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Chapter 23
Base-Line Toxicity Predicted by Quantitative Structure—Activity Relationships as a Probe for Molecular Mechanism of Toxicity Downloaded via TUFTS UNIV on July 7, 2018 at 09:19:25 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Robert L. Lipnick Office of Toxic Substances (TS-796), U.S. Environmental Protection Agency, 401 M Street, SW, Washington, DC 20460 Narcosis represents the most fundamental mechanism of the toxicity of nonelectrolyte organic compounds, and corresponds to minimum or baseline toxicity. Quantitative structure-activity relationships for chemicals acting by this mechanism for various organisms and routes of exposure provide a valuable probe for determining whether or not a candidate chemical acts via narcosis or by an electrophile, proelectrophile, cyanogenic, or other more specific molecular mechanism. Structure-activity relationships (SAR) and quantitative structureactivity relationships (QSAR) have attracted increased interest by the U.S. Environmental Protection Agency (1-3) in the review of new industrial chemicals prior to their manufacture under section 5 of the Toxic Substances Control Act (TSCA) ( 4 ) . There is also a strong impetus in Europe to develop QSAR models to assess the potential toxicity of industrial organic chemicals ( 5 ) . The applicability of such predictive models is dependent upon the availability of measured or predicted values of the parameters used in the QSAR model, and by the validity of the assumption that the mechanism of toxicity of the candidate chemical is the same as that of the compounds used to derive the QSAR, and that they encompass the same range in spanned substituent space ( 6 ) . The relationships that should ideally be satisfied for such models are illustrated in Figure 1. In the absence of more specific effects, nonelectrolyte organic compounds act by a narcosis mechanism, which represents minimum or baseline toxicity. Baseline toxicity QSAR models can be used as a probe to identify chemicals acting by more specific toxicological mechanisms. Demonstrating Commonality of Molecular Mechanism The assumption of the commonality of mechanism is rarely stated in a QSAR study, but can be based implicitly or explicitly on one or more of the following: This chapter not subject to U.S. copyright Published 1989 American Chemical Society
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
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PHYSIOLOGICAL RESPONSE
MECHANISM BASED MOLECULAR DESCRIPTORS
PREDICTION OF TOXICITY OF UNTESTED CHEMICALS
F i g u r e 1. Mechanism-based QSAR model and i t s r e l a t i o n s h i p t o c h e m i c a l and b i o l o g i c a l d a t a o f t h e m o l e c u l e s u s e d i n i t s d e r i v a t i o n . A q u a n t i t a t i v e p r e d i c t i o n o f t h e t o x i c i t y o f an u n t e s t e d c h e m i c a l r e q u i r e s t h e a v a i l a b i l i t y o f a QSAR model f o r r e l a t e d compounds a c t i n g b y a putative common m o l e c u l a r mechanism and t h e a b i l i t y t o measure o r p r e d i c t t h e r e q u i r e d mechanism-based m o l e c u l a r d e s c r i p t o r s u s e d i n t h e QSAR model.
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P R O B I N G BIOACTTVE M E C H A N I S M S
1. 2. 3. 4. 5.
Receptor b i n d i n g Symptomatology QSAR c o r r e l a t i o n Additivity of biological Chemical p r o p e r t i e s
activity
JReceptor Binding. The f i r s t c r i t e r i o n c o n s i s t s o f s i m i l a r t y p e s o f b i n d i n g w i t h i s o l a t e d r e c e p t o r s o r o t h e r m o l e c u l a r s i t e s o f a c t i o n and u n d e r s t a n d i n g o f t h e pathway o f c a s c a d i n g b i o c h e m i c a l and p h y s i o l o g i c a l p e r t u r b a t i o n s l e a d i n g t o t h e o b s e r v e d end e f f e c t . I n f o r m a t i o n from t h e e x a c t s t r u c t u r e o f and o t h e r r e c e p t o r s enzymes i s becoming an e x t r e m e l y p o w e r f u l t o o l i n t h e d e s i g n o f new drugs ( 7 ) . Symptomatology, A second criterion consists o f commonality o f syndromes, and b i o c h e m i c a l and p h y s i o l o g i c a l changes a s s o c i a t e d w i t h t h e t o x i c end e f f e c t . S i m i l a r symptomatology has p r o v i d e d a t r a d i t i o n a l c r i t e r i o n f o r a s s e s s i n g t h e d e g r e e t o w h i c h a group o f compounds may be a c t i n g by a common mechanism, and as e v i d e n c e f o r a change i n mechanism within a series. Chemicals producing a narcosis or anesthetic p h y s i o l o g i c a l r e s p o n s e a r e f r e q u e n t l y c l a s s i f i e d o n t h i s b a s i s due t o t h e l a c k o f a s p e c i f i c r e c e p t o r t h a t has been c h a r a c t e r i z e d a t t h e molecular level. More recently an attempt h a s been made t o m a t h e m a t i c a l l y t r a n s f o r m a l a r g e number o f q u a n t i t a t i v e symptomatology p a r a m e t e r s t o a s m a l l e r number o f o r t h o g o n a l d e s c r i p t o r s i n w h i c h symptomatology syndromes c o u l d be d e f i n e d t h r o u g h c l u s t e r a n a l y s i s ( f i ll). QSAR Correlation. S t a t i s t i c a l q u a l i t y o f QSAR c o r r e l a t i o n c a n be employed as a t h i r d c r i t e r i o n o f commonality o f mechanism. This a p p r o a c h c a n p r o v e v e r y m e a n i n g f u l when c o u p l e d w i t h a m e c h a n i s t i c i n t e r p r e t a t i o n o f t h e r o l e o f molecular d e s c r i p t o r s used i n the c o r r e l a t i o n , and w i t h t h e s i g n i f i c a n c e o f t h e s l o p e and i n t e r c e p t . The q u a l i t y o f s t a t i s t i c a l f i t and t h e i n t e r p r e t a t i o n o f t h e p a r a m e t e r o r parameters used i n the c o r r e l a t i o n can p r o v i d e a v a l u a b l e i n s i g h t i n t o m o l e c u l a r mechanism. R e c e n t l y , Hansch a n a l y s i s has been combined w i t h m o l e c u l a r g r a p h i c s and m o d e l i n g s t u d i e s i n w h i c h t h e a c t i v i t i e s o f a s e r i e s o f s u b s t r a t e s t o an enzyme r e c e p t o r have been r e l a t e d t o t h e h y d r o p h o b i c , e l e c t r o n i c , and s t e r i c r e q u i r e m e n t s f o r r e v e r s i b l e b i n d i n g (12). Additivity of Biological Activity. Additivity of t o x i c i t y i s a valuable means f o r d e m o n s t r a t i n g commonality o f mechanism. I n most c a s e s , compounds a c t i n g b y d i f f e r e n t mechanisms show t o x i c i - t i e s t h a t a r e l e s s t h a n a d d i t i v e ( 1 3 ) . I t has been d e m o n s t r a t e d t h a t t h e a q u a t i c t o x i c i t y o f up t o 50 n o n e l e c t r o l y t e o r g a n i c c h e m i c a l s a c t i n g by a n a r c o s i s mechanism e x h i b i t s s t r i c t l y a d d i t i v e b e h a v i o r (14-16). Chemical Properties. F i n a l l y , s i m i l a r i t y i n c h e m i c a l p r o p e r t i e s and r e a c t i v i t y b a s e d upon m e c h a n i s t i c and p h y s i c a l o r g a n i c c h e m i s t r y c a n a l s o be u s e d t o s u p p o r t a h y p o t h e s i s o f commonality o f mechanism ( 1 7 ) . By t h i s means, a t r a i n e d o r g a n i c c h e m i s t c a n s u g g e s t t h e l i m i t a t i o n s o f a mechanism even f o r d i s t a n t l y r e l a t e d compounds b a s e d upon t h e i r
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c h e m i c a l p r o p e r t i e s , thus p e r m i t t i n g t h e i d e n t i f i c a t i o n t h a t c a n p o t e n t i a l l y a c t b y more s p e c i f i c mechanisms. Discovery Solubility
of the Correlation and Molecular Weight
Between
Narcosis
o f chemicals
Potency
and
Mater
I n t e r e s t has e x i s t e d f o r some time r e g a r d i n g what p r o p e r t y o f a m o l e c u l e i s r e s p o n s i b l e f o r t h e p r o d u c t i o n o f a s p e c i f i c type o f b i o l o g i c a l response (28-20). I n the case o f n a r c o s i s o r a n e s t h e t i c response, t h i s was c o m p l i c a t e d b y t h e f i n d i n g t h a t n a r c o s i s c o u l d be p r o d u c e d b y a wide v a r i e t y o f d i f f e r e n t , a p p a r e n t l y u n r e l a t e d compounds, i n c l u d i n g s i m p l e saturated monohydric alcohols. Perhaps the e a r l i e s t systematic i n v e s t i g a t i o n o f t h e m e c h a n i s t i c b a s i s o f n a r c o s i s was t h a t o f C r o s a t t h e U n i v e r s i t y o f S t r a s b o u r g , who i n 1863 r e p o r t e d t h a t t o x i c i t y o f s i m p l e a l c o h o l s a d m i n i s t e r e d t o mammals i n c r e a s e s w i t h d e c r e a s i n g w a t e r s o l u b i l i t y , up t o a p o i n t o f maximum p o t e n c y , beyond w h i c h i t d e c r e a s e s , u n t i l t h e a l c o h o l s become v e r y i n s o l u b l e and a c t l i k e f a t t y s u b s t a n c e s (21). R i c h a r d s o n i n E n g l a n d (22) i n 1869 found t h a t t h e t o x i c i t y o f simple monohydric a l c o h o l s t o mammals and b i r d s increased with i n c r e a s i n g m o l e c u l a r w e i g h t , and t h i s r e l a t i o n s h i p h a s been r e f e r r e d t o as R i c h a r d s o n ' s l a w ( 2 3 ) . Rabuteau i n F r a n c e (24) i n 1870 c o n c l u d e d t h a t t h e i n c r e a s e i n t h e t o x i c i t y t o f r o g s immersed i n s o l u t i o n s o f a l c o h o l s r e f l e c t e d an i n c r e a s e i n c h a i n l e n g t h . Both o f these s c i e n t i s t s were a p p a r e n t l y unaware o f C r o s * e a r l i e r , more f u n d a m e n t a l d i s c o v e r y . A l t h o u g h C r o s * d i s c o v e r y was c o n f i r m e d s e v e r a l y e a r s l a t e r b y D u j a r d i n Beaumetz and A u d i g e (25-27), i t was a p p a r e n t l y n o t u n t i l 1893 t h a t t h e r e l a t i o n s h i p between water s o l u b i l i t y and n a r c o s i s - p r o d u c e d t o x i c i t y was i n v e s t i g a t e d more c a r e f u l l y . Georges H o u d a i l l e , a d o c t o r a l s t u d e n t o f Charles Richet a t the U n i v e r s i t y o f P a r i s , observed a c o r r e l a t i o n between water s o l u b i l i t y and minimum n a r c o s i s c o n c e n t r a t i o n t o f i s h and t a d p o l e s f o r a v a r i e t y o f h y p n o t i c agents (28). This relationship i s f r e q u e n t l y r e f e r r e d t o as R i c h e t * s l a w ( 2 9 ) . Discovery Coefficient
of
the Correlation
of
Narcosis
Potency
and
Partition
The d i s c o v e r y o f a parameter ( o l i v e o i l / w a t e r p a r t i t i o n c o e f f i c i e n t ) upon w h i c h a m e c h a n i s t i c i n t e r p r e t a t i o n f o r n a r c o s i s c o u l d be b a s e d was made i n d e p e n d e n t l y s i x y e a r s l a t e r b y C h a r l e s E r n e s t O v e r t o n a t t h e U n i v e r s i t y o f Z u r i c h (30-31) and b y Hans H o r s t Meyer (32) and h i s c o l l a b o r a t o r F r i t z Baum (33) a t t h e U n i v e r s i t y o f Marburg. Prior to t h i s d i s c o v e r y , W a l t e r D u n z e l t , a s t u d e n t o f Meyer, attempted t o c o n f i r m t h e H o u d a i l l e d a t a o n t h e r e l a t i o n s h i p between water s o l u b i l i t y and minimum t o x i c c o n c e n t r a t i o n , u s i n g t a d p o l e s and s m a l l f i s h ( 3 4 ) . D u n z e l t c o n c l u d e d i n h i s 1896 I n a u g u r a l D i s s e r t a t i o n (34) t h a t a l t h o u g h t h i s c o r r e l a t i o n seemed t o be g e n e r a l l y c o r r e c t , i t d i d n o t h o l d f o r two compounds. Bromal h y d r a t e was f o u n d t o be v e r y s o l u b l e i n w a t e r and p r o d u c e n a r c o s i s i n f i s h a t low c o n c e n t r a t i o n s . By c o n t r a s t , m e t h y l u r e t h a n e was found t o p r o d u c e o n l y a s l i g h t n a r c o t i c e f f e c t , even though i t was o n l y s l i g h t l y s o l u b l e i n w a t e r . T h i s f i n d i n g o f D u n z e l t may have p r o v i d e d Meyer w i t h t h e impetus t o s e a r c h f o r a n o t h e r c h e m i c a l property t h a t b e t t e r c o r r e l a t e d with n a r c o t i c potency. Meyer f u r t h e r
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supported the r e l e v a n c e o f p a r t i t i o n c o e f f i c i e n t t o the m e c h a n i s t i c b a s i s o f n a r c o s i s by d e m o n s t r a t i n g t h a t t h e t e m p e r a t u r e dependence o f n a r c o s i s i n t a d p o l e s f o l l o w e d t h e same t r e n d s as t h e c o r r e s p o n d i n g o l i v e o i l / w a t e r p a r t i t i o n c o e f f i c i e n t s (35). O v e r t o n ' s d i s c o v e r y e v o l v e d from s t u d i e s o f c e l l p e r m e a b i l i t y w i t h a l g a e , and l a t e r , t a d p o l e s (36-37). Overton p r o v i d e d c o n s i d e r a b l e s u p p o r t two y e a r s l a t e r f o r t h i s l i p o i d t h e o r y o f n a r c o s i s i n h i s c l a s s i c monograph " S t u d i e n iiber d i e N a r k o s e , " (32) whose f i n d i n g s have r e c e n t l y been r e v i e w e d (38). O v e r t o n ' s t a d p o l e d a t a have been employed i n s e v e r a l QSAR s t u d i e s (39-42) ( L i p n i c k , R.L. I n QSAR in Drug Design; F a u c h e r e , J . L . , Ed.; A l a n R. L i s s : New Y o r k , i n p r e s s . ) . More Recent
Studies
of
Narcosis
For the next f i v e decades, the c o r r e l a t i o n o f p a r t i t i o n c o e f f i c i e n t w i t h n a r c o s i s p o t e n c y c o n t i n u e d t o be an i m p o r t a n t a r e a f o r r e s e a r c h , w i t h s t u d i e s o f v a r i o u s compounds p e r f o r m e d u s i n g whole o r g a n i s m s , organs, c e l l s , and enzymes. T h i s work has been d i s c u s s e d i n a number o f major r e v i e w s ( 4 2 - 5 2 ) , and i n p a p e r s from an i n t e r n a t i o n a l c o n f e r e n c e on t h i s s u b j e c t h e l d i n P a r i s i n 1950 ( 5 2 ) . D e s p i t e t h e c o n s i d e r a b l e number o f s t u d i e s o f t h e mechanism o f n a r c o s i s , t h e d e t a i l s r e g a r d i n g i t s m o l e c u l a r b a s i s have p r o v e n v e r y e l u s i v e , and t h e t h e o r e t i c a l b a s i s f o r n a r c o s i s o r a n e s t h e s i a s t i l l r e p r e s e n t s a s u b j e c t o f c o n s i d e r a b l e debate. Current research i s f o c u s e d on two major t h e o r i e s , d i s o r g a n i z a t i o n o f membrane l i p o i d c o n s t i t u e n t s (53-54), and b i n d i n g t o one o r more enzymes o r p r o t e i n s (55-56). Linear
QSAR Models
for
Narcosis
Baseline
Toxicity
In t h e mid 1960s Hansch and co-workers employed r e g r e s s i o n a n a l y s i s t o develop quantitative structure-activity relationships (57). They r e p o r t e d a number o f l i n e a r QSARs f o r s i m p l e n o n e l e c t r o l y t e s a c t i n g by a n a r c o s i s mechanism ( 4 0 ) , i n t h e form, log
(1/C) - A l o g P + B
(1)
where C i s t h e m o l a r c o n c e n t r a t i o n p r o d u c i n g a s t a n d a r d b i o l o g i c a l r e s p o n s e , and P i s t h e n - o c t a n o l / w a t e r p a r t i t i o n c o e f f i c i e n t . When an o r g a n i s m i s p l a c e d i n an aqueous s o l u t i o n o f a t o x i c a n t , p s e u d o - s t e a d y - s t a t e p a r t i t i o n i n g t a k e s p l a c e between t h e t o x i c s i t e o f a c t i o n and t h e aqueous p h a s e . F o r organisms i n w h i c h a i r i s e x t r a c t e d from t h e w a t e r by means o f g i l l s , exchange o f t o x i c a n t t a k e s p l a c e m a i n l y v i a t h i s r o u t e , and t h e r a t e o f u p t a k e i s c o n t r o l l e d by t h e c r o s s - s e c t i o n a l a r e a , and t h e r a t e o f b l o o d f l o w a c r o s s t h e g i l l s . R e c e n t l y , a number o f i n v e s t i g a t o r s have r e p o r t e d l i n e a r QSARs f o r the t o x i c i t y o f simple n o n e l e c t r o l y t e s t o a q u a t i c organisms (58-63). A g e n e r a l r e p r e s e n t a t i o n o f s u c h QSARs and t h e i r l i m i t a t i o n s i s d e p i c t e d i n F i g u r e 2. These e q u a t i o n s a r e o f enormous v a l u e t o EPA and o t h e r r e g u l a t o r y agencies i n s e t t i n g t e s t i n g p r i o r i t i e s f o r chemicals i n commerce and f o r new i n d u s t r i a l c h e m i c a l s p r i o r t o t h e i r m a n u f a c t u r e . A c o r r e s p o n d i n g p s e u d o - s t e a d y - s t a t e p a r t i t i o n i n g t a k e s p l a c e between t h e t o x i c a n t v a p o r and t h i s same s i t e o f a c t i o n f o r gaseous a n e s t h e t i c
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DOMAIN OF EXCESS TOXICITY
BASELINE NARCOSIS MECHANISM QSAR
THEORETICAL HoO SOLUBILITY CUTOFF. LIQUID SOLUTES LOCAL QSAR ELECTROPHILE AND PROELECTROPHILE MECHANISMS
PHARMACOKINETIC H5O SOLUBILITY CUTOFF OF BILINEAR OSARs H2O SOLUBILITY LIQUID SOLUTES
Log P F i g u r e 2. Baseline narcosis aquatic t o x i c i t y QSAR model. For n o n e l e c t r o l y t e s a c t i n g b y a n a r c o s i s mechanism, no t o x i c i t y i s o b s e r v e d i f t h e p r e d i c t e d t o x i c c o n c e n t r a t i o n exceeds the w a t e r s o l u b i l i t y . W i t h decreasing t e s t d u r a t i o n , pseudo-s t e a d y - s t a t e p a r t i t i o n i n g i s not a c h i e v e d f o r v e r y h y d r o p h o b i c c h e m i c a l s , and t h e l o c a t i o n o f t h e water solubility cutoff shifts t o chemicals having a lower partition coefficient. Compounds a c t i n g b y more s p e c i f i c mechanisms p r o d u c e t o x i c i t y a t l o w e r aqueous c o n c e n t r a t i o n s t h a n p r e d i c t e d b y n a r c o s i s , and f a l l w i t h i n t h e domain o f e x c e s s t o x i c i t y .
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agents. I n t h i s c a s e , t h e o i l / g a s p a r t i t i o n c o e f f i c i e n t and n o t t h e o i l / w a t e r p a r t i t i o n c o e f f i c i e n t i s t h e a p p r o p r i a t e model p a r a m e t e r and y i e l d s a l i n e a r c o r r e l a t i o n as shown i n F i g u r e 3. By c o n t r a s t , o n l y s c a t t e r i s o b s e r v e d i f o c t a n o l / w a t e r i s u s e d as t h e model p a r a m e t e r as shown i n F i g u r e 4 ( 6 4 ) . Model Partitioning
Systems
O v e r t o n and Meyer b o t h u s e d o l i v e o i l as a p a r t i t i o n i n g system t o model t h e p h y s i c o c h e m i c a l p r o p e r t i e s o f t h e p u t a t i v e membrane l i p o i d s i t e o f a c t i o n . A l t h o u g h O v e r t o n attempted t o u s e m e l t e d c h o l e s t e r o l and o t h e r s u b s t a n c e s he t h o u g h t might s e r v e as a b e t t e r r e f e r e n c e phase, he abandoned this a p p r o a c h due t o problems w i t h the formation of i n s e p a r a b l e e m u l s i o n s ( 3 1 ) . C o l l a n d e r i n F i n l a n d (65) e x p e r i m e n t e d w i t h a v a r i e t y o f aqueous o r g a n i c s o l v e n t systems and f o u n d t h a t f o r many s i m p l e n o n e l e c t r o l y t e s , t h e v a l u e s were w e l l - c o r r e l a t e d a c c o r d i n g t o t h e following equation; l o g Pi « a l o g P
2
+ b
(2)
where Pi and ?£ a r e two s u c h p a r t i t i o n i n g s y s t e m s . The C o l l a n d e r e q u a t i o n s were i n v e s t i g a t e d mora f u l l y by Leo and Hansch. They c o n c l u d e d t h a t s o l u t e s a b l e t o a c t as e i t h e r s t r o n g hydrogen-bond donors o r a c c e p t o r s r e q u i r e an a d d i t i o n a l c o r r e c t i o n t o a c c o u n t f o r t h e r e l a t i v e a b i l i t y o f the o r g a n i c s o l v e n t s t o i n t e r a c t i n t h i s f a s h i o n w i t h r e s p e c t t o one a n o t h e r ( 6 6 ) . A l t h o u g h n - o c t a n o l i s now commonly u s e d as a model o r g a n i c phase, i t s h o u l d be k e p t i n mind t h a t i t may be a b e t t e r model f o r some b i o l o g i c a l systems t h a n f o r o t h e r s . Meyer and Hemmi (67) compared t h e a b i l i t y o f p a r t i t i o n c o e f f i c i e n t s from d i f f e r e n t s o l v e n t systems t o model n a r c o s i s d a t a , and t h e y f o u n d o l e y l a l c o h o l t o y i e l d the best r e s u l t s . F o r complex o r g a n i c m o l e c u l e s c o n t a i n i n g h y d r o g e n b o n d i n g f u n c t i o n a l g r o u p s , t h e c h o i c e o f a p a r t i c u l a r model s y s t e m c o u l d l e a d t o a p p a r e n t o u t l i e r s w h i c h may n o t r e f l e c t a t r u e change o f mechanism a t t h e m o l e c u l a r s i t e o f a c t i o n . Estimation
of Partition
Coefficients
The development o f t h e fragment c o n s t a n t methodology f o r p r e d i c t i n g log P values directly from chemical s t r u c t u r e (68-71) and i t s c o m p u t e r i z a t i o n (72-73) i s f u r t h e r i n g t h e use o f n - o c t a n o l as a s t a n d a r d r e f e r e n c e p h a s e . A n o t h e r a p p r o a c h t h a t has been p u r s u e d i s t h e use o f r e t e n t i o n t i m e s d e t e r m i n e d on a r e v e r s e d - p h a s e HPLC column t o e s t i m a t e l o g P, u s i n g a s e t o f s t a n d a r d s o l u t e s f o r r e f e r e n c e ( 7 4 - 7 6 ) . These c o r r e l a t i o n s d i s p l a y l i m i t a t i o n s s i m i l a r t o t h o s e i n c h a n g i n g from one p a r t i t i o n i n g system t o another i f hydrogen-bonding i n t e r a c t i o n s are significant. The i n t e r a c t i o n s o f t h i s t y p e o f s o l u t e w i t h b i o l o g i c a l s u b s t r a t e s have a l s o been modeled u s i n g s o l v a t o c h r o m i c p a r a m e t e r s ( 7 7 ) . Species
Sensitivity
to
Narcosis
G e n e r a l l y , t h e s l o p e s o f QSARs f o r n a r c o s i s a r e c l o s e t o u n i t y i n d i c a t i n g t h a t (1) n - o c t a n o l p r o v i d e s a r e a s o n a b l e model f o r t h e p h y s i c o c h e m i c a l p r o p e r t i e s o f t h e b i o l o g i c a l s i t e o f a c t i o n , (2) p s e u d o -
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
23. LIPNICK
Base-Line Toxicity Predicted by QSAR
0
0.5
1
1.5
2
373
2.5
Log K (Oil/Gas) F i g u r e 3. L i n e a r r e l a t i o n s h i p between o i l / g a s p a r t i t i o n c o e f f i c i e n t and minimum c o n c e n t r a t i o n i n a i r r e q u i r e d t o produce a n e s t h e s i a i n mice on a log log scale. (Reproduced w i t h p e r m i s s i o n from R e f . 64. C o p y r i g h t 1987 E l s e v i e r ) .
F i g u r e 4. L a c k o f a r e l a t i o n s h i p between o c t a n o l / w a t e r partition c o e f f i c i e n t and minimum c o n c e n t r a t i o n i n a i r r e q u i r e d t o p r o d u c e a n e s t h e s i a i n mice on a l o g l o g s c a l e . (Reproduced w i t h p e r m i s s i o n from R e f . 64. C o p y r i g h t 1987 E l s e v i e r ) .
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
374
PROBING BIOACTIVE
MECHANISMS
s t e a d y - s t a t e p a r t i t i o n i n g has been a c h i e v e d , and (3) any l o s s o f t o x i c a n t v i a metabolism i s reasonably constant w i t h i n the s e r i e s s t u d i e d . The i n t e r c e p t i n QSAR i s a measure o f t h e r e l a t i v e s e n s i t i v i t y of the organism. B o t h Meyer and O v e r t o n p o s t u l a t e d t h a t t h e r e l a t i v e s e n s i t i v i t y o f chemicals i s r e l a t e d t o the percent o f l i p o i d t i s s u e w i t h i n t h e o r g a n i s m , h i g h e r organisms b e i n g t h e most s e n s i t i v e due t o the h i g h c o n c e n t r a t i o n o f s u c h l i p o i d s i n n e r v e c e l l s . I n comparing r e l a t i v e s e n s i t i v i t i e s , i t i s e s s e n t i a l t h a t a common p h y s i o l o g i c a l e n d p o i n t be employed. Thus, QSAR e q u a t i o n s d e v e l o p e d from d a t a o n m u l t i - g e n e r a t i o n a l t o x i c i t y t o a l g a e , p r o t o z o a , and b a c t e r i a have i n t e r cepts t h a t r e f l e c t higher s e n s i t i v i t y than simple n a r c o s i s (78). D a t a from Fuhner (79) o n t h e n a r c o s i s by a l c o h o l s t o 23 d i f f e r e n t o r g a n i s m s r e p r e s e n t i n g a b r o a d range i n taxonomic c l a s s were a n a l y z e d t o examine t h e M e y e r - O v e r t o n h y p o t h e s i s . Two o f t h e o r g a n i s m s i n t h i s d a t a s e t were t e s t e d w i t h a s u f f i c i e n t number o f compounds t o s a t i s f y the T o p l i s s c r i t e r i o n (80) f o r s t a t i s t i c a l v a l i d i t y w i t h r e s p e c t t o t h e number o f t e s t s p e r p a r a m e t e r . The r e m a i n i n g o r g a n i s m s were t e s t e d u s i n g o n l y e t h a n o l and n - h e p t a n o l . N e v e r t h e l e s s , t h e u s e o f o n l y two p o i n t s p e r o r g a n i s m c a n be j u s t i f i e d i n t h i s c a s e b y t h e o b s e r v a t i o n o f common symptomatology, a s p e c i f i c p h y s i c o c h e m i c a l i n t e r p r e t a t i o n o f t h e l o g F p a r a m e t e r , and g e n e r a l a s s o c i a t i o n o f s a t u r a t e d monohydric a l c o h o l s w i t h a n a r c o s i s mechanism. The s l o p e s and i n t e r c e p t s d e r i v e d from t h e s e data o f Fuhner a r e a r r a n g e d i n order of increasing s e n s i t i v i t y i n Table I . T h e r e i s an e v i d e n t association of greater s e n s i t i v i t y with i n c r e a s i n g p h y l o g e n e t i c development. The p a r t i a l o v e r l a p between i n v e r t e b r a t e s and v e r t e b r a t e s may r e f l e c t d i f f e r e n c e s i n t h e s p e c i f i c b i o l o g i c a l e n d p o i n t c h o s e n b y Fuhner f o r o b s e r v a t i o n . The i n t e r c e p t s o b t a i n e d f o r f i s h and t a d p o l e s a r e s i m i l a r t o t h o s e r e p o r t e d i n t h e l i t e r a t u r e b a s e d upon o t h e r t e s t d a t a ( 8 2 - 8 2 ) .
Water solubility
cutoff
Pseudo-steady-state p a r t i t i o n i n g can take p l a c e i n a q u a t i c organisms immersed i n an aqueous s o l u t i o n o f t o x i c a n t o r v i a e x p o s u r e t o v a p o r by i n h a l a t i o n through the lungs. The c o n c e n t r a t i o n o f a t o x i c a n t a t t h e n a r c o s i s s i t e o f a c t i o n i s a f u n c t i o n o f b o t h i t s aqueous c o n c e n t r a t i o n and p a r t i t i o n c o e f f i c i e n t . I n c r e a s i n g l y l o w e r aqueous c o n c e n t r a t i o n s a r e r e q u i r e d t o p r o d u c e a common m o l a r c o n c e n t r a t i o n a t t h e s i t e o f action with increasing p a r t i t i o n c o e f f i c i e n t . These r e l a t i o n s h i p s a r e i l l u s t r a t e d i n F i g u r e 2. O v e r t o n p o i n t e d o u t i n h i s c l a s s i c monograph " S t u d i e n iiber d i e N a r k o s e " t h a t a c l a s s i f i c a t i o n e x i s t e d a t t h a t time o f s u b s t a n c e s w h i c h n a r c o t i z e b o t h p l a n t s and a n i m a l s ( 3 2 , 3 8 ) , and t h o s e s u c h as s u l f o n a l that n a r c o t i z e only animals. O v e r t o n p r o v i d e d a much s i m p l e r and more reasonable e x p l a n a t i o n f o r t h i s apparent dichotomy. The n a r c o t i z i n g c o n c e n t r a t i o n o f s u l f o n a l t o tadpoles i s v e r y c l o s e t o t h e water s o l u b i l i t y o f t h i s compound. O v e r t o n f o u n d t h a t a l g a e r e q u i r e d 6-7 times as g r e a t a c o n c e n t r a t i o n t o p r o d u c e n a r c o s i s as t a d p o l e s and o t h e r h i g h e r a q u a t i c o r g a n i s m s , and t h e r e f o r e r e q u i r e c o n c e n t r a t i o n s o f s u l f o n a l e x c e e d i n g i t s water s o l u b i l i t y t o p r o d u c e n a r c o s i s .
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Base-Line Toxicity Predicted by QSAR
LIPNICK
Table
375
I . R e l a t i o n s h i p Between S p e c i e s S e n s i t i v i t y t o N a r c o s i s and Taxonomic H i e r a r c h y 3
Species
Type
Noctiluca miliaris
Protozoa
0.33
Covoluta roseoffensis
Sea u r c h i n
0.63 0.64^
Physa fontinalis
Freshwater snail
0.65
1.04
Locomotion
Tomopteris onisciformis
Worm
0.70
1.00
Suppress swimming
Pec ten operculus
Small mussel
0.72
1.01
Muscle contraction on c o n t a c t
Soles (cutlellus) pellucidus
Mussel
0.72
1.01
Muscle contraction on c o n t a c t
Asterias rubens
Sea
0.72
1.01
Locomotion
Worm
0.72
1.01
Locomotion
Gammarus pulex
Arthropod
0.73
1.03
Swimming
My sis (macromysis) flexuosa
Marine crab
0.73
1.03
Swimming
Aeolis drummondi and rufibranchialis
Marine n i g h t snail
0.74
1.06
Locomotion
Amphioxus vulgaris
Acranian
0.75
1.13
Swimming o n contact
Spio
vulgaris
Sensitivity (Intercept)
star
c
Slope
Narcosis Endpoint
0.96
Tentacle movement c
0.98 0.98^
Suppress movement
Continued on next page
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
376
PROBING BIOACTIVE
Table
I . Continued
Slope
Narcosis Endpoint
1.00
Swimming
0.77
1.20
Swimming
Water f r o g
0.78
1.14
Narcosis
Cyclopterus lumpus
Fish
0.80
1.20
Narcosis
Cydippe pileus
C1eonphones
0.82
0.97
Tentacle paralysis
Tadpole
0.82
1.16
Narcosis
Triton vulgaris
Water salamander
0.83
1.12
Narcosis
Rana
Tadpole
0.85
1.14
Narcosis
Sepiola rondeletti
Cephalopod
0.88
1.25
Narcosis
Actinia equina
Sea
0.90
1.02
Tentacle paralysis
Phoxinus laevis
Minnow fish
Species
Type
Idothea tricuspidata
Arthropod
Pleuronectes platessa
Fish
Rana esculenta
Rana
a
MECHANISMS
fusea
agilis
Sensitivity (Intercept)
anemone
0.75
1.08
c
0.89
c
Narcosis
b
D a t a from Fuhner ( 7 9 ) . D a t a f o r e t h a n o l ( l o g F • -0.235) and h e p t a n o l ( l o g P = 2.410) were u s e d t o a l g e b r a i c a l l y o b t a i n t h e s l o p e (A) and t h e i n t e r c e p t (B) f o r t h e e q u a t i o n l o g (1/C) = A l o g P + B, where C i s the l i m i t i n g n a r c o s i s producing concentration i n moles/L. Calculated by r e g r e s s i o n analysis from data on 5 a l c o h o l s . C a l c u l a t e d f r o m d a t a f o r e t h a n o l and h e p t a n o l . C a l c u l a t e d by r e g r e s s i o n a n a l y s i s from d a t a f o r 10 a l c o h o l s . e
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
23.
LIPNICK
Base-Line Toxicity Predicted by QSAR
377
L i m i t i n g water s o l u b i l i t y a l s o accounts f o r t h e appearance o f a c u t o f f o r a b r u p t change from t o x i c t o n o n t o x i c w i t h i n a s e r i e s o f compounds ( F i g u r e 2 ) . O v e r t o n d e m o n s t r a t e d , however, t h a t p r i o r t o t h e a p p e a r a n c e o f s u c h a c u t o f f , an i n c r e a s e i n p a r t i t i o n c o e f f i c i e n t , s u c c e s s i v e l y l o w e r c o n c e n t r a t i o n s o f t o x i c a n t a c h i e v e t h i s same e f f e c t . T h i s i s accompanied b y t h e need f o r i n c r e a s i n g t e s t d u r a t i o n t o a c h i e v e p s e u d o - s t e a d y - s t a t e p a r t i t i o n i n g between t h e s i t e o f a c t i o n and t h e aqueous t e s t s o l u t i o n . Influence
of Melting
Point
on Water Solubility
Cutoff
The w a t e r s o l u b i l i t y c u t o f f f o r an o r g a n i c compound i s a f u n c t i o n o f t h e minimum c o n c e n t r a t i o n i n d u c i n g n a r c o s i s and t h e water s o l u b i l i t y ( F i g u r e 2). The l a t t e r i s r e l a t e d t o b o t h t h e p a r t i t i o n c o e f f i c i e n t and t h e m e l t i n g p o i n t o f t h e compound ( 8 3 ) . M e l t i n g p o i n t i s a measure o f t h e e n t h a l p y o f f u s i o n and r e f l e c t s t h e s t r e n g t h o f i n t e r m o l e c u l a r f o r c e s present i n the c r y s t a l l i n e state. These f o r c e s a r e c o n s i d e r a b l y s t r e n g t h e n e d by t h e p r e s e n c e o f h y d r o g e n bonds. Moreover, compounds containing a l i p h a t i c chains and o t h e r f u n c t i o n a l groups o f f e r i n g m u l t i p l e d e g r e e s o f c o n f o r m a t i o n a l freedom and l a c k i n g symmetry must l o s e t h e s e d e g r e e s o f freedom i n p a s s i n g f r o m t h e l i q u i d t o t h e s o l i d s t a t e (84-85). F o r example, phenanthrene and a n t h r a c e n e a r e i s o m e r s h a v i n g t h e same p a r t i t i o n c o e f f i c i e n t ( l o g P = 4.49). W h i l e t h e f o r m e r p r o d u c e d n a r c o s i s a t 0.0112 mmoles/L, t h e l a t t e r showed no e f f e c t a t saturation, regardless o f the duration o f exposure (37,40). Phenanthrene p o s s e s s e s a l o w e r degree o f symmetry t h a n a n t h r a c e n e , and a c o n s i d e r a b l y lower m e l t i n g p o i n t . The f o r m e r m e l t s a t 98°, and t h e l a t t e r a t 218° ( 3 7 ) . Bilinear
Relationships
and Pharmacokinetic
Cutoff
The t o x i c i t y o f c h e m i c a l s t o a q u a t i c organisms a c t i n g by a n a r c o s i s mechanism e x h i b i t s l i n e a r QSAR r e l a t i o n s h i p s w i t h t e s t s o f s u f f i c i e n t duration t o achieve pseudo-steady-state p a r t i t i o n i n g between t h e aquarium aqueous donor phase and t h e s i t e o f a c t i o n w i t h i n t h e f i s h . For s h o r t e r t e s t durations, a higher concentration i s r e q u i r e d t o permit t h e needed i n t e r n a l t o x i c c o n c e n t r a t i o n t o be a c h i e v e d , r e s u l t i n g i n a n o n - l i n e a r r e l a t i o n s h i p between t o x i c i t y and l o g P. Such d a t a have been f i t by a b i l i n e a r model ( 8 6 ) . T h i s r e l a t i o n s h i p i s i l l u s t r a t e d i n F i g u r e 2. I f the toxic concentration required at this shorter test d u r a t i o n exceeds t h e water s o l u b i l i t y , no t o x i c i t y w i l l be o b s e r v e d i n a s a t u r a t e d s o l u t i o n , even though i t w i l l be s e e n a t l o w e r c o n c e n t r a t i o n i n t e s t s o f longer duration. Thus, p e n t a c h l o r o b e n z e n e was r e p o r t e d t o be n o n t o x i c a t s a t u r a t i o n i n a 96-hour t e s t ( 6 0 ) , b u t e x h i b i t e d a 14day LC50 o f 0.18 mg/L ( 5 8 ) . B i l i n e a r r e l a t i o n s h i p s a r e a l s o observed i n r a t o r a l LD50 ( F i g u r e 5 ) , where t h e r e i s a l s o a l a c k o f e q u i l i b r i u m p a r t i t i o n i n g between t h e s i t e o f a d m i n i s t r a t i o n and t h e s i t e o f a c t i o n (64,87). Excess
Toxicity
N a r c o s i s r e p r e s e n t s t h e most f u n d a m e n t a l m o l e c u l a r mechanism o f t h e t o x i c i t y o f n o n e l e c t r o l y t e o r g a n i c compounds. QSAR c o r r e l a t i o n s d e r i v e d
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
378
PROBING BIOACTIVE MECHANISMS
2.5
2
0
I
-1
1
0 1
i
a
,„„
t
2
,.
3
t
i
4
l
5
l
6
7
8
Log P Figure 5. Bilinear relationship between o c t a n o l / w a t e r partition c o e f f i c i e n t and r a t o r a l LD50 o f s a t u r a t e d monohydric a l c o h o l s and s a t u r a t e d monoketones on a l o g l o g s c a l e . (Reproduced w i t h p e r m i s s i o n from R e f . 64. C o p y r i g h t 1987 E l s e v i e r ) .
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
23.
LIPNICK
Base-Line Toxicity Predicted by QSAR
379
from data on s a t u r a t e d monohydric a l c o h o l s and o t h e r c l a s s e s wella s s o c i a t e d w i t h a n a r c o s i s mechanism c a n be u s e d as a p r o b e t o examine t h e t o x i c o l o g i c a l b e h a v i o r o f o t h e r n o n e l e c t r o l y t e o r g a n i c compounds (Figure 2 ) . Mechanistic organic chemistry provides a r a t i o n a l basis for u n c o v e r i n g t h e m o l e c u l a r mechanism o f n o n e l e c t r o l y t e s more t o x i c t h a n predicted. N o n e l e c t r o l y t e o r g a n i c compounds a c t i n g b y a more s p e c i f i c mechanism c a n be i d e n t i f i e d b y comparing t h e i r t o x i c i t y w i t h that p r e d i c t e d by a baseline n a r c o s i s equation, according to the f o l l o w i n g equation, T
e
~
C
pred / o b s
(
C
3
)
where T i s t h e excess t o x i c i t y parameter ( 6 3 ) , and C and C are t h e b a s e l i n e QSAR p r e d i c t e d a n d o b s e r v e d t o x i c i t i e s , r e s p e c t i v e l y . T h e e x c e s s t o x i c i t y o f most n o n e l e c t r o l y t e s c a n be r a t i o n a l i z e d i n terms of an e l e c t r o p h i l e or proelectrophile m o l e c u l a r mechanism, using m e c h a n i s t i c o r g a n i c c h e m i s t r y as a b a s i s f o r p r e d i c t i n g s u c h r e a c t i v i t y (82,88-89). e
p r e d
o b s
Electrophile Mechanism. E l e c t r o p h i l e t o x i c a n t s undergo d i r e c t c o v a l e n t bond f o r m a t i o n w i t h n u c l e o p h i l i c f u n c t i o n a l groups s u c h as s u l f h y d r y l t h a t a r e p r e s e n t i n enzymes a n d o t h e r c r i t i c a l b i o l o g i c a l m a c r o m o l e cules. A schematic r e p r e s e n t a t i o n o f the b i o c h e m i c a l and p h y s i o l o g i c a l processes i n v o l v e d are i l l u s t r a t e d i n Figure 6. E l e c t r o p h i l i c i t y has b e e n a s s o c i a t e d f o r some t i m e w i t h b i o l o g i c a l a c t i v i t y ( 9 2 ) . T h e c o m p o u n d s p - n i t r o b e n z y l p y r i d i n e (90) a n d p - n i t r o t h i o p h e n o l (92) h a v e been employed as model n u c l e o p h i l e s , and t h e p s e u d o - f i r s t o r d e r r e a c t i o n r a t e s have been u s e d as p a r a m e t e r s t o c o r r e l a t e w i t h e l e c t r o p h i l i c toxicity. Examples o f three types o f e l e c t r o p h i l e t o x i c a n t s , those u n d e r g o i n g d i r e c t n u c l e o p h i l i c d i s p l a c e m e n t , M i c h a e l - t y p e a d d i t i o n , and S c h i f f base f o r m a t i o n w i t h amino g r o u p s , s u c h as e-amino groups o f l y s i n e a r e shown i n T a b l e I I . Within a series of electrophiles bearing a common reactive f u n c t i o n a l group i n a s i m i l a r e l e c t r o n i c environment, excess t o x i c i t y d e c r e a s e s w i t h i n c r e a s i n g p a r t i t i o n c o e f f i c i e n t . Thus, acetaldehyde has a n e x c e s s t o x i c i t y o f 1 3 1 , a n d b u t y r a l d e h y d e , 45 ( 8 8 ) . A m o d i f i c a t i o n i n the e l e c t r o n i c environment o f a f u n c t i o n a l group t h a t r e s u l t s i n i n c r e a s e d e l e c t r o p h i l i c i t y can produce an i n c r e a s e d excess toxicity, e v e n f o r a compound w i t h a h i g h e r p a r t i t i o n c o e f f i c i e n t . Thus, pentafluorobenzaldehyde has both a h i g h e r l o g F and g r e a t e r excess toxicity than trimethoxybenzaldehyde. The f o r m e r , however, is considerably more r e a c t i v e due t o t h e p r e s e n c e of five strongly e l e c t r o n w i t h d r a w i n g groups compared t o t h r e e e l e c t r o n d o n a t i n g groups i n the l a t t e r ( 8 8 ) . There i s a s i m i l a r t r e n d i n comparing the M i c h a e l type acceptors acrolein, 2-hydroxye thy1 a c r y l a t e , and a c r y l a m i d e . L i k e w i s e , a l l y l b r o m i d e a n d a l l y l c h l o r i d e h a v e a l m o s t t h e same l o g P v a l u e , b u t d i f f e r g r e a t l y i n t h e i r e x c e s s t o x i c i t y due t o t h e g r e a t e r a b i l i t y o f bromide r e l a t i v e t o c h l o r i d e t o a c t as l e a v i n g group ( 6 3 ) . Work i s i n p r o g r e s s i n quantifying these differences based upon electronic molecular descriptors. Proelectrophile Mechanism. P r o e l e c t r o p h i l e s , which produce electro p h i l e s b y means o f m e t a b o l i c t r a n s f o r m a t i o n , r e p r e s e n t a s e c o n d c l a s s
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
CHEMICAL IN AQUARIUM WATER
TRANSPORT TO METABOLIZING ENZYMES
CHE M IC A L IN FISH BLOOD
by n a r c o s i s ,
COVALENT BOND FORMATION WITH CRITICAL N U M B E R OF TARGET MOLECULES
LOSS O F BIOCHEMICAL ANO PHYSIOLOGICAL FUNCTION
e l e c t r o p h i l e , and p r o e l e c t r o p h i l e
toxicants mechanisms.
t o f i s h from
o f t h e p h y s i o l o g i c a l and b i o c h e m i c a l
I
TRANSPORT TO ELECTROPHILE SITE O F ACTION
REACTION OF ELECTROPHILE WITH NUCLEOPHILIC MOIETIES O F TARGET BIOLOGICAL MACROMOLECULES
BIOCHEMICAL CHAIN O F EVENTS
i nthe production o f l e t h a l i t y
Schematic r e p r e s e n t a t i o n
processes involved
acting
W
TRANSPORT TO ELECTROPHILE , SITE OF 1 ACTION
METABOLIC ACTIVATION OF PROELECTROPHILE TO REACTIVE ELECTROPHILE MOLECULAR SPECIES
^ ~
F i g u r e 6.
GILL UPTAKE
TRANSPORT TO NARCOSIS SITE OF ACTION
Ai
CRITICAL NARCOSIS M O L A R CONCENTRATION
DEATH OF ORGANISM
00
23.
Base-Line Toxicity Predicted by QSAR
LIPNICK
381
o f n o n e l e c t r o l y t e s showing e x c e s s t o x i c i t y . Some examples o f p r o e l e c t r o p h i l e s a r e i l l u s t r a t e d i n T a b l e I I I . A l l y l a l c o h o l undergoes m e t a b o l i c o x i d a t i o n by t h e u b i q u i t o u s enzyme a l c o h o l dehydrogenase t o a c r o l e i n , a M i c h a e l - t y p e a c c e p t o r e l e c t r o p h i l e ( 6 3 ) , shown i n T a b l e I I . I t h a s been p r o p o s e d t h a t t h e e x c e s s t o x i c i t y o f 1,3-dibromopropane (88) r e f l e c t s t h e same mechanism as was p r o p o s e d f o r i t s m u t a g e n i c i t y , i . e . , m e t a b o l i s m t o t h e e l e c t r o p h i l i c f o u r membered s u l f o n i u m c a t i o n . The e x c e s s t o x i c i t y o f p e n t a e r y t h r i t o l t r i a l l y l e t h e r c a n be a c c o u n t e d f o r b a s e d upon m e t a b o l i s m v i a a f r e e r a d i c a l mechanism t o t h e c o r r e s p o n d i n g h e m i a c e t a l , which can r e a d i l y cleave t o y i e l d a c r o l e i n ( 6 3 ) . Cyanogenie Mechanism. The a c u t e t o x i c i t y o f a t h i r d c l a s s o f s i m p l e n o n e l e c t r o l y t e s c a n be r e a d i l y r a t i o n a l i z e d i n terms o f a c y a n o g e n i c mechanism, i n v o l v i n g m e t a b o l i c r e l e a s e o f c y a n i d e . Free cyanide i s h i g h l y t o x i c t o f i s h w i t h a TLm o f 0.69 mg/L (93). Some examples o f cyanogenic t o x i c a n t s a r e shown i n T a b l e IV. Lactonitrile i s f u n c t i o n a l l y s i m i l a r t o a h e m i a c e t a l , and c a n r e a d i l y l o s e c y a n i d e by a s i m p l e mechanism. I n t h e c a s e o f m a l o n o n i t r i l e and a l l y l c y a n i d e , f r e e r a d i c a l m e t a b o l i c o x i d a t i o n y i e l d s a s t a b l e s p e c i e s which on f r e e radical perhydroxylation becomes functionally equivalent to lactonitrile. Chronicity
and
Ratio.
24-Hr
LC50/96-Hr
LC50
A q u a t i c t o x i c o l o g i s t s f r e q u e n t l y r e p o r t f i s h t o x i c i t y d a t a f o r 24 96-hr d u r a t i o n s . The c h r o n i c i t y r a t i o , J?, may be d e f i n e d a s , R = LC50 _ /LC50 _ 24
h
%
h
where LC50 4_h and L C 5 0 _ a r e t h e 24-h and 96-h t o x i c i t y v a l u e s , r e s p e c t i v e l y (88). V a l u e s o f t h i s r a t i o g r e a t e r t h a n 2 have been employed b y a q u a t i c t o x i c o l o g i s t s as an i n d i c a t o r o f t h e p o t e n t i a l need to perform c h r o n i c t e s t i n g on a chemical t o assess i t s p o t e n t i a l r i s k i f r e l e a s e d i n t o t h e environment (95). An a n a l y s i s o f d a t a f o r 37 n o n e l e c t r o l y t e s d e m o n s t r a t e d a c o r r e l a t i o n between e x c e s s t o x i c i t y and a c h r o n i c i t y r a t i o g r e a t e r t h a n 2 (88). This finding i s consistent with t h e h y p o t h e s i s t h a t c h r o n i c i t y c a n r e s u l t from c o v a l e n t b i n d i n g by an e l e c t r o p h i l e o r p r o e l e c t r o p h i l e t o x i c a n t , o r by a n o t h e r more s p e c i f i c mechanism s u c h as m e t a b o l i c r e l e a s e o f c y a n i d e . These r e s u l t s a r e i l l u s t r a t e d g r a p h i c a l l y i n F i g u r e 7. A l l c h e m i c a l s i n t h i s s t u d y (88) with a T v a l u e l e s s t h a n 6.7 have a c h r o n i c i t y r a t i o (R) o f 2 o r l e s s , while the m a j o r i t y o f those with T v a l u e s g r e a t e r t h a n 6.7 show c h r o n i c i t y r a t i o s g r e a t e r t h a n 2. R r e p r e s e n t s o n l y a s i n g l e t e m p o r a l probe f o r i n v e s t i g a t i n g c u m u l a t i v e t o x i c i t y . Certain highly reactive c h e m i c a l s h a v i n g R v a l u e s l e s s t h a n 2 may p r o d u c e c u m u l a t i v e damage within shorter test durations. Conversely, i f the r a t e o f metabolic t r a n s f o r m a t i o n t o t o x i c a n t i s slow o r r e q u i r e s a complex s e r i e s o f s t e p s , l o n g e r t e s t d u r a t i o n s may be r e q u i r e d t o a s s e s s s u c h p o t e n t i a l chronicity. 2
%
h
c
e
Use of Screening Mechanism
Data
to
Investigate
the
Limitations
of
the
Narcosis
The u s e o f QSAR f o r p r e d i c t i v e purposes i s p l a c e d upon a more s e c u r e f o u n d a t i o n i f a r a t i o n a l e c a n be d e v e l o p e d f o r why t h e c a n d i d a t e
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
382
PROBING BIOACTIVE MECHANISMS
Table I I .
E l e c t r o p h i l e s and E x c e s s
Chemical
Log P Nucleophilic
-0 .792
e
490 97 >A90 35 1960 86 21 11
-0 .273 1 .590 1 .450 0 .219 3 .866 4 .440 1 .972
Michael-type
addition 0 .101 -0 .058 -0 .859
aerylate
Sehiff
T
3
Substitution
Ethylene oxide Propylene oxide A l l y l bromide A l l y l chloride Chloroacetonitrile a,a-Dichloroxylene Phenyl d i s u l f i d e 3,4-Dichloro-l-butene
Acrolein 2-Hydroxyethyl Acrylamide
Toxicity
>81000 1540 180
base f o r m a t i o n
Acetaldehyde Butyraldehyde Pentafluorobenzaldehyde a,a,a-Trifluoro-m-tolualdehyd e Benzaldehyde 2,4,5-Trime thoxybenz a1dehyde
-0 .224 0 .834 2 .449 2 .594 1 .495 1 .381
131 45 51 40 31 11
3
C a l c u l a t i o n s o f T adapted from r e f s . 63 and 88, w h i c h were based upon l i n e a r o r b i l i n e a r b a s e l i n e t o x i c i t y QSAR models. e
Table I I I .
Proelectrophiles
Chemical
and E x c e s s
Log P
A l l y l alcohol 1,3-Dibromopropane Pentaerythritol t r i a l l y l
ether
-0.250 1.987 -1.599
Toxicity
T
e
16000 87 18000
3
C a l c u l a t i o n s o f T adapted from r e f s . 63 and 88, w h i c h were based upon l i n e a r o r b i l i n e a r b a s e l i n e t o x i c i t y QSAR models. e
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
3
23.
LIPNICK
Base-Line Toxicity Predicted by QSAR
383
T a b l e I V . Cyanogenic N o n e l e c t r o l y t e s and E x c e s s Toxicity
Chemical
Log P
3
Lactonitrile Malononitrile^ A l l y l cyanide
-0. 850 -1. 198 0 .120
a
c
Data from 93. ° D a t a from 94. 96-h LC50 v a l u e s .
Average
**e
23800 88700 16
c
o f three
c h e m i c a l i s l i k e l y t o a c t by t h e same mechanism as t h o s e c h e m i c a l s used to d e r i v e the e q u a t i o n . I n the case o f n o n r e a c t i v e n o n e l e c t r o l y t e s , the i d e n t i f i c a t i o n o f r e l a t e d compounds t h a t have been r e p o r t e d t o produce n a r c o s i s , a n e s t h e s i a , o r a c t as h y p n o t i c s (96) c a n be v a l u a b l e i n e s t a b l i s h i n g t h e l i k e l i h o o d o f a b a s e l i n e n a r c o s i s mechanism. Fish t o x i c i t y s c r e e n i n g d a t a have p r o v e n e s p e c i a l l y u s e f u l i n a s s e s s i n g t h e l i m i t a t i o n s o f t h e n a r c o s i s QSAR b a s e l i n e t o x i c i t y model t o t h e s e organisms ( 9 7 ) . D a t a r e t r i e v e d from f o u r s u c h s t u d i e s (98-101) were u s e d t o i n v e s t i g a t e t h e u t i l i t y and l i m i t a t i o n s o f t h e n a r c o s i s model f o r a l c o h o l s c o n t a i n i n g no o t h e r h e t e r o a t o m f u n c t i o n a l g r o u p s . A l t h o u g h t h e d a t a f o r most o f t h e s e compounds p r o v e d t o be c o n s i s t e n t w i t h t h e model, p r i m a r y and s e c o n d a r y p r o p a r g y l i c a l c o h o l s were f o u n d t o show excess t o x i c i t y . Acetylenic Alcohols. The f i n d i n g o f a more s p e c i f i c mechanism f o r p r i m a r y and s e c o n d a r y p r o p a r g y l i c a l c o h o l s was c o n f i r m e d i n a subsequent s t u d y o n t h e f a t h e a d minnow i n which 96-h LC50 v a l u e s were d e t e r m i n e d for a series of acetylenic alcohols. A l l p r i m a r y and s e c o n d a r y p r o p a r g y l i c a l c o h o l s were f o u n d t o produce e x c e s s t o x i c i t y , c o n s i s t e n t w i t h a p r o e l e c t r o p h i l e mechanism i n v o l v i n g t r a n s f o r m a t i o n by a l c o h o l dehydrogenase i n the f i s h t o the corresponding a,^-unsaturated p r o p a r g y l i c a l d e h y d e o r ketone e l e c t r o p h i l i c t o x i c a n t . F u r t h e r m o r e , t h e t o x i c i t i e s o f t e r t i a r y p r o p a r g y l i c a l c o h o l s , w h i c h c a n n o t undergo t h i s m e t a b o l i c t r a n s f o r m a t i o n , were v e r y c l o s e t o t h e QSAR p r e d i c t i o n s . P r i m a r y h o m o p r o p a r g l i c a l c o h o l s were a l s o f o u n d t o produce e x c e s s toxicity. A mechanism i n v o l v i n g t a u t o m e r i z a t i o n o f t h e a l d e h y d e m e t a b o l i t e t o t h e c o n j u g a t e d a l l e n e was p r o p o s e d . T h i s a l l e n e c a n a c t as a M i c h a e l - t y p e a c c e p t o r e l e c t r o p h i l e ( V e i t h , G.D.; L i p n i c k , R.L.; Russom, C.L. Xenobiotica, i n press). Local QSAR Models. F i s h t o x i c i t y s c r e e n i n g d a t a have a l s o been employed t o i n v e s t i g a t e t h e l i m i t a t i o n s o f " l o c a l " QSAR models ( F i g u r e 2) f o r p h e n o l s (102) and a n i l i n e s (203) u s i n g t h e s e same d a t a . Most o f t h e s e d a t a a r e from s t u d i e s c o n d u c t e d o r s p o n s o r e d b y t h e U.S. F i s h and W i l d l i f e S e r v i c e (USFWS). The S e r v i c e has s c r e e n e d thousands o f c h e m i c a l s f o r e f f e c t s u s i n g a wide range o f organisms and r o u t e s o f
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
384
PROBING BIOACTIVE MECHANISMS
Log T
e
F i g u r e 7. R e l a t i o n s h i p b e t w e e n e x c e s s t o x i c i t y (Tg) a n d c h r o n i c i t y r a t i o (R) f o r t h e t o x i c i t y o f 37 n o n e l e c t r o l y t e o r g a n i c c o m p o u n d s t o t h e f a t h e a d m i n n o w as f o l l o w s ( b y i n c r e a s i n g T g ) : 2,4,5-Trimethyloxazole (5), N , N - D i m e t h y l - p - t o l u i d i n e (6), 4 - M e t h y l o x a z o l e ( 7 ) , m-Bromobenzamide (8), 2 - F l u o r o t o l u e n e (9), n - B u t y l s u l f i d e (10), 1,2-Dichloropropane (11), 4,7-Dithiadecane (12), Naphthalene (13), 1,3-Dichloropropane (14), 4-Benzoylpyridine (15), 1,1,1,3,3,3-Hexafluoropropan-2-ol (16), t - B u t y l d i s u l f i d e ( 1 7 ) , Butan-2-one oxime ( 1 8 ) , s - T r i o x a n e ( 1 9 ) , F u r a n ( 2 0 ) , 2,4-Dichlorobenzamide (21), Pyrrole (22), Deca-1,9-diene (23), 2C y a n o p y r i d i n e ( 2 4 ) , 2-Adamantanone (25), H e x a n a l (26), Adamantane ( 2 7 ) , 1,4-Dicyanobutane ( 2 8 ) , C h l o r o m e t h y l s t y r e n e (29), 2 , 6 - D i p h e n y l p y r i d i n e ( 3 0 ) , 3 , 4 - D i c h l o r o b u t - l - e n e ( 3 1 ) , 2 , 4 , 5 - T r i m e t h o x y b e n z a l d e h y d e ( 3 2 ) , 4Nitrobenzamide ( 3 3 ) , Pentane-2,4-dione ( 3 4 ) , A l l y l cyanide ( 3 5 ) , P h e n y l disulfide (36), Benzaldehyde (37), 2,5-Diphenylfuran (38), a,a,aTrifluoro-m-tolualdehyde (39), Butanal (40), Pentafluorobenzaldehyde (41), a , a - D i c h l o r o - p - x y l e n e (42), 1,3-Dibromopropane (43), Acetaldehyde ( 4 4 ) , and C h l o r o a c e t o n i t r i l e ( 4 5 ) . ( F i g u r e adapted from data i n Tables 2 and 3 i n R e f . 88).
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
23.
UPNICK
Base-Line Toxicity Predicted by QSAR
385
a d m i n i s t r a t i o n (104). I n t h e e a r l y 1950s, Wood (98) t e s t e d 3,400 c h e m i c a l s f o r t o x i c i t y t o 3-4 s p e c i e s o f f r e s h w a t e r f i s h e s , f o l l o w e d by work o f H o l l i s and Lennon on t h e s e same o r g a n i s m s ( 9 9 ) , b o t h a t t h e Service's Laboratory i n Kearneysville, WV. The c h e m i c a l s were s u b s e q u e n t l y t r a n s f e r r e d t o a n o t h e r USFWS l a b o r a t o r y i n M i c h i g a n and u s e d as p a r t o f a s t u d y t o s e a r c h f o r a s e l e c t i v e l a m p r i c i d a l agent ( 2 0 0 ) . The most t o x i c c h e m i c a l s were t h e n s e n t t o t h e USFWS L a b o r a t o r y i n G a l v e s t o n , T e x a s , and were t e s t e d i n s e a r c h o f an agent s e l e c t i v e l y t o x i c t o t h e r e d t i d e d i n o f l a g e l l a t e ( 2 0 5 ) ; and s u b s e q u e n t l y t o t h e U n i v e r s i t y o f Idaho, where t h e y were t e s t e d f o r s e l e c t i v e t o x i c i t y t o v a r i o u s f i s h s p e c i e s ( 2 0 2 ) . The u s e o f c h e m i c a l s as p i s c i c i d a l a g e n t s has been r e v i e w e d i n a R u s s i a n p u b l i c a t i o n ( 2 0 6 ) . Conclusion QSAR models c a n be a v a l u a b l e means o f p r e d i c t i n g t h e t o x i c i t y o f untested n o n e l e c t r o l y t e organic chemicals. The models need t o be d e r i v e d from a s e r i e s o f c h e m i c a l s a c t i n g by a common m o l e c u l a r mechanism and encompass an adequate domain o f spanned s u b s t i t u e n t space i n t h e i r p h y s i c a l and c h e m i c a l p r o p e r t i e s . The a c u t e t o x i c i t y o f many classes of nonelectrolytes i s consistent with a narcosis or baseline t o x i c i t y mechanism. The a b i l i t y t o a p p l y s u c h models f o r p r e d i c t i v e purposes a l s o r e q u i r e s i n f o r m a t i o n t o suggest that the candidate c h e m i c a l a c t s b y t h e same mechanism. Acknowledgments The a u t h o r i s g r a t e f u l t o D r . James H. G i l f o r d , C h i e f , E n v i r o n m e n t a l Effects Branch, U.S. E n v i r o n m e n t a l Protection Agency forhis encouragement i n t h e p r e p a r a t i o n o f t h i s a r t i c l e . The a u t h o r w i s h e s t o t h a n k E l s e v i e r P u b l i s h i n g Company f o r k i n d l y p e r m i t t i n g t h e r e p r o d u c t i o n o f F i g u r e s from QSAR in Drug Design and Toxicology ( 6 4 ) .
Literature Cited 1. 2.
3. 4. 5.
6. 7. 8.
Lipnick, R.L. Environ. Toxicol. Chem. 1985, 4, 255-257. Veith, G.D. State-of-the-Art of Structure Activity Methods Development. U.S. Environmental Protection Agency, Environmental Research Laboratory, Duluth, MN. 1981; EPA-560/81-029; NTIS PB 81187-239. Auer, C.M.; Gould, D.H. J. Envir. Sci. Hlth. 1987, C5(1), 29-71. Toxic Substances Control Act, Public Law 94-469, October 11, 1976. Structure-Activity Relationships in Toxicology and Ecotoxicology: An Assessment. European Chemical Industry Ecology and Toxicology Center, Brussels, February 24, 1986, Monograph No. 8, 86 pages; ISSN 0773-6347. Hansch, C. In Biological Activity and Chemical Structure; Keverling Buisman, J . A . , Ed.; Elsevier: Amsterdam, 1977; pp. 47-61. Ariëns, E . J . In Innovative Approaches in Drug Research; Harms, A . F . , Ed.; Elsevier: Amsterdam, 1986; pp. 9-22. Drummond, R.A.; Russom, C . L . ; Geiger, D . L . ; DeFoe, D.L. In Aquatic Toxicology and Environmental Fate: Ninth Volume, Peston, T.M.; Purdy, R. Eds.; STP 921, American Society for Testing and Materials: Philadelphia, 1986; pp. 415-435.
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
386
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
35. 36. 37. 38. 39. 40.
PROBING BIOACTIVE MECHANISMS
McKim, J . M . ; Schmieder, P.K.; Niemi, G . J . ; Carlson, R.W.; Henry, T.R. Environ. Toxicol. Chem. 1987, 6, 295-312. McKim, J . M . ; Schmieder, P.K.; Niemi, G . J . ; Carlson, R.W.; Henry, T.R. Environ. Toxicol. Chem. 1987, 6, 313-328. McKim, J . M . ; Bradbury, S.P.; Niemi, G . J . Environ. Health Persp. 1987 71, 171-186. Hansch, C . ; Klein, T . E . Acc. Chem. Res. 1986, 19, 392. Broderius, S.; Kahl, H. Toxicology 1985, 6, 307-322. Könemann, H. Ecotox. Environ. Safety 1980, 4, 415-421. Könemann, H. Toxicology 1981, 19, 229-238. Hermens, J.; Canton, H . ; Jansen, P.; DeJong, R. Aquat. Toxicol. 1984, 5, 143-154. Magee, P.S. Chemtech 1981, 11, 378-384. Fränkel, S. Die Arzneimittel-Synthese: Auf Grundlage der Beziehungen zwischen Chemischen Aufbau und Wirkung; 4th edition; Julius Springer: Berlin, 1919; pp. 26-135. W.A. Sexton, Chemical Constitution and Biological Activity; 3rd edition; Van Nostrand: Princeton, 1963. Albert, A. Selective Toxicity: The Physicochemical Basis of Therapy; 7th edition, Chapman and Hall: London, 1985. Cros, A.F.A. Action de l'alcool amylique sur l' organisme; Thesis, F a c u l t éde Médecine de Strasbourg. Strasbourg, 1863. Richardson, B.W. Medical Times and Gazette (London) December 18, 1869, 2, 703-706. Munch, J.C.; Schwartze, E.W. J. Lab. Clin. Med. 1925, 10, 985-996. Rabuteau. L'Union Medicale 1870, 10 (3rd series), 165-173. Dujardin-Beaumetz; Audigé. C.R. Hebd. Seances Acad. Sci. 1875, 81, 192-194. Dujardin-Beaumetz; Audigé. C.R. Hebd. Seances Acad. Sci. 1876, 83, 80-81. Dujardin-Beaumetz; Audigé. Researches Expérimentelles sur la Puissance Toxique des Alcools; Octave Doin: Paris, 1879. Houdaille, G. Étude Expérimentelle et Critique sur les Nouveaux Hypnotiques; Thesis, Faculty de Medécine de Paris, Paris, 1893. Richet, C. C.R. Soc. Biol. (Paris) 1893, 54, 775-776. Overton, E . Vierteljahrsschr. Naturforsch. Ges. Zuerich 1899, 44, 88-135. Overton, E., Studien über die Narkose, zugleich ein Beitrag zur allgemeiner Pharmakologie; Gustav Fischer: Jena, Germany, 1901. Meyer, H. Arch. Exp. Pathol. Pharmakol. 1899, 42, 109-118. Baum, F. Arch. Exp. Pathol. Pharmakol. 1899, 42, 119-137. Dunzelt, W. Vergleichende Experimentaluntersuchungen über die Stärke der Wirkung einiger Narcotica; Inaugural Dissertation, Hohen Medicinischen Facultät der Universität Marburg: Marburg, Germany, 1896. Meyer, H. Arch. Exp. Pathol. Pharmakol. 1901, 46, 338-345. Overton, E . Vierteljahrsschr. Naturforsch. Ges. Zuerich 1895, 40, 159-201. Overton, E . Vierteljahrsschr. Naturforsch. Ges. Zuerich 1896, 41, 383-406. Lipnick, R.L. Trends Pharmacol. Sci. 1986, 5, 161-164. Leo, A . ; Hansch, C . ; Church, C. J. Med. Chem. 1969, 2, 766-771. Hansch, C . ; Dunn, W.J., III. J . Pharm. Sci. 1972, 61, 1-19.
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
23.
LIPNICK
Base-Line Toxicity Predicted by QSAR
387
41. L i p n i c k , R . L . In Aquatic Toxicology and Hazard Assessment: 11th Symposium; Suter, C.W., II, and Lewis, M . , E d s . ; STP 1007, American Society for Testing and M a t e r i a l s : P h i l a d e l p h i a , 1989; 468-489. 42. Winterstein, H . Die Narkose: In Ihrer Bedeutung für die Allgemeine Physiologie; 2nd e d i t i o n ; J u l i u s Springer: B e r l i n , 1926. 43. Kochmann-Halle, M. In Handbuch der Experimentelle Pharmakologie; Heffter, A . Ed.; J u l i u s Springer: B e r l i n , 1923; Vol. I, pp. 449469. 44. Henderson, V . E . Physiol. Rev. 1930, 10, 171-220. 45. McElroy, W.D. Quart. Rev. Biol. 1947, 22, 25-58. 46. B u t l e r , T.C. Pharmacol. Rev. 1950, 2, 121-160. 47. M u l l i n s , L.J. Chem. Revs. 1954, 54, 289-323. 48. Featherstone, R . M . ; Muehlbacher, C.A. Pharmacol. Rev. 1963, 15, 97121. 49. Seeman, P . Pharmacol. Rev. 1972, 24, 583-655. 50. Ueda, I.; Kamaya, H . Anesth. Analg. 1984, 63, 929-945. 51. Abu-Hamdiyyah, M. Langmuir, 1986, 2, 310-315. 52. Mécanisme de la Narcose, Centre Nationale de l a Recherche S c i e n t i f i q u e , Proceedings of an International Colloquium: P a r i s , April 19-26, 1950 (No. XXVI), P a r i s , 1951. 53. Miller, K.W.; Smith, B . E . In A Guide to Molecular PharmacologyToxicology; Featherstone, M . , Ed.; Marcel Dekker: New York, 1973; Part II, Chapter 11. 54. Miller, K.W. Int. Rev. Neurobiol. 1985, 27, 1-61. 55. Franks, N . P . ; L i e b , W.R. Nature 1982, 300, 487-493. 56. Franks, N . P . ; L i e b , W.R. Trends Pharmacol. Sci. 1987, 8, 169. 57. M a r t i n , Y.C. Quantitative Drug Design; Marcel Dekker: New York, 1978. 58. Könemann, H . Toxicology 1981, 19, 209-221. 59. L i p n i c k , R.L.; Dunn, W . J . , III. In Quantitative Approaches to Drug Design; Dearden, J.D., Ed.; E l s e v i e r : Amsterdam, 1983; pp. 265266. 60. V e i t h , G.D.; Call, D . T . ; Brooke, L . T . Can. J. Fish. Aquat. Sci. 1983, 40, 743-748. 61. V e i t h , G.D.; Call, D . T . ; Brooke, L . T . In Aquatic Toxicology and Hazard Assessment: Sixth Symposium; Bishop, W.E., E d . ; STP 802, American Society for Testing and M a t e r i a l s : P h i l a d e l p h i a , 1983; pp. 90-97. 62. Hermens, J.; Canton, H.; Jansen, P.; DeJong, R. Aquat. Toxicol. 1984, 5, 143-154. 63. L i p n i c k , R.L.; Watson, K . R . ; Strausz, A . K . Xenobiotica 1987, 17, 1011-1025. 64. L i p n i c k , R.L.; Pritzker, C . S . ; Bentley, D . L . In QSAR in Drug Design and Toxicology; Hadzi, D. and Jerman-Blazic, B., E d s . ; E l s e v i e r : Amsterdam, 1987; pp. 301-306. 65. Leo, A.; Hansch, C . ; Elkins, D. Chem. Revs. 1971, 71, 575. 66. Leo, A.; Hansch, C. J. Org. Chem. 1971, 30, 1539. 67. Meyer, K.H.; Hemmi, H. Biochem. Z. 1935, 277, 39. 68. Rekker, R . F . The Hydrophobic Fragmental Constant; E l s e v i e r : Amsterdam, 1977. 69. Hansch, C . ; Leo, A . Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley-Interscience: New York, 1979. 70. Leo, A . J. Chem. Soc. Perkin Trans. II 1983, 825-838. 71. Leo, A . J. Pharm. Sci. 1987, 76, 166-168.
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
388
PROBING BIOACTIVE MECHANISMS
72. Chou, J.T.; Jurs, P.C. J . Chem. Inf. Comput. Sci. 1979, 19, 172178. 73. Leo, A . ; Weininger, D. Medchem Software Release 3.33, Medicinal Chemistry Project, Pomona College, Claremont, CA, 1985. 74. Veith, G.D.; Austin, N.M.; Morris, R.T. Water Res. 1978, 13, 4347. 75. Burkhard, L . P . ; Kuehl, D.W.; Veith, G.D. Chemosphere 1985, 14, 1551-1560. 76. Tipker, J.; Groen, C.P.; Van Den Bergh-Swart, J . K . ; Van Den Berg, J.H.M. J. Chromatogr. 1988, 452, 227-239. 77. Kamlet, M.J.; Doherty, R.M.; Taft, R.W.; Abraham, M.H.; Veith, G.D.; Abraham, D . J . Environ. Sci. Technol. 1987, 21, 149-155. 78. Lipnick, R . L . ; Hood, M.T. Correlation of chemical structure and toxicity of industrial organic compounds to daphnia, algae, bacteria, and protozoa; Abstracts of papers, Seventh Annual Meeting, Society of Environmental Toxicology and Chemistry, Alexandria, VA, November 2-5, 1986. 79. Fühner, H. Z. Biol. 1912, 57, 465-494. 80. Topliss, J . G . ; Costello, R . J . J. Med. Chem. 1972, 15, 1066-1068. 81. Lipnick, R.L. In QSAR in Toxicology and Xenobiochemistry; Tichý, M., Ed.; Elsevier: Amsterdam, 1985; pp. 39-52. 82. Thurston, R.V.; G i l f o i l , T.A.; Meyn, E.L.; Zajdel, R.K.; Aoki, T.I.; Veith, G.D. Water Res. 1985, 19, 1145-1155. 83. Banerjee, S.; Yalkowsky, S.H.; Valvani, S.S. Environ. Sci. Technol. 1980, 14, 1227-1229. 84. Herbrandson, H . F . ; Nachod, F . C . In Determination of Organic Structures by Physical Methods, Braude, E.A. and Nachod, F . C . , Eds.; Academic: New York, 1955; pp. 3-23. 85. Valvani, S.C.; Yalkowsky, S.H. In Physical Chemical Properties of Drugs; Yalkowsky, S.H., Sinkula, A.A. and Valvani, S.C., Eds.; Marcel Dekker: New York, 1980; pp. 201-229. 86. Kubinyi, H. J. Med Chem. 1977, 20, 625-629. 87. Lipnick, R . L . ; Pritzker, C.S.; Bentley, D.L. In QSAR and Strategies in the Design of Bioactive Compounds; Seydel, J . K . , E d . ; VCH: Weinheim, FRG, 1985, pp. 420-423. 88. Lipnick, R.L. In Risk Assessment of Chemicals in the Environment; Richardson, M . L . , Ed.; Royal Society of Chemistry: London, 1988; pp. 379-397. 89. Lipnick, R.L. Environ. Toxicol. Chem. 1989, 8, 1-12. 90. Hermens, J.; Busser, F.; Leeuwanch, P.; Musch, A. Toxicol. Environ. Chem. 1985, 9, 219-236. 91. Cheh, A.M.; Carlson, R.E. Anal. Chem. 1981, 53, 1001. 92. Ross, W.C.J. Biological Alkylating Agents: Fundamental Chemistry and the Design of Compounds for Selective Toxicity; Butterworths: London, 1962. 93. McKee, J.E.; Wolf, H.W. Water Quality Criteria; 2nd ed., The Resources Agency of California, State Water Resources Control Board: Sacramento, CA, 1963. 94. Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas); Brooke, L . T . ; Call, D . J . ; Geiger, D . L . ; Northcott, C . E . , Eds.; Center for Lake Superior Environmental Studies, University of Wisconsin-Superior, vol 1, 1984.
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
23.
LIPNICK
Base-Line Toxicity Predicted by QSAR
389
95. Birge, W.J.; Black, J.A. In Aquatic Toxicology and Hazard Assessment: Eighth Symposium; Banner, R.C. and Hansen, D . J . , Eds.; STP 891; American Society for Testing and Materials: Philadelphia, 1985; p. 51. 96. Wheeler, K.W. In Medicinal Chemistry; Campaigne, E . E . and Hartung, W.H., Eds.; Wiley: New York, 1963; Vol. VI, pp. 1-245. 97. Lipnick, R . L . ; Johnson, D . J . ; Gilford, J.H; Bickings, C.K.; Newsome, L.D. Environ. Toxicol. Chem. 1985, 4, 281-296. 98. Wood, E.M. The Toxicity of 3400 Chemicals to Fish; U.S. Fish and Wildlife Service, Kearneysville, WV, 1953; In EPA Report No. 560/687-002; NTIS PB 87-200-275. 99. Hollis, E . H . ; Lennon, R.E. The Toxicity of 1085 Chemicals to Fish; U.S. Fish and Wildlife Service, Kearneysville, WV, 1953; In EPA Report No. 560/6-87-002; NTIS PB 87-200-275. 100. Applegate, V . C . ; Howell, J . H . ; Hall, A . E . , J r . The Toxicity of 4,346 Chemicals to Larval Lampreys and Fishes; Special Scientific Report, Fisheries No. 207, U.S. Fish and Wildlife Service: Washington, DC, 1957. 101. MacPhee, C . ; Ruelle, R. Lethal Effects of 1888 Chemicals upon Four Species of Fish from Western North America; University of Idaho; Forest, Wildlife, and Range Experiment Station: Moscow, ID, Bulletin No. 3, 1969. 102. Lipnick, R . L . ; Bickings, C.K.; Johnson, D . E . ; Eastmond, D.A. In Aquatic Toxicology and Hazard Assessment: Eighth Symposium; Bahner, R . C . ; Hansen, D . J . , Eds.; STP 891; American Society for Testing and Materials: Philadelphia, 1985; pp. 153-176. 103. Newsome, L.D.; Johnson, D . E . ; Cannon, D . J . ; Lipnick, R.L. In QSAR in Environmental Toxicology-II; Kaiser, K . L . E . , Ed.; D. Reidel: Dordrecht, Netherlands, 1987; pp. 231-250. 104. Walker, C.R.; Menzie, C.M.; Bowles, W.A., J r . J. Chem. Inf. Comput. Sci. 1981, 21, 29-35. 105. Marvin, K . T . ; Proctor, R.R., J r . Preliminary Results of the Systematic Screening of 4,306 Compounds as 'Red Tide' Toxicants; Data Report 2; U.S. Fish and Wildlife Service, Bureau of Commercial Fisheries Biological Laboratory, Galveston, TX: Washington, DC, March, 1964. 106. Sudakova, E.V. Izv. Gos. Nauchno-Issled. Inst. Ozern. Rechn. Rybn. Khoz. 1977, 121, 97-132; Chem. Abstr. 1978, 89, 71897W. RECEIVED July 14, 1989
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
