Risk Assessment
for Neurobehavioral Toxicity
Environmental
Health Perspectives, Volume 104, Supplement 2, April 1996
UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey
Key words: neuropsychological, neurotoxicants, chemical sensitivity, individual differences, psychiatric, vigilance
This paper was prepared as background for the Workshop on Risk Assessment Methodology for Neurobehavioral Toxicity convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held 12-17 June 1994 in Rochester, New York. Manuscript received 1 February; manuscript accepted 17 December 1995.
Address correspondence to Dr. Nancy Fiedler, UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, 681 Frelinghuysen Road, Room 210, Piscataway, NJ 08855. Telephone: (908) 932-0190. Fax: (908) 932-0127. E-mail: nfiedler@eohsi.rutgers.edu
Abbreviations used: CVMT, Continuous Visual Memory Test; MCS, multiple chemical sensitivities; MMPI-2, Minnesota Multiphasic Personality Inventory-2; NART-R, National Adult Reading Test-Revised; NES Battery, neurobehavioral evaluation system; PEA, phenyl ethyl alcohol; SBS, sick-building syndrome; UPSIT, University of Pennsylvania Smell Identification Test; VOC, volatile organic compound; WAIS-R, Wechsler Adult Intelligence Scale-Revised; WHO, World Health Organization.
While batteries vary in the specific tests used, the cognitive functions assessed are relatively consistent. Table 1 contains a list of the functions assessed and a sample of the tests used to assess these functions. Tests have been somewhat arbitrarily categorized into functional categories; however, as several other reviewers have suggested, any one test typically relies on more than one function for performance (5,6). For example, even relatively simple tasks such as simple reaction time require not only attention and concentration but also motor speed for accurate and quick responding. Thus, tests overlap functional categories.
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At this point, there may be sufficient literature on some organic solvents and heavy metals such as lead to conduct metaanalyses of the results across studies. These statistical methods have been used in other literatures to help consolidate disparate findings into a more cohesive picture. These methods could help clarify which tests are most sensitive for detecting effects due to specific neurotoxicants (46).
For the field of neurobehavioral toxicology to make meaningful advances in our understanding of the behavioral effects of neurotoxicants, more refined studies will be needed. Such studies will also require that neurobehavioral methods be improved. For example, rather than continue cross-sectional studies, prospective studies need to be developed in which workers are followed over a period of time to assess changes from baseline. These will require a better understanding of the behavior of neuropsychological tests under repeated measures conditions. Otto et al. (4) found significant practice effects for several of the tests on the NES battery. To avoid ceiling effects on these tests after repeated administration, he suggested that test parameters be altered to make the tasks more difficult and better suited to repeated measures design (4). Similarly, increasing demands are being made for neuropsychological methods to assess subtle effects in acute and unusually low-exposure circumstances. These conditions also require an increased sensitivity in neuropsychological test methods.
In summary, we need to take a more systematic approach toward identifying the most sensitive tests among those cited frequently in the literature. We then need to test the suitability of these tests for the study designs proposed to address present concerns such as low-level exposures. Further consideration of the parameters to be considered in these studies will be addressed in the subsequent sections of this paper.
For example, an increasing number of patients have vague complaints, including poor concentration and memory, in response to low-level chemical exposures. This symptom complex, labeled multiple chemical sensitivities (MCS), involves symptoms reflective of multiple organ systems, most prominently the nervous system. The question of whether these patients are uniquely susceptible to chemicals or are a variant of the psychiatric disorder, somatization, is frequently debated (47-49).
MCS patients may present unique susceptibilities to chemicals for several reasons. First, while no epidemiological studies have been conducted to date, most of the investigators observe that approximately 80% of these patients are women (49,50). This is in contrast to the literature on the neuropsychological effects of neurotoxicants, which is based largely on men. In one of the few studies of women, Parkinson et al. (51) reported no significant differences between solvent-exposed blue-collar women and controls on a relatively brief battery of standard neuropsychological tests. However, the highest exposure levels were significantly related to a number of neurologic and somatic symptoms including depression and headaches. When symptoms are reported by women, they are more likely to be attributed to psychosomatic causes such as stress rather than to physiologically based conditions (52). This is particularly true when objective tests do not substantiate symptom reports. However, it is also possible that women may have unique susceptibilities that wax and wane due to hormonal cycles not occurring in men. For example, women can vary in olfactory acuity according to hormonal cycles (53). Alternatively, women may simply be more aware of and likely to report symptoms that occur in response to an exposure or an illness than men. That is, women may be better observers of the early signs of physiologic changes (54). The challenge is to develop methodologies to measure these changes.
Second, MCS patients have a higher rate of psychiatric disorder (e.g., depression, anxiety) concurrent with and before the onset of MCS (49,50). Many use this information to suggest that MCS is not a unique susceptibility but simply a psychiatric condition that is attributed to chemicals. On the other hand, one may question whether individuals with psychiatric conditions are more susceptible to the effects of neurotoxicants. For example, Morrow et al. (55) reported that individuals with higher levels of psychological distress on the MMPI-2 were associated with poorer neuropsychological function at follow-up. From this study it is impossible to know whether the symptoms on the MMPI-2 were a reflection of continuing neurologic symptoms due to exposure or a premorbid personality style. Psychiatric and personality function, as a risk factor for the effects of neurotoxicants, has infrequently been evaluated and needs further exploration.
Only two studies to date have used standardized neuropsychological tests to evaluate the cognitive complaints of MCS patients (50,56). Overall, these cross-sectional studies did not find differences between the MCS and control groups (i.e., musculoskeletal patients, normal controls) on tests of concentration, memory, and visuomotor skills. However, these tests were not administered under controlled exposure conditions. A primary question is how to test the responses of MCS patients objectively. The typical evaluation paradigm in which the patient's neuropsychological performance and physical status is assessed at an arbitrary point in time is not likely to capture the symptomatic response that these patients observe in themselves under exposure conditions.
Studies more directly relevant to investigation of responses among MCS patients are exposure chamber studies with sick-building syndrome (SBS) patients (57,58). These patients are similar to MCS patients in that they are otherwise healthy individuals who report sensitivities in response to indoor air mixtures that other individuals apparently tolerate. Two controlled exposure studies evaluated the effects of a mixture of 22 volatile organic compounds (VOCs) on sick-building syndrome patients relative to asymptomatic controls (57,58). Along with increasing symptom reports of irritation with increasing VOC exposure (0, 5, 25 mg/m3), Molhave et al. (57) reported reduced performance on digit span among SBS subjects. This finding was not replicated, however, when this study was conducted with young, healthy male subjects (4). Kjaergaard et al. (58) also found impaired digit span performance in SBS-sensitive subjects but not among non-SBS subjects with exposure at 25 mg/m3 VOC mixture, which is roughly equivalent to 7 ppm toluene. Otto et al. (4) suggested that differential effects may be due to differential sensitivity of the subject groups as well as relative insensitivity of many of the current neurobehavioral methods.
To test the unique susceptibilities of MCS patients, several factors must be taken into account. First, like SBS patients, MCS patients report responses at exposure levels that most individuals tolerate. For example, in our current protocol we conduct olfactory threshold testing in response to phenyl ethyl alcohol (PEA), a pleasant olfactory stimulant. MCS patients reported significantly more symptoms than normal controls during threshold testing. At suprathreshold levels they reported PEA to be significantly more unsafe and unpleasant than did normal controls. From our estimations, the concentrations at the average olfactory threshold are comparable to 7 ppm, a level well below that expected to produce neurobehavioral performance decrements.
Second, an overriding concern is that symptomatic responses of MCS patients are conditioned responses to olfactory cues (59). Even among healthy individuals, odor has been shown to impact performance (60-62). Neither the studies on SBS subjects nor controlled exposure studies have adequately accounted for the impact of odor on performance.
Ideally, controlled exposures with MCS patients will need to occur below olfactory thresholds to control for psychological expectations due to odor. Detecting effects at such low levels of exposures (as low as 1 ppm) will require highly sensitive behavioral performance measures. Measures such as reaction time and vigilance tasks have been the most sensitive indicators in previous cross-sectional and chamber studies (2). Therefore, use of measures of attention and vigilance similar to those cited in the signal-detection literature may offer the best alternative to detect effects among susceptible individuals and low-level exposure conditions.
As has been suggested by other investigators, one method for detecting effects at lower exposure levels is to vary parameters within the performance test to increase its sensitivity to effects (4,63). Documentation of the effects of varied test parameters has been the subject of much attention within the experimental literature (e.g., signal-detection paradigms) and virtually no systematic attention within the neuropsychological literature or in the literature investigating the behavioral effects of neurotoxicants. For example, in the signal-detection literature, Jansen et al. (64) found that when signal probability was low, alcohol affected stimulus sensitivity and reaction time of hits, but the same dose of alcohol did not affect these parameters when signal probability was high. These findings were not replicated for Diazepam (65). The findings with alcohol were interpreted to suggest that reduced response accuracy to low probability signals would compromise driving performance since low and variable signals are likely. If only one stimulus intensity was used, this differential effect of alcohol would not have been detected.
Detection of effects under exposure conditions will also require that behavioral tests be repeated within a relatively short period of time. Therefore, more information is needed to document the effects of repeated test administration within a brief time period such as before, during, and after exposure. This will require that tests be of sufficient difficulty to allow variability in performance both within and between subjects.
Behavioral tests that focus on process rather than a single summary outcome will be important in the development of research on low-level exposures. Even in cross-sectional studies of exposed working populations, the detection of behavioral effects to objectify symptomatic complaints of poor memory and concentration has been problematic. This difficulty may be due to the fact that many of the neuropsychological tests applied to this field offer a summary score of performance (WAIS-R subtests) rather than assessment of learning curves or variables delineating the various functions that contribute to performance. Thus, several investigators have emphasized the application of information-processing paradigms and tasks to the assessment of neurotoxicants (43,66).
In our experience with MCS patients, the tasks most sensitive to behavioral performance decrements were those in which subfunctions of the task were assessed. For example, obtaining scores on signal-detection parameters for the Continuous Visual Memory Test (CVMT) (67) revealed that MCS patients recognized signals at the same rate as normals (hits) but over responded to nonsignals (false alarms). A summary score for this task would suggest impaired visual memory; however, analysis of the subfunctions suggests that response style may be a more important variable in their performance. Observation of the distribution of scores for this group of patients also suggests that only a subgroup of the total group (approximately 39%) exhibited significant impairment (Figure 1). This finding is consistent with the observation of hyperactive children of Weiss et al. (68). Inspection of individual performance was more important than looking at overall group means, which can mask a subgroup of hyperresponsive individuals. This is particularly important when case definitions for affected individuals such as MCS are not clear.
Figure 1. Continuous Visual Memory Test. Data from Fiedler et al. (50).
In addition to test parameters, a complete characterization of host factors such as psychiatric diagnoses and personality traits is important. For example, among the following variables in the MMPI-2--age, reading score, and depression--health concerns was the variable accounting for the highest percentage of variance in performance on the CVMT (Figure 2). Health concerns measures a range of somatic symptoms, some of which can be related to neurologic conditions and some to somatization (69). Previous exposure-chamber studies have not focused on individual difference variables, such as mood or the tendency to somatize, in assessing behavioral response to neurotoxicants. Documentation of these variables may be critical in understanding individual differences in performance among MCS patients, particularly since approximately 25% of MCS patients qualify for a diagnosis of depression (50,56). Little is known about how depression may interact with the effects of neurotoxicants in producing behavioral performance decrements.
Figure 2. CVMT and MMPI-2 health concerns, MCS subjects. Data from Fiedler et al. (50).
Finally, as mentioned above, various odorants may affect behavioral performance (62). In olfactory research, extensive literature documents the psychophysical properties and mechanisms of odor perception. However, this literature does not address the concentration at which symptoms and objective health effects occur. Studies use objective behavioral tests (e.g., digit span) to document the effects of an odorant but relate these effects to properties of the odor (e.g., pleasant vs unpleasant, irritating vs nonirritating) rather than to concentrations in toxicological terms (60). While these odor effects may not impact healthy individuals, the same cannot be presumed in studies of symptomatic individuals such as MCS patients. Therefore, control or measurement of the impact of odor is critical. For example, alternate methods for administering exposures such as dermal routes could be considered.
Documenting behavioral responses to neurotoxicants among highly susceptible individuals places greater demands on the sensitivity of neuropsychological methods. Developing sensitive methods to elucidate the responses of sensitive individuals will also improve our approaches in the entire field of neurobehavioral toxicology.
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