behavioral toxicology and environmental health science · particularly environmental toxicology,...

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Behavioral Toxicology and Environmental Health Science Opportunity and Challenge for Psychology Bernard Weiss University of Rochester School of Medicine and Dentistry ABSTRACT: Behavioral toxicology is now established as a component of the environmental health sciences. Its rise paralleled recognition that the adverse health impact of environmental chemicals should be gauged by how people feel and function, not solely by death or overt damage. Its compass extends across the total spectrum of environmental chemicals, including heavy metals, solvents, fuels, pesticides, air pollutants, and even food additives. Psychology can help resolve many critical issues in environmental health science. Odious waterways and corrosive smog are such tan- gible evidence of pollution that they evoke tangible remedies. But eliminating blatant pollution is no more than a first step in managing the environment and protecting human health. Some of the most toxic contaminants are also the most elusive. How can we assess the impact of chemicals that, in passing through the environment, may be transformed into other sub- stances, may be dispersed by atmospheric processes, may enter the food chain in unpredictable guises, or may trigger biological reactions whose consequences remain dormant for decades? To multiply this am- biguity, how do we evaluate toxic processes expressed other than as overt disease or death? Especially, how do we detect an insidious degradation of function, especially if it unfolds gradually over years of toxic exposure or after a latency of half a lifetime? The nascent discipline of behavioral toxicology arose as one response to such questions. Behavioral measures were seen to fulfill unique roles. One derives from the realization that many substances act pri- marily on the nervous system. They include heavy metals such as mercury, lead, and manganese; organic solvents such as carbon disulfide and toluene; pes- ticides such as the organophosphates; air pollutants such as carbon monoxide. A second reason is more subtle; it derives from the observation that many poi- sonings, before they bloom into overt clinical signs, may be heralded by vague, subjective, nonspecific psychological complaints. Finally, there are substances whose actions, although not mediated directly through nervous system mechanisms, produce distinct be- havioral reactions. For example, the main oxidant in photochemical smog, ozone, is a deep lung irritant eliciting subjective discomfort. This unique role for psychology grows out of a new perspective by the environmental health sciences, particularly environmental toxicology, and by public health leaders. Toxicology, the science of poisons, used to be a discipline ruled by the clear criteria of death and tissue pathology. The new issues that emerged from our delayed recognition of environmental haz- ards, however, stimulated new questions about adverse effects on health. Were death or tissue lesions the only feasible end points? What about disturbances of func- tion? Isn't it important to discover how people feel and perform or to intervene when "behavioral changes dangerous to a patient and others can occur before the individual realizes that he or she is poisoned" (Michael, 1982)? Once we were alerted to these ques- tions about function, it was a natural step to turn to the discipline whose business it had been for over a century to provide scientific answers to questions of this type. Behavioral toxicology is so young that its formal debut in the United States did not occur until June 1972, shortly after the winter snows had melted in Rochester (Weiss & Laties, 1975). Like many new disciplines, it coalesced from fragments of old ones: toxicology and its emphasis on pathology, behavioral pharmacology and its parallel inquiries about drug effects, industrial hygiene and its recognition of func- tional indexes as the basis for many standards of al- lowable exposure to workplace chemicals. It is also indebted to I. P. Pavlov, because his stature in Soviet science helped to elevate CNS function to a sovereign place in USSR hazard assessment (Glass, 1975). Behavior also was seen to have special virtues as a criterion of adverse effects. First, it is a nonde- structive assay: Its subjects' livers need not be fed into a blender to quantify damage. Also, it is an assay system (Weiss, 1978b) reflecting an Organism's total functional capacity, not simply one component of it. Such attractive attributes come at a price, however. 1174 November 1983 American Psychologist Copyright 1983 by the American Psychological Association, Inc.

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Page 1: Behavioral Toxicology and Environmental Health Science · particularly environmental toxicology, and by public health leaders. Toxicology, the science of poisons, used to be a discipline

Behavioral Toxicology and EnvironmentalHealth Science

Opportunity and Challenge for Psychology

Bernard Weiss University of RochesterSchool of Medicine and Dentistry

ABSTRACT: Behavioral toxicology is now establishedas a component of the environmental health sciences.Its rise paralleled recognition that the adverse healthimpact of environmental chemicals should be gaugedby how people feel and function, not solely by deathor overt damage. Its compass extends across the totalspectrum of environmental chemicals, including heavymetals, solvents, fuels, pesticides, air pollutants, andeven food additives. Psychology can help resolve manycritical issues in environmental health science.

Odious waterways and corrosive smog are such tan-gible evidence of pollution that they evoke tangibleremedies. But eliminating blatant pollution is no morethan a first step in managing the environment andprotecting human health. Some of the most toxiccontaminants are also the most elusive. How can weassess the impact of chemicals that, in passing throughthe environment, may be transformed into other sub-stances, may be dispersed by atmospheric processes,may enter the food chain in unpredictable guises, ormay trigger biological reactions whose consequencesremain dormant for decades? To multiply this am-biguity, how do we evaluate toxic processes expressedother than as overt disease or death? Especially, howdo we detect an insidious degradation of function,especially if it unfolds gradually over years of toxicexposure or after a latency of half a lifetime?

The nascent discipline of behavioral toxicologyarose as one response to such questions. Behavioralmeasures were seen to fulfill unique roles. One derivesfrom the realization that many substances act pri-marily on the nervous system. They include heavymetals such as mercury, lead, and manganese; organicsolvents such as carbon disulfide and toluene; pes-ticides such as the organophosphates; air pollutantssuch as carbon monoxide. A second reason is moresubtle; it derives from the observation that many poi-sonings, before they bloom into overt clinical signs,may be heralded by vague, subjective, nonspecificpsychological complaints. Finally, there are substanceswhose actions, although not mediated directly through

nervous system mechanisms, produce distinct be-havioral reactions. For example, the main oxidant inphotochemical smog, ozone, is a deep lung irritanteliciting subjective discomfort.

This unique role for psychology grows out of anew perspective by the environmental health sciences,particularly environmental toxicology, and by publichealth leaders. Toxicology, the science of poisons, usedto be a discipline ruled by the clear criteria of deathand tissue pathology. The new issues that emergedfrom our delayed recognition of environmental haz-ards, however, stimulated new questions about adverseeffects on health. Were death or tissue lesions the onlyfeasible end points? What about disturbances of func-tion? Isn't it important to discover how people feeland perform or to intervene when "behavioral changesdangerous to a patient and others can occur beforethe individual realizes that he or she is poisoned"(Michael, 1982)? Once we were alerted to these ques-tions about function, it was a natural step to turn tothe discipline whose business it had been for over acentury to provide scientific answers to questions ofthis type.

Behavioral toxicology is so young that its formaldebut in the United States did not occur until June1972, shortly after the winter snows had melted inRochester (Weiss & Laties, 1975). Like many newdisciplines, it coalesced from fragments of old ones:toxicology and its emphasis on pathology, behavioralpharmacology and its parallel inquiries about drugeffects, industrial hygiene and its recognition of func-tional indexes as the basis for many standards of al-lowable exposure to workplace chemicals. It is alsoindebted to I. P. Pavlov, because his stature in Sovietscience helped to elevate CNS function to a sovereignplace in USSR hazard assessment (Glass, 1975).

Behavior also was seen to have special virtuesas a criterion of adverse effects. First, it is a nonde-structive assay: Its subjects' livers need not be fedinto a blender to quantify damage. Also, it is an assaysystem (Weiss, 1978b) reflecting an Organism's totalfunctional capacity, not simply one component of it.Such attractive attributes come at a price, however.

1174 November 1983 • American PsychologistCopyright 1983 by the American Psychological Association, Inc.

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Behavior's global nature also may allow compensatorymechanisms to thwart the early detection of an ir-reversible pathological process. Behavioral assays areexpensive, especially when compared, for example,to in vitro tests of mutagenesis. Behavioral methodsalso offer a bewildering spectrum of choice, which isan advantage in pursuing a science of behavior, butan aggravating source of indecision for a chemicalmanufacturer or regulatory agency forced to definehazard. Perhaps most troublesome of all, how arefunctional measures to be evaluated? What actionsare implied by a finding that the current workplaceexposure standard for a volatile organic solventlengthens reaction time by 10%? Or by a report thatprenatal treatment with high doses of a common pes-ticide elevates locomotor activity in two-month-oldrats? These are not idle questions or academic ex-ercises; standards and regulations may be built onthem. The Toxic Substances Control Act (TSCA) of1976 specifies behavior as one of the criteria for judg-ing the safety of new chemicals. Unease about theimpairment of psychological development by leadhelped to diminish its role as a fuel additive. Thecarbon monoxide standard prescribed by the Envi-ronmental Protection Agency (EPA) is based partlyon behavioral data. These issues and questions becomeclearer in the context of specific substances. I've cho-sen, from many possibilities, a set of agents meantto illustrate the diversity of settings, issues, and con-taminants that entail psychological questions.

I will begin by discussing metals, because theyare the most ancient pollutants released by humanactivities. Metallic mercury demonstrates the im-portance of quantitative measures of motor functionin assessing subclinical impairment, as well as thelack of sound psychophysiological data about the totalsyndrome of mercury poisoning. Methylmercury, ahighly toxic organic compound of mercury, illustratesthe discipline and problems of behavioral teratology,that is, the consequences of prenatal toxic exposures.Another metal, lead, shows how difficult it still is,even after an immense outpouring of research, todisentangle toxic behavioral consequences from otherenvironmental variables and to relate them to ap-propriate biological measures of exposure. Organicsolvents illustrate even more graphically the issue of

Parts of this article are based on invited addresses presented duringthe past 10 years to the American, Eastern, and Midwestern Psy-chological Associations. Its preparation was supported in part byGrants ES-26676, ES-01247, and ES-01248 from NIEHS; MH-11752 from NIMH; and in part by Contract No. DE-ACO2-76EVO3490 with the U.S. Department of Energy at the Universityof Rochester Department of Radiation Biology and Biophysics,which has been assigned Report No. UR-3490-2218.

Requests for reprints should be sent to Bernard Weiss, Divisionof Toxicology and Environmental Health Sciences Center, De-partment of Radiation Biology and Biophysics, University of Roch-ester School of Medicine and Dentistry, Rochester, New York 14642.

quantifying nonspecific neuropsychological featuresof toxicity, especially early in the course of poisoningwhen many of them are likely to be subjective. Theyalso demonstrate how psychological approaches suchas psychophysics could help detect and trace subtlesensory impairment. A discussion of pesticides showshow monitoring adverse effects by psychological mea-sures may yield more information than monitoringthem by blood chemistry. Air pollutants are used toexemplify a class of contaminants whose effects maynot lie directly within the nervous system; in someinstances, these effects are best revealed by behavioralmethods. Finally, in a discussion of food additives," Itry to show how the neglect of behavior in safetytesting has provided misleading estimates of safetymargins.

MetalsMetals are so ubiquitous that many of them came toplay essential roles in the evolution of living systems(Weiss, 1978a). Other metals, perhaps because of theirgeological distribution, remained outside the orbit ofliving processes. But all metals, even the essentialones, can be toxic, and the margin between essentialand hazardous levels may be surprisingly narrow.Manganese and vanadium are both essential elements,yet they have been implicated in syndromes rangingfrom movement disorders resembling parkinsonismto manic-depressive psychosis. Excessive exposure tometals can damage many different organ systems andbiological processes and has been implicated in a re-markable range of adverse signs and symptoms in-volving the central nervous system (CNS) and be-havior (Figure 1).

Mercury

Among the best documented entries in Figure 1 arethose associated with mercury. This slippery, silverymetal, liquid at room temperature, is one of the metalsexploited by humans since antiquity. Its toxicity hasbeen recognized almost as long (Maurissen, 1981).The cardinal sign of mercury-vapor poisoning istremor, which begins to develop around the eyelidsand eventually invades the limbs, especially the hands.Inorganic mercury compounds at one time were usedto prepare animal hairs for felt hats. These processesreleased mercury vapor into the factory atmosphere,exposing workers to concentrations above the safetylimits prevailing at the time. Since Danbury, Con-necticut, was the center of the industry, the mercury-induced tremors came to be known as "hatter'sshakes" or "Danbury shakes."

Mercury has many other applications: as elec-trodes in the chlor-alkali process for producing chlo-rine and caustic soda from brine, in electrical equip-ment, in dental amalgams, in chemistry laboratories.In 1970, we encountered an instance of mercury poi-

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Figure 1Neurological and Psychological Signs andSymptoms, Collected From Clinical andExperimental Sources, Attributed to Metal Toxicity

ANOSMIAAPPETITE LOSSCONVULSIONSDEPRESSIONDISORIENTATIONDIZZINESSDYSARTHRIAFATIGUE, LETHARGYHEADACHEINCOORDINATION, ATAXIAINSOMNIAJITTERINESS, IRRITABILITYMENTAL RETARDATIONPARALYSISPARESTHESIAS-PERIPHERAL NEUROPATHYPOLYNEURITIS.PSYCHIATRIC SIGNSSOMNOLENCETREMORVISUAL DISTURBANCESWEAKNESS

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SYMPTOMS ASCRIBED TO METAL TOXICITY

Note. Based on Weiss, 1983.

soning in upstate New York. A woman employed bya large glassware manufacturer appeared at the Uni-versity of Rochester Medical Center with the suspicionthat she was suffering from mercury poisoning.Chemical analyses of her blood confirmed her sus-picion. She was one of several women who had thejob of calibrating glass pipettes. During one segmentof the calibration process, elemental mercury waspoured into the pipettes. Some of the mercury wasdispersed into the workroom atmosphere. It foundits way into hair, eyeglass frames, clothing seams.Since elemental mercury is quite volatile, the womeninhaled it. Elemental mercury enters the brain muchmore easily than its ionized form (Rothstein & Hayes,1964).

One of the women, who had worked at the jobfor 15 years, was almost disabled by the severity ofher tremor, and could hardly hold a glass of waterwithout spilling. Because we already had embarkedon a study of mercury-induced tremor in monkeys,and had a method available for measuring it, we wereasked to help quantify the tremor to better monitorthe course of treatment and recovery. The patientplaced her finger in a lucite trough attached to a straingauge and tried to apply a force between upper and

lower bounds (10 and 40 grams) designated by lightson a signal box (Wood, Weiss, & Weiss, 1973). Atfirst, tremor amplitude was remarkably high. Theoutput of the gauge was amplified, traced on a poly-graph, and transmitted to the analog-to-digital con-verter of a computer for quantitative processing. Afternine months without further exposure, both the mer-cury levels in her blood and the tremor fell to normallevels. There was a marked change in other charac-teristics of the tremor as well. Early in treatment, thespectrum of tremor frequencies showed multiplemodes. Nine months later, it was marked by a singledominant frequency.

Psychologists would hardly find it surprising thatwe felt it necessary to record, quantify, and analyzethe extent of this motor deficit. Psychologists havequantified motor function in contexts ranging frominfant development to human engineering to the ef-fects of brain lesions in monkeys. Clinical medicine,in contrast, typically evaluates tremor by visual in-spection and interprets it according to the physician'sexperience. The unsuitability of clinical criteria ledLangolf, Chaffin, Henderson, and Whittle (1978) toadapt our technique for monitoring chlor-alkaliworkers exposed to mercury. Now that exposures indental offices and laboratories are coming under in-creased scrutiny, psychologists might be asked whatother measures of psychophysiological function mighthelp detect subclinical toxicity. This is an importantquestion not only in itself, but because such measurescould help to identify some sources of the psycho-logical complaints accompanying mercury intoxi-cation. These complaints are an intriguing feature ofmercury poisoning and form a distinct enough clusterto have been given a label, erethism, a word from aGreek root meaning "to irritate." The characteristicfeatures of erethism resemble what psychiatrists usedto call neurasthenia. Hatter's shakes were typicallyaccompanied by erethism. Wright's (1922) survey of108 hatters turned up 53 with symptoms such asirritability, timidity, apprehension, restlessness, va-somotor disturbances, easy blushing, exaggerated re-flexes, and slight speech abnormalities. Improvisa-tional questionnaires and clinical medical surveyscannot substitute for careful psychometric and psy-chophysiological measures of symptoms, but currentworkplace standards are based on the former kindsof clinical data.

Another aspect of mercury poisoning provokeseven more serious questions. Methylmercury, an or-ganic compound of mercury, was first synthesizedduring the 19th century. It proved to be a potentnervous system poison but also an extraordinarilyeffective fungicide, especially in protecting seed grains,and it dissipates into the soil once the seeds areplanted. Great Britain encouraged its use duringWorld War II to ensure abundant grain crops. No

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one conceived of it as an ecological hazard until the1950s.

Minamata is a small fishing village on Kyushu,the southernmost of the major islands of the Japanesechain. Beginning about 1953, inhabitants of the areawere attacked by a central nervous system afflictionthat came to be known as "Minamata disease." Thevillagers called it Kibyo, or mystery illness, becauseno etiologic agent could be found. They did discover,however, that neurological abnormalities were inducedin cats fed fish and shellfish from Minamata Bay.Minamata disease finally was traced to methylmer-cury contamination of seafood from the bay (Tsubaki& Irukayama, 1977). A search for the source of theorganic mercury led Japanese scientists to a factorythat used inorganic mercury as a catalyst. The factorydumped its effluent into the bay, but only after ad-ventitiously converting the mercury into the potentorganic form, which then was incorporated into thefood chain and finally consumed by humans (Smith& Smith, 1975). A decade after Minamata, a similarepidemic erupted in the city of Niigata.

Until 1970, North America perceived such ep-isodes as remote aberrations. Then a graduate studentat the University of Western Ontario discovered thatfish in the Great Lakes bore unexpectedly high levelsof methylmercury. His disclosure instigated a surveyof contamination in the United States, which foundthat fish and wildlife in half the states carried excessivelevels of methylmercury. Even oceanic fish like tunaand swordfish, once thought to be free of contami-nation, revealed puzzlingly high concentrations ofmethylmercury, and swordfish were barred from in-terstate commerce. As governmental agencies soughtto assess the extent of hazard, we became aware ofhow little was known about this substance. Our in-formation came from a handful of rather crude lab-oratory animal studies, a few industrial accidents,and scattered disasters like Minamata. It was not asatisfactory basis for erecting safety standards.

When exposure standards are proposed for en-vironmental toxicants, they incorporate a safety mar-gin broad enough to reduce the community's risk toacceptable levels. Methylmercury cannot simply bebanned; the methylmercury in fish, particularly ma-rine species, is partly the contribution of geologicsources. Some of the methylmercury in freshwaterspecies may be the contribution of acid rain, whichpromotes the uptake of the poison by lowering thepH of the aquatic environment. Calculations of safetymargins determine which species from which areascan be marketed. But safety margins set on the basisof function are difficult to calculate, and the chiefexpressions of methylmercury poisoning arise becauseit destroys brain tissue, leading to sensory, motor, andnonspecific functional deficits,

Paresthesias (numbness and tingling) in the ex-

tremities and around the mouth seem to be the earliestsymptoms of intoxication in adults. They are difficultto quantify, however, and their baseline prevalencevaries markedly among populations. Visual deficitsalso are early features of intoxication, and they arisefrom cell death in the occipital cortex. Victims ex-perience constriction of the visual field (tunnel vision)and allied deficits such as loss of night vision. Suchdeficits have been reproduced in monkeys trained onvarious visual discrimination tasks (Berlin, Grant,Heilberg, Hellstrom, & Schultz, 1975; Evans, Laties,& Weiss, 1975;Merigan, 1980; Rice & Gilbert, 1982).Psychophysical experiments with primate species wereadopted as a strategy for correlating exposure vari-ables, brain damage, and performance because theliterature of neuropsychology provided a firm guidefor asking such questions. It told us what visual dys-functions arose from occipital lesions and convincedus that only primates could provide adequate animalmodels to the symptoms that arise in humans.

Minamata also suggested that methylmercurydamaged the fetus far more severely than the adult,a suggestion consistent with other findings about theenhanced susceptibility of the developing brain totoxic challenges such as alcohol. Teratology is thediscipline that studies what in lay terms are calledbirth defects. Like toxicology, it had emphasizedmorphology. With the realization that postnatal con-sequences might be expressed as functional ratherthan structural aberrations, a new discipline beganto emerge: behavioral teratology. Its role is exemplifiedby a question once put by David P. Rail, director ofthe National Institute of Environmental Health Sci-ences and of the National Toxicology Program. Sup-pose, he asked, that the drug thalidomide, instead ofinducing missing limbs and other deformities, hadsimply lowered intellectual potential by the equivalentof 10 IQ points. Would we ever have become awareof any adverse consequences? Given the difficulty ofconnecting even gross morphological consequenceswith thalidomide, the answer is disquieting enoughto have provoked several countries into requiring be-havioral teratology data for new drugs.

A later methylmercury episode provided themost cogent confirmation of what had been suggestedby Minamata. In the winter of 1971-1972, the gov-ernment of Iraq ordered 80,000 tons of seed grain(wheat, barley, and rye) from Mexico and the UnitedStates, specifying that it be treated with a methyl-mercury fungicide. Much of the grain was distributedto Iraqi peasants after the planting season, however.Although the farmers were told that the grain hadbeen treated with a poison, many were skeptical ofthe government's warnings. The bags were markedas poisonous, but in Spanish and English. Some ofthe farmers washed off the pink dye that identifiedthe treated grain, a maneuver that did not remove

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the fungicide. Other farmers conducted some prim-itive toxicology, feeding the grain to farm animals,or in one case, to the farmer's mother-in-law, withoutobserving toxic signs. They were misled by the latencyof several weeks before overt signs of poisoning wouldmanifest. The aftermath was a probable loss of about5,000 lives, with perhaps 10 times that many personsseriously poisoned.

Thomas W. Clarkson, a widely recognized experton mercury toxicology, and other members of theUniversity of Rochester faculty were called on to assessthe episode in collaboration with Iraqi physicians.The scope of the poisoning permitted them for thefirst time to construct dose-response functions basedon population samples of reasonable size (Clarkson& Marsh, 1976). These largely confirmed the profileof adult disabilities traced at Minimata and Niigata.Their assessments of fetal exposure, however, greatlymagnified the concerns engendered by Minamata.

Minamata mothers who had experienced onlyminimal symptoms, such as paresthesia, deliveredinfants who later exhibited appreciable developmentalretardation. There, however, the number was so smallthat a definitive assessment was impossible. Iraq pro-vided more compelling evidence. A sensitive analyticalmethod for measuring organic mercury in tissue per-mitted the Rochester scientists to trace the course ofexposure in pregnant and nursing women. Hair growsat a rather constant rate, about one centimeter permonth. Hair also serves as one of the eliminationpathways of methylmercury, maintaining a fairly sta-ble ratio of about 250:1 (hainblood). By choppingthe hair into centimeter sections, it was possible todetermine when the mother began eating the taintedbread, when she reached her peak body burden, wheningestion stopped, and the subsequent decline of bodyburden. Since maternal milk also contained meth-ylmercury (in a concentration about 3% of the bloodlevel) infants could consume considerable quantities.And in the Iraqi countryside, children are often fedat the breast until two years of age.

Once appropriate mother-infant pairs wereidentified and documented, Rochester and Iraqi ob-servers began periodic visits to the countryside torecord the development of the children. Although thekind of rigorous evaluation that might be performedin the United States was not feasible, the 93 childrenunder surveillance already have answered the mostpressing question. Even at relatively modest maternalblood levels, the offspring may be significantly re-tarded, showing delays in speech, motor function,and other indexes of development (Clarkson, Cox,Marsh, Myers, Al-Tikriti, Amin-Zaki, & Dabbagh,1981). Whether because of special vulnerabilities in-trinsic to the developing brain or the metabolic de-fenselessness, so to speak, of the fetus and neonate,the ecological hazard of methylmercury is amplified

in the young organism. Moreover, if Minamata andseveral laboratory animal studies (e.g., Bornhausen,Musch, & Greim, 1980; Eccles & Annau, 1982;Spyker, 1975) are reliable guides to the future, thedisabilities may become even more pronounced asthe children age. Now that these Iraqi children arebeing increasingly challenged in school, it is morecritical that they be evaluated by the best contem-porary techniques because there are many areas ofthe world whose inhabitants consume large quantitiesoffish containing substantial concentrations of meth-ylmercury. To set standards requires us to determineexposures producing subtle, not overt, impairment.What techniques might be suitable for assessing ruralchildren in an Arab country or in comparable non-Western settings? The ingenuity of current develop-mental psychology is sorely needed for these impor-tant issues—issues about safety margins that continueto arouse concern by the U.S. Food and Drug Ad-ministration, the World Health Organization, andmany governments. This concern stretches across al-most the entire spectrum of environmental contam-inants, including the polychlorinated biphenyls(PCBs) and the currently notorious dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD).

Lead

Mercury may be the most dramatic neurotoxic heavymetal, but lead is just as ancient, equally subtle, andmore dispersed in the environment. Its reproductivetoxicity has been held responsible for the decline ofRoman hegemony, since the Roman nobility storedwine and preserves in leaden casks and even addedlead compounds as sweetening agents (Gilfillan, 1965).Lead was first exploited so long ago that occasionalskeletons from the oldest civilizations may reveal signsof excessive concentrations of lead. It is now distrib-uted so pervasively through the environment (andliving tissue) that we can only guess at what the earlyevolutionary load might have been.

Overt lead toxicity in adults takes a multifacetedform. Stomatitis and colic are prominent in acute orsubchronic poisoning. Neurological and psychologicalfeatures prevail in low-level, chronic intoxication.Wrist-drop and foot-drop, once frequent amongpainters and other exposed workers, now are rarebecause of improved industrial practices and in-creased alertness to toxicity. But more subtle indexesof impairment are still detectable with precise psy-chological and neurological testing, even in workersdisplaying no clinical dysfunction and carrying bodyburdens well below the values previously associatedwith toxicity (Hanninen, Mantere, Hernberg, Sep-palainen, & Kock, 1979; Valciukas, Lilis, Eisinger,Blumberg, Fischbein, & Selikoff, 1978).

Our concerns about lead, however, stem mainlyfrom the amplified connection between exposure and

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consequence in the developing human. Even in thesuperficially clean setting of the suburbs, children ex-hibit body burdens of lead many times higher thanthose revealed by human skeletons in eras before thedevelopment of mining and smelting. Public healthconcerns are aroused even more in the aging coresof central cities, where the interiors of many buildingswere once covered with lead-based paints, where streetdust contains the combustion products of leaded gas-oline, and where many children manifest lead bodyburdens uncomfortably close to overtly toxic levels.Most communities and their health agencies are nowalert to the hazard of lead poisoning. Peeling, flakingsurfaces are repainted, blood lead determinations areroutine, and pediatricians are more prone to intervenewith drugs that accelerate lead excretion. But thedispute about what constitutes a hazardous body bur-den has only become more intense because the focalquestion is now more subtle: Do asymptomatic butelevated body burdens of lead express themselves aspsychological or behavioral impairment? Is there athreshold for toxic effects? The economic implicationsof what is defined as a "safe" level impinge not onlyon gasoline refiners, owners of urban real estate, andlead battery manufacturers, but on public agencies,because too high a level and its psychological after-math also is costly to society (Provenzano, 1980).

Despite a plethora of studies dating from theprovocative paper of Byers and Lord (1943), whoreported persisting behavioral deficits after recoveryfrom lead poisoning, the issue has been drifting towardresolution with frustrating slowness (Bornschein,Pearson, & Reiter, 1980a). Many studies have beenflawed by inadequate control groups, by inappropriatetests, by mistaken assumptions in their statisticalanalyses. Many also were hampered by two funda-mental biological problems. One is the lability ofblood lead concentration, which reflects only recentexposure but which typically has served as the bio-logical index of lead exposure. If peak intake occursbetween the ages of 12 and 36 months, when childrenexplore the world with their mouths and their nervoussystems are still immature, how useful is it to correlatetest performance with blood lead at age six or older?The second problem arises from the distribution ofsusceptibility. Especially when the questions centeron threshold, is it not reasonable to expect only amodest proportion of children to demonstrate adverseeffects?

Yet, despite these obstacles, objections, and flaws,a consensus is developing that current lead exposureindicators disclose a problem at even relatively modestvalues. One recent contribution was particularly pro-vocative. Needleman, Gunnoe, Leviton, Reed, Per-esie, Maker, and Barrett (1979), recognizing the in-herent defects of many earlier studies, turned to teethas a biological indicator. Deciduous teeth, like bone,

serve as lead repositories because dentine incorporateslead as it grows. An analysis of baby teeth, then,provides an integrated index of exposure during theearly years. Needleman and his group collected teethfrom over 3,000 children in the Boston area. Theythen selected children from the lowest and highestdeciles and subjected them to a broad psychologicalevaluation. The high-lead children had lower scoreson many dimensions: intelligence test scales, psycho-motor performance, and conduct. All of the childrenwho contributed teeth also were rated by their teachersaccording to a standard inventory. Perhaps the mostintriguing section of the entire study is the strikingrelationship between scores on individual inventoryitems and tooth lead concentrations, Systematic ob-servation in the classroom, using the techniques de-veloped by applied behavior analysis, is also a fruitfulapproach (Needleman, Note 1), yielding even moreconvincing relationships. Even so, some observers areunhappy about the possible influence of family socialand economic status and parental intelligence on theobserved differences, contending that treating theseas covariates and compensating for them statisticallyis not sufficient. For example, although Winneke etal. (1983) essentially verified Needleman et al., theyfound that social class played a statistically significantrole in performance differences. Winneke (Note 2)also has found, however, that lower social class en-hanced the risk of adverse effects from lead exposure,a finding parallel to those from the malnutrition lit-erature. Such interactions are a crucial argument forbehavioral assessments. Recent advances in psycho-metric techniques, such as structural equation meth-odology, have not been enlisted in pursuing thesequestions. Since both causes and consequences aresurely multivariate in character, such techniques couldgive a unique perspective on the issue.

The difficulties posed by studies of human pop-ulations make well-designed animal experiments thatmuch more crucial. Although many earlier animalexperiments suffered from major problems such asreduced food intake in exposed animals, most currentresearchers now carefully limit lead intake so as toeliminate undernutrition and, incidentally, to producemore realistic body burdens of lead. Even with theseprecautions, it is clear that a legacy of elevated leadduring development portends significant behavioraldisruption. Rice, Gilbert, and Willes (1979) detectedseveral subtle signs of deviant performance in rhesusmonkeys treated from birth to achieve blood levelswithin the range of values displayed by a significantproportion of urban children. For example, perfor-mance on fixed-interval schedules of reinforcementwas marked by high rates of responding, interruptedby long pauses, in the treated monkeys. Cory-Slechtaand Thompson (1979) reported that low concentra-tions of lead in drinking water consumed by young,

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weanling rats produced aberrant fixed-interval per-formance. Serial measures of blood lead, in a sys-tematic replication of this study (Cory-Slechta &Weiss, 1982), indicate that such aberrant performanceoccurs at concentrations approaching those of evenmany suburban children. Only a handful of properlyconducted studies now exist in the published literature(Bornschein, Pearson, & Reiter, 1980b), representinga tiny fragment of behavioral techniques with obviouspotential in this research. Schedule-controlled per-formance, for example, has been exploited only min-imally (Bornschein, Pearson, & Reiter, 1980b).

Solvents and FuelsVolatile organic solvents and fuels are traditional oc-cupational hazards because exposure mostly occursthrough inhalation, an exposure medium difficult tocontrol. The American Conference of GovernmentalIndustrial Hygienists (ACGIH, 1978), which publishesassessments of and recommendations for exposurestandards in the workplace (threshold limit values),defines the "short-term exposure limit" as: "the max-imal concentration to which workers can be exposedfor a period up to 15 minutes continuously withoutsuffering from 1) irritation, 2) chronic or irreversibletissue change, or 3) narcosis of sufficient degree toincrease accident proneness, impair self-rescue, ormaterially reduce work efficiency . . ." (p. 2).

The number and variety of volatile agents ableto exert potent central nervous system and behavioraleffects is staggering. Most dissolve easily in fat, aproperty that enhances their penetration of the blood-brain barrier. These agents are used in extractionprocesses, degreasing formulations, refrigerants, paintand lacquer thinners, glues, printing, electrical in-sulators, fumigants and pesticides, synthetic fiberproduction, and other industrial applications. Manyappear in consumer products. Synthetic fuel tech-nologies are certain to multiply both applications andexposures. Yet, even with their venerable history andbroad industrial penetration, the exposure standardsfor these salient neurobehavioral poisons springmainly from clinical observations and inchoate epi-demiology. A few examples illustrate the breadth ofpsychological questions and issues that they haveprompted.

Carbon Disulfide

During the cold curing of rubber, especially usefulin the manufacture of surgical appliances, thin stripsof rubber were dipped into a special solution con-taining the solvent carbon disulfide (Hunter, 1969).Prevalent in France in the middle of the 19th centuryas a cottage industry, this process subjected thousandsof workers to consequences as diverse as mania, head-ache, irritability, and polyneuritis. Delpech's precise

depiction in 1856 of carbon disulfide poisoning as atoxic neuropathy was challenged in 1889 by Charcot,one of Freud's most influential mentors, who ascribedmost of these signs and symptoms to his specialty,hysteria. Toward the end of the century, carbon di-sulfide assumed an even more important industrialrole with the introduction of the viscose process formanufacturing rayon, which liberates carbon disulfidevapor into the workroom atmosphere. About 350million kilograms of carbon disulfide were producedin the United States in 1974, but its role in commerceis not reflected by the volume of laboratory researchdevoted to it (Levine, 1976; Weiss, Wood, & Macys,1979; Wood, 1981).

Severe neurological impairment, however, is nolonger an issue because regulations in the UnitedStates and other nations limit exposure. Questionsabout hazards now center on the potential for subtlepsychological and neurological impairment. Even theissue of elevated suicide rates in viscose workers hasbeen raised (Mancuso & Locke, 1972). One of thepioneering applications of psychological testing toquestions stemming from industrial exposure wasundertaken in Finnish viscose workers by Hanninen(1971). She appraised three groups of workers, 150in total. One third had manifested overt features ofcarbon disulfide toxicity, one third had been exposedwithout clinically detectable toxicity, and one thirdhad been exposed occasionally or not at all. Hanninensubjected each worker to a psychological test batterycomprising the Wechsler Adult Intelligence Scale,several psychomotor tests, and even the Rorschach.To evaluate the pattern of differences, she performeda multivariate analysis that helped define three clus-ters. Adding indexes of disturbed ocular microcir-culation and coronary heart disease to the neuropsy-chological findings further enhanced the separationof exposed and control workers (Raitta & Tolonen,1980). Workers with clinical deficits were clearly dif-ferent from the others, but even the workers withoutclinical manifestations showed some evidence of im-pairment and could be distinguished from the unex-posed workers. Research groups in the United States,Italy, Scandinavia, and elsewhere have since adoptedsimilar approaches to assessing the long-term con-sequences of occupational exposure to solvents.Scandinavian investigators, in fact, now accept thevalidity of an "organic solvent syndrome" that em-bodies features such as depression, retardation ofmovement, and electrophysiological abnormalities.The issues involved here are not just current standardsof exposure, but, for example, the validity of a claimthat 20 years of employment in a certain industryhas led a worker to exhibit destructive personalitychanges. Such claims are now being presented to thecourts where, I am certain, clinical psychologists willbe called as expert witnesses.

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Toluene Solvents and Axonopathies

Toluene (methyl benzene) also is produced by themillions of kilograms, finding its way into manyproducts and processes. Unlike some other solventsclosely related to it chemically, it seems not to presentmajor threats to any organ system (such as the liver)or to be linked to cancer. Like other volatile solvents,however, its CNS properties can be abused. It is themain solvent in the model glues inhaled by U.S. teen-agers for their intoxicating properties, and upon whicheven very young children in some countries have be-come dependent (Sharp & Carroll, 1978). Glue-sniff-ing is not exclusively a teenage practice, however. Italso has exacted victims in the workplace. Vinyl chlo-ride is a major industrial chemical, serving as anintermediate in the production of the ubiquitouspolyvinyl chloride. It had been assumed to be rela-tively safe until incriminated in a series of workerdeaths from a rare fatal liver tumor and then, later,in other forms of cancer (Selikoff & Hammond, 1975).Since occupational epidemiology proceeds by tryingto quantify exposure, investigators requested estimatesof exposure from industrial hygiene and safety per-sonnel in 33 plants, grading the exposures as low,medium, or high. Adding to the intrinsic variabilityof such estimates were a few unique practices, how-ever, as described in a pioneering source of phar-macologic information:

Inevitably, some of the guys came to enjoy getting high onvinyl chloride. They would lean over into the vats andbreathe deeply . . . and then do it again. "Some wouldbecome like alcoholics," says one longtime Goodrich worker."They would breathe it again and again until they passedout." (Klein, 1976, p. 44)

Substance abuse, particularly of drugs, has en-listed the efforts of many psychologists, especiallythose specializing in behavioral pharmacology. Theirresearch has demonstrated that drugs of abuse areself-administered for their reinforcing properties, notsimply, say, to attenuate aversive withdrawal symp-toms. These demonstrations have been so cogent, infact, that self-administration data are required byregulatory agencies such as the Food and Drug Ad-ministration for evaluations of new drugs, such asanalgesics, that pose the threat of abuse liability. Thewidespread availability of intoxicating solvents is acogent reason for investigating their abuse potentialas well, and for taking measures, equivalent to de-naturing alcohol, to reduce this potential. Since pri-mates self-administer inhalants such as nitrous oxide("laughing gas"; Wood, Grubman, & Weiss, 1977)and toluene (Wood, 1979), we have available a modelsystem, based on a behavioral assay, for testing bothabuse liability and possible countermeasures. Bio-chemical assays cannot answer such a question.

The ultimate dangers of solvent abuse were highlightedby chronic solvent sniffers in Europe and Japan whodeveloped severe neuropathies from their habit. Mostof their problems arose from the solvent n-hexane,found in glues and petroleum ether. It is not an ex-tremely toxic material, but the high concentrationsto which the sniffers repeatedly exposed themselvesexacted a price. These events triggered investigationsinto the underlying mechanisms, and the discoverythat the neurotoxicity of n-hexane is actually a prop-erty of a metabolite, 2,5-hexanedione.

U.S. interest in this property quickened after anepisode in Columbus, Ohio (Allen, Mendell, Billmaier,Fontaine, & O'Neill, 1975). In June 1973, a 43-year-old man was admitted to the neurosurgery service ofOhio State University Hospital. He worked in theprinting department of a coated fabrics plant. Aboutfour months after becoming a printer operator hebegan to suffer symptoms such as weakness, stiffness,and difficulty in walking. On examination, he wasthought to have either a motor neuropathy or motorneuron disease. Two months later, during a secondvisit, he produced a list of five fellow workers withsimilar complaints. Suspecting a toxic etiology, thealert physician contacted the Ohio Department ofHealth, which confirmed the five additional cases.All six patients worked in the same plant and in thesame area. The plant manufactured vinyl-coated fab-rics and vinyl sheets used for wall coverings or au-tomobile interiors. Men in the print department wereexposed to inks and solvents containing methyl ethylketone (MEK) and methyl n-butyl ketone (MBK).Not only did they breathe the fumes evaporating fromthe printed fabrics and from the machines, but washedtheir hands or shoes in the solvents, and even ate inthe work area,

As intoxication progressed, both sensory andmotor deficits appeared. The sensory symptoms typ-ically began with paresthesias in the hands and feet.Motor deficits usually began later, and were markedby weakness of the intrinsic muscles of the hands andfeet. With some skillful chemical analyses, sensitiveepidemiology, and luck, MBK was incriminated asthe source of the outbreak and 2,5-hexanedione iso-lated as one of its metabolites. At the time, the thresh-old limit value for MBK was 100 parts per million(ppm). It is now 25 ppm. The National Institute forOccupational Safety and Health has recommendeda reduction of the 10-hour, time-weighted concen-tration to 1.0 ppm.

This history is not meant as a discourse on ep-idemiology. I recited it because it is a cogent exampleof the way in which early toxic manifestations tendnot to arouse suspicions because of their subtle andnonspecific nature. Psychology, however, has tools that

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could enable it to specify the nonspecific (Weiss,1983). MBK, n-hexane, and many other agents displaya commonality of effects on peripheral nerves oftenlabeled as a "dying-back" neuropathy or as a central-peripheral distal axonopathy (Schaumburg & Spencer,1979), because CNS tissue also is damaged. Retro-grade axonal degeneration, beginning at the distalend of the nerve, gradually advances centrally, withthe longer, larger, myelinated fibers degenerating be-fore the shorter, smaller diameter fibers. The exper-imental data have been accumulated mainly to verifythe neuropathologic mechanisms, and few behavioraldata have been published that could yield clues aboutthe correspondence between the early sensory changesand their neuropathologic and histochemical accom-paniments. Moreover, the sites of central damage,including the hypothalamus, suggest that even moresubtle, psychophysiological aspects of toxicity wouldemerge with appropriate experiments (Schaumburg& Spencer, 1978).

One reason that specific functional deficits mayremain undetected is the typical neurological or med-ical examination, which is directed not toward thedetection of subtle impairments but toward the di-agnosis of frank disease. An example of how easilyincipient sensory impairment could escape clinicalscrutiny comes from an experiment on acrylamide,a chemical adopted for applications ranging fromgrouting in mine and tunnel construction to strength-ening cardboard to helping to separate solids fromaqueous solutions. Because it creates distal axono-pathies and is easily administered in food or drinkingwater, it often serves as a prototypical neurotoxicant(Tilson, 1981). Maurissen and Weiss (1982) trainedmonkeys to discriminate vibratory stimuli applied toa finger. The monkeys, seated in a special Plexiglasenclosure during testing, released a lever when theydetected vibration applied to a finger by an electro-magnetically driven rod. The sense of touch is sosensitive that the amplitude of vibration had to becontrolled to tenths of a micron. Chronic acrylamidetreatment gradually raised the threshold for vibrationfor both low- and high-frequency stimuli, a shift thatdid not dissipate for many months after treatmentended. Consider how a neurological examinationmight assess decreased somatosensory sensitivity. Thepatient would be asked to report a pin or cotton wicklightly contacting the skin, or a tuning fork pressedagainst it. Even with a tuning fork, the most quan-titative of the methods, only one frequency would beexplored and its amplitude would be controlled onlyin the grossest sense. A recent publication (Merigan,Barkdoll, & Maurissen, 1982) suggests another easilyignored effect of acrylamide. These experimenterstrained monkeys to discriminate gratings on the faceof an oscilloscope to assess the intactness of spatialfrequency mechanisms. Such fundamental mecha-

nisms are believed by many visual scientists to un-derlie the discrimination of complex visual stimuli.Averaged visual-evoked potentials, generated by sim-ilar stimuli, also were examined. The monkeys re-ceived acrylamide until they began to show clear signsof toxicity. Once dosing ceased, the animals recoveredin all functions but one—visual acuity. Their abilityto resolve high-frequency gratings (narrow, closelyspaced bars) remained impaired, probably becauseof irreversible damage in the optic tract. This is justthe kind of effect that a worker would not notice andthat a clinician would be unlikely to detect, Animalpsychophysics has now alerted us to this possibility.These two examples indicate to me that psycho-physical methods, reflecting the elegance and precisiondeveloped by several generations of psychologists,should be the ultimate arbiters of incipient sensorysystem toxicity, especially if toxicity, should it occur,is to be arrested during its early, reversible phases.Some industrial organizations agree and are adoptingvibration sensitivity as a guide to excessive acrylamideexposure. But two studies hardly comprise a literature.

PesticidesAlmost every major pesticide acts by inducing neu-rotoxicity. It is not surprising, then, that pesticidesoffer similar hazards to humans. The literature ac-cumulated around this problem embraces nearly ev-ery technique found in psychology. As with many ofthe substances already discussed, the core argumentis not about hazard, but about the extent of risk. Itis a debate about dose—about how much exposureis a threat to health. It is a debate locked into am-biguity, as with lead, because the end points are sointangible. Consider how difficult it is to gauge whetherfarm workers exposed to low levels of pesticides sufferfrom subtle behavioral or neurological deficits. It isnot just defining what constitutes a deficit or applyingappropriate methods that present the challenge, butalso detecting a progression so subtle and vague thatit is ignored.

An instructive episode occurred in the 1970s.The pesticide and pesticide precursor Kepone (chlor-decone) had been manufactured until 1973 by AlliedChemical Corporation. Production was then trans-ferred, at the same site, to a newly established firmlargely operated by former Allied employees. In 1975,an alert internist in Hopewell, Virginia, the site ofthe plant, examined a patient with severe tremors.He requested that the Center for Disease Control, thefederal government's main agency for epidemiology,analyze a serum sample for Kepone. It proved to bemarkedly elevated (Cannon, Veazey, Jackson, Burse,Hayes, Straub, Landrigan, & Liddle, 1978), a resultthat stimulated investigations by both state and federalagencies. Inspectors found massive contamination at

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the site and indications of widespread toxicity. Themajor expressions consisted of nervousness, tremor,incoordination, weight loss, skin rash, sterility, ab-normal liver function parameters, ocular flutter, andjoint and pleuritic pain. Personality changes also oc-curred, marked by irritability, problems with recentmemory, and depression, but not every worker showedthe same collection of signs and symptoms. TheHopewell situation is uncommon because the ex-posure was so severe. Until the internist forwardedthe blood sample for analysis, however, neither man-agement nor the workers raised the issue of toxicityin public/There was convincing evidence, too, thatexposure to lower levels of Kepone could induce toxicresponses. Two wives of workers reported histories oftremor, presumably arising from dust carried homeon their husbands' clothing. The neurotoxic mani-festations of Kepone stimulated a literature on themechanisms of toxicity that is still expanding vig-orously (Tilson & Mactutus, 1982).

Other pesticide classes (Kepone is an organo-chlorine and a distant relative of DDT) present dif-ferent profiles of toxicity. The organophosphate in-secticides, chemically related to the most potent wargases, act by inhibiting the enzyme acetylcholines-terase, which inactivates the neurotransmitter ace-tylcholine after its release into synapses. Nervous tis-sue levels of acetylcholinesterase are so redundantthat, in many circumstances, they can be reduced bytwo thirds without notably impairing function. Also,tolerance quickly develops in rats to the acute be-havioral effects of organophosphates (Bignami, Rosic,Michalek, Milosevic, & Gatti, 1975). But is this trueof the skills required by crop-duster pilots whose bloodlevels of cholinesterase may have been reduced to onefourth of normal? Duffy and Burchfiel (1980) reportedenduring EEG abnormalities in workers exposed dur-ing manufacture to the organophosphate war gas sarin.Some organophosphates also induce structural dam-age, a.property responsible for several tragic outbreaksof neurotoxic poisoning (Morgan, 1982).

The organophosphate pesticide leptophos (Phos-vel) was implicated in a revealing outbreak. Exposedworkers in a Texas manufacturing plant (Xintaras &Burg, 1980), experiencing toxic reactions, consultedprivate physicians, who were puzzled by the peculiarconstellation of signs and symptoms. These includedanxiety, hallucinations, impaired memory, disori-entation, drowsiness, headache, tremulousness, diz-ziness, .paresthesias, diminished muscle tone, andataxia. Although organophosphate intoxicationseemed a possible cause, cholinesterase activity in theblood remained within normal bounds, leading theneurologists to suspect encephalitis or a demyelinatingdisease such as multiple sclerosis. This is a good il-lustration of how total reliance on an indirect chemicalor biological measure can lead an inquiry astray. Only

after they had weighed the delayed neurotoxicitycharacteristic of some organophosphates did the cor-rect diagnosis emerge. In reviewing this episode, Xin-taras and Burg (1980) note that, "The onset of someeffects, in fact probably most of the effects, is so in-sidious that the worker may not realize that anychange is taking place. The insidious nature of theeffects makes base-line data, taken at the beginningof employment and/or exposure to a suspected neu-rotoxic chemical, imperative to assess exposure ef-fects" (p. 673). Given the leptophos and Kepone ex-periences, should not a large component of these databe psychological? Of course, but how many of ourpersonality inventories, say, are suitable for the re-peated screening of large populations? How often, infact, do we ask such longitudinal questions, and whatmight we learn about the stability of psychologicalassessments over long time periods were we to do so?Such questions offer opportunities for advances inpsychology independent of a contribution to toxi-cology.

Air PollutantsThe Clean Air Act evolved from public resentmentof the esthetic unpleasantness and obvious healthmenace of polluted air. Some of the health impli-cations are not so obvious, however, and constitutequestions for behavioral toxicology. An agent neednot act directly on the CNS to evoke behavioral effects.It could act as a distracting irritant, for example, orproduce a nonspecific depression of function reflectedin a diminished capacity to perform certain tasks.

Some examples of what could be such indirecteffects can be drawn from claims in the Soviet lit-erature. In studies performed by Bustueva and herco-workers (National Air Pollution Control Admin-istration, 1970), humans exposed to sulfur dioxide,sulfuric acid mist, and other atmospheric pollutantswere alleged to show altered sensitivity to light. Forexample, during the course of dark adaptation, ele-vated sensitivity (lowered threshold) was claimed tofollow exposure to low concentrations of sulfur diox-ide, sulfuric acid mist, and combinations of the two.More recent work by Bokina, Eksler, Semenenko,and Merkur' yeva (1976) claims alterations in theEEG and visual evoked potentials from exposure tominimal concentrations of ozone. Like other Sovietclaims, these are not accompanied by convincingtechnical details.

Carbon monoxide is one of the agents singledout for control by the Clean Air Act. It exerts itstoxicity through its affinity for hemoglobin, whichtransports oxygen in the blood. Carbon monoxidedisplaces oxygen, combining with hemoglobin to formcarboxyhemoglobin and to deprive tissues of oxygen.The blood of heavy smokers may contain carboxy-

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hemoglobin levels of 5% to 7% or greater. A detailedreview of the carbon monoxide literature by Latiesand Merigan (1979) concluded that this level is closeto the threshold for observing impaired vigilance per-formance. Areas of dense automobile traffic can pro-duce high enough concentrations of carbon monoxideso that prolonged exposure (rush hour on the SanDiego freeway, say) might push some drivers into thatrange. Many questions remain, however, about theadequacy of the data. Their resolution embodies de-cisions with considerable economic significance.

A neglected aspect of the response to air pol-lutants is what might be called subjective state, whichis measured by psychologists to assess everything fromthe impact of psychotherapy to the effectiveness ofadvertising. Data from Great Britain, gathered beforethe radical cleansing of London air, indicated thatchronic bronchitis patients experienced a heightenedresponse to heavy smog. The response was reflectednot so much by measures of pulmonary function asby subjective indexes of discomfort. Direct sensoryirritation is yet another property of air pollutantsmostly unexplored by precise behavioral measures,especially in the laboratory. Eye irritation, for ex-ample, may be the earliest sign of excessive concen-trations of organic pollutants in smog. Alarie (1981)noted that 30% to 40% of all Threshold Limit Valuesand Federal Ambient Air Quality Standards are basedon subjective reports of irritation. Regulatory deci-sions may be based on such data because complaintscan serve as warnings of impending damage.

Behavioral measures assess a different facet ofthe adverse effects of airborne irritants than measuresof lung function. Ozone is an intensely irritating gasand the principal oxidant in photochemical smog. Athigh concentrations, it severely damages lung tissue.At moderate levels, it may produce biochemicalchanges and reversible pathology in the lung. At lowerlevels, it may elicit complaints of discomfort rangingfrom chest pains to lethargy to confusion, as reportedby air crews and passengers subjected to raised ozoneconcentrations during high-altitude jet flight. Sincesuch subjective reactions may herald impendingdamage and are undesirable in themselves, we un-dertook to more carefully define the behavioral con-sequences of ozone exposure.

After first examining lever-pressing (relativelysedentary) performance in rats during ozone exposure(Weiss, Ferin, Merigan, Stern, & Cox, 1981), weturned to a venerable psychological tool, the runningwheel (Tepper, Weiss, & Cox, 1982), because exerciseenhances the toxicity of ozone. Rats were adapted toliving in small enclosures attached to running wheels.For 12 hours every night, we recorded activity byattaching switches to the wheels and transmittingswitch closures to an online computer. The rats wereexposed to ozone during the middle six hours of this

period. We confirmed the contribution of exercise toozone toxicity. The rats reduced their activity sig-nificantly at concentrations of 0.12 parts per million,the EPA upper limit for human exposure, which isregularly exceeded in Los Angeles and elsewhere. Theydid so mostly by extending the pauses between suc-cessive bouts of running. In further experiments atthis concentration, they reduced lever-pressing re-sponses that released a brake from the wheel andfixed-interval-schedule running for food delivery(Tepper, Weiss, & Wood, 1983). We believe that thesereductions reflect the aversive consequences of exerciseduring ozone exposure, not physiological impair-ment—in other words, avoidance behavior. Wayne,Wehrle, and Carroll (1967) posited a similar inter-pretation in a study of high school cross-country run-ners. They found high inverse concentrations betweenperformance and oxidant concentration measured onehour before meets, and attributed their findings towhat might be called diminished motivation ratherthan to diminished physiological capacity. Other in-halation toxicologists and respiratory physiologistshave offered similar explanations for correspondingexperimental data in humans (e.g., Folinsbee, Sil-verman, & Shephard, 1977). There are no human"motivational" data as we understand them, however,only the results of symptom questionnaires accom-panied by measures by pulmonary function. In con-trast, consider the volume of psychological researchdevoted to questions that logically are congruent withthis one.

Direct sensory irritation can also be measuredby behavioral methods, which provide different in-formation than that provided, say, by reflex responsesof the respiratory system. Regulatory actions dependon many sources of information about adverse effects.In its recommendations for future research, a reporton air pollution states: "Photochemical reactions ofvapor-phase organic pollutants produce irritating ef-fects, but indices of such effects have received littleattention. Experimental tests in animals and system-atic studies of human reactions in normal and oc-cupationally polluted atmospheres should be carriedout" (National Research Council, 1976, p. 282). Psy-chologists are accustomed to measuring aversiveness.Wood (1979) adopted the tactic of training mice toterminate the flow of ammonia into a chamber byinserting their snouts into a metal cone equippedwith photocells. Latency to respond was inversely re-lated to concentration. The power of such techniqueshas led us to question the meaning of more traditionaldefinitions of irritation based solely on pulmonarymeasures such as disruption of respiratory pattern.Humans will not tolerate such concentrations, andno review board would allow tests in humans of anewly synthesized agent anyway. Humans avoid orescape noxious airborne substances, and animal test-

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ing should acknowledge that these responses are be-haviors.

Food AdditivesFood additives may not superficially seem to havemuch in common with air pollutants and organicsolvents, but they too have been alleged to elicit manypsychological and neurological complaints. People donot complain, after all, of enzyme inhibition or re-ceptor blockade; they complain of headaches, lack ofenergy, depression, and other symptoms with psy-chological content.

The possibility that food additives might promptbehavioral complaints and disturbances achieved al-most no recognition in the biomedical communityuntil Ben F. Feingold (1975) proposed that some ofthe children diagnosed as hyperactive or hyperkineticactually suffered from idiosyncratic responses to suchingredients. Although the validity of Feingold's claimsis disputed, he introduced an issue whose connota-tions transcend the limited question of the etiologyof hyperactivity (Weiss, 1982). Food additives areprobably the most ubiquitous products of modernchemistry. Since 1958, they have had to undergo tox-icity testing before market introduction. The test pro-tocols emphasize pathology, especially cancer. Theydo not include testing for behavioral toxicity. A dis-tinguished panel of toxicologists, reviewing currentprotocols for food additive toxicity testing, recom-mended, however, that "psychotoxicity" be consideredfor inclusion in such protocols (FASEB, 1977). Thisrecommendation gains even more cogency from someof the findings that emerged from trials of the Feingoldhypothesis and from experiments with animals dem-onstrating that young rats given food colors at levelsprevailing in the human diet (see Table 1) displaybehavioral abnormalities (Goldenring, Wool, Shay-witz, Batter, Cohen, Young, & Teicher, 1980; Shaywitz,Goldenring, & Wool, 1979). The Food and Drug Ad-ministration, however, still does not require behavioraltesting, in contrast with its reaction to the Canadianexperiments suggesting that saccharin, at levelshundreds of times greater than those consumed byhumans, may pose an increased risk of bladder cancer.

Some possible consequences of ignoring behav-ioral toxicity in food additive safety assessment areshown in Table 1. It compares the quantities of ar-tificial colors calculated as the mean daily intake ofCalifornia children between one and six years old(Weiss et al., 1980) with the Allowable Daily Intake(ADI). The latter is calculated from animal toxicitydata. The dose just short of toxic manifestations ina chronic feeding study (the no-effect level) is dividedby 100 to estimate the intake that should pose norisk for humans. The ADI for colors, based on tra-ditional toxicity testing, is over 50 times the dosereported to evoke behavioral toxicity in some children

Table 1Comparison of the Dose Used by Weisset al. (1980) and the Allowable Daily Intake (ADI)Calculated by the Food and Drug Administration onthe Basis of Two-Year Animal Feeding Studies

Color mg/Day ADI

Yellow 5Yellow 6Red 40Red 3Blue 1Blue 2Green 3

9.0710.7013.800.570.800.150.11

300300420150300

37.3150

(Weiss, 1982) and in young rats. The continuing ex-clusion of behavior from food additive testing pro-tocols is a puzzling breach of regulatory protection,although one of the reasons for its exclusion is a lackof confidence in currently proposed behavioral tests.I think that we behavioral toxicologists have been tootimid and unimaginative in exploiting psychology'svast legacy.

Psychology's Role in the EnvironmentalHealth SciencesBehavioral toxicology is now a recognized discipline,although behavior still is resisted in some quarters asa legitimate criterion of adverse effects. Too manypublic anxieties embrace psychological questions,however, for them to be dismissed by special interests.A proposed rise in the allowable lead content of gaso-line was stemmed by objections from scientists andphysicians concerned about the behavioral conse-quences for children. Acid precipitation enhances theuptake of methylmercury by fish, posing the questionof whether pregnant women should consume fish fromAdirondack lakes. More and more data are now con-firming the suspicion that even low levels of PCBsand other chemicals of that general class can producesubtle behavioral deficits, especially in the developingorganism, and that breast milk, because of the lipidsolubility of such substances, is the primary vehiclefor neonatal exposure (Barlow & Sullivan, 1982).Government agencies have to detemine how to quan-tify such issues, how to predict hazard to humansfrom animal testing, how to calculate risk on the basisof functional measures. Almost the total range ofpsychological techniques, specialties, and skills bearson these efforts.

Psychology is positioned to deal with many ofthe most troubling issues of environmental toxicology.Note the statements from a recent unpublished gov-

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ernment report on the potential health effects of toxicchemical dumps:

We do not have tests to recognize effects on the nervoussystem,

Another issue of concern in conducting epidemiologicalstudies is to design survey instruments (questionnaires)which are resistant to the emotional issues involved.

There are virtually no useful tests for preclinical stages. . .and diseases of specific organ systems such as the centralnervous system.

A few years ago at a regional meeting of psy-chologists, I delivered an address titled, "Help Wanted:25,000 Behavioral lexicologists." The title was notsupposed to be wholly serious, but perhaps it was notsuch a gross exaggeration after all.

REFERENCE NOTES

1. Needleman, H. L. Personal communication, 1981.2. Winneke, G. Personal communication, 1983.

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