14!

^ N1

CW

m

c

l 1 .̂ Lr

0

y R

t

r'O

3

rb7

R•

N

H

z

►—t

z1^1

0

rn

C

CC°

f

n L6 i. N n !e

d a a r"i a r^o y ^°U D ^^i vm'^^ ry cu X^ ^ • n,.: .^ ^ y n wp N c c^a 0%° ¢ry A' `^'' C rte. p q e 3' a b

ii

^ ^ 7 ^ to ^ n w C ••^ G tY ea m ^ ^,., ^ C D

p ^ fi ° ?^ O. O :. C ^• ^ ry y' °-'• e $ w ^' rCr+ `^ m ^u y a^ m a ^- r

aao o fir° = " :' 5' n o ^

n ^y "' O q C tic ^ , ry o m ro o , a p roKf° c namo::`"'C-It',ro^°,w.ti^'y^r+?vi ::^cX'v ^ce^a x7Cas y CA

•

3 a^w^S.'yrda^,^0`'..r.owo ^.^ ^ ro a+ o^ N i o^•^^• DSg°el

_.0 D G. Aw l c^i °^p N ^' a s ro Y :' n v+ C t o p - p

CG O Si ^ ^_ P ^C^. WC.

Y y 2Yen ^. t^1^

C ^^ O y QD O `t ro vi C3 r n G ro T: v

oc __rn° g o !races°' ' 1^^^. cn • c^ ?`•ca,'^^^ .- V' c`^s

7 n ^• G• .-' 7 ~ ^p p ".a -•^ O ^1 G ~i, `mow+' y

^•^ ^s, p

^, C .e7.^ w A

^ .G w

v; f+ E O 4 .» Q, y ^. eo p, ^_ 1 'a _ m i 'x

-ir" .-^ ^j G•

r' " Cs Oy f^ G^ ^. O^ G ^ 7 `. a

N •w-^ ,--, ^' •--^

Nd G '^ ^• fl. 9.

E^ a^x^w^oro^̂p wo'^oa^ ^o R ^^,u o_ oo a u ^ca °,^ orwn m Q' ^° N^ i^ 40'^ ^, .^' off+ p` cr ^C o i' r O afli

d k ^• ^O ^ "°'^ d ^ ^ G 7 y w ^ `^ ^ x n N [5 .^. O 0 ^ a_ ¢ ^ w ^• ai ^ni

, G `n 0 c`' Oro

O. ON v v¢i ..

a• n• w c: ry p O

y'' ("e ^y v O s^ fL C _. ^' t^ w ~ 7

Q0 N 'C^ 0, .ran n. ?^ R Q ran f^

• p N Ci•u -' moo

.+R s^ "a p sa. H . ro .

f o 0 o m° co ^ aco N"^, w cnG ^ a oc^•.'^ m7 7

•-ti 7 '^ r O .^- 4 p ^• a m 'x0 'O O 3 ^'• 0 Q• G•

7 N '^ 's ~ '' Phi^ o o a w^

o ca w^ p a o o as o w X v' % v, ^ °^ i, o ,G

`' , o a O A^

e n 0 D c a C

Ci c^`c O

v' G.{np d Q @- n• - O o -SO n C v ^i '^

`G ^'' y ^' ^p pc9 C O p [i v, L% ° A m 7 -1 ^n• 7'

r 6 f^

r' r ^, .r O<p w d ^ ^, G w tom, c y oat W ,o S• ^, r ^u -' — ^ 0

S ' " O O c^a y coo G ^' vi y^ o O q 7 p.: C 7 p a O y

n p a• [i i1 •y O

^ D ^ y G• C^ n ^•'^ w U C " ^n ^. ley Q• ^. f+ C P D `4

Q a m e%o o+ coo ^^ o p =^ g ^^_o ^ a ooa X^ a rn^ g^

t^ .F.'. fe a ' 5' N p w ^y [Cu O p D [ .C+ fr.7 (o C O p

9D ro cc x co d.,," o Q .,^sp a w

y o e^ o r. o %A o o Ar no ^' c o aHa ss ro 'd ^ o o ^ti i o

"y C -'c x R 08 ^`t`{ ° c^ ^ -' p.^^e a0 0 7 .. c -• Y^ n '0 ^. ry

^ m d o

^

_ fl

0 3 Gi '+ O vai 0 O R. " y G ^p ^J n C ^* .. r U

y T^ G y 4 p N N fry C Q A^ 4 p P o a p•.. s `C

^n

Q O. ? On B+ 3 to ^C

PA

auJ

spolpay&J

ua ^t ea s e(96r `ue

wleL) AaKs!Igndaq P] I s q p1oM still Jo a;ou A1eu!wrlaldd •oSEUG OJp cgGP IogoIc aantil i q Ioueq;awJO UOi) p!xo e41 UO ; ago £Jol^giqui InlzaMOdr. A;1axa Iouugpa 3s4; OJIIA ur UMO4s seM ;! Pucpanrasgo aiaM sPa ja U

115 • 'Pa!pn;s aiojaJa41SEnn Ioucy;aw Jo asop piepucls a jo uo!;cu!w!la ayauo Iou1e4;a to uo!;saSui JO 73aya aqy 'Ioueq;awpa5uegaun jo ;nd;no paszalau i us ut pa;aagaaq AI

noM uo!;rq!qut gons 2Ug2 1fla 111 pauiaas ;! pue`a;xuuoj ao ap tgaplewaoJ •$•a 'Ponpold a!xo; aloe]nubs o;us Iauey;aw jo uo!;Januao ay; Su!Iiq!quiAq clgs]nonej tan 24I!w Iougyfa 3 q1 paULaddoi '(6• '6i `1EJOd UOA pus '199H '.iau2V ! 6#,6I'an3uopeH pus uagoJ ! 91'6I `a^'j) Mwit sI^I;paw iyuo3 GAEL[ SUO!;Bnlasgo anlsuaaxa aiow pubauanbasgng •

Ioueq;a Jo uopsaRu! snoaurnlnw!s ay;Aq paonpi GJa loue paw jo sloaya sno!anfu! ay;imp papnloaaa Q^g sas 0sa41 uioJ{ pogra3sapaMMM Suruos!od Iounq;aw wo1 ,I Suriajjns s;uarlud 91JO sproaaa asca q iqM u! olgel!ens awumq (£f,61)o-I cQ 11oda3 L' Ssa12oid ul SEM )(JOM ST41 a1!4M

3unzos!oa Ioasq;GIA,I uo Ioucy;j JO 130113 oqL

'wxg2u! fl!gIe' (saanpord oilaq;u^iS pus . past 1310) sauasnpul

j iiiiit0 tU ioItuI sjssoi j o ui1d s^sa ;usIauc ay our 041 u; U!I!UA03d suonrnaoa 3^2nsanui01 A3!unpoddo u+2 jo p oio,Ialaga 03aM aM'aa!13erd leri;snpu! Jo suo!upuoo sapun suo!snpuoo{yt 1503 02 alge,!sap Si 1! ssuor;!puoa do2wogB1Japun no pa!.0 o aq (I>Jo ue t Uor)U2IISGAul ue tans42n0uj 'Spofgns urnunq q;iM pa!pn;s Guojaa04)31aM Iousgaaui JO ua.1nu!wcla PUB no!;dlosgy•UO ! 3

UI84ur aCq uogdiosqu JO ;oadsai

u! slewlue .raMO! ay; pus uvw u GOMIGq aauaaay!pa81'I a ;aadxa pinoM auo ',Lwlue aq) jo az!sa1i1 42M £lap!M sa!aen uaryM 'uo!;ra!dsas

,lo 03U1a41.Cq pauot; ►puoo rclaannl sr uoudiosclu Jo o1w alps qj.in_4 'asod]nd ;uasajd ay1 ao; onlgn 0I11!I30 a-IE s;Insai oq; SU01fl12UGOUO3 ]nod 42!q 1s,no paWea WOM SIUouivadxa ataq; se ;nq 'SSop puss3ea cq uo!;elnwnoE Jo a;sr 04) uo ua;IeuuoJUI jo1 unow8 u!i31a3 g u!e;uoo (L£6I) iva]gas

pue ;ue iPun ( I'1 61) 0P!OH lap UOA pu pa SMao-j jo s;]odalaq.L 'Aluzas a.IOW uana sr lnoden aq; Jo uo!JelequrRq loueq;aw Jo uo!;d]osge 34; 3o a^palMOU}I•

(oP6l 'J3IuadJUD : b£61 `Bloquaaj0 pun ps2-29H -' OP61 'uo)3l$83) loueq;a Jo uo!aeuiw!la 342uo 3mn;e]a1!I a4; u! punoj sr uo!sn

,Iuoo aerrwrs y

S. N!yaS Pdy!Paw g tj^!h1

£I IL'9i

11owPoIo3 PGUi .Ia33p •payiaads am 3 t p `paiap!sucu 3J •uoilwova ,Guuun sc ysnsWill si y,lyM ap,Ct{aplewsof 0) a;eUl'$U8u1Jdd pIJL' sws^ucysaw ayi^As>JayM •

^rnowa^ cu ju wsivayaocu ayl of sa sun^ljo FEtgaul .(q tJoI pl%Q San oAu! -dwnssc ,tut tnoyuM ^tpnq ayt ycowuw1 ^ouacpaw o aaunagSnoii ip aytI ^^ '(LZ6I) l4

ldM

ICqata^pur of pasn sr ,,unta! urwj^a „ at ayt aadndstyt tnoonoi 'pry! ncco lau:) !u

a

o^ q ^ sodo Jd 1 lleu!8!10 ;eyi

1 :Xpoq aq; ur lour, aw o uo!^e1 uaauoa a oP y

^ y yq Jo uong

ucuua)aQ qj ! 1 4a ) NMI-1odwd seen uorlcuiwrla Jo 03e1 ay; sop put S3BI43!M Imp papnlouoa 'JoAoMOq `

(6£61) S1aquaaJE)PUB PJB2 BH •(Poq 04) ur

uo!aw;uaauoo oq;Jo ;uapuadapui SUM slop q uo!;eu!ur!Ia JO 03W 043IN; paw!ulp (9£61) )pewp!M pus xiaiuco pue(9£6I) )I113w1aN •

S1Insw ou 1)310u03 paplari sail

pue uuw uuq; .ray;o slsw!ue u;!m ;no pa!IJUO uaaqseq lOUBgIaw JO UO!leu!u]!Ia a41 UO ) OM snornaid•UCUJ u! 1OUE4;aw Jo uo!;sulw!Ia put uondiosge

3o sossaaoid 043 Jo aspoFMOUx c sai!nbal slgj •ma;elslnoq 9I poraad 9ur^1oM ;xau oq; jo Su!uu!8aq acl;a.io,Iaq *Paleu!w!la ,cla;aldwoo oq IOU pinOM smoq249!a Jo pound SUi poM leuuou s ;Iurunp pagrosqvIODU4;aui JO )unowe 04; alaqnn suo!ipUoo 'sr 2B41`2n 1oo ,Sew roueq;aw Jo uo!;einwnaae garqM lapunsuol;!puoo wnw!urw 043 ou!uua;ap 01 pau2!sap *jaMsauaunuadxa aqy •

cusp tans u!n;go o; SUM )(JOMluosaad ay; Jo wig GU usumq q11Mpau!ti;qo eaap Jo aauasge 041 U! an]asar 4i!M pa;dmraq 010jo]aq) Isnw anoge paaonb s;iwtl c3oJes au

os (IDJIIua;OU sI s!ql 1e4; s;sa ns (9b6t) s.Jagllo pun Mawjo 11oda, oq1 inq 'louugla Jo s;unowu 2ur IcienJo uo!;dwnsuoa snoaue;Inw!s ay; 01 anp jlagJnj sruoiasilen 5!gi 1e4; s;sa83ns oo" (c161 }{oylgn ;9b6i`uoithr pus'sauuag'ioiiog'Maq 91'61'o2I) aaayoI[! inou;rM 5 oci pawnsuoa aneq sa043o 1S qm(LZ6I `323: 1Z6 'aa

120!Z ' 916I `aoS) •8 0£ uuqssal 3o uo!;dwnsuoO aa;,IU SuriCp slenpin!puc awns

`uew ur ,t;rnr;!suas IEnpinlpUI UT no!}sugn aprMU 1saG8ns Iouu ;aw UiUUp cg posnua sar2!!B1BJwosi E;BQ ' x/,W i UEII1 ssal ss f106{ uosslnodput (Et'6I) adtI Iq palew!Isas! asop Iuq;al a

wusJO3 •(Zt61 ')O3Uj i Put xnolmN : SZ61 `az;auMgpSPun yaunW) i!gqei aq't and $^[r< 8t+i of (0261`3q3BW) 3UO aya JOJ •

L / •2 L$ waai tiUn S RWIEM

( o;BJogel Ilews 1oJ asop p:420l ,(la;nas wnw!u!ur aq;

.ro3 sanicn •uosiod sup Jo slaa•I{a aqs of S Cwwewaallews aq; UB9I OA!;!suos a]ow yanw oq o; sreaddeuUW •(i£6I 'PiO3W -' 116I `aP!OH map UOA pugAMaov ,znodmn aq) se palUqui sr s!cp uagM Allujoadso(££61 PJO'JW PUB `zlaH `1lO0 : 9261 `uneagPUB [SOW) lOUBgaaw 01 If)!n!;!SUOS u! suouulaenap!M MO4S SIUWIUV tio;v,.IogeZ •

uopneo saambaisdBMle slewius 41IM s;uawtladxa u! pause;qosgnsoi jo swolgold uewnq a; u

onu3gddB ouj,'(It61) P1O3o IM Jo sotnpuy041 41!M 8urdaa ur . aaow ;Insaa u -sinoq

f,zf •Sb •bI 03 amen s!ya papuawu (9£61) 3fmuuz olq uBwpun sop uaaM;aq uosundwo5 .jupwis ,[g •s]noq bZu! paarurw!Ia ,Clangs oq ptnoo IoUBglow Jo •g b£ley; UUW Sq Iouuy3a Put s1!gctu iiq IODU4Ia put

TNIJIUM 7V1 ignaHt JO 7VNNInof HSLLPJUOZ

ments.

Inhalation Experiments: The subject was exposed toa known concentration of methanol vapour for two tofour hours and the absorption* of methanol was followedby analysis of urine voided at frequent intervals. Theexposures were carried out in a small room (22-9 cu.m.capacity) with no windows and two doors separated byan air lock. The doors were felted at the edges to preventthe escape of methanol, The desired concentration ofmethanol was established in the chamber by rapidevaporation of the calculated quantity of methanol byallowing it to drip from a burette on to a hot plate in thedraught of an electric fan. The subject then enteredthe chamber, and the methanol vapour concentrationwas maintained at a constant level by continuousevaporation of methanol at a predetermined rate. Theair of the chamber was kept in motion by the electric fan,and in each experiment the concentration of methanolwas determined at half-hour intervals by the methodoutlined above. In practice it was found that themethanol concentration in the chamber could easily bekept within 10% of the mean.

* It will he noticed that the " absorption" measured is really the

balance of methanol absorbed minus that eliminated during theperiod of exposure. The term accumulation more accurately describesthe overall process. but to avoid confusion this term is reserved forthe long term accumulation or methanol after repeated intermittentexposures.

METHANOL HAZARDS2E

_ d that the sensitizing effect of evidence that after giving ethanol to man there is a

ethanol on the determination increased with increase in constant relationship between blood concentration and

the concentration of ethanol to a maximum between concentration in urine contemporaneously secreted.

1 .2°x° and 1 .8% ethanol. Solutions under test were This is determined by the relative water content of the

therefore hiways adjusted to contain approximately 1 .5% two fluids, the kidney having no selective action on the

ethanol before analysis. This' gave maximal sensitivity distribution of the alcohol between them. Further, to

and eliminated the possibility of errors due to the presence justify the use of urinary methanol concentration as an

of small amounts of ethanol in the test samples. In index of methanol concentration throughout the bodycontrast to the experience of Wright it was found that

water, the constancy of the blood ]urine relationship was

both stages of the estimation were sensitive to temperature confirmed using cats as experimental subjects.

variations. The entire process was therefore carried out The cat was anaesthetized with chloralose (80 mg. per

in a thermostat at 25° C. Optical densities were deter- kg.) and the bladder emptied and cannulated, the bladder

mined with the Spekker absorptiometer using the yellow- contents being kept as a control samp1e. diluted twicegreen filter. With these modifications concentrations of dose of methanol (100-270 mg. per kg.), dmethanol up to 15 mg. per 100 ml. could be determined

Ringer solution, was then injected into the femoral vein

to within 3%•and samples of blood from the carotid artery and of

For the determination of methanol in urine, 10 ml. of urine were taken at intervals of 30 to 60 minutes for four

the urine were treated with 2 ml. 413 NH,,SO 4 and 1 ml. to five hours. The methanol concentration in each

10% sodium tungstate, and the mixture distilled in an sample was determined as described above. To promote

all glass apparatus (Nicloux, Le Breton, and Dontchetf: an adequate rate of urine flow it was found expedient to

1534). The first 5 ml. of distillate were collected in a give inje

ctions of 5 ml. of 75% sodium sulphate via the

graduated flask and analysed for methanol as described femoral vein at quarter-hour intervals.

above. In 15 control determinations the recovery of Experiments on Man.—The subjects were five adultadded methanol was 96 .4 n 1 .2% (standard error). males. The dose of methanol which varied from 2.5Normal urine from six human subjects gave small blank to 7 .0 ml. (29-84 mg. /kg.) was diluted to 100 ml. withvalues, the mean for 20 determinations being 0

.31ng. per water and taken immediately after emptying the bladder100 ml. expressed as methanol. As the experiments before breakfast. Urine was collected after one andcarried out were of a comparative nature, this blank two hours, and then every two hours for a period whichvalueformaldehyde

unimportant. Tests for the presence of varied in different experiments from l l to 16 hours.formaldehyde in the urine distillates were consistently The total volume at each voiding was noted and thenegative. urines were preserved with a small amount of H:SO,

For the determination of methanol in blood, de- and kept at 4- C. until the methanol concentrations hadproteinization was carried out by the usual Folin-Wu

-•^___, .._, '_: :

method, and 10 or 15 ml. of the filtrate were distilled.As in the case of urine, 5 ml. of distillate were collectedand used for the estimation. Recovery of addedmethanol was 94-96%, and normal blood (cat or human)gave no appreciable blank value.

For the determination of methanol in air, the air wasdrawn through a train of four drechsel bottles, eachcontaining 150 ml. of water, in series with a gas meter.The contents of the bottles were then mixed and themethanol content determined as above. Recovery ofmethanol evaporated into the air stream was 96-98%at methanol concentrations of 1-10 mg. per 1. and therate of flow about 21. per minute.

Assessment of Methanol Content of the Body.—In astudy or this kind with human subjects the toxicity of themethanol precludes the use of large doses. The concen-tration of methanol in the body water being thereforerather small, the analysis of urine, which is readilyavailable in comparatively large quantities, is a moreconvenient and practicable index of the concentration ofmethanol than is analysis of blood. According to Yantand Schrenk (1937), methanol administered to experi-mental animals becomes uniformly distributed about thetissues of the body according to their relative watercontent. The same has been demonstrated for ethanolby Nicloux (1934) and larger, 7•lulpieu, and Lamb(1937). Further, Haggard, Greenberg, Carroll, andMiller (1940.) and Eggleton (1942) have provided

22 BRITISH JOURNAL OF INDUSTRIAL MEDICINE

The bladder was emptied immediately before enteringthe chamber and at intervals of approximately 30minutes during the experiment. The urine was collectedin stoppered bottles and the methanol content deter-mined as described above. To promote the flow ofurine, water and coffee were taken before the experiment.

ResultsRelation between Concentrations of Methanol in

Blood and Urine.-The results of two experimentson cats are shown graphically in Fig. 1. The con-

centrations of methanol in blood and urine followa similar course. The constancy of the ratio(concentration in urine : concentration in blood)is seen in Table 1. The mean value of the ratio was1 .

29, agreeing well with the figure of 1 .3 found byHaggard and others (1940) for ethanol in man.The relationship was further checked by a fewdeterminations of the methanol content of blood inhuman subjects, during the elimination of methanol.The results are given in Table 2. The values forthe ratio (concentration in urine : concentrationin blood) are based on single determinations andshow more variation than in the experiments withcats, probably due to the difficulty of accuratelyestimating such low concentrations of methanol in

TABLE I

RELATION BETWEEN METHANOL CONCENTRATION IN BLOOD

AND URINE IN THE CAT

I i I mean 1 1.29' Each value for the blood (CB) is the mean or the last four deter-

minations in each experiment. and each value for the urine (CU) themean of the last three determinations. The concentratlons areexpressed in mg. per 100 mi. blood or urine.

TABLE 2

RELATION BETWEEN METHANOL CONCENTRATION IN BLOODAND URINE. IN MAN

SubjectDose of

Methanol(mg. per

kg.)

I TimeafterDose(hr.)

CB CU CU :CS

H.S.R. 71 2.5 5.33 7.5 1.414 .5 4 .2 5.4 1-29

L.J.Z. 83.5 2 7.6 9-2 1.214 6-75 8.4 l 1.24

GL. 71 3 4-7 6.40 1 1.35

5 3.2 41 1-28

Mean

_

1.30

Each value for blooe (CB) represents a single determination, thevalue for urine (CU) at the same time being obtained from the eorre.sponding elimination curve plotted as in Fig. 2. The concentrationsare e'cpressed in mg. per 100 ml or blood or urine.

blood. Taken together, however, the results inTables I and 2 suggest that, provided the bladderis emptied fairly frequently, the urinary methanolconcentration is a reliable index of the concentrationof methanol in the body water during the period ofsevretion.

Elimination of Methanol.-The variation ofurinary methanol concentration with time after theingestion of three different doses of methanol by thesame subject is shown in Fig. 2. These results aretypical of a number of experiments carried out withdifferent subjects. Evidence has been presented inthe foregoing section of this paper which justifiesthe assumption that the urinary methanol concen-trations may be taken fairly to represent the averagemethanol concentrations in the body-water during

CatNo.

I Dose of Methanol(mg. per kg.)

I CB*I

CU ' CU r'C B

3H 100 i 12.15 15.7

1.304H 250 27.0 i 35 .25H

I H +250

270 27-5 35.0 1-27

I 1-30I 31 .7 I 41 .2

i

METHANOL HAZARDS 23

the period of secretion of each specimen of urine.The curves indicate that the absorption of methanolwas rapid, as was to be expected with small doseson an empty stomach. After reaching a maximumwithin about one hour, the concentration fell rapidly

•at first, then more slowly, until control valueswere reached again a ter lii T6hours. WhiiEelogarithms of urinary concentrations are plottedagainst time, as in Fig. 3, the points conformclosely to straight lines. The curves in Fig. 3 maybe represented by an expression similar to thatderived by Gaddum'(1944), i.e.

log C = log Co -- ktwhere C,* and C are the urinary methanol concen-

EO0

4.

W

I2!(

TIME AFTER DOSE

FIG, 2.—The concentration of methanol in human urine afteringestion of methanol. Subject. G.L., weight 78

.5 kg.

2 4 6 a 10 12 141 0

^f r:r a .y

O SUfi k

X 9 .0 4X = k

x

cos

Q3m1. SMI. 7m1.

:. ... :.:. ^

METHANOL ° •;; ""' ^'OF .• rO3 INGESTION

02

O 1 HOURS 2 4 6 B to 12 14TIME AFTER DOSE

FSe. 3.—The concentration of methanol in urine after ingestion ofmethanol plotted on a half log. scale. Data as for Fig. 2.

y k^

CONCENTRATION OF VAPOUR iNHALED^K.+SIIF`^' 1 ^ ^ {}kP}4 .1: v^. Y{'^

y' SYl.

. 3

1 23mg. per I 0732 mg per I O.655mg per 4g

E :

WrI + w limo o! exit

from chamber

xis i L3 t \ }^k # x x x °x '... (^ Si.

HOURS i -,TIME OF EXPOSURE

FIG. 4.—Absorption of methanol by inhalation of the vapour.SubjecI, LJ.z.

trations at zero time and t hours respectively and ka constant for the individual. The values of kfor subject G.L. calculated from the data. plottedin Fig. 3 were 0 . 104, 0.099, and 0094 for the threedosage levels (C and C, expressed as mg. per 100 ml•urine and t in hours). Values obtained from similarexperiments with H.S.R. and L.J.Z. were 0.097,0 . 102, 0 . 106, and 0 . 108, 0-099, 0 . 101 respectively.Thus the course of methanol elimination under theseconditions was exponential and the rate of elimi-nation at any time was proportional to..the methanolconcentrat ion in the body at that time.

• C. is the hypothcticnl value for the concentration of methanolin the urine excrcicd at zero lime if the absorption and distributionof the methanol were instantaneous.

is

24 BRITISH JOURNAL OF INDUSTRIAL MEDICINE

TAnLE 3

ABSORPTION OF METHANOL BY INHALATION OF THE VAPOUR

Concentration of Urinary Methanol ; Urinary MethanolSubject Methanol in Air Concentration Rate ofAbsorption Concentration Rate of(mg. per I.) at 1 .6 hr. i at 2 .5 hr, Absorption

G.L. 0-7 0-56 0.50 ' 0.78 0-450.73

1.35

0.77

1.460.63

0.63

1-05 0-57

1 375 1.58 0.702.06 0-61

„

f1 .431 43 _

w^1.88200

0.790-84

2.56_

0.72-^^

Mean 0-68 Mean 0.59L.J.Z. •. 0- 65 00:6 ( 0.7

0 .771-031.32

0.640-721 .23 1-90 0.92! 2.54 0-84

Mean 0-80 Mean 0.73Values for the urinary methanol concentration are in mg. per too ml., and are co rrected for the control value (on entry into chamber). Valuesfor the rate of absorption were obtained by dividing the values in the preceding column by the time and the concentration of methanol inhaled

(cot. 2).

Only a very small fraction of such doses ofmethanol appears in the urine; in different experi-ments it varied between 0 .4 and 1-2% with a meanof 0 -7%. A small number of eterminations ofthe methanol content of the expired air indicatedthat the loss by expiration was of the same orderor slightly larger than the loss in the urine.

Absorption of Methanol by Inhalation.-Theincrease in urinary methanol concentration duringthe inhalation of various concentrations of methanolvapour are shown for two subjects in Figs. 4 and 5,Values for the urinary methanol concentration at100 and 150 minutes taken from these curves aregiven in Table 3. On theoretical grounds onewould expect the rate of absorption to decreaseexponentially with time (Haggard, 1924 ; Gaddurn,1944). The results do show such a trend but theexperiments reported are too few and of too shortduration to provide useful information on thispoint. Under the conditions of the experimentsexposures of three to four hours were as long ascould reasonably be tolerated.

Values for the rate of absorption given in Table 3show some variation, due in part to the difficulty ofcontrolling the conditions of such an experimentwhere the subject is also the operator. For thepurpose of these experiments, however, it may betaken that under these conditions the rate ofabsorption for each subject is approximatelyproportional to the concentration of vapour inhaled.

Effect of Ethanol on Elimination of Methanol.•-Ingestion of ethanol during the elimination ofmethanol had a striking effect on the elimination

0

E

HOURS 1 2 g 4

TIME OF EXPOSURE

FIG. 5.-Absorption or methanol by inhalation of the vapour.Subject, G.L.

curves. Figs. 6 to 8 show the results of expe rimentsin which ethanol was taken at various times duringthe elimination of a fixed dose (4.0 ml.) of methanol.

I

polaeaxa tow

5b1 St+•0 SL • Z 89 .0 96•£ IZ• [ 9C1 LS•0 89 .0 WE 86.0 8L• [ L6 .0 -gtaui JO *sop 10 ,

I 8.OE(Stu) palai

-x [ on glaw letoj • ia e6•Sb £ •Sl b•L8 9•[Z S•SZI i S • 8£ Z•£b Z•8[ L- IZ j [ • LOI 6-OC S•9S

(•Iw) patasaxa

££01 6L$' SLZI 96t ZZL[ LS8 960[ S88 988 tt9£[ 9ZL Z61 1 106 auu tun anlon Ut4L

(1w00[l'$w) acnun

uc uoI1eriva3uoo

OZ-L OL-L SL•6 LZ-L OZ •6 5£ • 8 09 .8 ZI-S } OS•S Z8 .8 [Z•L S6•L SO-9 loueq w 'load

j 'sA L•J419 a4 L01pug q

' c .S

O1do •aq , do 1il

^pUBI yaea

01 U1 I

'.q $b01 U

'sq S 'sq o '.iq 0 jq 0 '.tq 0IV S[ '° SI

Aq 0auoM auoi IV SI

'aq

5IV S[

'ai[ 0IV S[ auoly lOUVlp9

le Si 9u01IE 51 ie S[ 1B S[t'Iw)

ti t+ b b b b b b ti 1' b baural

oloz le)aso^

ougtjaay^[

It[ Z[ £I H ZI ZI ZI 401 Z[ ZI(•;q) 1u:>w

-I.tadxa ;o uoi; 1::_;ZI ftZI ZI

[ b'9'ZI.9b'9'S9ti'L'I 4b' 9'EZ9b'9Z `9b'9'bZ 9fi'9'6 19 9b'9'Ol9b'9 '£ 9b'L'0[ 9b'L S 9b'9'£ 9b'L'l atE^

3^!aM0-L5 'Z'f'7 'gK I .C9 ' Wd"I '8K 0•L9 IYH''d ,^pog Pug afgn5

S1 3tfln5 NVI+[!LH 93 IHL Ni 3htilln Ni 1ONVH1 30 NOU .3 X3 NO 1ONVHL3 dO .L333d3

ji 318VJ.

•$ 1 I • 19 NORM ••x

d•7

7s4gos 'A1sflo ue;Inwls lour.4ia pur. JOUCLI aua JO pus ;oacgtau<

Jo vopsa9u! lave auurt ul toueyww jo uapeilu»uao qj-9 •011

asoa n3J.1r awls

a34 1oue u[ •sinoq OM) )noge .tale 01+91 leui2!1O

Sil 01 pouanlai g3lq,%% `a0lle1IUoauo3 10ue1(0tu cpoque oulloop atv patsa1.le t[an»aapa It 'loueglow0q1 3a1JE sinoq 0.MJ ua1je1 SUM 1oue42a at[tluacuuadxa auo u[ L 2IJ Ul uaas 4ilseala a NOW sllouetpo Jo osop o1suls a JO ) 0p0 ivaisue11 oqj.

•9 •S}3 aK pOi9Jlsnill osle SI suaise3o}uaaaglp uo 10fgns Owes 041 ui san.na U0119u!wllaoqa JO pool aye; •pa2uoloid (Iqula-aadde jou sl Own uolaeulwi[a 10UU4)ow 1 etOl aqi1841 as '(z6[ uololosa) fpoq 041 uioij pateutwlla,Slalaldluoo [asl! sl Ian814la Jo osop s gons aural slq)uiq,lA% aaujs^luawt.t^o os to anoq Isry ay;,dutrnp enN StgI ul SOZUjOdO luo alanan^oq louagtaaqy uoilgp!xo '0•1 `uollvUluacla louetpow JOssaaoid ulew og1)o louetlla aq fq uolligiqui ue ofa zingji)W sc uotleiluaouoa 31Uad aq1 ul as'eataul 0111,lau 3a o aso $ ipns loa a snotngo lou SW

slanal [o.tluoo of uanlax of uol)EIlu0DuO3 jauzglautat .1oj paunbai atu 2 ate • '(9 '81-4) pool Iloueypw )o uoltetiu03u0a )(U aqf u i uoijo

pax.ieut a pasnea ` oue taus 0th3 3!•' ,f snoauel-(nWIs u0)(9) [ouegla jo •(ut Si Jo asap alouis d

•j alge L ur

uanl8 aae stuaunaadxo asagl 0) )uenalai e1Ep 104tp

J 1

experiment (Fig. 7) a dose of 15 ml. ethanolat four and a half hours was followed by fourfurther doses, each of 7-5 ml., at half-hour intervals.The flattening of the curve during this periodindicates the arrest of methanol elimination whilean adequate concentration of ethanol was main-tained in the body. Fig. 8 shows the resultsobtained in two subjects when a dose of 15 ml.ethanol taken with the methanol was followed byhourly doses of 10 ml. ethanol for seven hours.Throughout this time the body methanol concen-tration was maintained at a high level compared

ij

f;V

E

Methanol Concentration Rate ofRate of FallSubject Doset Fall perMa^k

(m/ (mg./100 unit ofMagnitudeml./hr.)

L.P.K. (a) 3-0 0.69 i 0.23

(b) 8.6 0.21 I 0.024

A.H.G. I (a) 4-6 0.77 0.15(b) 8.35 0.18 0.022

• Data taken from curves of Fig. 8, the figures referring to a timefour hours after the ingestion of the m ethanol.t (a) - 4 m!. nmethanol ; (6) 4 ml. malh:inol + ..n. «na y.. ,

and 10 ml. ethanol each hour afterward..

i s

,I,

f,

{

26 BRITISH JOURNAL OF INDUSTRIAL MEDICINE

too K W ^^r" . ^:'

sORAL DOSE

^ .'.' °' ` ' ^ t4aAanol 4ml. '.•>.'< Is tnl.^ 9 .:, _ ^Elhanal }dcsssand

f 101 1.Aaarly

elha^w7 ;':if - for 7 fwurs `gin te

^:+~ f^t s i^ ^`^^` . ^ : -Y `" Ki3 ^^Y {t ^ + JAS "^;

5 ' Mstharte! 4 mt i ' d:'

ZA

z i-' a : y ' ' 7'

} 85.7 ,V '. ^'

I Yj ^ `S f' y,1'^ ` .̂ s' Yn `3•Y.. ^[

g

k , qx, F':"

a ': ..v '::T :': [,m"h.:' ^[ i

•ry .. ,:rya'.

•a0 L P K. welghl 431 Kg •KQv] A H.G. irei ht 670Kg

O_.r

TIME AFTER OOSE

Fra. B.—Tha Concentration of m eibanol in the urine after an oraldose of methanol (a) without ethanol, and (b) with spatifiadoses or ethanol simultaneously and hou rly for seven hours.

a

rMETHANOL

; . is + 3 a that absorption of methanol from the alimentaryI . • tract is no longer a significant factor in determining 4m1 :: the course of the curves. A tangentuowea by i< ^• :.. has been

NOL t5 ml. drawn to each curve at the four-hour point, and the.5ml. at 5. 5hs.6.and b lhhcs. i <: slopes of these are ' iven in Table 5 as representingHOURS 2 4 6 s 10 12 rates of elimination of methanol. Each, however,.TIME AFTER DOSE

is associated with a different body methanol concen-Fto. 7.—The concentration or methanol in the urine after an oral tration, also given in the table. Evidence hasdose of (a) mathanol without ethanol (b) followed by ethanol,

and (c) followed by two doses or ethanol at specific intervals, already been provided that in this con centrationSubject L.S.Z., weight 57.0 kg.

TABLE 5with controls without ethanol. It declined slowly, FFEC' OF ET

HANOL ON RATE OF METHANOL ELIMINATLONwat a rate which might be entirel y accounted by BY aIA'Noss of methanol in the urine and expiredAbout two hours after the cessation of ethanoladministration, when the body ethanol might beexpected to be approaching zero again, the declinein methanol concentration accelerated to controllevels, indicating the release from inhibition of thechief mechanism of elimination. It is of interest toattempt a quantitative estimate of the effect ofethanol on the rate of elimination of methanol inthese experiments. This has been done in Table5. The data used were taken from the curves ofFig. 8, and refer to a time four hours after the in-gestion of methanol, when one may safely assume

METHANOL HAZARDS 27

atmosphere was sampled in all three places men-tioned, and urine samples were taken from workersin the methanol distillation and stripping plants.A brief description of conditions of testing in eachcase is given below.

The air was analysed as described under"Methods". The air-inlet of the sampling trainwas placed in positions most likely to give a concen-

Thration of methanol vapour in a place habituallyfrequented by the operatives. Fairly long samplingperiods (two to six hours) were used so as to yielda measure of the average concentration at theposition chosen. The results are shown in Table 6.

unit methanol concentration snow a close corres-pondence for the two subjects when ethanol waspresent, whereas in the absence of ethanol L.P.K.appears to have eliminated methanol appreciablymore rapidly than A.H.G. Significant individualdifferences seem less likely in the former case, ifonly physical processes of elimination dependenton escape in urine and expired air are then operating,than in the latter case when the major process is anenzymic oxidation.

Observations in a FactoryThe methanol synthesis plant formed an off-

hoot of the ammonia synthesis plant and the actualmethanol converters" in which methanol is

synthesized were housed in the same building as,ie ammonia converters. The converters were

used for synthesizing higher alcohols (ethyl, propyl,bur,'l, etc.), as well as methanol, and conditions

11 be varied to produce predominantly methanol- rmxrure of methanol and higher alcohols. The

uduct of the latter process was separated intohigher alcohols and methanol in a distillation plantreferred to as the " stripping plant ". The methanolfrom this distillation and from the other process wasrefined in the " methanol distillation plant ". The

TABLE 6

RESULTS OF AIR ANALYSIS AT f.C.t. METHANOL SYNTHESIS PLANT

Site, Duration of Volume of Air I MethanolConcentrationSampling Entrained (C) I`

(p.p.m.)

(1) Synthesis plant .. .. 11.40 a.m.- 2.25 p.m. 277 <52.35 p.m.- 4.30 p.m. 254

11.25 p.m.- 2.30 a.m. 175.510.30 a.m.- 4.35 p.m. i 378

(2) Methanol distillation plant.. I 11.02 a.m.- 1.43 p.m. 357 I 40.51.58 p.m.- 5.05 p.m. 248 64.0

(3)Stripping plant .. .. 10.30 a.m.-12.05 p.m. 133.3 821 2.17 p.m.- 1.46 p.m. 136.5 1161.53 p.m.- 4.08 p.m. 1 156 80

range the rate of elimination of methanol is pro-„,.^^..,^^a! toihe concentration of methanol in thebody. For purposes of comparison, therefore, eachrate of elimination has been divided by the corres-ponding methanol concentration, giving a rate ofelimination in mg. per 100 ml. per hr. per unitmethanol concentration. The reduction of this rate

90%by sthe giving of ethanol was by 9 in the case ofne subject, by 85% in the other. This •is a rough

approximation an it is audoubtful if significanceshould be attached to the difference between thetwo subjects. It is of interest, however, to notethat the figures in Table 5 for rate of elimination per

Synthesis Plant.—In this case the air inlet wassuspended at a height of about 7 ft. from the wire-mesh working platform at a point situated betweenthe sampling tray (which was equipped with tap-lines from the plant, by means of which sampleswere taken approximately hourly) and the controlpanel where the operatives spent most of theirtime. The air was tested during the day and onceduring the night shift. As the building was veryspacious and the plant a high pressure one, i.e.working at a high pressure, therefore completelyclosed in, the negative results appended are notsurprising.

Methanol Distillation Plant.—In this case the"still " and storage tanks were in the open air,whilst the control panel which the operativesattended was housed in a small building. The"sampling tray " was housed in a small passagealong the back of this building, and although theoperatives generally entered this part only once anhour to take samples, the air-inlet was placed closeto the sampling tray as this was the most likelyplace to find an accumulation of methanol vapour.In this instance urine samples were taken at thebeginning and end of shifts from six workers over

28 BRITISH JOURNAL OF INDUSTRIAL MEDICINE

{

three days. The analysis or all samples gavenegative results except for two end-of-shift samplesfrom one worker. The concentration found inthese two cases were so small, however, as to bealmost negligible.

Stripping Plant.—This plant smelt worst of thethree, though the smell was due to uncharacterized"volatile oils " separated in the distillation process.The housing containing the sampling trays, andcontrol panels was built round the columns of thestill some height above ground level. The air inletwas suspended in this case close to the controlpanels, one sample being taken at a remote samplingtray and the other two being taken from the spacebetween two other sampling trays where theoperatives bad table and chairs and spent most oftheir time. Samples were taken hourly. Urinesamples were taken at beginning and end of shiftsfrom three workers for three days and the .resultsof analysis were again negative.

DiscussionAssessment on Safety Limits for Exposure to

Methanol Vapour.—The initial aim of these experi-ments was to find the threshold for methanolaccumulation by finding (1) how much methanol aman could eliminate within 16 hours, and (2) theconcentration of methanol vapour which must beinhaled for eight hours to cause the retention ofsuch an amount in the body.

The experiments on the elimination of orallyadministered methanol showed that after the lapseof sufficient time for complete absorption, the rateof elimination was proportional to the concen-tration of methanol in the body water. The mech-anism of elimination is discussed below, but forthe present purpose the finding that eliminationfollows the equation

log C = log Ca — Ictallows us to calculate the urinary methanol concen-tration (C,) corresponding to an amount of methanolwhich may . be disposed of within 16 hours. Ifelimination is considered to be complete whenC = 0 .5 mg. per 100 ml. (average blank value forthese experiments), substitution of the observedmagnitudes for k in the above equation gives valuesfor C. of 19 . 1, 21 .5, and 21 . 6 mg, per 100 ml. forsubjects G.L., H.S.R., and L.J.Z. respectively. Asthe urinary methanol concentration has been shownto be a satisfactory index of the concentration ofmethanol in the body, these values can be useddirectly without further manipulation. The degreeof exposure giving rise to such urinary methanolconcentrations may be estimated using the resultsof the inhalation experiments. The rates of

absorption of methanol observed in experimentsare much lower than those observed with smalleranimals. Loewy and von der Heide (1914) founda methanol content of 45 mg. per 100 g. in thebodies of rats exposed to a vapour concentration of2,000 p.p.m, for two hours. The inhalation ofmethanol vapour at half this concentration (1.35mg. per 1., 1015 p.p.m.) by G.L. gave rise to a urinarymethanol concentration of 2 .4 mg, per 100 ml.corresponding to an even smaller concentration inthe body as a whole. Yant and Schrenck (1937)found blood methanol concentrations of 84 to 100mg. per 100 g. in dogs exposed to a methanolconcentration of 4,000 p.p.m. for 12 hours whichsuggests an average rate of absorption at least threetimes as great as the rates observed here. Thesediscrepancies emphasize the necessity for carryingout such experiments on man rather than on theusual experimental animals.

The values for the rate of absorption of methanolgiven in Table 3 may be used to estimate the methanolvapour concentration, by exposure to which foreight hours the two subjects would attain the criticalbody methanol content represented by the Co valuescalculated above. For G.L. the rate of absorptionwas found to be 0 . 59; the critical vapour concen-tration for this subject would therefore be

19-1/8 x 0.59 = 4 .04 mg. per 1. or 3,050 p.p.m.The corresponding calculation for L.3.Z. gives3 •70 mg. per 1. or 2,780 p.p.m., For these twosubjects, therefore, a concentration of approximately3,000 p.p.m. of methanol would involve a dangerof gradual accumulation of methanol in the body.

The accuracy of these estimates is limited chieflyby the accuracy of the determined rates of absorptionwhich are based on rather few experimerts. Extra-polation of the results of these experiments to covera period of eight hours may involve some error,but in so far as the rate of absorption may beexpected to fall as the duration of exposure in-creased, the critical vapour concentration would beunderestimated rather than overestimated. On theother hand, in using these data to judge conditionsin industry, it must be remembered that during theinhalation experiments the subjects were in acomparatively resting state. Vigorous activity bystimulating respiration would probably increasethe rate of absorption and increase the hazard.Further, as industrial conditions are more difficultto control than those in the laboratory, the per-missible maximum concentration should be set at amuch lower level, say 10°,% of the above, i.e. 300p.p.m. Below this level accumulation is veryunlikely to occur, and so far no untoward symptomshave been observed with doses liable to be absorbed

0

METHANOL HAZARDS29

an, by the than l°o of the dose taken, and respiratory loss

at this level. On this basis safety limits which have As the urinary loss representedt

te° 1t^h r^ s mustpreviously been proposed, e.g. 1 H little more, it is Ilea t

m by ce

International Labour Office and safety p.p. d By appropriate

von oettingen (1943), leave a good safety margin. have tbee

ano^e romptne^alet

in the light of these considerations ash investigated adrtinistrat^on o et ano1, it was found possible to

prevailing in the factory

harm for the operators. - . This striking effect cannot be attributed towere quite adequately controlled and ensured reduce the rate of methanol

onthe purely physical pro-

freedom from potential hIn positions where the highest vapour concenconcentration

actio s any

of elimination inat

may be expected the average vapour c

As the kidney, andliitntherefore identifies the ma in methanol

exceeded 1 40 p.p.m. in only one tes process under the conditions of our

only spent a proportion of the shift in these imme- eliminating p a

diate areas, the presence of no more than traces of xPer"'metabolic

is and sin Fur thersabsenc

po tof

fthaethanol

view

methanol in their urine is understandable. o

of which a rs in the ur^^Th

ested at for can be found in the data recorded in Table 4. The

in turn, confirms that the value suggestedano . A

the maximum permissible concentration of methanol saactua of ncreasehan t

vapour leaves an adequate safety margin. It mustbe pointed out, however, that the factory

appro-thefromresultstheofaveragesare

he hazard f

va

fractiontes excreted from 0 7° to a1^8 a d (These t

gated was designed with an awareness of

of methanol poisoning, and these observations do ingestion ethanol raise it to

not preclude the possibility of danger arising on priate experiments in Table 4.)

and Greenbergless well-controlled premises. The disagreement with Haggard

Elimination of Methanol.—

th

onEthanolofEffect

rYas regards the relative importimportance

resolved rwhen tore

Previo us

whe

o nthe elimination of methanol has differ nee readilymay be

ve doses of i to 4 g.i

been carried out on animals other than man and has Hae rd and G

take ga a into

e%d f rtt °[ .

yielded conflicting results. k (1936)r k far greater than can be used

Neymar and Widmark (1936)36) claimed that the Pe gper s d. It is most probable

rate of elimination from dogs was independent of to 0 a84 g!p the

e presec,cn t work doses off

the dose level. Haggard and

Greenberg o y methanol concentrations the

on the other hand, concluded that in rats and dogs t at

thethe rate of elimination was proportional to the alcohol is remove

d chiefly by reaction.an enzymic reaction

concentration of methanol in the body. According With increasing concentration, a limit to the rate of

to the latter workers the greaterexpired airha tagresult come baturated with sits substrate.

restricted ri ar

an

methanol was excreted in the rate respiratory elimination areof simple diffusion, and the rate

the concentration was T li

a dominant part.therefore directly proportional to the y a ^=omt h^ tat on

and a be expected

It highplay a dominant

conen-

in ire blood. Using rats, they recovered The exponential nature of the

t expired air 70% of the inmethanol which had disap-eliminationmethanol

r experimentspeared from the body, in an t ewhloleperiod methanol ucon entration

sug was t l beoe falling reth t

during which, however, only 6% ofh

o of thero , ilinl

n e regionwas eliminated. Asset (1914) and p Voltz and

d where reaction is roughly

enzyme, p'

Dietrich (1912) found, respectively, 53% and 3^ ^ .concentration.

of the dose excreted in the expired air of dogs. There is no reason to doubt that the enzymicIn the present work the experiments on man

showed that, after the lapse of sufficientmb ion oxidation.of

Lutwak-Mann (1938) d by a

mons rated the

ensure complete absorption, the rate of

of methanol was proportional re its the findings oxidize methanol,alcohol

tot he orres-

in the body water, and in this respect onding aldehyde, but the

of Haggard and Greenberg were confirmed, but p found rate of reaction

eexcretion via the lungs does not appear to have verson ofhniethanolnlhF aldehyd

e by alcohol

played a major part. Rough calculations usingrhyd n

Haggard and ,Greenberg's formula suggest that the d&nol hasgenasebeen

vitroshown tohas exert

been a powerful corn-

elimination of such doses of me effect on this oxidation. Inhibition

cx fired air alone u!d have taken v rat da s petitive inhibitory

»hereas in fact S 2 to 16 hours were found sufficient. was almost complete when the molar ratio of

r

30 BRITISH JOURNAL OF INDUSTRIAL MEDICINE

ethanol to methanol was as little as 1 to 15. Thisappears to justify the suggestion that the in vivoeffects of ethanol on methanol elimination weredue to an inhibition of the oxidation of methanolby alcohol dehydrogenase. Eggleton's observations(1942) indicate that the peak"blood ethanol concen-tration in man alter a dose of 15 ml. is about 30 mg.per 100 andntanci tha about 10 ml. of ethanol aremetabolizedper hour at such concentration levels.The method of recurrent ethanol administrationadopted in our experiments might be expectedtherefore to maintain a body ethanol concentrationhigh enough to suppress methanol oxidation.

Ina later review of 83 cases of methanol poisoningRoe (1946) felt confirmed in his earlier (1943)impression that the toxic symptoms of methanol

minimized by the concurrent drinking of ethanol(see also Derobert and Hadengue, 1949). There isa widespread belief that these toxic effects are notcaused by methanol itself, but by a metabolicproduct, probably formaldehyde and or formate(Keeser, 1931 ; Keeser and Alberty, 1948 ; Fluryand Wirth, 1936 ; Fink, 1943 ; Rpe, I943, 1946).Evidence in support of this view has been obtainedby experiments with surviving retina (to be reportedelsewhere). It was found that methanol had noeffect on the metabolism of ox retina even at aconcentration of M 20. Of the metabolic productsof methanol, formate had a weak inhibitory effecton retinal respiration and formaldehyde stronglyinhibited both aerobic respiration and anaerobicglycolysis.

Asser (1914) had previously found that simu l-taneous administration of ethanol, amyl alcohol, oracetone reduced the urinary excretion offormate bydogs after the ingestion of methanol, an effectrecently confirmed by Bastrtup (1947) in dogs andrabbits, but he concluded that these substances didso by increasing the permeability of cell membranesto formate thus facilitating further oxidation of thisproduct. Roe suggests an alternative explanation,that the diminished excretion of formate was causedby a reduction in the rate of formation due to thecapacity of ethanol "to displace methanol from thesurface of cells, its oxidation to formic acid beingthereby checked". More recently Agner andBelfrage (1947) observed a decreased rate of fall ofthe blood methanol concentration after the simul-taneous injection of ethanol in rabbits. Thisobservation and our own results provide a morerational basis for explaining a favourable effect ofethanol as the result of an inhibition of methanoloxidation, and might justify attempts to use ethanoltherapeutically in methanol poisoning in an en-deavour to maintain the inhibition long enough to

secure elimination of the methanol unchanged bythe respiratory and urinary routes. Such a use ofethanol has indeed recently been reported by Agner,Hook, and von Porat (1949). Only two patientswere treated, however, and of these, one recoveredand one died.

It is perhaps significant that only two or threecases of blindness have been reported from the—drinking of methylated spirits in this country,

although the drinking of this spirit is apparentlyquite widespread. The above results suggest thatthe large proportion of ethanol in the spirit (about95%) would indeed reduce very markedly the toxiceffects of the methanol.

Summary

Owing to the slow rate of elimination of methanolfrom the body, repeated exposure to the vapouror liquid may result in accumulation and under suchconditions the use of methanol would constitute atoxic hazard. The present work was carried out inorder to determine the maximum concentration ofmethanol vapour, exposure to which for eight hoursis consistent with complete elimination of absorbedmethanol during the subsequent 16 hours. Theabsorption and elimination of methanol were there-fore studied in man.

The concentration of methanol in the body wasfollowed by determination of the concentration inthe urine. The reliability of this procedure wasconfirmed by experiments with the cat and withhuman subjects.

The elimination of methanol after doses of 2.5to 7 .

0 ml, has been studied in five human subjects.At any time the rate of elimination was found to beproportional to the concentration of methanol inthe body. The significance of this finding isdiscussed. Only a very small fraction of theingested methanol (about 2%) was eliminated viathe respiratory and urinary routes.

The rates of absorption of methanol by twohuman subjects during exposure to vapour concen-trations of 0-6 to 1-5 mg. methanol per 1. (400--1,060p.p.m.) have been investigated. Over short periodsthe amount of methanol absorbed appears to beapproximately proportional to the duration ofexposure and to the concentration of vapour in theatmosphere.

By examination of the results of the absorptionand elimination experiments it was concluded thatexposure to a methanol vapour concentration ofabout 3,000 p.p.m. for eight hours a day maycause accumulation of methanol in the body andthus give rise to a toxic hazard. It is suggestedthat the maximum concentration of methanol

METHANOL (HAZARDS 31

vapour to which workers may be safely exposed is300 p.p.m.

Observations made at the methanol synthesizingplant of I.C.I. Ltd. are described. Estimation ofthe methanol co6centrations in the air and in theurine of the operatives showed that conditions weresatisfactorily controlled.

The ingestion of ethanol, together with orshortly after methanol, reduced the rate of elimi-nation of the latter by up to 90%. Evidence isadduced to show that this is due to inhibition ofthe metabolic oxidation of methanol.

These results provide a rational basis for ex-plaining the favourable effect of ethanol on thecourse of methanol poisoning such as Roe reports,and might justify attempts to use ethanol thera-peutically.

We should like to express our sincere thanks to the lateProfessor H. S. Raper, C.B.E. and Dr. L. P. Kendal fortheir constant interest in this work and their assistanceas experimental subjects; to Professor A. A. Harper,for assistance with the cat experiments, and to Dr. A. H.Gowenlock for being an experimental subject. Ourthanks are also due to Dr. Schilling and Messrs. LC.I.Limited for arranging the investigations at Billingham.

The cost of this work was partly defrayed by theMedical Research Council, to which we are also gratefulfor a grant to one of us (L.J,Z,).

REFERENCESAgner. K.. and Belrrage, K. C. (1947). Acra. physial, ,cued„ 13, 87.

-, Hoak. O., and von Porat, B. (1949). Qismi. J. Sind. Alcohol,9, 515.

Aster, E. (1914). Z. exp. Path. Thee., 15, 322.Bastrup, J. T. (1947). Acta phurmacol., 3, 312.Browning, G. (1937). Mcd. Res. Coun. Industrial Health Research

Board. Rep. no. 80.Carpenter. T. M. (1940). Quart. I. Stud. Alrohol, 1, 201.C how, W. B., Berger, E. H., Brines, O. A.. and Capron. M. J. (1946).

J. Amer. med. Ass., 130, 61.Oenighs, G. (1910). C.R. Aced. Sc?., Purls, 150, 529, 832.Dcroben, L., and Hadengue, A. (1949). Chem. Abut., 43, 3105.

Egg. C. (1927)• S,I,ath. tnnrf. I('schr., 8, 5.Egglcion, M. G. (1940). J. Plrysiol., Land., 98, 7.28, 239.--11942). Ibid.. 101, 172•Fink, S . H. t 1943). Aruer. J. Ophrlwl. 26, 694.Flur., F., and Wirth, W. (1936), Arch, Generbepoth. Ge rrrbe•hrg.,

7, 221.Gaddurn. J. H. (1944). Nature, Lund., 153, 494.Haggard, H. W. (1924), J. bfot, Chenr., 59, 753.-. and Greenberg, L. A. (1934). J. Pharntacol., 52,

ISp, 167.

--, -- (1939). lhfd., 66, 479.----, -.Carrol l, R. P., and Miller, D, P. (1940). J. Anter, used.

Ass., 115. 1680.Hamilton, A. (1925). "Industrial Poisons in the United States."

New York.Harger. R. N.. Hulpieu, H. R., and Lamb, E. B. (1937). J. bk,!.

Cher,., 120. 689,Humperdinck. K. (1941). Arch. Gewerbrparh, Gewerbehyg., 10. 569.Jacobson, B. 11., Russell. H. K., Grimm, J. J., and Fox, E. C. (1945),

Na,. used. Ba11., Nash., 44, 1099.Kaplan, A., and Levreault, G. V. (1945). Ibid., 44, 1107.Keeler, E. (1931). ,4rch. exp. Path. Pharmak., 160, 687.

--, and Alberty, J. (1948). KIM. lYschr., 26. 212•Loewy. A., and von der Heide, R. (1914). Bloehenr. Z., 65. 230.Luiu.,k-Mann, C. ((938). Biochem. J., 32, 1364.McCord. C. P. (1931). indusrr. Engng. Chem., 23, 931.McGregor, 1. S. (1943), Brit. J. Ophthal., 27, 523.Macht, D. 1. (1920). J. Phurmrrcnl., 16, 1.Munch, J. C., and Sehwartze, F. W. (1925). J. Lab. clip. Algid., 10,

985.Neymark. M. (19)6). Strand. Arch. Physic!.. 73, 227.-, and Widmark, E. M. P. (1936). ibid., 73, 283.Nicloux, M. (1934). Bull. Soc. Chim. bhrl., Pars, 16, 330.--, Le Breton, E., and Dontcheir A. (1934). !bid., 16. 1314.

- . and Placer. A. (1912). J. Physlol. Path. gin., 14, 916.Oettingen, W. F. von (1943). "The Aliphatic Alcohols." U.S. Pub.

Health Sera ice, Pub. Health Bull. No. 281. Govt. Pig. Office,Washington.

Poulsson, E. (1941). •• Lchrbuch der Pharmakotogie." 12th ed.Leipzig and Oslo.

Richardson. B. W. (1869). Afed. Times, Loud., 2, 703.Rua, O. (1943). Aria. med. scand., 113, 558.•-••--(1946). Ibid., 126, Suppl. 182.Rohr. F., and Braun, A. (1926). Arb. Releha4r.undhAnrr.. 57, 580.Sayers. R. P,.. Yant, W. P., Schrenk, H. H., Chornyak, 3., Pearce.

S. J.. Patty, F. A., and Linn. J. G. (1944). J. inthair. Hyg.,26, 255.

Scou, E., Hetz, M. K., and McCord, C. P. (1933). Amer. J. elk,.Path.. 3, 311.

Tyson. H. H., and Schoenberg, M. J. (1914). J' Amer. med. Ass.,63. 915,

Uhthotr, W. (1915). Kiln. Mbl. Augenheilk„ 54, (I), 48.Vbhr, W.. and Dietrich, W. (1912). Binchem. Z., 40, IS.Weese, H. (1928). Arch. exp. Path. Pharmak., 135, 118.Widmark, E. M. P. (1933). Biochem. Z.. 259, 285.Witte. R. (1933). Arch. Gewerbeparh. Gewerbehyt., 5, 58.Wright. L. O. (1927). lndnsrr. Ertgng. Chem, 19, 750.Yant, W. P., and Schreak, H. H. (1937). J. hsdusir. Hyg., 19, 337.

-and Sayers, R. R. (1931). Jndusrr. Engug. CJrarn., 23,551.Zatni 'an, L. J. (1946). Bloc/tern. J. Proc., 40. lxvii.Ziegler, S. L. (1921). J. Amer. user. Ass., 77, 1160,