Mutat10n Re5earch, 241 (1990) 261-271

261

E15ev1er MU76EN 01558

5a1m0ne11a muta9en1c1ty and r0dent carc1n09en1c1ty: Quant1tat1ve 5tructure-act1v1ty re1at10n5h1p5 8 e n j a m 1 n W. 81ake, K u r t En51e1n, V1jay K . 6 0 m 6 a r

and Har01d H. 80r95tedt

HD1, 183 Ea5t Ma1n 5treet, R0che5ter, N Y 14604 (U.5.A.)

(Rece1ved27 5eptem6er1989) (Rev1510nrece1ved2 January 1990) (Accepted15 January 1990) Keyw0rd5: 5AR; 5tructure-act1v1tyre1at10n5h1p5;5a1m0ne11aa55ay; Ame5te5t; D15cr1m1nantana1y515

5ummary 8a5ed 0n a c0mp11at10n 0f 222 rep0rt5 0f r0dent n0m1na1 11fet1me carc1n09en1c1ty 610a55ay5 6y the N C 1 / N 7 P 0n the 0ne hand, and c0rre5p0nd1n9 5a1m0ne11a muta9en1c1ty 610a55ay5 (Ame5 te5t5) 0n the 0ther, A5h6y and 7ennant (1988) have d1v1ded the carc1n09en5 and n0n-carc1n09en5 1nt0 9en0t0x1c (Ame5 te5t p051t1ve) and n0n-9en0t0x1c (Ame5 te5t ne9at1ve) 9r0up5 and d15cu55ed 5tructura1 character15t1c5 c0mm0n t0 each 0f the5e 9r0up5. 7he Ame5 te5t a10ne wa5 deemed t0 6e ade4uate f0r the 1dent1f1cat10n 0f 9en0t0x1c1ty 6ecau5e 0ther 5h0rt-term 610a55ay5, and even c0m61nat10n5, 0r 6atter1e5, appeared t0 0ffer n0 519n1f1cant advanta9e5. Fr0m the re5u1t5 0f th15 5tudy 1t 15 p055161e t0 ach1eve (1) a d1v1510n 0f the carc1n09en5 1nt0 the 5ame 9en0t0x1c and n0n-9en0t0x1c 9r0up5, and (2) a d1v1510n 0f the n0n-9en0t0x1c c0mp0und5 1nt0 the 5ame carc1n09en1c and n0n-carc1n09en1c 9r0up5, 501e1y 0n the 6a515 0f 5tructure-act1v1ty re1at10n5h1p5, w1th a c1a551f1cat10n accuracy 0f appr0x. 95%. (1) An e4uat10n c0mpr151n9 8 519ma m01ecu1ar char9e de5cr1pt0r5, 2 m01ecu1ar c0nnect1v1ty 1nd1ce5 (MC15), 2 kappa m01ecu1ar 5hape de5cr1pt0r5 and 0ne M 0 L 5 7 A C • 5u65tructure de5cr1pt0r ach1eved d15cr1m1nat10n 6etween 9en0t0x1c and n0n-9en0t0x1c carc1n09en5 w1th an accuracy 0f 94.5%. (2) An0ther e4uat10n c0mpr151n9 8 519ma m01ecu1ar char9e de5cr1pt0r5, 3 MC15, 0ne kappa 5hape de5cr1pt0r and 12 5u65tructura1 de5cr1pt0r5 ach1eved d15cr1m1nat10n 6etween n0n-9en0t0x1c carc1n09en5 and n0n-9en0t0x1c n0n-carc1n09en5 w1th an accuracy 0f 95.2%. 7he5e 5AR m0de15 are 5u1ta61e f0r the d15t1nct10n 6etween (1) 9en0t0x1c and n0n-9en0t0x1c carc1n09en5 and (2) carc1n09en1c and n0n-carc1n09en1c n0n-9en0t0x1n5, 60th 1n the a65ence 0f an1ma1 610a55ay data.

1. 1ntr0duct10n

A5h6y and 7ennant (1988) have c0mp11ed a 115t 0f 222 c0mp0und5 wh1ch had 6een te5ted f0r C0rre5p0ndence: Dr. Har01d H. 80r95tedt, HD1, 183 Ea5t Ma1n 5treet, R0che5ter, NY 14604 (U.5.A.), 7e1eph0ne (716) 546-1464.

r0dent CarC1n09en1C1ty 1n the Nat10na1 CanCer 1n5t1tute/Nat10na1 70x1c0109Y Pr09ram (NC1/ N7P). 7hey a150 ta6u1ated the c0rre5p0nd1n9 5a1m0ne11a h15t1d1ne rever510n muta9en1c1ty a55ay (Ame5 te5t) re5u1t5, a10n9 w1th re5u1t5 0f 0ther 5h0rt-term te5t5 0f 9en0t0x1c1ty. Ame5 te5t f1nd1n95 were u5ed t0 d15t1n9u15h 6etween 9en0t0x1c and n0n-9en0t0x1c carc1n09en5; the re5u1t5 0f the

0165-1218/90/$03.50 • 1990 E15ev1er5c1encePu6115her58.V. (810med1ca1D1v1510n)

262 0ther 5h0rt-term te5t5 d1d n0t c0ntr16ute mater1a11y t0 the d15t1nct10n; even c0m61nat10n5 0r 6atter1e5 0f te5t5 d1d n0t 1mpr0ve 1t. 7heref0re, 0n1y the Ame5 te5t re5u1t5 were u5ed 1n the pre5ent 5tudy. 7here were 116 carc1n09en5, w1th Ame5 te5t re5u1t5 115ted f0r 112 0f them. 0ne 9r0up 0f 65 carc1n09en5 wa5 def1ned a5 9en0t0x1c 6a5ed 0n p051t1ve Ame5 te5t re5u1t5; a 5ec0nd 9r0up 0f 47 carc1n09en5, the n0n-9en0t0x1c 0ne5, had ne9at1ve Ame5 te5t re5u1t5. 7here were 118 c0mp0und5 w1th ne9at1ve Ame5 te5t re5u1t5:47 were f0und t0 6e carc1n09en5 6y 610a55ay, 57 were n0n-carc1n09en5 and 14 had e4u1v0ca1 re5u1t5. 5tructure-act1v1ty re1at10n5h1p5 (5AR) fr0m d15cr1m1nant ana1y515 (DA) had prev10u51y 6een deve10ped f0r carc1n09en5 6y En51e1n et a1. (1987), and f0r muta9en5, 6a5ed 0n Ame5 te5t re5u1t5, 6y En51e1n et a1. (1986). 1t appeared rea50na61e t0 attempt t0 deve10p tw0 5eparate 5AR m0de15, 0ne t0 5eparate the 112 carc1n09en5 c0n51dered 6y A5h6y and 7ennant 1nt0 the 5ame 9en0t0x1c and n0n-9en0t0x1c 9r0up5 1dent1f1ed 6y the re5u1t5 0f the1r Ame5 te5t5, the 0ther 0ne t0 5eparate the 118 n0n-9en0t0x1c 5tructure5 1nt0 carc1n09en1c and n0n-carc1n09en1c 0ne5, a5 e5ta6115hed 6y NC1/ N7P 5tandard r0dent 610a55ay5. 80th e4uat10n5 were t0 6e 6a5ed 501e1y 0n 5tructura1 and phy51c0chem1ca1 parameter5 der1ved fr0m the data6a5e c0mp0und5, and n0t 0n the re5u1t5 0f actua1 610a55ay5.

7h15 paper ha5 tw0 5ect10n5: the f1r5t dea15 w1th the 5eparat10n 0f kn0wn carc1n09en5 1nt0 Ame5 te5t muta9en1c and Ame5 te5t n0n-muta9en1c 0ne5, and the 5ec0nd 5ect10n dea15 w1th the 5eparat10n 0f Ame5 n0n-muta9en1c 5tructure5 1nt0 carc1n09en1c and n0n-carc1n09en1c 0ne5. 2. Meth0d5 7he meth0d0109y f0r the deve10pment 0f the 5AR m0de15 15 c0mm0n f0r many 6101091ca1 endp01nt5, 1nc1ud1n9 the pre5ent 0ne5. 7he 9enera1 5chema 15 5ketched 1n F19. 1, each 5tep 15 then 6r1ef1y de5cr16ed 1n the c0ntext 0f the pre5ent 5tudy.

5tep 1. Data6a5e a55em61y 7he 5tructure5 and 6101091ca1 data 1n the5e 5tud1e5 were a11 taken fr0m A5h6y and 7ennant (1988). Certa1n mater1a15 115ted 6y A5h6y and 7ermant are n0t 5u1ta61e f0r m0de11n9 6ecau5e they are m1xture5, 1n0r9an1c, 0r 0r9an0meta111c, have n0 0r an e4u1v0ca1 a550c1ated 6101091ca1 endp01nt 0r the 610a55ay wa5 c0ntam1nated, 5uch a5 the carc1n09en1c1ty 610a55ay 0f tr1f1ura11n, 5ee L1j1n5ky(1988). 7he name5, CA5 num6er5 and 6101091ca1 f1nd1n95 f0r the c0mp0und5 actua11y u5ed 1n m0de11n9 are 115ted 1n 7a61e5 1 (102 muta9en1c and n0nmuta9en1c carc1n09en5) and 6 (93 n0n-muta9en1c carc1n09en5 and n0n-carc1n09en5) 1n the Re5u1t5 5ect10n.

57EP 1

A 5 5 E M 8 L Y 0f DA7A 8 A 5 E

57EP 2

6 E N E R A 7 1 0 N 0f P A R A M E 7 E R 5

57EP 3

51MPLE 57A71571C5

57EP 4

57EF~V15E R E 6 R E 5 5 1 0 N 0r 015CR1M1NAN7 ANALY515

57EP 5

1 1

1

1

ALL-P05518LE-5U85E75

RE6RE5510N

1

57EP 6

10EN71F1CA710N and REM0VAL 0f 1NFLUEN71AL 0 8 5 E R V A 7 1 0 N 5 and 0 U 7 L 1 E R 5

57EP 7

F1NAL 5 7 E P W 1 5 E R E 6 R E 5 5 1 0 N 0r D15CR1M1NAN7 ANALY515

57EP 8

VAL1DA710N

1

1

F19.1.5chemat1c0f 5AR m0de1deve10pment.

263

5tep 2. Parameter5 (5tructure de5cr1pt0r5) (A) M01ecu1ar c0nnect1v1ty 1nd1ce5 (MC15) are un1t1e55 de5cr1pt0r5 der1ved fr0m hydr09en-5uppre55ed 9raph5 0f m01ecu1e5, K1er and Ha11 (1986). 80th 51mp1e and va1ence-adju5ted MC15, a5 we11a5 the 5um5 0f and the d1fference5 am0n9 the 51mp1e and c0rre5p0nd1n9 va1ence-adju5ted MC15 were ca1cu1ated. 7he5e 1nd1ce5 4uant1fy d1fferent attr16ute5 0f m01ecu1ar 512e (Dearden, 1988), 5uch a5 num6er5 and type5 0f at0m5 and 60nd5, and de9ree 0f 6ranch1n9 and cyc11c1ty.

(8) Kappa 5hape md1ce5. 8a5ed 0n 60m6ar and Ja1n•5 (1987) exten510n 0f K1er•5 (1986) meth0d, kappa m01ecu1ar 5hape 1nd1ce5 0f 0rder5 1 thr0u9h 7 were 9enerated f0r the c0mp0und5. 7he5e t0p01091ca1 parameter5 4uant1fy the 5hape 0f m01ecu1e5 1n re1at10n t0 tw0 reference 5tructure5. 7hey have 6een f0und t0 6e c0rre1ated w1th a var1ety 0f phy51c0chem1ca1 pr0pert1e5. (C) Part1a1 at0m1c char9e5 (519ma) were ca1cu1ated acc0rd1n9 t0 the a190r1thm5 0f 6a5te19er and Mar5111 (1988). 7he5e char9e5 are u5efu1 t0 d15t1n9u15h am0n9 51m11ar 5u65tructura1 fra9ment5, 6a5ed 0n the1r e1ectr0n1c env1r0nment. 7w0 5et5 0f 519ma char9e de5cr1pt0r5 were 9enerated: 0ne 5et wh1ch c0n51der5 0n1y the 519ma char9e5 0f the n0n-hydr09en at0m5 1n the 5u65tructure5, and an0ther 0ne wh1ch 1nc1ude5 the char9e5 0n the hydr09en at0m5. (D) M015tac •

5u65tructura1 de5cr1pt0r5 (key5) de5cr16e 5u65tructure5 0f the c0mp0und5 1n the data6a5e. 7hey were 5e1ected fr0m a cata109 0f 0ver 2000 5u65tructure5 and 5tructure-der1ved parameter5. 0n1y key5 w1th a fre4uency 0f 0ccurrence e4ua1 t0 0r 9reater than 3 were u5ed 1n m0de1 deve10pment. Depend1n9 0n the1r d15tr16ut10n, the key5 were a5519ned va1ue5 0f un1ty 0r the actua1 key c0unt.

(E) M01ecu1ar we19ht5 were a150 u5ed. 5tep 3. 51mp1e 5tat15t1c5 51nce muta9en1c1ty and carc1n09en1c1ty are repre5ented 6y d1ch0t0m0u5 endp01nt5, 60th 11near

d15cr1m1nant ana1y515 and re9re5510n techn14ue5 were emp10yed t0 take advanta9e 0f the d1fferent d1a9n05t1c and p10tt1n9 pr09ram5 ava11a61e f0r the tw0 meth0d5. 51mp1e 5tat15t1c5 0n the parameter5 (1ndependent var1a61e5) were 06ta1ned t0 detect p0tent1a1 pr061em5 re1at1n9 t0 the d15tr16ut10n 0f the data and fre4uenc1e5 0f the parameter5. 1nfre4uent1y 0ccurr1n9 parameter5 were e1ther rem0ved 0r were c0m61ned w1th 0ther parameter5 de5cr161n9 51m11ar 5u65tructura1 feature5.

5tep 4. 5tepw15e re9re5510n and d15cr1m1nant ana1y515 A11 parameter5 wh1ch had a chance 0f c0ntr16ut1n9 t0 the exp1anat10n 0f the endp01nt were 91ven an 0pp0rtun1ty t0 enter the e4uat10n. Parameter5 w1th a c0rre1at10n 0f 9reater than 0.8 w1th an0ther parameter a1ready 1n the e4uat10n were rem0ved t0 av01d c0111near1ty pr061em5. When 5uch pa1r5 0f parameter5 were 1dent1f1ed, the 0ne w1th the 10wer part1a1 c0rre1at10n w1th the endp01nt wa5 de1eted. After the 115t 0f p0tent1a11y u5efu1 cand1date5 wa5 exhau5ted, parameter5 were rem0ved, 0ne at a t1me, 5tart1n9 w1th th05e wh1ch had c0ntr16uted 1ea5t t0 the exp1anat10n 0f the endp01nt, and c0nt1nu1n9 1n th15 fa5h10n unt11 the var1a61e w1th the 10we5t d15cr1m1nant p0wer 5t111 1nc1uded had an F-t0-rem0ve 0f 9reater than 1.7, C05tan2a and Af1f1 (1979).

5tep 5. A11-p055161e-5u65et5 re9re5510n After the 1n1t1a1 e4uat10n had 6een deve10ped 6y 5tepw15e re9re5510n and DA, 1t wa5 exam1ned f0r r06u5tne55, u51n9 the meth0d 0f a11-p055161e5u65et5 re9re5510n.

5tep 6. 1dent1f1cat10n and rem0va1 0f 1nf1uent1a1 065ervat10n5 and 0ut11er5 1nf1uent1a1 065ervat10n5 (c0mp0und5 w1th 1ar9e C00k•5 d15tance5) and 5tat15t1ca1 0ut11er5 (c0mp0und5 w1th 1ar9e re51dua15) may 6e the re5u1t 0f (1) 1nade4uate repre5entat10n 0f 5u65tructura1 feature5 6y the 1ndependent var1a61e5 0r (2) 5pec1f1c unc0mm0n mechan15m5 0f act10n 1nherent 1n the 5tructure5 1n 4ue5t10n. 065ervat10n-5en51t1ve parameter5 can a150 6e detected 1n th15 5tep 6y n0t1n9 1ar9e chan9e5 1n the

264

e4uat10n when 1nf1uent1a1 065ervat10n5 are rem0ved and the e4uat10n 15 reca1cu1ated. 0nce the 4ue5t10ned 065ervat10n5 a n d / 0 r parameter5 had 6een rem0ved, an0ther a11-p055161e-5u65et5 re9re5510n ana1y515wa5 perf0rmed. 7h15 5e4uence wa5 repeated unt11 the e4uat10n wa5 r06u5t.

5tep 7. F1na1 d15cr1m1nant ana1y515 A f1na1 DA wa5 perf0rmed, u51n9 the parameter5 1n the 1a5t a11-p055161e-5u65et5 re9re5510n e4uat10n, t0 pr0duce c1a551f1cat10n matr1ce5 1nd1cat1n9 the num6er 0f 065ervat10n5 c0rrect1y pred1cted 6y the f1na1 e4uat10n. 5tep 8. Va11dat10n 5nap1nn and Kn0ke (1985) have 5h0wn that err0r rate5 06ta1ned fr0m DA e4uat10n5 u51n9 the re5u65t1tut10n (jackkn1fe) meth0d, 1.e., e5t1mat1n9 err0r rate5 w1th 065ervat10n5 u5ed 1n the de519n 0f the e4uat10n, 15 e4u1va1ent t0 u51n9 1ndependent te5t 5amp1e5, a5 10n9 a5 (1) the c1a55e5 are 5uff1c1ent1y 5eparated, (2) the num6er 0f 065ervat10n5 15 1ar9e en0u9h, and (3) a n0-dec1510n 20ne 15 u5ed 6etween the 9r0up5. We have ch05en t0 repre5ent th15 20ne 6y the pr06a6111ty ran9e 0f 0.3-0.7, the 1ndeterm1nate ran9e. 7he re5u65t1tut10n meth0d 1nd1cate5 h0w we11 the e4uat10n exp1a1n5 the 065ervat10n5 u5ed 1n the deve10pment 0f a m0de1. 1n the cr055-va11dat10n meth0d, 065ervat10n5 are rem0ved, 0ne at a t1me, and the e4uat10n5 are reca1cu1ated each t1me 6a5ed 0n the rema1n1n9 065ervat10n5. 7he 065ervat10n5 wh1ch had 6een 1eft 0ut are then pred1cted. 7h15 meth0d 91ve5 an 1nd1cat10n 0f h0w weU the e4uat10n pred1ct5 065ervat10n5 n0t 1n the deve10pment 5et and 15, theref0re, preferred. 7he c1a551f1cat10n ta61e5 1n the Re5u1t5 5ect10n are 6a5ed 0n the cr055-va11dat10n meth0d. 3. Re5u1t5

3.1. 5eparat10n 0f muta9en1c and n0n-muta9en1c carc1n09en5 3.1.1. 7he data6a5e 10 c0mp0und5 had t0 6e rem0ved fr0m the 0r191na1 5et 0f 112 carc1n09en5 f0r the rea50n5

5tated 1n 5ect10n 2.1. 7a61e 1 115t5 the 102 c0mp0und5 actua11y u5ed 1n the deve10pment 0f the m0de1, t09ether w1th the1r c0rre5p0nd1n9 muta9en1c endp01nt5.

3.1.2. R06u5tne55 te5t1n9 Dur1n9 the te5t1n9 0f the r06u5tne55 0f the m0de1, 3 c0mp0und5 were rem0ved. 7he1r name5 and the rea50n5 f0r the1r rem0va1 are 5h0wn 1n 7a61e 2. An0ther a11-p055161e-5u65et5 re9re5510n ana1y515 wa5 perf0rmed 0n the rema1n1n9 99 c0mp0und5. Exam1nat10n f0r r06u5tne55 1nd1cated that there were ne1ther rema1n1n9 1nf1uent1a1 065ervat10n5, 5tat15t1ca1 0ut11er5, n0r p00r1y 6ehaved parameter5. 3.1.3. 7he f1na1 e4uat10n 7a61e 3 5h0w5 the parameter5 1n the f1na1 DA e4uat10n, 115ted 1n the1r 0rder 0f 1mp0rtance. 7he 519n 0f a c0eff1c1ent mu1t1p11ed 6y the 519n 0f 1t5 a550c1ated parameter 1nd1cate5 whether the parameter dr1ve5 the e5t1mate t0ward p051t1v1ty ( + ) 0r ne9at1v1ty ( - ) . 7he c0eff1c1ent5 are the va1ue5 0f the parameter5 06ta1ned fr0m the DA. 7he F-t0rem0ve va1ue5 1nd1cate the re1at1ve 1mp0rtance 0f the parameter5 1n the f1na1 DA e4uat10n. 3.1.4. E0a1uat10n 0f the d15cr1m1nant funct10n C0mp0und5 were c1a551f1ed a5 1ndeterm1nate when the pr06a6111ty 0f muta9en1c1ty wa5 ca1cu1ated t0 11e 6etween 0.3 and 0.7, 1.e., the pr06a6111t1e5 were t00 near t0 chance f0r a dec1510n t0 6e made a5 t0 p051t1v1ty 0r ne9at1v1ty. M15c1a551f1ed c0mp0und5 are th05e wh05e endp01nt5 have 6een 1nc0rrect1y pred1cted 6y the f1na1 DA e4uat10n, even th0u9h they had n0t 6een 1dent1f1ed a5 0ut11er5 dur1n9 the check5 f0r r06u5tne55 0f the m0de1. 0 f the 99 c0mp0und5 u5ed 1n the deve10pment 0f the f1na1 DA e4uat10n, the meth0d 0f cr055va11dat10n m15c1a551f1ed 5 c0mp0und5 and c1a551f1ed 8 a5 1ndeterm1nate5, a5 115ted 1n 7a61e 4. 0 f the 91 n0n-1ndeterm1nate c1a551f1cat10n5, 86 are c0rrect, y1e1d1n9 an accuracy 0f 94.5%. 7a61e 5 115t5 the m15c1a551f1ed and 1ndeterm1nate c0mp0und5 and the1r c0rre5p0nd1n9 5a1m0ne11a muta9en1c1ty endp01nt5.

265 7A8LE 1 (c0nt1nued)

7A8LE 1 CARC1N06EN1C C 0 M P 0 U N D 5 DA7A8A5E CA5 N0.

Name

Ame5 te5t

CA5 N0.

Name

muta9en1c1ty 57-06-7 A11y1150th10cyanate 75-56-9 1,2-Pr0py1ene 0x1de 82-28-0 1-Am1n0-2-methy1anthra4u1n0ne 90-94-8 M1ch1er•5 ket0ne 91-93-0

+ + + +

94-52-0 95-06-7 95-80-7

3,3 •-D1meth0xy6en21d1ne-4,4 •d1150cyanate 5(6)-N1tr06en21m1da201e 5u1fa11ate 2,4-D1am1n0t01uene

+ + + +

95-83-0 96-12-8 99-55-8 99-59-2

4-Ch10r0-0-pheny1ened1am1ne 1,2-D16r0m0-3-ch10r0pr0pane 5-N1tr0-0-t01u1d1ne 5-N1tr0-0-an151d1ne

+ + + +

muta9en1c1ty 1836-75-5 1955-45-9 2185-92-4 2243-62-1

N1tr0fen P1va101act0ne 2-81pheny1am1ne •HC1 1,5-Naphtha1ened1am1ne

+ + + +

2475-45-8 2784-94-3 2832-40-8 5131-60-2

C.1. D15per5e 81ue H.C. 81ue 1 C.1. D15per5e Ye110w 3 4-Ch10r0-m-pheny1ened1am1ne

+ + + +

5307-14-2 6109-97-3 6959-48-4 13552-44-8

2-N1tr0-p~pheny1ened1am1ne 3-Am1n0-9-ethy1ear6a201e- HC1 3-Ch10r0methy1pyr1d1ne•HC1 4,4•-Methy1ened1an111ne•2HC1

+ + + +

17026-81-2 39156-41-7 50-55-5 67-72-1

3-Am1n0-4-eth0xyacetan111de 2,4-D1am1n0an1501e5u1fate Re5erp1ne Hexach10r0ethane

+ +

101-80-4 4,4 •-0xyd1an111ne 102-50-1 m-Cre51d1ne 103-33-3 A206en2ene 105-11-3 p-8en204u1n0ne d10x1me

+ + + +

106-88-7 106-93-4 107-06-2 108-60-1

+ + + +

76-01-7 76-44-8

8en2ene D1ch10r0d1pheny1d1ch10r0ethy1ene Pentach10r0ethane Heptach10r

117-79-3 2-Am1n0anthra4u1n0ne 119-34-6 4-Am1n0-2-n1tr0phen01 120-71-8 p-Cre51d1ne 121-14-2 2,4-D1n1tr0t01uene

+ + + +

78-42-2 78-59-1 79-00-5 79-01-6

7r15-(2-ethy1hexy1)-ph05phate 150ph0r0ne 1,1,2-7r1eh10r0ethane 7r1ch10r0ethy1ene

121-66-4 2-Am1n0-5-n1tr0th1a201e 122-66-7 Hydra206en2ene 126-72-7 7r15-(2,3-d16r0m0pr0py1)ph05phate 129-15-7 2-Methy1-1-n1tr0anthra4u1n0ne

+ +

79-34-5 80-08-0 85-68-7 86-30-6

1,1,2,2-7etrach10r0ethane 4,4 •- 5u1f0ny1d1an111ne 8uty1 6en2y1 phtha1ate N-N1tr050d1pheny1am1ne

133-06-2 Captan 133-90-4 Ch10ram6en 134-29-2 0-An151d1ne.HC1 135-20-6 Cupferr0n

+ + + +

87-29-6 88-06-2 95-79-4 101-61-1

C1nnamy1anthran11ate 2,4,6-7r1ch10r0phen01 5-Ch10r0-0-t01u1d1ne 4,4•-Methy1ene-615-(N, N •d1methy1)6en2enam1ne

136-40-3 Phena20pyr1d1ne. HC1 137-17-7 2,4,5-7r1methy1an111ne 139-65-1 4,4•-7h10d1an111ne 139-94-6 N1th1a21de

+ + + +

103-23-1 105-55-5 108-78-1 115-32-2

D1-(2-ethy1hexy1)-ad1pate N, N •-D1ethy1th10urea Me1am1ne D1c0f01

156-10-5 p-N1tr050d1pheny1am1ne 512-56-1 7r1methy1ph05phate 542-75-6 1,3-D1ch10r0pr0pene 569-61-9 C.1. 8a51c Red 9. HC1

+ + + +

117-81-7 120-62-7 123-91-1 124-48-1

D1-(2-ethy1hexy1)-phtha1ate P1per0ny15u1f0x1de 1,4-D10xane Ch10r0d16r0m0methane

+ + + +

128-66-5 139-13-9 142-04-1 510-15-6

C.1. Vat Ye110w 4 N1tr110tr1acet1cac1d An111ne.HC1 Ch10r06en211ate

602-87-9 609-20-1 636-21-5 1777-84-0

1,2-Ep0xy6utane 1,2-D16r0m0ethane 1,2-D1ch10r0ethane 815-(2-ch10r0-1-methy1ethy1)-ether

5-N1tr0acenaphthene 2,6-D1ch10r0-p-pheny1ened1am1ne 0-701u1d1ne.HC1 3-N1tr0-p-acet0phenet1d1ne

+ +

Ame5 te5t

71-43-2 72-55-9

-

-

266 7A8LE 1 (c0nt1nued) CA5 N0.

597-25-1 630-20-6 961-11-5 1163-19-5 1596-84-5

7A8LE 3

Name

Ame5 te5t muta9en1c1ty

D1methy1m0rph011n0ph05ph0r0ate 1,1,1,2-7etrach10r0ethane 7etrach10rv1nph05 Deca6r0m0d1pheny1 0x1de

1897-45-6 2432-99-7

5ucc1n1cac1d 2,2-d1methy1hydra21de 2,3,7,8-7etrach10r0d16en20-pd10x1n Ch10r0tha10n11 11 -Am1n0undecan01c ac1d

2489-77-2 2835-39-4 3165-93-3

7r1methy1th10urea A11y1150va1erate 4-Ch10r0-0-t01u1d1ne •HC1

1746-01-6

3546-10-9 12789-03-6 17924-92-4

-

-

Phene5ter1n Ch10rdane 2eara1en0ne

3.2. 5eparat10n 0f the carc1n09en1c and n0n-carc1n09en1c n0n-muta9en5 3.2.1. 7he data6a5e 0 f t h e 101 n 0 n - m u t a 9 e n 5 w1th u n e 4 u 1 v 0 c a 1 carc1n09en1c1ty re5u1t5, 8 c 0 m p 0 u n d 5 w e r e rem 0 v e d f 0 r t h e r e a 5 0 n 5 5 t a t e d 1n 5 e c t 1 0 n 2 . 1 . 7 a 6 1 e 6 115t5 t h e 93 c 0 m p 0 u n d 5 u 5 e d 1n t h e d e v e 1 0 p m e n t 0 f th15 m 0 d e 1 a n d the1r c 0 r r e 5 p 0 n d 1 n 9 c a r c 1 n 0 9en1c e n d p 0 1 n t 5 .

PARAME7ER5 1N 7 H E F1NAL EQUA710N F 0 R CARC1N06EN5 Parameter de5cr1pt10n 519ma char9e 0n an 0xy9en at0m d0u61e-60nded t0 a n1tr09en at0m 5um 0f 519ma char9e5 0n an ar0mat1c C at0m 60und t0 a 51n91e-60nded n1tr09en Kappa 6 (a1pha) t0p01091ca1 mea5ure 0f cyc11c1ty 5um 0f 519ma char9e5 0n an a11phat1c car60n at0m 60und t0 a 51n91e-60nded n1tr09en at0m 519ma char9e 0n a car60n at0m 1n a 5aturated a1ky1 6r0m1de fra9ment 5um 0f 519ma char9e5 0n an ary1 a20 fra9ment Kappa 4 (a1pha) t0p01091ca1 mea5ure 0f 3-d1men510na11ty 519ma char9e 0n a n1tr09en at0m d0u61e-60nded t0 any car60n at0m MC1 cha1n 0rder 4 (51mp1e) 5um 0f 519ma char9e5 0n an ary1 am1ne fra9ment 5um 0f 519ma char9e5 0n an ary1 ether fra9ment 1 E1ectr0n-w1thdraw1n9 9rp and 2 e1ectr0n-re1ea51n9 9r0up5 (1,3,4) 0n a 51n91e tr1-5u65t1tuted 6en2ene r1n9 MC1 cha1n 0rder 7 (d1fference 6etween va1enceadju5ted and 51mp1e 1nd1ce5)

Effect

C0eff1c1ent

F-t0rem0ve

+

- 27.8

43.6

+

- 12.4

31.8

-

- 1.06

30.8

-

17.0

16.9

+

- 80.6

13.3

+

- 38.7

11.3

+

2.44

10.4

+ +

- 24.4 33.7

10.2 9.72

+

- 16.2

9.67

+

-40.6

6.61

-

- 4.67

6.35

+

9.94

5.70

3.2.2. R06u5tne55 te5t1n9 Dur1n9 the deve10pment, the data6a5e. the1r r e m 0 v a 1

r 0 6 u 5 t n e 5 5 te5t1n9 p r 0 c e 5 5 0 f m 0 d e 1 6 c0mp0und5 were rem0ved fr0m 7he1r name5 and the rea50n5 f0r a r e 5 h 0 w n 1n 7 a 6 1 e 7.

7A8LE 2 CARC1N06EN5 EL1M1NA7ED D U R 1 N 6 M 0 D E L DEVEL0PMEN7 CA5 N0.

Name

Rea50n f0r rem0va1

95-06-7 108-60-1 88-08-0

5u1fa11ate 815-ch10r0methy1 ether Dap50ne

1nf1uent1a1 065ervat10n 1nf1uent1a1065ervat10n 5tat15t1ca1 0ut11er

A n 0 t h e r a11-p055161e-5u65et5 re9re5510n ana1y515 wa5 p e r f 0 r m e d 0 n t h e r e m a 1 n 1 n 9 87 c 0 m p 0 u n d 5 . R 0 6 u 5 t n e 5 5 te5t1n9 r e v e a 1 e d t h a t t h e r e w e r e n 0 r e m a 1 n 1 n 9 1nf1uent1a1 0 6 5 e r v a t 1 0 n 5 , 5tat15t1ca1 0 u t 11er5 0 r p 0 0 r 1 y 6 e h a v e d p a r a m e t e r 5 .

3.2.3. 7he f1na1 e4uat10n 7 a 6 1 e 8 5h0w5 t h e p a r a m e t e r 5 1n t h e f1na1 D A e 4 u a t 1 0 n , 115ted 1n 0 r d e r 0 f 1 m p 0 r t a n c e . 7 h e 519n 0 f a c0eff1c1ent mu1t1p11ed 6 y t h e 519n 0 f 1t5 a550c1a t e d p a r a m e t e r 1nd1cate5 w h e t h e r t h e p a r a m e t e r dr1ve5 t h e e 5 t 1 m a t e t 0 w a r d p051t1v1ty ( + ) 0 r n e 9 a -

267 7A8LE 4

7A8LE 6

PERF0RMANCE 0 F 7HE D15CR1M1NAN7 FUNC710N F 0 R CARC1N06EN5 EVALUA7ED 8Y CR055-VAL1DA710N

N 0 N - M U 7 A 6 E N 1 C C 0 M P 0 U N D 5 DA7A8A5E

Actua1

Pred1cted

N0n-rnuta9en1c ( - ) Muta9en1c (+) 70ta1 1ndeterm1nate5 Fa15e p051t1ve5 Fa15e ne9at1ve5 0vera11 accuracy Adju5ted accuracy

Ne9at1ve

P051t1ve 1ndeterm1nate

37 3 40

2 49 51

8/99 2/99 3/99 86/99 86/91

= = = = =

4 4 8

8.1% 2.0% 3.0% 86.9% 94.5% a

a Exc1ude5 1ndeterm1nate5.

t1V1ty ( - - ) . 7 h e C0eff1C1ent5 a r e t h e Va1Ue5 0 f t h e parameter5 06ta1ned fr0m the DA. 7he

F-t0-re-

m 0 v e va1ue5 1nd1cate t h e re1at1ve 1 m p 0 r t a n c e 0 f t h e p a r a m e t e r 5 1n t h e f1na1 D A e 4 u a t 1 0 n .

3.2.4. EVa1uat10n 0f the d15Cr1m1nantfUnCt10n F 0 r t h e 87 C 0 m p 0 U n d 5 U5ed 1n t h e d e V e 1 0 p m e n t 0 f t h e f1na1 D A e4Uat10n, 4 Were m15C1a551f1ed a n d

CA5 N0.

Name

Carc1n09en1c1ty

Re5erp1ne Hexach10r0ethane 8en2ene D1ch10r0d1pheny1d1ch10r0ethy1ene

+ + +

76-01-7 76-44-8 78-42-2 78-59-1

Pentach10r0ethane Heptach10r 7r15-(2-ethy1hexy1)-ph05phate 150ph0r0ne

+ + + +

79-00-5 79-01-6 79-34-5 80-08-0

1,1,2-7r1eh10r0ethane 7r1ch10r0ethy1ene 1,1,2,2-7etrach10r0ethane 4,4 •- 5u1f0ny1d1an111ne

+ + + +

85-68-7 86-30-6 87-29-6 88-06-2

8uty1 6en2y1 phtha1ate N-N1tr050d1pheny1am1ne C1rmamy1anthran11ate 2,4,6-7r1ch10r0phen01

+ + + + +

103-23-1 105-55-5

5-Ch10r0-0-t01u1d1ne 4,4•-Methy1ene-615-(N, N •d1methy1)6en2enam1ne D1-(2-ethy1hexy1)-ad1pate N, N •-D1ethy1th10urea

108-78-1 115-32-2 117-81-7 120-62-7

Me1am1ne D1c0f01 D1-(2-ethy1hexy1)-phtha1ate P1per0ny15u1f0x1de

+ + + +

123-91-1 124-48-1 128-66-5 139-13-9

1,4-D10xane Ch10r0d16r0m0methane C.1. Vat Ye110w 4 N1tr110tr1acet1cac1d

+ + + +

124-04-1 510-15-6 597-25-1

An111ne-HC1 Ch10r06en211ate D1methy1m0rph011n0ph05ph0ram1date 1,1,1,2-7etrach10r0ethane

+ +

50-55-5 67-72-1 71-43-2 72-55-9

95-79-4 101-61-1

+

+ + +

4 Were C1a551f1ed a5 1 n d e t e r m 1 n a t e . 7 a 6 1 e 9 5h0W5 t h e re5U1t5 0 f t h e Cr055-Va11dat10n m e t h 0 d .

7A8LE 5 1NDE7ERM1NA7E AND M15CLA551F1ED 6EN5 CA5 N0. 86-30-6 87-29-6 95-83-0 128-66-5 133-30-4 135-20-6 542-75-6 2489-77-2 90-94-8 101-61-1 107-06-2 142-04-1 6959-48-4

CARC1N0-

Name

a

Ame5 te5t muta9en1c1ty

N-N1tr050d1pheny1am1ne C1nnamy1anthran11ate 4-Ch10r0-0-pheny1ened1am1ne C.1.Vat Ye110w 4 Ch10ram6en Cupferr0n D1ch10r0pr0pene 7r1methy1th10urea M1eh1er•5 ket0ne 4,4•-Methy1ene-615-(N, Nd1methy1)-6en2enam1ne 1,2-D1ch10r0ethane An111ne 3-(Ch10r0methy1)pyr1d1ne. HC1

1 1 1

+

a 1, 1ndeterm1nate; M, m15c1a551f1ed.

630-20-6 1 1 1 1 1 M M M M M

+ + + + + +

961-11-5 1163-19-5 1596-84-5 1746-01-6 1897-45-6 2432-99-7 2489-77-2 2835-39-4

+ +

7etrach10rv1nph05 Deca6r0m0d1pheny1 0x1de 5ucc1n1cac1d 2,2-d1methy1hydra21de 2,3,7,8-7etrach10r0d16en20p-d10x1n

+ +

Ch10r0tha10n11 11-Am1n0undecan01c ac1d 7r1methy1th10urea A11y1150va1erate

+ + + +

+ +

268 7A8LE 6 (c0nt1nued)

7A8LE 6 (c0nt1nued)

CA5 N0.

Name

Carc1n09en1c1ty

3165-93-3 3546-10-9 12789-03-6 17924-92-4

4-Ch10r0-0-t01u1d1ne•HC1 Phene5ter1n Ch10rdane 2eara1en0ne

+ + + +

50-29-3 50-81-7 51-03-6 56-72-4

DD7 L-A5c0r61cac1d P1per0ny16ut0x1de C0amaph05

58-89-9 64-77-7 69-65-8 72-20-8

L1ndane 7016utam1de D-Mann1t01 Endr1n

72-43-5 73-22-3 75-35-4 77-65-6

Meth0xych10r L-7rypt0phan V1ny11d1nech10r1de Car6r0ma1

77-79-2 82-68-8 85-44-9 88-96-0

3-5u1f01ene Pentach10r0n1tr06en2ene Phtha11canhydr1de Phtha1am1de

89-25-8

1-Pheny1-3-methy1-5pyra2010ne Ch10rpr0pam1de 1,2-D1ch10r06en2ene 3-Ch10r0-p-t01u1d1ne

94-20-2 95-50-1 95-74-9 97-77-8 101-05-3 101-54-2 103-85-5

7etraethy1th1uram d15u1f1de An11a21ne N- Pheny1-p-pheny1ened1am1ne 1-Pheny1-2-th10urea

105-60-2 108-95-2 109-69-3 114-86-3

Capr01actam Phen01 n-8uty1 ch10r1de Phenf0rm1n

116-06-3 118-92-3 119-53-9 121-75-5

A1d1car6 0-Anthran111cac1d 8en201n Ma1ath10n

127-69-5 128-37-0 134-72-5 148-18-5

5u1f150xa201e 8uty1ated hydr0xyt01uene Ephedr1ne 5u1fate 50d1um d1ethy1d1th10car6amate

150-38-9 333-41-5 434-13-9 536-33-4

ED7A (tr1-Na 5a1t) D1a21n0n L1th0ch011cac1d Eth10nam1de

CA5 N0.

Name

968-81-0 1212-29-9 1634-78-2 2438-88-2 2783-94-0 3567-69-9 6358-85-6 15356-70-4 15481-70-6

-

-

Carc1n09en1c1ty

Acet0hexam1de N,N•-D1cyc10hexy1th10urea

-

Ma1a0x0n 2,3,5,6-7etrach10r0-4-n1tr0an1501e FD • C Ye110w 6 C.1. Ac1d Red 14 D1ary1an111deYe110w D1-menth01 2,6-701uened1am1ne •2HC1

-

0 f the 83 n0n-1ndeterm1nate c1a551f1cat10n5, 79 were c0rrect, y1e1d1n9 an accuracy 0f 95.2%. 7a61e 10 115t5 the m15c1a551f1ed and 1ndeterm1nate c0mp0und5 and the1r c0rre5p0nd1n9 carc1n09en1c endp01nt5. C0mp0und5 wh1ch had 6een 1nc0rrect1y c1a551f1ed 6y the DA funct10n were exam1ned f0r 5tructura1 51m11ar1t1e5. 1f an ent1re c1a55 0f c0mp0und5 had n0t 6een hand1ed we11 6y a DA funct10n, 9enerat10n 0f add1t10na1 parameter5, wh1ch w0u1d ref1ect 5tructura1 character15t1c5 0f that c1a55, wa5 attempted. 7he funct10n wa5 then reca1cu1ated u51n9 the new parameter(5). 7he three ch10r0-t01u1d1ne c0mp0und5 1n th15 data6a5e have 6een 1dent1f1ed a5 1ndeterm1nate 0r m15c1a551f1ed, a5 5een 1n 7a61e 10. N0ne had 6een c1a551f1ed a5 an 1nf1uenta1 065ervat10n 0r a5 an 0ut11er dur1n9 the r06u5tne55 te5t1n9 0f m0de1 deve10pment. A new parameter de5cr161n9 the pre5ence 0f a ch10r0-t01u1d1ne wa5, theref0re, 1mp1emented and the d15cr1m1nant funct10n wa5 reca1cu1ated, 6ut th15 parameter d1d n0t enter the 7A8LE 7 N 0 N - M U 7 A 6 E N 5 EL1M1NA7ED DUR1N6 M 0 D E L DEVEL0PMEN7

CA5 N0. Name

Rea50n f0r rem0va1

69-65-8 108-78-1 124-48-1 139-13-9 142-04-1 630-20-6

1nf1uent1a1 065ervat10n 1nf1uent1a1 065ervat10n 5tat15t1ca10utf1er 5tat15t1ca1 0ut11er 5tat15t1ca1 0ut11er 5tat15t1ca10ut11er

D-Mann1t01 Me1am1ne Ch10r0d16r0m0methane N1tr110tr1acet1ca c 1 d An111ne.HC1 1,1,1,2-7etrach10r0ethane

269 7A8LE 9

7A8LE 8 PARAME7ER5 MU7A6EN5

1N

Q5AR

EQUA710N

F0R

Parameter

Effect

Kappa 6 (a1pha) 5hape 1ndex > = 1 E1ec w / d r a w 9rp (a1pha) and 2 e1ec w / d r a w 9rp (6eta) 6nd t0 ethane 0r ethene 51mp1e path/c1u5ter MC1 0rder 5

+

5.61

48.8

+

2.08

48.2

+

1.41

A20 f9mt (6eta pheny1) N-Ethane 60und t0 n0n-C D1fference cha1n MC1 0rder 5

-

- 26.6 - 5.52

5ummed c1u5ter MC1 0rder 4 Unfu5ed pheny1 r1n9 Char9e 0n a11cyc11c 0xy9en

-

+ +

2 E1ectr0n-w1thdraw1n9 9r0up5 60nded t0 N H 1,2-D1-ch10r0 5u65t1tut10n 0n ar0mat1c r1n9 519ma char9e5 0n a11cyc11c car60n5 1n C-0n1y r1n95 (0ther than 4u1n0ne5 0r f1u0rene5)

- 143

+

31.7 29.5 28.3

- 14.7

22.3

2.60

21.6

P E R F 0 R M A N C E 0 F 7 H E D15CR1M1NAN7 F U N C 7 1 0 N F0R N0N-MU7A6EN5 EVALUA7ED 8Y CR055VAL1DA710N Actua1

Pred1cted

N0n-carc1n09en1c ( - ) Carc1n09en1c (+ ) 70ta1 1ndeterm1nate5 Fa15e p051t1ve5 Fa15e ne9at1ve5 0veraU accuracy Adju5ted accuracy

Ne9at1ve

P051t1ve

1ndeterm1nate

44 3 47

1 35 36

3 1 4

4/87= 1/87 = 3/87 = 79/87 = 79/83 =

4.6% 1.1% 3.4% 90.8% 95.2% a

a Exc1ude5 1ndeterm1nate5.

re5u1t1n9 DA e4uat10n, 1.e. 1t wa5 n0t 1mp0rtant en0u9h t0 6e u5ed 1n the e4uat10n. 0m15510n 0f the5e three c0mp0und5 fr0m the DA funct10n d1d n0t 5u65tant1a11y a1ter 1t5 perf0rmance. 1t may 6e n0ted that the carc1n09en1c1ty 0f the5e n0n-muta9en1c ch10r0-t01u1d1ne5 appear5 t0 6e re5tr1cted t0 m1ce.

22.2

19.4

15.3

18.0

16.4 15.2

17.9 17.2

12.6

15.0

1.91

14.6

1NDE7ERM1NA7E A N D M15CLA551F1ED N 0 N - M U 7 A 6EN5

- 26.8

12.0

CA5 N0.

14.6

10.1

-

Char9e 0n 5 d0u61e-60nded t0 0 Char9e 0n a11phat1c C 1n 5at a1ky1 ch10r1de Char9e 0n any car60n d0u61e-60nded t0 0xy9en

8.68

25.2 24.1 22.6

-

N 5u65t w 2 e1ec re1 9rP5 and 1 dec w / d r a w 9rp C1 6nd t0 n0n-ar0m r9 C (a1pha 5a0 5um 0f char9e5 0n a11phat1c am1ne

F-t0rem0ve

- 17.0 0.41 - 20.5

-

2 E1ec re1 9rP5 (a1pha) 60und t0 ethene 519ma char9e5 0n 51n91e-60nded N 5ec. 0r tert. a11ph, a1c0h01

5um 0f char9e5 0n ary1 ch10r1de N H 5u65t w 1 e1ec re1 9rp and 1 e1ec w / d r a w 9rp Ethane 0r ethy1ene 6etw 2 dec re1 9rp5

C0eff1c1ent

N0N-

4. D15cu5510n

A maj0r d1fference 6etween pred1ct10n5 9enerated w1th 5AR techn14ue5 and pred1ct10n5 6a5ed 0n the k1nd 0f ••a1ert1n9 5tructure5•• der1ved 6y 7 A 8 L E 10

279

9.72

95-50-1 95-74-9 101-54-2

- 9.05

9.04

101-61-1

- 37.8

+ -

Name

a

Catc1n09en1c1ty

1,2-D1ch10r06en2ene 3-Ch10r0-p-t01u1d1ne N-Pheny1-p-pheny1ene d1am1ne 4,4•-Methy1ene-615( N , N •-d1methy1)-6en2enam1ne

1 1

-

1 1

+

Phen01 8en2ene 5-Ch10r0-0-t01u1d1ne 4-Ch10r0-0- t01u1d1ne • HC1

M M M M

+ + +

8.89

5.03

7.85

3.31

6.44

108-95-2 71-43-2 95-79-4 3165-93-3

1, 1ndeterm1nate; M, m15da551f1ed.

270 A5h6y and 7ennant (1988) 15 that, 1n 5AR e4uat10n5, the effect5 0f the parameter5 0n the endp01nt5 are add1t1ve 6ut n0t exc1u51ve. 7 h e a1ert1n9 5tructure5 are u5ed un1d1rect10na11y 1n an a11-0rn0th1n9 fa5h10n; the1r mere pre5ence c0n5t1tute5 a warn1n9. 1n the k1nd 0f d15cr1m1nant ana1y515-6a5ed 5AR m0de15 de5cr16ed here, each 0f the m01ecu1ar 5u65tructure5 and 5tructure-der1ved phy51c0-chem1ca1 de5cr1pt0r5 0f m01ecu1ar feature5 ha5 a 5ca1ed p051t1ve 0r ne9at1ve 1nf1uence 0n the end re5u1t, 1.e. the pr06a6111ty 0f carc1n09en1c1ty 0r 0ther m0de1ed 6101091ca1 end-p01nt. A n0n-muta9en1c c0mp0und may c0nta1n certa1n 5u65tructure5 hav1n9 a p051t1ve 1nf1uence 0n carc1n09en1c1ty a5 we11 a5 0ther5 wh1ch dr1ve the carc1n09en1c1ty e5t1mate 1n the 0pp051te d1rect10n. 7he p051t1ve 1nf1uence 0f 50me parameter5 may thu5 6e 0verc0me 6y the ne9at1ve 1nf1uence 0f 0ther5, pr0duc1n9 a n0ncarc1n09en1c re5u1t, and v1ce ver5a. 0 f the 5tructure5 115ted 6y A5h6y and 7ennant (1988) wh1ch c0u1d 6e u5ed 1n th15 5tudy due t0 the ava11a6111ty 0f c0rre5p0nd1n9 Ame5 te5t re5u1t5, 76% are n0t part 0f the data6a5e u5ed 1n the muta9en1c1ty 5AR m0de1 0f En51e1n et a1. (1986). 7 h e accuracy 0f pred1ct1n9 Ame5 muta9en1c1ty 6y mean5 0f that 9enera1 m0de1 15 94.6%, a5 determ1ned 6y cr055-va11dat10n, v1rtua11y the 5ame a5 that ach1eved 1n the current 5tudy f0r kn0wn carc1n09en5. 7hu5, a1th0u9h the re1at10n5h1p5 m a y 6e d1fferent, the muta9en1c1ty 0f carc1n09en5, a5 a 9r0up, can 6e m0de1ed w1th the 5ame de9ree 0f accuracy a5 the muta9en1c1ty 0f a m0re 9enera1 p0pu1at10n 0f 5tructure5. 1n the 5ec0nd part 0f th15 5tudy, carc1n09en1c1ty wa5 e5t1mated fr0m a p0pu1at10n 0f kn0wn n0n9en0t0x1c 5tructure5. 7 h e accuracy 15 near1y 1dent1ca1 t0 the accuracy ach1eved 1n the 9enera1 carc1n09en1c1ty m0de1 0f En51e1n et a1. (1987). A9a1n, th15 5h0w5 that, a1th0u9h the parameter5 1nv01ved 1n the e4uat10n5 0f the5e tw0 m0de15 may 6e d1fferent, 1t 15 p055161e t0 m0de1 carc1n09en1c1ty 0f n0n-muta9en1c 5tructure5 w1th a60ut the 5ame de9ree 0f accuracy a5 that 0f a 9enera1 p0pu1at10n 0f c0mp0und5. 1n c0n51der1n9 the accuracy f19ure5, 1t 5h0u1d 6e n0ted that the m0de15 were deve10ped f0r 5pec1f1c 5et5 0f chem1ca15. C0nf1dence 1n e5t1mate5 decrea5e5 a5 the de5cr1pt10n 0f the 5tructure5 6y the

var1a61e5 1n the e4uat10n decrea5e5. 1f the m0de15 were t0 6e app11ed t0 6r0ader 5et5 0f chem1ca15, accuracy w0u1d, theref0re, a150 decrea5e t0 50me de9ree, and 50mewhat unpred1cta61y, dependent up0n the nature 0f the add1t10na1 5tructure5. M01ecu1ar 51mp11c1ty 15 n0t nece55ar11y an a55et when 1nve5t19at1n9 5tructure-act1v1ty re1at10n5h1p5. 7he 1e55 c0mp1ex a m01ecu1e, the fewer re1at10n5h1p5 can 6e 1dent1f1ed; carr1ed t0 the extreme, kn0w1ed9e 0f the t0x1c1ty pattern5 0f an e1ement perm1t5 n0 c0nc1u510n5 a60ut that 0f an0ther. 1t 15, 0f c0ur5e, techn1ca11y fea5161e t0 deve10p m0de15 f0r 0ther p055161e permutat10n5, 1.e., (1) the pred1ct10n 0f muta9en1c1ty fr0m a p0pu1at10n 0f n0n-carc1n09en5 and (2) the pred1ct10n 0f carc1n09en1c1ty fr0m a p0pu1at10n 0f muta9en5 are the0ret1ca11y p055161e, 6ut, 1n pract1ce, the f0rmer 15 hampered 6y a 1ack 0f re11a61e data and, 1n e1ther ca5e, 5uch an exerc15e w0u1d have 11tt1e pract1ca1 519n1f1cance. Heur15t1c m0de15, wh1ch d0 n0t c0n51der mechan15m5 0f act10n, etc., 5h0u1d funct10n 1n 5u65tant1a11y the 5ame manner, whether the data 5et5 t0 wh1ch they are app11ed are 1n 50me way pre5e1ected 0r n0t. 7 h e app11cat10n 0f a muta9en1c1ty m0de1 t0 a 9r0up 0f kn0wn carc1n09en5 and the app11cat10n 0f a carc1n09en1c1ty m0de1 t0 a 9r0up 0f kn0wn n0n-muta9en5 5eem t0 6e n0 except10n t0 th15 ru1e.

Reference5 A5h6y, J., and R.W. 7ennant (1988) Chem1ca1 5tructure, 5a1m0ne11a muta9en1c1ty and the extent 0f carc1n09en1c1ty a5 1nd1cat0r5 0f 9en0t0x1c carc1n09en1c1tyam0n9 222 chem1ca15 te5ted 1n r0dent5 6y the U.5. NC1/N7P, Mutat10n Re5., 204, 17-115. C05tan2a, M.C., and A.A. Af1f1(1979) C0mpar150n0f 5t0pp1n9 ru1e5 1n f0rward d15cr1m1nant ana1y515,J. Am. 5tat. A550c., 74, 777-785. Dearden, J.C., 5.J.A. 8rad6urne, M.7.D. Cr0n1n and P. 501an5k1(1988) 7he phy51ca1519n1f1cance0f m01ecu1arc0nnect1v1ty, Pr0c. 3rd 1nt1. W0rk5h0p 0n Quant1tat1ve 5tructureAct1v1tyRe1at10n5h1p51n Env1r0nmenta170x1c0109y,Kn0xv1Ue,7N (U.5.A.). En51e1n, K., 8.W, 81ake, M.E. 70m6 and H.H. 80r95tedt (1986) Pred1ct10n 0f Ame5 te5t re5u1t56y 5tructure-act1v1ty re1at10n5h1p5, 1n V1tr0 70x1c01., 1, 33-44. En51e1n, K., H.H. 80r95tedt, M.E. 70m6, 8.W. 81ake and J.8. Hart (1987) A 5tructure-act1v1ty pred1ct10n m0de1 0f carc1n09en1c1ty 6a5ed 0n NC1/N7P a55ay5 and f00d add1t1ve5, 70x1c01. 1nd. H1th., 1, 267-287.

271 6a5te19er, J., and M. Mar5111 (1988) 1terat1ve part1a1 e4ua112at10n 0f 0r61ta1 e1ectr0ne9at1v1ty - - a rap1d acce55 t0 at0m1c char9e5, 7etrahedr0n, 36, 3219-3228. 60m6ar, V.K., and D.V.5. Ja1n (1987) Quant1f1cat10n 0f m01ecu1ar 5hape and 1t5 c0rre1at10n w1th phy51c,0-chem1ca1 pr0pert1e5, 1nd1an J. Chem., 26A, 554. K.1er, L.8. (1986) 5hape 1ndexe5 0f 0rder5 0ne and three fr0m m01ecu1ar 9raph5 , Quant. 5truct.-Act1v. Re1at., 5, 1-7.

K1er, L.8., and L.H. Ha11 (1986) M01ecu1ar C0nnect1v1ty 1n 5tructure-Act1v1ty Ana1y515, W11ey, New Y0rk. L1j1n5ky, W. (1988) Per50na1 c0mmun1cat10n. 5nap1nn, 5.M., and J.D. Kn0ke (1985) An eva1uat10n 0f 5m00thed c1a551f1cat10n err0r rate e5t1mat0r5, 7echn0metr1c5, 27, 199-206.

Salmonella mutagenicity and rodent carcinogenicity: quantitative structure-activity relationships.

Based on a compilation of 222 reports of rodent nominal lifetime carcinogenicity bioassays by the NCI/NTP on the one hand, and corresponding Salmonell...
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