id . A bou t s ix to e ig h t ho ursa fte r adm ission an ery th em atou s rash app eared on h isth ig h an d hands . T he rash deve loped in to a la rge firstdegree burn . N o lesion s w ere seen in h is m outh . In sp iteo f th e fac t tha t th e ch ild d id no t app ear to have inges tedany paraqua t, it w as presen t in h is u r in e. T h is caseillu stra tes tha t p araq ua t is a lso ab sorb ed th roug h hum ansk in .

A s p o in ted ou t ea rlier , pa raqua t is reg is te red in cer-ta in ins tan ces fo r sp ray in g by a irp lane in the U nitedS ta tes . Fo rtu na tely , th e partic le size is la rge en ough sotha t d irec t inh ala tion do es no t seem to presen t a p rob lemunless h igh pressu re sp ray or a ir b las t equ ipm ent is u sed .A ccord ing to C age4 the no-e ffec t leve l fo r a resp ira-b le paraqua t ae roso l in the ra t is abou t 0 .1 m g/M fo rrepea ted six -h our exposures , w h ich w ould sugges t tha t0 .1 m g/M w ou ld no t b e excess iv e fo r occupa tiona lexp osu re. T he th resho ld lim it va lu e fo r p araq ua t inw ork room air in the U nited S ta tes se t by the Am ericanC onfe rence of C overnm ent Ind ustria l H yg ien is ts is 0 .5m g/M a t p resen t.

Pa tien ts have on occasion had nose b leeds due to aloca l e ffec t o f paraqua t on the nasa l m ucosa. If pa raqua tis sp lashed in to the eye , pa rticu lar ly the paraqua t con-cen tra te , sev ere eye in ju ries have occurred , an d in

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F IGURE 1. Section of lung of rativen 160 mg/kg paraquatby stomach tube. Rat died six days later. A lveoli containedema fluid, inflammatory cells and macrophages (PA S stain,x 50).

V., .

66S 16TH A SPEN LUNG CONFERENCE C HE S T 6 5 : 4 , AP R IL, 1 9 7 4 S UP P LE ME NT

addition, injuries to the fingernails, nail beds and skinhave also been reported.6 A ll of these injuries are pri-marily due to the local corrosive effect of this product.

D eath following paraquat poisoning is usually theresult of progressive f ibrosis and epithial proliferation inthe lungs. This effect has been described in humanbeings, rats, guinea pigs, mice and dogs.1

W e2 have studied the effect of paraquat on the lungof the Sherman rat. T he early effect of paraquat after asingle oral dose of 150 mg/kg by stomach tube, waspulmonary edema w ithin 48 hours.

Examination of the affected lungs w ith the electron-microscope showed swelling and large vacuoles in thecytoplasm of the membranous pneumocytes. D arkprominent granules were also seen in the cytoplasm andwere thought to represent ribosomes. W idening of thebasement membrane with separation of the epithelialcells from the basement membrane was noted. Pulmo-nary edema and red blood cells were observed in thealveoli.2 A rat which died four days after a single oraldose of 160 mg/kg of paraquat in water showed firmdark lungs on gross inspection, and microscopic exami-

F IGURE 2. Section of lung of rat given 150 mg/kg of paraquatby stomach tube. Rat died ten days later. N ote extensive areasof proliferation of fibrous and epithelial cells. N uclei of someepithelial cells are enlarged hyperchromatic H& E x 125).

FIGURE 3. Section of lung from rat receiving 40 mg/kg parR -quat, killed eight weeks later.Note pigment staining w ithPerl stain within macrophages (Per! stain 500).nation revealed edema and hemorrhage.

Rats dying six days af ter a single dose of paraquatshowed an inflammatory reaction in the lungs (Fig 1).Polymorphonuclear leukocytes, macrophages and edemafluid were observed in the alveoli. Evidence of the earlierhemorrhage was still present. A brown pigment whichstained positive for iron with Perl s stain was observed,and probably represented hemosiderin. A highlyeosinophiic PAS-positive membrane lining the alveoliwas also noted. In rats surviving ten days following asingle toxic dose of paraquat the lungs showed begin-ning proliferation of fibrous and alveolar cells (Fig 2).Rats given a single oral dose of 40 mg/kg body weight,killed eight weeks later showed fairly extensive areas ofconsolidation. M icroscopic examination of these finngrayish areas revealed extensive fibrosis and a brownpigment positive for iron with Pen s stain (Fig 3), whichwas consistent with hemosiderin findings. Slight pro-liferation of epithelial cells was also observed.

W hen rats were fed 500 ppm paraquat daily in theirdiet (20-30 mg/kg body weight) an occasional rat de-veloped areas of consolidation. T hese areas of consoli-dation contained proliferated epithelial cells which weresurrounded by inf lammatory cells and fibroblasts. Aprominent amorphous material was also observed in the

FIGURE 4. Electronmicrograph show ing electron dense mate-rial in alveoli (arrow). L ead citrate and uranyl acetatex6,745).



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CHEST 65 : 4 , APR IL , 1974 SUPPLEM EN T 1 6 TH AS P E N LUNG C O NF E R E NC E 6 7 S

F IGURE 5. Elec tronmicrograph illustrating large whorl ofelectron dense material within cytoplasm of alveolar epi-thelial cell. L ead citrate, uranyl acetate (x 3,30).alveoli. Electronmicroscopic examination (Fig 4,5)showed this material to be striated or to form whorls ofelectron dense material reminiscent of surfactant andlamellar bodies. Fletcher and W yatt9 recently reported alarge increase in arachidonic acid and a small increase inthe cholesterol esters in the lungs of rats sixa y s a f t e rpoisoning w ith paraquat. I t is possible that the increasei n t h e f a t t y a c i d s i s d u e t o t h ematerial accumulated int h e a l v e o l i , wh i c h was just i l l u s t r a t e d . A hypocho-l e s t e r e mi c d r u g AY 9 9 4 4 a p p a r e n t l y s h o ws a s i mi l a r a c -cumulation of material within the alveoli of the lungs.10

There is a possibility that paraquat is absorbed by thelungs, then may become reactivated in the lung byo x y g e n . T h e t r e a t me n t o f p a t i e n t s s u f f e r i n g f r o mparaquat poisoning w ith oxygen probably aggravates thelung lesion, a n d o x y g e n s h o u l d t h e r e f o r e n o t b edmin-istered. Paraquat is absorbed on bentonite, fuller s earthand related materials, and becomes deactivated. Thesevarious absorbents are most effective when given orallywithin one hour or less after the poisoning by ingestionhas occurred. B rown11 has recommended the suspensionof 300 gm of finely divided fuller s earth, previouslysterilized to kill bacterial spores, in 1 liter of water to begiven promptly after the initial lavage. Forced diuresismay also have an effect in treating the poisoning, al-though this has not been definitely proved. Paraquat is

DISCU SSIO ND r. C orrin : I think it is important to re-emphasize thepoint that you made, and that is the route by whichparaquat reaches the lung. I know of no fatal cases ofparaquat poisoning in which the route to the lung hasbeen the respiratory tract. A ll the fatalases that havebeen reported are those in which the paraquat is in-gested. In our experimental preparations, the data agreeclosely w ith yours in that the epithelium is the major siteof damage. There is some endothelial degeneration butthe epithelial damage can proceed to complete necrosiswith the endothelium being apparently quite normal.T his is particularly interesting when one realizes thatthis toxic substance had reached the alveolar wall via thecirculation and not via inhalation. This material is soextremely toxic that one might ask what we can do toreduce the hazard of this material. One might initially

fortunately not well absorbed by the skin or the gastro-intestinal tract. T herefore, most patients who have takenthe 5 percent solution have survived. I f about .05 mg/kgbody weight paraquat in water is instilled directly intothe trachea in rats, localized f ibrosis is produced in therat lung. This finding illustrates that not very muchparaquat needs to reach the lung in order to producef i b r o s i s . 2

I n summarizing the sequence of events following alesion on the lung caused by paraquat, the follow ingseems to take place: the alveolar epithelium becomesvacuolated and degenerated; the alveoli fill w ith edemafluid; basement membranes are w idened; and red bloodcells appear in the alveoli. T hese events are followed byinfiltration of the lung with inf lammatory cells, fibrosisand epithelial proliferation, and accumulation in thealveoli of electron dense material that resembles lamellarbodies and surfactant.

REFERENCES1 A nonymous: Paraquat poisoning. L ancet 11:1018-1019,

1 9 7 12 K imbrough RD , Gaines TB: Toxicity of paraquat to rats

and its effect on ratungs. T oxicol A ppl Pharmacol 17:679-690, 1970

3 M cD onagh BJ, M artin J: Paraquat poisoning in children.A r c h D is child 45:425-427, 1970

4 Gage JC: Toxicity of paraquat and diquat aerosols gen-erated by a size-selective cyclone. Effect of particle sizedistribution. Br J I nd M ed 25:304-314, 1968

5 Cant JS, Lewis DRH : Ocular damage due to paraquatand diquat. Br M ed J 2 : 2 2 4 , 1968

6 Samman PD , Johnson ENM : Nail damage associated withhandling of paraquat and diquat. Br M ed 1:818-819,1969

7 C lark DG , M cElligot TF, H urst EW : Theoxicity ofparaquat. Br J I nd M ed 23:126, 1966

8 K imbrough RD , U nder RE: The ultrastructure of theparaquat lung lesion in the rat. (Environ Res in press)

9 Fletcher K ,Wyatt J: The composition of lung lipids afterpoisoning w ith paraquat. Br J Exp Pathol 51:604-610,1970

10 K ikkawa Y , Suzuki K : A lteration of cellular and acellulara l v e o l a r a n d b r o n c h i o l a r wa l l s p r o d u c e d b y h y p o c h o l e s -teremic drugs A Y 9944. L ab Invest 26:441-447, 1972

11 Browne TD : T reatment of paraquat ingestion (letter toeditor). Br M ed J 3:580, 1971

suggest that we ban the sale of this material but ourfarming friends tell us that this is an extraordinarilyvaluable chemical and a ban would put a great burdenon them.D r. K im broug h: I think it would be far better if the lawcould be changed and the dilute form of paraquat wouldbe the only form available on the market. T his woulddecrease the number of cases of such fatal poisonings.D r. K . F isher: I would like to extend D r. K imbroughsremarks on the role of oxygen in paraquat poisoning. W ehave found that paraquat is far more rapidly and uni-formly fatal in animals breathing an atmosphere of oxy-gen than in those breathing room air. W e have alsofound that concentrations of paraquat which are bac-teriostatic to aerobically grown E co li have no effect onanaerobic growth of coli .



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DOI 10.1378/chest.65.4_Supplement.65S1974;65; 65S-67SChest

Renate D. KimbroughToxic Effects of the Herbicide Paraquat

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Toxic Effects of Paraquat

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