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

1174 November 1983 • American Psychologist Copyright 1983 by the American Psychological Association, Inc. Behavior's global nature also may allow compensatory quantifying nonspecific neuropsychological features mechanisms to thwart the early detection of an ir- of toxicity, especially early in the course of poisoning reversible pathological process. Behavioral assays are when many of them are likely to be subjective. They expensive, especially when compared, for example, also demonstrate how psychological approaches such to in vitro tests of mutagenesis. Behavioral methods as psychophysics could help detect and trace subtle also offer a bewildering spectrum of choice, which is sensory impairment. A discussion of pesticides shows an advantage in pursuing a science of behavior, but how monitoring adverse effects by psychological mea- an aggravating source of indecision for a chemical sures may yield more information than monitoring manufacturer or regulatory agency forced to define them by blood chemistry. Air pollutants are used to hazard. Perhaps most troublesome of all, how are exemplify a class of contaminants whose effects may functional measures to be evaluated? What actions not lie directly within the nervous system; in some are implied by a finding that the current workplace instances, these effects are best revealed by behavioral exposure standard for a volatile organic solvent methods. Finally, in a discussion of food additives," I lengthens reaction time by 10%? Or by a report that try to show how the neglect of behavior in safety prenatal treatment with high doses of a common pes- testing has provided misleading estimates of safety ticide elevates locomotor activity in two-month-old margins. rats? These are not idle questions or academic ex- ercises; standards and regulations may be built on Metals them. The Toxic Substances Control Act (TSCA) of Metals are so ubiquitous that many of them came to 1976 specifies behavior as one of the criteria for judg- play essential roles in the evolution of living systems ing the safety of new chemicals. Unease about the (Weiss, 1978a). Other metals, perhaps because of their impairment of psychological development by lead geological distribution, remained outside the orbit of helped to diminish its role as a fuel additive. The living processes. But all metals, even the essential carbon monoxide standard prescribed by the Envi- ones, can be toxic, and the margin between essential ronmental Protection Agency (EPA) is based partly and hazardous levels may be surprisingly narrow. on behavioral data. These issues and questions become Manganese and vanadium are both essential elements, clearer in the context of specific substances. I've cho- yet they have been implicated in syndromes ranging sen, from many possibilities, a set of agents meant from movement disorders resembling parkinsonism to illustrate the diversity of settings, issues, and con- to manic-depressive psychosis. Excessive exposure to taminants that entail psychological questions. metals can damage many different organ systems and I will begin by discussing metals, because they biological processes and has been implicated in a re- are the most ancient pollutants released by human markable range of adverse signs and symptoms in- activities. Metallic mercury demonstrates the im- volving the central nervous system (CNS) and be- portance of quantitative measures of motor function havior (Figure 1). in assessing subclinical impairment, as well as the lack of sound psychophysiological data about the total Mercury syndrome of mercury poisoning. Methylmercury, a Among the best documented entries in Figure 1 are highly toxic organic compound of mercury, illustrates those associated with mercury. This slippery, silvery the discipline and problems of behavioral teratology, metal, liquid at room temperature, is one of the metals that is, the consequences of prenatal toxic exposures. exploited by humans since antiquity. Its toxicity has Another metal, lead, shows how difficult it still is, been recognized almost as long (Maurissen, 1981). even after an immense outpouring of research, to The cardinal sign of mercury-vapor poisoning is disentangle toxic behavioral consequences from other tremor, which begins to develop around the eyelids environmental variables and to relate them to ap- and eventually invades the limbs, especially the hands. propriate biological measures of exposure. Organic Inorganic mercury compounds at one time were used solvents illustrate even more graphically the issue of to prepare animal hairs for felt hats. These processes released mercury vapor into the factory atmosphere, Parts of this article are based on invited addresses presented during exposing workers to concentrations above the safety the past 10 years to the American, Eastern, and Midwestern Psy- limits prevailing at the time. Since Danbury, Con- chological Associations. Its preparation was supported in part by Grants ES-26676, ES-01247, and ES-01248 from NIEHS; MH- necticut, was the center of the industry, the mercury- 11752 from NIMH; and in part by Contract No. DE-ACO2- induced tremors came to be known as "hatter's 76EVO3490 with the U.S. Department of Energy at the University shakes" or "Danbury shakes." of Rochester Department of Radiation Biology and Biophysics, Mercury has many other applications: as elec- which has been assigned Report No. UR-3490-2218. trodes in the chlor-alkali process for producing chlo- Requests for reprints should be sent to Bernard Weiss, Division of Toxicology and Environmental Health Sciences Center, De- rine and caustic soda from brine, in electrical equip- partment of Radiation Biology and Biophysics, University of Roch- ment, in dental amalgams, in chemistry laboratories. ester School of Medicine and Dentistry, Rochester, New York 14642. In 1970, we encountered an instance of mercury poi-

November 1983 • American Psychologist 1175 lower bounds (10 and 40 grams) designated by lights Figure 1 on a signal box (Wood, Weiss, & Weiss, 1973). At Neurological and Psychological Signs and first, tremor amplitude was remarkably high. The Symptoms, Collected From Clinical and output of the gauge was amplified, traced on a poly- Experimental Sources, Attributed to Metal Toxicity graph, and transmitted to the analog-to-digital con- verter of a computer for quantitative processing. After UJ nine months without further exposure, both the mer-

2 cury levels in her blood and the tremor fell to normal O Q levels. There was a marked change in other charac- § S 2 TELLURIUM Si -J THALLIUM VANADIUM

ANOSMIA , a spectrum of tremor frequencies showed multiple APPETITE LOSS a a a a 6 modes. Nine months later, it was marked by a single CONVULSIONS a 9 dominant frequency. DEPRESSION DISORIENTATION s I , , * Psychologists would hardly find it surprising that a DIZZINESS • a a a we felt it necessary to record, quantify, and analyze DYSARTHRIA • • the extent of this motor deficit. Psychologists have FATIGUE, LETHARGY a * a • • • e a a • a a quantified motor function in contexts ranging from HEADACHE • a INCOORDINATION, ATAXIA • • • e • infant development to human engineering to the ef- INSOMNIA fects of brain lesions in monkeys. Clinical medicine, JITTERINESS, IRRITABILITY e « e • • MENTAL RETARDATION , a in contrast, typically evaluates tremor by visual in- PARALYSIS a spection and interprets it according to the physician's PARESTHESIAS- . e e PERIPHERAL NEUROPATHY e a • a a experience. The unsuitability of clinical criteria led POLYNEURITIS. a Langolf, Chaffin, Henderson, and Whittle (1978) to * * PSYCHIATRIC SIGNS m .,* . , adapt our technique for monitoring chlor-alkali SOMNOLENCE e * TREMOR e , .. a workers exposed to mercury. Now that exposures in VISUAL DISTURBANCES • a • • • e a dental offices and laboratories are coming under in- WEAKNESS creased scrutiny, psychologists might be asked what other measures of psychophysiological function might SYMPTOMS ASCRIBED TO METAL TOXICITY help detect subclinical toxicity. This is an important Note. Based on Weiss, 1983. question not only in itself, but because such measures could help to identify some sources of the psychological complaints accompanying mercury intoxi- soning in upstate New York. A woman employed by cation. These complaints are an intriguing feature of a large glassware manufacturer appeared at the Uni- mercury poisoning and form a distinct enough cluster versity of Rochester Medical Center with the suspicion to have been given a label, erethism, a word from a that she was suffering from mercury poisoning. Greek root meaning "to irritate." The characteristic Chemical analyses of her blood confirmed her sus- features of erethism resemble what psychiatrists used picion. She was one of several women who had the to call neurasthenia. Hatter's shakes were typically job of calibrating glass pipettes. During one segment accompanied by erethism. Wright's (1922) survey of of the calibration process, elemental mercury was 108 hatters turned up 53 with symptoms such as poured into the pipettes. Some of the mercury was irritability, timidity, apprehension, restlessness, va- dispersed into the workroom atmosphere. It found somotor disturbances, easy blushing, exaggerated re- its way into hair, eyeglass frames, clothing seams. flexes, and slight speech abnormalities. Improvisa- Since elemental mercury is quite volatile, the women tional questionnaires and clinical medical surveys inhaled it. Elemental mercury enters the brain much cannot substitute for careful psychometric and psy- more easily than its ionized form (Rothstein & Hayes, chophysiological measures of symptoms, but current 1964). workplace standards are based on the former kinds One of the women, who had worked at the job of clinical data. for 15 years, was almost disabled by the severity of Another aspect of mercury poisoning provokes her tremor, and could hardly hold a glass of water even more serious questions. Methylmercury, an or- without spilling. Because we already had embarked ganic compound of mercury, was first synthesized on a study of mercury-induced tremor in monkeys, during the 19th century. It proved to be a potent and had a method available for measuring it, we were nervous system poison but also an extraordinarily asked to help quantify the tremor to better monitor effective fungicide, especially in protecting seed grains, the course of treatment and recovery. The patient and it dissipates into the soil once the seeds are placed her finger in a lucite trough attached to a strain planted. Great Britain encouraged its use during gauge and tried to apply a force between upper and World War II to ensure abundant grain crops. No

1176 November 1983 • American Psychologist one conceived of it as an ecological hazard until the tremities and around the mouth seem to be the earliest 1950s. symptoms of intoxication in adults. They are difficult Minamata is a small fishing village on Kyushu, to quantify, however, and their baseline prevalence the southernmost of the major islands of the Japanese varies markedly among populations. Visual deficits chain. Beginning about 1953, inhabitants of the area also are early features of intoxication, and they arise were attacked by a central nervous system affliction from cell death in the occipital cortex. Victims ex- that came to be known as "Minamata disease." The perience constriction of the visual field (tunnel vision) villagers called it Kibyo, or mystery illness, because and allied deficits such as loss of night vision. Such no etiologic agent could be found. They did discover, deficits have been reproduced in monkeys trained on however, that neurological abnormalities were induced various visual discrimination tasks (Berlin, Grant, in cats fed fish and shellfish from Minamata Bay. Heilberg, Hellstrom, & Schultz, 1975; Evans, Laties, Minamata disease finally was traced to methylmer- & Weiss, 1975;Merigan, 1980; Rice & Gilbert, 1982). cury contamination of seafood from the bay (Tsubaki Psychophysical experiments with primate species were & Irukayama, 1977). A search for the source of the adopted as a strategy for correlating exposure vari- organic mercury led Japanese scientists to a factory ables, brain damage, and performance because the that used inorganic mercury as a catalyst. The factory literature of neuropsychology provided a firm guide dumped its effluent into the bay, but only after ad- for asking such questions. It told us what visual dys- ventitiously converting the mercury into the potent functions arose from occipital lesions and convinced organic form, which then was incorporated into the us that only primates could provide adequate animal food chain and finally consumed by humans (Smith models to the symptoms that arise in humans. & Smith, 1975). A decade after Minamata, a similar Minamata also suggested that methylmercury epidemic erupted in the city of Niigata. damaged the fetus far more severely than the adult, Until 1970, North America perceived such ep- a suggestion consistent with other findings about the isodes as remote aberrations. Then a graduate student enhanced susceptibility of the developing brain to at the University of Western Ontario discovered that toxic challenges such as alcohol. Teratology is the fish in the Great Lakes bore unexpectedly high levels discipline that studies what in lay terms are called of methylmercury. His disclosure instigated a survey birth defects. Like toxicology, it had emphasized of contamination in the United States, which found morphology. With the realization that postnatal con- that fish and wildlife in half the states carried excessive sequences might be expressed as functional rather levels of methylmercury. Even oceanic fish like tuna than structural aberrations, a new discipline began and swordfish, once thought to be free of contami- to emerge: behavioral teratology. Its role is exemplified nation, revealed puzzlingly high concentrations of by a question once put by David P. Rail, director of methylmercury, and swordfish were barred from in- the National Institute of Environmental Health Sci- terstate commerce. As governmental agencies sought ences and of the National Toxicology Program. Sup- to assess the extent of hazard, we became aware of pose, he asked, that the drug thalidomide, instead of how little was known about this substance. Our in- inducing missing limbs and other deformities, had formation came from a handful of rather crude lab- simply lowered intellectual potential by the equivalent oratory animal studies, a few industrial accidents, of 10 IQ points. Would we ever have become aware and scattered disasters like Minamata. It was not a of any adverse consequences? Given the difficulty of satisfactory basis for erecting safety standards. connecting even gross morphological consequences When exposure standards are proposed for en- with thalidomide, the answer is disquieting enough vironmental toxicants, they incorporate a safety mar- to have provoked several countries into requiring begin broad enough to reduce the community's risk to havioral teratology data for new drugs. acceptable levels. Methylmercury cannot simply be A later methylmercury episode provided the banned; the methylmercury in fish, particularly ma- most cogent confirmation of what had been suggested rine species, is partly the contribution of geologic by Minamata. In the winter of 1971-1972, the gov- sources. Some of the methylmercury in freshwater ernment of Iraq ordered 80,000 tons of seed grain species may be the contribution of acid rain, which (wheat, barley, and rye) from Mexico and the United promotes the uptake of the poison by lowering the States, specifying that it be treated with a methyl- pH of the aquatic environment. Calculations of safety mercury fungicide. Much of the grain was distributed margins determine which species from which areas to Iraqi peasants after the planting season, however. can be marketed. But safety margins set on the basis Although the farmers were told that the grain had of function are difficult to calculate, and the chief been treated with a poison, many were skeptical of expressions of methylmercury poisoning arise because the government's warnings. The bags were marked it destroys brain tissue, leading to sensory, motor, and as poisonous, but in Spanish and English. Some of nonspecific functional deficits, the farmers washed off the pink dye that identified Paresthesias (numbness and tingling) in the ex- the treated grain, a maneuver that did not remove

November 1983 • American Psychologist 1177 the fungicide. Other farmers conducted some prim- in the young organism. Moreover, if Minamata and itive toxicology, feeding the grain to farm animals, several laboratory animal studies (e.g., Bornhausen, or in one case, to the farmer's mother-in-law, without Musch, & Greim, 1980; Eccles & Annau, 1982; observing toxic signs. They were misled by the latency Spyker, 1975) are reliable guides to the future, the of several weeks before overt signs of poisoning would disabilities may become even more pronounced as manifest. The aftermath was a probable loss of about the children age. Now that these Iraqi children are 5,000 lives, with perhaps 10 times that many persons being increasingly challenged in school, it is more seriously poisoned. critical that they be evaluated by the best contem- Thomas W. Clarkson, a widely recognized expert porary techniques because there are many areas of on mercury toxicology, and other members of the the world whose inhabitants consume large quantities University of Rochester faculty were called on to assess offish containing substantial concentrations of meth- the episode in collaboration with Iraqi physicians. ylmercury. To set standards requires us to determine The scope of the poisoning permitted them for the exposures producing subtle, not overt, impairment. first time to construct dose-response functions based What techniques might be suitable for assessing rural on population samples of reasonable size (Clarkson children in an Arab country or in comparable non- & Marsh, 1976). These largely confirmed the profile Western settings? The ingenuity of current develop- of adult disabilities traced at Minimata and Niigata. mental psychology is sorely needed for these impor- Their assessments of fetal exposure, however, greatly tant issues—issues about safety margins that continue magnified the concerns engendered by Minamata. to arouse concern by the U.S. Food and Drug Ad- Minamata mothers who had experienced only ministration, the World Health Organization, and minimal symptoms, such as paresthesia, delivered many governments. This concern stretches across al- infants who later exhibited appreciable developmental most the entire spectrum of environmental contam- retardation. There, however, the number was so small inants, including the polychlorinated biphenyls that a definitive assessment was impossible. Iraq pro- (PCBs) and the currently notorious dioxin (2,3,7,8- vided more compelling evidence. A sensitive analytical tetrachlorodibenzo-p-dioxin, or TCDD). method for measuring organic mercury in tissue permitted the Rochester scientists to trace the course of Lead exposure in pregnant and nursing women. Hair grows Mercury may be the most dramatic neurotoxic heavy at a rather constant rate, about one centimeter per metal, but lead is just as ancient, equally subtle, and month. Hair also serves as one of the elimination more dispersed in the environment. Its reproductive pathways of methylmercury, maintaining a fairly sta- toxicity has been held responsible for the decline of ble ratio of about 250:1 (hainblood). By chopping Roman hegemony, since the Roman nobility stored the hair into centimeter sections, it was possible to wine and preserves in leaden casks and even added determine when the mother began eating the tainted lead compounds as sweetening agents (Gilfillan, 1965). bread, when she reached her peak body burden, when Lead was first exploited so long ago that occasional ingestion stopped, and the subsequent decline of body skeletons from the oldest civilizations may reveal signs burden. Since maternal milk also contained meth- of excessive concentrations of lead. It is now distrib- ylmercury (in a concentration about 3% of the blood uted so pervasively through the environment (and level) infants could consume considerable quantities. living tissue) that we can only guess at what the early And in the Iraqi countryside, children are often fed evolutionary load might have been. at the breast until two years of age. Overt lead toxicity in adults takes a multifaceted Once appropriate mother-infant pairs were form. Stomatitis and colic are prominent in acute or identified and documented, Rochester and Iraqi ob- subchronic poisoning. Neurological and psychological servers began periodic visits to the countryside to features prevail in low-level, chronic intoxication. record the development of the children. Although the Wrist-drop and foot-drop, once frequent among kind of rigorous evaluation that might be performed painters and other exposed workers, now are rare in the United States was not feasible, the 93 children because of improved industrial practices and in- under surveillance already have answered the most creased alertness to toxicity. But more subtle indexes pressing question. Even at relatively modest maternal of impairment are still detectable with precise psy- blood levels, the offspring may be significantly re- chological and neurological testing, even in workers tarded, showing delays in speech, motor function, displaying no clinical dysfunction and carrying body and other indexes of development (Clarkson, Cox, burdens well below the values previously associated Marsh, Myers, Al-Tikriti, Amin-Zaki, & Dabbagh, with toxicity (Hanninen, Mantere, Hernberg, Sep- 1981). Whether because of special vulnerabilities in- palainen, & Kock, 1979; Valciukas, Lilis, Eisinger, trinsic to the developing brain or the metabolic de- Blumberg, Fischbein, & Selikoff, 1978). fenselessness, so to speak, of the fetus and neonate, Our concerns about lead, however, stem mainly the ecological hazard of methylmercury is amplified from the amplified connection between exposure and

1178 November 1983 • American Psychologist consequence in the developing human. Even in the serve as lead repositories because dentine incorporates superficially clean setting of the suburbs, children ex- lead as it grows. An analysis of baby teeth, then, hibit body burdens of lead many times higher than provides an integrated index of exposure during the those revealed by human skeletons in eras before the early years. Needleman and his group collected teeth development of mining and smelting. Public health from over 3,000 children in the Boston area. They concerns are aroused even more in the aging cores then selected children from the lowest and highest of central cities, where the interiors of many buildings deciles and subjected them to a broad psychological were once covered with lead-based paints, where street evaluation. The high-lead children had lower scores dust contains the combustion products of leaded gas- on many dimensions: intelligence test scales, psycho- oline, and where many children manifest lead body motor performance, and conduct. All of the children burdens uncomfortably close to overtly toxic levels. who contributed teeth also were rated by their teachers Most communities and their health agencies are now according to a standard inventory. Perhaps the most alert to the hazard of lead poisoning. Peeling, flaking intriguing section of the entire study is the striking surfaces are repainted, blood lead determinations are relationship between scores on individual inventory routine, and pediatricians are more prone to intervene items and tooth lead concentrations, Systematic ob- with drugs that accelerate lead excretion. But the servation in the classroom, using the techniques de- dispute about what constitutes a hazardous body bur- veloped by applied behavior analysis, is also a fruitful den has only become more intense because the focal approach (Needleman, Note 1), yielding even more question is now more subtle: Do asymptomatic but convincing relationships. Even so, some observers are elevated body burdens of lead express themselves as unhappy about the possible influence of family social psychological or behavioral impairment? Is there a and economic status and parental intelligence on the threshold for toxic effects? The economic implications observed differences, contending that treating these of what is defined as a "safe" level impinge not only as covariates and compensating for them statistically on gasoline refiners, owners of urban real estate, and is not sufficient. For example, although Winneke et lead battery manufacturers, but on public agencies, al. (1983) essentially verified Needleman et al., they because too high a level and its psychological after- found that social class played a statistically significant math also is costly to society (Provenzano, 1980). role in performance differences. Winneke (Note 2) Despite a plethora of studies dating from the also has found, however, that lower social class en- provocative paper of Byers and Lord (1943), who hanced the risk of adverse effects from lead exposure, reported persisting behavioral deficits after recovery a finding parallel to those from the malnutrition lit- from lead poisoning, the issue has been drifting toward erature. Such interactions are a crucial argument for resolution with frustrating slowness (Bornschein, behavioral assessments. Recent advances in psycho- Pearson, & Reiter, 1980a). Many studies have been metric techniques, such as structural equation meth- flawed by inadequate control groups, by inappropriate odology, have not been enlisted in pursuing these tests, by mistaken assumptions in their statistical questions. Since both causes and consequences are analyses. Many also were hampered by two funda- surely multivariate in character, such techniques could mental biological problems. One is the lability of give a unique perspective on the issue. blood lead concentration, which reflects only recent The difficulties posed by studies of human pop- exposure but which typically has served as the bio- ulations make well-designed animal experiments that logical index of lead exposure. If peak intake occurs much more crucial. Although many earlier animal between the ages of 12 and 36 months, when children experiments suffered from major problems such as explore the world with their mouths and their nervous reduced food intake in exposed animals, most current systems are still immature, how useful is it to correlate researchers now carefully limit lead intake so as to test performance with blood lead at age six or older? eliminate undernutrition and, incidentally, to produce The second problem arises from the distribution of more realistic body burdens of lead. Even with these susceptibility. Especially when the questions center precautions, it is clear that a legacy of elevated lead on threshold, is it not reasonable to expect only a during development portends significant behavioral modest proportion of children to demonstrate adverse disruption. Rice, Gilbert, and Willes (1979) detected effects? several subtle signs of deviant performance in rhesus Yet, despite these obstacles, objections, and flaws, monkeys treated from birth to achieve blood levels a consensus is developing that current lead exposure within the range of values displayed by a significant indicators disclose a problem at even relatively modest proportion of urban children. For example, perfor- values. One recent contribution was particularly pro- mance on fixed-interval schedules of reinforcement vocative. Needleman, Gunnoe, Leviton, Reed, Per- was marked by high rates of responding, interrupted esie, Maker, and Barrett (1979), recognizing the in- by long pauses, in the treated monkeys. Cory-Slechta herent defects of many earlier studies, turned to teeth and Thompson (1979) reported that low concentra- as a biological indicator. Deciduous teeth, like bone, tions of lead in drinking water consumed by young,

November 1983 • American Psychologist 1179 weanling rats produced aberrant fixed-interval per- depiction in 1856 of carbon disulfide poisoning as a formance. Serial measures of blood lead, in a sys- toxic neuropathy was challenged in 1889 by Charcot, tematic replication of this study (Cory-Slechta & one of Freud's most influential mentors, who ascribed Weiss, 1982), indicate that such aberrant performance most of these signs and symptoms to his specialty, occurs at concentrations approaching those of even hysteria. Toward the end of the century, carbon di- many suburban children. Only a handful of properly sulfide assumed an even more important industrial conducted studies now exist in the published literature role with the introduction of the viscose process for (Bornschein, Pearson, & Reiter, 1980b), representing manufacturing rayon, which liberates carbon disulfide a tiny fragment of behavioral techniques with obvious vapor into the workroom atmosphere. About 350 potential in this research. Schedule-controlled per- million kilograms of carbon disulfide were produced formance, for example, has been exploited only min- in the United States in 1974, but its role in commerce imally (Bornschein, Pearson, & Reiter, 1980b). is not reflected by the volume of laboratory research devoted to it (Levine, 1976; Weiss, Wood, & Macys, 1979; Wood, 1981). Solvents and Fuels Severe neurological impairment, however, is no Volatile organic solvents and fuels are traditional oc- longer an issue because regulations in the United cupational hazards because exposure mostly occurs States and other nations limit exposure. Questions through inhalation, an exposure medium difficult to about hazards now center on the potential for subtle control. The American Conference of Governmental psychological and neurological impairment. Even the Industrial Hygienists (ACGIH, 1978), which publishes issue of elevated suicide rates in viscose workers has assessments of and recommendations for exposure been raised (Mancuso & Locke, 1972). One of the standards in the workplace (threshold limit values), pioneering applications of psychological testing to defines the "short-term exposure limit" as: "the max- questions stemming from industrial exposure was imal concentration to which workers can be exposed undertaken in Finnish viscose workers by Hanninen for a period up to 15 minutes continuously without (1971). She appraised three groups of workers, 150 suffering from 1) irritation, 2) chronic or irreversible in total. One third had manifested overt features of tissue change, or 3) narcosis of sufficient degree to carbon disulfide toxicity, one third had been exposed increase accident proneness, impair self-rescue, or without clinically detectable toxicity, and one third materially reduce work efficiency . . ." (p. 2). had been exposed occasionally or not at all. Hanninen The number and variety of volatile agents able subjected each worker to a psychological test battery to exert potent central nervous system and behavioral comprising the Wechsler Adult Intelligence Scale, effects is staggering. Most dissolve easily in fat, a several psychomotor tests, and even the Rorschach. property that enhances their penetration of the blood- To evaluate the pattern of differences, she performed brain barrier. These agents are used in extraction a multivariate analysis that helped define three clus- processes, degreasing formulations, refrigerants, paint ters. Adding indexes of disturbed ocular microcir- and lacquer thinners, glues, printing, electrical in- culation and coronary heart disease to the neuropsy- sulators, fumigants and pesticides, synthetic fiber chological findings further enhanced the separation production, and other industrial applications. Many of exposed and control workers (Raitta & Tolonen, appear in consumer products. Synthetic fuel tech- 1980). Workers with clinical deficits were clearly dif- nologies are certain to multiply both applications and ferent from the others, but even the workers without exposures. Yet, even with their venerable history and clinical manifestations showed some evidence of im- broad industrial penetration, the exposure standards pairment and could be distinguished from the unex- for these salient neurobehavioral poisons spring posed workers. Research groups in the United States, mainly from clinical observations and inchoate epi- Italy, Scandinavia, and elsewhere have since adopted demiology. A few examples illustrate the breadth of similar approaches to assessing the long-term con- psychological questions and issues that they have sequences of occupational exposure to solvents. prompted. Scandinavian investigators, in fact, now accept the validity of an "organic solvent syndrome" that em- Carbon Disulfide bodies features such as depression, retardation of During the cold curing of rubber, especially useful movement, and electrophysiological abnormalities. in the manufacture of surgical appliances, thin strips The issues involved here are not just current standards of rubber were dipped into a special solution con- of exposure, but, for example, the validity of a claim taining the solvent carbon disulfide (Hunter, 1969). that 20 years of employment in a certain industry Prevalent in France in the middle of the 19th century has led a worker to exhibit destructive personality as a cottage industry, this process subjected thousands changes. Such claims are now being presented to the of workers to consequences as diverse as mania, head- courts where, I am certain, clinical psychologists will ache, irritability, and polyneuritis. Delpech's precise be called as expert witnesses.

1180 November 1983 • American Psychologist Toluene Solvents and Axonopathies

Toluene (methyl benzene) also is produced by the The ultimate dangers of solvent abuse were highlighted millions of kilograms, finding its way into many by chronic solvent sniffers in Europe and Japan who products and processes. Unlike some other solvents developed severe neuropathies from their habit. Most closely related to it chemically, it seems not to present of their problems arose from the solvent n-hexane, major threats to any organ system (such as the liver) found in glues and petroleum ether. It is not an ex- or to be linked to cancer. Like other volatile solvents, tremely toxic material, but the high concentrations however, its CNS properties can be abused. It is the to which the sniffers repeatedly exposed themselves main solvent in the model glues inhaled by U.S. teen- exacted a price. These events triggered investigations agers for their intoxicating properties, and upon which into the underlying mechanisms, and the discovery even very young children in some countries have be- that the neurotoxicity of n-hexane is actually a prop- come dependent (Sharp & Carroll, 1978). Glue-sniff- erty of a metabolite, 2,5-hexanedione. ing is not exclusively a teenage practice, however. It U.S. interest in this property quickened after an also has exacted victims in the workplace. Vinyl chlo- episode in Columbus, Ohio (Allen, Mendell, Billmaier, ride is a major industrial chemical, serving as an Fontaine, & O'Neill, 1975). In June 1973, a 43-year- intermediate in the production of the ubiquitous old man was admitted to the neurosurgery service of polyvinyl chloride. It had been assumed to be rela- Ohio State University Hospital. He worked in the tively safe until incriminated in a series of worker printing department of a coated fabrics plant. About deaths from a rare fatal liver tumor and then, later, four months after becoming a printer operator he in other forms of cancer (Selikoff & Hammond, 1975). began to suffer symptoms such as weakness, stiffness, Since occupational epidemiology proceeds by trying and difficulty in walking. On examination, he was to quantify exposure, investigators requested estimates thought to have either a motor neuropathy or motor of exposure from industrial hygiene and safety per- neuron disease. Two months later, during a second sonnel in 33 plants, grading the exposures as low, visit, he produced a list of five fellow workers with medium, or high. Adding to the intrinsic variability similar complaints. Suspecting a toxic etiology, the of such estimates were a few unique practices, how- alert physician contacted the Ohio Department of ever, as described in a pioneering source of phar- Health, which confirmed the five additional cases. macologic information: All six patients worked in the same plant and in the same area. The plant manufactured vinyl-coated fab- Inevitably, some of the guys came to enjoy getting high on rics and vinyl sheets used for wall coverings or au- vinyl chloride. They would lean over into the vats and tomobile interiors. Men in the print department were breathe deeply . . . and then do it again. "Some would become like alcoholics," says one longtime Goodrich worker. exposed to inks and solvents containing methyl ethyl "They would breathe it again and again until they passed ketone (MEK) and methyl n-butyl ketone (MBK). out." (Klein, 1976, p. 44) Not only did they breathe the fumes evaporating from the printed fabrics and from the machines, but washed Substance abuse, particularly of drugs, has en- their hands or shoes in the solvents, and even ate in listed the efforts of many psychologists, especially the work area, those specializing in behavioral pharmacology. Their As intoxication progressed, both sensory and research has demonstrated that drugs of abuse are motor deficits appeared. The sensory symptoms typ- self-administered for their reinforcing properties, not ically began with paresthesias in the hands and feet. simply, say, to attenuate aversive withdrawal symp- Motor deficits usually began later, and were marked toms. These demonstrations have been so cogent, in by weakness of the intrinsic muscles of the hands and fact, that self-administration data are required by feet. With some skillful chemical analyses, sensitive regulatory agencies such as the Food and Drug Ad- epidemiology, and luck, MBK was incriminated as ministration for evaluations of new drugs, such as the source of the outbreak and 2,5-hexanedione iso- analgesics, that pose the threat of abuse liability. The lated as one of its metabolites. At the time, the thresh- widespread availability of intoxicating solvents is a old limit value for MBK was 100 parts per million cogent reason for investigating their abuse potential (ppm). It is now 25 ppm. The National Institute for as well, and for taking measures, equivalent to de- Occupational Safety and Health has recommended naturing alcohol, to reduce this potential. Since pri- a reduction of the 10-hour, time-weighted concen- mates self-administer inhalants such as nitrous oxide tration to 1.0 ppm. ("laughing gas"; Wood, Grubman, & Weiss, 1977) This history is not meant as a discourse on ep- and toluene (Wood, 1979), we have available a model idemiology. I recited it because it is a cogent example system, based on a behavioral assay, for testing both of the way in which early toxic manifestations tend abuse liability and possible countermeasures. Bio- not to arouse suspicions because of their subtle and chemical assays cannot answer such a question. nonspecific nature. Psychology, however, has tools that

November 1983 • American Psychologist 1181 could enable it to specify the nonspecific (Weiss, nisms are believed by many visual scientists to un- 1983). MBK, n-hexane, and many other agents display derlie the discrimination of complex visual stimuli. a commonality of effects on peripheral nerves often Averaged visual-evoked potentials, generated by sim- labeled as a "dying-back" neuropathy or as a central- ilar stimuli, also were examined. The monkeys re- peripheral distal axonopathy (Schaumburg & Spencer, ceived acrylamide until they began to show clear signs 1979), because CNS tissue also is damaged. Retro- of toxicity. Once dosing ceased, the animals recovered grade axonal degeneration, beginning at the distal in all functions but one—visual acuity. Their ability end of the nerve, gradually advances centrally, with to resolve high-frequency gratings (narrow, closely the longer, larger, myelinated fibers degenerating be- spaced bars) remained impaired, probably because fore the shorter, smaller diameter fibers. The exper- of irreversible damage in the optic tract. This is just imental data have been accumulated mainly to verify the kind of effect that a worker would not notice and the neuropathologic mechanisms, and few behavioral that a clinician would be unlikely to detect, Animal data have been published that could yield clues about psychophysics has now alerted us to this possibility. the correspondence between the early sensory changes These two examples indicate to me that psycho- and their neuropathologic and histochemical accom- physical methods, reflecting the elegance and precision paniments. Moreover, the sites of central damage, developed by several generations of psychologists, including the hypothalamus, suggest that even more should be the ultimate arbiters of incipient sensory subtle, psychophysiological aspects of toxicity would system toxicity, especially if toxicity, should it occur, emerge with appropriate experiments (Schaumburg is to be arrested during its early, reversible phases. & Spencer, 1978). Some industrial organizations agree and are adopting One reason that specific functional deficits may vibration sensitivity as a guide to excessive acrylamide remain undetected is the typical neurological or med- exposure. But two studies hardly comprise a literature. ical examination, which is directed not toward the detection of subtle impairments but toward the diagnosis of frank disease. An example of how easily Pesticides incipient sensory impairment could escape clinical Almost every major pesticide acts by inducing neu- scrutiny comes from an experiment on acrylamide, rotoxicity. It is not surprising, then, that pesticides a chemical adopted for applications ranging from offer similar hazards to humans. The literature ac- grouting in mine and tunnel construction to strength- cumulated around this problem embraces nearly ev- ening cardboard to helping to separate solids from ery technique found in psychology. As with many of aqueous solutions. Because it creates distal axono- the substances already discussed, the core argument pathies and is easily administered in food or drinking is not about hazard, but about the extent of risk. It water, it often serves as a prototypical neurotoxicant is a debate about dose—about how much exposure (Tilson, 1981). Maurissen and Weiss (1982) trained is a threat to health. It is a debate locked into am- monkeys to discriminate vibratory stimuli applied to biguity, as with lead, because the end points are so a finger. The monkeys, seated in a special Plexiglas intangible. Consider how difficult it is to gauge whether enclosure during testing, released a lever when they farm workers exposed to low levels of pesticides suffer detected vibration applied to a finger by an electro- from subtle behavioral or neurological deficits. It is magnetically driven rod. The sense of touch is so not just defining what constitutes a deficit or applying sensitive that the amplitude of vibration had to be appropriate methods that present the challenge, but controlled to tenths of a micron. Chronic acrylamide also detecting a progression so subtle and vague that treatment gradually raised the threshold for vibration it is ignored. for both low- and high-frequency stimuli, a shift that An instructive episode occurred in the 1970s. did not dissipate for many months after treatment The pesticide and pesticide precursor Kepone (chlor- ended. Consider how a neurological examination decone) had been manufactured until 1973 by Allied might assess decreased somatosensory sensitivity. The Chemical Corporation. Production was then trans- patient would be asked to report a pin or cotton wick ferred, at the same site, to a newly established firm lightly contacting the skin, or a tuning fork pressed largely operated by former Allied employees. In 1975, against it. Even with a tuning fork, the most quan- an alert internist in Hopewell, Virginia, the site of titative of the methods, only one frequency would be the plant, examined a patient with severe tremors. explored and its amplitude would be controlled only He requested that the Center for Disease Control, the in the grossest sense. A recent publication (Merigan, federal government's main agency for epidemiology, Barkdoll, & Maurissen, 1982) suggests another easily analyze a serum sample for Kepone. It proved to be ignored effect of acrylamide. These experimenters markedly elevated (Cannon, Veazey, Jackson, Burse, trained monkeys to discriminate gratings on the face Hayes, Straub, Landrigan, & Liddle, 1978), a result of an oscilloscope to assess the intactness of spatial that stimulated investigations by both state and federal frequency mechanisms. Such fundamental mecha- agencies. Inspectors found massive contamination at

1182 November 1983 • American Psychologist the site and indications of widespread toxicity. The after they had weighed the delayed neurotoxicity major expressions consisted of nervousness, tremor, characteristic of some organophosphates did the cor- incoordination, weight loss, skin rash, sterility, ab- rect diagnosis emerge. In reviewing this episode, Xin- normal liver function parameters, ocular flutter, and taras and Burg (1980) note that, "The onset of some joint and pleuritic pain. Personality changes also oc- effects, in fact probably most of the effects, is so in- curred, marked by irritability, problems with recent sidious that the worker may not realize that any memory, and depression, but not every worker showed change is taking place. The insidious nature of the the same collection of signs and symptoms. The effects makes base-line data, taken at the beginning Hopewell situation is uncommon because the ex- of employment and/or exposure to a suspected neu- posure was so severe. Until the internist forwarded rotoxic chemical, imperative to assess exposure ef- the blood sample for analysis, however, neither man- fects" (p. 673). Given the leptophos and Kepone ex- agement nor the workers raised the issue of toxicity periences, should not a large component of these data in public/There was convincing evidence, too, that be psychological? Of course, but how many of our exposure to lower levels of Kepone could induce toxic personality inventories, say, are suitable for the re- responses. Two wives of workers reported histories of peated screening of large populations? How often, in tremor, presumably arising from dust carried home fact, do we ask such longitudinal questions, and what on their husbands' clothing. The neurotoxic mani- might we learn about the stability of psychological festations of Kepone stimulated a literature on the assessments over long time periods were we to do so? mechanisms of toxicity that is still expanding vig- Such questions offer opportunities for advances in orously (Tilson & Mactutus, 1982). psychology independent of a contribution to toxi- Other pesticide classes (Kepone is an organo- cology. chlorine and a distant relative of DDT) present different profiles of toxicity. The organophosphate in- secticides, chemically related to the most potent war Air Pollutants gases, act by inhibiting the enzyme acetylcholines- The Clean Air Act evolved from public resentment terase, which inactivates the neurotransmitter ace- of the esthetic unpleasantness and obvious health tylcholine after its release into synapses. Nervous tis- menace of polluted air. Some of the health impli- sue levels of acetylcholinesterase are so redundant cations are not so obvious, however, and constitute that, in many circumstances, they can be reduced by questions for behavioral toxicology. An agent need two thirds without notably impairing function. Also, not act directly on the CNS to evoke behavioral effects. tolerance quickly develops in rats to the acute be- It could act as a distracting irritant, for example, or havioral effects of organophosphates (Bignami, Rosic, produce a nonspecific depression of function reflected Michalek, Milosevic, & Gatti, 1975). But is this true in a diminished capacity to perform certain tasks. of the skills required by crop-duster pilots whose blood Some examples of what could be such indirect levels of cholinesterase may have been reduced to one effects can be drawn from claims in the Soviet lit- fourth of normal? Duffy and Burchfiel (1980) reported erature. In studies performed by Bustueva and her enduring EEG abnormalities in workers exposed dur- co-workers (National Air Pollution Control Admin- ing manufacture to the organophosphate war gas sarin. istration, 1970), humans exposed to sulfur dioxide, Some organophosphates also induce structural dam- sulfuric acid mist, and other atmospheric pollutants age, a.property responsible for several tragic outbreaks were alleged to show altered sensitivity to light. For of neurotoxic poisoning (Morgan, 1982). example, during the course of dark adaptation, ele- The organophosphate pesticide leptophos (Phos- vated sensitivity (lowered threshold) was claimed to vel) was implicated in a revealing outbreak. Exposed follow exposure to low concentrations of sulfur diox- workers in a Texas manufacturing plant (Xintaras & ide, sulfuric acid mist, and combinations of the two. Burg, 1980), experiencing toxic reactions, consulted More recent work by Bokina, Eksler, Semenenko, private physicians, who were puzzled by the peculiar and Merkur' yeva (1976) claims alterations in the constellation of signs and symptoms. These included EEG and visual evoked potentials from exposure to anxiety, hallucinations, impaired memory, disori- minimal concentrations of ozone. Like other Soviet entation, drowsiness, headache, tremulousness, diz- claims, these are not accompanied by convincing ziness, .paresthesias, diminished muscle tone, and technical details. ataxia. Although organophosphate intoxication Carbon monoxide is one of the agents singled seemed a possible cause, cholinesterase activity in the out for control by the Clean Air Act. It exerts its blood remained within normal bounds, leading the toxicity through its affinity for hemoglobin, which neurologists to suspect encephalitis or a demyelinating transports oxygen in the blood. Carbon monoxide disease such as multiple sclerosis. This is a good il- displaces oxygen, combining with hemoglobin to form lustration of how total reliance on an indirect chemical carboxyhemoglobin and to deprive tissues of oxygen. or biological measure can lead an inquiry astray. Only The blood of heavy smokers may contain carboxy-

November 1983 • American Psychologist 1183 hemoglobin levels of 5% to 7% or greater. A detailed period. We confirmed the contribution of exercise to review of the carbon monoxide literature by Laties ozone toxicity. The rats reduced their activity sig- and Merigan (1979) concluded that this level is close nificantly at concentrations of 0.12 parts per million, to the threshold for observing impaired vigilance per- the EPA upper limit for human exposure, which is formance. Areas of dense automobile traffic can pro- regularly exceeded in Los Angeles and elsewhere. They duce high enough concentrations of carbon monoxide did so mostly by extending the pauses between suc- so that prolonged exposure (rush hour on the San cessive bouts of running. In further experiments at Diego freeway, say) might push some drivers into that this concentration, they reduced lever-pressing re- range. Many questions remain, however, about the sponses that released a brake from the wheel and adequacy of the data. Their resolution embodies de- fixed-interval-schedule running for food delivery cisions with considerable economic significance. (Tepper, Weiss, & Wood, 1983). We believe that these A neglected aspect of the response to air pol- reductions reflect the aversive consequences of exercise lutants is what might be called subjective state, which during ozone exposure, not physiological impair- is measured by psychologists to assess everything from ment—in other words, avoidance behavior. Wayne, the impact of psychotherapy to the effectiveness of Wehrle, and Carroll (1967) posited a similar inter- advertising. Data from Great Britain, gathered before pretation in a study of high school cross-country run- the radical cleansing of London air, indicated that ners. They found high inverse concentrations between chronic bronchitis patients experienced a heightened performance and oxidant concentration measured one response to heavy smog. The response was reflected hour before meets, and attributed their findings to not so much by measures of pulmonary function as what might be called diminished motivation rather by subjective indexes of discomfort. Direct sensory than to diminished physiological capacity. Other in- irritation is yet another property of air pollutants halation toxicologists and respiratory physiologists mostly unexplored by precise behavioral measures, have offered similar explanations for corresponding especially in the laboratory. Eye irritation, for ex- experimental data in humans (e.g., Folinsbee, Sil- ample, may be the earliest sign of excessive concen- verman, & Shephard, 1977). There are no human trations of organic pollutants in smog. Alarie (1981) "motivational" data as we understand them, however, noted that 30% to 40% of all Threshold Limit Values only the results of symptom questionnaires accom- and Federal Ambient Air Quality Standards are based panied by measures by pulmonary function. In con- on subjective reports of irritation. Regulatory deci- trast, consider the volume of psychological research sions may be based on such data because complaints devoted to questions that logically are congruent with can serve as warnings of impending damage. this one. Behavioral measures assess a different facet of Direct sensory irritation can also be measured the adverse effects of airborne irritants than measures by behavioral methods, which provide different in- of lung function. Ozone is an intensely irritating gas formation than that provided, say, by reflex responses and the principal oxidant in photochemical smog. At of the respiratory system. Regulatory actions depend high concentrations, it severely damages lung tissue. on many sources of information about adverse effects. At moderate levels, it may produce biochemical In its recommendations for future research, a report changes and reversible pathology in the lung. At lower on air pollution states: "Photochemical reactions of levels, it may elicit complaints of discomfort ranging vapor-phase organic pollutants produce irritating ef- from chest pains to lethargy to confusion, as reported fects, but indices of such effects have received little by air crews and passengers subjected to raised ozone attention. Experimental tests in animals and system- concentrations during high-altitude jet flight. Since atic studies of human reactions in normal and oc- such subjective reactions may herald impending cupationally polluted atmospheres should be carried damage and are undesirable in themselves, we un- out" (National Research Council, 1976, p. 282). Psy- dertook to more carefully define the behavioral con- chologists are accustomed to measuring aversiveness. sequences of ozone exposure. Wood (1979) adopted the tactic of training mice to After first examining lever-pressing (relatively terminate the flow of ammonia into a chamber by sedentary) performance in rats during ozone exposure inserting their snouts into a metal cone equipped (Weiss, Ferin, Merigan, Stern, & Cox, 1981), we with photocells. Latency to respond was inversely re- turned to a venerable psychological tool, the running lated to concentration. The power of such techniques wheel (Tepper, Weiss, & Cox, 1982), because exercise has led us to question the meaning of more traditional enhances the toxicity of ozone. Rats were adapted to definitions of irritation based solely on pulmonary living in small enclosures attached to running wheels. measures such as disruption of respiratory pattern. For 12 hours every night, we recorded activity by Humans will not tolerate such concentrations, and attaching switches to the wheels and transmitting no review board would allow tests in humans of a switch closures to an online computer. The rats were newly synthesized agent anyway. Humans avoid or exposed to ozone during the middle six hours of this escape noxious airborne substances, and animal test-

1184 November 1983 • American Psychologist ing should acknowledge that these responses are be- haviors. Table 1 Comparison of the Dose Used by Weiss Food Additives et al. (1980) and the Allowable Daily Intake (ADI) Food additives may not superficially seem to have Calculated by the Food and Drug Administration on much in common with air pollutants and organic the Basis of Two-Year Animal Feeding Studies solvents, but they too have been alleged to elicit many Color mg/Day ADI psychological and neurological complaints. People do not complain, after all, of enzyme inhibition or re- Yellow 5 9.07 300 ceptor blockade; they complain of headaches, lack of Yellow 6 10.70 300 energy, depression, and other symptoms with psy- Red 40 13.80 420 chological content. Red 3 0.57 150 The possibility that food additives might prompt Blue 1 0.80 300 behavioral complaints and disturbances achieved al- Blue 2 0.15 37.3 Green 3 0.11 150 most no recognition in the biomedical community until Ben F. Feingold (1975) proposed that some of the children diagnosed as hyperactive or hyperkinetic actually suffered from idiosyncratic responses to such ingredients. Although the validity of Feingold's claims is disputed, he introduced an issue whose connota- (Weiss, 1982) and in young rats. The continuing ex- tions transcend the limited question of the etiology clusion of behavior from food additive testing pro- of hyperactivity (Weiss, 1982). Food additives are tocols is a puzzling breach of regulatory protection, probably the most ubiquitous products of modern although one of the reasons for its exclusion is a lack chemistry. Since 1958, they have had to undergo tox- of confidence in currently proposed behavioral tests. icity testing before market introduction. The test pro- I think that we behavioral toxicologists have been too tocols emphasize pathology, especially cancer. They timid and unimaginative in exploiting psychology's do not include testing for behavioral toxicity. A dis- vast legacy. tinguished panel of toxicologists, reviewing current Psychology's Role in the Environmental protocols for food additive toxicity testing, recommended, however, that "psychotoxicity" be considered Health Sciences for inclusion in such protocols (FASEB, 1977). This Behavioral toxicology is now a recognized discipline, recommendation gains even more cogency from some although behavior still is resisted in some quarters as of the findings that emerged from trials of the Feingold a legitimate criterion of adverse effects. Too many hypothesis and from experiments with animals dem- public anxieties embrace psychological questions, onstrating that young rats given food colors at levels however, for them to be dismissed by special interests. prevailing in the human diet (see Table 1) display A proposed rise in the allowable lead content of gaso- behavioral abnormalities (Goldenring, Wool, Shay- line was stemmed by objections from scientists and witz, Batter, Cohen, Young, & Teicher, 1980; Shaywitz, physicians concerned about the behavioral conse- Goldenring, & Wool, 1979). The Food and Drug Ad- quences for children. Acid precipitation enhances the ministration, however, still does not require behavioral uptake of methylmercury by fish, posing the question testing, in contrast with its reaction to the Canadian of whether pregnant women should consume fish from experiments suggesting that saccharin, at levels Adirondack lakes. More and more data are now con- hundreds of times greater than those consumed by firming the suspicion that even low levels of PCBs humans, may pose an increased risk of bladder cancer. and other chemicals of that general class can produce Some possible consequences of ignoring behav- subtle behavioral deficits, especially in the developing ioral toxicity in food additive safety assessment are organism, and that breast milk, because of the lipid shown in Table 1. It compares the quantities of ar- solubility of such substances, is the primary vehicle tificial colors calculated as the mean daily intake of for neonatal exposure (Barlow & Sullivan, 1982). California children between one and six years old Government agencies have to detemine how to quan- (Weiss et al., 1980) with the Allowable Daily Intake tify such issues, how to predict hazard to humans (ADI). The latter is calculated from animal toxicity from animal testing, how to calculate risk on the basis data. The dose just short of toxic manifestations in of functional measures. Almost the total range of a chronic feeding study (the no-effect level) is divided psychological techniques, specialties, and skills bears by 100 to estimate the intake that should pose no on these efforts. risk for humans. The ADI for colors, based on tra- Psychology is positioned to deal with many of ditional toxicity testing, is over 50 times the dose the most troubling issues of environmental toxicology. reported to evoke behavioral toxicity in some children Note the statements from a recent unpublished gov-

November 1983 • American Psychologist 1185 ernment report on the potential health effects of toxic Cannon, S. B., Veazey, J. M., Jackson, R. S., Burse, V. W., Hayes, chemical dumps: C., Straub, W. E., Landrigan, P. J., & Liddle, J. A. Epidemic Kepone poisoning in chemical workers. American Journal of We do not have tests to recognize effects on the nervous Epidemiology, 1978, 707, 529-537. system, Clarkson, T. W., Cox, C, Marsh, D. O., Myers, G. J., Al-Tikriti, S. K., Amin-Zaki, L., & Dabbagh, A. R. Dose-response rela- Another issue of concern in conducting epidemiological tionships for adult and prenatal exposures to methylmercury. In studies is to design survey instruments (questionnaires) G. G. Berg & H. D. Maillie (Eds.), Measurement of risks. New which are resistant to the emotional issues involved. York: Plenum, 1981. Clarkson, T. W., & Marsh, D. O. 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