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Chapter 14

PESTICIDES

*Chief, Pesticide Monitoring Branch, Entomological Sciences Division, U.S. Army Environmental Hygiene Agency†Pesticide Coordinator, Entomological Sciences Division, U.S. Army Environmental Hygiene Agency, Aberdeen Proving Ground, Maryland 21010-5422‡Lieutenant Colonel, U.S. Army; Medical Advisor for Clinical, Occupational, and Environmental Health, U.S. Army Biomedical Research andDevelopment Laboratory, Fort Detrick, Frederick, Maryland 21702-5010

EDWARD S. EVANS, JR., Ph.D.*; KENNETH L. OLDS, M.A.†; AND TIMOTHY B. WEYANDT, M.D., M.P.H.‡

INTRODUCTION

MILITARY USES OF PESTICIDESProtecting Human HealthProtecting Stored ProductsProtecting Natural Resources and Military PropertyProtecting Against Exposure

PREPARATION OF PESTICIDESFormulationsTechnical-Grade Components

CLASSIFICATION AND TOXICITY OF PESTICIDESToxic Categories and Labeling RequirementsComparative HazardsHazard as a Function of ToxicityPesticide Selection

EXPOSURE EPIDEMIOLOGY

PHARMACOLOGY OF PESTICIDES USED BY THE MILITARYCholinesterase-Inhibiting InsecticidesOrganochlorine InsecticidesBorate InsecticidesBotanical PesticidesRodenticidesHerbicidesSodium Arsenite

PESTICIDE LEGISLATIONThe Federal Food, Drug, and Cosmetic ActThe Federal Insecticide, Fungicide, and Rodenticide ActThe Environmental Protection AgencyOccupational Safety and Health Regulation

THE U.S. ARMY PESTICIDE OCCUPATIONAL HEALTH PROGRAMHealth Reports, Records, and FormsEmergency Medical TreatmentPest-Control Equipment and FacilitiesPesticide ApplicationsMedical SurveillanceAction Levels for Removal and Return-to-Work Policies

SUMMARY

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INTRODUCTION

A pesticide is any substance or mixture of substancesthat prevents, destroys, repels, or mitigates any pest. Apest is any animal or plant that can injure the environ-ment or the health of populations in that environment.This definition allows any of the following terrestrialor aquatic plant or animal life to be classified as pests:insects, rodents, nematodes, fungi, weeds, viruses,bacteria, or other microorganisms (except those on orwithin living humans or other animals). The admin-istrator of the Environmental Protection Agency (EPA)determines which organisms qualify as pests.1

As part of a unified effort, all scientists, managers,and those who apply pesticides must consider thepotential risks associated with the applications ofpesticides before using them. Military goals are to (a)use pesticides judiciously and (b) minimize introduc-ing these toxic materials into the environment. Non-chemical pest-control measures are given first consid-eration; chemical controls are initiated only ifnonchemical control measures fail, or if the situationdictates that chemical controls are the only option.

Pesticides are unique among toxic materials: to beeffective, they must be purposely introduced into thepests’ environments. Not only other animals and

plants but also humans share this environment withthe pests. Excessive residues that result from misap-plication and residues that migrate from target areasinto areas of environmental concern, such as ground-water, are just two of the serious problems associatedwith pesticide use.

The risks of using pesticides must be weighed againstthe benefits. The problem has been and continues to beour inability to fully identify the risks associated withthe introduction of pesticides into the environment.For example, the thinning of bird eggshells from thebioaccumulation of dichlorodiphenyltrichloroethane(DDT) and the controversy that surrounded the defo-liant Agent Orange (a mixture of approximately 50%dichlorophenol [2,4-D] and 50% trichlorophenol [2,4,5-T], with trace amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] contamination) after the Vietnam Warwere unanticipated pesticide risks. Although the acuteeffects on both the environment and human healthmay be known, there is a paucity of information on thechronic effects that result from long-term exposures topesticide residues. Therefore, every precaution andform of protection must be taken whenever pesticidesare used.

Pesticides are necessary in the military to protect (a)human health, (b) products in storage, (c) naturalresources, and (d) property, just as they are in civilianlife. The military has an enormous investment inhuman resources, facilities, and natural resources,and adequate protection of this investment often re-quires the use of pesticides.

Protecting Human Health

The mission of the U.S. Army Medical Department(AMEDD) is to conserve the fighting strength. Be-cause arthropod-borne diseases are major risks tohuman health, this mission requires that pesticides beused; worldwide contingency operations necessitatethat AMEDD be prepared to protect its troops ad-equately against diseases such as malaria, typhus,plague, leishmaniasis, encephalitis, and dengue. Inthe United States, Lyme disease has emerged as animportant tick-borne disease and has renewed theeffort for using skin and clothing repellents to protecttroops during field exercises. Pesticides used both as

personal protection (such as repellents and pedic-ulicides [louse powders]) and area control (such asmosquito larvicides and adulticides) are available toassist in preventing the spread of pest-borne diseases.

To protect against the health hazards associatedwith pesticides, the military must also conduct ad-equate risk-benefit analyses before using them. Forexample, herbicides were used as defoliants duringthe Vietnam War to help members of the U.S. militarysee the enemy in the dense jungle. Agent Orange wasused widely. Its formulation was contaminated withdioxin, however, and because the contaminant is toxic,controversy raged for years in the United States overthe use of Agent Orange. This controversy under-scores the need for adequate risk-benefit analyses tobe conducted when military forces could be presentwhile pesticides are being applied or might be ex-posed to them after their application. Specifically, theassessment must evaluate the risk to the troops fromthe pest (arthropod-borne diseases or dense vegeta-tion providing cover for enemy soldiers) versus therisks to troops if pesticides are used to minimize these

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risks. If the benefits of using pesticides outweigh therisks associated with their use, then pesticides shouldbe considered weapons.

Roosting birds can cause serious health problems inhospitals and dusty work areas. Bird feces can containnumerous pathogens that cause psittacosis and suchmycotic diseases as histoplasmosis and cryptococcosis.These can be transmitted throughout a hospital via itsventilation system, especially if bird feces contami-nate the ducting. When fecal-contaminated dust trav-els as suspended particulates in air and is inhaled,unprotected individuals can contract clinical illnessessuch as mycoses or respiratory diseases, or developskin lesions or subclinical infections manifested onlyby subtle changes in specific antibody titers.

The military uses more pesticides to control cock-roaches than to control any other pest species. Cock-roaches transmit disease organisms mechanically: thisis the major reason for the continued effort to controlthem. They are associated with the spread of entericdiseases such as salmonellosis, dysentery, or typhoid.In addition, there is increasing evidence of allergies inhumans, which has resulted from cohabiting indoorswith cockroaches. While nonchemical control meth-ods—such as appropriate sanitation and reduction ofcockroach harborage—are far more effective in con-trolling cockroach populations, pesticide treatmentsin food areas and in military housing continue to benecessary.

Protecting Stored Products

The Stored Products Pest Management Program,conducted within the Department of Defense (DoD),consists of an integrated system of storage, qualityassurance, and pest-management activities. Theseactivities are designed to prevent or control insects androdents that attack infestable stored products such asfood and fiber items. Failure to comply with properstorage procedures may result in substantial economiclosses caused by pest damage. Pesticides are anintegral part of this program. Applied as residualtreatments or airborne area sprays, pesticides providea barrier between the pests and the stored products.Without such protection, insects (such as grain beetles,moths, and weevils) and rodents (such as mice andrats) would contaminate or destroy items such asflour, cereal, rice, and dried fruit.

Protecting Natural Resources and Military Property

The military, with millions of acres of land on itsinstallations and bases, uses pesticides to protect valu-able natural resources such as forests and wildlife and

protect against pest populations that inhibit militaryactivities or damage property. For example, trees area valuable natural resource that need to be protectedfrom the gypsy moth. Wooden buildings need to beprotected from termites and other wood-destroyinginsects.

Populations of rodents such as prairie dogs or ratsmay exceed the natural carrying capacity of the area;rodenticides may be needed to reduce these popula-tions, especially if the burrows impede the use ofmilitary equipment in the area or a plague outbreakshould occur that may threaten human populations.In these instances, pesticides may be required to re-duce the rodent population quickly, rather than relyon natural controls such as predation.

Pests such as birds that congregate near airports arehazardous to aircraft, crews, and passengers; an avi-cide can promptly reduce the hazard. Birds, particu-larly pigeons, can also become a serious problemwhen they roost in warehouses. In addition to theirassociation with illness and contamination of storedfoods, roosting birds’ acidic feces can deface buildingsand accelerate the deterioration of equipment.

Termites and other wood-destroying insects causetremendous building damage and economic loss onmilitary installations. However, as a result of theenvironmental persistence of the chemical constitu-ents of pesticides and the potential for adverse humanhealth effects from these constituents, the militaryuses of pesticides to control termites have changedfrom the use of persistent chlorinated hydrocarbonpesticides (such as chlordane) to less persistent pesti-cides (such as chlorpyrifos). These changes in termitemanagement—more frequent applications of less per-sistent termiticides—have, paradoxically, increasedthe risk of exposure.

Protecting Against Exposure

The safe application of pesticides requires that pre-cautions be taken to protect against acute or chronicexposures to pesticide residues that may cause poison-ing. While acute pesticide poisoning symptoms arewell documented, a paucity of information exists oneffects of long-term exposure to pesticide residues. Forthis reason, protecting against the unknown chronichealth effects, as well as acute health effects, warrantsminimizing human exposure to pesticide residues.

Routes of Exposure

The purposeful introduction of pesticides into theenvironment can cause not only the worker who ap-plies the pesticide (the applicator) but also unsuspect-

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ing bystanders or passersby to be exposed to pesticideresidues via (a) dermal contact, (b) inhalation, and (c)ingestion.

Dermal contact, the most frequent route of pesti-cide exposure, can occur during applications of liquidsprays, dusts, and granules. Preparing mixed ordiluted solutions from concentrated pesticides maycause considerable dermal exposure if a spill occurs.

Pesticides can cause mild-to-severe skin injury de-pending on the particular pesticide and formulationinvolved. Severe internal poisoning may occur ifsufficient pesticide is absorbed through the skin intothe blood, and is transported to the internal organs.

Inhalational or respiratory exposures can also oc-cur from pesticides during mixing or application, al-though this exposure route is usually much lesslikely than the dermal route. If inhaled, pesticides canbe absorbed into the lungs and transported to otherorgans via the blood.

Ingestion is not usually a significant hazard forcareful workers, but it can be a dangerous exposureroute, especially if pesticide spray or dust is splashedinto the mouth during mixing or application, or ifcontaminated foods or beverages are consumed. Pes-ticides can also be ingested if the applicator smokeswhile mixing or applying them. Ingested pesticides,after passing through the linings of the mouth,stomach, and intestine, are easily absorbed into theblood.

Reducing the Hazards

The hazards that pesticides present to human healthare mitigated by using personal protective equipment(PPE) and the appropriate engineering controls; PPEmust be used whenever pesticide exposure will occurin excess of accepted action levels2 or the permissibleexposure limit.3 By consensus, unless otherwise de-fined, action levels are usually defined as a concentra-tion equal to one-half the Occupational Safety andHealth Administration’s (OSHA’s) permissible expo-sure limit (PEL), which is the statutory exposure limit.The American Conference of Governmental Indus-trial Hygienists (ACGIH) recommends acceptable ex-posure limits, known as Threshold Limit Values (TLVs,a registered trademark of the ACGIH).2 Protectionfrom exposure should be provided at whichever ac-tion level is lowest (either the limit required by OSHAor the limit recommended by the ACGIH).

Protecting Pesticide Workers

Protection against pesticide exposure to militarypersonnel who apply pesticides is afforded by both

engineering controls and PPE. Engineering controlsare aimed at containing or reducing the spread ofpesticides. These measures are particularly impor-tant for the activities performed in pest-control facili-ties, such as diluting and mixing pesticides. Engineer-ing controls can pertain to the design of ventilatingsystems, plumbing, fire protection, emergency showerand eyewash fountains, and personnel locker andbathing facilities.

PPE provides a barrier that precludes or limits anindividual’s exposure to pesticides (Table 14-1). De-pending on the pest-management operation beingconducted, more than one type of PPE may be neces-sary. For example, a waterproof jacket and pantsshould be worn if a spraying operation could causethe required coveralls to become wet. In addition,label instructions may indicate that a specific respira-tor be used with that product. Such respirators mightinclude a dust mask, canister-type gas mask, or self-contained breathing apparatus.

Training is essential for pesticide applicators, toprevent or reduce their potential exposures. Specificissues that must be addressed in training include thebenefits of using engineering controls, as well as theappropriate selection and use of PPE. Other essentialtraining issues include the hazards of specific pesti-cides, possible adverse health effects from exposure,emergency first aid, decontamination procedures, andemergency responses to spills. Workers must beinformed that a subtle exposure hazard potential maybe associated with pesticides that have long-lastingresidues. The training must emphasize that workerscould be chronically exposed to pesticides if engineer-ing controls fail to operate properly or if the PPE isdefective or worn improperly.

All workers who receive, handle, store, and applypesticides must

• demonstrate proper handling of pesticides,• know proper clean-up procedures for pesti-

cide spills,• initiate appropriate spill notification or re-

porting, and• have access to a pesticide-spill kit.

Cleanup procedures, including a notification chan-nel, should be posted in the vicinity of the kit. Aftertraining, workers should be able to demonstrate thatthey are capable of

• recognizing the inherent toxicity of the par-ticular pesticide products they apply,

• using available engineering controls and rec-ognizing when the controls are functioning

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PPE Requirement

TABLE 14-1

PERSONAL PROTECTIVE EQUIPMENT (PPE)

Apron Waterproof, made from synthetic material or rubber; use for mixing pesticides.

Boots Waterproof, made from synthetic material or rubber.

Clothing Clean coveralls or outer clothing; change daily; waterproof jacket or pants ifusing liquid formulations. Do not wear over street clothes.

Faceshield Use when handling or mixing.

Goggles or full-face respirator Use when handling or applying.

Gloves Waterproof, unlined, made from synthetic material or rubber.

Hat Waterproof, wide-brimmed with nonabsorbent headband.

Respirator Cartridge-type approved for pesticide vapors, unless label specifies another type(dust mask, self-contained breathing apparatus).

hazard to these individuals is often largely reduced ifappropriate techniques are followed during applica-tion and if diluted pesticides are used.

Those who apply pesticides to buildings (offices,homes, barracks, and so forth) should carefully advisethe occupants of the potential hazards. The occupantsshould be instructed to alert the pesticide applicatorsif there are signs of inappropriate application such aswet spots or puddles. The occupants should also becarefully instructed concerning their time of reentryinto the treated building and safety practices associ-ated with baits and traps. Pesticides that have asignificant residual time are hazardous to humans ifapplication procedures have been faulty.

improperly,• determining when PPE is necessary,• properly donning and doffing PPE to limit

exposure potential,• properly disposing of unused pesticides, and• properly decontaminating equipment.

Protecting Bystanders

It is equally important to protect other people fromexposures that may occur during or after the applica-tion of pesticides. This type of exposure is insidiousbecause the individual may not be aware of the pesti-cide and its potential exposure hazard. However, the

PREPARATION OF PESTICIDES

Pesticide chemicals as they are produced by themanufacturer are usually highly concentrated, willnot mix well with water, and may not be chemicallystable. To enhance storage, handling, and applicationof pesticides, carriers (solvents, clays, surfactants, orstabilizers) are added to the active ingredient to createa pesticide formulation.

Formulations

The most common pesticide formulations are (a)sprays, (b) dusts, (c) granules, (d) aerosols, and (e)fumigants. Sprays can be prepared from a number ofliquid formulations with various carriers such as wa-ter, oil, and other adjuncts (Table 14-2). Dusts are

finely ground materials of either undiluted pesticideor the pesticide mixed with an inert diluent. Granularpesticides are small pellets manufactured from inertclays that are sprayed with a solution of the pesticide.Aerosols are pressurized sprays that use a propellantto disperse the pesticide, while fumigants are gaseousforms of a pesticide.

Pesticides must be formulated to improve proper-ties such as storage, mixing, application, efficacy, andsafety before they can be used. For example, certainingredients of pesticide formulations are designed toincrease water solubility for their use as diluted sprays,or incorporated into solid matrices for their use asgranules. The resulting product (or formulation) in-cludes not only chemicals (in pure or technical-grade

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TABLE 14-2

FORMULATIONS OF PESTICIDE SPRAYS

Formulation Type Definition

Emulsifiable concentrate Concentrated oil solution of technical-grade pesticide to which an emulsifier, adetergent-like material, is added. When added to water, the emulsifier

causes the oil to disperse uniformly.

Wettable powder Pesticide dusts to which a wetting agent is added to facilitate the mixing of thepowder with water.

Flowable or sprayable Blend of a technical-grade pesticide with a dust diluent and a small quantity ofsuspension water. This finely ground, wet formulation mixes well with water.

Water-soluble powder Finely ground technical-grade pesticide that dissolves when added to water.

Oil solution Technical-grade pesticide dissolved in oil and applied as an oil spray.

Ultra-low-volume Technical-grade pesticide dissolved in a minimum of solvent. The highconcentrate concentration of the pesticide's active ingredient (usually > 50%) is applied via

special ground or aerial equipment that greatly reduces the volume of pesticideformulation applied.

form) that are active as pesticides but also chemicalsthat are inactive (or poorly effective) as pesticides.Inactive or inert ingredients also include chemicalsthat are added to the pesticide, and are intended toimprove its distribution and use. In this context, theterm inert refers to the pesticide’s activity againstspecific pests and is unrelated to the chemical’s inher-ent potential toxicity to other species, including hu-mans. For example, the formulation’s carrier (orvehicle), included to enhance the solubility in water,may be a petroleum-based product that has no directeffect on the pest, but which could be a hazard to thosewho apply the pesticides if they were to use theproduct improperly.

Technical-Grade Components

Most pesticides are produced through a series ofcomplex chemical reactions that eventually result inchemically impure mixtures of reaction products. Evenwhen chemically pure, chemicals are used to initiatethe industrial process reactions for development ofthe final pesticide, and the resultant product mixtureis chemically diverse. Similarly, naturally occurringpesticides extracted from biological sources are chemi-cally complex mixtures with comparable physical andchemical solvent-extraction characteristics.

Technical-grade pesticide products are complexchemical mixtures that have been developed and li-

censed for incorporation into commercial pesticideformulations. Technical-grade products contain nu-merous related, intermediate, production-process-as-sociated compounds. The production of chemicallypure organic compounds is technically difficult, ex-pensive, and usually unnecessary to afford acceptablepractical activity for use against pests. As a result,technical-grade production chemicals are often usedto formulate pesticides and therefore often demon-strate chemical impurities. Technical-grade productsderived from controlled chemical reactions conformto a range of chemical diversity. The acceptable rangeof product purity is defined by the manufacturer’sdesign quality control specifications for each intendeduse. As a result, chemical mixtures generated forincorporation into pesticide formulations, or subse-quent sale for use, usually demonstrate a degree ofacceptable variability in the final product.

It is imperative that healthcare providers recognizethat pesticides are usually impure mixtures resultingfrom production-process chemicals that have beencombined with other chemicals to produce the finalformulation. As such, “pesticides” are not mixtures ofpure, chemically discrete unreacted compounds, butare technical-grade quality mixtures, and have sol-vents or other chemicals added to improve their dis-persion or solubility properties.

Similarly, it is important for healthcare providers torecognize that pesticide products stored beyond the

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stated shelf life or released into the environment mightbe contaminated with decomposition products. Thepresence of technical-grade, intermediate compoundsor degradation products can substantially alter thetoxic effects of the chemical mixture (in comparisonwith the pure compound) on biological systems.

The complexity of potential problems can be formi-dable. For example, the use of chlordane as a termiticidein structures owned by all military services was chal-lenged on the basis of possible long-term sequelaeamong potentially exposed military members and de-pendents. All services were required to determine theextent of use of chlordane on every installation, and todefine the possible extent of exposures of all familymembers. It became immediately apparent that sam-pling and analysis for chlordane products required defi-nition in order to evaluate the possibility for exposure.

The commercial pesticide product chlordane is acomplex chemical during both its production and itsenvironmental degradation (Figure 14-1). It is anexample of the composition of a technical-grade pesti-cide. The product is no longer registered for sale to thepublic, but it is extremely persistent in the environ-ment. As a result, it became the focus of substantialmilitary interest during the 1980s. The controversyconcerning potential acute and chronic health effectsof this product on military members and their depen-dents will probably continue to resurface periodi-cally. Therefore, a review of the chemical compositionof chlordane serves both as a point of historical inter-est and as a practical demonstration of the complexityof human exposure and health-risk determination.

Toxicological testing of several of the individualcomponents has resulted in the assignment of differ-ential human-health risks from exposure to the sepa-rate compounds of technical-grade chlordane. Forexample, both chlordane and heptachlor demonstratevariable degrees of activity at the same target organs(ie, both are potential hepatotoxins). Reported differ-ences in acute toxicity in rodents usually indicate thatheptachlor is approximately 5-fold more potent thanchlordane. In addition, heptachlor has been recog-nized as a substantially more potent carcinogen thanchlordane.4

In addition to the concern for environmental degra-dation over time, the technical-grade composition ofchlordane had been reported to change with time.Formulations of chlordane produced before 1951 areknown as “early chlordane.” The temporal differencesin specific composition of technical grade may berelated to differences between the incidence of re-ported hepatoma in mice in 1977 to 1979 and 1989. Thelater studies have failed to demonstrate an increasedincidence of hepatoma reported in earlier studies.5

Toxicological and biological activity associated withchemical stereoisomers of the same chemical moietyhave been documented for numerous compounds. Asan example, the acute toxicity of permethrin is directlycorrelated with the cis/trans ratio, with most mamma-lian toxicity attributable to the cis isomer.6,7

The best-recognized example is probably the unde-sirable human toxicity associated with exposure to anintermediate, unwanted, contamination product foundin a technical-grade, market formulation of AgentOrange (Figure 14-2). An intermediate compound inthe production of the herbicide 2,4,5-trichlorophenol(2,4,5-T) was found to cause a positive response in therabbit ear toxicology evaluation.8 The compound thatwas subsequently identified as the cause of chloracnein humans and hyperkeratosis in livestock was thecontaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD). The chemical TCDD is an undesired reaction

Fig. 14-1. A chromatogram is produced during the analysisof chlordane on federal installations. Careful review revealsa complex composition. Technical-grade chlordane has beenidentified and selectively defined for compound identifica-tion by the ratio of the percentage composition of four of themajor components in the mixture. The four major compo-nents are electively labeled A, B, C, and D, based on theirretention times—from shortest to longest, respectively—using carefully prescribed chromatographic specifications.Peak A is an otherwise unspecified chemical substanceknown as “compound C.” Peak B represents the chemicalcompound heptachlor, peak C represents trans-chlordane,and peak D represents cis-chlordane. If the ratio of peaksA+B/C+D approximates 0.8 (range 0.4–1.6), the sample isaccepted as representative of technical-grade chlordane.

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O CH2

COOH

Cl

Cl

O

O

Cl

Cl

Cl

Cl

O CH2

COOH

Cl

Cl

Cl

TCDD

Fig. 14-2. Agent Orange. The chemical structures of the herbicides (a) dichlorophenoxyacetic acid (2,4-D) and (b) 2,4,5-trichlorophenoxyacetic acid (2,4,5-T); (c) represents the structure of the undesirable intermediate dioxin contaminant2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

product identified in the production of phenols andhexachlorophene, which is now often chemically re-moved from technical-grade products before they areformulated. TCDD has neither pesticide nor phenolactivity. It is, however, by scientific consensus, thechemical believed to represent the main health hazardassociated with exposure to Agent Orange. Anotherexample of undesirable reactions associated withunreacted chemical intermediates was the dermal andrespiratory toxicity identified for the chemicalhexachlorocyclopentadiene, a contaminant of earlychlordane. Specifications for chlordane produced af-ter 1951 limited hexachlorocyclopentadiene concen-

trations to less than 1%, with a resultant decline inacute adverse dermal and respiratory effects.5

In addition to recognizing the differences in toxic-ity between separate compounds in the marketedpesticide formulation, it is important to recognize thepossibility for chemical interactions that may result inexposure consequences for an individual. In selectedcases of patient poisonings, healthcare providers maybe required to carefully review the available toxicol-ogy database for a pesticide to determine if the testinghas been done on the isolated, separate, chemicalcomponents, technical-grade chemicals, or pesticideformulations.

Pesticides must be approved for use by and regis-tered with the EPA. They can be classified in numer-ous ways, including their mechanism of action andtheir chemical structure.

Pesticides do not necessarily kill pests, but in factmay kill, repel, or attract them (Exhibit 14-1). Pesti-cides are also used as plant regulators, defoliants, anddesiccants. Some pesticides are used as chemosterilants,which prohibit or limit propagation of the next pestgeneration. Growth regulators retard the growth ofplants and insects; defoliants remove the leaves ofplants; and desiccants enhance the destructive dryingof plants. Even antimicrobials (which include disinfec-tants, sanitizers, and bacteriostatics) are classified aspesticides and must be registered with the EPA. How-ever, for purposes of this chapter, the word pesticide isused in its more traditional sense and is limited to themajor categories: insecticides, rodenticides, and her-bicides (Table 14-3).

Specific toxicological evaluations to identify poten-tial adverse biomedical responses that could affectworkers who apply pesticides, the general public, andthe environment are required before the EPA will

EXHIBIT 14-1

CLASSIFICATION OF PESTICIDESBY ACTIVITY

Amphibian and reptile poisons and repellents

Antimicrobial agents

Attractants

Bird poisons and repellents

Defoliants

Desiccants

Fish poisons and repellents

Fungicides

Herbicides

Insecticides

Invertebrate animal poisons and repellents

Mammal poisons and repellents

Plant regulators

Rodenticides

Slimicides

cba

CLASSIFICATION AND TOXICITY OF PESTICIDES

2,4,5-T2, 4-D

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Category Example Category Example

TABLE 14-3

CATEGORIES OF PESTICIDES

Insecticides

Chlorinated DDT, lindane, aldrin, chlordanehydrocarbons

Organophosphates malathion, naled, dichlorvos,parathion

Carbamates carbaryl, propoxur, carbofuran

Foramidines chlordimeform, amitraz

Dinitrophenols dinitrocresol, dinoseb

Organotins cyhexatin, fenbutatin-oxide

Botanicals pyrethrum, nicotine, rotenone

Pyrethroids allethrin, d-phenothrin,fenvalerate

Synergists piperonyl butoxide, MGK 264

Inorganics sulfur, arsenic, boron

Fumigants methyl bromide, ethylene oxide,ethylene dibromide

Microbials Bacillus thuringiensis, Heliothis

Insect growth methoprene, diflubenzuronregulators

Repellents diethyl-m-toluamide (DEET)

Rodenticides

Phosphorus zinc phosphide, yellow

phosphorus

Coumarins warfarin, fumarin

Indanediones pindone, diphacinone

Botanicals red squill, strychnine

Organochlorines endrin

Source: Ware GW. Fundamentals of Pesticides—A Self-instruction Guide. Fresno, Calif: Thomson Publications; 1982.

register a pesticide. A number of specific types oftoxicological evaluations are considered before EPAregistration and as an integral part of the Agency’songoing review. The classical descriptive toxicologi-cal tests are customarily divided into two broad cat-egories: acute or chronic, based on the duration ofexposure to the administered toxicant under study.

An acute toxicological evaluation is based on mea-sured biological responses to a single dose (or occa-sionally several doses) of a test compound within a 24-hour period. When the toxicity of a compound is low,the necessary volume to achieve the required doseoften cannot be administered as a single dose, butmust be administered in repetitive doses given within

that 24-hour period. The observation period follow-ing exposure is customarily 7 days, but effects may berecorded for up to several weeks following the admin-istration of acute exposure doses in selected circum-stances. The most common acute studies simplyrecord lethal effects; however, some studies recordobservations of toxic signs such as ataxia, feedingdifficulty, or lethargy. (Like its use in clinical medi-cine, a “sign” in animal studies is defined as a discreteevent that can be seen by the observer.)

Toxicological effects are either quantum or con-tinuum responses. A quantum response is a discrete,yes or no, all or none, numeric phenomenon such aslethal outcome. A continuum response is a graded

Herbicides

Inorganic ammonium sulfate, sodiumtetraborate

Organic arsenicals cacodylic acid, disodiummethanearsonate

Phenoxyaliphatic acids 2,4-D; 2,4,5-T; silvex

Substituted amides propanil, diphenamid, alachlor

Nitroanilines and benefin, trifluralin, monuron,substituted ureas diuron

Carbamates propham, terbucarb

Thiocarbamates pebulate, metham, butylate

Heterocyclic nitrogens atrazine, simazine, prometon,picloram

Aliphatic acids dalapon, trichloroacetic acid(TCA)

Arylaliphatic acids dicamba, dimethyl tetrachloro-terephthalate (DPCA)

Phenol derivatives dinoseb, pentachlorophenol

Substituted nitriles dichlobenil, bromoxynil

Bipyridyliums diquat, paraquat

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response associated with a normal, or accepted, nu-merical range as well as abnormal levels (those thatare reported outside the normal range, such as quan-titative concentrations of enzymes identified in asample of whole blood).

The EPA requires carefully controlled performanceand documentation of acute lethality studies, usingselected animal models, before a pesticide productcan be registered. A specific, acute, toxic response toexposure required by the EPA is the LD50 (the dose ofthe pesticide that is lethal to 50% of the test populationof animals under specified test conditions).1

Other types of toxicological evaluations that may beuseful during the EPA registration process requirerepetitive administration of test doses of the pesticideover progressively increasing periods of time. Basedon the duration of repetitive dosing, toxicology testshave been categorized as subacute, subchronic, orchronic. Subacute toxicological evaluations employrepeated administration of doses of the test compoundover a duration of several days to 1 month. Subchronicevaluations are defined as repetitive exposures ad-ministered over a period of 1 to 3 months, whilechronic studies require administration of the toxicantfor longer than 3 months. While subchronic evalua-tions are customarily used to identify effects of long-term, low-dose exposures on target organs, bothsubchronic and chronic exposures often focus on theoccurrence of carcinogenicity as the measured response.A common form of chronic toxicological study is the2-year, rodent-lifetime study.

Several additional kinds of evaluations may berequired for scientists, regulators, and health profes-sionals to more completely assess potential pesticidetoxicity. These evaluations include screening tests forthe in vivo or in vitro changes in genetic material thatcould subsequently be associated with possible carci-nogenic sequelae. Of these studies, the most com-monly performed screening tool is the Ames test. Inthis test, the use of a specific strain of histidine-requir-ing bacteria allows scientists to measure changes ingrowth and replicative ability of the organisms afterexposure to the test compound (see also Chapter 9,Explosives and Propellants). As an adjunct, extractsof rat liver homogenate are added to the usual culturemedia to simulate the hepatic metabolism of the testmaterial in the “activated” Ames test.

In simplistic terms, positive findings reported fromthe Ames test result from the interaction of geneticmaterials and the test pesticide or its activated prod-uct. Positive results are recorded following an in-creased number of bacterial colonies (genetically al-tered clones) on the test-compound-treated growthmedia, when compared with the number of colonies

recorded on the control bacterial-growth medium. Inother words, the potential of the test compound toaffect genotoxic alterations is recorded as an increasein the number of colonies on the histidine-deficient,test-compound-treated media, compared to histidine-deficient control culture plates.

Other forms of possible toxicological evaluationsinclude assessments for potential skin or eye effects(the rabbit Draize test), reproductive effects (domi-nant lethal or multigeneration tests), and human ef-fects (patch testing or epidemiological studies). Theapproved uses and cumulative toxicity reports associ-ated with any specific pesticide are monitored as anongoing, continuous EPA administrative process. Asa result of these routine reviews or pesticide-use com-plaints from the general public, a pesticide productregistration may be revised or revoked based on accu-mulated toxicological data and human epidemiologi-cal experience.

Both acute and chronic adverse health effects froma host of possible, likely, presumed, and confirmedpesticide exposures have been reported in humans.When applied to the circumstances surrounding hu-man exposures, and subsequent effects, the differen-tiation between acute and chronic human health ef-fects is based on the total frequency and duration of theexposure profile. Acute exposure effects are those thatoccur after short-duration, high-concentration, or high-potency exposures. This type of exposure usuallyresults from cutaneous contact during improper appli-cation or handling of the more potent pesticide prod-ucts. Chronic exposures occur over extended periods,with the slow accumulation of the pesticide ultimatelyresulting in signs or symptoms of exposure. Chronicpoisoning can occur as a result of partial failures ofPPE, engineering controls, or worker complacency. Asa result, repeated exposures to dilute or relativelynontoxic, but biologically cumulative, pesticide prod-ucts can cause chronic poisoning in pesticide applicators.

“Chronic poisoning” is not comparable to the term“chronic health effect.” The health effects associatedwith chronic poisoning may vary between transient,totally remitting signs or symptoms and permanent,adverse, health sequelae. For example, one who en-joys gardening could suffer exposure to chlordaneretained in previously contaminated soil. As a resultof the accumulated dose from exposures over time,the gardener could develop a nonspecific convulsivedisorder. Correct diagnosis and removal from subse-quent exposure could result in complete recoverywithout adverse sequelae. In comparison, a chronichealth effect is a persistent, possibly unremitting con-sequence of either acute or chronic exposure.

Individuals who have adverse effects after either

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acute or chronic exposures are routinely reported inthe medical literature in the generic category of “pes-ticide poisoning.” Information gleaned from animal-toxicity studies must be combined with the reportedhuman health effects from pesticide exposure to com-pile comprehensive disease prevention and medicalcare programs. Data from both animal-toxicity studiesand reported human health effects provide clinicallyuseful information for employee occupational healthpromotion and symptomatic patient management.

Management of both asymptomatic, healthy work-ers and symptomatic, poisoned workers can be spe-cifically tailored for the individual, based on the knownchemical composition and associated toxic effects ofthe pesticides in question. Essential information re-lated to biological monitoring, medical surveillance,patient examination, and medical management can berecommended and provided using available cumula-tive data. However, healthcare providers must exer-cise caution when human experiences with the pesti-cide products are limited, or when toxicologyinformation is indirectly extrapolated from animaldata without reference to compound-specific, relativeinterspecies variability.

In workers, acute toxic or chronic exposure effectscan occur during manufacture, formulation, mixing,or application of pesticide products. If short-termexposures to high pesticide concentrations occur, thesymptomatic onset of poisoning is usually rapid andeasily correlated with the coincident exposure profile.In contrast, when relatively low-dose exposures occurover prolonged periods, the pathophysiological re-sponses from the chronic-exposure profile may beextremely difficult to correlate clinically with pesti-cide-associated sequelae. For example, the etiology ofseizure activity associated with acute poisoning dur-ing pesticide application is rather easily identifiedduring a cursory history. But the cumulative, chronicretention of pesticide residues may not be recognizedas the cause of seizures in the gardener who experi-ences subtle, prolonged exposures to carbamatepesticides during grounds maintenance, but who doesnot display the usual associated acetylcholinesterasedepression.

Workers associated with pesticide application, thegeneral population, and the environment can be af-fected either acutely or chronically by exposure topesticide products or residual products of degrada-tion. Chronic biomedical responses to low-level, long-term exposure profiles may range from no apparentadverse health impact to overt clinical signs of poison-ing. The possibility of chronic health impacts result-ing from subtle exposures provides the theoreticaland philosophical bases for biological monitoring and

medical surveillance in pesticide-associated workers.Pesticides that resist biological degradation or have

limited environmental translocation are said to beenvironmentally persistent; such pesticides can causesubtle, prolonged human exposures. There may be noknown correlation between low-level exposures toresidual pesticide concentrations and known healtheffects. However, residual levels of organochlorineinsecticides that have low comparative acute toxicitieshave been associated with the onset of seizures in gar-deners, and have been predicted to cause an increasedrisk for carcinogenicity in exposed populations.4

Acute and chronic adverse health effects based onthe duration of exposure to pesticides have been re-ported in humans. Patients said to be “poisoned” or“intoxicated” have adverse clinical signs or symptomsfollowing pesticide exposure. Acute poisoning canresult from mixing and applying pesticides, when theexposure to relatively high concentrations of the pes-ticide occurs over a relatively short time. Obviously,this type of intoxication is of particular concern toindividuals who manufacture, formulate, or applypesticides. These are the workers most likely to be seenwith the chronic toxic effects that result from long-term exposures to relatively small quantities of pesti-cides that produce no apparent acute adverse bio-medical effect, but which produce an accumulative,detectable alteration with increasing exposure time.

Workers who apply pesticides and those in thegeneral public who continually experience involun-tary exposures secondary to environmental contami-nation can have adverse health effects from chronicexposure to pesticides. The public may be exposed topesticide residues on foods, at work, during recre-ational activities, and in their homes. Pesticides thatare resistant to environmental degradation may beextremely persistent and thus may result in prolongedexposure potentials. As noted previously, the envi-ronmental degradation products may vary dependingon the specific pesticide and environmental circum-stances (such as temperature, soil type, and moisture).As a result, it is not possible to make a generic state-ment concerning pesticide degradation and the pos-sible, consequent, proportional environmental toxicity.

Toxic Categories and Labeling Requirements

When pesticides are registered with the EPA, theyare assigned a toxicity category that indicates thedegree of toxicity that has been determined by animalexperimentation and documented instances of hu-man poisoning. The toxicity classification includesfour categories (I, II, III, and IV) for each of five hazardindicators: three related to the LD50 associated with

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oral, inhalational, and dermal exposures; and tworelated to topical eye and skin exposure effects (Table14-4).9 Within these categories, a particular pesticidemay be highly toxic for one hazard indicator, such asthe oral LD50, while it has only a slight degree oftoxicity by another indicator, such as the dermal LD50.In cases where hazard indicators differ, the most toxichazard indicator determines the official EPA registra-tion category.

The EPA also requires the use of signal words (DAN-GER, POISON, WARNING, CAUTION) on labels toindicate the potential hazard of the pesticide. Themost toxic pesticides are classified as Category I andmust display the signal word DANGER. Addition-ally, if this category is based on the oral, dermal, orinhalation LD50, the product label must contain theword POISON in red on a contrasting background,and the skull-and-crossbones symbol, which is famil-iar to most adults. Category II pesticides are moder-ately toxic and are labeled WARNING. Pesticides inCategories III and IV are both labeled CAUTION.With few exceptions, all pesticides are also labeled,“Keep out of the reach of children.”

The toxicity classification and corresponding label-ing apply primarily to pesticides on the basis of theiracute toxicity. If a pesticide is known to cause signifi-cant chronic toxic effects in humans (such as carcino-genicity or teratogenicity), the pesticide is also subjectto a restricted-use classification, which is noted on thelabel. This classification requires that the pesticide be

applied by or under the direct supervision of trainedand certified pesticide applicators.

If medical personnel are aware of the differentrequirements for EPA registration and of the spec-trum of potential adverse health effects that pesticidescan cause, they can provide better medical care topatients who present with signs and symptoms ofpossible pesticide poisoning. Pesticide labels mustinclude medically useful information, such as acutetoxicology categorization and a statement of practicalpoisoning treatment. In addition, medical surveil-lance, patient examination, and biological monitoringcan be specifically tailored to individuals who may beexposed to pesticides, based on the known toxicologi-cal effects. As a result of possible differences intoxicological responses between species, however,care must be exercised when toxicological informa-tion is extrapolated from the animal model to patients.

Comparative Hazards

The differences between organophosphorus andorganochlorine pesticides can be used to illustrate thecomparative levels of hazard and the relative poten-tials to cause adverse health effects (Table 14-5). Or-ganochlorine insecticides were used extensively fromthe 1940s through the 1960s because they were highlyefficacious and were generally less acutely toxic thanorganophosphorus compounds of the same period.The organochlorine derivatives have recently fallen

*Numbers listed apply to the pure substance only; dilutions may be considerably less toxic

TABLE 14-4

I Highly < 50 < 0.2 < 200 Corrosive; corneal opacity Corrosive DANGERtoxic not reversible within 7 d POISON (only if Cat. I

based on Oral, Inhal.,and Dermal LD50s)

II Moderately 50–500 0.2–2 200–2,000 Corneal opacity reversible Severe irritation WARNINGtoxic within 7 d; irritation at 72 h

persisting for 7 d

III Slightly 500–5,000 2–20 2,000–20,000 No corneal opacity; Moderate irritation CAUTIONtoxic irritation reversible at 72 h

within 72 h

IV Practically 5,000 > 20 > 20,000 No irritation Mild or slight CAUTIONnontoxic irritation at 72 h

TOXICITY CATEGORIES AND HAZARD INDICATORS OF PESTICIDES

ToxicityCategory Hazard Indicators Signal Word onLabel

Oral LD50 Inhal. LD50 Dermal LD50No./Description mg/kg* mg/L* mg/kg* Eye Hazards Skin Effects

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were substituted because of their more rapid environ-mental biodegradation and increasing availability.Later, selected carbamate pesticides, which were lesspersistent and more specific against the targeted pests,were substituted for many of the organophosphoruscompounds.

Hazard as a Function of Toxicity

The toxicity of a pesticide is not synonymous withthe hazard associated with use of the chemical. Thehazard involved in the application of a pesticide is aresult of the interactions among three elements: tox-icity, exposure, and time. This relationship is ex-pressed by the equation

Hazard = Toxicity • Exposure • Time

where hazard is the risk of pesticide poisoning, toxicityis a measure of the pesticide’s potential for harm,exposure is a multivariate function, and time is associ-ated with the cumulative dose.10 In addition to time,the exposure dosage is dependent on the physicalstate of the pesticide formulation, application tech-nique, and degree of personal protection. The cumu-lative association between the exposure concentra-tion and the duration of the exposure is often calledthe exposure dosage and is expressed by the abbrevia-tion Ct (ie, concentration • time). If any of the threevariables on the right side of the equation equal zero,the hazard also equals zero.

Although a pesticide’s toxicity can never actually bezero, selection of an appropriate formulation can re-duce the associated hazard. Toxicity can be decreasedby selecting a pesticide with (a) a lower dermal toxic-ity, (b) a less toxic formulation, and (c) a lower concen-tration for application. As a practical example, a rela-tively toxic pesticide could represent a diminishedhazard if it is applied in a very dilute form or in aformulation that restricts its skin absorption potential.

It is possible to reduce the hazard of application,based on the hazard equation, in several practicalways. For example, a pesticide applicator could electto substitute malathion for parathion in an eradicationeffort. As another example, the use of appropriateengineering controls or PPE would serve to decreasethe exposure and, therefore, diminish the hazard.

The physical state of a pesticide’s formulation influ-ences the degree of hazard associated with its use. Ingeneral, solids are less hazardous than liquids. Liquidemulsifiable concentrates are probably the mostwidely used formulations, but these can pose signifi-cant hazards due to the highly flammable solventsthat may be in the product. The presence of solventsmay result in an increased potential for dermal ab-

Acute Oral LethalityPesticide (mg/kg) (Rat LD50)

TABLE 14-5

SELECTED PESTICIDES:ACUTE LETHALITY LEVELS IN RATS

Sources: (1) Smith AG; Chlorinated hydrocarbon insecticides. In:Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. NewYork: Academic Press, Harcourt Brace Jovanovich; 1991; Chap 15.(2) Gallo MA, Lawryk NJ; Organic phosphorous pesticides. In:Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. NewYork: Academic Press, Harcourt Brace Jovanovich; 1991; Chap 16.

Organochlorines

DDT (powder) 500–2500

Lindane 88–200

Chlordane 150–700

Aldrin 10–74

Organophosphoruses

Schradan 9–42

Parathion 3–30

Dichlorvos 46–80

into disfavor, however, because of their persistence inthe environment, tendency for bioaccumulation with-in the food chain, tendency to accumulate in humantissues, and possible potential to cause human carci-nogenicity. Commonly used organochlorine pesti-cides of the early periods of production and use in-cluded DDT, lindane, aldrin, and chlordane.

An example of the perceived safety of the organo-chlorine class of pesticides is demonstrated by thelarge number of scientific studies directed toward theevaluation of DDT pharmacokinetics after oral ad-ministration in humans. DDT was administered tohealthy human volunteers in single doses as high as1,500 mg and, in separate studies, repetitive doses of35 mg/person/day for 18 months.

In contrast, many of the early organophosphoruscompounds were found to be highly toxic duringacute exposure. Some were produced as weapons byseveral countries as nerve agents, a class of chemicalwarfare gases. Despite their demonstrated potency,several of the early organophosphorus compoundswere developed and used as medications for treat-ment of myasthenia gravis and glaucoma. When theenvironmental persistence and the possibility of ad-verse, cumulative toxicity of the organochlorine com-pounds were recognized, however, their use fell intodisfavor. Less toxic organophosphorus compounds

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sorption. Of the liquid formulations, solutions pen-etrate skin more readily than suspensions.10

The exposure potential and correlated hazard po-tential are related to both the physical state of thepesticide formulation and the application techniqueemployed. To minimize the hazard potential, thetechniques and equipment should allow the pesticideto be directed as accurately as possible at the pest andshould minimize the pesticide’s unwanted drift ormovement.

Indoor pesticide applications present greater expo-sure potentials to both the applicator and the occu-pants. Pesticides that are considered extremely haz-ardous should not be used indoors, especially if theproduct label does not contain the indoor applicationsite.

Pesticide Selection

While efficacy is a major consideration in the selec-tion of a pesticide, selection should be influencedequally by the inherent hazard, of which the acutetoxicity of the active ingredient plays an importantrole. One simple method to evaluate the suitability ofseveral pesticides is to compare the ratio of mamma-lian to pest toxicity. The higher the ratio of the LD50for a mammal, such as a rat, and the lower the LD50 fora given pest, such as a German cockroach, the lowerthe potential hazard for humans. That is, the higher

the mammalian LD50, the safer the product may be forhumans, while the lower the LD50 for a pest species,the less active ingredient may be required to controlthe pest. Although toxicity/efficacy ratios provide anindication of relative hazards, they do not provideinformation on the effectiveness of the pesticide againstthe pest in the field.

Other factors that influence the level of control thatis achieved for a specific pest population include thepest’s resistance to the pesticide, the application tech-niques, and the type of surfaces treated. For example,military use of the pesticide d-phenothrin was seri-ously hampered when cockroach resistance to thispesticide was found. The application of pesticides tocracks and crevices, rather than broad baseboard treat-ments, has been found to be more effective becausethe pesticide is placed in locations where the pestis more likely to be found. Some surfaces such aswood, concrete or surfaces painted with latex paintmay absorb the pesticide application, reducing theamount of surface pesticide available when contactedby the pest.

Although oral and inhalational toxicities may besignificant, dermal absorption may represent a moresignificant hazard to those who apply pesticides. Care-ful selection by comparing the dermal toxicities ofselected pesticides and calculating dermal toxicityversus efficacy ratios may be helpful in keeping theapplicators safe.

EXPOSURE EPIDEMIOLOGY

There are no published epidemiological data aboutpesticide exposures resulting from military applica-tions. Because of the federal regulatory requirements,however, civilian and military applications of pesti-cides are similar; therefore, data accumulated throughcivilian reports may represent potential qualitativehealth effects in military applications.

The requirements for reporting medical data arestringent in California, especially for worker’s com-pensation: health-effects data from patients with sus-pected acute pesticide poisonings have been collectedand reported for more than 40 years.11 As a result ofthe increasingly stringent medical reporting require-ments, these data may be the best quantitative sourceon which to base estimates of the potential for symp-tomatic human pesticide exposures, both occupationaland nonoccupational. The epidemiological value ofthe data is compromised (degraded), however, by anumber of factors that influence the adequacy of thedata collection. In an uncompromised quantitativeratio, the number of patients who demonstrated signs

or symptoms caused by pesticide exposure (the nu-merator) would be compared to the total number ofindividuals with pesticide exposure (the denomina-tor). Uncertainties that could influence the numeratorinclude physiological differences among patients, fail-ure of minimally or mildly symptomatic patients toseek healthcare, failure of medical personnel to reportall pesticide-associated illnesses, and the possibilitythat the etiology of a presumed pesticide-associatedillness is inaccurately assigned.

Even if technically flawed for strict scientific ex-trapolation, the California epidemiological data pro-vide valuable insights into the magnitude of potentialpesticide exposures and the subsequent health effects.Another indicator of the widespread potential forpesticide exposure (and the subsequent health effects)is the quantity sold: 268,749,526 kg of pesticides weresold in California in 1988.11 The California State Abstractfor 1989 estimates that the population of Californiawas 28,314,000 in 1988; therefore, pesticide use wouldhave approximated 9.5 kg of pesticide per Californian.

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Of these quantities, approximately 49% were used inagriculture, 17% in the home or garden, 19% in indus-try, and 13% in institutions within the state. The U.S.Census of Agriculture for 1987 estimates that about 31million acres were available for agricultural use inCalifornia in 1988. If all the purchased pesticides in thestate were applied on agricultural land within itsborders, approximately 8.7 kg would have been ap-plied per agricultural acre.

The earliest summary of information that providesinsight into the epidemiology of pesticide poisoningswas collated in 1950. In that year, a total of 293 cases ofreported occupational diseases were associated withagricultural chemicals.11 Unfortunately, absolute num-bers, rather than incidence rates, of poisonings werereported. For 1950, in California, the profile of theleading causes of pesticides poisoning was parathion(n=52), DDT (n=27), sulfur (n=21), arsenic (n=9), nico-tine (n=8), and tetraethyl pyrophosphate (n=6).

The introduction of about 500 new EPA-registeredpesticides between 1949 and 1970, associated withmore carefully regulated use practices and withdrawalof registration for some compounds, resulted in achange in the exposure profile. In 1987, approxi-mately 17,000 pesticide poisonings were reported inCalifornia; of these, 1,507 were occupational illnesses.

Of the several hundred registered products identi-fied, the most serious poisonings were reported fromexposures to the cholinesterase inhibitors and methylbromide.11 The organophosphate insecticide parathionwas the most frequently reported pesticide correlatedwith systemic poisonings (n=90) in California in datareported for the years 1982 through 1986; these dataare similar to those reported in 1950. Mevinphos(n=58), methomyl (n=51), methamidophos (n=44),methyl bromide (n=32), sulfur (n=28), dimethoate(n=27), dinitrophenol (n=25), methidathion (n=22),and malathion (n=20) were the next-most-commonlyreported compounds.12

The American Association of Poison Control Cen-ters reported 1,581,540 human poison exposures in1989. With respect to the poisonings caused by pesti-cides, insecticides were the most commonly reportedclass with regard to the frequency of poisoning report,number of patients treated in healthcare facilities,number of symptomatic patients, and number of pa-tient lethalities (n=12). Of the insecticides, organo-phosphates were by far the most commonly reportedpoisons in all age groups and were associated withseven of the reported deaths. Arsenicals, the next-most-implicated class of pesticides, were associatedwith three deaths.13

PHARMACOLOGY OF PESTICIDES USED BY THE MILITARY

Like other chemicals, pesticides can be categorizeda variety of ways. The characteristics pesticides aremost commonly used for are (a) mechanism of action(eg, the cholinesterase-inhibiting substances); (b)chemical composition (eg, the chlorinated hydrocar-bons); (c) target pest classes (eg, the rodenticides); and(d) source of derivation (eg, the botanical extracts).Although the pharmacology of pesticides is not mili-tarily unique, medical officers need to be familiar with

• the classes of pesticides most frequently usedby the military,

• their mechanisms of toxicity,• the manifestations of acute poisoning,• the antidote, reversal, or therapeutic intervention,• the biological monitors and surveillance pa-

rameters, and• the potential long-term effects.

Table 14-6 summarizes these aspects of the follow-ing pesticide classes: organophosphates, carbamates,chlorinated hydrocarbons, anticoagulants, boric acid,and the pyrethroids. This chapter treats only themajor pesticides that are used by the military.

Information concerning the pharmacology of pesti-cides and the medical management of poisonings accu-mulates exponentially. Consequently, most militaryemergency rooms subscribe to information sourcessuch as the POISONDEX Information System.14 Infor-mation compiled from this source is the basis for muchof the management practices that follow. The three-volume Handbook of Pesticide Toxicology, published in1991, thoroughly reviews the current, scientific litera-ture related to general pesticide toxicology.15 Addi-tional sources of information concerning pesticidetoxicity and the emergency medical response to poi-soning include

• local poison control centers;• the EPA publication Recognition and Manage-

ment of Pesticide Poisonings, which providesvaluable information for emergency manage-ment of a wide range of pesticide intoxications;

• the National Pesticide TelecommunicationsNetwork (the telephone number is 1-800-858-7378); and

• the DoD Pesticide Hot Line (the telephonenumber is 1-410-671-3773).16–18

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Organophosphate Cholinesterase inhibition, phosphorylation, Muscarinic, nicotinic, and CNStime-dependent aging effects

Carbamate Cholinesterase inhibition, carbamylation Muscarinic, nicotinic, and CNS(rapidly reversible without aging) effects

Chlorinated hydrocarbon Na, K, Ca channels Highly variable, nonspecific:Chlorinated ethane derivative psychological, sensory, motor

(eg, DDT)

Chlorinated cyclodiene, CNS stimulation (transmitter release at Convulsions(eg, dieldrin) synapse)

Cardiac arrythmias possible

Anticoagulant (rodenticide Antimetabolites of vitamin K Internal hemorrhagebaits) Prolonged prothrombin times,

depressed levels of factors II(prothrombin),VII, IX, X

Pyrethroid (repellants, Delayed closure of Na channels Skin irritation, allergyinsecticides) Eye irritation, allergy

ParesthesiaAllergic bronchospasmRare: salivation, tremor, vomiting,

incoordination

Boric acid (roach control) Metabolic acidosis Nausea, vomiting, diarrhea, anuria,Electrolyte abnormalities electrolyte imbalance, tremors,

convulsions, skin erythemaprogressing to desquamation

TABLE 14-6

MECHANISIMS OF ACTION AND RECOMMENDED MEDICAL MANAGEMENT OF SELECTEDPESTICIDE CLASSES

Chemical Class Mechanism of Action Manifestations of Acute Poisoning

Cholinesterase-Inhibiting Insecticides

Military applications of insecticides are usuallyrestricted to selected organophosphates (includingchlor-pyrifos, parathion, diazinon, and malathion)and carba-mates (including aldicarb, propoxur, andcarbaryl), which are cholinesterase inhibitors; andorganochlorines and borate derivatives, which arediscussed later in this chapter.

The toxicities of these insecticides vary widely de-pending on their route of absorption, pharmacologi-cal interactions after absorption, degree of metabolicdegradation, degree of reversible enzymatic binding,and rate of excretion. Although these insecticides canalso be absorbed via inhalation or ingestion, mostoccupational effects have been reported followingdermal exposures.

Organophosphate and carbamate insecticides ex-

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Atropine (antidote) RBC acetylcholinesterase (AChE), (detectible acute or Delayed neuropathy possible2-PAM Cl (reversal) chronic decremental change from individual baseline) Possible neurotoxic esteraseAnticonvulsant Plasma cholinesterase (detectible acute decremental effect

change)

Atropine (antidote) RBC AChE (possible short-term, acute depression; None reported2-PAM Cl CONTRAINDICATED usually near normal level)Anticonvulsant

No known antidote Specific chemical analysis possible; standard levels Bioaccumulation in lipidunknown; results related to known toxic response tissuescase reports

Environmental persistence

Anticonvulsant Chemical epoxides in some cases Possible carcinogenesis(cholestyramine mayenhance biliary excretion ofsome compounds)

Vit. K1 is the SPECIFIC ANTIDOTE Prothrombin time Warfarin reported teratogenic(K3 and K4 ineffective),fresh blood for bleeding

Topical corticosteroids None reported Possible carcinogenesisTopical therapyVit. E oil for paresthesiaAntihistamines, occasionally

bronchodilators or steroidsNo known antidote

Syrup of ipecac for acute Serum borate level (mg/L blood) (0–7.2 = normal; No direct sequelae reportedindigestion (charcoal not < 340 mg/L rarely shows toxic effect)efficacious) Anti-

convulsant, monitor EKG,Fluid management, dialysisTopical skin therapy

Antidote, Reversal, Biological Monitor andTherapeutic Intervention Surveillance Parameter Long-Term Effects

ert their pharmacological influences as a result of theirinhibition of a family of cholinesterase enzymes invarious tissues. There are clear toxicological similari-ties between both classes of cholinesterase inhibitors,but there are also significant differences between theirpharmacodynamic interactions and the recommendedmedical therapeutic managements. Regulatory con-trols introduced by the EPA, greater awareness of theassociated hazards by applicators, and an intensive

effort by pesticide producers to develop safer, moreefficacious products, have resulted in a decline in bothtoxicity and the numbers of human poisonings associ-ated with these chemicals. As a group, the readyavailability, widespread use, and relatively toxic na-ture of the cholinesterase inhibitors still cause a num-ber of human fatalities annually.13,17

To review, an enzyme is a protein molecule thatinduces chemical changes in another molecule with-

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out being changed itself; therefore, an enzyme is acatalyst. The substrate is the molecule on which theenzyme exerts an influence and that is changed togenerate the enzymatic reaction product. For ex-ample, the enzyme acetylcholinesterase catalyzes thehydrolytic chemical conversion of the neurotransmit-ter acetylcholine. An inhibitor is a chemical thatcompetes with or prohibits the enzymatic interactionwith the substrate. Many enzymes are named on thebasis of the customary substrate or characteristic chemi-cal reaction type, followed by the terminal identifier -ase. For example, the enzyme acetylcholinesterasecatalyzes the hydrolytic chemical conversion of theneurotransmitter acetylcholine.

Cholinesterase enzymes are widely distributedwithin the body. They are localized within numeroustissues, fluids, and cells including heart muscle, cho-linergic synapses, myoneural junctions, plasma, anderythrocytes. Although a number of different cho-linesterase enzymes are known to be distributedthrough the body, this discussion will focus specifi-cally on the enzyme acetylcholinesterase, the cho-linesterase enzyme characteristically associated withthe erythrocyte. A different enzyme of the cholinest-erase class, pseudocholinesterase (also calledbutyrylcholine esterase), is found in the plasma frac-tion of whole blood. Although the chemical substrateinteractions and substrate degradation mechanismsare similar between these two types of cholinesteraseenzymes, they differ with respect to their preferredsubstrate, rate of enzymatic activity, site of produc-tion, and rate of regeneration after poisoning. Thesedifferences will be discussed later in this chapter, withreference to specific pesticide poisoning, emergencymedical management, and occupational surveillance.

To catalyze the hydrolysis of acetylcholine, its pre-ferred natural substrate, the acetylcholinesterase pro-tein molecule utilizes a specific, selective binding site(Figure 14-3). The acetylcholine binding site is thoughtto be composed of two specific binding areas that havebeen identified on the enzyme molecule.18 A nega-tively charged anionic site of the enzyme is believed toattract and form an electrostatic bond with the posi-tively charged nitrogen atom of the choline moleculeof the transmitter acetylcholine. The ionic bond, andsecondary attractions between the methyl groups ofthe choline moiety, and surface of the enzyme mol-ecule appear to be prerequisites to the bond formedbetween the protonated acidic carboxyl group of theacetylcholine ester molecule at the esteratic site.19 In theprocess of acetylation, a covalent linkage forms be-tween the transmitter and enzyme at the esteratic siteof the enzyme. Under normal metabolic conditions,the enzyme-substrate complex rapidly dissociates to

form a molecule of choline and an acetylated enzyme.The acetylated enzyme undergoes a hydrolytic reaction,releasing acetate and regenerating the active enzyme.

Cholinesterase-inhibiting insecticides preferentiallybind with cholinesterase enzymes, and as a conse-quence, cause interference with the normal enzymaticactivity. This causes acetylcholine, the substance re-sponsible for impulse transmission, to accumulate.Poisoning occurs in exposed humans because of inter-actions between the inhibitors and the enzyme withincentral and peripheral cholinergic synapses and withinmyoneural junctions. As a consequence of its func-tional activity, this enzyme controls nerve-impulsetransmission from nerve fibers to autonomic ganglia,muscle, glandular cells, and other nerve cells withinthe central nervous system (CNS). Should an indi-vidual be exposed to a sufficient dose of cholinesteraseinhibitors, the loss of the enzyme function results inthe accumulation of acetylcholine at the cholinergicreceptor sites. The pathophysiological response to

Fig. 14-3. These diagrams illustrate (a) the active site of theacetylcholinesterase molecule; (b) its usual natural sub-strate, acetylcholine chloride; and (c) the enzyme-substrateinteraction. The electron-rich anionic site of the acetylcho-linesterase molecule is represented as a negatively chargedarea; the serine residue at the esteratic site is represented inthe hydroxylated state.

c

a

b

H3C C

O

O

H2C C

H2

N

CH3

CH3

H3C

Cl+

Acetylcholine Chloride

N : H O

Acetylcholinesterase

Anionic Site Esteratic Site

N H O

H2CC

H2N

H3C

H3C

CH3+

O

C

O

CH3

+

Enzyme–Substrate Chemical Interaction

Anionic Site Esteratic Site

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unimpeded overstimulation of neuromuscular tissuesby acetylcholine is manifested by a spectrum of poten-tial medical signs and symptoms related to the degreeof poisoning. While clear toxicological similarities aredemonstrable between the organophosphate and car-bamate insecticides, there are significant differencesbetween the pharmacodynamic interactions and rec-ommended medical therapeutic management.

Organophosphates

The first organophosphate pesticide, the highly toxiccompound tetraethyl pyrophosphate (TEPP), was in-troduced as an insecticide in 1939, although it wasinitially chemically synthesized and identified in 1894.20

Closely related, highly toxic compounds later classi-fied as nerve agents were identified during attempts tosynthesize alternative pesticides and were secretlyproduced in Germany during World War II. Althoughthey were never used as insecticides, warfare nervegases such as tabun and soman were produced insubstantial quantities and stored for possible use dur-ing the war. The partnership between applied toxicol-ogy and the chemical pesticide industry has resultedin the production and use of safer, more specificorganophosphate pesticides for the target pest.

Many organophosphate pesticides have been de-veloped, but those most commonly used for militaryapplications are chlorpyrifos, diazinon, and malathion(Table 14-7 ).20 Parathion is occasionally used; how-ever, the EPA has currently been reviewing its regis-tration. As a result of the intense scrutiny, the registra-tion of parathion might be revised by the manufacturerwith EPA approval, or revoked or revised by the EPA.

Route of Exposure. Most organophosphate insecti-cides are readily absorbed by all routes of exposure.Intentional ingestion of pesticide products is a com-monly reported form of attempted suicide. Therefore,much of the information on medical management oforganophosphate poisoning is derived from suicideattempts. Military scientific and medical experienceswith the chemically similar nerve agent war gaseshave resulted in substantial contributions in the basicscientific literature and accumulated medical knowl-edge concerning organophosphate pesticides.

While some compounds such as mevinphos aremore toxic when the exposure route is dermal, most ofthese compounds are more toxic if they are ingested.Some of the compounds, such as trichlorfon anddiazinon, are severalfold more toxic if ingested orinhaled than if they absorbed through the skin.Chlorpyrifos and malathion are readily absorbed andmay manifest equally toxic effects as a result of cuta-neous contact, inhalation, and ingestion.14

Mechanism of Action. Much of the toxicologicalinformation concerning the mechanism of action oforganophosphates has been gained through study ofthe more toxic chemicals such as the nerve agents andparathion.

Organophosphate insecticides interact with theesteratic site of the acetylcholinesterase enzyme mol-ecule by the process of phosphorylation. The interac-tion, and subsequent chemical events that may occurbetween the enzyme and insecticide inhibitor, can beshown by the equation:

EOH + IL <—> {EOH}{IL} —> L– + H+ + EOI —>EOH + I– + L–

where EOH represents the enzyme, IL represents thepesticide, {EOH}{IL} represents the reversible enzyme-insecticide complex, L– represents the leaving group,H+ represents the hydrogen ion, EOI represents thephosphorylated or carbamylated enzyme, and I– rep-resents the pesticide remnant that remains after hy-drolytic dephosphorylation or decarbamylation hasoccurred.

Hepatic metabolic activity may influence organo-phosphate pesticide activity as a result of pesticidedegradation, activation, or both.4,16,20 In addition tothe enzymatic degradation of organophosphate pesti-cides through the acetylcholinesterase pathway, he-patic metabolization of organophosphate insecticidesis sometimes important in pesticide detoxification.Enzymes that perform phase I metabolic activation inthe liver—through hydrolysis, oxidation, or reduc-tion of the parent insecticide—are primarily localizedwith-in the hepatocyte endoplasmic reticulum. Hy-drolytic, oxidation, or reduction rates and the types ofmetabolic products vary, depending on the particularpesticide. With some insecticides, breakdown may besufficiently slow that temporary storage of the pesti-cide can occur in body fat. With other insecticides (eg,parathion, chlorpyrifos, and malathion), the metabo-lites of hepatic enzymatic pathways are more potentthan the parent compound (the marketed pesticide).For example, the hepatic metabolites paraoxon andmalaoxon cause much more pronounced toxic (cho-linesterase inhibitory) effects than those produced bythe parent compound.4,16,20 For those compounds thatare metabolically activated by the liver (includingparathion, malathion, and chlorpyrifos), the onset ofsigns and symptoms may be delayed for several hoursafter exposure because the actual toxicity is almostexclusively due to its metabolic product, an oxygenanalog.14,19

If the chemical reaction of the phosphorylated cho-linesterase enzyme complex (EOI) results in hydro-lytic dealkylation rather than dephosphorylation, an

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TABLE 14-7

TOXICOLOGY OF SOME ORGANOPHOSPHATE INSECTICIDES

*Values obtained in standardized tests in thesame laboratory

†Maximum rate of intake (usually 3-mo, 2-yrfeeding studies) that was tested and didnot produce significant toxicologic effects(as listed in the monographs issued jointlyby the Food and Agriculture Organizationof the United Nations and the World HealthOrganization, as developed by joint meet-ings of expert panels on pesticide residuesheld annually, 1965–1972)

‡Acceptable daily intake (ADI) = the dailyintake of a chemical that, during a lifetime,appears to provide the practical certaintythat injury will not result (in man) duringa lifetime of exposure. Figures taken fromWorld Health Organization (1973).

Reprinted with permission from MurphySD. Toxic effects of pesticides. In: KlaassenCD, Amdur MO, Doull J, eds. Casarett andDoull's Toxicology: The Basic Science of Poi-sons. 3rd ed. New York: McGraw-Hill; 1986:529.

Table 14-7 is not shown because the copyrightpermission granted to the Borden Institute, TMM,does not allow the Borden Institute to grant per-mission to other users and/or does not includeusage in electronic media. The current user mustapply to the publisher named in the figure legendfor permission to use this illustration in any typeof publication media.

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irreversible enzyme-phosphate product (phosphoryladduct) is generated.16 As a result, the enzyme cannotbe regenerated and remains inactivated; that is, it issaid to become aged. The reaction can be shown by theequation:

EOI —> alkyl group product + phosphoryl adduct

For example, in the enzymatic reaction with the or-ganophosphate diisopropyl fluorophosphate (DFP),the initial enzyme-DFP complex releases its leavinggroup (fluoride) as a result of the hydrolytic reaction.The reaction results in the generation of the phospho-rylation product, a diisopropylphosphoryl-enzymecomplex and hydrofluoric acid. Subsequent hydro-lytic dephosphorylation of the phosphorylated en-zyme complex results in the release of a phosphoricacid derivative, diisopropyl phosphate, and the regen-eration of the active enzyme. Because the rate ofdephosphorylation is slow for the diisopropylphos-phoryl-enzyme complex, an alternative degradationpathway through hydrolytic dealkylation is possible.As a consequence, the concentration of the enzyme-monoisopropyl phosphate complex (the aged enzyme)rises following DFP exposure. The rate of organophos-phate-enzyme detoxification by hydrolytic dephos-phorylation and resultant active enzyme regenerationstrongly depends on the type of organophosphorusinhibitor involved. (In contrast, as a class, carbamateinsecticides are considered reversible inhibitors of cho-linesterase and are not associated with aging.20)

Parathion is another organophosphate insecticidethat ages the cholinesterase molecule (Figure 14-4).During the conversion process, parathion is metabo-lized to the active cholinesterase inhibitor, paraoxon,by desulfuration within the endoplasmic reticulum.Paraoxon reacts with the esteratic site of cholinest-erase by phosphorylation. As a result of dearylation,p-nitrophenol is released as the leaving group fromthe initial, transient enzyme-insecticide complex. Afterdearylation, the phosphorylated-enzyme complex isvery stable, with only limited subsequent hydrolysisto regenerate the active enzyme and release diethylphosphate. Most of the phosphorylated complex isslowly converted to the extremely stable (aged)ethylphosphonate-enzyme adduct by dealkylation.19,21

Reactivation of a phosphorylated enzyme is pos-sible using oxime therapy. However, reactivation ofthe aged enzyme-phosphorylated adduct complex isnot possible and is, therefore, refractory to oximetherapy. The rate of pesticide-enzyme complex agingdepends on the specific organophosphate inhibitorinvolved. For example, the nerve agent soman rap-idly reacts with the enzyme through phosphorylationand the enzyme becomes aged within seconds to a few

minutes. Other selected organophosphate-enzymecomplexes may be reactivated 1 or 2 days after initialbinding. The aged acetylcholinesterase associatedwith erythrocytes in the peripheral circulation is nor-mally regenerated only as a consequence of erythrocyte

Fig. 14-4. The acetylcholinesterase molecule ages afterorganophosphate poisoning with parathion. The chemicalreactions between paraoxon, the active chemical metaboliteof parathion, and acetylcholinesterase favor enzyme aging;enzyme regeneration also occurs, but at a slower rate.

O2N O P

O

OC2H5

OC2H5

O2N OH

Enzyme

O

P

O

OH

OC2H5

Enzyme

O

P

O

C2H5O

C2H5O

OH

Enzyme

Paraoxon

p-Nitrophenol

HO P

(Phosphorylated Enzyme)

O

OC2H5

OC2H5

+ H20

OH

Enzyme

Ezyme

O

P

O

OC2H5

OC2H5

+

+

+

(Aged Complex)

(Regeneration)

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production and replacement in the circulation. Con-sistent with the life span of the mature erythrocyte,regeneration of erythrocyte-associated aged acetyl-cholinesterase occurs at a rate of about 1% per day.

Chlorpyrifos. Chlorpyrifos is one of the safer or-ganophosphorus insecticides. When sufficient dosesare absorbed to elicit a toxic response, however,chlorpyrifos produces clinical effects in humans thatare indistinguishable from other organophosphoruscompounds. In contrast to many organophosphateinsecticides, chlorpyrifos is an active inhibitor ofplasma cholinesterase, but is characterized as only amoderate inhibitor of the erythrocyte-associated en-zyme. As a result, normal exposure causes selectivedepression of cholinesterase activity in the plasmarather than in erythrocytes. Depression of erythro-cyte-enzyme levels is often seen, however, when sys-temic effects are clinically apparent.14

When ingested by humans, oral doses of chlorpyrifosof 0.03 mg/kg/day had no detectable effect on plasmacholinesterase (also called pseudocholinesterase) lev-els. Enzyme depression (inhibition) of 70% has beenreported to cause only mild symptoms in some cases.Human subjects who ingested 0.1 mg of chlorpyrifos/kg/day for 4 weeks were found to have statisticallysignificant decreases in plasma cholinesterase. Pest-control operators who were exposed to 8-hour time-weighted average (TWA) exposures of 27.6 mg ofchlorpyrifos/m3 of air revealed significant inhibitionof plasma acetylcholinesterase when compared withage- and sex-matched controls; however, they had noclinical signs or symptoms of exposure.14

Information related to chronic neurological sequelaeof chlorpyrifos exposure in humans is limited. Anadult male ingested 300 mg/kg of chlorpyrifos. Heexhibited varying degrees of severity of cholinergicsigns for more than 2 weeks. Although his electro-physiological studies of peripheral nervous functionwere reportedly normal 1 month after ingestion, hisneurotoxic esterase (lymphocytic neuropathy targetesterase, NTE) was approximately 60% inhibited.About 2 weeks later, the patient complained of pares-thesia and lower-extremity weakness. A clinical ex-amination and laboratory evaluation demonstratedclassical findings of delayed axonal peripheral neur-opathy.14

Delayed neurotoxicity has been reported followingchlorpyrifos administration in the standard hen as-say; however, the effects were reported to be revers-ible.19 Delayed neurotoxicity was not seen followingadministration in the mouse model.14 However, it isthe hen, not the mouse, that is considered to be thestandard assay of neurotoxic effect.1

The delayed CNS neuropathy following acute ex-

posures to the organophosphate insecticides may beslowly reversible or remain irreversible, associatedwith axonal degeneration. A delayed onset, mixedsensory-motor peripheral neuropathy has been re-ported, with onset between 6 and 21 days after mala-thion exposure. After malathion exposures, recoveryfrom the delayed neuropathy may be slow or incom-plete. After diazanon exposures, sensory-motor pe-ripheral neuropathy has occurred; however, the onsetof the neurological abnormalities may be delayed forseveral weeks. Recovery may be slow or incomplete.14

Organophosphorus ester–induced delayed neuro-toxicity (OPIDN) is the classical clinical syndromeassociated with organophosphate insecticides. Theearly clinical description of OPIDN was associatedwith workplace exposures to tri-ortho cresol phos-phate. The clinical findings of OPIDN include arapidly progressive paralysis of the lower and upperextremities with limited recovery. The classical patho-logical lesion occurs within the CNS and peripheralnervous system (PNS) and is characterized as axonaldegeneration and demyelinization of the long motorand sensory neurons. (The adult female hen is thepreferred and accepted scientific standard model forthe study of neurotoxic effect.) Neurotoxic esterasehas been reported to be the putative target of OPIDN.The enzyme 2´,3´-cyclic nucleotide 3´-phosphohy-drolase (CNPase) has recently been reported as asensitive indicator of myelin loss, and may be a sensi-tive indicator for OPIDN.22

Chlorpyrifos exposure did not result in teratogenicor fertility effects in the rat. Chlorpyrifos demon-strated no carcinogenic potential following chronicadministration in studies using rats and mice. Nochanges in microbial mutation or sister chromatidexchanges have been reported following chlorpyrifosexposures. Semen quality changes have been re-ported in bulls exposed to chlorpyrifos.14

Parathion. In a human dose-response study, adultswho consumed more than 6 mg of parathion per dayfor 30 days had some decrement in cholinesteraselevel. Several individuals who consumed more than7.5 mg for 16 days had erythrocyte cholinesteraselevels inhibited to 50% and 52% of pretest levels. Noadverse signs or symptoms were noted in any of thestudy subjects. In a separate study, a total daily dosageof 0.078 mg/kg of parathion resulted in depression ofboth erythrocyte cholinesterase (16% decrease) andplasma cholinesterase (33% decrease) levels comparedto baseline values. The no-effect daily dose of para-thion administered to adults was between 0.058 and0.078 mg/kg when administered over time durationsbetween 25 and 70 days. The acute dose that could belethal in an adult has been estimated to be 120 mg.14

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Parathion has been shown to be fetotoxic, but notteratogenic, in laboratory studies. However, methylparathion has been associated with human birth defects.Although parathion has demonstrated effects of pos-sible genotoxicity in rodents (induced DNA alterations)and in vitro studies (Ames and sister chromatid ex-change assays), it is not considered to be carcinogenic.14

Diazanon. In contrast to parathion, the estimatedadult oral fatal dose for diazinon is approximately 25g. In addition to cholinesterase inhibition, increasedprothrombin time has been reported with both mala-thion and diazinon exposure.14

Malathion. Manifestations related to the degree ofacute toxic response seen after malathion exposuredepend on the total dose absorbed, manner of expo-sure, and duration of the exposure profile. The toxicityof malathion is probably due to its metabolic oxidationto malaoxon, which has been estimated to be approxi-mately 1,000-fold more potent than malathion itself asa cholinesterase inhibitor. The cholinergic toxicity isregarded as the principle hazard associated with expo-sure. Malathion and its metabolites appear to affectboth erythrocyte cholinesterase and serum butyryl-choline esterase enzymes. Malathion has relatively lowacute toxicity: an oral dose of 24 mg/day was requiredto depress cholinesterase activities in adult volunteers.

The estimated fatal oral dose exceeds 70 mg/kg.14

Malathion has been reported to cause mild skin andupper-respiratory irritation in humans, and repetitiveexposures have been reported to cause allergic cuta-neous sensitization. A case of transient renal dysfunc-tion secondary to a malathion-induced, immune-com-plex nephropathy has been reported.14

Malathion exposure has been studied in humanlymphoid cell culture. An increase in sister chromatidexchange was noted with increasing doses of cellularexposure. Metabolic activation with liver homoge-nate had no demonstrable effect on the exchange. Atthe highest dosage, cytotoxicity was demonstrated bythe loss of approximately 50% of the cultured cells. Astudy of malathion-intoxicated individuals identifiedan increased frequency of chromatid breaks and un-stable structural chromosomal aberrations. How-ever, a causal association could not be demonstrated.14

Signs and Symptoms of Intoxication. Clinical signsand symptoms of organophosphate insecticide poi-soning depend on the type and exposure dosage of thechemical pesticide involved and are usually reportedwithin several hours of exposure (Table 14-8). Theasymptomatic individual may have cholinesterasedepression. Clinical signs of exposure vary from lim-ited local effects to severe systemic effects such as coma.

SIGNS AND SYMPTOMS OF ORGANOPHOSPHATE POISONING

TABLE 14-8

Organ System Effects

Muscarinic (parasympathetic)

Visual Dimness of vision, blurring of vision, unilateral or bilateral miosis

Respiratory Rhinorrhea, breathing difficulty, cough, tightness of chest, bronchoconstriction, increasedbronchial secretions, wheezing

Cardiovascular Bradycardia, systemic hypotension, atrial or ventricular arrhythmia

Gastrointestinal Salivation, nausea, vomiting, diarrhea, involuntary defecation

Cutaneous Sweating

Genitourinary Frequent, involuntary urination

Nicotinic (sympathetic and neuromuscular)

PNS (ganglia) Peripheral vasoconstriction, tachycardia, hypertension, hyperglycemia

Musculoskeletal (striated) Localized or generalized fasciculation, respiratory insufficiency or paralysis, weakness,cramps, twitching

CNS (mixed muscarinic and nicotinic)

CNS Anxiety, giddiness, restlessness, headache, emotional lability, excessive dreaming, nightmares,confusion, tremor, ataxia, coma, cardiorespiratory depression, cyanosis, hypotension, convul-sions, apnea

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Signs and symptoms of acute cholinesterase inhibi-tion and subsequent cholinergic intoxication are highlydose dependent. Direct skin contact can cause localfasciculation or sweating without other effect. Simi-larly, local ocular exposure to an organophosphateinsecticide aerosol may cause unilateral or bilateralmiosis without systemic manifestations.14

The systemic effects of this group of pesticides arethe (a) muscarinic, (b) nicotinic, and (c) the combined,more severe CNS responses.18

Muscarinic Response. The classical postjunctionalmuscarinic response to acetylcholine stimulation isassociated with activation of specific receptor sites ofpostganglionic parasympathetic effector cells. Post-ganglionic muscarinic receptors are found primarilyin smooth muscle, exocrine glands, and the heart.Muscarinic signs and symptoms are associated withcardiac, ocular, pulmonary, cutaneous, genitourinary,and gastrointestinal manifestations. Severe bradycar-dia, miosis, wheezing associated with bronchocon-striction and bronchial secretions, sweating, involun-tary urination, nausea, vomiting, diarrhea, andinvoluntary defecation are common muscarinic re-sponses. Exposed workers may present with giddi-ness, complaints of blurred vision, headache, nausea,abdominal cramps, breathing discomfort, or with vari-ous degrees of more severe distress. Military medi-cine uses the acronym SLUDGE to aid rapid fieldrecognition of the signs and symptoms of the musca-rinic response: salivation, lacrimation, urination, def-ecation, gastrointestinal complaints, and emesis.

Atropine, in sufficient dosage, is an effective anti-dote for muscarinic signs associated with the cardiac,respiratory, and CNS responses. Atropinization causesthe gastrointestinal and genitourinary effects to im-prove; however, atropinization is only partially effi-cacious because it neither results in enzyme regenera-tion nor affects nicotinic receptors.

Nicotinic Response. Nicotinic responses to acetyl-choline occur at myoneural junctions of striated muscle,preganglionic autonomic synapses with ganglia, andwithin the CNS. Although several types of site-spe-cific nicotinic receptors have been identified, theacetylcholine effect on nicotinic sites is independentof those differences. Muscular responses to stimula-tion of nicotinic receptors range from easy fatigue,mild weakness, twitching, or localized fasciculation,to severe, generalized fasciculations that result inrespiratory embarrassment and cyanosis.

The effects of stimulation of the nicotinic receptorsof sympathetic ganglia can result in pallor. At higherlevels of sympathetic nicotinic stimulation, hyperten-sion and hyperglycemia may occur. In addition,tachycardia that results from ganglionic nicotinic re-

ceptor stimulation, which overrides the bradycardiceffects of muscarinic stimulation, may be observed.The nicotinic receptors of the CNS appear to be impor-tant in nicotine dependence; headaches, paresthesia,and tiredness have been reported with nicotine ad-ministration.14 Other nicotinic actions on the CNScause tremor, convulsions, initial respiratory stimula-tion followed by respiratory depression, and vomit-ing (the latter action being caused by direct action onthe area postrema of the brain stem).7

Central Nervous System Response. Signs and symp-toms of CNS poisoning include anxiety, apathy, toxicpsychosis, restlessness, fatigue, headache, nightmares,tremors, seizures, and depression of cardiac and res-piratory centers, which can progress to coma.16,18 At-ropinization and oxime therapy are efficacious formanagement of the CNS toxic effects. Anticonvulsantsare indicated to provide therapeutic management ofseizure control.

Chronic health effects from both high-dose, short-term and low-dose, chronic exposures to organophos-phate compounds have been reported in humans.16,23

Neuromuscular signs and symptoms associated withthis neuropathy include paresthesias, easy fatigabil-ity, cramps, and may progress to gait abnormalities.Pathologically, the delayed peripheral neuropathydemonstrates peripheral demyelinization. The de-layed peripheral effects may be related to organo-phosphate binding of a “neurotoxic esterase” enzyme.16

Neurobehavioral signs and symptoms include manydifferent complaints such as anxiety, depression, in-somnia, and irritability. Most residual neurologicalsymptoms appear to resolve within a year followingacute intoxications.18

Parathion Intoxication. The onset of signs and symp-toms induced by parathion has been uniformly ac-cepted as the standard general description of organo-phosphate poisoning. It is important to recognize thatthe signs or symptoms can recur for days, despitetherapeutically efficacious medical management. Carefulpatient monitoring and administration of indicatedtherapeutic management must be assured for daysafter parathion or other organophosphate poisoning.

Clinical signs and symptoms seen in children aremost often seen by alterations of central neurologicalstatus. CNS depression, stupor, flaccidity, and comaare the most common signs in children. Dyspnea iscommonly seen in children.

Ingestion usually results in nausea, followed byincreased salivation, abdominal cramps, vomiting, anddiarrhea. Hypothermia may occur as an early sign,but is not a usual finding. Alterations in mental statuscan manifest as confusion, anxiety, or giddiness.

Inhalation is usually followed by rhinorrhea, then

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chest tightness as exposure doses increase. Althoughmiosis may occur with eye pain, ciliary muscle spasm,and blurring of vision in topical or inhalation expo-sure, miosis is not a dependable sign for ingestion orcutaneous exposures. In fact, mydriasis is not anuncommon finding, possibly as a result of a sympa-thetic, reflex, adrenal response.

Although alveolitis, followed by progressive pul-monary fibrosis, has been reported in a parathion-intoxicated patient,14 alveolitis and fibrosis are muchmore common following paraquat exposures.24 Chemi-cal alveolitis is probably associated with other chem-icals in the pesticide formulation, rather than as aresult of exposure to the cholinesterase-inhibiting in-secticide itself.

CNS effects such as decreased vigilance, alteredexpressive language, diminished cognitive function,impaired memory, depression, anxiety, and irritabil-ity have been reported.14 Other signs and symptomsmay include visual hallucinations, auditory halluci-nations, and psychosis.

Cardiac signs of organophosphate insecticide poi-soning characteristically include bradycardia andhypotension, although reflex tachycardia, despite sig-nificant poisoning, has been reported. Heart rate,alone, is an unreliable sign for both the degree ofexposure and efficacy of therapy. It has becomeincreasingly apparent that acetylcholine in the coro-nary circulation can cause intense vasospasm result-ing in atrial arrhythmias, hypotension, chest pain, andheart block.14,25

Acute respiratory failure is the major cause of deathin organophosphate poisoned patients. Dyspnea,bronchorrhea, and tachypnea represent significantclinical signs of respiratory difficulty. Bronchospasmoccurs as a typical pharmacological muscarinic effect.Respiratory responsiveness, such as diminished res-piratory secretions and decreased ventilatory resis-tance are reliable indicators of inhalation toxicity andthe efficacy of medical management. Delayed respi-ratory crisis may occur for 2 to 3 weeks followingacute poisonings.14

Chlorpyrifos Intoxication. Muscular weakness, fati-gability, and fasciculations are commonly reported inassociation with chlorpyrifos poisoning. They may bedelayed in onset and paralysis may occur.14

Miosis, lacrimation, and blurred vision are com-mon signs of chlorpyrifos poisoning. Mydriasis isunlikely, but has been reported in association withsevere poisonings.14 Excessive salivation is a commonpost-exposure sign.

Sweating is a common sign of chlorpyrifos expo-sure, but does not occur as a universal finding. Dermalirritation and sensitization have been reported but are

uncommon. Other uncommon effects of exposure in-clude a reported alteration in prothrombin time andthe occurrence of hyperglycemia in severe poisoning.14

In addition to nausea, vomiting, and diarrhea, ab-dominal pain and fecal incontinence may occur withcholinesterase inhibition. Urinary frequency and, insevere cases, urinary incontinence have been reported.

Diazanon Intoxication. Nausea is often the firstsymptom that follows diazinon exposure. Other signsand symptoms range in severity from mild gastroi-ntestinal or respiratory effects to cholinergic crisis.Vomiting, diarrhea, abdominal cramps, and saliva-tion are commonly reported, especially with cutane-ous or gastro-intestinal absorption. Inhalation expo-sures are more commonly associated with rhinorrheaand chest tightness. Ocular effects from exposureinclude tearing, miosis, ciliary muscle spasm, and eyepain. Paradoxical mydriasis has been reported withdiazinon poisoning and probably is the result of asympathetic reflex response.14 Weakness, local fas-ciculations, drowsiness, dizziness, headache, and be-havioral changes represent mild to moderate neuro-muscular responses to exposure. Loss of muscularcoordination, generalized twitching, and convulsionsrepresent more severe neurological consequences ofpoisoning with diazinon.

Malathion Intoxication. It is important to note thatsymptoms occur after high-dose exposures to mala-thion, which are possible only in unusual circum-stances such as an incorrect application. Inhalation ofmalathion results in ocular and respiratory effects asfirst signs of exposure. Ingestion results in a loss ofappetite, nausea, vomiting, abdominal cramps, anddiarrhea, which may appear within several hours.After skin absorption, local signs of sweating andtwitching may occur within minutes or may be de-layed for several hours. Severe signs may occurfollowing exposure by all routes.

Clinical manifestations of malathion exposure inchildren may differ from the predominant signs andsymptoms associated with adults exposure. CNSsigns, such as CNS depression, stupor, loss of muscu-lar tone, and coma are the most commonly reportedsigns of exposure in children; respiratory difficultyhas also been reported.14

Other signs and symptoms have also been reported:fever may persist for several days; alterations in pro-thrombin time may occur; and hyperglycemia, glyco-suria, and metabolic acidosis without ketosis havebeen reported associated with severe poisoning.14

Medical Treatment. If a strong likelihood of acuteorganophosphate poisoning exists, the patient shouldbe treated immediately without waiting for labora-tory results. The usual ABCs of emergency care apply:

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healthcare providers must ensure that the patient hasa patent airway, is breathing, and has adequate circu-latory function without apparent hemorrhage. Oxy-gen should be provided, if the patient’s conditionindicates. Individuals who attend the victim shouldavoid direct contact with heavily contaminated cloth-ing, vomitus, skin, and hair by wearing PPE such asrubber gloves (at a minimum).

Plasma and erythrocyte cholinesterase enzyme ac-tivities should be measured, but the degree of correla-tion between the levels of cholinesterase inhibitionand clinical effects is imprecise. In some cases, adepression of only 50% of the enzyme activity may beassociated with signs of cholinergic crisis. The corre-lation between cholinesterase levels and clinical ef-fects is unreliable and should not be used for medicalmanagement.

In addition to the determinations of erythrocyteand plasma cholinesterase levels, some clinical labo-ratories may perform urinalyses for p-nitrophenol,the parathion leaving group. As with cholinesteraselevels, the determination of parathion-metabolite lev-els is often not a readily available emergency testprocedure. As a result, medical management of theparathion-poisoned patient should be directed by thepatient’s clinical responsiveness, with cholinesteraseor pesticide-metabolite levels in urine serving only assubsequent measures of confirmation of exposure.

Clinical decisions concerning medical management mustbe based on the type and degree of signs exhibited by theacutely poisoned patient. Medical therapeutic interven-tion should not depend on the degree of depression ofmeasured cholinesterase activity for the followingreasons:

• The correlation between enzyme levels andclinical effects is poor.

• The test is not universally available.• Laboratory report times are too time consum-

ing.• Baseline information is absent in many acute

poisoning cases.

As a result, the measured enzyme inhibitions mayconfirm the diagnosis of cholinesterase inhibitor in-toxication, but will not contribute substantially toacute patient management.

Asymptomatic patients with documented depres-sion of cholinesterase levels should be carefully moni-tored, but they require no atropine unless signs andsymptoms of poisoning evolve. Follow-up evalua-tions of cholinesterase levels for adequately treated orclinically stable asymptomatic patients whose levelshave been acutely depressed may be done at weekly

intervals unless the patient’s condition dictates morefrequent analyses.

Because early-onset respiratory depression and gen-eralized convulsions are expected after serious expo-sures such as intentional ingestion, induction of eme-sis is contraindicated. If necessary, gastric aspirationor lavage can be performed. Protection of the airwayis critical during nasogastric procedures and may beaccomplished by cuffed endotracheal intubation. Iflavage is performed, the return volume should ap-proximate the amount of fluid administered.

In the management of ingestion, an activated char-coal slurry should be administered as quickly as pos-sible. A total of 30 to 100 g of charcoal should beadministered to adults, and 15 to 30 g to children.14

Administration of a cathartic, either with the charcoalor separately, is recommended.

Atropine Therapy. In addition to respiratory dis-tress, patients with severe signs of intoxication haveprofuse nasal, oral, and airway secretions. It is im-perative to maintain control of a patent airway, usingsuction if necessary, until the degree of atropinizationis adequate to control secretions and relieve broncho-spasm. If hypoxia is suspected, administration ofoxygen (if available) before atropine is injected isrecommended. Atropine administration has beenassociated with the precipitation of ventricular fibril-lation in hypoxic patients.

Atropine administration for symptomatic patientsis imperative. Timely administration is crucial, re-gardless of the route of pesticide exposure. Atropinesulfate should be given intravenously, if possible, butis effective when injected intramuscularly, especiallyif administered via the current military Mark I atro-pine autoinjector. Signs of adequate atropine admin-istration include drying of the airway secretions andimprovement of respiratory efforts. Atropine admin-istration should be continued as necessary until signsof organophosphate poisoning no longer recur, some-times days after the acute poisoning event. The fever,disorientation, and delirium associated with atropineuse reflect signs of excessive atropine administration;they indicate at least temporary discontinuation ofatropine. Atropine administration does not affectacetylcholinesterase regeneration.

The typical adult dose of atropine is 2 to 4 mg,which can be administered every 10 to 15 minutes asneeded. The dosage of atropine useful for managinga poisoned child is 0.05 mg/kg every 10 to 15 minutesas needed.14 Treatment of cholinesterase inhibition isrequired for hours or days, depending on the indi-vidual patient and the circumstances of exposure. Thetreatment of patients poisoned with organophosphateinsecticides may require a total of several grams of

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atropine over the course of acute recovery from poi-soning.

Oxime Therapy. There is no effective, medicallyapproved antidote for the nicotinic effects of cholines-terase-inhibiting substances. If therapeutic interven-tion precedes enzyme aging, oxime therapy, such asadministration of 2-pyridine aldoxime methyl chlo-ride (2-PAM Cl), acts as a reversal compound (Figure14-5). Improved levels of active enzyme within theacetylcholine-receptor regions results in improveddisposition of free acetylcholine, with resultant im-provement in the patient’s signs and symptoms. Oximetherapy is recommended for patients with signs ofsevere pesticide intoxication such as severe twitchingor fasciculation, significant weakness, or respiratoryembarrassment.16,23 2-PAM Cl does not relieve bron-chospasm or bronchorrhea, which are treated withconcurrent administration of atropine.23

Pralidoxime Therapy. Pralidoxime therapy is oftenhelpful in acute organophosphate poisonings. It isimperative that pralidoxime be administered to severelypoisoned patients who have neuromuscular effects suchas fasciculations, weakness, and respiratory paralysis.The typical dose for individuals who are 12 years oldor older is 1 g of pralidoxime delivered intravenouslyover a minimum of 2 minutes. Children younger than12 years of age should be given an intravenous dose of20 to 30 mg/kg slowly, over at least 2 minutes.14

Pralidoxime is often helpful in acute organophos-phate poisonings and is indicated in severe cases oforganophosphate insecticide poisoning that are ac-companied by profound weakness and respiratorydepression. The recommended adult dose ofpralidoxime is 1.0 g, administered intravenously, at arate of 0.5 g/minute or infused in 250 mL of normalsaline over 30 minutes. For initial management, thedose can be repeated up to three times. It may beadministered in intervals of 6 to 12 hours if muscleweakness is not relieved or if the patient remainscomatose. A continuous pralidoxime infusion (500mg/h) may be administered; however, this alterna-tive is considered to be controversial.14

For a poisoned child, pralidoxime may be adminis-tered intravenously at a dosage of 25 to 50 mg/kg over30 minutes. Further administration may be necessaryif muscle weakness and associated respiratory de-pression remain uncorrected.14

Anticonvulsant Therapy. Medical personnel shouldbe prepared to promptly administer benzodiazapines(diazepam) as anticonvulsants for seizure activity asso-ciated with poisoning. The occurrence of clinicallyapparent convulsions has been recognized as a sign ofneurological electrophysiological seizure activity. Ifconvulsions occur, timely administration of diazepam

as a direct intravenous bolus is imperative to precludefurther neurological damage from hypoxia. The typi-cal adult dose is 5 to 10 mg initially, which maybe repeated every 15 minutes, as necessary, up to 30mg. For the convulsing child, a dosage of 0.25 to 0.4mg/kg up to 10 mg total dose is recommended. Intra-muscular injections are slowly absorbed and shouldbe avoided, if possible. If seizures are uncontrol-lable or recur, phenytoin or phenobarbital should beadministered.14 Physostigmine, succinylcholine, or othercholinergic agents are contraindicated and should not beadministered.

Complications. Pulmonary edema may result frominhalation of pesticide formulations or occur as acomplication of medical management. Oxygenationand ventilation must be maintained and arterial bloodgases must be carefully monitored. If PO2 remains lowin spite of oxygen administration, it may be necessaryto add positive end expiratory pressure (PEEP) orcontinuous positive airway pressure (CPAP). Carefulfluid management is essential and a central line orSwan-Ganz catheter should be placed to monitor fluidstatus.

If significant inhalation exposure or coincident as-piration occurs, a baseline X ray should be obtained.This is especially important if the pesticide formula-tion was concentrated, contained irritant or hydrocar-bon compounds, or was of unknown composition.Determining arterial blood gases and testing pulmo-nary function may be necessary during complicatedmedical management of some patients.

Hypotension may occur and should be treated byadministering intravenous fluids and placing the pa-tient in the Trendelenburg position, if necessary. Pa-tients with blood pressure that is unresponsive tofluid administration may require careful pressuretitration using dopamine (2–5 µg/kg/min) or norepi-nephrine (0.1–0.2 µg/kg/min).14

Carbamates

Carbamate insecticides are cholinesterase inhibi-tors (see Table 14-6). These compounds are an associ-ated group of chemical esters with the general struc-tural composition shown above, where R representsan oxime, alcohol, or phenol, and is the leaving groupassociated with inhibition of the cholinesterase mol-ecule16; R´ represents an N-methyl or hydrogenatom.2,20,26 The most commonly used carbamates in

R O C

O

N

CH3

R'

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Fig. 14-5. If organophosphate-inhibited acetylcholinesterase is treated before it ages with pralidoxime chloride (2-PAM Cl,an oxime), the enzyme can be reactivated.

P

OR

OR

O

C

H

N OH

H3C

C

H

N POR

ORO

OR

OR

O

O

CH3

C

H

N P

N O

O

N: OH

H

N

N

CH3

N

O

Phosphorylated Enzyme

+ +

Cl

2 - PAM Cl

+

Combination Reaction

+ H2O

Organic Phosphorous Moiety

Active Enzyme

Oxime Derivative

:

+

+

_

_

_

_

+

N

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the military are carbaryl and propoxur, representa-tives of the N-methylcarbamate group (Table 14-9).20

Route of Exposure. Carbamates are absorbed viaall routes of exposure, although dermal absorption isslight.16 The degree of acute toxic effect depends onboth the rapidity of absorption and the cumulativedose. Many carbamate insecticides have low dermaltoxicity.18

Mechanism of Action. Inhibition of the acetylcho-linesterase molecule by the N-methylcarbamate pesti-cide group differs from the phosphorylation reactionsin organophosphate insecticides. In contrast to therather stable organophosphate phosphorylation at

the esteratic site, carbamylation of the enzyme ap-pears to involve attachment of the carbamate at boththe anionic and esteratic sites, which is similar to theaction of acetylcholine. Because of the ready dissocia-tion of the enzyme-carbamyl complex and the subse-quent regeneration of the active enzyme molecule,carbamate compounds are rapidly reversible inhibi-tors of acetylcholinesterase.

Like other cholinesterase-inhibiting substances, car-bamates are not directly measured in blood. Indirectmeasurement of exposure to carbamates is deter-mined by measuring blood cholinesterase activity.Because the interaction between the carbamate and

TABLE 14-9

EXAMPLES OF RANGE OF ACUTE TOXICITIES OF SOME CARBAMATE INSECTICIDES

*Values obtained in standardized tests in the same laboratoryReprinted with permission from Murphy SD. Toxic effects of pesticides. In: Klaassen CD, Amdur MO, Doull J, eds. Casarett and Doull'sToxicology: The Basic Science of Poisons. 3rd ed. New York: McGraw-Hill; 1986: 540.

Table 14-9 is not shown because the copyrightpermission granted to the Borden Institute, TMM,does not allow the Borden Institute to grant per-mission to other users and/or does not includeusage in electronic media. The current user mustapply to the publisher named in the figure legendfor permission to use this illustration in any typeof publication media.

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cholines-terase is spontaneously reversible, the re-sidual cholinesterase activity usually fails to correlatewith the clinical significance of the exposure.14

Rapid reversibility of the carbamylated enzymecomplex decreases the duration of the clinical signs ofpoisoning, allows a wider dosage range between theonset of symptoms and death, and decreases the slightchance of documenting the level of depression ofenzyme levels, unless a blood sample is analyzedalmost immediately after exposure.16,18,20

Metabolism of carbaryl involves N-demethylation,hydroxylation, hydrolysis, and conjugation. Hydroly-sis results in the urinary excretion of (a) 1-naphthol,which accounts for more than 20% of an administereddose, and (b) p-hydroxycarbamyl, which accounts forapproximately 4% of the administered dose. Urinaryconcentration of 1-naphthol has been used as a bio-logical exposure index of carbaryl exposure. Unex-posed subjects have been reported to have urinaryconcentrations of 1-naphthol below 0.23 mg/L.Asymptomatic workers who were exposed to ambi-ent air concentrations of carbaryl as high as 31 mg/m3

were found to have urinary 1-naphthol concentra-tions of more than 42 mg/L. Although no standardshave been established for carbaryl metabolites in urine,urinary 1-naphthol concentrations in excess of 4 mg/L ofurine may represent significant exposure to carbaryl.14

Dose-dependent inhibitions of platelet aggregationand arachidonic acid metabolism in platelets havebeen demonstrated to be inhibited by carbamate insec-ticides. In these evaluations, the most potent carbam-ate compound found was carbaryl, which was shownto inhibit platelet aggregation and diminish productsof the enzyme cyclooxygenase at concentrations as lowas 10 µM. However, radiolabeled carbaryl was shownto bind covalently with numerous platelet proteins, incontrast to acetylsalicylic acid, which acetylates onlya single platelet protein. Acetylsalicylic acid is knownto specifically inhibit cyclooxygenase enzyme activ-ity, which is similar to the action of carbaryl.14

Despite its widespread use by the World HealthOrganization as an insecticide to control the mosquitovector of malaria, only a few mild cases of propoxurpoisoning have been reported. A human volunteeringested 1.5 mg/kg of propoxur. The erythrocytecholinesterase fell to 27% of the baseline within 15minutes. The subject experienced nausea, vomiting,blurred vision, sweating, and tachycardia. By 2 hoursfollowing ingestion, the subject had no residual signsor symptoms and the enzyme levels were withinnormal limits. Adult humans have ingested single 90-mg doses without any apparent symptoms.14

Although delayed neurotoxicity has been reportedwith carbaryl exposure in one 75-year-old man, epide-

miological studies of human carbaryl exposures havenot demonstrated delayed neuropathy. Male humanvolunteers who ingested carbaryl dosages of 0.06 and0.12 mg/kg for a study period of 6 weeks had nodemonstrable changes in their electroencephalogrampatterns. Inadequate data from human studies andthe uncertain relevance of existing data from animalstudies limit the final conclusions that can be drawnconcerning delayed neurotoxic or myotoxic effects inhuman populations.14

Signs and Symptoms of Exposure. Much of what isknown concerning the signs and symptoms of humanexposures to carbamates has been based on studies ofa closely related chemical compound, physostigmine.26

The clinical signs and symptoms of carbamate poison-ing are identical to those associated with organophos-phate poisoning (see Table 14-6). Carbamates arebelieved to have a wide safety margin because thesigns of cholinesterase poisoning, which resolve soonafter the exposure is discontinued, are rapidly revers-ible. The most common signs and symptoms includelacrimation, salivation, miosis, convulsion, and death.4

Exposure to carbamate insecticides may lead toclinical manifestations of cholinergic crisis similar tothose found with the organophosphate insecticides.The classic signs and symptoms associated with cho-linergic activity may include increased salivation, lac-rimation, urinary incontinence, diarrhea, gastro-in-testinal cramping, and emesis. Clinical CNS signs andsymptoms of carbamate poisoning are less intenseand shorter in duration than those associated withcomparable organophosphate pesticides.14

Ocular signs of exposure, including miosis, tearing,ciliary spasm, severe ocular or retroorbital pain, anddiminished accommodation, may occur. Miosis maybe either unilateral or bilateral and is often recognizedby the patient as visual blurring, especially in a dark-ened room. Mydriasis may occur as a result of reflexadrenergic stimulation, although this is unusual.14

Respiratory responses to carbaryl intoxication in-clude rhinorrhea, increased bronchial secretions, bron-chospasm, wheezes, rhonchi, and rales. The patientmay also experience chest tightness.

The major cutaneous sign associated with localdermal absorption is localized sweating. On carefulobservation of the skin, fasciculations may be ob-served in the underlying skeletal muscle.14

In addition to the localized fasciculations, otherneuromuscular effects may include generalized lossof muscle tone, widespread muscular twitching, andovert convulsive activity, which can result from sys-temic stimulation. Other neurological responses in-clude weakness, lassitude, incoordination, and slurredspeech. Death is primarily the result of central respi-

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ratory depression and paralysis, and is usually pre-ceded by or associated with generalized convulsions,fecal or urinary incontinence or both, and coma.

In addition to the direct effects of the pesticide,bronchopulmonary sequelae may result from inhala-tion of the components of the pesticide formulation.For example, inhalation of the supposedly inert dustor the hydrocarbon vehicle may cause throat irrita-tion, dyspnea, pneumonitis, or pulmonary edema.

If the individual who is exposed to the pesticidedemonstrates cardiac effects, bradycardia is the mostcommon sign; tachycardia can occur, however, possi-bly as a result of reflex response to bradycardia.

Disseminated intravascular coagulation and kid-ney damage have been reported, and delayed periph-eral neuropathy, similar to that caused by some organo-phosphorus compounds, was reported in one case.14

With more severe exposures, mental confusion,loss of muscle coordination, tremors, or convulsionsmay occur. Death can result from respiratory arrest ofCNS origin, paralysis of respiratory musculature, orintense bronchorrhea with bronchoconstriction.14

Medical Treatment. The administration of basiclife-saving practices and decontamination of the skinwith soap and water, if indicated by circumstances,are the essential elements of early first aid and medicalcare. Analysis of the plasma and erythrocyte cholines-terase levels are of no benefit in the medical manage-ment of these patients. Even in circumstances wheredepressed enzyme levels could be demonstrated, thedelay in obtaining the results would severely compro-mise the usefulness of the enzyme levels as diagnosticand prognostic tools. Because the interaction betweenthe carbamate pesticides and cholinesterase moleculesis readily reversible, enzyme levels may be normaldespite overt signs of poisoning. In addition, thetremendous variability between laboratory method-ologies and reported cholinesterase activity units se-verely compromises meaningful interpretation of re-ported results in typical patients.

Induced emesis is not recommended following car-bamate ingestion. After nasogastric suction has beenperformed, administration of activated charcoal and acathartic is recommended. The adult dose of acti-vated charcoal is usually between 30 and 100 g; forchildren, 15 to 30 g.14

Direct eye contact or splash should be treated byirrigation with copious amounts of water for at least 15minutes. Medical evaluation is recommended in mostcircumstances, especially if signs of irritation such aspain, chemosis, lacrimation, or photophobia persist.

If significant inhalation exposure or coincident as-piration occur, a baseline chest X ray should be ob-tained. This is especially important if the pesticide

formulation was concentrated, contained irritantor hydrocarbon compounds, or was of unknown com-position.

Atropine administration for symptomatic patients isimperative. Timely administration is crucial, regardless ofthe route of pesticide exposure. Although best adminis-tered intravenously in life-threatening circumstances,atropine is also effective if administered intramuscu-larly, particularly if delivered by the atropineautoinjector. Atropine administration should be ti-trated to the patient’s need based on resultant signs ofatropinization. In cases of carbamate poisoning, themost reliable sign of atropine adequacy is the degreeof drying of the pulmonary secretions.

The typical adult dose of 2 to 4 mg may be carefullyadministered every 10 to 15 minutes as needed. Thedosage of atropine useful for the management of apoisoned child is 0.05 mg/kg every 10 to 15 minutes asneeded.14 The treatment of cholinesterase inhibitionassociated with carbamate poisoning may be requiredfor hours or days, depending on the individual pa-tient and the circumstances of exposure.

Clinically apparent convulsions have been acceptedhistorically as a sign of neurological seizure activity. Ifconvulsions occur, timely administration of diazepam as adirect intravenous bolus is imperative. The typical adultdose is 5 to 10 mg initially, which may be repeatedevery 15 minutes as needed up to 30 mg. For theconvulsing child, the recommended dosage is 0.25 to0.4 mg/kg, up to 10 mg total dose. Intramuscularinjections are slowly absorbed and should be avoided,if possible. If seizures are uncontrollable or recur,phenytoin should be administered.14 Physostigmineadministration is contraindicated, and its use should beavoided.

The administration of pralidoxime is contraindi-cated in pure carbamate poisonings. The addition ofoximes such as 2-PAM Cl markedly increase carbam-ate toxicity and may cause death.16,18,27 Use ofpralidoxime is controversial in carbamate poisoningsthat are complicated by other factors such as knownorganophosphate-combined poisoning or unknowncircumstance of poisoning. Although atropine is ef-fective against the muscarinic manifestations of car-bamate poisoning, it is ineffective against the nicotinicmanifestations.

However, some authorities recommend thatpralidoxime should be given when life-threateningsymptoms are present.14 The recommended adultdose is 1.0 g administered intravenously at a rate of0.5 g/min, or infused in 250 mL of normal saline over30 minutes. The dose may be repeated up to threetimes for initial management. Praladoxime may beadministered in intervals of 6 to 12 hours if muscle

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weakness is not relieved. As an alternative, an infu-sion of 500 mg/hour may be administered.

For a poisoned child, pralidoxime may be adminis-tered intravenously at a dosage of 25 to 50 mg/kg over30 minutes. Further administration may be necessaryif muscle weakness and associated respiratory de-pression remain uncorrected.14

Organochlorine Insecticides

The four classes of organochlorine insecticides are(1) DDT and related derivatives of chlorinateddiphenylethane; (2) cyclodienes, including dieldrin,heptachlor, and chlordane; (3) lindane (the gammaisomer of hexachlorocyclohexane); and (4) toxaphene(a mixture of chlorinated terpenes).28 Substances in thisgroup are known for their low biodegradability in theenvironment, accumulation in human and animal adi-pose tissues, and carcinogenicity in laboratory animals.

The acute toxicity and human hazard potential oforganochlorine insecticides are highly variable andare influenced by the rate of exposure, route of expo-sure, and specific chemical compound (see Table 14-6).For example, dermal absorption is much greater ofhexachlorocyclohexane (the technical grade includesthe gamma isomer lindane) and the cyclodiene deriva-tives than for the ethane derivatives. The potentialacute human toxicity hazard for these compounds is,from highest to lowest, endrin, aldrin, dieldrin, chlor-dane, toxaphene, chlordecone, heptachlor, DDT, andmethoxychlor. Dicofol, methoxychlor, and hexachlor-obenzene have limited CNS toxicity; however, in ex-treme overdoses, CNS depression may occur.14

Organochlorine insecticides are primary represen-tatives of the broader group of chlorinated hydrocar-bon pesticides. Other representatives of the chlori-nated hydrocarbons have been used as fumigants,herbicides, fungicides, and nematocides.5 The chemi-cal structures and selected toxicological activities forrepresentative organochlorine insecticides are foundin Table 14-10 .

The precise mechanism of action of many of theorganochlorine insecticides remains unknown.16 Since1944, DDT has been known to affect the nervoussystem; however, the precise mechanism of actionremains incompletely described.24 DDT is thought toexert its complex toxicological action through its im-pact on the fluxes of sodium, potassium, and calciumacross the nerve cell membrane, but measurements ofionic potentials differ among species. In addition, inrabbit brain, DDT has been shown to inhibit the actionof Na+–K+–Mg++ adenosine triphosphatase (ATPase ), anenzyme responsible for ion movement in the nervoussystem.24 The net effect of these ionic and enzymatic

interactions is a slowed closing of the sodium channel,with prolongation of the hyperexcitable state of thenerve cell following nerve-impulse transmission.28,29

In contrast to DDT, lindane and the cyclodienes (eg,dieldrin) appear to exert their toxic effects at the nervesynapse, where their action results in increased sponta-neous and evoked release of neurotransmitter.28 Lin-dane and dieldrin act on the ganglion, rather than theaxon, where increased membrane permeability to cal-cium was demonstrated. In addition, they appeared toinhibit Ca++–Mg++ ATPase, which influences the rate ofcalcium extrusion. Dieldrin, lindane, and heptachlorepoxide have all recently been shown to be potent,competitive, stereospecific inhibitors of the picrotoxinreceptor. As a result of this inhibition, γ-aminobutyricacid (GABA) and GABA-related transmission is af-fected. GABA-induced chloride permeability is in-hibited, with the result that the nerve cell remainshyperexcitable after stimulation. DDT and mirexwere not found to bind to the picrotoxin receptor.28,30

Animal experimentation and human epidemiologi-cal studies have demonstrated that chronic exposureto chlorinated hydrocarbons results in bioaccumulationin adipose tissues. Experimental observations withinthese test groups demonstrate significant differencesin the metabolism and storage in the adipose tissuedepots.

Numerous nonspecific signs and symptoms havebeen reported after acute organochlorine exposures.Sensory disturbances such as hyperesthesia or pares-thesia may be either early or low-dose, acute effects ofDDT poisoning. Headache, dizziness, vomiting, in-coordination, and tremor may progress to myo-clonicjerking, convulsions, or both. Individuals who areexposed to cyclodienes may present with convulsionsas the first sign of poisoning as long as 48 hours afteracute exposure. Increased neuronal irritability resultsin excitation, convulsions, and possibly coma at highdoses. Cardiac dysrhythmia may also occur.16,23

Several of the organochlorine insecticides (eg, al-drin and heptachlor) stimulate hepatic microsomalenzymes and undergo xenobiotic transformationthrough epoxide derivative intermediates (Figure 14-6). The development and storage of these intermedi-ates, and, in animal models, evidence for their carci-nogenic potential, have reinforced the concern thatmany of these compounds are suspect human car-cinogens.4 Histopathological changes have been notedin the livers of chlordecone workers; however, eleva-tion of their hepatic enzymes indicative of damagewas not observed. Reductions in sperm counts havebeen noted in workers who have been exposed tochlordecone and dichlorobromopropane. Blindnesshas been reported in sheep that have been exposed to

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TABLE 14-10

TOXICOLOGY OF SELECTED ORGANOCHLORINE INSECTICIDES

*Values obtained in standardized tests in thesame laboratory

†Maximum rate of intake (usually 3-mo, 2-yrfeeding studies) that was tested and did notproduce significant toxicologic effects (aslisted in the monographs issued jointly bythe Food and Agriculture Organization ofthe United Nations and the World HealthOrganization, as developed by joint meet-ings of expert panels on pesticide residuesheld annually, 1965–1972)

‡Acceptable daily intake (ADI) = the dailyintake of a chemical that, during a lifetime,appears to provide the practical certaintythat injury will not result (in man) during alifetime of exposure. Figures taken fromWorld Health Organization (1973).

Reprinted with permission from Murphy SD.Toxic effects of pesticides. In: Klaassen CD,Amdur MO, Doull J, eds. Casarett and Doull'sToxicology: The Basic Science of Poisons. 3rd ed.New York: McGraw-Hill; 1986: 540.

Figure 14-10 is not shown because the copy-right permission granted to the Borden Institute,TMM, does not allow the Borden Institute to grantpermission to other users and/or does not includeusage in electronic media. The current user mustapply to the publisher named in the figure legendfor permission to use this illustration in any typeof publication media.

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Fig. 14-6. When the parent pesticide compound heptachlor is metabolized by the hepatic P-450 enzyme system, the resultantmetabolite heptachlor epoxide, a suspect carcinogen, is formed. The metabolism of chlordane to chlordane epoxide, also asuspect carcinogen, is similar.

Cl 2

Cl

Cl

ClCl

Heptachlor Heptachlor Epoxide

Cl

Cl 2

Cl

Cl

ClCl

ClO

endosulfan, and mirex has caused cataracts in therodent model.16,20,23 Chronic exposure to chlordeconehas been associated with weight loss, weakness,tremor, slurred speech, cognitive changes, and abnor-mal liver-enzyme profiles.

Chlordane

Chlordane has been widely used as an environ-mentally persistent, highly effective termiticide. As aresult of its efficacy and popularity, large numbers ofpesticide operators and members of the general popu-lation have been exposed. The xenobiotic metabolismof chlordane has been evaluated in pest-control op-erators: chlordane and its metabolites (oxychlordane,heptachlor epoxide, and trans-nonachlor) were iden-tified in the blood of some of the pest-control opera-tors but not in the control subjects. The concentrationof chlordane and its metabolites correlated well withthe number of spraying days in the previous 3 months.As a result, the concentration of chlordane and itsmetabolites has been suggested as a biological moni-tor for chlordane-exposed workers. Although thechemical compounds can be identified at rather lowconcentrations in blood, no correlation between bloodconcentrations and health effects has been published.Consequently, the utility of the biological monitoringcapability for chlordane and its metabolites remainsspeculative and is not routinely recommended.14

Purified chlordane has been reported to inducecytotoxic effects in human liver cell cultures. In thatsystem, chlordane exposure resulted in growth inhi-bition and alterations of cellular morphology.

The fatal dose of chlordane for an adult has beenestimated to be between 6 and 60 g. Onset of clinicalsigns and symptoms would be expected between 45minutes and several hours.14

Route of Exposure. Chlordane and its formulationsare lipophilic and may be readily absorbed followingskin contact, inhalation, and ingestion. As a result ofits widespread use, persistence, ease of cutaneousabsorption, lipophilic nature, and preferred in vivolipid-affiliated storage, the EPA identified almostubiquitous presence of chlordane in samples of bodyfat and breast milk from human populations.4

Signs and Symptoms of Exposure. Because chlor-dane and related pesticides disrupt nervous systemfunctions, patients may present with a spectrum ofCNS-stimulation findings. The earliest signs of poi-soning are related to increased sensitivity to stimuli.Hyperexcitability of the CNS usually manifests asnervousness, agitation, irritability, amnesia, and gen-eralized hyperactive reflexes. Cycles of excitementfollowed by depression may occur repeatedly. More-severe signs include muscle twitching, tremor, inco-ordination, and ataxia. The most severe neurologicalsigns include clonic convulsions, with or withoutcoma.14

Respiratory depression may occur as an unusualresult of chlordane intoxication. Aspiration of chlor-dane formulations that contain petroleum distillatesmay result in chemical pneumonitis.14

Gastrointestinal effects such as nausea, vomiting,and diarrhea have been reported following ingestionof chlordane. Extensive cutaneous contact may resultin dermal irritation.14

The EPA considers chlordane and related com-pounds to be potential human carcinogens.4 How-ever, epidemiological studies of workers in the chlor-dane-producing industry have failed to identify anincreased occurrence of cancer. Exposure to chlor-dane, heptachlor, or both has been related to aplasticanemia and acute leukemia in several cases, but therelationship between these chemicals and the adverse

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health effects was inadequate to reflect a causal asso-ciation. In another retrospective study, an uncertaincause-and-effect relationship was suggested betweenthe occurrence of neuroblastoma in several childrenand possible chlordane or heptachlor exposure.14

In a prospective mortality study directed towardemployees of a chlordane production plant, workerswith the highest risk of exposure appeared to demon-strate an inverse relationship between exposure andcancer risk. The study identified an unexplainedexcess of deaths due to cerebrovascular disease.14

Medical Treatment. As with any pesticide-poi-soned patient, basic life support and early decontami-nation procedures are essential elements of medicalmanagement. After the contaminated clothing hasbeen removed, the patient should be decontaminatedwith soap and water, then topical alcohol, and thensoap and water again.14

In alert patients, emesis should be induced withsyrup of ipecac in cases of recent, substantial inges-tion. In addition, administration of activated charcoaland a cathartic is recommended.14

As a consequence of the increased myocardial irri-tability associated with organochlorine poisoning,administration of epinephrine or other adrenergicamines may precipitate refractory ventriculararrhythmias.14

Seizure activity should immediately be treated withdiazepam administered by intravenous bolus. Thetypical adult dose is 5 to 10 mg initially, which may berepeated every 15 minutes, as needed, up to a totaldose of 30 mg. For seizure activity in a child, therecommended dosage of 0.25 to 0.4 mg/kg should beadministered intravenously. In the child, diazepamdoses may be repeated up to a total dose of 10 mg.Uncontrollable or recurrent seizures should be man-aged through administration of phenytoin.14

Excretion of chlordane (and a related organochlo-rine pesticide, chlordecone) may be accelerated byoral administration of cholestyramine, which fostersremoval from the cycle of enterohepatic circulation.Dialysis, exchange transfusion, and hemoperfusionare probably ineffective.14

Heptachlor

Heptachlor epoxide has been identified as a me-tabolite of heptachlor in both animals and humans. Intransformed human cell cultures, exposures both toheptachlor and to its epoxide induce unscheduledDNA synthesis, indicating possible genetic damage.14

Heptachlor is absorbed following cutaneous contact,inhalation, and ingestion. The dose required to in-

duce acute toxic effects in humans varies with theroute and rate of exposure (see Figure 14-6).

Signs and Symptoms of Intoxication. Increasedsensitivity to external stimuli and CNS hyperexcitabil-ity are the first adverse signs of exposure to hep-tachlor. Acute toxic signs of exposure include hyper-active reflexes, muscular twitching, tremors, ataxia,and clonic convulsions with or without coma. Respi-ratory depression may occur concurrently with con-vulsions. Repetitive cycles of excitability and depres-sion may be seen. Cardiac irritability and contractilityalterations can initiate dysrythmias.23 Ingestion maycause nausea, vomiting, diarrhea, gastroenteritis, an-orexia, or a delayed-onset hepatitis. Skin irritation hasbeen reported following cutaneous contact.14

Aplastic anemia and neuroblastoma have been re-ported in patients following possible heptachlor ex-posures; however, a causal association has not beenidentified. If ingestion and subsequent aspiration ofheptachlor pesticide formulations occurs, chemicalpneumonitis should be anticipated.14

Medical Treatment. Patients contaminated withheptachlor should be decontaminated with soap andwater. Some authorities recommend an alcohol washfollowing the soap and water, followed, in turn, byanother soap and water wash. Three soap-and-waterdecontamination procedures have been recom-mended. Particular attention to decontaminating thehair is essential.14

Obtaining levels of chlorinated hydrocarbons orheptachlor in whole blood or serum is not useful inacute toxic exposures.14 In most cases, blood levels ofheptachlor or its metabolites reflect cumulative, ratherthan acute, exposures. Furthermore, these blood-chemistry analyses are usually not routinely availablein most clinical laboratories. Because laboratory re-sults will probably not be available to assist with earlydiagnosis or therapy, treatment must be based on acareful workplace—or intentional poisoning—histori-cal profile. As with other organochlorine poisonings,if a history of heptachlor exposure is obtained, theadministration of adrenergic amines is to be avoided: theymay increase myocardial irritability and precipitate refrac-tory ventricular arrhythmias.14

If an alert patient has ingested a possibly toxic doseof heptachlor, emesis should be induced with syrup ofipecac. Emesis is most effective within 30 minutes ofingestion of the poison. An activated charcoal slurryand cathartic should also be administered. Throughinterference with the enterohepatic circulation of thecompound, cholestyramine has been reported to in-crease excretion of chlorinated hydrocarbons such aschlordecone and chlordane. Hemodialysis and ex-

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change transfusion probably would not be effectivetherapeutic modalities for heptachlor poisonings.14

If seizures occur, diazepam should be carefullyadministered as an intravenous bolus of 5 to 10 mg.Diazepam may be repeated every 15 minutes, not toexceed a cumulative dose of 30 mg. If convulsions failto respond to diazepam, or if they recur after initialtherapy, phenytoin should be administered.14

Borate Insecticides

Boric acid, H3BO3, is also known as boracic acid ororthoboric acid. Its main use is as a common tabletformulation for pesticide management of cockroachinfestation. Although the mechanism of action inhumans is unknown, the end result is a metabolicacidosis with associated electrolyte abnormalities.Signs or symptoms of toxic exposure are not seenunless boron concentrations in the brain reach levelsabove 10 ppm (see Table 14-6).31

Routes of Exposure

Crawling children can be exposed to boric acid ifpesticide applications of the powder or pellet formu-lations are careless or inappropriate. Intact skin pro-vides an effective barrier to absorption. Abraded orburned skin allows efficient absorption, however,although no mechanism for enhanced absorptionacross abraded skin has been proposed.

Borates are well absorbed following ingestion. Inrare instances, infants have been inadvertently poi-soned when powder formulations were mixed in theirinfant formula.31

Signs and Symptoms of Exposure

The signs and symptoms associated with exposureto and absorption of borate insecticides include ab-dominal pain, nausea, protracted vomiting, diarrhea,and hematochezia. These have been associated withabsorption across burned or abraded skin. Topicalexposure has been associated with a bright erythema-tous rash that may progress to extreme exfoliation.Restlessness, headache, weakness, and tremors mayprecede convulsions in severely poisoned patients.Cyanosis and shock may precipitate acute renal fail-ure associated with metabolic acidosis from boric acidin severe cases of intoxication. Poisoning may beconfirmed by blood borate concentrations. Normalranges in nonexposed individuals are between zeroand 7.2 mg of borate per liter of blood with a mean of1.4 mg/L. Concentrations lower than 340 mg/L have

rarely been associated with toxicity. Urine boratetests may yield false-positive results.16

Medical Treatment

Potentially contaminated skin should be washedwith soap and water. Treatment of boric acid poison-ing includes administering syrup of ipecac to childrenwho weigh less than 30 kg, if the child has ingestedmore than 200 mg/kg as an acute dose. Larger individ-uals who have ingested a dose of more than 6 g are alsotreated with syrup of ipecac. If acute doses exceedthese levels, emergency medical specialists may preferto use gastric lavage as an alternative to inducing emesis.16

Activated charcoal does not absorb borate andshould not be used unless there are special ingestioncircumstances (eg, the ingestion of multiple sub-stances). A blood sample drawn 2 to 3 hours afteringestion should be obtained to assess the severity ofpoisoning. If massive quantities have been ingestedover several days, careful monitoring and medicalmanagement to prevent the adverse sequelae of meta-bolic acidosis and electrolyte abnormalities must beprovided.16 Excretion of boric acid is efficient andforced diuresis may afford some benefit. Exchangetransfusion and peritoneal dialysis are efficacious.31

Anticonvulsants are indicated for treatment of con-vulsions.16

Botanical Pesticides

Pesticides that are derived from living biologicalsystems are chemically and pharmacologically di-verse. In the broadest sense, this group includesrelatively simple but potent molecules such as nico-tine, complex proteinaceous poisons such as ricin, andthe neurotoxin produced by Clostridium botulinum,which causes botulism. Many individuals share thecommon belief that a pesticide derived from naturalsources has a greater margin of safety than a commer-cially manufactured pesticide. Carefully performedtesting using standardized and accepted laboratorymodels has demonstrated, however, that some of themost potent poisons are derived from natural sources.

The mechanisms of action and possible antidotetherapeutics for selected toxic compounds of biologi-cal origin have been carefully evaluated in themilitary’s biological defense program. However, re-view and discussion of these toxins, their toxic mecha-nisms, and antidotes are not relevant to this discus-sion. Numerous pesticides derived from biologicalsources are available; however, the military uses onlya few botanical derivatives such as the pyrethrins toeradicate or manage pests.

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Nicotine cost and to improve light stability, more than 1,000synthetic compounds known as pyrethroids have beensynthesized, some of which show significant struc-tural differences and pest selectivities from the parentpyrethrum molecule (Figure 14-7).7 Pyrethroids arelight stable, biodegradable, and highly specific. Forexample, deltamethrin is approximately 3,000- to 5,000-fold more toxic to houseflies than to rats.7,16,20,23

Permethrin, one of the pyrethroid products, is arepellent that is used extensively by the military as auniform impregnant (see Table 14-6). Some pyre-throids are approved for use as clothing spray formu-lations and others are used as pediculocides.

Route of Exposure. Pyrethrins are poorly absorbedvia the dermis but appear to be well absorbed via theinhalational and ingestional routes. Although pyre-throids, if they are administered intravenously intolaboratory animals, may cause extreme neurotoxiceffects (convulsions), dermal and inhalation exposuresare associated with only limited systemic toxicity.16

Mechanism of Action. Pyrethrins and pyrethroidshave a high affinity for the sodium channel of theafferent neuron and produce their toxic effects as aconsequence of neuronal hyperexcitability. As a con-sequence, pyrethroids cause a delay in channel clo-sure, which results in a prolonged tail current of theaction potential. The interaction slows the influx ofsodium during the end of the depolarization phase,increases the depolarizing afterpotential, and resultsin repetitive discharges.7,16,20 Pyrethroids are openchannel blockers (ie, they selectively affect the active,or open, sodium channel). At high concentrations ofpyrethroid, the nerve membrane may depolarize com-pletely and excitability may be blocked.7

Allethrin and DDT have been shown to cause so-dium channel effects in the lateral line organ of thetoad. At the receptive portion of the peripheral affer-ent neuron, both chemicals cause a hyperexcitablestimulus response that results in the generation of arepetitive series of impulses. In the conductive por-tion of the afferent neuron, both compounds appear toimpede the closing of the sodium channel, whichresults in an increased phase of hyperexcitability.29

Within the CNS, pyrethroids exhibit effects consis-tent with several mechanisms of action. ProposedCNS mechanisms of pyrethroid effects include an-tagonism of the GABA-transmitter pathway, modifi-cation of nicotinic cholinergic transmission, enhance-ment of norepinephrine release, and alteration ofcalcium-ion fluxes. The primary effects of pyrethroidsmay be the result of changes in the functional sodiumchannel activity of the afferent neuron; the toxic CNSeffects appear to be secondary.7

Nicotine is one of the most frequently recognizedplant-derived pesticides. In addition to its commer-cial use as a fumigant and stomach poison for leaf-eating insects, its scientific use has provided valuableinsight into the functions of the cholinergic compo-nents of the human nervous system. The toxicologicalmechanisms for cholinesterase inhibitors were clari-fied because of nicotine’s cholinergic properties andreaction with specific sites (nicotinic receptors) withinthe CNS and PNS. Nicotine is not itself a cholinest-erase inhibitor, but does have CNS, autonomic, andneuromuscular effects similar to excessive acetylcho-line stimulation at nicotinic sites. Nicotine can exist intwo isomeric forms: the synthetic R isomer is up to 8-fold more toxic than the natural S isomer.

There is no specific antidote for nicotine poisoning,but atropine administration may be somewhat effica-cious in emergency medical management. In nico-tine-poisoned dogs, artificial respiration has beenshown to be life-saving if respiratory assistance wasinstituted prior to severe hypotension.7

Pyrethrum, Pyrethrins, and Pyrethroids

The insecticidal properties of the Chrysanthemum(Dalmatian pyrethrum flower) have been known formore than 100 years. Commercial growth of the flow-ers and production of the natural pyrethrum extracts(pyrethrins) made pyrethrum and pyrethrins avail-able for domestic and agricultural pesticide use.6 Wide-spread agricultural uses were initiated during the1970s.7 The naturally occurring pyrethrum compo-nents are produced from an oleoresin extract of driedchrysanthemum flowers and contain six active insec-ticidal ingredients collectively known as pyrethrins.These are used in a number of pesticide products,particularly aerosol products for indoor pest control.Advantages of pyrethrum and pyrethrins includetheir relatively low mammalian toxicity, rapid “knockdown” and kill of pests, and the absence of environ-mental persistence. Disadvantages include the highcost of application and poor light stability.

As a result of efforts to decrease the unit production

N

N

CH3

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Fig. 14-7. The chemical structures for representative pyrethrin and pyrethroid pesticides. Source: Ray DE. Pesticides derivedfrom plants and other organisms. In: Hayes WJ Jr and Laws ER Jr, eds. Handbook of Pesticide Toxicology. New York: HarcourtBrace Jovanovich, Academic Press Inc; 1991; Chap 13.

C

C

H3C

C

R

CH3H

C

O

O H

H

CH3

R'

O

Pyrethrins of the Form

C

C

H3C

C

H

CH3H

C

O

OR'

R

Pyrethroids of the Form

CH

C

H3C CH3

CH2

Cl

O

O

Barthrin

CH

C

Cl Cl

CH

C N

O

Cypermethrin

CH

C

Br Br

CH

C N

O

Deltamethrin

CH

C

Cl Cl

CH2

O

Permethrin

CH

C

H3C CH3

CH2

O

Phenothrin

Compound R R'

C CH CH2 CH

O

CH2 CH3

CH2 CH2

C CH

O

C CH

O

CH2 CH

CH2 CH3

CH2 CH2

Compound R

Pyrethrin I (CH3)2

R'

CH CH CH2

Pyrethrin II CH3 C(O) CHC(CH3)

Cinerin I CH

Cinerin II

CH

Jasmolin I CH CH3CH

Jasmolin I

(CH3)2

CH3 C(O) CHC(CH3)

(CH3)2

CH3 C(O) CHC(CH3)

CH CH CH2

CH CH

CH CH3CH

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523

Each pyrethrin and pyrethroid compound mayform at least four isomers, and interaction with thesodium channels is highly dependent on the isomericform. Permethrin and pyrethrum form isomers at thethird carbon of the cyclopropane ring, with the cis andtrans forms both demonstrating insecticidal activity.In mammalian systems, however, the cis isomers areapproximately 10-fold more potent than the trans.7

Crude pyrethrum is a dermal and respiratory aller-gen; the refined pyrethrin products are less sensitiz-ing and less irritating. A strong cross-reactivity withragweed pollen has been shown. Pyrethrins do notinhibit the enzyme cholinesterase.7,16 The rapid rate ofhydrolysis of both the natural and synthetic mol-ecules within the hepatic circulation probably ac-counts for the low acute toxicity in mammals, com-pared to the selective toxicity for insects.7,16,20

Most authorities agree that topical and systemictoxicities of the pyrethroids should be consideredseparately. In addition, most agree that there are twodistinct types of systemic poisoning syndromes.6,7

The different syndromes have been used to separatemost pyrethroid compounds into two groups, types Iand II, based on their clinically different manifesta-tions of poisonings. In the rodent, the type I syndrome(tremor) is first recognized by an increased aggres-siveness, followed by the rapid onset of tremor, hy-peractivity, hyperthermia, clonic convulsions, anddeath. The type II syndrome (choreoathetosis withsalivation) begins with profuse salivation, followedby a coarse body tremor, spontaneous writhing, tonic-clonic convulsions, and death.6

Permethrin and cismethrin are examples of type Icompounds. Effects of cismethrin poisoning can beinduced by placing a small quantity of the chemicalwithin the CNS; as a result, the poisoning effects arebelieved to arise from central stimulation. In contrast,type II compounds such as deltamethrin and cyfluthrinact on a broader range of tissues and produce a morecomplex poisoning syndrome.7

Signs and Symptoms of Exposure. Acute intoxica-tion with pyrethroids is uncommon. Patients maypresent with signs or symptoms of allergic skin reac-tion, eye irritation, skin irritation, or pulmonary aller-gic mediated bronchospasm. Extreme doses maycause salivation, tremor, incoordination, vomiting,and diarrhea. Irritability to sound has also beenreported. Paresthesia has been associated with expo-sure to pyrethroids in humans who have experiencedeffects through local volatilization or liquid contact.Facial discomfort is reported most commonly; how-ever, paresthesia of the neck, forearms, and hands aresometimes noted. Heat, sweating, sun exposure, andmoisture may aggravate symptomatology. Paresthe-

sia, itching, and/or burning sensations may progressto numbness.16 Possible long-term effects in humansinclude the potential for carcinogenesis.32

Medical Treatment. Rapid decontamination is amainstay of therapy; therefore, contaminated skinshould immediately be washed with soap and water.Antihistamines are efficacious in controlling mostallergic reactions. Severe asthmatic reactions mayrequire bronchodilators and corticosteroid therapy.Vitamin E oil preparations are effective in relievingsymptoms of local paresthesia. Corn oil is somewhathelpful, but zinc oxide aggravates the sensation.7,16

Contact dermatitis may require prolonged use of topi-cal corticosteroid preparations.16

After acute ingestion, careful gastric lavage may befollowed by administering activated charcoal and acathartic. There are no approved antidotes.16

As a precautionary note, the EPA states that al-though several drugs have been useful in the treat-ment of intentionally poisoned animals, none hasactually been tested in humans. Therefore, neither theefficacy nor the safety of the therapeutic compoundshas been evaluated.16

Some authorities recommend that therapy shouldbe directed toward managing the functional neuro-pathological effects (hyperthermia, choreoathetosis,and seizures) until the pyrethroids are metabolized.The sedatives phenobarbital and pentabarbitol areeffective against type I neurological effects when admin-istered in anesthetic concentrations. Clomethiazole hasbeen shown to be beneficial in deltamethrin poisoning(type II), especially when used with diazepam andatropine. Diazepam, when used alone, was found tobe of limited benefit in the rodent model and onlymoderately effective in the canine model.7

Rodenticides

Rats and mice may ingest or spoil large quantitiesof stored food. Rodents may also directly transmitdisease and cause discomfort or disease through bites.In addition, rodent parasites can be disease vectors.Efforts to control the rodent population may be di-rected toward removal of harborage, introduction ofpredators, use of traps, and use of chemicals directedtoward poisoning of the rodent species.

Although numerous chemical compounds have beenlisted as rodenticides, including thallium, strychnine,phosphorous, phenyl- (PNU) and thio- (ANTU) ureas,and red squill,23 civilian and military uses are usuallyassociated with the anticoagulant compounds becausethey have a wider margin of safety (see Table 14-6).

The anticoagulant dicoumarol, first isolated fromspoiled, sweet-clover hay, was identified as a cause of

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lethal hemorrhagic disease in cattle during the 1920s.The beneficial medical therapeutic and possiblerodenticidal properties were readily recognized andseveral related compounds were rapidly synthesized.Warfarin, a synthetic analog, was introduced for clini-cal trial in 1952 and used to treat President Dwight D.Eisenhower in 1955.33

Anticoagulant rodenticides are typically appliedas baits, either in liquid or solid form. Bait formula-tions must meet these four requirements: they mustbe (1) effective in small quantities, undetected byrodents; (2) formulated to avoid bait shyness; (3)lethal without the rodents’ becoming suspicious of thecause; and (4) used in a concentration safe for acciden-tal human ingestion or formulated in a concentrationspecific to the target species.20

Mechanism of Action

Regardless of the anticoagulant bait form, the ac-tive ingredient is a derivative of coumarin, such aswarfarin or fumarin; or a derivative of 1,3-indanedione,such as pival or diphasin. These compounds havesimilar modes of action. They are highly toxic whenpure, but are incorporated into bait formulations inlow concentrations. For example, warfarin concentra-tions incorporated into most baits range between0.025% and 0.05%. Although detectable reductions ofprothrombin can be identified in rodents within 24 to48 hours of initial ingestion, the onset of actual hem-orrhage in rodents generally follows ingestion of 1 to2 mg daily for one week.16,23

Coumarins and indanediones are effective antico-agulants. In addition to its anticoagulant properties,warfarin damages capillary integrity, which precipi-tates internal hemorrhage. Indanediones induce signsof neurological and cardiopulmonary injury in therodent toxicological model, but have not been shownto cause neurological or cardiopulmonary effects inhumans.16,23

Warfarin is an antimetabolite of vitamin K and assuch, warfarin depresses the hepatic vitamin K–de-pendent synthesis of essential clotting factors II (pro-thrombin), VII, IX, and X. The antiprothrombin effectis the best known and is the basis for detection andassessment of clinical poisoning. Lengthened pro-thrombin time from a toxic dose of coumarins orindanediones usually reaches a maximum 36 to 72hours after acute ingestion. Newly developedsuperwarfarin compounds are much more potent andtheir anticoagulation effects more persistent. War-farin has also been identified as a human teratogenthat causes microcephaly, brain malformations, opticatrophy, nasal hypoplasia, and mental retardation.16,23

Route of Exposure

Gastrointestinal absorption of anticoagulant ro-denticides is efficient, with warfarin well absorbedwithin 2 to 3 hours of ingestion. In a study of 14 subjectvolunteers, warfarin was administered orally at adosage of 1.5 mg/kg. Maximal concentrations ofwarfarin were measured in plasma between 2 and 12hours after ingestion. The maximal decrease in pro-thrombin activity was demonstrated between 36 and72 hours after ingestion.33

Dermal absorption is slow but measurable in therodent. Dermal absorption has not been reported as acause of human poisoning. Toxic ingestion may occurif the bait is unintentionally consumed by a child or isintentionally consumed in a suicide attempt.

Signs and Symptoms of Intoxication

Signs and symptoms of anticoagulant ingestioninclude epistaxis, bleeding gums, petechial rash, he-matomas, hemarthrosis, cerebral hemorrhage, shock,and death.

Medical Treatment

Medical treatment is probably not required if onlya few grams of bait are ingested. If larger amountshave been ingested, syrup of ipecac followed by acti-vated charcoal and cathartics may be efficacious. Ifthe amount of the anticoagulant rodenticide ingestedis unknown, phytonadione (vitamin K1) given orallywill protect against the anticoagulant effect with mini-mal risk to the patient. Phytonadione specifically isrequired: vitamin K3 and vitamin K4 are not antidotesfor these anticoagulants.

If the patient is bleeding actively, careful intrave-nous administration of vitamin K1 consistent with thespecified dosage-administration rates is indicated,recognizing that adverse reactions and fatalities havebeen reported in association with this procedure. Ac-tively bleeding patients should receive fresh frozenplasma or fresh blood transfusions in cases of severebleeding.

Prothrombin times may be helpful in judging theseverity of intoxication if the ingestion occurred dur-ing the preceding 15 days. The peak prothrombin effectoccurs after about 3 days and prothrombin times shouldbe followed to document peak effect and recovery.16,23

Herbicides

The compound 2,4-dichlorophenoxyacetic acid (2,4-D) has been used as a growth-regulating substance

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with herbicidal activity since the early 1940s (seeFigure 14-2).8 2,4-D has only moderate oral toxicitywhen administered to a variety of animal species.Large doses cause death quickly in animals, probablyas a result of ventricular fibrillation. Lower doseswere associated with myotonia, ataxia, paralysis, andcoma. Of the mammalian species tested, the dog wasthe most sensitive, with an oral LD50 of 100 mg/kg.The no-effect level in a 2-year canine study was ap-proximately 12 mg/kg/day.34

Limited information is available with respect tohuman exposures and toxic doses. In humans, 100%of the radiolabeled dose administered by intravenousinjection was recovered in the urine. In contrast, only5.8% of the topically applied dose was excreted in theurine, suggesting that dermal absorption is limited.34

Route of Exposure

Workers exposed to herbicides via inhalation, in-gestion, or dermal contact may experience clinicaleffects. Skin contact is the more common exposureroute; however, dermal absorption is not efficient.34

Inhalation and ingestion are also possible routes ofexposure.14

Signs and Symptoms of Intoxication

Although a wide variety of clinical reactions toexposure is possible, depending on the exposure routeand dose, irritant responses are most commonly re-ported effects of exposure.14 Irritant responses havebeen reported from cutaneous contact, airborne orinhalation exposure, and ingestion. Chloracne fromthe dioxin contaminants in the related herbicide 2,4,5-T has been reported in heavily exposed workers (seeFigure 14-2).

Eye, nose, and throat irritation may be associatedwith airborne exposures. Pulmonary edema has beenreported following inhalation exposures. Ingestionhas been reported to cause mouth, esophagus, andstomach irritation sometimes associated with vomit-ing and diarrhea. Elevated liver enzymes—lacticdehydrogenase (LDH), serum glutamic-oxalacetictransaminase (SGOT), and serum glutamic-pyruvictransaminase (SGPT)—have been reported.14

Neurological consequences of occupational expo-sures have been reported to include vertigo, headache,malaise, and paresthesias. Higher doses may producemuscle fasciculations, followed by profound muscleweakness and unconsciousness. Rhabdomyolysis andmyotonia have been reported in severely poisonedpersons.14

Tachycardia has been reported as a common mani-

festation of cardiac toxicity but the occurrence of actualarrhythmia has been uncommonly reported. Reportedrenal effects include albuminuria and azotemia.14

Headache, dizziness, stomach pains, nausea, leu-kopenia, fever, urinary incontinence, hypertonia, andconstipation have been reported in humans after acci-dental or intentional ingestion. Skeletal muscle fas-ciculations have also been reported. Although myoto-nia is the most frequently identified sign of poisoningin animals, it is unusual in poisoned humans. Degen-eration of the renal convoluted tubule, glomerularprotein deposition, and limited fatty infiltration of therenal parenchyma have been reported in an accidentalingestion by a farmer.34 Serious acute human poison-ings have been reported after the ingestion ofmultigram doses.14 An analog of 2,4-D, clofibrate, isused clinically to lower cholesterol levels.34 Theseherbicides can be measured directly in plasma andurine by gas liquid chromatography. They do notaffect cholinesterase levels.14

Medical Treatment

If eye exposure occurs following a splash, the eyesshould be irrigated with copious amounts of water forat least 15 minutes. If a direct splash into the eyes hasoccurred, the patient should be taken to a medicaltreatment facility (MTF) for evaluation and necessaryeye care.14

In cases of skin contact, the affected area should bethoroughly cleansed with soap and water. If acuteirritation occurs, evaluation at the health clinic isindicated.14

Although massive overexposure could require thebasic life-saving interventions such as airway manage-ment, this is usually unnecessary. Respiratory depres-sion, hypotension, metabolic acidosis, hyperthermia,or seizures may occur in severely poisoned individuals.14

Emesis is indicated, using syrup of ipecac, if inten-tional ingestion has occurred and if the patient isconscious. This emetic is most effective when admin-istered within 30 minutes of ingestion. Removal of thestomach contents via nasogastric intubation is indi-cated if the patient is obtunded, comatose, or convuls-ing. Activated charcoal administration and catharsisare recommended following ingestion of chlorphenoxypesticides.14

If ingestion could result in toxic clinical manifesta-tions, the following baseline determinations shouldbe obtained: complete blood count, arterial pH, bicarbon-ate, serum creatinine, blood urea nitrogen (BUN),liver enzyme levels, urinary protein, myoglobin, anderythrocyte losses; urinary output should also be mea-sured. Liver enzymes should be monitored to evalu-

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ate the significance of possible hepatic injury. Becausemuscular tissue destruction may occur, baseline lev-els of serum creatine phosphokinase and myoglobinshould be measured. Ongoing evaluations of liverenzymes and myoglobin levels should be performedfollowing intentional ingestion. When significantmyoglobinuria is seen, alkaline diuresis should beinstituted to enhance elimination.14 Alkaline diuresisappears to improve renal clearance of 2,4-D.

If inhalation has occurred in an enclosed area, thepatient should be removed to fresh air. The patientmay experience irritation of the respiratory tract asburning discomfort in the airway. Cough and respi-ratory distress may follow high-dose inhalation expo-sures as evidence of pulmonary edema. Bronchitis orpneumonitis may occur. Supplemental humidifiedoxygen or assisted ventilation may be required inextreme cases.14 The treatment of 2,4-D exposure issymptomatic, with this exception: quinidine sulfatehas been used in the management of tachycardiaand may be helpful in treating the skeletal muscledystonia.34

Many chronic adverse health effects from expo-sures to this group of pesticides have been alleged.However, in a 20-year follow-up of the health status ofU.S. Air Force veterans who were exposed to herbi-cides in Vietnam, only basal cell carcinoma was morefrequently identified among the herbicide handlers.35

The possibility that the association was spurious hasbeen noted.36

Sodium Arsenite

Sodium arsenite (NaAsO2) is used as aqueous solu-tion for weed control, and it has limited use as aninsecticide.16 Arsenical compounds demonstrate aspectrum of toxicity based on their chemical composi-tion and arsenic valence state. The generally acceptedorder of toxicity is from the more toxic arsine (triva-lent); through the organo-arsine derivatives, arsenites(trivalent); arsenoxides (trivalent); arsenates (pen-tavalent); other pentavalent organic compounds; ar-sonium metals (monovalent); to the least toxic, metal-lic arsenic. The active component of sodium arseniteis the arsenite, or trivalent arsenic, moiety. Arsenitehas been shown to be much more toxic than thepentavalent form, arsenate.14,16

Mechanism of Action

Acute ingestion of more than 100 mg of the arsenitecompound has been reported to be associated withsignificant toxicity. Ingestion of 200 mg of a relatedcompound, arsenic trioxide, may be fatal in an adult.14

Sodium arsenite has been reported to be a potentcause of a number of cutaneous lesions, includingcorrosive ulceration. In addition, among pesticideapplicators, it has been associated with erythema,papular dermatitis, and folliculitis. Among previ-ously sensitized patients, some cases of folliculitis mayactually be seen at low-exposure concentrations as aresult of allergic cutaneous responsiveness. Ulcer-ation of the hands, feet, and scrotum have been re-ported. While trivalent arsenic compounds are associ-ated with skin corrosion, arsenic trioxide and pentoxidecompounds are usually reported as skin sensitizers.14

Although arsenic compounds have been associ-ated with both skin and pulmonary cancer in humanepidemiological studies, arsenic has not yet been re-ported as a carcinogen in standard laboratory animalmodels. Arsenic is identified as a human carcinogenin the statutory occupational requirements promul-gated by OSHA. The EPA has been actively reviewingthe issue of potential carcinogenicity and has recentlyacted to withdraw product registrations.

Small doses of arsenic-containing compounds in-duce vasodilation. Increasing doses stimulate capil-lary dilatation and increase capillary permeability.Transudation of a large volume of plasma may causeprofound hypotension with secondary arteriolar andmyocardial damage. Abnormalities of the electrocar-diographic record may persist for months followingacute poisonings.14

Inorganic arsenicals cause increased blood flowthrough the bone marrow, which alters the marrow’scellular composition. Moderate doses of inorganicarsenicals depress the production of both erythro-cytes and leukocytes, possibly through inhibitory ac-tions on folic acid interactions.14

Inorganic arsenicals are considered to be potenthepatotoxins. Poisonings have been associated withcentral necrosis, fatty infiltration, and cirrhosis. Acuteyellow atrophy and death may occur.

In a 1977 report concerning the state of California,291 of 2,228 pesticide exposures involved sodiumarsenite ingestion. Dosages as low as 1 mg/kg mayinduce serious toxicity and dosages as low as 2 mg/kgmay be lethal.14

Route of Exposure

Acute poisonings are associated with both inten-tional and accidental ingestion. Chronic oral intoxica-tion is associated with arsenical compounds used asmedicaments. Skin contact may result in localizedpathology but has not been associated with poison-ings. Inhalational exposure is possible, depending onthe exposure circumstances.14

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Signs and Symptoms of Intoxication

Acute symptoms usually occur within 30 minutesto 1 hour from the time of ingestion unless simulta-neously consumed food delays absorption. A garliclikeodor may be noticeable in the breath or feces. Dysph-agia, esophageal pain, stomach pain, colic, and pro-fuse, watery—sometimes bloody—diarrhea have beenreported. Dehydration, hypotension, tachycardia, andfluid and electrolyte disturbances are common. Hy-povolemic shock, sometimes with associated intesti-nal blood loss, and cardiac abnormalities includingtachycardia, QT interval prolongation, alterations inthe T wave, and ventricular fibrillation have beenreported in acute exposures. Chronic exposures havebeen associated with myocarditis.14

Acute exposures by direct contact with trivalentarsenic–containing compounds can cause eye, mouth,and skin corrosion. Chronic exposures have beenassociated with cutaneous and nasal septal ulcer-ations, and nasal septal perforations have been re-ported. Cutaneous responses to chronic arsenicalexposures may include hyperpigmentation, keratoses,and epidermoid carcinomas.14

Acute arsenic exposures have been associated withCNS and PNS effects including alterations of mentalstatus, convulsions, toxic delirium, chemical-inducedencephalopathy, and delayed peripheral neuropathy.Hematuria and acute tubular necrosis have been re-ported complications of acute arsenic poisoning.14

Acute poisoning can cause hemolysis. Chronicarsenic exposures have been associated with bonemarrow depression, pancytopenia, aplastic anemia,and leukemia.14 Inorganic arsenicals may cross theplacenta and have been associated with fetal death ifchelation therapy was not prompt.14

Medical Treatment

Individuals with a history of possible acute arsenicingestion require careful medical evaluation and timelymedical management. A complete blood count, uri-nalysis, and baseline levels of serum electrolytes, liverenzymes, BUN, and creatinine should be obtainedimmediately. Urinary and blood arsenic levels shouldbe obtained. A 24-hour urine specimen should beanalyzed for arsenic excretion. Urinary arsenic excre-tions exceeding 100 µg have been reported to indicateabnormal excretory levels.14 However, individualswho consume diets rich in seafood may excrete 200 µgor more of arsenic per day.16 Individuals with possiblesurface contamination should be washed with soapand water. Decontamination of all areas, includingthe hair, should be thorough.14,16

Chest and abdominal X rays should be obtained forall patients being evaluated for arsenical ingestion.Timely, thorough gastric lavage is indicated for pa-tients with acute, possibly toxic, ingestion. Whole-bowel irrigation has been recommended if radiogra-phy identifies arsenicals in the intestinal contents.Although activated charcoal has somewhat specula-tive benefit, its use is recommended following lavage.If there is no primary diarrhea associated with thearsenic ingestion, the administration of sodium sulfateas a cathartic should be considered.14 Morphine maybe administered in cases of intense abdominal pain.

Aggressive fluid and electrolyte management isrequired for individuals who ingest arsenicals, and isespecially critical for those who are hypovolemic. Ahigh output of alkaline urine should be maintained.14

In some circumstances, pulmonary edema has beenassociated with arsenic poisoning.14

Symptomatic patients should be promptly treatedwith the chelating agents dimercaprol (2,3-dimercap-topropanol, also known as British anti-Lewisite [BAL])and penicillamine. To avoid adverse effects from BALadministration, it should be administered intramus-cularly at a rate of 3 to 5 mg/kg/dose every 4 to 12hours. The dose requirement and frequency of ad-ministration should be correlated with the degree ofarsenical poisoning. Tapered doses of BAL should becontinued for 5 to 8 days in patients who are allergicto penicillin.14 Another authority recommends some-what lower dosages: 2.5 to 3.0 mg/kg/dose every 4hours and tapered over about 2 weeks.16

As the signs and symptoms of acute arsenic poison-ing subside as a consequence of BAL therapy, penicil-lamine should be prescribed as soon as possible forpatients who have no history of penicillin allergy. Foradults, the recommended dose for oral administrationof D-penicillamine is 100 mg/kg/day up to 2 g daily,provided in four divided doses for a total of 5 days.The recommended dosage for children is 25 mg/kg/day in four divided doses daily, not to exceed a totalof 2 g.14 Another authority recommends, for childrenyounger than 12 years, 100 mg/kg/day in 4 divideddoses, not to exceed 1 g daily.16

Combined BAL and penicillamine therapy shouldbe considered for severely poisoned patients. Thedosages of chelating agents must be adjusted if renalcomplications occur as a result of the arsenic expo-sure. Hemodialysis may be necessary if renal functionis impaired and if removal of the chelated arsenicalcomplex is desired. Dimercaptosuccinic acid is cur-rently being investigated as an alternative to BAL.14

Complications associated with the administrationof BAL include acute signs and symptoms such asnausea, headache, restlessness, anxiety, paresthesia,

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pain, tearing, tachycardia, and hypertension. In se-lected patients, antihistamines may be beneficial inmanaging these complications. Other common sideeffects from BAL administration include maculo-

papular rash, fever, depressed leukocyte counts, eosi-nophilia, lymphadenopathy, and joint pain. BALtherapy has also been implicated in a number of other,less common complications.14,16

PESTICIDE LEGISLATION

Numerous federal, state, local, and DoD regula-tions have been promulgated to ensure the proper useand disposition of pesticides. A brief history of fed-eral pesticide legislation may help the reader under-stand the political concerns about pesticides.

Pesticide legislation is in a constant state of flux.Current laws continue to be amended and new lawscontinue to be enacted. The purpose of this legislationis to protect those who apply pesticides, the bystand-ers, and the environment from the harmful effects ofpesticide residues. Therefore, all participants in thepesticide section of the occupational health programmust be familiar with the current, pertinent militaryregulations and the requirements of federal, state, andlocal regulations.

The Federal Food, Drug, and Cosmetic Act

The first federal law regarding pesticides was theFood and Drug Act of 1906. It required that foodshipped in interstate commerce be pure and whole-some. Although pesticide residues were not addressedin this act, their exclusion was eventually identifiedand the act was completely rewritten. The 1938 legis-lation was called the Federal Food, Drug, and Cos-metic Act; it established the allowable levels of pesti-cide residues on foods. This legislation was the federalgovernment’s first attempt to protect consumers fromfoods that had been contaminated with pesticides.

In 1954, Public Law 518, commonly called the MillerAmendment, amended the 1938 Federal Food, Drug,and Cosmetic Act. This amendment established pesti-cide tolerances (allowable residues on a raw agricul-tural commodity). The Miller Amendment stated thata commodity could be considered adulterated if (a) itcontained a pesticide residue that had not been clearedfor safety or (b) it exceeded the allowable tolerance.

The Food Additives Amendment, enacted in 1958,further amended the Federal Food, Drug, and Cos-metic Act in 1958; it regulated the use of food addi-tives and established pesticide tolerances in processedfoods. An extremely important part of this amend-ment was the Delaney Clause, which prohibited theuse of a pesticide or a food additive that had beenshown to cause malignant tumors in laboratory ani-mals at any dose.

The Federal Insecticide, Fungicide, and Rodenticide Act

The first law regulating the transportation of pesti-cides in interstate commerce was enacted in 1910: theFederal Insecticide Act was designed to protect farm-ers from the distribution of fraudulent and substan-dard pesticide products. In 1947, the Federal Insecti-cide, Fungicide, and Rodenticide Act was enacted. Itsuperseded the 1910 Act and required that pesticideproducts be registered and labeled with the U.S. De-partment of Agriculture before being shipped in inter-state commerce. The Federal Insecticide, Fungicide,and Rodenticide Act also attempted to ensure the safeuse of pesticides by requiring them to be labeled with

• the manufacturer’s name and address;• the name of the pesticide;• the net contents;• a statement of ingredients;• warnings to prevent injury to humans and

other animals, plants, and organisms that arenot targets; and

• directions for use that would protect the userand the public.

In 1972, the most important revision of the FederalInsecticide, Fungicide, and Rodenticide Act was com-pleted; this revision, entitled the Federal Environ-mental Pesticide Control Act, prohibited the use ofany pesticide that was inconsistent with the warningsand directions on the label. In other words, the labelwas the law. Another provision of the 1972 revisionregulated pesticides within states, not only those in-volved in interstate commerce; this was an importantdevelopment in the regulation of pesticides on a na-tional level.

The Federal Environmental Pesticide Control Actalso required that pesticides be categorized as GeneralUse Pesticides and Restricted Use Pesticides. GeneralUse Pesticides are those pesticides that the publicuses. Restricted Use Pesticides must be applied by, orunder the direct supervision of, trained and certifiedpersonnel. A certification program was mandatedwithin each state to train and certify the personnelwho could apply the pesticides included in the Re-stricted Use category.

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The Environmental Protection Agency

In 1969, the National Environmental Policy Actbecame a law and established the EPA. The legislationtransferred the authority for pesticide regulation andregistration from the U.S. Department of Agricultureto the EPA. At the same time, the authority to estab-lish pesticide tolerances was transferred from theFood and Drug Administration to the EPA. However,the authority for enforcement of tolerances remainswith the Food and Drug Administration.

Occupational Safety and Health Regulation

In 1970, the Williams-Steiger Occupational Safetyand Health Act was enacted into law. OSHA wasestablished as the regulatory authority to implementthe act and establish policy under the U.S. Depart-ment of Labor. The National Institute for Occupa-tional Safety and Health (NIOSH) was established, asan integral requirement of the act, to provide scientificguidance and recommendations for the regulatoryauthority. Executive Order 12196, dated 26 February1980, required federal agencies to comply with OSHArequirements. OSHA promulgates regulatory require-ments and documents the current annual require-ment in the most recent volume of Title 29, Code ofFederal Regulations (CFR), part 1910, OccupationalSafety and Health Standards. OSHA publishes periodicupdates and revisions of 29 CFR 1910 in the Federal

Register (FR) and documents revisions to the pub-lished requirement or interim supplementation withnew requirements. When the annual copy of the CFRis published, the new edition automatically incorpo-rates all interim changes published in the periodic FRsupplements. In addition to providing regulatoryrequirements, the CFR also documents the current,mandated PELs. In some cases, specific medical re-quirements are identified.

DoD Directive 1000.3 (29 March 1979, with Change1, 17 April 1979) established military policy and pro-vided implementation guidance for occupationalsafety and health. Health specific requirements forthe Department of the Army (DA) are identified inArmy Regulation (AR) 40-5, Preventive Medicine, Healthand Environment.

For occupational health professionals to provideappropriate care for military employees and soldiers,they must be aware of the legal and regulatory re-quirements that direct the provisions for care. Federallegal requirements mandate that occupational illnessesand injuries are to be reported on the OSHA log.Army regulatory requirements specify that workersdiagnosed with occupational illnesses, such as symp-tomatic pesticide-exposed workers, are to be identi-fied in military occupational and safety health re-ports. State legal requirements are variable. Marylandand California are examples of states that requirephysicians who are licensed by the state to report allillnesses of occupational etiology.

THE U.S. ARMY PESTICIDE OCCUPATIONAL HEALTH PROGRAM

sent to the command headquarters. Confirmed or sus-pected health-related problems associated with occu-pational exposure to pesticides must also be reported.The purposes of the report are to (a) provide essentialinformation about the circumstances associated withthe problem, (b) identify additional resources that arenecessary to solve the problem, and (c) provide infor-mation concerning problem resolution.

Extensive occupational health records, personnelrecords, and exposure monitoring records are requiredto provide and document the healthcare provided toall workers who handle pesticides (see Chapter 3, U.S.Army Health Programs and Services). The personneloffice should work closely with the pesticide programmanagement to assure that all job descriptions clearlydelineate the worksite requirements and the medicalconditions that cannot be accommodated in the pesti-cide-workshop environment.

After employment, preplacement examinationsmust be provided for pesticide applicators. These

Any organization, installation, or activity that usesor stores pesticides must have an Occupational HealthProgram to monitor pesticide use and to implementprocedures to protect the health of workers. The pro-gram addresses (a) health reports, records and forms,(b) protective equipment, (c) emergency medical treat-ment, (d) pesticide handling and applications, (e) pest-control equipment and facilities, (f) field occupationalhealth, (g) medical surveillance, and (h) action levelsfor medical removal and return-to-work policies.

Health Reports, Records, and Forms

Command headquarters (eg, Health Services Com-mand [HSC] or Army Materiel Command [AMC])must be informed—through mandatory commandhealth reports—of environmental releases and health-related problems involving pesticides. Environmentalaccidents resulting from the use, storage, or disposalof pesticides should be identified on any health report

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document the patient’s baseline health status andensure that PPE can safely be used (eg, respirator fitand heat tolerance). Careful administrative manage-ment procedures must be provided to ensure thatthere is appropriate coordination between all healthand safety personnel who are required to generate ormaintain (or both) records related to employment.

Comprehensive records and forms should be main-tained for all pest-control or pesticide-handling work-ers. To ensure that working conditions are in compli-ance with OSHA requirements, appropriate industrialhygiene site-visits, pesticide-applicator monitoringdata, and safety-surveillance records are vitally im-portant. Accurate sampling, analysis, recording, andinterpretation are necessary in work areas where po-tential pesticide exposures may occur (eg, in pest-control shops and pesticide-storage warehouses). Theseresults should also be prominently posted in the workarea to notify employees and their supervisors.

An important method used to identify the need tomitigate exposure or to modify work practices is toobtain workplace data concerning pesticide concen-trations associated with storage or use. As noted prev-iously, the concentrations and durations of potentialexposure to a pesticide are critical variables in thishazard evaluation. Exposure data should be carefullyobtained by industrial hygienists when circumstancesindicate that unacceptable exposures could occur in theworkplace. The industrial hygienist should (a) collectdata and keep a documented record, (b) formally notifythe employee, area supervisor, and occupationalhealthcare provider, (c) identify corrective actions,and (d) ensure their implementation to reduce poten-tial exposures, if monitoring data reveal concentrationsof pesticides above the action level. Documented expo-sures above the action level and all pertinent informa-tion must be provided to the occupational health clinic inorder to allow appropriate planning for medical care.

Individuals who are required to perform poten-tially hazardous operations (using engineering con-trols or PPE to mitigate or prevent their exposures)should also be afforded appropriate medical surveil-lance examinations to document that their health ismaintained. The absence of adverse health effectsamong these workers may be useful to demonstratethe efficacy of engineering controls and PPE.

The health history obtained from employees priorto, periodically, and at the termination of employ-ment must be carefully documented and retained fora minimum of 30 years after the termination of em-ployment.3 In addition, results from any atmosphericsampling should be included and retained in themilitary or civilian worker’s medical records. Theseresults should be identical to those that have been

posted in the work area. The results of continuingmedical surveillance or exposure-related medical ex-aminations or clinical laboratory analyses must becarefully reviewed, compared with the preexistinginformation, and documented. Special care should beexercised to properly document and report work-place accidents, injuries, and illnesses in the medicalrecords. Healthcare providers must ensure that De-partment of Labor forms for reporting illness or injuryand compensation are completed in a timely fashion.

Emergency Medical Treatment

All employees who store, handle, and apply pesti-cides should be trained and able to practice emer-gency measures that ensure both the safe removal ofexposed individuals from the contaminating sourceand their careful decontamination. All employeesshould receive some basic life-support training. Em-ployees should demonstrate the appropriate use ofPPE to preclude self-contamination and be able toimplement the necessary procedures to assure thatthe spread of contamination will be limited.

Because pesticide antidotes are prescription medi-cations, such antidotes should not be provided foremployees to use unless the individual employees areproperly trained and granted clinical privileges toprovide emergency-response medical care. In certaincircumstances where extremely toxic chemicals areinvolved—such as military nerve agents—employeesmay be allowed to carry the antidote, administer buddyaid, and inject themselves. Nonmedical personnelwho are expected to use prescription antidotes andperform emergency care must learn to recognize the

• events that precipitate use,• quantity and frequency of administration, and• adverse effects associated with such use.

Unless access to first-aid kits can be carefully con-trolled, they are used only by trained individuals, orthe work is being performed at a remote site, first-aidkits should not be available or used at the workplace.If managers decide that first-aid kits should be placedin work areas, medical personnel must approve thekits’ contents, and pesticide workers must receiveapproved first-aid training. Procedures for safe first-aid kit use, kit resupply, accident reporting, and ap-propriate medical follow-up evaluation should becarefully documented.

The healthcare facilities that provide occupationalhealth or general medical services must maintain apharmaceutical inventory with necessary quantitiesof specific and appropriate antidotes, reversal agents,

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and anticonvulsants. In addition, the facility mustincorporate sufficient emergency-support equipmentto manage an emergency situation, and healthcareproviders must be properly trained and medicallycredentialed. Emergency-support agreements withnearby evacuation services and hospitals should beimplemented and continuously revised to assure thattimely support is available.

Pest-Control Equipment and Facilities

Industrial hygiene, safety, and occupational healthpersonnel should ensure that (a) pest-control equip-ment is compatible with the pesticide formulationthat is being applied, (b) the equipment is availableand calibrated properly, and (c) the pesticides aretransported properly. Engineering controls and PPEshould be certified as operational. The appropriatecare and use of the equipment should be documented.The following factors must also be considered in thetransportation of pesticides:

• Vehicles used to transport pesticides, particu-larly pest-control vehicles, should be equippedwith lockable storage areas and separate cabsfor passengers.

• Transporting pesticides in the cabs should beprohibited.

• Vehicles assigned to the pest-control shopshould be used only for pest-control activities.

• Pesticide spill kits should be placed on eachvehicle.

• A portable eyewash should be available onvehicles that are located at remote pesticide-application sites.

• Emergency telephone numbers should beposted on pest-control vehicles.

Pesticide storage and mixing facilities must con-form to not only federal workplace safety and healthrequirements, but also to state and local fire codes.3,37

Pesticide labels, Material Safety Data Sheets, safetydata prepared by the manufacturer, and a currentpesticide inventory for the pesticides that are storedand in use should be available for the employees’review. Plans to adequately contain a pesticide fire atthe facility should be prepared and updated annually.Copies should be provided to the local fire department,police department, hospitals, and safety offices.38

Pesticide Applications

Only personnel who are trained and certified shouldapply pesticides or supervise their application. Sched-

uled, periodic pesticide treatments should be prohib-ited unless a pest-control professional specificallyapproves, and these preventive treatments should bedone only if surveillance has indicated past or currentproblems with pests. Furthermore, at least two pestcontrollers should perform pesticide operations suchas fumigation that are particularly hazardous.

Food-handling areas and MTFs require special con-siderations for pest management; nonchemical pest-control methods should be attempted before chemicalmeasures are considered. In food-preparation areas,pesticide treatments should be conducted only (a)when the food-preparation area is not in operationand (b) according to the pesticide label’s instructions.Pesticides should not be applied routinely in MTFs,but only when the pest infestation warrants the use ofa pesticide and then only administrative or storageareas should be treated. Pesticides should not beapplied in patient-sensitive areas such as intensivecare wards, emergency rooms, or infant nurseries. Itis particularly important that pesticides not be appliedin neonatal wards: infants have low blood cholinest-erase; cholinesterase-inhibiting pesticides used in neo-natal wards could cause serious health problems.

A pest-management coordinator should be ap-pointed in each MTF. All pest sightings should bereported to the coordinator and any actions taken tocontrol pests in the facility, including the use of pesti-cides, should be documented and maintained by thecoordinator. Specific guidance for pest managementoperations in medical treatment facilities is providedin Armed Forces Pest Management Board TechnicalInformation Memorandum 20.39

Medical Surveillance

Comprehensive medical surveillance is an essen-tial element of a functional occupational health pro-gram. As a program element, the term medical surveil-lance is a misnomer. The surveillance element iscomposed of (a) general medical and specific occupa-tional exposure history review, (b) target-organ-sys-tem-focused medical examination, (c) selected clinicallaboratory analyses, and (d) medical intervention,depending on examination findings. In contrast to itsuse as a program element, in general preventive medi-cine the term medical surveillance is a separate, de-scriptive term. In that context, medical surveillance isa type of secondary prevention, directed toward iden-tification of exposure effects at the time of organ-system injury, prior to the onset of permanent damage(impairment). For comparison, the term biologicalexposure index (BEI) is used as an element of primaryprevention to identify and measure the specific chemi-

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cal, or its metabolites, in biological fluids. Measure-ment of the chemical or its metabolite may not proveto be medically useful except to define whether apossible exposure has occurred. For the BEI to havemaximal utility, a dose-response relationship for hu-mans must have been determined for the chemical ormetabolite that has been measured.

The toxicities of the chemical materials, the poten-tial for cumulative effect, and the potentially seriousmedical consequences of long-term, low-dose expo-sures make a medical surveillance program essentialfor pesticide workers. The interdependent industrialhygiene, safety, and medical factors that exert impor-tant influences on the type and extent of medicalsurveillance programs, include

• the number, amount, and toxicity of the pesti-cides being handled;

• the potential hazards associated with the for-mulations;

• the potential hazards associated with the ap-plications that are being performed;

• the presence or absence of a well-ventilated,properly designed and constructed pest-con-trol shop or warehouse;

• the degree of compliance with procedures thatare intended to minimize pesticide health haz-ards; and

• the extent of industrial hygiene surveys re-lated to personnel exposures and the resultsthat are obtained with a workplace environ-mental survey program.

As a tool to tailor medical surveillance for the indi-vidual pesticide worker, a health and safety hazardevaluation is necessary to fully analyze the cumulativeimportance of the factors. For example, potential ex-posures of pesticide workers are, as a rule, not re-stricted to one particular substance. Usually a numberof pesticides, formulation components, solvents, andcleaning agents with very different modes of action anddegrees of toxicity are used intermittently and simul-taneously. The comprehensive set of employee-spe-cific exposure possibilities represents the individual’sexposure profile. A comprehensive medical surveil-lance program is optimally developed to identify theemployee who has had a gradual decrement in cho-linesterase as a result of ongoing organophosphateexposure before the worker experiences symptomsfrom the application of a carbamate insecticide.

Medical surveillance examinations—preplacement,periodic, and termination—should be specifically de-signed for each employee: the contents of the medicalevaluation should be determined by the potential

exposure profile of that employee. Specific medicalsurveillance tests or appropriate biological exposureindices should be identified for the employee on acase-by-case basis. If a generalized exposure potentialto numerous chemicals exists, an extensive surveil-lance examination is usually required. The healthcareprovider should coordinate with industrial hygien-ists, safety professionals, and supervisors to designspecific examinations focused to the individual em-ployee. Although coordination among these indi-viduals fosters a better medical understanding of theworkplace, the healthcare provider must remember tomaintain the confidentiality of medical information.

Medical surveillance examinations of pesticideworkers are provided for all employees who have thepotential for exposure to pesticides in excess of eitherthe statutory (29 CFR 1910) or the recommendedexposure levels. The ACGIH annually publishes thecurrent, revised set of recommended exposure limitsand action levels. Both OSHA and ACGIH limitsidentify levels that should be safe for the traditionalworker exposure (40 h/wk for the duration of em-ployment). This examination is provided for anyemployee who has the potential to become exposed ator above the legal, regulatory, or advisory exposurelevels despite the presence or use of engineering con-trols and PPE or if administrative work practices fail.

Preplacement Examination

Preplacement examinations are performed beforean employee is assigned to the worksite. As a result ofthe Americans with Disabilities Act (ADA, which be-came effective in 1992, and by 1994 will cover compa-nies with more than 15 employees), the character andtype of examination performed prior to employmentor job assignment has changed dramatically.40 In short,before the statutory requirement was implemented,individuals presumed to be at increased risk fromexposure could be excluded from employment orparticular positions. Since the ADA became effective,however, it is illegal to refuse employment or place-ment for the individual who may be ill-suited to performthe job unless specific conditions of employment arepublished in the job description. If a potentially sus-ceptible employee is hired in the absence of specificexclusions (conditions of employment), the work sitemust be reconfigured to accommodate the employee.

The preplacement examination for potential pesti-cide workers, performed by a physician or properlyprivileged and supervised healthcare provider, shouldinclude

• a comprehensive medical and work history;

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• a physical examination with particular atten-tion to the cardiovascular and respiratory sys-tem to evaluate the employee’s ability to userespiratory protective equipment;

• an examination of the hepatic and renal sys-tems to ensure that employees will not beunusually susceptible to ill effects from pesti-cides, formulation products, solvents, or clean-ing materials;

• examinations of the musculoskeletal and ner-vous systems to identify preexisting neuro-logical disorders, including° evaluations of PNS and CNS functions, and° mental status and limited neuropsychiatric

evaluations;• a chest X ray;• spirometry, including° forced vital capacity (FVC) and° forced expiratory volume at 1 second (FEV1);

• a complete blood count;• liver function tests (such as SGOT and LDH);• renal function tests (such as creatinine and

BUN).

The preplacement examination may include a vari-ety of other elements if indicated by the potentialexposure profile. For example, for individuals whowill be required to work with the organophosphateinsecticides, one component of the examination is thedetermination of the baseline erythrocyte cholinester-ase level. Subsequent analyses during periodic ex-aminations or after suspected exposures will be evalu-ated by comparing with the baseline level.

The erythrocyte cholinesterase baseline determi-nation is defined as the average value of three separateerythrocyte-associated cholinesterase measurementsobtained during a 9- to 14-day period. Cholinesterasemeasurement methods must be subjected to judiciousquality control procedures, both inside and outsidethe laboratory. Quality control is essential to assureconsistently reproducible and reliable results. Labo-ratory consistency is critical because “normal” levelsvary widely among individuals, but change very littleover time in the same individual. Several methodshave been developed for the analysis of cholinesteraselevels.41 Extreme care must be taken to ensure that allsubsequent samples are analyzed by the same, care-fully controlled, technique. Results of each test mustbe reviewed by an individual who has been grantedclinical privileges to provide this type of care.

The erythrocyte cholinesterase baseline and all sub-sequent test results should be documented graphically(Figure 14-8). Individuals whose erythrocyte cholines-terase is depressed more than 25% should receive an

immediate medical evaluation and then be removedfrom further exposure to cholinesterase inhibitors.Individuals can be cleared to return to work when theenzyme levels reach 80% of the patient’s baseline.

Plasma cholinesterase (sometimes called pseudo-cholinesterase or butyrylcholinesterase) may be sig-nificantly changed with short-term, relatively high-dose exposures to cholinesterase inhibitors. Thereactivation and replacement kinetics of the plasma-associated enzyme do not permit their being used inroutine surveillance, although the plasma measure-ment can be used to confirm a very recent pesticideexposure.

Periodic Examinations

A physician or privileged healthcare providershould perform a periodic examination, based on theworker’s potential for exposure to pesticide levelsabove the action levels identified by OSHA or theACGIH. The examination should be focused withinthe scope of the preplacement examination and shouldbe dependent on the potential exposure hazard. Thefrequency of this examination is arbitrary; it can rangefrom annually to a frequency that depends on theworker's age and health. For example, an age-relatedexamination could be performed on individuals witha minimal potential for pesticide exposure: workersyounger than 40 years of age would be examinedevery 4 years; workers 40 to 49 years of age would beexamined every 2 years; and workers 50 years andolder would be examined annually.

Periodic examinations must be performed on work-ers who require PPE to verify that the level of protec-tion is adequate. The examining healthcare provideris responsible for coordinating with the personnelwho characterize and document exposure profiles sothat appropriate and timely periodic examinationsare provided to all appropriate workers.

The need for more extensive surveillance increasesin situations when

• more toxic or hazardous pesticides are used,• medical examinations indicate that more fre-

quent monitoring is necessary, or• a health- or safety-hazard evaluation reveals

that potential pesticide exposures could affectworkers’ health.

If the medical surveillance program is extendedbecause of potential—or actual—unfavorable work-ing conditions, the extension should be considered asan interim measure until more-effective controls areinstalled.

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Fig. 14-8. The Clinical Record-Plotting Chart (SF 512) is an approved form for entry in a medical treatment facility’semployee outpatient medical record. The graphic record should indicate an action line, (eg, a 20% depression from baselinevalues). When an employee approaches the action line, a set of patient-management practices, such as careful medicalexamination or return to work, may be implemented. A medical removal line should be drawn at the level of 25% depression.The change in pH (∆ pH units, the ordinate) is the difference in the pH of the erythrocyte environment before and after theaddition of a buffer, as a measure of cholinesterase activity.

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Regardless of the worker’s age, a brief, focusedinterim review of history should be documented. Acarefully elicited history of a general pesticide workerwho has a wide potential for exposure, should, at aminimum, evaluate the organ systems mentioned inTable 14-11. Liver- and kidney-function tests and acomplete blood count should be performed annually.If other occupational exposures exist (such as highnoise levels from the vehicles or aircraft used forspraying pesticides), appropriate medical surveillanceof the effects from these other occupational exposuresshould also be provided.

The frequency of periodic determinations of eryth-rocyte cholinesterase levels should be carefullyplanned for each individual, focusing on the potentialfor significant exposure to organophosphate insecti-cides or similar, militarily unique substances. If anemergency or a worker’s breach of protection hascaused an exposure, the results of the cholinesteraseanalysis should be charted immediately on the clinicalgraph and compared to the individual’s baseline. Inaddition, a cholinesterase determination and com-parison with the baseline are required when a symp-tomatic individual is evaluated.

Determinations of erythrocyte cholinesterase lev-els should be performed more frequently when work-ers are required to handle, store, mix, or use organo-phosphate insecticides. For example, if frequentapplications are required during the summer, monthlydeterminations of the enzyme level should be docu-mented as a prudent medical practice. In winter, if nopotential exists for exposure, no determination ofcholinesterase levels would be required.

The results of periodic examinations should be nega-tive. If deviations from the normal baseline occur foroccupationally related reasons, more frequent or moreextensive examinations may be indicated. At the sametime, an investigation should be initiated into thecause of the deviation, with specific attention directedtoward engineering controls, PPE, and work practices.

Pretermination Examination

For employees who have been associated withpesticide use, pretermination examinations should beperformed within 30 days of the termination of theiremployment. And as was previously discussed, theemployee’s total employment health history—obtained

TABLE 14-11

HISTORY AND PHYSICAL EXAMINATION FOR PESTICIDE WORKERS

Evaluation Categories Areas of Emphasis

General History Appetite, unexplained weight change, fatigue, work-site exposure potential

Visual Acuity, need for prescription inserts, dimness and blurring of vision, unilateral or bilateralmiosis, pressure, chemosis, allergic conjunctivitis

Respiratory Rhinorrhea, breathing difficulty, cough, tightness of chest, bronchoconstriction, increasedbronchial secretions, wheezing asthma, recurrent respiratory allergies, respirator wear (usetest), claustrophobia, pulmonary-function testing, if needed

Cardiovascular History of cardiovascular difficulty, atrial or ventricular arrhythmia, fainting, evidence ofcardiac susceptibility, blood pressure history, family history

Gastrointestinal History of ulcer or chronic bowel disease, neurological assessment for sphincter tone, historyof incontinence or soiling

Cutaneous Sweating disorders, heat tolerance, metabolic or genetic disorders, beard pattern, eczema,exfoliation, contact dermatitis, hematoma, easy bruising, petechiae

Genitourinary Frequency, incontinence, history of renal disease

Musculoskeletal Localized or generalized fasciculation, respiratory insufficiency (paralysis), weakness, cramps,twitching, strength, symmetry, family history

Nervous Anxiety, giddiness, restlessness, depression, emotional lability, excessive dreaming, tremor,nightmares, confusion, headache, ataxia, apnea, convulsions, paresthesia, mental statusexam, general neurological evaluation, affect, mood, memory, judgment

Hematological Erythrocyte cholinesterase baseline (for organophosphates)

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from preplacement, periodic, illness or injury, andpretermination examinations—must be retained for aminimum of 30 years.3 All normal findings, togetherwith any details of exposure and abnormal findingsthat could be ascribed to pesticide exposure, must beevaluated and documented before the employee’srecord is further disposed or retired.

Action Levels for Removal and Return-to-WorkPolicies

In general, any abnormal finding that could berelated to pesticide exposure should cause the em-ployee to be removed from further exposure until acomplete evaluation is made with respect to the extent,cause, and significance of the finding. The employee’sreturn to work should not be recommended if pesti-cide exposure could further harm the worker’s health,even if pesticide exposure did not cause the abnormality. If

SUMMARY

Pesticides are used to prevent, destroy, or mitigatepests. To be effective, however, they must be appliedinto the pest’s environment—the same environmentshared by other animals, plants, and humans. Tominimize adverse effects of pesticides to the environ-ment or human health, the risks of applying a pesti-cide must be weighed against the benefits of its use.The inability to fully identify the risks associated withintroducing pesticides into the environment is a con-tinuing problem.

Although in some instances the acute effects maybe known, there is a paucity of information on chroniceffects that result from long-term exposures to pesti-cide residues—not only to those who apply pesticidesbut also to bystanders. For this reason, the safe appli-cation of pesticides requires that precautions be takento protect against acute or chronic exposures to theresidues. Human exposures to pesticides during their

application are minimized by using PPE and appro-priate engineering controls.

The pharmacology of pesticides is not militarilyunique. However, medical officers need to be familiarwith the mechanisms of toxicity, their signs and symp-toms of intoxication, and the recommended medicalmanagement practices, occupational exposure sur-veillance end-points, and long-term effects. Medicalofficers also need to be familiar with the numerouspesticide-related federal, state, local, and DoD regu-lations.

The inherent hazards to humans, during and afterpesticide application, dictate that a comprehensiveoccupational medicine program be implemented.This includes monitoring the workplace for pesticideuse and disposition. In addition, the program pro-vides mechanisms to investigate alleged incidents ofpesticide exposure.

REFERENCES

1. 40 CFR, Parts 152–180.

2. American Conference of Governmental Industrial Hygienists. 1990–1991 Threshold Limit Values for Chemical Substancesand Physical Agents and Biological Exposure Indices. Cincinnati, Oh: ACGIH; 1990.

3. 29 CFR, Parts 1900–1910.

4. US Environmental Protection Agency. Analysis of the Risks and Benefits of Seven Chemicals Used for Subterranean TermiteControl. Washington, DC: EPA; Nov 1983. Technical Report 540/99-83-005.

the worker is found to have depressed levels of eryth-rocyte cholinesterase, which is fully reversible overtime if no additional exposure occurs, the followingpolicies should be adopted:

• The worker must be removed from work whenthe erythrocyte cholinesterase activity is de-pressed to 75% or less of its baseline value.

• The worker should be permitted to return towork when the erythrocyte cholinesterase activ-ity has returned to 80% or more of its normalvalue, provided that this level is confirmed bya second test. In addition, the worker must beasymptomatic and have had no exposure tocholinesterase inhibitors for at least 1 week.

• The erythrocyte cholinesterase levels shouldnot routinely be evaluated more frequentlythan once per week because the normal recov-ery rate is approximately 1% per day.

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5. Smith AG. Chlorinated hydrocarbon insecticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. NewYork: Academic Press, Inc; 1991: Chap 15.

6. Gray AJ. Pyrethroid structure-toxicity relationships in mammals. Neuro Toxicol. 1985;6:127–138.

7. Ray DE. Pesticides derived from plants and other organisms. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of PesticideToxicology. New York: Academic Press; 1991: Chap 13.

8. Gasiewicz TA. Nitro compounds and related phenolic pesticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of PesticideToxicology. New York: Academic Press 1991: Chap 18.

9. 40 CFR, Part 156 § 10.

10. Plestina R. Prevention, Diagnosis and Treatment of Insecticide Poisoning. Geneva, Switzerland: World Health Organiza-tion, Vector Biology and Control; 1984. WHO Document WHO/VBC 84.889.

11. Maddy KT, Edmiston S, Richmond D. Illness, injuries, and deaths from pesticide exposures in California 1949–1988.Reviews of Environmental Contamination and Toxicology. 1990;114:57–123.

12. Krieger R, Edmiston S. Ranking of Pesticides According to the Number of Systemic Illnesses Related to Agricultural PesticideUse in California 1982–1986. California Department of Food and Agriculture, Division of Pest Management, Environ-mental Monitoring and Worker Health and Safety Branches, 1220 N Street, PO BOX 942871, Sacramento, California94271-0001; n.d.

13. Litovitz TL, Schmitz BF, Bailey KM. 1989 Annual Report of the American Association of Poison Control CentersNational Data Base System. American Journal of Emergency Medicine. 1990;8:394–442.

14. Rumack BH, Spoerke DG. POISINDEX Information System. Denver, Colo: Micromedex Inc. CCIS CD-ROM Vol 68;edition exp May 1991.

15. Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. New York: Academic Press; 1991.

16. US Environmental Protection Agency. Recognition and Management of Pesticide Poisonings. Washington, DC: EPA; 1989.Technical Publication EPA 540/9-88-001.

17. Douville J, Licker MD, eds. International Pest Control. New York: Von Nostrand Reinhold; 1990.

18. Koelle GB. Anticholinesterase agents. In: Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics; 4th ed.New York: Macmillan; 1970: Chap 22.

19. Gallo MA, Lawryk NJ. Organic phosphorous pesticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of PesticideToxicology. New York: Academic Press; 1991: Chap 16.

20. Murphy SD. Toxic effects of pesticides. In: Klaassen CD, Amdur MO, Doull J, eds. Casarett and Doull’s Toxicology: TheBasic Science of Poisons. 3rd ed. New York: Macmillan; 1986: Chap 18.

21. Hodgson E, Silver IS, Butler LE, Lawton MP, Levi PE. Metabolism. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of PesticideToxicology. New York: Academic Press 1991: Chap 3.

22. Olajos EJ. Biochemical evaluation of organophosphorus-ester induced delayed neuropathy (OPIDN): The role of 2´,3´-cyclic nucleotide 3´-phosphohydrolase. Neuro Toxicol. 1987;8:211–222.

23. Ellenhorn MJ, Barceloux DG. Medical toxicology. In: Pesticides. New York: Elsevier Science Publishing; 1988: Chap 38.

24. Santone KS, Powis G. Mechanisms of and tests for injuries. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of PesticideToxicology. New York: Academic Press; 1991: Chap 4.

25. Roth A, Zellinger I, Arad M, Atsmon J. Organophosphates and the heart. Chest. 1993;103:576–582.

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26. Baron RL. Carbamate insecticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. New York:Academic Press; 1991: Chap 17.

27. Clark JH, Sultan WE, Meyer HG, Lieske CN. Studies of the Amplification of Carbaryl Toxicity by Various Oximes. US ArmyMedical Research Institute of Chemical Defense; 1990. Technical Report USAMRICD-TR-90-13.

28. Woolley DE, Zimmer L, Dodge D, Swanson K. Effects of lindane-type insecticides in mammals: Unsolved problems.Neuro Toxicol. 1985;6:165–192.

29. Woolley DE. Application of neurophysiological techniques to toxicological problems: An overview. Fundamental andApplied Toxicology. 1985;5:1–8.

30. Matsumura F. Involvement of picrotoxin receptor in the action of cyclodiene insecticides. Neuro Toxicol. 1985;6:139–164.

31. Clarkson TW. Inorganic and organometal pesticides. In: WJ Hayes Jr, ER Laws Jr, eds. Handbook of Pesticide Toxicology.New York: Academic Press; 1991: Chap 12.

32. Archibald SO, Winter CK. Pesticide residues and cancer risks. California Agriculture. 1989;43(6):6–9.

33. Pelfrene AF. Synthetic organic rodenticides. In: WJ Hayes Jr, ER Laws Jr, eds. Handbook of Pesticide Toxicology. NewYork: Academic Press; 1991: Chap 19.

34. Stevens JT, Sumner DD. Herbicides. In: WJ Hayes Jr, ER Laws Jr, eds. Handbook of Pesticide Toxicology. New York:Academic Press; 1991: Chap 20.

35. Wolfe WH, Michalek JE, Miner JC, et al. Health status of Air Force veterans occupationally exposed to herbicides inViet Nam: I. Physical health. JAMA. 1990;264:1824–1831.

36. Emmett EA. Herbicides and pesticides. Critical reviews. In: Emmett EA, Brooks SM, Harris RL, Schenker MB, eds.Yearbook of Occupational Medicine 1992. St. Louis, Mo: Mosby=Year Book; 1992: 89–90.

37. US Department of the Army. Design of Pest Management Facilities. Washington, DC: DA; 1991. Military HandbookMIL-HDBK-1028/8A.

38. Armed Forces Pest Management Board. Pesticide Fires: Prevention, Control and Cleanup. Washington, DC: AFPMB; 1981.Technical Information Memorandum 16.

39. Armed Forces Pest Management Board. Pest Management Operations in Medical Treatment Facilities. Washington,DC:AFPMB; 1989. Technical Information Memorandum 20.

40. Americans with Disabilities Act. Pub L No. 101-336. 26 July 1990.

41. Watson AP, Munro NB. Reentry Planning: The Technical Basis for Offsite Recovery Following Warfare Agent Contamination.Oak Ridge, Tenn: Oak Ridge National Laboratory; 1990. Technical Report ORNL-6628.

RECOMMENDED READING

Ecobichon DJ, Joy RM. Pesticides and Neurological Diseases. Boca Raton, Fla: CRC Press; 1982.

Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. , New York: Academic Press; 1991.

Morgan DP. Recognition and Management of Pesticide Poisonings. 4th ed. Washington, DC: Environmental ProtectionAgency; 1989. US EPA Report 540/9-88-001.

Ware GW. Fundamentals of Pesticides—A Self-Instruction Guide. Fresno, Calif: Thomson Publications; 1982.