Pesticides and Health: Myth vs. Realities, a position paper of the ...

Keshet 4 th Graders Begin First:The 4 th grade students and other students new to the Keshet program will have two sessions prior to the 5 th and 6 thgraders. These two sessions will be held on Wednesdays, August 28 th and September 11 th from 4:30 – 6:15 p.m.They allow the 4 th graders and extra few sessions to review their skills from 3 rd grade, and acclimate to Wednesdayafternoons. The 4 th grade students will continue meeting as a separate group until November 6 th , when they will beassigned to a specific color group of mixed grades.Keshet First Night Colors:5 th and 6 th graders should wear their Keshet color on the first night of class, Wednesday, September 18 th . Unlessotherwise notified, Keshet students return to the same color team as last year.Keshet Parent Orientation:There will be an important Keshet Parent Orientation on Wednesday, October 2 nd from 5:30 p.m. – 6:15 p.m.Worship will begin at 5:30 p.m. this evening, and following worship, information will be shared regarding the Keshetprogram and parent responsibilities. Additionally, parents will have the opportunity to meet the teachers in theirclassrooms.Sorting Kippah & Chag ha Siddur:On Wednesday, November 6 th , we’ll begin tefillah at 5:30 p.m., and our 4 th graders and new students will receivetheir own siddurim and be notified which color group they are joining. Parents are encouraged to join their childrenat worship every week, and to particularly be in attendance for this Sorting Kippah ritual.Keshet Worship:Each week from 5:50 p.m. - 6:15 p.m. Keshet teams reinforce their classroom curriculum by joining for mandatoryworship in the sanctuary. Experiencing the prayers “in action” and in the context of a real service is an importantpart of the learning process. Keshet worship also allows us to encourage greater community between the threedifferent color teams, and provides an opportunity for 6 th grade students to transcend their color groups andcollaboratively lead worship. Each 6 th grader will be randomly assigned a partner and parents will be notified inadvance of this assignment. Student leaders will meet briefly with Rabbi Reice and Linda Matorin-Sweenie beforethey lead worship and will be provided with a “script.” If your student is going to miss Wednesday evening worship,we ask that you notify Marcia Rittmaster and Rabbi Reice in advance. Make up opportunities will be madeavailable.Parents are strongly encouraged to attend Keshet worship as often as possible. At the conclusion of Keshetworship, we will also make important announcements regarding homework, upcoming special events, andrecognition of important milestones for Keshet students. Keshet worship is a required part of the program andattendance is taken at the conclusion of worship, with attendance at worship counting towards the 70% minimumattendance guidelines of our program.Keshet Read-Ins:Students receive Prayer Check books to track their progress in learning the prayers from the morning and eveningworship services. Twice during the year adult volunteers come to listen to students read from their Prayer Checkbooks and sign off prayers for students who read well. The dates for the Keshet Read-Ins are:December 11, 2013April 9, 2014Keshet students will set goals in their teams for each Read-In and their progress will be encouraged by theirteachers. Be sure to ask your Keshet students how they did during the evening in accomplishing their stated goals!Keshet Homework:Because Hebrew homework is particularly critical for the progression of skills, we use a learning resource called Ha-Siddur Sheli (My Prayerbook) that offers on-line support for the student. You and your child can access the websitefor Hebrew reinforcement by going to www.barvazpress.com and clicking on the duck (barvaz in Hebrew). Thiswebsite offers games and activities that go along with our classroom materials, but more importantly students can clickon a particular prayer and read along as a voice recites the prayer line-by-line. Several other websites are available tohelp you and your children learn/reinforce the aleph-bet. Try:http://www.laits.utexas.edu/hebrew/heblang/tutorials/b1tutor/new/recognition.htmlClick on any letter and you'll hear its name while you're looking at it. Keep clicking on the arrow at the bottom rightfor new challenges. The parallel site for vowels ishttp://www.laits.utexas.edu/hebrew/heblang/tutorials/b1tutor/new/vowels.html.8

A Rationale for Confronting Myths about Pesticide Technologyment may not be an insurmountable task. After all,legislatures mandate regulation of the technology.Regulators themselves, therefore, must understandfundamental biochemical principles, as they regulatemany kinds of chemicals.Yet simply educating regulators may not be an effectiveway to dispel misconceptions. Comparisons oflay and expert opinion about chemical hazards in generalrevealed unpredictable disagreements about thehazard and risk of chemical technology among experts(for example, regulators and academic or industry researchersengaged in some aspect of toxicology) thatwere not too different from those expected betweenconsumers and experts (Kraus et al. 1992; Mertz etal. 1998). If there is as wide a divergence of opinionamong experts themselves as that which occurs betweenexperts and consumers, one cannot expect tobe very successful at risk communication unless someof these perceptions are addressed directly. Perhapswithin the technical community itself insufficient attentionhas been paid to “common wisdom” in orderto determine operational misconceptions about pesticidetechnology in general.This report is a response to a need expressed forfactual information among legislative authorities, butit also addresses experts themselves by consideringtenuous the assumption of agreement about the risksof chemical technologies. Our analysis substitutes factualinformation (some fundamental principles of toxicologybased on biochemical concepts, an overviewof properties of modern “reduced risk” pesticides, anda delineation of pesticide benefits to human wellbeing)for misconceptions specifically about pesticidetechnology.To communicate the fundamental principles oftoxicology necessary for appropriately regulating pes-ticide technology, this report will first state misconceptionsor myths about pesticides that can be gleanedfrom a combination of risk perception literature, aswell as examining pesticide stories in the media (Felsot2010). After stating a myth, the reality based onbiochemical principles will be explained. Similarly,misconceptions related to the real benefits of pesticideuse will be answered with examples of how pesticidesactually contribute to protection of human health anda general improvement in wellbeing. Finally, to illustratehow misunderstandings of the nature of toxicologyand epidemiology studies contribute to a skewedconflation of hazard and risk, the report will reviewsome commonly used biodegradable pesticides andattempt to alleviate issues of specific concern. By discussingmisconceptions and realities about pesticidetechnology, and highlighting particular pesticides,this report can provide risk communicators within thebusiness community and government with a strongertechnical basis for discussing pesticide issues.One caveat needs emphasis up front. Argumentspromoting global benefits from pesticide technologiesas they’ve evolved over the past 40 years are not argumentsagainst ensuring that these compounds havelittle risk as they are used. Rather, our regulatory systemfor pesticides has actually been quite precautionary.Ironically, as calls for adoption of a “precautionaryprinciple” in place of a risk assessment process havebegun to permeate governmental regulatory activity,pesticides are arguably the one technology where socalledtenets of this principle are actively practiced.Thus, another objective of this report is to clarifymultiple aspects of pesticide technology that mustbe known if we wish to move past the myth that wehave not properly considered hazards in the midst ofoverwhelming benefits.4

Pesticides with Benefits for All:An Agricultural PerspectiveMyth: Farmers use pesticides for their own economic gain without regard for needor a social responsibility to protect the environment. Pesticides are not needed forfarming, as has been proven by the increasing adoption of organic farming.Agricultural Reality: The Economic PerspectivePesticide and fertilizer use has been recorded sinceancient times, suggesting that ecosystem managementis not a recent cultural attribute. In the context of modernagriculture, the objectives of pesticide use are toincrease production efficiency and yields; reduce thecost of food and, especially, to increase the availabilityof grains, fruits, and vegetables; improve food qualityand losses during transport and storage; improve soilconservation; and ensure a stable and predictable foodsupply (NRC 2000).Pesticide use is widespread on farms, but moreimportantly, different classes of pesticides are differentiallyused (NRC 2000; Padgitt et al. 2000), suggestingthat growers make decisions based on need ratherthan solely on prophylaxis. For example, in the U.S.during 2002 approximately 303 million acres of cropswere harvested, and 95% were treated with some typeof pesticide. However, 64% of the acreage was treatedto control weeds (i.e., herbicide use), 22% to controlinsects (insecticide use), 6% to control diseases andnematodes (fungicide and nematicide use). Another4% of the crop acreage was treated with a plant growthregulator for fruit thinning, growth control, or defoliation(Felsot and Racke 2007).5The proportional use of different kinds of pesticides(i.e., herbicides, insecticides, fungicides, etc.) shows thatfarmers do not monolithically use the chemicals on everyacre. Rather, the data show that use is tied to specificneed. Furthermore, the intensity of specific pesticideclasses also varies significantly by crop. Grains tend tobe disproportionately treated with herbicides, but fruitand vegetables mostly receive insecticide and fungicideapplications (Table I). Farmers use the technologythat controls the pest at hand — but, importantly, useis driven by need as influenced by weather conditions,anticipated and actual pest infestations, and the balancingof costs and returns.The benefits of crop protection chemicals for improvingand protecting crop productivity is difficultto separate from the effects of hybrid seed technologyand other plant breeding advances. Nevertheless,an examination of crop yields relative to land underproduction shows that both types of technologieshave had major contributions. For example, the greatestproportion of U.S. farmland is devoted to cornproduction. A historical examination of area of land,yields, and the introduction of different technologiesover time suggests that insect control (mainly of the

Pesticides with Benefits for All: An Agricultural Perspectivecorn rootworm complex) has greatly enhanced theeffectiveness of hybrid seed technology (Figure 1).Furthermore, the introduction of modern syntheticherbicides facilitated widespread adoption of conservationtillage in the Corn Belt, which in turn greatly reducedthe major cause of environmental degradationin North America—soil erosion and sedimentation inrivers (Pimentel et al. 1995).Perhaps an even more compelling case for the roleof crop protection chemicals, especially fungicidesand fumigants, in crop production efficiency is suggestedby potato production statistics. In 1900, nearly3 million acres of potatoes were harvested, yielding anaverage of 52 cwt/acre (USDA 2005). In 1950, averageyields were 153 cwt/acre. In crop year 2004, 1.2million acres of harvested potatoes yielded an average752 cwt/acre. Surely, advances in plant breeding playan important role in production increases, but by the1950s, fumigants for control of nematodes becamewidely available — nearly coincidentally with theTable 1. Percentage Use of Pesticide Classes on Major CropsDuring Crop Years 2003 or 2004Crop Herbicide Insecticide FungicideCorn 95 29

Pesticides & Health: Myths vs. Realitieswidespread adoption of mineralized fertilizers. But theproduction trends strongly suggest an environmentalbenefit because presently seven times more potatoesare produced per acre than were produced in 1900. Ifone thus extrapolates for other crops that yields haveincreased owing to adoption of modern technologieslike improved breeding using biotechnology andchemical pesticides, then a large benefit is a return offarm land to other uses, such as forests and/or prairiesand conservation of natural areas, as well as residencesfor a burgeoning population.What is more, the aggregate economic benefitsassociated with pesticide use have been subjected tovarious empirical modeling exercises and expressedas the loss of production if pesticides were not used(NRC 2000). Production losses during the mid-1980swere estimated to be as high as 37% of total output(Pimentel et al. 1992). This estimated loss occurreddespite pesticide use, but the estimate seems ratherhigh when assessed against specific crop analyses. Forexample, one of the most destructive pests of potatoes,late blight disease, broke out in the Columbia Basin ofWashington State and Oregon during 1995. Fungicideuse rose from typically two applications per season toas many as 12 ( Johnson et al. 1997). However, yielddifferences between the pre- and post-blight outbreakwere only 4-6 percent. On the other hand, without anymanagement, the blight epidemic could have reducedyields 30-100 percent.Other economic analyses have projected the effecton fresh and processed vegetable and fruit yieldsif pesticide use were reduced 50 percent or simplynot used at all (Knutson et al. 1993). Reductionsin fresh fruit yields were 40 percent and 75 percent,respectively. Substantial reductions were projected ingrain production under conditions of no herbicideuse (Fernandez-Cornejo et al. 1998). Another studyestimated that a total pesticide use ban would requirean additional 2.5 million acres of vegetable and fruitproduction to make up for the yield loss (Taylor1995). Although modeling estimates of the impactsof decreased pesticide use or no use seem large, theactual decrease in yields (and consequent effects onconsumer prices) would depend on the availability ofother alternative crop protection technologies or practices(NRC 2000). For example, field crops like corncan be grown with minimal herbicide use if tillage isused more frequently. Additionally, hand weeding, asis often practiced in certified organic crop production,along with tillage, can substitute for herbicide use.However, aggregate analysis of grain, vegetable, andfruit crop management, assuming only hand weedingand tillage without herbicide use, showed an averageyield reduction of 20 percent (Gianessi and Reigner2007). Furthermore, substitution of increased tillagefor weed control would counter the benefits of reducedtillage for soil conservation.Vegetable and fruit production would likely bethe most adversely affected by wholesale loss of use ofinsecticides and fungicides, owing to their disproportionalproblems with insect pests and plant pathogens.Loss of pesticide availability would also adversely affectconsumer prices, and potentially mean a loss ofdomestic sources of supply as production is relocatedto other regions (Zilberman et al. 1991).It’s important to realize that the economic returncostratio for pesticide use is generally favorable. Theratio depends on the specific crop because the annualcommodity price must be factored in, as well as thesite-specific yield and expenses due to chemical purchases.Nevertheless, older estimates for return rangedfrom $4-$29 for every $1 spent (Metcalf and Luckman1975), and more recent estimates suggest a $3-$6 rateof return per $1 spent (Zilberman et al. 1991; Pimentelet al. 1992). Significant for the grower is the comparativelylow incremental cost of pesticide use relative toall production expenses. The most recent estimate(crop year 2002) is that purchase of pesticides represents4.4% of total expenses, compared to the 12.7%of expenses for hired and contract farm labor (USDA2004). Pesticides themselves help lower costs by substitutingfor labor. For example, fruit thinning required7

Pesticides with Benefits for All: An Agricultural Perspectivein the pome fruit industry is mostly done by chemicalthinners but still requires some hand thinning if loadsare deemed excessive.Perhaps the most popular misconception amongconsumers of organic foods is that such products lackpesticide residues and other additives. The basis forthis belief is the often-repeated argument that organicagriculture distinguishes itself from conventionalproduction methods because no synthetic pesticidesare used. Prolonged pronouncements of no syntheticpesticide use easily evolve into a consumer perceptionof no pesticide use. Contraction of no synthetic useto the equivalency of no use at all may be facilitatedby the myth that somehow synthetic substances aregenerically different in their adherence to thermodynamiclaws and reactivity than natural substances.The reality is that U.S. rules for certification oforganic production allow for the willful use of approvedcrop protection products. Under the FederalInsecticide, Fungicide, and Rodenticide Act (FIFRA)many of theses products are legally pesticides andmust be registered with EPA (Felsot and Racke2007). However, organic growers by rule cannot usesynthetic materials unless approved by the NationalOrganic Standards Board (NOSB). But no pesticide(NOSB-approved or otherwise) can be used in anytype of farming practice unless vetted by EPA first.EPA does a comprehensive risk assessment on allchemicals submitted for registration, using the rawdata submitted by a prospective pesticide registrant.Similarly, NOSB contracts with the Organic MaterialsResearch Institute (OMRI) to do a comprehensivehazard assessment of materials proposed for certifiedorganic production. In that case, similar questionsare asked, except that the OMRI speculates whethera candidate product is really needed and therefore acredible substitute. One criterion would be that it is“less hazardous.” Although a perspective of hazard differsfrom one that uses hazard along with exposure tocharacterize risk, some of the active ingredients usedby nonorganic growers are the same as those usedby certified organic growers. For example, spinosadinsecticide, a complex macrocyclic lactone saccharidederived from a bacterial fermentation culture, is usedby today’s cherry growers regardless of their productionphilosophy. Even though NOSB policy tends toavoid substances that are toxic, spinosad has a biochemicalmode of action that would classify it as a typeof neurotoxin (Sparks et al. 2001; Orr et al. 2009).The “purity” of organic food is further dispelledby analytical surveys of organic commodities to revealthat some contain synthetic pesticide residues bothbanned and currently registered, albeit much less frequentlythan so-called conventional foods (Baker etal. 2002). Residues in organic commodities are likelyinadvertent, due to airborne transport and deposition,as well as soil residues from past use. Recognizingthe ubiquity and mobility of environmental residues,NOP rules allow inadvertent pesticide residues upto 5 percent of the established federal tolerance levelwithout a loss of organic certification. Whether onelikes or dislikes pesticide use, past practices influenceresidues in food. However, current residue studiesindicate that the vast majority of conventional foodshave no detectable pesticide residues (FDA 2009;USDA AMS 2009).In summary, various economic analyses are inagreement that pesticide use has been definitely associatedwith profitable returns to farmers (and thusto society), and it is not true that pesticides are usedon every crop indiscriminately. The reality is thatsome crops require disproportionately more herbicideuse and some crops require more insecticide and/orfungicide use. Thus, efforts to globally limit pesticideuse fail to take into account specific and local needsfor crop protection. Furthermore, certified organicproducers have an array of pesticides they can use underthe rules of the NOSB. Past land practices have ledto detections of pesticide residues in organic food, butcurrent analytical surveys show that so-called conventionallyproduced food most often has no detectablepesticide residues.8

Pesticides & Health: Myths vs. RealitiesAgricultural Reality: Practical & EnvironmentalAdvantages of Crop Protection ChemicalsIn addition to their economic benefits accruingfrom the objectives for which they are used, pesticideshave certain advantages over other practices for cropprotection (as well as production) that make them veryconvenient, efficient, and cost-effective (Metcalf andLuckman 1975). First, for most cropping systems, pesticidesare the only practical available technology becauseother technologies are not available, unproved,or do not work efficiently. For instance, hybrids of certaincrops may lack a pest-resistant cultivar. In othercases, a nonchemical pest control practice fails to workover time. An example of the latter situation is the apparentadaptation of western corn rootworms to thepractice of annual corn-soybean rotations that werevery successful in reducing the need for soil insecticides(Sammons et al. 1997; Rondon and Gray 2004).Second, pesticides have rapid curative action inpreventing loss of crop yield or protecting human andanimal health. Thus, they can be used when a pestpopulation becomes intolerable. One of the tenetsof integrated pest management (IPM) is eschewingprophylactic sprays in favor of “as needed” treatments.Thus, there may be a very short window of time duringwhich the pest needs to be controlled, and nonchemicalmethods may lack a rapid enough action.Third, the diversity of locations where crops aregrown means different pest complexes thrive undera wide range of climatic conditions. Pesticides havea wide range of properties, uses, and methods of applicationthat can cover many problems as they arise.The inorganic pesticides used during the first half ofthe 20 th century and the first wave of synthesized pesticidesafter 1950 were generally broad spectrum but notnecessarily adequate for all cropping systems (Stern etal. 1959). Over the last thirty years new chemistrieshave been introduced to narrow the spectrum of activity.Along with new formulations and applicationmethods, modern pesticides can be better tailored tospecific crops’ pest problems. Similarly, insecticidesintroduced over the last 15 years are also much lesstoxic to the natural biocontrol organisms than thebroad-spectrum synthetics introduced during the1950s. Furthermore, modern pesticides rapidly degradein the environment and do not bioaccumulatein lipid tissues as did the chlorinated hydrocarbon andcyclodiene pesticides that were heavily used prior totheir ban in the early 1970s.A fourth benefit stems from herbicide use in grainproduction throughout the Corn Belt. Before the adventof synthetic chemical herbicides like atrazine, erosionwas severe on even gently sloping lands becausefarmers relied on the moldboard plow and furthercultivation of the soil during crop growth to controlweeds. Many environmental scientists agree that eutrophicationand sedimentation of aquatic resourcesdue to runoff and erosion from agricultural land is themost important cause of water quality impairment,not to mention being reponsible for transportationproblems as rivers backfill with sediment. By the1960s, a few herbicides were commercially availableThe diversity of locations where crops are grown means differentpest complexes thrive under a wide range of climatic conditions.Pesticides have a wide range of properties, uses, and methodsof application that can cover many problems as they arise.9

Pesticides with Benefits for All: An Agricultural Perspectiveand allowed farmers to consider substituting chemicalcontrol of weeds for turning the soil over and therebymaking it highly susceptible to the erosion caused bywind and spring rains on bare soil. No-till agriculturebloomed, especially in corn production, because farmerswere able to rely on herbicides. Aggregate soil erosionfrom tilled soil in four Corn Belt states (Illinois,Indiana, Iowa, Nebraska) was estimated at 14.9 tons/acre/year but only 2.8 tons/acre/year from untilledgrain fields (Gianessi and Reigner 2006).Furthermore, by eliminating the need to till soil,herbicides also allow for the conservation of fuel. Over111 million gallons of fuel may be saved by using herbicidesinstead of tillage in the aforementioned fourCorn Belt States (Gianessi and Reigner 2006). Loweredemissions of greenhouse gases are also associatedwith a reduction in fuel use (Robertson et al. 2000).In addition to fuel reductions, an increased yieldfor every dollar invested in agricultural productionsignificantly reduces per acre increases in carbon emissions;this is by virtue of avoiding the land clearingotherwise necessary to maintain sufficient productionfor an increasing population (Burney et al. 2010).Thus, current analyses support the idea that pesticidetechnology also contributes to environmental qualityby virtue of enhancing yield.Two other recent analyses also support the conclusionthat there are both direct and indirect benefitsto pesticide technology. Although the direct benefitsof suppression of pest density, and thus suppressionof damage, are obvious, indirect benefits can also beconsiderable. Some examples of the latter includeincreased financial resources for a community, dueto greater producer profits; increased consumer accessto fresh fruits and vegetables; and an increase inlands available for wildlife conservation (Cooper andDobson 2007). Direct control of human and livestockpests (as discussed in the following sections) createsimilar secondary benefits for economic productivity,public health, and longevity.An analysis of historical and contemporary managementof cotton pests provides another affirmationof the benefit of pesticide technology and also suggestsindirect benefits beyond a specific crop (Naranjoand Ellsworth 2009). Cotton has historically been acrop requiring arguably the highest per acre intensityof pesticide use. Cotton pest management in Arizonahas evolved into a highly strategic system that employsboth natural biological control organisms (i.e., predatorsand parasitoids) but also relies on highly selectiveinsecticides for controlling the most important pests,which include the pink bollworm and whiteflies.Pink bollworms have been managed by use of cottoncultivars bred to contain the highly selective bacterialtoxin protein derived from the naturally occurringinsect pathogen Bacillus thuringiensis. Deploymentof such cultivars can conserve predator populations.The whitefly, on the other hand has, been successfullymanaged by judicious integration of highly selectiveinsecticides that affect insect development. The availabilityof such insecticides has not only increased profitsby reducing the overall need for pesticides, it hasalso indirectly benefited other regional crops attackedby whiteflies: These now show an overall reduction intheir populations. Thus, innovative pesticide technologyhas resulted in “an unprecedented stability of ecosystemservices and major economic and environmentalgains in Arizona cotton that has extended to benefitthe entire agroecosystem of the region” (Naranjo andEllsworth 2009).10

Pesticides with Benefits for All:A Public Health PerspectiveMyth: Pesticides offer no benefit to public health and, arguably, detract from it.The Public Health Reality: Historical and ModernDaily life in the developed countries of the Westis not likely plagued by insect-transmitted infectiousdiseases. While it is true that the yellow fever vectormosquito Aedes aegypti once haunted the streets ofNew Orleans, a program of publicly financed mosquitocontrol arose in the 1960s and spread throughoutthe U.S. to dampen the disease-transmission potentialof insects. Even so, over the last decade, West Nilevirus, transmitted by the bite of the Culex mosquito,has spread from New York to California, becomingendemic in every state (Artsob et al. 2009). Lyme disease,a spriochete bacterium transmitted by the bite ofthe tiny deer tick, disables nearly 20,000 people eachyear (Bacon et al. 2008); it is in many places now inthe U.S., although the epicenter is in New England.Insect bites are mostly a nuisance to citizens in highlydeveloped countries, but the last decade of West Nilevirus epidemiology shows the need for vigilance aboutinfectious disease control even as megacities and exurbspave over widening expanses of natural lands.Furthermore, the widespread outbreak and spread ofWest Nile virus has had observably negative impactson bird populations (LaDeau et al. 2007).Recent experience indicates the need for vigilanceagainst arthropod-vectored diseases even in developedcountries—but the situation is surely more direon a continent like Africa, where publicly financedprograms are infrequent, and poor when they exist.Anopheles mosquitoes today still transmit per annumover 500 million cases of malaria (WHO 2010), adisease caused by Plasmodium falciparum, a protist requiringboth the mosquito and human body in whichto complete its life cycle. Malaria causes paroxysmsof fever, often several times each day. With so manyinfected, economies become inefficient as workers arestruck ill. And because infant and child nutrition isso deficient in these countries, a nearly unimaginable800,000 children die from mosquito-transmitted malariaeach year.But many countries have malaria under control.They adopted the use of DDT, the chemical technologyused by the military during WWII and by theEuropean Command after the war to control mosquitopopulations. Data on malaria incidence beforeand after the advent of DDT proved that the pesticidecould be effective without causing acute harm (Hayes1991). The evidence for lack of acute harm becameapparent when millions of Europeans were directlydusted to control lice that transmitted a form of typhuscaused by the bacterium Rickettsia.However, DDT was essentially banned in the U.S.in 1972 when the recently-created EPA decided to11

Pesticides with Benefits for All: A Public Health Perspectivesuspend its registration for any agricultural use. (Infact, the decision was entirely the work of EPA’s firstadministrator, William Ruckelshaus.) Unfortunately,the history of agricultural use of DDT and its demiseas an effective pest control technology on crops hasbeen conflated with its continued success with mosquitocontrol in lesser developed countries of Africa,parts of Latin America, and parts of Asia. AlthoughDDT was memorialized into infamy by Rachel Carson’sSilent Spring, it was the agricultural use of thechemical that got it into trouble, not the public healthuse. Even so, since Carson’s time, how DDT is used inpublic health has been the key to its successful controlof mosquitoes where they matter, in the house. Duringand shortly after WWII, spraying of DDT was widespreadin the environment. However, by the 1950s itwas well known that mosquitoes rested on walls andceilings of buildings. Thus, by the late 1950s researchershad already established the efficacy of a “spacespray,” wherein only resting areas on walls would betreated (Barlow and Hadaway 1956).To this day, the public likely does not understandhow DDT is actually used, and thus visions of SilentSpring dominate the conversation. So prevalent is themisunderstanding that a number of countries decidedto eschew its use — with devastating consequencesfor malarial incidence. Re-adoption of the limitedspraying of house walls was associated with a rapiddecline in malarial incidence (Roberts et al. 1997).However, aerial spraying for mosquitoes is still viewedas effective under certain circumstances for someinsect vectored diseases. The benefits of using adulticidesto control West Nile virus mosquito vectors havebeen shown to substantially exceed costs as well as effectivelyprotect human health without adverse healtheffects or ecological problems from pesticide exposure(Peterson et al. 2006; Davis et al. 2007; Carney et al.2008; Barber et al. 2010).Pertinently, public health protection specialistshave long known that DDT alone is not enough tocontrol the scourge of malaria-infested mosquitoes.Mosquito larval, egg-laying, and breeding habitatmust be monitored and managed. Western countriesnow use insecticides based on microbial toxins, namelyBacillus thuringiensis israeliensis (Bti) and Bacillussphaericus. Bti and B. sphaericus are incredibly specific,naturally occurring bacteria that are toxic only wheningested by mosquito larvae. These organisms are stilldeemed pesticides, specially regulated under EPA’sbiopesticides program (EPA 2010).In addition to habitat management for mosquitocontrol, individuals are encouraged to protect themselveswith mosquito netting around their beds atnight. Emphasis has been placed on using insecticideimpregnatedbed netting, which can be effective whenwhole communities are included in control programs.However, even such relatively passive control measuresare very much influenced by the type of insecticidedeployed (e.g., irritant vs. non-irritant effects)(Curtis and Mnzava 2000), further illustrating that thebenefits of pesticides depend on the appropriate use ofspecific chemicals.One aspect of protecting public health that isnot often mentioned is the potential of pesticides toreduce microbial contamination and the associatedproduction of fungal toxins. Overlooked is the use ofchlorine and other disinfectants, all of which are registeredpesticides, in water treatment. U.S. consumersappreciate water devoid of bacterial contaminants andknow implicitly that bacterial infection from drinkingwater is very rare here. However, inadequately treatedpublic supplies do occur, as evidenced by the outbreakof cryptosporidium in a Wisconsin water supply during1993 (MacKenzie et al. 1994). A water-borne outbreakof pathogenic E. coli in Walkerton, ON during2000 was also definitively connected to inadequatechlorination (Hrudey et al. 2003).Anti-pesticide activists may try to assert that pesticideuse is all about blemish-free fruit and vegetables.True, use of crop protection technologies reducesmarking and scarring, thereby filling to overflowingproduce counters with picture-book food. But insect12

Pesticides & Health: Myths vs. Realitiesfeeding causes harm that makes a food more susceptibleto fungal invasion. Certain fungi commonlyassociated with crops produce mycotoxins that havewell-documented physiological effects in mammals,including humans and livestock (Marasas 2001). Allowinginsect or plant disease injury to progress withoutprotecting a crop only increases the likelihood ofmycotoxin residues. Indeed, the problem’s gravity isevidenced by an international standard for maximumallowable residues of mycotoxins. Furthermore, thevalue of protecting crops against direct insect feedinghas been proven with the adoption of corn geneticallybred with a gene from Bacillus thuringiensis (called Btcorn) to produce a very insect-specific protein thatkills the European corn borer. This insect damagescorn and is arguably the major cause of fungal mycotoxincontamination, as damaged seed is pushed intostorage. Mycotoxins are considered both human andlivestock hazards with carcinogenic, neurotoxic, andteratogenic effects. However, Bt corn has substantiallylower levels of mycotoxin contamination than corn notprotected against corn borers (Bakan et al. 2002; Wu2006). Thus Bt corn, which is regulated as a pesticide,helps keep grain quality within established regulatorystandards that protect against mycotoxin exposure.One practical benefit of pesticide use that is oftenoverlooked is tied both to public health protection ofworkers as well as economics of production. Herbicides,which are used more frequently and in greaterquantities than any other pesticide class, are quicklyapplied to all kinds of crops and thus eliminate theneed for hand labor to hoe out weeds (Gianessi andReigner 2007). Hand labor is expensive, and its availabilityis diminished by a shortage of people willing tobecome part of a migrant worker culture that movesfrom farm to farm. One application of herbicides forweed control in a single field is worth the hand labor oftens to hundreds of workers. The aggregate numbersare startling for just four major Belt States alone (i.e.,Illinois, Indiana, Iowa, Nebraska). Economic analysisof labor requirements in the absence of herbicide usehas estimated the need for a total of 338 million hoursof work by over two million workers (Gianessi andReigner 2006). Considering that less than 2% of theentire US population (approximately 6 million people)works on farms, replacing chemicals with peopleis not practical.Perhaps just as important is to question how peoplewould fare doing strenuous physical labor in thesun for a typical 8-hour work day. Sun exposure mayexplain elevated lip cancer risks, as well as the slightlyelevated skin cancer risk, among farmers (Aquavellaet al. 1998). Musculoskeletal health would likely beseriously impaired, given the physical nature of handpullingand hoeing weeds. As evidence of such physicallyadverse impacts, California instituted an administrativepolicy prohibiting the use of short-handledhoes. Organic lettuce growers rely on hand weedingto attain profitable production and have petitionedthe State of California against stricter labor rules,ostensibly because sufficiently effective approved herbicidesare unavailable ( James 2005). Thus the lackof appropriate available pesticides adds to labor costsas it simultaneously raises the issue of hand-weedinglabor’s impact on worker health.The foregoing story of public health benefits nowcomes full circle, back to the historical roots of usingpesticides directly to affect insects afflicting our bodies.The flowers of chrysanthemums (specifically Chysanthemumcinerariaefolium) were used in the early 1800sby Southeastern Europeans and Persians to produce anextract called pyrethrum that alleviated a lice sufferer’sscourge. Thus, over a span of less than 200 years, wehave taken and improved upon Mother Nature’s chemistryto improve our own public health. Which leads tothe next myth about chemical pesticides.13

Synthetic Chemistry for CropProtection: Humans ImitatePlants and BacteriaMyth: Synthetic chemical pesticides are unnatural and cannot be degraded. Thus,they are particularly dangerous in comparison with natural products derived fromplants.Technological Reality: We’ve Always Copiedthe Good Ideas of Plants and BacteriaMany organisms, especially plants, produce chemicalsincidental to their normal energy-producing biochemistrythat function to ward off predators, protectseeds, or attract insects for pollination (Ames et al.1990a, 1990b; Ames and Gold 1997). Sometimes,these chemicals are just by-products of metabolismthat may serve other purposes, or they are perhapsexcretory products that would be toxic if allowed toaccumulate in the cells. Sometimes we can only speculateabout the evolutionary role of these chemicals.For example, apples contain acetic acid. Although it’sa natural component of apples, the acid is neverthelesslisted as a hazardous substance, and the MSDS sheetlists horrific adverse effects from exposure, includingvomiting, diarrhea, ulceration, bleeding from intestinesand circulatory collapse. Perhaps the evolutionarybenefit of such a metabolic pathway and storagein fruit accrued from the known antiseptic qualities ofacetic acid (Levine 1940). Similarly, bacteria producewell-known toxins that ostensibly provide some pro-14tection against predaceous protists or other bacteria.A pertinent example of humans using such hazardousbacterial metabolites is the subcutaneous injection ortopical epidermal application of the highly toxic botulinimneurotoxin, which is derived from the anaerobicfood spoilage organism Colstridium botulinin; it iscommonly used for cosmetic or corrective purposes(Collins and Nasir 2010).The examples of acetic acid and botulinin, as wellas other instances of natural toxins in food, are butsome examples of the many incidental chemicals producedby plants and/or bacteria that are quite toxic inhigh doses. Certain fungi of the genus Aspergillus growon cereals and produce chemicals called aflatoxins thatare hundreds of times more potent than any syntheticpesticide synthesized by humans. Yet our perspectiveabout the risks of pesticides does not apply to Aspergillus,as our concerns are focused on the timely applicationof a fungicide on stored grains—the right thing todo in order to protect food and avert health problems.

Pesticides & Health: Myths vs. RealitiesBecause chemicals produced by plants are functional,evolution has arguably resulted in a form ofchemical technology. Through our own chemicaltechnology, aren’t we just “imitating” our botanicaland bacterial counterparts? For example, Swiss cheeseresults from bacterial species that produce substantialamounts of propionic acid when growing on milkproducts. The propionic acid is a by-product, alongwith the carbon dioxide formation that creates the familiarholes, but it also suppresses prolific fungal (i.e.,mold) growth (Suomalainen and Mayra-Makinen1999). Today, humans add synthesized propionates tobaked goods to obtain the same protection.Members of indigenous cultures have long usedplants as their medicines. The knowledge of whichplants to use, how to prepare them, and the amountsto administer has been passed from generation togeneration. Isn’t the use of flora for our benefit, oursurvival, a form of chemical technology? Perhaps weshould consider generations of trial and error in discoveringbeneficial and harmful plants as analogous toa risk assessment process.Humans have always used chemical technology.Whether the chemicals are made by plants, bacteria,or by our own hands is irrelevant. Some have maintainedthere is a difference between chemicals fromthe tropical rain forests and chemicals from the giantchemical industries. But principles of environmentalchemistry would dictate that behavior of a chemicalis governed primarily by thermodynamics, not howit was made.Some would say that our coevolution with plantsover many generations has allowed us to detoxify manyof the natural dietary chemicals. Consider, however,that many of our foods are recent inventions of selectivebreeding that still possess the same potentiallytoxic chemicals as their wild ancestors.In considering synthetic pesticides, a credibleargument can be made for the human use of tools tosynthesize other useful tools, e.g., pesticides, as anevolutionary adaptation. This adaptation is analogousto the evolution of secondary metabolic pathwaysin plants that result in biochemicals protectiveof their survival.15

You’ve Come a Long Way, BabyMyth: Pesticides used today are all just like DDT, and thus just as dangerous. Allpesticides are alike and have not changed since DDT. All synthetic chemicals areequally hazardous.The Reality of Modern Pesticide Technology:Dynamics & EvolutionThe arguments set forth in this report by no meansdefend the properties of DDT as ideal. Rather, theaforementioned discussion focused on DDT’s effectivenessin controlling resting adult mosquitoes when thecompound is used in a very specific and locally confinedmanner inside of a dwelling. Furthermore, it is usednot solely but as an adjunct to pyrethroid insecticideimpregnatedmosquito netting. Ideally, governmentfundedprograms of habitat management would accompanyindividuals’ attempts at mosquito control.All chemicals have distinct physicochemical propertiesthat make them behave differently from eachother. Chemicals with similar structural elements, i.e.,arrangement of the same atoms, will behave similarlyyet still possess idiosyncratic properties. Chemicalshaving divergent structural elements will be even moreunlike one another. Thus, to conclude that all pesticides,because they can kill pests, are just like DDT is to seriouslylack an understanding of basic chemistry, not tomention the complexity of biochemical interactions.The specific physicochemical properties of DDTthat made it unique were very low water solubility (it ispractically insoluble in water) and resistance to extensivedegradation in organisms or on plant surfaces. Onthe other hand, the very low water solubility of DDTand its one environmental oxidation product, DDE,drove it to move readily into the atmosphere. Such amechanism, commonly called “phase partitioning” inthe field of environmental chemistry, was arguably themost influential process in widespread environmentaldistribution of DDT. Unfortunately, its properties ofpersistence, along with broad-spectrum biological activityagainst pests and beneficial insects (e.g., predatorsand parasitoids feeding on the pests) alike madeit a poor choice for use in agriculture after WWII. Addthe rapid development of insects resistant to its effects,and the stage was set for entomologists—long beforethe publication of Silent Spring—to recommend that itnot be used on field and orchard crops.Evidence of the dynamic nature of industry’s responseto changing pest-control needs, and thus itsability to synthesize and test new chemical designs, isa new group of chemicals called organophosphorus(OP) insecticides that were introduced into commercialagriculture in the late 1960s. Soon thereafter, a secondgroup, called methyl carbamate (CB) insecticides,was introduced. OP and CB insecticides had shortpersistence in the environment, and at least somewere not quite as toxic to predators and parasitoids.At the very least, they gave growers more options for16

Pesticides & Health: Myths vs. Realitiesintegrating chemical use with biological control (Sternet al. 1959).As DDT and related compounds fell into disfavorin agriculture, and pressure from regulatory decisionsmounted, growers became heavily reliant on OP andCB insecticides. Overreliance on one technology oftenleads to pest resistance, but again the dynamic natureof the technology shone: The British had started workingon modifying the natural insecticidal componentsof pyrethrum extracts, i.e., the pyrethrins, to producelight-stable compounds, and thus longevity in the fieldbeyond a few hours. Fortunately, such compoundswere far less toxic than the OPs to mammals, whichis always of concern for worker health, as well as forbirds. Unfortunately, fish were quite susceptible to thenew synthetic derivative of the natural pyrethrins —just as they were to the natural products. However, theamounts used dropped from two or more pounds appliedper acre to ranges of 0.1-0.2 pounds per acre. Appropriatetiming of application, combined with goodsoil management practices to protect against erosion,could resolve the likelihood of runoff into aquatic habitatsin sufficient quantities for fish kills. Thus anotherchemical with a different mode of biochemical actionwas added to the grower’s toolbox. Unfortunately,overreliance on a particular chemical again resulted indevelopment of resistant insects.By the time of pyrethroid development, insecticidemanufacturers had begun to focus on the conceptof biorational design of chemicals with insecticidalactivity (Menn and Henrick 1981). This concept tooktwo forms. First, natural products with biological activitycould be tinkered with, altering their structureto more precisely target their activity. Development ofsynthetic pyrethroids were initially based on structuresof the natural pyrethrins. By the late 1970s, new insectgrowth regulators were synthesized based on naturalhormones or plant metabolites that exhibited eitherjuvenile hormone agonistic or antagonistic activity(Menn and Henrick 1981). The latter endeavors wereenhanced by basic research on specific biochemicaland physiological systems of pests. The second formof biorational design was the combination of moretraditional synthesis methods with the optimizationof structure-activity relationships, which occasionallyresulted in compounds that could affect specific physiologicalmechanisms of insect pests. For example, anarray of compounds have been synthesized based onthe model compound diflubenzuron, serendipitouslyfound to inhibit the synthesis of chitin in the insectexoskeleton (Menn 1980). These types of compoundsare still being used today, and more recent discoveriesof their effective use as termiticides have won EPAPresidential Green Chemistry Awards. Many of thesecompounds with effects on specific insect physiologicalsystems could be used at low rates per acre, owingto their potent effects on the pests — even better, theirimpacts on predators were low, because they have tobe directly eaten for maximal biological effect.The idea of a silver bullet, as exemplified byDDT’s deployment and overuse in agriculture, haddisappeared from the mindset of industrial researchby the mid 1980s; this was because new discoveries ofchemicals with completely different modes of actioncontinued unabated. The new bevy of chemicals sincethe late 1980s eventually were recognized by EPA asmeeting their criteria for “reduced risk” (EPA 1993).These chemicals were ultimately used at lower userates than many other chemicals previously marketed,and they were even less toxic to mammals, birds, fish,The idea of a silver bullet, as exemplified by DDT’s deploymentand overuse in agriculture, had disappeared from the mindset ofindustrial research by the mid 1980s.17

You’ve Come a Long Way, Babyand aquatic invertebrates (Table 2, Figures 2-5). Withsome exceptions, these chemicals tended to be moreselective for killing pests rather than predators. Thus,even more opportunity arose for compatibly integratingthese new chemistries into programs that wouldtry to deploy ecologically-based, integrated pest managementstrategies.The historical use of herbicides and the evolutionof chemical classes parallel that of the insecticides —with a major exception. Prior to WWII, about the onlyherbicides available that could be practically used onfields were dinitrophenolic compounds like dinoseband DNOC. These uncouplers of oxidative phosphorylationhad a general mechanism of toxicity that madethem nonselective for weeds, insects, and fungi. However,by the 1940s 2,4-D was discovered and found tomimic the natural plant hormone auxin (indole-3-aceticacid), ushering in the discovery of a very specific plantmechanism of toxic action. Thus, biological activityat field application rates was only applicable to plantsand not animals. Surprisingly, 2,4-D was only toxic tocertain dicotyledon (broadleaf) plants. Thus, 2,4-Dcould be applied to a bluegrass lawn or a field of wheatwithout damaging it. Interestingly, dichlorophenol, aputative metabolite of 2,4-D, is synthesized naturallyby a soil fungus and its isomeric analog is used by someticks as a sex pheromone, as well as an ant repellent bya grasshopper species (Gribble 1998). The discoveryof the specific biological activity of 2,4-D reiterates animportant concept in biochemistry alluded to before —selectivity. Thus, as manifested by the aforementionedevolution of insecticide chemistry, synthetic organicchemical herbicides invented circa WWII allowed forbiological selectivity between animals and plants butalso within the Plant Kingdom itself.By the late 1950s, the most intensely used pesticideof all time, atrazine, was synthesized and discoveredto have only one biochemical effect at fieldapplication rates—namely, inhibition of a particularelectron acceptor in Photosystem II of plants. Atrazine’spotency is selectively limited to broadleaf weedsbut has no activity against grasses like corn. To curtaila long story, herbicide synthesis continued to producecompounds with other modes of action specific toTable 2. Comparative mammalian toxicity of insecticides registered over the lastdecade and designated as ‘reduced risk’ by EPA.ActiveIngredientCommercialFormulationOral LD50(mg/kg)Dermal LD50(mg/kg)NOAEL(mg/kg/d)Azinphos-methyl Guthion 4.4 155 0.149Chlorpyrifos Lorsban 223 222 0.03Acetamiprid Assail 1064 >2000 7.1Indoxacarb Advion 1277 >5000 2Pyriproxyfen Esteem 4253 >2000 35Methoxyfenozide Intrepid >5000 >2000 10.2Novaluron Rimon >5000 >2000 1.1Pymetrozine Fulfil >5000 >2000 0.377Spinosad Success >5000 >2000 2.7Rynaxypyr Altacor >5000 >5000 158To place the concept of reduced risk in perspective, parameters for azinphos-methyl and chlorpyrifos are shown because these weredeveloped prior to EPA’s initiative, stated in PR Notice 93-2 (EPA 1993).18

Pesticides & Health: Myths vs. Realitiesplants and with zero potency at field application ratesto any other types of organisms.Perhaps the ultimate in the development of newchemistry with limited impact on anything but the targetedpest was Monsanto’s synthesis and developmentof glyphosate herbicide. Considered by the EuropeanUnion as well as EPA to be a reduced risk herbicidewith no toxicological concerns at the designated legalrates of field application, glyphosate has become themost widely used herbicide in the agricultural sector,especially with the development of crops like soybean,corn, and cotton that can resist its phytotoxicity.The history of pesticide synthesis as a dynamicprocess, with researchers adapting their skills in biologyand chemistry to ever more selectively bioactivecompounds, leads to another myth about pesticides.As will be explained, this next myth also reveals a seriousmisunderstanding of concepts like toxicity, hazard,and risk — as well as a lack of knowledge about basicbiochemistry.Figure 2. Acute toxicity of new insecticides to fish (rainbow trout or close relative).In this graph and subsequent ones, parameters for chlorpyrifos and azinphos-methyl are shown for comparison.pymetrozineacetamipridspinosadrynaxypyrmethoxyfenozidenovaluronindoxacarbpyriproxyfenchlorpyrifosazinphos-methylLC 501 10 100 1000 10000 100000ppb (µg/L)Figure 3. Acute toxicity of new insecticides to the aquatic invertebrate Daphnia magna.pymetrozineacetamipridspinosadmethoxyfenozideindoxacarbpyriproxyfenrynaxypyrazinphos-methylnovaluronchlorpyrifosLC 500.01 0.1 1 10 100 1000 10000 100000ppb (µg/L)19

You’ve Come a Long Way, BabyFigure 4. Acute toxicity of new insecticides to birds (quail).rynaxypyrmethoxyfenozidepymetrozinepyriproxyfenspinosadnovaluronacetamipridindoxacarbazinphos-methylchlorpyrifosAcute Oral LD 500 500 1000 1500 2000 2500mg A.I. per kg body weight(mg/kg)Figure 5. Application rates per acre of new insecticides.chlorpyrifosazinphos-methylpymetrozinenovaluronmethoxyfenozideacetamipridspinosadindoxacarbpyriproxyfenrynaxypyr0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0Pounds per Acre20

It’s Still About the Dose(and Timing)Myths: Exposure to pesticides results in adverse health effects. Hazards of pesticidesare equivalent to the risk of adverse effects.The Reality of A Modern Biochemical Perspectiveon Toxicity, Hazard, and RiskUltimately, consumers want to know whether anytechnology is “safe”. The concept of chemical safetyamong regulatory toxicologists is understood not as aquantitative unitary concept but rather as a descriptionof a probability of a reasonable certainty of no harm.The validity of the concept of reasonable certainty ofno harm, which is actually more science policy thanscience, depends on a distinction among the terms“toxicity,” “hazard,” and “risk.” Distinguishing theseterms and, moreover, defining them from a biochemicalperspective, is crucial for a rational argument aboutthe nature of pesticide use in modern society.Toxicity is an inherent property of both a particularmolecule (called the substrate or ligand) and anyorganismal enzymes or receptors (tissue cell macromolecules)that it can react or interact with. Such interactionresults in a physiological reaction that couldbe inimical to the survival of an organism, and thusthe substrate or ligand would be called a toxicant. Bydefinition, pesticides are inimical to the lives of pests,thus pesticides are toxicants. The concept of “inherentproperty” refers to the fact that the three-dimensionalstructure of any toxicant must be complementaryto the three dimensional structure of an enzyme orreceptor for any interaction to occur. In addition tostructure, molecular interactions are also influencedby physicochemical properties related to molecularcharges and hydrophobicity. Such interactions occurvery readily if the structures of a toxicant and itsreceptor are highly complementary. In such cases, thesubstance is considered highly potent. Interactionswould occur with structures not as complementaryonly under conditions of inordinately high toxicantconcentrations, typically those not likely to be foundin the environment but certainly possible to createin the lab when animals are tested. A toxicant requiringextremely high concentrations in order to havean interaction with an enzyme or receptor, and thuscause an adverse physiological reaction, would beconsidered to have low potency. In summary, then,toxicity is a property inherent to any molecule, allowingit to elicit an adverse physiological response whenan organism has specific enzymes, receptors, or othermacromolecules whose three-dimensional structuresare complementary.The nature of fundamental thermodynamic and kineticlaws governing chemical interactions prescribesthat any molecule could, hypothetically, interact with21

any other molecule. However, the concentration of thetwo molecules must be sufficiently high for the interactionto have any reasonable probability of occurring.This latter concept leads to the definition of “hazard.”Hazard describes the potential of a chemical to causeharm under a particular set of conditions. In otherwords, toxicants are not inherently hazardous unlessthe context is conducive to the sufficient interaction ofthe toxicant with the particular enzymes or receptorsto which it is complementary. To study how chemicalsinteract with organisms, scientists in the laboratoryalways create conditions in which the subject chemicalwill be hazardous. Often the conditions are concentrations(or doses) of chemical sufficient to cause anobservable response in a test population of organisms.If the conditions of the exposure change (for example,using a very low dose) then the hazard may change orsimply disappear altogether.Experiments repeatedly show that natural andsynthetic substances at one dose may have no adverseeffects on an organism, but at another higher dose cancause harm. This concept, frequently called “the dosemakes the poison”, is the fundamental principle guidingtoxicological studies, and it is discussed in all basictoxicology textbooks. Of course, that popular toxicologicalaphorism belies more complex interactionsbetween a substance and its effects on an organism.The dose required to cause deleterious effects withina population of organisms can vary depending on theroute of exposure (oral, dermal, or inhalational), thelength of time over which it is administered (acuteversus chronic), and the age, sex, and health of an organism.Nevertheless, the appearance or magnitude ofan effect of any substance is tied to its dose. Hazard,therefore, can be thought of as a substance’s dose-relatedarray of possible deleterious effects on an organismof a specific age, gender, and health status exposed viaoral, dermal, and/or inhalational pathways.Should the knowledge that a substance is hazardous,i.e., potentially harmful under a specific set of circumstances,precipitate a corresponding (and urgent)It’s Still About the Dose (and Timing)22reaction to do something about it? We are cautious bynature and thus want to be careful when we have knowledgeof potential harm. The problem is knowing theappropriate amount of resources (financial, intellectual,etc.) to expend on managing what may be only potentialharm, since—because hazard is contextual—it maynever be manifested, or it may be manifested only underthe most extreme conditions of chemical use.To judge just how worried we should be about atoxicant in the environment, and therefore allocatethe appropriate attention to its hazardousness, wehave to understand the risk of adverse effect. Risk isalso contextual, but a simple definition is the probability(likelihood) that adverse effects would occurunder a specific situation or set of conditions. Often,regulatory toxicologists will express risk as a functionof toxicity and exposure. Thus, risk is the probabilityor likelihood that the array of known hazards of asubstance will actually occur if or when an organismis exposed. If exposure is nonexistent, then the likelihoodof an effect is nil. If exposure does occur, thenthe likelihood of the substance being a hazard is conditionednot only on the dose but also on the age, gender,and health of that organism as well as the specificroute of exposure. The important point is that the riskof adverse effects after exposure to a substance may below or high, depending on all the factors affecting thehazards of that substance.ThresholdsLow levels of exposure, even to a highly potenttoxicant, may have a low probability of causing an adverseeffect. In any case of exposure, whether throughskin contact, inhalation, or oral ingestion, a number ofphysiological processes occur to modulate the dose orconcentration of toxicant arriving at the cellular level,and thus the probability of interaction with enzymesor receptors. All of these physiological processes thatdetermine what amount of toxicant arrives at the siteof the cell enzymes or receptors is described by phar-

Pesticides & Health: Myths vs. Realitiesmacokinetics. Pharmacokinetic studies examine rateand extent of chemical uptake processes followingdermal, oral, and inhalational exposures. The amountof toxicant entering into the systemic circulation(bloodstream) is studied and then followed to itssubsequent distribution among all body regions downto the cellular level. The toxicant amount changes as itis degraded by enzyme systems and excreted (sometimesunaltered) from the body. Whatever toxicantis left over from all these pharmacokinetic processesarrives at the site of the potential enzymes or receptorscomplementary enough in structure to have anyprobability of interaction. The specific interactions arecalled pharmacodynamics.The combination of pharmacokinetic processesand the kinetics of pharmacodynamic interactionsmay result in adverse physiological effects. Generallyspeaking, the physiological systems most often studiedare the nervous and endocrine system, althoughthe immune system is necessarily included becausethese three systems communicate with one another.Researchers studying the interaction of toxicantswith whole animals (in vivo studies) or with animaltissues, cells, and macromolecules (in vitro studies)attempt to establish a threshold for a physiological orbiochemical reaction. They use a wide range of doses(exposures) and concentrations. The threshold isoften reported as an empirical dose level in which noobservable adverse effect (i.e., the NOAEL) occurs.To determine the NOAEL, however, the researchermust expose an animal to sufficiently high concentrationsto see what a typical response looks like. Thedose just causing a reaction is called the LOAEL(lowest observable adverse effects level). For anyone specific response, the proportion of animals respondingforms a monotonic functional relationshipwith the dose that is mathematically depicted as anS-shaped curve (Figure 6). For any effect, therefore,the researcher can estimate the proportion of thepopulation responding to a particular dose. Similarly,the researcher can estimate when no responses in apopulation will occur.Figure 6. Typical monotonic relationship between increasing dose(or concentration) and population response.100%50% Response (median)SlopeNumbers RespondingDose (mg/kg)or Concentration (mg/L)Population Response(Cumulative %)50%0%NOAELLOAELLD 50; LC 50ED 50; EC 50Dose (mg/kg)or Concentration (mg/L)The relationship can be expressed as the numbers responding to any given dose metric. If the numbers are transformed to the cumulativeproportion (i.e., percent) of the population responding, then an ‘S’-shaped curve results, which can be described by a logistic mathematicalfunction. At some dose, no measurable response is observed, and this dose is designated the no observable adverse effect level (NOAEL)or concentration (NOAEC). The LOAEL represents the dose at which an adverse effect is statistically significantly different from theresponse in the control. The LD50 and ED50 represent the median response in the population (i.e., 50% response) for either lethality(L) or any other measured response (E).23

It’s Still About the Dose (and Timing)The type of experiment that allows constructionof the aforementioned dose-response curves and determinationof a no-effects threshold falls under therubric of regulatory toxicology. These experimentsare most useful for assessing risk of an adverse effectfollowing exposure under environmental conditions.Furthermore, experiments that attempt to define athreshold for an effect are quite different in objectivethan experiments that are designed to understandthe mechanism of an effect. These latter experimentsdominate the published toxicology literature today.However, those experiments necessarily use highenough doses so that an effect is always manifestedand can therefore be studied. Although informativefrom the perspective of a basic biochemical understanding,mechanistic experiments are not very usefulfor characterizing the risk of effects following chemi-cal exposure in the environment (i.e., outside of thelaboratory).In summary, then, the toxicity of a chemical is aninherent property related to its structural ability to interactwith some complementary enzyme or receptorin a cell. If the structures are highly complementary,such that the probability of interaction is high, then thetoxicant is considered highly potent; but if structuralcomplementarity is low, the toxicant has low potency.Regardless of potency, pharmacokinetic processesmodify the probability of pharmacodynamic interactions,and thus all toxicants have thresholds for aneffect. Pertinently, these interactions and thresholdsapply to all chemicals, natural and synthetic, becauseall are under control of the fundamental laws of thermodynamicsand kinetics.24

Endocrine Disruption:Is It Just Hormonal?Myth: Consideration of endocrine disruption changes the paradigm of what weknow about pesticide effects. “Dose makes the poison” is no longer relevant becausepesticides affect the endocrine system at levels equivalent to environmental exposures.The Reality: Confusion Between a Changing Paradigmand a Shift in Focus, Away from Cancer, to a DifferentPhysiological SystemIn the history of biology, those remembered byposterity are individuals who have created a paradigmshift in thinking about fundamental life processes.Perhaps at the pinnacle of paradigm shifters is CharlesDarwin. Indeed, an often-quoted paraphrase is “nothingin biology makes sense except in the light of evolution”(Dobzhansky 1964), and of course we have Darwinto thank for generating a line of inquiry leading tothe modern theory of biological evolution. Crackingthe genetic code, following the discovery of the structureof DNA, resulted in a plethora of new methods tostudy how life works at the molecular level. Of course,as we study different levels of organization, from cellsto tissues to organs to whole organisms, new propertiesemerge that are increasingly difficult to describe insimple molecular terms.In the context of biological history, perhaps weshouldn’t be surprised that some researchers wouldenjoy being called paradigm shifters. However, changingthe focus of study from one physiological systemto another is not a paradigm shift, because all possibleinteractions of toxicants in the ‘new’ system are still25constrained by fundamental laws of thermodynamicsand kinetics. More specifically, over the last severaldecades, toxicological focus has shifted from carcinogenicresponses to endocrine system responses.Whereas the 1950s through the 1980s focused on carcinogenicmechanisms largely tied to interactions withthe genome, during the time between the late1980sand now, focus has shifted to chemicals (synthetic andnatural) and their interactions with receptors of theendocrine system. At first, the estrogen receptor, owingto intense interest in reproductive biology, was theobject of most scrutiny, but now the testosterone (i.e.,androgen) and thyroid receptors have been throwninto the mix.A handful of studies putatively indicating thatchemicals at very low levels of exposure could result inendocrine-mediated alterations in tissues of neonatalrodents, especially male prostate gland structure, suggestedthat a new perspective on toxicants was needed(vom Saal et al. 1997). Of course, one’s perceptionof what constitutes a low dose requires temperingby how the dose is administered and a query as to

Endocrine Disruption: Is It Just Hormonal?whether the “specified” dose was chosen, because anydose lower would not result in the measured effect atall. In addition to observations of a slight difference inmale prostate gland weight between dosed and controlanimals (vom Saal et al. 1997), as one example of anendocrine system paradigm-changing effect, the doseresponserelationship accompanying the observationwas nonmonotonic. In other words, the observed effectson gland weight did not vary in a lockstep linearfashion with increasing doses (Figure 7). The highestdose caused loss of gland weight and mid-dosescaused increase in gland weight. The validity of theconclusions of these early reports has been questionedon grounds of statistical inadequacies (Haseman et al.2001) or have been judged inconclusive, imprecise,and of uncertain biological relevance (Melnick etal. 2002). Nevertheless, the problem in interpretingnonmonotonic responses arises when two differentphysiological phenomena are actually being measuredby the same endpoint, such as gland weight changes.For example, no pathology other than gland weightchanges may occur at low doses, but at high dosestoxicity may set in and gland weight changes are actuallydue to a different phenomenon, such as greatlyincreased cell death.Regardless of the cause of a nonmonotonic response(assuming the same physiological response isactually being measured on each side of the dosagerange), receptor (e.g., estrogen receptor) interactionswith ligands (e.g., estrogen or a toxicant) are governedby the principles of biochemical kinetics. Thus, theparadigm has not shifted; concentration of the ligandstill influences receptor-ligand complexation. Kineticanalyses of molecule-molecule interactions can showthe probability of those interactions as a function ofdose (or concentration). An illustration of this conceptcan help dispel the myth that low doses fromenvironmental exposures of hormonally active agentsare inordinately hazardous. Thus, Figure 8 shows thatligand-receptor complexes, the kinetic mechanism initiatinga hormonally induced physiological response,Figure 7. Effects of DES(diethylstilbestrol) on mouse prostategland weight measured eight monthsafter birth.Prostate Gland ChangeRelative to Control (%)140120100806040200AAB0 0.002 0.02 0.2 2 20 200Diethylstilbestrol Dose (µg/kg body weight)are incredibly low if the ligand concentration is low.Similarly, ligand-receptor interactions are reducedand slowed down as a chemical’s potency decreases(Figure 9). Therefore, no paradigm has really shifted.Recall the premise that mechanistic studies are not designedto show the threshold level of plausible effects.Yet reexamination of Figure 7 does show a definitivethreshold (i.e., at 0.002 µg/kg), even for the drug DES,arguably of similar or greater potency to estrogen inbinding to the estrogen receptor (Okluicz and Leavitt1988; Hendry et al. 1999, 2004).BBABDES, a drug given to reduce miscarriages during the 1960s, andalso used as a stimulatory hormone in cattle feed, has a potencysimilar in magnitude to that of estradiol. This graph is basedon the one presented in vom Saal et al. (1997) that arguablyinitiated concerns about nonmonotonic effects of hormonallyactive agents. The data are shown as percentage change in glandweight relative to the control (100%), and the graph has beenrescaled to start from zero change. Bars with the same lettersare not significantly different from one another (probably

Figure 8. Receptor-ligand interactions.1.0Pesticides & Health: Myths vs. RealitiesConcentration of Receptor,Ligand, & Complex0.8 –0.6 –0.4 –0.2 –––––00 0.2 0.4 0.6 0.8 0.2 0.4 0.6 0.8Time (seconds)27

Vetting and Regulating PesticidesMyth: We know very little about the effects of pesticides. EPA registers pesticideswithout fully considering all of their adverse effects.The Reality of Pesticide Regulation in the U.S.:An Example of Moving the Precautionary Principlefrom Idealistic Philosophy to Real World ImplementationAnalytical technology to detect chemical residuesin the environment, including our own bodies, has advancedby orders of magnitude over the last 60 years(Figure 10). Before the introduction of specialized instrumentssuch as GC-MS (gas chromatography-massspectrometry) and LC-MS (liquid chromatographymassspectrometry) became available to everyone’sbenchtop, identifying and quantifying environmentalresidues of chemicals was a slow and imprecise processthat basically worked on one chemical entity at a time.Often, only concentrations of chemicals equivalent toparts per thousand, or perhaps tens of parts per million,could be detected. Today, routine measurementsare finding anthropogenic chemicals in the environmentat levels of parts per trillion and even parts perquadrillion. Perhaps comprehension of the small magnitudeof these minuscule amounts has been taintedby repeated reports of extraordinary congressionalspending of billions of dollars. To place our abilities inperspective, 1 part per trillion of any compound foundin water is equivalent to a purity of 99.9999999999%(Felsot 1998). The accuracy of quantifying such alevel of contamination strains analytical abilities. Yet, areport of this level of contamination often provokes acacophony of calls for more regulatory responsibility.On this basis, EPA is often criticized for inadequatelyregulating pesticides, perhaps because, historically, wehave focused analytical efforts on them and can detecttheir residues in food and water. Ironically, monitoringpesticide residues routinely has grown out of intenseregulation, not lax regulation.Historically, regulation of pesticides grew out oflaws during the first decade of the 20th century (PureFood Act of 1906 and Insecticide Act of 1910). Theselaws eventually evolved by congressional statute intothe Federal Food, Drug, and Cosmetic Act (FFDCA)and the Federal Insecticide, Fungicide, and RodenticideAct (FIFRA). These two federal statutes operatein parallel to one another, but frequently they are justthought of as FIFRA only. During 1972, FIFRA administrationwas transferred to EPA from the USDA(U.S. Department of Agriculture), while the FDA stillhad authority under the FFDCA.FIFRA has been amended many times by Congressto improve its oversight of chemical safety in theregistration process, as well as to control better use ofpesticide technology. The epitome of all amendmentswas born with the 1996 passage of the Food QualityProtection Act (FQPA). The FQPA was a milestonein regulating pesticide technology because, for the first28

Figure 9. Receptor Ligand Interactions.1.0Pesticides & Health: Myths vs. RealitiesConcentration of Receptor,Ligand, & Complex0.8 –0.6 –0.4 –0.2 –––––––––00 0.2 0.4 0.6 0.8 1 2 3 4 5 5 10 15Time (seconds)The graphs depict three different chemicals, each with a different affinity to a specific receptor. The middle graph and right graph depictligands that are approximately 10 and 100 times less potent than the ligand depicted in the graph on the left. These interactions withcompounds of different potencies illustrate that the receptor is not only quantitatively less bound as potency decreases, but the time forbinding to occur is also slowed down. Both effects would lower the probability of an adverse effect.time the law was mandated to be concerned only aboutrisks of pesticide residues to consumers rather thanbenefits to farmers, and by extrapolation, to society.To implement such a change in perspective, Congressmandated that EPA examine more closely whether achemical might be more hazardous to children than toadults, and to consider during registration of pesticideingredients whether children’s exposure might behigher than that of adults. EPA would have to changeits exposure analyses to include all sources of exposurebeyond food, such as from chemical residues indrinking water and from home and garden use. Thuspesticide residues in water, soil, air, and vegetationbecame important in assessing risk to human health inaddition to the historical focus on food.Congress also told EPA that they must considerfor registration decisions whether a chemical washormonally active in the endocrine system. Cancerpotential was also reemphasized but somewhat down-Figure 10. Analytical TechnologyHas Advanced Faster than BiologicalUnderstandingGramsPerLiterg/L10 010 -310 -610 -910 -12ppthppmppbpptppq???10 -15 1950 1960 1970 1980 1990 2000 2010YearDepiction of change in detection limits (1 ppm = 10 -3 g/L)over the last 60 years of contaminant monitoring. For year2010, uncertainty is expressed owing to the unreliability ofdetections reported at parts per quadrillion (ppq) and lackof articles reporting detections lower than 1 part per trillion(ppt).29

Vetting and Regulating Pesticidesplayed by the new concerns about putative “disruption”of the endocrine system by exogenous chemicalresidues, whether synthetic or naturally occurring.Finally, EPA would have to develop procedures forcumulating exposure to multiple pesticide residuesif the pharmacodynamics of the specific pesticideswere identical. In short, the FQPA was a regulatoryparadigm shift. Nevertheless, the basic procedure ofcollecting toxicological and exposure data remainedin effect, perhaps with the exception of greater focuson measuring parameters that could reflect endocrinesystem effects. Furthermore, the objective of assemblingthe data for risk assessment has remained theoperational paradigm for making regulatory decisionsto register a chemical for use as a pesticide.The history of pesticide regulation in the U.S.gives evidence of the law actually being a form of theprecautionary approach in operation. For example,the regulations written by EPA are vetted publicly forcomment, with EPA responding directly to all stakeholders.The regulations are dynamic and respond tonew concerns. Testing and data collection is fundedby developers of the technology who are requestingregistration. The data is audited for quality assuranceby agents independent of the owners of the pesticidetechnology. The raw data are independently assessedby EPA for risk of adverse effects. After a registrationand commercialization, the technology is continuouslymonitored from the viewpoint of new toxicologicalinformation and residue amounts present inthe environment. This activity is shared by all stakeholders,including EPA, industry, academia, and evenenvironmental advocacy groups. The law prescribesthat any adverse effects findings or reports be turnedover by industry to EPA (CFR 1997). In making decisionsto register, re-register, or decline registration ofa pesticide, EPA can and does consider whether saferproducts are already on the market, or if the new productwill replace an older, more hazardous product.Thus, modern pesticide law in the U.S. meets the idealismof the precautionary approach (Tickner 2002):it is increasingly based only on analysis of hazard; itis democratic, involving many stakeholders; it meetsthe “polluter pays” principle; it’s dynamic and changesto accommodate new information; it monitors the effectsof the decisions to register a product; and it is setup to encourage development and commercializationof incrementally safer products.The history of pesticide regulation in the U.S.gives evidence of the law actually being a formof the precautionary approach in operation.30

Pesticides & Health: Myths vs. RealitiesThe Reality of Pesticide Regulation: Truckloads ofData on Every Conceivable Effect from Studies withOverlapping and Redundant ObjectivesAs delineated in Figure 11, the prime objective ofmodern pesticide law is setting a tolerance, also knownworldwide as a maximum residue limit (MRL), forpesticide residues in foods. In fact, FDA and USDAtesting shows no detectable pesticide residues in themajority of all foods (FDA 2009, USDA AMS 2010).When detected, insecticide residues specifically occurdisproportionately in less than half of commercialfruits. Few fungicides are detected, and almost no herbicideresidues are detected. Nevertheless, despite thesetting of a tolerance for pesticide residues in food as arequirement of registration, all toxicological and environmentalchemistry studies are brought to bear on thetask. Thus, a full-blown risk assessment is required forevery pesticide, no matter what the end use is. Even if apesticide is oriented for home use, the toxicological andenvironmental data available are universally required.The difference is that, for agricultural use, certain exposureassumptions are made, while for home use, other,more appropriate exposure routes are assumed.Given that the requirement for risk assessment data ismonolithic, regardless of how a pesticide might be used,the types of studies are well designed in order to acquirethe most useful and informative data. Thus, the generalprotocol requirements for all tests needed to assess humanhealth effects and, likewise, ecological effects, areaccessible to the public through EPA Office of ChemicalSafety and Pollution Prevention (OCSPP) web siteknown as the Harmonized Test Guidelines (http://www.epa.gov/ocspp/pubs/frs/home/guidelin.htm)Figure 11. Schematic overview of modern laws regulating pesticide registration anduse (reprinted from Felsot 2010).FIFRA(1947)FEPCA(1972)Risk AssessmentFFDCA(1938)Tolerance (“MRL”)Miller (1954)Delaney (1958)LabelingFQPA(1996)RegistrationBoth FIFRA (Federal Insecticide, Fungicide, Rodenticide Act) and FFDCA (Federal Food, Drug, Cosmetic Act) arguably evolved fromearlier laws known as the Insecticide Act (1910) and the Pure Food Act (1906), respectively. The laws work in parallel under the directionof EPA. Both have been amended many times (e.g., Miller Amendment; Delaney Amendment), with the latest major amendment beingthe Food Quality Protection Act (1996). The FEPCA (the Federal Environmental Pesticide Control Act) essentially created a riskmanagement standard of “reasonable certainty of no harm” to the environment and workers. The FQPA basically changed the historicrisk-benefits balancing of FIFRA to a risk consideration only; furthermore, they broadened consumer-exposure analysis to includeresidential use of products in addition to food and water.31

Vetting and Regulating Pesticides(Table 3). The total number of tests for all aspects ofthe chemicals proposed for registration is 276. However,50 of the tests pertain only to pesticides classifiedas ‘biochemical’, which are typically natural productsand pesticides developed from microorganisms (i.e.,microbial pesticides). Thus, over 220 different tests onconventional chemical pesticides are required beforeregistration. Of this total, 49 tests address a wide arrayof health effects, and 51 address ecological effects. 11test protocol guidelines have been issued specificallyfor endocrine effects.The tests for a wide array of physiological effectson the nervous and immune system are covered underthe Health Effects Test Guidelines. These tests focuson acute toxicity (from a single high exposure) toeffects from repeated exposures over the life span ofthe test animals. The array of measurements includes,but is not limited to, reproductive and developmentaleffects (which also are indicative of endocrine systemeffects [Stevens et al. 1997]), multiple generation effects,carcinogenicity, and blood enzyme levels.The test animals are usually rodents, but for olderchemicals, beagle dogs also have been used to supplementthe rodent tests. The rodents are always testedin groups by gender, and frequent measurements aremade to assess specific parameters and general wellbeingof the test animals. Pertinently, the tests that EPArelies on most for characterizing the risk of adverseeffects are the 90-day and 2-year continuous feedingstudies. In these subchronic and chronic exposuretests, respectively, a rodent is exposed through diet toa test chemical at the stated dosage every day. Thus,each day the amount of food eaten is recorded so thatthe exact daily dose can be monitored throughout thestudy. In addition to frequent monitoring of animalsfor signs of overt toxicity, the animals are sacrificed atthe end of the study to generate thousands of tissuespecimens for examination.Table 3. EPA Harmonized Test Guidelines requirements (EPA 2010).Test SeriesNumberTest Guidelines SeriesIdentification GroupingNumber of IndividualTests in the Series810 Product Performance 8830 Product Properties 35835 Fate, Transport & Transformation 42840 Spray Drift 2850 Ecological Effects 51860 Residue Chemistry 17870 Health Effects 49875 Occupational & Residential Exposure 13880 Biochemicals 7885 Microbial Pesticide[s] 41890 Endocrine Disruptor Screening Program 11Each new pesticide data package will be required to address the individual test detailed in each section of the test guidelines, unless EPAwaives the test owing to lack of relevance or, in the case of re-registrations, availability of sufficient data in the files.32

Pesticides & Health: Myths vs. RealitiesWhose Data Are They?Under mandates of the FIFRA and the FFDCA,manufacturers seeking registration of new pesticideproducts or re-registration of older products mustsubmit data that covers the required subject areas inthe Harmonized Test Guidelines (Table 3). Thesestudies are best characterized as regulatory toxicologybecause they are intended to discover thresholdsof toxicity for an array of adverse effects. Most of thetoxicity tests use three dosages and a non-dosed controlgroup (typically rodents and beagle dogs). Basedon preliminary range-finding studies, the dosages arechosen so that most will define a specific but observedNOAEL, with the next two doses likely producingsome measurable effect.Regulatory toxicology tests differ fundamentallyfrom more basic research in that the latter is designedto study mechanisms of effects but not necessarilythresholds of effects. Although chemical manufacturersmay also carry out basic research once they havediscovered a potential commercially useful product,most research is carried out at public institutions (e.g.,NIH and EPA labs) and universities. The studies aredesigned so that definitive reactions are observed butoften do not define thresholds for the reactions as doregulatory studies. Basic research could be useful foridentifying hazards under the context of the specificlaboratory conditions, but they are not useful for riskcharacterization because they do not seek a NOAEL.Another major difference between basic toxicologicalresearch carried out by chemical manufacturersand universities or public institutions is that the formerare required to conduct all studies according to GoodLaboratory Practice (GLP) standards. GLP standardsallow EPA to independently audit the generation ofall pieces of data, as well as determine if studies wereconducted according to pre-written protocols. Thus,every “data point” is tracked, audited, and validated.Such meticulous attention to validating data and ensuringcompliance with written protocols is not a re-quirement for grant-funded research. For this reason,EPA often does not use research not conducted underGLPs to make regulatory decisions about pesticideregistrations. However, EPA uses the basic research toinform the agency of new issues or peculiarities whentesting responses that may need more scrutiny.How EPA Determines Safety Underthe Mandates of the LawWith piles of data at hand, EPA first validates itsorigin and then uses the raw data to conduct its ownrisk characterizations. EPA follows the long usedand vetted tenets of risk characterization that involveproblem formulation followed by the steps of hazardidentification, dose-response assessment, exposure assessment,and risk characterization. The latter definesthe risk by integrating exposure and the toxicologicalendpoint or benchmark of concern defined in thedose-response assessment.Of the array of all types of effects that EPA examines,the agency looks for the one that has occurredat the lowest dose tested. The NOAEL from such astudy is then used as the benchmark level from whichto compare possible exposures to the pesticide. For example,many herbicides in the sulfonylurea class are ofsuch low toxicity that exposure to hundreds or thousandsof milligrams per kilogram of body weight arerequired to produce any effect. Often such effects areincreased loss of body weight in females compared tothe non-dosed population. Thus, simple body weightloss becomes the endpoint of concern and is thenused to characterize risk. More specific effects can bemeasured when organophosphorus (OP) insecticidesare tested. Specifically, this group of compoundsinhibits the neurotransmitter-degrading enzyme acetylcholinesterasein the central nervous system. Thiseffect is quite specific and due to a known singularbiochemical mechanism (Mileson et al. 1998). So, forassessing safety of OP insecticides, EPA would chooseenzyme inhibition as the most sensitive endpoint of33

Vetting and Regulating Pesticidestoxicological concern. To reiterate, hazard identificationcharacterizes the array of possible adverse effects,and dose-response assessment defines the thresholdsfor an effect and determines which effect specificallybecomes the toxicological endpoint of concern. Thephilosophy behind this methodology is that, if youprotect nontarget organisms from the most sensitiveeffect (i.e., the effect occurring at the lowest dose),then you can protect them from all other effects.Once the most sensitive endpoint is chosen, thenEPA applies uncertainty factors (a.k.a. safety factors)to ensure that any potential exposures are likely to beat least 100-fold lower than the NOAEL. One type ofrisk management device is called the Rf D (referencedose), which is obtained by dividing the NOAEL(units of mg/kg/day) by 100. Next, EPA examinesthe database of pesticide residues in food and modelsan estimate of drinking water residues. EPA thencompares the exposure to the NOAEL, concludingeither that exposure is below the Rf D or exceeds theRf D. If the estimated exposure exceeds the Rf D, thenEPA will demand some mitigation, such as restrictingcertain product uses or, in rare cases, refusingregistration.34

Some Case Studies: Reportsof Hazards Do Not Reflect RisksThe next several sections examine more closely three specific pesticides(atrazine, chlorpyrifos, glyphosate) and the homologous group of pyrethroidsin order to determine the validity of claims of imminent harm.These pesticides were first registered by EPA 30-50years ago but are still commonly used. Owing to theirwidespread use, more toxicological and epidemiologicaltesting focusing on these compounds has arguablybeen conducted and published than on any othercurrently registered pesticide. Many of the publishedtests have examined few doses and were not designedto develop NOAELs for risk assessment, but often theresearchers have extrapolated the adverse responses tohuman exposure. Few papers have challenged the resultsof these extrapolations on the basis of fundamentaltoxicological principles operational at the likelyenvironmental or worker-associated exposures. Thus,choosing these highly studied pesticides offered anopportunity to examine critically the dosing regimesand biological plausibility of the purported effects inlight of realistic exposures.In reviewing the literature of these compounds,we deliberately avoided EPA analysis in order to determineif just relying on the open scholarly literatureitself could lead to a more skeptical attitude towardclaims of adverse effects. In every case, the main concernsabout health or ecological impacts are explained,and rebuttals are made using the peer-reviewed literature.However, EPA-regulatory reference doses or generallyacceptable acute toxicity parameters are used as35background for comparative perspectives about thechemical’s safety.AtrazineTo call atrazine the “DDT” of herbicides wouldnot be a hyperbolic exaggeration if a number ofnewspaper stories and research articles are added up.For example, searching Google Scholar for journal researcharticles yields over 58,000 hits on atrazine but268,000 on DDT. This four-fold difference, however,reflects DDT’s development and widespread use as aninsecticide in the 1940s in contrast to atrazine’s laterdevelopment and commercialization, in the late 1950s.However, the comparison remains apt, consideringthe growing number of articles ascribing to atrazineever more adverse effects, as have long been reportedfor DDT. Also, atrazine has long supplanted DDT asthe most frequently detected pesticide in the environment,albeit not in food, where it is hardly ever found.One big difference between DDT and atrazine can beexpressed by the following analogy: DDT is to bird declinesas atrazine is to frogs’ sexual development. But isit true? And, should atrazine be judged solely by frogs,as if this taxon were the proverbial canary in the coalmine? The concerns about atrazine generally divide

Some Case Studies: Reports of Hazards Do Not Reflect Risksbetween potential chronic effects on human healthand effects on diminishing frog populations throughdisruption of the endocrine system.In separating the myths and realities of atrazinetoxicity, hazards, and risks, knowing that it was firstregistered in 1958, and thereafter intensively usedmainly in corn production throughout the Westernworld, should lend some perspective to the mostrecent reports suggesting that the compound poses arisk to human health as well as to amphibians. Giventhe massive amounts and intensive use of atrazinein the Corn Belt over the last 50 years, new riskconcerns seem odd because problems should havebeen noticeable within a short time after atrazine’scommercialization. The reason for this conclusionis that atrazine was first reported in water wells andpotable water supplies in the early 1970s (Richard etal. 1975). Once scientists start looking for a needlein the haystack, they usually will find it—but not becauseit wasn’t present in the environment from thebeginning of use.Based on our current knowledge of the environmentalchemodynamics of soil-applied chemicals,atrazine is likely to have worked its way into shallowground water of the Corn Belt after the first year ofuse. Furthermore, atrazine residues are not being increasinglydetected in the environment because use isincreasing. In fact, use has gone down, if not remainedstable. However, atrazine detection frequency is aclassic story of detection sensitivity improvements(Kolpin 1995), not an indication of an exponentialincrease in residues entering the environment. Thus,contemporary stories raising alarms about atrazine inwater supplies are just not plowing new ground butrepeating information known for a very long time.The question about residues in water, especially drinkingwater supplies, generally raises the question ofwhether humans are adversely affected. The answer tothis question rests on understanding atrazine’s toxicologyand the potential for exposure based on residuesfound in environments relevant to drinking water.According to EPA, atrazine is considered tobe of low toxicity, having an LD50 from single oralexposures of 1,869 mg/kg and dermal exposures of>2000 mg/kg (EPA 2002a). Its acute reference dosewas developed by EPA as 0.10 mg/kg (EPA 2002b).Pertinently, this regulatory benchmark was based onhighly dosed rodents, wherein an effect on bone developmentoccurred at a dose rate of 70 mg/kg/day,but no effect occurred at 10 mg/kg/day. Among allthe tests that were conducted, 10 mg/kg/day was thelowest dose without any effect, and thus it was specificallydesignated as the NOAEL. Also pertinently, thisNOAEL is at least two orders of magnitude greaterthan the estimated 95th percentile exposure of 0.09mg/kg/day following mixing/loading and application(Gammon et al. 2005). In fact, at levels of humanexposure that potentially occur during legal rates ofapplication of atrazine for control of weeds, the compoundhas only one known definitive mode of causingtoxicity. Atrazine inhibits plant physiology by disruptingphotosynthesis, specifically in a biochemicalpathway called Photosystem II (Devine et al. 1993).Animals, however, do not possess biochemical pathwaysthat atrazine, at possible environmental levels,could affect. The latter statement is not to deny thattesting of highly exaggerated doses causes physiologicaleffects, but how much is used and the likelihood ofcomparable exposures must always be weighed.EPA integrated the results from toxicology testswith volumes of water drunk in a day by adults or childrento yield a maximum contaminant level (MCL)of 3 µg/L (ppb). This regulatory rule was developedunder the mandate of the Safe Drinking Water Act.Although developed back in ~1989, the regulatorystandard of 3 ppb has not been altered since. PerhapsEPA was not motivated to change this standard overthe last thirty years because toxicological informationhas not pointed to any problem not already covered inthe experiments submitted by the registrants for riskcharacterization by EPA. Indeed, EPA (2010) has stated,“Based on all the available test data, the Agency’s36

Pesticides & Health: Myths vs. Realitiesevaluation, and scientific peer review, atrazine is notlikely to be a human carcinogen”. Because both rodentstudies and available human epidemiology studiesusing workers handling atrazine failed to show anyrelationship between atrazine dose and cancer, EPAseems to be practicing the precautionary principle inasking for more epidemiological data. Yet the EPA hasstated its skepticism for finding any correlations. Theongoing multi-year National Cancer Institute studycalled the Agricultural Health Study concluded in2004, “Our analyses did not find any clear associationsbetween atrazine exposure and any cancer analyzed”(Rusiecki et al. 2004). Such a conclusion is remarkable,given that nearly every study in the AHS consortiumclaims that there is an association between somepesticide and cancer or several other health effects.Significantly, the AHS study includes a cohort of over70,000 pesticide workers and adult family membersin Iowa and North Carolina. Thus, the pesticide usersrepresent farms associated with grain production(corn and soybeans) and specialty crops (diversity offruit and vegetables that are grown in the mid Atlanticregion). Further concerns about atrazine’s adversely affectinghuman health via chronic exposure were mostrecently dispelled by the World Health Organization.WHO (2010) is recommending a drinking water qualityguideline for atrazine of 100 µg/L, a value notablyhigher than all previous guidelines.Atrazine residues are not found in food, given thatthe chemical is applied directly to the soil of basicallyonly one crop (i.e., corn) (USDA AMS 2009), so theonly contemporary pathway of exposure would bedrinking water derived ultimately from field runoff orsubsurface drainage in the Corn Belt. Thus, a very limitedgeographically located population of consumerswould be comparatively most exposed if atrazine residuessurvive water treatment and appear in finisheddrinking water supplies. Given that the MCL is basedon a non-cancer endpoint that took into considerationthe results of reproductive and developmental toxicitytests that would indicate endocrine system effects,a logical question is how likely is it that people will beexposed to the MCL? Remembering that the MCL hasapplied to it a very large safety factor of 1000 (Richardsand Baker 1995), one should be aware that evenstudies in the 1990s concluded that very few people(perhaps less than 1 person in 1,000) would be exposedto atrazine near the MCL (Richards and Baker1995). The picture has only improved, with atrazinedetectable concentrations in water dropping since1996—due in part to changes in use rates and practices(Sullivan et al. 2009). The picture should becomeincreasingly clear as even less atrazine is used with newhybrids of corn that resist glyphosate or other herbicides,thereby further reducing the need for atrazine.The California EPA’s independent study of likelyhuman health effects from consumer and workerexposure to atrazine essentially concluded very littlerisk, largely because exposure was so low relative toeffects seen in animal testing (Gammon et al. 2005).Although human exposure to atrazine seems to beinsufficient to warrant concerns for risk to health,residue levels sometimes found in the water are putativelycausing ecological effects through disruptionof amphibian endocrine physiology. Addressing thequestion of whether frogs are being sexually transformedby exposure to low levels of atrazine in theenvironment first requires a determination of the basisfor concern regarding frog development. The secondconsideration would take into account the likelihoodof a frog being exposed to “low” levels of atrazine.Without a consideration of both factors, the risk cannotbe placed in the context of human concerns.Atrazine toxicity is very low to virtually all aquaticorganisms except perhaps plants (which it is designedto kill), as shown in the accumulation of studies byEPA during the compound’s reregistration process.For example, most aquatic organisms do not die unlessconcentrations approach mg/L levels (EPA 2002c;Solomon et al. 1996). To place this concentration inperspective, atrazine is found most frequently in waterat levels between 0.001 and 1 µg/L.37

Some Case Studies: Reports of Hazards Do Not Reflect RisksWhile EPA is only now requiring that amphibiansbe tested, reports of effects of atrazine on gonadal developmentappeared in the early 2000s, a time of nonregulatorytesting. Specifically, several papers exposedthe African claw-toed frog (Xenopus laevis) to atrazinein water at levels ranging from 0.1 µg/L to 100 µg/L.The most cited report (Hayes et al. 2002) suggested thatfrogs were becoming feminized. In this case, feminizationwas measured as either the occurrence of oocytesin male testis tissue or a reduction in size of pharyngealmuscle that aids male frog sexual calling. A follow upstudy also showed the presence of oocytes in testis tissue,along with testicular dysgenesis (Hayes et al. 2003).However, in the latter study, no correlations were foundbetween the intensity of the putative endocrine systemeffect and levels of atrazine in aquatic systems wherethe frogs were collected. Furthermore, frog populationsfrom across eight regions in the U.S. under scrutinyseemed to be quite healthy, as determined from populationabundance observations. However, a more recentstudy (Hayes et al. 2010) of sexual transformation frommale to female upon exposure to atrazine in the lab hasstirred popular media headlines, as have earlier studies.If science made definitive conclusions about theways of the world based on only one laboratory, thechances for misunderstanding a natural phenomenonwould be quite high. For this reason, that differentlaboratories try to repeat each other’s work is preferablein order to determine whether observations aregeneralizable across species or are even likely in theactual environment. Thus, other independent laboratorystudies of the effect of atrazine on frog gonadaldevelopment, both of Xenopus and several other species,have failed to repeat the observations of Hayes etal. (2002, 2003) (Carr et al. 2003; Coady et al. 2004,2005; Du Preez et al. 2008; Kloas et al. 2008; Oka et al.2009; Spolyarich et al. 2010). Field studies also do notfind positive correlations between atrazine concentrationsin breeding habitats and adverse histological orsex ratio patterns (Du Preez et al. 2005, 2009; Smith etal. 2005; McDaniel et al. 2008).In addition to a number of studies failing toconclude that atrazine is affecting gonadal developmentof frogs, these studies have generally made twoimportant points that should l substantially lessen anyconcerns about atrazine functioning as an endocrinedisrupting chemical. First, the putative mechanism bywhich Hayes et al. (2002, 2005) have proposed thatatrazine feminizes male frogs works through aromataseenzyme induction. Induction of the enzyme couldresult in greater rates of transformation of testosteroneto estradiol, thus depleting male androgen hormoneconcentrations during key stages of development.However, studies that do not show any hormonallyrelated effects of atrazine also fail to detect any inductionof aromatase. (Hecker et al. 2004, 2005; Murphyet al. 2006; Oka et al. 2008). Male frogs collectedfrom agriculturally-dominated habitats do not showsignificant differences in estradiol hormone levels orestradiol/testosterone ratios from non-agriculturallandscapes (McCoy et al. 2008). Hormone levels infrogs collected from diverse non-agricultural and agriculturalhabitats did not, in fact, correlate with atrazinelevels (McDaniel et al. 2008). Thus, little support for ahypothesis of aromatase induction has been observedin studies that relate field-collected frog parameters toatrazine residues.The second informative point is atrazine’s lack ofeffect on reproductive success. Thus, allowing exposedtadpoles to complete development and then materesults in no impairment of fecundity or fertility (DuPreez et al. 2008). So, even if atrazine were having anon-detectable effect on frogs, the ecological consequencesare moot, owing to a lack of effect on fertility.Indeed, this laboratory observation echoes what Hayeset al. (2003) observed in the field when they examinedfrogs across eight U.S. regions. To quote from the latterresearch, “Juvenile R. pipiens were abundant at allof our collection sites, however, including agriculturalareas in Iowa and Nebraska. The abundance of frogs atthese sites suggests that the effects are reversible, thatsome percentage of the population does not show this38

Pesticides & Health: Myths vs. Realitiesresponse, that these developmental abnormalities donot impair reproductive function at sexual maturity,and/or that continuously exposed populations haveevolved resistance to atrazine.”More recent research has questioned whether frogsmake good “canaries in the coal mine” (Kerby et al.2010). In fact, the conclusions were that amphibians arenot as sensitive to environmental contaminants as otheraquatic organisms are. Thus, newspaper accounts thatexpress alarm at the findings from one laboratory overatrazine’s potential to disrupt the endocrine system, regardingthese as a bellwether for human concern, seemsto belie all the data that has been published within thelast five years. Ironically, the same newspaper accountsof recent atrazine effects from the Hayes lab seemedto have forgotten their own publication two years earliershowing that frog populations were in much poorercondition around urban influenced aquatic systemsthan around agricultural systems (Barringer 2008).Given that atrazine is not permitted or used in urbansettings, the facts from the environment contrast withone scientist’s observations in the lab.One thing is certain, however: Studies will continueon atrazine as long as it is used. Indeed, EPA iscontinuing to examine data on human cancer epidemiology,as well as effects on amphibians, noting in anApril 2010 web posting, “Although EPA is not currentlyrequiring additional testing of atrazine on amphibians,as discussed earlier on this Web page, EPA has begun acomprehensive reevaluation of atrazine’s ecological effects,including potential effects on amphibians, basedon data generated since 2007” (EPA 2011). No onecan rightly claim that EPA is not practicing precautionwhen it comes to atrazine.ChlorpyrifosChlorpyrifos is an organophosphorus ester insecticide(specifically, O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate) that was first commercializedin 1965. Before the passage of the FQPAin 1996, chlorpyrifos was arguably the most usedinsecticide in the world. By 2002, however, its use ondeveloping fruit and as a termiticide and home andlawn insecticide had been voluntarily suspended byits manufacturer, Dow AgroSciences, in an agreementwith EPA. Chlorpyrifos is still registered for some vegetablecrops (e.g., plants in the Family Cruciferae, suchas cabbage, collards, kale and Family Alliaceae —suchas onions), including field and sweet corn, but its majoruse today is restricted to dormancy season sprayson pome fruits (apples and pears) and nuts. Dormantsprays occur when no fruit is growing; thus the opportunityfor exposure through fruit and nut consumptionis nil. Because potential chlorpyrifos hazards aredependent on the degree of exposure, examination offood residue data foretells the likelihood of adverse effects.Data from the USDA’s most recently publishedcomprehensive survey of pesticide residues, in distributioncenters around the U.S., are informative forpredicting trends. The latest data indicate that only 3%of more than 10,000 individual food items analyzedhad detectable residues of chlorpyrifos (USDA AMS2009). The levels found were typically 100-1000-foldless than the residue tolerance, or the legal concentrationthat has been set, in part, to protect human healthas required under the Food Quality Protection Act(1996; Title IV, Section 405(b)(2)(A)(i and ii)).Chlorpyrifos, like other organophosphorus esters,inhibits the nerve membrane enzyme called acetylcholinesterase(AChE). AChE breaks down the neurotransmitteracetylcholine, which functions as thesignaling compound between nerve axons and dendritesin the central nervous system as the electricalcurrent traveling down stimulated nerve membranesis transduced to chemical energy in the region of thesynapse. AChE is anchored on the post-synaptic (i.e.,dendritic) membranes near the acetylcholine receptorproteins. By breaking down and thus lowering the concentrationof acetylcholine neurotransmitter before itcan bind to the receptors, AChE functions to dampenthe stimulatory electrical signals originating distally39

Some Case Studies: Reports of Hazards Do Not Reflect Risksfrom up the nerve axon. When OP insecticides bindto the enzyme, they inhibit its function. Inhibitionof AChE allows excessive concentrations of AChE topersist in the synapse and, consequently, stimulationof the nerve axons continues unabated.Inhibition of AChE is the only known biochemicaleffect of chlorpyrifos at exposure levels associated withlegal rates of application in the environment. However,chlorpyrifos itself is not functional in inhibiting acetylcholinesterase.Rather, chlorpyrifos has to be metabolizedto an oxidized form called chlorpyrifos oxonto have biological activity. Therefore, of public healthinterest is whether chlorpyrifos oxon is detected infood. The USDA AMS (2009) reported no findings ofoxon residues in food, thus validating very minimal exposureof human populations to chlorpyrifos. Athoughchlorpyrifos can be metabolized to its oxon form withinan organism, its further metabolism and excretion inhumans is so fast that it cannot be detected even withinhours after dosing (Timchalk et al. 2002).Despite the low potential for current exposure ofU.S. citizens to chlorpyrifos insecticide residues, theliterature is replete with data showing widespread detectionof an essentially nontoxic breakdown productcalled trichloropyridinol in human urine, as well as alkylphosphate metabolites (Payne-Sturges et al. 2009).Thus, the perception that people today are widelyexposed to chlorpyrifos residues is generated fromthese studies. However, these studies reflect the resultsfrom urine samples collected when chlorpyrifos waswidely used and before the significant restrictions onits use. Furthermore, evidence suggests that the nontoxicalkyl phosphate metabolites occur already on thefruit before consumption (Zhang et al. 2008). Thus,detection of these chlorpyrifos degradation productsin urine is not an accurate reflection of exposure to thetoxicant. Because dietary exposure, rather than housedust, has been considered a primary pathway of exposureto children (Morgan et al. 2005), detection ofchlorpyrifos residues in households is also not directlyapplicable to actual exposure levels. Thus, the pres-ent perception of hazards from chlorpyrifos (as wellas the few other OP insecticides still used), based onolder studies of residues in households and urine biomonitoring,are inconsistent with the studies showingchlorpyrifos residues are only infrequently detectedin food—as well as the fact that the compound is nolonger used directly on fruit or in urban environments.Indeed, within two years after removal of chlorpyrifosfrom urban uses, researchers could detect lower exposures,concluding that aggregate potential doses ofchlorpyrifos were well below published reference dosevalues (Wilson et al. 2010).Any compound that affects any of the nervous systembiochemical parameters is considered automaticallyto be a neurotoxicant. As is true for all biochemicals,the probability of causing observable neurotoxicresponses to chlorpyrifos and similar chemical compoundsdepends on dose, or the degree of exposure.When there is proven exposure in a case-controlledepidemiological study, the results do not support acase for hazardousness. For example, applicators ofchlorpyrifos-based termiticides were logically a veryexposed subset of the population. Thus, if chlorpyrifosis a potent neurotoxicant in adults, one would predictsevere neurotoxicology problems in applicators. Yet,an epidemiological study of 191 applicators, whoseurine proved they were over 100 times more exposedthan a non-applicator control population, concluded,“The exposed group did not differ significantly fromthe nonexposed group for any test in the clinical examination.Few significant differences were found innerve conduction velocity, arm/hand tremor, vibrotactilesensitivity, vision, smell, visual/motor skills, orneurobehavioral skills” (Steenland et al. 2000). Thelatter observational results would be considered moreobjective than questions seeking subjective informationabout applicators’ personal experiences. The onlysubgroup where personal experiences regarding illnesscould be reliably measured were the eight applicators(of a total of 191) who had a past acute illness associatedwith chlorpyrifos use.40

Pesticides & Health: Myths vs. RealitiesOne concern about chlorpyrifos exposure voicedfrequently in the literature is the potential neurotoxiceffects on developing fetuses, newborns, andadolescents. Many of the reports suggesting potentialeffects in these vulnerable age groups stem from oneresearch lab at Duke University starting in the 1990sand continuing through today, although other labshave reached similar conclusions (cf. literature reviewsin Slotkin 1999; Eaton et al. 2008). Studies have includedboth in vivo exposure of neonate rat pups (e.g.,Campbell et al. 1997; Whitney et al. 1995; Song et al.1997; Dam et al. 1998, 1999; Aldridge et al. 2005a)and occasionally mothers (e.g., Qiao et al. 2003; Meyeret al. 2003; Aldridge et al. 2005b) and in vitro studieson axonal type cell cultures (e.g., Jameson et al. 2006;Yang et al. 2008; Slotkin et al. 2010). The conclusionof all of the aforementioned types of studies is thatchlorpyrifos may cause developmental neurotoxicitythrough mechanisms other than through cholinergiceffects (Slotkin et al. 2006).Several issues are raised by the plethora of researchon chlorpyrifos and putative mechanisms ofdevelopment neurotoxicity, owing to the policy thatEPA has adopted for regulating organophosphorusinsecticides. Presently, EPA regulates this group bydefining the NOAEL for acetylcholinesterase inhibition.In particular for chlorpyrifos, however, a plasmaresidingform of acetylcholinesterase, popularly called“pseudocholinesterase,” or just plasma cholinesterase,is actually more sensitive to inhibition than trueacetylcholinesterase, which is found in the centralnervous system as well as in red blood cells (Eaton etal. 2008). Thus, inhibition of plasma cholinesteraseis the most sensitive endpoint chosen to characterizerisk and calculate an Rf D. For example, based onthe NOAEL for plasma cholinesterase inhibition andapplication of a 100-fold safety factor, EPA has set anRf D of 0.005 mg/kg/day for short-term (acute) chlorpyrifosexposure. To protect children under six yearsold, EPA included an additional 10-fold safety factorto yield a population-adjusted reference dose (calleda PAD) of 0.0005 mg/kg/day). The comparable longterm(chronic) PAD, which included the combined1000-fold safety factor, was designated as 0.00003mg/kg/day. EPA’s final decision for re-registrationof chlorpyrifos in 2006 was predicated on no furtherurban uses and no uses on fruit trees post-bloom or oncertain vegetables, like tomatoes (EPA 2006a). Pertinently,EPA uses the Rf D as an exposure guideline toensure the congressional mandate of “safe”, meaninga “reasonable certainty that no harm will result fromaggregate exposure to the pesticide chemical residue,including all anticipated dietary exposures and allother exposures for which there is reliable information”(Food Quality Protection Act 1996).EPA cited the growing developmental neurotoxicityliterature at the time of its reregistration decision,noting that a noncholinergic mechanism could be atwork (i.e., a mechanism that does not inhibit acetylcholinesterase).The most recent literature based on invitro studies suggests that acetylcholinesterase functionsas a morphogen — i.e., the intact enzyme stimulatesgrowth of nerve axons. Simple binding to theenzyme without inhibiting its activity could reducethis morphogenic functionality (Yang et al. 2008).Another proposed mechanism is the altered regulationof genes that code for neurotrophic factors thataffect nerve growth (Slotkin et al. 2010). AlthoughEPA did not consider these effects when delineatingits Rf D for protection of infants and children, a recentrisk characterization for school children by the CaliforniaEnvironmental Protection Agency proposed achild specific Rf D of 0.0001 mg/kg/day after consideringthe noncholinergic mechanisms that may affectthe developing central nervous system and applying a300-fold safety factor to a NOAEL for such effects.A second issue raised by a putative novel mechanismof action of chlorpyrifos, and perhaps other OPinsecticides that are either no longer used or have veryminimal usage today (i.e., parathion and diazinon, respectively),is what level of exposure for either pregnantmothers or newborns/infants might be associated with41

Some Case Studies: Reports of Hazards Do Not Reflect Risksthe developmental neurological effects. A disproportionatenumber of studies that have shown developmentaleffects through noncholinergic mechanismshave used exposure routes and dosages that do notreflect environmental reality. For example, many studiesuse subcutaneous injections of chlorpyrifos in dimethylsulfoxide, a solvent that promotes rapid penetrationthrough biological tissues (Pathan and Setty 2009).Furthermore, dosages of chlorpyrifos have ranged fromabout 0.5 mg/kg body weight to 1-5 mg/kg. The realityof exposures is that humans would be exposed as afetus through the mother’s placental barrier, or as aninfant through mother’s milk, or as a child through thefood supply. Note that chlorpyrifos is no longer usedaround homes, so consideration of this specific route ofexposure is not relevant to characterizing the remaininguses of chlorpyrifos. Also, exposure would be dividedthroughout any one day and not a single acute bolus, asoccurs in many lab studies that focus on mechanisms ofan effect rather than on likely risks of an effect. An analysisof the effect of route, vehicle, and divided doses onpharmacokinetics and concentrations of chlorpyrifosand metabolites in blood suggest that single bolus dosesin vehicle (corn oil or dimethylsulfoxide) raise bloodlevels higher than levels from divided doses in the diet(Marty et al. 2007).Although the routes of exposure and concentrationin the preponderance of developmental neurotoxicitystudies do not reflect reality, one could still usethe data to determine whether chlorpyrifos exposuresare likely to have the effects seen in neonatal laboratoryanimals. Such an analysis would require informationabout the likely intake of chlorpyrifos residues.The analysis would also benefit from informationabout blood and/or tissue levels of chlorpyrifos or itsdetoxification metabolite TCP (trichlorpyridinol) forcomparison to effects observed during in vitro studies.As part of its decision to re-register chlorpyrifos,EPA estimated the aggregate intake of residues ifcertain agricultural, and all urban uses, were to becurtailed. For example, such restricted use patternsof chlorpyrifos would result in a worst-case aggregateintake from food, water, and mosquito control use forchildren one to six years of age, of ~0.00067 mg/kg(EPA 2006a). Thus, EPA’s estimated exposure for currentuse patterns of chlorpyrifos would be nearly 1000-fold lower than the lowest doses given to neonatal ratsin many studies of developmental neurotoxicity. Forexample, in one study concluding that adverse neurodevelopmentaleffects follow gestational exposures,pregnant rats were dosed subcutaneousy by injectionwith 1-5 mg/kg chlorpyrifos (Aldridge et al. 2005b).Neonatal rats and post-natal rats were dosed by injectionwith one and five mg/kg, respectively.Studies conducted in vitro using model cell culturesof nerve axon growth are not directly comparableto dosages from in vivo studies. One problem isthat in vitro cell culture studies place the toxicant atthe surface of cell membranes, an exposure situationthat is completely devoid of all the pharmacokineticmechanisms that would significantly reduce concentrationsarriving at target sites through transport in theblood stream. However, the concentrations in in vitrostudies can be compared to blood concentrations ofchlorpyrifos or TCP that have been measured in associationwith known dosages either to neonates or topregnant females.To perform a risk characterization that would beconservatively protective in perspective, one shouldexamine a study that has found an adverse effect atthe lowest dose relative to other studies. Recently, awell-conducted study showed that axon growth bylengthening was reduced when cultured rat dorsalganglion cells from the brainstem were exposed to0.001 µM (equivalent to a chlorpyrifos concentrationof 0.351 µg/L) (Yang et al. 2008). Although anotherstudy from the same lab showed no significant responseuntil the concentration was 0.01 M, one coulduse 0.001 µM as a benchmark for comparison to whata fetus or neonate might have in its blood. One studyshowed that “fetuses of dams given 1 mg/kg/day hada blood CPF level of about 1.1 ng/g (0.0011 µg/g),42

Pesticides & Health: Myths vs. Realitiesbut had no inhibition of ChE of any tissue” (Mattssonet al. 2000). Thus, this study proved that chlorpyrifoscould be detected in blood without any cholinergiceffects. If blood is assumed to have a density close to1 g/mL, then 0.0011 µg/g translates to about 1 µg/L.Although a dose of 1 mg/kg is frequently described as“low” in the published literature, EPA estimated thatworst-case aggregate exposures (i.e., food, water, andmosquito control combined) may be about 0.00067mg/kg/day. If there is a numerically linear relationshipbetween what is in the blood and the dose, suchas the findings suggested in Mattsson et al. (2000), orthose reported in Eaton et al. (2008), then a pregnantmother exposed at the aggregate exposure level estimatedby EPA (i.e., 0.00067 mg/kg/day) may resultin exposure to the fetus at a level of ~0.00067 µg/L,which is not likely to be detectable with typical detectionlimits of ~ 4 µg/L (Marty et al. 2007). So, even invitro mechanistic studies designed to show an effect atvery low levels are still using doses that are unlikely tobe seen in fetal or even neonatal rats.A preponderance of studies have now shown thatchlorpyrifos, and a few other OP insecticides at doses100 or more times higher than current EPA estimates ofexposure, have mechanisms different than those causingacute or subchronic toxicity. Thus far, no studies haveshown that these effects occur at the known environmentallevels. The whole issue may soon become moot,as manufacturers are either not re-registering OP insecticidesor EPA is further canceling their uses. Nevertheless,one could question whether any evidence supportsneurobehavioral effects during the time that these typesof insecticides were heavily used. Several neurologicalendpoints might be probed to answer this question. Forexample, one could look at trends in autism spectrumdisorders or IQ in general as being related to exposureto neurotoxicants. Thus, one hypothesis would be thatif chlorpyrifos were as potent as mechanistic lab studiesare interpreted, then trend data would show a downwarddirection, especially when these compounds weremost intensely used.The present literature on autism spectrum disordersdoes not indicate that neurotoxicant pesticideslike chlorpyrifos are etiologic factors in this diseasephenomenon (e.g., Newschaffer et al. 2007). Furthermore,trend data indicates a rapid rise in diagnosedcases during the late 90s and early 2000s (Spzir 2006)at a time when OP insecticide use was declining.Another curious observation relates to trends inIQ, which of course can be a controversial subject initself, as discussions devolve into the classic nurture vs.nature debate. Nevertheless, there has been a trend inrising IQs since the 1950s (Lynn and Pagliari 1994;Blair et al. 2005), a period when some of the first OPinsecticides became commercially available. (Majorintelligence improvements are seen in the domain ofabstract problem-solving ability on cultural-free tests(Colom et al. 2005).) The phenomenon of rising IQs(know as the Flynn effect, after seminal research byFlynn 1984, 1987) in many countries worldwide maybe slowing down in recent years (Teasdale and Owen2008), but ironically the hypothesized recent trendseems coincident with severe restrictions on OP insecticideuse and even outright cancellations of uses.Thus, if OP insecticides were potent enough to causeneurodevelopmental anomalies in association withlevels of real-world exposures, one would predict botha direct correlation with use and trends in macro-leveleffects like autism and IQ. Yet such a correlation is notpresent, or is opposite what would be predicted.Pyrethroid InsecticidesThe term “pyrethroid” refers to all synthetic versionsof insecticidal compounds based on the structureof components of the botanical extract called pyrethrum.Chrysanthemum cinaerifolium, one of about30 species in the genus Chrysanthemum, is particularlyuseful as a source of pyrethrum extracts that becomeconcentrated in the flowers. While gardeners still telltales of planting chrysanthemums to ward off insectpests around their gardens, in fact only C. cinaerifolium43

Some Case Studies: Reports of Hazards Do Not Reflect Risksis a useful source of pyrethrum, and it is not commerciallyproduced in the U.S. This particular species isstill cultivated commercially for its trove of pyrethrumcomponents, but the geographic foci include Kenya,Rwanda, Ecuador, and Australia (Gullickson 1995;Wainaina 1995; MacDonald 1995). Pyrethrum and,more specifically, pyrethrins, which are componentsof the whole extract, are sold commercially, and areone of the few neurotoxic insecticides approved forcertified organic agricultural production under theUSDA National Organic Program and various Stateorganic program rules (WSDA 2010).Because the synthetic pyrethroids have generallythe same mechanism of biochemical toxicity as thenaturally occurring pyrethrins, consideration of thehistorical aspects of the invention of these compoundsand their use helps elucidate the modern safety recordof these compounds. Pyrethrum-containing flowerswere likely first used as palliatives for warding offbody and head lice in the early 1800s among tribesof the Caucasus region and in Persia (Casida 1980).Pyrethrins, and also permethrin—which is a syntheticanalog of the natural products—have medicinal usestoday to treat head lice infestations occasionally affectingyoung public school-age children. However,use of pyrethrins and pyrethroids in this manner isstrictly under regulatory control of the Food and DrugAdministration (FDA) rather than EPA.Pyrethrum, a complex mixture of at least six bioactivecomponents, is concentrated in C. cinaerifoliumflowers. Each flower contains about 3-4 mg of pyrethrins,the most insecticidal components of the pyrethrummixture (Casida 1980). Flowers were dried andtraditionally applied to the body as a powder. In Japanduring the early 1900s, the flowers were extracted andcomponents partially elucidated (Katsuda 1999),with more definitive structural determinations madein Germany. In the 1920s, flowers were extracted commerciallywith kerosene to isolate and concentrate theactive principal components (Casida 1980).One important aspect of the early work on pyrethrummixture chemistry was the discovery that the individualcomponents consisted of a melange of threedimensionallydistinct structures called stereoisomers.Stereoisomers are molecules that share the same molecularformula and sequence of bonded atoms but areFigure 12.1 R trans permethrinBioactive Insecticide1 S trans permethrinNot ActivePyrethrins and their synthetic analogs exist as enantiomeric mixtures that consist of identical molecules existing in two distinct threedimensionalconfigurations that are mirror images of each other, much like a left hand cannot be superimposed on a right hand. Suchchemistry is significant from the perspective of biological activity, as noted above for the synthetic pyrethroid permethrin.44

Pesticides & Health: Myths vs. Realitiesdifferent in the three-dimensional spatial orientationsof their atoms (Moss 1996). The pyrethrins and theirsynthetic derivatives, for example, are special types ofstereoisomers called enantiomers because they exist inat least two different three-dimensional configurationsthat are mirror images of each other. Molecules thatare mirror images are not superimposable, analogousto the right and left hand of an individual (Figure 12).Research has proven that enantiomers have differentlevels of toxicity and also rates of environmentaldegradation (Elliott and Janes 1977; Qin et al. 2008).Thus, to simply talk about potency of most pyrethrinsand their synthetic derivatives is misleading because,in reality, they are enantiomeric mixtures, and notall the components are insecticidal. Nevertheless,elucidation of the complexity of three-dimensionalstructure gave impetus to the discovery of syntheticanalogs that could potentially enhance insecticidalqualities of the natural product (Katsuda 1999). Suchenhancements lead to more selective compounds thatare more potent against pests and thus can be appliedin comparatively lower amounts.Pyrethrins can be rapid-acting and extraordinarilytoxic to a number of insect pest species, yet ofextraordinarily low toxicity to mammals. However,pyrethrins have little to no use in agriculture becausethey literally degrade in hours when exposed to sunlight(Elliott 1976). This environmental lability is arguablyone rationale that the USDA National OrganicStandards Board (NOSB), under recommendationof the Organic Materials Research Institute (OMRI),has used to approve natural toxins for use by certifiedorganic farmers. Ironically, if a pest infestationis not controlled sufficiently by using the unstablepyrethrins, a farm manager may feel justified in makingrepeated applications, which of course requiresmore labor, more chemical cost, and increased fueland water usage. Thus, the ideal would be to “invent”a compound with the safety (i.e., very low toxicity) ofpyrethrins but with sufficient environmental longevitysuch that one application would typically be suf-ficiently effective, especially if a well thought-out IPMplan were deployed.With goals of increasing biological activity andenvironmental persistence of the natural pyrethrumconstituents, Michael Elliott and coworkers obtainedfunding from the British government to examine waysto alter the pyrethrin structure to increase environmentalstability against sunlight without losing its safetywith respect to birds and mammals. Tinkering with thestructure, Elliott and his team were credited with inventingthe first stable synthetic pyrethroids (Elliott et al.1973a), as well as pyrethrin analogs with greater insecticidalactivity but even lower vertebrate toxicity than thenatural products (Elliott et al. 1973b). This research laidthe groundwork for synthesis of many analogs, whereintinkering with the basic pyrethrins structure increasedpersistence without substantially altering mammaliansafety and high potency as an insecticide.Closer examination of the reasons why pyrethrinsand derivatives are safe for mammals and birds butnot for insect pests is consistent with the themes ofselectivity among species and the role of pharmacokineticsin predicting the likelihood of biological effect.Pyrethrins are quickly metabolized to non-toxiccompounds by birds and mammals, and thus whenexposed via the skin, as would be typical of environmentalor medicinal use, these components areextraordinarily safe yet effective at killing insect pests.Part of the selectivity from environmental dermalexposures comes from very low penetrability (~1% inhuman skin) (Ray and and Forshaw 2000). In general,the synthetic derivatives, which have evolved in structureover the last 30 years, have similar properties ofextraordinary safety and effectiveness. In addition tolow potential for pyrethroids to cross the epidermis,selectivity among insects and mammals and birds isdue to differences in the ability of pyrethroids to bindto vertebrate and insect nerve membranes, differencesin metabolic pathways between mammals and insects,and the fact that insects are “cold-blooded” (Casidaand Quistad 2004; Narahasi et al. 2007).45

Some Case Studies: Reports of Hazards Do Not Reflect RisksFirst, the natural pyrethrins and synthetic versionsall bind to proteins in the nerve cell membranes alongthe signal conducting axon. These proteins act likegated channels, allowing the influx of sodium into theaxon, but they only open and close briefly in responseto an electrical stimulus (i.e., a voltage change acrossthe membrane caused by an oncoming nerve signal).Pyrethroids bind to the protein, preventing it fromclosing quickly, causing a prolongation of nerve signaling(Narahashi 1987; Soderlund and Bloomquist1989). However, vertebrate sodium channels have avery low binding affinity for pyrethroids, but the insectchannel protein is bound very readily by extremelysmall quantities of pyrethroid. Thus, pyrethroids aretypically hundreds to thousands of times less toxic tomammals than to insects (Elliott 1976; Casida et al.1983; Katsuda 1999). Such differences mean that verysmall amounts of pyrethroids can be deployed to controlinsects, and these amounts are vastly lower thanthe amounts that might cause harm to mammals. Secondly,mammals can very rapidly detoxify pyrethroidswith two types of enzyme systems (i.e., esteratic andoxidative enzymes), but insects cannot because theyare deficient in esterases that are active against thesechemicals.A third reason for differential toxicity between insectsand mammals is that toxicity of pyrethroids risesas temperature falls, a phenomenon not seen by otherextant types of insecticides (Narahashi 2007). Thehighly protective role of the skin in preventing entry oftoxic substances into the blood stream (i.e., systemiccirculation) is illustrated in lab experiments whereindirect injection of natural pyrethrins into the bloodresults in lethality at doses quite similar to the mostneurotoxically potent OP insecticides like the bannedparathion. The continued approval of certain formulationsof pyrethrins for use in organic agriculture (e.g.,Long et al. 2005; Zehnder et al. 2007; Reganold 2010)leads to the conclusion that at least some advocateshave realized how toxicity is greatly modified by pharmacokineticphenomena.The insecticidal activity of pyrethrins and certainolder synthetic derivatives can be enhanced by anadditive called piperonyl butoxide (PBO). Althoughformulations including PBO are not permissible foruse in certified organic agriculture, many householdversions of pyrethrins that are sold to consumers docontain PBO. PBO functions as a synergist that inhibitsmicrosomal oxidase enzymes (Hodgson andLevi 1998), further reducing the ability of insects todetoxify the pyrethrins. Because humans can detoxifypyrethrins by a different metabolic pathway than do insects(i.e., via esterase cleavage (Abernathy and Casida1973)), PBO is of very low concern for human healthunder permissible usage conditions. Interestingly, thetoxicity of the modern pyrethroids is not enhancedsufficiently by PBO to warrant adding this synergist totheir commercial formulations.The historical record and knowledge of toxicologicalmechanisms accumulated over the last 50 yearsshows that use of a naturally occurring botanical componentand its synthetic derivatives has a high degree ofsafety. So, what are the objections to using such technology?Aside from the general disdain for use of syntheticchemicals in agriculture (or other social sectors) amongcertain advocates, rumblings questioning the safety ofthese compounds have emerged over the last few years.Atypically, however, long-term concerns about canceror neurodevelopment do not seem to be strong motivatorsfor these concerns, as are those that have beenobserved for older chemistries. After all, the literatureshows the pyrethroid structures are not mutagenic(Pluijmen et al. 1984; Miyamoto et al. 1995). Furthermore,the environmental use rates are at least 10-foldlower than the use rates for the older chemistries, andthus exposure potential is quite limited. Pyrethroids areused in commercial agriculture, but their use tends tobe limited to field crops, including cotton and corn, andsome vegetables rather than to fruit crops. Entomologistsare wary of recommending pyrethroids in fruitcrops, owing to their tendency to knock out beneficialpredacious mites and thus stimulate a pest mite out-46

Pesticides & Health: Myths vs. Realitiesbreak (Hoyt et al. 1978; Hull et al. 1985). Indeed, thejudicious use of pyrethroids is evidenced by monitoringdata that shows most fruit and vegetables do not havepyrethroid insecticide residues (USDA AMS 2009).Perhaps the biggest factor in pushing newspaperstories that question pyrethrins, and thus pyrethroidssafety, comes from the use of lice control shampooformulations. As stated above, such use is consideredpharmaceutical and under control of the FDA. Flameswere fanned within the last several years over an advocacyreport that questioned whether pyrethroidchemistries were actually as safe as advertised (Pelland Morris 2008). Recent reassessments of safety,leading to re-registration of the pesticides, delineatedthe overall low acute and chronic toxicity of thesecompounds (EPA 2006), but such documentationwas ignored in favor of a database of complaints frompeople using pyrethroids at home for lice control. Theadvocacy report led off with a story about a child whodied following the parents’ use of a pyrethrin productto rid her of head lice. However, the report did notquestion whether the product was used strictly asdirected, which is expected of consumers using anytype of medication. Indeed, the report mentioned thechild being in the bathtub while her parents washeddown her hair, but it did not connect the two events.In fact, product labels strictly tell parents to apply theinsecticidal shampoo dry by rubbing directly into thescalp and then washing off after a short contact time(Frankowski et al. 2002). The label informs parents theproduct should not be administered in the bath, whichwould easily cause the active ingredient to penetratehighly penetrable body regions such as the genitalia.Head lice products may be applied one more timewithin 7-10 days after the first application. When thisstricture is violated, transient toxicity could result—aswas reported for a toddler whose parents applied apyrethrin product three times within a 12-day period(Hammond and Leikin 2008).Reports to poison centers following use of pyrethrin-typeproducts has a long history, partly becausethese products have been on the market a long time.But most reports involve some kind of skin sensitivityor irritation. Such observations are especiallytrue with pyrethrum extracts for two reasons. First,because the extracts are derived from flower parts,allergic reactions are possible. Indeed, head lice shampooproducts warn against use if allergy to ragweedis suspected, although modern extraction techniquesminimize the co-extraction of allergens (Frankowskiet al. 2002). Second, natural pyrethrin extracts havelong been known to cause a skin tingling and burningsensation called parasthesia (Ray and Forshaw 2000).However, the sensations associated with parasthesiaare temporary effects that are incidental to the specificneurotoxicological effects of the insecticides knownfrom insect and rodent studies.A second recent issue seems to be restricted toCalifornia, where pyrethroid insecticides are heavilyused in urban environments. Extensive monitoringstudies of urban streams have shown the presence ofmultiple types of pyrethroid insecticides in the bottomsediments. Pyrethroid residues will bind very tightlyto sediments, limiting bioavailability to species likefish swimming in the water column (You et al. 2008).Indeed, very few, if any, residues can be measured inwater because the water solubility of most pyrethroidsis extremely low. Bioassays with sediments collectedfrom urban waterways in California have been testedusing Hyalella azteca, a sediment-dwelling amphipod.A positive correlation has been reported with increasingdetections of multiple pyrethroid insecticide residuesand lethality of the sediments to the amphipod(Weston et al. 2005; Amweg et al. 2006). However, aclear NOAEC is present in the dataset. Furthermore,similar monitoring in Tennessee, another State wherepyrethroid use in urban areas is likely prevalent,showed few pyrethroid detections in the sediment andno toxicity to amphipods (Amweg et al. 2006). Theseobservations suggest that urbanites in California maybe disproportionately disposing of pyrethroid rinsewater on hard surfaces following lawn and house pest47

Some Case Studies: Reports of Hazards Do Not Reflect Riskscontrol, thereby increasing the chance of direct runoffinto sewage drains. Further studies should elucidatepathways of contamination and suggest improvededucational programs for homeowner disposal of pesticidewaste.Now that OP insecticide use has decreased significantlyin agriculture and been practically eliminatedfrom urban use, pyrethroid insecticides have becomethe dominant insecticides, especially in residentialareas. Thus, increasing focus on sublethal effectswill be seen in the literature, and claims of low doseeffects are likely to be made, somewhat similarly tothose claimed for the effects of chlorpyrifos on neurodevelopment.Indeed, some studies have shown thatpyrethroid insecticides can interact with the estrogenor androgen receptors (Du et al. 2010). However, theflaw in assessing hazard, let alone risk, from this newcrop of studies remains the same. The premise thatthe studies represent low-dose exposures is not consistentwith exposure estimates. Furthermore, in vitrostudies use doses that are orders of magnitude higherthan estimates of pyrethroid residues in blood, whichcould be considered a surrogate for understandingconcentration effects at the cellular level. Also, in vitrostudies tend to use dimethyl sulfoxide to dissolve thehydrophobic pyrethroid insecticides, thereby creatingan artificially high bioavailability that does not occurin living organisms.An example of ignoring how concentration is relatedto effects is illustrated in perhaps the first studyto suggest that pyrethroids have endocrine receptorbinding activity in cultures with estrogen responsivecell lines (Garey et al. 1998). Examination of thegraphs in this report suggests that binding may haveoccurred with doses of fenvalerate around 420 µg/L(~1 µM). To place this concentration in perspective,examination of blood levels of pyrethroids is useful.One study of blood samples from 45 human volunteerswho had been exposed nightly to repellent uses ofpyrethroids for mosquito control found no pyrethroidresidues were detected at a limit of 0.5 µg/L(Rameshand Ravi 2004). This fenvalerate detection limit is 800times lower than the levels causing a positive responsein vitro . To place the lack of potency of fenvalerate inperspective, let alone the high dose tested relative toblood levels (or lack thereof), estrogen (i.e., estradiol)gave a similar cell response as fenvalerate at a concentrationof ~0.006 µg/L (Garey et al. 1998). Thus, inthe cell culture assay, estradiol is about 70,000 timesmore potent than fenvalerate. A baseline estradiol levelin the blood of human males is ~0.028 µg/L (Ravenet al. 2006). Thus, normal males have about five timesas much estradiol in their blood as has been proven tocause an in vitro response in estrogen-responsive cells.Yet, after chronic environmental exposures, maleshave no detectable levels of fenvalerate, suggesting thatconcerns about endocrine system effects are unwarrantedif one considers that natural titers of estrogenthemselves are far more potent than fenvalerate. Otherstudies that show an estrogenic response from pyrethroidexposures in vitro suffer the same logical flaw ofconflating concentrations used in the laboratory withactual environmental exposures. Furthermore, suchstudies ignore the titers of the highly potent naturalhormone estradiol.GlyphosateGlyphosate-containing formulations have beenmarketed since about 1975. Glyphosate itself is bestchemically described as a phosphonated amino acid.In fact, part of the structure is actually glycine, a natural,non-essential amino acid. The only known primarymechanism of biochemical toxicity of glyphosate atthe rates of use as a herbicide is through inhibition ofthe EPSPS enzyme (Schonbrunn et al. 1991; Sikorskiand Gruys 1997). This enzyme is specific to plantmetabolism, although it also occurs in some bacteria.Specifically, plants synthesize aromatic amino acids inthe shikimic acid pathway that involves EPSPS. Animals,lacking the pathway, must acquire these typesof compounds from their diet. For this reason, any48

Pesticides & Health: Myths vs. Realitiesenvironmental residues resulting from legal uses ofglyphosate-containing formulations are often ordersof magnitude lower than doses causing lethality toaquatic or terrestrial organisms. The World HealthOrganization (WHO 2005), the EnvironmentalProtection Agency (EPA 1993), and the EuropeanUnion (EC 2002) have extensively reviewed the fullrange of toxicological information about glyphosate,pronouncing it of extremely low toxicity and thusnear-zero risk. In addition to scrutiny by the variousregulatory agencies, numerous risk assessments havebeen published in the scholarly literature (for example,Geisy et al. 2000; Williams et al. 2000; Solomon et al.2007). These latter publications pertinently considerall the toxicological endpoints that have been defined,including both the regulatory and mechanistic toxicologydata, and integrate the most sensitive effectswith the likely exposures. None have suggested anyenvironmental or human health hazard from routinelegally sanctioned uses of glyphosate.Glyphosate has broad spectrum activity againstmost plants, and thus it historically had very limiteduses in growing agricultural crops. Furthermore, onlyyoung weeds are susceptible to glyphosate at the levelsthat are allowed for use. Once weeds grow and developextensive root systems, glyphosate is much lesseffective at complete control and thus does not holdany greater potency than other less broad-spectrumherbicides. With the advent of soybeans, corn, andcotton in the U.S. bred using biotechnological techniquesinvolving a resistant bacterial EPSPS gene ora modified resistant plant EPSPS gene, glyphosate inthe mid 1990s began to be used widely on these fieldcrops. Today, glyphosate-containing formulations arethe most widely used herbicides, ostensibly owingto the disproportionately large acreages of the threeaforementioned crops (USDA NASS 2009). As wouldbe predicted from environmental chemistry models,the greater volumes of glyphosate used would lead todetections of residues in water and occasionally in unprocessedsoybeans or corn. However, despite the vastacreages treated, fewer than one-third of monitoredwater samples have detectable levels of glyphosate,and the concentrations are typically less than 1 µg/L(Battaglin et al. 2005).For glyphosate to be optimally effective againstplants, it is applied in conjunction with a surfactant.Thus far, Monsanto, the original patent holder andstill the main manufacturer of glyphosate products,continues to formulate glyphosate in formulationsthat contain the surfactant POEA. Various versionsof the formulation called Roundup are typically themost prevalently used form of glyphosate in the U.S.This polyethoxytallowamine surfactant seems to bestfacilitate the penetration of glyphosate through leafsurfaces. Of all the herbicides in the market today, thepresence of POEA has created the most confusionregarding the question of glyphosate toxicity versusits formulations toxicity. POEA is a comparativelypotent surfactant and, given the well-known mechanismof surfactant interactions with cell membranes(Bonsall and Hunt 1971; Jones 1999), its presence informulations of glyphosate are predictably more toxicto aquatic organisms than glyphosate alone. However,the amounts of POEA in any glyphosate formulationare approximately three times lower than the concentrationsof glyphosate itself. Furthermore, POEA rapidlydegrades in the presence of sediment if it shouldrun off or drift into water (Wang et al. 2005).Because of the general mistrust in Europe of cropsbred using genetic modification, such as the RoundupReady crops, glyphosate-containing herbicides havebeen the focus of intense scrutiny by environmentaladvocates. Thus, in addition to raising doubts aboutthe safety of the crops themselves, despite the plethoraof scholarly papers proving a lack of adverse effects,environmental advocacy groups have highlighted twoareas of research that stem from one specific laboratoryin the U.S. and two laboratories in Europe. Thepublished papers from these labs are discussed to illustratewhy regulatory agencies still consider glyphosateto be of essentially zero risk for all approved uses.49

Some Case Studies: Reports of Hazards Do Not Reflect RisksFirst, on the heels of concerns about the effect oflow aquatic concentrations of atrazine on the Africanleopard frog, reports from a U.S. lab suggested adverseeffects of Roundup on several different frog species (seeRelyea 2005a,b,c,d). While the press releases based onlab research stir up strong feelings, they do not focuson the critical aspect of these studies that make themirrelevant to assessing whether the actual agriculturaluse of glyphosate can harm frog populations. Specifically,the concentrations in water that putativelycause frog lethality in the aforementioned publishedexperiments are at least an order of magnitude higherthan what is found in the environment, even after anoverspray (Battaglin et al. 2009; Goldsborough andBeck 1989; Goldsborough and Brown 1993; Newtonet al. 1984; Scribner et al. 2007, Tsui and Chan 2008).Although an overspray of a Roundup formulationacross a body of water is expressly prohibited by theproduct label, glyphosate itself rapidly dissipates inwater within 24 hours. Under laboratory conditionsrepresenting direct application of Roundup to water,toxicity to the subject frog species was detected onlyfollowing 10 days of exposure. Thus, the extrapolationof observations from a lab study to the environment isnot supported by simply examining known concentrations.Furthermore, even when caged frogs were testedduring actual commercial applications, no unusualadverse effects were noted, either following exposureto expected environmental concentrations (Wojtaszeket al. 2004) or residues resulting from commercialforestry spray operations (Thompson et al. 2004). Adeterministic and probabilistic risk assessment appliedto direct oversprays of glyphosate-containingherbicides also concluded little impact on a diversityof aquatic species (Solomon and Thompson 2003).The second set of studies from two laboratories inEurope has been interpreted to find that sub-agriculturaluse rates of glyphosate can cause cytotoxicity invarious types of cells (e.g., Marc et al. 2002; Benachourand Seralini 2009). Pertinently, the data from thesestudies strongly suggest that the toxicity is more likelydue to the surfactant POEA in the Roundup formulationsthan due to the glyphosate active ingredient itself.The problem with these studies, however, is that thelevels of exposure (i.e., body dose) from using Roundupformulations mixed in a spray tank are many orders ofmagnitude lower than the concentration in the spraytank. The authors of the European studies have mistakenlyinterpreted their data as representing what workersand perhaps the general public are exposed to. Thesubject studies have all been in vitro examinations ofcell cultures and/or enzyme systems exposed to eitherRoundup formulations or glyphosate. The authors ofthose studies end their papers by concluding that the10-1000 ppm of Roundup equivalents that the cells areexposed to represent actual human worker exposures.In none of the papers have the authors attempted touse any of the pharmacokinetic data from controlledexposure of rodents or any of the clinical literature toexamine whether their cell exposure levels make sensefrom an environmental perspective. For example, inone of the latest papers (Benachour and Seralini 2009),the authors begin to see some cellular toxicity in a cellculture exposed to one Roundup formulation with aglyphosate dose equivalent to 20 µg/mL. While thisconcentration seems low to the authors, in reality it isequivalent to a blood level exposure about five timeshigher than that measured in the blood of rodentsafter an extreme exposure to an oral dose of 400 mg/kg glyphosate in corn oil, a notably effective solvent atfacilitating toxicant or drug absorption (Anadon et al.2009). To put this dose in perspective, the worst caseexposure to an adult female pesticide applicator from allpossible exposure routes has been estimated at ~0.125mg/kg, or 3200 times less than the exposure given totest rodents. Yet, the authors of the cytotoxicity studiesfailed to critically analyze their data in comparisonto the 4.6 µg/mL level in blood following the extremerodent exposure. Furthermore, the authors ignored thefact that skin exposure only results in about 3% absorptionof glyphosate in a 24-hour period, and absorptionfrom the intestine is less than 40%.50

Pesticides & Health: Myths vs. RealitiesIn summary, pronouncements of adverse effectsof glyphosate and its surfactant seem relegated solelyto the laboratory; in the environment, exposure isjust too low for any measurable effects. Indeed, theEuropean authors own studies show clear thresholdsfor an effect. In other words, their studies show that,at some concentrations in the cell cultures, nothinghappens. Proclaiming that spray tank concentrationsof glyphosate expose workers to hazardous levels ofglyphosate and its surfactants defies logic in the lightof actual exposure measurements and in vivo rodentstudies. The interpretation of in vitro studies is realisticonly when concentrations reflect levels likely to occurin blood and/or interstitial fluids.51

ConclusionsIn the new world of 24/7 information demands, we seemingly have more headlineswith less informational content. In the world of toxicology, basic researchdominates all published subjects, and thus just about any chemical ever studiedis perceived as having an adverse effect. These studiesthat overwhelmingly are mechanistic in focus becomethe fodder for the 24/7 info-news culture. On theother hand, the risk assessment reports that EPA issueswith each pesticide registration decision, or theinfrequently published but still accessible regulatorytoxicology research papers are not very interesting toa society hooked on the adrenaline rush of a disastermovie. Perhaps this pronouncement is harsh aboutour modern perspectives, but an honest assessmentof the wide array of pesticide studies and applicationof the risk assessment paradigm does not support theperspective of widespread adverse health effects, oreven ecological effects, from modern pesticide use. Indeed,in the four cases highlighted within this report,so-called low dose effects are not really caused by lowdoses when one examines the actual exposures. Furthermore,in some cases, as is true for atrazine, one setof studies is directly refuted by another set of studies.Certainly, all studies should be subjected to vigorousdebate, as science should endeavor to make happen.But in a press release world of communication, onlythe truly scary stories get told.Some advocates have been pressing the idea thatthe paradigm for toxicological phenomena has shiftedover the last fifteen years from a focus on cancer to afocus on endocrine system effects. Some advocatesargue that current pesticide regulations fail to keep upwith modern techniques for examining hormonally activeagents. But upon close examination to determinewhat is missing, one finds a plethora of in vitro testingthat overestimates by large amounts what is expectedin a whole person’s blood, bolus exposures that defythe reality of environmental exposures, and measuringof tissues without definition of what it means to thewhole organism. To claim that industry has not beentesting for endocrine system effects is to ignore thevalue of whole organism developmental and multigenerationalreproductive toxicity tests mandated formany years by EPA (Stevens et al. 1997). The systemof testing has not been static, as EPA has incorporatednew measurable endpoints.Another paradigm being pushed involves the ideathat organisms are exposed to multiple residues ofcontaminants. The response to such a paradigm shifteris, frankly, yes. When an organism eats any food, butespecially plants, they are exposed to multiple highlybioactive biochemicals, a number of which haveknown “toxicological” effects when tested at sufficientdoses, just like all other xenobiotic chemicals. So, nothingseems new here. Indeed, counter-analysis suggeststhat concerns about pesticide mixtures are overblownbecause the environmental levels of exposure are justtoo low to have measurable effects (Carpy et al. 2000).Missing from much of the public debate are thebenefits of chemical technology, especially as applied52

Pesticides & Health: Myths vs. Realitiesto crop protection. Negative critiques of modern agricultureare vaguely familiar as echoes of complaintsnearly 40 years ago, just prior to the suspension byEPA of DDT use for agriculture. The report herein didnot engage in trying to defend old chemical technologybecause agriculture has moved far beyond it. Cropprotection specialists themselves began long ago toargue for the judicious use of crop protection agents.Industry long ago began to examine the problems ofthe most persistent chemicals with broad spectrumsof toxicity to nontarget organisms and synthesize newcompounds with less persistence, less toxicity, andgreater selectivity for specific pests versus nontargetorganisms. Furthermore, the amounts of new chemicalsneeded to control pests today are small fractionsof what they were just 20 years ago.Some advocates call for wholesale adoption oforganic agriculture. But if the calls are motivated byconcerns about pesticide use, then disappointmentwill reign because USDA rules for certification oforganic agriculture do allow pesticide use. But it is a“pick your poison” choice of eschewing certain productsin favor of others. Ironically, some of the sameactive ingredients with known nervous system toxicityused by so-called conventional growers are also usedby practitioners of organic agriculture.Finally, we in the United States take for grantedour country’s lack of serious outbreaks of epidemicdisease transmitted by insect vectors. We ignore thefact of 300 million new cases of malaria elsewhere eachyear and the devastating effects on an economy. Thelist of vectored diseases is large, but we do not thinkabout the important contributions of pesticide use tothe protection of our public health. Yet communitiesbesieged by outbreaks of biting mosquitoes clamorfor their communities to be treated with mosquitocontrol insecticides, as long as it is done out of sight atnight. Studies have proven that bans of DDT in SouthAmerica were correlated with increased incidences ofmalaria that plummeted when spraying of wall surfacesresumed. If one doesn’t like DDT, one still cannotignore the effectiveness of pyrethroid-treated bed netsto protect sleeping kids and their parents from feedingmosquitoes. Indeed, such nets, which would cost usthe equivalent of pennies, are expensive commoditiesto many in the world.The point is, chemical technology has improved,and will continue to improve, human health, whetherhelping to make vegetables and fruits of high qualitymore abundant and cheaper or to preserve the healthof individuals who can then help their society toprogress.53

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BOARD OF TRUSTEESBOARD OF SCIENTIFIC AND POLICY ADVISORSOFFICERSErnest L. Abel, Ph.D.C.S. Mott CenterHinrich L. Bohn, Ph.D.University of ArizonaElizabeth McCaughey, Ph.D.Chairman of ACSH BoardCommittee to Reduce InfectionDeathsHon. Bruce S. GelbVice Chairman of ACSH BoardNew York, NYElizabeth M. Whelan, Sc.D., M.P.H.President, American Council onScience and HealthPublisher, healthfactsandfears.comGary R. Acuff, Ph.D.Texas A&M UniversityCasimir C. Akoh, Ph.D.University of GeorgiaPeter C. Albersen, M.D.University of ConnecticutBen Bolch, Ph.D.Rhodes CollegeJoseph F. Borzelleca, Ph.D.Medical College of VirginiaMichael K. Botts, Esq.Alexandria, VANigel Bark, M.D.Albert Einstein College of MedicineDonald Drakeman, J.D., Ph.D.Advent Ventures Life SciencesJames E. Enstrom, Ph.D., M.P.H.University of California, Los AngelesMyron C. Harrison, M.D., M.P.H.The Woodland, TXNorman E. Borlaug, Ph.D.(1914-2009)(Years of Service to ACSH: 1978-2009)Father of the “Green Revolution”Nobel LaureateMEMBERSKevin Holtzclaw, M.S.Boulder, COPaul A. Offit, M.D.Children’s Hospital of PhiladelphiaThomas P. Stossel, M.D.Harvard Medical SchoolFOUNDERS CIRCLEHarold D. Stratton, Jr., J.D.Brownstein Hyatt Faber Schreck LLPFredrick J. Stare, M.D., Ph.D.(1910-2002)(Years of Service to ACSH: 1978-2002)Founder, Harvard Department ofNutritionJulie A. Albrecht, Ph.D.University of Nebraska, LincolnPhilip Alcabes, Ph.D.Hunter College, CUNYJames E. Alcock, Ph.D.Glendon College, York UniversityThomas S. Allems, M.D., M.P.H.San Francisco, CARichard G. Allison, Ph.D.Federation of American Societies forExperimental BiologyJohn B. Allred, Ph.D.Ohio State UniversityKarl E. Anderson, M.D.University of Texas, Medical BranchJerome C. Arnet, Jr., M.D.Helvetia, WVDennis T. AveryHudson InstituteRonald Bachman, M.D.Kaiser Permanente Medical CenterHeejung Bang, Ph.D.Weill Medical College of CornellUniversityRobert S. Baratz, D.D.S., Ph.D., M.D.International Medical ConsultationServicesStephen Barrett, M.D.Pittsboro, NCThomas G. Baumgartner, Pharm.D.,M.Ed.University of FloridaW. Lawrence Beeson, Dr.P.H.Loma Linda UniversityElissa P. Benedek, M.D.University of Michigan MedicalSchoolSir Colin Berry, D.Sc., Ph.D., M.D.Pathological Institute, Royal LondonHospitalWilliam S. Bickel, Ph.D.University of ArizonaSteven Black, M.D.Kaiser Permanente Vaccine StudyCenterBlaine L. Blad, Ph.D.Kanosh, UTGeorge A. Bray, M.D.Pennington Biomedical ResearchCenterRonald W. Brecher, Ph.D., C.Chem.,DABTGlobalTox International Consultants,Inc.Robert L. Brent, M.D., Ph.D.Thomas Jefferson University / A. I.duPont Hospital for ChildrenAllan Brett, M.D.University of South CarolinaKenneth G. Brown, Ph.D.KbincChristine M. Bruhn, Ph.D.University of CaliforniaGale A. Buchanan, Ph.D.University of GeorgiaPatricia A. Buffler, Ph.D., M.P.H.University of California, BerkeleyGeorge M. Burditt, J.D.Bell, Boyd & Lloyd LLCEdward E. Burns, Ph.D.Texas A&M UniversityFrancis F. Busta, Ph.D.University of MinnesotaElwood F. Caldwell, Ph.D., M.B.A.University of MinnesotaZerle L. Carpenter, Ph.D.Texas A&M University SystemRobert G. Cassens, Ph.D.University of Wisconsin, MadisonErcole L. Cavalieri, D.Sc.University of Nebraska MedicalCenterRussell N. A. Cecil, M.D., Ph.D.Albany Medical CollegeRino Cerio, M.D.Barts and The London HospitalInstitute of PathologyMorris E. Chafetz, M.D.Health Education FoundationSam K. C. Chang, Ph.D.North Dakota State UniversityBruce M. Chassy, Ph.D.University of Illinois, Urbana-Champaign65

BOARD OF SCIENTIFIC AND POLICY ADVISORS (continued)David A. Christopher, Ph.D.University of Hawaii at MãnoaMartha A. Churchill, Esq.Milan, MIEmil William Chynn, M.D.New York Eye and Ear InfirmaryDean O. Cliver, Ph.D.University of California, DavisF. M. Clydesdale, Ph.D.University of MassachusettsDonald G. Cochran, Ph.D.Virginia Polytechnic Institute and StateUniversityW. Ronnie Coffman, Ph.D.Cornell UniversityBernard L. Cohen, D.Sc.University of PittsburghJohn J. Cohrssen, Esq.Arlington, VAGerald F. Combs, Jr., Ph.D.USDA Grand Forks Human NutritionCenterGregory Conko, J.D.Competitive Enterprise InstituteMichael D. Corbett, Ph.D.Omaha, NEMorton Corn, Ph.D.Johns Hopkins UniversityNancy Cotugna, Dr.Ph., R.D., C.D.N.University of DelawareH. Russell Cross, Ph.D.Texas A&M UniversityWilliam J. Crowley, Jr., M.D., M.B.A.Spicewood, TXJames W. Curran, M.D., M.P.H.Rollins School of Public Health,Emory UniversityCharles R. Curtis, Ph.D.Ohio State UniversityTaiwo K. Danmola, C.P.A.Ernst & YoungIlene R. Danse, M.D.Bolinas, CASherrill Davison, V.M.D., M.D., M.B.A.University of PennsylvaniaThomas R. DeGregori, Ph.D.University of HoustonPeter C. Dedon, M.D., Ph.D.Massachusetts Institute of TechnologyElvira G. de Mejia, Ph.D.University of Illinois, Urbana-ChampaignRobert M. Devlin, Ph.D.University of MassachusettsMerle L. Diamond, M.D.Diamond Headache ClinicSeymour Diamond, M.D.Diamond Headache ClinicDonald C. Dickson, M.S.E.E.Gilbert, AZRalph Dittman, M.D., M.P.H.Houston, TXJohn E. Dodes, D.D.S.National Council Against Health FraudJohn Doull, M.D., Ph.D.University of KansasTheron W. Downes, Ph.D.Seneca, SCMichael P. Doyle, Ph.D.University of GeorgiaAdam Drewnowski, Ph.D.University of WashingtonMichael A. Dubick, Ph.D.U.S. Army Institute of SurgicalResearchGreg Dubord, M.D., M.P.H.Toronto Center for Cognitive TherapyEdward R. Duffie, Jr., M.D.Savannah, GALeonard J. Duhl. M.D.University of California, BerkeleyDavid F. Duncan, Dr.Ph.Duncan & AssociatesJames R. Dunn, Ph.D.Averill Park, NYJohn Dale Dunn, M.D., J.D.Carl R. Darnall Hospital, Fort Hood,TXHerbert L. DuPont, M.D.St. Luke’s Episcopal HospitalRobert L. DuPont, M.D.Institute for Behavior and Health, Inc.Henry A. Dymsza, Ph.D.University of Rhode IslandMichael W. Easley, D.D.S., M.P.H.Florida Department of HealthGeorge E. Ehrlich, M.D., F.A.C.P.,M.A.C.R., FRCP (Edin)Philadelphia, PAMichael P. Elston, M.D., M.S.Rapid City, SDWilliam N. Elwood, Ph.D.NIH/Center for Scientific ReviewEdward A. Emken, Ph.D.Midwest Research ConsultantsNicki J. Engeseth, Ph.D.University of Illinois66Stephen K. Epstein, M.D., M.P.P.,FACEPBeth Israel Deaconess Medical CenterMyron E. Essex, D.V.M., Ph.D.Harvard School of Public HealthTerry D. Etherton, Ph.D.Pennsylvania State UniversityR. Gregory Evans, Ph.D., M.P.H.St. Louis University Center for theStudy of Bioterrorism andEmerging InfectionsWilliam Evans, Ph.D.University of AlabamaDaniel F. Farkas, Ph.D., M.S., P.E.Oregon State UniversityRichard S. Fawcett, Ph.D.Huxley, IAOwen R. Fennema, Ph.D.University of Wisconsin, MadisonFrederick L. Ferris III, M.D.National Eye InstituteDavid N. Ferro, Ph.D.University of MassachusettsMadelon L. Finkel, Ph.D.Cornell University Medical CollegeLeonard T. Flynn, Ph.D., M.B.A.Morganville, NJWilliam H. Foege, M.D., M.P.H.Seattle, WARalph W. Fogleman, D.V.M.Tallahassee, FLChristopher H. Foreman, Jr., Ph.D.University of MarylandGlenn W. Froning, Ph.D.University of Nebraska, LincolnVincent A. Fulginiti, M.D.Tucson, AZRobert S. Gable, Ed.D., Ph.D., J.D.Claremont Graduate UniversityShayne C. Gad, Ph.D., D.A.B.T., A.T.S.Gad Consulting ServicesWilliam G. Gaines, Jr., M.D., M.P.H.Scott & White ClinicCharles O. Gallina, Ph.D.Professional Nuclear AssociatesRaymond Gambino, M.D.Quest Diagnostics IncorporatedJ. Bernard L. Gee, M.D.Yale University School of MedicineK. H. Ginzel, M.D.University of Arkansas for MedicalSciencesWilliam Paul Glezen, M.D.Baylor College of MedicineJay A. Gold, M.D., J.D., M.P.H.Medical College of WisconsinRoger E. Gold, Ph.D.Texas A&M UniversityReneé M. Goodrich, Ph.D.University of FloridaFrederick K. Goodwin, M.D.The George Washington UniversityMedical CenterTimothy N. Gorski, M.D., F.A.C.O.G.University of North TexasRonald E. Gots, M.D., Ph.D.International Center for Toxicologyand MedicineHenry G. Grabowski, Ph.D.Duke UniversityJames Ian Gray, Ph.D.Michigan State UniversityWilliam W. Greaves, M.D., M.S.P.H.Medical College of WisconsinKenneth Green, D.Env.American Enterprise InstituteLaura C. Green, Ph.D., D.A.B.T.Cambridge Environmental, Inc.Richard A. Greenberg, Ph.D.Hinsdale, ILSander Greenland, Dr.P.H., M.A.UCLA School of Public HealthGordon W. Gribble, Ph.D.Dartmouth CollegeWilliam Grierson, Ph.D.University of FloridaF. Peter Guengerich, Ph.D.Vanderbilt University School ofMedicineCaryl J. Guth, M.D.Advance, NCPhilip S. Guzelian, M.D.University of ColoradoTerryl J. Hartman, Ph.D., M.P.H., R.D.Pennsylvania State UniversityClare M. Hasler, Ph.D.The Robert Mondavi Institute of Wineand Food Science, University ofCalifornia, DavisVirgil W. Hays, Ph.D.University of KentuckyClark W. Heath, Jr., M.D.American Cancer SocietyDwight B. Heath, Ph.D.Brown UniversityRobert Heimer, Ph.D.Yale School of Public HealthRobert B. Helms, Ph.D.American Enterprise Institute

BOARD OF SCIENTIFIC AND POLICY ADVISORS (continued)Zane R. Helsel, Ph.D.Rutgers University, CookCollegeJames D. Herbert, Ph.D.Drexel UniversityRichard M. Hoar, Ph.D.Williamstown, MATheodore R. Holford, Ph.D.Yale University School ofMedicineRobert M. Hollingworth,Ph.D.Michigan State UniversityEdward S. Horton, M.D.Joslin Diabetes Center/Harvard Medical SchoolJoseph H. Hotchkiss, Ph.D.Cornell UniversityClifford A. Hudis, MD.Memorial Sloan-KetteringCancer CenterPeter Barton Hutt, Esq.Covington & Burling, LLPSusanne L. Huttner, Ph.D.Berkeley, CALucien R. Jacobs, M.D.University of California, LosAngelesAlejandro R. Jadad, M.D.,D.Phil., F.R.C.P.C.University of TorontoRudolph J. Jaeger, Ph.D.Environmental Medicine, Inc.William T. Jarvis, Ph.D.Loma Linda UniversityElizabeth H. Jeffery, P.h.D.University of Illinois, UrbanaJohn C. Kirschman, Ph.D.Allentown, PAWilliam M. P. Klein, Ph.D.University of PittsburghRonald E. Kleinman, M.D.Massachusetts GeneralHospital/HarvardMedical SchoolLeslie M. Klevay, M.D., S.D.in Hyg.University of North DakotaSchool of Medicine andHealth SciencesDavid M. Klurfeld, Ph.D.U.S. Department ofAgricultureKathryn M. Kolasa, Ph.D.,R.D.East Carolina UniversityJames S. Koopman, M.D,M.P.H.University of Michigan Schoolof Public HealthAlan R. Kristal, Dr.P.H.Fred Hutchinson CancerResearch CenterStephen B. Kritchevsky, Ph.D.Wake Forest UniversityBaptist Medical CenterMitzi R. Krockover, M.D.SSB SolutionsManfred Kroger, Ph.D.Pennsylvania State UniversitySanford F. Kuvin, M.D.University of Miami Schoolof Medicine/ HebrewUniversity of JerusalemCarolyn J. Lackey, Ph.D., R.D.North Carolina State UniversityJay H. Lehr, Ph.D.Environmental EducationEnterprises, Inc.Brian C. Lentle, M.D.,FRCPC, DMRDUniversity of BritishColumbiaScott O. Lilienfeld, Ph.D.Emory UniversityFloy Lilley, J.D.Fernandina Beach, FLPaul J. Lioy, Ph.D.UMDNJ-Robert WoodJohnson Medical SchoolWilliam M. London, Ed.D.,M.P.H.California State University,Los AngelesFrank C. Lu, M.D., BCFEMiami, FLWilliam M. Lunch, Ph.D.Oregon State UniversityDaryl Lund, Ph.D.University of Wisconsin,MadisonJohn Lupien, M.Sc.University of MassachusettsHoward D. Maccabee, Ph.D.,M.D.Alamo, CAJanet E. Macheledt, M.D.,M.S., M.P.H.Houston, TXHenry G. Manne, J.S.D.George Mason University LawSchoolKarl Maramorosch, Ph.D.Rutgers University, CookCollegeJoseph P. McMenamin, M.D.,J.D.McGuireWoods, LLPPatrick J. Michaels, Ph.D.University of VirginiaThomas H. Milby, M.D.,M.P.H.Boise, IDJoseph M. Miller, M.D.,M.P.H.Durham, NHRichard A. Miller, M.D.Principia Biopharma, Inc.Richard K. Miller, Ph.D.University of RochesterWilliam J. Miller, Ph.D.University of GeorgiaA. Alan Moghissi, Ph.D.Institute for RegulatoryScienceGrace P. Monaco, J.D.Medical Care OmbudsmanProgramBrian E. Mondell, M.D.Baltimore Headache InstituteJohn W. Morgan, Dr.P.H.California Cancer RegistryStephen J. Moss, D.D.S., M.S.New York University Collegeof Dentistry/HealthEducation Enterprises,Inc.Brooke T. Mossman, Ph.D.University of Vermont Collegeof MedicineAllison A. Muller, Pharm.D.The Children’s Hospital ofPhiladelphiaThomas J. Nicholson, Ph.D.,M.P.H.Western Kentucky UniversityAlbert G. NickelLyonHeart (ret.)Robert J. Nicolosi, Ph.D.University of Massachusetts,LowellSteven P. Novella, M.D.Yale University School ofMedicineJames L. Oblinger, Ph.D.North Carolina StateUniversityJohn Patrick O’Grady, M.D.Tufts University School ofMedicineJames E. Oldfield, Ph.D.Oregon State UniversityStanley T. Omaye, Ph.D.,F.-A.T.S., F.ACN, C.N.S.University of Nevada, RenoMichael T. Osterholm, Ph.D.,M.P.H.University of MinnesotaMichael W. Pariza, Ph.D.University of Wisconsin,MadisonStuart Patton, Ph.D.Pennsylvania State UniversityJames Marc Perrin, M.D.Mass General Hospital forChildrenJay Phelan, M.D.Wyle Integrated Science andEngineering GroupTimothy Dukes Phillips, Ph.D.Texas A&M UniversityGeoffrey C. Kabat, Ph.D., M.S.Albert Einstein College ofMedicineMichael Kamrin, Ph.D.Michigan State UniversityJohn B. Kaneene, Ph.D.,M.P.H., D.V.M.Michigan State UniversityP. Andrew Karam, Ph.D., CHPMJW CorporationKathryn E. Kelly, Dr.P.H.Delta ToxicologyGeorge R. Kerr, M.D.University of Texas, HoustonGeorge A. Keyworth II, Ph.D.Progress and FreedomFoundationMichael Kirsch, M.D.Highland Heights, OHJ. Clayburn LaForce, Ph.D.University of California, LosAngelesRobert G. Lahita, M.D., Ph.D.Mount Sinai School ofMedicineJames C. Lamb, IV, Ph.D., J.D.The Weinberg GroupLawrence E. Lamb, M.D.San Antonio, TXWilliam E. M. Lands, Ph.D.College Park, MDBrian A. Larkins, Ph.D.University of ArizonaLarry Laudan, Ph.D.National AutonomousUniversity of MexicoTom B. Leamon, Ph.D.Liberty Mutual InsuranceCompanyJudith A. Marlett, Ph.D., R.D.University of Wisconsin,MadisonLawrence J., Marnett, Ph.D.Vanderbilt UniversityJames R. Marshall, Ph.D.Roswell Park Cancer InstituteRoger O. McClellan, D.V.M.,M.M.S., D.A.B.T.,D.A.B.V.T., F.A.T.S.Albuquerque, NMMary H. McGrath, M.D.,M.P.H.University of California, SanFranciscoAlan G. McHughen, D.Phil.University of California,RiversideJames D. McKean, D.V.M., J.D.Iowa State UniversityIan C. Munro, F.A.T.S., Ph.D.,FRCPathCantox Health SciencesInternationalHarris M. Nagler, M.D.Beth Israel Medical Center/Albert Einstein Collegeof MedicineDaniel J. Ncayiyana, M.D.Benguela HealthPhilip E. Nelson, Ph.D.Purdue UniversityJoyce A. Nettleton, D.Sc., R.D.Denver, COJohn S. Neuberger, Dr.P.H.University of Kansas School ofMedicineGordon W. Newell, Ph.D.,M.S., F.-A.T.S.Cupertino, CAMary Frances Picciano, Ph.D.National Institutes of HealthDavid R. Pike, Ph.D.Champaign, ILSteven Pinker, Ph.D.Harvard UniversityHenry C. Pitot, M.D., Ph.D.University of Wisconsin,MadisonThomas T. Poleman, Ph.D.Cornell UniversityGary P. Posner, M.D.Tampa, FLJohn J. Powers, Ph.D.University of GeorgiaWilliam D. Powrie, Ph.D.University of BritishColumbia67

BOARD OF SCIENTIFIC AND POLICY ADVISORS (continued)C.S. Prakash, Ph.D.Tuskegee UniversityMarvin P. Pritts, Ph.D.Cornell UniversityDaniel J. Raiten, Ph.D.National Institutes of HealthDavid W. Ramey, D.V.M.Ramey Equine GroupR.T. Ravenholt, M.D., M.P.H.Population Health ImperativesRussel J. Reiter, Ph.D.University of Texas, SanAntonioWilliam O. Robertson, M.D.University of WashingtonSchool of MedicineJ. D. Robinson, M.D.Georgetown UniversitySchool of MedicineBrad Rodu, D.D.S.University of LouisvilleBill D. Roebuck, Ph.D.,D.A.B.T.Dartmouth Medical SchoolDavid B. Roll, Ph.D.Granbury, TXDale R. Romsos, Ph.D.Michigan State UniversityJoseph D. Rosen, Ph.D.Cook College, RutgersUniversitySteven T. Rosen, M.D.Northwestern UniversityMedical SchoolStanley Rothman, Ph.D.Smith CollegeStephen H. Safe, D.Phil.Texas A&M UniversityWallace I. Sampson, M.D.Stanford University School ofMedicineHarold H. Sandstead, M.D.University of Texas MedicalBranchCharles R. Santerre, Ph.D.Purdue UniversitySally L. Satel, M.D.American Enterprise InstituteLowell D. Satterlee, Ph.D.Vergas, MNMark V. Sauer, M.D.Columbia UniversityJeffrey W. SavellTexas A&M UniversityMarvin J. Schissel, D.D.S.Roslyn Heights, NYEdgar J. Schoen, M.D.Kaiser Permanente MedicalCenterDavid Schottenfeld, M.D.,M.Sc.University of MichiganJoel M. Schwartz, M.S.Reason Public Policy InstituteDavid E. Seidemann, Ph.D.Brooklyn College/YaleUniversityDavid A. Shaywitz, M.D.,Ph.D.The Boston Consulting GroupPatrick J. Shea, Ph.D.University of Nebraska,LincolnMichael B. Shermer, Ph.D.Skeptic MagazineSarah Short, Ph.D., Ed.D.,R.D.Syracuse UniversityA. J. Siedler, Ph.D.University of Illinois, Urbana-ChampaignMarc K. Siegel, M.D.New York University Schoolof MedicineMichael Siegel, M.D., M.P.H.Boston University School ofPubic HealthLee M. Silver, Ph.D.Princeton UniversityMichael S. Simon, M.D.,M.P.H.Wayne State UniversityS. Fred Singer, Ph.D.Science & EnvironmentalPolicy ProjectRobert B. Sklaroff, M.D.Philadelphia, PAAnne M. Smith, Ph.D., R.D.,L.D.Ohio State UniversityGary C. Smith, Ph.D.Colorado State UniversityJohn N. Sofos, Ph.D.Colorado State UniversityLaszlo P Somogyi, Ph.D.SRI International (ret.)Roy F. Spalding, Ph.D.University of Nebraska,LincolnLeonard T. Sperry, M.D.,Ph.D.Florida Atlantic UniversityRobert A. Squire, D.V.M.,Ph.D.Johns Hopkins UniversityRonald T. Stanko, M.D.University of PittsburghMedical CenterJames H. Steele, D.V.M.,M.P.H.University of Texas, HoustonRobert D. Steele, Ph.D.Pennsylvania State UniversityStephen S. Sternberg, M.D.Memorial Sloan-KetteringCancer CenterDaniel T. Stein, M.D.Albert Einstein College ofMedicineJudith S. Stern, Sc.D., R.D.University of California, DavisRonald D. Stewart, O.C.,M.D., FRCPCDalhousie UniversityMartha Barnes Stone, Ph.D.Colorado State UniversityJon A. Story, Ph.D.Purdue UniversitySita R. Tatini, Ph.D.University of MinnesotaDick TaverneHouse of Lords, UKSteve L. Taylor, Ph.D.University of Nebraska,LincolnLorraine ThelianKetchum, Inc.Kimberly M. Thompson, Sc.D.Harvard School of PublicHealthAndrea D. Tiglio, Ph.D., J.D.Townsend and Townsend andCrew, LLPJames E. Tillotson, Ph.D.,M.B.A.Tufts UniversityDimitrios Trichopoulos, M.D.Harvard School of PublicHealthMurray M. Tuckerman, Ph.D.Winchendon, MARobert P. Upchurch, Ph.D.University of ArizonaMark J. Utell, M.D.University of RochesterMedical CenterShashi B. Verma, Ph.D.University of Nebraska,LincolnWillard J. Visek, M.D., Ph.D.University of Illinois Collegeof MedicineLynn Waishwell, Ph.D., CHESUniversity of Medicine andDentistry of New Jersey,School of Public HealthBrian Wansink, Ph.D.Cornell UniversityMiles Weinberger, M.D.University of Iowa Hospitalsand ClinicsJohn Weisburger, Ph.D.New York Medical CollegeJanet S. Weiss, M.D.The ToxDocSimon Wessely, M.D., FRCPKing’s College London andInstitute of PsychiatrySteven D. Wexner, M.D.Cleveland Clinic FloridaJoel Elliot White, M.D.,F.A.C.R .Danville, CAJohn S. White, Ph.D.White Technical ResearchKenneth L. White, Ph.D.Utah State UniversityRobert J. White, M.D., Ph.D.Shaker Heights, OHCarol Whitlock, Ph.D., R.D.Rochester Institute ofTechnologyChristopher F. Wilkinson,Ph.D.Wilmington, NCMark L. Willenbring, M.D.National Institute on AlcoholAbuse and AlcoholismCarl K. Winter, Ph.D.University of California, DavisJames J. Worman, Ph.D.Rochester Institute ofTechnologyRussell S. Worrall, O.D.University of California,BerkeleyS. Stanley Young, Ph.D.National Institute of StatisticalScienceSteven H. Zeisel, M.D., Ph.D.The University of NorthCarolinaMichael B. Zemel, Ph.D.Nutrition Institute, Universityof TennesseeEkhard E. Ziegler, M.D.University of IowaThe opinions expressed in ACSH publications do not necessarily representthe views of all members of the ACSH Board of Trustees, Founders Circle andBoard of Scientific and Policy Advisors, who all serve without compensation.68

Year in and year out, agricultural pesticides have been the subjectof considerable fear-mongering, leaving the typical consumerwith the impression that these chemicals taint much of our foodsupply and are harmful to human health. In fact, just the opposite is closerto the truth. The published scholarly literature has failed to turn up evidenceof adverse human health effects from use of modern pesticides in the realworld. Furthermore, in light of the current economic perturbations, as wellas the progressive severity of worldwide food shortages and the resultingmalnutrition and spiking prices of basic food commodities, the claims thatthese pesticides pose a threat to human health are false, misleading—anddangerously irresponsible. In Pesticides and Health: Myths vs. Realities,environmental toxologist Allan S. Felsot explains the real benefits—both health-related and economical—of an informed use of pesticides.The American Council on Science and Health is a consumer education consortium concerned withissues related to food, nutrition, chemicals, pharmaceuticals, lifestyle, the environment and health.It was founded in 1978 by a group of scientists concerned that many important public policies related tohealth and the environment did not have a sound scientific basis. These scientists created the organization toadd reason and balance to debates about public health issues and bring common sense views to the public.American Council on Science and Health1995 Broadway, Second FloorNew York, New York 10023-5860Tel. (212) 362-7044 • Fax (212) 362-4919URL: http://www.acsh.org • Email: acsh@acsh.org