Partition coefficients of some industrial aliphatic hydrocarbons (C5-C7) in blood and human tissues

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1 British Journl of Industril Mediine 1985;42: Prtition oeffiients of some industril liphti hydrorbons (C5-C7) in blood nd humn tissues L PERBELLINI, F BRUGNONE, D CARETTA, AND G MARANELLI From the Institute of Ouptionl Mediine, University of Veron, Veron, Itly ABSTRACT Sline/ir, blood/ir, olive oil/ir, nd tissue/ir (lung, kidney, liver, brin, musle, hert, nd ft) prtition oeffiients were determined for nine liphti hydrorbons: n-pentne, 2,2-dimethylbutne, 3-methylpentne, 2-methylpentne, methylylopentne, n-hexne, ylohexne, 3-methylhexne, nd n-heptne. Blood/ir prtition oeffiients were found to rnge between -38 (n-pentne) nd 1*9 (n-heptne) nd the vlue of the tissue/ir prtition oeffiients rose from n-pentne to n-heptne. The tissue/ir prtition oeffiients were signifintly orrelted with the blood/ir prtition oeffiients (r = ). Aording to the slope of the regression lines, the men solubility of the nine liphti hydrorbons in the different tissues ws higher thn in blood by the ftors: lung 1-4 (rnge ), hert 3.9 (rnge ), liver 5-6 (rnge ), kidney 5-2 (rnge ), brin 6*5 (rnge ), musle 7*6 (rnge ), nd ft 25 (rnge ). The blood/ir nd olive oil/ir prtition oeffiients were signifintly orrelted with the boiling points nd the moleulr weights of the liphti hydrorbons studied. The uptke nd distribution of industril solvents re importnt in the understnding of their phrmokinetis, body burden, nd physiopthologil effets. A knowledge of the blood/ir nd tissue/ blood prtition oeffiients of these solvents will give some insight into the rte of pulmonry exhnge nd tissue kinetis. For few produts (yloproprne, hloroform, diethyl ether, ethyl hloride, trihloroethylene) whih in the pst were used s nesthetis, the solubility in blood nd in the most importnt tissues hve been reported.' 2 On the other hnd, for most ompounds used s solvents in industry nd in the home, lthough the solubility in wter nd in other solvents n be found in reports the solubility in blood or body tissues nnot, lthough the solubility of few romti hydrorbons, ketones, lohols, nd hlogented hydrorbons in the blood nd in olive oil hs reently been studied.37 We report on the findings of study of the solubility of nine liphti hydrorbons in blood, sline, olive oil, nd in the most importnt humn tissueslung, liver, kidney, ft, brin, hert, nd musle. We Reeived 23 Februry 1984 Aepted 2 April 1984 lso disuss reltions between the prtition oeffiient of these solvents nd their physil properties. Mteriis nd methods The following solvents were used: n-pentne, 2,2- dimethylbutne, 2-methylpentne, 3-methylpentne, n-hexne, ylohexne, methylylopentne, 3-methylhexne, nd n-heptne. All were obtined from C Erb (Miln) nd were more thn 98% pure. Humn tissues (lung, kidney, hert, brin, liver, musle, nd ft) were olleted from two men who hd died suddenly from hert ttk when ged 3 nd 4 respetively. No histologil bnormlities were found in the tissues used. The individul tissues were homogenised in sline nd frozen t -75 C until the experiments. Stored humn blood ws obtined from hospitl blood bnk. The solubility of the solvents in sline, blood, olive oil, nd homogented tissues ws determined ording to the method desribed by Sto nd Nkjim4 with minor modifitions. Five smples of 2 ml of eh homogenised tissue were put in to test tubes of 11-6 ml pity. We dded 1-2,ug of eh solvent (orresponding to 2-4,Ag/ml of tissue) to the test tubes ontining 2 ml of homogen- 162 Br J Ind Med: first published s /oem on 1 Mrh Downloded from on 2 August 218 by guest. Proteted by

2 Prtition oeffiients ofsome industril liphti hydrorbons (CS-C7) in blood nd humn tissues 163 ised tissue. For eh test tube ontining solvents nd tissue, test tube ontining solvents only ws lso prepred. The test tubes were seled with srew p lined with rubber nd Teflon nd were kept for 12 hours in rotting gittor in room t 37 C. The onentrtions of solvents were then mesured in the hed spe of the test tubes, both with nd without the homogenised tissues. In order to test the solubility in sline, blood, or olive oil these liquids were used in ple of the solid tissues. For the solubility in sline 7 ml of the solution ws used in flsks of 75 ml pity. The solvents were put in two flsks, one ontining the sline nd the other empty. To determine the solubility of the solvents in olive oil nd blood, *5 ml nd 2 ml respetively were used. The gs hromtogrphi determintions of the solvent onentrtions in the hed spe were rried out with Perkin Elmer GC mod F 17 or C Erb GC mod 416 s previously desribed89 onneted with Spetr-Physis integrtor mod SP 427. To vlidte the method we mde some preliminry mesurements of the solubility of trihloroethylene in sline, blood, olive oil, nd the vilble tissues. The results we obtined were similr to those lredy reported.2 The blood/ir nd olive oil/ir prtition oeffiients reported here re the rithmetil men of 1 smples, wheres the tissue/ir prtition oeffiients re the men of five smples. The best fit of the liner nd exponentil regression lines ws lulted by the method of lest squres. Results The tble shows the solubility of the liphti hydrorbons in blood, olive oil, nd tissues. The solubility in sline ws low, with prtition oeffiient in the rnge 1 to -4 for ll nine ompounds studied. The solubility ws gretest in olive oil prtition oeffiients rnging from 47 (pentne) to 452 (nheptne). As my be seen from the tble, the blood/ir prtition oeffiient is -38 for pentne nd rises to -8 for n-hexne, to 1-3 for ylohexne, nd to 1 9 for n-heptne. In the tissues the solubility of the individul hydrorbons follows similr trend to tht in the blood, being lowest in pentne to n-hexne, ylohexne, nd gretest in n-heptne (tble, fig 1). The solubility of the solvents shows grdul grdient from blood to liver, but inreses steeply from liver to ftty tissues (fig 1). In figs 2-8 the solubility in blood (blood/ir prtition oeffiient) hs been ompred with the solubility in the tissues (tissues/ir prtition oeffiient) nd it my be seen tht the two re signifintly orrelted for ll nine hydrorbons onsidered together (r between *92 nd.98). From the slope of the grphs it n be determined tht the men solubility of these solvents in the hert, lung, liver, kidney, brin, musle, nd ft is 3 9 (rnge ), 1.4 (rnge 1.2-2), 5 6 (rnge ), 5 2 (rnge ), 6-5 (rnge ), 7-6 (rnge ), nd 25 (rnge ) times tht in the blood respetively. The solubility of the hydrorbons in ft ws times tht in the blood nd ws similr to the solubility in olive oil ( times the solubility in blood). The olive oil/ir prtition oeffiients (y) nd the blood/ir prtition oeffiients (x) were signifintly orrelted (y = 244 x -12; r = -99; n = 9; p < 1). The solubility of the solvents in blood, olive oil, nd in the other tissues inresed exponentilly ording to the inrese in the boiling point of the individul hydrorbons. The exponentil orrel- Olive oil/ir, blood/ir, nd tissues/ir prtition oeffiients of the C5-C7 liphti hydrorbons. (Stndrd devition in prentheses) Solvents Oil Blood Liver Kidney Brin Ft Musle Hert Lung n-pentne (2-3) (.8) (-9) (-3) (5) (2-6) (.4) (.4) (.3) 2,2-Dimethylbutne O.5.6 (5-5) (.8) (1-1) (1-1) (.3) (4-) (.8) (.4) (.6) 2-Methylpentne (7.3) (-7) (1-1) (1-1) (-3) (7.) (.9) (.8) (-6) 3-Methylpentne (8-) (-7) (1-) (1-) (.4) (8-) (.8) (.8) (-6) n-hexne (6.9) (.8) (.7) (1-1) (.4) (1.) (-9) (-9) (-7) Methylylopentne (11-) (-8) (1-) (1-1) (-8) (1-) (.8) (.8) (-4) Cylohexne (11-) (- 1) (-9) (1-) (1-4) (1 1-) (-7) (1-) (- 1) 3-Methylhexne (24-) (.1) (1-1) (2.1) (1.6) (24-) (.7) (1-2) n-heptne (2.) (-1) (1-) (1-2) (2-1) (13-) (.6) (1.4) (.2) Br J Ind Med: first published s /oem on 1 Mrh Downloded from on 2 August 218 by guest. Proteted by

3 164 Perbellini, Brugnone, Crett, nd Mrnelli i -- l...iii!j Bloo/ ir prtition oeffiint 1- {x' -Fig2 Correltionbetweenhert/irndblood/ir 8,!_. -,- ---;.- tjr - oeffiients of CS-C7 liphti hydrorbons prtition In.I - 1, '. J.-~'~**_- -i; (1= n-pentne, 2 = 2,2-dimethylpentne, _,' --!.,!, '.!.^ S 1. 3 = 2-methylpentne, 4 = 3-methylpentne, 5 = n-hexne, X,,'*l J4.S-'t-'--S 't1! 6 = methylylopentne, 7 = ylohexne, 8 ',,.' L./ E 8 = 3-methylhexne, 9 = n-heptne). Hw. ', -~ f '";.tion : oeffiients between blood nd ir nd between 1Gf/,,..' /-, tissues s * 1 nd blood re importnt sine the former F t.o ' ṯi ' I! : regultes the uptke of blood nd the ltter the tis-. i ' sue distribution in the body. The blood solubility of.d.l,ithe. hydrorbons whih re studied ws low, rng f, Al ; ing between -38 (pentne) nd 1-9 (n-heptne), B' II.; - inditing tht their respirtory bsorption is lso low. The lveolr retention of n-hexne nd its Iv isomers hs been found experimentlly, in workers, to be between 15% nd 2% nd tht of ylohexne nd its isomer, 2-9% nd 15-4% 2,>S,*^8 <(S respetively Fig 1 Blood nd tissuelir prtition oeffiients ofliphti hydrorbons (C5-C7), (A = pentne, B = 2,2-dimethylbutne, C = 2-methylpentne, D = 3-methylpentne, E = n-hexne, / F= Methylylopentne, G = ylohexne, H = 3-methylhexne, I = n-heptne). 8 C tion of the solubility of eh solvent in the olive oil./ nd blood nd its boiling points is shown in fig 9 (r = nd -93). The solubility of the solvents in?l A= blood, olive oil, nd in the tissues ws lso orre- (Q lted with their moleulr weights, but in liner 2I Y=1.4x+.2 fshion (fig 1). ' ') R= 9152 Signifint orreltions between the prtition p<. oeffiients of the solvents nd their melting points nd their densities ws not found. 1 2 Disusson Blood/ir prtition oeffiient For mny biologilly tive ompounds, the prti- Fig 3 Correltion between lunglir nd bloodlir prtition oeffiients of CS-C7 liphti hydrorbons. Br J Ind Med: first published s /oem on 1 Mrh Downloded from on 2 August 218 by guest. Proteted by

4 Prtition oeffiients of some industril liphti hydrorbons (C5-C7) in blood nd humn tissues 165 (!YF' Y= 5.6X.2 R = 928 p<. 1 2 Blood/ir prtition oeffiient Fig 4 Correltion between liverlir nd bloodlir prtition oeffiients of C5-C7 liphti hydrorbons. The tissue solubility of the hydrorbons ws lwys higher thn in blood, for ny tissues studied. With the exeption of ft solubility whih ws times tht of blood, the solubility in other tissues ws, on verge, between 1-4 nd 7-6 times the blood solubility. The lowest tissue/blood prtition oeffiient ws found for lung tissue (1-4 rnge ) nd the highest ws for musle (7.6, rnge ). Eger reported tht the tissue solubility of inhled nesthetis rnged between one nd four times the solubility in blood, exept for ft solubility.' It is interesting to note tht kidney/blood, musle/blood, liver/blood, nd brin/blood prtition 1 Blood/ir prtition oeffiient Y = 5.2X - -2 R=.9714 p<1 Fig 5 Correltion between kidney/ir nd blood/ir prtition oeffiients of CS-C7 liphti hydrorbons. t 6- u ạ. Y=6-5X..9 R=.9697 p< Blood/ir prtition oeftiient Fig 6 Correltion between brinlir nd blood/ir prtiton oeffiients of C5-C7 liphti hydrorbons. oeffiients (figs 4-7) were similr for ll the hydrorbons onsidered individully. These findings refute the ommon belief tht industril solvents use neurotoxi effets beuse the nervous system ontins high mount of lipids whih they n esily dissolve nd umulte. Our dt show tht whtever the ontent of lipids in the nervous system (lipoproteins nd sphingomyelins minly), the solubility of liphti hydrorbons in brin tissue is no higher thn tht in musle, liver, or kidney tissue. This result is in ordne with other dt whih show tht the solubility of trihloroethylene nd - : U 8.Y 4, Utl L. 2 Blood/ir prtition oeffiient Y=7.6X- 7 R= 9668 p<1 Fig 7 Correltion between musle/ir nd blood/ir prtition oeffiients of CS-C7 lipht hydrorbons. 2 Br J Ind Med: first published s /oem on 1 Mrh Downloded from on 2 August 218 by guest. Proteted by

5 .A 3 I. 2 S._ - 1' CLL Y= 25X -8.7 R = P<.1 Blood/ir prtition oeffiient Fig 8 Correltion between ftlir nd bloodlir prtition oeffiients of C5-C7 liphti hydrorbons C3. Y= 12.leO 362X R= ~ ~ ~ ~ 1, I 5 1 Boiling point Perbellini, Brugnone, Crett, nd Mrnelli other nesthetis in the brin is similr to tht in the other tissues.' 2 Our study hs lso shown tht the solubility of some hydrorbons in blood nd in olive oil ws diretly orrelted with their boiling points ording to n exponentil urve (fig 9). A liner orreltion ws found between solubility nd moleulr weight (fig 1). We hve lso exmined dt on the solubility of romti hydrorbons, ketones, nd hlorinted hydrorbons in wter, blood, nd olive oil reported by Sto nd Nkjim.4' By ontrst with these uthors, we found good orreltion between the solubility of hydrorbons in olive oil nd their boiling points. Figure 11 shows the exponentil orreltion between the boiling points nd the solubility in olive oil for the hydrorbons studied by us nd for those studied by Sto nd Nkjim.45 With the exeption of the ketones n exponentil orreltion.t 4) 4, U _ Y=.8eO 3O8X R = 938 p<.1 I 1 5 Boiling point Fig 9 Correltion between olivelir nd bloodlir prtition oeffiients nd boiling point of C5-C7 liphti hydrorbons Y= 13.8X+77-1 R=.811 p<(= Blood /ir prtition oeffiient Olive oil /ir prtition oeffiient Fig 1 Correltion between bloodlir nd olive oillir prtition oeffiients nd moleulr weights ofsolvents studied..e - ' ~ o ~~~~~~~~ 8 Y=.61 X.77.1 R=.8597 P<O Br J Ind Med: first published s /oem on 1 Mrh Downloded from on 2 August 218 by guest. Proteted by

6 Prtition oeffiients of some industril liphti hydrorbons (C5-C7) in blood nd humn tissues 167 MP 1: harodti hydrorbon o Aliphti hydrorbon * Chlorinted hydrorbon I* Ketones This work ws in prt supported by the Itlin Ntionl Reserh Counil (CNR): finlised projet on preventive nd rehbiltive mediine, subprojet SP5, "Toxiologil Risk," grnt No Requests for reprints to: Dr Luigi Perbellini, Istituto di Mediin del Lvoro, Polilinio Borgo Rom, Veron, Itly. Referenes o 1. * * 'Eger El. Anestheti uptke nd tion. Bltimore: Willims nd Wilkins, Stewrt A, Alliot PR, Cowles AL, Mpleson WW. Solubility oeffiients for inhled nesthetis for wter, oil nd biologil medi. Br J Anesth 1973;45: * 3Morgn A, Blk A, Belher DR. The-exretion of breth of * some liphti hlogented hydrorbons following dministrtion by inhltion. Ann Oup Hyg 197; 15: Y= 12.2eO423X Sto A, Nkjim T. Prtition oeffiients of some rdmti hyd- R=.8449 rorbons nd ketones in wter, blood, nd oil. Br J Ind Med p<o1 1979;36: (n-48) 5Sto A, Nkjim T. A struture-tivity reltionship of some hlorinted hydrorbons. Arh Environ Helth 1979;2: Sherwood RJ. Ostwld solubility oeffiients of some industrilly importnt substnes. Br J Ind Med 1976;33:16-7. Vn Rees H. The prtition oeffiients of styrene between blood tl nd ir nd between oil nd blood. Int Arh Arbeitsmed ;33: Boiling poin 8 Brugnone F, Perbeilini L, Grigolini L, Apostoli A. Solvent Fig 11 Correltion between olive oillir prtition exposure in shoe upper ftory. I. n-hexne nd etone oeffiients nd boiling points ofdi'ifferent solvents onentrtion in lveolr nd environmentl ir nd in blood. (liphti hydrorbons: our dt, kfferentoindustrilmsolent Int Arh Oup Environ Helth 1978;42: I; ketones, romi nd 9 Perbellini L, Brugnone F, Grigolini L, Cunegtti P, Toni A. hlorinted hydrorbons: dt o) fsto nd Nkjim).5 Alveolr ir nd blood dihloromethne onentrtion in shoe sole ftory workers. Int Arh Oup Environ Helth ws found between blood ssolubility (Y) of the 1977;4& romti, liphti, nd hlorinted hydrorbons ' Brugnone F, Perbellini L, Gffuri E, Apostoli P. Biomonitoring nd their boiling points (X) () Y = x e 3 Arh of industril Oup Environ solvent Helth exposures 198;47: in workers' lveolr ir. Int r = -59; n = 39; p < -1) Br J Ind Med: first published s /oem on 1 Mrh Downloded from on 2 August 218 by guest. Proteted by