Adoption of an adult environmental neurobehavioral test battery

Neurotoxicologyand Teratology,Vol. 16, No. 5, pp. 525-530, 1994 Copyright ©1994ElsevierScienceLtd Printed in the USA.All rights reserved 0892-0362/94 $6.00 + .00

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Adoption of an Adult Environmental Neurobehavioral Test Battery R O B E R T W . A M L E R , * J E F F R E Y A . L Y B A R G E R , * W . K E N T A N G E R , 1 "l B E T T Y L. P H I F E R , * WILLARD CHAPPELL~t AND LESLIE HUTCHINSON§

*Agency for Toxic Substances and Disease Registry, Atlanta, GA 30333 ~fOregon Health Sciences University, Portland, OR 97201 :~University o f Colorado at Denver, Denver, CO 80217 §Hutchinson Consultants, PC, Atlanta, GA 30211 R e c e i v e d a n d A c c e p t e d 1 J u n e 1994 AMLER, R. W., J. A. LYBARGER, W. K. ANGER, B. L. PHIFER, W. CHAPPELL, L. HUTCHINSON. Adoption ofan adult environmentalneurobehavioral test battery. NEUROTOXICOL TERATOL 16(5) 525-530, 1994.- Nationally recognized experts participated in a 3-day workshop to discuss the complex issues associated with neurobehavioral testing in environmental health settings, and to propose basic and focused test batteries for use in evaluating populations living near hazardous chemical sites. The Adult Environmental Neurobehavioral Test Battery (AENTB), which evaluates major neurobehaviorai domains and functions, was adopted by the Agency for Toxic Substances and Disease Registry (ATSDR) for use as a basic screening panel in field studies. Pilot testing of the AENTB demonstrated an examiner training requirement of 3-6 practice sessions, a mean total testing time of 58.0 min (SD = 9.6), and, for 9 of the component tests, a sample size requirement of fewer than 140 (or = 0.05, 95070power) to detect a 20070difference between study groups. ATSDR administered the AENTB to 467 persons, selected randomly from 1,382 participants in field study sites in three states. Total testing time varied noticeably by participant age and study site, suggesting an ongoing need for site-specific controls in each field study using the AENTB. Also planned is adoption of a pediatric test battery to evaluate the domains and functions most relevant at major stages of child development. Neurotoxic disorders Hazardous substances

Behavioral tests Environmental toxicology Pollution Superfund ATSDR

T H E A G E N C Y for Toxic Substances and Disease Registry (ATSDR) and the Emory University School of Public Health convened a workshop in September 1991 to assist in developing standardized neurobehavioral test batteries for use in environmental health field studies. The strategy was to build on the past success of using neurobehavioral test batteries to evaluate persons exposed to neurotoxicants in occupational settings (12). This article reviews the purpose and principal results of the workshop and summarizes steps taken by A TSD R to adopt and implement neurobehavioral test batteries in its health investigations of communities located near hazardous chemical sites. BACKGROUND ATSDR was created by Congress to implement the healthrelated portions of the Comprehensive Environmental Re-

Environmental health study

sponse, Compensation, and Liability Act of 1980 (CERCLA), also known as Superfund. ATSDR is mandated to conduct environmental health studies to determine the relationships between human exposures to hazardous substances and adverse health effects. To accomplish this mission, ATSDR must characterize many detailed events in a continuum that begins with a pathway of environmental exposure and proceeds, if unimpeded, to adverse organ effect, disease, or in the extreme, death (4). To focus Agency resources on the most serious health problems associated with exposure to hazardous substances, ATSDR has chosen to emphasize seven priority health conditions, one of them neurotoxic disorders (1). At least 750 toxicants have the potential to cause neurotoxic effects in humans after short- or long-term exposures or latent periods (6). Of 50 chemical substances designated as high priority by ATSDR, 31 are associated with neurotoxicity (2). In addition, of the 10

= Requests for reprints should be addressed to ATSDR Division of Health Studies, Attn: Chief Medical Officer, 1600 Clifton Road (E-31), Atlanta, GA 30333. 525

526

AMLER ET AL.

substances most frequently identified at hazardous chemical sites proposed or designated by the U.S. Environmental Protection Agency for the National Priorities List (March, 1991), 9 are known neurotoxicants. Several neurobehavioral test batteries have been standardized in occupational settings. In particular, the World Health Organization recommended Neurobehaviorai Core Test Battery (NCTB) and the Neurobehavioral Evaluation System (NES) have been used extensively and have become acceptable standards for occupational neurobehavioral testing (5,10,14). However, community-based study populations often include people from diverse age groups and cultures, who are usually not found in occupational cohorts. People who are prepubertal, pregnant, or elderly, for example, may be more sensitive to neurotoxicants than the "healthy worker" populations typically studied in occupational settings. Specialized environmental batteries are needed to assess such people. WORKSHOP A 3-day workshop was convened to discuss the complex issues associated with neurobehavioral testing in environmental health settings. The discussions were structured to help ATSDR develop environmental neurobehavioral test batteries for adults and children, and to inform attending professionals of ATSDR's plans in this field. The discussants were nationally recognized experts in neurotoxicology, neuropsychology, neurology, psychology, pediatrics, and epidemiology (7, 13,17). The workgroup chairpersons prepared position papers in advance to serve as a stimulus for discussion. Workgroup members addressed four basic questions: 1. How could existing tests be combined into test batteries to evaluate alterations in neurobehavioral functions o f adults and children? 2. What strategies, including existing models, could be considered for test selection? 3. How might neurobehavioral test batteries he modified periodically, and what criteria would be used to add or delete tests? 4. How could test batteries be tailored to evaluate exposures to specific neurotoxicants. The workgroup members were not asked to develop a consensus on the issues addressed. In some instances, considerable agreement occurred; in other cases, there were conflicting views. The workgroup members discussed numerous existing neurobehavioral tests and test batteries. They proposed grouping tests according to a three-tier scheme used by the National Research Council for similar purposes (15). The first tier (Level 1) consisted o f an initial group ("core") of screening tests, encompassing domains and functions previously shown to be most sensitive to neurotoxicants. The second tier (Level 2) consisted of tests that assess a specific group of functions; the need for such assessment might be indicated by symptoms or toxicants identified at a particular study site. The third tier (Level 3) was reserved for tests intended principally for basic research in neurobehavioral toxicology.

Workgroup 1: Adult Neurobehavioral Testing Members of this workgroup proposed a selection strategy based on specific domains and functions of the central nervous system (CNS) previously shown to be most sensitive to neurotoxicant effects. They also proposed tests to assess the

peripheral nervous system (PNS). They proposed 14 tests for a Level 1 battery to assess the cognitive, motor, sensory, and affective domains and 16 tests for a Level 2 battery to assess a broad group of l0 functions (7).

Workgroup 2: Pediatric Neurobehavioral Testing Unlike adult neurobehavioral testing, pediatric neurobehavioral testing does not have an existing body of background information and experience derived from occupational health studies. Because the most salient feature of childhood is developmental change, the ideal pediatric neurobehavioral test battery will encompass the major stages of child development. Therefore, the members of this workgroup began their deliberations at a conceptual stage. They formulated a developmental matrix by dividing the sequence of development into several stages and identifying the relevant domains for testing during each stage. Although they did not propose a specific battery of tests, they provided an extensive list of candidate tests (13).

Workgroup 3: Progressive Modification of Test Batteries Members of this workgroup identified several key issues to consider when modifying a battery of neurobehavioral tests. For example, it is important to determine whether a component test promotes the most effective collection of valid, specific information. When a test is to be added to an existing battery, it must contribute new information and accurately measure the domain for which it is intended. In addition, the test must be replicable, task-acceptable to examinees, and capable of being administered repeatedly to the same examinee. When tests are to be deleted, at least one test should be retained that measures each of the four broad domains (cognitive, motor, sensory, and affect) deemed essential to neurobehavioral assessment. Coding of test results must be planned in advance of data collection and in accordance with study objectives (17). The workgroup chairpersons and rapporteurs circulated summaries of the deliberations to workgroup members for comment before submission of the summaries to ATSDR and, subsequently, for publication here (7,13,17). ATSDR staff members, after auditing the workgroup discussions and reviewing the workgroup reports, selected the tests and considered other actions that would provide the needed populationbased evaluations. ADULT TEST BATTERY ATSDR adopted a 12-test battery for Level 1 testing of adults and named it the Adult Environmental Neurobehavioral Test Battery (AENTB) (Table 1). This battery was shortened from the 14 tests proposed by the workshop members (7) to cover all major domains and functions in 66 instead of 82 minutes (mean). The Rey Auditory Verbal Learning Test was omitted and the tests of visual acuity and contrast sensitivity were combined. The shorter testing time was considered essential to maximize participation rates, compliance, and performance, and to leave time available for other data collection procedures (e.g., blood drawing and questionnaire administration; 11). ATSDR contracted with Oregon Health Sciences University (OHSU) to conduct a pilot test and train staff to administer the new battery of tests.

Pilot Test The Dalles, Oregon, was chosen for the pilot test because it is adjacent to a National Priorities List site that did not

ADOPTION OF ADULT TEST BATTERY

527

TABLE 1 ATSDR ADULT ENVIRONMENTALNEUROBEHAVIORALTEST BATTERY AdministrationTime(Minutes) Domains Test Visual acuity & contrast sensitivity Color vision Vibrotactile threshold Santa Ana Dynamometer with fatigue assessment Raven Progressive Matrices (revised) Symbol-digit (NES) with delayed recall** Tapping (NES) Simple reaction time (NES) Serial digit learning (NES) Vocabulary (NES) Mood scale (NES)

Sensory

Motor

Cognitive A f f e c t

+ + + + + + + +

+ + + + + +

All tests

Workshop Estimate

Pilot Test (mean)*

3 3 8 5 5 10 5 4 11 4 4 4

4.1 5.6 4.4 6.7 2.3 6.8 7.0 2.2 10.7 3.5 3.2 2.8

66

58.0

*Source: AENTB pilot test, The Dalles, Oregon, 1993; **A single matrix of 9 symbols is presented 20-30 min after the serial digit learning test to assess delayed recall.

have evidence of off-site migration of toxicants (3). Thus, the residents were demographically similar to those who would typically be encountered in environmental health studies, but they were unlikely to have significant environmental exposures to neurotoxicants. The AENTB was administered to 50 residents who responded to advertisements in the local newspaper and radio stations. All were adults above the age of 18; 64070 were women. The mean age was 35.9 years (SD = 15.5); the mean reported years of education was 12.9 (SD = 2.1). The total mean time of administration of all the component tests in the AENTB was 58.0 min (SD = 9.6). The manual (individually administered) tests and computerized (NES) tests required 29.9 and 29.4 min, respectively (Table 1) (9), as contrasted with the time estimated by members of Workgroup 1 (7).

Sample Size Calculations For most of the AENTB component tests, populationbased reference data were not available (5,9). The pilot test provided a basis for estimating the statistical power of the tests (except the color vision test) and for projecting the sample size that would be needed in future health studies using the AENTB (8,9). Anger and Sizemore reported the sample size required to detect a 10070, 20070, or 30070 difference between target and comparison groups on the bases of c~ = 0.05 and 95070 power (8). These measures were also corrected for multiple comparisons within each of eight groupings (corresponding to neurobehavioral functions cited earlier by Workgroup 1), using the conservative Bonferroni approach (16). Nine AENTB component tests evaluated required fewer than 140 total test participants (Bonferroni-corrected), or fewer than 115 total test participants (Bonferroni-corrected by functional grouping), to detect a 20°70 difference between target and comparison groups. Two component tests, serial digit learning and dynamometer fatigue, both required several hundred test participants to obtain the same statistical power.

Examiner Training Of 20 examiner trainees, 15 completed certification at the pilot test site and at ATSDR field study sites in three states. The study sites were Caldwell Systems Inc., Caldwell County, NC (August, 1993); Cornhusker Army Ammunition Plant, Grand Island, NE (September-October, 1993); and McClellan Air Force Base, Sacramento, CA (April, 1994). All examiners were trained to administer the tests consistently-by following the written protocol exactly and reliably, and by avoiding inappropriate actions such as freelance directing and response interpretation. Each trainee practiced administering the tests to naive volunteers under instructor supervision. Some learned correct performance after three practice administrations; others displayed a lack of confidence and made errors until they had completed five or six practice administrations. To be certified, trainees were required to administer the tests without error to at least one naive volunteer. A quality assurance check was provided at mid-study to verify that each examiner continued to meet certification criteria.

Implementation ATSDR administered the AENTB to 467 participants (239 women; 228 men) selected randomly from subsets of the 1,382 study participants at the three study sites. The participants ranged in age from 16 to 75 years; 108 were 16 to 29 years, 155 were 30 to 49 years, 164 were 50 to 69 years, and 40 were 70 to 75 years of age. The time required to complete the AENTB varied noticeably by participant age and study site, and to a lesser extent by sex (Table 2). The investigators also noticed differences in administration time between examiners, although this is not quantified here. The total testing time (start time to stop time) for the six noncomputcrized (i.e., manual) component tests of the AENTB, ranged from 15 to 57 min (mean 33.2, SD = 7.0). Median testing time varied by 7 to 10 min between the youngest and oldest age groups within a single study site.

L~ t,J Oo

26 25 32 36

23 20 25 32

19 22 24 29

Caldwell 16-29 30-49 50-69 70-75

Cornhusker 16-29 30-49 50-69 70-75

McClellan 16-29 30-49 50-69 70-75 24.5 27 31 #

28 30 35 35

30 35 35 u

25

29 33 35 ~

32 33 37.5 40

33 35 37.5 #

50

Percentile

33 36 38 m

35 35 44 45

43 40 43 M

75

Men

44 48 52 55

45 48 53 50

45 55 52 55

1(30

18 32 28 4

23 14 24 14

11 29 25 6

n

30.2 32.8 35.3 43.0

32.1 33.2 39.1 38.1

35.4 37.3 37.7 44.2

Mean

6.9 6.4 6.0 10.7

5.7 7.2 7.7 10.9

6.8 7.2 9.5 7.3

SD

22 23 20 39

25 27 28 31

30 30 27 15

0

24 30 26.5 #

26.5 30 35.5 m

32 35 35 #

25

28 32 32 ~

30 35 40 #

35 38 38 m

50

Percentile

32 36 36 #

35.5 38 45 #

40 45 42 w

75

47 40 55 45

47 48 57 52

44 54 56 50

100

Women

24 29 26 3

20 17 32 9

12 34 29 4

n

29.8 33.0 35.1 41.3

31.9 35.4 40.5 44.4

36.1 39.4 39.0 36.3

Mean

6.7 4.7 7.8 2.6

6.7 6.3 7.1 6.7

4.7 5.7 7.2 15.5

SD

19 22 20 29

23 20 25 31

26 25 27 15

0

24.5 29.5 29.5 #

27 30 35 38

30 35 35 36

25

29 32.5 35 #

30 34 38 40

35 37 38 42

50

Percentile

33 36 37 m

35 38 45 47

40 43 42 50

75

47 48 55 55

47 48 57 52

45 55 56 55

100

Both Sexes

*Caldwell County, NC, 1993; Cornhusker Army Ammunition Plant, NE, 1993; McClellan Air Force Base, CA, 1994; XInsufficient data. SD = standard deviation.

0

Study Site* and Age Group

TABLE 2 AENTB MANUAL TESTING TIME (MINUTES) BY AGE GROUP, SEX, AND STUDY SITE, 1993-1994

42 61 54 7

43 31 56 23

23 63 54 10

n

30.0 32.9 38.7 42.2

32.0 34.4 39.9 40.6

35.7 38.5 38.4 41.0

Mean

6.8 5.6 11.1 7.8

6.1 6.7 7.3 9.8

5.7 6.5 8.3 11.2

SD

ADOPTION OF ADULT TEST BATTERY

529

Conversely, median testing time varied by 0 to 6 min between study sites within each age group evaluated. In the majority of groupings by age and study site, women had longer median testing times (by 0.5 to 7 min) than men. However, in some of these groupings, women had shorter median times (by 1 to 3 rain) than men. Other important factors have emerged from these initial studies. Investigators have recognized the need to maintain optimal lighting and to minimize noise and other background distractions in the testing room. Different models of room configuration and participant flow have been explored to increase efficiency and reduce variability in the data. Using experienced examiners from previous studies also improved efficiency and reliability of test administration.

in the pilot study and, for the manual tests, SD = 5.2-11.2 min) provides guidance on session duration, by age, for scheduling a field study using the AENTB. Thus, while the mean or median session duration is approximately 1 h, almost 80% of participants will have completed the AENTB within 1 h and 20 min, and approximately 97% of participants will have completed testing in 1 1/2 h. ATSDR's final reports of the three field investigations will contain results of the AENTB component tests. Analysis of AENTB results in any study population will depend on several criteria: reference data, clinical relevance, and neurotoxic plausibility. These criteria will undergo further development as the AENTB is used in studies of different populations and toxicant exposures.

DISCUSSION ATSDR's adoption of the AENTB represents important progress in the Agency's initiative to evaluate health endpoints in communities located near hazardous chemical sites. The workgroup discussions provided sufficient information to adopt a basic, time-effective panel of tests for use in evaluating neurobehavioral function in such communities. Following this successful model of test panel development, ATSDR has convened additional workshops and promulgated basic test batteries for other priority health conditions. ATSDR also plans to develop a pediatric environmental neurobehavioral test battery to evaluate the domains and functions that are most relevant at major stages of child development. ATSDR's experience with administration of the AENTB to more than 500 people at pilot and field study sites in four states, has defined practical factors that are extremely important in field studies. Such factors include requirements for examiner training, sample size, and coordination of the AENTB with questionnaire interviews and collection of blood and urine specimens. The variability of test administration times found among different participants (e.g., SD = 9.6 min

ACKNOWLEDGEMENTS We express special appreciation to the workshop participants and field study staff. The workshop co-chairs were Barry L. Johnson and Howard Frumkin. The workshop rapporteur was Philippe Grandjean. The workshop planners were Sharon S. Campolucci, Joyce Smith, and Charles Xintaras. O.J. Sizemore co-authored the AENTB Examiner Training Manual with one of the authors (WKA). Julie Glasser and Jo Brown provided scheduling and testing support in the pilot test (Oregon). The ATSDR field study principal investigators were G. Brent Hamar (Nebraska), Paul A. Jones (California), and Helena Y. Zabina (North Carolina). The ATSDR project officer was Alvin Hall. Rosaline Dhara provided summary statistics. This pubfication was supported wholly by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund through the Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services. The use of company or product names is for identification only and does not constitute endorsement by the Agency for Toxic Substances and Disease Registry, the Public Health Service, the U.S. Department of Health and Human Services, or the collaborating universities.

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