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372 FROM THE LITERATURE DIZ'I'~IUI~ (~,,YCIX, TOXICITY DLethyLene glycol Ls not only found Ln vine these days, Lt seems. 1"oe scandal into vth/cb LcresponsLble Austrian vintne/s and their govecn- merit vst©hdogs corkscrewed this summer has drawn attention to a toxic c/~emlcal tl~t has tucned up In all socts of unexpected, places. In vlev of l~ 81;qxtconULy tempt/rig econcml© and ocgsnolepClc qual/tles, tt JLs vocth reviewing d/ethylene glycol'8 toxlcLty p¢oflle. Human experience Insight Into the lethality of dIethylene glycol (DE:G) was gained when In 1937 a new and prevtously untried 'ellxJL[ of sulphanllam/de' preparation made by the S.E. HaasengLll Co. containing ?lt DE(; killed lOS people (Calvery& Klumpp, Sth. mad. J., Nashville 1939, 32, 1105). The lowest total dose of the HassengLll eltxL~ reported to cause death in the child/on involved, the youngest aged only 7 months, was S ml (3.6 ml DEG); total doses Ln the adults that died ranged from 20-240 nl of the ellxlr (14-170 nl DEG). No dose-response data ace available, but a cumulative dose of 14 ml DEG in an adult weighing 60 kg Is equivalent to a total intake of about 0.23 ml/kg: the average fatal dose Ln adults was about 71 ml DEG, or 1.2 mL/kg (I.e. about 1.3 g/kg*). Some of the survivors tolerated much higher doses. The first symptoms of poisoning wets nausea and vomiting, with pain felt over the k/dney region and abdomen. Afte~ an /n/tim1 increase, urine production decreased and finally stopped. Drowsiness and coma usually preceded death, which occurred 2-22 days after the first dose of the elixir. Host of the fe~ clinical studies shoved albumin, casts and ~ed blood cells Ln the urine and elevated levels of urea nitrogen Ln the blood. Levels of c/cculatLng white blood calls were also Lnc~eased, possibly due to concentration of the blood (Calvecy& Kl,-upp, loc. cir.; Ruprecht & Nelson, J. Am. ned. Ass. 1937, 109, 1537). Similar signs and symptoms were again seen In seven Cape Town children who died after receiving sedative mixtures in which DEG had been substituted for the. usual vehicle, propylene glycol. Ha data on the Level of DEG In the mLxtuces or the amounts consumed ate repotted (Bowie & McKenzle, S. Arc. mad. J. 1972, 46, 931). ............. Pathological---exa~l~b~i~-n--~C-th~'dea~ In both Incidents identified the kldney as the p~Lnclpal target; the liver was also affected. Typically the kidneys became pale and swollen. Microscopically the LesLon consisted mainly of hydroplc degenerat/on of the convoluted tubules, desquamatLon of the tubular epithelia and blockage o£ the J 0 0 • The specific qravtty of dlethylene glycol Is 1.118.

3"73 tubules by casts. The g2omerulI were largely unaffected. Some evt.djnce of tubular epithelial regeneration usa also seen. The livers shoved centcLlobulac hydroptc degeneration (Boule & HclCenzteo Zoo. O£~. ; Cannon, J. Am. ned. ~ss. 1937, ]LOS, 1536; Rupcecht & Nelson, ~oo. e~,t. ). Animal data Estimates of the oral r, Dse tot DE(; In cats range from about L3 to 32 g/kg. Some of the lover figures have been associated with lover boLILng point ~ractIonJ thought to contain more nonoethylene 91¥col (HEG), a customary contaminant of corn, cell1 DIS; (Laug 8¢ aZ. J. Ind. Wyg. ToxLco]l. 2939, 22° 173; Smyth 4t a7- 3. Ind. Hyg. ].941e 23, 259; Weatherby & Williams, 3. Am. pharn. Ass. 1939° 28, 22). The oral [,I)50 In nLce Ls reported to be Ln excess o~ 20 g/kg (Bornmann, AczneLnlttel-Forsch. 1954, 4, 643; Laug #~ aZ. ~oc. o~.t.). Other species appear to be somewhat more susceptible, with oral LD50 values or about 4-13 g/kg recorded for the guinea-pLg, rabbit, cat and dog (baug c~ GZ. ZOo. o1~t.; Snyth #t a~. Zoc. oit • ). The acute symptoms observed Ln animals have generally Indicated central nervous syste= depression and renal damage. They Include increased thirst end urination In the early stage £olloved by severely reduced urine production with heavy protein excretion, lethargy, prostration, shortness of breath and coma prior to death in 1-5 days. Patholog/cal exert/nation revealed that hydropLc degeneration, partic- ularly In the convoluted kidney tubules but also Ln the centrLlobula~ port/on of the liver, was the me,or nLcroscopLc Lesion (Laug e~ ~l. lOC. c{t.; Smyth e= QI. 7~:)O. Cir.). 575o~¢-te~m to=~t.V Five dogs given daily oral doses equivalent to 5.25 nl OEG/kg/day dLed after cumulative doses oE 21-94.5 ml DI[G/kg (4-18 days). Forty daily doses of 5.25 ml/kg/day were not fatal In cats, however. Slng]le or divided doses o£ 7.S ml DEG/kg/diy killed five rats In 26 days (total dose 30-]l95 ml/kg); the other nine oaly died sgter at ]least 40 days (total dose 231-450 nL/tg) (Westhetby & WlL1Lams, Zoo. ~£t .). Zn another series of atud|esj cats were given divided dally doses o~ 0.5-4 nl DEG ~or up to 8 days. Host anLnaLs st the Lowest dose level survived In apparently good health. Doses equivalent to 2 ml/kg/day killed all the animals (total dose 14-18 mL), with symptoms matching those described a~ter single oral doses. Stellar e~fects were also observed Ln groups of rabbits and dogs treated w/th DEG or the Massengtll ellxLr (Ge~Linq e¢ ...... The pathological lesions described In lets, rabbits and do~s that d/ed a~tet repeated dosing vtth DZG or one o[ the elixirs In the short- term were sLmtlar to those seen In man (Cannon lo~. o~= Kesten et ~. 3. Am. med. Ass. 1937, 109, 1509; Weatherby & ~/lllams ~O~. o~t.). Zn one study, none o~ 30 rats qlven I~ DEG In their drtnktn9-~ater (about 0.6 ml/kq/day) (or 33-174 days died or su([ered kidney d~mage, thOUgh a proportion o~ those tats given 3~ o[ S~ died during shorter ,mm.~ O O O% emb

374 tl;eatasnt pe¢lods (Kesten St aZ. ZOo. c~t .). In another dcLnklng-vate: study of 20 :ats given 0.)t (about 0.6 g/kg/dsy) and 20 ,ats-gLyj~n It (about 2 g/kg/day), only rye rats In each group died ducln9 the f/rat 100 days. Hone of the rats treated for an additional 75 days died (Heatherby & HLllams ~o~. o/~C.). [x~g-tem ~ozie{ty The ms)or finding of interest In Zong-term rodent studies has been the formation of bladder stones. Zn the ea:Ztest chronic study oE DE(;, three out of the 20 rats ~ed 2.7 or ).4t (about $50 mg/kg or 1.7 g/kg) D~G Ln the diet had bladder atones. Analysis suggested that these vete lacgeZy made up of calcium oxaZate. DZG-tceate4 rats aZso dlspZayed slight kidney and ILvec damage (Horrls sl~ aZ, J. Pharsac. exp. Thee. 1942, 74, 265). Zn another study, groups of 12 tats vece I~ed diets containing 1, 2 or 4t DF..G for :2 y: (PLtzhugh & Helson0 3. Ind. Byg. Toxlcot. 1945, 28, 40). Survival and grovth tares vece [educed at the highest dose level. HlCroscopIc examination of a vide tangs of tissues fron haZf the anJLmaZs again revealed dose-related effects on the kldneys and 11ve[. These included, at the highe, doses, hydcoplc degeneration and focaZ necrosis In the 11ver, and ~ocsl tubular atrophy, hyallne cast formation, hydroplc degeneration, caZcifLcstlon an~ 9Lomerular atc0phy in the kidneys. These effects vere absent or sZlght •t the Low dose (500 ag/kg). BLadder •tones vere found In 11, 7 and 2 antra•Z• •t the high, inter- mediate and Zow doses, respectively. About half of the animals at each of the top two doses (I and 2 g/k9) also had bladder t~our•, and In alt but one case, bladder stones vete also detected. The tuaours vere genecaXly benign papillomas vlth some showing varying degrees o£ malig- nancy and one being distinctly mal;gnant. The Investigators suggest the development of the turnouts was due to chronic Licit•fiSh by the stones. UnfortunateZy, the report• o~ the•e tvo studies provide no details on the purity of the DZG samples. It Is possible that the toxic ef~ects vere influenced by HZG conta~nation, since this *s knovn to cause kidney damage and ox•Zate bladder stones (HQcrIa st GI. lOo. c{C .). In the report o~ another Zong-te~ DEG study c•r:ted out •1Jest 20 yeats •fret the first tvo, CarroZ We12 and co21e•gues from the Hellon InstLtut• In Ptttsbu:gh state that ~bey used DP.G contain/rig only 0.03t M~G. Rats o£ different ages (ve•nX/ng, 2 months, 1 yr) vere fed D~G for 2 yr, /n/tJ•lly st dketary Zevels of 2 or 4t. The levels g/yen to the side: rats vere adjusted during the Elrst 6 months of the study in order to provide them vtth the same dose level as the youngest rats. A£te~ the ~Lrst 6 months, the males at the high dose vere receiving about 2-] q/ kg/d•y. Yt~tuaZZy none o~ the male yearZtngs survived one year o£ treatment, vhsteas a21 the ~emales at the high dose remained •live at this time. The mortaZtty of mazes that vere in the stud~ Erom ve•nln9 st (Arch• envtr. Xlth 1965, 11, 569). Bladder stones vere ~ound tn SOt o~ the 60 males In the high-dose ~roup, but not Ln veanZ/ng mazes ~llled a~te[ ) months, In high-dose ~em41es, or in elther sex glven the 1or dose o: the control diet. ~he onZy bZadde¢ tun~ut ~ound va• [n • hlqh-dose male. roZZovlng surgical Implantation o~ bladder stones derlve,~ from rats fed hlqh levels o~ OEG Into untreated tats, atones veto (ound in 48~ o( 37 recipient males and O~

375 26.?t of 30 recipient females at death, vhlle same 10t of-both qroup• developed bladder tumours. The Implantation of glass beads, in the bladders of untreated recipient•, and the operative procedure alone, vere also associated vlth the formation of bladder •tone• and the occasional bladder turnout. Ha bladder turnout• ve=e found Ln the absence of stone• oc a bead. These result• again suggest that the tumours seen tn OEG-treated cats vere probably due to mechanical irritation. In an unpubli•hed BIBI~ •tudy, rats of each sex vere given 0, 0.4, 2 or 4t DE(; in the diet for 99 days or 0, 0.08S, 0.27, 0.4 or 2t for 225 days. The DEG used ¢ontaLned less than 0.0It KEG. At 4t £n the diet (equivalent to • daily dose of about 3 g/kg tn males and 3.7 g/kg in females) DI~ caused the death of 6 of the IS male• In the group, vlth signs of kidney damage. The sucvlv£ng eninals •hoYed increased v•tec intake and urine output, effect• on kidney function and k£dney veLght, oxslate crystals in the urine and histological evidence of kidney damage. Zn add/lion, the males shoved reduced veight ga/n, signs of blood concentration and hsemstu:La, and the females •hoved liver lesions. At 2t in the diet effects on kidney function, increased viler intake and signs of blood concentration vere found in the males. In both sexes, relative Kidney ve£ghts vere increased after 225 day• and the urine cGntained oxalate crystals. EvLdbnce of Kidney damage vas seen In one of the miles. Dietary level• of 0.4t (about 300 mg/kg) produced oxalste crystals in the urine, particularly In females, and mild defects Ln kidney function in the males, but no histological damage. Only a margins1 increase in ur/naty oxalate levels in male rats van seen at 0.1?t (100 mg/kg) and no effects vere noted at 0.08St (S0 mg/kg). Conclu• loss The toxicity in animals of single oral doses of DEC; Ls 9enerally low. Repeated admLnisttatLon of 7.5 nl/kg/day k111• cats and dogs v/thin a short period, hoveve:. Lethal effects in man have been observed at rather lover doses; cumulative intakes, possibly as low as 0.23 mZ/kg but on average 1.2 ml/kg, over a period of days vere fatal in the su~phanLl- am~de elixir incident. Nevertheless, In •pits of[ the observed inter- • perle• and £ntsr-lndivtdual differences in susceptibility, there Ls a st:ISLing consLstency in the •pptcms and pdthologLcal findings. The mtln effect tn both human• and animal• L• kidney damage. The liver 1• • 18o affected but to • lesser extent. The levels of DE(; found Ln contaminated vine analysed tn the UK, usually less than 3 g/lilts, vould sees unlikely to represent a hazard to those consuming part (or even all) of a bottle of adulterated vine on s one-off basis. Hoverer, DEG concentrat tons have occastonally been reported In other countries to be much higher tn same bottles. One of these consumed £n their entirety by one person might conceivably deliver ............ ; ~a~g~'~Os~y-h'i~'~ dos;~-. ........ The unpublished 81B1~ study provides the best indication of the toxic risks that might be associated vlth the long-term ingestion o£ DEG. Zt used a DE(; sample v/th the lovest relx~rted KEG contamination and an unusually broad range of doses. At 100 mg/kg the only trearJent-related finding vss the presence of a 8sail amount of oxalic acid in the urine. Whtlst changes in kidney function and the presence of crystals in the urine observed at higher doses are und,)ubted 1 y toxic or(eelS, the o C7% ~J~

°, m 376 l pctsence of • urlnicy metiboLlte, albeit one which at htgh levels Is likely to be the cause of the Kidney Lesions, cannot vtth any fairness be described as a toxic finding. A no-toxic-effect Level of 100" mg/kg therefore seems Justified. A tradLtIonaL 200-fold safety factor appZ/ed to this figure would produce a maximum tolerable dally IntaKe foc man of I mg/k9 body velght. But Ls the lO0-foLd factor the best choice In the present case? The LO0-fold figure Is said to be made up of two factocs of 10, one to take account of possible 8pec/es dIffecences, the othe~ to cope vith Lnter-indivtduaZ vat/alton. The suspicion, based on the Hassenglll incident, that man might be very much since susceptible than the :at tO DEG'• •hoot-term toxicity (even mote than a 10-fold difference), tngethe¢ vItb the knoeledge that I~ete Is a vide (and maybe greater than L0-fold) Inte:-indlvLdual response to DEG In man, might lead some to suggest that the traditional choice on this occasion may be a little on the liberal s/de. A mote conse:v•ttve 200-i~old safety facto: vould lead to a maximum tolerable dally Intake of 0.S mg/Kg. Drinkers of v/me contaminated at 0.S g/l/ere mould ingest this Level If they took one o: tee glasses • day. Furthecnore, the response of male rats to 300 mg/kg suggests that Kidney function in man night be Impaired by a daily t/pple of from a half to a full contaminated bottle if this habit vece maintained for a con- siderable time. However, It vould have been 8 particularly unlucky UX shopper to continually pick the DEG-contalnlng product from the shelves :oc such a period. ~loce realistically, vhLlst not all of the committed drinkers' liquid ~ntake vould have contained DE(;, Lt vouLd certainly all have contained alcohol. Long-teem consumption of these volumes of ethanol would probably threaten the liver more than the associated DEG would threaten the kidney. Lym~Resser PIIIm(X, 011T~JP Zn January 1984 about rye million consumers Ln the north-vest Of Er~illand and po£ts of Wales yore exposed to phenol from their vats: supply relieving 8 ch~/cal spill /nee the Rivet Dee In North Nales. Routine chlorination of the vats: apparently converted much of the phenol to chlorinated phenols (mostly 2,4,6-trichlorophenoL) which, unlike phenol, generally possess a taste and edour detectable at low levels. Xnitial assessment led the rater authorities to believe that at th~ levels involved there yam no health risk. However, a repotted increase In gastro-lntestLnal complaints prompted scientists f[om the Communicable Disease Surveillance Centre and the Clv~! Public Health Authority to per~m_.#~e~r¢sp~c_tL~___su_C~_ey_~_~hg_~n~ldence of illness in the ve_ek ....... follo~ln9 contam|nation (Jarvis et ~l. St. ned. J. 1985, 290, 1800). C~ Q A questionnaire 8eat to households receiving polluted rater from C~ either of eve resevo~rs fed by the Dee, oc to households receiv~ng C~ unpolluted upland rater, p~ovLded Information on 754 exposed people and --~ 448 unexposed people. Respondents vere asked vhether any of seven specific symptoms had occurred (diarrhoea, nausea, vomiting, abdominal C7~ pain, headache, r.mSh and malaise). The results sho~ed that each sy~ptom

2Pad /~l, gs,~t l.a?~ Pro jr ~,~.~ht~fer. rAT CI qar~t t q~-F obr I kpn r~!, 211Of! PmC~urq 3~, Po~tfach 30 ~ ~0. tJF.ST C,I[P~t~qY. f'*Ar rrlrdltet'. rollow~p~ .v~,.~ t@l,phnne ~.onvPrsatlnn udth P|ct'ar~. q~. ~e t.ellect.-~I ~p~jet.l~r Sur.h tnf~r,q~t|on as ve have it hand qlne~ q:.tm L.q~9 r~rrpq;Fcmd~nc~, fPn dIp.l:l~l~.pe ~lycel, t.l:* ~tn ¢nncern hpre has tpnde¢ tn b@ ,ccmpta~lltty -f ,~.-.e In Ser~. terrtt.ort~.~ ~r@ s~ert~.~os of ~t~er h;~'~ct,nts nr ~lvent.~ I,~ l~d t~ sn~.- arrllcatfo~,. T~.e apr.,r~Is~l o~close~ (.%tr~l ln.?.?Y) tnd|cate~ e.n acceptable lave1 of M.~2. on r, tr;er~tt~t ~,hlCl~ t/~ I,sv~ ,sP~ to ~valuate t~p.~rAry acc~.~ta~cM. The ¢~py of ~.hp ..~ frr~ qurke |e~cles~d) rrevl~s a c~ev~nlent l l~.-r~t,r@ s,~rch up to that tl--~. ] ~n n,t ,~arp pf any ~orl, I~cent pu.~llcptlo~s. ~ut ~te 4re a~IP.? R|.~RA tO pradu¢~ lP ,l~lat@d |urv~.y and ¢~ent nn th~ subJ@ct. Alsn e,tclos,d Is • cnp~ of an offtclal t.~ resFe.~$@ of 1,1~ to a pr~$,l on tobacco gsaSa. Two ~ai~rs puhll~he4 slate tq¢o en eth~lp~ Q1ycel are of rns~thle tater*st tn vte~ef th* ~etght glwn to t~ Pffect~ ef @thy|ene ~lycel tn aSS~Ss~.ntq of PfG. The c~fnrta~.le v~ ~n i, ropyle~e 31ycel hl~ ~.e~n te r-.~,r~, tt nq r~@boltz@d dlfferentl3, qpd thrr@~ar@ ne~. s,m]~ct t~ t.,~ s~. ~q:lq@q ftlr ¢rmc~rn. Sor~. r~her ~$r~cte dld ~rts~ v~qc~ !,-t tO the atf.acl,t,d hrt*f .~ fur~.~r ivr.~s~,r~, o~ fr.s ~,se ~tther far f~d er toha¢cn o~|lcntl~n~ .~. far. t~n .111 rem.,eSt conflr~atlop of thls polnt fr.,'~ ~IP.P~.. ^ recept Japaees, per.~r, no~.tPllly on ~af@t.v ef erel,yl@ne pl~'c,1 (.~.~.nvesht ~.t ,l.. Cosmetics Tetletr1-s qP0 ~'ct.,5~r. q3-q|, lee4)t |s rn.qtrtc.t@d t~ ce~r..~re nn at~pltc|~|en to tkt~"~, r'.e ~ther ¢n~r.drjt.~ p~q~se4 n~ tn lt~ ',.~ *. Fltvn0~r 0 0 C~ C~

*2* .° o Q Altho~ of perloi~r•l tnt.lrest al~ presMt, ! m encle•tn9 • note on polyelr~lene glycols. We alse have • repor~ on acute lOaletien toxtclt¥ of FTG ~I0 chltld S.,gRI, D fron york tn tim USAD should this be of arts InterniSt, Pleese 1or ~ kn~ iY ~ Can be of help in Yolloving up a~y of these topics. Ymirs •tACerely, T.G. MtT¢Itf:,LL (I~CS. CO: S~ro R. 611ms 0 0 r~