Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 111
Pesticide Resistance: Strategies and Tactics for Management.
1986. National Academy Press, Washington, D.C.
Chemical Strategies for
Resistance Management
BRUCE D. HAMMOCK and DAVID M. SODERLUND
The possible roles of chemical and biochemical research in al-
leviating the problems caused by pesticide resistance are explored.
Pesticides play ~ central role in current and future crop protection
strategies, and there is a need for the continued discovery of new
compounds. Constraints, both real and perceived, have limited the
discovery and development of new compounds by the agrochemical
industry. Industry has responded to these constraints in a variety of
ways. Several areas of research must be emphasized if chemical
approaches are to have significant impact on the management of
resistance. Administrative changes also might foster increased re-
search activity in these areas or might increase the probability that
novel approaches will be developed by the agrochemical industry or
otherwise be made available for use in integrated pest-management
programs.
INTRODUCTION
The Critical Role of Insecticides in Insect Control
The overuse and misuse of insecticides have caused target pest resurgence,
secondary pest outbreaks, and environmental contamination (Metcalf and
McKelvey, 19761. Nevertheless, it is difficult to foresee how insect pests
can be controlled effectively without chemical intervention. Highly produc
insects.
iWe use the term insecticide in its broadest meaning as any foreign ingredient introduced to control
111
OCR for page 112
112 MECHANISMS OF RESISTANCE TO PESTICIDES
live agricultural practices and the high density of human population have
been achieved at the expense of ecological balance. To maintain this im-
balance in our favor, we must continue to use ecologically disruptive tools,
including insecticides. Even novel pest-control strategies such as pest-resis-
tant plant cultivars will not eliminate the need for chemical pest control.
Given the choice of a more expensive and pest-infested food supply or
pesticide use, we will continue to use pesticides (Boyce, 1976; Krieger,
1982; Ruttan, 1982; Mellor and Adams, 19841. Therefore, the chemicals
available for insect control must lend themselves to rational and environ-
mentally sound use.
Integration of Chemical and Nonchemical Control Tactics
During the past two decades the concept of the judicious use of pesticides
has been formalized in integrated pest management (IPM). A key strategy
of IPM is to use insecticides only when damage is likely to exceed clearly
defined economic thresholds. Such procedures constitute the most funda-
mental approach to resistance management by minimizing the selection pres-
sure leading to resistance. Reduced pesticide use not only decreases selection
pressure on pest insects but preserves natural enemies and other nontarget
species, reduces environmental contamination, reduces the exposure of farm
workers and consumers to potentially toxic materials, and may reduce phy-
totoxicity. Thus, IPM increases agricultural profitability, improves public
health, and reduces environmental contamination. Most IPM programs con-
sider pesticides as nonrenewable resources and stress their judicious use. The
limited availability of compounds that are compatible with IPM may restrict
the broad application of this approach.
The Need for New insecticides
Effective insect control requires not only the continued use of existing
insecticides but also the continued availability of new insecticides. Existing
compounds will probably continue to vanish from the market because of
problems with human or environmental safety. Compounds that survive these
challenges may still be lost, owing to the development of resistance. Other
compounds, although technically still available, may become obsolete as a
result of changing agricultural practices or may be replaced by compounds
that offer a greater profit margin to the user.
Of these new agricultural practices, the one having the greatest impact on
pesticide use patterns is likely to be low-till (or conservation-till) agriculture.
Adoption of this practice will be encouraged by the lower costs resulting
from reductions in energy consumption, erosion, and loss of filth (Lepkowski,
1982; Hinkle, 1983~. Since tillage is a major means of pest control, this
OCR for page 113
CHEMICAL STRATEGIES
113
practice will change pesticide use patterns and increase pesticide usage.
Without suitable compounds, low-till agriculture will probably increase en-
vironmental and resistance problems.
The potential for loss of effective compounds to resistance has provided
impetus for formulating resistance management strategies. The effective man-
agement of pesticide resistance, however, involves not only the judicious
use of existing compounds but also the discovery and development of new
chemical control agents. No management strategy can prolong the useful life
of pesticides indefinitely. New chemical tools will be needed, particularly
those that exploit new biochemical targets. Thus, rather than removing us
from a "pesticide treadmill," IPM and resistance management will only slow
the treadmill, thereby extending the usefulness of available chemicals.
Integrated pest management also requires new insecticides. That IPM pro-
grams use existing compounds is a credit to the skills of agricultural ento-
mologists, because few if any of these compounds were developed for IPM.
At best they are marginally compatible with IPM programs.
TRENDS IN INSECTICIDE DISCOVERY AND DEVELOPMENT
The Declining Rate of Insecticide Development
Although new and better insecticides are needed, there are fewer insec-
ticides on the market, fewer compounds being developed, and fewer com-
panies searching for novel compounds than a decade ago. A number of
reasons for this decline have been proposed (Metcalf, 19801. The following
four constraints are of particular concern.
Increased Cost of Discovery The cost of discovering new insecticides
has increased dramatically. First, the cost of synthesis of new compounds
for evaluation has increased because most of the simple molecules have been
made and multistep, expensive syntheses are now required. Second, the
discovery of highly potent groups of compounds, such as the pyrethroid
insecticides and sulfonylurea herbicides, has raised the standards of com-
parison for new compounds. Levels of insecticidal activity that seemed highly
competitive a decade ago are no longer competitive, particularly if the chem-
istry involved is complex. Third, the abandonment of complete dependence
on random screening requires a commitment to the rational discovery and
optimization of insecticidal activity. Such a commitment requires more so-
phisticated, and hence more expensive, biological assays.
Increased Costs of Registration The costs of registration can be reduced.
Long-term toxicology testing accounts for most of the registration costs.
Despite their imperfections these studies are essential to ensure that insec
OCR for page 114
114
MECHANISMS OF RESISTANCE TO PESTICIDES
ticide-related hazards are identified and minimized. The development of
short-term assays may reduce registration costs, but the Environmental Pro-
tection Agency (EPA) generally requires new short-term assays while con-
tinuing to require the major long-term toxicology studies. In the absence of
regulatory requirements, insecticide manufacturers would still conduct many
of these studies to protect themselves against unanticipated adverse effects.
Administrative delays and apparently capricious policy shifts also increase
costs and stifle the development of new compounds.
Increaser! Costs of Production Increased chemical complexity increases
production costs. Recently introduced compounds require expensive starting
materials, multistep syntheses, isomer separations, and sometimes the prep-
arative resolution of optical isomers. These costs are also indirectly increased
by the costs of energy and petroleum-based feedstocks, transportation, and
more stringent regulations regarding worker safety and chemical waste dis-
posal. Although high production costs increase the level of profitability re-
quired of a product, they are not the most serious barrier to development.
When a company has a promising product, careful market evaluations provide
data needed to support decisions regarding capital investment. Continued
improvements in production technology alone are unlikely to have a major
impact on the rate at which new compounds are made available for use.
Increased Competition The market for agrochemicals is mature and di-
versif~ed, and growth in most product areas is less than 5 percent per year
(Storck, 1984~. Most major insecticide markets are divided among several
similar products. This competition increases the requirements for developing
a successful compound.
Relative Importance of Problems
Limiting Development of New Compounds
The four factors interact synergistically to make the development of in-
secticides unattractive despite the promise of one of the highest profit margins
in the chemical industry. Agricultural chemical companies often emphasize
the costs of production and registration as the major roadblocks to developing
new compounds. Although high, these costs are not the only barriers to
development. The cost and risk involved in the discovery process are sig-
nificant and often unrecognized impediments. Discovery requires a large
long-term investment that is separated by years or even decades from ultimate
profit. Moreover, it can be addressed most readily by changes in policy.
OCR for page 115
CHEMICAL STRATEGIES
Current Strategies and Approaches in the Agrochemical Industry
115
Industry has adopted several conservative strategies to minimize risk. The
most drastic has been withdrawal from the agrochemical field. As some of
these companies retire from the marketplace, society loses tremendous ex-
pertise in the development of pest control agents. This also reduces the
diversity of chemicals that will become available, a diversity that is essential
if IPM is to be a sophisticated management strategy rather than simply an
exercise in timing insecticide applications.
A second strategy is for a company to emphasize its expertise in devel-
opment or marketing while leaving the high risks involved in actual discovery
to other firms (i.e., licensing compounds that have been discovered and
patented by other companies). Thus, fewer organizations have the respon-
sibility for new compound discovery. A related approach is to de-emphasize
insecticide development and to emphasize development of materials such as
herbicides that are perceived to be less risky or less expensive to register.
For example, some of the explosive growth of industrial research in agri-
cultural biotechnology has been at the expense of research on crop chemicals.
A third strategy involves increasing a product's market life. Petitions to
register tank mixtures and combinations of existing pesticides are increasing.
Use of mixtures or combinations may result in less environmental contam-
ination a new approach in resistance management or may lead to the
development of new classes of pesticides. The toxicological and environ-
mental effects of such combinations, however, may include phenomena not
predicted from studies on the individual components; therefore, these should
be closely scrutinized.
A second example of this strategy is the patenting and development of
derivatives of existing compounds. Many of these derivatives are "propes-
ticides," which degrade to give an established compound as the active in-
gredient. Such derivatives may improve safety or environmental behavior.
The major advantage of these approaches is that industry can capitalize
on its investment in a mature product without the high risks inherent in new
chemistry. Maintaining a mature product on the market has little risk. The
profits from an established agricultural chemical can support a great deal of
maintenance, and the profits are immediate. When they become uneconom-
ical, they can be dropped quickly without a great loss of invested capital.
The extreme measures taken by some companies to maintain cyclodiene
insecticides on the market exemplify this approach. Integrated pest manage-
ment systems keyed to particular chemicals can also contribute to this ap-
proach if practitioners of these systems feel that the continued availability
of a certain compound is critical.
Product maintenance can also indirectly benefit the development of new
compounds. The future development of new compounds becomes more at
OCR for page 116
116
MECHANISMS OF RESISTANCE TO PESTICIDES
tractive because recovery of development costs can be expected over a longer
period.
Companies actively seeking new insecticides have attempted to minimize
risk by narrowing the scope of their development efforts. Most new insec-
ticides are developed for one of only two markets: foliar application to cotton
or soil application to corn. These two markets are perceived to be sufficiently
large and stable so that a company can recover development costs and make
a profit during the compound's patent life. Although these compounds may
be registered for other uses, they are often forced into secondary uses for
which they are not well-suited. This narrow targeting severely limits the
diversity of insecticides available for use in pest management.
Companies also avoid risk by emphasizing "me too" chemistry. In this
approach a competitor's product is used as a lead to identify related but
patentable compounds. This action results in a series of active structures and
produces large families of similar pesticides. It diverts resources from the
development of novel compounds and may accelerate the development of
resistance. Moreover, it does not promote industrial cooperation in resistance
management. There is little incentive to preserve susceptibility in pest pop-
ulations because it also preserves market opportunities for competitors. In
contrast, companies that are sole exploiters of a chemical family have a great
incentive to preserve their market through resistance management.
CHEMICAL AND BIOCHEMICAL SOLUTIONS TO PROBLEMS
CAUSED BY RESISTANCE
Understanding Resistance to Existing Insecticides
Resistance management is based on the belief that rational and informed
decisions on insecticide use can be made and that these decisions will prevent,
delay, or reverse the development of resistance. To make such decisions,
we must know why resistant populations are resistant and know (or estimate)
the frequency of resistant genotypes. Resistance management may be very
difficult without a comprehensive knowledge of the mechanisms by which
insects become resistant.
To date, some resistance mechanisms have been identified: reduced rates
of cuticular penetration; enhanced detoxication by elevated levels of mono-
oxygenases, esterases, or glutathione-S-transferases; and intrinsic insensitiv-
ity of target sites. Knowing these mechanisms exist, however, is not enough
on which to base resistance management decisions. Simple, rapid biochemical
assays to detect the presence of these mechanisms in individual insects must
be developed.
With such assays resistance mechanisms in field populations can be char
OCR for page 117
CHEMICAL STRATEGIES
117
acterized and the relative abundance of resistant and susceptible individuals
in a population can be determined. This information will benefit IPM systems
and programs of resistance management. Sometimes the assays will be able
to distinguish between heterozygous and homozygous individuals or deter-
mine the extent of gene amplification in resistant individuals.
Assays may be developed simply on the basis of a correlation between
resistance and an observed phenotype, such as the presence of a particular
isozyme. Advances in immunochemical technology are such that it may be
possible to identify antigens present in a resistant population, but not a
susceptible population. Although they are expedient, methods of detection
based on fortuitous correlation rather than the measurement of actual resis-
tance mechanisms may be misleading and must be used with great care even
when based on hybridoma technology. Techniques such as internal imaging
with monoclonal antibodies may help to explain resistance phenomena.
Research resources must focus on the developing biochemical diagnostic
procedures. For enhanced detoxication the challenge is simply to develop
microanalytical techniques to determine the level of activity of enzymes of
interest in individual insects. Simple microassays can also be developed for
one major type of intrinsic insensitivity, such as the altered cholinesterase
involved in organophosphate and carbamate resistance. For some mechanisms
of resistance, additional fundamental research is needed before diagnostic
assays can be devised. An important example is nerve insensitivity resistance
to DDT and pyrethroids. Although this type of resistance is well documented
in a few species and is suspected in many others, there is no way at present
to detect this resistance through diagnostic assays. Behavioral mechanisms
may contribute significantly to some resistance. Ultimately, behavioral re-
sistance must have a physiological basis, but it is likely to be even more
difficult to find reliable markers for such resistance mechanisms (Lockwood
et al., 19841. For these areas the development of diagnostic antigens may
be expedient and may even help to discover the true resistance mechanism.
Diagnostic assays such as those outlined are extremely useful in identifying
and characterizing resistance that results from a single mechanism. A po-
tentially more serious problem involves the synergistic interaction of two or
more mechanisms. To evaluate the underlying causes of polygenic resistance,
we must conduct more studies of the distribution and fate of insecticides in
both resistant and susceptible individuals. These pharmacokinetic studies
have barely been exploited in insects, yet they are essential for us to under-
stand how specific genetic changes act and interact to modify the availability
and persistence of insecticides at their sites of action in living insects.
We also must study the metabolism and mechanism of action of insecticides
in insect species important in agriculture, animal health, and medicine before
resistance develops. Knowledge of sites of action and critical pathways of
detoxication is essential when devising strategies to impede the development
OCR for page 118
118
MECHANISMS 0P RESISTANCE TO PESTICIDES
of resistance to a particular compound in a particular control system. The
use of insect strains that are either resistant or susceptible to related insec-
ticides or to other widely used insecticides can enhance the predictive value
of these studies. Similarly, to identify potential resistance mechanisms, these
studies must use insect species that exhibit natural tolerance.
Clearly, we need to expand the research base for rational strategies of
resistance management. We must support and pursue research ranging from
analytical biochemistry to insecticide neuropharmacology. These approaches
are a necessary adjunct to more familiar experimental approaches if the rapid
detection, characterization, and management of insecticide resistance is to
become an integral part of pest management.
Discovering New Insecticides
Approaches to Finding and Optimizing Biological Activity The agro-
chemical industry is very skilled at optimizing the biological activity of a
series of chemicals (Magee, 1983; Menn, 19831. Recent technological ad-
vances, many of which have been adopted by industrial research laboratories,
are certain to refine and enhance this expertise. The use of linear free-energy
parameters to establish quantitative structure/activity relationships has proved
very effective in optimizing activity in some series. As computer time be-
comes less expensive, graphics capability more sophisticated, instruments
easier to use, and software more powerful, these approaches will become
even more useful.
Computer-assisted design in biochemistry, analogous to procedures already
used in architecture, is becoming more accessible and affordable. These
techniques use X-ray crystallographic data to generate three-dimensional
images of complex macromolecules. The scientist can then view the structure
of a target macromolecule in three dimensions as it interacts with a ligand,
inhibitor, or substrate. These tools will be of tremendous benefit in optimizing
chemical structures in a rational, cost-effective manner. The creative potential
of these tools is of even greater importance, because they are a powerful
resource for making logical transformations, not only from one substituent
to another but also from a biologically active peptide to something as dis-
similar as a synthetic hydrocarbon. In the field of spectroscopy, nuclear
magnetic resonance (NMR) technology is evolving rapidly, not only to sup-
port structure elucidation but as a tool to probe the active sites of biological
molecules and even physiological function in vivo.
The elucidation of enzyme-substrate interactions and enzyme reaction
mechanisms has provided new paradigms for the discovery of new com-
pounds. Several laboratories are applying transition-state theory, which de-
scribes the mechanisms of enzyme-catalyst reactions, to the design of
exceptionally powerful enzyme inhibitors. A related approach involves the
OCR for page 119
CHEMICAL STRATEGIES
119
design of compounds that interact with enzymes as suicide substrates, which
trick the enzyme into self-destructing in the process of catalysis. The pro-
liferation of these sophisticated, targeted approaches depends on the contin-
ued growth of fundamental information about enzymes, receptors, and other
regulatory macromolecules.
Recent advances in genetic engineering and biotechnology are facilitating
basic research on many fronts. For example, the ability to isolate and sequence
small quantities of peptides and proteins, to isolate their messages and genes,
and to measure them with immunochemical and other tools will provide new
leads for using classical chemistry. Moreover, these biological messages may
be directly useful in developing microbial pesticides or for enhancing crop
resistance to pests. Microbial pesticides may bridge the gap between classical
chemical and classical biological control. The current industrial effort to
develop avermectins, a group of fungal toxins with high insecticidal activity,
illustrates that a very complex molecule can be made by a fermentation
process that is competitive with classical industrial chemistry. This concept
greatly expands the variety of structural types that might be used commer-
cially for insect control and indicates that rigorous screening of plant and
microbial natural products may meet with still further success. The Bacillus
thuringiensis toxins represent another level of complexity, in which the mar-
keted toxins are proteins (Kirschbaum, 1985~. The potential for selectivity
among these toxins is very exciting. The B. thuringiensis gene can also be
expressed in both a crop plant and a plant commensal organism and may
herald a new phase in research on plant resistance, in which the insecticide
chemical or biochemical is produced by the plant itself or by an associated
microorganism.
Advancing biotechnology also offers the prospect of new opportunities for
exploiting insect viruses (Miller et al., 1983~. These highly selective agents
have shown considerable promise for insect control, but their wide use has
been limited by difficulties in registration and, more seriously, problems in
devising in vitro production systems. Continuing improvements in insect
tissue culture may improve the economic feasibility of these materials. It
may also be feasible to clone messages into viruses to block a critical phys-
iological process in insects in viva at very low levels of infection, while still
allowing the virus to propagate in vitro.
Research in these areas may drastically alter our concepts of what an
insecticide is. The move toward biorational design and genetically engineered
biological insecticides or insect pathogens does not mean, however, that the
resulting products will be free from the hazards we associate with classical
insecticides. These novel materials will still require thorough investigation
for their possible toxicological and environmental effects. For pathogens,
suitable registration guidelines remain to be established, and answers to the
public concern over the release of genetically engineered pathogenic organ
OCR for page 120
120
MECHANISMS OF RESISTANCE TO PESTICIDES
isms into the environment must be formulated. Resistance to these materials
could develop if they are used in ways that lead to high selection pressure.
New Targets for Insecticide Development The four major classes of syn-
thetic organic insecticides developed since 1945 are neurotoxins. Yet, most
insecticides act at only two sites in the nervous system. Thus, genetic mod-
ifications that change the sensitivity of these sites of action (altered acetyl-
cholinesterase for carbamates and phosphates, nerve insensitivity resistance
for DOT and pyrethroids) produce cross-resistance that renders entire classes
of compounds ineffective against resistant populations. These resistance
mechanisms cannot be overcome by synergists. Resistance management strat-
egies based on rotating compounds that differ in their sites of action have
not been tested in the field and are limited by the lack of diversity of sites
of action in our current armament of insecticides.
Ample opportunities exist for discovering insecticides that act at new sites
in the nervous system. The discovery that both the chlorinated cyclodienes
and the avermectins apparently act at the y-aminobutyric acid (GABA) re-
ceptor (Merlin et al., 1983; Matsumura and Tanaka, 1984) highlights the
potential significance of this target. Similarly, the discovery that chlordi-
meform acts at the insect octopamine receptor (Hollingworth and Murdock,
1980) has stimulated renewed interest in the formamidines as a class and in
novel structures acting at this site. These compounds illustrate that successful
control can be achieved without kill.
Beyond these, several novel sites remain to be exploited as advances in
fundamental neurobiology define their properties. Several neurotransmitter
systems are promising targets: the acetylcholine receptor in the insect central
nervous system, the glutamate receptor at the insect neuromuscular junction,
and receptors for peptide neurotransmitters and neurohormones are just now
being discovered. Both the acetylcholine and glutamate receptors have pre-
viously been targets of insecticide development in industry without great
success, but their significance as targets may increase as more information
about the pharmacology of these sites accumulates. Other targets also exist
beyond the level of transmitter receptors. The enzymes involved in metab-
olizing or maintaining homeostatic levels of transmitters are potential sites
of action, as are the processing enzymes involved in the release of neuro-
peptides from precursor proteins and the peptidases that degrade bioactive
peptides. The success of the drug Captopril, which inhibits the angiotensin-
converting enzyme, illustrates the potential for biological activity in com-
pounds that interfere with normal neuropeptide processing.
Targets also exist outside the nervous system (Mullin and Croft, in press),
such as compounds that act on the insect endocrine system (e.g., juvenoids)
and on the biochemical processes involved in insect cuticle formation (acyl
ureas). The selective action of these insect growth regulators makes them
OCR for page 121
CHEMICAL STRATEGIES
121
highly suitable for IPM systems. They act only at specific times in insect
development, however, and the interval between application and effect can
be several days rather than a few hours, as with neurotoxic compounds.
(Fast-acting herbicides once were the industry standard until highly effective
slow-acting compounds became available.) Many developmentally active
compounds exhibit a degree of selectivity that makes them more suitable
than broad-spectrum neurotoxicants for use in IPM systems. Under current
economic and regulatory constraints, however, they are less effective than
neuroactive compounds.
Even a cursory knowledge of insect physiology shows numerous systems
that may be exploited to control insects. For instance, the regulation of oxygen
toxicity and water balance are critical in an insect, and therefore are sus-
ceptible to disruption. Phytophagous insects have unique systems for using
phytosteroids that may provide biochemical leverage for the design of se-
lective compounds. Exploitation of some of these systems may lead to the
fast-acting toxins we have come to expect in agriculture.
Some of these targets may yield compounds very selective for pest insects
versus beneficials (Mullin and Croft, in press). The term pest has no sys-
tematic basis, however, and the bionomics of pest versus beneficial insect
interaction is unknown for many cropping systems. Although there are some
limited generalizations regarding the comparative biochemistry and toxicol-
ogy of pest versus beneficial insects, their general applicability is unknown
(Metcalf, 1975; Granett, in press). It is not necessary to develop selectivity
among insects by planned exploitation of a biochemical lesion. Once high
biological activity is discovered, such selectivity can be developed by syn-
thesizing compounds to exploit differences in xenobiotic metabolism or sim-
ply by testing a series of chemicals on pest and beneficial insects as part of
the evaluation process. Just as industry invested in resistance management
when it became financially advantageous, many companies will eventually
include selectivity as a major criterion in the future selection of compounds.
Encouraging Fundamental Research
Although there are ample opportunities to discover novel insecticides, the
critical problem lies in incentives to pursue these opportunities. Historically,
the agrochemical industry has succeeded by optimizing biological activity in
a series of compounds. Industry has not pursued sustained in-house research
to discover new leads. One reason is the expense of long-term commitments
of personnel and facilities to do basic research on insect biochemistry. More-
over, scientists attempting to pursue these efforts under the cloak of industrial
secrecy are isolated from the free interchange of ideas and the honing influ-
ence of peer review in publication and the pursuit of funding. Consequently,
basic research in an industrial setting runs the risk of losing contact with the
OCR for page 122
122
MECHANISMS OF RESISTANCE TO PESTICIDES
leading edge of knowledge, particularly in some of the more progressively
fast-paced fields of academic research (Webber, 19841.
This argument may imply that such research is most appropriately pursued
in academic laboratories. Yet, we found very few academic scientists actively
pursuing the definition of possible new sites for insecticide action, and the
funds that were spent came largely from projects funded for other reasons.
More scientists must be enticed into these areas by convincing them that a
career based on such research is socially responsible and professionally prof-
itable. There are a variety of mechanisms to accomplish this end, a few of
which follow. Our suggestions raise questions regarding the role of the public
sector in fundamental agricultural research. Ruttan (1982) argued that in-
centives are not adequate to encourage private research and that social return
on public investment in agricultural research may exceed private profit. He
concluded that "simultaneous achievement of safety, environmental, and
productivity objectives in insect pest control will require that the public sector
play a larger role in research and development."
National Institutes of Health and the National Science Foundation If
gold stars were to be awarded to agencies for funding work leading to the
discovery of new targets for insecticide development, the National Institutes
of Health (NIH) and the National Science Foundation (NSF) would receive
them. Most of this work is outside the mandates of these agencies, but they
have provided a base level of funding presumably because the proposed
science is good and because the agencies see some social value in the research
product. Our observations on pesticides appear to apply to agriculture in
general (Lepkowski, 19821. Some slight changes could be made in the man-
dates of certain institutes at NIH to facilitate the funding of such work "up
front." For instance, a great deal of work is supported on the deleterious
effects of pesticides on mammalian systems. One way to improve human
health would be to encourage the development of insecticides that are less
risky to humans and the environment. Ironically, the National Institute of
Environmental Health Statistics (NIEHS) has recently designated such re-
search as "peripheral" and "no longer relevant."
An agency like NSF, which funds the pure pursuit of knowledge, is of
tremendous value to the scientific community. Its resources must not be
diluted, because much of the work on fundamental chemistry and biochem-
istry that it funds is of great value in the elucidation of new targets for
insecticides even when insects are not the subject of investigation. Yet, NSF
should not eliminate from consideration good basic research simply because
a pest insect is used as a model organism to evaluate a fundamental question
in biology. Among the very best models for asking basic questions in biology
are those related to resistance. The excitement demonstrated in this publi-
cation from population biologists is one illustration. The availability of strains
OCR for page 123
CHEMICAL STRATEGIES
123
of insects either susceptible or resistant to the toxin provides an unparalleled
opportunity to determine the impact of altered biochemical processes on the
functioning of intact organisms. The value of insects as models when in-
vestigating fundamental biological processes has been illustrated often.
U.S. Environmental Protection Agency Research funding by the U.S.
Environmental Protection Agency (EPA) is generally restricted to areas that
require additional information to support a regulatory decision. Nevertheless,
EPA has funded some of the most exciting and innovative work on the
development of new insecticides; it has also funded research that will improve
environmental quality and encourage implementation of IPM programs. Cer-
tainly, research that leads to the discovery and development of insect control
agents that promise fewer environmental and nontarget problems is a logical
extension of the above programs.
U.S. Department of Agriculture Responsibility to support fundamental
research as a basis for pesticide development is part of the U.S. Department
of Agriculture's (USDA) mandate. Unfortunately, USDA has failed to fulfill
this responsibility. This failure is due partly to the negative connotations that
surround the idea of promoting pesticide research or pesticide use in any
way and the obvious difficulties of selling the need for such work in the
present political climate. To reverse this trend USDA must take a position
of informed advocacy for these research needs rather than capitulating to
prevailing public opinion.
The USDA is the only federal agency with an in-house research effort
capable of addressing this problem. A recent review of USDA research
recommended a renewed emphasis on basic research directed toward solving
agricultural problems of national importance (Lepkowski, 19821. Research
to define targets for novel insecticides fits within this recommendation. A1-
though some excellent research has been done by USDA scientists, admin-
istrative neglect of these priorities and concomitant emphasis of other programs
has left USDA laboratories with little in-house expertise in this area. A
renewed USDA effort in target biochemistry would require not only a policy
decision but also a commitment to hire new professional staff.
Fostering an environment of creativity and free scientific interchange within
the USDA is essential. There is a constant tension within the USDA between
the need for directed research and the negative impact of excessive direction
on innovation. Several initiatives might improve the productivity and crea-
tivity of all research programs within USDA's broad mandate. Programs to
encourage collaboration between some USDA laboratories and universities
have been very successful and could be expanded. Additional funds could
be designated, and individuals might be encouraged to take sabbatical leave
at USDA laboratories. The development of an in-house career development
OCR for page 124
124
MECHANISMS OF RESISTANCE TO PESTICIDES
program could greatly increase the level of innovative work as well as research
esprit de corps. Researchers could be granted salary and support funding for
five years, based on past performance or a competitive proposal.
The most immediate impact of USDA support of target biochemistry would
be felt in universities. Academic laboratories already possess the expertise
to pursue this research. The U.S. Department of Agriculture, through its
Competitive Grants Program, can provide the opportunity. Unfortunately,
the current guidelines for the program virtually exclude research in this area.
Simply broadening the objectives of the Competitive Grants Program would
be of little help, as the program is too small to fund even the high-quality
proposals submitted under current guidelines. Instead, we suggest an increase
in funding specifically to support a new program area in target biochemistry.
For example, supporting 50 research projects at a level of $60,000 per year
($40,000 in direct costs and $20,000 in indirect costs) would cost $3 million
per year, a modest amount compared to the nearly $20 million increase
recently designated to establish funding through the Competitive Grants Pro-
gram for research in agricultural biotechnology.
Despite the need for this type of funding, the future of the entire Com-
petitive Grants Program is regularly threatened in the budget process. The
most recent example is the elimination of all funding for this program in the
proposed executive budget for fiscal year 1986. If competitive funding is to
have a large impact on research productivity, it must be a stable, integral,
and significant part of the annual USDA budget.
Another approach would be to institute a strong, competitive postdoctoral
program for in-house and extramural positions. This program, patterned after
the highly successful NIH program, would encourage new Ph.D.s to prepare
research proposals relating to fundamental problems in agriculture. It would
encourage young scientists from a variety of disciplines to enter the field
and, if properly administered, would further excellence in agricultural re-
search. A second approach would be to establish a grant program to support
new assistant professors in fundamental research related to agriculture. Such
a program would encourage individuals in basic science departments to ex-
ploit the exciting models offered in agriculture. Once a young scientist has
established a research direction related to agriculture, long-term funding
might be obtained from other agencies. A similar approach might be taken
with starter grants to encourage scientists to extend their research into new
areas. Ideally these grants would be limited to two or three years and would
be nonrenewable for a similar period. Such a system would encourage in-
dividuals to seek other support and prevent the funding from going only to
a few established laboratories. These three programs would acquire for ag-
riculture more basic research than agriculture actually supported. Such a
course may be initially defensible, but ultimately, there is also the need to
establish stable, long-term support for the fundamental science that will
OCR for page 125
CHEMICAL STRATEGIES
125
maintain our high level of agricultural productivity and profitability while
still protecting the environment.
Universities Universities can increase research on target biochemistry.
Experiment station directors and land-grant institutions can immediately en-
courage such work. Scientists lacking experiment station appointments could
be encouraged to carry out collaborative projects in these areas.
The major commitment that a university must make is to hire faculty to
work in the area of target biochemistry and physiology. It takes more than
a two-week short course to convert an organic chemist into a creative leader
of a biorational pesticide development program. The chemist must have either
extensive cross training or colleagues who speak a similar language. Who
will train these individuals? Many of the pioneers of post-World War II
pesticide development have retired and have not been replaced. A teaching
cadre in this area is critical if work along these lines is to continue.
Although agrochemical companies have the chemical expertise to exploit
a biochemical system, they lack the in-house expertise in biology and bio-
chemistry. Acquiring such expertise by extensively retraining existing per-
sonnel or hiring new staff is an expensive, long-term commitment. Collaborating
with a university laboratory having the required expertise is a more logical
solution.
Collaborative arrangements benefit both parties, but they are relatively
rare in this country (Webber, 19841. Therefore, universities must develop
reasonable guidelines to permit and encourage interaction with industry.
Collaboration means far more than just accepting money. Acceptance carries
with it the obligation to conduct research that will be meaningful to the
sponsoring company. In return, industry must appreciate that university lab-
oratories do not exist solely for subcontracting proprietary research. A great
deal of basic research can be accomplished on a minimal budget in a university
setting, but a major professor must protect the careers of students and post-
graduates. Thus, industry must be willing to make a commitment to multiyear
support and must have realistic expectations of productivity for research
undertaken in the context of graduate and postdoctoral training. Areas of
research must be explicitly defined so that university collaborators are not
barred from publishing their results, and patent agreements must respect the
rights of the university as well as the research sponsor.
Private and public investment in university-based agricultural research is
sound (Ruttan, 19821. Such research is complementary to graduate education
in agriculture. Public investment in a university setting will draw scientists
from a variety of areas into agriculture. Since industry is in need of in-house
scientists capable of developing new pest-control agents by both classical
and molecular procedures, industrial support of university research provides
OCR for page 126
126
MECHANISMS OF RESISTANCE TO PESTICIDES
not only the data needed but a pool of well-trained potential employees as
well.
Chemical Industry The pesticide chemical industry invests roughly 10
percent of its gross profits in research, making it one of the most research-
intensive industries (Ruttan, 19821. Companies must establish sufficient in-
house expertise in insect biochemistry and physiology and must initiate basic
research programs that are relevant to the company's objectives and com-
plementary to university research efforts. The agrochemical industry tends
to hire basic scientists and then assumes that basic research is simply the
screening of experimental chemicals on an elegant in vitro preparation. Such
work is important, but it should be a minor portion of the duties of an industrial
scientist. The scientists must be free to explore new opportunities for chemical
exploitation and to define the biorational models for directed chemical syn-
thesis programs. Another problem is that industrial scientists doing basic
research are often prevented from testing the validity of their ideas through
publication in peer-reviewed journals. Companies can remedy this by estab-
lishing a tradition of peer review and publication of in-house basic research
after an appropriate delay to allow its oroorietarv use.
State IPM and Commodity Groups
Funding available to state IPM pro-
grams and commodity groups varies dramatically from state to state. The
funding is characteristically applied to local problems, not to fundamental
research on target biochemistry. Developing selective materials is to their
benefit. These groups should support legislative efforts to encourage fun-
damental research in agriculture even if the expected benefits extend beyond
the individual state. When possible, these groups should fund long-term basic
research directly, partly because they can have a more profound influence
on growers to use selective materials.
ENCOURAGING REGISTRATION AND DEVELOPMENT
Industry will use any available information on target biochemistry to dis-
cover new compounds. Although broad-spectrum compounds will be devel-
oped, selective compounds are desperately needed for IPM programs, especially
since regulatory law and economic constraints impede the development of
diverse crop chemicals.
A variety of modifications of patent law and enforcement can encourage
development. For instance, legislation to start the patent clock ticking when
registration is granted has already been proposed. Patent life could be further
extended for compounds considered to have exceptional value to IPM pro-
grams, especially if the compounds act by a unique mechanism. An extended
patent life would give the company owning the compounds a major incentive
to avoid resistance problems (Djerassi et al., 19741.
OCR for page 127
CHEMICAL STRATEGIES
127
Although many regulatory costs cannot be reduced, costly delays in reg-
ulatory decisions can be eliminated. The EPA has often appeared to avoid
making bad decisions by avoiding any decisions. An effort by EPA to process
registration petitions as rapidly as possible would be of great benefit, par-
ticularly if extensions in patent life cannot be obtained.
Changes in the ways in which toxicological risks are evaluated would
promote the development of novel, selective compounds. Current regulatory
procedures may inadvertently encourage the registration of compounds that
are acutely toxic to mammals over selective materials (Retnakaran, 1982;
Ruttan, 1982~. The evaluation of the toxicological risks of insecticides must
be relevant to the expected routes and levels of exposure rather than requiring
toxicological evaluation at maximum tolerated doses. To do this, we need
well-trained, courageous regulators acting with legislative support. The pub-
lic must understand that a blind effort to obtain zero-risk may only increase
.
rls. (.
Further expanding the subsidized registration of pesticides for minor crop
uses would give IPM practitioners a greater variety of compounds to work
with. Eliminating some registration requirements for several closely related
IPM-compatible compounds by the same company might encourage the de-
velopment of highly selective compounds. Although registration cost will
probably not decrease dramatically, some scientific improvements can be
made. For instance, immunochemical technology can reduce the cost of
residue analysis. Since efficacy and residue analyses are the major costs
involved in minor crop registration, this technology could greatly expand the
effectiveness of the JR-4 program with no increase in budget (Hammock and
Mumma, 19801.
Another option is an orphan pesticide development program to encourage
the development of compounds that cannot be developed economically by
industry but are likely to be of great benefit. The recently established orphan
drug program provides both a precedent for this approach and an adminis-
trative model for its operation.
CONCLUSION
Many resistance management tactics tend to focus on existing resistance
problems and attempt to preserve the utility of compounds currently available.
Although these efforts are valuable, we believe that the effective management
of resistance to pesticides depends on the continued development of new
compounds, as well as on the judicious use of existing materials. Therefore,
the recent decline in the rate of development of new insecticides is a serious
limitation to resistance management and the development of sophisticated
pest-management strategies.
There is a great need to stimulate both basic research on the biochemistry
and physiology of target species and development of selective insecticides.
OCR for page 128
128
MECHANISMS OF RESISTANCE TO PESTICIDES
We have identified many avenues of research in insect biochemistry that
appear promising for the design of novel insecticides, and there are many
more that we have not mentioned. Federal agencies and the agrochemical
industry must recognize that research is critically needed.
The stimulation of the industrial development of new compounds is a more
complex problem. Potent, broad-spectrum pesticides will continue to be
developed, but economic and regulatory constraints work against the devel-
opment of more selective compounds. The agrochemical industry exists to
discover and sell products at a profit, not to develop ideal pesticides for pest
management. They will not develop compounds that are perceived to be
unprofitable or excessively risky. If, however, an increase in our knowledge
of the biochemistry of target species and the impact of new technologies can
decrease the cost of discovery, if the time and cost of regulatory compliance
can be minimized without detriment to the public good, and if patent lives
of compounds can be extended to compensate for marketing time lost in
regulatory review, then the search for and development of novel insecticides
will be perceived to be a sound, profitable business, and the tremendous
potential that we see for the development of safe and selective pesticides by
both chemical and molecular approaches will be realized.
ACKNOWLEDGMENTS
This work was supported by NIEHS Grant ES02710-05, Research Career
Award 5 K04 ES500107, and a grant from the Herman Frasch Foundation
to Bruce D. Hammock and by NIEHS Grant ES02160-06 to David M.
Soderlund. We thank the Ciba-Geigy Corporation for supporting David Sod-
erlund on sabbatical leave. We extend our thanks to many colleagues for
critical comments on this manuscript.
REFERENCES
Boyce, A. M. 1976. Historical aspects of insecticide development. Pp. 469-488 in The Future for
Insecticides: Needs and Prospects, R. L. Metcalf and J. J. McKelvey, Jr., eds. New York: John
Wiley and Sons.
Djerassi, C., C. Shih-Coleman, and J. Diekman. 1974. Insect control of the future: Operational and
policy aspects. Science 186:596-607.
Granett, J. In press. Potential of benzoylphenyl ureas in integrated pest management. In Chiten and
Benzoylphenyl Ureas, J. E. Wright and A. Retnakaran, eds. The Hague: Junk Press.
Hammock, B. D. 1985. Regulation of juvenile hormone titer: Degradation. Pp. 431-472 in Com-
prehensive Insect Physiology, Biochemistry and Pharmacology, G. A. Kerkut and L. I. Gilbert,
eds. New York: Pergamon.
Hammock, B. D., and R. O. Mumma. 1980. Potential of immunochemical technology for pesticide
residue analysis. Pp. 321-352 in Recent Advances in Pesticide Analytical Methodology, J. Harvey,
Jr. and G. Zweig, eds. Washington, D.C.: American Chemical Society.
Hinkle, M. K. 1983. Problems with conservation tillage. J. Soil Water Conserv. May-June:201-
206.
OCR for page 129
CHEMICAL STRATEGIES
129
Hollingworth, R. M., and L. L. Murdock. 1980. Formamidine pesticides: Octopamine-like actions
in a firefly. Science 208:74-76.
Kirschbaum, J. B. 1985. Potential implication of genetic engineering and other biotechnologies to
insect control. Annul Rev. Entomol. 30:51-70.
Krieger, H. 1982. Chemistry confronts global food crisis. Chem. Eng. News. 60:9-23.
Lepkowski, W. 1982. Shakeup ahead for agricultural research. Chem. Eng. News 60:8-16.
Lockwood, J. A., T. C. Sparks, and R. N. Story. 1984. Evolution of insect resistance to insecticides:
A reevaluation of the roles of physiology and behavior. Bull. Entomol. Soc. Am. 30:41-51.
Magee, P. S. 1983. Chemicals affecting insects and mites. Pp. 393-463 in Quantitative S~ucture-
Activity Relationships of Drugs, J. G. Topliss, ed. New York: Academic Press.
Matsumura, F., and K. Tanaka. 1984. Molecular basis of neuroexcitatory actions of cyclodiene-
type insecticides. Pp. 225-240 in Cellular and Molecular Neurotoxicology, T. Narahashi, ed.
New York: Raven.
Mellin, T. N., R. D. Busch, and C. C. Wang. 1983. Postsynaptic inhibition of invertebrate neu-
romuscular transmission by avermectin BY. Neuropharmacology. 22:89-96.
Mellor, J. W., and R. H. Adams, Jr. 1984. Feeding the underdeveloped world. Chem. Eng. News
62:32-39.
Me=, J. J. 1983. Present insecticides and approaches to discovery of environmentally acceptable
chemicals for pest management. Pp. 5-31 in Natural Products for Innovative Pest Management,
D. L. Whitehead, ed. New York: Pergamon.
Metcalf, R. L. 1975. Insecticides in pest management. Pp. 235-274 in Introduction to Insect Pest
Management, R. L. Metcalf and W. H. Luckmann, eds. New York: John Wiley and Sons.
Metcalf, R. L. 1980. Changing role of insecticides in crop production. Annul Rev. Entomol. 25:219-
256.
Metcalf, R. L., and J. J. McKelvey, Jr. 1976. Summary and recommendations. Pp. 509-511 in
The Future for Insecticides: Needs and Prospects, R. L. Metcalf and J. J. McKelvey, Jr., eds.
New York: John Wiley and Sons.
Miller, L. K., A. J. Lingg, and L. A. Bulla, Jr. 1983. Bacterial, viral and fungal insecticides.
Science 219:715-721.
Mullin, C. A., and B. A. Croft. In press. An update on development of selective pesticides favoring
arthropod natural enemies. ln Biological Control in Agricultural Integrated Pest Management
Systems, M. A. Hoy and D. C. Herzog, eds. New York: Academic Press.
Retnakaran, A. 1982. Do regulatory agencies unwittingly favor toxic pesticides? Bull. Entomol.
Soc. Am. 28:146.
Ruttan, V. W. 1982. Changing role of public and private sectors in agricultural research. Science
216:23-38.
Storck, W. J. 1984. Pesticides head for recovery. Chem. Eng. News 62:35-59.
Webber, D. 1984. Chief scientist Schneiderman: Monsanto's love affair with R and D. Chem. Eng.
News 62:6-13.
Representative terms from entire chapter:
pest management
