CHRONIC NEUROLOGICAL SEQUELAE
OF ACUTE ORGANOPHOSPHATE
PESTICIDE POISONING:
AN EPIDEMIOLOGIC STUDY
Final Report
Eldon P. Savage, Ph.D.., Project Director
Thomas J. Keefe, Ph.D./ Director of Statistical Services
Lawrence M. Mounce, B.S., Field Studies Coordinator
Epidemiologic Pesticide Studies Center
Institute of Rural Environmental Health
Colorado State University
Fort Collins, Colorado 80523
James A. Lewis, M.D., Neurologist
Robert K. Beaton, Ph.D., Clinical Psychologist
Departments of Neurology and Psychiatry
University of Colorado Medical Center
Denver, Colorado 80220
Leland H. Parks, Ph.D., Assistant Project Director
Epidemiologic Studies Program, School of Medicine
Texas Tech University Health Services Centers
San Benito, Texas 78586
April 1982
The information in this document has been funded wholly or
in part by the United States Environmental Protection Agency
under contract 68-01-4663 to Colorado State University. It
has been subjected to the Agency's publications review process
and has been approved for publication as an EPA document. Mention
of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
-------
TABLE OF CONTENTS
Page
LIST OF TABLES iii
ACKNOWLEDGEMENTS vi
INTRODUCTION 1
MATERIALS AND METHODS . 3
Case Participants 3
Selection of Matched Pair Control Participants 5
Participant Interview 6
Quality Control Assurances 6
Comprehensive Examination Protocol 7
Pesticide Residue and Cholinesterase Testing 7
Physical Examinations 7
Neurological Evaluation , 8
Electroencephalographic Examination 8
Neuropsychological Testing 9
Statistical Analysis 15
RESULTS 17
Demographic Data 17
Acute Organophosphate Pesticide Poisoning Histories 29
Physical Examination and Clinical Laboratory Data 30
Clinical Laboratory Results 33
Neurological Data 33
Neuropsychological Findings 50
Blood Pesticide Residues and ChE Assays 58
SUMMARY AND DISCUSSION 66
REFERENCES 74
-------
LIST OF TABLES
Table Page
1 Occupations of organophosphate pesticide poisoning cases ... 18
2 Age means and standard deviations (S.D.) of all study
participants ......................... 19
3 Mean Hollingshead social class and standard deviation (S.D.)
of case and control participants ............... 20
4 Age and Hollingshead social position scales for study
participants by matched pairs ................. 21
5 Elapsed time in days from last poisoning to neuropsychologi-
cal examination .................... . . . . 29
6 Organophosphate pesticides implicated in the primary poisoning
incidents ........................... 31
7 Summary of abnormal conditions identified in participants
during physical examination ................. 32
8 Summary of the statistical comparison of the cases and controls
with respect to selected laboratory test variables ...... 34
9 Summary of the results of the encephalogram (EEG) evaluation
of case and control participants ............... 35
10 Summary of the statistical comparison of the cases and controls
with respect to mental status, cranial nerves, and motor
system ............................ 37
11 Evaluation of case and control participants with respect to
the summary and components of the mental status category of the
neurological examination ................... 38
12 Evaluation of case and control participants with respect to
the state of consciousness and mood from the mental status
category of the neurological examination ........... 40
13 Evaluation of case and control participants with respect to
the cranial nerve category summary evaluation of the neuro-
logical examination ...................... 40
14 Evaluation of case and control participants with respect to
the knee jerk (right and left combined) test of the neuro-
logical examination ...................... 41
15 Evaluation of case and control participants with respect to
the ankle jerk (right and left combined) test of the neuro-
logical examination
iii
-------
LIST OF TABLES (Continued)
Table Page
16 Evaluation of case and control participants with respect
to the motor system score test of the neurological
examination 41
17 Summary of the statistical comparison of the cases and
controls with respect to the sensory system 42
18 Evaluation of case and control participants with respect
to the pin upper right extremity test of the neurological
examination 43
19 Evaluation of case and control participants with respect
to the pin upper left extremity test of the neurological
examination 43
20 Evaluation of case and control participants with respect
to the pin lower right extremity test of the neurological
examination 44
21 Evaluation of case and control participants with respect
to the pin lower left extremity test of the neurological
examination 44
22 Evaluation of case and control participants with respect
to the vibration, right test of the neurological examina-
tion 45
23 Evaluation of case and control participants with respect
to the vibration, left test of the neurological examina-
tion 45
24 Summary evaluation of case and control participants with
respect to the sensory system of the neurological examina-
tion 46
25 Summary of the statistical comparison of the cases and
controls with respect to integrative function and other
miscellaneous examinations 47
26 Evaluation of case and control participants with respect
to the finger-nose right test of the neurological examina-
tion 48
27 Evaluation of case and control participants with respect
to the finger-nose left test of the neurological examina-
tion 48
28 Summary evaluation of case and control participants with
respect to the integrative function of the neurological
examination 49
IV
-------
LIST OF TABLES (Continued)
Table Page
29 Summary evaluation of case and control participants with
respect to other miscellaneous exams of the neurological
examination 49
30 Psychological test score means, standard error of the
difference of means, and the probability level of the
analysis of variance test for the case-control comparison
for the Halstead-Reitan Battery and the WAJS Battery .... 51
31 Psychological test score means, standard error of the
difference of means, and the probability level of the
analysis of variance test for the case-control comparison
for the Peabody and Individual Achievement Test and Added
Ability Tests 52
32 Psychological test score means, standard error of the
difference of means, and the probability level of the
analysis of variance test for the case-control comparison
for the MMPI Battery 53
33 Patient's assessment of own functioning: Test score means,
pooled estimate of the standard error (S.E.) of each mean,
and probability level of the analysis of variance test for
the case-control comparison 56
34 Relative's assessment of patient's functioning: Test score
means, pooled estimate of the standard error (S.E.) of each
mean, and probability level of the analysis of variance test
for the case-control comparison 59
35 Analysis of variance summary with subgroup means and
standard deviations for the total organochlorine pesticide
residue in the blood 62
36 Analysis of variance summary with subgroup means and
standard deviations for red blood cell cholinesterase. ... 64
37 Analysis of variance summary with subgroup means and
standard deviations for plasma cholinesterase 65
-------
INTRODUCTION
LJhe increased use of organophosphate (OP) pesticides in the last three
decades has been accompanied by numerous acute organophosphate poisonings.
The World Health Organization (WHO) has stated that the problem of acute
pesticide poisonings is extensive and serious and may number as many as
500,000 cases annually throughout the world (1)J In the United States, a
national study of hospitalized pesticide poisoning cases from 1971 through
*
1973 resulted in an estimated 8241 admissions of which 31% were due to
organophosphate pesticides. Of these, over 70% of the organophosphate
pesticide poisonings were due to occupational exposure (2).
The OP pesticides are cholinesterase inhibitors. In the poisoned
individual cholinergic synapses cannot degrade the transmitter, acetylcholine,
released during normal function. This condition leads to excitation,
followed by paralysis, of the extensive peripheral and central cholinergic
nervous system. Symptoms in patients experiencing OP poisonings include
flushing, salivation, fasciculations, tremors, restlessness, agitation, ataxia,
weakness, convulsions and coma; these symptoms develop immediately after
exposure. Once the cholinergic imbalance has been corrected the neurological
signs and symptoms usually disappear completely (3).
In acute OP poisonings plasma and/or red blood cell (RBC) cholinesterase
activity is depressed. Plasma depression may last from one to three weeks
while depression of RBC acetylcholinesterase may persist for as long as 12
weeks. If the treatment of acute organophosphate poisoning cases is inade-
quate, a delayed but invariably transient syndrome with similar features
may appear (4).
It has been shown in animal studies that the OP anticholinergic com-
pound, tri-o-cresyl phosphate (TOCP), can produce chronic and progressive
-------
degeneration of lower motor neurons (5). Bidstrup et al. have suggested that
the OP pesticides could produce a similar effect (6). The presence of long-
term neuropsychiatric disturbances in humans following acute exposure to OP
compounds has been reported by Gershon, Shaw and others (7,8). Drenth noted
a high percentage of electromyogram (EMG) abnormalities among workers in OP
production plants (9). Abnormal electroencephalograms (EEGs), similar to
those obtained from epileptic patients, have been observed by several investi-
gators in individuals following acute pesticide intoxications (10,11). Met-
calf and Holmes (12) described less dramatic abnormalities in the EEGs after
recovery from acute poisoning. Duffy et al. (13) suggested that the persis-
tence of known short-term OP effects, when taken in conjunction with the
reported long-term behavioral effects of OP exposure, provide parallel evi-
dence that human exposure to OP compounds can culminate in brain function
alterations.
In spite of the number of investigators who have reported the above
findings, a number of other scientists have disagreed with these conclusions
(14,15). An epidemiologic analysis of patients following acute OP intoxica-
tions did not reveal increased incidence of psychiatric disorders (16).
Tabershaw and Cooper found no "serious sequela of high incidence" in patients
reported as having "occupational disease attributed to organic pesticides"
(17). Clark, in an extensive literature review of experimental animal
studies, was unable to find consistent evidence supporting the hypotheses
that exposure to OP pesticides may result in abnormal behavior (18).
Many of these clinical studies have not included epidemiologic design.
For example, they have not included one or more of the following: matched
-2-
-------
controls, complete documentation of acute exposures, sufficient quantitative
measures of neurologic and behavioral functioning, and complete statistical
analyses. The major objective of this epidemiologic study which was designed
to overcome many of the aforementioned shortcomings, was to determine the
chronic adverse health effects, if any, following an acute organophosphate
poisoning.'
This study was a cooperative effort of the following institutions: the
Epidemiologic Pesticide Studies Center of the Institute of Rural Environmental
Health of Colorado State University (Colorado Center) in Fort Collins, Colorado
the Epidemiologic Studies Program, Texas Tech University School of Medicine
(Texas Program) in Lubbock, Texas; and the Departments of Neurology and Psy-
chiatry, University of Colorado Medical Center (UCMC) in Denver, Colorado.
The Colorado Center served as coordinator on the project.
MATERIALS AND METHODS
The study population consisted of 100 individuals (cases) who had
previously experienced acute poisoning from OP pesticide exposures. Each
case was carefully matched by age, sex, race, occupation, and educational
level to a control participant. Participants in the control cohort had not
experienced organophosphate poisonings. The study was specifically designed
to detect any chronic neurological or neuropsychological effects in the case
participants.
Case Participants. A roster of potential case participants was compiled
from various health data records available in Colorado and Texas. The
Colorado roster consisted of approximately 443 organophosphate pesticide
poisoning cases, all of which occurred from 1950 through 1976. Holmes (19),
and Savage, et al. (20) and other investigators have reported on a number
of pesticide poisoning cases that occurred in Colorado. Gallaher (21) and
Hatcher and Wiseman (22) and other investigators have reported on poisoning
-3-
-------
cases from the Rio Grande Valley in Texas. The potential case participant
roster in Texas consisted of about 400 individuals who had experienced
acute pesticide exposures from 1960 through 1976. After screening
both the Colorado and Texas rosters for completeness of poisonings documenta-
tion, a revised roster of approximately 303 potential OP poisoned participants
was developed, and exhaustive attempts were made to locate all of the potential
participants. Of the 303 potential participants, a total of 200 (approximately
66%) were located.
The potential participants were carefully screened for acceptance. The
screening process criteria included: 1) a documented history of at least
one OP poisoning; 2) diagnosis by a physician including symptoms consistent
with OP poisoning; 3} a minimum age of 16 years at the time of follow-up
contact; and 4) an understanding of the English language sufficient to
complete the neuropsychological test. Participants were excluded if they
had any of the following in their medical histories: 1) organophosphate
poisonings within three months prior to testing; 2) diseases or injuries
to the central nervous system including periods of unconsciousness totaling
more than 15 minutes; 3) congenital defects of the central nervous system;
or 4) alcohol, drug, or narcotic abuse.
Of the 200 potential participants that were located, a total of 12 (6%)
were deceased; 47 persons (23.5%) did not meet the screening process criteria;
and 27 (13.5%) declined to participate in the study. The remaining 114
potential case participants agreed to participate in the study. Of these, a
total of 100 case participants completed the study. Examination scheduling
difficulties such as great travel distances and conflicting work requirements
prevented 14 cases from participating during the time period of the study.
-4-
-------
Selection of Matched Pair Control Participants. Control participants
were selected and matched to corresponding case participants with respect to
age, sex, race, level of education, occupational class, social position,
and ethnic background. Controls were identically matched for sex and race,
and in the case of Mexican Americans, for ethnic background. Age was
matched to within one year for participant ages 16 through 20; two years
for ages 21-23; three years for ages 24-25; and five years for ages 26
through 70. The age matching criteria were established to be compatible
with normal performance curves on the neuropsychological test battery.
Persons younger than 15 were excluded from the study because the adult
neuropsychological test battery is not appropriate for them, and persons
older than 70 were excluded because more extreme "normal aging" effects
on neuropsychological performance would be expected for such subjects.
Education, occupation, and social position were matched within one level
based on scales prescribed by the Hollingshead Two Factor Index of Social
Position (23). The educational scale was divided into seven levels with the
highest level of educational achievement scored as 1 and the lowest level
scored as 7. The occupational scale was also divided into seven levels with
the highest level of occupational achievement scored as 1 and the lowest as
7. The social position index was composed of five levels with a score of 1
representing the highest level.
The control cohort participants were recruited primarily from the state
of Colorado and from the Lower Rio Grande Valley of Texas. A total of 35
participants were recruited through referrals from case and control parti-
cipants; 24 controls were recruited through rosters of employees furnished
by businesses and public agencies; 37 participants were recruited through
investigator solicitation; and in 4 cases recruitment reference source data
-5-
-------
were incomplete. The controls were also screened to make certain they did
not have histories of drug or alcohol abuse and that they had not previously
experienced CNS injuries.
Participant Interview. Specially trained field epidemiologists inter-
viewed the matched pair case and control cohorts. The interview form
(Appendix A) included: demographic data, informed consent form, occupational
history, pesticide exposure history, OP poisoning history (for cases) and an
abbreviated medical history. In addition, the spouse or a close relative
completed a questionnaire rating the participant's personality and several
functioning tests. The physical, neurological and neuropsychological
examinations were usually scheduled at the conclusion of the interviews.
Quality Control Assurances. A continuous effort was made to conduct
the study in Colorado and Texas in a similar manner. Two field epidemiologists
from the Texas Program worked with their counterparts at the Colorado Center
to standardize interview techniques and the recording of data to insure
uniformity.
The neuropsychological examiner who conducted tests on the Texas cohorts
was trained and supervised by personnel from the UCMC Neuropsychological
Laboratory. The physicians conducting the neurological evaluations in Texas
and Colorado worked together to standardize their procedures prior to the
start of the study and at intervals throughout the period of the study.
Physical exams, neurological testing and neuropsychological testing of
Colorado participants were performed at UCMC in Denver, and Texas participants
were evaluated at the Texas Program offices and at the office of a practicing
neurologist in Brownsville, Texas. These examinations took a total of two days
for each participant to complete. Since the protocol consisted of a blind
study design, the participants were instructed not to reveal whether they were
-6-
-------
a case or control to the investigators conducting the physical, neurological
and neuropsychological evaluations. All participants received monetary com-
pensation as reimbursement for their time, travel, and expenses.
Comprehensive Examination Protocol. The testing program about to
be described was designed by board certified persons and other recognized
experts to be comprehensive in the sectors of physical, neurological and
neuropsychological examinations. The testing program received peer review
and modification before starting. Generally accepted categories within
these examinations were evaluated by the examiners using generally accepted
objective tests wherever possible. Individual tests that were redundant,
expensive, elaborate or very specific to annual diseases or states of
impairment were avoided.
Pesticide Residue and Cholinesterase Testing. Blood samples were
collected from the participants at the time of neurological examination.
These samples consisted of a volume of 10 ml of venous blood collected in a
heparinized tube for Cholinesterase (ChE) assay (Appendix B) and another 10
ml of venous blood collected in a non-heparinized tube for chlorinated hydro-
carbon pesticide residue analyses.
Physical Examinations. All case and control participants were given
medical examinations consisting of physical examinations, neurological
evaluations, electroencephalographic examinations, and neuropsychological
testing. The routine physical examination consisted of complete medical
histories, audiometric and ophthalmic examinations, and clinical blood
evaluations. The medical histories and routine physical exams were conducted
by the examining neurologist. The audiometric and ophthalmic examinations
were conducted by qualified technicians. Clinical blood evaluations were
performed at the hospital or office with which the examining neurologist was
associated. All data were thoroughly reviewed by the neurologist at UCMC.
-7-
-------
Although every attempt was made to screen potential case participants and
controls prior to these evaluations, the results were used to detect and
screen out participants with chronic diseases such as diabetes, renal
failure, pernicious anemia and other conditions that may produce neurologic
impairment. Although no such cases were found in the Colorado participants,
a few participants were eliminated from the Texas group. Standard forms used
for the physical examination are contained in Appendix D. The participants
were informed of significant findings on their physical examination and,
if indicated, they were advised to seek independent medical follow-up.
In addition, significant findings of test results were summarized by the
neurologist and given to the participant's personal physician.
Neurological Evaluation. As previously mentioned, all subjects were
instructed not to reveal their status as either a case or a control partici-
pant during their neurological evaluation. The neurological history and
formal review of systems were recorded on standard forms by the examining
neurologist. This was followed by a neurological examination which consisted
of an evaluation of mental status, cranial nerve function, motor system
function, sensory system function, and tests of cerebellar function and
coordination. Tests used in each of these categories are shown in Appendix D.
Electroencephalographic Examination. All study participants were
subjected to a routine clinical electroencephalogram on either 8 or 16
channel Instruments* manufactured by either the Grass or Beckman Companies.
Electrodes were applied with paste according to the International 10-20
placement system. All tracings were recorded without patient sedation;
photic stimulation and hyperventilation were done on all participants, and
sleep phase recordings were obtained when possible. During the course of
the waking record, all patients had nine minutes of data from four channels
recorded onto a Vetter EM tape recorder for offline computer analysis. The
-8-
-------
records were read visually in a standard clinical fashion and interpreted as
either normal or abnormal; details of the activity seen were recorded on a
research report form (Appendix E).
Neuropsychological Testing. The study participants were presented
to the neurological technicians "blind". All subjects were administered
the neuropsychological tests in approximately the same order to eliminate
any bias associated with the order of test administration. Each participant's
testing was completed in a single work day.
The tests consisted of the Wechsler Adult Intelligence Scale (WAIS)
(24) and an expanded version of the test battery originally developed by
Halstead (25) and Reitan (26). Numerous studies published over the last 30
years have shown that these tests are sensitive to focal and diffuse cerebral
lesions caused by diverse neurologic conditions. Recent literature reviews
are presented by Reitan and Davison (27) and Russel et al. (28).
The expanded Halstead-Reitan battery included measures of intelligence,
attention, various cognitive functions, motor proficiency, sensory-perceptual
functions, aphasia and related disorders, and learning and memory. An objec-
tive personality test was also given in an effort to determine whether
pesticide-case participants showed increased tendencies toward psychiatric
disturbances. The following are brief descriptions of the specific tests
and test scores used in this study. More detailed descriptions can be
found in the references provided.
Wechsler Adult Intelligence Scale (WAIS) (24): The WAIS is a well
known and widely used measure of adult intelligence (29). The WAIS is also
known to be sensitive to acquired brain lesions. Scores used in the WAIS
include the Verbal, Performance, Full Scale IQ Values, and the scaled scores
on the individual subtests (Information, Comprehension, Arithmetic, Similari-
-9-
-------
on the individual subtests (Information, Comprehension, Arithmetic, Similari-
ties, Digit Span, Vocabulary, Digit Symbol, Picture Completion, Block Design,
Picture Arrangement, and Object Assembly).
Halstead Category Test (25,30): This is a relatively complex nonverbal
test of abstraction and concept formation. The subject's goal in the first
six subtests is to determine a unifying principle that, when applied to each
item on the subtest, would give the correct answer. A seventh subtest is a
review group where the subject tries to remember the answer to items seen in
the earlier subtests. The score is determined by the number of errors on
the total of 208 items.
Tactual Performance Test (25,30): In this test there are three trials
in which the subject is blindfolded and asked to place ten geometrically
shaped blocks into their correct spaces on a form board. The first trial is
done with the dominant hand, trial two with the nondominant hand, and on the
third trial both hands are used. The three trials are timed, and a maximum
of ten minutes is alloted for each trial. The measure used to reflect psycho-
motor problem solving efficiency is the time (minutes) taken per block for
the three trials combined.
There are also two measures of incidental memory generated on the
Tactual Performance Test. The subject Is not told in advance to remember
anything about the blocks or the board. However, after the three trials are
completed the board is removed, the blindfold is taken off, and the subject
is asked to draw a picture of the form board from memory. "Memory" points
are earned for correctly recalling the shapes on the board, and "location"
points for shapes correctly localized on the drawing. A maximum of ten
points is possible on each of the measures.
Speech Sounds Perception Test (25,30): This test requires sustained
attention, accurate perception of verbal auditory stimuli, and the ability
-10-
-------
to match simple spoken words with their written versions on an answer sheet.
Sixty nonsense words are presented from a tape recorder, each having a
middle "ee" vowel sound and different consonant combinations at either end.
Each of the 60 spoken nonsense words must be selected (underlined) from among
4 written alternatives on the answer sheet. The score recorded is the number
of errors made on the 60 items.
Seashore Rhythm Test (25,30,31 )' This test requires sustained attention,
fine discrimination among nonverbal auditory stimuli, plus short-term memory
for such stimuli. The subject is presented 30 pairs of rhythms via a tape
recorder, and for each pair, is required to indicate whether the second
rhythm is the same or different than the first rhythm. The score recorded
is the number of correct judgments out of a possible 30.
Finger Oscillation Test (25,30): This test of upper extremities' motor
speed requires the subject to tap as fast as possible with the index finger,
using an apparatus which resembles a telegraph key. The mean number of taps
on five 10-second trials is recorded for each hand, and in this study these
two fingers are summed to give a final measure of tapping speed.
Halstead Impairment Index (25,30): In current practice, this summary
measure of generalized neuropsychological deficit uses seven of the test
scores described above: Category; Tactual Performance Test Total Time,
Memory, and Location: Seashore Rhythm; Speech Sounds Perception; and Finger
Oscillation with the dominant hand only. The index is the proportion of
scores on these tests which is in the range characteristic of patients with
documented cerebral lesions. Higher index scores increase the probability
of impaired cerebral functioning.
Trail Making Test, Part B (30,32): This paper-and-pencil test requires
general alertness, spatial analysis, motor speed, and the ability to follow
-11-
-------
correct sequences of numbers and letters in an alternating fashion. The
score is determined by the number of seconds taken to complete the test.
Aphasia Screening Examination (30,33): This is Reitan's modified ver-
sion of the Halstead-Wepman aphasia screening test (34). This test is
designed to screen for deficits in the participant's ability to: name common
objects; spell simple words; identify letters and numbers; read and write
simple words and short statements; enunciate; repeat a short statement and
explain Its meaning; work simple mathematical problems; demonstrate the use
of a common object such as a key; and discriminate right from left. A
total aphasia score, which can range from 0 to 75, was derived from the
scoring and item weighing system of Russell et al. @8).
Spatial Relations (28): This is a-measure of constructional dyspraxia,
or degree of spatial distortion apparent in the subject's reproductions of
geometric designs. The score is based upon the subject's drawing of the
Greek cross from the aphasia screening exam and his scaled score on the WAIS
block design subtest (28,33).
Reitan-Klove Sensory Perceptual Examination (30): During this examina-
tion, tests are administered for finger tip number writing imperception
(graph-esthesia), tactile finger recognition errors (finger dysgnosia), and
sensory suppressions (tactile, auditory, and visual extinction phenomena).
For each test, all error scores for both sides of the body are totaled to
provide a total perceptual error score.
Average Impairment Rating (28): This score is the average of the
ratings, which range from 0 (better than average) to 5 (severely impaired),
received by the participant on 11 of the Halstead-Reitan battery tests
described above and 1 WAIS measure. The Average Impairment Rating differs
from the Halstead Impairment Index in that the former includes more tests
-12-
-------
and reflects the degree of overall impairment rather than the range of
abilities affected.
Reitan-Klove Tactile Form Recognition (30): This test of stereognosis
requires the study participant to discriminate among four flat plastic
shapes by touch alone. A vertically positioned board is used, in which
copies of the shapes are mounted on the board. The score is derived from
the time (seconds) taken to complete 16 trials (8 trials with each hand).
Smedley Hand Dynamometer: This test of grip strength is often included
in the Hal stead-Reitan battery for clinical and research investigations (27 ).
Two trials are given with each hand, and the average strength for each trial
is recorded in kilograms (kg). The final score is the sum of the mean scores.
Klove-Matthews Motor Steadiness Battery (27): The grooved pegboard test
and the hole-type steadiness test are used in this study. The grooved peg-
board (Lafayette Instrument Co., No. 32035) measures speed and fine motor
coordination with the upper extremities. This test requires the subject to
place 25 small metal pegs into holes on a horizontal board as quickly as
possible. The holes have grooves on one side, so the pegs will not fit unless
they are positioned properly. A trial is given with each hand. The number of
seconds taken to place all 25 pegs are recorded and totaled. The hole-type
steadiness test (Lafayette Instrument Co., No. 32011) is a test of static
steadiness. The study participant is asked to hold a stylus in the center
of six successively smaller holes, trying not to let the stylus touch the
sides. The stylus is connected to a recorder. Both hands are tested for all
six holes, and error scores are totaled for the 12 trials.
Peabody Individual Achievement Test (35): The Reading Recognition,
Reading Comprehension and Spelling subtests are administered to provide
coverage of these academic skills. Percentile scores are used.
-13-
-------
Thurstone Word Fluency Test (36): In Part A of this written fluency test,
the study participant is given five minutes to write as many words as possible
that begin with the letter "S". In Part B the participant is given four
minutes to write as many four letter words as possible that begin with the
letter "C". The total score is the number of words written in these two
trials.
Word Finding Test (37): In this test of verbal problem solving ability,
the study participant attempts to guess the identity of a word from its con-
texts within a series of five sentences. After hearing each sentence, the
participant is given five seconds to guess the word. Then the next sentences
are presented successively to provide additional clues about the word. After
the test is completed the participant is given a point for each time the word
is correctly identified within the five-second deadline. There are 20 words,
each with five trials. A maximum score of 100 is theoretically attainable.
Wisconsin Card Sorting Test (38,39 ): In this test of perseverative
thinking, the study participant is given a deck of cards with printed figures
that vary in number (one to four), shape (circle, square, triangle, cross),
and color (red, green, blue, yellow). Each card in the deck is sorted to
one of four stimulus cards that vary along the same dimensions. After each
sort, the participant is told only "right" or "wrong". The participant is
never told the correct sorting rule, which initially is set as color. As
soon as the participant sorts 10 cards in a row to color, the sorting rule
is changed (without warning) to shape. Any further sorts to color are
counted as perseverative responses. Then, after the participant makes 10
consecutive sorts according to shape, the rule is changed (again, without
warning) to number; further sorts to shape are counted as perseverative.
The test proceeds in this fashion until the participant successfully sorts
through six rule changes, or until 128 cards are sorted (whichever occurs
first). The score is the total number of perseverative responses.
-U-
-------
Modified Reitan Story Memory Test, Part A (40): This is a test of
verbal learning and memory. During the learning phase the study participant
listens to a tape recording of a short story and is asked to repeat as much
of the story as possible. If the participant cannot give a minimum of 15
of the 28 pieces of information in the story, up to 4 more learning trials
are given to reach this criterion. Memory testing for the story is done four
hours after the learning phase is completed. Efficiency of learning is
operationally defined as the number of learning trials necessary to reach the
above criterion. The memory score is the percent change in the amount of
information reported at the last learning trial and the amount of information
recalled four hours later.
Minnesota Multiphasic Personality Inventory (MMPI): The MMPI provides
objective measures of major dimensions of psychopathology: Hypochondrias!s;
depression; hysteria; psychopathic deviance; paranoia; psychasthenia;
schizophrenia; and mania (41,43).
Each participant and an adult relative were asked to independently rate
the participant's functioning with respect to many abilities, objectively
assessed by the neuropsychological test battery. These independent ratings
were completed using questionnaires developed by the staff at the UCMC Neuro-
psychology Laboratory. Although these rating scores were not expected to be
as sensitive as standardized laboratory tests, the rating scores were included
to provide additional evaluation of the participants' everyday functioning,
as perceived by the participants themselves and by their close relatives.
Statistical Analysis. As previously described, each case was carefully
matched with a control participant within each of the two geographic locations
in this study. If the grouping of study participants by geographic location
were ignored, the standard paired t-test would be the appropriate statistical
-15-
-------
analysis of any single quantitative variable (for example, Average Impairment
Rating or Hal stead Impairment Index). Whereas matching of cases and controls
was made on the basis of age, education, and socioeconomic level, differences
did exist among pairs with respect to age, education, and socioeconomic level.
Such differences were important in order to avoid limitations of the study to
a restricted age, education, or socioeconomic group.
The statistical analysis appropriate for the study design was an analysis
of variance procedure typically referred to as a split-plot analysis but, in
this study, more appropriately called a "split-pair" analysis (44). If
differences in age and education were to exist among the Colorado and Texas
participants, then geographic location would be a potential source of varia-
tion.
Correlation coefficients were calculated for the primary neuro-
psychological scores relative to the plasma and RBC cholinesterase values
and the total organochlorine pesticide residues.
Data from the comprehensive neurological examination were qualitative
in that the results of each specific neurological test were typically
recorded as "normal" or "abnormal". For some neurological tests, the results
were classified in more than two categories. Because of the matching of cases
with controls in this study, the proper unit for statistical analysis was the
matched pair rather than the individual case. Thus, in the case of a dichot-
omous outcome, the appropriate statisitcal test was McNemar's chi-square test
rather than the usual unpaired chi-square test (45). In the case of a poly-
chotomous outcome, the Stuart chi-square test for matched-pairs was applied
(46).
In addition to the analysis of variance of each neuropsychological score,
the set of 34 neuropsychological variables (i.e., the subtests from the WAIS,
-16-
-------
Halstead-Reitan, Peabody, and Added Ability batteries) were analyzed simul-
taneously via a multivariate analysis of variance procedure for matched-
pairs designs (47). To further evaluate differences between the case and
control cohorts, each of the above four batteries of neuropsychological tests
were statistically analyzed via the same multivariate analysis of variance
procedure.
RESULTS
Demographic Data. The study population consisted of 100 matched pairs
(41 pairs from Colorado and 59 pairs from Texas). Except for one pair, all
study participants belonged to the white race. With respect to ethnic group
there were 14 pairs of Mexican-Americans (6 pairs from Colorado and 8 pairs
from Texas). Most of the Mexican-Amen"can study participants belonged to
the agricultural labor force.
All of the participants were male except one matched pair of females.
It was anticipated at the start of the study that a number of female pairs
would be recruited; although it was never a goal of the study to study sex
differences. However, only one female pair could be recruited for the
study.
Ninety-six percent of the organophosphate pesticide poisonings were
occupationally related, and four percent were nonoccupationally related. The
occupations of the cases are summarized in Table 1. Agricultural aircraft
mixers-loaders-flagmen, accounted for 38 of the 96 occupationally related
cases; agricultural aircraft pilots and mechanics accounted for 19 of the
cases; formulating plant employees, 13; fanners and ranchers, 11; agricultural
specialty workers (greenhouse, nursery and ornamental plant workers and
horticulturists), 7; and farm laborers and field workers, 4. No pest
control operators were among the cases studied. Of the four cases non-
-17-
-------
Table 1. Occupations of organophosphate pesticide poisoning cases.
Neuro-organophosphate Study, 1979.
Occupational Group
Occupationally Related Cases
Formulating Plant Worker
Agricultural Chemical Sales
Commercial Applicator Related
Aircraft Mixer-Loader, Fl agger
Pest Control Operators (PCOs)
Aircraft Spray Pilot, Mechanic
Ground Sprayer Crew
Farmer/Rancher
Agricultural Worker - Misc. Related
Farm Laborer, Field Worker
Greenhouse Operator, Nursery-Ornamental
Worker, Horticulturist
Non-occupational ly Related Cases
Child
Machinist
Student
Colorado
9
0
0
11
0
2
2
6
1
2
6
1
1
0
Texas
4
1
0
27
0
17
0
5
0
2
1
1
0
1
TOTAL
Total
13
1
0
38
0
19
2
11
1
4
7
2
1
1
100
-18-
-------
occupationally related, two were children at the time of poisoning, one was
a machinist, and the fourth was a college student.
Table 2 presents the age means and standard deviations for the case
and control study cohorts. The mean age for all participants at the time of
the study was approximately 35 years. The difference between the age means
for the study and control participants was approximately four months. The
mean age for the participants from Colorado was 39 years; the participants
from Texas were somewhat younger. The age of the study participants ranged
from 16 to 66.
Table 2. Age means and standard deviations (S.D.) of
all study participants*. Neuro-organophos-
phate Study, 1979.
All
Participants
Colorado
Participants
Texas
Participants
Mean
Mean
S.D.
Mean
S.D.
Cases
35.01
12.53
38.85
12.02
32.34
12.28
Control s
35.28
13.02
39.20
12.28
32.56
12.92
Cases and
Controls
35.15
39.02
12.08
32.45
12.55
*Data is based on age at time of physical and neurological
examinations.
A summary of the Hollingshead Index of Social Position, a function of
both education and occupation, is shown in Table 3. The mean value calculated
for all participants was 3.05. Although the mean HolUngshead social class
value fell within the lower middle class scale, the Hollingshead values for
the matched pairs represented a much wider range of social class positions.
-19-
-------
As measured by the Hollingshead Index, Colorado participants were from a
slightly lower social class position than Texas participants. The age and
Hollingshead Index of Social Position are listed for the 100 matched pairs
in the study in Table 4.
Table 3. Mean Hollingshead social class and standard
deviation (S.D.) of case and control partici-
pants*. Neuro-organophosphate Study, 1979.
Cases and
Cases Controls Controls
Mean 3.22 2.88 3.05
All
Participants S.0^ 1^50 1.71 li§l__
Mean 3.15 3.44 3.29
Colorado
Participants S.D. 1.59 1.16 1.39
Mean 3.27 2.49 2.88
Texas
Participants S.D. 1.45 1.92 1.74
*Data is based on age at time of physical and neurological
examinations.
-20-
-------
Table 4. Age and Hollingshead social position scales for study participants
by matched pairs. Neuro-organophosphate Study, 1979.
Hollingshead Social Position
Study
Pair No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
36
34
36
32
57
52
37
35
40
39
40
45
46
42
47
45
54
55
40
40
45
49
23
24
43
45
40
42
36
33
Education
Scale
5
4
2
1
5
3
2
4
5
4
1
1
3
3
3
3
6
4
3
3
4
4
5
4
5
6
4
3
4
5
Occupation
Scale
5
5
3
3
4
4
2
2
3
4
1
1
2
2
3
4
3
5
4
3
2
2
5
6
3
3
3
3
4
5
Index
Score
55
51
29
25
48
40
22
30
41
44
11
11
26
26
33
40
45
51
40
33
30
30
55
58
41
45
37
33
44
55
Social
Class
IV
IV
III
II
S
IV
III
II
III
III
IV
I
I
III
III
III
III
IV
IV
III
III
III
III
IV
IV
III
IV
III
III
IV
IV
-21-
-------
Table 4. (Continued)
Study
Pair No.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
39
42
25
28
55
56
25
26
52
53
62
66
41
44
19
19
57
57
35
34
39
44
22
23
39
39
38
40
18
19
Holl
Education
Scale
3
3
4
4
2
2
4
4
2
3
6
6
4
4
4
4
3
3
2
3
6
6
3
3
3
3
7
7
4
4
lingshead Social Position
Occupation
Scale
5
4
5
4
3
3
6
6
2
3
7
5
4
3
7
7
4
3
4
3
5
6
7
5
5
5
7
7
7
7
Index
Score
47
40
51
44
29
29
58
58
22
33
73
59
44
37
65
65
40
33
36
33
59
66
61
47
47
47
77
77
65
65
Social
Class
IV
III
IV
IV
III
III
IV
IV
II
III
V
IV
IV
III
V
V
III
III
III
III
IV
V
V
IV
IV
IV
V
V
V
V
-22-
-------
Table 4 . (Continued)
Hollingshead Social Position
Study
Pair No.
31
32
33
34
35
36
37*
38
39
40
41
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
36
35
19
19
44
46
48
44
23
22
36
34
19
20
46
45
48
48
26
26
62
64
Education
Scale
6
6
4
4
4
4
4
4
4
4
2
3
4
4
5
4
1
2
4
4
4
4
Occupation
Scale
6
4
6
6
4
5
4
4
5
6
2
3
4
4
6
7
1
2
3
5
5
5
Index
Score
66
52
58
58
44
51
44
44
51
58
22
33
44
44
62
65
11
22
37
51
51
51
Social
Class
V
IV
IV
IV
IV
IV
IV
IV
IV
IV
II
III
IV
IV
V
V
I
II
III
IV
IV
IV
* Female pair.
-23-
-------
Table 4. (Continued)
Study
Pair No.
42
43
44
45
46
47
48
49
50
51
52
53
54
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
54
60
36
33
22
23
22
25
49
48
21
22
50
48
51
54
27
29
47
53
27
29
16
17
35
35
Hoi
Education
Scale
3
4
1
1
4
4
4
4
5
4
4
4
4
4
1
2
2
2
1
1
5
3
5
5
1
1
lingshead Social Position
Occupation
Scale
3
5
1
1
5
5
5
5
3
5
5
7
4
4
2
3
3
3
1
2
5
6
7
7
1
1
Index
Score
33
51
11
11
51
51
51
51
41
51
51
65
44
44
18
29
24
29
11
18
55
34
69
69
11
11
Social
Class
III
IV
I
I
IV
IV
IV
IV
III
IV
IV
V
IV
IV
II
III
II
III
I
II
IV
III
V
V
I
I
-24-
-------
Table 4. (Continued)
Hollingshead Social Position
Study
Pair No.
55
56
57
58
59
60
61
62
63
64
65
66
67
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
53
54
34
31
26
26
26
24
22
20
25
26
23
23
36
36
27
29
29
32
39
42
25
25
31
30
Education
Scale
7
4
3
3
4
3
2
2
6
6
3
4
3
4
2
3
3
3
4
4
4
4
3
3
3
3
Occupation
Scale
2
3
5
2
6
7
4
3
5
6
4
6
5
5
3
4
3
3
3
6
4
2
5
3
5
3
Index
Score
42
37
47
26
58
61
36
29
59
66
40
58
47
51
29
40
33
33
37
58
44
30
47
33
47
33
Social
Class
III
III
IV
II
IV
V
HI
III
IV
V
III
IV
IV
IV
III
III
III
III
III
IV
IV
III
IV
III
IV
III
-25-
-------
Table 4. (Continued)
Study
Pair No.
68
69
70
71
72
73
74
75
76
77
78
79
80
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
19
19
47
47
27
24
25
25
28
32
17
17
27
27
27
28
22
21
23
24
26
28
17
17
20
19
Hnll
Education
Scale
4
5
6
5
4
2
3
3
5
3
5
5
2
2
4
4
3
3
5
7
4
3
4
4
6
5
ing^hpaH Snri
Occupation
Scale
7
6
4
6
6
4
3
4
6
7
7
7
4
3
5
5
4
4
6
7
4
3
5
7
5
7
al PnQiti
Index
Score
65
62
52
62
58
36
33
40
62
61
69
69
36
29
51
51
40
40
62
77
44
33
51
65
59
69
on
Social
Class
V
V
IV
V
IV
III
III
III
V
V
V
V
III
III
IV
IV
III
III
V
V
IV
.III
IV
V
IV
V
-26-
-------
Table 4. (Continued)
Hollingshead Social Position
Study
Pair No.
81
82
83
84
85
86
87
88
89
90
91
92
93
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
22
23
19
18
29
28
56
55
50
51
52
53
55
56
47
48
26
27
64
66
56
57
31
26
23
22
Education
Scale
3
2
5
4
2
2
4
3
4
4
2
2
3
3
3
3
3
3
3
4
4
3
2
2
4
3
Occupation
Scale
3
2
5
7
2
2
4
3
7
5
3
1
3
2
3
4
5
4
3
3
4
7
3
2
5
7
Index
Score
33
22
55
65
22
22
44
33
65
51
29
15
33
26
33
40
47
40
33
37
44
61
29
22
51
61
Social
Class
III
II
IV
V
II
II
IV
III
V
IV
III
I
III
II
III
III
IV
III
III
III
IV
V
III
II
IV
V
-27-
-------
Table 4 . (Continued)
Hollingshead Social Position
Study
Pair No.
94
95
96
97
98
99
TOO
Case or
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Case
Control
Age at
Interview
29
29
29
32
27
25
22
20
28
25
34
34
27
29
Education
Scale
3
2
2
2
3
3
4
4
3
3
3
4
4
4
Occupation
Scale
4
2
1
2
5
5
5
5
5
4
5
5
7
3
Index
Score
40
22
13
22
47
47
51
51
47
40
47
51
65
37
Social
Class
III
II
I
II
IV
IV
IV
IV
IV
III
IV
IV
V
III
-28-
-------
Acute Organophosphate Pesticide Poisoning Histories. The year of the
primary OP pesticide poisoning reported by the case participants ranged from
1950 to 1976. There were 11 participants in the case cohort who reported
more than one noteworthy OP pesticide poisoning: eight of these experienced
two poisonings, one experienced three poisonings, and two reported four
poisonings. One case reported a poisoning as early as July 1948. Documentary
information usually was not available on the multiple poisonings other than
for the primary incident.
The mean time for all cases from the primary poisoning to the time of
the neurological and neuropsychological examinations was about nine years.
The time from the index poisoning incident to the date of the neurological
and psychological examinations is important because examination close to the
time of poisoning could be measuring adverse results which were, in fact,
reversible acute poisoning responses rather than long-term effects. The
elapsed time from the last poisoning case to the date of neuropsychological
examination is given in Table 5 below for the case cohort. There was a longer
mean elapsed time for the Colorado cases, 4228 days (about 11 years, 7 months)
than for the Texas cases, 2574 days (about 7 years, 19 days). The mean
elapsed time from the date of the last poisoning case to neuropsychological
Table 5. Elapsed time in days from last poisoning to
neuropsychological examination. Neuro-
organophosphate Study, 1979.
All cases
Colorado
Texas
Number
of Cases
100
41
59
Range
117-9640
650-8065
117-9640
Mean
3252
4228
2574
-29-
-------
testing for all cases was 3252 days (about 8 years, 11 months). The shortest
time period from date of poisoning to date of examination was 117 days. It
is of interest that the RBC and plasma cholinesterase values on this person
were well within the normal range at the time of the study examinations.
Among the 100 case participants, 10 different OP pesticides were impli-
cated as the cause of the primary poisoning (Table 6). Detailed information
on these chemicals, such as chemical structure, toxicity, and uses is given
in Appendix F. Methyl parathion was implicated tn 54 cases, more than any
other chemical; ethyl parathion was implicated in 42 poisonings. These two
chemicals accounted for 79% of the total episodes. The two chemicals are
very similar in structure, toxicological effects, in practical field use, and
sometimes they are applied in combination. Their predominance as a cause
of human poisoning may be explained by the fact that they have been in use
for a number of years, are highly toxic, and are among the most widely used
pesticides in the United States. All of the incidents involving methyl
parathion were among the Texas case participants, whereas ethyl parathion was
involved in poisonings in both Colorado and Texas.
Physical Examination and Clinical Laboratory Data. Abnormalities
detected during the physical examinations were recorded on the physical exam
forms (Appendix D). Table 7 summarizes the findings of the physical exami-
nation of case and control participants. Abnormalities were observed by the
examining physicians in 11 of the 15 categories on the physical examination
forms. Slightly more abnormalities were observed among the controls (48)
than among the cases (44), but the difference was not statistically signifi-
cant.
-30-
-------
Table 6. Organophosphate pesticides implicated in the primary
poisoning incidents*. Neuro-organophosphate Study,
1979.
Number of Cases
OP Pesticide
Methyl parathion
Parathion
Disulfoton (Di-Syston)
Mai a th ion
Mevinphos (Phosdrin)
Dicrotophos (Bidrin)
TEPP
Dioxathion (Delnav)
DEF
Phorate (Thitnet)
TOTAL
Colorado
0
24
8
6
5
1
1
0
0
1
Texas
54
18
0
0
0
1
1
1
1
0
Total
54
42
8
6
5
2
2
1
1
1
122
*The occurrence of OP pesticides exceeds the number of cases in the
study because more than one OP pesticide was implicated in some
incidents.
-31-
-------
Table 7 . Summary of abnormal conditions identified in participants during
physical examination. Neuro-organophosphate Study, 1979.
n = 98 pairs
Category
General appearance
Skin
Head
Ears
Eyes
Nose
Mouth
Neck
Thorax
Breasts
Lungs
Heart
Vessels
Abdomen
Skeletal
Total
Cases
3
10
0
2
3
0
0
0
0
1
7
2
3
2
11
44
Controls
1
11
0
0
4
0
0
0
1
0
7
4
6
4
10
48
Total
4
21
0
2
7
0
0
0
1
1
14
6
9
6
21
92
-32-
-------
Skin and skeletal were the two most frequently recorded abnormalities
as each abnormality was observed 21 times. Abnormalities in the category of
the lungs was the third highest and occurred in 7% of the participants.
Abnormal breath sounds was the dominant finding among the lung abnormalities.
The frequency of occurrence of abnormalities in the other categories were
varied and no abnormalities were found in four categories. However, the
slight differences between cases and controls with respect to the physical
examination categories were not statistically significant.
Although no participants were excluded from the study due to physical,
audiometric, ophthalmic, or clinical blood examination results, three poten-
tial participants were excluded from the study because of previous medical
conditions identified during the medical history taken by the examining
physician.
Clinical Laboratory Results. The blood samples collected from the study
participants were evaluated using standard laboratory tests (Appendix D).
The results of 28 different laboratory tests were recorded for each partici-
pant. Results were recorded as normal and abnormal. Statistical analysis
of the hematology, creatinine, and urea nitrogen test results were based on
the chi-square test for matched pairs, as described in the Methods section.
Hone of these chi-square tests were statistically significant (Table 8).
Neurological Data. The neurological testing was an important aspect of
this study and included two categories: neurological examinations and the
electroencephalographic examinations. The neurological examinations shown
in Appendix D consisted of the following general categories: mental status,
cranial nerves, motor system, sensory system, integrative functions and other.
The electroencephalogram (EEG) is a relatively subtle indicator of
structural and functional integrity of the cerebral cortex. Evaluation of
-33-
-------
Table 8. Summary of the statistical comparison of the cases
and controls with respect to selected laboratory test
variables. Neuro-organophosphate Study, 1979.
Test Variable
Lab Tests
White blood cells
Red blood cells
Hemoglobin
Hematocrit
Lymphocytes
Eos inoph lies
Urea nitrogen
Creatinine
Degrees of
Freedom
2
2
2
2
2
1
2
2
Chi-square
Statistic
2.00
.80
2.82
3.27
.04
1.23
2.14
1.93
p- Level
.368
.670
.244
.195
.980
.267
.343
.381
the EEG is usually a subjective process depending on pattern recognition by
the electroencephalographer. Recognition and descriptions of specific
patterns are often based on scientific intuition. The EEG has been an
important tool in determining overall cortical function In many clinical
and research situations.
Based on the visual analysis of EEG, as well as the descriptive inter-
pretation of the EEG, each study participant's EEG results were categorized
as normal or as abnormal (mild, moderate or severe). A summary of the results
of the encephalograms are shown in Table 9. Statistical analyses of the
electroencephalogram results yielded a 1.06 chi-square value (p = .589, with
2 degrees of freedom) approximately 83 per cent of the cases and 88 per cent
of the controls had normal readings. Although computer spectral analyses
were planned to supplement the visual interpretation, the spectral analyses
were not completed due to computerization problems at the University of
Colorado Medical Center.
-34-
-------
Table 9. Summary of the results of the encephalogram (EEC)
evaluation of case and control participants.
Neuro-organophosphate Study, 1979.
Abnormal
Cases
Controls
Moderate
2
1
Mild
14
10
Normal
83
88
Total
99
99
The neurological exam was divided into six general categories: Mental
Status, Cranial Nerves, Motor System, Sensory System, Integrative Functions,
and Other. Each of the six general categories consisted of a number of
separate examination components. The components were rated and coded on the
exam form by the neurologist as normal, not significant, or abnormal (Appendix
10). A summary evaluation of the separate components for each general
category was similarly assigned by the neurologist.
Table 10 shows the summary of the statistical comparison of the cases
and controls with respect to Mental Status, Cranial Nerves and Motor System
categories. The following six tables (Tables 11-16) present a summary of the
data used in calculating the chi-square values in summary Table 10.
There were several components of the overall Mental Status evaluation:
State of Consciousness; Orientation; Language; Memory; Serial Subtraction;
Abstraction; and Mood. The results of the neurological evaluation of these
components of Mental Status are summarized in Table 11. Although the State
of Consciousness results showed the cases to be more anxious than the controls,
the difference between these groups was not statistically significant. With
respect to Orientation (time; place; and person) and Language (Pressure and
Structure), there was little or no difference between the cases and controls
(Table 10). Similarly, for three parts of the Memory evaluation (Numbers
Forward; Numbers Backward; and Remote Memory), the difference between cases
-35-
-------
and controls was not statistically significant. However, one part of the
Memory component (Three-Pairs-of-Item) showed over twice as many abnormal
classifications in the cases as in the controls (p = .006). Based on the
matched-pairs analysis, there was no significant difference between the cases
and controls in Serial Subtraction component. Of the ten abnormal classifica-
tions in the Abstraction component, nine belonged to the case cohort (p = .028).
The neurological evaluation of Mood is an important aspect of Mental Status.
It is of considerable interest that six of the case participants and none
of the control participants were classified as "depressed" (p = .0003). Based
on the neurologist's summary evaluation of Mental Status, 64 of 99 case
participants and 45 of 99 control participants were categorized as abnormal.
The matched-pairs analysis found this difference between the two cohorts
to be highly significant (p = .013).
The summary evaluation of the Cranial Nerve category showed no
significant difference between the case and control participants (Table 10).
The individual components of the Cranial Nerve category, such as Bilateral
Neurosensory Hearing, Eye Mobility and Sense of Smell, were not found to be
significantly different between the two cohorts. Table 12 shows that 64
cases and 59 controls were evaluated as normal on the Cranial Nerve summary.
Twenty-three components (Appendix D) were considered by the neurologist
in the evaluation of the Motor System. Although the difference in summary
evaluations for the case and control cohorts was not statistically significant,
(Table 10), some of the individual components were significantly different.
For example, in the knee jerk test, the case cohort was significantly different
from the control cohort (p = .024). However, in the ankle jerk test, the
difference between the case and control cohorts was not statistically significant.
The data on selected components of the Motor System are presented in Tables
14 and 15 and the data on the Motor System summary evaluation are presented in
Table 16.
-36-
-------
Table 10. Summary of the statistical comparison of the cases and controls
with respect to mental status, cranial nerves, and motor system.
Neuro-organophosphate Study, 1979.
Degrees of
Test Variable Freedom
MENTAL STATUS
Mental Status Summary Evaluation
State of Consciousness
Orientation
Time
Place
Person
Language
Pressure
Structure
Memory
Numbers Forward
Numbers Backward
Three Pairs of Items
Remote
Serial Subtraction
Abstraction
Mood
CRANIAL NERVES
Cranial Nerve Summary Evaluation
MOTOR SYSTEM
Right and ieft Knee Jerk
Right and Left Ankle Jerk
Motor System Summary Evaluation
1
1
1
1
1
1
1
1
1
1
1
2
1
2
2
8
7
2
Chi -Square
Statistic
6.35
0.07
0.00
0.00
0.00
0.00
0.00
0.55
3.03
7.50
0.00
3.08
4.90
18.00
1.41
17.64
8.52
2.90
P-
Value
.013
.791
.481
.086
.006
.290
.028
.001
.494
.024
.289
.235
-37-
-------
Table 11. Evaluation of case and control participants with respect to the
summary and components of the mental status category of the neuro-
logical examination. Neuro-organophosphate Study, 1979.
Test Variable
Abnormal
Normal Total
Summary Evaluation
of Mental Status Cases
Controls
Orientation
Time Cases
Control s
Place Cases
Controls
Person Cases
Control s
Language
Pressure Cases
Controls
Structure Cases
Control s
Memory
Numbers Forward Cases
Controls
Numbers Backward Cases
Controls
64
45
1
0
0
1
0
0
0
1
0
0
23
18
25
14
35
54
98
99
99
98
99
99
99
98
99
99
76
81
74
85
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
-38-
-------
Table 11 (continued)
Test Variable
Abnormal
Normal Total
Memory (continued)
Three Pairs of Items
Remote
Serial Subtraction
Abstraction
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
30
14
0
0
28
21
9
1
69
85
99
99
71
78
90
98
99
99
99
99
99
99
99
99
-39-
-------
Table 12. Evaluation of case and control participants with respect to the
state of consciousness and mood from the mental status category OT
the neurological examination. Neuro-organophosphate Study,
1979.
Test Variable
Anxious
Normal
Total
State of Consciousness
Cases
Controls
8
6
91
93
99
99
Mood
Euphoric Depressed Normal
Cases 1 6 92
Controls 0 0 99
99
99
Tabie
tion. Neuro-organophosphate Study, 1979.
Normal
Cases
Controls
64
59
Abnormal
Nonsignificant
Significant
9
7
26
33
Total
99
99
-40-
-------
Table 14. Evaluation of case and control participants with respect to the
knee jerk (right and left combined) test of the neurological
examination. Neuro-organophosphate Study, 1979.
Cases
Controls
Table 15.
Cases
Controls
Table 16.
Cases
Controls
One 0
Other 0
2
2
One 0 One 1 One 1 One 2
Other 1 Other 1 Other 2 Other 2 Total
1 75 9
6 64 9
0 = Absent
1 - Normal
2 = Hyperactive
Evaluation of case and control participants with
ankle jerk (right and left combined) test of the
examination. Neuro-organophosphate Study, 1979.
One 0
Other 0
3
6
10 95
16 97
respect to the
neurological
One 0 One 1 One 1 One 2
Other 1 Other 1 Other 2 Other 2 Total
10 75 1
10 67 0
0 = Absent
1 = Normal
2 = Hyperactive
8 97
14 97
Evaluation of case and control participants with respect to
the motor system score test of the neurological examination.
Neuro-organophosphate Study, 1979.
Normal
61
54
Abnormal
Nonsignificant Significant
8 30
16 29
Total
99
99
-41-
-------
The sensory system was further evaluated through a series of 10
additional clinical tests. The tests included response to pin pricks, touch,
vibration, position identification, discrimination, graphesthesia, and stereog-
nosis (Appendix D). Table 17 summarizes the results of the statisitical
analyses of the sensory system tests and the sensory system summary score.
There were no statistically significant differences between the case and
control cohorts on any of these tests or on the sensory system summary evalua-
tion. Tables 18-24 present the summary results of the sensory system tests.
Analyses showed there were slight differences in the pin prick lower left
extremity where a total of 96 controls were normal compared to 89 cases that
were normal (Table 21), but the results were not statistically significant
(D = .072).
Table 17. Summary of the statistical comparison of the cases
and controls with respect to the sensory system.
Neuro-organophosphate Study, 1979.
Test Variable
SENSORY SYSTEM
Pin Upper Right Extremity
Pin Upper Left Extremity
Pin Lower Right Extremity
Pin Lower Left Extremity
Vibration, Right
Vibration, Left
Sensory System Evaluation
Degrees of
Freedom
5
5
3
3
4
5
2
Chi-Square
Statistic
5.20
8.00
3.20
7.00
5.10
4.03
3.54
P-
Level
.392
.156
.362
.072
.277
.545
.170
-42-
-------
Table 18. Evaluation of case and control participants with respect to the pin upper right
extremity test of the neurological examination. Neuro-organophosphate Study, 1979.
U)
I
Cases
Controls
Table 19.
Cases
Controls
Normal
94
92
Evaluation
extremity
Normal
93
95
Mild
0
2
of case
test of
M1ld
0
2
Peripheral
Moderate
1
0
Severe
1
0
and control participants with
the neurological examination.
Peripheral
Moderate
1
0
Severe
1
0
M1ld
2
3
Focal
Moderate
0
1
Severe
0
0
respect to the pin upper left
Neuro-organophosphate Study,
M1ld
3
0
Focal
Moderate
0
1
Severe
0
0
Total
98
98
1979.
Total
98
98
-------
Table 20. Evaluation of case and control participants with respect to the pin lower right
extremity test of the neurological examination. Neuro-organophosphate Study, 1979.
Cases
Controls
Normal
91
95
M1ld
0
0
Peripheral
Moderate
2
0
Severe
1
0
Mild
3
2
Focal
Moderate
0
0
Severe
0
0
Total
97
97
Table 21. Evaluation of case and control participants with respect to the pin lower left
extremity test of the neurological examination. Neuro-organophosphate Study, 1979.
Peripheral Focal
Normal Mild Moderate Severe Mild Moderate Severe Total
Cases 89 0 3 1 40 0 97
Controls 96 0 0 0 10 0 97
-------
Table 22. Evaluation of case and control participants with respect to the vibration, right test
of the neurological examination. Neuro-organophosphate Study, 1979.
Cases
Controls
Normal
74
66
Mild
10
13
Peripheral
Moderate
6
8
Severe
1
0
Mild
0
0
Focal
Moderate
0
2
Severe
0
0
Total
91
91
Table 23. Evaluation of case and control participants with respect to the vibration, left test
of the neurological examination. Neuro-organophosphate Study, 1979.
Peripheral Focal
Normal Mild Moderate Severe Mild Moderate Severe Total
Cases 70 13 5 1 2 0 0 91
Controls 65" 16 6 0 22 0 91
-------
Table 24. Summary evaluation of case and control participants with respect
to the sensory system of the neurological examination. Neuro-
organophosphate Study, 1979.
Abnormal
Cases
Controls
Normal
66
62
Nonsignificant
2
1
Significant
30
35
Total
98
98
-46-
-------
Table 25 is a summary of the matched-pairs analyses of selected integra-
tive function tests and other miscellaneous examinations. Appendix D includes
examination forms used in these tests. A total of seven individual component
tests were used in the integrative function summary evaluations. These compo-
nent lists included posture, balance, gait, and cerebellar functions, such
as finger to nose and heel to skin. Tables 26-29 present a summary of the
results of the individual component tests. The integrative function summary
evaluation was normal for 77 cases and 85 controls out of 99 matched pairs
(p = .185).
Other miscellaneous examinations included examination of the skull,
carotids, and back (Appendix D). Based on the chi-square test for matched
pairs (Table 25), there was no statistical difference between the case and
control cohorts on the summary evaluation of other miscellaneous examinations
(Table 24). As seen from Table 29, there were 98 cases and 95 controls normal
on the other miscellaneous examination summary evaluation.
Table 25. Summary of the statistical comparison of the cases
and controls with respect to integrative function
and other miscellaneous examinations. Neuro-
organophosphate Study, 1979.
Degrees of
Test Variable Freedom
Finger-nose Right
Finger- nose Left
Integrative Function Evaluation
Other Misc. Exam Evaluation
3
3
2
2
Chi -Square
Statistic
3.92
0.60
3.38
2.00
P-
Level
.270
.896
.185
.368
-47-
-------
Table 26. Evaluation of case and control participants with respect to the finger-nose right test
of the neurological examination. Neuro-organophosphate Study, 1979.
oo
i
Abnormal Peripheral
Cases
Control s
Table 27.
Normal
85
88
Mild
10
5
Evaluation of case
of the neurological
Moderate
0
2
and control
examination
Severe
0
0
Mild
1
1
Abnormal Focal
Moderate
0
0
Severe
0
0
participants with respect to the finger-nose
. Neuro-organophosphate Study, 1979.
Abnormal Peripheral
Cases
Controls
Normal
86
87
Mild
7
5
Moderate
2
3
Severe
0
0
Mild
1
1
Abnormal Focal
Moderate
0
0
Severe
0
0
Total
96
96
left test
Total
96
96
-------
Table 28. Summary evaluation of case and control participants with respect
to the integrative function of the neurological examination.
Neuro-organophosphate Study, 1979.
Abnormal
Normal
Nonsignificant Significant Total
Cases
Control s
77
85
2
0
20
14
99
99
Table 29 Summary evaluation of case and control participants with respect
to other miscellaneous exams of the neurological examination.
Neuro-organophosphate Study, 1979.
Cases
Controls
Abnormal
Normal
98
95
Nonsignificant Significant Total
1
3
0
1
99
99
-49-
-------
Neuropsychological Findings. Results of neuropsychological evaluations
are presented in this section according to three subdivisions: objective
tests administered in the neuropsychological laboratory; results of the
participant-completed Patient Assessment of Own Functioning Inventory which
was administered at the time of neuropsychological examination; and results
of the Relative's Assessment of Patient-Functioning Inventory that was com-
pleted at the time of interview. As mentioned previously, these data were
analyzed via an analysis of variance procedure specific to designs involving
matched-pairs. The detailed results of the analysis of variance of the
neuropsychological test battery and the MMPI are presented in Appendix F.
These results are summarized in Tables 30-32, which present the mean score
for the case and control cohorts and the probability-level (p-level) for the
analysis of variance test comparing the case and control means.
Results of the Halstead-Reitan Battery revealed that the case cohort was
significantly more impaired than the control cohort on both summary measures
Average Impairment Rating and Halstead Impairment Index (p < .001 and p =
.020, respectively). Although both of the group means are in the normal range
on these measures, 24 of the cases and only 12 of the controls obtained scores
in the "impaired" range on one or both of the measurements. That is, on the
basis of previously validated limits (1.55 for the Average Impairment Rating
and 0.5 for the Halstead Index), twice as many case participants as control
participants showed an overall level of neuropsychological deficit that is with-
in the range characteristic of individuals with documented cerebral lesions.
Based on the matched-pairs chi-square analysis, this difference between the
case and control cohorts was statistically significant (p < .05). In the
Halstead-Reitan battery, the performance level of the cases was lower than
that of the controls on nine of the eleven individual tests; however, the
-50-
-------
Table 30. Psychological test score means, standard error of the difference
of means, and the probability level of the analysis of variance
test for the case-control comparison for the Halstead-Reitan
Battery and the WAIS Battery. Neuro-organophosphate Study,1979.
Variable
Neuropsychological Summary Scores
Average Impairment Rating
Hal stead Impairment Index
WAIS Verbal IQ
WAIS Performance IQ
WAIS Full Scale IQ
Halstead-Reitan Battery
Category
Trails-B
Speech Sounds Perception
Seashore Rhythm
Tactual Performance-Memory
Tactual Performance-Location
Tactual Performance-Time
Finger Oscillation Test3
Perceptual Disordersb
Aphasia Exam0
Spatial Relations0
WAIS Subtest Scaled Scores
Information
Comprehension
Arithmetic
Similarities
Digit Span
Vocabulary
Digit Symbol
Picture Completion
Block Design
Picture Arrangement
Object Assembly
Means
S.E. p-level*
Cases
1.07
0.30
105.40
108.41
107.05
39.55
75.31
7.78
26.65
7.62
4.57
13.07
100.80
4.68
5.59
2.81
10.73
11.32
11.15
11.10
9.80
10.49
9.71
11.13
11.24
10.02
10.60
Controls
0.91
0.23
111.86
110.13
111.77
31.57
67.72
5.92
27.16
7.78
4.45
11.88
103.69
4.17
4.55
2.71
11.83
12.13
12.40
12.09
10.95
11.68
10.64
11.00
11.75
9.95
10.72
.05
.03
1.31
1.46
1,32
2.59
4,09
.51
,33
.17
.25
.77
1.41
.63
.58
,13
.28
.34
.32
.31
.43
,30
,26
,28
.38
,35
.33
<.001
.020
<-001
.242
<.001
.002
.067
.001
.120
.125
.042
.075
.001
.020
.001
.002
.008
:.001
:.001
.187
(a) Scores summed for both hands
(b) Ratings defined 1n Russell et al_. (1970)
k The p-level 1s not shown 1f the F-ratio is less than unity.
-51-
-------
Table 31. Psychological test score means, standard error of the difference
of means, and the probability level of the analysis of variance
test for the case-control comparison for the Peabody Individual
Achievement Test and Added Ability Tests. Neuro-organophosphate
Study, 1979.
Variable
Peabody Individual Achievement Test
Reading Recognition
Reading Comprehension
Spelling
Means
Cases Controls
29.00
54.32
35.19
36.71
63.06
45.81
p-level*
2.32 .001
3.26 .008
3.65 .004
Added Ability Tests
Tactile Form Recognition9
Hand Dynamoneter
Grooved Pegboard3
Hole-Type Steadiness b
Wisconsin Card Sorting Test
Thurstone Word Fluency-Total
Word Finding Test0
Story Memory Test-Learning
-Memory
20.34
96.87
148.34
59.39
17.07
43.92
36.04
1.87
.11
19.98
97.34
137.96
62.82
12.91
50.79
40.36
1.67
.10
,75
,93
,26
6.76
.18
.33
.33
.02
.10
.002
.001
.003
.002
.045
(a) Scores summed for both hands
b) Score available for 91 of 100 pairs
c) Score abaiTable for 99 of 100 pairs
The p-level is not shown if the F-ratio is less than unity.
-52-
-------
Table 32. Psychological test score means, standard error of the difference
of means, and the probability level of the analysis of variance
test for the case-control comparison for the MMPI Battery.
Neuro-organophosphate Study, 1979.
Means
p-level*
MMPI (T-Scores)
Lie (L)
Validity (F)
Defensiveness (K)
Hypochondriasis (Hs)
Depression (D)
Hysteria (Hy)
Psychopathic Deviate (Pd)
Masculinity Femininity (Mf)
Paranoia (Pa)
Psychasthenia (Pt)
Schizophrenia (Sc)
Hypomania (Ma)
Social Introversion (Si)
Cases
50.62
56.42
50.68
52.47
55.72
54.00
56.65
56.25
56.40
56.70
56.02
58.95
53.83
Controls
49.30
53.36
54.79
52.94
54.28
57.12
56.41
55.97
54.00
55.32
53.45
57.21
50.65
1.04
1.25
1.23
1.40
1.57
1.21
1.45
1.23
1.21
1.47
1.57
1.32
1.30
.114
.008
.018
.202
.095
.027
.200**
.058**
.119
.050
*The p-level is not shown if the F-ratio is less than unity.
**The p-level for the F-test for interaction in the analysis of variance was
significant at the 5% level of significance.
-53-
-------
difference between case and control means was significant in only three of
these none tests. When compared to their matched controls, the cases showed
impairment on tests of logical analysis and abstract reasoning (Category Test),
fine discrimination among isolated speech sounds (Speech-Sounds Perception
Test), and motor speed with the upper extremities (Finger Oscillation Test);
although not statistically significant, the cases showed some impairment on
tests of efficiency in following sequential procedures (Trail Making Test, Part
B) and language skills (Aphasia Exam). There was no difference between the
two cohorts on the Sensory Perceptual Examination.
In general, both cohorts showed above average Intellectual functioning
on the WAIS. However, the case cohort obtained a mean Full Scale IQ that was
almost five points lower than the mean of the control cohort. This difference
was highly significant (p <.001). The case cohort also did significantly
worse than the controls on all six verbal subtests and on one of the five
performance subtests (Digit Symbol).
The case cohort also performed at a significantly lower level than the
controls on the Reading Recognition, Reading Comprehension, and Spelling sub-
tests of the Peabody Individual Achievement Test. Cohort differences were
also significant on five of the ten "added" ability tests: tests of written
verbal fluency (Thurstone Word Fluency Test), verbal problem solving ability
(Word Finding Test), perserverative thinking (Wisconsin Card Sorting Test),
fine motor coordination with the upper extremities (Grooved Pegboard Test),
and learning (Story Memory Test-Learning). The case and control cohorts did
not differ significantly in the test of memory (Story Memory Test-Memory).
Although the mean scores from the MMPI are'well within normal limits for
both case and control cohorts, results of four of the thirteen scales were
statistically significant. The differences on the Validity (F) and Defen-
siveness (K) scales do not imply any problems with the validity of either
-54-
-------
group's profiles, but they do suggest that the case participants were some-
what more likely than the controls to report emotional problems on the MMPI.
In addition, the case participants scored higher than the controls on the
MMPI Paranoia and Social Introversion scales. These findings suggest slightly
greater social anxiety and tendencies towards suspiciousness and/or sensi-
tivity to criticism or to other social stresses among the cases.
Table 33 summarizes the results of the statistical comparisons between
cohorts on the Patient Assessment of Own Functioning Inventory. Significant
cohort differences were obtained on 11 of the 32 items. All of the signifi-
cant differences indicated that the case cohort reported more problems with
their everyday functioning than did their matched pair.
It is also of interest that there appears to be some relationship between
the specific problem areas mentioned in the self-reports completed by case
participants and those cases shown to be most impaired on formal objective
testing in the neuropsychological laboratory. Thus, when compared to those
of the controls, the patient assessment of own functioning from the case
cohort disclosed somewhat more difficulty with verbal comprehension, word
finding abilities, reading and math skills, general problem solving, efficiency
in following directions and instructions, and manipulatory efficiency. Further-
more, the case cohort participant gave evidence of relative impairment in all
of these areas of formal neuropsychological testing. By contrast, there was
no difference between the case and control cohorts with respect to self-
assessments of memory; this result agrees with.a similar result (i.e., no
significant difference) in the formal objective testing of memory abilities.
The statistical results for each of 32 items used in the Patient Assessment of
Own Functioning Inventory are presented in detail in Appendix G.
-55-
-------
Table 33. Patient's Assessment of (ton Functioning: Test Score Means, Pooled Estimate of the Standard
Error (S.E.) of Each Mean, and Probability Level of the Analysis of Variance Test for the
Case Control Comparison. Neuro-organophosphate Study, 1979.
in
en
i
Patient Self-Report: Memory
For verbal communications 1n last day or two
For events occurring 1n last day or two
For people met 1n last day or two
For things known a year or more ago
For people met a year or more ago
Losing track of time
Forgetting what patient 1s doing
Forgetting how to do things
Losing things by forgetting where they are
Forgetting obligations
Patient Self-Report; Language and Communication
Difficulties understanding speech of others
Difficulties recognizing printed or written words
Difficulties understanding reading material
Difficulties with enunciation
Difficulty thinking of names of things
Other word finding difficulties
Difficulty forming letters correctly
Difficulty spelling
Means
Cases
1.95
1.22
1.46
1.93
1.91
1.43
.79
.90
1.98
1.31
Controls
1.77
1.06
1.30
2.04
1.98
1.40
.76
.72
1.95
1.37
S.E.
.10
.11
.14
.12
.13
.11
.10
.09
.11
.11
P- level
.210
.310
-
-
-
-
-
-
-
-
1.71
1.22
1.14
1.66
2.02
1.93
1.28
1.77
1.31
.80
.76
1.41
1.73
1.83
1.05
1.42
.11
.11
.12
.13
.10
.14
.13
.14
.014
.008
.024
.163
.037
-
.224
.071
-------
Patient Self-Report: Use of Hands
Difficulty performing tasks with right hand
Difficulty performing tasks with left hand
Patient Self-Report: Perceptual Functions
Difficulty feeling with right hand
Difficulty feeling with left hand
Difficulty with vision
Patient Self-Report; Cognitive/Intellectual Functions
Thoughts seem confused or illogical
Distracted from what doing or saying
Confusion about where patient is
Difficulty finding way
Difficulty calculating
Difficulty planning and organizing activities
Difficulty solving problems
Difficulty following directions
Difficulty following instructions
Means
Cases
.69
1.21
.26
.25
.81
.96
1.23
.51
.46
1.05
1.03
.96
.84
1.12
Controls
.29
1.29
.12
.27
.48
.90
1.01
.42
.48
.66
.85
.69
.54
.69
S.E.
.11
,14
.06
.06
.10
.10
.10
.09
.09
.10
.11
.09
.10
.10
P-level1
.010
-
.126
-
.019
.133
-
-
.009
.241
.036
.044
.004
*The p-level 1s not given in cases for which the F-ratio is less than unity.
-------
Results of the Relative Assessment of Patient Functioning Inventory showed
few significant differences between the case cohort and control cohort (see
Table 34). As shown in Table 34, significant differences did occur on 4 of
30 items in the ability areas (p < .05). All of the significant differences
measured by the relative's assessment showed that the case cohort had more
difficulty in functioning than the control cohort. The difficulties were in
the general areas (language and communication, cognitive and intellectual
functions, and use of hands). In addition, results of the relatives * assess-
ment of the study participants were significantly different between the case
and control cohorts on 4 of the 22 personality scale items: depression, irri-
tability, social withdrawal, and confusion. The statistical results of the
individual relative's assessment evaluations are presented in detail in
Appendix H.
Blood Pesticide Residues and ChE Assays. Blood samples were taken from
each case and control participant at the time of their physical examination.
All blood samples were analyzed for organochlorine pesticide residues and for
cholinesterase depression. The results from the residue analyses, reported in
ppb, were then totaled for each participant to give a single cumulative organo-
chlorine pesticide residue value. The logarithm of these cumulative residue
values was statistically analyzed using the matched-pairs analysis of variance
procedures (Table 35). The mean residue value for the case cohort was 62.07
ppb, which was significantly higher than the corresponding mean value for the
controls, 33.33 ppb. DOT and its metabolite, DDE, account for the large
majority of these residues. As stated previously, 96% of the acute organo-
phosphate exposures were occupationally related. Since a wide spectrum of
pesticides, especially the OP and organochlorine insecticides, is conroonly
found in pesticide related occupations it is not surprising that the mean
-58-
-------
Table 34. Relative's Assessment of Patient's Functioning: Test Score Means, Pooled Estimate of the
Standard Error (S.E.) of Each Mean, and Probability Level of the Analysis of Variance
Test for the Case-Control Comparison. Neuro-organophosphate Study, 1979.
vo
I
Relative Rating: Personality
Depression
Irritability
Seriousness
Withdrawal
Careless in appearance
Careless in activities
Suspidousness
Confusion about what 1s happening
Confusion about what he/she is doing
Indifference
Unpredictable and changeable in attitudes
Unpredictable and changeable in behavior
Inappropriate 1n social situations
Selfish
Upset by new problems
Upset by changes in plans
Demanding of others' attention
Dependent upon others
Dependability
Desirability as family member
Means
Cases
2.04
2.15
2.64
1.74
1.05
1.27
1.66
1.03
.79
1.29
1.72
1.78
1.24
1.26
2.03
2.00
1.87
1.34
1.20
1.06
Controls
1.66
1.63
2.56
1.44
.88
1.17
1.45
.73
.67
1.16
1.50
1.44
1.23
1.36
1.78
1.88
1.87
1.26
1.04
.80
S.E.
.09
.11
.10
.11
.10
.11
.12
.10
.08
.09
.10
.10
.07
.11
.13
.13
.11
.11
.10
.11
P-level
.005
.001
-
.046
.150
-
.229
.036
.301
.287
.125
-
-
-
.175
-
**
-
.280
.112
-------
o
i
Relative Rating; Personality (Continued)
Appreciation by others
Confabulation
Relative Rating; Memory
For verbal communications in last day or two
For verbal communications a year or more ago
For events occurring 1n last day or two
For events occurlng a year or more ago
For people met 1n last day or two
For people met a year or more ago
Losing track of time
Forgetting what he/she 1s doing
Forgetting how to do things
Losing things by forgetting where they are
Forgetting obligations
Relative Rating: Language and Communication
Difficulties understanding speech of others
Difficulties recognizing printed or written words
Difficulties understanding reading material
Difficulties with enunciation
Difficulty thinking of names of things
Other word finding difficulties
Means
Cases
.85
.77
1.54
1.46
.65
1.02
.42
.96
1.02
.51
.37
1.58
1.30
1.12
.79
.68
.79
1.10
.92
Controls
.84
.70
1.45
1.51
.58
1.07
.62
1.13
1.07
.56
.28
1.68
1.29
.78
.47
.50
.66
.78
.69
S.E.
.09
.12
P-level*
.12
.14
.10
.11
.10
.11
.13
.10
.07
.15
.12
.12
.11
.10
.12
.10
.09
.176
.248
.049
.053
.198
.035
.087
-------
Relative Rating: Language and Communications (Cont'd)
Difficulties forming letters correctly when writing
Others have difficulty reading his/her writing
Difficulty spelling
Relative Rating; Use of Hands
Difficulty performing tasks with right hand
Difficulty performing tasks with left hand
Relative Rating: Cognitive/Intellectual Functions
Thoughts seem confused or illogical
Distracted from what doing or saying
Confusion about where patient is
Difficulty finding way
Difficulty calculating
Difficulty planning and organizing activities
Difficulty solving problems
Difficulty following directions
Difficulty following instructions
Means
Cases
.60
.70
1.52
.38
.43
.68
.44
.25
.34
.97
.85
.81
.52
.75
Controls
.41
.66
1.39
.29
.94
.40
.55
.20
'.24
.86
.81
.70
.60
.67
S.E.
.09
.13
.13
.10
.12
.09
.07
.08
.07
.11
.09
.07
.08
.06
P-level*
.155
* The p-level 1s not given 1n cases for which the F-rat1o 1s less than unity.
**The F-test for Interaction between exposure groups and states is significant at the 5% level.
.003
.028
.297
.274
-------
Table 35
Analysis of Variance Summary*
with Subgroup Means and Standard Deviations
for the Total Organochlorine Pesticide Residue in the Blood
Source of
Variation
Between Pairs
States
Error A
Within Pairs
Exposure
C+^^A 9 E**r*
btate & txp.
Error B
Degrees of
Freedom
-85.
1
84
86
1
1
I
84
Mean
Square F-ratio
29
13.30 15.77
.84
.91
10. T3 12.63
-.. <!
.74
-------
blood residue levels of the persistent organochlorine pesticides were signifi-
cantly higher in the cases than in the controls.
The Texas participants in both the control and case cohorts had signifi-
cantly higher residue values than the Colorado participants. This result
might be expected since previous studies have shown that the body burden of
organochlorine pesticide residues in residents of southern states is signifi-
cantly greater than that of residents of northern states.
One of the purposes of testing the cases and controls for ChE depression
was to determine if any of the participants showed evidence of exposure to
OPs at the time of examination in as much as some of the controls as well as
cases were in occupations where occupational or accidental exposure to OPs
was possible.
Laboratory data on RBC and plasma ChE were statisitcally analyzed using
the matched-pairs analysis of variance procedure; the results are presented
in Tables 36 and 37, respectively. As seen in Tables 36 and 37, both the
case and control cohorts were well above the lower limits of normal RBC ChE
and plasma ChE. The approximate lower limits of normal for the pH STAT method
are 8.0 yM/min/ml for RBC and 2.3 yM/min/ml for plasma. The mean values for
plasma ChE for the control cohort was significantly lower than that for the
case control.
Since the residue data showed a statistically significant difference
between the case and control cohorts, this variable was analyzed to determine
its potential influence on significant neurological findings. In particular,
correlation coefficients were computed between the five most comprehensive
neuropsychological measurements and the organochlorine residue level and the
ChE levels. As previously mentioned, on four of these five neurospychological
measurements, the control cohort preformed significantly better than the
case cohort. The correlation analysis, failed to show any significant
-63-
-------
Table 36
Analysis of Variance Summary
with Subgroup Means and Standard Deviations
for Red Blood Cell Cholinesterase
Source of
Variation
Between Pairs
States
Error A
Within Pairs
Exposure
State & Exp.
Error B
Degrees of
Freedom
85
1
84
86
1
1
84
Mean
Square F- ratio
11.25
442.38 72.31
6.12
6.21
1.99
-------
Table 37
Analysis of Variance Summary
with Subgroup Means and Standard Deviations
for Plasma Cholinesterase
Source of
Variation
Between Pairs
States
Error A
Within Pairs
Exposure
State & Exp.
Error B
Degrees of
Freedom
85
1
84
8£
, 1
1
84
Mean
Square F- ratio
1.29
.55
-------
association between organochlorine residue and any of the summary neuro-
psychological variables. Thus, any assumptions of influence toward impaired
neuropsychological function from exposure to organochlorine pesticides were
not supported by these data. Similarly, the correlations of the ChE levels
with the summary neuropsychological variables were not statistically signifi-
cant. In fact, none of the correlation coefficients exceeded .25.
SUMMARY AND DISCUSSION
A basic hypothesis of this research was that individuals with previous
documented acute organophosphate pesticide poisonings may experience latent
chronic neurological effects. It should be emphasized that the study partici-
pants were not merely exposed to organophosphates, but they were made severely
ill by the exposure to the organophosphate. The exposures were of such magni-
tude to require hospitalization in 78 per cent of the cases. It should also
be emphasized that the mean number of days from post poisoning to neurological
testing was 2574 days. This study was conducted by using matched-pairs to
compare a cohort of 100 previous organophosphate poisoning cases to a cohort
of 100 controls. The matching characteristics included age, sex, race, ethnic
background, and social economic factors. All participants and controls
came from the states of Colorado and Texas. In the blind study design, each
study participant received a physical examination, neurological examination,
electroencephalogram (EEG), and neuropsychological testing. Blood samples
were collected from each participant for analyses for organochlorine pesticide
residues and cholinesterase levels. In addition, the blood samples were
evaluated for hematology, morphology, urea nitrogen and creatinine. All
of the data obtained in this study were statistically analyzed using appropriate
matched-pairs analyses.
-66-
-------
The results of the physical examination revealed no significant differ-
ences between the case and control cohorts. Evaluations of the blind phases
of this study revealed that the clinical EEG could not discriminate the case
cohort from the matched control cohort. Previous investigators have indicated
an association between EEG changes and exposure to organophosphate compounds.
For example, Duffy et a]_. (13) reported on the brain electrical activity of
workers exposed to sarin compared to that of control subjects; statistically
significant group differences included increased beta activity, increased
delta and theta slowing, decreased alpha activity and increased amounts of
rapid eye movement during sleep in the exposed population. -Duffy et al_. con-
cluded that their results, when considered with the long-term behavioral
effects of OP exposure, "provided parallel evidence that OP exposure could
produce long-term changes in brain function". The EEG data obtained in this
study neither confirmed nor refuted these findings; whereas Duffy's results
were based on quantitative data derived from the power spectral analysis of
EEG's, the EEG data obtained in this study were clinically interpreted from
visual readings by the electroencephalographer. (As mentioned previously,
the computer breakdown at the University of Colorado Medical Center prevented
the use of digitized spectral analyses of the EEG's).
However, this study found that some neurological deficiencies (e.g.,
mental status exam and peripheral sensory findings) occurred more frequently
in the case participants. Although only a few of the differences between the
two cohorts in the neurological examination were significant, several major
differences between the case and control cohorts were found through the
neuropsychological evaluations. Each of the five summary scores and each
of the 34 subtest scores from the neuropsychological examination was analyzed
using a matched-pairs analysis of variance procedure to determine the
-67-
-------
statistical significance for the difference between the case and control
cohorts. In summary of the neuropsychological results, it was found that
the participants in the case cohort were significantly worse than the controls
on four of five summary measures and on 18 of 34 individual subtest scores
used in the study. The differences occurred on tests of widely varying
abilities, including intellectual functioning, academic skills, abstraction
and flexibility of thinking, and simple motor skills (speed and coordination).
The case cohort did not perform significantly better than the control cohort
on any of the subtests.
A total of 24% of the case cohorts obtained Halstead-Reitan Battery
summary scores in the range that strongly suggested cerebral damage or
dysfunction, whereas only 12% of the controls performed at the same level
on these tests. Based on the matched-pairs chi-square test, this difference
in proportions between the case and control cohorts was statistically signifi-
cant (p <.05). It should be noted that the Halstead-Reitan Battery is the
most comprehensive and best validated neuropsychological test battery
currently available. In contains a number of tests, because it was designed
to measure a wide range of adaptive abilities that can be affected by brain
lesions involving various cerebral locations. Considering the complexity of
the brain and the behaviors it subserves, the use of two or three tests of
"organicity" in this study would have been inadequate. There are two summary
measures from this battery that are more sensitive to brain lesions than are
any of the individual tests (the Halstead Impairment Index and the Average
Impairment Rating). The pesticide poisoned subjects did significantly worse
than the controls on both of these measures. It should be noted that both
cohorts showed above average intellectual functioning on the WAIS Battery.
-68-
-------
The overall difference between the case cohort and the cohort of matched
controls was further evaluated by analyzing simultaneously all 34 subtest
scores in the neuropsychological evaluation. This analysis (a multivariate
analysis of variance procedure for matched-pairs designs) found the total
difference between the two cohorts to be highly significant (p = .0076).
Furthermore, the lack of significance in the statistical test for "Inter-
action" in the multivariate analysis of variance confirmed that the differ-
ence between the case and control cohorts was consistent for the study cohort
subgroups (i.e., Colorado and Texas). The subtests from each battery of
neuropsychological tests (i.e., WAIS, Halstead-Reitan, Peabody, and Added
Ability Tests) were also analyzed simultaneously using the same multivariate
analysis of variance procedure. For each battery of tests, the difference
between the case and control cohorts was statistically significant (the
p-levels for the above four batteries were .0001, .0311, .0066, and .0055,
respectively). For each battery, this difference between case and control
cohorts was consistent for the two study subgroups from Colorado and Texas.
Results from the Patient Assessment of Own Functioning Inventory were
similar to the findings of the objective neuropsychological testing. In the
Patient Assessments, the difference between case and control cohorts was
significant with respect to everyday functioning on 10 of 32 aspects of
language and communication, memory, cognitive intellectual functions, and
perceptual functions. The case participants also demonstrated significantly
lower abilities in the same subject areas on objective testing as they did
on the Patient Assessment Inventory.
Results from the inventory of Relative's Assessment of Patient Function-
ing showed fewer significant differences between the case and control cohorts
than either the objective neuropsychological testing or the Patient Assess-
ment of Own Functioning Inventory. The Relative's Assessment showed the case
-69-
-------
cohort to have significantly more problems on four of 22 personality scale
items: depression (p = .005); irritability (p = .001); confusion about what
is happening (p = .036); withdrawal (p = .046). Based on the relative's
assessment the case cohort was found to have significantly more difficulties
in understanding speech of others (p = .049) and in thinking of names of
things (p = .035).
MacMahon (51) has noted that, in the absence of experimental data,
three types of considerations are useful in distinguishing between epidemi-
olgical associations that are causal and those that are secondary. These
include time sequence, strength of association between two events, and
consonance with existing knowledge.
Since the study was designed to investigate the chronic effects that
might be associated with a previous acute organophosphate pesticide (OP)
poisoning, the study purposely included those cases that had experienced
severe OP intoxications. In particular, the study design for this research
included only cases that had experienced an organophosphate poisoning of
such severity to usually require hospitalization. The time lapse from the
poisoning experiences to neurological examination ranged from 117 days for
one case to 9640 days with the mean time lapse being 2574 days. To make
certain that study participatants had not experienced recent OP exposures,
blood samples were collected and anlayzed for cholinesterase depression.
With respect to the strength of association between acute organophosphate
pesticide poisoning and neuropsychological deficits, one might reasonably
expect the greater the dose the greater the neurological deficit this is,
assuming the degree of neuropsychological deficits to be related to the dose
(concentration, route of exposure, toxicity) at the time of the OP poisoning
experience. Because of the lack of specific dose-type data, the study was
-70-
-------
unable to relate degree of OP poisoning severity to the degree of neuro-
phychological deficit. However, the strength of the association between
acute organophosphate exposure and neuropsychological deficits is reflected,
not only in the number of statistically significant differences between the
exposed and control cohorts, but more importantly in the consistency of
these significant differences.
Obviously, in any epidemiologic study of this type, there is the potential
for several confounding variables, including multiple exposures to low levels
of OP compounds and other pesticides. In addition, there was a variation in
the length of the latent induction period prior to the neuropsychological
evaluations. There is also the question of the exact type of cerebral lesions
in the exposed population. For example, does the pattern of deficits resemble
diffuse arteriosclerosis, lead encephalopathy, or other diseases? It should
be emphasized that there is some danger of overinterpreting patterns of
group mean scores on neuropsychological test batteries, because this fre-
quently implies more consistency than actually exists among the individual
subjects in the group. Some research on use of the Minnesota Multiphasic
Personality Inventory (MMPI) has been criticized on this basis. Also since
no consistently focal or lateralized brain changes were expected in the poi-
soned group, the research design did not concentrate on looking for specific
patterns of deficits among the cases. For example, although one might postulate
that the case group data would include more involvement of the frontal areas
than of the other cerebral areas this would probably be an overinterpretation
of the results. The pattern of results on the WAIS battery, such as the
greater group differences on Verbal than on Performance subtests, introduces
the potential confounding variable of control selection. Although one might
argue that an Inadvertent bias in the selection of study controls could account
-71-
-------
for the observed group differences on the WAIS, a selection bias of this
nature would not account for the greater number of poisoned subjects scoring
in the brain damaged range on the Halstead-Reitan Battery.
It might be argued that residual effects from cerebral anoxia due
to organophosphate poisoning may cause the observed neuropsychological
differences. However, selection criteria were designed to eliminate both
cases-and controls who were known to be unconscious for a significant period
of time (more than 15 minutes) in his or her lifetime, regardless of the cause.
In addition, the selection criteria eliminated any subjects whose medical
history included any disease that might adversely influence the neurological
and neuropsychological testing. In particular, the subject screening procedures
excluded any subjects who had a past history of neurological illness, signfi-
cant head trauma, or substance abuse.
The neurological and neuropsychological evaluations are obviously comple-
mentary in that each emphasizes different aspects of dysfunction. The
clinical neurological examinations focus primarily on sensory and motor
functioning with very little attention to the higher level cognitive and
intellectual functions that are very sensitively assessed by the neuropsy-
chological procedures. Both examinations found no differences between the
case and control cohort participants with respect to sensory-perceptual
functioning. The neuropsychological exam found some mild impairment of
fine coordination and motor speed with the upper extremities in the case
cohort. The major neuropsychological differences between case and control
cohorts appeared on tests of abilities that receive limited evaluation in
the clinical neurological examination. The two methods of evaluation, taken
together, thus provide a more complete evaluation of brain function not
possible utilizing either examination alone. Hopefully future research will
-72-
-------
help to further elucidate the important interrelationships {person-place-
time chemical) between acute organophosphate exposure and chronic neuro-
psychological health effects.
-------
REFERENCES
1. Expert Committee on Insecticides. Safe Use of Pesticides. 20th Report,
WHO Tech. Rep. Ser. No. 513, World Health Organization, 1973. p. 42.
2. Colorado Epidemiologic Pesticide Studies Center. A Study of Hospitalized
Acute Pesticide Poisonings in the United States, 1971-1973. Colorado
State University, Fort Collins, Colorado, 1975. p. 32.
3. Durham, W.F. and W.J. Hayes, Jr. Organic Phosphorus Poisoning and-Its
Therapy. Arch. Environ. Health 5:21-53, 1962.
4. Murphy, S.D. Pesticides. In: Toxicology - The Basic Science of Poisons,
L. J. Casarett and J. Doull, eds~MacMillian Publishing Co., Inc., New
York, 1975. p. 424.
5. Hunter, D. The Diseases of Occupations. English University Press,
London, England, 1975. pp. 368-377.
6. Bidstrup, P.L., J.A. Bonnell, and A.G. Beckett. Paralysis Following
Poisoning by a New Organic Phosphorus Insecticide (Mipafox). Brit.
Med. 0. 1:1063-1072, 1953.
7. Gershon, S. and F.H. Shaw. Psychiatric Sequelae of Chronic Exposure to
Organophosphorus Insecticides. Lancet 1:1371-1374, 1961.
8. Dille, J.R. and P.M. Smith. Central Nervous System Effects of Chronic
Exposure to Organophosphate Insecticides. Aerosp. Med. 35:475-475, 1964.
9. Drenth, H.J. Neuromuscular Function in Agricultural Workers Using
Pesticides. Arch. Environ. Health 25:395-398, 1972.
10. Grob, D. and A.M. Harvey. The Effects and Treatment of Nerve Gas
Poisoning. Amer. J. Med. 14:52-63, 1953.
11. Brown, H.W. Electroencephalographic Changes and Disturbance of Brain
Function Following Human Organophosphate Exposure. Northwest Med. 70:
845-846, 1971.
12. Metcalf, D.R. and J.H. Holmes. EEG, Psychological and Neurological
Alterations in Humans with Organophosphorus Exposure. Ann. N.Y. Acad.
Sci. 160:357-365, 1969.
13. Duffy, F.H., J.L. Burchfiel, P.H. Bartels, M. Gaon, and V.M. Sim.
Long-Term Effects of an Organophosphate upon the Human Electoencephalogram.
Toxicol. Appl. Pharmacol. 47:161-176, 1979.
14. Barnes, J.M. (Letter). Lancet 2:102-103, 1961.
15. Bidstrup, P.L. (Letter). Lancet 2:103, 1961.
16. Stroller, A., J. Krupinski, A.J. Christophers, and A.K. Blanks. Organo-
phosphorus Insecticide and Major Mental Illness. Lancet 1:1387-1388, 1965,
-74-
-------
17. Tabershaw, I.R. and W.C. Cooper. Sequelae of Acute Organic Phosphate
Poisoning. J. Occ. Med. 8:5-10, 1966.
18. Clark, G. Organophosphate Insecticides and Behavior, a Review
Aerospace Med. 42:735-740, 1971.
19. Holmes, J.H., Clinical Studies of Exposure to the Organophosphorus
Insecticides. In: Research in Pesticides. C.O. Chichester, ed
Academic Press, New York, 1965. p. 315-327.
20. Savage, E.P., Bagby, J.R. , Jr., Mounce, L.M. , Williams, L.P., Jr.,
Cholas, G.: Pesticide Poisonings in Rural Colorado. Rocky Mt.
Medical Journal, April 1971.
21. Gallaher, G.L. "Low Volume" Insect Control and Parathion Poisoning.
Texas Med. 63:39, 1967.
22. Hatcher, R.L. and J.S. Wiseman. Epidemiology of Pesticide Poisoning
in the Lower Rio Grande Valley in 1968. Texas Med. 65:40-43, 1969.
23. Hollingshead, A.B. The Two Factor Index of Social Position. Mimeo
Yale University, New Haven.
24. Wechsler, D. Manual for the Wechsler Adult Intelligence Scale. The
Psychological Corporation, New York, 1955. - -
25. Halstead, W.C. Brain and Intelligence: A Quantitative Study of the
Frontal Lobes. University of Chicago Press, Chicago, 1947. -
26. A Research Program on the Psychological Effects of Brain Lesions in
Human Beings. In: International Review of Research in Mental
Retardation, N.R. Ellis, ed. Academic Press, New York, 1966.
27. Reitan, R.M. and L.A. Davidson (ed.). Clinical NeuropsvcholoQv
Current Status and Applications. Wi 1 ey' & Sons, New York, 1974.
28. Russell, E.W., C. Neuringer, and G. Goldstein. Assessment of Brain
Damage: A Neuropsychological Key Approach. Wiley-Interscience, New
29. Matarazzo, J.D. Wechsler's Measurement and Appraisal of Adult Intel li-
gence. Williams & Wilkins, Baltimore, 1972. - ~" -
30. Heaton, R.K. (Private Publication) Manual for Administration of Neuro-
psychological Test Batteries for Adults and Children. Indian^rnr;
31. Saetveit, J.G., D. Lewis, and C.E. Seashore. Revision of the Seashore
Measure of Musical Talents. University of Iowa Press, Iowa City, 1940.
32. Armitage, S.G. An Analysis of Certain Psychological Tests Used for
the Evaluation of Brain Injury. Psychol. Monogr. 60:1, 1946.
33. Wheeler, L. and R.M. Reitan. The Presence and Lateral ity of Brain
Damage Predicted from Responses to a Short Sphasia Screening Test
Percept. Mot. Skills 15:783, 1962.
-75-
-------
34. Halstead, W.C. and J.M. Wepman. The Halstead-Wepman Aphasia Screening
Test. J. Speech Hearing Dis. 14:9, 1949.
35. Dunn, L.M. and S.C. Markwardt, Jr. Peabody Individual Achievement Test
Manual. American Guidances Service, Circle Pines, Minnesota, 1970.
35 Thurstone, L.L. Primary Mental Abilities. University of Chicago Press,
Chicago, 111., 1938.
37 Reitan, R.M. Verbal Problem Solving as Related to Cerebral Damage.
Percept. Mot. Skills 34:515-524, 1972.
38. Berg, E.A. A Simple Objective Technique for Measuring Flexibility in
Thinking. J. Gen. Psycho!. 39:15-22, 1948.
39. Grant, D.A. and E.A. Berg. A Behavioral Analysis of Degree of Reinforce-
ment and Ease of Shifting to New Responses in a Weigl-Type Card-Sorting
Problem. J. Exp. Psycho!. 38:404-411, 1948.
40. Reitan, R.M. Unpublished Test Modified by R.K. Heaton, University of
Colorado Medical Center, Denver, Colorado.
41. Hathaway, S.R. and J.C. McKinley. The MMPI Manual. The Psychological
Corporation, New York, 1951.
42. Dahlstrom, W.G., G.S. Welsch, and I.E. Dahlstrom. An MMPI Handbook,
Vol. 1: Clinical Interpretation. University of Minnesota Press,
Minneapolis, 1972.
43. An MMPI Handbook, Vol. II: Research Application. University of
Minnesota Press, Minneapolis, 1975.
44. Winer, B.J. Statistical Principles in Experimental Design. McGraw Hill
Book Company, New York, 1962. pp. 191-195.
45 Fleiss, J.L. Statistical Methods for Rates and Proportions. John Wiley
& Sons, New York, 1973. pp. 72-80.
46 Stuart, A. A Test for Homogeneity of the Marginal Distribution in a
Two-Way Classification. Biometrika 42:412-416, 1955.
47 Morrison, D.F. Multivariate Statistical Methods. McGraw-Hill Book
Co., New York, 1967T
48. Milner, B. Some Effects of Frontal Lobectomy in Man. In: Frontal
Granular Cortex and Behavior, J.M. Warren and K. Akert, eds. McGraw-
H111, New York, 1964.
49- Drewe, E.A. The Effect of Type and Area of Brain Lesion on Wisconsin
Card Sorting Test Performance. Cortex 10:159-170, 1974.
50- Wechsler, D.E. A Standardized Memory Scale for Clinical Use. J.
Psycho!. 19:89-95, 1945.
51. MacMahon, B. and Thomas, F.P. Epidemiology Principles and Methods.
Little, Brown and Company, Boston, 1970.
-76-
------- |