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Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton (FL): CRC Press/Taylor & Francis; 2006.

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Chapter 6Animal Models of Cognitive Impairment Produced by Developmental Lead Exposure


Maine Center for Disease Control and Prevention

Lead is probably the most-studied environmental contaminant with respect to the effects of developmental exposure on cognition in children or animal models. It has been known since the 1940s that lead poisoning in children can result in permanent behavioral sequelae, including poor school performance, impulsive behavior, and short attention span [1], that were observations later replicated by other investigators [2–4]. Early in the 1970s, deficits in intelligence quotient (IQ), fine motor performance, and behavioral disorders such as distractibility and constant need for attention were observed in children who had never exhibited overt signs of toxicity [5, 6]. In 1979 Needleman et al. [7] reported decreased IQ and increased incidence of distractibility and inattention in middle-class children who had not been exposed to lead from paint.

Early studies of the effects of developmental exposure to lead in animals focused on determining deficits on a wide variety of tasks characterizing the constellation of the effects of lead [8]. Exposures in various studies included postnatal, lifetime, in utero, or in utero plus postnatal. Researchers also sought to identify a dose or body burden that did not produce adverse effects. A series of experiments with monkeys in our laboratory documented adverse effects in a group of monkeys with peak blood lead concentrations averaging 15 μg/dl during infancy, with steady-state levels over most of the lifespan averaging 11 μg/dl. Animals with lower body burdens have apparently not been assessed. The current CDC (Centers for Disease Control) “level of concern” is 10 μg/dl for children, although it is clear that there are adverse effects on cognition at blood concentrations below 10 μg/dl [9, 10]. More recently, experimental researchers have focused on developing paradigms to explore the behavioral mechanisms responsible for the constellation of effects observed in previous studies; these studies generally used doses that are known to produce robust impairment.

Intermittent Schedules of Reinforcement

Intermittent schedules of reinforcement have been used in behavioral pharmacology and toxicology for over 50 years. Descriptions of these schedules are available from numerous sources (e.g., [11, 12]). Simple schedules such as fixed interval (FI), variable interval (VI), fixed ratio (FR), and differential reinforcement of low (response) rate (DRL) schedules are acquired reasonably rapidly by animals, and performance is similar across species, including humans. The schedule used most often in lead research was the FI, presumably because it offers a number of advantages. Although this schedule requires the subject to make only one response at the end of a specified (uncued) interval, FI performance is typically characterized by an initial pause followed by a gradually accelerating rate of response, terminating in reinforcement. The schedule does not differentially reinforce any particular response rate (other than no or very low rate of responding) and may therefore be sensitive to toxicant-induced differences in the rate of response. In addition, temporal discrimination can be examined by measuring the shape of the response pattern across the interval (e.g., quarter life or index of curvature). Lower doses of lead produced increased response rates on the FI schedule in rats and monkeys [13–21], whereas high doses resulted in lower response rates [22, 23]. In general, temporal discrimination per se, as measured by the pattern of responses across the interval, was not affected by lead (but see Rice [20] and Mele et al. [24]). When a time-out (TO) period (during which responses had no scheduled consequences) was included in the assessment of performance on the FI, lead exposure resulted in increased TO rates of response [18, 19].

Attention deficit hyperactivity disorder (ADHD) was associated with increased response rates on FI performance in 7- to 12-year-old boys, as well as a “bursting” pattern of response produced by a run of closely spaced responses separated by a short pause [25]. This pattern was also observed in 3-year-old monkeys exposed to lead from birth (Figure 6.1) [18]. Children with ADHD also responded more in the extinction (TO) portion of the schedule, as did lead-exposed monkeys. FI performance predicted poorer performance on a test of impulsivity in normal children [26, 27]: children with high response rates and shorter post-reinforcement pause times chose a smaller immediate reinforcer rather than a larger but delayed reinforcer. This was interpreted as evidence of impulsive behavior in the children with ADHD. Thus the FI schedule has numerous important advantages: equipment and computer programming required for the FI schedule (and other simple intermittent schedules) is minimal compared with more complicated testing procedures, acquisition of performance is relatively rapid, FI performance is similar across species, the FI schedule is sensitive to changes induced by lead (and other contaminants), and FI performance is predictive of performance on a test of impulsivity.

FIGURE 6.1. A: Cumulative records for session 10 for the four control (top) and four lead-treated (bottom) monkeys on an FI-TO schedule of reinforcement.


A: Cumulative records for session 10 for the four control (top) and four lead-treated (bottom) monkeys on an FI-TO schedule of reinforcement. Each lever press stepped the pen vertically; time is represented horizontally. The reinforced response in each (more...)

In contrast to the FI schedule, the DRL schedule requires a specified time between responses for reinforcement; responding before the specified time resets the contingency. Therefore the DRL schedule punishes failure of response inhibition. The DRL schedule also proved sensitive to developmental lead exposure. For example, DRL performance was assessed in groups of monkeys in which increased rates of response on the FI had been observed. The schedule required the monkey to space consecutive responses at least 30 sec apart to be reinforced. Monkeys with peak blood lead levels of 100 μg/dl and steady-state levels of 40 μg/dl exhibited a higher number of nonreinforced responses, a lower number of reinforced responses, and a shorter average time between responses over the course of the experiment than control monkeys [28]. Performance on this DRL schedule was also examined in a group of monkeys having steady-state blood lead levels of 11 or 13 μg/dl [29]. Lead-treated monkeys were able to perform the DRL task in a way that was indistinguishable from controls. However, they learned the task at a slower rate, as measured by the increment in reinforced responses and decrement in nonreinforced responses over the course of the early sessions. Increased rates of response [30] and increased frequencies of responses emitted close together (short interresponse times) [31] have been reported in rats performing on a DRL schedule with no previous exposure to intermittent schedules. Postnatal blood lead concentrations are also associated with failure to inhibit responding on a DRL schedule in 9-year-old children (Paul Stewart, personal communication).

Effects of lead were examined on schedules similar to the DRL that assessed temporal discrimination. Response duration performance was assessed on a task in which rats exposed to lead beginning at weaning were required to depress a lever for at least 3 sec to be reinforced [32]. Lead-treated rats depressed the lever for a shorter time than controls. In addition, introduction of a tone signaling the 3-sec interval was effective in improving performance of control but not treated rats. Infant monkeys exposed to lead in utero, with maternal blood lead concentrations of 61 or 72 μg/dl for two dose groups, were tested on a task in which responses were required to be emitted after 10 sec but before 15 sec had elapsed (a DRL with a limited hold contingency) [33]. Treated infants did not make premature responses (before 10 sec) but rather had an increased number of failures to respond before 15 sec. These results, observed at relatively high lead exposure, were similar to the decreased behavioral output observed on FI at high blood lead levels. However, there may also be a differential sensitivity of prenatal versus postnatal exposure.

The fixed ratio (FR) schedule requires the subject to emit a fixed number of responses to be reinforced and typically generates a high response rate. This schedule appears to be less sensitive to lead-induced changes than is the FI. Low doses of lead sometimes resulted in increased rates of response, often transiently, whereas higher doses decreased response rates. This was true for both rats [22, 34, 35] and monkeys [19, 36]. Unfortunately, performance on this schedule had apparently not been assessed in lead-exposed children.

In summary, the DRL task proved sensitive to lead exposure in both animals (rats and monkeys) and humans. FI performance was affected by lead in reproducible ways in animals in numerous studies. FI performance in children with ADHD was virtually identical to that in lead-treated animals, including a “bursting” response pattern. Performance on an FI schedule predicted performance on a relatively more complicated test of impulsivity in children. Therefore, it appears that these simple intermittent schedules predict important sequelae of lead exposure in children.


Developmental lead exposure was associated with decreased IQ in numerous studies [37]. Deficits in reading, math, spelling, language, and other academic skills were associated with increased childhood lead exposure [38–43]. Deficits in color naming were also associated with increased blood lead concentrations [44]. It is difficult to determine the degree to which poor performance in school is the result of learning deficits as opposed to attentional or other deficits in cognitive or sensory function. The experimental literature may help to elucidate the various behavioral mechanisms responsible for impaired cognitive functioning in children.

Deficits in acquisition of tasks (learning) have been demonstrated in experimental studies on a variety of tasks. Perhaps the simplest of these is visual discrimination. Rats exposed to a very high dose of lead (1000 mg/kg to the dam) during gestation and lactation were impaired on both a brightness and shape discrimination in a water-escape T-maze [45]. Lead-exposed rats had shorter swim times, and the authors suggested that the increased errors in the lead-treated group might result from a failure to attend to relevant discriminative cues, a hypothesis for which there would be substantial support in later studies.

Sheep exposed to lead in utero at maternal blood levels of 34 μg/dl (but not at 18 μg/dl) were assessed on a series of nonspatial visual discrimination tasks [46]. The first five discrimination problems were form discriminations and the sixth was a size discrimination. The lead-treated sheep were only impaired on the sixth problem, which was also the most difficult for the control group. It may be that the lead-exposed sheep were impaired on the last problem simply because it was difficult; alternatively, it may have been because the relevant stimulus dimension was changed from form to size. Similarly, rats exposed to lead prenatally were not impaired on a visual discrimination problem that was easy for control rats (vertical vs. horizontal stripes), whereas these lead-exposed rats were severely impaired on a difficult discrimination (bigger vs. smaller circle) [47]. As in the study in sheep, the discrimination that was the more difficult for controls also changed stimulus dimension from line orientation to size. These two studies provided a preview of two findings that would be consistently observed in later studies: difficult tasks are more sensitive to lead-induced impairment than easier ones, as are studies in which there is a change in the relevant stimulus-response class.

A strategy adopted early in the research on the developmental effects of lead was the introduction of two additional requirements to the visual discrimination task: the requirement for reversal performance on an already-learned discrimination task and the addition of irrelevant cues. In a discrimination reversal task, the formerly correct stimulus becomes the incorrect one, and vice versa. This task requires extinction of the previously learned response and the learning of a new (opposite) one. These requirements presumably make cognitive demands not required by the initial acquisition of the discrimination task. The introduction of irrelevant cues assesses reasoning and attentional processes, as well as providing the opportunity to change relevant stimulus dimension, further taxing cognitive abilities.

In the nonspatial version of the discrimination reversal 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. This allows the degree of improvement in performance across reversals to be assessed, which is indicative of how quickly the subject learns that the rules of the game change in a predictable pattern. Nonspatial discrimination reversal performance was impaired by postnatal exposure in rhesus monkeys tested during infancy [48] and cynomolgus monkeys tested as juveniles [49]. Cynomolgus monkeys with blood lead levels of 15 or 25 μg/dl during infancy and steady-state levels of 11 or 13 μg/dl were impaired on a series of nonspatial discrimination reversal tasks with irrelevant cues as juveniles [50]. Lead-treated monkeys were not impaired on the acquisition of any of the three tasks; however, they were impaired over the set of reversals of a form discrimination, which was their introduction to a discrimination reversal task, and on a color discrimination with irrelevant cues, their introduction to irrelevant cues. Analysis of the kinds of errors made by treated monkeys revealed that they were attending to irrelevant cues in systematic ways, either responding on or avoiding a particular position or stimulus. This suggests that lead-treated monkeys were being distracted by these irrelevant cues to a greater degree than controls, which may have been responsible at least in part for their apparent learning deficit.

In a subsequent study on possible sensitive periods for deleterious effects produced by lead, monkeys were exposed to lead either continuously from birth, during infancy only, or beginning after infancy [51]. Lead levels were about 30 to 35 μg/dl when monkeys were exposed to lead and given access to infant formula, and 19 to 22 μg/dl when monkeys were dosed with lead after withdrawal of infant formula. These monkeys were tested as juveniles on the same nonspatial discrimination reversal tasks described above. Both the group dosed continuously from birth and the group dosed beginning after infancy were impaired over the course of the reversals in a way similar to that observed in the study discussed above, including increased distractibility by irrelevant cues. The higher exposure levels in this study were reflected in impairment on all three tasks, whereas in the previous study lead-treated monkeys were impaired on only the first two tasks. The group exposed only during infancy was unimpaired on these tasks. In addition, the group dosed continuously from birth was impaired in the acquisition of the task in which irrelevant cues were introduced; there were no other impairments in acquisition.

Performance on spatial discrimination reversal tasks, analogous to the nonspatial discrimination reversal tasks already described, also proved sensitive to disruption by developmental lead exposure. A subset of the monkeys in the Bushnell and Bowman study [48], in which effects on both spatial and nonspatial discrimination reversal had been found during infancy, exhibited impairment on a series of spatial discrimination reversal tasks with irrelevant color cues at 4 years of age, despite the fact that lead exposure had ceased at 1 year and blood lead levels at the time of testing were at control levels.

In the group of monkeys with stable blood lead levels of 11 or 13 μg/dl discussed above [50], deficits were also observed on a series of three spatial discrimination reversal tasks, the first one with no irrelevant cues and the subsequent two with irrelevant cues of various types [52]. Treated monkeys were impaired relative to controls over the series of reversals in the presence, but not in the absence, of irrelevant stimuli. Moreover, the lower dose group was impaired only during the first task after the introduction of irrelevant cues but not on the second task with irrelevant cues, when irrelevant stimuli were familiar. As in the nonspatial discrimination reversal task, there was evidence that lead-exposed monkeys were attending to the irrelevant stimuli in systematic ways, suggesting that this behavior was responsible for, or at least contributing to, the impairment in performance. This is also suggested by the fact that lead-treated monkeys were impaired in the presence of but not in the absence of irrelevant stimuli. In the group of monkeys in which the relevance of the developmental period of exposure was being assessed, described above [51], spatial discrimination reversal performance was also assessed [53]. Treated monkeys were the most impaired over the series of reversals on the first task after the introduction of irrelevant cues, although performance was impaired on all three tasks. Contrary to the result of the nonspatial discrimination reversal task in which the group dosed only during infancy was unimpaired, all three dose groups were impaired to an equal degree. These data suggest that spatial and non-spatial tasks may be affected differentially, depending on the development period of lead exposure.

Deficits on visual discrimination problems have also been observed in the absence of the requirement for reversal performance under some circumstances, such as high blood lead levels or increased task difficulty. Infant Rhesus monkeys exposed in utero to lead, with maternal blood lead levels of 61 to 72 μg/dl for two dose groups, were impaired on a three-choice consecutive form discrimination task [33]. In this task, one of three possible form stimuli was presented at each trial, and the monkey was required to respond to one but not the other two. Lilienthal et al. [54] studied the effects of developmental lead exposure on learning-set formation, in which a series of visual discrimination problems was learned sequentially. Rhesus monkeys were exposed to lead in utero and continuing during infancy at doses sufficient to produce blood lead concentrations up to 50 μg/dl in the lower dose group and 110 μg/dl in the high dose group. When tested as juveniles, both groups of lead-exposed monkeys displayed impaired improvement in performance across trials on any given problem, as well as impaired ability to learn successive problems more quickly as the experiment progressed. Such a deficit represents impairment in the ability to take advantage of previous exposure to a particular set of rules. This deficit is reminiscent of the failure of lead-treated monkeys to improve as quickly as controls over a series of discrimination reversals.

Concurrent discrimination performance was assessed in the group of monkeys described above in which the contribution of the developmental period of exposure to the behavioral toxicity of lead was explored by exposing them to lead continuously from birth, during infancy only, or beginning after infancy [55]. Monkeys were required to learn a set of six problems concurrently; after criterion was reached on all six pairs, a second set of six was introduced. All three treated groups learned more slowly than controls, although monkeys dosed during infancy only were less impaired than the other two groups. Treated monkeys were most impaired on the first task, upon introduction of a new set of contingencies. In addition, all three treated groups exhibited perseverative behavior, responding incorrectly more often than controls at the same position that had been responded on in the previous trial.

Rats exposed to lead via the dam’s milk until weaning at 21 days of age, with blood lead levels following 20 days of exposure of 11 (control), 29, or 65 μg/dl, were impaired on the acquisition of a light-dark simultaneous visual discrimination (i.e., the discriminative stimuli were presented at the same time) at 120 days of age [56]. Treated groups were not impaired on a successive visual discrimination task beginning at 270 days of age, nor on what was termed a go/no-go discrimination task beginning at 330 days of age. In the successive discrimination, one of two possible stimuli were presented in a trial (light on or off), and the rat was required to turn left or right in a maze, depending on the stimulus. The go/no-go discrimination task was actually an FR 20/extinction (TO) task, in which responses were reinforced in the presence of a light but not in its absence. Following acquisition, a reversal was implemented in which responses were reinforced only in the absence of light. There was a trend toward retarded acquisition of the reversal that did not reach statistical significance. Because performance on the three tasks was tested at such different ages, it is impossible to know whether the tasks were differentially susceptible to disruption by lead or whether the effects of lactational exposure to lead were at least partially reversible.

Olfactory discrimination reversal was examined in rats exposed to lead during gestation and lactation, or during lactation only (two doses) [57]. Blood lead levels at weaning were very high: 130 to 160 μg/dl. Rats performed three reversals following initial acquisition. There were no differences in the total number of errors to criterion for the initial acquisition or the three reversals despite the high blood lead levels. However, analysis of error pattern during different phases of the acquisition of the reversals revealed differences between treated and control groups. Groups were not different during the initial phase of the reversal, in which responses were made predominantly to the previously rewarded stimulus. This was termed the “perseverative phase” by the authors. Subsequent performance was divided into a “chance” phase, a “postchance” phase (between 63 and 88% correct), and the “final” phase. The “postchance” phase was significantly longer for the treated groups. “Response bias” was defined as 12 or more successive responses on the same lever. The group exposed gestationally and lactationally exhibited response bias by this strict criterion, as well as more lenient criteria of strings of five or eight responses. (Note that in discussion of results from our laboratory, “perseveration” for position is defined as all additional incorrect responses after the first, a quite different definition, and less strict than the definition of lever bias by Garavan et al. [57].) The authors argue that the increased errors in the postchance phase are the result of lever bias and “impaired ability to associate cues and/or actions with effective consequences.”

Similar results were found over a series of five olfactory discrimination reversals in rats exposed from conception onward with blood lead concentrations of 28 or 51 μg/dl [58]. Lead-treated groups were also impaired on an “extradimensional shift” task immediately following the olfactory reversal task, in which olfactory cues were present but the relevant stimulus domain was spatial (left or right odor-delivery port). These results are reminiscent of results in monkeys on discrimination reversal tasks in which the relevant stimulus dimension was changed. However, the results of this study are less straightforward, since treated groups were still impaired on the last reversal of the olfactory task. In the monkey studies, groups did not differ over a number of reversals before the shift.

In a study of the siblings described in the previous paragraph [59], rats exposed chronically to lead beginning prenatally were tested on a three-choice visual discrimination task as adults. Blood lead concentrations were 26 and 51 μg/dl both at birth and during adulthood in the two treated groups. Performance was analyzed during the “chance phase” and “postchance phase,” the latter defined as the point at which percent correct was greater than 46% in a session. Treated groups required more trials to criterion for both the chance and postchance phases. The authors interpreted the results as indicative of an associative deficit, although deficits in attentional processes may be involved. It is interesting that rats were impaired over the entire course of the reversal in the visual discrimination but not the olfactory discrimination tasks. In contrast to humans, rats rely more heavily on the olfactory system than the visual system for information about the environment. (Rats have keen olfactory capabilities and rather poor spatial vision.) Therefore, the olfactory discrimination task may be more “natural” for them than visual discrimination tasks.

An intermittent schedule of reinforcement was used to examine the ability of squirrel monkeys exposed in utero to lead to change response strategy in response to changes in reinforcement density [60]. Monkeys whose mothers had blood lead levels of 21 to 79 μg/dl were tested at 5 to 6 years of age on a concurrent random interval–random interval schedule, in which two random interval (RI) schedules operated separately on two levers. (On an RI schedule, reinforcements are available at unpredictable times, but with some average time such as15 sec.) Reinforcement densities were varied across the experiment in such a way that the left or right lever was programmed to produce a greater reinforcement density. Under steady-state conditions, monkeys exposed in utero to over 40 μg/dl lead in maternal blood were insensitive to the relative “payoff” on the two levers, and exhibited lever bias (responding on a favorite lever irrespective of schedule contingencies). When the relative reinforcement densities on the levers changed, control monkeys gradually switched their responding pattern to the appropriate ratio (e.g., 70% right, 30% left). In contrast, performance of these lead-exposed monkeys changed slowly, not at all, or in the wrong direction (Figure 6.2). Monkeys whose mothers had lower blood lead concentrations learned to apportion their responses appropriately, but they learned at a slower rate than controls. The results were interpreted as “insensitivity to changing reinforcement contingencies” (p. 6) and “insensitivity to changes in the consequences of behavior” (p. 11). These results are consistent with results on other tasks, described above, in which lead-treated animals persisted (perseverated) in nonadaptive response patterns, seemingly unresponsive to changing environmental contingencies or the consequences of their own behavior.

FIGURE 6.2. Representative transitions showing behavior change subsequent to a change in the reinforcement densities on the two levers for a control monkey (top) and lead-exposed monkey (bottom) on a concurrent RI-RI schedule.


Representative transitions showing behavior change subsequent to a change in the reinforcement densities on the two levers for a control monkey (top) and lead-exposed monkey (bottom) on a concurrent RI-RI schedule. The ordinate is relative response rates (more...)

The effect of lead exposure was assessed in a visual discrimination reversal task in 6- to 15-year-old children [61]. Pairs of twins discordant for blood lead concentrations were tested on a size discrimination task and one reversal. Average blood lead concentrations were 30 to 50 μg/dl for the lower-lead twins and 43 to 80 μg/dl for the higher-lead twins. The higher-lead twins had a lower percentage of correct responses and made more errors reaching a criterion of 100 correct responses. The testing time required was only 20 minutes. These results suggest that effects in animals are congruent with those in children on this task, and that this task might be a useful addition to testing paradigms in children.

The Cambridge Neuropsychological Testing Automated Battery (CANTAB) was used to assess cognitive function in 5.5-year-old children in relation to average lifetime blood lead concentrations [62]. This battery is a computer-based set of cognitive tests, including tests of attention, spatial and nonspatial memory, and executive function. Blood lead concentrations were associated with poorer performance on “intradimensional” and “extradimensional” shift. In this task, the original discrimination required attention to colored (filled) shapes. Following acquisition, a reversal for shape was instituted (intradimensional shift). Irrelevant stimuli (white lines) were then introduced. The stimulus class was then changed from filled shapes to white lines (extradimensional shift). This task is virtually identical to the non-spatial discrimination reversal task with irrelevant cues assessed with monkeys, and the congruence of effects in children and animal models is reassuring.

The evidence for learning impairment in animals exposed to lead is extensive, and the conditions under which it occurs are relatively well characterized. Lead exposure may produce impairment on acquisition on difficult discriminations or at higher lead levels. The requirement to reverse a previously learned discrimination, a change in the stimulus dimension or response class, or the introduction of novel stimuli (irrelevant cues) all may result in impaired performance, even at low blood lead concentrations. Lead-exposed children were also impaired when required to shift stimulus dimension [62]. However, most studies in children have used endpoints that were a terminal result of learning (school performance) or a compilation of a number of processes, including various types of learning (IQ). Therefore the experimental literature is more informative than the epidemiological literature in the elucidation of the behavioral mechanisms underlying the observed learning impairment produced by lead.


In contrast to the substantial evidence for deficits in learning produced by lead exposure in animals, interpretation of the studies designed to assess memory is more difficult. There is no question that lead produces impairment on such tasks, but whether the deficits are the result of impairment in memory is less clear. Rats exposed in utero or pre- plus postnatally to lead, with blood lead concentrations of 34 μg/dl, were impaired on the retention of a size discrimination task 42 days after initial task acquisition in the absence of deficits on initial acquisition [63]. Performance in a radial arm maze (RAM) was also assessed in these rats. The RAM apparatus consisted of a central compartment with eight alleys radiating from it like spokes of a wheel. Food reinforcers were placed in each arm of the maze. Treated groups took longer to eat all the pellets during the initial acquisition and a retention task four weeks later. However, treated groups were not different from controls on the number of arms visited before the first error (i.e., entering an alley already entered), nor did lead exposure affect the number of arms visited on the first eight choices. It therefore appears that the lead-treated rats exhibited no deficit in spatial memory, although they were impaired on retention of the size discrimination task. Lactational exposure to lead at levels that produced drastic effects on weight gain and overt signs of toxicity also had minimal effect on radial arm maze performance [30].

The effects of developmental lead exposure were assessed on performance in the Morris water maze [64, 65]. The Morris water maze requires the subject to learn the location of a submerged platform to escape submersion in a pool of water. In the first experiment, rats exposed to lead throughout gestation and lactation showed increased time to find the hidden platform at weaning, but not at 56 or 91 days of age. In the second experiment, rats were exposed during gestation and/or lactation at three times the dose as the first experiment, resulting in blood lead concentrations at weaning of 60 μg/dl. Performance on the Morris water maze was assessed beginning at 100 days of age. Deficits in escape latency and increased swim path length were observed in the group exposed prenatally only, but not groups exposed pre- plus postnatally or postnatally only, despite the high blood lead concentrations. The results of these studies taken together suggest that spatial memory may be relatively unaffected by lead exposure in rodents. The Morris water maze may be an insensitive test, since normal rats acquire the performance in four to five trials. However, the radial arm maze is a more difficult task that has proved sensitive to contaminants such as polychlorinated biphenyls (PCBs) [66, 67].

A task used in monkeys that is conceptually similar to the radial arm maze is the Hamilton Search Task. In this task, a row of boxes is baited with food and then closed. The monkey lifts the lids to obtain the food. The most efficient performance requires that each box be opened only once, necessitating that the monkey remember which boxes have already been opened. Monkeys exposed postnatally to doses of lead sufficient to produce blood lead levels of approximately 45 or 90 μg/dl or in utero at blood lead concentrations of 50 μg/dl were impaired in their ability to perform this task at 4 to 5 years of age [68]. These results were replicated in another group of monkeys exposed postnatally to higher lead levels and tested at 5 to 6 years of age [69]. However, error pattern was not analyzed, so it is impossible to know whether the results are due to a memory impairment per se or a nonadaptive response strategy such as perseveration or position bias.

A task that has proved particularly sensitive to disruption by lead exposure in monkeys is the delayed spatial alternation task. In this task, the subject is required to alternate responses between two positions; there are no cues signaling which position is correct on any trial. Delays may be introduced between opportunities to respond in order to assess spatial memory. Rhesus monkeys exposed to lead from birth to 1 year of age, with peak blood levels as high as 300 μg/dl and levels of 90 μg/dl for the remainder of the first year of life, were markedly impaired on this task as adults [68]. Delays between 0 and 40 sec were assessed within each session; a greater deficit was observed at shorter rather than longer delay values. This indicates that the poorer performance of the lead-exposed monkeys was not the result of a memory impairment, but rather some type of associative deficit.

In our laboratory, increasingly longer delays were introduced over successive sessions in adult monkeys from two studies, those with steady-state blood lead levels of 11 or 13 μg/dl [70] and the groups in which potential sensitive periods were assessed (dosed during infancy only, beginning after infancy, or continuously from birth [71]). In contrast to the study discussed above, the task included a “correction” procedure, such that if the monkey responded incorrectly on a button, a correct response on the opposite button was required before the alternation schedule resumed. Sessions consisted of 100 correct trials; thus each incorrect response extended the session. All treated groups in both studies were impaired on the acquisition of this task because of indiscriminate responding on both buttons. Treated monkeys were impaired at the beginning of the experiment (short delays), unimpaired at intermediate delay values, and increasingly more impaired at the 5- and 15-sec delays. In the study assessing sensitive periods, all three lead-exposed groups were impaired to an approximately equal degree, as was the case on the spatial version of the discrimination reversal task, thus providing further evidence of a lack of sensitive period for lead-induced impairment on spatial tasks. In addition, treated monkeys in this latter study responded more during the delay periods than did controls, indicating failure to inhibit inappropriate responding. However, analysis of error pattern revealed that this was not responsible for the increased number of errors in the treated group. Treated monkeys in both studies also displayed marked perseveration for position, responding on the same position repeatedly, in some instances for hours at a time (Figure 6.3). Because of the marked perseverative behavior displayed by some treated monkeys, it was actually not possible to assess memory capabilities at the 5- and 15-sec delay value. Memory impairment certainly does not account for the poor performance of the treated groups in these experiments.

FIGURE 6.3. Top: Session length and number of incorrect responses on a delayed spatial alternation task in monkeys for all sessions at the 15-sec (longest) delay.


Top: Session length and number of incorrect responses on a delayed spatial alternation task in monkeys for all sessions at the 15-sec (longest) delay. Each point represents the geometric mean for the dose group: <control; % low dose; = high dose. (more...)

Spatial delayed alternation performance was examined in rats with chronic postweaning exposure to lead, with blood lead levels of 19 and 39 μg/dl in the two treated groups [72]. Testing began at 52 weeks of age. Lead-treated groups were not impaired in the acquisition of the alternation task. Following acquisition, delays of 0, 10, 20, or 40 sec were presented within each session. Treated groups exhibited an impairment of constant magnitude across all delays, suggesting that the performance deficit was not the result of memory impairment. Exploration of error pattern revealed that the higher dose group exhibited position bias. Analysis of the error pattern with respect to the effect of the actual delay time consequent to the rat responding during the delay (which reset the time) and the influence of whether the previous response had been correct or incorrect revealed no lead-related differences. The observed position bias is consistent with effects in monkeys observed on a number of tasks, including spatial delayed alternation.

Improved performance on delayed alternation was observed in young and old rats but not in rats exposed as adults [73]. The training procedure in this study consisted of many sessions of a cued alternation procedure; i.e., the rat had only to respond on the lever associated with a cue light as it alternated between positions from trial to trial. The authors interpreted the improved performance of the lead-treated groups as perseveration of the alternation behavior as a result of the extensive training procedure.

A delayed matching to sample task was used to assess both spatial and nonspatial memory in a group of monkeys with preweaning blood lead values of 50 μg/dl and postweaning values of 30 μg/dl [74]. In the nonspatial version of the task, one of three colors appeared on a sample button on which the monkey responded a specified number of times, which turned off the stimulus and initiated a delay. After a delay period, one of the three colors appeared on each of the three test buttons, and the monkey was required to respond on the button corresponding to the sample color. Colors were balanced for position and correct choice across trials. For the spatial version, one of the three test buttons was lit green; response on that button a specified number of times turned it off and instituted a delay. Following the delay, all three buttons were lit green, and the monkey was required to respond on the sample position. The nonspatial task was assessed twice, with the spatial task in between. For the first assessment of the nonspatial task and spatial task, a series of sessions with increasing constant delays from 1 to 32 sec was instituted. Following the constant-delay sessions, a series of variable-delay sessions was instituted on each task, consisting of a short delay and increasingly long delays to determine the value at which performance reached chance. Lead-exposed monkeys were impaired on both the spatial and nonspatial versions of this task. They were not impaired in their ability to learn the matching tasks or at 0-sec delay. On the constant-delay sessions, treated monkeys had poorer overall performance than controls on the spatial but not the nonspatial task. On the variable-delay schedules, lead-exposed monkeys reached chance performance on the nonspatial task at shorter delays than controls the first time it was tested. When performance on the nonspatial task was assessed the second time, there was no overlap in the delay value at which chance performance was reached (Figure 6.4). The delay at which chance performance was reached in the spatial variable-delay sessions was marginally significant. Treated monkeys were not different from controls on the short delay in the variable-delay sessions.

FIGURE 6.4. Delay value at which control (C) and lead-treated (T) monkeys performed at chance levels on a nonspatial delayed matching-to-sample task (A) and the ratio of incorrect responses made on the button that had been responded to correctly in the previous trial (B).


Delay value at which control (C) and lead-treated (T) monkeys performed at chance levels on a nonspatial delayed matching-to-sample task (A) and the ratio of incorrect responses made on the button that had been responded to correctly in the previous trial (more...)

Investigation of the error pattern revealed that for the nonspatial matching task, lead-exposed monkeys responded incorrectly on the position that had been responded on correctly on the previous trial. This type of behavior may be considered to represent perseverative behavior and is reminiscent of the perseverative errors in other groups on delayed alternation. On the other hand, it may be considered to be the result of increased distractibility by irrelevant cues by lead-treated monkeys, similar to the increased attention to irrelevant cues displayed in the discrimination reversal tasks. (These interpretations are not mutually exclusive.) This behavior is at least partly responsible for the poorer performance at long delays observed in lead-treated monkeys on the nonspatial matching-to-sample task, although other mechanisms may also play a part. The lack of interference from previous trials on the spatial version of the task, however, may indicate a pure deficit in spatial short-term memory. The fact that lead-exposed monkeys were not impaired at 0-sec delay or on the short delays on the variable-delay tasks, but reached chance performance at shorter delay values, provides evidence overall for a deficit in memory in these monkeys. The deficit across the constant-delay sessions of the spatial task, on the other hand, may be a consequence of the change in relevant stimulus dimension from nonspatial to spatial.

Assessment of spatial learning and memory in the rat revealed an interesting pattern of errors responsible for the overall poorer performance of lead-treated subjects [75]. Rats were exposed to lead in drinking water beginning at weaning, with blood lead concentrations of 25 and 73 μg/dl, and tested beginning at 55 days of age on a task with two components. The repeated acquisition component of the schedule required the rat to learn a new sequence of lever presses every day. In the performance component, the rat was required to perform the same sequence of lever presses during every session. Significant impairment of performance was observed on the repeated acquisition component but not on the performance component in lead-exposed rats compared with controls. Analyses of error patterns revealed that the decrease in the percent of correctly completed sequences in lead-treated rats on the repeated acquisition component was the result of specific types of perseverative behavior.

Apparently little attention has been paid to the effects of lead on memory in epidemiological studies. Exploration of the effects of lead on working memory in children can be included as part of a battery of cognitive tests, such as an assessment of IQ. However, scores on various subtests of standard IQ tests (e.g., Digit Span) were often not reported in epidemiological studies of the effects of lead. The California Verbal Learning Test (CVLT) and Story Recall were assessed in the Boston prospective cohort at 10 years of age [76]. There was little evidence of effect on either test. Blood lead levels of the children at 24 months of age were marginally associated with poorer performance on Digit Span in the Wechsler Intelligence Scale for Children – Revised (WISC-R). Digit span score on the WISC-III was associated with concurrent blood lead concentrations in 7.5-year-old children [77], whereas lead was not associated with deficits on story memory or verbal learning. However, performance on Digit Span reflects attentional and higher-order sensory processes at least as much as it does memory.

Deficits as a function of lead exposure in children were observed on two tests of spatial memory on the CANTAB battery [62]. One test was logically equivalent to the Hamilton Search Task, described above, in which impairment was observed in lead-exposed monkeys [68, 69]. In the other task, the child was required to remember the sequence in which stimuli (boxes) changed color on the computer screen. The sequence varied from trial to trial. This task is logically equivalent to the repeated acquisition task on which deficits were observed in lead-exposed rats [75].

It is difficult to draw conclusions concerning the congruence of effects of lead on memory in animals and humans. Memory has been little explored in children, and most tests employed relied on language and assessed encoding and higher-order auditory processing rather than memory per se. In animals, perseverative responding to position and interference from responses on previous trials were observed in a number of studies in various tasks, and were responsible for, or at least contributed to, the poorer performance by lead-exposed animals. In addition, lead-treated animals were impaired to an equal degree across all delay values in some studies, suggesting a deficit other than memory impairment. Perhaps the strongest evidence for impaired memory is the results of the delayed matching to sample task in monkeys, in which treated monkeys were not impaired at short delays but reached chance performance at shorter delays than controls. However, the overall evidence for memory deficits produced by lead in experimental studies is not compelling.


Nonadaptive behavior in children has repeatedly been interpreted as deficits in attention in human studies. Increased lead body burden was associated with increased inattentiveness, distractibility, impulsivity, and lack of persistence on teachers’ and parents’ rating scales [7, 41, 42, 77, 78]. Impairment on the “learning” studies in animals described above may result at least in part from deficits in attentional processes. The increased systematic response to irrelevant cues on discrimination tasks may reflect attentional deficits. Inability to inhibit responding, such as on the DRL task, may also represent a type of attention deficit. However, responding during delays on trial tasks was observed in some circumstances but not others. For example, in the delayed alternation task in which some lead-treated monkeys perseverated on the same response button for hours at a time, no increase in delay responses was observed at lower blood lead concentrations [70], and delay responses did not contribute to the increased error rate at higher blood lead concentrations [71]. Perseveration has also been interpreted as indicative of attentional impairment [75, 79].

The deficits in ability to change response strategy in response to new schedule contingencies, observed in the monkey studies, may also be considered to represent an attention deficit. For example, a task that has been used in lead-exposed children is the Wisconsin Card Sort Test (WCST). This task is logically equivalent to the discrimination reversal task with irrelevant cues used in monkeys, in that it requires the ability to extract general rules and change response strategy. In this task, correct responses depend on generalizing whether the relevant domain is color, number, or shape. The investigator can change the relevant stimulus class at any time; the subject must infer the rule by whether a series of responses is correct or incorrect. Errors on the WCST are considered to test ability to shift attention, which is considered one of the factors in at least one theoretical framework of attention [80, 81]. Increased total and perseverative errors at 10 years were related to 57-month blood lead concentrations in the Boston prospective study [76], and perseverative errors were related to dentine lead levels in the first or second grade in 19- and 20-year-olds [82]. An increased number of errors was also observed on the WCST in a study of 246 7.5-year-olds; perseverative errors were not different after control of confounders [77]. These results are similar to those observed in monkeys, in which the lead-exposed groups made more errors than controls in initial reversals within a set of reversals, and responded more than controls to previously relevant stimuli when the relevant stimulus domain was changed [50, 51].

The effects of lead on sustained attention in children were explored in a number of studies using reaction time tasks, either on a simple reaction time task, in which the subject is asked to respond as quickly as possible to a single stimulus, or on a vigilance task, in which the subject is required to respond to a target stimulus and refrain from responding to others. Stimuli are presented at variable intervals, and the task is sufficiently long to require sustained attention. Increased reaction times were observed in groups of children with blood lead concentrations of 17, 24, or 35 μg/dl compared with those with average lead levels of 7.4 μg/dl [42, 83], as well as at higher blood lead concentrations [84], with the greatest impairment occurring at a 12-sec compared with a 3-sec delay, and at the end of the task compared with the beginning. Increased reaction time compared with controls was also observed on a simple reaction time task in a group of 20-year-olds with a history of lead exposure as children [85]. In contrast, no effect on simple reaction time task was observed in the group of monkeys exposed to lead from birth, with preweaning blood lead values of 50 μg/dl and steady-state blood lead levels of 30 μg/dl, when they were adults [86]. Reaction times of lead-treated monkeys did not differ from those of controls over a number of delay values, although treated monkeys exhibited an increased incidence of holding the bar longer than the maximum 15 sec allowed. They were also able to react as quickly as controls when required to respond as quickly as possible.

Performance on a vigilance task was assessed in two cohorts of German children [87–90]. Two different signal presentation rates (approximately 1 to 2 sec) were used. Correct responses, false hits (errors of commission), and failure to respond to correct stimuli (errors of omission) were analyzed. In the first study [88, 90], there was an indication of an effect in the absence of an effect on the German WISC-R as a function of tooth lead in 9-year-old children. In a subsequent study in 6- to 9-year-old children, a robust effect was observed [87]. Effects were greater at the higher signal rate. As in the previous study, there was a greater effect on errors of commission than on errors of omission. These results have been replicated using the same device in a population of Greek children with higher blood lead levels [84]. In a later study by the German group [91], 384 6-year-old children were assessed on components of the Neurobehavioral Evaluation System 2 (NES2), including simple reaction time, pattern memory, and a vigilance task, in addition to IQ on the WISC. Increased errors of omission and commission were related to increased blood lead levels (geometric mean = 4.25 μg/dl), even after controlling for IQ. No effect was observed on simple reaction time or the memory task. Sustained attention on a vigilance task was assessed using either visual or auditory stimuli in the study of 7.5-year-old children [77]. An increased number of incorrect responses was observed as a function of increased blood lead levels in the visual but not auditory version of the task, with no increase in errors of commission. (Errors of omission were apparently not measured.) In a study in first-graders in Denmark, performance was marginally associated with dentine lead levels [92]; errors of commission showed a greater correlation than errors of omission. In contrast, Bellinger et al. [82] found no effect in 19- or 20-year-olds on reaction time or on errors of commission or omission related to dentine levels in childhood.

Vigilance performance was studied in rats exposed to lead beginning at weaning, with blood lead concentrations of 16 or 28 μg/dl [93]. The low-dose group made more errors of commission during sessions with long or variable interstimulus intervals, whereas the high-dose group showed an increase in errors of commission only during sessions with long interstimulus intervals. These inconsistent effects were interpreted as evidence of no effect of lead on sustained attention.

Effects of lead exposure were reported on a vigilance task in rats exposed either during lactation only (two groups) or during gestation and lactation [94]. Blood lead concentrations in all three groups were very high on day 24 (131 to 158 μg/dl for the three dose groups), and may have been even higher by weaning at 30 days of age. These lead levels were sufficiently high to produce impaired body weight gain. Groups did not differ for the percent correct responses or on responses in the absence of a stimulus. Treated groups exhibited increased omission errors at stimulus delays greater than 0 sec, and on trials following an incorrect response. However, the magnitude of effect was modest, despite the very high blood lead levels.

An FR schedule was used as one component of a study to explore underlying behavioral mechanisms responsible for the observation that lead produces inappropriate responding on a wide array of tasks [95]. Exposure began at weaning, with blood lead concentrations of 11 and 29 μg/dl in the two dosed groups. Rats were trained, after 40 days of exposure, to respond on an FR 50 schedule of reinforcement (i.e., 50 responses were required for reinforcement). Following each FR, the rat could receive “free” reinforcements for waiting an increasingly long period of time (2, 4, 6, etc., sec). Lead-exposed rats exhibited faster response rates on the FR, and they waited a shorter period of time in the “free” reinforcement portion of the schedule before responding, which initiated another FR. The lead-treated rats actually received more reinforcements. The results were interpreted as indicative of “an inability to manage delays in reinforcement.” It is also possible, however, that the pattern of responses of the lead-exposed rats was maintained by the higher reinforcement density produced (which the authors acknowledge). The results of this study are not necessarily inconsistent with other studies documenting failure to inhibit responding by lead-exposed subjects. In fact, the results of this study are more difficult to interpret because the response strategy adopted by the lead-exposed rats was adaptive rather than nonadaptive or neutral, as in most other studies.

The effects of lead on sustained attention as measured by simple reaction time or vigilance tasks seem inconsistent between humans and animals. Increased response time on simple reaction time tasks was observed in children in four studies, but not in a fifth study at very low blood lead concentrations and not in monkeys at relatively high blood lead levels. However, the monkeys had a substantial history of performance on a number of behavioral tasks, such that the simple reaction time task may have made minimal demands on attention in such experienced monkeys. On vigilance tasks, effects were observed in six studies in children, including one with very low lead concentrations, but not in a seventh. Two studies in rats were largely negative, including one at high blood lead concentrations. The reason for negative effects observed in rats is somewhat unclear. However, the number of sessions required to train the task was substantial in both studies. Each study included contingencies that resulted in a low rate of stimulus presentation. It may be that the extensive familiarity with the task or the low rate of stimulus presentation rendered the task insensitive to disruption by lead.

Sensory Dysfunction: Possible Contribution to “Cognitive” Effects

It is clear that lead exposure in animals and humans may result in impairment in visual and auditory function. An inability to perceive or process sensory information would obviously interfere with performance on any particular test. More importantly, however, deficits in higher-order sensory processing would make it difficult for the child to learn and respond appropriately to the environment. In fact, it is difficult to define the point at which deficits in sensory processing may be defined as “cognitive” deficits. Whereas there have been studies of first-order sensory function in both animals and children, higher-order sensory processing has been studied in very few instances in either children or animals.

Elevated auditory thresholds in the range of speech frequencies were observed as a function of increasing blood lead concentrations in children in the Second National Health and Nutritional Survey (NHANES) II [96]. A study in Poland documented higher auditory thresholds across a range of frequencies as a function of blood lead levels, including blood lead concentrations below 10 μg/dl [97]. Monkeys exposed to lead from birth, with blood lead concentrations of 30 μg/dl at the time of testing, exhibited impaired detection of pure tones at 13 years of age, with the pattern of impairment being somewhat idiosyncratic [98]. A number of electrophysiological studies in animals demonstrated impairment at various parts of the auditory pathway in monkeys and other animals related to lead exposure [99–103], although electrophysiological changes have not been universally observed [104].

Pure-tone thresholds provide only basic, first-level information concerning auditory function. For example, an individual may have normal pure-tone detection and still have difficulty distinguishing speech. Speech generally comprises small but rapid changes in frequency and amplitude. Frequency and amplitude difference thresholds (i.e., the threshold for detection of a change in frequency or amplitude) have been assessed in various animal species, including monkeys and guinea pigs, and may be more sensitive to disruption by toxic exposure than pure tone detection thresholds [105]. 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, there was evidence that developmental lead exposure impaired the ability of young monkeys to discriminate speech sounds (“da” and “pa”) based on an electrophysiological procedure [106]. Lead-exposed children are impaired on the Seashore Rhythm Test [7, 77], which requires the subject to discriminate whether pairs of tone sequences are the same or different. This is a simplified discrimination compared with analysis of speech sounds. Lead-exposed children also had a decreased ability to identify words when frequencies were filtered out (i.e., when information was missing [107]). Increased lead body burdens were associated with impaired language processing on difficult but not easy tasks [108], with impairment of the development of word recognition [109], and with impaired auditory comprehension [110]. The degree to which the deficits in language development are the result of deficits in higher-order auditory processing is unknown.

Lead also produces deficits in visual function. Altmann et al. [111] reported changes in visual evoked potentials in a cohort of over 3800 4-year-old children with average blood lead concentrations of 42 μg/dl, but no differences in visual acuity or spatial contrast sensitivity functions. In a study in infant monkeys with very high lead levels (300 to 500 μg/dl), one infant appeared to develop temporary blindness [112]. Monkeys exposed to lead during the first year of life with blood lead concentrations during exposure of 85 μg/dl, but not those with 60 μg/dl, had impaired scotopic (very low luminance) spatial contrast sensitivity at 3 years of age [113]. Both spatial and temporal (motion) contrast sensitivity were examined in monkeys with lifetime exposure to lead, with steady-state blood lead concentrations of 25 to 35 μg/dl [114]. Lead-exposed monkeys exhibited deficits in temporal vision at low and middle frequencies under low-luminance conditions, with no other impairments. Lead-induced changes in electrophysiologic responses have also been observed in monkeys exposed developmentally to lead, particularly under low-luminance conditions [100, 115, 116]. Consistent with these findings, rod function was found to be preferentially affected by lead in rats [103].

Only the most basic level of visual function has been assessed in either children or animals with respect to potential effects of lead exposure. Half of the primate brain is devoted to visual processing, yet neither experimental nor epidemiological researchers have explored the effects of lead exposure in higher-order visual processing.

Lead impairs primary sensory function in both animal models and children. The only study higher-order function in animals (discrimination of speech sounds) identified impairment produced by lead. There are also hints from studies in children of sensory system impairment. All of the “cognitive” endpoints assessed in children require higher-order processing in the visual or auditory systems, including tests of memory, attention, executive function, learning, or any other categorization of performance. Yet there has been virtually no exploration of higher-order sensory processing in either children or animal models; therefore, the degree to which deficits identified as cognitive are actually sensory is unknown. This failure is of considerable practical relevance, since intervention strategies may be different depending on the actual nature of the deficit.


Lead-induced impairment in learning has been observed in numerous studies in animals. Performance on simple discrimination problems is impaired at high blood lead concentrations. Introduction of a requirement to shift response strategies revealed lead-induced impairment, often in the absence of impairment on initial task acquisition. These results suggest that impairment in attentional processes (attentional shift) underlies the learning deficits, at least in some cases. Deficits in attentional shift were also observed in lead-exposed children. In contrast, the evidence for deficits in sustained attention in animals is weak, despite the fact that deficits on similar tasks were observed in lead-exposed children. Most studies of effects of lead on memory in animals were either confounded by perseveration of various sorts or provided evidence for an associative rather than a memory deficit. In fact, a number of investigators proposed that one of the effects of lead is a failure to associate behavior (response) and the consequences of that behavior. Memory has received little attention in epidemiological studies, and the tests that to some degree assessed working memory also assessed attention and higher-order sensory processing. The effects of lead on intermittent schedules of reinforcement in animals predicted performance in lead-exposed children or were consistent with effects in children with attentional deficits. Unfortunately, the effects of lead on higher-order sensory processing have received scant attention in epidemiological or experimental studies. It has been known for a couple of decades that lead impairs primary auditory and visual function. Nevertheless, the extent to which sensory impairment from lead exposure contributes to what is broadly labeled as “cognitive” deficits in children remains unknown.


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