16 Metabolic Aspects of Pesticide Toxicology G. W A Y N E IVIE Veterinary Toxicology and Entomology Research Laboratory, Agricultural Research, Science and Education Administration, U.S. Department of Agriculture, College Station, T X S. KRIS B A N D A L
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Agricultural Products, 3M Company, St. Paul, M N
55101
At least 1500 organic and inorganic chemicals are used in a manner such that they can be called pesticides (1). These chemicals are indispensable in the management of a seemingly endless variety of pest organisms, including insects, weeds, fungi, bacteria, pest birds and mammals, and others. Pesticides are intentionally applied to many components of the environment, and they or their degradation products often move quite freely through the environment by mechanisms such as runoff, leaching, and volatilization. The production and use of pesticides on a world scale exceeds 3 billion pounds annually ( 1 ) , and it can safely be said that residues of various pesticides interact at some level with virtually all components of the environment. Pesticides by design are meant to be toxic! Although a major goal of the discipline of modern pesticide chemistry is to develop pesticides and consequent use patterns that confine pesticide toxicity to pest organisms, such a goal is seldom attained easily. All living organisms have much in common biochemically, and successful exploitation of the often relatively minor biochemical differences between pest and non-pest species is almost always difficult and is, in fact, sometimes impossible. Thus, i t is often necessary to use pesticides that are toxic not only to the pest species but to other organisms as well. Even when we succeed in developing what appear to be highly efficacious yet selective pesticides, we are always concerned that interactions of these chemicals or their transformation products with non-target species, particularly man, may result in some unforeseen toxic consequences. From t h e human p e r s p e c t i v e , t h e d i r e c t t o x i c o l o g i c a l i m p l i c a t i o n s o f p e s t i c i d e use t o o u r own s p e c i e s m e r i t t h e most t h o r o u g h and serious consideration. Most would a g r e e t h a t t h e j u d i c i o u s use of p e s t i c i d e s contributes i n a p o s i t i v e way t o many a s p e c t s o f human w e l f a r e , b u t we a l s o r e c o g n i z e t h a t t h e s e c h e m i c a l s h a v e g e n u i n e p o t e n t i a l f o r a d v e r s e human e f f e c t s . Therefore, i f the proposed use p a t t e r n s of a pesticide create a substantial l i k e l i h o o d t h a t i n t e r a c t i o n s w i t h man may o c c u r , i t i s p r u d e n t t o
0097-6156/81/0160-0257$07.00/0 © 1981 American Chemical Society In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
T H E
258
PESTICIDE
C H E M I S T
A N D
M O D E R N TOXICOLOGY
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define both the extent of these interactions and their toxicological significance. Our discussion w i l l center on the r o l e p l a y e d by m e t a b o l i s m i n t h e e x p r e s s i o n o f p e s t i c i d e t o x i c i t y and t h e e v a l u a t i o n o f t o x i c o l o g i c a l s i g n i f i c a n c e . We w i l l b r i e f l y d i s c u s s the importance of m e t a b o l i s m s t u d i e s i n d e v e l o p i n g more efficacious and selective pesticides. We will discuss the rationale and appropriate methodology used by metabolism s c i e n t i s t s i n t h e d e s i g n and e x e c u t i o n o f s u c h s t u d i e s . Finally, and most i m p o r t a n t l y , we w i l l a t t e m p t t o show how the metabolism o f p e s t i c i d e s may a f f e c t t h e i r t o x i c i t y , and how t h e d a t a from p e s t i c i d e m e t a b o l i s m s t u d i e s are used i n the p r o c e s s of e v a l u a t i n g t o x i c o l o g i c a l r i s k to man. The
Nature of
Metabolic
Reactions
Pesticides are transformed by living organisms through a great d i v e r s i t y of metabolic r e a c t i o n s . T h e s e r e a c t i o n s can be conveniently grouped into two categories, primary or phase I reactions, which are those that create or modify functional g r o u p s , and s e c o n d a r y or phase I I r e a c t i o n s , which are conjugations. A few e x a m p l e s a r e shown i n F i g u r e 1. Some a u t h o r s (2) feel that the terms phase I and phase II are not totally satisfactory because numerous e x a m p l e s a r e known o f phase II reactions preceding phase I r e a c t i o n s ( e . g . , d i r e c t conjugations of c h l o r i n a t e d phenols, Figure 1). Most p e s t i c i d e s , h o w e v e r , do not l e n d t h e m s e l v e s to phase I I r e a c t i o n s w i t h o u t p r i o r phase I modifications. Although i t is generally true that phase I metabolism of pesticides effects partial or complete detoxification, at least from an acute toxicity standpoint, m e t a b o l i c a c t i v a t i o n s do o c c u r and can be o f g r e a t t o x i c o l o g i c a l significance. Phase I I o r c o n j u g a t i o n r e a c t i o n s more o f t e n t h a n n o t s e r v e t o r e n d e r p e s t i c i d e s o r t h e i r m e t a b o l i t e s more p o l a r f o r more efficient excretion (e.g., in urine of mammals) or to f a c i l i t a t e transport for i n t e r n a l storage i n organisms that lack efficient excretory systems (e.g., plants). It is probably c o r r e c t t h a t most l i v i n g o r g a n i s m s can m e t a b o l i z e p e s t i c i d e s v i a b o t h p h a s e I and p h a s e I I m e t a b o l i c p a t h w a y s . The s c h e m a t i c shown i n F i g u r e 2 i s d e s i g n e d t o r e p r e s e n t the m a j o r m e t a b o l i c and d i s p o s i t i o n p a t t e r n s t h a t d i f f e r e n t p e s t i c i d e t y p e s might undergo i n h i g h e r animal systems. We have somewhat arbitrarily grouped pesticides into four categories, based on polarity. A very few p e s t i c i d e s , p r i m a r i l y some organochlorine i n s e c t i c i d e s and p a r t i c u l a r l y the i n s e c t i c i d e mirex, are highly l i p o p h i l i c , a r e q u i t e m e t a b o l i c a l l y s t a b l e , and t e n d t o be stored i n f a t w i t h m i n i m a l o r no m e t a b o l i s m . D i r e c t e l i m i n a t i o n through l i p i d c o n t a i n i n g a n i m a l b y p r o d u c t s ( m i l k o r eggs) t e n d s a l s o t o be an a p p r e c i a b l e t o m a j o r d i s p o s i t i o n mechanism f o r s u c h h i g h l y l i p o p h i l i c compounds. Most i n s e c t i c i d e s a r e l i p o p h i l i c , y e t are r a p i d l y m e t a b o l i z e d by b o t h phase I and phase I I r e a c t i o n s and are u l t i m a t e l y excreted from t h e b o d y . Some p e s t i c i d e s , i n c l u d i n g
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
Phase II Metabolite
Figure L Examples of Phase I and Phase II metabolites of the carbamate insecticide carbanolate, the synthetic pyrethroid insecticide permethrin, and the wood preservative pentachlorophenol
PERMETHRIN
Pesticide
Phase I Metabolite
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THE
260
PESTICIDE CHEMIST
A N D M O D E R N
TOXICOLOGY
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phenolics, amines, e t c . , are r e a s o n a b l y polar compounds that generally have functionalities that permit direct conjugation reactions. O t h e r s , such as h e r b i c i d e s formulated as s a l t s , o r compounds that contain moieties that readily ionize at physiological pH, c a n be c o n s i d e r e d h y d r o p h i l i c and a r e o f t e n e x c r e t e d r a p i d l y w i t h o u t any m e t a b o l i s m a t a l l . Phase I a n d phase I I p e s t i c i d e m e t a b o l i t e s , and p o s s i b l y e v e n t h e p a r e n t p e s t i c i d e , may have t h e p o t e n t i a l f o r c h e m i c a l sequestration (i.e., covalent b i n d i n g , F i g u r e 2 ) w i t h t i s s u e components t h a t may u l t i m a t e l y l e a d t o the e x p r e s s i o n o f c h r o n i c t o x i c i t y . Most o r g a n i s m s , r e g a r d l e s s o f c o m p l e x i t y , s h a r e a number o f biochemical pathways f o r m e t a b o l i z i n g pesticides. Examples can r e a d i l y be f o u n d t o show t h a t many t y p e s o f p l a n t s and a n i m a l s m e t a b o l i z e p e s t i c i d e s by each of the four b a s i c types o f m e t a b o l i c changes: o x i d a t i o n , r e d u c t i o n , h y d r o l y s i s , and c o n j u g a t i o n (3_). Of course, species do d i f f e r i n the metabolism of p e s t i c i d e s , t h e s e d i f f e r e n c e s a r e sometimes q u i t e d r a m a t i c , and t h e y c a n be o f great significance in interpreting comparative toxicological effects. A l s o , s p e c i e s d i f f e r e n c e s i n p e s t i c i d e m e t a b o l i s m , once i d e n t i f i e d , q u i t e o f t e n p r o v i d e i m p e t u s t o t h e d e v e l o p m e n t o f more s e l e c t i v e p e s t - c o n t r o l agents. It i s not our purpose here to e x t e n s i v e l y review the l i t e r a t u r e on t h e m e t a b o l i s m o f i n d i v i d u a l p e s t i c i d e s b y a v a r i e t y of l i v i n g organisms. Numerous s u c h r e v i e w s a r e a v a i l a b l e , some a r e p e r i o d i c a l l y u p d a t e d , and we r e f e r t h e r e a d e r to several of t h e s e f o r an o v e r v i e w o f t h e v o l u m i n o u s l i t e r a t u r e i n t h i s field (4-14). Metabolic
Basis
for Pesticide
Selectivity
In t h e use o f p e s t i c i d e s , a t t e m p t s a r e a l w a y s made t o d i r e c t t h e i r t o x i c a c t i o n s t o w a r d an i n d i v i d u a l o r g r o u p o f p e s t s p e c i e s , and i t i s a major goal of the p e s t i c i d e s c i e n t i s t to develop e f f i c a c i o u s p e s t i c i d e s and use p a t t e r n s such t h a t l i t t l e o r no t o x i c i t y to other l i f e forms o c c u r s . Such an a p p r o a c h i s c l e a r l y desirable from an e n v i r o n m e n t a l standpoint, but i t often has d e f i n i t e e c o n o m i c a d v a n t a g e s a l s o ( e . g . , p r o t e c t i n g p r e d a t o r s and parasites while controlling a pest insect). In some circums t a n c e s , a degree o f s e l e c t i v i t y i s a b s o l u t e l y e s s e n t i a l f o r the i n t e n d e d use ( e . g . , h e r b i c i d e s c a n n o t be l e t h a l t o t h e p r o t e c t e d crop) . Metabolism s t u d i e s i n the pest s p e c i e s , i n the s p e c i e s b e i n g p r o t e c t e d , and i n a s s o c i a t e d n o n t a r g e t o r g a n i s m s , c a n and o f t e n do p r o v i d e a w e a l t h o f u s e f u l i n f o r m a t i o n . Such s t u d i e s may lead t o a more thorough understanding o f t h e mechanisms o f p e s t i c i d a l a c t i o n , and t h i s knowledge o f t e n l e a d s i n t u r n t o t h e d e v e l o p m e n t o f more e f f i c a c i o u s , s e l e c t i v e , and environmentally acceptable pest c o n t r o l agents. W h i l e n o t a l w a y s s o , s e l e c t i v e t o x i c i t y c a n q u i t e o f t e n be attributed p r i m a r i l y i f not t o t a l l y to metabolic differences between s p e c i e s , e i t h e r i n the r a t e o f m e t a b o l i s m o r the n a t u r e o f
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
16.
iviE AND
products
Metabolic
BANDAL
formed.
The
w e l l - k n o w n example to to
a number
of pest
mammals.
i t i s very
(Figure 4 )
i s also
species, at
least
is
determines process Figure in
that 5)
to
serves
mammals by
to
these
to
Another
While
no
illustration.
an
N-hydroxylation
and
or
In
pig
any
species
the
guinea
appreciable
detoxification are
of
examples
influence the
with
T h i s compound
subsequent
pesticides
conjugation
to
lemming, N - h y d r o x y l a t i o n AAF
(AAF,
i s metabolized
and
and
on
metabolic
7-hydroxylation
extent,
to
Species
i s not
to
yield
inactive does
carcinogenic
I.
Differences in Its
% N-OH
Species pig
Lemming
of
0
72
trace
42
1-15
19-27
Rabbit
13-30
15-29
Hamster
15-20
35-39
Rat
Dog
5
Man
4-14 Smith
(Ref
(AAF)
Metabolism
Dose 7-OH
of
detoxification
metabolic
nature
occurs
examples
(Table I ) .
Related
From
ragweed,
by
Table
Guinea
of
and
in
C a r c i n o g e n i c i t y of 2 - A c e t y l a m i n o f l u o r e n e
Mammalian as
whereas
2-acetylaminofluorene
carcinogen
in
herbicide crop,
linuron
dramatic
as
rate
the
metabolic
the
the
slower
of
N-demethylation
of
mind,
that
monocarboxylic
rates
and
kind
toxicity
fact
i n metabolic
metabolic
involve
in
the
a
toxic
Carrot, a tolerant
by
rate
metabolites,
metabolites. occur
the
low
by
much
differences
Malathion
could
occurs.
carcinogenic not
which
toxicity
come r e a d i l y
to
linuron,
selectivity.
selective
a
nonherbicidal products,
(J_6 ) .
slowly in
due
at
is
i s highly
nontoxic
selectivity
linuron
s u s c e p t i b l e to
pesticides
The
a
i n some c a s e s .
metabolizes
more
to
occurs
(_1_5 ) .
linuron
which
explained
malathion
reaction
to
are
3)
(Figure
species, yet
between
much
malathion
insect
differences
261
Toxicology
Malathion
this
N-demethoxylation
Pesticide
selectivity.
insects
rapidly
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insecticide
metabolize
whereas
susceptible
of
such
These
mammals r e a d i l y acid,
of
Aspects
Carcinogenicity
+ + + +
25-30
17).
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
262
T H E
PESTICIDE
PESTICIDAL HYDROPHILIC
POLAR
CHEMIST
A N D M O D E R N
TOXICOLOGY
CHEMICALS LIPOPHILIC
HIGHLY LIPOPHILIC (Metabolically Stable) -I
PHASE I
PHYSICAL
METABOLISM
SEQUESTRATION
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11 (Fat)
(Ox., Red., Hydr.)
χ PHASE II
CHEMICAL
METABOLISM
SEQUESTRATION (Tissue Binding)
(Conjugation)
1
UNABSORBED DOSE
|
1 1
\
τ
BILIARY EXCRETION sENTEROHEPATIC
i
RENAL EXCRETION
|
CIRCULATION
MILK ^ /
URINE
FECES-
EGGS
Figure 2. Schematic of the major metabolic and disposition patterns of pesticides in higher animal systems. Pathways indicated by dashed lines are generally minor ones from a quantitative standpoint.
s H CCUI
o
S II
Q
H CO 3
hUCOvH H CO
15
I
3
2 H Ο
MALATHION Figure 3.
2 5
/
O M
J 2 H Ο
2 5
MALATHION «-MONOACID
Metabolic detoxification of the insecticide malathion
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
IVIE
AND
B A N D A L
Metabolic
Aspects of Pesticide
Toxicology
263
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16.
Figure 5.
Mammalian metabolism of AAF to carcinogenic and noncarcinogenic metabolites
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
THE
264
PESTICIDE
CHEMIST
A N D M O D E R N
TOXICOLOGY
With the r a t , r a b b i t , hamster, and dog, however, AAF i s m e t a b o l i z e d t o a p p r e c i a b l e amounts o f t h e N - h y d r o x y m e t a b o l i t e , and AAF i s carcinogenic to these animals. Man likewise m e t a b o l i z e s AAF b y N - h y d r o x y l a t i o n , and w h i l e t h e c a r c i n o g e n i c i t y o f AAF t o man i s n o t c l e a r l y e s t a b l i s h e d , t h e i m p l i c a t i o n s a r e o b v i o u s (J_7 ) . More d e t a i l e d t r e a t m e n t s o f t h e m e t a b o l i c b a s i s f o r p e s t i c i d e s e l e c t i v i t y a r e a v a i l a b l e ( 4 , JJ5, VB_) .
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Metabolism
S t u d i e s and S a f e t y E v a l u a t i o n
E v a l u a t i n g the t o x i c o l o g i c a l s i g n i f i c a n c e of p e s t i c i d e s to man i s seen t o be a h i g h l y complex a f f a i r when one c o n s i d e r s t h e v a r i o u s ways t h a t p e s t i c i d e s a r e u s e d , t h e r o u t e s b y w h i c h man may be e x p o s e d t o them a n d , p e r h a p s most i m p o r t a n t l y , t h e m u l t i t u d e o f chemical transformations that pesticides often undergo before man's e x p o s u r e t o them. Thus, while i t i s s u r e l y a p p r o p r i a t e to define the t o x i c o l o g i c a l interactions of a p e s t i c i d e ' s active i n g r e d i e n t i n e x p e r i m e n t a l a n i m a l s f o r e x t r a p o l a t i o n t o man, i t i s e n t i r e l y p o s s i b l e t h a t s u c h s t u d i e s may i n some c a s e s have l i t t l e relevance to real world human exposure. Because of the environmental i n s t a b i l i t y o f most o r g a n i c p e s t i c i d e s , i t seems reasonable and i n f a c t l i k e l y t h a t t h e g r e a t m a j o r i t y o f human exposure to p e s t i c i d e r e s i d u e s i s to products of t h e i r decompos i t i o n r a t h e r than to the p a r e n t m o l e c u l e . T h u s , n o t o n l y must we as m e t a b o l i s m s c i e n t i s t s d e l i n e a t e t h e b i o c h e m i c a l pathways o f p e s t i c i d e s i n e x p e r i m e n t a l a n i m a l s t h a t a r e r e p r e s e n t a t i v e o f man, we must as w e l l c l e a r l y d e f i n e t h e n a t u r e o f t h e i r environmental t r a n s f o r m a t i o n s , _ i f the products generated are l i k e l y t o i n t e r a c t w i t h man. While environmental t r a n s f o r m a t i o n s o f p e s t i c i d e s may o c c u r as t h e r e s u l t o f e i t h e r b i o c h e m i c a l ( m e t a b o l i c ) o r p h y s i c o chemical (e.g., photochemical) r e a c t i o n s , and b o t h have toxicological implications, our purpose here i s to consider only metabolic transformations. F o r any g i v e n p e s t i c i d e and use p a t t e r n , i t i s e a s i l y seen t h a t s e v e r a l t y p e s o f m e t a b o l i s m s t u d i e s may be needed t o p r o v i d e a framework f o r e v a l u a t i n g t h e t o x i c o l o g i c a l s i g n i f i c a n c e o f t h e compound t o man. As an e x a m p l e , we c a n c o n s i d e r a systemic i n s e c t i c i d e used as a s o i l - i n c o r p o r a t e d g r a n u l a r f o r m u l a t i o n f o r i n s e c t c o n t r o l on c o r n . B e c a u s e c o r n i s consumed b y b o t h man and h i s food a n i m a l s , s e v e r a l types o f metabolism s t u d i e s a r e approp r i a t e , i n c l u d i n g s t u d i e s o f t h e p e s t i c i d e i t s e l f i n one o r more l a b o r a t o r y monogastric mammals considered t o be human models. Metabolism s t u d i e s i n c o r n a r e needed t o determine t h e n a t u r e o f r e s i d u e s t o w h i c h man may be e x p o s e d t h r o u g h c o n s u m p t i o n o f c o r n from t r e a t e d c r o p s . S t u d i e s a r e a l s o needed i n food a n i m a l s t h a t a r e g i v e n c o r n i n t h e d i e t ( e . g . , c a t t l e , s w i n e , and p o u l t r y ) t o a s s e s s t h e e x t e n t t o w h i c h t h e p e s t i c i d e o r i t s m e t a b o l i t e s may a p p e a r i n meat, m i l k , p o u l t r y o r e g g s i n t e n d e d f o r human consumption. D a t a from a s o i l m e t a b o l i s m s t u d y m i g h t l i k e w i s e be needed if potentially toxic soil metabolites a r e a s s i m i l a t e d by the
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
i v i E AND BANDAL
16.
treated or
crop.
With
alternative
emphasized distinctions and
a r e from
must
means
study, or
of
question more
we
are attempting
changes
recognize
an e n d .
importantly,
here
standpoint
t o make u n d e r that
pesticide
265
additional I t must be
to
physicochemical
For the u l t i m a t e
segregate ones,
rather
field
such
arbitrary
conditions.
metabolism
organisms to
assess
value
plants, birds,
of data
toxicological
t o lower
Toxicology
studies
a s an end i n t h e m s e l v e s ; b u t r a t h e r , t h e y a r e
i s i t s yield
the
from
a toxicological
be i t i n m i c r o o r g a n i s m s ,
whatever,
ment
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toward
of Pesticide
p e s t i c i d e s and use p a t t e r n s ,
may be d i f f i c u l t
always
c a n n o t be c o n s i d e r e d a
Aspects
s t u d i e s may be a p p r o p r i a t e .
although
or metabolic
i n any case We
other
metabolism
that,
biochemical
Metabolic
valuable
significance (i.e.,
of a
toward of
further
the
i t s environmental
toxicological
metabolism
l a b o r a t o r y mammals, assess-
pesticide
in
impact) o r ,
significance
t o man
himself. Methodology, Goals,
and R e g u l a t o r y
Considerations
A l t h o u g h t h e word " m e t a b o l i s m " ( G r . m e t a b o l e , c h a n g e ) h a s a rather limited connotation, a "pesticide metabolism study" i s u s u a l l y considered i n a broad s e n s e t o encompass n o t o n l y t h e metabolic a l t e r a t i o n s of the chemical i n question but also the a b s o r p t i o n , t r a n s p o r t , s t o r a g e , and e x c r e t i o n o r e l i m i n a t i o n o f t h e p a r e n t p e s t i c i d e and i t s m e t a b o l i t e s b y t h e e x p o s e d o r g a n i s m . The schematic i n F i g u r e 6 shows t h a t p e s t i c i d e " m e t a b o l i s m " c a n be considered a s more o r l e s s synonomous w i t h the toxokinetic phase of a pesticide/organism interaction. Of c o u r s e , a n y metabolic transformation that occurs i n the gut p r i o r to a b s o r p t i o n o f t h e p e s t i c i d e would be c o n s i d e r e d , and i s i n f a c t , metabolism. B e c a u s e p e s t i c i d e use p a t t e r n s o f t e n d i c t a t e t h a t m e t a b o l i s m s t u d i e s be c o n d u c t e d i n a number o f w i d e l y d i v e r g e n t l i f e forms, i t i s c l e a r t h a t no s i n g l e a p p r o a c h i s a p p r o p r i a t e f o r a l l c i r c u m stances. Thus, metabolism studies i n microorganisms, plants, mammals, e t c . , require specialized approaches based on t h e i n h e r e n t n a t u r e o f t h e o r g a n i s m and t h e g o a l s o f t h e s t u d y i t s e l f . Quite often t o o , the p o t e n t i a l use p a t t e r n s o f p e s t i c i d e s may d i c t a t e d i f f e r i n g m e t h o d o l o g i e s f o r s t u d i e s i n t h e same s p e c i e s . F o r e x a m p l e , m e t a b o l i s m s t u d i e s i n c a t t l e w i t h a p e s t i c i d e u s e d on f e e d g r a i n s o r f o r a g e c l e a r l y need be done o n l y w i t h o r a l administ r a t i o n , b u t i f a p r o d u c t i s t o be u s e d f o r e c t o p a r a s i t e c o n t r o l on c a t t l e a s a d e r m a l s p r a y , t h e d e r m a l r o u t e o f e x p o s u r e w o u l d a l s o be a p p r o p r i a t e . Given a s u i t a b l e experimental d e s i g n , what t h e n i s o u r g o a l as m e t a b o l i s m scientists i n conducting such a study? It i s , simply put, to define a c c u r a t e l y and t o t h e f u l l e s t extent p o s s i b l e t h e k i n e t i c and m e t a b o l i c b e h a v i o r o f t h e p e s t i c i d e u n d e r s t u d y i n an a p p r o p r i a t e o r g a n i s m u n d e r t h e c o n d i t i o n s c h o s e n . We want t o know how and a t what r a t e t h e p e s t i c i d e i s a b s o r b e d i n t o the living s y s t e m , t o what p r o d u c t s i t i s metabolized, and t o
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
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266
THE
PESTICIDE
CHEMIST
A N D
M O D E R N
TOXICOLOGY
where and t o what e x t e n t t h e s e p r o d u c t s a r e t r a n s p o r t e d , stored, and e x c r e t e d . Our most i m p o r t a n t and u s u a l l y most d i f f i c u l t t a s k i s , o f c o u r s e , t o d e f i n i t i v e l y c h a r a c t e r i z e the c h e m i c a l n a t u r e o f a s many o f the m e t a b o l i t e s as p o s s i b l e , g i v e n the l i m i t a t i o n s of our a n a l y t i c a l and spectrometric techniques and of our own scientific capabilities. I f the study i s d e s i g n e d to d e f i n e the m e t a b o l i s m of a p e s t i c i d e i n l a b o r a t o r y m o n o g a s t r i c mammals ( e . g . , the rat) for extrapolation to man, then a l l aspects of the pesticide's kinetics and metabolism are crucially important. Other studies may have aspects of various importance. For e x a m p l e , the c h a r a c t e r i z a t i o n o f low l e v e l s of r e s i d u e s in the seed of food crops (e.g., rice) is more significant than comparable identification of p o s s i b l y much h i g h e r residues in o t h e r , b u t i n e d i b l e , p o r t i o n s o f the p l a n t . F o r t h e same r e a s o n , r e s i d u e s r e t a i n e d by e d i b l e t i s s u e s o r s e c r e t e d i n t o the m i l k o r e g g s o f t r e a t e d f o o d a n i m a l s , s u c h as c a t t l e o r p o u l t r y , a r e of more t o x i c o l o g i c a l s i g n i f i c a n c e t h a n r e s i d u e s i n u r i n e o r f e c e s . One o f t h e b u r d e n s t h e m e t a b o l i s m s c i e n t i s t must b e a r i s t h a t the products of pesticide metabolism that are often of the g r e a t e s t p o t e n t i a l t o x i c o l o g i c a l s i g n i f i c a n c e (e.g., those i n the e d i b l e p a r t s o f many p l a n t s o r i n m i l k , e g g s , o r e d i b l e t i s s u e s o f f o o d a n i m a l s ) a r e o f t e n p r e s e n t o n l y i n e x c e e d i n g l y low c o n c e n t r a tions. Such p r o p e r t i e s of a p e s t i c i d e a r e , of c o u r s e , highly desirable ones t h a t more o f t e n than not represent accomplished g o a l s of p e s t i c i d e development. However, the c h a r a c t e r i z a t i o n o f such r e s i d u e s u s u a l l y demands the f u l l c a p a b i l i t i e s o f b o t h the scientist and his instrumentation, and in some cases these residues cannot be identified with the technology currently available· Of increasing importance to the design and execution of pesticide metabolism studies i s the impact of the regulatory requirements of pesticide-regulating agencies. In the United States, such r e g u l a t i o n s are issued by the U.S. Environmental P r o t e c t i o n A g e n c y , and t h e y must be c a r e f u l l y c o n s i d e r e d before i n i t i a t i n g most p e s t i c i d e m e t a b o l i s m s t u d i e s , p a r t i c u l a r l y t h o s e that have d i r e c t i m p l i c a t i o n s f o r human h e a l t h . In i t s most r e c e n t issuance of proposed g u i d e l i n e s f o r r e g i s t e r i n g p e s t i c i d e s in the United States (_19_) , t h e Agency states several major p u r p o s e s f o r mammalian m e t a b o l i s m s t u d i e s . These i n c l u d e : 1) t o i d e n t i f y and quantify s i g n i f i c a n t metabolites, 2) to determine p o s s i b l e b i o a c c u m u l a t i o n or b i o r e t e n t i o n of the t e s t p e s t i c i d e or i t s m e t a b o l i t e s , 3) t o d e t e r m i n e a b s o r p t i o n as a f u n c t i o n o f d o s e , 4) t o c h a r a c t e r i z e r o u t e s and r a t e s o f p e s t i c i d e e x c r e t i o n , 5) t o r e l a t e a b s o r p t i o n t o the d u r a t i o n of e x p o s u r e , and 6) t o e v a l u a t e the b i n d i n g of the t e s t p e s t i c i d e or i t s m e t a b o l i t e s i n p o t e n t i a l target organs. The p r o p o s e d r u l e s c o n t a i n r a t h e r g e n e r a l requirements f o r d o s a g e l e v e l s , d o s a g e r o u t e s , and o t h e r a s p e c t s o f s u c h s t u d i e s , i n c l u d i n g sample a n a l y s i s ( 1 9 ) .
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
i v i E AND
16.
Toxicity If
the
metabolism defined
appropriate
information
living
to
inherent
of
the
mammals
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representative
of
i s often
toxicology
parent
usually
Far
subchronic
genicity the
ments
would
circumstances
due
such
separate
metabolites
every
nor
to
possible
man.
tution
they
represent
difficult
a
of
the
no
are
consequence
of as
being
relative
often
significance, "minor"
and
money
with
any
This expendi-
that require-
toxicity in
of
case
some o f
the
t o be
those studies
are
to
such of
pesticide under
most
either
least
predict biologic
of
may
in
toxicologic
"minor"
given been
t o be
of
factors.
fashionable
or
a
data,
present
system.
that
to
based A
"major"
greater p o t e n t i a l
r e g u l a t o r y sense,
than
However, i t seems c l e a r
that
has
essentially
related
differ
formed
consti-
become
has
i n the
chemical
Others
"major"
formed
interact
significant
i t has
of
possibly
detailed
are
appro-
behavior
preexisting
sort.
preclude
(V2_) .
selection
without
of
money
toxicologically
that
may
basis
any
closely
fact,
a p p e a r s t o be
of
classification
because
Thus, the
be the
construed
at
potentials that most
toxicological
distinction
category
significance
may
amounts
somehow a r e
semiquantitative
animal
carcinodone
It i s usually neither
limitations,
toxicological
for
in
chronic
i t s metabolites.
chronic
the
and
this
i n the
likely
and
by p e s t i c i d e
always
some w o u l d a r g u e
that
time
of
toxicological
reactive.
tests
rapid
evaluate
almost
with
on
hazard
problems
metabolites upon
logical
a
posed
to
pesticide that
judged,
such
usually
a
given
or
natural
such
toxicity
give
be
studies
justify
evaluate products
little
Perhaps because
metabolites
quantities for
acute
the
to
be
Limitations
consider
considered appropriate
are
the
the
can
synthetic
tests.
those
to
of
Some o f
that
be
the
(20^).
metabolite
with
of
tremendous time
of
the
assess-
accurately assess
s t u d i e s , but
difficult
the
l a b o r a t o r y mono-
can
hazards
this
of
products
not
the
use
the
effects
to
is
sufficient
h a z a r d s t h a t may
and
to
that
has
pesticide in
of
feeding
studies be
step
metabolites
acute
well, i.e.,
significance
synthesis
its to
job
products dog)
Minor V e r s u s Major M e t a b o l i t e s . priate
267
toxicologist
Comparative
the
chronic
is partly
for
of
pesticide
r e q u i r e d by
his
first
to provide
and
Full-scale other
the
studies.
estimate
parent
limitation
required
toxicological
and
of
the
rabbit,
more d i f f i c u l t
metabolites.
tures
Toxicology
a particular
does the
Chemical
pesticide
reliable
question.
rat,
man.
done
toxicological
toxicity
definitive the
the
Generally,
(e.g.,
metabolites
only
Pesticide
f a t e of
s y s t e m s , how
evaluate
ment
or
of
has
metabolic
generated?
gastric
scientist
the
metabolites
of
Aspects
Assessment
thoroughly the
Metabolic
BANDAL
by
chemicals
orders
of
significant
i n small "major"
toxicological foundation
(20,
often
metabolites
"minor"
have
are
in are
highly
metabolites
significance 21,
toxico-
magnitude;
amounts and
over
no
22).
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
in
man
THE
268
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Toxicological
Significance
PESTICIDE
CHEMIST
A N D
M O D E R N
TOXICOLOGY
of Pesticide Metabolites
Detoxification and Activation Reactions» From an acute toxicity standpoint, the metabolism of pesticides by most organisms usually results i n their c o n v e r s i o n to p r o d u c t s of lesser biological activity. T h e r e a r e s e v e r a l r e a s o n s why such w o u l d be e x p e c t e d , n o t t h e l e a s t o f w h i c h i s t h e f a c t t h a t t h e d e t o x i f i c a t i o n s y s t e m s o f l i v i n g o r g a n i s m s have e v o l v e d f o r j u s t such a purpose. Certainly, too, structure-activity relationships a r e u s u a l l y so c r i t i c a l t h a t t o x i c i t y , e s p e c i a l l y i n the acute sense, i s often greatly reduced or t o t a l l y eliminated as the result of e s s e n t i a l l y any chemical transformation. Numerous examples of m e t a b o l i c r e a c t i o n s l e a d i n g to m o r e - o r - l e s s complete p e s t i c i d e d e t o x i f i c a t i o n c o u l d be c i t e d , b u t t h e ο - d e e t h y l a t i o n o f chlorfenvinphos and the ester hydrolysis of carbaryl, both insecticides, are shown as somewhat representative examples (Figure 7). W h i l e most m e t a b o l i c r e a c t i o n s r e s u l t in total or nearly t o t a l d e t o x i f i c a t i o n s , some do n o t , and i t i s such t r a n s f o r m a t i o n s t h a t most c o n c e r n t h o s e who a t t e m p t t o e v a l u a t e t h e t o x i c o l o g i c a l significance of p e s t i c i d e metabolites. Classical examples of m e t a b o l i c a c t i v a t i o n are the o x i d a t i v e d e s u l f u r a t i o n o f phosphorot h i o n a t e s and the N - h y d r o x y m e t h y l a t i o n of schradan (Figure 8 ) . W h i l e p a r a t h i o n and s c h r a d a n p e r s e a r e e s s e n t i a l l y n o n t o x i c , t h e indicated metabolic reactions convert them to potent a n t i c h o l i n e s t e r a s e s , and t h u s m e t a b o l i s m i s o b l i g a t o r y to their toxicity. O t h e r p e s t i c i d e m e t a b o l i t e s o f t e n have d e g r e e s o f a c u t e t o x i c i t y t h a t a r e o n l y m o d e r a t e l y above o r b e l o w t h o s e o f t h e p a r e n t compounds. Examples of moderate a c t i v a t i o n i n c l u d e the s u l f o x i d a t i o n o f m e t h i o c a r b and the 5 - h y d r o x y l a t i o n o f p r o p o x u r t o yield metabolites that are 8to 10-fold more active as a n t i c h o l i n e s t e r a s e a g e n t s {23_, F i g u r e 9 ) . An example o f m e t a b o l i c transformations that lead to moderate detoxification is the N - h y d r o x y m e t h y l a t i o n o f N - m e t h y l c a r b a m a t e s s u c h as m e x a c a r b a t e t o p r o d u c t s t h a t a r e somewhat l e s s a n t i c h o l i n e r g i c (23^ F i g u r e 1 0 ) . I t s h o u l d be e m p h a s i z e d t h a t even i f the p r o d u c t s of p e s t i c i d e metabolism retain partial or full inherent toxicity, the s t r u c t u r a l a l t e r a t i o n s t h a t r e s u l t from m e t a b o l i s m may facilitate r a p i d e l i m i n a t i o n from t h e body o r f u r t h e r m e t a b o l i s m t o n o n t o x i c p r o d u c t s which, of course l e a d s to g r e a t l y reduced toxicological potential· As an example, a r o m a t i c h y d r o x y l a t i o n of a given pesticide may not always diminish inherent t o x i c i t y , (e.g., p r o p o x u r ) but the p r e s e n c e of the h y d r o x y l group i n the m o l e c u l e w o u l d be e x p e c t e d t o l e a d t o r a p i d c o n j u g a t i o n and e x c r e t i o n by mammals. Pesticide Conjugates. A l t h o u g h the p r i m a r y m e t a b o l i s m of p e s t i c i d e s does n o t n e c e s s a r i l y r e s u l t i n a d i m i n u t i o n o f a c u t e t o x i c i t y , secondary or c o n j u g a t i v e r e a c t i o n s almost always do. P e s t i c i d e conjugates are u s u a l l y h i g h l y polar (e.g., g l u c o s i d e s ,
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
16.
iviE A N D BANDAL
Metabolic
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(G.I. Tract, Skin, Lungs)
TOXODYNAMIC PHASE
ABSORPTION
DISSOLUTION OF
Available for Absorption
DISTRIBUTION
Available
METABOLISM
for Action
PESTICIDE/METABOLITE RECEPTOR
Aspects of pesticide-organism interactions
. Vc-o-< W
O C
CI
TOXIC "EFFECT
INTERACTION
EXCRETION
Figure 6.
a-f
269
Toxicology
TOXOKINETIC PHASE
EXPOSURE PHASE
PESTICIDE
Aspects of Pesticide
CI
CHCI O Vc-o-p;
o w
H
2 5 CI
CHLORFENVINPHOS
Figure 7.
Examples of metabolic detoxification of the insecticides chlorfenvinphos and carbaryl
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
270
THE
\
2
/
X
OC H 2
PESTICIDE
CHEMIST
A N D M O D E R N
\ = /
2 5
TOXICOLOGY
OC H 2
5
PAR Α Τ Η I O N
H C
/CH H X /
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J
Ν
Ο \ | | ^ P - O - P
3
ν /CH~ N
3
C /
0
2
N
O
\ j |
Ο
Y /
N
;P-O-PC
C H . 3
Ν
3
C H
/CH OH
N
HX/ N.
H
3
H C/
/CH N
3
C H
3
0
SCHRADAN
Figure 8.
Figure 9.
Metabolic activation of the insecticides parathion and schradan
Metabolic transformations leading to moderate activation of the insecti cides methiocarb and propoxur
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
16.
iviE AND
glucuronides, excreted acute
by
biological
studies plant
shown
metabolite
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significantly offer
a It
may
not
be
the
i s well reactive
case
compounds may Bound conducted the
be
in
occur, can
such
be
of as
made
least
of
of
to
be
gastric
The
(_25^
and
mutagenic
of or
to
or
aspect the
carcinogenic considered
is
beyond
papers
of
exocon
always
represent but
(vide
conjugates
i n some
as
thus
innocuous
circumstances. studies
frequently at
a
removal
regarding dietary
formed
infra);
metabolism and
animal
such
the
are
portion
from
the
toxicological
I f bound
exposure
is
residues likely
t i s s u e s , some
to
estimation
t o x i c o l o g i c a l s i g n i f i c a n c e , or by
mammalian
several from
most
their
feeding
p e s t i c i d e s have
the
digestive
i t may
be
that
pesticides will
gauge
pesticide events
effects,
carcinogenicity
scope
of
reviews in this
to
be
this of
an
paper.
these
the
e f f e c t s on
carcinogenic
molecular
generally
other
or
21) , and
of
is
the
not
presumably
s u l f a t e conjugates are
naturally arise.
accurately
and
published
is
is
been
tract such
have
at
studies. of
found mono-
chemically
little
or
no
Carcinogenicity
mutagenicity
to
would
and
toxicological effects.
attempts
human
absorbed
particularly
important
discussion
all
potential
produce mutagenic
most
sulfate
significance.
ability
pesticides,
major
extensively
standpoint,
carcinogens
pesticide
plant
from
The
a
1-naphthol
almost
pesticide
that
26^,
is
or
acute
techniques,
residues
is
i n c a s e s where t h e
chronic
or
some
bioavailability,
residues
Mutagenicity
can
their
mammals
toxicological
of
residues
edible
bound
an
Questions
appreciably
unidentified
from
defies
such
in
their
Fortunately, not
such
matrices
exist.
which
reactions
inappropriate
study.
be and
l i b e r a t e d 1-naphthol
acid
conjugates
Most
radioactivity under
the
metabolite,
indeed
Although
their
radiotracer
always
significant.
similar
Re s i due s .
readily
significant may
carbaryl,
protection
glucuronide
totally
using
significance occur
of
regarding
of
does
example,
reconjugation
are
of
conjugate
toxic
glucuronic
(.24 ) ·
intermediates
consideration
matrix
with
pesticide
known t h a t
for
they
course,
However, t h e
t o x i c o l o g i c a l hazard
It
of
that
a
insecticide 11).
degree
of
potential
is toxicologically
as the
the
t o x i c , such
i s true
reduced
this
urine
significant
(aglycone)
regenerate
(Figure
the
is,
271
Toxicology
devoid
innocuous
1-naphthol,
reconjugated
in
Pesticide
usually
There
to
of
of
acids, etc.),
are
otherwise
of
in rats
rapidly
they
that
conjugate
excreted
a
an
cleaved
have
hydrolyzed
and
effects.
that
metabolically glucoside
Aspects
s u l f a t e s , mercapturic mammals,
possibility
is
Metabolic
BANDAL
chronic
hereditary
responses
toxicity material
i n mammals, i s
toxicological evaluation.
leading or
of
(and
up
the
also
acute
to
expression
the A of
r e l a t i o n s h i p s between teratogenicity,
which
t o x i c o l o g i c a l phenomenon)
Rather, the
subjects
the
of that
(28,
reader 29 ) and
i s referred to
volume.
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
several
272
THE
PESTICIDE
CHEMIST
A N D M O D E R N
TOXICOLOGY
Ο II
0-C-NHCH OH
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2
MEXACARBATE Figure 10.
Metabolic N-hydroxymethylation leading to moderate detoxification of N-methylcarbamate insecticides such as mexacarbate
Figure 11.
Mammalian metabolism of the glucoside conjugate of 1-naphthol, a major plant metabolite of the insecticide carbaryl
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
16.
iviE AND
Metabolic
BANDAL
Carcinogenicity chronic
effects
potential for
of
at
countries. (usually
the
least rat
and
mouse),
over
the
expected,
there
effects
of
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to
make
direct
the
only
do
pesticide
pervading
likely
of
of p e s t i c i d e s
most
developed species
involve
doses
literature
of
chronic the
As
on
species,
test
would
the
be
carcino-
mostly
mammals,
However, s i n c e
long-term
invariably
done
with
the
i t i s usually
parent
impossible
c a r c i n o g e n i c i t y , when
se,
a
i t
occurs,
from
under
endogenous
of
itself
be
which
or
likely
be
to
vivo
proper
metabolites
the
appear
likely
significance,
to
and
be
that
of
adequate
circumstances,
of
that
origin
that the
as
from
enter
would might
that are
novel
the
pesticide study
for
not be
are
generate pesticide
in structure,
potential
human
a
more
circumstance
separate
they
is
of
not
parent
a
the
i t
safety
could
Examples
considerable
could
than
negatives"
the
be
"false
"false
require
compound. animal
likely
i s i n i n s t a n c e s where humans
metabolites
parent
of p l a n t or
metabolite
give
only appropriate
might
effects
the would
more
studies
the
extrapolation,
could
about
be
compound
such
studies
seem t h a t
what
or
to
pesticide
different
learned
from
to
of
then
toxicological
totally
In
be
obtained
from
metabolites
30).
could
carcinogenic
by
otherwise
How
mutagenic
parent
would,
vivo,
patterns
the
studies
c o n c e i v a b l y even
metabolites
mammalian
in
metabolite
exposed
a
of
in
such
pesticide
mutagenic
of
If
excess
{20_,
I t would
that
data
likewise
appear
chronic
far
from
(20) ·
the
that
compound
anything
pesticide
of
for
would
also,
disposition
metabolite
there
from
is
tests.
evaluated
humans
overwhelming
that
reliably
doses
m e c h a n i s m s , and
consequence doubtful
in
i t
a l l pesticide
appropriate.
parent
by
or
cases
consideration
in
the
most
experimental
mutagenicity
properly
separate
nor
metabolite
probably
protective
in vitro be
direct
metabolites,
consideration
metabolites
positives"
that
that
obtain
pesticide
In
necessary is
be
formed
in
and
high
(28).
i f ever
or
hazard?
of
neither
metabolite
in
of
s u b j e c t most
JLn v i v o
logic
behavior
given
seldom
metabolites
carcinogenic
per
we
to r o u t i n e l y
a b a t t e r y of
can
is
correlations
approval
potential
carcinogenic
(18-24 m o n t h s ) .
various
almost
of
generally
i t s metabolites,
c a r c i n o g e n i c i t y of
impractical to
of
in
of the
o r more mammalian
they
reviewed
are
any
the
States
i n two
volume
feared
metabolism. Not
on
tests
not
to
273
Toxicology
assessment
relatively
pesticides been
most
lifespans
large
has
carcinogenicity
with
a
Pesticide
an
and
to
normal
is
some o f t h i s and
required
animals
their
the
and United
be
of
of
prior
the
may
exposure
pesticide
in
Tests
pesticide genic
is certainly pesticides,
i s usually required
use,
and
Aspects
toxicological
food
chain
through
most
logical
contaminated f o o d s t u f f s . Certainly, means
of
hazards
of
chemical
most
best
prevalent
judgments
pesticide structures
carcinogens. the
the
making
This
procedure
about
metabolites to
process
and the is
perhaps simply
those
of
may
imprecise,
available
be for
the
mutagenic by
recognized but
determining
or
carcinogenic
relating mutagens i t is what
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
their or
probably pesticide
THE
274
PESTICIDE
CHEMIST
A N D
M O D E R N
TOXICOLOGY
metabolites merit concern or more detailed study. Even i f t a r g e t e d m e t a b o l i t e s give p o s i t i v e r e s u l t s i n i n v i v o or i n v i t r o tests for mutagenicity, i t must c o n t i n u a l l y be remembered t h a t s u c h f i n d i n g s can o n l y be c o n s i d e r e d , a t m o s t , s u g g e s t i v e e v i d e n c e o f a p o t e n t i a l m u t a g e n i c o r c a r c i n o g e n i c h a z a r d t o man. Further, c o n s i d e r a t i o n of the mutagenic potency of the m e t a b o l i t e s , the probable extent of human exposure to them, and other considerations, may often indicate that a mutagenic or c a r c i n o g e n i c hazard t o man, even i f i t e x i s t s , i s exceedingly low.
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Metabolic
Aspects
of P e s t i c i d e
C a r c i n o g e n i c i t y and
Mutagenicity
In recent years, i t has become evident that for many well-studied chemical carcinogens, metabolic activation to a reactive intermediate in the host i s required i n order for r e a c t i o n w i t h DNA and o t h e r c e l l u l a r m a c r o m o l e c u l e s t o o c c u r (31, 32 ) . T h u s , many c a r c i n o g e n s a p p e a r t o be p r e c a r c i n o g e n s , which are metabolized i n v i v o to t h e i r r e a c t i v e forms, or ultimate carcinogens. The u l t i m a t e c a r c i n o g e n s i d e n t i f i e d o r p o s t u l a t e d so f a r , a l t h o u g h t h e y o f t e n have no common s t r u c t u r a l f e a t u r e s p e r s e , c o n t a i n r e l a t i v e l y e l e c t r o n - d e f i c i e n t atoms t h a t can react c o v a l e n t l y , without the a i d of enzymes, w i t h electron-rich or nucleophilic atoms i n c e l l u l a r components, e s p e c i a l l y in such m a c r o m o l e c u l e s as the n u c l e i c a c i d s and p r o t e i n s (32.)· Thus, c a r c i n o g e n i c p o l y c y c l i c aromatic hydrocarbons are m e t a b o l i z e d to several carcinogenic electrophiles, including epoxides, radical cations, and dihydroxy epoxides (Figure 12). Carcinogenic aromatic amines, amides, and nitro compounds appear to be subjected to N - h y d r o x y l a t i o n , then conjugation with glucuronic a c i d o r s u l f a t e t o a more r e a c t i v e s p e c i e s ( F i g u r e 1 3 ) . With nitroso compounds, some o f w h i c h are potent carcinogens, the ultimate alkylating species is likewise thought to be an e l e c t r o p h i l i c m e t a b o l i t e , probably a diazonium or carbonium i o n ( F i g u r e 14). On t h e b a s i s o f 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 among known c a r c i n o g e n s , some g e n e r a l i z a t i o n s can be made r e g a r d i n g t h e t y p e s of reactive f u n c t i o n a l i t i e s i n p e s t i c i d e s or t h e i r metabolites t h a t might convey mutagenic or c a r c i n o g e n i c p o t e n t i a l · Because electrophilicity i s a s s o c i a t e d w i t h many u l t i m a t e mutagens and carcinogens, any pesticide transformation to an electrophilic s p e c i e s c o u l d be o f p o t e n t i a l s i g n i f i c a n c e . However, upon r e v i e w o f the m u l t i t u d e of mechanisms t h r o u g h which v a r i o u s p e s t i c i d e s are, or can be metabolized, one quickly realizes that the generation of potentially reactive species, or of their precursors, is rather commonplace. Aromatic and aliphatic e p o x i d a t i o n s , N - h y d r o x y l a t i o n s , the g e n e r a t i o n of amines t h a t can f o r m n i t r o s a m i n e s , and o t h e r r e a c t i o n s o f p o t e n t i a l significance a r e w e l l documented i n the p e s t i c i d e literature, yet there i s l i t t l e i n d i c a t i o n t h a t most p e s t i c i d e s c o n s t i t u t e any significant
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
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16.
i v i E A N D BANDAL
Figure 12.
Metabolic
Aspects
of Pesticide
Toxicology
275
Examples of metabolic activation of polycyclic aromatic hydrocarbons to reactive electrophiles
DNA
Figure 13.
Metabolic activation of an aromatic amine that ultimately can lead to the formation of a reactive electrophile and alkylation of DNA
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
THE
276
PESTICIDE
CHEMIST
A N D
M O D E R N
TOXICOLOGY
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mutagenic or c a r c i n o g e n i c h a z a r d . C l e a r l y , t h e mere g e n e r a t i o n o f reactive metabolites does not assure that an expression of toxicity will follow. Subsequent r a p i d d e t o x i c a t i o n of r e a c t i v e metabolites no doubt occurs i n many i n s t a n c e s , the reactive s p e c i e s may f o r m a d d u c t s w i t h n o n c r i t i c a l m a c r o m o l e c u l e s o r o t h e r b o d y c o n s t i t u e n t s , and even i f r e a c t i v e m e t a b o l i t e s do alkylate e s s e n t i a l c e l l u l a r m a c r o m o l e c u l e s , subsequent e v e n t s , such as DNA r e p a i r m e c h a n i s m s , may n e g a t e any p o t e n t i a l t o x i c e f f e c t s ( 3 3 ) . I n most i f n o t a l l c a s e s i n w h i c h p e s t i c i d e s have i n f a c t been shown t o be carcinogenic (2j8 ) , t h e r e has b e e n no clear d e f i n i t i o n o f the r o l e t h a t m e t a b o l i s m t o r e a c t i v e i n t e r m e d i a t e s may o r may n o t have p l a y e d i n c a u s i n g such e f f e c t s . On t h e b a s i s of our current understanding of the mechanisms of chemical carcinogenicity, metabolism of at least some carcinogenic p e s t i c i d e s to r e a c t i v e e l e c t r o p h i l e s i n v i v o may occur as an a c t i v a t i o n step. A l t e r n a t i v e l y , i t may be t h a t most c a r c i n o g e n i c pesticides are epigenetic carcinogens rather than genotoxic carcinogens, i.e., they are cancer promoters rather than a l k y l a t i n g agents. I t i s g e n e r a l l y a c c e p t e d t h a t some c h e m i c a l s may i n d u c e tumor f o r m a t i o n w i t h o u t d i r e c t l y i n i t i a t i n g n e o p l a s t i c changes in any cell. Thus, chemicals that depress immune responses o r a l t e r the h o r m o n a l b a l a n c e in a particular tissue might provide the appropriate c o n d i t i o n s f o r the preferential g r o w t h o f p r e e x i s t i n g tumor c e l l s ( 3 2 . ) · Further, chemicals that induce or i n h i b i t the a c t i o n o f d r u g m e t a b o l i z i n g enzymes may promote cancer by enhancing the activation or inhibiting the d e t o x i f i c a t i o n of other chemical carcinogens. It i s therefore possible t h a t m e t a b o l i s m t o r e a c t i v e e l e c t r o p h i l e s may not be i n v o l v e d a t a l l i n the e x p r e s s i o n o f c a r c i n o g e n i c a c t i o n o f many o r most c a r c i n o g e n i c p e s t i c i d e s . One o r more o f s u c h p r o m o t i o n m e c h a n i s m s m i g h t e x p l a i n the c a r c i n o g e n i c i t y o f t h e insecticide m i r e x , w h i c h i s r e p o r t e d t o be a hepa t o c a r c i n o g e n i n m i c e ( 3 4 ) , even though t h e r e i s s t r o n g evidence t h a t l a b o r a t o r y r o d e n t s are unable to metabolize t h i s i n s e c t i c i d e ( 3 5 , 3 6 ) . Pesticide
M e t a b o l i t e s and
the
Regulatory
Process
All pesticides can be considered to present at least a p o t e n t i a l t o x i c o l o g i c a l h a z a r d to man, and c e r t a i n l y t h e primary g o a l i n the r e g u l a t i o n o f t h e s e chemicals i s to minimize such risks as much as p o s s i b l e . Because r i s k t o man is clearly a function of exposure, risks are g e n e r a l l y minimized by the r e g u l a t i o n of exposure. T h i s i s done t h r o u g h the setting of tolerances. Tolerances represent maximum limits (expressed u s u a l l y i n p a r t s p e r m i l l i o n ) of a p e s t i c i d e , i t s m e t a b o l i t e s , o r b o t h , t h a t may l e g a l l y a p p e a r i n human f o o d s t u f f s , a n i m a l feeds, etc., as a result of pesticide use. The determination of w h e t h e r a t o l e r a n c e w i l l be g r a n t e d and a t what l e v e l i t w i l l be s e t can be a c o m p l i c a t e d p r o c e s s , b u t s e v e r a l f a c t o r s a r e u s u a l l y involved. These i n c l u d e t h e i n h e r e n t t o x i c i t y o f t h e pesticide
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
16.
iviE AND
and/or
its
proposed or
metabolites,
use
human
of
the
food),
sources,
the
of
In
man. Depending
pesticide
low
tolerance
significant likely
be
P=S
(37,
P=0
Figure
considered
from
equivalent
to
minimal
of
existing
the
tolerance
is
mutagenic
actions
15).
in
sulfur
The
esters
quite or
both
The
for
any
possible
and
phenols, and the
toxicological
effect
Extrapolation
t o Man:
To
t a k e n by
our
use
most
types
of
insecticide
animal
systems
hydrolysis
analogs activity
of
the
and
are
toxicologically
other
hand,
included
form
or
for
knowledge,
a regulatory
pesticide
i s seen w i t h The
both
particularly could
pesticide
a
the not
retain
will
are
of
under
the
toxicological characteristics
behavior,
of
on
a of
inclusion may
ester
be
be
commodity. that
for
to
are
carcinogenic
been
and
and
sulfone
standpoint
metabolites,
toxicity
of
of
to
therefore
plant
risk
pesticide
their Others
organophosphate
pesticide
have y e t
that
oxidation,
the other
sufficiently
judged
Examples
sulfoxide
registrations.
demonstrated
at
retain anticholinesterase
regulatory
registration
be
and
a l l
and
components
unnecessary.
the
i s metabolized
sulprofos.
individual
denying
in
from
significant
as
importance
t o x i c o l o g i c a l importance
sulprofos It
seen
set of
may
feed
application,
significance,
metabolites
tolerance.
conversion,
phosphate
are
the
animal
exposure
absence
properties
action,
as
methods,
included
i s deemed
under
be
which
to
38,
intact
can
the
be
toxicological
included
sulprofos,
Some
toxicological
metabolites by
not
limits
human
toxicological
may
toxic
(e.g.,
pesticide
tolerances
assure
their
or
tolerance.
sufficiently within
upon
may
of
277
Toxicology
their
analytical
a l l cases,
to
of
proposed
available
l e v e l s t o , presumably,
Pesticide
commodity
extent
the
low
metabolites
nature
likely
for
the
considerations.
the
Aspects of
contaminated
the
need
sensitivity
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Metabolic
BANDAL
the
Problem of
demonstrated
the
however,
a g e n c y on
metabolite, parent Species
basis
for
revocation the
unless
no
of such
basis the
of
same
compound. Variations
The primary purpose of evaluating the metabolic and t o x i c o l o g i c a l b e h a v i o r of p e s t i c i d e s i s to a s s e s s the r i s k to man that may result from their use and subsequently to take appropriate regulatory steps to minimize such r i s k s . Obvious ethical and other considerations prevent direct studies of p e s t i c i d e s i n humans e x c e p t i n most u n u s u a l c i r c u m s t a n c e s , t h u s e x t r a p o l a t i o n s t o man must u s u a l l y be made on the b a s i s o f d a t a obtained with monogastric laboratory mammals. Unfortunately, laboratory research animals are generally chosen more for convenience than f o r r a t i o n a l , s c i e n t i f i c r e a s o n s . The handling and housing requirements, incidence of disease, supply and, p e r h a p s most i m p o r t a n t , c o s t , a r e among the f a c t o r s c o n s i d e r e d in choosing a species for research (39.)· p e s t i c i d e metabolism s t u d i e s , t h e r a t a n d / o r mouse i s u s u a l l y t h e s p e c i e s o f choice. We q u i t e w i l l i n g l y assume, p e r h a p s b e c a u s e no o b v i o u s a l t e r n a t i v e s F
o
r
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
278
THE
R-H C 2
R-hLC
N
/
PESTICIDE
OH I R-HC
N-NO
CHEMIST
A N D M O D E R N
TOXICOLOGY
R-C
N-NO
N-NO
R'-H C
R-H C
2
2
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DIALKYLNITROSAMINE
R-H C
N-NO
2
R—H C
/
R-H C
/
2
ALKYLATED DNA
R-H C-N^N 2
,N=N
.OH
2
Figure 14. Metabolic activation of a dialkylnitrosamine leading to the generation of reactive electrophiles and ultimately to the alkylation of DNA
(O) / ~ ~ \
ll/O-C Η
(O) C
ft f~\
Î
H
"/°- ? 5
N/°- 2 5 S-C H
f~\
C
3
SULPROFOS
SULPROFOS
OH
Figure 15.
SULPROFOS
PHENOL
SULFOXIDE
SULFONE
•OH
•OH
\_/ PHENOL
SULFOXIDE
H
3
PHENOL
SULFONE
Structures of the insecticide sulprofos and its major plant and animal metabolites
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
7
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16.
IVIE
A N D B A N D A L
Metabolic
Aspects of Pesticide
Toxicology
279
e x i s t , t h a t r e s u l t s from m e t a b o l i s m s t u d i e s w i t h t h e s e a n i m a l s a r e i n f a c t p r e d i c t i v e o f what w i l l happen i n man, o r a t l e a s t t h a t a n y d i f f e r e n c e s w i l l n o t be t o x i c o l o g i c a l l y " s i g n i f i c a n t . " Yet t h e r e a r e c l e a r i n d i c a t i o n s t h a t , i n metabolism as w e l l as other toxicological phenomena, considerable species differences do i n d e e d e x i s t (2J_, 40_). L a b o r a t o r y r o d e n t s , i n f a c t , appear t o be poor metabolic p r e d i c t o r s f o r man! In a comparison o f t h e m e t a b o l i c p a t h w a y s f o r 21 d r u g s and o t h e r compounds i n t h e r a t and man (4Y), t h e r a t p r o v i d e d a "good" m e t a b o l i c model f o r man w i t h o n l y 4 compounds and was a " p o o r " o r " i n v a l i d " model ( m e t a b o l i c p a t h w a y s q u i t e d i f f e r e n t ) w i t h 15 o f t h e compounds s t u d i e d ( T a b l e II). However, t h e r h e s u s monkey o r marmoset p r o v i d e d "good" m e t a b o l i c m o d e l s f o r man w i t h 16 o f t h e 21 compounds. Iti s reasonable t o assume t h a t s i m i l a r results w o u l d be s e e n with various pesticides, and t h u s many o f t h e m e t a b o l i s m s t u d i e s c u r r e n t l y used as a b a s i s f o r e x t r a p o l a t i n g t o x i c o l o g i c a l results w i t h p e s t i c i d e s t o man may be o f l i m i t e d p r e d i c t i v e v a l u e · The potential toxicological consequences o f t h i s a r e , of course, unknown·
Table I I . C o m p a r i s o n o f L a b o r a t o r y R o d e n t s and Sub-human P r i m a t e s a s M e t a b o l i c M o d e l s f o r Man METABOLIC SIMILARITY TO M A N MONKEY
RAT
COMPOUND Amphetamine Chlorphentermine 4-Hydroxy-3,5-diiodobenzoic acid Indolylacetic acid Norephedrine*
Invalid
Good
Poor
Good
Fair
Good
Τ
τ Good j_
Phenmetrazine* Phenylacetic acid Sulphamethomidine 1 - Naphthylacetic
acid
Sulphadimethoxine Sulphadimethoxypyridine
1
Halofenate Methotrexate Sulphasomidine Hydratropic acid Diphenylacetic acid Indomethacin Morphine Oxisuran 2 - Aceta m idof luorene Phencyclidine From Smith and Caldwell (Ref 41 ).
Good J_ Poor
Fair
Fair
Fair
Good J_
Fair
Poor
Poor
Marmoset, all others rhesus
_L
monkey
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
280
THE
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P e s t i c i d e Metabolism:
PESTICIDE CHEMIST AND
Prospects and
MODERN TOXICOLOGY
Problems
P e s t i c i d e metabolism studies are, without question, very important components i n the evaluation of the toxicological s i g n i f i c a n c e of p e s t i c i d e s to man. The r a t e , extent, mechanisms, and products of metabolism are i n e v i t a b l y l i n k e d to the expression of t o x i c a c t i o n , and a c l e a r d e f i n i t i o n of p e s t i c i d e b i o t r a n s f o r mation is often a necessary prerequisite to understanding mechanisms of t o x i c i t y and to the formulation of approaches for assessment and management of p o t e n t i a l l y undesired t o x i c e f f e c t s . What does the future hold? Can p e s t i c i d e metabolism studies and the data they generate be more e f f e c t i v e l y used i n the safety e v a l u a t i o n process? Can these studies be made more p r e d i c t i v e and thus more t o x i c o l o g i c a l l y r e l e v a n t to man? I t i s , of course, d i f f i c u l t i f not impossible to foresee the future a c c u r a t e l y . We w i l l , however, make a few observations on these and other matters · Only a few years ago, a p e s t i c i d e metabolism study was considered successful i f only the major metabolites were c h a r a c t e r i z e d , and t h i s was often done s o l e l y by chromatographic means -- without s p e c t r a l confirmation of s t r u c t u r e . Today i t i s not uncommon to see r e p o r t s i n which most i f not a l l of the detected metabolites of a p e s t i c i d e i n a given system are f u l l y and unequivocally characterized by s p e c t r a l means. Several f a c t o r s have contributed to such advancements, i n c l u d i n g the f a c t that many of us now have a v a i l a b l e i n our research l a b o r a t o r i e s a f u l l complement of up-to-date, often s t a t e - o f - t h e - a r t a n a l y t i c a l , chromatographic, and spectrometric instrumentation. Advances i n our c a p a b i l i t i e s to c h a r a c t e r i z e organic compounds, p a r t i c u l a r l y advances in microspectrometric techniques such as GLC-mass spectroscopy, FT-NMR, and FT-IR make p o s s i b l e the i d e n t i f i c a t i o n of many metabolites at the microgram l e v e l . The versatility, a c c e s s i b i l i t y , and o v e r a l l importance of r a d i o t r a c e r techniques to the metabolism s c i e n t i s t have never been greater. Stable isotopes (e.g., ^H, ^C, ^N) are beginning to find more use in p e s t i c i d e metabolism s t u d i e s , and with mass spectroscopy or NMR, s t a b l e isotopes can be very u s e f u l t o o l s f o r both metabolite c h a r a c t e r i z a t i o n and mechanistic studies (42_) · In the metabolism study of the f u t u r e , there w i l l continue to be, and r i g h t l y so, great emphasis placed on definitive characterization of a l l metabolites p o s s i b l e . Hopefully, we w i l l see i n the future continuing advances i n our c a p a b i l i t i e s to more f u l l y c h a r a c t e r i z e p e s t i c i d e conjugates and "bound" residues, because these products often comprise the bulk of the total residue and their t o x i c o l o g i c a l s i g n i f i c a n c e , p a r t i c u l a r l y chronic e f f e c t s , i s far from clear· Species v a r i a t i o n s that may s e r i o u s l y a f f e c t the v a l i d i t y of l a b o r a t o r y animal metabolism studies as p r e d i c t i v e models for man are a problem without apparent s o l u t i o n . For proper e v a l u a t i o n of the t o x i c o l o g i c a l s i g n i f i c a n c e of p e s t i c i d e s to man, metabolism
In The Pesticide Chemist and Modern Toxicology; Bandal, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
281
16. IVIE AND BANDAL Metabolic Aspects of Pesticide Toxicology
studies
i n humans
totally should
be
f a r more
acceptable Because to
and and
subhuman
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studies
with
destructive proper
of
pesticides
levels,
number
present
some
enzyme
contrast
to
other
the
will to
Historically, specific believe
that
such
a pattern
metabolism methodology this
field
However,
requirements be
groups a period
such
metabolism
need
of
Such
philosophy
primates
an
approach
and
could
induction
of
would
possibly
of
to
pesticide
us
quite
yield
could
o f many y e a r s f o r
i t seems
likely
the
be
will
that
the
minor
data
i n that
there that in
chemistry,
toxicological
required
and
to
in
of
much
have
even the
i s concern further
on
moves
metabolism and
more
and
pesticide
part
toward
studies
may
innovative
to Few
agencies i n
support the
more
reason
i n the f u t u r e .
to
as of
future.
more
is little
of regulatory
studies
imaginative
in
become
there
as well
evaluation
become
agencies
not continue
or p r o p r i e t y
metabolism
scientists
may
totally
be
realistically,
progressed,
t h e wisdom
counterproductive
be
However,
and
over
requirements
has
registrations.
may
not
small
regulatory
regulatory
detailed
respect
toxicological
use o f r a d i o i s o t o p e s
low l e v e l
in
doubt
pesticide
time
question
respect
t o man.
involved no
more
resource,
merits
studies
However,
are,
as
requiring
as
with
pesticide
of p e s t i c i d e metabolism
disciplines
responsive
i n vivo
chemicals.
advantages—the
discipline
pesticides,
would
such
p r e d i c t i v e value
The
or data
systems.
disadvantages
primates
these
i n regulatory
problems,
metabolizing potential
single
of p e s t i c i d a l
adjustments
to
as
metabolism.
limited that
are
primates
present
animals
very
the j u d i c i o u s
metabolic
require
at
treasure
using
because
With
a
clearly
pesticide
a l l circumstances.
apply
primates
of
as
subhuman
reasons, conventional
even
not
invaluable
large
scientific
or
than
models
represent
For these
of l i f e .
dosage
provide
are a
should
just
p o s i t i o n of these
they
i n most
restrictions
yet
used
human
use.
investigations
better
effectively
accurate
primates
the wisest
needed,
I t seems, h o w e v e r , t h a t
because
inappropriate
a
clearly
o f the e v o l u t i o n a r y
man,
and
are
inappropriate.
of
some
specific well
research
be in
discouraged.
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