environmental chemistry and toxicology laboratory, university of california at berkeley

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DOI: 10.1039/b006237p Pesticide Outlook – August 2000 1 3 5 This journal is © The Royal Society of Chemistry 2000 The Environmental Chemistry and Toxicology Laboratory (ECTL) at the University of California (U.C.), Berkeley, founded and mentored by Professor John E. Casida, is recognized internationally for a multitude of significant contributions to understanding the mode of toxic action for a structurally diverse variety of pesticides and molecular targets. This brief profile considers the ECTL history, scientific advances and. idiosyncrasies which may foster its success (for an alternate perspective, see Hammock and Casida, 1998). History Insect toxicology has a rich history at U.C. Berkeley. The first third of the 1900s featured inorganic and botanical insecticides. The next third was led by Professor William Muriece Hoskins who taught the first course anywhere in insect toxicology and emphasized insect biochemistry as a basis for exploring the toxic interactions between chemicals and insects. The current era with Professor Casida began in 1964 with the immigration of his research group from the University of Wisconsin at Madison to U.C. Berkeley. Funding was largely provided by the National Institute of Environmental Health Sciences through an unusual single- principal-investigator Program Project, a unique marriage of chemistry and toxicology in the basement of Wellman Hall. The composite funding of 5–6 separate (but related) subproject research areas allowed synergistic interactions between synthetic chemists and biochemists with easy access to state-of-the-art instrumentation (particularly NMR and mass spectrometry). In early investigations the metabolism of insecticides was the foundation to unravel mechanisms for bioactivation and degradation involving, e.g., cytochrome P450, esterases and glutathione S-transferases. The preferred model insect was the housefly, established in colony by Professor Hoskins and still used. Since most investigations emphasized fundamental science, the more complicated rearing of major economic pests (e.g. lepidopterans) was not required. Synthetic chemists have always been essential in ECTL research since they provide the authentic candidate metabolites, as well as radiolabeled pesticides and probes. In 1976 the mission of the research was formalized as the Pesticide Chemistry and Toxicology Laboratory (PCTL). This designation lasted until 1994 when greater emphasis on environmental chemistry suggested mutation to ECTL. Programmatic changes also occurred with a greater attention to toxicology, particularly of mammals. The mouse became a primary model to study problems with relevance to human health. Likewise, the numerical balance of ECTL scientists shifted from chemistry to toxicology and new expertise was aquired in cell culture for model systems to explore toxicological mechanisms. A more pragmatic basis for academic funding meant less justi- fication to synthesize better insecticides (that job was for industry), but preparation of potent chemical probes was acceptable if they aided in the elucidation of toxic mechanisms in mammals (or to some extent selective toxicity toward insects). ENVIRONMENTAL CHEMISTRY AND TOXICOLOGY LABORATORY, UNIVERSITY OF CALIFORNIA AT BERKELEY Gary Quistad from the laboratory provides the history, scientific advances and philosophy of this unique research group PROFILE JOHN CASIDA APPOINTMENTS 1954–1963 Assistant, Associate, Full Professor of Entomology, University of Wisconsin, Madison 1964–present Professor of Entomology and Director, Environ- mental Chemistry and Toxicology Laboratory, University of California, Berkeley 1996–2001 William Muriece Hoskins Chair in Chemical and Molecular Entomology, UC Berkeley HONOURS AND AWARDS 1991 Member of the National Academy of Sciences (USA) 1993 Wolf Prize in Agriculture 1994 Founders Award, Society of Environmental Toxicology and Chemistry 1995 Koro-Sho Prize, Pesticide Science Society of Japan 1997 Honorary Member, Society of Toxicology 1998 Foreign Member of the Royal Society (UK) Published on 01 January 2000. Downloaded by University of Pittsburgh on 31/10/2014 20:00:03. View Article Online / Journal Homepage / Table of Contents for this issue

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Page 1: Environmental Chemistry and Toxicology Laboratory, University of California at Berkeley

DOI: 10.1039/b006237p Pest ici de Outlook – August 2000 1 3 5

This journal is © The Royal Society of Chemistry 2000

The Environmental Chemistry and Toxicology Laboratory(ECTL) at the University of California (U.C.), Berkeley,founded and mentored by Professor John E. Casida, isrecognized internationally for a multitude of significantcontributions to understanding the mode of toxic action fora structurally diverse variety of pesticides and moleculartargets. This brief profile considers the ECTL history,scientific advances and. idiosyncrasies which may foster itssuccess (for an alternate perspective, see Hammock andCasida, 1998).

HistoryInsect toxicology has a rich history at U.C. Berkeley. Thefirst third of the 1900s featured inorganic and botanicalinsecticides. The next third was led by Professor WilliamMuriece Hoskins who taught the first course anywhere ininsect toxicology and emphasized insect biochemistry as abasis for exploring the toxic interactions between chemicalsand insects. The current era with Professor Casida began in1964 with the immigration of his research group from theUniversity of Wisconsin at Madison to U.C. Berkeley.Funding was largely provided by the National Institute ofEnvironmental Health Sciences through an unusual single-principal-investigator Program Project, a unique marriage ofchemistry and toxicology in the basement of Wellman Hall.The composite funding of 5–6 separate (but related)subproject research areas allowed synergistic interactionsbetween synthetic chemists and biochemists with easy accessto state-of-the-art instrumentation (particularly NMR andmass spectrometry).

In early investigations the metabolism of insecticides wasthe foundation to unravel mechanisms for bioactivation anddegradation involving, e.g., cytochrome P450, esterases andglutathione S-transferases. The preferred model insect wasthe housefly, established in colony by Professor Hoskins andstill used. Since most investigations emphasized fundamentalscience, the more complicated rearing of major economicpests (e.g. lepidopterans) was not required. Syntheticchemists have always been essential in ECTL research sincethey provide the authentic candidate metabolites, as well asradiolabeled pesticides and probes. In 1976 the mission ofthe research was formalized as the Pesticide Chemistry andToxicology Laboratory (PCTL). This designation lasted until1994 when greater emphasis on environmental chemistrysuggested mutation to ECTL. Programmatic changes alsooccurred with a greater attention to toxicology, particularlyof mammals. The mouse became a primary model to study

problems with relevance to human health. Likewise, thenumerical balance of ECTL scientists shifted from chemistryto toxicology and new expertise was aquired in cell culturefor model systems to explore toxicological mechanisms. Amore pragmatic basis for academic funding meant less justi-fication to synthesize better insecticides (that job was forindustry), but preparation of potent chemical probes wasacceptable if they aided in the elucidation of toxicmechanisms in mammals (or to some extent selectivetoxicity toward insects).

ENVIRONMENTAL CHEMISTRY AND TOXICOLOGY LABORATORY,UNIVERSITY OF CALIFORNIA AT BERKELEY

Gary Quistad from the laboratory provides the history, scientific advances and philosophy of this uniqueresearch group

PROFILE

JOHN CASIDA

APPOINTMENTS1954–1963 Assistant, Associate, Full Professor of Entomology,

University of Wisconsin, Madison1964–present Professor of Entomology and Director, Environ-

mental Chemistry and Toxicology Laboratory,University of California, Berkeley

1996–2001 William Muriece Hoskins Chair in Chemical andMolecular Entomology, UC Berkeley

HONOURS AND AWARDS1991 Member of the National Academy of Sciences

(USA)1993 Wolf Prize in Agriculture1994 Founders Award, Society of Environmental

Toxicology and Chemistry1995 Koro-Sho Prize, Pesticide Science Society of Japan1997 Honorary Member, Society of Toxicology1998 Foreign Member of the Royal Society (UK)

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Page 2: Environmental Chemistry and Toxicology Laboratory, University of California at Berkeley

Scientific achievementsThe success of the ECTL in insect toxicology and insecticidechemistry is probably unparalleled by any single academiclaboratory. ECTL investigations have produced over 650publications and 30 patents, involving more than 210graduate students, postdoctoral fellows, and visitingscholars. Most of these investigators still work in pesticide-related fields and many are distinguished worldwide.Citation frequency is one measure of scientific impact. Usingdatabases from the Institute for Scientific Information, theECTL has 15 publications with over 100 citations. Thegeneral theme of the most cited papers is understanding themechanisms of selective pesticidal action, particularly asthey relate to metabolic bioactivation. The most citedpublication (>566) (Squires et al., 1983) describes thediscovery of [35S]tert-butylbicyclophosphorothionate (TBPS)as a radioligand useful in probing the molecular architectureof the γ-aminobutyric acid (GABA)-gated chloride channel,the site of action for important chlorinated hydrocarboninsecticides such as lindane, toxaphene and α-endosulfan.Other high-impact publications involve characterization ofthe calcium-activated calcium channel using the botanicalinsecticide ryanodine, metabolism by mixed functionoxidases (organotin compounds and synergists), and the

mode of selective action (pyrethroids with two types ofeffects, tri-o-cresylphosphate conversion to an activatedcyclic metabolite, dichloroacetamide herbicide antidotecausing an increase in glutathione and its transferase, andthiocarbamate sulfoxides as potent, selective, biodegradableherbicides).

Analysis of “citations per year” is a method of evaluatingthe impact of more recent investigations. Since 1985 ninepapers from ECTL have been cited an average of more than5 times per year and each involves radioligand binding toreceptor proteins. The two most cited (12–13 per year) ofour recent papers report advances in understanding theryanodine receptor (solubilization, characterization;mechanism of sensitivity and intensity modulation bymagnesium, caffeine and adenine). Our second most citedarea involves 1-methyl-4-phenylpyridinium ion (MPP+)i n t e r a c t i o n w i t h t h e r o t e n o n e b i n d i n g s i t e o fNADH:ubiquinone oxidoreductase. Similar interest hasbeen evoked by publications on protein phosphatase (identi-fication as the cantharidin/endothall binding protein; andcharacterization of the site); the nicotinic acetylcholinereceptor (high-affinity binding of [3H]imidacloprid ininsects; [125I]azidonicotinoid photoaffinity labeling of theinsecticide binding subunit from Drosophila) , and the

136 Pest ic ide Outlook – August 2000

PROFILE

INSECT TOXICOLOGY 2000

The conference organized by the ECTL was held from July 17–19, 2000 at the Clark Kerr Campus of the University of California at Berkeley,emphasizing insects in a toxic environment. Participants (113) came from 12 countries, with Japan contributing the major foreign delegation(11). The impact of the ECTL on insect toxicology was evidenced by the 35 alumni included among attendees. The scientific program featured34 oral presentations over 2.5 days and 18 posters. A major theme of most of the research presented was understanding the molecular modeof action for insecticides at the voltage-gated sodium channel, nicotinic acetylcholine receptor and GABA-gated chloride channel. Insectresistance to insecticides was explained relative to target protein mutations, with metabolism providing selective toxicity. Several papersconsidering ecdysone agonists, the insect cuticle as a vulnerable site, and alternatives to chemical control (baculoviruses, B. thuringiensis) werereviewed, as well as ways in which insecticidal natural products (ryanodine, rotenone) have facilitated the understanding of basic biochemicalmechanisms. The conference concluded with a discussion of the status and destiny of insect toxicology as a discipline. It is clear that academicfunding applications should be tailored to the needs expressed by available sources, emphasizing benefits to human health and the environment.

Attendees at Insect Toxicology 2000. John Casida is sixth from the right on the front row. Gary Quistad, the author of thisarticle, is seventh from the right in the front row.

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Page 3: Environmental Chemistry and Toxicology Laboratory, University of California at Berkeley

GABAA receptor [tert-butylbicycloorthobenzoate (TBOB) asa new radioligand; modulation of chloride influx by bicy-cloorthocarboxylates, bicyclophosphorus esters, polychloro-cycloalkanes and other cage convulsants].

The ECTL philosophyCertain facets of the ECTL are unique relative to most otherresearch laboratories. Grant funding is viewed as anenabling act to do creative science; although specific aimsare satisfied, they do not limit the direction of research.Fundamentally intriguing questions are posed, or completelydifferent approaches to old problems are sought, thenmeaningful experiments are designed to test the hypothesesin as many ways as possible, particularly looking for thetotally unexpected—the new discovery. The aim (policy) isto maximize the productivity of investigators by emphasis

on individuality, combined with leadership in the directionof alternative proposals or explanations. Many ECTLachievements are tied closely to optimal usage of theNational Tritium Labeling Facility, which is close to thecampus and essential for synthesis of radioligands andphotoaffinity probes.

The construction of manuscripts is an adventure inmeticulous detail . The laboratory always has 5–10manuscripts in progress. All details are rigorously checkedand rarely will a final manuscript involve less than 5 drafts.This allows time to “digest” the results and avoid mistakesin the final version.

While ECTL science centers around the chalkboard andchemical structures, the group culture includes “Gripes”, anaffectionate term for the ECTL lunchtime group meetingwhich is held weekly with religious zeal. It is a blend ofscience, food and, yes, sometimes complaints (usuallyconstructive). Science also provides an opportunity forsocializing, evidenced by symposia on Pesticides and Alternatives (Crete, 1989). and Insect Toxicology (Berkeley,2000). Christmas and theme (e.g. Oktoberfest) parties at theCasida home are about the only occasions largely (but notentirely) devoid of science. Even there science lingers by wayof the many guests who have inscribed their names ontoKati Casida’s wooden studio floor with felt pens. Science isan addiction in the ECTL and inspiration often is followedby dated notes concluding with “ Thanks, see John”.

ReferencesHammock, B. D.; Casida, K. F. (1998) For the fun of science: a

discussion with John E. Casida. Arch. Insect Biochem. Physiol.,37, 1–7.

Squires, R. F.; Casida, J. E.; Richardson, M.; Saederup, E. (1983)[35S]tert-Butylbicyclophosphorothionate binds with highaffinity to brain-specific sites coupled to γ-aminobutyric acid-Aand ion recognition. Molec. Pharmacol., 23, 326–336.

Pest icide Outlook – August 2000 1 3 7

PROFILE

Gary Quistad is a research toxicologist and has been codirector ofthe ECTL for the last 8 years. The research of this laboratory hasbeen a source of fascination since his undergraduate years withFukuto/Metcalf at U.C. Riverside, followed by 19 years in industry(Zoecon, Sandoz).

ECTL LANDMARK ACHIEVEMENTS

Characterization of:

● Metabolic basis for selective toxicity and environmental fate oforganophosphates, methylcarbamates and pyrethroids

● Mode of action of synergists as inhibitors of mixed-functionoxidases.

● Nicotinic acetylcholine receptor, the target of imidaclopridinsecticide.

● NADH:ubiquinone oxidoreductase, the target of rotenoneinsecticide/piscicide.

● Kynurenine formamidase inhibition as the target for organophos-phate-induced avian teratogenesis.

● Calcium-activated calcium channel with the botanical insecticideryanodine.

● Protein phosphatase 2A as the target of cantharidinvesicant/endothall herbicide.

Discovery of:● Trioxabicyclooctanes and dithianes as potent insecticides.● TBPS and EBOB as probes for the molecular architecture of the

GABA-gated chloride channel.● Tri-o-cresyl phosphate bioactivation to a neurotoxicant lays the

background for understanding organophosphate-induced delayedneuropathy.

EVER THOUGHT OF WRITING AN ARTICLE FOR PESTICIDE OUTLOOK?

The Editor would welcome articles for inclusion in Pesticide Outlook. The aim of the journal is to publish readable up-to-date,interesting articles for a wide audience, which should be understandable without any assumed specialist knowledge. Theyshould have an introduction, a few sections of “meat” arranged to give a logical flow of argument, and end with a conclusionsumming things up and pointing the way forward. Articles can range in length from 500–2000 words. Photographs, diagrams,tables etc. are welcomed to increase the visual appeal of the article.

Please note that contributions are refereed by two members of our Editorial Board and so publication is not guaranteed. Asmall honorarium is paid on publication.

Please send manuscripts to Hamish Kidd, Pesticide Outlook, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF. FAX +44 (0)1223 420247; email [email protected].

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