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Jan 9, 1990 - runs on an IBM-compatible microcomputer and uses a linear solvation energy relationship (LSER) to predict acute toxicity to four represe...
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Chapter 7

An Expert System for Prediction of Aquatic Toxicity of Contaminants James P. Hickey, Andrew J. Aldridge, Dora R. May Passino, and Anthony M. Frank

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U.S. Fish and Wildlife Service, National Fisheries Research Center—Great Lakes, 1451 Green Road, Ann Arbor, MI 48105 The National Fisheries Research Center-Great Lakes has developed an interactive computer program i n muLISP that runs on an IBM-compatible microcomputer and uses a linear solvation energy relationship (LSER) to predict acute toxicity to four representative aquatic species from the detailed structure of an organic molecule. Using the SMILES formalism for a chemical structure, the expert system identifies all structural components and uses a knowledge base of rules based on an LSER to generate four structure-related parameter values. A separate module then relates these values to toxicity. The system i s designed for rapid screening of potential chemical hazards before laboratory or f i e l d investigations are conducted and can be operated by users with little toxicological background. This i s the f i r s t expert system based on LSER, relying on the f i r s t comprehensive compilation of rules and values for the estimation of LSER parameters. The N a t i o n a l F i s h e r i e s R e s e a r c h C e n t e r - G r e a t L a k e s , U.S. F i s h and Wildlife Service, has t e n t a t i v e l y identified more t h a n 500 c o n t a m i n a n t s i n the t i s s u e s o f w a l l e y e s ( S t i z o s t e d i o n v i t r e u m v i t r e u m ) and l a k e t r o u t ( S a l v e l i n u s namaycush) from the G r e a t Lakes b a s i n ( 1 ) , and 362 s u b s t a n c e s have been v e r i f i e d i n the G r e a t Lakes system ( 2 ) . A s y s t e m a t i c assessment o f the b i o l o g i c a l h a z a r d s o f t h e s e compounds i s underway ( 3 - 5 ) . I t i s , however, p h y s i c a l l y and e c o n o m i c a l l y i m p o s s i b l e t o r u n b i o a s s a y s on e v e r y compound, e s p e c i a l l y s i n c e hundreds o f new compounds a r e b e i n g i n t r o d u c e d i n t o t h e environment each y e a r . By u s i n g m a t h e m a t i c a l models based on q u a n t i t a t i v e s t r u c t u r e a c t i v i t y r e l a t i o n s h i p s (QSAR), one can q u i c k l y d e t e r m i n e the compounds that merit f u r t h e r i n v e s t i g a t i o n (5-9). Use o f t h e s e p r e d i c t i v e models s e r v e as a r a p i d , i n e x p e n s i v e s c r e e n i n g t e c h n i q u e , e s p e c i a l l y f o r compounds n o t c o m m e r c i a l l y a v a i l a b l e . Such models, however, a r e complex and much o f the knowledge r e q u i r e d t o a p p l y them i s This chapter not subject to U.S. copyright Published 1990 American Chemical Society

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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q u a l i t a t i v e o r n o t w e l l d e f i n e d . One approach t o making t h e s e models u s a b l e as an assessment t o o l f o r t o x i c o l o g i s t s , i n l i e u o f a b i o a s s a y , or managers who l a c k t e c h n i c a l e x p e r t i s e i n t o x i c o l o g y and c h e m i s t r y i s t o c r e a t e a computer program c a p a b l e o f u s i n g q u a l i t a t i v e i n f o r m a t i o n f o r d e c i s i o n - m a k i n g (a s o - c a l l e d e x p e r t system). Expert systems are s p e c i a l - p u r p o s e programs t h a t i m i t a t e the performance o f human e x p e r t s i n s o l v i n g problems on s p e c i a l i z e d , o f t e n h i g h l y t e c h n i c a l s u b j e c t s ( 1 0 ) ; they do so u s i n g the h e u r i s t i c knowledge o f the human e x p e r t , w i t h the e x p e r t ' s q u a l i t a t i v e r e a s o n i n g t o s o l v e the problem ( 1 1 ) . E x p e r t systems have p o t e n t i a l f o r r e c o g n i z i n g and managing e n v i r o n m e n t a l problems. P r o t o t y p e e x p e r t systems b e i n g d e v e l o p e d i n c l u d e s i t e assessment systems used t o i d e n t i f y and q u a n t i f y hazards a t "superfund" s i t e s . A l s o i n c l u d e d are p r e d i c t i v e systems such as the Hazardous Waste and Management E x p e r t System d e s i g n e d t o p r o v i d e a d v i c e about r e d u c i n g h e a l t h and e n v i r o n m e n t a l r i s k s a t hazardous waste s i t e s (12.) . We d e v e l o p e d the f i r s t e x p e r t system t h a t i n c o r p o r a t e s a w o r k i n g set o f r u l e s f o r a type o f QSAR r e f e r r e d t o as a l i n e a r s o l v a t i o n energy r e l a t i o n s h i p o r LSER (13-17) t o p r e d i c t LSER v a r i a b l e v a l u e s from SMILES s t r i n g f o r m a l i s m . The program a l s o uses t h e s e LSER r e s u l t s and i n f o r m a t i o n about t o x i c i t y t o p r e d i c t a c u t e t o x i c i t y t o f o u r r e p r e s e n t a t i v e organisms: t h e f a t h e a d minnow (Pimephales p r o m e l a s ) , t h e c r u s t a c e a n s Daphnia magna and Daphnia p u l e x . and P h o t o b a c t e r i u m phosphoreum. t h e l u m i n e s c e n t agent i n the M i c r o t o x test. System Overview The e x p e r t system i s d e s i g n e d t o p r e d i c t LSER v a r i a b l e v a l u e s from a c h e m i c a l s t r u c t u r e f o r m a l i s m , and an a d d i t i o n t o the s o f t w a r e uses t h e s e v a l u e s t o p r e d i c t acute t o x i c i t y ( F i g u r e 1 ) . The program i s w r i t t e n i n the muLISP computer language and runs on a n IBM-compatible p e r s o n a l computer. I t can be used by anyone who has even a l i m i t e d background i n t o x i c o l o g y o r c h e m i s t r y . I t adheres t o a b a s i c d o c t r i n e of e x p e r t system methodology: the s e p a r a t i o n o f the knowledge base from t h e methods o f p r o c e s s i n g t h e knowledge makes t h e system r e l a t i v e l y easy t o modify and debug ( 1 0 ) . E x p e r t systems a r e d e s i g n e d to be used b y n o n - t e c h n i c a l p e r s o n n e l ( 1 8 ) ; i n o u r example t h e u l t i m a t e u s e r c o u l d be a n a t u r a l r e s o u r c e manager. To o p e r a t e o u r system, t h e u s e r e n t e r s a r e p r e s e n t a t i o n ( s t r u c t u r e o r s u i t a b l e i d e n t i f i c a t i o n number) o f a c h e m i c a l compound i n t o the computer. No other i n t e r a c t i o n i s required. The program can be d i v i d e d i n t o t h r e e main s e c t i o n s : the f i r s t s e c t i o n determines the s t r u c t u r a l elements o f the c h e m i c a l compound; the second e s t i m a t e s the v a l u e s f o r the LSER model v a r i a b l e s ; and the t h i r d p r e d i c t s the t o x i c i t y o f the compound. A l l t h r e e s e c t i o n s are c o n t r o l l e d by the main r e a s o n i n g s e c t i o n , c a l l e d the i n f e r e n c e e n g i n e . To i d e n t i f y the compound the i n f e r e n c e engine q u e r i e s the u s e r f o r e i t h e r a CAS (Chemical A b s t r a c t s S e r v i c e ) i d e n t i f i c a t i o n number o r a SMILES r e p r e s e n t a t i o n o f t h e compound s t r u c t u r e ( d e f i n e d l a t e r ) . Next, the s t r i n g i s decomposed by a f r a g m e n t a t i o n p r o c e s s and two r u l e bases a r e c o n s u l t e d . The i n f e r e n c e engine c o n s t r u c t s a secondary i n t e r n a l knowledge base u s i n g these fragments b y f o r w a r d c h a i n i n g o f

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

USER INPUT

Figure 1. Physical Data Flow Diagram.

(*•, α, &Vj)

Ring Parameter Values

Confidence

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RING LOOKUP FILE

OUTPUT SCREEN AND PRINTER

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the r u l e bases and s t o r e s the i n f o r m a t i o n i n a dynamic, g l o b a l , i n t r i n s i c d a t a type c h a r a c t e r i z e d by LISP programmers as a " p r o p e r t y list". V a l u e s f o r the f o u r LSER v a r i a b l e s (V./100, 7Γ*, β, α, v i d e i n f r a ) a r e a s s i g n e d t o the i n d i v i d u a l fragments o f the compound by the second r u l e base and accumulated. The i n f e r e n c e engine t h e n i n v o k e s the r e g r e s s i o n and c o n f i d e n c e i n t e r v a l c a l c u l a t i o n s , u t i l i z i n g the LSER v a r i a b l e s as i n p u t s . F i n a l l y , the e s t i m a t e d LSER v a r i a b l e s and the p r e d i c t e d t o x i c i t i e s w i t h t h e i r c o n f i d e n c e i n t e r v a l s a r e d i s p l a y e d to the u s e r . SMILES S t r i n g s The e x p e r t system determines the s t r u c t u r e o f an o r g a n i c m o l e c u l e from a s t a n d a r d c h e m i c a l n o t a t i o n known as a SMILES s t r i n g . The S i m p l i f i e d M o l e c u l a r I n p u t L i n e E n t r y System was developed by the U.S. E n v i r o n m e n t a l P r o t e c t i o n Agency (19. 20) a t the E n v i r o n m e n t a l Research L a b o r a t o r y , D u l u t h , M i n n e s o t a , f o r the QSAR Research Program (20-23) and was based on work w i t h the M e d i c i n a l C h e m i s t r y P r o j e c t a t Pomona College, Claremont, California (24). A SMILES s t r i n g is a l i n e a r i z a t i o n o f the t h r e e - d i m e n s i o n a l r e p r e s e n t a t i o n o f an o r g a n i c compound. The n o t a t i o n has f o u r b a s i c s y n t a x r u l e s t h a t a l l o w the u s e r t o r e p r e s e n t a m o l e c u l e i n a form t h a t can be e a s i l y u s e d by the muLISP language (19-21). A s y n o p s i s o f the r u l e s w i l l be g i v e n here f o r the p r o s p e c t i v e u s e r ; i n the f u t u r e , the use o f the SMILES f o r m a l i s m w i l l n o t be so n e c e s s a r y . The f i r s t r u l e d e s i g n a t e s a s e t o f b a s i c symbols ( T a b l e I ) . A l l m o l e c u l e s a r e r e p r e s e n t e d as hydrogen-suppressed, and s i n g l e bonds a r e assumed by d e f a u l t . For example, CO assumes a s i n g l e bond between the c a r b o n and oxygen, and C-0 i n d i c a t e s a double bond. The bond between two l o w e r c a s e symbols i s a r o m a t i c . Table I .

B a s i c Symbols Used i n the F o r m u l a t i o n o f SMILES S t r i n g s

Symbol C,c N,n 0,o S,s P.P

Designation Normal Normal Normal Normal Normal

and and and and and

a r o m a t i c carbon aromatic n i t r o g e n a r o m a t i c oxygen aromatic s u l f u r a r o m a t i c phosphorus

Symbol BR, Br CL,C1 I, F

-,# *

Designation Bromine Chlorine I o d i n e and f l u o r i n e Double, t r i p l e bonds A r o m a t i c bond

The second r u l e d e f i n e s s i m p l e c h a i n s i n m o l e c u l e s . A s i m p l e c h a i n of atoms i s r e p r e s e n t e d by atomic symbols i n t e r s p e r s e d w i t h t h e i r r e s p e c t i v e bond symbols. For example, CC r e p r e s e n t s ethane; C«=C ethene; and CCCCCO, n - p e n t a n o l . The t h i r d r u l e d e f i n e s s i m p l e branches i n m o l e c u l e s . A branch from the main c h a i n i s e n c l o s e d i n p a r e n t h e s e s . The s t r i n g i n p a r e n t h e s e s i s p l a c e d d i r e c t l y a f t e r the symbol f o r the atom t o which the b r a n c h i s connected. I f i t i s connected by a m u l t i p l e bond, the bond symbol i m m e d i a t e l y f o l l o w s the l e f t p a r e n t h e s i s . More than one

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b r a n c h i s i n d i c a t e d by u s i n g more t h a n one s e t o f p a r e n t h e s e s : ( ) ( ) and ( ( )) are s i m p l e forms t h a t may be used. For example, I C ( I ) 0 represents diiodomethanol, and CCCCC(C(C)C)CC-C represents 3isopropyloctene. The f o u r t h r u l e d e f i n e s r i n g s t r u c t u r e s . A r i n g i s c l o s e d by u s i n g a p a i r o f r i n g c l o s u r e numbers. I n C1CCCCC1, a s i n g l e bond c o n n e c t s the "1" a f t e r the f i r s t c a r b o n w i t h the o t h e r c a r b o n f o l l o w e d by a "1". For m u l t i p l e r i n g s , we use d i f f e r e n t r i n g numbers ( e . g . , 1,2,3,4), and p a i r s o f carbons w i t h l i k e numbers a r e c o n n e c t e d t o c l o s e the r i n g s . For example, c l c c 2 c c c c c 2 c c l r e p r e s e n t s n a p t h a l e n e , where c l i s j o i n e d w i t h c l and c2 w i t h c2 t o form the two f u s e d r i n g s . I n f e r e n c e mechanics The p r o b l e m - s o l v i n g system i s b u i l t around r u l e s t h a t c o n s i s t o f an a n t e c e d e n t " i f " p a r t and a c o n c l u s i o n "then" p a r t . These r u l e s are p r o c e s s e d by c o n c e n t r a t i n g on the r u l e s ' a n t e c e d e n t s , a p r o c e s s r e f e r r e d t o as f o r w a r d c h a i n i n g ( 1 1 ) . When a l l o f the a n t e c e d e n t s i n a r u l e t e s t t r u e , the r u l e i s s a i d t o be t r i g g e r e d . I f an a c t i o n i s performed ( i . e . , a c o n c l u s i o n i s added t o the secondary knowledge b a s e ) , the r u l e i s s a i d t o be f i r e d . S e v e r a l r u l e s may be t r i g g e r e d a t once, r e q u i r i n g c o n f l i c t r e s o l u t i o n s t r a t e g i e s t o determine w h i c h o f them s h o u l d be f i r e d (25)· The c o n f l i c t r e s o l u t i o n s t r a t e g i e s we use a r e termed c o n t e x t l i m i t i n g and r u l e o r d e r i n g . I n c o n t e x t - l i m i t i n g s t r a t e g y , r u l e s are grouped i n such a way t h a t few r u l e s are a c t i v e a t the same t i m e . The r e s u l t i n g groups are d i s j o i n t s u b s e t s o f the s e t o f a l l r u l e s . Because the i n f e r e n c e engine a c t i v a t e s and d e a c t i v a t e s r u l e groups, i t needs o n l y t o h a n d l e c o n f l i c t s w i t h i n a group. W i t h i n each s u b s e t , r u l e o r d e r i n g i s used t o r e s o l v e c o n f l i c t s . Rule o r d e r i n g r e q u i r e s t h a t the r u l e s be o r g a n i z e d i n a s i n g l e p r i o r i t y l i s t i n w h i c h the f i r s t t r i g g e r i n g r u l e i n the l i s t has the h i g h e s t p r i o r i t y and the o t h e r s are i g n o r e d ( 2 5 ) . The i n f e r e n c e engine i s o l a t e s the b a s i c s k e l e t a l s t r u c t u r e s , ( r i n g s o r c h a i n s ) and a l l o t h e r f u n c t i o n a l groups composing the compound, and passes t h e s e t o the f i r s t knowledge base t h a t i d e n t i f i e s them. R i n g s are the most d i f f i c u l t s t r u c t u r e s to i s o l a t e because one compound may c o n t a i n many r i n g s w i t h some a t t a c h e d t o each o t h e r . The SMILES s t r i n g i s t h e r e f o r e put i n a t r e e s t r u c t u r e , and the s h o r t e s t p a t h t o the numbers i n the c h a i n are i d e n t i f i e d by u s i n g a b r a n c h and bound search (25). For example, Figure 2a shows a tree for decahydro-2,3dimethylnaphthalene for which the SMILES string is (C(C(CCC1)CC(C2C)C)(C1)C2). The i n f e r e n c e engine f i r s t f i n d s the "1" r i n g and then proceeds to the "2" r i n g . Once the s h o r t e s t p a t h t o one o f the numbers o f the numbered r i n g i s found, the system b a l a n c e s the t r e e and runs the s e a r c h a g a i n . The f i r s t number found becomes the r o o t ( F i g u r e 2b). T h i s s h o r t e s t p a t h t h e n becomes the a c t u a l r i n g s u b s t i t u e n t , w h i c h i s s t o r e d f o r l a t e r i d e n t i f i c a t i o n by the f i r s t r u l e base i n the secondary knowledge base. The i n f e r e n c e engine t h e n b e g i n s a n o t h e r s e a r c h f o r a n o t h e r r i n g , r e p e a t i n g the s e a r c h sequence. A l l n o n - r i n g fragments a r e a l s o i s o l a t e d and s t o r e d i n the knowledge base o f the secondary p r o p e r t y

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C

/l\ c c c

/ / / \ 1 2 C

/

C

/

/ Λ / 1

c

c

/

c

2

\ c (a)

Figure 2a. SMILES string tree representation C(C(CCC1)CC(C2C))(C1)C2.

for decahydro-2,3-dimethylnaphthalene,

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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1

\ c

\ c

/\ /

c

c

/\ C

2

C

/

\ c

C

/

/\

c

c e

/

/

1

2

/ c (b) Figure 2b. SMILES string tree representation for SMILES string tree from a with C l as root.

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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list. Only a f t e r a l l fragments o f the c h e m i c a l compound have been i s o l a t e d and s t o r e d i n a p r o p e r t y l i s t does the program p r o g r e s s t o the f i r s t knowledge base f o r fragment i d e n t i f i c a t i o n . The s o f t w a r e i s coded t o r e c o g n i z e a c e r t a i n l a r g e b u t f i n i t e number o f fragments ( o r f u n c t i o n a l groups). I f a p a r t i c u l a r f u n c t i o n a l group i s n o t r e c o g n i z e d , the system w i l l i d e n t i f y p a r t s o f i t and p r o c e e d . I f a f u n c t i o n a l group i s r e c o g n i z e d and no v a l u e s a r e a v a i l a b l e , the system s k i p s them, e f f e c t i v e l y a s s i g n i n g d e f a u l t v a l u e s f o r the atoms making up the u n i t . Once the s u b s t i t u e n t s have been i d e n t i f i e d and t h e i r names s t o r e d i n the p r o p e r t y l i s t , the program p r o g r e s s e s t o t h e second knowledge base used t o g e n e r a t e the f o u r LSER v a r i a b l e v a l u e s .

L i n e a r S o l v a t i o n Energy R e l a t i o n s h i p In the LSER model (13-17) the t o x i c i t y o f a contaminant i s r e l a t e d t o i t s s t r u c t u r e (26). The g e n e r a l i z e d LSER e q u a t i o n c o n t a i n s t h r e e s i m p l e and c o n c e p t u a l l y e x p l i c i t t y p e s o f terms: t o x i c i t y - c a v i t y term + d i p o l a r term + hydrogen b o n d i n g terms In this system each fragment o f t h e contaminant m o l e c u l e c o n t r i b u t e s b o t h t o the energy r e q u i r e d t o o r d e r s o l v e n t m o l e c u l e s (water o r b i o s y s t e m medium) around the m o l e c u l e and t o the e n e r g i e s g a i n e d o r l o s t t h r o u g h f o r m a t i o n o f e l e c t r o s t a t i c and hydrogen bonds between the contaminant and the medium. The g e n e r a l form o f t h e e q u a t i o n used i n our e x p e r t system i s l o g ( t o x i c i t y ) - mV,/100 + s7T* + b0 + aa 1 0

where m, s, b, and a a r e c o n s t a n t s . N u m e r i c a l v a l u e s o f f o u r LSER v a r i a b l e s a r e g e n e r a t e d f o r each fragment: mV,/100 i s an e n d o e r g i c energy term t h a t measures the f r e e energy r e q u i r e d t o s e p a r a t e s o l v e n t m o l e c u l e s and p r o v i d e a s u i t a b l y s i z e d c a v i t y f o r the contaminant m o l e c u l e , and V,/100 i s the i n t r i n s i c (van der Waals) m o l e c u l a r volume s c a l e d b y a f a c t o r o f 100, t o g i v e magnitudes comparable t o the o t h e r t h r e e v a r i a b l e s . The d i p o l a r i t y / p o l a r i z a b i l i t y term sir*, measures the g e n e r a l l y e x o e r g i c e f f e c t s o f s o l u t e - s o l v e n t , d i p o l e - d i p o l e , and d i p o l e - i n d u c e d d i p o l e i n t e r a c t i o n s , and 7Γ* i s a measure o f t h e m o l e c u l e ' s a b i l i t y t o s t a b i l i z e a n e i g h b o r i n g charge o r d i p o l e b y n a t u r e o f n o n - s p e c i f i c d i e l e c t r i c i n t e r a c t i o n s . The hydrogen b o n d i n g terms bβ and a a measure the e x o e r g i c e f f e c t s o f hydrogen b o n d i n g , i n v o l v i n g the s o l v e n t as hydrogen bond donor a c i d and the s o l u t e as hydrogen bond a c c e p t o r base β , and the s o l u t e as hydrogen bond donor a c i d and the s o l v e n t as hydrogen bond a c c e p t o r base a.. E s s e n t i a l t o the program a r e the complete s e t s o f v a r i a b l e v a l u e s f o r each fundamental s t r u c t u r e and fragment we have e n c o u n t e r e d o r t h a t we a n t i c i p a t e w i l l e x i s t i n an e n v i r o n m e n t a l sample. Some o f t h e s e v a l u e s have been f o r m u l a t e d by the few p u b l i s h e d r u l e s (27. 28) , b u t most were computed p r i m a r i l y b y e x t r a p o l a t i o n from o t h e r v a l u e s t a k e n from the l i t e r a t u r e (6. 7. 13-17. 27-41) and c o d i f i e d i n t o rules. A m a n u s c r i p t l i s t i n g the comprehensive s e t o f r u l e s i s i n preparation. S e v e r a l c o n v e n t i o n s o f the volume term a r e a v a i l a b l e m

m

Λ

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98

E X P E R T SYSTEMS FOR ENVIRONMENTAL APPLICATIONS

(39-42) . The p r e s e n t system uses the c o n v e n t i o n V, and makes use o f c o n t r i b u t i o n s f o r a i l fragments and fundamental s t r u c t u r e s b a s e d on e x t r a p o l a t i o n s from p r e v i o u s l y r e p o r t e d v a l u e s ( 6 . 7. 13-17. 27-41). The same p r o c e s s was used t o d e v i s e v a l u e c o n t r i b u t i o n s o f t h e ΤΓ*, /3, and α v a r i a b l e s . The p r e s e n t complete s e t o f v a r i a b l e e s t i m a t i o n r u l e s a l l o w s p r e d i c t i o n o f the LSER v a r i a b l e s f o r a l m o s t any o r g a n i c compound. W i t h r e g a r d s t o the a c c u r a c y o f these e s t i m a t e d v a l u e s , p r e d i c t i o n s f o r V,/100 a r e g e n e r a l l y ±.02 o f l i t e r a t u r e v a l u e s , as volumes a r e s t r i c t l y a d d i t i v e . F o r α and β, t h e l i m i t e d e x p e r i m e n t a l d a t a a v a i l a b l e from M. H. Abraham e t a l . (43. 44) show t h a t t h e p r e d i c t e d v a l u e s g e n e r a l l y agree w i t h i n ±.03 o f t h e e x p e r i m e n t a l l y determined data. F o r 7Γ*. t h e r e a r e no e x p e r i m e n t a l d a t a a v a i l a b l e , b u t p r e d i c t e d v a l u e s agree ±.03 w i t h p u b l i s h e d v a l u e s ( 6 , J_ 13-17. 27-41). Downloaded by PURDUE UNIV on July 5, 2016 | http://pubs.acs.org Publication Date: July 5, 1990 | doi: 10.1021/bk-1990-0431.ch007

t

B i o a s s a v Data S e t s and M u l t i p l e L i n e a r R e g r e s s i o n E q u a t i o n s The e x p e r t system p r e d i c t s the acute t o x i c i t y o f a c h e m i c a l t o f o u r r e p r e s e n t a t i v e a q u a t i c organisms and r e p o r t s t o x i c i t y as e i t h e r EC50- i s the e f f e c t i v e c o n c e n t r a t i o n a t which e i t h e r 50% o f t h e a n i m a l s (Daphnia p u l e x o r D. magna) were i m m o b i l i z e d o r 50% o f t h e luminescence ( t h e M i c r o t o x t e s t ) was d i m i n i s h e d - - o r LC50, t h e l e t h a l c o n c e n t r a t i o n f o r 50% o f the f i s h ( f a t h e a d minnows) i n t h e s t u d y . The r e g r e s s i o n e q u a t i o n s were d e r i v e d by u s i n g one s e t o f t o x i c i t y d a t a c o l l e c t e d under c o n t r o l l e d c o n d i t i o n s f o r each s p e c i e s . The d a t a f o r Daphnia p u l e x (7) were o b t a i n e d a t the N a t i o n a l F i s h e r i e s R e s e a r c h C e n t e r - G r e a t Lakes, under the t e s t c o n d i t i o n s o f a 48-hour exposure a t 20°C i n r e c o n s t i t u t e d h a r d water. The EC50 v a l u e s were d e t e r m i n e d by p r o b i t a n a l y s i s . The d a t a s e t s f o r the M i c r o t o x t e s t , P h o t o b a c t e r i u m phosphoreum ( 3 6 ) , Daphnia magna ( 7 ) , and f a t h e a d minnows, Pimephales promelas (45-48) were t a k e n from the l i t e r a t u r e . A l l d a t a s e t s were examined c l o s e l y f o r c o n t i n u i t y and a p p l i c a b i l i t y o f t e s t c o n d i t i o n s , c l o s e adherence t o r i g i d q u a l i t y assurance and q u a l i t y c o n t r o l schemes (49-52), and r e p r e s e n t a t i v e o f a wide v a r i e t y o f c h e m i c a l c l a s s e s and s t r u c t u r a l subunits. Each LSER model i s b e s t d e v e l o p e d by u s i n g a d a t a s e t c o n t a i n i n g the w i d e s t s e l e c t i o n o f c h e m i c a l c l a s s e s and s t r u c t u r e s , which a r e g e n e r a l l y r e p r e s e n t a t i v e o f e n v i r o n m e n t a l samples. The r e g r e s s i o n e q u a t i o n s used i n t h e p r e s e n t system ( T a b l e I I ) were p r e v i o u s l y developed and d i s c u s s e d (7. 9. 3 6 ) . R e s u l t s and D i s c u s s i o n Our e x p e r t system i s the o n l y p r e d i c t i v e s o f t w a r e a v a i l a b l e b a s e d on the LSER model. T h i s system a l s o r e p r e s e n t s t h e f i r s t total c o d i f i c a t i o n o f the r u l e s and fragment c o n t r i b u t i o n v a l u e s f o r s y n t h e s i s o f the f o u r parameter v a l u e s . P r e v i o u s p u b l i c a t i o n s have e i t h e r l i s t e d p a r t i a l g u i d e l i n e s f o r s p e c i f i c c l a s s e s (27. 28) o r have a l l u d e d t o them (7. 13-17. 27-41). T a b l e I I I demonstrates the p r e d i c t i v e a b i l i t y o f the s o f t w a r e f o r b o t h the LSER parameters and contaminant t o x i c i t y . The LSER parameter v a l u e s a r e composed from a sum o f t h e c o n t r i b u t i o n s from each o f the fragments, and the p r e d i c t e d v a l u e s a r e g e n e r a l l y c l o s e t o t h e v a l u e s composed by hand. F o r some compounds (such as acenaphthene) , the v a l u e s f o r 7Γ', /3, and a may n o t be a c c u r a t e l y r e p r e s e n t e d by a s i m p l e sum o f fragment v a r i a b l e

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

H I C K E Y E T AL.

Table I I .

Log

10

Prediction ofAquatic Toxicity of Contaminants

E x p e r t System M u l t i p l e L i n e a r R e g r e s s i o n E q u a t i o n s G e n e r a l Equation* ( t o x i c i t y ) - ( i n t e r c e p t ) - mV,/100 - s7T* + bo

- aa

b

1) The M i c r o t o x T e s t ( P h o t o b a c t e r i u m phosphoreum) . μΜ/L log(EC50) - 7.49 - 7.39 V./100 - 1.38 π' + 3.70 β - 1.66 α Ν - 40, R - 0.966, s d - 0.319 2

c

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2) Daphnia p u l e x . μΜ/L log(EC50) - 4.09 - 4.33 V,/100 -0.05 τΤ-0.13 β-0.22 a N - 38, R - 0.868, s d - 0.418 2

c

3) Daphnia magna . mM/L log(EC50) - 4.18 - 4.73 V./100 - 1.67 π' + 1.48 β - 0.93 α Ν - 53, R - 0.948, s d - 0.221 2

d

4) Fathead minnow (Pimephales p r o m e l a s ) . M/L l o g ( L C 5 0 ) - - 0.34 - 5.26 V./100 - 0.80 7Γ* + 3.98 β - 0.80 α Ν - 76, R - 0.970 s d - 0.218 2

a. b. c d.

see t e x t f o r e x p l a n a t i o n o f symbols. (36) (2) (£)

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

EXPERT SYSTEMS FOR E N V I R O N M E N T A L APPLICATIONS

100

T a b l e I I I . P r e d i c t e d (Ρ) v s E x p e r i m e n t a l (E) LSER Parameter V a l u e s and Acute T o x i c i t i e s f o r t h e M i c r o t o x T e s t (MT), Daphnia p u l e x (DP), Daphnia magna (DM), and t h e Fathead Minnow (FM) LSER v a l u e s log(Acute T o x i c i t y ) 2

Compound

P/E

c

V,

π

0

β

a

100

MT EC50 (/IM)

Well-behaved compounds

DM

FM

EC50 (mM)

LC50 (M)

c

Ρ Ε

0.,633 0. 40 0..42 0.,35 0.,690 0. 40 0..45 0.,35

3.,23 2.,71

2. 12

0.,81 0. 32

-2.,63 -3.,02

n-Heptanol Ρ Ε

0.,731 0.,40 0,.42 0.,35 0.,789 0.,40 0,.45 0.,33

2.,51 1.,93

1.,69

0.,35 -0.,09

-3.,15 -2.,53

2-Butanone Ρ Ε

0.,478 0.,65 0,.48 0..00 0.,477 0.,67 0,.48 0..00

4.,84 4.,85

2.,85

1.,54 2.,09

-1. ,51 -1. .35

4-Methyl2-pentanone

Ρ Ε

0.,674 0.,65 0,.48 0..00 0.,663 0.,63 0,.48 0..00

3.,39 2..90

2.,00

0.,61 1..17

-2..54 -2..30

1,2-Dichlo roethane Ε

Ρ0.,376 0.,70 0,.20 0..00 0..442 0.,81 0,.10 0,.00

4..49 4..05

3.,26

1..52 1.,13

-2..10 -2..92

Iodocyclo- Ρ hexane Ε

0..779 0..32 0,.05 0,.00 0..779 0.,32 0,.05 0,.00

Cyclohexane

Ρ Ε

0..598 0.,00 0,.00 0,.00 0..598 0..00 0,.00 0..00

1..35 0..61

-3,.48 -4..27

0MTA

Ρ Ε

1..544 0..06 0 .00 0,.00 1,.444 0,.04 0 .00 0..00

Benzene

Ρ Ε

0,.491 0..59 0 .10 0,.00 0,.491 0,.59 0 .10 0,.00

3,.42 3,.31

2..75

1..01 1..16

-3..01 -3,.40

ο-Xylene

Ρ Ε

0..687 0..59 0 .12 0,.00 0..671 0..51 0 .12 0,.00

2..04 1,.94

1..90

0..12 0..15

-3,.96 -3,.82

Chlorobenzene

Ρ Ε

0..581 0..71 0 .07 0,.00 0..581 0..71 0 .07 0,.00

2,.48 2,.12

2..35

0..34 0..44

-3,.69 -3..77

Naphtha­ lene

Ρ Ε

0..753 0..70 0,.15 0,.00 0..753 0..70 0,.15 0,.00

1,.51

1..61 1..58

-0..33

-4,.28 -4,.32

9HFluorene

Ρ Ε

0..958 0..66 0,.21 0,.00 0..960 0.,66 0 .20 0,.00

n-Hexanol Downloaded by PURDUE UNIV on July 5, 2016 | http://pubs.acs.org Publication Date: July 5, 1990 | doi: 10.1021/bk-1990-0431.ch007

DP EC50 (μΜ)

d

1.,50 1.,53 3..07

2..30

-1. .80 -1. .74

0..68 0..11

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

7.

HICKEY E T AJL

Prediction ofAquatic Toxicity ofContaminants Table III. Continued LSER v a l u e s *

Compound

P/E

c

V,

π

log(Acute T o x i c i t y ) β

a

100

0

MT

DP

DM

FM

EC50 (/IM)

EC50 (μΜ)

EC50 (mM)

LC50 (M)

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Troublesome compounds Acenaphthene

Ρ Ε

0..855 1.,83 0.,30 0..00 0..896 0.,62 0.,17 0..00

-0,.24

1,.13

-2..49

-5,.10 -4,.95

Camphor

Ρ Ε

1..594 0.,68 0.,48 0.,00 1..106 0.,68 0.,59 0.,00

-3,.11 -1. .79

-3.,58

-7,.16 *-3..92

Diethylphthalate

Ρ Ε

1..177 0.,93 0.,82 0.,00 1.,153 0.,90 0.,70 0.,00

0,.10 -0..16

-1. ,91 *-0.,52

-4,.55 -3,.87

2,4-Pentanedione

Ρ Ε

0.,662 1.,30 0.,96 0.,00 0.,595 0. 90 0.,90 0.,00

4,.36

2..08

Phenol

Ρ Ε

0..536 0.,72 0.,33 0.,61 0.,536 0.,72 0.,33 0.,60

2,.74 2,.63

2,.46

0.,36 -0.,48

-2,.94 -3,.94

2-Methylphenol

Ρ Ε

0..634 0.,72 0.,34 0..61 0.,634 0. 70 0.,33 0.,57

2,.06 2..28

2,.03

-0.,09 -0.,75

-3,.42 -3,.77

Aniline

Ρ Ε

0..562 0.,71 0.,50 0..23 0..562 0.,73 0..50 0..26

3,.83

2,.44

0..86 *-2..27

-2,.10 -2,.84

4-Chloroaniline

Ρ Ε

0..652 0.,83 0.,47 0.,23 0..652 0.,73 0.,40 0..31

2,.88

2,.04

0.,19 *-1. .59

-2,.79 -3,.62

4-Fluoroaniline

Ρ Ε

0.591 0.74 0.45 0.28 0.591 0.73 0.47 0.23*

3.46

2.31

0.62

-2.40 *-3.82

4-Nitroaniline

Ρ Ε

0.702 1.13 0.70 0.23 0.702 1.25 0.48 0.42

-0.21 -0.76

-2.40 -3.04

Butylamine Ρ Ε

0.472 0.25 0.69 0.00 0.535 0.32 0.69 0.00

6.21

2.93

2.55 -0.33 *0.02 *-2.44

Triethanolamine

Ρ Ε

0.803 1.35 1.95 1.05 0.840 1.35 2.00 0.85

5.16

1.39

0.03 1.10 0.97 *-1.10

Pyridine

Ρ Ε

0.470 0.87 0.44 0.00 0.470 0.87 0.44 0.00

4.44 4.51

2.87

1.15 0.48

Nicotine

Ρ Ε

1.041 1.01 1.14 0.00 0.975 1.01 1.17 0.00

0.,29 -1, .13 0.,00 *-2,.98

-1.80 -2.93

0.18 *1.34 Continued on next page

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

101

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E X P E R T SYSTEMS FOR

ENVIRONMENTAL APPLICATIONS

Table III. Continued

a. b.

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c.

d.

See t e x t f o r d e f i n i t i o n s o f LSER symbols. * D e s i g n a t e s a c t u a l t o x i c i t y v a l u e s g r e a t e r t h a n 2 o r "sigma" from the p r e d i c t e d t o x i c i t y . Ρ - p r e d i c t e d v a l u e s when e x p e r t system i s used. Ε - h a n d - c a l c u l a t e d LSER parameter v a l u e s o r e x p e r i m e n t a l l y determined t o x i c i t y f o r a s p e c i e s . For h a n d - c a l c u l a t e d LSER v a r i a b l e v a l u e s , the c o n t r i b u t i o n s from a l l fragments were summed. Some o f the v a l u e s f o r 7Γ*, 0, and α were a d j u s t e d t o r e f l e c t e i t h e r some predominant c o n t r i b u t i o n o r a v e c t o r sum, w h i c h can account f o r most o f the d i s c r e p a n c i e s between p r e d i c t e d and e x p e r i m e n t a l v a l u e s . B l a n k t o x i c i t y e n t r i e s (P o r E) i n d i c a t e no d a t a were a v a i l a b l e . " W e l l Behaved Compounds" have LSER s y s t e m - p r e d i c t e d v a l u e s t h a t agree ±.01 w i t h h a n d - c a l c u l a t e d v a l u e s and p r e d i c t e d t o x i c i t i e s w i t h i n ±1 l o g u n i t o f a c t u a l v a l u e . "Troublesome Compounds" can have LSER v a l u e s >±.03 w i t h handc a l c u l a t e d v a l u e s b u t g e n e r a l l y have a c t u a l t o x i c i t i e s ±1 t o 3 l o g u n i t s d i f f e r e n t from the p r e d i c t e d v a l u e s . OTMA: octahydro-1,4,9,9-tetramethy1-1H-3a,7-methanoazulene

Hushon; Expert Systems for Environmental Applications ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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7.

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Prediction ofAquatic Toxicity of Contaminants 103

c o n t r i b u t i o n s (which i s t h e p r e s e n t s i t u a t i o n ) ; a v e c t o r sum o r a sum w i t h a fragment h i e r a r c h y o f importance (use o r n o t use, and t o what degree) may g i v e a more a c c u r a t e v a l u e . T h i s approach i s done o c c a s i o n a l l y t o compute h a n d - c a l c u l a t e d v a l u e s found i n T a b l e I I I and a c c o u n t s f o r the d i s c r e p a n c i e s o c c a s i o n a l l y seen between p r e d i c t e d and e x p e r i m e n t a l v a l u e s f o r LSER v a r i a b l e s . Even when t h e e x p e r t system's e s t i m a t e s o f LSER parameter v a l u e s match o u r hand c a l c u l a t i o n s , p r e d i c t e d t o x i c i t i e s c a n d i f f e r from t h e observed t o x i c i t y b y one t o t h r e e o r d e r s o f magnitude ( s e e "Troublesome Compounds" i n Table I I I ) . Our e x p e r t system was d e v e l o p e d t o p r e d i c t t o x i c i t i e s a c c o r d i n g t o one mode o f a c t i o n - nonpolar, non-reactive n a r c o s i s - - f o r n e u t r a l organic molecules w i t h no s p e c i a l p h y s i c a l p r o p e r t y c o n s i d e r a t i o n s . T o x i c i t i e s f o r such compounds have been p r e d i c t e d by o u r system w i t h i n one o r d e r o f magnitude o f t h e observed v a l u e and g e n e r a l l y w i t h i n ± a f a c t o r o f 5. Compounds t h a t r e a c t w i t h t h e b i o s y s t e m ( e . g . , aldehydes and amines) g e n e r a l l y a r e 10 t o 1000 times more t o x i c t h a n p r e d i c t e d b y t h e p r e s e n t system; and compounds t h a t i o n i z e a t t e s t pH c o n d i t i o n s ( o r g a n i c a c i d s ) , t h a t a r e h i g h l y v o l a t i l e ( e . g . , camphor), t h a t have low w a t e r s o l u b i l i t y , o r t h a t do n o t d i f f u s e a c r o s s c e l l membranes ( v e r y l o n g c h a i n a l c o h o l s ) w i l l have an o b s e r v e d t o x i c i t y o f o n l y 1/10 to 1/100 o f t h a t p r e d i c t e d h e r e . T o x i c i t y would a l s o be d i f f i c u l t t o e s t i m a t e f o r o r g a n i c e s t e r s ( l i k e p h t h a l a t e s ) and amides because h y d r o l y s i s under t h e t e s t c o n d i t i o n s would produce a t l e a s t two d i f f e r e n t , p o s s i b l y t o x i c , molecules (19). E x p e r t System C a p a b i l i t y . U t i l i t y , and L i m i t a t i o n s The e x p e r t system i s c a p a b l e o f e v a l u a t i n g compounds w i t h e i t h e r r i n g o r c h a i n s k e l e t o n s , double and t r i p l e bonds, and a l l common f u n c t i o n a l groups ( e . g . , a c i d s , a l c o h o l s , amines, e s t e r s , and h a l i d e s ) . The r i n g s t r u c t u r e s i n c l u d e cyclohexane and benzene d e r i v a t i v e s ; m u l t i p l e , and condensed r i n g s t r u c t u r e s such as p o l y c h l o r i n a t e d b i p h e n y l s (PCBs), n a p h t h a l e n e s , and h i g h e r p o l y n u c l e a r a r o m a t i c h y d r o c a r b o n s and t h e i r heterocyclic analogs such as n i c o t i n e and p y r r o l e ; and t h e c o r r e s p o n d i n g s a t u r a t e d r i n g systems. The LSER models p r o v i d e c o n s i s t e n t l y b e t t e r c o r r e l a t i o n s w i t h t o x i c i t y than do o t h e r w i d e l y used QSAR models t h a t depend s i m p l y on the p a r t i t i o n i n g o f contaminants i n t o o c t a n o l and w a t e r , (28). The LSER models have thus f a r been a p p l i e d t o o n l y a few d a t a s e t s f o r a q u a t i c organisms ( 7 . 9. 36-38) a l t h o u g h they c o u l d be used t o p r e d i c t t o x i c i t y t o a wide v a r i e t y o f a q u a t i c organisms, as w e l l a s to model s p e c i f i c mechanisms o f t o x i c i t y (37. 3 8 ) . We a r e c u r r e n t l y u s i n g t h e e x p e r t system t o h e l p e s t i m a t e t o x i c i t y o f c h e m i c a l s b e f o r e we b e g i n b i o a s s a y s , t o s h o r t e n t h e time spent on r a n g e - f i n d i n g t e s t s . The system a l s o may be used as p a r t o f a h a z a r d assessment scheme, t o e v a l u a t e t h e t o x i c i t y o f compounds d e t e c t e d i n e n v i r o n m e n t a l samples by gas chromatography/mass s p e c t r o m e t r y (GC/MS). The system c o u l d a c t as a s c r e e n i n g t o o l i n an i n i t i a l e v a l u a t i o n o f contaminants d e t e c t e d a t a s i t e o f c o n c e r n . Some l i m i t a t i o n s o f the system i n c h e m i c a l r e c o g n i t i o n and i n the e s t i m a t i o n o f v a l u e s o f LSER v a r i a b l e s must be improved. As i n any v i a b l e , e v o l v i n g e x p e r t system, t h e r e a r e s t i l l s o f t w a r e problems and l i m i t a t i o n s b e i n g s t u d i e d . F o r

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example, c e r t a i n SMILES d e s i g n a t i o n s cannot be a n a l y z e d c o r r e c t l y , and c e r t a i n obscure c h e m i c a l fragments ( c l a s s t y p e s ) a r e identified incorrectly. A l s o , t h e r e i s no p r o v i s i o n t o d i f f e r e n t i a t e between p o s s i b l e g e o m e t r i c ( c i s vs t r a n s ) o r o p t i c a l isomers o f compounds. The d i f f e r e n t forms have d i f f e r e n t observed t o x i c i t i e s , but no a p p l i c a b l e w e i g h t i n g scheme o r i n p u t d e s i g n a t i o n has been developed f o r the p r e s e n t system. Future The s o f t w a r e now uses s t r u c t u r a l l y i n t r i n s i c parameters f o r o n l y one QSAR model (LSER) and the r e s u l t s a r e used t o p r e d i c t one p r o p e r t y (acute toxicity) to four aquatic species by one mechanism ( n o n r e a c t i v e , n o n - p o l a r n a r c o s i s ) ; however, we i n t e n d t o c o n t i n u e t o r e f i n e our e q u a t i o n s as databases grow, i n c o r p o r a t e o t h e r models, p r e d i c t o t h e r p r o p e r t i e s , and i n c l u d e o t h e r organisms. We will attempt t o d i f f e r e n t i a t e between modes o f t o x i c a c t i o n and improve our e s t i m a t e s a c c o r d i n g l y . For the w i d e l y d i v e r g e n t c l a s s e s o f c h e m i c a l s and types o f e n v i r o n m e n t a l b e h a v i o r , no one model w i l l b e s t d e s c r i b e e v e r y s i t u a t i o n and no one s p e c i e s i s the o p t i m a l organism to m o n i t o r . As the s o f t w a r e e v o l v e s , the e x p e r t system s h o u l d choose the b e s t model b a s e d on the contaminant, the s p e c i e s , and the p r o p e r t y to be p r e d i c t e d ( e . g . , t o x i c i t y o r b i o a c c u m u l a t i o n ) . I n a d d i t i o n , we e n v i s i o n an i n t e r a c t i v e s c r e e n system f o r d a t a e n t r y t h a t w i l l bypass the SMILES n o t a t i o n and a l l o w the u s e r t o d e s c r i b e the m o l e c u l e by p o s i n g a s e r i e s o f q u e s t i o n s about the compound's backbone and f u n c t i o n a l groups. The responses w i l l t r a n s l a t e d i r e c t l y i n t o v a l u e s o f LSER v a r i a b l e s . A p r e l i m i n a r y v e r s i o n o f t h i s system i s now a v a i l a b l e . Our u l t i m a t e o b j e c t i v e i s t o produce a u s e r - f r i e n d l y e x p e r t system f o r use i n the e v a l u a t i o n o f contaminants a t s p e c i f i c s i t e s . Acknowledgments We d e d i c a t e t h i s work t o the memory o f the l a t e Mortimer J . Kamlet whose i n s p i r a t i o n and d r i v e h e l p e d b r i n g h i s LSER concept t o a w o r k a b l e h y p o t h e s i s t h a t made t h i s work p o s s i b l e . We thank Dr. Amjad Umar ( U n i v e r s i t y o f M i c h i g a n ) f o r concepts and guidance i n a r t i f i c i a l i n t e l l i g e n c e and Dr. M i c h a e l H. Abraham ( U n i v e r s i t y C o l l e g e London) f o r h i s c o n s u l t a t i o n and encouragement i n LSER t h e o r y and p r a c t i c e . Use o f t r a d e names does not c o n s t i t u t e Government endorsement o f commercial p r o d u c t s .

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