From Animals to Humans: Models and Constructs

From Animals to Humans: Models and Constructs DEBORAH C. RICE ENVIRONMENTAL AND OCCUPATIONAL HEALTH PROGRAM DEPARTMENT OF HEALTH AND HUMAN SERVICES, MAINE CENTER FOR DISEASE CONTROL AND PREVENTION, AUGUSTA, MAINE

I.

INTRODUCTION

This chapter focuses on tests in animal models that assess the domains aVected in developmental disabilities. There are many choices of test procedures to assess a multiplicity of functional domains, from so‐called ‘‘screening tests’’ that are capable of detecting relatively severe impairment to very sophisticated tests that provide detailed information on sensory, motor, and cognitive capabilities. Screening batteries have been developed by national and international agencies to detect and characterize developmental neurotoxicity, such as the U.S. Environmental Protection Agency Developmental Neurotoxicity Test (EPA, 1998) and those developed by the Organization for Economic Cooperation and Development (OECD, 1999). These batteries include tests of locomotor activity and crude assessment of learning, sensory, and motor integration. Considerable eVort was devoted to validation and standardization of such tests, including comparison among various batteries (Buelke‐ Sam et al., 1985; Catalano, McDaniel, & Moser, 1997; Elsner et al., 1986; Tilson et al., 1997; Vorhees, 1985). These screening batteries are not designed to, nor are they capable of, characterizing in detail types of impairment produced in specific domains, or indeed, in many instances, of identifying the domains aVected. Thus, extrapolation from results of screening tests to specific deficits in children is problematic. Nonetheless, identification of neurotoxicity with screening procedures indicates that the chemical under study is probably also neurotoxic to the developing human. Various functional domains may be assessed in detail, using a variety of tests suitable for rodents and other animals. Fine and gross motor function INTERNATIONAL REVIEW OF RESEARCH IN MENTAL RETARDATION, Vol. 30 0074-7750/06 $35.00

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may be assessed in various ways, as well as numerous aspects of sensory function. Cognitive domains that are aVected in developmental disabilities may also be assessed using animal models. There are numerous tests available for assessing learning and memory. In addition, however, the components of executive function can be examined in animal models: attention, distractibility, impulsivity, adaptability, and temporal and spatial organization of behavior. Although children are capable of more complex behavior than are animals, the basic functional domains constituting these behaviors can nonetheless be assessed in animal models. However, many of these testing procedures require extensive training of the animals and considerable expertise on the part of the experimental researcher. Interpretation of the results from animal experiments requires an understanding of the diVerences between humans and the species under investigation, as well as the appropriateness of the dosing regimen to exposure in humans. It is, of course, crucial to understand the diVerences in nervous system anatomy and physiology and their potential contribution to species diVerences. In addition, metabolic diVerences between humans and other species may be important determinants of eVects. The parent compound may be metabolized to a less toxic or nontoxic chemical, or to the toxic entity, and these conversions may be species‐specific. The rate of metabolism is also important. Typically, laboratory species metabolize and/or excrete chemicals more quickly than humans, often by many times. Therefore, the external dose administered to the animal often produces a lower body burden following repeated exposure than the same dose would in humans. If at all possible, the body burden (blood or tissue levels of the active agent) should be determined in the animal model, so that the appropriate comparison can be made to human body burden. EVects of developmental neurotoxicants may be observed at approximately the same body burden in humans and experimental animal models, whereas the external dose necessary to produce eVects in animals can overestimate the dose (exposure) required to produce eVects in humans (Rice, de DuVard, DuVard, Iregren, Satoh, & Watanabe, 1996a). The body burden of a toxicant can be a determinant of the type of toxicity produced. High doses may not be good predictors of eVects at lower levels of exposure. For example, high levels of lead produce encephalopathy in both humans and animals. It was impossible to predict, based on this massive response to toxic insult, the fact that, at lower body burdens, lead produces deficits in attention and impulse control. The developmental period during which exposure occurs may also be an important determinant of the type and severity of damage produced. The nervous system develops by a series of processes that are exquisitely choreographed temporally and spatially. The timing of these processes during fetal and postnatal developments is known for humans and experimental

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animals (Rice & Barone, 2000) and diVers among species. For example, it is important to keep in mind, when designing experiments or interpreting results, that some events that are prenatal in humans occur postnatally in rats and mice. Experiments should be designed to mimic the timing of human exposure as much as possible. This chapter discusses a sampling of tests that may be used to characterize the neuropsychological eVects of developmental neurotoxicants in animal models. The environmental chemicals that have been the most studied with regard to developmental neurotoxic eVects are lead, methylmercury, and polychlorinated biphenols (PCBs). A number of longitudinal prospective studies have characterized the consequences of exposure to these agents, including decreased IQ, attention problems, impulsivity, distractibility, perseverative behavior, and sensory and motor impairment. Therefore, eVects of these chemicals on tasks assessing these functional domains are used as examples of the use of animal models to elucidate specific deficits. For these chemicals, eVects in humans and animals are remarkably congruent. This chapter is not a review of the neurotoxic eVects of chemicals in animals. It is also not a compendium of available techniques. A number of books and workshops have addressed methodological issues in behavioral toxicology (cf. Weiss & Elsner, 1996; Weiss & O’Donoghue, 1994). The intention of this chapter is simply to present examples of the techniques available to identify and characterize neurotoxic eVects produced by developmental exposure in animal models.

II.

TESTS OF COGNITION

Perhaps the most typically measured endpoint in studies of the neuropsychological eVects of exposure to environmental chemicals in children is standardized tests of intelligence, or IQ. Lead (Canfield, Henderson, Cory‐Slechta, Cox, Jusko, & Lanphear, 2003; Rice, 1996b), methylmercury (Kjellstro¨ m et al., 1989), and PCBs (Schantz, Widholm, & Rice, 2003) produce IQ deficits. There are no standardized intelligence tests per se for animals. However, aspects of intelligence, including learning ability and memory, can readily be assessed in almost any species. Other aspects of cognition, including so‐called executive functions such as impulse control, attention, and ability to respond appropriately to the consequences of one’s actions, may also be assessed in animal models, often using tasks the same as or similar to those used in humans (Paule, 1990; Paule, Chelonis, BuValo, Blake, & Casey, 1999). These behavioral domains are often impaired by exposure to neurotoxic agents, perhaps more frequently than IQ. Impairment in these specific domains has important consequences in terms of ability to learn and function in society.

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Deborah C. Rice Learning

A wide variety of tasks may be used to assess learning ability in animal models. Avoidance tests have a long history of use with rodents, usually rats. In an active avoidance task, the subject has to learn to move from one compartment to another to avoid a shock. In passive avoidance, the subject is required to stay in a nonpreferred lit compartment rather than moving to a preferred unlit one in order to avoid being shocked. (Rats are nocturnal and will move to the dark compartment preferentially.) These tests do not tax the learning ability of the rat, and therefore assess only gross cognitive impairment. In addition, general arousal level will influence performance on this task, since increased arousal will make it more likely that the animal will move (advantageous for active avoidance and disadvantageous for passive avoidance). Somatosensory impairment will also particularly confound the results of these tasks. Therefore, results must be interpreted with caution in the absence of information on other factors that may influence performance. Perhaps a more sensitive but still simple test of learning is the discrimination task. Discrimination tasks are usually assessed in the visual domain, even in rodents, despite the fact that the spatial vision of laboratory rodents is relatively poor compared to ours (see section on sensory function). In such tasks, the subject learns to choose one stimulus rather than another (or others). For example, the subject may have to respond to a specific shape (nonspatial discrimination) to be reinforced. Discrimination performance may be assessed using automated computer‐controlled equipment or non‐ automated procedures such as mazes. Discrimination tasks have proved sensitive to developmental exposure to lead (Rice, 1996b), methylmercury (Buelke‐Sam et al., 1985; Elsner et al., 1988), and PCBs (Rice, 1999b). However, the sensitivity of discrimination tasks in detecting toxicant‐ induced impairment is dependent upon task diYculty: there may be no eVect on tasks that are simple for the subject to learn. For example, rats exposed to lead during development were impaired on a diYcult but not easy nonspatial discrimination task (Winneke, Brockhaus, & Baltissen, 1977) (Fig. 1). A series of discrimination problems may also be presented. Normal animals will typically learn successive discrimination problems more quickly. This ‘‘learning set formation,’’ or learning to learn, represents the ability of the organism to take advantage of past exposure to a particular set of rules. Monkeys exposed developmentally to lead displayed impaired ability to learn successive problems more quickly as the experiment progressed, in addition to impaired acquisition of the individual discrimination tasks (Lilienthal, Winneke, Brockhaus, & Malik, 1986). Requiring the subject to perform a reversal of the original discrimination problem is often more sensitive to toxicant‐induced impairment than the

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FIG. 1. Number of errors on a simple and diYcult visual discrimination task in rats. Lead‐ treated rats were impaired on a task that was diYcult for controls but not on one that was easy. From Winneke et al., 1977.

initial acquisition of the task. In a discrimination reversal task, the formerly correct stimulus becomes the incorrect one and vice versa. In the nonspatial version of the task, the relevant stimulus dimension is form or color, for example, rather than the position of stimuli. Typically, the subject is required to perform a series of such reversals, which is indicative of how quickly the subject learns that the rules of the game change in a predictable manner. Nonspatial discrimination reversal performance was impaired by developmental exposure to lead (Bushnell & Bowman, 1979; Rice, 1985; Rice & Gilbert, 1990a; Rice & Willes, 1979). At lower or moderate body burdens of lead, monkeys were impaired on discrimination reversal problems even though they were not impaired on the initial acquisition of the task (Rice, 1985; Rice & Willes, 1979) (Fig. 2). Acquisition of performance (learning) can be assessed in any number of other tasks, including tasks designed to measure other domains, such as memory. A task that has been used frequently in behavioral toxicology is spatial alternation. In this task, the subject is required to alternate responses between locations (levers in a computer‐controlled task or alleys in a maze in a non‐automated task), with no cues provided to indicate correct location. This task requires the subject to abandon the position that has just produced a reward on the preceding trial, and thus requires the ability to adapt to an

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FIG. 2. Performance of lead‐treated (filled circles) and control (open circles) monkeys on the initial acquisition (0) and series of 20 reversals of a visual discrimination task. Treated monkeys were not impaired on acquisition of the task, but failed to learn the reversal task over successive reversals as quickly as did controls. Introduction of 150 extra trials on the correct stimulus for reversal 5 disrupted both groups to an equal extent, with treated monkeys making more errors per reversal for reversals 6 to 10. Five hundred extra trials following reversal 10 disrupted the performance of both groups.

imposed and arguably unnatural rule. Delays may be implemented between opportunities to respond to assess spatial memory. The ability to learn this task was impaired in monkeys exposed developmentally to PCBs (Rice & Hayward, 1997) or lead (Rice & Gilbert, 1990b; Rice & Karpinski, 1988), and rats exposed to PCBs (Schantz, Seo, Moshtaghian, Peterson, & Moore, 1996; Schantz, Seo, Wong, & Pessah, 1997). The repeated acquisition task is a task designed to assess the ability to learn new information repeatedly. This task requires the subject to learn a new sequence of responses multiple times, for example, in every daily session. The sequence may be spatial (learning to respond on a series of levers in a specific sequence) or nonspatial (learning to respond in sequence to a set of colors or shapes). Such a task assesses the ability of the subject to learn and remember new information and ignore previously learned response patterns. Learning, memory, attention, and adaptability are all components of this task. This task proved sensitive to lead exposure in rats (Cohn, Cox, & Cory‐Slechta, 1993). In particular, rats were not impaired on the performance

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component of the schedule, which did not change across sessions, but were impaired on the acquisition component, which required learning a new sequence every session. Lead exposure in children is associated with an inability to follow complex sequences of directions (Needleman et al., 1979). Although repeated acquisition performance is not directly comparable, both deficits indicate an inability to hold information online and to organize behavior in time or space. Deficits in such abilities are indicative of impairment in executive function. Another type of task that requires repeated learning and adaptation to changing environmental contingencies is concurrent schedules of reinforcement. In a concurrent schedule, diVerent ‘‘rules’’ are in eVect on diVerent levers (usually two) at the same time. The subject should learn to apportion responding according to the schedule contingencies. For example, if one lever pays oV with a reinforcer twice as often following a response as a second lever, the most adaptive strategy is to respond on the first lever twice as often. In addition, the relative payoV of the levers can be changed by the experimenter within a session or across a number of sessions, and the ability of the subject to adapt to the new contingencies can be determined. Rats exposed developmentally to methylmercury exhibited impairment in their ability to respond to changing contingencies during old age (Newland, Reile, & Langston, 2004). Impairment in transitions was also observed in monkeys exposed to either lead or methylmercury (Newland, Yezhou, Lodgberg, & Berlin, 1994). When relative reinforcement densities were changed, treated monkeys changed their behavior slowly, not at all, or in the wrong direction. B.

Memory

There are many tasks that may be used to assess memory. Retention of passive or active avoidance performance (described previously) in rodents may be assessed following a delay, typically 24 hours. This is a crude test of memory, however, and negative results (no memory impairment) should be interpreted with caution. A test of spatial learning and memory commonly used with rodents is the Morris water maze task. The subject is put into a circular pool, and must locate a submerged platform to escape the water. The time to locate the platform on subsequent trials is considered an indication of memory. The location of the platform may also be changed to assess ability to learn a new location (and cease searching for the old). This task has proved sensitive to toxicant exposure (Viberg, Fredriksson, & Eriksson, 2003). This test is sensitive to hippocampal damage in rodents (D’Hooge & De Deyn, 2001; Redish & Tourtezky, 1998). It should not be assumed that the results of this task measure all aspects of ‘‘memory,’’ but rather only very specific abilities.

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A task that is often used to assess spatial memory is delayed spatial alternation. As has been discussed, this task not only measures memory but also requires the subject to choose a location diVerent from the one that last produced a reinforcement, which may be considered a measure of adaptability. This task may be tested in a maze or using automated equipment (response buttons or levers). This task has proved sensitive to developmental exposure to PCBs in monkeys (Levin, Schantz, & Bowman, 1998) and rats (Schantz, Moshtaghian, & Ness, 1995), as well as lead in monkeys (Rice & Gilbert, 1990b; Rice & Karpinski, 1988) and rats (Cory‐Slechta, Pokora, & Widzowski, 1991) (Fig. 3). Another test of spatial memory used with rats is radial arm maze performance. The apparatus consists of a central compartment with alleys (typically eight) radiating from it like spokes of a wheel. Food reinforcers may be placed in some or all of the compartments. In some studies, reinforcements are placed in the same compartments on every test session, to test the subjects’ ability to remember across longer periods of time (so‐called reference memory). Other compartments may be baited on some trials or sessions

FIG. 3. Average latency to respond on a T‐maze delayed alternation task in male and female rats exposed to a high or low dose one of three ortho‐substituted PCBs. Exposed females had latencies similar to those of males, suggesting a masculinizing eVect. PCB‐treated female but not male rats also had more total errors than did controls. These results highlight the importance of testing both sexes, as well as the importance of assessing a number of performance measures from a study, which may provide diVerent types of information. From Schantz et al., 1995.

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and not others (working memory). The most eYcient response pattern is to enter each alley only once. The time taken to collect all reinforcements and the number of unbaited arms entered or re‐entered are determined. This task has proved sensitive to developmental dioxin (Seo, Powers, Widholm, & Schantz, 2000) and methylmercury (Dore´ et al., 2001; Goulet, Dore´ , & Mirault, 2003) exposure. Individual PCB congeners were tested in the same laboratory on both radial arm maze and delayed alternation (Schantz et al., 1995, 1996, 1997). Interestingly, the congeners impaired performance on one test and not the other; which test was aVected was congener‐specific. This suggests that these tasks measure diVerent behavioral domains, and highlights the importance of assessing behavior on a number of tasks, even tasks that purportedly measure the same aspect of behavior (such as spatial memory). A task that is used more often with monkeys than with rodents, and is also suitable for use in children, is the delayed matching to sample task. In the nonspatial version of the task, the subject is presented with a particular stimulus (such as color or form) to remember. Following a delay period, a number of unique stimuli are presented, including the sample stimulus. The requirement is to choose the (previously) sample stimulus. The spatial version of this task requires a match to a previously presented position. Monkeys exposed developmentally to lead were not impaired in the acquisition of either a nonspatial or spatial matching to sample task (Rice, 1984), but lead‐treated monkeys performed more poorly than did controls under delay conditions. Control monkeys reached chance performance at longer delay values than treated monkeys. C.

Attention

Attentional deficits are a common consequence of developmental exposure to environmental toxicants in humans, including lead (Fergusson, Fergusson, Horwood, & Kinzett, 1988), methylmercury (Grandjean et al., 1997), and PCBs and dioxins (Patandin, Veenstra, Mulder, Sewnaik, Sauer, & Weisglas‐Kuperus, 1999). Attentional deficits may also result from developmental exposure to drugs such as maternal tobacco smoking, cocaine, or marijuana (Fried & Smith, 2001; Fried & Watkinson, 2001; Leech, Richardson, Goldschmidt, & Day, 1999; Richardson, Ryan, Willford, Day, & Goldschmidt, 2002). Assessment of attentional processes in animals has received considerable attention over many years. This section will describe only a few of the available procedures. For an excellent review of the literature, see Bushnell, 1998. A task that has proved sensitive to developmental toxicant exposure in a number of studies is a vigilance task, which is typically assessed using a

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computer for stimulus presentation and recording of responses (Grandjean et al., 1997; Stewart et al., 2003a; Winneke, Brockhaus, Collet, & Kraemer, 1989). The child is asked to respond to one stimulus and not to respond to others. Typical stimuli are animal pictures for younger children or letters for older ones. Stimuli are presented one at a time. The main dependent variable is reaction time, or the time between presentation of the stimulus and the response. The child is told to respond as quickly as possible. Errors of commission (false positives) and omission (false negatives) should also be recorded. This task is one form of a signal detection task. Another form of signal detection task used to measure attention in animals is also called the go–no go procedure. In this task, the subject is asked to respond when one stimulus type is presented and to withhold responding when a diVerent one (or none) is presented. This task is often used to study the ability of the subject to detect or discriminate between stimuli. This test may be used in both humans and animals (including rodents) to test sensory thresholds. This task has been used in both humans and rodents to test attention using suprathreshold stimuli (Bushnell, Benignus, & Case, 2003; Oshiro, Krantz, & Bushnell, 2001). A task similar to the signal detection task is the complex reaction time task, which requires the subject to respond to a particular stimulus rather than to others presented simultaneously. A similar task that is probably less sensitive to attentional deficits is a simple reaction time task, in which the subject is required to respond as quickly as possible to presentation of an invariant stimulus. Monkeys exposed to methylmercury from birth to adulthood were not impaired on a simple reaction time task or a series of complex reaction time tasks in either reaction time or accuracy (Rice, 1998a). Similarly, developmental lead exposure did not aVect performance on a simple reaction time task (Rice, 1988). However, treated monkeys did display an increased incidence of failure to respond to the stimulus within a specified time period. In addition, several groups of lead‐ or methylmercury‐exposed monkeys were tested on a number of very diYcult sensory assessments, which required response to stimuli at or near threshold. The reaction times of treated monkeys were not diVerent from those of controls, in terms of average response time or distribution of responses. Nor did they change across the course of the often lengthy session, indicating that attention was sustained for long periods of time. These negative results are in contrast to the eVects of lead or methylmercury on performance on vigilance tasks in children (Grandjean et al., 1997; Winneke et al., 1989). It may be that eVects would have been observed on a vigilance task in lead‐exposed animals, since the eVects in children were on errors of commission (i.e., responding to nontarget stimuli) rather than reaction time, which may reflect impairment in

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impulse control rather than attention. On the other hand, increased reaction times were observed on a simple reaction time task in lead‐exposed children (Needleman, 1987). Parsing the behavioral mechanisms responsible for deficits on tasks meant to assess attention is diYcult, in either animal models or humans. Increased errors of commission may be the result of failure to inhibit inappropriate responding rather than to attentional deficits (see following text). Sensory deficits, particularly in higher‐order sensory processing, may masquerade as attentional problems. Obviously, motor deficits would interfere with performance on reaction time tasks. Impaired learning ability may be interpreted as attentional deficits. It is important to test subjects, human or animal, until stable performance is attained, and cognition should be assessed independently on other tasks. D.

Distractibility

A behavioral domain that is linked to attention is distractibility: the lack of ability to stay on task in the presence of irrelevant stimuli. Lead‐exposed children were rated by their teachers as being more distractible (Needleman et al., 1979; Yule, Urbanowicz, Lansdown, & Millar, 1984). On a rating scale used in a study in New Zealand, the ‘‘attention’’ subscale included ‘‘short attention span’’ as well as ‘‘inattention, easily distracted’’; both were impaired as a function of increased lead exposure (Fergusson et al., 1988). Distractibility may be tested directly by the systematic introduction of irrelevant cues, and/or by identifying systematic response patterns associated with irrelevant stimulus dimensions. For example, irrelevant cues were introduced into a nonspatial discrimination task in two studies of lead‐exposed monkeys (Rice, 1985; Rice & Gilbert, 1990a). Even though lead‐treated monkeys had learned the task as well as controls, they performed more poorly after introduction of irrelevant cues, and attended to (responded on) the irrelevant cues in systematic ways. E.

Impulsivity

One of the hallmarks of developmental lead exposure is inability to inhibit inappropriate behavior (Needleman et al., 1979; Rice, 1996b). Increased impulsivity as a result of developmental PCB (Patandin et al., 1999; Stewart et al., 2003a) or lead (Raab, Thomson, Boyd, Fulton, & Laxen, 1990) exposure is evidenced by increased errors of commission on a vigilance task. Developmental methylmercury exposure was associated with increased reaction time and omission errors; eVect on commission errors was not reported (Grandjean et al., 1997).

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There are a number of ways to measure the ability of animals to inhibit inappropriate responding. In many cognitive tasks assessed in experimental animals, opportunities to make a response choice are separated by short periods (inter‐trial intervals) during which responding is neither punished nor rewarded. Similarly, incorrect responses are often punished with a short ‘‘time out’’ period in addition to withholding a reinforcement (reward). Increased responding during these periods indicates failure of impulse inhibition. For example, developmental lead exposure produced increased responding in schedule components in which responding was never reinforced in monkeys (Rice, 1992a; Rice, Gilbert, & Willes, 1979) and rats (Angell and Weiss, 1982). A simple task that assesses the ability to inhibit responding is the DRL (diVerential reinforcement of low rate) schedule of reinforcement. This schedule has been used in animals for decades, initially in the pharmaceutical industry and, more recently, in the study of the eVects of environmental chemicals. Under this schedule, the subject is required to wait a specified amount of time between responses (or between reinforcement and the next response) to be reinforced; responding before the elapsed time results in the time requirement’s being reset. This schedule is suitable for many species, including rodents, monkeys, and humans. In a study of monkeys exposed postnatally to PCBs, control animals learned over the course of a number of sessions to space the majority of responses at least 30 sec apart, the time required to be rewarded (Rice, 1998b) (Fig. 4). In contrast, the average interval between responses for the PCB‐treated monkeys was still less than 30 sec even after 50 days of testing. In consequence, PCB‐treated monkeys received fewer reinforcements and made more nonreinforced responses. In other words, they failed to inhibit responding even when punished for not doing so. Lead‐exposed rats also performed more poorly than did controls on a DRL task (Alfano and Petit, 1981; Dietz, McMillan, Grant, & Kimmel, 1978). This schedule has also been used in children exposed to PCBs. Failure to inhibit responding was associated independently with in utero exposure to PCBs or methylmercury, or postnatal exposure to lead in school‐age children (Paul Stewart, personal communication). Thus, there was congruence between animal and human data on the same schedule for the eVects of developmental PCB exposure. EVects on IQ identified in early childhood were not present as the children got older (Stewart et al., 2003b). The eVects observed on this schedule indicate that the DRL schedule is measuring something diVerent from IQ. The use of the DRL in this study was based directly on results from the monkey study, and exemplifies the potential for a two‐way fertilization between epidemiological and experimental research.

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FIG. 4. The mean time between responses (inter‐response time or IRT) and the ratio of reinforced/nonreinforced responses for controls and monkeys exposed postnatally to PCBs. An IRT of at least 30 sec was required for reinforcement. The mean IRT of the treated group was still less than 30 sec after 50 sessions (days) of testing. Their response pattern was less eYcient that the control group; they made many more responses for each reinforcement. From Rice, 1998b.

Another schedule that has been used extensively to assess the eVects of drugs and chemicals on behavior is the fixed interval (FI) schedule of reinforcement. Under this schedule, the subject is required to make one response after a specified elapsed time to be reinforced. Unlike the DRL schedule, premature responding under the FI schedule has no scheduled consequences. After the subject learns the schedule, responding is typically characterized by a pause at the beginning of the interval, followed by a gradually accelerating rate of response terminating in reinforcement. Developmental lead exposure resulted in increased rates of response in both

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monkeys (Rice, 1992a; Rice et al., 1979) and rats (Angell and Weiss, 1982; Cory‐Slechta, Weiss, & Cox, 1983, 1985) (Fig. 5). Similarly, monkeys exposed developmentally to PCBs exhibited increased rates of response (Rice, 1997a). The FI schedule does not specifically punish high rates of response. Nonetheless, high response rates represent at least ineYcient behavior, and may be viewed as representing failure of response inhibition.

F.

Perseveration

Another nonadaptive response pattern is perseveration—persisting in response patterns that do not pay oV or have ceased to pay oV. Perseveration represents failure to adapt appropriately to environmental contingencies or changes in those contingencies. A test used in humans that assesses perseveration and adaptability is the Wisconsin Card Sort Test. In this test, the experimenter presents a sample card, and then several possible test cards that match the sample card in one or more domain. Responding correctly depends on the ability to generalize whether the relevant stimulus domain is color, number, or shape, which must be inferred from the consequences of responses (verbal feedback on whether the choice was correct or not). The investigator may change the relevant stimulus class at any time, and the subject must infer the new rule by whether responses are identified as correct or incorrect. Concurrent blood lead levels in children were associated with an increase in perseverative errors on this task (Chiodo, Jacobson, & Jacobson, 2004; Stiles & Bellinger, 1993). That is, more highly lead‐exposed children continued to respond as if the experimenter had not changed the ‘‘rule’’ of which stimulus class was relevant. Perseveration may be assessed in animals in a number of ways. In the delayed nonspatial discrimination task, already described, the relevant stimulus class was also changed, similar to the Wisconsin Card Sort Test. Lead‐ exposed monkeys attended to the newly irrelevant stimulus class longer than did controls (Rice, 1985; Rice & Gilbert, 1990a). Marked perseverative behavior was observed in a spatial delayed alternation task in monkeys exposed developmentally to lead (Rice & Gilbert, 1990b; Rice & Karpinski, 1988). In that task, the monkey was required to alternate responses between two buttons. If the monkey responded incorrectly, a response had to be made on the opposite correct button before a response on the alternate button was considered correct. Delays were interspersed to assess short‐term memory. At even very short delays, lead‐treated monkeys perseverated on the same button, responding incorrectly for sometimes hours at a time without switching to the other button (Fig. 6). Increased perseverative behavior on a delayed alternation task has also been observed in rats

FIG. 5. The number of responses per second emitted on an FI schedule by lead‐exposed (triangles) and control (asterisks) monkeys. Monkeys were exposed to lead from birth onward (Group 2), during infancy only (Group 3), or beginning after infancy (Group 4). Lead‐treated monkeys in all groups responded at a higher rate. Lead exposure during infancy only was suYcient to produce this eVect, as was exposure beginning after infancy. This suggests that eVects are irreversible, and that exposure during infancy is not necessary for lead‐induced impairment. From Rice, 1992a.

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FIG. 6. The session length and total number of incorrect responses on a delayed spatial alternation task in controls (triangles) and monkeys exposed to a low dose (Xs) or higher dose (inverted triangles) of lead from birth. The session ended after 100 correct responses. Each incorrect response extended the session by one response. Treated monkeys made many perseverative errors, in some cases, hundreds in a row, which resulted in much longer session lengths as well as an increased number of errors.

exposed to lead (Cory‐Slechta et al., 1991) and in monkeys exposed developmentally to PCBs (Rice & Hayward, 1997). Lead‐exposed monkeys also perseverated for position on the concurrent discrimination task (Rice, 1992b). Treated monkeys responded incorrectly

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on the previously correct position more often than did controls, even though position was irrelevant in the task. Lead‐exposed monkeys also perseverated on a previously correct position on the nonspatial delayed matching to sample task already discussed (Rice, 1984). Detection of the types of deficits identified on the tasks discussed often required detailed analysis of response sequences and error patterns. Simply tallying errors would have provided little or no insight into the specific functional domains aVected by toxicant exposure.

III.

SENSORY FUNCTION

There are many chemicals that produce sensory deficits in humans and animals, including metals, solvents, and pesticides. Animal models, including rodents, can provide useful information concerning sensory system impairment. Extrapolation of results from evaluation of sensory system function in animals is relatively straightforward for a couple of reasons. First, if the stimulus presentation is well controlled, the variance of the control group for the function being measured should be relatively small. This allows smaller changes in sensory system function to be detected in treated groups compared to other endpoints such as learning or memory. Second, the results are readily interpretable, and usually can be extrapolated to humans in a relatively straightforward manner. Although sensory function varies among species in sensitivity and the range in which stimuli can be detected, sensory loss in one species predicts a similar loss in another species. A.

Vision

Humans and other Old World primates have better spatial vision than most other animals, as well as trichromatic color vision. There are important diVerences with respect to visual function between nocturnal rodents (rats and mice) and humans. Half of the primate (including human) brain is devoted to visual processing. In contrast, rodents rely largely on olfaction and audition, as well as somatosensory information via the vibrissae (whiskers) to receive information about the environment. Humans also have binocular vision, and therefore good depth perception. We thus are able to detect and interpret the visual world in considerable detail. The spatial frequencies that delineate objects are analyzed by our visual system by sorting them into their sine wave components. Therefore, determining the ability of the visual system to detect sine waves over a number of frequencies assesses the fundamental function of the system, at least in the orientation of testing (usually, vertical sine waves). The ability to detect high

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frequencies may be considered roughly equivalent to tests of visual acuity, which measure only one point on the frequency threshold curve. The spatial visual function of macaque monkeys is almost identical to that of humans (Fig. 7). In contrast, the ability of nocturnal rodents to detect spatial frequencies is poor. Albino animals, including albino rats, have abnormal visual anatomy and physiology, and therefore poor spatial vision compared to normally pigmented members of their species. Rats and mice also have retinas composed almost exclusively of rods, and therefore have little or no color vision. Rodents also do not have binocular vision. Therefore, rodents have limited utility for the study of some aspects of human visual function, although basic mechanisms of toxicity may be studied, as has been done for lead, for example (Fox et al., 1994, 1997, 1998). Spatial vision was assessed in our laboratory in several groups of monkeys exposed to methylmercury or lead during various developmental periods. To perform the task, the monkey sat in a restraining chair in a light‐tight chamber facing two oscilloscopes. On one was a sine wave grating, and the other displayed a blank field of equal average luminance. The monkey was required to press a button corresponding to the scope displaying the grating. For each of a number of spatial frequencies (a few wide bars to many narrow bars on the screen), the contrast between the lightest and darkest part of the grating was varied systematically across trials, and the contrast at which the monkey could not distinguish the scope displaying the grating from the blank scope was determined. That point was considered the threshold for that frequency. Monkeys exposed to moderate levels of methylmercury exhibit deficits in high‐frequency spatial vision under high luminance conditions, whether exposure was prenatal only (Burbacher et al., 2005), postnatal only (Rice & Gilbert, 1982), or pre‐ plus postnatal (Rice & Gilbert, 1990c). When tested under very low luminance conditions (comparable to dim starlight) that

FIG. 7. Left panel: Contrast sensitivity (CS) functions for a number of species. The CS is the inverse of the minimum contrast between the light and dark gradations across a sine wave grating that can be distinguished by the subject; higher contrast sensitivity represents better spatial vision. Note the three y‐axes. Right panel top: CS of humans and macaque monkeys under five luminance conditions. CS is best in bright light and worst under very low luminance conditions. Right panel bottom: CS of control monkeys (solid lines) under high and low luminance conditions, and two monkeys exposed to methylmercury from birth. One methylmercury‐treated monkey (left) had a high spatial frequency deficit under high luminance conditions, and a small deficit across all frequencies under low luminance conditions. The other monkey (right) had very impaired CS at high luminance at all but very low frequencies as well as impairment in CS across frequencies at low luminance. This monkey navigated her environment in an apparently normal manner, including in the large exercise cages she shared with others. From Rice, 1990.

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required a significant period of dark adaptation (rod vision), spatial vision was impaired across most frequencies (Rice & Gilbert, 1982, 1990c). Deficits in spatial visual function were also reported in children exposed to methylmercury in utero (Altmann et al., 1998) and adults exhibiting methylmercury poisoning (Mukuno et al., 1981). Motion detection is another important aspect of visual function. Humans sacrifice motion sensitivity in favor of spatial and color vision. Predatory species, such as domestic cats, have superior motion vision compared to humans, but cats have poorer spatial vision than do humans. Although cats have been used extensively to study the physiology of vision, they have been little used in toxicology. The eVect of developmental methylmercury or lead exposure on motion vision was also studied in monkeys using forced‐choice discrimination, with one screen displaying a sine wave flicker and the other an unflickering blank field. The behavioral paradigm was the same as that used for testing of spatial vision. Methylmercury exposure resulted in superior temporal vision under low luminance conditions (Rice & Gilbert, 1990c). This finding was interpreted as possibly resulting from selective remodeling of the visual system, with damage to the parvocellular system (important for high‐frequency spatial vision) allowing for expansion of the magnocellular system (important for detection of flicker). In contrast, developmental lead exposure produced no eVect on spatial vision but deficits in motion vision (Rice, 1998c). It was important to test several aspects of visual function to characterize or, in some cases, even to detect, deficits in visual function. One of the hallmarks of methylmercury poisoning in adults is constriction of visual fields (Takeuchi & Eto, 1999). This finding was replicated in adult macaque monkeys exposed chronically to methylmercury during adulthood (Merigan, 1980). Deficits in visual fields were not observed in monkeys in our laboratory as young adults, based on an assessment using a simple non‐ automated system. Monkeys fixated on a treat in the center of a cardboard circle, and treats were moved in from the sides until the monkey moved its gaze to the treats. This procedure tested only the binocular visual field, not the field for each eye, and was undoubtedly much less sensitive than automated systems designed to test visual fields. Nonetheless, some individuals exhibited mild constriction of visual fields during old age compared to age‐matched controls (Rice, 1996c). This suggests a delayed eVect of methylmercury many years after cessation of methylmercury exposure, and/or an interaction of previous methylmercury exposure and aging (Rice, 1996c). Only Old World monkeys, apes, and humans have a color discrimination system based on three receptor types, which are sensitive to red, green, or blue light. Our discrimination of color is based on ‘‘averaging’’ the input of these receptor types, which is why combinations of many diVerent

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frequencies can look like the same shade to us. Other monkeys may have only two receptor types, and other animals may have one or none. The most common defect of color vision in humans is red–green color blindness, which is typically caused by a genetic deficit that results in abnormal red or green receptors. In contrast, solvent exposure in adults produces a characteristic loss of blue–yellow color vision (Campagna et al., 2001), which is associated with damage to external retinal layers, or more extensive color vision loss, which may include damage to internal retinal layers and/or optical nerve (Geller & Hudnell, 1997). Color vision loss has been demonstrated in monkeys exposed to acrylamide (Merigan, 1989). Testing for color vision deficits predictive of those in humans would preferably be performed in animals with comparable color vision systems, particularly if the type of deficit is unknown. If human data suggest a particular type of color vision deficit that may be explored in other species, for example, New World monkeys with two receptor types, then those species may be used. Birds have very good color vision, and have long been used in the study of behavior and behavioral pharmacology. They have a tetrachromatic visual system, which uses oil droplet filters in the detection of various wavelengths. The diVerential eVect of a toxicant on mammals versus birds is diYcult to predict, making birds a less desirable model than primates for color vision research. However, birds have been used to study the eVects of drugs on color vision and other aspects of visual function (Bradley & Blough, 1993). B.

Audition

Unlike the visual system, the anatomy and physiology of the auditory system of mammals is similar across species. (As is true for the visual system, however, albino animals may have impaired auditory function.) Frequencies are detected individually by excitation of receptors at a specific location on the cochlear membrane. Rats and Old World monkeys can hear frequencies about twice as high as humans, with low‐ and mid‐frequency detection being similar. A simple test of audition is often included in screening tests of the neurotoxicity of chemicals using rats. The startle response to a loud noise is a test of the overall integrity of the nervous system, and may reveal deafness or serious hearing impairment as well as motor impairment. The response may be dependent upon the stimulus parameters (Marable & Maurissen, 2004). Often, the frequency or frequencies delivered and amplitude (loudness) are not well characterized. However, this basis approach can be used to determine hearing thresholds over a range of frequencies using well‐controlled stimulus presentation. A loud stimulus that would elicit a startle is preceded by a stimulus of the same frequency but lower amplitude.

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If the first stimulus is detected (heard), the animal does not startle, or the startle is attenuated. The threshold can be determined by varying the amplitude of the first stimulus. This ‘‘pre‐pulse inhibition’’ paradigm has been used to assess the ototoxicity of a variety of agents. For example, low‐ frequency hearing deficits were identified in rats developmentally exposed to a PCB congener (Crofton & Rice, 1999). A standard clinical test suitable for use in adults or children is pure‐tone audiology, the determination of the threshold for a number of frequencies. Pure tones are delivered through an earphone to each ear separately. Typically, a number of amplitudes are presented at each frequency, and the person indicates when a tone is detected. The lowest amplitude (loudness) detected is considered the threshold. Both developmental lead (Schwartz & Otto, 1987) and methylmercury (Murata, Araki, Yokoyama, Uchida, & Fujimura, 1993) exposure produce deficits in detection of pure tones in children. Monkeys have been used to examine the eVects of developmental exposure to lead and methylmercury on pure‐tone thresholds. The monkey sat in a primate chair with earphones, so that stimuli could be presented to each ear independently in a controlled manner. The monkey indicated detection of a tone by breaking contact with a metal bar (a signal detection task). This method of response allows determination of the latency to respond, which provides important information concerning behavioral control and threshold. (Latencies should increase close to threshold, and should be reasonably consistent across presentations of the same amplitude and frequency combinations.) Thresholds were determined in each ear over a number of frequencies. Monkeys exposed to methylmercury from birth to adulthood exhibited increased thresholds at high frequencies (Rice & Gilbert, 1992) (Fig. 8), as did monkeys exposed continuously to lead from birth (Rice, 1997b), whereas monkeys exposed pre‐ plus postnatally exhibited impaired hearing over a wide range of frequencies. Pure‐tone thresholds provide only basic, first‐level information concerning auditory function. An individual may have normal pure‐tone detection and still have diYculty distinguishing speech, for example. Speech is comprised of generally small but rapid changes in frequency and amplitude. It is technically straightforward to test frequency or amplitude ‘‘diVerence thresholds’’ (ability to detect changes in frequency or amplitude) in animals exposed to toxicants, although this has not typically been done. DiVerence thresholds for frequency were a more sensitive indicator of auditory impairment following aminoglycoside antibiotic exposure in monkeys (Stebbins, Clark, Pearson, & Weiland, 1973). On the other hand, amplitude diVerence thresholds were unimpaired in guinea pigs in the presence of deficits in pure tone thresholds (Prosen, Moody, Stebbins, & Hawkins, 1981).

FIG. 8. Thresholds for pure tones in each ear for control and five monkeys dosed with methylmercury from birth. Only monkey 34 had normal detection of pure tones. Other monkeys had varying degrees of middle‐ to high‐frequency hearing loss, and could not be tested at the higher frequencies tested in controls. Monkey 34 had the most impaired visual function of any in her methylmercury‐exposed cohort (Fig. 7). The results of these studies highlight individual sensitivity: in this case, sensitivity within a subject for impairment in two sensory systems. Individual sensitivity among subjects is routinely observed in toxicology experiments. From Rice & Gilbert, 1992.

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An alternative approach is to study the eVects of toxicants on language discrimination directly. A test that is used clinically to evaluate auditory (language) processing is the determination of the infant’s ability to distinguish ba and da and, at a later age, bi and di. Monkeys can also discriminate human speech sounds. In a study with rhesus monkeys, it was reported that developmental lead exposure impaired the ability of young monkeys to discriminate speech sounds (da and pa) using an electrophysiological procedure (Molfese et al., 1986). Lead‐exposed children are impaired on the Seashore Rhythm Test (Needleman et al., 1979), which requires the subject to discriminate whether pairs of tone sequences are the same or diVerent. Lead‐exposed children also have a decreased ability to identify words when frequencies were filtered out (i.e., when information was missing [Dietrich, Succop, Berger, & Keith, 1992]). Interestingly, rats are apparently also able to discriminate between human speech sounds using the same mechanisms used by humans (Reed, Howell, Sackin, Pizzimenti, & Rosen, 2003; Toro, Trobalon, & Sebastian‐Galles, 2005). This observation presents new possibilities for studying the eVects of toxicants on auditory processing using rodents. This would allow information of significant relevance to humans to be collected in an inexpensive and well‐studied toxicological model.

C.

Somatosensory Function

Somatosensory information is composed of several modalities—light touch, pressure, pain, temperature, vibration, and joint proprioception. These modalities are subserved by diVerent receptor types, and associated nerve fibers may be either myelinated or unmyelinated. DiVerent receptor or nerve types may be diVerentially sensitive to impairment by toxic agents. Many neurotoxicants produce impairment of somatosensory function in humans, which has been most completely documented in adults. Lead produces a peripheral neuropathy that is characterized by both motor and sensory impairment (Seppalainen, Hernberg, Vesanto, & Koch, 1983; Zimmermann‐Tansella, Campara, D’Andrea, Savonitto, & Tansella, 1983 ). A characteristic symptom of methylmercury poisoning is paresthesia in the distal extremities (‘‘stocking and glove’’ paresthesia), as well as perioral paresthesia (Tsubaki & Irukayama, 1977; WHO, 1990). In fact, a number of metals, in addition to solvents and pesticides, produce impairment of somatosensory function as a consequence of peripheral neuropathy (Rice, 1999b). Somatosensory function in humans is typically assessed clinically using crude procedures and uncontrolled stimuli (Rice, 1997c). This may include asking the individual whether she or he detects light touch, pinprick, or a

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tuning fork placed against the skin. These procedures may identify large deficits, but are not adequate to detect less severe changes in function. Screening tests in rodents may include relatively crude assessment of somatosensory function, including infliction of pain/pressure (pinching the feet with the fingers or forceps), pain (electric shock), or pain/heat (hot water). Reacting to the stimulus or drawing away from it is considered to indicate detection. As with other sensory system testing, assessment of subclinical impairment requires careful control of stimulus presentation and a well‐defined response. Probably the easiest stimulus to control is vibration. Depending on the frequency, vibration is detected by several types of end organs and nerve fibers, and so may be diVerentially aVected by neurotoxic exposure. Vibration sensitivity was assessed in monkeys exposed to lead beginning at birth, or exposed to methylmercury either postnatally or pre‐ plus postnatally (Rice & Gilbert, 1995). The monkey’s hand was positioned so that the tip of the middle finger made slight contact with a dull needle. The needle was vibrated, with the frequency and amplitude controlled precisely by computer. The monkey signaled detection of the stimulus by breaking contact with a bar with the other hand. Developmental lead exposure resulted in moderately elevated thresholds at higher frequencies, whereas methylmercury exposure produced severe impairment in some individuals. A similar technique was used to determine somatosensory impairment produced by acrylamide and misonidazole following adult exposure in monkeys (Maurissen, Weiss, & Davis, 1983; Maurissen et al., 1981). This procedure can be used in humans with little or no modification. It could also be modified for use with other species. In addition, other modalities could be tested using similar procedures.

D.

Olfaction and Taste

These senses receive little attention in developmental behavioral toxicity testing, so the degree to which they may be aVected is largely unknown. These senses may be impaired or have other abnormalities in syndromes such as autism, and may contribute to strange food preferences or aversions (P. Rodier, personal communication). The perception of the taste of food is largely dependent on olfaction; there are only five types of taste receptors (sweet, sour, bitter, salt, and umami). Olfaction is an important sense in rats and mice, as evidenced by the large olfactory bulb. An olfactory discrimination task may be used with rodent pups as a simple test of learning (Buelke‐Sam et al., 1985); the pup is required to find a location containing its home‐cage bedding. Olfactory ability could be assessed using test procedures

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similar to those used for other modalities. Testing requires adequate control of stimulus presentation, but that is true for all sensory system testing.

IV.

MOTOR FUNCTION

Motor function may somewhat arbitrarily be divided into gross movement, including postural control and stability, and fine motor function. Both may be aVected by exposure to a variety of chemicals as a result of occupational exposure, including metals, solvents, and pesticides. Motor development was assessed in infants in a number of epidemiological studies of the eVects of developmental exposure to neurotoxicants using an infant assessment battery, including methylmercury (Grandjean et al., 2001), PCBs (Huisman et al., 1995; Stewart, Reihman, Lonky, Darvill, & Pagano, 2000), and drugs of abuse (Morrow et al., 2001). Many studies included assessment of motor function in young children using the Bayley Scales of Infant Development, which includes tests of postural stability, and gross and fine motor function (e.g., Bellinger, Leviton, Needleman, Waternaux, & Rabinowitz, 1986). There are a number of procedures available in rodents for assessment of gross movement (Ossenkopp, Kavaliers, & Sanberg, 1996). Probably the one most often used in toxicology is the ability to stay on a ‘‘rotorod,’’ which is a cylinder that can be rotated at various speeds. The latency to fall from the rod is recorded. Additional tasks include climbing a rope, an inclined plane, or a screen. Swimming ability may also be assessed. Such tests would seem to be directly comparable to motor tests in children, and can be interpreted in a straightforward manner. For example, developmental PCB exposure in rats results in impairment on rotorod performance (Roegge et al., 2004) and methylmercury exposure produced deficits in swimming ability and posture (Spyker et al., 1972). Another common test used in rodents is grip strength, the measurement of the ability of the rodent to hold onto a rod being pulled away by an experimenter. The force required for the rodent to break its hold with the front or hind feet is determined. This is a semiquantitative measure of strength (and somatosensory function) that will probably detect moderate neuropathy, but is not a well‐controlled procedure and therefore would not be expected to detect small deficits. Another test of gross motor integrity is hindlimb foot splay. The rodent is dropped from a specific height, and the distance between the inked hind paws is measured. Grip strength, rotorod performance, and hind limb foot splay may be diVerentially sensitive to toxicant exposure (Gilbert & Maurissen, 1982; Youssef & Santi, 1997). Locomotion is also typically measured as part of a screening battery for developmental neurotoxicity in rodents. Locomotor activity may be

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considered an apical test, integrating the output of the entire nervous system (sensory, motor, arousal, cognitive, etc.). It may also be influenced by toxicity in other organ systems; if the animal feels ill, for example, motor activity will likely be aVected. Thus, locomotor activity is not a specific test, in that it may be aVected by many factors not directly related to nervous system toxicity. In addition, it provides little or no information concerning what behavioral domains may be aVected by a particular exposure. Locomotion may be recorded electronically using photocells, either in a rectangular area (‘‘open field’’) or in a ‘‘figure‐eight maze,’’ which is an intersecting alley shaped like a figure‐eight (Vorhees, 1985). An alternative method is to place the subject in an open field sectioned into grids and manually observe the number of grids entered. In addition to horizontal movement, rearing is often quantified separately. Total activity may also be measured using some kind of transducer under the cage containing the subject; this method will also record grooming, scratching, etc. Rodents typically engage in higher levels of both horizontal and rearing activity when first introduced into a novel environment, which is interpreted as exploratory behavior. Activity decreases over time; usually, there is a marked decrease in activity over an hour or so (Fig. 9). This is referred to as habituation, and

FIG. 9. Habituation of motor activity in normal rats across time from six diVerent testing laboratories using various measuring devices. Data are normalized to percentage of initial activity. Habituation was observed in all laboratories, despite marked diVerences in experimental conditions and total activity ‘‘counts.’’ From Crofton & MacPhail, 1996.

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is often considered to be indicative of cognition. Decreased habituation has been observed as a result of developmental exposure in mice to PCBs (Eriksson & Fredriksson, 1996) or polybrominated diphenyl ether (PBDE) flame retardants (Viberg, Fredriksson, & Eriksson, 2004). Normal rodents also spend the majority of their time near the sides of the enclosure rather than in the middle. All of these variables may be influenced by exposure to a toxicant. Any toxicant will aVect locomotor performance at some dose, because the animal is ill. This is also true for any neurotoxicant, which at some dose will produce central nervous system depression. Stimulants such as amphetamine produce increased locomotion at lower doses, and decreased locomotor behavior at high, toxic doses (Buelke‐Sam et al., 1985). This same pattern results from developmental exposure to lead in rodents (Rice et al., 1979). However, increased locomotion in rodents is not comparable to ‘‘hyperactivity’’ in children (attention deficit hyperactivity disorder or ADHD). This syndrome is characterized by increased impulsivity and attention problems, although increased activity may also be present. A DRH (diVerential reinforcement of high rate) schedule of reinforcement was used to assess performance in aging rats exposed developmentally to methylmercury (Newland & Rasmussen, 2000). The rats were required to respond on a lever a specified number of times within a short time period. As the treated rats aged, they were increasingly less able to perform the task. This may well represent motor impairment that was not apparent upon observation of the rats, although cognitive deficits may also be at least partially responsible. The eVects of prenatal lead exposure were studied on gross motor movement and strength during adulthood in monkeys (Newland, Yezhou, Logdberg, & Berlin, 1996). Monkeys were required to pull back a bar under load on either an FI schedule or a fixed ratio (FR) schedule, the latter engendering a high rate of response. Treated monkeys made fewer completed responses under the FR schedule but not the FI schedule, which generates a lower response rate. This suggests that eVects were due to motor impairment rather than some other factor, such as motivation. Postural stability may also be sensitive to exposure to developmental toxicants in children. Commercially available instruments measure several elements of postural sway under various experimental conditions. Lead exposure aVects a number of aspects of postural stability in children (Bhattacharya, Shukla, Bornschein, Dietrich, & Keith, 1990; Despre´ s et al., 2005). It would be diYcult to measure postural stability directly in four‐ footed animals, so that indirect evidence, such as impaired motor dexterity, is relied upon. A number of motor behaviors may be tested in preweaning

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rodents, for example, for which the ontogenetic development has been determined (see review by Rice & Barone, 2000). Fine motor control may also be sensitive to impairment by exposure to developmental neurotoxicants. Lead (Chiodo et al., 2004; Stiles & Bellinger, 1993) and methylmercury (Grandjean et al., 1997) aVect fine motor performance in children, for example. Fine motor control was assessed in monkeys exposed developmentally to methylmercury (Rice, 1996c). Monkeys retrieved fruit pieces from a series of compartments with varying depths. Methylmercury‐treated monkeys took longer to retrieve the fruit, and some had diYculty retrieving from the deeper compartments. In contrast, these monkeys did not exhibit deficits in gross arm movement, as measured by an automated reaction time experiment (Rice, 1996c). These monkeys also exhibited an intension tremor in their hands during old age (unpublished), which is characteristic of methylmercury poisoning. Since these monkeys had somatosensory impairment in their fingers, it is quite likely that the fine motor impairment was due, at least in part, to somatosensory deficits.

V.

CONCLUSIONS

There is a wealth of testing procedures for assessing cognitive, sensory, and motor function in animal models. These range from screening tests or batteries to very sophisticated and detailed assessment of functional abilities of the subject. Many of the same cognitive domains can be studied in animals as those that have been found sensitive to toxicant exposure in children: learning, memory, adaptability, attention, impulsivity, distractibility, and perseverative behavior. Motor function can be assessed in animal models by numerous techniques, and results are directly applicable to humans. The visual system of typical animal models (nocturnal rodents) lacks good color and spatial vision; therefore, important aspects of human vision are diYcult to assess. However, visual loss in rodents may nonetheless be predictive of loss in the same function in humans, and mechanisms of toxicity can be productively studied in rodents. For senses other than vision, the physiological processes of animals and humans are the same or at least very similar, such that deficits identified in animals are readily extrapolated to humans. It is important to be cognizant of certain caveats, however. Simple (screening) tests may be nonspecific or insensitive (or both). If the cognitive capability of the animal is not suYciently taxed, the test will be insensitive to all but gross impairment. Failure to assess a number of behavioral domains risks not detecting even relatively severe impairment. Lack of good stimulus

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control for sensory system assessment results in increased variability and therefore decreased sensitivity. Similarly, assessment of motor performance requires adequate control of both response requirement and motor response. Finally, contribution of dosing and dosing regimen, developmental period of exposure, and diVerences in metabolic capabilities between humans and animal models to outcome must be kept in mind, and understood as well as possible, in the interpretation of results from studies in animal models of developmental neurotoxicity of environmental chemicals.

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