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Cll C12[CAS N0. 75-09-2]

!j, !; j;E 50 ppm (170 mg/, 3): ::;!C ' i 1 ;i lOO PPm (340 nig/m')

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, ,#nn?! 3, > (DCM) 1, :, 5i. +lit 84.94, i;!!. - 96.8 C ,i!1!, 39.8 C , ; ;it!;E440 mmHg (25 C ), 5i. B, { !;t 1.25(log P, .,) @>. fi;jfttjt!T;'C':r. ' / -i, ;j; !; @>* fg. i 1! ti:tan3 : L*,'4'v. 7j<: , , p! 3 j4:tr':{*'c'35 ;s . t! *, 1- ;ilRltmi; ftl, 1;tll i;titi. i, 7 * -A !2 i im;Ei !; 11, 7 { ), A 1!f it 1, , , ittj ;0>tlljll!j; ;jj, .Z. 7 D V', Vh!:5;' ;;!={ 1jl *1. Z, . {!:m! !:: 1075 F > nt{ 'C', :5;iit7!t ;t t .!. !ttl' *'L, g, *< 3* />1!j!*;i J#! L t*V*.2 1!&4i! i;FiU:50 ~ 200 ppm7.511#!"11 7*1!;!t;;t1* 60 ~ 70 %7i*1 qi! *'L, llLjj;:rl, j j jg: ;:ll :jWt51Zjftj!=j ';' ,>,. $ L!elay*t%:'C'!,:, 30 6i'i !. lT, $it @> DCM i&!;t75{fit;lc l= t ,g,. 1! , 1;*:-T j O ntni rl" DCM @>3j:j i!" 1t 40 5j. i;!1:,,, 1jjWjrj" 1= j!.

lr L7!: DCM l*ff:* !=ltt ;irt'1. *$t - ,. 1740 mg/m'(500 ppm) 0>* 11*, 1"11 ,%:ti'!d:, {{:;!fliE , 0- :{bt !: A . n E' > 7!**jjj;j. L t: * iV ;j . - * A , e y o i, >(COHb) L, , ivl* t:li$:lUiiMlin L;; li' 6 .3. {'t;!t

DCM@>{ ;!tl=ld:, cytochrome P-450 2El (CYP2El)l= J: b ii;:{L;!;i'L. dichloromethanol, formyl chloride Orj. jiar{t;!iPE! ,:i t-i {bbt , .a {i: ; ; z, * ,l(CYP pathway) !: glutathione S-transferase Tl-l(GST Tl-1) != J: b 7 " 'f' * > +a ' *'L S-chloromethyl glutathione, formaldehyde, formic acidOO> 4. 1!1j{ ;!fi!E! ! $ 'C =, {bt 1. { t *L ,{ B3

(GST pathway) 7!, t,>.>,. CYP pathway !*?*X, v } , i= F !: , !. j j 1;!1 ,;;1=*slf, 6 3={ 1i tiiti'd5 1) ,u } ld:, 200~ 1000 ppm" , :it:!t, 500 ppm *l!!;E "t:'t;9*U : ,. F1!;3t! :t '@>50, 100, 150, 200 ppm DCM7.5 11*:1"11 fii;i O COHb i 19:!d:, 19 %, 3.4 % , 5.3 %,6.8 %t:'d5 b , lOO ppm rl. * !1 0; 'f"i@>i iiff'C'!t COHbld: 5 % :'4!3 . *: v ..

- ', GST pathway !d: ii! 1;El ,!$C'{ J LIJi , ii, ti:f!&:;.:**e!,,>1. Reitz et al. " iJ:, P344 v F, B6C3F 7,> x , SG A A x 3'' - , !1ii; #E L. " \+:f;;ti" ig\ !: ;:: o t:f!!'iit AO\ iliji*. , cytosolic fraction $! 5i'AL LDCM ' ir!1 ; . t GST i i, ; 4;!' il! ii: L t: * i !! , Vmax(nmol product formed / min /mg protein) @>li;t:*:tlEii:fi 1*, ? '> X, :? v } , /\A x , -, ic } olllitl=,118.2, ;ij'jj: ;jj , 'j'$j:7j< , 6.04 ~ 7.05 (2 jO range)C'tt>0/::. :4/::, 7, >X ;> y F, /\AX '-. 1= F@>ljl. *s J: OSlliji $:. m v . i:: in "tt, 0 @:i'@> DCM !iit, 1;{ ;41i4;1 '$'

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il!ll:;i> L i!:*!i!1 'C'ld:, GST pathway iiS""E1, : ? * 7!. i5t '1 l. jSjv. . ? t, X !: tLi!X ~.g, !: E F @>ft;!;i9;1;:1* F+ 1=i!E< , Reitz et al. " , Bogaards et al. " , Graves et al. "

@>*i !!i : ';t, *?. t 'i:: 39 jO E l* "T GST pathway !it <{ ;!iii;li!5 i : : !: &> .6 !:, t ?< !gg . Lt: j7? , ? ,>x J: b -tjj, 1* < :> v l* @> i!!tt @>* 7 ;1cd5 0 t: ";::*s, A GSTTl : t{ 'f',<ti!@> il'Ei'lt, d. 1 1/\ 64.4 %(n = 45), ;d!1 1A 60.2% (n = 103), 7 7 U 7b, ;i ?Kt; lA(n = 119) 21.8%, ,L <1:1A 20.4% (n = 442), ?!

, - :.,. *1 j lA 9.7% (n = 73) 't;d5 b " , GSTTl"!t{ +' .

!;!!: DCM {t;!t@> phenotype l, :-! :.;'.>, "4. 1= 1. ; . t4:1 4!!; !.. 1";1 , 1 @> g, 1 * !t"1"1 *ilij !=*t ' Zil a 1 1l t; ,Z,. 1!i!ttl a1 !*, 100~ 300 ppm, 2.000 ppm 305i'!;!.L. 0>1 j . c!,:i , t;6, , &5 : \* :!f@>!j g:! B*4 4}:, 7.000 ~ 10,000 ppm 'C'1*1!Um:@> UOt*t. . 20.000 ppm't;1, ; 30 5i. 'Ci 1;!E*4!t !. ;::,g,. DCM o>t 'ilB. fitl;E l= ,a li'Z, fi *U; ;$itlE!*i i < , ;!;$ t::T<+5i';*:4ki 'C'!* 1!. t E# 1;E l-:i$; " .>,. si ' > 5' 4 7 1= J: ; ,;1e. ' 1! , ! g t l*,

200 ppm 1.5 ~ 3 1!lW"1!!& ;;'C'i i :7J@>{ T, 300 ppm 955i'lU ,%:'C';pl!* ;j '\0> !, 700 ppm l" nffl! i 'C'*11t:t; t!:{t* 1111:6'J t!!$; *LC , *; 2i.5, 1= } ! :i;ll ,%:!= J:; , j! %!1 (g6ij*A. ., , i!tj :E. i!t'1:Ed:' < )

Ott et al. " !*, DCM ll;;jg: '3i :, 5' { 7 266 :tj (! t":*: 61%) }: * ' :t \;: 251 :t!i ( iil!43 55%) @>nn. fi;it: :i ' ' t o i::. DCM @> 8 1i !lllj\j 5jZ:1:jl&*,%j j;g 1, :, 11 43 7b*

*b60 ppm, 162:;d75*140 ppm, 65:t57!t475 ppm, 284 t280 ppm 'C'35 0 ;t:. i 1 1\53'*1f'C' DCM 1 ,!;7!t; ' ;!=t* o i!:j :E;: iEllt, ;* lL. $R;i ;!;tl 1 , COHb, * 1<' U iLl, ' >, ASTtd50 it:. * :1, U iP !, >t. ${-it, 41$1:1!: Lt {>, jlUA !: Lt {>, ll @>lfl;4tE;1 ;*. i ;im }: @>j j 7!*;:: < ::; *, <1!a t:'d5 0 /::. : /::, ,L*i; ,!g. t%tE@> > ,ll:,i5:i i'tr 24 :i5 0> 60~ 475 ppm O DCM i;;!5:!: 2645 @> i !A;@> 24 11 11U, C. il! 1 ' @:.= ' - L t:. L :'1 ! 3+"X , ,L* $, 1!L!!!3, +ili{*i , ST 3 E{1:1d:&!!;; *'L *: **o t:.Soden" iJ:, J=3i: !: tiq -4j$j3j'C' !O fF!;!L DCM l=1!! ,;;L, 8 1 1ru ifi;3pt 11! ?4i&1;$ 475 ppm 0> 150 4;i@>{ ;* ',;!s J: Ot, *J::;gi; i n , Jl!J!a6 !=*E1 L t:, i! U =. x 5. iPx

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L i:: jl%ll lO ,Fi;LL. 0{ 'i,j' 260 :Ei $! a 7 F n - ),\}: L'C, i*j 1;Xj tjtj , ,L*f j . . j ;, llj*1 f fiEt ,1:, l! :;b; , i:, 26g;iB @>nniii} :{E *, s J: U, ; t mj $!. ! ti! L i!:*i ;!!, Pi\\ 1 1= : 1t :7!. 0 t:.Lash et al. " ' lit, 1758450>i!!!i! t:!;:j;t' , "it2;:131@>ti3 *; 1,L @> *-/*-* - i1, { $ !. 6 fFi J:f;tl!1, 1, , ;i3 !: !1"!t{F;* t5y j225 ppm, F ll;ftf $ t5F jlOO ppm O> DCM l. lU , 1; Ltfy*/:: flliT (fit?ci&

i, : 826 ppm) 25 4 !: , :fij;&i; lll ,%0>! : A !:ti!!75, o/::{'1: : ' 21 :ti E:. ;7 > yA l=i:31ig L i::. WAIS, Beck ;io !1, ! , 1:jE! :jm \H ;, *llli Ol t ; jkjU: ;,7J , P300 !!Fg\1 !;fltft, 1!;!itl!4li , f!, lt, EEG, i, lli; j, *JJJt ,i:, ,L* !t :fi: !' ! imi L /::* !1-, ilil W" !. '

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6 W ft, / B , 5 B /;E1, 2 &FIMl!!*t; 1 @>\1'1=** '*~;4, NOAELIJ: 250 ppm""', 7 ,> X tj'jd: 90 B lla, 75 ppm l ,%:t:'l!i:!lli!liii ilEl, ln':iEft! 'iJn;5t t!!% f$ *, Lc v . ,d, 13i.7. ,1:Et;\*:!1:4!$i!tKelly'"' 1*, d. tlZtl i;;;iatfiEl ;gtGreater CincinnatiOccupational Health Center l=;jel$i; L ;!:t61-T. i;! 34 i3O DCM l t!$f ;! "4:' aa:b: L. /::. 8 :ii (fF 20 ~ 47 h; ,t t !9 !an 0.4 ~ 2.9 fp) 75t*!i!j , *j'j!j;L{*, fitr: :1;!;iti !.

1; ;. t:. 8 :i5 1* DCM @>Xo t=/<45- v 1=:;3' . i li', DCM .. 7' >!.+ v # i !jfy!li 1;6H t=*i b *. if. t ;*:'{ @> t@>5! imi . C b li:: !=t 41LtL. i!:. F19g 9 ' 6 A@>1 t * . T7!. ,; lim : 'C'@>U W"*s J: Zl* COHb 1*:, 4i- * , 24 " l!fi 5.6%, 161 M 6.4%, 16R*rui 5.1%, 811;:\a 1.2%,90 11#1!8 1.2 %, 4 U fta ll. 0 %'C'3> 0 it:. *!ii!:i jqX!. i 7iL t: 4 :7i@>*i! -!;k!,:, l ml;t5 /:: b 200 7i~ 2.600 751 !: i;,:*. 1=id;,!, L, il!oni*ft+; !,: 2.000 7ilm !T, *il . iij;?!\: f>jej**0 ;t:. C 0 4 i5 1=0 v. t !;t, !E! !; 4i:0 !EtE 4. ii 1* : < E%A ;@> 3 A@> 'j *5 2 Al= 1, :DCM ll! , 1;{'F iitr 1=+{ 7!'2E : *'L, ll t!$!!ff W, 2.9 fjZ@> j : j!,:, 4 1;E O l :fE 7:' V. ' ' *'L f) * iT- ;k ii co!i1!2 75* > tj: v * .NIOSH i5< ' @> f !C ;t*i i!115i ; ' tf o i:: *tj!j , DCM sjZj j68 ppm (range 3.3~ 154.4) 'C't4, o t: ;*: *Rt '1* ,DCM lc*ft $!$, **i7,.d, c !: .;j L t\*.*, *t *ijij; 4iE4i: " COHb !, ,< )1, (*15i !U1 13 U ) t: !:'7!* i;, 4!1t8i';' .d, !: ,NIOSH @>iftlii { !d:; , 1*!= {:mij$ ltt\. t5 !: *118j ~, , O*t-2t-;! t:';t) 6 .NTP" ' @> DCM **A, 9 Si:t;'lt , fitl;elt;1!U 1 0 35 . ,?*;<.**!it2 i (contr01 0%, 2.000 ppm 8%, 4.000ppm 62% ) !: 9 !!t7;;;;ff (contr01 12% , 2.000 ppm60%, 4,000 ppm 74 %) 7!tt!t:;; *Li:,Nitschke et al. " ' 1*, "tt!t30 1!E@> F344 v F (F )l=, 0, 100, 500, 1500 ppm DCM :'6 h/d, 5d/w, 14;Ul;U1! 3;$ L , ; :1 j; .it', F, ' . t i::. F @>"tt!t v } 30!!E; i > yA !=i:9tR L, 17;UllB DCM lg!t L,

'2 :'t '::. 1 :*ii , 1, '0>*f '{ X !: ! {E:, ! . :; : ;,- ;oj !=ov*. c;d:* 1;4i 1!, , B j ?j; :. ffo t:. \i !: L

t@> F, , F, , {7 !: LCO F, , F, !: {>!=3i! 'i7i;j. i3:;*: < ,l. 500 ppm !! i;; t:'!* F344 v F IC, E;j!fl !i7j;i!. 1*:,2:*7j*0 "".8. ;i75t, 4. ,. 8.1 .*- rj, f Ott et al. "', Lanes et a1. "+t@> . *- F l, f37t:'1;t, &P $ *ny4 i :;::t "U75, 4 , V. /;: *ttv. i::jl, j j .; *tA, 7j* tqg;$! M@> !: !: j, 1. ,;jj. :, **jj gF ue v*/:. Hearne et al. " ' ***Rf . L t: =ry .? ' *t@> =7 *- } 1Jf? t:'!3;, ti9; !5;,!, 1\75tA, 1=: ; ti:J "n**i . i *'Lt:7!' &!t3;$i!fffo, @>&!E !: !: *, 1. ; 1 ' *tj ;t: L C \*t:, i;!_b@> 2 0@>*R{ . t!'lt, 4 ;iU11150 8 !=

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l! 28i;*t:' t. !*tA, ' ' 'Cl i E:1 fftl t; !;*t ' i**A, @>-i :; tWm*'e \ *.d,. : i::, jjj. ::1 *tA, *EC!;k!= !d:, 4i'; :z:'id: t: v .*tli: ~ 1;:li;1!q{ :bS!-. , *'Lt: }: LtV*.d . L*. L, ; 1 1t,=. f'L l;, @>* !j iJ:t611 1 fi LtV. ,{n@>{1: e4t j!=1 !' ;5 0>tld;::V. 7!' !: L'CV* Z, .Shannon et al. " ' jd:, fjj .j:g! jj :Ettgj!k$L7!tA, +! ;ti b'A, 7fy'mJ11;9111ffOi;*V .i 'C'Oi !13 !1:, ,;i :; tWm !t!!:;$ L, Blajr et al. ""' jtajjg7j ;%:jj :Et$L*tA, 0>:jj' :ti:t "n . t!; ; U<,*: , j, @>@> (n = 4, 95 % CT 10 ~ 8.8),DCM !;\;F@> 7jtA, . 7j* ! 8 *'Lt ,*.d t;,!j0> 4 j @> ;a ( F U ' D D Z. + P 7, :j<1 0*jj!*ii 1 ) 7, t :, b ,DCM != J: . , u ;!.

, t m7, * !:.;j *. i*:4<!!q'@3:,.4,.Tomenson et aj. " ' 0>*&jjj, .c'j, :, SF11! 3 i!!El;E 19 ppmt, i5tA, @>j !#E',!tftg;;$ *'L ', t!!1;*;{;*it1 , 8;i!i: (> 800 ppm-years) <i' {>i 1!! Ei=1* :*. o it:. Ott et al. " ' 0>*Rj . tlg:, ll! , j;j!!$1;E@> Bi ltti:fy * , @>@>, ii ,;;5j. ij, 1!! , S ;!: ; !!7Ei=i= 1 !j*E,.! *L;;: *. o i::.8.2 ;iE 1*1 !!1Jf3 Heineman et al. " ' j*;, jjj !j:;}:*jli ljjjj=ov. t@> U ;!.;!, ,$:. i18, <, 1!Ut;3{1:t!f ; DCM, } U :>' . u ..:.+ u > ,5" } :>' D P .:.+ U :, 1!!*31;1*: U >!. ' *{i!> .d, L C ,..Z,,Cantor et aj. " ' jt, $L7j*A, !: 0>j!!jj!!*t;j 1 *'L. , f> O!: Lt, 7. + P :,, DCM, 1!g:!;E{b :;!:, *=i, A 7 )P. 7"l, }', &ft:fl!@> ii;7!:{1:!io, i; X F !;! !i*t, *Z, . L**L , iitiWf3E !: {> , 1!! ,%@>iiTi!E, 14: , i i : L, -,< i, 0>5 &7 i=7i* ii D ;:1 1 ' 7!* > 6 C !:, 1! 3 1, ,<JP !: ft! !!j !!: @>l!!li!E!= -. ' L 4, -j!t, :6* !. , *L v. . != . {j: ft , *,:: *

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' 4*igt: !: ,6 v } SDA * 4 JP X != J: 6 sialo-dacryoadenitis 7i*36!i; L'CV. /::.NTP" ' !,:, iljttjt B6C3F, v ,> X 4$?\ 50 1!E!= 0, 2.000,4.000 ppm, "tt!$ F344/N ' v F - \ 50 D 1= 0, 1,000,2.000, 4,000 ppm O DCM 102 iU 1!;!. 7*" 3S (6 hrs/day,5 days/'wk) .$1BtiiL;t:,v .> x t?!*, iltt!E!: t, !Clij ,Tl=*g,!=qgij= ,k ; s!$jjj@>* ;ia**i:$;;$' *Li::. 0, 2.000, 4.000 ppm ., 333g'Cftiifi . :fS' *tA, 03g ! 7!*tlEti' 2, 10, 28, ittt'C' 1/50,13, 29, fil'*ilfti!ii!1@ : t::1*1+;;mfiai!tA. 0;3!1=*t $'C' 22,24, 33, il*'t?3, 16, 40t:';*,-0t=. v l. t!d, 0, 1.000, 2,000, 4,000 ppm@>fi. 1! , 8:tl*'C, fiiio*!i! !1 @>t ;fy"i*iltdt *: {, i= t**. o i=. T'c!*,ius'C'M;;;* *;3 J: U'B+illa*tA, *{2, 1, 4, 5 !: =o, t ;lyUi@it611Cz!5 0 t:7!S tlE'C'1* 2, 3, 4, 1 'C';*, o t:. $Ll !l ,1!E$;s J: 0, *1$1;!Mib< t!lt:'0, 0, 2, 5, il"t:'5, ii,13, 23 !:1! i$ft l= i ; Ctt iin L t v*i!=. t:, $Ll ! ! Ol;ETO*la*lEM 13.' 1*11@1>att:'1, 1, 2, 5 !:t jjrrl, t v. i::. L :6* L R ltt i, El*!ld:tlt'C'1, : 1 i B> 3 t:.! '*',"t'C' B> * ;lyU L t V* ;:* 7!. 0 i::.i;!. LJ: b l{TP l*:, DCM @>33:5tA. 1!L *:., * F344/N y l~'C'some euide, ace ofe@rei"oge"eei$y, il*F344/N v F <i'c!e@r euidence of c@rcinogenecity, ltt;tlt B6C3F,? ,> X'C'c!e@r euidence of corcinogenecity !:*i $ihLCV*; ".

Nitschke et al. " ' 1;t, ";g$SD y l~lC0, 50, 200,500 ppmDCM $:

. 6"*'M/ B , 5 B 116/iU, 2, tj=R1@>!1 , 8

gi1 . 9 t"L7=. COHb i, :!i,*: { :a:itt!=_L -L, i 500 ppm!a"3 :1!\'C'ftF*llla , 11*500 ppm11 ,$:3 't l ;1+ *mff !@>** n, ;! 1 {1: it 0 :v*$Liaff"%;@>ttiln7i* ,o i:::6* 1 !*g3 E:; :t 1*m@:0g !E. !\;'G , o t:. C. @>* ;j *. , ll* "E SD v } @> DCM !!g: A ! 3$ 1= $is l* ; ,NOAEL 1*200 ppmt3iioi!:.National lnstitute of Environmental Health Sciences(NELHS) ld:, DCM != J: , fiih*a .k Ogll'*tA, @>\3:5tA. ?t* = >C A ,1:. ia '.8, B 'C', ill;{!E B6C3F, ? * X 1400l!E1= 2.000 ppm DCM , ' 6 "1:1!,/B , 5 B /iB, :1 31: 104 iB 11 ,$5g 1 '53t3 Lit:. ng!tav * X 0 24 7, }Bi @>ffF75tA. , ffib7!*A, Og : E!=ov. 'C!*, *1"l:! ' 75tlllg!1'*;E, J: bl V. i !!Et:'3 !m. L, , !ib**A, , 1+7jtA, gm t:!*:iJ, 46.3 %,51.5%t, * * !!? ,> X @>3 , 1;:; 6%, 16% J: b ;ti: ;!:jgj!\:t?;*, , j:: 28). "F7, tA, ogg j: ?! :b = ;<A o>-0 $: :jg. ., .G, *L , \;lB 0: *! @? *;i;i" !t , DCM1!;$39 !. J: b S-phase l. *S l* , DNA t;i. li!:i5*tr L , jd:,!> Lt: C !: 1= ,k bj!j;jj Bjt;*, b , DCM lt peroxisome proliferator l=j* :L ;:: , * C !: 75t;j !;g *'Lt= an'. "ih;:mft !@>* ;tilC O V. 'C l>! ;@{1$j!g b jJ:&$ *L;::75.0 *: 30). *tA. .j!!j . f. j. o,* c ia:, 1+i5tA, *lffgi@> H. ,@s ia:{ '}'. tig1!L{1:*s J: 0*"ih75<A,*mla@> K-r@s 7!, A, i!j{ 'j'. jjg, {b : {, j= = 7 F n- JP?,>x : !,:;:: < " ', p53 tumor suppressor gene O pointmutatiOn {> t :lB ' *'Ltb :6.0 7:: 32).8.4 1di!1*i;; . 4 - . 3m75*A, :Serota et ai. " . " ' @>DCMj; . j . 3!;j:t:'ld:, F344

v } , B6C3F, 't ,>' X ic*j' ', 3 7i{A, i;Ei*;!gtfit' :7!. 0 t, .9. iR{ T. 1;f :1:$S@!mo"e!!@ ipfoi", t, ,i"m, Esche, ichi" coli;;a@>; , {'R;;!tj , 13:{1;0>: * !=1 *> i *', 1 j *m '@1, ; DCM g ;, 3*'C' a ! ;i*; -! ' 75' , ,:b' ! ,a"E! i;t*' ' b ', i i l1E'C'85 1) , ")P , ., f' > ,a J: 0* GST t3, 1!El=ti: L, t v.. , 2).f*t$;*lUla!=OV. t ld:, iRf '1'. : ,;:!: ; (gene muta-tion assay, GM) <', M$L"ji!1*l;ar !=*t '4'. , Z<5 :;!lDNA i'il$ i\!;* (unscheduled DNA synthesis. TJDS) 1;tl; '1!EC850 t:. ln utt, 0 !=, S!* , j -+ ;::*M1 !03! ;{* 31.;:g9i: (chrom6somal aberration. CA) !,:, 1;3' 'C3>. , i5S*ih@*3; f 5i. f*; i; (SCE)i, :, 1; , 8i>; v. 1*\1; <ftE'ei*,.8,. Zn utuoO ;i C' CA, ,i. i ;;it!;;: (micronu-cleus test, MN), UDSO . < 1;tl i!Lt35 b , ie;iRl;!:ll iS;0, B6C3F, v ,> X ; 'i \ *i::;;;'C'@>; ., i; 1!31;!;'1;E* ! 7i'j 1G *'Lt, * , 2).Casanova et al. " ' 1, :, B6C3F ?,>X, SG/\AX '- !=, ll , R:Wrrtti11\'4.500 ppm, 6 R*'ll"i 1= 2.500 ppm @>"C. DCM :.!i% L , "C. * iv A 7 )V . '!= j?!: DNA ODNA-protein crosslink (DPX) !'i!! i: L7t:*i , 7*.7< Bl"C'0 Ll !1! U 7t:.Greves et ai. '. " . " ' !,:, DNA. single strand break(DNA. ss) !: DPX l. 0, .C-i !OIJf$ . LCv. , ,.CHO;;ll ll <' lt DNA-ss !: DPX l* DCM !: v ,> X iiFcytosol fraction <i'@> . DNA li; !;7bC; !E L, GST path-way i!*j!q, - L t \*. , C *:.;j<lg8 L 7t:. ,i= JL A 7 JV5" t,Ftili;!$ 1 . 1 ,*C * JP A 7 iL 5" 1= 1. , 1!: gultathioneta' '{*0)j ijj $:. 5j. 1;E , , !: , DPX IJ:lrti;! ii "" t:'ti, iE B$ it?!:75t DNA-ss lt33:9t L it:. ? , X ' gultathionelili lti' t&! :a!'$~, ' !: , DNA l! a;:@> 1, ,*:i!,*tT7i, o i!:. -*'L l;, @>*i !i 7l. 1;,, DPX l= ld: * ,, A 7 i, .7" 1= }?i5tj;$ !B- L ,DNA:ss != 1* glutathionet3, i .{**tj!U!$. L t ,* . ? ,x , :> v } Olf 1\a . DCM !: 4 >., t' z - } ' !:DNA-ss ;5, ;3:!;1'$'.8, 7it ? ,> X t;'lJ: DCM i!*1;E 0.4 mMt:"33 !1t . , @> !.*l L, v l* Ci'1* 30 mM . 'tit:, 6 . :r::, /\ A X :9' -ffF M <, 8 4;;@> != } M';iffl !i= 5~ 90mM @> DCM . i iillL'C t. , DNA-ss 13:3 1t L. :::\..Casanova et al. " ' lt, DPX !: RNA. 31sibA 7, V5" t,F{tlin{* (RFA) 3:. 5i. Rlt*li *lf1!ll1!'C'tb!! L/::. DPX

*lllll t@> Lj jf! *L, F344 :? v F ,SG /* A X - , 1: } if ll, t!'C'!*li 'ft! *'L ;6:. . 0 i::.RFA lti!t f ;i' GST7'1 , GS7'Mi 75t4<fft L t v. ;g:v*"jj!jl1'Cld:t tll *L, '0>t :ld:? 7 X 'C' v 1, @> 4 j , E: F@> 7f8' /* A X ' - 0 14j 'C'i*> o t: GS77'1 :GS7'MZ null O l= } 'C lt , RFA !ti:till; *'L ti:75* 0 i::.l= } lf lll tl, :, DCM 1!!3, 8al!* 1;!:ii*ti: lO. OOO ppm 'C' B,DPX l, :1$:111 *L'::*. o t:. Li5. L, * iVA 7 iv '*l= F@>i!i;, 1:1d: GSTTl ;tt f T'75, null'C';:: ,*1 b .{2 . ' C'1dt v*;5' :;,, 13:i8tfit@> DPX 75<m !E *'L ,'njj , !d: *j;j:iC, ta

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iltf g"i!$' @> 'Fm7!tllll %"!= ;,:.6,.l) ;6i5tA, itj{ -,=i\:, j:i. j ',*,:t:'1 : 'flftiARC" ' 1*:, \6*tA, ' , . 2B !: 1:m L t \*;i,. ipcs"l*, $6i *A, 3!:! :'C'm v . i i'L6 J: ;) ,:: ! ft !: '*'L J: b {i l lfljjt@>flifi 2: t ld:, CYP, GST @>f ;!ii;i;, 6@>ii ' 1. ,1<

i::ii *tdb , !: * j L , WHO j!i;1.1.1 !ijj$ 1;$ "" !,:, 1pCsexpert group O>*;i;i :':;;:;; L, E F $ i75tA, !t U X ? 7.{z X ?! > } 0> critical endpoint <i'! ;:: V. 2: ;:;i;iib L t \. ,*OSHA" i3:, 4it:; t19 n!i!. 1=0\. t!d;, Gibbs et a1.20'

@> *&'; '1=0 L .'C, jjj:iZ1 75*A, ,) x ' @>lMirU ld:lt - 1;eli 1!U{;;**tt> o t: C !: >*g' . , t: DCM @>1 i 1. "J ; j 'C ,

til*1, '.@)t * .,{ng@>*R '1. *s l*' ,

t!!3;f\17!t;:: ,\.=. !: 7!. i:> "suggestive rather than con-clusive" !:*;iii;iL, Heineman et al. "'' 0>*&j!j, j=ov\tl*:, fii ! .:li:*lllj8j, ft@> U X ' !=o v . t, lij;75. !=1!, t%:'fff*ft!=j %gz *a5 6 j= L 'c {i, c @>*&f .@>*i !1 7i{ !!!.! ' , R'c,lt;*: < Wtilit4;$ t: DCM l!! t%:0>1 !!!,:, ""strongly suggest a possible association" ;: 'Flmi Ltv. tZi. . @>{@0>4;8 ;:, %n ;L {>i$:: t L t , OSHA lt , ;!E, -*t\ i5tA, . 1=,!;5j nky :*R j! !=0 * .t !d\ *tA, ,1!E *:. 1 ,*'C' ;2,1 ;:'0>-j-

5j. ti:1 {U;li i* ;9: L. !: L , : t:, GS7'Tl @)j!"; 0>;1 3 !=o v*t 13:5;::5i!., S;:?;Ft t , {i O@:'ld:;:: V . !: L t, DCMjt "potential occupational carcinogen" !: Lt, *. ,. ' @> {gt:'1t , B 'f: E t;i! '\' !* $i$ 2 \ B"

,',U. S. EPA !t B2" ', ACGIH!d: A3""', DFG (* 3" ' !: \miLtv* ,.i!tf 'f' ! ' @):ii'1!En 3fjnn!=OV*t ld:, * ,, A 7 JV '1=l, E! hT E' 1t, GS7'7'1 i i{ 'i'7 t null'C';:: \. A'C'13+fn .c, !t tj: v .7!* i;, 38), ,jt j . r. j!ti; !g, E !: v * :. J: ,) .2) \ 7itA, ;itf +i!t'M:1. "U ' ,; fit finn

4; * '- ' *. , jj; 6r *Aj 0>$ j jh 1:mj ' , f *f1*ti: v .U. S. EPA" ' 1J: NTP"'' @> 36z5tA3! !; 'C'1& k> $!tfot;'C';3>

o t: B6C3F, ltt;, ? * >!. @> liti*s J: 0*1jTjit4!$ @> 5"- ' $:' m\*t U X ' :' f : L, !it {, ;*: V. ,) X #' '$t:1{1 L 7:: 1in-earized multistage (LMS) model !. J:. ,. z. = .y } V x? j*4. i x io ~ '. c;;>o t:. i:>!.. E F !: ?,> x@>{ ;4fi ;'1!L@>*Bi;E 'iill* L t: PB-PK model :. ilaifi U C + :

*'. , !:, 4.7 x lO ~ ' !: t;:0 ;t:. ;!k*;5, GST pathway i i!L!*? ,> x oli 71;{i!i!: L ti;1. *i: L 'Cv. 6 .ECEToc46) !*.. ?* ;!., j . y i. , ,\A7. -, \: i*O in uiuo *S ,k Cl'in uitro $1 S :'Ct , i'Li!: kinetic con-stant*3J:U'metabolic constant !mL* GST pathway

'C'! li: '$~ ; rl. 1&i { ;!t!1*1 3:' 1 1' \ i*t A, 4f1 ,t !: L tNTP" ' @>1 ;\36*tA, :!i!;i:0":? * ;!. @>5'*- ' (adeno-

ma/carcinoma) . ig v. t, pB. pK @:, 5**iV != J: b ;;j'm: '@>3g7btA, U X @>3j:m 3;:. j 0 /::. jf7!*A, + ffibbtA. 0>j; : !Eii ; u x i x i0- 4 : jt: jt i x i0- 6 !: -. , !:LMS model'Clit1!f 3;;ie!1;Ei!S 1.390 ppm :it:lt 80 ppm 'C';#> -, /:: .

Reitz et al. " 1, :, tjbj!EF344 v l*, B6C3F, 7 ,? X,

b j 6 !: : '. . i::*t 35 *

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SG AA X ' - , Pii ;:: !:!!. J: b ,El= L;t:1= F Olll' lliiO cytosolic fraction. microsomal fraction ' 5i'Wit LGST ii '1!E, cytochrom P450 j! i!! \;! i 1 ;1$; :. jjlj5j: L ,t , *L;t:*;i *a J: 0*: :Mk{itt $il v. t PB-PK modell. ,J

.Z U ;!. Flit i :'tTo i!:. LMS mode17i*{i f>:}c ;:: U 7.# :. ii L , 50 ppm DCM 11 ;! 'kkll;!,;;ll3:@> U X # 1* ,!. 8 x i0 ~ 5 .@jtjo i::.Casanova et ai. " ' id: e F jT llja. co> 1 !! *;j;1 75* ,,

GS7'Ti : t j +75t36 1!'4'. , A 011' DPX 3t ;tl= *d' L DCM

IO ppm, 30 ppm. lOO ppm l!; , S1=, 51f;!i ,!:i!E U X 'it,LMS model{ i iLl t 75' '*'L. '*'L 9 x j0 ~ '. 3 xi0 ~ ', 2 x lO ~ ", Benchmark method t!*, 9 x i0 ~ 6,3 x iO ~ ', i x io ~' !:j;f :Lt, *;* .OSHA" !*, DCM l, :i 1!En i::iER; :1! i%!;t!;t'C0>3675'A, !1 jj (potential occupational carcinogen) t:'!*>Z, !:Lt, ltti4*1'7'- , ::i;1 1=3

3**A, :5*i 0> i* ,: '@>f ;E' :1 B 1!: L, Permissible exposure limits (PEL) !:L t 25 ppm ' ! ;ii* L 7::. $f:;;'1= 1*, ! i (NTP 0'7'> X @>ftiblit4g5"- ') ;b. 1 A, '\0>;,}jty!= PB-PK .E 5" JP

'ilt \'t +$i: L t:* ;1 , ;;!;;j i!Bt!, 'ii@ Lt: 25 ppm @>1 ;!:1! 3 :1* 1.000 A@>9tfm;;k'1=* Lt 3.62 A@> Bi= U X '*'d56 !:ik, fij , ,*Lt: (AOg\ ;Oj j!E7 t? * X J: D f v* . !: 3:. irn1 *:'f" 6, !: , 1.23/1000 t: ! $i:ii! $ *Li::) . . *L i O$*:ii;!=i9 5 !:, ,= *L 'C@> PEL 500ppm 'C'1t:, 1.000A i:: b 126 A El='C, 25 ppm t= ,>, = !:'Z:'+5j't: UX 0 1jdjlCt: b , t:, 1 *3.1i !C economic analysis*'1;> !i. t "! t L, JVt!*, * 7.6/1000 ~ 126/LOOO ,) UX 7b*3 . j , : *'L, C. @>*1 ml:b*iigi *; *'L*'L1 !', 5p j U X 'lt, 1.7/1000 * !1;E !. :: Z, !: !.*it {> ,5 t'L;t=.3) 3 'fFi !;E@>1;!! ;!j;E, ;Lh lC IJ:; *, A, 0> Ej!Llt <+5j. ti'35:6 C !: , 1 1;, *.::*3gz5tA. , :;j * B6C3F, ? ,:, X !: A'C'1*, 3gij*A, @, j i:1 !: ;::;5; rj. j { ;!tPi !1 . i ": ~Z, GST { jj :!=/< ii*

:, b , B6C3F, , ',? X 'C' !1 *'Li:: *tA, .l= } 1=#*t4i . , C !: 1** .: !: :\'; . 1 *Lt:V. C !:, 1= F t'@>it{ 'i'*!i' 36 ! 1, : +: u !: j* v. ; .. ti: v. , @>0;3 g. != *~,*, j! j :1, : F,jtlCj6iV. C !: *. 1;,, 8i' i!EfE '; ; *'; 1=t t: o C13:36*7, tA, ' k:' critical endpoint }: ';~ . , C !: lt .;j. ; . ,< <L7b* L-75't'lt, DCM O>t !*U;;t;t:tB;ld: 440 mmHg !:} iv. /::&>!=, i! : 'cit' 1!. i 1 1 3%75, 4E 'Z, Tat;1:t75<t > b , .@>;1 t . lc l, : GS7'Ti "tj +7bt :tR L 'Cv.::v. j*i . 0"*{ +i , u x ,!,j; < ;:: , t:'35z; 5 .!;!1:. iJ, COHb :!= 3: , t, t *ty**; '\0% F :ktLl= L, , ittf '. itt3g U x ,s J: Ug\ 7!{A, ,) x # 75* Bj lC!! t . t .*ii 1;E !: L'C, 8t"t iRl;E 50 ppm, ?<3t' i!31;E IOO ppm ;'1 ' , .

;:,*:s, ; j lO t' :i!11 1;:1, :, 25 ppm: OSHA, 35 ppm:Sweden, Norway, 50 ppm: Australia, Canada,ACGTH, Belgium, Denmark, lOO ppm: Austria,Finland, France, Germany, The Netherlands,Switzerland, U. K, 'tt3>. ,.

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l) OSHA. Occupational exposure to methylene chloride;final rule. Federal Register V01.62. N0.7: 1494-619. U. S.Occupational Safety and Health Administraiion. 1997.

2) 1PCS. Environmental Health Criteria 164. Meihylene chlo.

ride. WHO. Geneva. 1996.3) Reitz RH. Mendrala AL. Park CN. Andersen ME.Guengerich FP. lncorporation of in vitro enzyme data

into the physiologically-based pharmacokinetic (PB-PK)model for methylene chloride: implications for risk

assessment. Toxicol Let 1998: 43: 97.116.

4) Boggards JJP. van Ommen B. van Bladeren PJ.lnterindividual difference in the in viiro conjugation of

merhylene chloride with glutathione by cytosolic glu-tathione S-transferase in 22 human liver samples.

Biochem Pharmac01 1993; 45: 2166-9.5) Graves Rj. Coutts C. Green T. Methylene chloride-induced DNA damage: an interspecies comparison.

Carcinogenesis 1995: 16: 1919-26.6) Nelson HH. Wiencke jK. Christiani DC. et al. Ethnic dif.

ferences in the prevalence of the homozygous deletedgenotype of glutathione S-transferase theta.Carcinogenesis 1995: 16: 1243-5.

7) Pemble S. Schroeder KR. Spencer SR. et al. Human glu-tathione S-transferase Theta (GSTTl): cDNA cloning andthe characterization of a genetic polymorphism. BiochemJ 1994; 300; 271-6.

8) 0tt MG. Skory LK. Holder HH, Bronson JM. Williams

PR. Health evaluation of employees occupationally

exposed to methylene chloride. Scand J Work EnvironHealth 1983: 9; suppl L 1-38

9) Soden KJ. An evaluation of chronic methy!ene chloride

exposure. J Occup Med 1993: 35: 282-6.IO) Lash AA. Becker CE. SO Y. Shore M. Neurotoxic effectsof methylene chloride: Are they long !asting in humans?

Brit J lnd Med 1991; 48: 418-26.ll) Merck lndex. 12th edition. (CD ROM version 12: 2),Chapman & Ha11. 1998.

12) Nitschke KD. Burek JD. Bell TJ. Kociba RJ. Rampy LW.MCKenna MJ. Methylene chloride: a 2-year inhalation

toxicity and oncogenicity study in rats. Fund Appl

Toxic01 1988: 11: 48-59.13) Kjellstrand P. Bjerkemo M. Adler-Maihofer M. Holmquist

B. Effects of methylene chloride on body and organweight and plasma butyrylcholinesierase activity in mice.Acta Pharmacol Toxicol (Copenh) 1986: 59: 73-9.

14) Kelly M. Case reports of individuals witli oligospermiaand methylene chloride exposure. Reproduct Toxicol1988; 2: j3-7.

15) NTP. Toxicology and carcinogenesis studies of

dichloromethane (methylene chloridej in F344/N rats and

B6C3F, mice (inhalation studies). NTP Technical reportseries N0. 306. U. S. DHHS 1986.

16) Nitschke KD. Eisenbrandt DL. Lomax LG. Rao KS.

Methylene chloride: Two-generation inhalation repro-

duction study' in rats. Fundam Appl Toxic01 1988; 11:60-7.

17) Lanes SF. Cohen A. Rothman Kj. Dreyer NA. Soden Kj.Mortality of cellulose fiber production workers. Scan JWork Bnviron Health 1990; 16: 247-51.

18) Lanes SF. Rothman KJ. Dreyer NA. Soden Kj. Mortaliiy

update of cellulose fiber production workers. Scand J

C)

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