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Identifying Neurobehavioral Effects of Automotive Emissions and Fuel Components RONALD W. WOOD New York University Medical Center Neurobehavioral Effects and Mechanisms of Toxicity / 632 Identifying Acute Hazards / 633 Toxicity in Repeated or Continuous Exposures / 634 Identifying Subtle Effects / 634 Pursuing the Mechanisms of Toxicity / 636 Evaluating Whole Emissions, Fuels, and Their Components / 638 Whole Emissions and Their Photochemical By-products / 638 Carbon Monoxide / 644 Petroleum Hydrocarbons / 646 Methanol / 647 Metals and Inorganic Compounds / 648 Conclusions / 649 Summary / 650 Summary of Research Recommendations / 651 Air Pollution, the Automobile, and Public Health. (it) 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 631
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632 Identifying Neurobehavioral Effects The automobile can be regarded as a mixed blessing. Although it has become a neces- sary part of daily life, the changes poten- tially induced by automotive emissions are not necessarily welcomed. Among these are adverse neurobehavioral effects that range in severity from the annoyance pro- voked by unpleasant odors and the eye irritants to overt behavioral and neurolog- ical dysfunction. Airborne contaminants can alter behav- ior and the functions of the nervous system in a variety of ways. Chemicals can damage the structure of the nervous system di- rectly, or can alter behavior and nervous system function without pathological changes by affecting neurotransm~tter sys- tems, perturbing membranes, or altering cellular metabolism. Since behavior de- pends upon a wide variety of nervous sys- tem functions, behavioral changes can sometimes provide early indications of ad- verse effects on other organ systems. Automotive emissions can also alter be- havior by stimulating sensory systems. These stimuli may be unpleasant events that alter the conduct of daily life, or may serve as important discriminative or warn , . ing stimu. At. The neurobehavioral toxicity of the chemicals involved in automotive technol- ogy is not well understood. Emissions may not produce obvious effects at concentra- tions commonly found in the environment; moreover, some individuals may be ex- posed occupationally to higher levels. A1- though people are exposed to the chemicals in automotive emissions environmentally as well as occupationally, and although studies of such people offer unique oppor . . . . . . . tunes, it Is Inappropriate to re .y entire By on these exposures to detect neurotoxicity, especially when suitable techniques exist . . using anlma. .s. In this chapter, methods are described for the detection of adverse neurobehavioral effects of automotive emissions, and rec- ommendations for research in this area are offered. First, ways are described of identi- fying, in laboratory animals, the adverse neurobehavioral effects of hazardous sub- stances following acute exposures and re- peated exposures, of characterizing subtle effects, and of determining mechanisms of . . tOXlClty. Second, a review is provided of what is currently known about the neurobehav- ioral toxicity of automotive emissions and fuel constituents. Third, recommendations are offered on how to proceed with a program to address this class of health effects. Although there is reason to suspect that many emissions and fuel constituents are hazardous, little information is available for most. To address this large group of chemicals, a committee should select the substances to test and the order of testing. For the substances about which some knowledge exists, focused recommenda- tions are offered for detailed evaluation of their hazards. These include whole emis- sions, carbon monoxide (CO), petroleum hydrocarbons, methanol, and metals and their compounds. Neurobehavioral Effects and Mechanisms of Toxicity The behavioral and neurological sciences have made extraordinary progress in the past 25 years. Although further progress will continue to yield new methods, in areas ranging from the subcellular to the behavioral levels of analysis, adequate methods are now available to explore the neurobehavioral effects of automotive emissions and fuel components. Various approaches to neurobehavioral hazard identification have been recom- mended over the years by a variety of experts. Although no single comprehensive approach has yet been formalized, a re- sponsible screening effort should include: ~ identification of the acute hazards of chemicals this includes seeking evidence of mortality, morbidity, and morphologi- cal changes (as in any acute toxicity evalu- ation), but with particular emphasis ac- corded behavioral function, learned as well as unlearned; ~ characterization of their toxicity in repeated or continuous exposures this provides an opportunity to characterize
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Ronald W. Wood 633 toxicity that is delayed or cumulative, to observe the development of tolerance (or reverse tolerance), and to characterize the reversibility of adverse effects; and · detailed study of mechanisms of injury and special impairments this includes ini- tial screening for subtle sensory or percep- tual impairments, affective disorders, or cognitive and intellectual dysfunction, and appropriate specialized evaluations using refined neuropathological, neurochemical, and neurophysiological techniques. The U. S. Environmental Protection Agency (EPA) has issued a series of test guidelines that are appropriate for use in acute and chronic neurobehavioral toxicity evaluation. These include guidelines for the examination of neuropathology (U.S. Envi- ronmental Protection Agency 1985c), motor activity (U. S. Environmental Protection Agency 1985b), schedule-controlled behav- ior (U.S. Environmental Protection Agency 1985f), and a functional observation battery (U. S. Environmental Protection Agency 1985a). Identifying Acute Hazards It is important to determine the acute ef- fects of chemicals on behavior and nervous system function. Acute performance im- pairment can increase accident proneness and lower work efficiency; thus there can be serious consequences of even small lapses of coordination, vigilance, or visual sensitivity in operators of all types of trans- portation machinery. Irritation and sensory effects perhaps the most common com- plaints elicited by automotive emissions- reduce the perceived quality of life, cause people to change their lifestyles (by allocat- ing their time to less distressful activities), and Incapacitate sensitive individuals. Hence, even apparently reversible adverse effects are of concern. In fact, acute but reversible effects may well be the ones of most concern (see discussion in Whole Emissions and Their Photochemical By- products), and information about them, therefore, is of particular importance when describing acceptable limits of exposure. With care, it is possible to design and conduct statistically valid experiments to accurately estimate the pollutant concentra- tions that produce small but consistent ad- verse effects (Wood and Colotla 1986; Wood and Cox 1986~. ~. . . · 1 . Acute tOXlClty testing requires evaluation of function and morphology, and can have outcomes that are positive or negative with respect to either. Thus the possible outcomes can be expressed in array form as: No Effect Effect Morphology No Effect Erect A B C D Morphological changes (outcomes B or D) are clearly of immediate concern. How- ever, many chemicals can produce observ- able functional changes without any mor- phological correlates (outcome C). Lead, for example, is an automotive emission that produces functional impairments in hu- mans and animals without marked neuro- pathological changes. Consequently, a complete safety evaluation requires func- tional tests at levels of exposure so low that they do not produce detectable morpholog- ical changes. Examinations of conditioned behavior can be constructed to detect impairment of a variety of functions. Evaluation of func- tion may, however, fail to warn of mor- phological changes in the nervous system (outcome B) until the loss of"functional reserve" is sufficiently great (outcome D). Challenges with pharmacological agents may be useful in such situations to unmask silent damage (outcome A or B). Behavioral tests detect performance dis- ruptions that are indirect results of effects on other systems, just as a disinclination to dance might precede the onset of diar- rhea (Dews 1975~. Thus motor activity or food and water consumption can be changed by chemicals that do not enter the central nervous system, and without con- comitant changes in body weight (Evans et al. 1986~. Irritation is another possible in- direct manifestation of toxic impairment,
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634 Identifying Neurobehavioral Effects and is discussed further under Whole Emis- sions and Their Photochemical By-prod- ucts. There are important gaps in our knowledge of the relationship between ex- posure and the acute behavioral changes it produces. Toxicity in Repeated or Continuous Exposures After acute toxicity has been examined, repeated exposure experiments should be undertaken, typically 28- or 90-day sub- chronic exposures with routine examina- tion of neuropathology, measurement of motor activity (preferably in the home cage), and routine use of functional obser- vational batteries. With the insights af- forded by the acute toxicity experiments, repeated-exposure experiments can be tai- lored to further characterize those effects and to yield improved sensitivity. For ex- ample, special histological studies might be indicated; examining learned behavior in detail can provide important insights into the nature of toxic impairment (Laties and Wood 1986~. Such repeated-exposure experiments be- come particularly important if acute studies indicate the potential for irreversible toxic- ity. In such cases, for example, tolerance may play an important role, and the re- peated administration of other compounds or reference substances as probes may dem- onstrate a forward or reverse tolerance. The mechanism of tolerance may then be revealed with an appropriate design, such as taking concurrent blood level and behav- ioral measurements or using satellite groups of animals for tissue-level determinations of whether tolerance results from an in- crease in metabolism or elimination of the toxic substance. In some cases, the mecha- nism of tolerance may be behavioral, and may depend only on an animal's opportu- nity to respond in the presence of the material. The observations of Kane and Alarie (1977) with formaldehyde and acro- lein illustrate how the context of previous experience with the toxicant can affect bi- ological response (see Conditioned Re- sponses to Exposure). Identifying Subtle Effects Many sensory and perceptual deficits, af- fective disorders, and cognitive and intel- lectual dysfunctions are sufficiently subtle that they can be missed in routine acute and subchronic studies. Sensory and Perceptual Deficits. There is a recognized need for rapid screening pro- cedures (National Institutes of Health 1977), as well as comprehensive studies of the complex functions of sensory systems. Vision. Toxic effects on this highly complex sensory system are easily missed, especially when studies are undertaken with . rodents. For example, experiments with rodents do not reveal the profound restriction of visual fields produced by methylmercury in humans and nonhuman primates. Carbon disulfide can produce se- lective impairment of the discrimination of coarser features of visual stimuli, leaving the discrimination of fine features unim- paired (Merigan et al. 1985b). Carbon di- sulfide also affects color vision and hue discrimination (Raitta et al. 1981), an effect that can only be observed in experimental animals having color vision. Agents that produce peripheral neuropa- thies (for example, hexacarbons) are likely to affect vision. Measurement of visual function in primates apparently provides a very sensitive index of central nervous sys- tem injury (Eskin et al. 1985; Merigan et al. 1985a). Appropriate studies in primates as well as rodents might support the inference of a defensible safety factor from rodent data on peripheral neuropathy. However, inferences about other compounds (for ex- ample, those with a cortical distribution of injury) are much more problematic, and reveal functional deficits only with detailed evaluation. Audition. In most species, the inner ear is difficult to remove from the surrounding bone, so its pathologies are rarely uncov- ered. Lesions may be missed if specific functional evaluations are not performed. Toluene, whose toxicity has been the focus of much study for years, offers an excellent illustration. It was only recently that Pryor
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Ronald W. Wood 635 and coworkers (1984a,b) and Rebert and colleagues (1983) documented a selective high-frequency hearing loss following in- tense toluene exposure. They discovered this damage using a pole-climb avoidance test that required animals to jump on a pole to avoid shock in response to a warning stimulus; they varied the characteristics of the tone to demonstrate the frequency-specific loss. Techniques have also been developed that do not rely on training, for example, the inhibition of noise-elicited startle by barely detectable sounds (Hoffman and Ison 1980; Young and Fechter 1983~. The loss of sensation can readily be de- tected using psychophysical procedures with animals, but detecting the loss of , . . .. perception poses a more Cult prob- lem. Some chemicals produce no impair- ment of hearing for pure tones, but pro- duce profound impairment of"perceptual speed." Thus methylmercury poisoning does not alter "hearing" per se, but does impair language comprehension in such a way that individuals function only when spoken to extremely slowly. Recommendation 1. Quick and sim- ple tests of sensory impairment should be developed that can be used for screening in conjunction with functional observation batteries. At the same time, psychophysical procedures that are more comprehensive should be developed; these should be di- rected at specific sensory and perceptual im- pairments, for example impairment of com- plex auditory and visual discriminations. Olfaction, Gustation, Somesthesis, and Pro- prioception. Toxic effects on these func- tions might be detected following high doses of chemicals, albeit with great uncer- tainty. Experiments could be designed to assess these end points in detail. The tech- nologies are readily available, but knowing when best to use them can be a problem, except for chemicals that affect or react with the olfactory mucosa (and potentially the olfactory nerve and bulb), such as oxi- dants, aldehydes, and large particles. Changes in olfactory sensitivity may or may not be reversible, and they can alter behavior and quality of life without the affected individual's being aware of it. Peo- ple with injuries to their sense of smell complain of burning their food while cook- ing, or of having bouts of food poisoning from eating undetected spoiled food. These effects, as well as the techniques for study- ing them, have been reviewed (Wood 1982~. Olfactory psychophysics is a highly developed research area in which trained observers (human or animal) are used to establish thresholds for detection of odors or for the detection of differences in inten- sity of odor (Cain and Moskowitz 1974; Moulton et al. 1975~. Pursuing research in this area on human subjects could bear fruit. Neurophysiological techniques can detect acute alteration of nasopalatine nerve function following 1-fur exposures to form- aldehyde or ozone (03) (Kulle and Cooper 1975~. Odor preference studies with animals are readily done but offer little predictive util- ity for human preferences. Subjective re- sponses to environmental odors have been studied in humans (see, for example, Turk et al. 1974) including work on diesel odor (Springer 1974~. Recommendation 2. Studies of olfac- tory sensitivity following aldehyde and ox- idant exposures should be undertaken in humans and rodents. Affective Disorders. Exposure to some chemicals can produce apparently aberrant "affective" or "emotional" behavior in an- imals. Normally docile strains of rats ex- posed to inorganic mercury vapor and housed in groups have been observed to spontaneously assume aggressive postures in the home cage (Beliles et al. 1968~. Inorganic mercury vapor is well known for its early production of a "neurotic" syn- drome in humans. Other chemicals may exaggerate startle responses to sudden stimulation, or make animals very difficult to handle. Carbon disulfide can make dogs extremely aggressive (Lewey 1941~; its ef- fects on humans range from the induction of affective disorders to suicide (Wood 1981b). These effects, some of which can be
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636 Identifying Neurobehavioral Effects detected only by a careful observer, have received insufficient attention (National In- stitutes of Health 1977~. Procedures that rely on conditioned behavior to detect af- fective changes produced by toxic chemi- cals have yet to be put to use; avoidance or punishment procedures should be well suited for this purpose. Recommendation 3. Behavioral mod- els of affective disorders should be devel- oped. The models should be calibrated with reference substances, drugs as well as toxicants, before their application to test chemicals or mixtures. Cognitive and Intellectual Dysfunction. Short of epidemiologic investigations, the only practical way to study the impairment of normal cognitive or intellectual func- tioning resulting from the intake of chem- icals is to undertake conditioning experi- ments with animals (National Institutes of Health 1977; Laties 1982~. Studying simple performances in well-trained animals can provide useful information, but the find- ings may not necessarily be associated with learning impairments. More complex per- formances conditioned explicitly to exam- ine learning can provide us with insight into the likelihood of injury to this impor- tant function. The repeated-acquisition technique has been used considerably as a model of learn- ing impairment (Thompson and Moersch- baecher 1978~. This procedure requires an animal to perform two tasks, both requir- ing the animal to respond in a particular sequence. For one task, the response se- quence is constant from day to day, so that performance of a well-learned task is mea- sured; for the second task, the sequence is changed daily. The animal "learns to learn" a new sequence every day, so that acquisi- tion of a response pattern can be studied repeatedly. Toxicants and psychoactive drugs disrupt this acquisition of new re- sponse sequences. A variety of other pro- cedures could also be used to model other aspects of intellectual functioning, includ- ing alternation procedures, conditional dis- criminations, and respondent conditioning procedures, to name a few. Recommendation 4. Existing proce- dures should be used to examine whether toxicants of concern impair learning, mem- ory, cognition, and intellectual functioning. Pursuing the Mechanisms of Toxicity The detection of toxicity in either acute or subchronic tests will generate questions that should be pursued, since the conclusive demonstration of physiological or bio- chemical mechanisms of action can be enormously important. Neurochemical Evaluation. Normal be- havioral activities of animals (Sparber and Tilson 1972) as well as adverse behavioral effects of exposure result in neurochemical changes. It is therefore difficult to interpret the significance of acute neurochemical changes without correlated functional ob- servations. If large numbers of false posi- tives are acceptable, then routine neuro- chemical evaluation may be desirable as a screening test; otherwise, such use of neu- rochemical tests is likely to be a poor allo- cation ot resources. Neurochemical evaluations can be very useful as adjuncts to other tests and to determine mechanisms of toxicity. Manga- nese (Mn) is an example where such studies could be especially useful, because Mn is likely to have specific interactions with neurochemical substrates. Furthermore, Prolonged or irreversible changes in neuro- transm~tter (or neuromodulator) levels, turnover rates, or receptor numbers, which might be suspected following the observa- tion of other forms of toxicity, are always important. Several good examples exist in the literature on sympathomimetic amines. Repeated amphetamine administration can produce behavioral changes and death in animals, in the absence of obvious pathol- ogy. Amphetamine-like drugs can also produce long-lasting reductions in dopa- mine and serotonin, and a decreased num- ber of uptake sites in brain (Ricaurte et al. 1985~. The changes found would not be obvious in a first-pass neuropathological examination. However, the destruction of some receptor populations could be dem- onstrated histochemically (using Fink
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Ronald W. Wood 637 Heimer silver stains), after the identifica- tion of neurochemical changes. There probably will not be tests for neurobehavioral toxicity comparable to in vitro tests for mutagenicity (that is, the Ames test). A high rate of false positives could be expected from most such test systems; an effect in the test tube does not mean that an effect will necessarily occur in viva, because the agent may not reach the site of action. False negatives might occur less frequently, but be of greater concern. However, nerve culture techniques will assist in clarifying the mechanisms of neu- rotoxicity (Veronesi et al. 1980~. On the other hand, biochemical tests can contribute to identifying particular kinds of neurotoxicity. Assays for neurotoxic ester- ase induction in the brain and the spinal cord have been useful for the identification of neuropathic organophosphates, and an EPA test guideline has been written for this purpose (U. S. Environmental Protection Agency 1985d). Glial fibrillary acidic pro- tein assays reflect the astrocytic response to central nervous system injury, and may be useful as a screening technique (Brock and O'Callaghan 1987~. chemical assays may be able to help steer the process of chemical synthesis; thus if a test indicates possible toxicity for a chemi- cal being developed, further synthesis work might be directed toward developing less toxic alternatives. Neuropathological Examinations. Neu- ropathological examinations should be in- cluded in toxicity assessment; frequently, the same animals can be used for behavioral testing and Neuropathological examination. Subsequent studies of mechanisms of tox- icity, of special systems, or of chronic effects may require the study of satellite groups because immersion tissue fixation and routine staining procedures are inade- quate for the description of some types of nervous system injury. For example, histo- chemical techniques (fluorescence, metal stains, Golgi) and immunohistochemistry can provide insights into the mechanisms underlying the neurotoxic effects of certain chemicals. Such techniques are not rou- tinely used for hazard identification. Furthermore, bio Special procedures are sometimes re- quired for some classes of injuries; for example, techniques to examine axoplas- mic transport. Most such techniques are incompatible with routine toxicologic eval- uation. Similarly, nerve teasing and elec- tron microscopy can demonstrate subtle neuropathies. Both are extremely labor in- tensive. Neuropathological studies can use special chemicals for studies of the mecha- nisms of toxic injury. The description of the role of fly diketones in the production of hexacarbon neuropathies offers a good exam- ple; subsequent studies of 3,tdimethyl-2,5- hexanedione have examined accelerated pyr- role formation and its role in potential neurofilament cross-linking (Anthony et al. 1983a,b). Neurophysiological Examinations. Peri- pheral nerve conduction velocity is used clinically to assess peripheral nerve function in humans. In animals, hind limb weak- ness, gait disturbance, and peripheral neu- ropathology provide adequate sensitivity for hazard identification, given that the exposure concentrations contemplated are high enough to induce frank peripheral neuropathy. Measurement of peripheral nerve conduction velocity may be useful for the detection of demyelination, and the U. S. Environmental Protection Agency (1985e) has promulgated a test standard for this purpose. However, it may not detect axonopathies. Most important, the reversi- bility of peripheral nerve impairments need not imply the reversibility of central ner- vous system injury. Evoked-potential studies might be cost- e~ective for some classes of sensory effects, especially to determine low-level effects. Brainstem auditory evoked responses are useful in detecting hearing loss; the sensi- tivity of these procedures is comparable to that for behavioral procedures (Rebert et al. 1983). Flash-evoked responses are less infor- mative about injuries to the visual system than are counterphase spatial-frequency re- versal experiments. More advanced proce- dures are available to characterize the inter- play of structural and functional alterations produced by toxicants. By simultaneous measurement throughout a brain structure, it
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638 Identifying Neurobehavioral Effects should be possible to describe the pathophys 1 r 1ologlca progression or 1nJury. Evaluating Whole Emissions, Fuels, and Their Components Although it is possible to study whole emissions directly as complex mixtures, this is usually not the most fruitful course to pursue. The difficulties encountered in studying such complex mixtures are pro- found, because the myriad interactions pos- sible among the reactive components of automotive emissions may result simulta- neously in potentiation of, and protection against, adverse effects. The study of mix- tures should not preclude the continued evaluation of the toxicity of individual components of mixtures, especially since the reduction or elimination of a single component could have major health im- pacts. We learn relatively little from the study of a single idiosyncratic mixture or simulated automotive emission; indeed, in such studies, the data collected on the ref- erence substance used to calibrate the sen- sitivity of the experiment may well consti- tute a greater scientific contribution than the data from the mixture (Laties 1973; Horvath and Frantik 1974~. More information about the behavioral effects of carcinogenic emissions is needed. When testing for carcinogenesis, pollutant doses and concentrations are usually maximum tolerated doses; those that typi- cally produce behavioral effects are often much lower. Thus, under ambient condi- tions of exposure, the behavioral, rather than the carcinogenic, effects of carcino- genic components of emissions may be the principal effects of concern; these effects might include malaise or performance deg- radation. Whole Emissions and Their Photochemical By-products Air pollution episodes alter human behav- ior. Weather reports in certain metropoli- tan areas regularly include air quality reports, and the elderly, those with respi ratory problems, and athletes modify their behavior accordingly. The description of atmospheric conditions (even an erroneous prediction) may change the activities peo- ple engage in; for example, in a form of conditioned avoidance behavior, the heightened probability of chest discomfort in a smog alert may lead an athlete to change his or her training regimen. During the 1984 Olympics in Los Angeles, concern about the potential effects of automotive emissions and photochemical products on performance and health prompted recom- mendations for the siting of athletic com- netitions and for traffic control, as well as for training and competition schedules (McCafferty 1981). Even if individuals cannot articulate the association between verbal warnings about air quality and discomfort during exercise, they may nevertheless avoid the circum- stances in which unpleasant sensations oc- cur~ without directly attributing their avoidance to atmospheric quality. The ex- tent to which unpleasant or uncomfortable sensations alter the behavior patterns of dally llle has not been recognized. Nervous system function can be directly affected by constituents of whole emis- sions, such as CO. Emissions can also produce effects mediated by less direct mechanisms. Functional disturbances that . . . Occur in response to emissions may ae conditionable in and of themselves, as one might condition a dog to salivate following the ringing of a bell; the evidence for such conditioning will be discussed later. Eye Irritation. Eye irritation is the most frequent complaint evoked by emission exposure. Numerous studies have docu- mented the increasing frequency of com . . . . . P alnts Wit n increasing contaminant con- centrations. In a report on O3 and other photochemical oxidants, the National Academy of Sciences (1977a, p. 430) as- serted "For the two most prevalent symp- toms related to photochemical-oxidant ex . . . . . posurc- eye irritation anc ~ ~ .acrlmatlon no method of quantification has been devel- oped. Eye irritation, although real, is a subjective response of the subject, and no measurement, other than the complaint it
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Ronald W. Wood 639 self, has yet been developed...." In an- other report on pollutants, the National Academy of Sciences (1976) stated that the first uncomfortable reactions are usually felt in the eye tissues. That report examined several studies of eye irritation, including one by Schuck and collaborators (1966~. Those investigators conducted eye-only exposures, and permitted subjects to turn a knob that adjusted the position of a pointer on a scale to indicate the eye irritation intensity experienced at any instant during the 5-min exposure. Concurrently, the rate of eye blinking was measured. Orderly functional relationships to exposure emerged from this study, demonstrating the value of such experiments. Comparable studies were undertaken more recently with formaldehyde and sidestream ciga- rette smoke (Weber-Tschopp et al. 1977~. Studies are most frequently performed by having questionnaires completed by members of exposed populations (for ex- ample, Heuss and Glasson 1968; Hagberg et al. 1985), or by exposing panelists to test atmospheres, measuring the elapsed time to a complaint, and eliciting a subjective rat- ing (Bender et al. 1983~. Such scaling stud- ies could profit from better utilization of psychophysical scaling procedures devel- oped for the study of odorants (Cain and Moskowitz 1974~. The development of procedures to assay eye irritancy in animals would be desirable. In vitro tests designed to replace the Draize test (instillation of chemicals into the eye of a rabbit) are currently being validated, but neither in vitro tests nor the Draize test can directly address the subjective response to low-level sensory irritation. Blink rate measurements are useful, but with repeated experience in the test situation. animals . . . . . . may learn to close their eyes to avow exposure. Procedures that permit animals to terminate but not to avoid graded con- centrations of irritants are discussed in some detail below. These latter procedures give the animal the opportunity to control the unpleasant stimulation, unlike tech- niques that require measurement of struc- tural changes following instillation of the material into the eye. Another potential advantage of these procedures is that the cornea is served by the trigeminal nerve, and stimulation of this nerve decreases res- piratory and heart rate. These physiological changes are of interest per se and may yield sensitivity comparable to behavioral mea- surements without training the subject. In any circumstance, the sensitivity of these tissues to irritants may permit the identifi- cation of the threshold for aversive stimu lation. Recommendation 5. Quantitative pro- cedures should be developed using eye- only exposures to provide estimates of aversiveness derived from behavior under the control of irritant stimulation, and from measuring blink, heart, and respiratory rates. Behavioral Effects. Wheel Running. Sev- eral experiments describing the effects of whole emissions on animal behavior pro- vide leads for further work. Boche and Quilligan (1960) accustomed mice to run- ning wheels, and then put one in a cham- ber with filtered air, and another in a smog-like mixture of O3 and gasoline. The mice were moved from one chamber to the other every day (three 1-day exposures in each chamber), permitted to rest for a week, and then subjected to the same proc- ess at a higher smog concentration (figure 1~. Although there was no assessment of running in the exposure chamber in the absence of smog, a concentration-related reduction in running was observed. This set the stage for a series of experiments demonstrating the utility of behavior for the study of emissions and photochemical products. Gage (1979) exposed mice in running wheels to emissions from an automobile engine burning unleaded gasoline. The ex- haust from the engine under lean tuning suppressed running in proportion to expo- sure concentration. The exhaust of an op- timally tuned engine had no effect. Ultra- violet irradiation of the exhaust simulated photochemical smog, which suppressed running to a greater extent than nonirradia- ted exhaust. Activity returned to normal several days after the termination of irradi- ated exhaust exposure. However, termina
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640 Identifying Neurobehavioral Effects E ° o cr) rat co us Cot co a, cat ~ tD co to m ~ arc t~ ~ CO tr) t£ ~Us U) ~ ~ rat ~ a) Q O O O O O O O O Z ^ 44 E ° ~ o, a, ,~ u, ~cut _ to us co a) co ~ a, CO ~ CO CD CO - O C\l C\l C~J ~ ~ ~ N X Q - - - - - C\i C~J 1 -~:~-.o~~;8.8,,°;8~ ~ ,, 104 At o t; 103 Is lo2 o LAB AIR o PURIFIED AIR · SMOG MOUSE 5 MOUSE 6 , 0 5 10 o~.c,.o ·o O .'o-~_O a. O ° 1 'o_0~° 1.11 1;4 I ~I ~1 ~1 1 15 20 25 DAYS Figure 1. Spontaneous wheel-turning activity of two C57 black male mice in different environments. The total oxidant and O3 determinations are shown at the top of the graph for each day of exposure to synthetic air pollutant mixture of O3 and gasoline. (Adapted from Boche and Quilligan 1960.) lion of nonirradiated exhaust produced re- bound hyperactivity (figure 2, upper right panel). This study was not the first report of exhaust-induced hyperactivity (Hueter et al. 1966; Emik and Plata 1969; Stinson and Loosli 1979~. These studies could have been improved by more complete report- ing of the effects across time, and of their relationship to concentration. Several investigators have used wheel running to examine biological effects of smog constituents (see, for example, the review by Murphy 1964~. Murphy and colleagues (1964) observed a 46 percent reduction in activity following a 6-fur ex- posure to 0.2 ppm 03, and a 20 percent reduction following exposure to 7.7 ppm nitrogen dioxide (NOT. Campbell and co- workers (1970) demonstrated that peroxy- acetyl nitrate, a constituent of photochem- ical air pollution, depressed running in pro- portion to the exposure concentration. Emik and Plata (1969) and Emik et al. (1971) set mice in wheel-running cages between the lanes of the Hollywood free- way and demonstrated an association be- tween oxidant concentration and depressed running. Because humans complain following ex- ercise in 03, Tepper and colleagues (1982) undertook a detailed analysis of the tempo- ral patterning of wheel-running behavior that revealed disruption during 6 hr of exposure to 0.12 ppm 03, the current ambient air quality standard. Low concen- trations increased the duration and number of pauses, but did not change the speed at which the animal ran, or the length of an individual running burst. Unlike the effects on learned behavior described below (Weiss et al. 1981), effects were obvious in the first hour at lower concentrations, and performances declined throughout expo- sure. Thus low concentrations of automotive emissions or photochemical reaction prod- ucts can impair wheel-running perform- ance. The mechanism by which these changes are produced should be a focus of the research agenda because it is of interest per se and because it contributes to risk analysis.
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Ronald W. Wood 3o[; he ~ 20 G co JO x he 20 g of: :5 10 641 30- 2a 10 ~_ CO Cone (ppm) I 0 1 100 1 25 1 50 1 75 1 100 1 25 1 50 1 75 1 100 1Days Atmosphere I Air I CO I Nonirredated I Irradiated I Exposure A O Hb~es EM Females Exposure B 301~ 30 20 10 O Control r O Nonirradisted, 100 ppm CO j ~ Irradiated, 100 ppm CO i .SS ~'a 0~s\~' /! I 1 1 1 1 1 1 1 1 1 2 3 4 5 6 7 8 9 | ~ EXPOSED ~ | Exposure C 1;1~!1!~!1)1'l1'-.: , CO Cone (ppm) 1 0 1 100 1 50 1 75 1 100 1 50 1 75 1 100 0 1 100 1 50 1 75 1 100 1 50 1 75 1 100 1 Atmosphere I Air I CO I Nonirrad~ated I Irredated I I Air I CO I Nonirredated I Irredated l Figure 2. Mean daily activity of mice groups during emission exposure periods of the three exposure tests. Exhaust level is described by the nominal CO concentration. During exposures A and C, engine was tuned to factory specifications. During B. engine was optimally tuned. Upper right panel shows activity over the course of exposure A for male and female mice exposed to concentrations indicated. (Adapted with permission from Gage 1979.) Mechanistic Experiments. Several mech- anistic experiments indicate that the sup- pression of wheel running performance was probably not due to acute aversive- ness of O3 Wood (1979, 1981a) developed a procedure that permits direct behavioral assessment of the aversive properties of inhaled materials. Mice poked their noses into a conical recess to terminate the deliv- ery of an irritant, and simultaneously pro- duced a facial shower of clean air. Tepper and Wood (1985) demonstrated that O3 reliably maintained escape behavior, and that its aversive properties were not depen- dent on previous experience with irritants. Performance was related to concentration,
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648 Identifying Neurobehavioral Effects There are a number of clinical reports of damage to the basal ganglia, delayed motor dysfunction resembling parkinsonism, and gross brain injury following methanol ex- posure (Erlanson et al. 1965; Guggenheim et al. 1971; Aquilonius et al. 1978, 1980; Lev and Gall 19831. This has vet to be studied In primate models of methanol . . . ntoxlcatlon. · Recommendation 17. An animal model of methanol-induced motor disor- ders should be developed. Such a model would assist in determining if acidosis is a necessary precondition for the emergence of methanol-induced motor disorders and if antidotes are effective. It has been demonstrated that the expres- sion of acidosis is mediated by a folate- dependent metabolic pathway, and that the inhibition of methionine synthetase (pro- duced with nitrous oxide exposure) can provoke methanol-induced acidosis in rats, a normally insensitive species. Furthermore, following a few hours of exposure to nitrous oxide, monkeys treated with 1 g metha- nol/kg body weight developed acidosis (Eells et al. 1983~; this is a much lower dose than is normally required to produce the acute syn- drome. This observation might provide a basis for a more sensitive model. Recommendation 18. More sensitive animal models of methanol toxicity should be developed, perhaps through the manip- ulation of folate metabolism. Repeated or continuous exposure to low concentrations of methanol should then be undertaken to determine if acidosis can be produced, and if systemic acidosis is a precondition for the expression ot toxicity. · Recommendation 19. Clinical trials should be undertaken with 4-methylpyra- zole, a new drug that is a promising meth- anol antidote and a candidate for wide- spread deployment in emergency facilities. Metals and Inorganic Compounds Lead (Pb) is the prototypical metallic auto . . . . . . . . motive emission; it IS instructive to review our experience with Pb before other metals are added to automotive fuels. The fuel additive tetraethyllead has been responsible for multiple deaths from neurotoxicity and was the focus of a major public health controversy (Rosner and Markowitz 1985~. The neurobehavioral toxicity of Pb would most probably have been detected had some systematic approach to testing been in place. Exposure increases the frequency of conditioned behavior of rats at blood levels of Pb below the current clinical definition of elevated Pb burden that re- quires further diagnostic intervention (Cory-Slechta et al. 1985~. Morphological changes in the brain that accompany these functional changes have not been identi- fied. Another metal, manganese (Mn), how- ever, can produce functional as well as morphological changes. Methylcyclopen- tadienyl manganese tricarbonyl (MMT) is a potential gasoline additive that has anti- knock properties. When used in diesel fuels, Mn additives improve combustion and reduce smoke. The chronic toxicity of the emission product may be subtle, de- layed, and readily confused with diseases of other etiology. The syndrome progresses from manic psychosis and disturbances of speech and gait in the early phase, to dis- turbances of speech, a fixed jovial facial expression, clumsiness and hyperemotion- alism in the intermediate stage, and later, muscular hypertonic and tranquil euphoria with memory loss and intact sensory func- tion (Rodier 1955; Mena et al. 1967; Bar- beau 1984~. The National Academy of Sciences (1973) reviewed the toxicity of Mn, ex- pressed concern about the Mn emission problem, and made twenty-five research recommendations. Although Mn is not now regulated as a hazardous pollutant, knowledge of the health effects of Mn is limited, especially about the relationship of exposure concentration and duration to ef- fects. The existing data are inadequate to conduct a risk analysis. The risk of adverse health effects from Mn emissions should be characterized as unknown but not necessar- ily unlikely. The potential injuries are great enough to warrant further study before any
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Ronald W. Wood 649 . . . . . s~gn~cant Increase In exposure Is contem- plated. Mn is an essential trace element, but at some higher dose it becomes toxic. The relationship between dose and adverse ef- fect remains unclear, despite the fact that the toxicokinetics of Mn have received fairly detailed attention (Dastur et al. 1971; Newland et al. 1987~. The literature pro- vides only limited insight into whether increased exposure increases the severity of effect, as well as the number of individuals affected, or merely shortens the time to toxicity. Children, in particular, may be at high risk, because, as with Pb emissions, (1) the amount of Mn in dust and soil should increase with proximity to the emis- sion source, (2) children put their hands and many other things in their mouths, (3) children become more mobile at 6 months of age, and (4) younger organisms absorb a larger proportion of the adminis- tered dose (Cahill et al. 1980; Rehnberg et al. 1981~. Most of the clinical literature consists of effects reported following an idiosyn- cratic exposure, rather than well-controlled experiments. The emphasis has been on identifying toxicity, and not on generating an orderly dose/effect or dose/response function. There are anecdotal reports of delayed toxicity commencing several years after the termination of exposure (Cook et al. 1974~. Changes in human behavior from exposure to Mn at levels that are 20 percent of current recommended exposure limits have been reported by Roels et al. (1985~. · Recommendation 20. Should any in- crease in Mn emissions be contemplated, an expert committee should be formed to re- view the neurotoxicity of Mn and the ade- quacy of current exposure estimates, and to consider the benefits of a chronic study in primates. If significant exposure is contem- plated, several experiments must be under- taken to provide data for risk analysis that provide close attention to neurobehavioral function, and consequent regional neuro- chemical assessment. Early signs of altered dopaminergic function should be exam- ined. · Recommendation 21. Should any in- crease in Mn emissions be contemplated, kinetic studies of Mn should be under- taken, with the emphasis on brain uptake and the ingestion of accumulated dust by neonates. Estimates of possible intake should be modeled; exposure of neonatal primates and evaluation of neurobehavioral toxicity should be considered. Studies of the acute toxicity of MMT have identified seizures and Clara cell ne- crosis as sequelae to exposure. The delayed effects of acute or chronic low doses have not been well characterized, and are of interest per se; the nervous system is of interest because of the greater access an organic metal should have to the central nervous system and because of the evident neurotoxicity of Mn in primates. Organic complexes or salts might facilitate entry and shorten the time to toxicity. Recommendation 22. The acute and chronic neurobehavioral toxicity of MMT should be more adequately characterized. Conclusions Determining the acute effects of chemicals on behavior and nervous system function is important to the evaluation of neurotoxic- itv: acute reversible effects may be the effects of major concern. Similarly, re- peated or continuous exposures are needed to characterize toxicity that is delayed or cumulative, to observe the development of tolerance (or reverse tolerance), and to characterize the reversibility of adverse ef- fects. Initial screening for subtle sensory or perceptual impairments, affective disor- ders, or cognitive and intellectual dysfunc- tion needs to be conducted, and, finally, highly focused studies may be needed to fully characterize hazards using methods that are dictated by the nature of the system or function affected, such as specialized eval- uations and refined neuropathological, neu- rochemical, and neurophysiological tech- n~ques. Since the neurobehavioral toxicity of
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650 Identifying Neurobehavioral Effects many compounds present in automotive Summary emissions is unknown, they should be studied systematically, proceeding from acute, then through repeated administra tion, experiments and subchronic expo sures, and finally to detailed characteriza tions of injuries and mechanisms. The U.S. Environmental Protection Agency has promulgated guidelines for a variety of neurobehavioral studies, including neuro pathology (1985c), motor activity for ex ample, wheel-runnin~ studies (1 98-c~h1 schedule-controlled ,, ~. , O ~ ,, (learned) behavior t~Ybbl), and a battery of structured func- tional observations (1985a). Adopting such tests and incorporating them into a more comprehensive testing strategy is a logical step in developing a rational approach to answering the many unanswered questions surrounding safety evaluation of automo- tive emissions and their fractions. Such a testing strategy, depending on a network of methods and techniques, offers several advantages. First, it reduces the likelihood of overlooking a hazard or class of hazards, which any single screening method might miss. Second, it can be structured in "tiers," in such a way that each tier provides es- sential information for subsequent tiers as well as useful information in its own right. Such a tiered format is likely to speed up the testing process as well as achieve significant economies in laboratory opera- tions that would serve to offset the po- tential expense of an extensive screening program. For example, acute toxicity eval- uations may serve a dose-ranging func- tion for subsequent repeated-exposure ex- periments; the findings in both may later give direction to detailed mechanistic stud- ies. ~ Recommendation 23. The neurobe- havioral toxicity of many constituents pres- ent in automotive emissions is unknown and should be studied using a tiered-testing strategy. An expert committee should pri- oritize the selection of compounds for a systematic testing program, and recom- mend specialized evaluations when appro- priate. This chapter has described adverse neuro- behavioral effects of automotive emissions and offered research recommendations to facilitate their detailed characterization. · Neurobehavioral toxicity has not been evaluated thoroughly for most of the com- pounds that are known to produce adverse effects, nor have screening and evaluation procedures for such toxicity been applied systematically to the universe of chemicals that mobile sources produce. · To some extent, the absence of data Is attributable to a lack of process. Those deficits could be remedied by subscribing to a tiered-testing strategy, with its initial agenda of test substances prescribed by an expert committee. The strategy will pro- vide a disciplined approach, relying on animal studies and supplemented by avail- able literature, for dealing with a large collection of chemicals with largely un- known effects. However, many new tests, procedures, and models need to be devel- oped to assess the adverse health effects that can reasonably be expected to be encoun- tered. · To another extent, the lack of visibil- ity, prominence, and/or appreciation ac- corded to neurobehavioral toxicity, even with respect to substances where such ef- fects are well-documented and widespread, contribute to the data shortage. In particu- lar, we should be immediately concerned with: -Sensory irritation and/or repeated and chronic effects that may alter the quality of life; -Effects of CO on complex human performances, and on special popula- tions with exaggerated sensitivity (for example, the fetus, the infant, and the aged); -Effects of petroleum hydrocarbons on behavior, and brain structure and func- t~on; -Methanol hazards, should methanol come into wider use; and -Metallic fuel additives, especially Mn, should that come into wider use.
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Ronald W. Wood 651 Summary of Research Recommendations Although the behavioral and neurosciences have already been used to good effect in toxicity evaluation, some areas need further research and development effort, both to demonstrate feasibility and to improve cost-effectiveness. Such a research effort should include attempts to: · Undertake testing via a tiered approach for chemicals about which little is known (Recommendation 23) before sophisticated and expensive procedures are used to examine candidate toxicants for their capacity to impair learning, memory, cognition, and intellectual functioning (Recommendation 4~. · Develop rapid tests of sensory impairment that can be used in conjunction with functional observation batteries, and develop comprehensive psychophysical studies directed at specific func- tional impairments, including impairments of complex auditory and visual discriminations (Recommendation 1~. · Develop animal models of affective disorders. Selected refer- ence substances, drugs as well as toxicants, should be used to validate these models before they are used to test uncharacterized chemicals or mixtures (Recommendation 3~. In addition, more specific recommendations for certain automo- tive emissions can be made immediately. These are outlined here according to priority and contingent upon increases in the level of exposure to a particular emission or deployment of new tech- nology. HIGH PRIORITY Recommendations Whole emissions and photochemical by-products deserve imme 6, 23 diate attention. Acute and repeated-exposure wheel-running stud ies should be used to characterize emissions, to differentiate the behavioral consequences of materials that affect primarily the upper or lower airways, and to determine whether the observed effects are attributable to alterations in irritant receptors in lung or lung innervation, frank lung injury, or actual alterations in the periph eral or central nervous systems. The agents responsible for rebound hyperactivity should be determined. Recommendation 5 Eye irritation is one of the most frequently complained-about effects of automotive emissions and photochemical products. Quantitative procedures should be developed using eye-only ex posures to provide estimates of aversiveness derived from behavior under the control of irritant stimulation, and from measurement of blink, heart, and respiratory rates. The development and validation of animal models would be particularly useful. Recommendation 8 Signs and symptoms of exposure to automotive emission and photochemical by-products, ranging from asthmatic attacks to com
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652 Identifying Neurobehavioral Effects plaints of breathing difficulties, may be conditioned to occur after exposure to concentrations that evoke no response in naive subjects. Experiments to define the exposure parameters that produce condi- tioned alterations in sensitivity to airborne irritants are needed. Recommendation 12 Prenatal exposure to CO can alter the behavior of offspring. Such effects may be of great importance and should be studied further with the techniques of modern developmental neurobiol ogy. Recommendation 14 The neurobehavioral toxicity of petroleum hydrocarbons in unleaded automotive fuels has received virtually no serious atten tion. Acute performance impairment should be a major focus of investigation; acute effect determinations are also necessary to ascertain if preventing acute effects will prevent chronic toxicity. MEDIUM PRIORITY Recommendation2 In humans and rodents, the reduction in olfactory sensitivity produced by oxidants and aldehydes should be described as a function of concentration and duration of exposure. Recommendation 7 A model of human populations with compromised pulmonary function should be developed, because such populations are more sensitive than others to oxidant exposure. Experimental models of chronic obstructive pulmonary disease should be developed that will permit quantitative estimation of exaggerated oxidant sensi tivity and display behavioral effects that resemble those produced by chronic exposure to oxidants. Recommendations The aspects of performance most susceptible to disruption by 9,10,11 CO should be identified. The relative importance of different exposure parameters in determining the extent of behavioral im pairment should be described. Exaggerated sensitivity in the eld erly and those with cardiovascular or respiratory insufficiency should be examined. Recommendation 13 Repeated-exposure studies utilizing quantitative morphometric neuropathology should be undertaken in experimental animals exposed to petroleum hydrocarbons. Chronic solvent exposure usually does not produce gross central nervous system lesions, but rather a selective wasting syndrome that may not be evident in measurements of gross brain weight. Recommendation 15 A primate model of the solvent syndrome should be developed. Repeated-acquisition procedures would be an appropriate baseline ---I ~ 1- - - - - rid - -- - - - - jar -I for the study of learning impairment; procedures for the explicit evaluation of memory impairment would assist in clarifying the nature of any learning impairment observed. CONTINGENT PRIORITY Recommendation 16 Because methanol offers special risks to the visual functions of
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Ronald W. Wood 653 primates, additional work should be performed to assist in charac- terizing the hazards and their relationship to exposure. Recommendation 17 An animal model of methanol-induced motor disorder should be developed. Such a model would assist in determining if acidosis is a necessary precondition for the emergence of methanol-induced motor disorders, and if antidotes are effective. Recommendation 18 More sensitive animal models of methanol toxicity should be developed, perhaps through the manipulation of folate metabo lism. Repeated or continuous exposure of susceptible individuals to low concentrations of methanol should be undertaken to determine if acidosis can be produced, and if systemic acidosis is a precondi tion for the expression of toxicity. Recommendation 19 Clinical trials should be undertaken with 4-methylpyrazole, a drug that is a promising methanol antidote, and a new candidate for widespread deployment in emergency facilities. Recommendation 20 Should any increase in Mn emissions be contemplated, an expert committee should be formed to review the neurotoxicity of Mn and the adequacy of current exposure estimates, and to consider the benefits of a chronic study in primates. If significant exposure is contemplated, several experiments must be undertaken to provide data for risk analysis that provide close attention to neurobehav ioral function, and consequent regional neurochemical and neuro pathological assessment. Early signs of altered dopaminergic func tion should be examined. Recommendation21 Toxicokinetic studies of Mn should be undertaken, with the emphasis on brain uptake and the ingestion of dust by neonates. Crawling infants ingesting Mn accumulated in dust may be of great concern, as indicated by past experience with Pb. Estimates of possible intake should be modeled; exposure of neonatal primates and evaluation of neurobehavioral toxicity should be considered. Recommendation 22 The acute neurobehavioral toxicity of any Mn additive should also be evaluated. The delayed ejects of single, lower doses have not been well characterized and would be of some interest per se, as might chronic, lower-level exposure. Organic Mn compounds should be very interesting to study in the primate. References Alarie, Y. 1966. Irritating properties of airborne ma- terials to the upper respiratory tract, Arch. Environ. Health 13:433049. Correspondence should be addressed to Ronald W. Wood, Department of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016. Alarie, Y. 1973. Sensory irritation by airborne chem- icals, CRC Grit. Rev. Toxicol. 2:299-363. Albert, R. E., Sellakumar, A. R., Laskin, S., Kuschner, M., and Nelson, N. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat, J. Nat. Cancer Inst. 68: 597~03. Anthony, D. C., Boekelheide, K., and Graham, D. G. 1983a. The effect of 3,~dimethyl substitu- tion on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by
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Representative terms from entire chapter: