1228
Specialia
s u b s t a n c e s . A n o t h e r cause of t h i s n o n - s u s c e p t i b i l i t y m a y reside i n t h e egg nucleus, since t h e fish egg c o m p l e t e s t h e m a t u r a t i o n divisions a f t e r t h e s p e r m a t o z o o n h a s e n t e r e d t h e egg. H o w e v e r , in 2 e x p e r i m e n t s w i t h C r e n i l a b r u s p a v o , we o b s e r v e d t h a t a b o u t o n e - f o u r t h of t h e p r e t r e a t e d eggs g a v e rise t o e m b r y o s w i t h d i s t u r b a n c e s of t h e s k e l e t o n . W h e n , o n tile o t h e r h a n d , t h e s p e r m a t o z o a are p r e t r e a t e d (2 rain in 10-4-10 .5 M t h a l i d o m i d e ) t h e r e s u l t s were v e r y clear, a n d in a g r e e m e n t w i t h t h o s e p r e v i o u s l y o b t a i n e d w i t h sea u r c h i n l a r v a e 6. A f t e r p r e t r e a t m e n t of t h e sperm, t h e d i f f e r e n t i a t i o n of t h e n o t o c h o r d b e c o m e s d i s t u r b e d . Also t h e g e n e r a l d e v e l o p m e n t of t h e l a r v a is clearly a f f e c t e d a n d t h e d e v e l o p m e n t of t h e v a r i o u s l a r v a l o r g a n s is d e l a y e d or suppressed. A v e r y e v i d e n t effect of pret r e a t m e n t of t h e s p e r m a t o z o o n is t h e d e f e c t i v e different i a t i o n of t h e d i s t a l p a r t of t h e n o t o c h o r d (cf. figures 1, c o n t r o l , a n d 2, t h a l i d o m i d e ) . B. T r e a t m e n t w i t h t h a l i d o m i d e a f t e r f e r t i l i z a t i o n . A t r e a t m e n t for o n l y 3 h, s t a r t e d a t v a r i o u s i n t e r v a l s a f t e r f e r t i l i z a t i o n , b r o u g h t a b o u t severe d i s t u r b a n c e s of t h e d e v e l o p m e n t of t h e n o t o c h o r d a n d t h e r e s o r p t i o n of t h e y o l k sac was likewise affected. T h e r e was, m o r e o v e r , a n a c c u m u l a t i o n of p i g m e n t ; figures 3 a (control) a n d 3 b (10 -5 M t h a l i d o m i d e for 3 h) s h o w t h e effect of t h a l i d o m i d e o n t h e d i f f e r e n t i a t i o n of t h e e m b r y o . Cleavage was i n f l u e n c e d n e g a t i v e l y a n d h a t c h i n g b e c a m e delayed,
EXPERIENTIA 33/9
w h i c h i n d i c a t e s t h a t n o t o n l y t h e m e s o d e r m is a f f e c t e d b y t h e drug. T h o u g h t h e t r e a t e d e m b r y o s h a t c h i n t o frees w i m m i n g l a r v a e , t h e l e t h a l i t y is h i g h a n d no a d u l t anim a l s are likely t o be formed. Discussion. I t is a r e m a r k a b l e f a c t t h a t t h e r e s p o n s e to t r e a t m e n t w i t h t h a l i d o m i d e d u r i n g e m b r y o n a l life of w a r m - b l o o d e d a n i m a l s d i s p l a y s a r i c h v a r i a t i o n , w h i c h is e v i d e n t l y c o r r e l a t e d w i t h t h e p a r t i c u l a r s t r a i n of a n i m a l s used in tile e x p e r i m e n t s 2-4. W e i n t r o d u c e d g a m e t e s a n d e m b r y o s f r o m sea u r c h i n s as a m a t e r i a l for t e s t i n g t o x i c i t y o n t h e cellular a n d e m b r y o n a l level 6, 7. T h e p r e s e n t e x p e r i m e n t s w i t h m a r i n e fishes c o r r o b o r a t e t h e r e s u l t s f r o m our p r e v i o u s w o r k o n e c h i n o d e r m s . T h e species of fishes used are v e r y d i f f e r e n t a n d t h e y live a n d reproduce under very different environmental conditions. T h e r e s p o n s e to t h a l i d o m i d e was u n i f o r m , a n d n o t speciesrelated, a n d t h e m a i n m o r p h o g e n e t i c effects were conc e n t r a t e d to t h e d i f f e r e n t i a t i o n of t h e m e s o d e r m . T h e full effect w a s o b t a i n e d a l r e a d y b y p r e t r e a t i n g t h e sperm a t o z o o n for o n l y 2 m i n in a 10 .5 M s o l u t i o n of t h a l i d o mide. Since t h e s p e r m a t o z o o n m a i n l y consists of a n u cleus, it is w a r r a n t e d to c o n c l u d e t h a t t h a l i d o m i d e interacts with the genome, and particularly with the genes w h i c h g o v e r n t h e d i f f e r e n t i a t i o n of t h e skeleton. 7 B.E. Hagstr6m and S. L6uning, Experientia 32, 744 (1976).
Simple theoretical criterion of chemical carcinogenicity V. V e l j k o v i d a n d D. 1. L a l o v i d
Laboratory/or Theoretical Physics, Boris Kidrig Institute, l lO01 Belgrade (Yugoslavia), 21 January 1977 Summary. T h e c o r r e l a t i o n b e t w e e n t h e a v e r a g e q u a s i - v a l e n c e n u m b e r a n d c a r c i n o g e n i c i t y of organic c o m p o u n d s h a s b e e n e s t a b l i s h e d a n d discussed. I n o u r r e c e n t w o r k 1, we h a v e e s t a b l i s h e d t h e c o r r e l a t i o n between the pseudoatomic potential 2 and carcinogenicity. T h e c o m p l e x f o r m of t h e p s e u d o a t o m i c p o t e n t i a l , e m p l o y e d in t h e p r e v i o u s work, c o n t a i n e d C o u l o m b i n t e r a c t i o n a n d P a u l i r e p u l s i o n c o m p o n e n t s , a n d i t was r a t h e r difficult for c a l c u l a t i o n b y lion-specialists. Since in t h i s p o t e n t i a l t h e a v e r a g e q u a s i - v a l e n c e n u m b e r Z*, d e f i n e d as : m
27 NlZi i~1 z* - - m
(1)
27 Ni i~l
where Ni is the n u m b e r of atoms of the i-th type in the given molecule, Zi is the n u m b e r of valence electrons in the a t o m of the i-th type 3, and m is the n u m b e r of chemical elements in the molecule, plays a very important role 4,5, w e decided to look for the possible existence of a correlation b e t w e e n t h e a v e r a g e q u a s i - v a l e n c e n u m b e r a n d c a r c i n o g e n i c i t y Of c h e m i c a l s u b s t a n c e s . C a l c u l a t e d v a l u e s of t h e a v e r a g e q u a s i - v a l e n c e n u m b e r for a b o u t 400 organic c o m p o u n d s of k n o w n c a r c i n o g e n i c activity strongly correlate with their carcinogenic p r o p e r t i e s . I n t h e t a b l e , we p r e s e n t d a t a for t h e a n a l y z e d c o m p o u n d s biologically t e s t e d i n m a m m a l s . O n t h e b a s i s of a v a i l a b l e biological results, we h a v e c o n c l u d e d t h a t p o t e n t i a l c a r c i n o g e n s h a v e Z * v a l u e s b e l o w 3.20, while n o n c a r c i n o g e n s are c h a r a c t e r i z e d b y Z* a b o v e 3.20. T h e
b o r d e r l i n e v a l u e of 3.20 h a s b e e n c h o s e n o n t h e b a s i s of e m p i r i c a l biological d a t a . T h e L y o n ( I n t e r n a t i o n a l A g e n c y for R e s e a r c h o n Cancer) c r i t e r i o n for c a r c i n o g e n i c i t y h a s b e e n used i n t h i s work. T h e classification of a b o u t 400 organic c o m p o u n d s e i n t o 2 categories: potential carcinogens and noncarcinogens is c o n n e c t e d w i t h all e r r o r of a b o u t 8 % . C o r r e s p o n d i n g e r r o r for c o m p o u n d s t e s t e d in m a m m a l s a n d r e p o r t e d in L y o n ' s m o n o g r a p h s is o n l y 5 % . In connection with the above average quasi-valence n u m b e r criterion, one s h o u l d n o t i c e t h e following: a) T h e c r i t e r i o n is b a s e d o n t h e use of m o l e c u l a r f o r m u l a a n d i t is i n s e n s i t i v e t o t h e effects of isomerisms. b) I n v e s t i g a t i o n s of t h e p r i m a r y m o l e c u l a r f o r m a l t e r a t i o n s d u e t o m e t a b o l i c processus h a v e s h o w n t h a t t h e a v e r a g e q u a s i - v a l e n c e n u m b e r of o r i g i n a l molecule is n o t c h a n g e d b y m o r e t h a n 10%. T h i s e x p l a i n s some of tile
1 V. Veljkovid and D. I. Lalovid, Cancer Biochem. Biophys. l, 295 (1976). 2 V. Veljkovid and D. I. Lalovid, Phys. Lett. 45A, 59 (1973). 3 In case of halogen elements instead of Z = 7, Z = 1 should be taken. 4 V. Veljkovid, Phys. Lett. 45A, 41 (1973). 5 V. Veljkovid and D. I. Lalovid, Phys. Rev. 11, 4242 (1975). 6 In the table we included all those substances for which we found well established biological data obtained from mammalian systems.
15.9. 1977
1229
Speelalia
Correlation between the quasi-valence number and earcinogenieity of the organic chemical compounds Compound
Molecular formula
Z*
Carcinogenicity~' ~
Compound
Molecular formula
Z*
Careinogenieity', s
Carbon tetrachloride Chloroform Tetramethyllead Tetraethyllead Vinyl chloride 1,2-Diethylhydrazine Polychlorinated biphenyls 1,1-Dimethylhydrazine Bis(ehlormethyl)ether Chlormethyl methyl ether N-Nitroso-di-n-butylamine Hydrazine Mirex Heptachlor Aldrin N-Nitrosodiethylamine Aramite | Benzene DDT DDD (TDE) Diehlorbenzene Dieldrin Auramine 3, 3'-Dimethylbenzidine Methoxychlor Dihydrosafrole 4, 4'-Methylenedianiline 4-Aminobiphenyl Aminoazotoluene Benzidine Dxmethylaminoazobenzene Naphtylamine Chrysoidine N -Nitrosodimeth ylamine 3, 3'-Dimethoxybenzidine Urethane Benzanthraeene Chlorobenzilate Yellow OB Diacetylaminoazotoluene Sudan II Safrole Azobenzene Ethylenethiourea Sudan red 7B Dibenzanthraeene Aminoazobenzene Propylthiouracil Benzofluoranthene 7H-Dibenzoearbazole Oil orange SS Sudan brown RR Aeetamide Dibenzopyrene C. I. Disperse Yellow 3 Dibenzacridine 4-Hydroxyazobenzene Citrus red No. 2 Thiourea Cyeasin Methylazoxymethanol Nitrosoethylurea 4-Nitrobiphenyl Streptozotoein Methyl methanesulphonate Dicetene Adenosin Salicyelic acid Quintezene Piperonyl Orange I Dimethylsulphate
CCI4 CHCI~ Pb(CHs) 4 Pb(C2H~) 4 C~HsC1 C4H12N~ Cl~Cla0 C2HsN2 C2H4C1~O CzHsC10 CsHlsN20 N2H 4 C10C112 C10HsCt~ ClzHsCI~ C~HxoNzO C12H23C104S CsIt e C14H9C15 Ca4H10C1~ CeH4c12 CI~HsCI~O C17H21Ns C14H16Nz ClsHtselsO2 Ca0H100z ClsHI4N ~ C12HnN Ca4HI~Ns Ca~HlzNz C1,H15Ns C10HgN C12HlsCINi CzH6N~O C1,HasNzO~ CsH:NO ~ CasHx~ C~,HxiCl20 a C17H~N s CasHx~NsO~ ClsHlnN~O C~oH100z CI~H10Nz C3HeN~S C2~H21N~ C~Hx4 Ca~HnN s C7H10N2OS CxoH~ C,0H~N CxTHa4NzO Cx~Hx~N~ C~H~NO C~HI~ C~Hx~NsOz C~IHIsN Ca~Hx0N20 C~HI~N~Os CHiN~S CsH~eN~O7 C4HsN20 s CsFITNsO~ CI~HgNOz CsH~NsO7 C~H6OsS C4H~O~ C~0HasN~O~ CTH~% C~CI~NO2 CsH~Oa C~HnN~NaO~S C~HeO~S
1.60 1.60 1.88 1.93 2.00 2.11 2.12 2.17 2.22 2.22 2.28 2.33 2.36 2.36 2.38 2.47 2.49 2.50 2.50 2.50 2.50 2.52 2.54 2.56 2.61 2.67 2.67 2.67 2.69 2.69 2.69 2.70 2.73 2.73 2.76 2.77 2.80 2.80 2.80 2.81 2.81 2.82 2.83 2.83 2.84 2.84 2.85 2.86 2.88 2.88 2.88 2.88 2.89 2.90 2.91 2.92 2.94 2.97 3.00 3.03 3.06 3.07 3.08 3.15 3.17 3.20 3.20 3.26 3.28 3.29 3.31 3.38
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + -----
Alizarin Ammonium urate acid 5-Nitro-2-furaldehide semiearbazone Carmoisine Evens blue 2-(2-Furyl)-3-(5-nitrofuryl)acrylamide 6-Mercaptopurine Sunset yellow FCF Amido-G-acid Amarath Alizarin orange Xantin 1-](Nitrofurfurylidine) amino]hydantion 5-Nitro-2- furamidoxime Alloxantin Alloxan
C14HsO4 CsHTNsOs
3.38 3.50
---
CsHnN404 C20H12N2Na40~S2 C~4H2oN6Na4014S4
3.50 3.51 3.53:
----
CnHsN20 ~ C~H4N4S C16H10N2Na2OTS z C14H804 C20HnNaaN2OnS s C14HTNO~ C5H~N40~
3.54 3.57 3.59
--------
CsH6N40 s CsHsN:~O * CsH4N40 s C4H2N20 ,
3:83 3.76 4.08 4.17
-
-
---
3.71 3.71 3.73
---
-
--
e r r o r s in t h e o r e t i c a l p r e d i c t i o n of n o n c a r c i n o g e n i c i t y i n c a s e of c h e m i c a l c o m p o u n d s h a v i n g Z* close t o t h e b o r d e r l i n e v a l u e of 3.20. c) I n case of n o n c a r c i n o g e n e c i t y t h e q u a s i - v a l e n c e n u m b e r is n e c e s s a r y a n d s u f f i c i e n t c r i t e r i o n . F o r c a r c i n o g e n i c a c t i v i t y it is n e c e s s a r y b u t n o t s u f f i c i e n t . F o r t h i s r e a s o n , w e c l a s s i f y all s u b s t a n c e s in p o t e n t i a l c a r c i n o g e n e s a n d noncarcinogenes. O n t h e b a s i s of r e s u l t s o b t a i n e d w e c o n c l u d e t h a t t h e a v e r a g e q u a s i - v a l e n c e n u m b e r of o r g a n i c c o m p o u n d s c a n b e u s e d f o r t h e o r e t i c a l p r e d i c t i o n of p o t e n t i a l c a r c i n o g e n i c i t y of o r g a n i c c o m p o u n d s . V e r y s i m p l e c a l c u l a t i o n of t h e a v e r a g e q u a s i - v a l e n c e n u m b e r ( t h e r a t i o of t h e s u m of all a t o m i c v a l e n c e e l e c t r o n s a n d t h e n u m b e r of a t o m s in t h e g i v e n m o l e c u l e ) allows one to check and use the above correlation. T h e e s t a b l i s h e d c o r r e l a t i o n c o u l d be of p r a c t i c a l b e n e f i t in s e l e c t i o n a n d u s e o f o r g a n i c c o m p o u n d s , a s well a s s h e d d i n g s o m e n e w l i g h t o n t h e m e c h a n i s m of c a r c i n o genesis. Interesting relationships between other biological activities of o r g a n i c c o m p o u n d s a n d t h e i r a v e r a g e q u a s i v a l e n c e n u m b e r s h a v e also b e e n f o u n d a n d will b e d i s c u s s e d elsewere.
7 8
IARC Monographs, Evaluation of Carcinogenic Risk, vol. 1-8. Lyon 1972-1975. Ann. N.Y. Aead. Sci. J63, 589 (1969).
Specialia
s u b s t a n c e s . A n o t h e r cause of t h i s n o n - s u s c e p t i b i l i t y m a y reside i n t h e egg nucleus, since t h e fish egg c o m p l e t e s t h e m a t u r a t i o n divisions a f t e r t h e s p e r m a t o z o o n h a s e n t e r e d t h e egg. H o w e v e r , in 2 e x p e r i m e n t s w i t h C r e n i l a b r u s p a v o , we o b s e r v e d t h a t a b o u t o n e - f o u r t h of t h e p r e t r e a t e d eggs g a v e rise t o e m b r y o s w i t h d i s t u r b a n c e s of t h e s k e l e t o n . W h e n , o n tile o t h e r h a n d , t h e s p e r m a t o z o a are p r e t r e a t e d (2 rain in 10-4-10 .5 M t h a l i d o m i d e ) t h e r e s u l t s were v e r y clear, a n d in a g r e e m e n t w i t h t h o s e p r e v i o u s l y o b t a i n e d w i t h sea u r c h i n l a r v a e 6. A f t e r p r e t r e a t m e n t of t h e sperm, t h e d i f f e r e n t i a t i o n of t h e n o t o c h o r d b e c o m e s d i s t u r b e d . Also t h e g e n e r a l d e v e l o p m e n t of t h e l a r v a is clearly a f f e c t e d a n d t h e d e v e l o p m e n t of t h e v a r i o u s l a r v a l o r g a n s is d e l a y e d or suppressed. A v e r y e v i d e n t effect of pret r e a t m e n t of t h e s p e r m a t o z o o n is t h e d e f e c t i v e different i a t i o n of t h e d i s t a l p a r t of t h e n o t o c h o r d (cf. figures 1, c o n t r o l , a n d 2, t h a l i d o m i d e ) . B. T r e a t m e n t w i t h t h a l i d o m i d e a f t e r f e r t i l i z a t i o n . A t r e a t m e n t for o n l y 3 h, s t a r t e d a t v a r i o u s i n t e r v a l s a f t e r f e r t i l i z a t i o n , b r o u g h t a b o u t severe d i s t u r b a n c e s of t h e d e v e l o p m e n t of t h e n o t o c h o r d a n d t h e r e s o r p t i o n of t h e y o l k sac was likewise affected. T h e r e was, m o r e o v e r , a n a c c u m u l a t i o n of p i g m e n t ; figures 3 a (control) a n d 3 b (10 -5 M t h a l i d o m i d e for 3 h) s h o w t h e effect of t h a l i d o m i d e o n t h e d i f f e r e n t i a t i o n of t h e e m b r y o . Cleavage was i n f l u e n c e d n e g a t i v e l y a n d h a t c h i n g b e c a m e delayed,
EXPERIENTIA 33/9
w h i c h i n d i c a t e s t h a t n o t o n l y t h e m e s o d e r m is a f f e c t e d b y t h e drug. T h o u g h t h e t r e a t e d e m b r y o s h a t c h i n t o frees w i m m i n g l a r v a e , t h e l e t h a l i t y is h i g h a n d no a d u l t anim a l s are likely t o be formed. Discussion. I t is a r e m a r k a b l e f a c t t h a t t h e r e s p o n s e to t r e a t m e n t w i t h t h a l i d o m i d e d u r i n g e m b r y o n a l life of w a r m - b l o o d e d a n i m a l s d i s p l a y s a r i c h v a r i a t i o n , w h i c h is e v i d e n t l y c o r r e l a t e d w i t h t h e p a r t i c u l a r s t r a i n of a n i m a l s used in tile e x p e r i m e n t s 2-4. W e i n t r o d u c e d g a m e t e s a n d e m b r y o s f r o m sea u r c h i n s as a m a t e r i a l for t e s t i n g t o x i c i t y o n t h e cellular a n d e m b r y o n a l level 6, 7. T h e p r e s e n t e x p e r i m e n t s w i t h m a r i n e fishes c o r r o b o r a t e t h e r e s u l t s f r o m our p r e v i o u s w o r k o n e c h i n o d e r m s . T h e species of fishes used are v e r y d i f f e r e n t a n d t h e y live a n d reproduce under very different environmental conditions. T h e r e s p o n s e to t h a l i d o m i d e was u n i f o r m , a n d n o t speciesrelated, a n d t h e m a i n m o r p h o g e n e t i c effects were conc e n t r a t e d to t h e d i f f e r e n t i a t i o n of t h e m e s o d e r m . T h e full effect w a s o b t a i n e d a l r e a d y b y p r e t r e a t i n g t h e sperm a t o z o o n for o n l y 2 m i n in a 10 .5 M s o l u t i o n of t h a l i d o mide. Since t h e s p e r m a t o z o o n m a i n l y consists of a n u cleus, it is w a r r a n t e d to c o n c l u d e t h a t t h a l i d o m i d e interacts with the genome, and particularly with the genes w h i c h g o v e r n t h e d i f f e r e n t i a t i o n of t h e skeleton. 7 B.E. Hagstr6m and S. L6uning, Experientia 32, 744 (1976).
Simple theoretical criterion of chemical carcinogenicity V. V e l j k o v i d a n d D. 1. L a l o v i d
Laboratory/or Theoretical Physics, Boris Kidrig Institute, l lO01 Belgrade (Yugoslavia), 21 January 1977 Summary. T h e c o r r e l a t i o n b e t w e e n t h e a v e r a g e q u a s i - v a l e n c e n u m b e r a n d c a r c i n o g e n i c i t y of organic c o m p o u n d s h a s b e e n e s t a b l i s h e d a n d discussed. I n o u r r e c e n t w o r k 1, we h a v e e s t a b l i s h e d t h e c o r r e l a t i o n between the pseudoatomic potential 2 and carcinogenicity. T h e c o m p l e x f o r m of t h e p s e u d o a t o m i c p o t e n t i a l , e m p l o y e d in t h e p r e v i o u s work, c o n t a i n e d C o u l o m b i n t e r a c t i o n a n d P a u l i r e p u l s i o n c o m p o n e n t s , a n d i t was r a t h e r difficult for c a l c u l a t i o n b y lion-specialists. Since in t h i s p o t e n t i a l t h e a v e r a g e q u a s i - v a l e n c e n u m b e r Z*, d e f i n e d as : m
27 NlZi i~1 z* - - m
(1)
27 Ni i~l
where Ni is the n u m b e r of atoms of the i-th type in the given molecule, Zi is the n u m b e r of valence electrons in the a t o m of the i-th type 3, and m is the n u m b e r of chemical elements in the molecule, plays a very important role 4,5, w e decided to look for the possible existence of a correlation b e t w e e n t h e a v e r a g e q u a s i - v a l e n c e n u m b e r a n d c a r c i n o g e n i c i t y Of c h e m i c a l s u b s t a n c e s . C a l c u l a t e d v a l u e s of t h e a v e r a g e q u a s i - v a l e n c e n u m b e r for a b o u t 400 organic c o m p o u n d s of k n o w n c a r c i n o g e n i c activity strongly correlate with their carcinogenic p r o p e r t i e s . I n t h e t a b l e , we p r e s e n t d a t a for t h e a n a l y z e d c o m p o u n d s biologically t e s t e d i n m a m m a l s . O n t h e b a s i s of a v a i l a b l e biological results, we h a v e c o n c l u d e d t h a t p o t e n t i a l c a r c i n o g e n s h a v e Z * v a l u e s b e l o w 3.20, while n o n c a r c i n o g e n s are c h a r a c t e r i z e d b y Z* a b o v e 3.20. T h e
b o r d e r l i n e v a l u e of 3.20 h a s b e e n c h o s e n o n t h e b a s i s of e m p i r i c a l biological d a t a . T h e L y o n ( I n t e r n a t i o n a l A g e n c y for R e s e a r c h o n Cancer) c r i t e r i o n for c a r c i n o g e n i c i t y h a s b e e n used i n t h i s work. T h e classification of a b o u t 400 organic c o m p o u n d s e i n t o 2 categories: potential carcinogens and noncarcinogens is c o n n e c t e d w i t h all e r r o r of a b o u t 8 % . C o r r e s p o n d i n g e r r o r for c o m p o u n d s t e s t e d in m a m m a l s a n d r e p o r t e d in L y o n ' s m o n o g r a p h s is o n l y 5 % . In connection with the above average quasi-valence n u m b e r criterion, one s h o u l d n o t i c e t h e following: a) T h e c r i t e r i o n is b a s e d o n t h e use of m o l e c u l a r f o r m u l a a n d i t is i n s e n s i t i v e t o t h e effects of isomerisms. b) I n v e s t i g a t i o n s of t h e p r i m a r y m o l e c u l a r f o r m a l t e r a t i o n s d u e t o m e t a b o l i c processus h a v e s h o w n t h a t t h e a v e r a g e q u a s i - v a l e n c e n u m b e r of o r i g i n a l molecule is n o t c h a n g e d b y m o r e t h a n 10%. T h i s e x p l a i n s some of tile
1 V. Veljkovid and D. I. Lalovid, Cancer Biochem. Biophys. l, 295 (1976). 2 V. Veljkovid and D. I. Lalovid, Phys. Lett. 45A, 59 (1973). 3 In case of halogen elements instead of Z = 7, Z = 1 should be taken. 4 V. Veljkovid, Phys. Lett. 45A, 41 (1973). 5 V. Veljkovid and D. I. Lalovid, Phys. Rev. 11, 4242 (1975). 6 In the table we included all those substances for which we found well established biological data obtained from mammalian systems.
15.9. 1977
1229
Speelalia
Correlation between the quasi-valence number and earcinogenieity of the organic chemical compounds Compound
Molecular formula
Z*
Carcinogenicity~' ~
Compound
Molecular formula
Z*
Careinogenieity', s
Carbon tetrachloride Chloroform Tetramethyllead Tetraethyllead Vinyl chloride 1,2-Diethylhydrazine Polychlorinated biphenyls 1,1-Dimethylhydrazine Bis(ehlormethyl)ether Chlormethyl methyl ether N-Nitroso-di-n-butylamine Hydrazine Mirex Heptachlor Aldrin N-Nitrosodiethylamine Aramite | Benzene DDT DDD (TDE) Diehlorbenzene Dieldrin Auramine 3, 3'-Dimethylbenzidine Methoxychlor Dihydrosafrole 4, 4'-Methylenedianiline 4-Aminobiphenyl Aminoazotoluene Benzidine Dxmethylaminoazobenzene Naphtylamine Chrysoidine N -Nitrosodimeth ylamine 3, 3'-Dimethoxybenzidine Urethane Benzanthraeene Chlorobenzilate Yellow OB Diacetylaminoazotoluene Sudan II Safrole Azobenzene Ethylenethiourea Sudan red 7B Dibenzanthraeene Aminoazobenzene Propylthiouracil Benzofluoranthene 7H-Dibenzoearbazole Oil orange SS Sudan brown RR Aeetamide Dibenzopyrene C. I. Disperse Yellow 3 Dibenzacridine 4-Hydroxyazobenzene Citrus red No. 2 Thiourea Cyeasin Methylazoxymethanol Nitrosoethylurea 4-Nitrobiphenyl Streptozotoein Methyl methanesulphonate Dicetene Adenosin Salicyelic acid Quintezene Piperonyl Orange I Dimethylsulphate
CCI4 CHCI~ Pb(CHs) 4 Pb(C2H~) 4 C~HsC1 C4H12N~ Cl~Cla0 C2HsN2 C2H4C1~O CzHsC10 CsHlsN20 N2H 4 C10C112 C10HsCt~ ClzHsCI~ C~HxoNzO C12H23C104S CsIt e C14H9C15 Ca4H10C1~ CeH4c12 CI~HsCI~O C17H21Ns C14H16Nz ClsHtselsO2 Ca0H100z ClsHI4N ~ C12HnN Ca4HI~Ns Ca~HlzNz C1,H15Ns C10HgN C12HlsCINi CzH6N~O C1,HasNzO~ CsH:NO ~ CasHx~ C~,HxiCl20 a C17H~N s CasHx~NsO~ ClsHlnN~O C~oH100z CI~H10Nz C3HeN~S C2~H21N~ C~Hx4 Ca~HnN s C7H10N2OS CxoH~ C,0H~N CxTHa4NzO Cx~Hx~N~ C~H~NO C~HI~ C~Hx~NsOz C~IHIsN Ca~Hx0N20 C~HI~N~Os CHiN~S CsH~eN~O7 C4HsN20 s CsFITNsO~ CI~HgNOz CsH~NsO7 C~H6OsS C4H~O~ C~0HasN~O~ CTH~% C~CI~NO2 CsH~Oa C~HnN~NaO~S C~HeO~S
1.60 1.60 1.88 1.93 2.00 2.11 2.12 2.17 2.22 2.22 2.28 2.33 2.36 2.36 2.38 2.47 2.49 2.50 2.50 2.50 2.50 2.52 2.54 2.56 2.61 2.67 2.67 2.67 2.69 2.69 2.69 2.70 2.73 2.73 2.76 2.77 2.80 2.80 2.80 2.81 2.81 2.82 2.83 2.83 2.84 2.84 2.85 2.86 2.88 2.88 2.88 2.88 2.89 2.90 2.91 2.92 2.94 2.97 3.00 3.03 3.06 3.07 3.08 3.15 3.17 3.20 3.20 3.26 3.28 3.29 3.31 3.38
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + -----
Alizarin Ammonium urate acid 5-Nitro-2-furaldehide semiearbazone Carmoisine Evens blue 2-(2-Furyl)-3-(5-nitrofuryl)acrylamide 6-Mercaptopurine Sunset yellow FCF Amido-G-acid Amarath Alizarin orange Xantin 1-](Nitrofurfurylidine) amino]hydantion 5-Nitro-2- furamidoxime Alloxantin Alloxan
C14HsO4 CsHTNsOs
3.38 3.50
---
CsHnN404 C20H12N2Na40~S2 C~4H2oN6Na4014S4
3.50 3.51 3.53:
----
CnHsN20 ~ C~H4N4S C16H10N2Na2OTS z C14H804 C20HnNaaN2OnS s C14HTNO~ C5H~N40~
3.54 3.57 3.59
--------
CsH6N40 s CsHsN:~O * CsH4N40 s C4H2N20 ,
3:83 3.76 4.08 4.17
-
-
---
3.71 3.71 3.73
---
-
--
e r r o r s in t h e o r e t i c a l p r e d i c t i o n of n o n c a r c i n o g e n i c i t y i n c a s e of c h e m i c a l c o m p o u n d s h a v i n g Z* close t o t h e b o r d e r l i n e v a l u e of 3.20. c) I n case of n o n c a r c i n o g e n e c i t y t h e q u a s i - v a l e n c e n u m b e r is n e c e s s a r y a n d s u f f i c i e n t c r i t e r i o n . F o r c a r c i n o g e n i c a c t i v i t y it is n e c e s s a r y b u t n o t s u f f i c i e n t . F o r t h i s r e a s o n , w e c l a s s i f y all s u b s t a n c e s in p o t e n t i a l c a r c i n o g e n e s a n d noncarcinogenes. O n t h e b a s i s of r e s u l t s o b t a i n e d w e c o n c l u d e t h a t t h e a v e r a g e q u a s i - v a l e n c e n u m b e r of o r g a n i c c o m p o u n d s c a n b e u s e d f o r t h e o r e t i c a l p r e d i c t i o n of p o t e n t i a l c a r c i n o g e n i c i t y of o r g a n i c c o m p o u n d s . V e r y s i m p l e c a l c u l a t i o n of t h e a v e r a g e q u a s i - v a l e n c e n u m b e r ( t h e r a t i o of t h e s u m of all a t o m i c v a l e n c e e l e c t r o n s a n d t h e n u m b e r of a t o m s in t h e g i v e n m o l e c u l e ) allows one to check and use the above correlation. T h e e s t a b l i s h e d c o r r e l a t i o n c o u l d be of p r a c t i c a l b e n e f i t in s e l e c t i o n a n d u s e o f o r g a n i c c o m p o u n d s , a s well a s s h e d d i n g s o m e n e w l i g h t o n t h e m e c h a n i s m of c a r c i n o genesis. Interesting relationships between other biological activities of o r g a n i c c o m p o u n d s a n d t h e i r a v e r a g e q u a s i v a l e n c e n u m b e r s h a v e also b e e n f o u n d a n d will b e d i s c u s s e d elsewere.
7 8
IARC Monographs, Evaluation of Carcinogenic Risk, vol. 1-8. Lyon 1972-1975. Ann. N.Y. Aead. Sci. J63, 589 (1969).
