Chlorinated Insecticides: Retrospect and Prospect - ACS Symposium

1 Chlorinated Insecticides: Retrospect and Prospect G. T. BROOKS

Downloaded by UNIV OF CONNECTICUT on October 3, 2013 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0037.ch001

Agricultural Research Council, Unit of Invertebrate Chemistry and Physiology, University of Sussex, Brighton, BN1 9QJ, England

The story of the discovery of the chlorinated hydrocarbon derived insecticides i s one of outstanding achievement which deserves due recognition. Indeed, the discovery within so few years of DDT, γ-HCH ( γ-BHC), the cyclodiene group and toxaphene, chlorinated insecticide types with distinct origins and synthetic principles, i s truly remarkable. The continuing value of DDT and some other chlorinated com pounds i n Third World crop protection and human health programmes i s widely recognised, whilst at the research l e v e l , chlorinated insecticides have already helped to elucidate the basic processes of insecticide metabolism which are a c r i t i c a l feature of insecti c i d a l action. Many questions remain outstanding i n regard to the mode of interaction of these compounds with insect nerve and i t s resistance to them; the answers to some of these questions may arise at any time as our knowledge progresses and may contribute to a better understanding of nerve function. For this Symposium on Pesticide Chemistry in the 20th Century, in the American Bicentennial year, it seemed appropriate to view this immense subject i n a h i s t o r i c a l context, leading up to the present day situation. Benzene Hexachloride In one sense, the story of the chlorinated insecticides begins i n 1774, since in that year the Swedish apothecary Karl Wilhelm Scheele discovered chlorine. Michael Faraday, who was born in 1791, first assisted Sir Humphry Davy and later succeeded him as Professor of Chemistry at the Royal Institution i n London. In the Philosophical Transactions of 1825 Faraday reported that benzene reacted with chlorine i n sunlight to give a "solid body" and dense, viscous f l u i d , which was undoubtedly the f i r s t sample of technical BHC. During the next 87 years several investigations established i t s constitution to be C^H^Cl, and showed that i t con tained a- and β-isomers and afforded tricnlorobenzenes when treated with a l k a l i . In 1912, the Belgian chemist Van der Linden 1

In Pesticide Chemistry in the 20th Century; Plimmer, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

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PESTICIDE CHEMISTRY IN THE 20TH CENTURY

discovered the δ- and Y- isomers. The l a t t e r comprises only ΙΟ Ι 5% o f the t e c h n i c a l m a t e r i a l and has come to be known as l i n d a n e , after i t s discoverer. Since Z e i d l e r had synthesised DDT i n a p u r e l y chemical cont ext i n l & 7 4 i t i s evident t h a t during much of the e x p l o s i v e European i n d u s t r i a l development o f the 1 9 t h Century, with i t s attendant disease t o l l and demand f o r i n c r e a s e d food production, two of the most remarkable pest c o n t r o l agents o f a l l time were already s i t t i n g on l a b o r a t o r y sheIves1 One hundred and seven years a f t e r F a r a d a y s f i r s t reported p r e p a r a t i o n o f BHC, Harry Bender o f the Great Western E l e c t r o Chemical Company i n C a l i f o r n i a , was l o o k i n g f o r new uses o f chlorine. He added benzene to l i q u i d c h l o r i n e i n a Dewar f l a s k i n the open a i r and n o t i c e d t h a t part o f the product which s p i l l e d on the ground ' a t t r a c t e d and k i l l e d f l i e s and bees'. Thus, although compounds such as p-dichlorobenzene had been used as fumigants s i n c e World War I and BHC i s s a i d to have been used i n smoke screens during t h a t war, Bender's o b s e r v a t i o n made i n 1932-3 and r e f e r r e d to only f l e e t i n g l y i n the l i t e r a t u r e ( 1 ) was the f i r s t i n d i c a t i o n t h a t t e c h n i c a l BHC had unusual i n s e c t i c i d a l p r o p e r t i e s . U n f o r t u n a t e l y , the d i s c o v e r y was l e s t because samples sent to Berkeley were r e c r y s t a l l i s e d there before being t e s t e d ; the Yisomer was r e j e c t e d with the mother l i q u o r s and no a c t i v i t y was found. The subsequent development of BHC was b e d e v i l l e d by t h i s a s s o c i a t i o n o f high a c t i v i t y only with the w i l l - o ' - t h e - w i s p Yisomer and i t i s evident t h a t only samples c o n t a i n i n g mainly the l e s s s o l u b l e a- and β- isomers, contaminated with small and v a r i a b l e amounts o f l i n d a n e , were t e s t e d between 1933 and 1942. In the e a r l y 1930s t e c h n i c a l BHC was made at the A l k a l i D i v i s i o n o f Imperial Chemical I n d u s t r i e s i n Widnes, as a pre cursor o f t r i c h l o r o b e n z e n e s u s e f u l as non-flammable d i e l e c t r i c s . Samples o f white, c r y s t a l l i n e BHC were screened r o u t i n e l y at ICI's J e a l o t t ' s H i l l l a b o r a t o r y and according to an account by Dr. C. C. Tanner ( 2 ) , were found 'not to be s t r i k i n g l y o v i c i d a l or a p h i c i d a l ' . Another r e p o r t ( 3 ) suggests t h a t i n 1937 the samples were found to be 'quite a c t i v e ' but the o b s e r v a t i o n was n e i t h e r followed up or p u b l i s h e d . When ICI's search f o r D e r r i s s u b s t i t u t e s began i n 1942, the samples o f BHC were again added to the screening l i s t because f a i r l y l a r g e amounts were available i n s t o r e from the d i e l e c t r i c days. They soon proved to be the only m a t e r i a l s with worthwhile a c t i v i t y a g a i n s t t u r n i p f l e a b e e t l e . F i n a l l y , i n the summer o f 1942, the pure a - and β-isomers, the only compounds b e l i e v e d at that time to be present i n the crude, c r y s t a l l i n e BHC, were i n d i v i d u a l l y t e s t e d and shown to be i n a c t i v e . The search f o r the a c t i v e component then began i n earnest and t h i s was shown to be the Y-isomer by Burrage, e a r l y i n 1943 (4)· In France, Dupire noted the i n s e c t i c i d a l a c t i v i t y of t e c h n i c a l BHC to c l o t h e s moths i n 1940-41 and the m a t e r i a l was subsequently evaluated against a g r i c u l t u r a l i n s e c t pests ( 5 ) . f


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DDT I n complete c o n t r a s t to the chance d i s c o v e r y o f l i n d a n e , M u l l e r ' s d i s c o v e r y o f the i n s e c t i c i d a l a c t i v i t y o f DDT i n 1939 was the c u l m i n a t i o n of a more or l e s s r a t i o n a l a p p l i c a t i o n o f expe r i e n c e and i n t u i t i o n i n the development and improvement o f e x i s t ing moth-proofing agents based on c h l o r i n a t e d benzenes* In e f f e c t , DDT evolved from water s o l u b l e moth-proofing agents v i a the benzene s o l u b l e moth-proofing agent Eulan BL o f I* G. F a r b e n i n d u s t r i e ( F i g u r e 1) and the s u l f o n e (B, F i g u r e 1) by an a p p l i c a t i o n o f the now c l a s s i c a l n o t i o n t h a t t o x i c a n t molecules c o n s i s t of 'toxophores' t h a t are c a r r i e d to the s i t e of a c t i o n by appropriate l i p o p h i l i c s t r u c t u r e s or f u n c t i o n a l groups. Eulan BL combines 3*4-dichlorobenzene, a l i p o p h i l i c r e s p i r a t o r y and contact poison, with the more p o l a r sulfonamide moiety. The sulfone (B, F i g u r e 1) i s a powerful stomach poison whereas i t s methaned e r i v e d analogue (C), l a c k i n g the e l e c t r o n e g a t i v e - SO^-group, has n e i t h e r good stomach poison nor good c o n t a c t a c t i v i t y . Hence, the i d e a arose t h a t f o r contact a c t i v i t y the moiety separating the benzene n u c l e i had to c o n t a i n a s t r o n g l y e l e c t r o n e g a t i v e , yet p r e f e r a b l y l i p o p h i l i c group and the trichloromethane group o f chloroform, a h i g h l y l i p o p h i l i c i n h a l a t i o n n a r c o t i c then became an obvious candidate. Thus, the DDT molecule must represent one o f the most remarkably s u c c e s s f u l examples o f a l l time of the f a b r i c a t i o n o f a new b i o a c t i v e molecule from simpler s t r u c t u r e s which have t h e i r own apparently d i s t i n c t b i o l o g i c a l e f f e c t s . ICI S c i e n t i s t s working on lindane r e c e i v e d the news o f the new Swiss i n s e c t i c i d e , but not i t s s t r u c t u r e , around Christmas time i n 1943· So s i m i l a r were the r e p o r t e d i n s e c t i c i d a l p r o p e r t i e s o f DDT to those o f lindane t h a t there was s p e c u l a t i o n as to whether the two compounds were v a r i a n t s of the same chemical. Cyclodiene I n s e c t i c i d e s The double event d e s c r i b e d above seems remarkable enough, but the d i s c o v e r y of the c y c l o d i e n e s and toxaphene, two f u r t h e r types o f broad spectrum c h l o r i n a t e d i n s e c t i c i d e s with d i s t i n c t o r i g i n s , was already imminent. The 'indene-derived' group. At the V e l s i c o l Chemical C o r p o r a t i o n i n Chicago i n 1943, Dr. J u l i u s Hyman was seeking new uses f o r the cyclopentadiene which was a by-product o f U.S. s y n t h e t i c rubber production and was already used by V e l s i c o l f o r the manufacture o f r e s i n s and varnishes by the D i e l s - A l d e r r e a c t i o n ( 6 ) . A l i t e r a t u r e search r e v e a l e d Straus's 1930 synthe s i s o f hexachlorocyclopentadiene (•hex ) and, s i n c e c h l o r i n a t e d dienes are f r e q u e n t l y r a t h e r i n e r t , Hyman was i n t e r e s t e d to determine i f 'hex would p a r t i c i p a t e i n the D i e l s - A l d e r r e a c t i o n , e i t h e r with i t s e l f or with cyclopentadiene. S u r p r i s i n g l y , 'hex r e a d i l y gave mono- and bis-adducts with 1

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Figure 2. Synthesis of Chlordene (A), the chlordane isomers (B and C), heptachlor (D), and heptachlor epoxide (8). Toxicities to house flies in μ&ι female (55) are underlined. /



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cyclopentadiene, and these were q u i c k l y t e s t e d f o r i n s e c t i c i d a l a c t i v i t y by P r o f e s s o r C. W. Kearns at the U n i v e r s i t y of I l l i n o i s - on the ground t h a t every new c h l o r i n a t e d hydrocarbon might be a p o t e n t i a l DDT (7). Great excitement attended the f i n d i n g that the mono-adduct (chlordene) was about one f o u r t h as t o x i c as DDT, which was newly appearing i n the U.S. Chlordene (A, F i g u r e 2) could be made more cheaply than DDT but was u n f o r t u n a t e l y too v o l a t i l e to compete with i t as a p e r s i s t e n t r e s i d u a l i n s e c t i c i d e . T h i s problem was overcome by c h l o r i n a t i n g the r e a c t i v e double bond to give chlordane (8) which a l s o was more v o l a t i l e than DDT but now s u f f i c i e n t l y p e r s i s t e n t f o r p r a c t i c a l purposes and s e v e r a l times more t o x i c than DDT to a number of i n s e c t s (housef l y LD50s i n ^ig/female u n d e r l i n e d i n F i g u r e 2)· Chlordane cont a i n s 40% or more of the c i s and t r a n s - products o f double bond c h l o r i n a t i o n (B and C, Figure 2 ) , about 10% o f heptachlor (D), and v a r i o u s other compounds ( 9 ) · I t has found many a p p l i c a t i o n s i n both p u b l i c h e a l t h programmes and a g r i c u l t u r e . R. Riemschneider o f the Free U n i v e r s i t y of B e r l i n was undoubtedly examining the r e a c t i o n s o f 'hex* i n 1945-46 and publ i s h e d on the i n s e c t i c i d a l a c t i o n o f chlordane e a r l y i n 1947 (10)· T h i s i s i n t e r e s t i n g i n view o f the communication d i f f i c u l t i e s o f the time and may be one example o f the f r e q u e n t l y observed spontaneous appearance of s i m i l a r s c i e n t i f i c d i s c o v e r i e s at nearly the same time i n d i f f e r e n t p a r t s of the world. 1

The 'naphthalene-derived group. Sometimes thus c a l l e d because of t h e i r s t r u c t u r a l o r i g i n s , the nevertheless nonaromatic compounds, a l d r i n , d i e l d r i n , i s o d r i n and e n d r i n arose from Hyman's d i s c o v e r y that cyclopentadiene r e a c t s with acetylene to give b i c y c l o [ 2 . 2 . 1 J hepta-2,5-diene (norbornadiene; A, Figure 3) as a s t a b l e product p r e v i o u s l y supposed incapable o f existence, I t was then l o g i c a l to t e s t i t s r e a c t i o n as a d i e n o p h i l e with •hex*. T h i s D i e l s - A l d e r r e a c t i o n occurs r e a d i l y and l e d to the f i r s t p r e p a r a t i o n o f a l d r i n e a r l y i n 1948 (HHDN; D, F i g u r e 3 ) . Attempts to reduce the v o l a t i l i t y o f a l d r i n without e l i m i n a t i n g i t s i n s e c t i c i d a l p r o p e r t i e s soon l e d to the d i s c o v e r y o f the corresponding epoxide, d i e l d r i n (HEOD; E, F i g u r e 3 ) , by Soloway ( 6 , 11). I n F i g u r e 3, h o u s e f l y LD50s i n ug/female are underlined. I f the d i e n o p h i l e (norbornadiene) i s c h l o r i n a t e d i n s t e a d , e i t h e r v i a the r e a c t i o n o f 'hex' with v i n y l c h l o r i d e followed by d e h y d r o c h l o r i n a t i o n , or d i r e c t l y with acetylene, to give 1,2,3«4, 7,7-hexachlorobicyclo[2.2.1 J] hepta-2,5-diene (hexachloronorbornadiene; B, F i g u r e 3 ) , t h i s compound r e a c t s with cyclopentadiene to give i s o d r i n (C; precursor o f the epoxide, endrin) having the opposite (endo-,endo-) stereochemistry to a l d r i n (and d i e l d r i n ) , r e s p e c t i v e l y (12). I s o d r i n has not found commercial use but e n d r i n has been widely used i n t r o p i c a l and s u b - t r o p i c a l a g r i c u l ture - to c o n t r o l c o t t o n pests, f o r example. The 'indene' and 'naphthalene' d e r i v e d compounds may be




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Figure 3.

Synthesis of isodrin (C), aldrin (D), and dieldrin (E) (11, 12). Housefly toxicities in ^g/female (55) are underlined.

Figure 4. Products (middle row) of camphene chlorination in the dark (15, 1β) and toxic compounds (bottom row) recently isohted from toxaphene (17,18)


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regarded as the core d i s c o v e r i e s of the c y c l o d i e n e s e r i e s , although another important and widely used c y c l o d i e n e , endosulfan, was d i s c o v e r e d by Dr. Heinz Frensch and h i s c o l l a b o r a t o r s at Farbwerke-Hoechst i n the mid 1950s ( 1 3 ) . Endosulfan i s a hydrol y s a b l e c y c l i c s u l f i t e e s t e r d e r i v e d i n d i r e c t l y from hex' and i s environmentally much l e s s p e r s i s t e n t than most other c y c l o d i e n e s . Another c y c l o d i e n e , isobenzan, had too great a mammalian t o x i c i t y to achieve p r a c t i c a l use. An obvious p o i n t of c o n t r a s t with the DDT or lindane s t o r i e s i s the number o f h i g h l y e f f e c t i v e i n s e c t i c i d e s d e r i v e d from •hex that have a c t u a l l y achieved commercial use. e


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Toxaphene The dark c h l o r i n a t i o n of camphene was f i r s t r e p o r t e d i n 1919 by L a n g l o i s , who assigned c o r r e c t s t r u c t u r e s to two of the products. In 1944, the Russians Khanenia and Zhuravlev, seeking chemicals to c o n t r o l b o d y - l i c e , noted that the m i l d t o x i c i t y of terpenes contained i n t u r p e n t i n e was g r e a t l y enhanced by c h l o r i n a t i o n . A l s o , about t h i s time Dr. G. A. Buntin o f the Hercules Research Center l a b o r a t o r i e s i n Wilmington was aware of the e x i s t ence o f D D T and was conducting a s y n t h e t i c programme d i r e c t e d toward household i n s e c t c o n t r o l . The f i r s t sample of toxaphene was prepared at Hercules and found to be t o x i c t o h o u s e f l i e s i n March 1944. L a t e r that year, t e s t s by the USDA showed toxaphene to be t o x i c to a wide range o f c o t t o n i n s e c t s and p i l o t s c a l e p r e p a r a t i o n began at Wilmington i n September 1945 (14). Two independent r e p o r t s i n I965 ( 1 5 » 16) e s t a b l i s h e d the major products o f dark r e a c t i o n (middle row, F i g u r e 4) f i r s t i n v e s t i g a t e d by L a n g l o i s , but toxaphene i t s e l f i s a much more complex product r e s u l t i n g from photochemical c h l o r i n a t i o n o f camphene to a c h l o r i n e content o f 6 7 - 6 9 % , corresponding to an average formula ^ Q I Q Q According to recent r e p o r t s ( 1 7 , 1 8 ) , toxaphene c o n t a i n s at l e a s t 175 C - c h l o r i n a t e d hydrocarbons. A recently i s o l a t e d C l ^ compound (B, F i g u r e 4) and a mixture o f isomeric C l g compounds (A^ and A^) comprise 2 and 6% r e s p e c t i v e l y , of t h i s mixture ( 1 7 ) · These two i s o l a t e s are present i n r e l a t i v e l y l a r g e amounts compared with many other components and are considered t o c o n t r i b u t e s i g n i f i c a n t l y to the mammalian t o x i c i t y o f the comm e r c i a l product. Although these two i s o l a t e s are more t o x i c than the t e c h n i c a l mixture ( r e s p e c t i v e l y , 6x and l 4 x more t o x i c to mice and 2x and 4x more t o x i c to h o u s e f l i e s ) , they are l i k e l y to be biodegradable, so that a study o f t h e i r s t r u c t u r e s i n r e l a t i o n to those of other c h l o r i n a t e d p o l y c y c l i c i n s e c t i c i d e s i s of t h e o r e t ical interest. Toxaphene has been very widely used i n both a g r i c u l t u r e and p u b l i c h e a l t h programmes. Since i t s i n t r o d u c t i o n , one b i l l i o n l b have been a p p l i e d to crops and l i v e s t o c k f o r i n s e c t c o n t r o l . I t i s s t i l l used at the r a t e of 40 m i l l i o n l b annually, mostly combined with methyl p a r a t h i o n f o r treatment o f c o t t o n . I t was formc

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e r l y combined with DDT f o r t h i s purpose and i n 1964, toxaphene and DDT together comprised about 4 6 % o f the t o t a l p e s t i c i d e s used i n the U.S. The c o t t o n market absorbed h a l f of the t o t a l i n s e c t i c i d e s used and accounted f o r 70% o f the DDT, 6 9 % of the toxaphene and 86% o f the endrin employed ( 1 9 ) · For comparison, the corn market absorbed 10% of the t o t a l i n s e c t i c i d e usage and accounted f o r 96% o f the a l d r i n and 8 4 % o f the heptachlor used, an i l l u s t r a t i o n of the d i f f e r e n t s p e c t r a o f crop p r o t e c t i o n u t i l i t y f o r the v a r i o u s c h l o r i n a t e d i n s e c t i c i d e s .


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R e c a l l i n g that parathion was developed as an i n s e c t i c i d e by a y e r i n 1944 and that the Geigy Company were developing the carbamate a n t i c h o l i n e s t e r a s e s f o r t h i s purpose i n the l a t e 1 9 4 0 s , we see t h a t the 1950s were entered with ( i n c l u d i n g toxaphene) no l e s s than four new c l a s s e s of c h l o r i n a t e d i n s e c t i c i d e s and two new c l a s s e s o f a n t i c h o l i n e s t e r a s e i n s e c t i c i d e s - a t r u l y unique situation. With t h i s array of i n s e c t i c i d a l compounds a v a i l a b l e and f o l l o w i n g the s p e c t a c u l a r wartime success of DDT, i t seemed that the t o t a l e l i m i n a t i o n of i n s e c t vectors of disease was at hand and that unheard of b e n e f i t s to a g r i c u l t u r e l a y ahead. Nevertheless, many o f the e c o l o g i c a l problems that might r e s u l t from the use of DDT and other p e r s i s t e n t compounds i n a g r i c u l t u r e were already recognised and the prospects f o r DDT i n a g r i c u l t u r e were viewed with some c a u t i o n i n 1944. However, i t i s doubtful whether the p o s s i b i l i t y o f i n s e c t r e s i s t a n c e to the new i n s e c t i c i d e s had been considered, so the appearance o f DDT-resistance i n Sweden and Denmark i n 1946, and subsequently i n other areas, was a cons i d e r a b l e shock to those engaged i n i n s e c t c o n t r o l . Control f a i l u r e s were f r e q u e n t l y b e l i e v e d to be due to f a u l t s i n the technology of DDT a p p l i c a t i o n r a t h e r than to changes i n the i n s e c t s themselves; a s i t u a t i o n which o f t e n l e d to e x t r a t r e a t ments with the t o x i c a n t and hence to greater s e l e c t i o n pressure f o r r e s i s t a n c e i n the i n s e c t populations. The onset o f DDT-resistance i n i t i a t e d the f i r s t i n v e s t i g a t i o n s i n what has come to be known as Insect Toxicology and the great value of r a d i o t r a c e r s f o r such work soon became apparent. The 1951 r e p o r t by Winteringham (20) o f the comparative metabolism of l , l , l - t r i c h l o r o - 2 , 2 - b i s ( p - C Brjphenyl)ethane( Br-DDT ) i n s u s c e p t i b l e (S-) and r e s i s t a n t (R-) h o u s e f l i e s must have been one of the e a r l i e s t a p p l i c a t i o n s o f t h i s technique to the metabolic f a t e o f an organic i n s e c t i c i d e i n i n s e c t s . Metabolites were separated on paper chromatograms which were then analysed r a d i o m e t r i c a l l y using s t r i p - s c a n n e r s designed and made i n the Slough laboratory. Enzymatic d e h y d r o c h l o r i n a t i o n proved to be l a r g e l y responsi b l e f o r DDT-resistance i n some i n s e c t s t r a i n s , as was demonstrated by the f a c t that DDT-analogues which i n h i b i t e d the enzyme i r i Q



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v i t r o and i n v i v o could synergise DDT i n such s t r a i n s ( 2 1 ) . T h i s observation generated a great i n t e r e s t i n s y n e r g i s t i c combinations* I n a d d i t i o n , the b e n z y l i c d e u t e r a t i o n o f DDT ( 2 2 , 23) suppressed d e h y d r o c h l o r i n a t i o n only i n c e r t a i n mosquitoes, whereas a s i n g l e -chlorine suppressed i t i n h o u s e f l i e s (24), thereby demonstrating i n t e r s p e c i f i c d i f f e r e n c e s i n the substrate speci f i c i t y o f the enzyme. Kearns and h i s c o l l e a g u e s concentrated the enzyme from R - h o u s e f l i e s i n 1954 and s t u d i e d i t e x t e n s i v e l y i i the l a t e 1950s ( 2 5 ) ; i t s n a t u r a l f u n c t i o n i s s t i l l unknown. I t i s not present i n s i g n i f i c a n t amounts i n DDT-S s t r a i n s o f housef l i e s , although some o f these c o n t a i n an enzyme with d i f f e r e n t substrate s p e c i f i c i t y . Resistance to the c y c l o d i e n e s was evident by t h i s time and was known to extend t o lindane and toxaphene but not to DDT. These c r o s s - r e s i s t a n c e patterns were s t u d i e d by J. R. Busvine a t the London School o f Hygiene. H i s p a r t l y d i e l d r i n r e s i s t a n t s t r a i n o f M. domestica v i c i n a from the Sudan became 1 0 0 0 - f o l d r e s i s t a n t when subjected to intense pressure with d i e l d r i n a t Slough. . i ! 9 5 7 I d e v i s e ^ the f i r s t s y n d e s e s o f £ C J i s o d r i n and L CJendrin ( 2 6 ) . £ c}aldrin and C c] d i e l d r i n were l a t e r made at the Radiochemical Centre a t Amersham, so i t was p o s s i b l e to compare the f a t e o f a l l these compounds i n S- and R- h o u s e f l i e s . The w e l l known e p o x i d a t i o n r e a c t i o n occurred e q u a l l y w e l l i n both s t r a i n s but there appeared to be no other s i g n i f i c a n t metabolism or any obvious d i f f e r e n c e s to account f o r the r e s i s t a n c e ( 2 7 ) * We now know t h a t a s i n g l e gene on chromosome IV i s r e s p o n s i b l e f o r d i e l d r i n r e s i s t a n c e i n h o u s e f l i e s . The mechanism i s s t i l l obscure, although recent work has shown t h a t h o u s e f l i e s do metabolise small amounts o f d i e l d r i n ( 2 8 ) . Before I 9 6 0 , there was a widespread b e l i e f that the c y c l o dienes were m e t a b o l i c a l l y i n e r t , apart from the epoxidation r e a c t i o n . By 1955» i t was appreciated that mammalian l i v e r conv e r t s c e r t a i n organophosphorus compounds i n t o a c t i v e a n t i c h o l i n e s t e r a s e s by o x i d a t i v e r e a c t i o n s and O'Brien ( 2 9 ) showed t h a t these conversions were e f f e c t e d by l i v e r microsomes f o r t i f i e d with NADPH. Drug metabolism s t u d i e s were about to be a c c e l e r ated by f u r t h e r important developments; the microsomal mixed f u n c t i o n oxidases (MFO) that are i n v o l v e d i n drug metabolism i n mammals were d e s c r i b e d i n 1 9 5 6 - 7 , and about the same time, c y t o chrome P 4 5 0 , the CO-binding pigment r e s p o n s i b l e f o r oxygen a c t i v a t i o n by these enzymes, was discovered i n mammalian l i v e r . A l i n k with c h l o r i n a t e d i n s e c t i c i d e (OC) metabolism i n i n s e c t s appeared between 1958 and i 9 6 0 when the b e n z y l i c hydroxyl a t i o n o f DDT was n o t i c e d by Japanese ( 3 0) and American i n s e c t t o x i c o l o g i s t s ; i n i 9 6 0 the American group showed t h a t i t r e s u l t e d from MFO a t t a c k ( 3 1 ) . A l s o i n i 9 6 0 , Sun and Johnson (32) showed that p y r e t h r i n s y n e r g i s t s such as benzodioxole d e r i v a t i v e s i n h i b i t e d the o x i d a t i v e d e t o x i c a t i o n o f i n s e c t i c i d e s and at l a s t solved the long-standing mystery o f p y r e t h r i n synergism by these I

n



10


compounds i n i n s e c t s ; i t now seemed c e r t a i n t h a t they were MKO i n h i b i t o r s jln v i v o . At t h i s time I was i n t e r e s t e d i n the n a t u r a l t o l e r a n c e o f h o u s e f l i e s to s t r u c t u r a l analogues o f d i e l d r i n and, with Harrison. I soon showed t h a t whereas t o l e r a n c e t o c y c l o d i e n e s was o f t e n r e l a t e d to o x i d a t i v e d e t o x i c a t i o n and could be reduced or e l i m i n ated by benzodioxole s y n e r g i s t s , d i e l d r i n - r e s i s t a n c e i n housef l i e s d i d not respond t o synergism and was apparently not a con sequence o f o x i d a t i v e d e t o x i c a t i o n ( 3 3 ) · Several l a b o r a t o r i e s ( f o r t h e i r subsequent reviews see 3 4 - 3 6 ) confirmed the importance of o x i d a t i v e b i o t r a n s f o r m a t i o n s i n i n s e c t s and i n 1 9 6 4 - 5 , a t Slough, J. W. Ray showed t h a t microsomal preparations from housef l i e s and other i n s e c t s contained cytochrome P450 ( 3 7 ) · Thus, the l i n k s between i n s e c t and mammalian biochemical pharmacology were f i n a l l y and f i r m l y e s t a b l i s h e d . Several i n v e s t i g a t i o n s ( 3 8 - 4 θ ) between i 9 6 0 and 1965 f i n a l l y d i s p e l l e d the myth o f d i e l d r i n s metabolic i n e r t n e s s i n mammals and s i n c e then numerous l a b o r a t o r i e s have shown t h a t c y c l o d i e n e s conform t o the e s t a b l i s h e d p r i n c i p l e s o f drug metabolism (41). Molecular s t r u c t u r e has a profound i n f l u e n c e on the exposure o f the non-chlorinated p o r t i o n s o f these molecules to enzymatic a t t a c k and the low p e r s i s t e n c e o f e n d r i n , as com pared to d i e l d r i n , i n mammalian t i s s u e s appears l a r g e l y due t o the stereochemical d i f f e r e n c e (42). The b i o t r a n s f o r m a t i o n s o f d i e l d r i n are summarised i n F i g u r e 5 · With the a p p l i c a t i o n o f e l e c t r o n - c a p t u r e (EC) and microcoulometric d e t e c t i o n to gas chromatograph e f f l u e n t s from i 9 6 0 , the e r a o f the measurement o f nothing i n everything had a r r i v e d and the environmental controversy was t r u l y on. I t was e a s i e r t o make an e f f e c t i v e EC d e t e c t o r than t o i n t e r p r e t the a n a l y t i c a l r e s u l t s c o r r e c t l y and many o f the i d e n t i f i c a t i o n s o f c h l o r i n a t e d i n s e c t i c i d e (OC) r e s i d u e s made i n the e a r l y 1960s a r e undoubt edly suspect, e s p e c i a l l y since i t was found i n 1966 that wide spread p o l y c h l o r o b i p h e n y l (PCB) contamination i n the bio-sphere can simulate OC i n gas chromatographic a n a l y s i s . In the United Kingdom i n 1960-1 we had the episodes o f b i r d poisoning due t o seed d r e s s i n g s t r e a t e d with d i e l d r i n and hepta c h l o r epoxide, and the controversy about the d e c l i n e o f the peregrine f a l c o n . Government and Industry then agreed t o reduce the use o f OCs and environmental l e v e l s f e l l i n the mid to l a t e 6 0 s , as i n d i c a t e d by the residue content o f human adipose t i s s u e , mutton f a t and shag's eggs. S i m i l a r r e s t r i c t i o n s i n c e n t r a l Europe have a l s o r e s u l t e d i n f a l l s i n r e s i d u e l e v e l s and there appears to have been a s i t u a t i o n o f d e c l i n e , or a t l e a s t stab i l i t y , i n the U.S. s i n c e about 1964. Extensive work i n the 1960s on the pharmacokinetics o f d i e l d r i n i n b i r d s and i n mammals, i n c l u d i n g man, together with e x i s t i n g data f o r DDT and other OCs, led Dr. John Robinson ( 4 3 ) to make the f o l l o w i n g p o s t u l a t e s : 1. OC l e v e l s i n d i f f e r e n t t i s s u e s are f u n c t i o n a l l y related. 1


1.

BROOKS 2.

Chlorinated

T i s s u e l e v e l s are f u n c t i o n a l l y r e l a t e d to the d a i l y intake o f OC. T i s s u e concentrations depend on the time of exposure. When exposure ceases t i s s u e l e v e l s d e c l i n e exponentially.

3. 4·

COMPARTMENT II INERT STORAGE Q,


11

Insecticides

COMPARTMENT I ACTIVE POOL ίΦ £0 DIELDRIN

JXADIELDRIN

ODA

HCE

CI Dieldrin M

l

M

2

Analogs

:

S

A

Blowfly

LD 5 0 ; /

DIELDRIN

CI

Cl

Cl

Cl

0.017

a

,

C

MD

Η

Cl

Cl

Cl

0.022

a

'

b

SD

Cl

Cl

H

Cl

0.046 »

d

AD

b

Cl

Cl

Cl

H

1.047

BD

H

H

Cl

Cl

0.0049

MSD

H

Cl

H

Cl

0.10

SBD

H

H

H

Cl

0.020

ABD

H

H

Cl

H

0.42

e

d

Figure 8. Planar structure of dieldrin and partial structures of some dieldrin analogs (each containing six chlorine atoms) referred to in the text. Table below gives toxicities for dechlorinated derivatives of dieldrin (see key in figure) to adult female blowflies, Calliphora erythrocephala. Similar superscripts indicate significant difference at 95% probability level (63).



1.

BROOKS

Chlorinated

Insecticides

17

d i e l d r i n bridge appear superfluous as f a r as molecular bulk i s concerned ( 6 2 ) · Now although replacement of c h l o r i n e by hydrogen may i n c r e a s e metabolic p o s s i b i l i t i e s and a l s o a l t e r e l e c t r o s t a t i c i n t e r a c t i o n s with the t a r g e t , these deductions from models appeared to accord with the l i m i t e d t o x i c i t y data a v a i l a b l e . The above i n f o r m a t i o n suggested t h a t , f o r d i e l d r i n at l e a s t , three s p e c i f i c c h l o r i n e atoms might be r e p l a c e d without l o s s i n t o x i c i t y (62) and confirmatory t o x i c i t y data f o r b l o w f l i e s (C. erythrocephala) are shown i n F i g u r e 8 . I n the molecule SBD, the r e d u c t i o n i n t o x i c i t y e f f e c t e d by replacement o f the s y n - c h l o r i n e o f d i e l d r i n to give SD appears to be o f f s e t by an i n c r e a s e (compare BD) e f f e c t e d by f u r t h e r replacement of the v i n y l i c c h l o r i n e s , so that SBD i s s i m i l a r to dieldrin in toxicity. I n c o n t r a s t , AD and ABD, which r e t a i n the syn-chlorine« are poor t o x i c a n t s . In t h i s s e r i e s there was no a p p r e c i a b l e synergism with the MFO i n h i b i t o r sesamex, i n d i c a t i n g t h a t when i n c r e a s e d LD50s were seen, these were not the r e s u l t o f enhanced MFO a t t a c k consequent upon the p r o g r e s s i v e replacement of c h l o r i n e . The C l ^ - d i e l d r i n analogues ODA and HCE are biodegradable due to o x i d a t i v e and/or h y d r a t i v e a t t a c k on t h e i r u n c h l o r i n a t e d r i n g s shown i n F i g u r e 8 . Can c h l o r i n e be r e p l a c e d by hydrogen i n such analogues without s e r i o u s l o s s , or perhaps even with an i n c r e a s e i n acute i n s e c t t o x i c i t y ? The products, having l o s t 1 to 3 c h l o r i n e atoms, should be more v u l n e r a b l e to enzymatic detoxication i n the t i s s u e s of higher animals and t h e i r t e r m i n a l r e s i d u e s more amenable to b a c t e r i a l degradation. The r e s u l t s f o r c e r t a i n dec h l o r i n a t e d analogues of e n d r i n , o x a d i e l d r i n , ODA and HCE are presented elsewhere (63) and p r e l i m i n a r y data (unpublished) are a v a i l a b l e f o r d e r i v a t i v e s o f endosulfan, isobenzan and alodan. T h i s y e t incomplete study shows t h a t i n a l l s e r i e s f o r which i n f o r m a t i o n i s a v a i l a b l e , the bridge a n t i - C l ( A ) i s indeed more important than the syn-C1 (s) f o r t o x i c i t y , but replacement o f the v i n y l i c c h l o r i n e s does not n e c e s s a r i l y confer the t o x i c i t y i n c r e a s e found i n the d i e l d r i n s e r i e s . The resemblance between lindane and the c y c l o d i e n e s t r u c t u r e i s p a r t i c u l a r l y s t r i k i n g i f one compares models of lindane and the photoisomer of the molecule SD (Figure 8 ) , i n which the S - c h l o r i n e i s r e p l a c e d by hydrogen and the usual double bond i s absent. There i s a l s o some s i m i l a r i t y , not very obvious from two dimensional s t r u c t u r e s , between models o f these molecules and of the t o x i c components (Figure 4;A,B) i s o l a t e d from toxaphene by Casida's group ( l j ) . T h i s i s to be expected from i n s e c t c r o s s r e s i s t a n c e p a t t e r n s and s i m i l a r i t i e s i n the poisoning syndrome produced by the three types of compound. For cyclohexane d e r i v a t i v e s , c o n v u l s i v e a c t i v i t y i s a s s o c i a t e d , apparently s p e c i f i c a l l y , with a p a r t i c u l a r molecular topography t h a t i s only achieved with the aaaeee arrangement o f substituents. However, the norbornene and camphene carbon skeletons apparently permit the attainment of a s i m i l a r topography



18


w h i l s t allowing a greater molecular v a r i e t y and hence a l a r g e r number o f t o x i c products. With the c y c l o d i e n e s i n p a r t i c u l a r , greater s t r u c t u r a l v a r i a t i o n i s p o s s i b l e i n the non-chlorinated p o r t i o n o f the molecules and t h i s has r e s u l t e d i n a number o f commercially v i a b l e a l t e r n a t i v e s with d i f f e r e n t uses. I t i s con c e i v a b l e that other carbon skeletons may be used to a t t a i n the same end and Mirex, f o r example, i s d e r i v e d from the s p i n d l e shaped f u s i o n product o f two cyclopentadiene n u c l e i . In c o n c l u s i o n , our knowledge o f i n t e r s p e c i f i c d i f f e r e n c e s i n drug metabolism i s already being a p p l i e d to the question o f greater environmental a c c e p t a b i l i t y o f c h l o r i n a t e d as w e l l as other types o f i n s e c t i c i d e s . For example, the simple replacement of p - c h l o r i n e s by p-ethoxy-groups i n the w e l l known DDT-relative P r o l a n g i v e s the biodegradable compound D (Figure 6 ) , which has low mammalian t o x i c i t y and has been shown i n extensive f i e l d t r i a l s to be e f f e c t i v e against a wide range o f i n s e c t s p e c i e s ( 6 4 1 At the more fundamental l e v e l , mode o f a c t i o n s t u d i e s with c h l o r i n a t e d i n s e c t i c i d e s may y e t lead to novel i n s e c t i c i d a l compounds. We must accept that no device o f man w i l l ever be p e r f e c t . W h i l s t remaining watchful f o r the i n e v i t a b l e p i t f a l l s , we should never f o r g e t the many p o s i t i v e achievements already recorded i n the f i e l d o f i n s e c t c o n t r o l by chemicals.

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9· 10. 11. 12. 13. 14. 15· 16. 17.

Bender, H. U.S. Patent 2,010,841 (1935). Cited in Brooks G.T. 'Chlorinated Insecticides' Vol. I, p. 186, CRC Press, Cleveland, 1974. Holmes, E. Agr. Chem. (l951) 6 (12), 31. Slade, R.E. Chem. Ind. (Lond.) (1945) 64, 3l4. Dupire Α., and Raucourt, M. C.R. Acad. Agric. Fr. (1943) 29, 470. Hyman, J. Private communication. Kearns, C.W., Ingle, L., and Metcalf, R.L. J. Econ. Entomol. (1945) 38, 661. Hyman, J. Brit, patent 6l8,432 (1949). Gab, S., Parlar, Η., Cochrane, W.P., Fitzky, H.G., Wendisch, D., and Korte, F. Justus Liebigs Ann. Chem. (1976) 1. Riemschneider, R. World Rev. Pest Control (1963) 2, 29. Lidov, R.E., and Soloway, S.B. Brit, patent 692,547 (1953). Bluestone, H. U.S. Patent 2,676,132 (1954). Frensch, H. Med. Chem. (1957) 6, 556. Buntin, G.A. Private communication. Jennings, B.H., and Herschbach, G.B. J. Org. Chem. (1965) 30, 3902. Richey, H.G.Jr., Grant J.E., Garbacik, T . J . , and Dull, D.L. J. Org. Chem. (1965) 30, 3909. Khalifa, S., Mon, T.R., Engel, J.L., and Casida, J.E. J. Agric. Food Chem. (1974) 22, 653.


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18. 19·

20. 21.


22. 23. 24. 25·

26. 27. 28. 29. 30. 31· 32. 33· 34. 35·

36. 37· 38. 39. 40. 41. 42.

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