Document ppJ0d0O4gYdVyem7kMKokLZE7

<* x WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE FAD/FA/7a.U (a) FIGLIbu Ui.LZ JOlhX FAQ/dHO 3CF2RT C0i::iIT22 Gl /COG AD HIT/id spdcificaticis foe identity aid iueity c? food ADliX-lx/ijo .^D XiiwXR iO.viG0ijClJA v. ..xu,iXu.< t ottcs, zj**RfiwxXOti .owL*a.. xxi iw-D wbP.x-,iA. g..*uj2 .jL;u,oi.\i.Cjio AID './.Oi. i,?L*b 00* Sx0ij.0-'S Oil ."i.DXxz. Jl*j X.- o.'iUl xGCD Geneva. 2'. June - 2 July 1370 ,,*11 _ -1 nr ' -- * t*-1-1* (Fthyl.. Alcohol) by Dr. ?. S. Lilias (Gens'll ta.r;t) Bjolplip.-il Data Biochemical ascocta Ethyl alcohol is rapidly and readily oxddiz-sd to C0,, acid water. Tbs toxicity is iLninisnsd ii substances vhich increase tissue c-.dLuticn arc river. ce: ores and. The pathway is yar.era' '' * T. o ce initial cui leu no ccetnli:- hyde, conversion so acetyl oc-~ t.e n acetic acid, xi.u ox sex on in and liver no COp^ and water y~.i:v:} 1965/. luny tissue can also convert ethanol to GG0 (llasoro et ai., 1953)* Gr.trahcpxtic metabolism probably accounts for 1G ter cent.'cf eliminnticn (Larsen ex xl., 1361). ..Icci.ol leapbror-mtasa centrals t.ae initial o:ddatior. to acetalieny is. I he er.nyre is i cur.a nair.lv in vu l:v-=r and a little in the hidr.ay. -a probacly requires the presence ox ..AD. Luc encyne contains 2n which contributes to the binding cf DPI.' with the er.syns. dehydrogenase controls the farther oxidation , =* ,, Acer aide. F'-s --ruoy. u s i n~ j -led aiconol at uas seen snovr. t.aat rats exhale ; re: cent, as CQ? in 5 hours and 90 per cent, in 10 hours, wo t: cent, is eiimin unchanged iS the urine and expired air, while G.5-1.0 ;:uer cent, xx ccnyanatcu excreted in the urine as ethylglucurcniie (.partisan a iamett, 1949, haa:ii et 1953). Clearance of ethanol from blood depends on the amount of dosa-re. For lew desire it is proportional to the amount present, for laraer doces.it varies with time ar. the same animal (billions, 1959}. Ihe rat ms-taco dices alcohol mere slowly than the mouse and faster than the dtp (Aull ct al., 1956). in dojs alcohol cusses The iesua of ttw cocuwcnt Coes not constitute forma: publication. it mould not bo reviewed, abtiractad or ovct:d without toe m'se.ment of th? Wer'd P;s:ci Or- vua'oa. Authcra CO") are responsible for viawa expressed in sijned articles. Co document no ccrstitue pas uno oubiica.ion. i! lie doit faire 1`ciiet <1 aucun co-rote rer.Cu cu rcouina m d'aucune c.Lvo.i rc-s ! a jtc ./..acn ou i'Oi'Stnioni.u.c t,'cni;a;o c la I'm*.::. Los on nicra exp.'lnsee cJeos !es article sicnes necgaga.u quo lours auteurs. ASI 00004222 ;'AJ/FA/70.11 (a) page 2 through the kidneys by simple diffusion. During absorption from the G.I. tract the concentration of ethyl alcohol was a little lover in peripheral veins compared with arterial levels. 2--4;= of total ingested alcohol was eliminated by kidneys and 4-j in the expired air (freon, 1953). Decent evidence suggests that man metabolises alcohol at a rate depending upon the concentration present if catalase handles oxidation cut independent of concentration in the human body if alcohol dehydrogenase handles oxidation, the action of tetraethylthiuram disulphide may increase the tissue concentration of acetaldehyde necessary to achieve netabolim to acetic acid. Other possibilities are- prevention of the oxidation of ethanol and the production of disulphide metabolites, Any acetic acid formed joins the body acetate pool (freon, 1953). dthanol is distributed unifomily in body water (Gamps, 1963). Zthar.ol has o direct effect o.: liver cells in vitro, decreases DPI; and increases jMK and therefore effects more acetate incorporation into fatty acids (Lie'oer A Schmid, 1961). Acute ethanol induced fatty liver differs from that induced by chronic small amounts in that the latter responds to choline but r.ot the former. Hence hepatic fat nay increase by a) increased mobilisation of fat from, depots, b) increased fat synthesis and esterification in the liver itself, c) inducing a relative choline deficiency, ail leading to the picture of fatty infiltration and fibrosis (Hintskin, lyol). decreased fat oxidation in the liver may contribute to the fat accumulation (Isselcacher _* Greenbermer, 1964). Sthdnol proauces'a narked increase in serum cholesterol in the dog, while in man a small but significant increase occurs after large intakes. Hyperiipaemic subjects show greater rise (Grande i Amatuzio, 1969). Rthar.ol has a moderate short-lastinTM effect on adrenal This is probably due to sympathetic stimulation (Reman, 1961). Alcohol is not absorbed through normal skin tut can be absorted through abraidsd areas (Camp, iy-:3). Acute toxicity Animal Route r/- rf vei ^109 i/ke body weight References Frog Mouse s.c. oral Rat Guinea-pig Rabbit Cat Dog Man s.c. 1 i. v. inhalation oral i.p. inhalation i.p. inhalation oral oral oral oral i.p. i.v. i.v. oral s* c i.v. oral 9483 1973 - 13660 5000 - 5560 -- 6300 9500 - * - - 7100-7900 .. 4700 29300 Don 12700 Dpn M 21900 pen 7390 9000-10000 3500 9400 3945 55CC-6500 6000-3000 5365 6000-3000 Spector, 1956 Spector, 1956 2 rovr.ing, 1953 Spector, 1936 Spector, 1956 Spector, 1956 Browning, 1965 Spector, 1956 Browning, 1965 Spector, 1956 Spector, 1956 Spector, 1956 Breaming, 1953 Browning > 1953 Spector, 1956 Spector, X V "3 O Spector, 195 u Spector, 1956 Spector, 1956 von Gottingen, 1943 A$I 00004223 rr FAD/FA/70.11 (a) page 3 Ethyl alcohol acts principally on the brain whether invested or inhaled, by first inhibiting higher functions and then as anaesthetic. The lethal dose for man is 3-10 cc per kg body-weight or one quart-whiskey'or a blood level of 0.5 per cent, or more (Haag et al., 1951, von Oettir.gen, 1943). Death occurs fror. severe and probably irreversible injury to the Oho. Acute intoxication affects visual acuity, fields of vision, oye coordination and distance judgement. The vapour is a manor irritant to the eye and respiratory tract mucosa. Anim-.Ia as m.ucii as tolerance. Dors intoxicated bv ir.mssticn showed liver injury o* c jllular oedema at the ocripnary Lobules and increase in lipid which regressed subsequently (kcchider, 1933). Inhalation of high concen trations caused reversible fatty infiltration of the liver (i/eese, 1925). The TL7 is 1090 cpm (ratty, 1953). However concentrations up to 3500 ppm do not produce irritation or any subjective symptoms nor any rise in blood alcohol concentration (freon, 1953). Short-term studies house. C-roups of 10 nice were fed for 5 weeks on a control diet but drinking water was either normal water or 0.3 per cent., 4 per cent, and 20 per cent, ethyl alcohol, .ortality increased with dose but there 'was little effect on the mean weight of survivors (College Pharmaceutical Society, 1962). Groups -of male and female mice were given ethyl alcohol (unknown composition i.p. for 6 months, ho tumours were noted (Larsen 1 Heston, 1945). f "i 't', % ^^ ys'i w. 1 9 -* T --1 / ^ -m - ^ r*. - ^ ** * ^ * '" - ^ 3 times per week for 41 days, ho tumours were observed (ILusseHet al., 1341). Line groups of rats containing 5-25 ani.rn.al3 received 20 oar cent, alcohol in their driiuiing water sued additional cys tint with or without choline in tnsir diet. Observation extended from 8 to 24 weeks, ho tumours were observed (Hanscher, 1953). 15 rats received 15 per cant, alcohol in water :r up to 14 weeks. tumours were observed (Baumann et al., 1942).* Groups of male rats received 15 eer cent, alcohol in their drinking water. Aiwfer x/ i xiy s 'srG **o 'wuziours 3.x. 9 -- 24 rats were giver. 15 per cent, alcohol in their drinking water. After 120 days there ware no tumours (hlatskin et al., 1951). .In another experiment rats were given ethyl alcohol in their foci for 300 days without any oatholocical cnan res having been observed (ha.-mhara a Lori, 1939). Rabbit. 6i rabbits were given 20 ner cent, alcohol ir. water bv stomach tube in quantifies from 20-100 ml daily for 304 days, -hireoar. died of ir.fect:.:n but ro tumours ware seen in the rest (Connor, 1940). Pog.^ Twenty-three dogs received a 40 per cent, aqueous solution at a rata of 10 ml/kg body-weight daily for 6 to 2o months without any signs of tumour development (kachider 1 Donnelly, 1932). 1 ASI 00004224 FAD/FA/70. IX (a) Page 4 Human observation In man ethyl alcohol acts as a mental depressant; moderate doses stimulate the appetite and food absorption. Higher concentrations irritate the gastric mucosa (Jacobs, 1947). Ingestion of less than 0.5 g/kg dees not effect the behaviour of man, 0.5-2.0 g/kg cause some disturbance and hoses above 2 g/kg cause serious drunkenness (von Getting?.-!, 1943). The effect of inhalation depends on whether the person is accustomed to drinking alcohol, .-desorption by the skin is rare, -one visual impairment is seen in chronic ingestion as well as some incoordination of voluntary muscles (Brcwnir.a, 1965). Chronic intake of alcohol amounting to over 160 g pure alcohol per da;; for more than 10 years leads to hepatic cirrhosis in man (Thaler, 1969). Long-term studies house. 16 micereceived 0,1 ml of a 50 per cent, alcoholic solution every two days rectally for 547 days. Two animals developed tumours of which one was a sarcoma. In another onperiment, 10 male and female mice received 0.1 mi of a 50 per cent, alcoholic solution every two days orally for 554 days. Two tumours of the back were observed (Krebs, 1920). Alll3. y J * O % tj r, Roberts, W.J., , Bartlett, G. *T<?.* Baumann, C.A * > h Barnet, _ C S w0T*j w t *i-*4 '*X* i i j G .r. f *1 . -4 y * ., Luc' Browning, B. i \ 1953) Bro-.ning, 3. f\ 1965) lent citv v 1 ? X <" :1 - k!d. J.. 2, 1001 -i--4 Camps, 3.3. Vf t- 965) J. me r^ 4o-- .' College of the f karmao-.uvital sccic-sy \,13o2; deport to BZMA Connor, C.L. (1940) Arch. Path.. Z2> 165 Grande, ?. 4 Arntusio, 0.4. (I960) Minnesota had.. 13. 731 Haag, H.2., lilvomtau. T. l/ktye, 4. (1731) T- harm. I. --n.. 103. 344 .-,.3* (lv47) o.r...m,y..sc .'tea --,.u;unc~s, "ran i..cytrana wo. ASI 00004225 FAD/FA/70.11 ( page 5 Kamil, I.A., Smith, J.K. & Williams, R.T. (1953) Biochem. J. 53f 129, 137 & 5k> 390 Klatshin,'G., Gewin, K.H. i Krehl, V/.A. (1951) Yale J. Biol, 4 Wei.. 21, 317 Klatsuin, G. (1961) -'---er, J. Clin. :ltr.. 1, 439 Krebs, C. (1923) 4tsch. In-run. a:---.. Ir.er-p.. g-?, 203 Larsen, 0.0. 7: Hosier.,. 0.1. (194;;) C-::c:r >c^:rch, 592 Larsen, J.A., Ivyssra?, 0. 1 'dialler, K. (1911) J. Clin. Invest. 11, 11 Lieber, C.3. i Schmid, 1. (19=1) J. Cl:n. I--it.. 10, 394, 1355 Kacl'ider, W. de B. -1 Donnelly, -G.L. (1932) Bros. osc. err. Biel. Led.. 29, 5B1 KaeKider, W. da 3. (1333) 0. ?h;~TCcl. ea, l-mr.. 49, 100 lasoro, 3.T., Abramoviteh, H. 1 Birchard, 0.?.. (1953) Physiol.. 173. 37 Kalahari, W. -'lari, K.. (1939). Free. Ac^d.. Jan.. 15, 2/3 _ VV.i c-*., >i... __j - I -- G.-.ja, Tw.0* 0 33TV Isselracher, K.J. i Gree.nborrsr, O'.J. (l?6i) 0lari. 4, 270. 351 ar-d 402 Patty, (1953) -Cnura-dal Ky-lsr.- 9 Is"ier-'_o"v. ar.carsci sr.ee, Kev York Ferman, 4.3. (1961) Ac:n. ?': J /, ^ CO Russell, n.r.., rage, r..Ct, Aatnr.av:;:, 4.3,, Scnvrabe, 3.L. 2.uery, F.Z. (1941) Zr.dorrlnslorr. 23, 397 Specter, m.g. (rrrn} m-Tr "sou od Tcrrtcolcrv. W.B, Saunders 4 Co Thaler, (I9u9) -'V.scn ..--a. ..scar.. yr_, 1213 Treon, J.?. (1353) ir. A. Fetpv, Tr.d'Ttr* nl Yv-icr.? 1 ?c::icolc7v (1953) Yol.l1 Wanscher, 0. (1353) /-eta Barb. iicr-A:7/ I. o-ni.. ?2. j--< 'S V/eese, H. (l92o) Arch, em. Fas del. rhamnlol.. 135. 11 V4 n TO T / 7 ^ ' 7 T_Tn'' . *4.AAL'.v.Jt *.*i* . ' , IT * t m -o,*- ASI 00004226