DOI: 10.1039/b308497n Pest ic ide Outlook – August 2003 155

This journal is © The Royal Society of Chemistry 2003

IntroductionThe 3rd PPCPS was held in Hilton Hawaii Village, June 1-4,2003. The lectures and posters were divided into twosections: Topic A covered New Discoveries and Topic B,Environmental Fate and Safety Management. TheConference Chairs were N.K. Umetsu (Otsuka Chem., JP)and B. Cross (Barrington Cross Consulting, USA) and theprogram chairs were H. Ohkawa (Kobe Univ., JP) and J.M.Clark (Univ. MA, USA). The proceedings will be publishedin due course in two volumes (A and B) and will comprise ofall of the platform lectures (including poster presentations),along with three posters each from Topics A and B, thatwere awarded prizes for being considered the best.

The opening, plenary lectures were given by S. Oba(Sumitomo, JP) and H. Strang (Bayer, USA). In the first, thespeaker stressed the need for a continual supply of novel andsafer products to protect not just food crops with attendantenvironmental safety but also to protect humans andlivestock from tropical diseases, which appear to be creepinginto more temperate regions due to global warming. In thisregard, he was pleased to mention a breakthrough bySumitomo (described in detail later by T. Itoh) in the form ofa long-lasting insecticide net (LLIN) for mosquito control.This net was impregnated with pyrethroids and retainedeffectiveness even after 4 washings, thus satisfying a WHOcriterion for a LLIN. In the second talk, it was stressed thatpesticides were making food cheaper and better and that weshould be doing more to convince the authorities and thegeneral public about these and other benefits of pesticides.He talked about the “phantom risks,” first used by BruceAmes, of minute residues of pesticides in foods comparedwith the enormous benefits of having an abundant andcheap supply of foods available.

Combinatorial chemistryFive lectures and several posters on combinatorial chemistrydescribed the intense efforts being devoted to this promisingapproach for agrochemical discovery. At Bayer, in the last 5years, >500,000 new compounds have been synthesized,covering >230 different types of chemistry, according to M.Es-Sayed (Bayer, Germany). Each compound is profiledbased on over 30 molecular descriptors, including clogP, M.Wt., polar surface area etc. A novel approach to producingcompound libraries was described by K. Fukase (Osaka

Univ., JP). This was known as SAS or synthesis based onaffinity separation and using this method allowed for theseparation of only those compounds having the desirablemolecular properties; undesirable impurities etc. werewashed off. In two lectures from Dow AgroSciences, firstJ.M. Ruiz described how synthetic and computationalchemists collaborated at an early stage to bias the selectionof input parameters. J.A. Turner then described how thecurrent trend in combinatorial chemistry is to move awayfrom producing millions of compounds but instead,producing highly focussed libraries of only a few hundredchemicals. An example was a search for a post-emergentherbicide with systemicity. Phloem mobility is oftenassociated with weak acidity (pKa~3 – 6) and moderatelipophilicity (logP<3). Therefore, pyridine carboxylates withonly these attributes were chosen for this particularsynthetic strategy. At DuPont, R.J. Pasteris (Newark, USA)described how combinatorial chemistry had made contribu-tions to lead discovery and optimization in fungicide,herbicide and insecticide development programs. Onereaction type, consisting of a 3-compartment system ofanilines, ketones and electron-deficient olefins, led to thesynthesis of miticidal 1,4-dihydropyridines approaching thelevel of commercial activity. In a mixture synthesis designedto increase throughput, inhibitors of melanin biosynthesiswere targeted. The result was a new, potent inhibitor ofscytalone dehydratase (I50 ~ 1nM), a key enzyme in riceblast pathogenesis. In a solid phase synthesis approach, N-azolylphenoxypyrimidine inhibitors of carotenoid biosyn-thesis were optimized. Using a fourth approach, librarydesign tools, a novel powdery mildew fungicide wasdiscovered, an oxadiazaspirodecane.

FormulationFive papers addressed aspects of improving formulations forimproved delivery and reduced worker exposure. T. Sato(Monsanto, JP) discussed surfactant properties, C.M. Elsik(Huntsman, USA) reviewed aspects of formulationtechnology leading to innovative products, D. Kishi (MitsuiChem., JP) described controlled-release formulations for ahighly water-soluble neonicotinoid insecticide in rice, M.Inoue (Sumitomo, JP) described a yellow tape impregnatedwith pyriproxyfen for the control of whiteflies in tomatoand W. Taylor ((Hardi International, Denmark) discussedinternational efforts to improve efficacy while reducingworker exposure, using tropical crop sprayers as anexample.

THIRD PAN PACIFIC CONFERENCE ON PESTICIDE SCIENCE†

Derek Gammon reports on some of the many topics discussed at a conference in Honolulu, Hawaii, from 1–4 June 2003

CONFERENCE REPORT

† The views expressed are the author’s and do not necessarily reflect thepolicies of California EPA

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MetabolismThere were six lectures on pesticide metabolism, startingwith R.M. Zablotowicz (USDA, USA) who reviewedcomparative metabolism in plants and microbes. K. Ohyama(IET., JP) described the metabolism of methoxychlor inprecision-cut liver slices from rat, mouse, quail and trout.Some differences in the patterns of O-demethylation wereobserved. C. Preston (Univ. Adelaide, Aus) reviewed themetabolism of herbicides by weeds and crop plants, acommon mechanism that is often responsible for bothselectivity and weed resistance. The metabolism of thefungicide diethofencarb in grapes was described by T.Fujisawa (Sumitomo, JP). He demonstrated that a novelthiolactic acid conjugate was formed. Molecular biologicalapproaches to the soil degradation of pesticides weredescribed by D.E. Crowley (UC Riverside, USA) leading tothe prospect of new approaches to the phytoremediation ofsoils. The role of herbicide safeners in increasing GSTenzymes to reduce herbicide levels was discussed by D.E.Riechers (Univ IL, USA). It appears that GST and conjugatesmay accumulate in the vacuoles of plants.

GM cropsVarious issues surrounding GM crops were described,starting with M.S. Bleeke (Monsanto, USA). She reviewedthe genetic modifications in glyphosate-tolerant crops. Oneof two genes is incorporated into the genome of these crops:a gene for EPSPS (5-enolpyruvyl-shikimate-3-phosphatesynthase, the target enzyme inhibited by glyphosate) whichis resistant to glyphosate or a gene for GOX (glyphosateoxidoreductase, the enzyme that metabolizes glyphosate). Inone crop, canola, both genes were incorporated. It wasshown that the metabolism of glyphosate was qualitativelyidentical in conventional and genetically modified crops. It isthus suggested that there are not anticipated to be anytoxicity concerns with such modified crops, when they arecompared with conventional crops. By incorporating genescoding for two human cytochrome P-450 monoxygenasesinto rice, H. Kawahigashi (NIAS., JP) found that ricemetabolized various herbicides more rapidly than wildtyperice, giving the same metabolites. The safety assessment ofcorn derived from gene-modified and conventional cropswas described by W.P. Ridley (Monsanto, USA). In chickensand rats, significant differences were not found in feedperformance endpoints and toxicological parameters. ILSI(Washington D.C, USA) have established a website tomonitor biological and nutritional parameters in variousfood crops (http://www.cropcomposition.org). Current andfuture issues regarding the development of transgenic cropsin Japan were discussed by K. Oono (Kobe Univ., JP). Inrice, glyphosate-tolerant crops developed by Monsanto wereblocked by pressure groups. Thus future efforts will be madein safety assessment and consumer acceptability oftransgenic crops. The issue of the toxicity of Bt corn pollento monarch butterfly larvae was revisited by M.K. Sears(Univ. Guelph, Canada). He showed, in a series of controlledfield experiments, that although there might be a theoreticalrisk to these non-target insects, in practice, there was a verylow probability of an adverse effect at the population level.

A transgenic plant system for monitoring types of endocrinedisruptors was described by H. Inui (Kobe Univ., JP). Genesincorporated into Arabidopsis plants included those for thearylhydrocarbon receptor (AhR) and an estrogen receptor(ER). It was shown that 20-methyl cholanthrene could bedetected in environmental samples at 2 ppb and, forestradiol, at 0.001 ppb.

Medical entomologyAspects of medical entomology were discussed in a series oflectures. A combination of factors has caused a worldwideupsurge in the incidence of several vector-borne diseases andthis topic was reviewed by J.D. Edman (UC Davis, USA).Examples include malaria, which is at epidemic levels in 90countries, and causing 1.5 to 2 million deaths per year,mostly children. The range is expanding and in 2002, therewas an outbreak in Virginia, USA. The continuing epidemicof West Nile virus encephalitis and the dengue feveroutbreak in Hawaii recently are further examples ofmosquito-borne diseases affecting the USA. Also, Lymedisease, a tick-borne infection, has become widespread sincethe 1980s. In the tropics, Leishmaniasis, transmitted by asandfly, affects ~10 million people and there is littleimprovement observed. However, some success has beenachieved with oncocerciasis (River blindness) and lymphaticfilariasis e.g. elephantiasis, using ivermectin. Also, Chagas’disease in Latin America has been reduced by usingpyrethroids in and around peoples’ homes to control thehemipteran vectors (Schofield, 1977). A program to controldengue fever was described by J. Jones (US Army, Thailand).This disease, transmitted by mosquitoes, is more prevalentthan ever before, with 50 – 100 million cases and 24,000deaths per year. Most people over 15 years of age living inaffected areas of the world have become immune, but not sofor recent arrivals, such as the US Army. Larvicides usedincluded Bt israeliensis and pyrethrins were used asadulticides, usually with cyhalothrin or deltamethrin addedfor residual control.

ResistanceThere were nine lectures on the topic of resistance, mostlyon insects, but also on herbicides and fungicides. J.M. Clark(Univ MA, USA) described the problem of pediculosiscaused by the human head louse. A technique of DNAgenotyping has been developed which enables criticalmutations to be determined in key genes for individualinsects. An insecticide resistance action committee (IRAC) isproposed for the Pacific region, according to C.Staetz (FMCCorp., USA). Resistance management in the diamond-backed moth (Plutella xylostilla) in Hawaii was described byR.F.L. Mau (Univ. HI, USA). Enamectin benzoate,indoxacarb and spinosad had been used and resistance tothe latter only had been observed in the field. Although B.t.resistance has been obtained in the laboratory by selection,it has not emerged as a problem in Arizona B.t. cotton in thefield, according to T.J. Dennehy (Univ. AZ, USA). It ispossible that fitness costs associated with the resistance areinsurmountable in the field. Careful annual monitoring and

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refuges remain in place to avoid resistance development.Head louse resistance in Japan was assessed by T. Tomita(NIID., JP), where d-phenothrin has been the sole registeredcontrol agent since 1981. Many of the same point mutationsin gene(s) for the sodium channel were found as had beenreported in USA and UK populations of pyrethrum andpermethrin-resistant lice. Weeds resistant to ALS (acetolac-tate synthase) inhibiting herbicides are a worldwide problemand T. Shimizu (Kuniai Chem., JP) described efforts todefine the genetic mutations responsible in 12 resistantweeds in Japan. It was interesting that some of the mutantsshowed greatly divergent resistance factors for the four mainclasses of commercial herbicides acting on ALS: the sulfony-lureas, imidazolinones, triazolopyrimidines and pyrimidinylcarboxylates. H. Shibaike (NIAES., JP) described thegenotypes of specimens of a species of annual rice paddyweed. He was able to suggest ways in which resistance toALS inhibitors became widespread. Rice blast control hasbeen obtained using two classes of melanin biosynthesisinhibiting (MBI) fungicides: reductase inhibitors anddehydratase inhibitors, according to H. Sawada (Bayer, JP).The former have not shown signs of resistance in over 20years of use but the latter, after only three seasons. Amolecular diagnosis showed that a small number ofmutations were responsible for reduced MBI control. Thus,monitoring could be conducted on geographicallywidespread populations and differences established in thegenetic profile along with resistance to the MBI(s). A reviewof resistance management strategies for fungicides in Japanby H. Ishii (NIAES., JP) stressed the need to determine modeof action for fungicides because this was the main issue inresistance development in agriculture.

Analytical techniquesAnalytical techniques used for residue analysis in crops andenvironmental samples were reviewed by J.N. Seiber (USDA,USA). Multi-residue methods in food samples in Japan weredescribed by F. Satoh (JFRL., JP). Using LC/MS, 50pesticides (plus six metabolites and two isomers) in 10classes could be detected simultaneously, at 0.02 ppm. Y.Akiyama (Hyogo PIPHE., JP) provided a detaileddescription of pesticides in domestic and imported foodsover a 7-year period, 1995-2002. Organophosphates andfungicides were the most commonly detected. In domesticvegetables, only 4 out of 701 samples were violations (aboveMRL). Over 50% of these samples had residues below 10%of the MRL. Imported vegetables also had a low level ofviolations. Overall, the results appeared to be similar tothose obtained in the USA and EU.

Mode of actionThere were six lectures on mode of action topics. AtDuPont, the HTS (high throughput screen) procedure islinked to site of action analysis, according to S. Gutteridge(USA). The establishment of a target site early in the processleads to more effective discovery of new leads. A 3-D modelhas been developed by A. Ito (Kureha Chem., JP) of theinteraction between CYP51 (sterol 14-alpha demethylase)

and azole fungicides, such as metaconazole, which inhibitthis enzyme. Several classes of natural products with knownor anticipated activity as herbicides were described by S.O.Duke (USDA, USA). H. Matsumoto (Univ. Tsukuba, JP)discussed the mechanism of inhibition of HPPD by thepyrazole herbicides. By analyzing the treated plant extractsusing HPLC, it was established that pyrazolate andpyrazoxyfen are converted into a common active metabolite,the hydroxypyrazole. A novel target for nematicides wasdemonstrated by S.C. Trowell (CSIRO, Aust.). Using C.elegans as a model, it was shown that an excitatory receptor(5HT3-like) in the pharynx could be disrupted, leading tomortality. The molecular pharmacology of the neonicotinoidreceptor (nAChR) has been studied in great detail, and wasdescribed in a lecture and two posters by K. Matsuda (KinkiUniv., JP). The role of individual amino acid residues in thebinding of agonists is being explored in an effort to developa molecular understanding of the selective toxicity ofnitromethylene neonicotinoids to insects vs. mammals.

Natural productsSix lectures were given on the subject of natural productleads for pesticides. J. Coats (Iowa State Univ., USA)described his latest work on insect repellents, a veryimportant field given the current epidemics of mosquito-borne diseases. Several of these plant-derived sesquiterpeneshave been identified and found to possess activitycomparable to DEET. In a similar area, M.B. Isman (Univ.BC, Can.) described the identification of components ofrosemary oil along with their toxicity to insects. Amechanism for host plant location identification by motilezoospores of a fungal phytopathogen was described by S.Tahara (Hokkaido Univ., JP). An attractant chemical,cochliophilin, is released by the roots of spinach and sugarbeets and the zoospores are able to swim through the soilwater to the plant. In a related area, fungal extracts werebeing assayed for nematicidal properties by Y. Kimura(Tottori Univ., JP) and some interesting chemistrydiscovered. The advantages of using ecological theory in theselection of natural products for automated screening weredescribed by M.R. Berenbaum (Univ. IL, USA). The identifi-cation and synthesis of several lepidopteran sex pheromoneshas been accomplished by T. Ando (Tokyo Univ., JP).Progress is also being made in elucidating the biosyntheticpathway(s) in female moths, with a view to eventuallyfinding a way to disrupt it.

Environmental fateEnvironmental fate and safety management were addressedin three lectures. Methods used to measure the movement ofagrochemicals in air were described by V.R. Hebert (WAState Univ., USA). These included modeling field studieswith laboratory simulations and special attention was beinggiven to organophosphates, organochlorines and dinitroani-line herbicides. A description of herbicide run-off problemsfrom residential uses was given by J.J. Gan (UC Riverside,USA). He particularly focussed on 2,4-D and dicamba andshowed that large differences in persistence and run-off

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potential occur as a function of ground coverage. MHayatsu (Shizuoka Univ., JP) described experiments inwhich soil microbial populations were raised to metabolizefenitrothion and carbaryl. The genes for enzymes involvedwere sequenced as a guide to identification of the microbialspecies involved.

Environmental risk assessmentEnvironmental risk assessment was considered in fivelectures. Examples of four modeling scenarios were providedby W.M. Williams (Waterborne Environ. Inc., USA)describing pesticide movement in various matrices. Themain goal of such efforts was for conducting ecological riskassessments. The issue of the return of rice paddy watercontaining herbicides to rivers and lakes and its impact onalgae were described by S. Ishihara (NIAES., JP). Since2000, toxicity tests on algae have been required in Japan inorder to reduce the chances of ecological damage. Anecological risk assessment of the triazine herbicide atrazinewas described by K.R. Solomon (Univ. Guelph, Can.). Usinga weight-of-the-evidence approach, there was no indicationof population-level effects on frogs. Endocrine effects couldnot be associated with increased atrazine levels in laboratoryor the field. This work was partially funded by Syngenta andit will be interesting to see whether or not the conclusionsare borne out by the USEPA committee that is currentlyconducting a review on the same subject. Estimates ofincreased cancer risk following pesticide use in Canada havebeen calculated by L. Ritter (Univ. Guelph, Can.). A particu-larly important part of this determination has been theestimation of exposure. Y Matoba (Sumitomo Chem., JP)has compared three commonly used models for estimatingoccupational exposure i.e. PHED (USA/Canada), POEM(UK) and the BBA model (Germany). It was pointed out thatnew application techniques or products may require highertier exposure studies to be conducted.

PostersIn addition to the lectures described above, a total of 14poster authors gave oral presentations of ca. 15 min.duration.

In section A: the search for possible herbicides in secondarymetabolites of fungi was described by H. Araya (NIAES.,Japan). Y. Ozoe (Shimane University, Japan) described phar-macological properties of the insect tyramine receptor, a

possible novel target site for insecticides. The insect moltinghormone receptor, was characterized in vitro by C.Minakuchi (Kyoto University, Japan) using[3H]ponasterone. A novel toxin (mol. wt.. = 578) producedby Streptomyces spp. was identified in potato russet scabtissue by M. Natsume (Tokyo, Japan). Plant growthregulators and herbicides based on the hormones (+)-absicicand (-)-jasmonic acids were described by H. Kiyota (TohokuUniv., Japan). The development of a new class of insecticidesacting on the GABA-activated chloride channel wasdescribed by J.W. Lyga (FMC Corp., USA). The startingpoint for the series was a chlorophenyl-methyl-trifluoro-methylpyrimidindione and the assay used was the [3H]-EBOB radioligand. The miticidal and insecticidal activity ofa series of novel 2-substituted-3-trifluoro-methylquin-oxalines was described by Y. Fukushima (Otsuka Chem.,Japan).

In section B: a rapid method for analyzing fipronil (and its 3major metabolites) was described by S. Campbell (Universityof Hawaii, USA). The method could be used for soil samplesas well as for cotton gauze. Models to predict the volatiliza-tion of pesticides from bare soil surfaces have beendeveloped by S.R. Yates (USDA, USA). Two computerprograms that have been developed to estimate dietaryexposure to pesticides were compared in a dietary riskassessment for methamidophos by D.W. Gammon(California EPA, USA). In addition, comparisons were madebetween USEPA and California EPA methods. The grassweed Lolium rigidum has developed multiple resistance toherbicides and H. Tsujii (Kobe University, Japan) describedhow a family of P450 enzymes was induced in resistantstrains. One particular group, the CYP71 gene family,appeared to be expressed frequently. The occurrence ofglyphosate-resistant horseweed in Tennessee was announcedby T.C. Mueller (University of Tennessee, USA), indicatingthat alternative control measures may be needed. A methodwas described for measuring plant cuticular penetrationwithout using radiolabeled pesticides by Y. Maekawa(Nippon Soda, Japan). Another approach to measuringplant uptake of xenobiotics using Fick’s first law of diffusionwas described by W.A. Forster (Forest Research, NewZealand).

ReferenceSchofield, C.J. (1997). Control of Chagas’ disease, Pesticide

Outlook, 8(3), 12

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