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OCR for page 226
D
Pesticide Innovation
TRENDS IN INNOVATION
EARL R. SWANSON
The role of innovation in a pesticide regulatory action depends on the scope
of the benefit analysis. Neither FIFRA nor the FDC Act (section 408) prescribes
in detail the nature of the benefit analysis. For example, there is no legal
requirement for a formal benefit-cost analysis and no specification of the future
time period to be considered. Benefit assessments performed by the EPA
usually focus on short-run economic impacts (three to five years) and consider
only currently registered chemical and nonchemical controls as alternatives.
There are cases, however, in which the EPA risk/benefit decision process has
taken into account pending registrations. For example, in the Rebuttable
Presumption Against Registration (RPAR) process on trifluralin (Treflan), the
pending registrations of pendimethalin (Prowl) were considered.2
One of the reasons for the focus on short-run impacts in the EPA benefit
analyses is the difficulty of forecasting the rates of innovation in pest control
methods. Nevertheless, the committee believes that the EPA should give added
emphasis in benefit analysis to alternative pest control technologies under
development. The methodology for such evaluation, however, is not well
developed at present. Ideally, information at each stage of the development of
a pesticide would be useful. Although there is considerable firm-to-firm and
compound-to-compound variation in the discovery and development process,
the stages suggested by Gorings are informative. In terms of sequence, these five
components may overlap and some are performed simultaneously:
1. Synthesis, screening, and preliminary field research;
2. Expanded field research, field development, and sales support;
226
OCR for page 227
PESTICIDE INNOVATION 227
3. Metabolism, environment, residues, and toxicology;
4. Formulation, process, and pilot plant; and
5. Registration.
In this appendix, broad perspectives of the changes that are occurring
in methods for control of insects and weeds are presented.
The partial inventory of compounds undergoing testing presented in
Chapter 6 illustrates one type of data that might be used in expanded
nsklbenefit analyses. Other sources of information include examination of
chemical patents and applications to the EPA for registration. Searches of
the trade literature may also provide an indication of particular pest control
innovations at venous stages of development. Certain limitations in the data
sources should be noted. The field testing done under the auspices of public
agencies and reported, for example, in the Fungicide and Nematicide Tests
published by the American Phytopathological Society may underestimate
the actual level of testing activity for new compounds. Universities and
experiment stations are becoming less willing to perform tests on expenmen-
tal pesticides, and an increasing amount of such testing is now conducted in
the private sector and thus not reported. Nevertheless, the efficacy data on
experimental compounds available in the reports of professional associations
provide evidence of possible replacements for compounds presently used.
Clearly, a systematic methodology needs to be developed for assessing the
innovation process at its various stages and integrating such assessments into
the benefit analysis.
If the EPA were to emphasize the prospects for new pest control
technologies in its benefit analyses, such a shift to a wider range of
alternatives would decrease the long-run benefits of the pesticide under
consideration, but not necessarily the more immediate impacts of its
withdrawal. In principle, the broadened scope of benefit analysis would
increase the risklbenefit ratio and the probability of cancellation of a
registered pesticide or the rejection of the application of an unregistered
pesticide. If this expanded benefit analysis by the EPA is perceived by
industry to be reasonably stable, pesticide manufacturers may be ex-
pected to respond by increasing production of registered substitutes
and/or developing new pesticides for a changed market.
NOTES
1. 7 USC § 136 (1978) and 21 USC § 346(b) (1984).
2. U.S. Environmental Protection Agency. 1982. Trifluralin (Treflan). Position Document 4.
Office of Pesticides and Toxic Substances. Washington, D.C., pp. 59~0.
3. Goring, C.A.I. 1977. The costs of commercializing pesticides. Pp. 1-33 in Pesticide
Management and Insect Resistance, David L. Watson and A.W.A. Brown, eds. New
York: Academic Press.
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228 APPENDIX D
HERBICIDES
WEED CONTROL
FRED H. TSCHIRLEY
During the past 15 years, the use of herbicides on crops in the United
States has increased dramatically. Farm use of herbicides totaled 215
million pounds in 1971, 376 million pounds in 1976, 445 million pounds in
1982, and 435 million pounds in 1984.' Herbicides now account for about
65 percent of the total pesticide use on farms. This increase occurred
because their use produces an economic benefit for growers.
Although cultivation is still practiced for the control of weeds, and crop
rotation provides some weed control, synthetic organic herbicides have
become the predominant technology. Led by the discovery of the
herbicidal properties of the phenoxy alkanoic acids in the early 1940s,
chemistry soon followed that provided different mechanisms of action, a
wider range of herbicidal activity on weeds, and differing selectivities to
crops.
Modern herbicides represent a large number of chemical classes, many
of which have only one or a few herbicides in the entire class. Important
classes include the phenoxy alkanoic acids, s-triazines, substituted
amides, carbamates and thiocarbamates, substituted ureas, and
nitroanilines. Herbicides in other classes are also important, including
amitrole, paraquat and diquat, bensulide, chloramben, DCPA, endothall,
picloram, and nitrogen. Herbicides used for weed control on corn and
soybean crops, which represent 93 percent of the farm use of herbicides,
are listed in Table D-1.
Certainly, the past rate of increase of use will not continue. In fact,
there are indications that use has already leveled off. Ninety-three percent
or more of the acreage planted to corn, soybeans, cotton, peanuts, and
rice was treated with herbicides in 1982. In addition, 71 percent of the
tobacco acreage; 59 percent of grain sorghum; and 40 to 45 percent of the
wheat, barley, and oat acreage was treated with herbicides. Although
marked increases in herbicide usage are not expected in the foreseeable
future, neither is a marked decrease expected, and herbicides will surely
continue to be the predominant technology for weed control.
NEW CHEMISTRY
Manufacturers have become more sophisticated in designing new
molecules with a reasonable expectation that they will have herbicidal
activity. Researchers can target a specific enzyme system that is known to
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PESTICIDE INNOVATION 229
TABLE D-1 Herbicidal Active Ingredients Used on Corn and Soybeans
During 1982
Active Ingredient (million lbs.)
Herbicide Corn Soybeans
Single applications
Acifluorfen 0.9
Alachlor 19.7 10.3
Atrazine 22.4
Bentazon 6.7
Butylate 22.4
Chloramben 2.7
Cyanazine 4.9
2,4-D 3.3
Dicamba 0.9
Fluchloralin 2.6
Glyphosate 2.2
Linuron 1.3
Metolachlor 3.2 6.9
Metribuzin 2.2
Trifluralin 20.4
Other 9.5 5.5
Total 86.3 61.7
Tank mixes
Acifluorfen + bentazon 0.3 + 0.7
Alachlor + metribuzin 6.9 + 1.7
Alachlor + linuron 8.1 + 3.2
Alachlor + naptalam + dinoseb 1.5 + 1.3 + 0.6
Atrazine + alachlor 16.4 + 21.2
Atrazine + butylate 8.7 + 23.7
Atrazine + cyanazine 2.7 + 3.6
Atrazine + metolachlor 8.7 + 10.7
Atrazine + simazine 1.3 + 1.2
Bentazon + 2,4-D 0.4 + *
Chloramben + alachlor 1.5 + 1.8
Chloramben + trifluralin 0.9 + 0.5
Cyanazine + alachlor 6.1 + 7.6
Cyanazine + butylate 2.7 + 4.9
Cyanazine + metolachlor 0.9 + 1.2
Dicamba + 2,4-D 1.0 + 1.6
Dinoseb + naptalam 1.2 + 2.4
Metolachlor + metribuzin 4.2 + 1.6
Metolachlor + atrazine + simazine 3.2 + 2.6 + 1.3
Metolachlor + cyanazine + atrazine 1.4 + 0.6 + 0.6
Oryzalin + linuron 0.4 + 0.3
Paraquat + others 0.4 + 1.7
Trifluralin + metribuzin 8.8 + 3.8
Other 8.9 11.1
Total 142.8 65.3
Total herbicides 229. 1 127.0
*Less than 100,000 pounds.
SOURCE: Adapted from Delvo, H. W. November 1984. Inputs: Outlook and Situation
Report. Washington, D.C.: U.S. Department of Agriculture, Economic Research Service.
OCR for page 230
230 APPENDIX D
be affected by one or more functional groups. Unfortunately, mechanisms
of action are not completely known for all active ingredients. For
example, the mechanism of action of the phenoxy herbicides is still
unknown, even after 40 years of use. Nevertheless, the discovery of new
herbicides has a firmer scientific base today than 10 years ago.
Several compounds representing new chemistry have been commer-
cially introduced in the past several years, and others, now being tested
under experimental permits, can be expected to reach commercial use in
the next few years. An exciting aspect of this new chemistry is the
remarkably low rates needed for weed control. Older herbicides were
applied in pounds per acre; some of the new materials are effective at
ounces per acre. For example, control of annual and perennial grass
weeds is accomplished with 4 to 8 ounces of fluazifop per acre, 3 to 7.5
ounces of sethoxydim per acre, 1 to 5 ounces of sulfometuron methyl per
acre, and 0.17 to 0.5 ounce of chlorsulfuron per acre.
Such herbicidal activity is remarkable. One-sixth of an ounce per acre
is only 0.09 mg per square foot. Ten or more other herbicides for which
rates of fractions of an ounce or a few ounces per acre are needed are in
various stages of development. Moreover, they are being developed by
several manufacturers, and their chemistry varies, rather than being mere
analogs of one basic molecule.
An increase in the use of the potent (low-application-rate) herbicides
would significantly decrease the quantity of herbicides being applied, and
presumably, lower residues in raw agricultural commodities. At present,
the crops on which these potent materials are registered is limited.
Chlorsulfuron is registered only on wheat, spring oats, and barley;
fluazifop on cotton and soybeans; and sethoxydim on soybeans, cotton,
sugar beets, and nonbearing food crops. Sulfometuron methyl is not yet
registered on any crops. Thus, registration of these herbicides is required
on a far greater number of crops before herbicide use will significantly
decrease. Herbicidal activity at such low rates requires cautious ap-
praisal, however. If a material with high biological activity is resistant to
degradation, its use would have to be limited to avoid carryover damage
to other crops. In fact, carryover potential for the new classes of soybean
herbicides is a matter of growing concern for weed scientists.
BIOLOGICAL CONTROL
Weed control by insects has been studied by a few scientists for a long
time, and successful control has been accomplished for numerous weeds
occurring in noncrop areas. However, it has not been successful in
cropland, because crops are planted in fallowed land, which is ideal for
the germination of weed seeds, phytophagous insects must have a specific
host or a narrow host range so that weeds are destroyed without danger
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PESTICIDE INNOVATION 23 ~
to crops, and there is usually a complex of weed species in cultivated
crops, so controlling one will simply provide a,competitive edge to the
remaining weeds. At best, the control of weeds by phytophagous insects
might be feasible in perennial crops, such as orchards, or for particularly
troublesome weeds, such as nutgrass (Cypercus sp.) or downy
bromegrass (Bromus tectorum). Nutgrass and other sedges, however, are
important beneficial plants in other habitats, and downy bromegrass
provides forage for animals on rangelands.2
Recently, interest in plant pathogens to control weeds has increased,
and several notable successes have occurred. Northern jointvetch in rice
can be controlled with an endemic fungal disease,3 and milkweed vine in
citrus is now controlled by a pathotype of Phytophthora.4 More recently,
Walkers~8 reported the successful control by pathogens of spurred anode,
prickly side, velvetleaf, and sicklepod. For this technology, spores are pro-
duced in the laboratory, incorporated into an appropriate carrier, and then
distributed in a selected area at the appropriate time. Combining spores of
different fungi, Boyette and coworkers9 applied pathogens for the simulta-
neous control of winged waterprimrose and northern jointvetch.
The limited number of scientists pursuing research in this field may
impede its rapid advance. Control by pathogens has the promise of
contributing to the development of integrated weed control systems.
Further success requires the discovery of more pathogens so that weed
complexes can be controlled rather than just a single species. Moreover,
for sustained success, farmers must be weaned away from the synthetic
organic herbicides that ensure effective weed control.
In a similar vein, increased emphasis has recently been given to natural
phytotoxins from pathogens that might be formulated and applied to
weeds. This bypasses the problem of introducing a living organism into
the environment, which, through mutation, could persist and become
destructive rather than beneficial. There is no assurance, however, that a
natural phytotoxin would be any less hazardous to human health and the
environment than the synthetic molecules now in use.
ALLELOPATHY
Allelopathy, coined by Hans Molisch in 1937, refers to the release of
chemical inhibitors by certain plants, which adversely affect other plant
species. Specific cases of allelopathy have been observed in crops,
forests, grasslands, deserts, and even aquatic systems.~° The inhibiting
chemicals may be released from living plants via exudation from roots,
from litter on the soil surface, or from decomposing organic matter.
Although, theoretically, allelopathy seems to offer a direct impact on
weed control technology, the greatest benefits may come from spin-offs of
allelopathic research. Although genotypes of some crops, such as cucum-
OCR for page 232
232 APPENDIX D
her, inhibited some important weeds in the laboratory and greenhouse,
the results were less dramatic and consistent in the field, perhaps because
the concentrations of the allelopathic chemicals in the soil were too low to
inhibit the weeds. Allelopathy could be effective in crops such as
turfgrass, cereal grains, and forage legumes, because of a higher concen-
tration and more even distribution of the inhibitory chemicals. Develop-
ing the technique requires the identification of allelopathic properties and
their incorporation into crops.
Once allelopathic chemicals are identified, they might be synthesized as
herbicides. That route engenders the same problems that now beset
organic herbicides synthesized de nova. As with phytotoxins, natural
products may be no less hazardous to humans and the environment than
ones first synthesized by man.
GENETIC ENGINEERING
Conceivably, crop varieties could be developed for allelopathic control
of weeds. For example, Putnam~° reported that some wild progenitors of
modern crop varieties demonstrate greater allelopathy than the varieties
now in use. Attention has also been given to breeding varieties that have
greater tolerance for herbicides, so that rates to control weeds can be
used without endangering the crop.
Incorporation of herbicide resistance in the crop has been achieved in
three ways:'2
1. By the transfer of a metabolic detoxification mechanism (in which an
enzyme inactivates the herbicide) from a resistant plant to a susceptible
one. A good example is the herbicide atrazine, which is used widely in
corn. Weeds lack the rapid detoxification pathway of corn that replaces
the chlorine atom with a peptide via a conjugation reaction. Several
laboratories have shown that the enzyme is glutathione-S-transferase. In
principle, it should be possible to transfer the glutathione-S-transferase
gene into, for example, soybeans, to make it herbicide resistant. Research
is still needed, however, before application is practical.
2. By the transfer of a restricted uptake or translocation trait. A new
plant variety has emerged in Egypt that is resistant to paraquat. The
phytotoxicity of paraquat results from its chemical reductions in the
chloroplasts, which generates free radicals that destroy the plant. In the
Egyptian biotype, an unknown process restricts the paraquat to the veins
of the leaves, preventing it from entering the cells that contain the
chloroplasts. Today, however, the probability of genetically transferring
this sort of trait from one crop to another is low.
3. By modification of the target of the herbicide. In the short term,
target site modification looks promising. A herbicide translocated to a
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PESTICIDE INNOVATION 233
specific target in the plant interacts with that target, blocking some
metabolic event and killing the plant. If, through genetic manipulation,
the target site could be altered so that it no longer recognizes the
herbicide, the plant would be resistant. An example is pigweed, which is
resistant to atrazine because a natural mutation occurred that changed the
protein that normally binds the atrazine. The protein in susceptible plants
contains the amino acid serine, which is required for hydrogen bonding of
the triazine molecule to the protein. In resistant plants, this amino acid
had been replaced by glycine, with which triazine cannot bond. This
mechanism of resistance has been exploited to develop a triazine-resistant
tobacco plant.
Another example comes from scientists of Calgene, Inc., who incorpo-
rated a mutant EPSP synthase gene, isolated from glyphosate-resistant
Salmonella, into tobacco. Other scientists from Monsanto Chemical
Company achieved greater glyphosate resistance in petunia plants by
inducing them to make 20 to 40 times the usual amount of normal petunia
EPSP synthase.
DuPont researchers used both chemical and random mutations to
isolate mutant plants that varied in response to chlorosulfuron and
sulfometuron methyl. Various tests and correlations established the site
of action as acetolacetate synthase. Production of an insensitive form of
the enzyme is the basis for resistance.
CONCLUSIONS
Since their introduction in the early 1940s, synthetic organic herbicides
have dominated weed control. Although alternative weed control tech-
nologies hold some promise and may become more important, synthetic
organic herbicides seem certain to be the preferred technology until the
end of the century. Development of alternative technologies will require
not only time and research, but also practical demonstrations to convince
farmers that the alternatives will be as economical and dependable as
synthetic organic herbicides.
NOTES
1. Delvo, H. W. November 1984. Inputs: Outlook and Situation Report. Washington,
D.C.: Department of Agriculture, Economic Research Service.
2. Morrow, L. A., and P. W. Stahlman. 1984. The history and distribution of downy
brome (Bromus tectorum) in North America. Weed Sci. 32(Suppl. 1):2- 6.
3. Daniel, J. T., G. E. Templeton, R. J. Smith, Jr., and W. T. Fox. 1973. Biological
control of northern jointvetch in rice with an endemic fungal disease. Weed Sci.
2 1 :303-307.
OCR for page 234
234 APPENDIX D
4. Ridings, W. H., D. J. Mitchell, C. J. Shoulties, and N. E. El-Ghell. 1976. Biological
control of milkweed vine in Florida citrus groves with a pathotype of Phytophthora
citrophthora. Pp. 22~240 in T. E. Freeman, ea., Proceedings of the IV International
Symposium on Biological Control of Weeds.
5. Walker, H. L. 1980. Alternaria macrospora as a potential biocontrol agent for spurred
anode: Production of spores for field studies. U.S. Science Education Administration,
Advanced Agricultural Technology, South. Ser. (ISSN 0193-3728), No. 12, 5 pp.
6. Walker, H. L. 1981. Granular formulation of Alternaria macrospora for control of
spurred anode (Anoda cristata). Weed Sci. 29:342-345.
7. Walker, H. L. 1981. Fusarium lateritium: A pathogen of spurred anode (Anoda
cristata), prickly side (Sida spinosa), and velvetleaf (Abutilon theophrasti). Weed Sci.
29:629~31.
8. Walker, H. L., and J. A. Riley. 1982. Evaluation of Alternaria cassiae for the biocontrol
of sicklepod (Cassia obtusifolia). Weed Sci. 30(6):651~54.
9. Boyette, C. D., G. E. Templeton, and R. J. Smith, Jr. 1979. Control of winged
waterprimrose (Jussiaea decurrens) and northern jointvetch (Aeschynomene virginica)
with fungal pathogens. Weed Sci. 27:497-501.
10. Putnam, A. 1983. Allelopathic chemicals: Nature's herbicides in action. Chem. & Eng.
News April 4, 1983, pp. 34 ~ 5.
. Marx, J. L. 1985. Plant gene transfer becomes a fertile field. Science 230(4730):
1148-1150.
12. Chemical and Engineering News, October 29, 1984, p. 16.
INSECT CONTROL
T. ROY FUKUTO
INTRODUCTION
Because they are effective, economical, and fast-acting, insecticides
and acaricides are unique tools for relegating damaging insect and mite
populations to subeconomic levels. Thus, despite problems such as the
development of insecticide-resistant pest populations and undesirable
nontarget effects, they will remain one of the basic tools for managing
insects and mites in crops.
Virtually all major insecticides that are widely used on crops, except
organochlorines, are acute neurotoxins and fall into the chemical classes
of organophosphates, carbamates, and pyrethroids. Owing to their per-
sistence in the environment and unfavorable toxicological properties,
most of the organochlorine insecticides either have been banned or are
used only in special situations. Pyrethroids are now receiving the greatest
attention from industry. These broad-spectrum insecticides are highly
effective at application rates measured in ounces and fractions of an
ounce instead of the 0.5 to 2 pounds applied per acre of most compounds
in the other classes.
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PESTICIDE INNOVATION 235
Advances in insect physiology, toxicology, and analytical chemistry
are responsible for discoveries of new compounds with novel modes of
action that disrupt the normal growth of insects. The juvenile hormone
analogs, for example, prevent the insect from molting to the adult stage.
Unfortunately, because the larval stages typically are most damaging to
crops, these compounds appear to have limited use in crop protection.
They will, however, control such insects as fleas and biting flies, which
are pests in the adult stage. Antijuvenile hormones causing insects to molt
prematurely to adults have been discovered and offer more promise for
managing agricultural insect pests. The relatively recent discovery of
compounds that disrupt the molting process of insects by interfering with
the synthesis and deposition of chitin (a principal component of the
exoskeleton of insects) also holds promise. One such chitin inhibitor,
Diflubenzuron (Dimilin) is registered for control of cotton boll weevils and
gypsy moths.
Similarly, advances in natural products chemistry and the study of
plant defenses against insects are leading to the identification of numer-
ous, naturally occurring, insecticidal and acaricidal compounds with
novel modes of action. To date, biologically active, natural products have
been looked to by the agrochemical industry as leads for the chemical
synthesis of structurally related compounds with improved biological and
physical properties that are amenable to large-scale chemical synthesis.
This latter requirement may ultimately become less important with
advances in genetic engineering, since even complex molecules can be
produced on a large scale, using fermentation processes with genetically
. . .
englneerec . microorganisms.
NEW CHEMISTRY
Motivation for the discovery of new pest control agents by the chemical
industry originates from the ongoing desire to develop a proprietary agent
with superior pesticidal activity and favorable environmental and toxico-
logical properties. Although a significant amount of effort is still being
devoted to research on organophosphates, carbamates, and pyrethroids,
the chemical industry is turning to other classes of compounds in seeking
new control agents. Increased attention to unconventional chemicals has
been hastened by the prospect of the development of insect resistance to
present-day insecticides.
During the past decade, novel insecticides with different modes of
action have been discovered. With the elucidation of their modes of
action, the way has been paved for further search within these classes for
new insect control agents. Areas that have been or are currently being
explored for new insect control agents are described below.
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236 APPENDIX D
Octopamine Agonists
Chlordimeform (Fundal, Galecron) and amitraz are formamidine deriv-
atives that effectively control phytophagus mites, ticks, and a limited
range of insects, for example, many Lepidoptera, Hemiptera, and some
Homoptera.2 The formamidine derivatives are most effective as ovicides
although they are also toxic to nymphs and adults. In addition to
mortality, the formamidines also cause unusual behavioral effects, for
example, on locomotion, flight, dispersal, and oviposition. Due to adverse
human health effects, chlordimeform is registered for use only on cotton.
Evidence accumulated over the past decade supports an octopamino-
mimetic mechanism of action for chlordimeform and related compounds.
The elucidation of the mechanism of action of this compound has
stimulated work on the design and synthesis of compounds with
octopaminomimetic activity. Octopamine, a biogenic amine that serves as
neurotransmitter and neuromodulator, is found primarily in invertebrates
and, therefore, compounds mimicking its action are expected to be
selectively toxic to insects and acarines.
Avermectins and Milbemycines
The avermectins and milbemycins are natural products obtained by
fermentation of the soil fungus species Streptomyces, which have dem-
onstrated potent anthelmintic, acaricidal, and insecticidal activities.34
For example, the avermectins are highly effective against common
veterinary ectoparasites, phytophagus mites, nematodes, and various
insect species of Lepidoptera, Coleoptera, and Homoptera. They are
highly complex molecules consisting of eight major components.
Ivermectin, a commercial product currently under development, is a
hydrogenated derivative of avermectin B~, the most active of the eight
components. The avermectins behave as agonists or cause the release of
the inhibitory neurotransmitter~y-aminobutyric acid (GABA).
Avermectins and milbemycins exhibit unusually potent insecticidal and
acaricidal activities, but have highly complicated structures. Therefore,
work has been started on the synthesis and evaluation of analogs of less
structural complexity.S 6 This work is expected to result in new analogs
with similar modes of action.
A new class of insecticide, the 1,4-disubstituted-2,6,7-trioxabicyclo-
t2,2,2]octanes, has recently been discovered.7 These compounds appear
to act at the neuromuscular junction by inhibiting GABAergic synaptic
transmission, possibly by closing off chloride channels. The high insecti-
cidal potency of the avermectins, milbemycins, and trioxabicyclof2,2,21-
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238 APPENDIX D
carbamate by a plant, animal, or microorganism in order for intoxication to
occur. Thiodicarb (a derivative of the carbamate methomyl) and carbosulfan
(a derivative of the carbamate carbofuran) are examples of procarbamate
insecticides that have attained commercial importance. Both are highly
effective insecticides and are substantially less acutely toxic to mammals
than the parent carbamates. Several other procarbamate insecticides are
currently undergoing commercial development.
Nereistoxin, a substance found in a poisonous marine annelid, has been
derivatized to form another type of proinsecticide. Nereistoxin paralyzes
insects by a blocking action on the central nervous system. Examples of
nereistoxin proinsecticides are cartap and bensultap. Bensultap, a more
recent discovery, has shown excellent effectiveness against the Colorado
potato beetle and different lepidopterous larvae.'3
Natural Products
Much effort is being devoted to the study of various plant products that
could be used for protection against plant-feeding insects. ~4 For example,
pellitorine, a potent insecticidal amide recently isolated from the root of
a compositae, has stimulated the synthesis and examination of structural
analogs. ~5 Pellitorine, although highly insecticidal, unfortunately is unsta-
ble in a field environment.
Other types of plants being sought as control agents are insect growth and
behavior regulators, morphogenetic agents, insect juvenile hormones and
phytochemical analogs, antijuvenile hormones, sex and alarm pheromones,
and antifeedants.'4 The examination of plant products for antifeedant com-
pounds has recently attracted much attention.'6 A number of plants are
recognized for their elaborate chemical defense systems against phytophag-
ous insects, and various naturally occurring compounds are being discovered
that permanently impede feeding by specific insects. In general, natural
products occurring in plants, animals, and microorganisms provide a rich
source for new types of insect control agents.
Although synthetic organic chemicals remain the principal pest control
materials, other types of control agents or methods are currently in use or
have the potential to provide effective pest control. They may be divided
into three major categories biological control, natural products ap-
proach, and plant modification. These are briefly described below.
GENETICALLY ENGINEERED MICROORGANISMS
Strategies and methods have been proposed for the use of microorga-
nisms for pest control. Among the microorganisms showing promise are
bacteria, viruses, and fungi. The potential for microorganisms as pesti-
OCR for page 239
PESTICIDE INNOVATION 239
cides has been increased by progress in genetic engineering, which is
expected be important in the development of bacterial, viral, and fungal
pesticides effective enough to displace the synthetic chemicals, which
dominate the market today.~7
Bacterial Insecticides
The sporeforming bacteria Bacillus thuringiensus kurstaki has been
developed commercially and is registered by the EPA as a bacterial
insecticide for use on field and vegetable crops, trees, ornamentals, and
stored products (primarily grain and grain products) to control lepidopter-
ous larvae. However, the bacteria's effectiveness is limited to certain
species of Lepidoptera.
Monsanto is attempting to engineer a microbial pesticide by taking the
b-endotoxin gene from B. thuringiensis kurstaki and placing this toxin
gene in another kind of bacteria, for example, Pseudomonas puorescens,
that can colonize the roots of plants such as corn.~9 When root-eating
pests ingest the genetically engineered bacteria on the plant roots, the
toxin in the bacteria will get into the gut of the pests where it will be
activated and will intoxicate them. Unfortunately, agricultural pests that
are vulnerable to this microbial pesticide are still mainly lepidopterous
species (tobacco hornworms, black cutworms, cabbage and soybean
loopers, and corn earworms) that do not attack plant roots.
Discovery of other B. thuringiensis isolates producing proteins toxic to
root-feeding species would be required for this particular strategy to
work. However, the same general strategy might work using genes from
presently available B. thuringiensis strains and bacteria that colonize
plant foliage. Monsanto reasons that since these engineered strains are
not toxic to beneficial insects such as honeybees, their genetically
engineered bacterial pesticides will have the same attributes.
There is under way considerable research directed toward identifying
strains of B. thuringiensis that produce more virulent toxins and are
effective against a wider diversity of insect pests. Research of this type
has already led to the commercial development of B. thuringiensis var.
israelensis, which is an effective control agent for mosquito larvae and
will very likely expand the spectrum of crop pests that can be controlled
by bacterial insecticides.
RESISTANCE
Resistance is a preadaptive phenomenon, and since insects and bacteria
have been together in nature for ages, it is conceivable that low levels of
resistance to the bacterial toxins already exist.
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240 APPENDIX D
Evidence has not been provided for the development of insect resis-
tance to B. thuringiensis in the field although a recent report has
demonstrated that resistance to B. thuringiensis could be selected for in
the laboratory. In a microbial control program, development of pest
resistance can be averted by the following strategies:
· Use of multifunctional agents (B. thuringiensis produces several
toxins), because the greater the number of targets in the insect the less
likely it is that mutations will lead to increased resistance;
· Simultaneous use of chemical and microbial agents for the same
reason more than one target is involved; and
· Use of an agent—microbiological or chemical with a rapid toxic
action, to avoid a lasting selection pressure for resistance since the
number of mutants produced will be proportional to exposure time.
However, in a stable environment such as in stored grains where the
bacterial toxin is stable, the insect can breed for successive generations in
contact with B. thuringiensis. In this situation, resistance is very likely to
develop.
This scenario has recently been observed with the Indian meal moth
Plodia interpunctella, which developed a 100-fold increase in resistance
after 15 generations on diets treated with bacterial toxin.20 In this case,
the resistance was inherited as a recessive trait.
Fortunately, in field crop situations, the instability of foliarly applied B.
thuringiensis and the transitory nature of plant pest interactions decrease
the possibility of resistance. The use of B. thuringiensis over a wide
geographic area for several years would be required to expose the pests
for many successive generations.
PRODUCT NAMES AND USES
A number of biological insecticides exist on the market that have B.
thuringiensis as their active ingredient. These include
· Thuricide, having B. thuringiensis Berliner as the active species;
· Thuricide-HP, also derived from B. thuringiensis Berliner. However,
unlike Thuricide, it is twice as concentrated; and
· Bactospeine, Javelin, and Dipel all contain B. thuringiensis Berliner
var. kurstaki as their active ingredient. However, with regard to concen-
tration, the ratio of active ingredients among the three is 1:2:4, re-
spectively.
These formulations of B . thuringiensis are active over a broad range of
lepidopterous pests in a vast array of crops, including vegetables, cotton,
and various fruits. Among the disadvantages, however, is the slow killing
OCR for page 241
PES TI CIDE INNO VA TI ON 24 ~
action that allows more damage before death. These materials are also
less toxic to large worms.
MUTATIONS
Dangerous mutations may be of two types: mutation to infect a
mammal and mutation to produce a toxin harmful to mammals. The
most useful test for detecting the ability of B. thuringiensis to mutate is
serial passage of the agent in an environment in which the mutants in
question would have a selective advantage over the parent agents and so
reveal their presence in the mammalian body.
TOXICITY
In Europe and North America, new B. thuringiensis products have
been subjected to extensive toxicological tests, which confirmed their
innocuity. However, regulatory agencies have not specified what tests
should be required for new B. thuringiensis products. Recently, the toxin
of B. thuringiensis israelensis, when dissolved and injected intravenously
into mice, was found to be highly toxic (LDso 1.3 mg/kg), being more so
to the mouse than to the American cockroach and cabbage looper.22
FUTURE OF SAFETY TESTING
Work has been started on the improvement of industrial strains of B.
thuringiensis. It is still mainly at the stage of selecting from existing
strains, with a start being made toward utilization of genetic engineering
to transfer and to amplify characteristics for example, the possible use
of B. subtilis to mediate change in B. thuringiensis. Unique codes of
safety are being formulated worldwide for genetic engineering. Safety
problems are not expected during manipulation of pest-control pathogens,
because factors harmful to pests rather than to humans are being
manipulated. From this viewpoint, it has been postulated that bacterial
insect pathogens are ideal systems for basic work on genetic engineering.
However, mediator organisms must be selected with care and a watch
kept to avoid undesirable contaminants entering the systems.
B. THURINGIENSIS USAGE
Since bacterial control agents are not restricted-use materials, quanti-
tative information on the usage of B. thuringiensis in agriculture is difficult
to obtain. An annual report on pesticide use is published by the California
Department of Food and Agriculture (CDFA). The most recent report
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242 APPENDIX D
(1983) provides quantitative data for virtually all pesticides used in
California, giving amounts used on different crops, but figures were not
available for bacterial agents. Therefore, it was necessary to approach
manufacturers of B. thuringiensis (for example, Abbott Laboratories and
Sandoz-Zoecon) for this information.
T. Hsieh of Sandoz-Zoecon indicated that Javelin, a recent B. thuringi-
ensis isolate developed by his company, is used primarily for the control
of forest insects (gypsy moth, spruce budworm) and vegetable and alfalfa
insects. He estimates that in the first two-and-one-half months on the
market, 70,000 to 90,000 gallons of Javelin was sold in the United States
alone. One to two quarts of Javelin are required per acre. Hsieh admitted
that growth in the use of B. thuringiensis has been very slow, attributable
mainly to the relatively low cost and effectiveness of conventional
insecticides. Further, as a stomach poison, Javelin is restricted primarily
to lepidopteran larvae that chew. However, recently a B. thuringiensis
isolate has been discovered in Germany which is highly active against the
Colorado potato beetle.
Hsieh's estimate of the total amount of conventional B. thuringiensis
(not including Javelin) sold by Sandoz-Zoecon last year is around 2
million gallons. This material is sold in many developing countries to
control vegetable crop pests that can no longer be controlled by conven-
tional insecticides.
Phillip Grau of Abbott Laboratories estimates worldwide sales of
Abbott's B. thuringiensis (Dipel) to be in the neighborhood of 3.5~.0
million pounds. It has been sold mainly for use on vegetables (lettuce,
cole crops, tomatoes, mixed vegetables) and mosquito control. More
recently, it is finding increasing use against forest insects. However, use
on vegetable crops is being supplanted to some degree by the pyrethroids
since they are registered for use on vegetables.
B. thuringiensis is also used effectively to control mosquito larvae.
According to recent annual reports of the California Mosquito and Vector
Control Association, the following amounts of B. thuringiensis were used
for mosquito control in California: 1983- 5,547 x 109 biological units
(approximately 20,350 pounds); 198~18,630 x 109 biological units
(approximately 68,370 pounds). For 1985, usage is expected to have
doubled over that of 1984.
According to M. Mulla (University of California, Riverside) and Hsieh,
approximately 1 million gallons per year of B. thuringiensis are being used
in West Africa against black flies (vector of onchocerciasis) by the World
Health Organization. Mulla stated that a new bacterium (B. sphaericus) is
being developed for use specifically on mosquitoes. It is more persistent
than B. thuringiensis and will be used to complement B. thuringiensis.
From discussion with a number of individuals, including those men-
OCR for page 243
PESTICIDE INNOVATION 243
tioned above, it is clear that the use of bacterial agents for insect control
will increase substantially in the immediate future. However, it must be
pointed out that the total amount of these materials used compared to
synthetic organic chemicals is still extremely small, probably less than 0.5
percent.
Viral Insecticides
A typical nucleopolyhedrosis virus (NPV) is Baculovirus heliothis
which produces crystal-like, irregular, proteinaceous polyhedral inclusion
bodies (PIB) in nuclei of infected cells.23 Development of the NPV of
Heliothis sp. began in 1961, progressed through various research and
development phases, and attained technical realization as the first com-
mercial viral pesticide. An exemption from the requirement of a tolerance
was granted in May 1973 by the EPA and a label was approved in
December 1975. Currently, B. heliothis is marketed as safe and effective
for use on cotton against Heliothis sea under the name Elcar (Sandoz,
Inc.~; Nutrilite products, Inc., has an equivalent experimental product
called Biotrol-VHZ.
RESISTANCE
Selection pressures of LCs~7O maintained for 20 and 25 generations did
not yield resistance in H. sea. Similar results were obtained with
laboratory populations of H. armigera selected for resistance over 22
generations.
There is no record of indisputable resistance of insects to viral agents in
field trials or control programs. However, these agents have not been
used for long and it is possible that low levels of resistance are present but
are not readily detectable.
In one case, NPV collected from distant plantations was more effective
against the wattle bagworm, Kotochalia junodi, than virus collected from
the local plantation in which tests were performed. Resistance might have
been acquired by the local insects to the local virus or the observation
might reflect differing levels of virulence among virus isolates.
STABILITY, SENSITIVITY, AND PERSISTENCE
Natural sunlight-ultraviolet radiation (> 290 nm) is the major environ-
mental factor inactivating B. heliothis and probably most insect viruses.
Although field temperatures of 15°-45°C had no effect on the stability of
FIB, viral replication was inhibited at 40°C. In general, high temperatures
(70°-80°C) and the presence of water completely inactivate FIB. Acids
OCR for page 244
244 APPENDIX D
and alkalis disrupt FIB and thus presumably destroy viral activity. Early
field and lab studies have indicated that most insecticides or insecticidal
adjuvants are compatible with B. heliothis.
TOXICOEOGICAE STUDIES
The baculovirus of H. zea and Lymantria dispar exhibited no harm to
mammals, fish, birds, or beneficial insects (including parasitic insects), had
no relationship to arboviruses, and had no effect on aquatic invertebrates.24
Extensive safety testing of Neodiprion lecontei NPV and N. sertifer
NPV was undertaken; carcinogenicity tests on newborn hamsters and a
two-year carcinogenicity test on rats were among the battery of tests.
There was no evidence that the viral preparation has any harmful effects.
PRODUCTION
B. heliothis can be produced only in Heliothis larvae, although several
sophisticated processes have been suggested. Production of sawfly (N.
sertifer) NPV is complicated by the fact that there are no synthetic diets
or established cell cultures for sawhies.25 Hence, for virus production,
larvae must be reared on their host food plant, infected with virus, and
then harvested and processed.
FIEED TRIAES
Control by B. heliothis generally was as effective on cotton as with
standard insecticides. Control was less effective on corn than with standard
insecticides. Although all spray treatments were effective on soybeans,
poorer results were obtained by releasing virus-infected larvae. Desired
levels of control were not obtained on tobacco and tomatoes. Results on
sorghum were comparable to those obtained with carbaryl and endosulfan.
With the notable exception of sawflies, little is known of viruses
pathogenic for nonlepidopteran insects, and continuous cell cultures from
such important groups as the Hymenoptera, Coleoptera, and Orthoptera
are lacking.
FUTURE DEVELOPMENTS
Several procedures for producing baculoviruses in either homologous
or nonhomologous hosts have been proposed. Although B. heliothis
produced in cell lines was as effective as that from larvae and it will
replicate in cell lines, this technology will not be commercially practical
for a long time. Significant development in production of B. heliothis will
OCR for page 245
PESTICIDE INNOVATION 245
probably come from new techniques such as production in nonhomolo-
gous hosts coupled with recombinant DNA techniques.
A key to the development of viral products is whether they can be
safely released into the environment.26 Lois Miller, University of Idaho,
is studying the replication of the baculovirus DNA, which could lead to a
better understanding of how to enhance the virus' pathogenicity and
expand its host range as well. EPA scientist Daphne Kamely observed
that the fate of the baculovirus and retroviruses in the environment is not
well understood. Studies are currently going on at Harvard University
and at the National Institutes of Health to develop risk assessment models
that may help the EPA to evaluate the consequences of the release of
viruses into the environment.
Fungal Insecticides
Although mycoses caused by the entomopathogenic Fungi Imperfecti,
Beauveria bassiana, Metarhizium anisopliae var. anisopliae and var.
major (the color of the spores) have been studied for about a century, it
is principally during the past 15-20 years that special attention has been
focused on them to develop new methods of microbial control of
insects.27 For many years they were regarded as biological agents of
secondary interest, due to pessimistic conclusions from the first field trials
in several countries at the end of the last century. However, in the 1950s
East European countries started investigations, particularly with B.
bassiana, as part of a general strategy to control the Colorado potato
beetle, Leptinotarsa decemlineata.
PRODUCTION
A new stage technique for mass production of B. bassiana
conidiospores is used in the USSR. First the biomass is produced as
mycelium in a fermenter, and subsequently surface-cultured in trays of
nutrient medium for sporulation. A similar technique is used for the mass
production of M. anisopliae. The preparations have a limited viability of
2 or 3 months, a serious failure that considerably limits their industrial
potential. In addition, production costs are high.
TOXICITY
In numerous safety tests, no infections have been induced in mammals
with the common microbiological control fungi. These include short-term
tests (feeding, inhalation, and intravenous and subcutaneous injection)
and 90-day subacute inhalation and feeding studies of B. bassiana and M.
OCR for page 246
246 APPENDIX D
anisopoliae in rodents; two-year intraperitoneal and subcutaneous injec-
tion, lactatation and fertility tests in rats; and three-month and one-and-
a-half-year studies of dusting effects on rats and mice.
RESISTANCE
Since these pathogens have been in nature for a long time, it is
reasonable to presume that insects have developed low levels of resis-
tance to them. With regard to infectivity, fungi reach their sites of action
in the haemocoel through the cuticle, or possibly through the mouth parts
and not via the gut wall as do bacteria and viruses. They become
established only when the infective phase interacts with a susceptible host
(that is, one that does not produce local reactions to ward off penetration).
These factors are sobering reminders that fungi and their products as
pest control agents do not have an unlimited potential.
PRODUCTS AND USES
Boverin, the trade name under which B. bassiana is marketed, is not
used in the United States possibly because of economic considerations,
which may not have been taken into account in the USSR in evaluating
effectiveness, or because of climatic considerations. The climate in the
Ukraine has justified the combined use of Boverin and reduced dosages of
chemical insecticides such as chlorophos or malathion. However, when
summers are particularly dry and hot, results are poor.
Mycar, a preparation of Hirsutella thompsonii, was marketed by
Abbott Laboratories until recently. The product was discontinued be-
cause it was expensive to produce and large quantities were needed for
each application.
It is well established now that entomopathogenic fungi have a certain
specificity. In the same species of fungus, different strains can have very
different activity.
FUTURE DEVELOPMENTS IN MICROBIOLOGICAL AGENTS
The success of B. thuringiensis as an insecticide has initiated research
to incorporate its toxin-coding genes into plant genomes in a manner that
will allow them to be expressed and the toxin to occur either symplasti-
cally or apoplastically within plants.
One idea is to nick the circular B. thuringiensis plasmid and join it
directly to a plant plasmid in vitro. Upon reintroduction of the now
extended plasmid into a plant cell, it is conceivable that the B. thuringi-
ensis toxin could be one of the translation products of its expression.
OCR for page 247
PESTICIDE INNOVATION 247
Since gene-incorporated traits are generally transmissible to future prog-
enies, the B. thuringiensis gene might well end up in new seeds on the
market. This was accomplished in tobacco by the Rohm and Haas Co.
The plant did not produce enough insecticide, however, to kill insects.
Another idea is to transfer the B. thuringiensis plasmid through the
intermediacy of gall-producing bacteria to plants. A possible plasmid
carrier could be attenuated Agrobacterium tumefasciens or its antagonist
A. radiobacter.
Plasmid transfer to the nitrogen-fixing bacteria in the Rhizobium genus
and eventual expression inside the root system of the plant is also a
possibility. Since these bacteria are already used commercially to inocu-
late legumes, it is only one step to incorporate an extra gene into them for
B. thuringiensis toxin production.
One cautionary note in these ideas is whether the B. thuringiensis
toxin-producing genes can or will be transferred through the plant
plasmids to weeds, thereby having an adverse affect on the beneficial
insects that suppress the proliferation of weeds.
SUMMARY
The potential of microbiological insecticides has barely been tapped.
The advent of new viral, bacterial, and fungal insecticides with remark-
able insect toxicity to selected target pests and negligible mammalian
toxicity is possible. The pragmatic view of biological insecticides taken by
regulatory agencies is likely to continue and anecdotal reports of toxicity
such as that of B. thuringiensis israelensis to mice by intravenous
administration will be placed in their proper perspective.
Viral insecticides are particularly promising for the future. Safety
prospects are also good and the chances of mutation to forms that are
virulent to mammals and other vertebrates are practically nonexistent.
The future is also likely to see structure-activity studies on the microbial
toxins to determine if any underlying common molecular rationale exists to
explain their mode of toxic action. These studies and the topographic details
of the toxins derivable from them could also form the basis for a new
generation of highly selective chemical insectides with high toxicity to only
a very narrow spectrum of pests. These new chemicals are expected to better
withstand scrutiny by the Delaney Clause.
NOTES
1. National Research Council. 1986. Pesticide Resistance: Strategies and Tactics for
Management. Washington, D.C.: National Academy Press.
OCR for page 248
248 APPENDIX D
2. Hollingworth, R. M. and A. E. Luna. 1982. Pesticidal Mode of Action, J. R. Coats, ea.,
New York: Academic Press.
3. Albers-Schonberg, G., B. H. Arison, J. C. Chabala, A. W. Douglas, P. Eskola, M. H.
Fisher, A. Lusi, H. Mrozik, J. L. Smith, and H. L. Tolman. 1981. J. Amer. Chem. Soc.
103:4216.
Fisher, M. H. 1985. Pp. 53-72 in Recent Advances in the Chemistry of Insect Control,
N. F. Janes, ed. London: Burlington House.
5. Kay, I. T., and M. D. Turnbull. 1985. Pp. 229-244 in Recent Advances in the Chemistry
of Insect Control.
6. Baker, R., C. J. Swain, and J. Head. 1985. Pp. 245-256 in Recent Advances in the
Chemistry of Insect Control.
7. Palmer, C. J., and J. E. Casida, 1984. J. Agr. Food Chem. 33: 976.
8. Hollingshaus, J. G., and R. J. Little. 1985. Abstract. Agrochemicals Division National
Meeting, American Chemical Society, Miami Beach, Fla., April 28-May 3.
9. Grosscurt, A. C. 1978. Pestic. Sci. 9:373.
10. Cohen, E., and J. E. Casida. 1982. Pestic. Biochem. Physiol. 17: 301.
11. Janes, N. F., ed. 1985. Recent Advances in the Chemistry of Insect Control. London:
Burlington House.
12. Fukuto, T. R. 1984. ACS Symposium Series, No. 255. Washington, D.C.: American
Chemical Society, pp. 87-101.
13. Sakai, M. 1983. Abstracts. 5th International Congress on Pesticide Chemicals, IIa-2,
Kyoto, Japan.
14. Bowers, W. S. 1985. Pp. 53-72 in Recent Advances in the Chemistry of Insect Control.
15. Miyakado, M., I. Nakayama, A. Inoue, M. Hatakoshi and N. Ohno. 1985. J. Pestic. Sci.
10:11.
16. Lay, S. V. 1985. Pp.305-322 in Recent Advances in the Chemistry of Insect Control.
17. Agrios, G. N. 1978. Plant Pathology, 2nd ed. New York: Academic Press.
18. Dulmage, H. T. 1981. Insecticidal activity of isolates of Bacillus thuringiensis and their
potential for pest control. P. 193 in Microbial Control of Pests and Plant Diseases
(1970-1980), H. D. Burges, ed. London: Academic Press.
19. Kolata, G. 1985. Genetically engineered organisms in agriculture. Science 229
(5 July):34.
20. McGaughey, W. H. 1985. Insect resistance to the biological insecticide Bacillus
thuringiensis. Science 229(12 July): 193-195.
21. Burges, H. D. 1981. Safety, safety testing and quality control of microbial pesticides. P.
737 in Microbial Control of Pests and Plant Diseases (1970-1980).
22. Roe, M. R., P. Y. K. Cheung, B. D. Hammock, D. Buster, and R. A. Alford. 1985.
Endotoxin of Bacillus thuringiensis var. israelensis broad spectrum toxicity and neural
response elicited in mice and insects. Pp. 279-292 in Bioregulators for Pest Control,
P. A. Hedin, ea., ACS Symposium Series 276.
23. Ignoffo, C. M., and T. L. Couch. 1981. The nucleopolyhedrosis virus of Heliothis
species as a microbial insecticide. P. 330 in Microbial Control of Pests and Plant
Diseases (1970-1980).
24. Lewis, F. B. 1981. Control of the gypsy moth by a Baculovirus. P. 363 in Microbial
Control of Pests and Plant Diseases (1970-1980).
25. Cunningham, T. C., and P. F. Entwistle. 1981. Control of Sawflies by Baculovirus.
379 in Microbial Control of Pests and Plant Diseases (1970-1980).
P.
26. Sun, M. 1985. Biotechnology focus on viruses. Science 228 (14June):129~1295.
27. Ferron, P. 1981. Pest control by the Fungi Beauveria and Metarhizium. P. 465 in
Microbial Control of Pests and Plant Diseases (1970-1980).
Representative terms from entire chapter:
pesticide innovation
