United States

Environmental Protection

Agency

Prevention, Pesticides

and Toxic Substances

(7101)

EPA 712–C–96–242

June 1996

Health Effects Test

Guidelines

OPPTS 870.6855

Neurophysiology:

Sensory Evoked

Potentials

‘‘Public Draft’’
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INTRODUCTION

This guideline is one of a series of test guidelines that have been

developed by the Office of Prevention, Pesticides and Toxic Substances,

United States Environmental Protection Agency for use in the testing of

pesticides and toxic substances, and the development of test data that must

be submitted to the Agency for review under Federal regulations.

The Office of Prevention, Pesticides and Toxic Substances (OPPTS)

has developed this guideline through a process of harmonization that

blended the testing guidance and requirements that existed in the Office

of Pollution Prevention and Toxics (OPPT) and appeared in Title 40,

Chapter I, Subchapter R of the Code of Federal Regulations (CFR), the

Office of Pesticide Programs (OPP) which appeared in publications of the

National Technical Information Service (NTIS) and the guidelines published by the Organization for Economic Cooperation and Development

(OECD).

The purpose of harmonizing these guidelines into a single set of

OPPTS guidelines is to minimize variations among the testing procedures

that must be performed to meet the data requirements of the U. S. Environmental Protection Agency under the Toxic Substances Control Act (15

U.S.C. 2601) and the Federal Insecticide, Fungicide and Rodenticide Act

(7 U.S.C. 136, et seq.).

Public Draft Access Information: This draft guideline is part of a

series of related harmonized guidelines that need to be considered as a

unit. For copies: These guidelines are available electronically from the

EPA Public Access Gopher (gopher.epa.gov) under the heading ‘‘Environmental Test Methods and Guidelines’’ or in paper by contacting the

OPP Public Docket at (703) 305–5805 or by e-mail:

guidelines@epamail.epa.gov.

To Submit Comments: Interested persons are invited to submit comments. By mail: Public Docket and Freedom of Information Section, Office

of Pesticide Programs, Field Operations Division (7506C), Environmental

Protection Agency, 401 M St. SW., Washington, DC 20460. In person:

bring to: Rm. 1132, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA. Comments may also be submitted electronically by sending

electronic mail (e-mail) to: guidelines@epamail.epa.gov.

Final Guideline Release: This guideline is available from the U.S.

Government Printing Office, Washington, DC 20402 on The Federal Bulletin Board. By modem dial 202–512–1387, telnet and ftp:

fedbbs.access.gpo.gov (IP 162.140.64.19), or call 202–512–0132 for disks

or paper copies. This guideline is also available electronically in ASCII

and PDF (portable document format) from the EPA Public Access Gopher

(gopher.epa.gov) under the heading ‘‘Environmental Test Methods and

Guidelines.’’
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OPPTS 870.6855 Neurophysiology: sensory evoked potentials.

(a) Scope—(1) Applicability. This guideline is intended to meet testing requirements of both the Federal Insecticide, Fungicide, and

Rodenticide Act (FIFRA) (7 U.S.C. 136, et seq.) and the Toxic Substances

Control Act (TSCA) (15 U.S.C. 2601).

(2) Background. This guideline was developed jointly between the

Office of Pesticide Programs and the Office of Pollution Prevention and

Toxics in cooperation with the Office of Research and Development of

the Environmental Protection Agency. The source material used in developing this harmonized guideline is 40 CFR 798.6855 Neurophysiology:

sensory evoked potentials.

(b) Purpose. The techniques in this guideline are designed to detect

and characterize changes in the sensory aspects of nervous system function

that result from exposure to chemical substances. The techniques involve

neurophysiological measurements from adult animals and are sensitive to

changes in the function of auditory, somatosensory (body sensation) and

visual sensory systems. These procedures can be used in two ways:

(1) To detect sensory dysfunction produced by compounds in the absence of relevant information.

(2) When there are reasons to expect that particular sensory functions

are specifically sensitive to the test compound. The procedures employed

during a particular study will be selected on a case-by-case basis depending on information available at the time of the study design, signs of toxicity observed during the study, and/or the purpose of the study. It will

be the responsibility of those submitting to justify the selection of a specific test from the categories of electrophysiological tests available. The

tests are adaptable so that they may be used in sum or in part, and either

alone or in conjunction with other tests including: A functional observational battery, motor activity, neuropathology, and general toxicity studies.

These studies may involve acute, subchronic, or chronic exposures.

(c) Definitions. The definitions in section 3 of the Toxic Substances

Control Act (TSCA) and the definitions in 40 CFR Part 792—Good Laboratory Practice Standards apply to this test guideline. The following definitions also apply to this test guideline.

Neurotoxicity is any adverse effect on the structure or function of

the nervous system related to exposure to a chemical substance.

Toxic effect is any adverse change in structure or function of an experimental animal as a result of exposure to a chemical substance.

(d) Principle of the test method. The test substance is administered

to several groups of experimental animals, each group receiving a different

dose level. Electrodes for recording brain electrical activity are temporarily
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or permanently affixed to the test animals. After electrodes are in place

and, if appropriate surgical recovery, stimuli for the visual, auditory or

somatosensory sensory systems are presented to the test animals, and the

resulting brain electrical potentials are recorded. The electrical potentials

recorded from animals treated with the test compound are compared to

those recorded from control animals. The results are interpreted regarding

the extent to which treatment with the test compound altered the normal

function of the sensory systems tested.

(e) Test procedure—(1) Animal selection—(i) Species and strain.

Testing should generally be performed in the laboratory rat, preferably a

pigmented strain. Albino strains of animals have abnormalities of the visual and auditory systems (see paragraphs (g)(4), (g)(5), and (g)(13) of this

guideline), including: The absence of pigment from the retinal pigment

epithelial layer, high incidence of spontaneous retinal pathologies, problems of photogenic retinopathy (under paragraph (g)(7) of this guideline),

abnormal pattern visual evoked potentials (under paragraph (g)(1) of this

guideline), lack of normal pigment in the stria vascularis of the cochlea

(see paragraph (g)(17) of this guideline) and differential susceptibility to

ototoxic noise and drugs from pigmented strains (under paragraphs (g)(2)

and (g)(3) of this guideline). However, it is recognized that under some

circumstances, use of another species or an albino strain may be justified.

If another species or an albino strain is used, the user must submit justification.

(ii) Age. Animals should be young adults (42–120 days of age, for

rats) at the start of exposure. Implantation of chronic electrodes in rats

younger than 60 days of age is not advised.

(iii) Sex. (A) In order to reduce the number of animals used, only

one sex is required. Male rats may be preferred because there is more

existing data on them. If, on the other hand, females are known or expected

to be more sensitive to the test agent, they may be used. The user should

provide justification for the sex selected.

(B) If females are used, they should be nulliparous and nonpregnant.

(2) Number of animals. A final sample size of at least 10 animals

should be used in each dose and control group. The number of animals

to be used should be based on appropriate statistical methods and an allowance for attrition due to anticipated problems such as loss of electrode

preparations, etc. Note that the rate of attrition should be estimated based

on the experience of the laboratory performing the testing. If interim

neurophysiological evaluations are planned in long-term dosing studies,

it may be advisable to include an additional number of animals sufficient

for the interim studies. Animals should be randomly assigned to treatment

and control groups. If groups are not randomly assigned, justification must

be provided.
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(3) Control groups. (i) A concurrent (‘‘sham’’ exposure) vehicle

control group is required. Subjects should be treated in the same way as

an exposure group except that administration of the test substance is omitted. If the vehicle used has known or potential neuroactive properties, both

untreated and vehicle-control groups are required.

(ii) Positive control groups exhibiting functional changes in the sensory systems to be tested are required in order to demonstrate the capability of the laboratory performing the testing to conduct the procedures. Separate setups for each sensory system are acceptable, but not necessary.

In addition, for each sensory modality in vehicle or untreated control group

data, it should be demonstrated that the mean of an amplitude-sensitive

dependent measure increases monotonically as a function of stimulus intensity as defined in paragraph (e)(7)(v)(D) of this guideline. Use of historical positive controls collected in the laboratory conducting the test is acceptable in order to demonstrate adequate characterization of treatmentrelated changes by the approach outlined in this guideline.

(4) Dose levels and dose selection. (i) At least three dose levels

should be used in addition to the vehicle control group. Ideally, the data

should be sufficient to produce a dose-effect curve. We encourage the use

of equally spaced doses on a logarithmic scale, and a rationale for dose

selection that will enable detection of dose-effect relations to the highest

degree possible. For acute studies, dose selection may be made relative

to the establishment of a benchmark dose (BD). That is, doses may be

specified as successive fractions, e.g. 0.5, 0.25 of the BD. The BD itself

may be estimated as the highest nonlethal dose as determined in a preliminary range-finding study. A variety of test methodologies may be used

to determine a BD, and the method chosen may influence subsequent dose

selection. The goal is to use a dose level that is sufficient to be judged

a limit dose, or clearly toxic. Alternatively, the BD may be specified as

a dose of the test compound producing clear neurotoxic effects in previous

studies.

(ii) Acute studies. The high dose need not be greater than 2 g/kg.

Otherwise, the high dose should result in significant neurotoxic effects

or other clearly toxic effects, but not result in an incidence of fatalities

that would preclude a meaningful evaluation of the data. This dose may

be estimated by a BD procedure as described above, with the middle and

low dose levels chosen as fractions of the BD. The lowest dose should

produce minimal effects or, alternatively, no effects.

(iii) Subchronic and chronic studies. The high dose need not be

greater than 1 g/kg/day. Otherwise, the high dose level should result in

significant neurotoxic effects or other clearly toxic effects, but not produce

an incidence of fatalities that would preclude a meaningful evaluation of

the data. The middle and low dose should be fractions of the high dose.

The low dose should produce minimal effects, or alternatively, no effects.
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(5) Route of exposure. Selection of route may be based on several

criteria: The most likely route of human exposure, the greater likelihood

of observing effects, the practical difficulties, the likelihood of producing

nonspecific effects, and existing data regarding the test compound. Because more than one route of exposure may be important for many materials, these criteria may conflict with one another. The route that best meets

these criteria should be selected.

(6) Combined protocol. The tests described herein may be combined

with any other toxicity study, as long as none of the requirements of either

is violated by the combination.

(7) Study conduct—(i) Preparation of animals for recording. (A)

For electrophysiological recording it usually will be necessary to implant

animals with chronic in-dwelling electrodes using stereotaxic surgical procedures. In some circumstances, acute attachment of temporary electrodes

may be acceptable if criteria for humane treatment of animals, for recording without undue anesthesia, and for data acceptability detailed below

can be met. Chronic implantation of electrodes will require surgical anesthesia and surgical techniques appropriate for the species as outlined in

current laboratory animal care guidelines under paragraph (g)(16) of this

guideline. Standard animal surgical practices should be followed as outlined in a number of standard references (e.g. paragraph (g)(10) of this

guideline). Once anesthetized, animals are usually placed in a stereotaxic

device in order to position the head firmly. The stereotaxic device should

be designed to prevent trauma to the tympanic membranes and, for auditory studies, tympanic membranes should be examined after removal from

the stereotaxic device.

(B) Care should be taken during surgery to prevent drying of the

cornea through means such as regular application of fluids such as mineral

oil, saline, or artificial tear solution. Once the animal is positioned in the

stereotaxic device and the implantation site is prepared, the electrodes

should be positioned with reference to standard skull markings and/or to

published brain atlas coordinates (see paragraph (g)(11) or (g)(12) of this

guideline).

(C) For recording potentials which are generated in sensory cortex,

the recording or active electrodes are to be positioned as close as possible

to the brain sites generating the response. For ‘‘far-field’’ potentials such

as the brainstem auditory evoked potential, which are conducted through

cranial tissues from sites relatively distant to the recording electrodes, the

location of the recording electrodes should be such as to provide good

resolution of the major waveform components, but need not be as close

as possible to the generator sites. The site of the reference electrode for

differential recordings should be indifferent with respect to stimulusevoked electrical activity to the extent possible. A ground electrode should

also be included. The electrodes should be made of a material that is not
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toxic to neural tissue. The electrodes should be made of a nonpolarizable

material, such as silver-silver chloride, if potentials of a frequency less

than approximately 1 Hz are to be reported. However, extra caution should

be exercised in this case to avoid toxic effects of such electrodes. Electrodes should be described as to composition, size, shape, and position.

(D) Wound sites should be treated and closed so as to prevent infections and to protect the integrity of the electrodes. Following surgery, electrode impedance should be measured in order to verify that electrode connections are intact and functional. Following surgery, animals should be

given sufficient time to recover from the anesthetic and surgical trauma

prior to testing; ordinarily a period of one week is recommended. Prior

to testing, the wound site should be inspected for signs of infection or

inflammation, and any animal showing such signs should be removed from

the experiment.

(E) For acute studies, it is necessary to perform surgery prior to administering the test compound. In repeated dosing, it may be necessary

to implant the electrodes during the course of treatment with the test

compound due to the limited time which electrode preparations may be

expected to remain intact. It may be advisable to prevent exposure to the

test compound on the day of surgery due to possible interactions of the

effects of the test compound and the anesthetic agent. The time between

surgical implantation of electrodes and testing should be equal for all animals or, if unequal, balanced across the treatment groups. Animals losing

electrode preparations between time of surgery and testing should be removed from the study and not submitted to another surgery. At termination

of the study, postmortem examination of each animal should be used to

determine if the electrodes were incorrectly positioned, or if the presence

of epidural electrodes damaged the underlying neural tissue. If either of

these two conditions is found, the data from the involved animal should

be discarded.

(ii) Testing environment. (A) Electrophysiological testing should be

conducted in a chamber or room which is isolated from extraneous light

and noise and controlled for temperature. Background noise, light, and

room temperature should be reported. Where possible, testing should be

conducted without the use of restraint or anesthetics. The use of restraint

may be necessary when a specific orientation to, or distance from, the

stimulation equipment is required, or when movement of the animal would

interfere with recording.

(B) For auditory testing of unrestrained, unanesthetized animals,

acoustic stimuli should be of equal sound pressure level wherever the animals’ ears may be placed during data acquisition. The animal enclosure

should be acoustically transparent to sound in the frequency band of the

stimulus spectrum. The use of anesthetic is permissible when considerations of animal discomfort prohibit testing awake animals, and when it
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can be reasonably expected that the effects of the test agent would not

be substantially different under anesthesia. If recording is to be performed

on anesthetized animals, body temperature should be maintained within

a normal range during testing. In addition, if recording from anesthetized

animals, the power spectrum of the spontaneous electroencephalogram

(EEG) should be measured in order to control depth of anesthesia. Position

of the stimulation device or devices relative to the appropriate sensory

organs should be specified.

(iii) Electrophysiological recording. (A) Electrophysiological recording procedures should follow generally accepted practice such as is

found in standard reference texts (under paragraph (g)(8) or (g)(15) of

this guideline). Typically, it is appropriate to differentially record between

active and reference electrodes using an amplifier with high common mode

rejection and high input impedance relative to that of the electrodes.

(B) Electrical shielding and grounding should be used to eliminate

activity in the electrophysiological recording at the frequency of the power

lines reflecting inductive noise. Electrophysiological amplifiers and filter

bandpass settings must be appropriate to the signal being measured. For

example, ac-coupling is appropriate for most applications, but dc-coupling

should be used if steady potentials are to be measured. Analog electrical

activity is typically digitized using an analog-to-digital converter operating

at a rate at least twice, preferable higher, the highest frequency passing

the input filters. Analog or digital filtering of data is appropriate to improve signal-to-noise ratios. If using analog filtering, the decay functions

of the high and low bands of the filters should be specified, and filtering

parameters should be selected to avoid amplitude reductions or phase shifts

in the frequency bands of the signal to be measured.

(iv) Signal averaging. (A) Signal averaging of the input data synchronized with the stimulation is appropriate to increase the signal-to-noise

ratio. The number of trials averaged should be sufficient to yield reliable

data, and a waveform in control animals for which the maximum amplitude measure to be reported at the minimum intensity stimulus is at least

50 percent greater in amplitude than the recording noise level. The duration of the sampling epoch should be sufficient to encompass all major

components of transient evoked potentials. Automated artifact rejection

routines may be employed to reject occasional spurious data provided that

no greater than 50 percent of the original trials are rejected for any given

waveform, and all final averaged waveforms for a given stimulus condition

are based on an equal number of trials.

(B) The data for cases in which greater than 50 percent of the trials

are rejected due to artifacts should be discarded, and the recording conditions improved, if possible, to allow more suitable data collection. The

recording noise level should be determined in order to illustrate the signalto-noise ratio. Acceptable methods to do so include: examining a portion
7

of the data preceding the presentation of the stimulus, but following the

last of the evoked activity from the previous stimulus in transient evoked

potentials; averaging an equal number of trials as the recording session

but without presentation of the eliciting stimulus (for visual stimuli this

should be accomplished by temporarily blocking the test subjects view

of the stimulus with an opaque material); averaging alternate trials of inverted polarity during the standard recording session, or reaveraging the

original raw data from the standard recording session over a similar number of trials in a manner nonsynchronous with the eliciting stimulus. The

voltage gain and temporal response properties of the electrophysiological

recording equipment should be calibrated for each experiment, or more

frequently as needed. The same recording conditions should be used on

all animals tested.

(v) Stimulation. The selection of stimulation parameters will depend

upon the specific goals of the study. Tests should include measures of

visual, auditory and somatosensory systems, unless there are reasons to

limit testing to particular aspects of sensory function. The testing of multiple sensory systems in the same animal has been demonstrated (see paragraphs (g)(9) and (g)(14) of this guideline). The order of presentation of

the different tests to individual subjects be either random, balanced across

treatment groups, or fixed. If the test order is fixed, justification for the

test order should be provided.

(A) Visual stimuli. Visual testing should include separate tests involving light flashes and patterned stimuli. Visual pattern testing should

employ stimuli with a sinusoidal spatial luminance profile, and should include a range of pattern sizes which encompass the low, middle and high

spatial frequency ranges of the contrast sensitivity function of the test species. Techniques for recording visual evoked potentials using both flashed

(under paragraph (g)(6) of this guideline) and patterned stimuli (under

paragraph (g)(1) of this guideline) are available for laboratory rats.

(B) Auditory stimuli. Auditory testing should include a stimulus of

broadband frequency characteristics, such as a click. In addition, pure tone

stimuli reflecting the low, middle and high frequency portions of the

audiometric function of the test species should be used. Techniques for

recording auditory evoked potentials using both click and pure tone stimuli

(under paragraph (g)(14) of this guideline) are available for laboratory rats.

(C) Somatosensory stimuli. Somatosensory testing should include

electrical stimuli delivered to the tail or distal portions of the lower extremities. Techniques for recording somatosensory evoked potentials are available for laboratory rats (under paragraph (g)(14) of this guideline).

(D) Stimulus levels. (1) For studies designed to detect a change in

sensory function produced by a compound for which little is known, it

is sufficient to use a single stimulus level for each visual, auditory or
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somatosensory evoked potential. Justification for the stimulus level selected should be provided. For studies designed to characterize a sensory

effect, at least three different levels of flash intensity, pattern contrast,

acoustic click stimulus sound pressure level or somatosensory stimulus

current are required for each stimulus condition. The stimulus levels

should be chosen on the basis of prior experience and/or pilot studies.

(2) In control animals, the low level should be near the response

threshold, but large enough to produce a response amplitude at least 50

percent greater than the recording noise level. Specification of the high

stimulus level varies with stimulus type. For flashed visual stimuli the high

stimulus level should either produce a maximal response, or be the maximum output available from a conventional stimulator (e.g. Grass model

PS-22 photic stimulator). For patterned visual stimuli the high stimulus

level should either produce a maximal response, or be below the highest

level of contrast within the linear range of the input-voltage/stimulus-contrast calibration function of the stimulus screen. For somatosensory stimuli

the high stimulus level should either produce a maximal response, or be

at or below a current which produces minimal reflexive muscle movement

or other indications of discomfort. For acoustic stimuli the high stimulus

level should be below approximately 80 decibels sound pressure level in

order to avoid production of temporary or permanent threshold shifts.

(3) For all types of stimuli, the middle stimulus level should produce

a response intermediate between high and low stimulus levels. The physical and temporal parameters of stimuli should be calibrated against known

standards for each experiment using commonly accepted procedures.

(4) Visual stimulus luminance and contrast, or for flashes integrated

power, should be calibrated with an appropriate radiometer or photometer

against a known standard. Acoustic stimuli should be calibrated for level

using equipment which meets standards of the American National Standards Institute (ANSI) for sound level meters. Stimuli should be measured

and reported as peak levels, maximum root mean square (max RMS), or

‘‘peak equivalent’’ sound pressure levels. In addition, the polarity of the

electrical stimulus and the transduction system for acoustic stimuli should

be reported.

(vi) Measurement. (A) Dependent measures should be taken from

each evoked potential which are sensitive to changes of both amplitude

(voltage) and latency (time after stimulus onset) for transient evoked potentials or phase for steady-state evoked potentials. Enough measures

should be taken to adequately reflect the shape of the evoked potential

in control animals.

(B) A variety of measurement schemes may be acceptable, provided

they are specified a priori, do not ignore major portions of the waveform,

yield ratio-scale values, and meet the criterion for positive controls speci-
9

fied in paragraph (e)(3)(ii) of this guideline. If the measurement scheme

involves inspection of each waveform by an operator and scoring of the

waveform, the criteria for scoring should be objective and stated.

(C) The experiment also must be conducted so that the experimental

personnel are unaware of the treatment of individual animals at the time

of scoring. Measurement schemes that minimize the scoring by personnel

of each response are preferred. The same data scoring procedure must be

used on all subjects.

(D) Previously collected data demonstrating selective effects of the

test compound may be used to restrict the number of test parameters and/

or the number of measured endpoints in order to examine more restricted

hypotheses. Colonic temperature should be measured at the time of each

electrophysiological recording. Body weight should be measured on each

test day.

(vii) Acute. Testing should be timed to include the estimated time

of peak effect.

(viii) Repeated dosing. Testing should be conducted after the completion of dosing with the test compound when it can be expected that

transient effects of the final treatment have dissipated. Additional testing

may be conducted during the course of treatment in order to provide information on the emergence of toxic effects.

(f) Data reporting and evaluation. The following should be reported:

(1) Description of the test methods. This must include:

(i) Positive control data from the laboratory performing the test which

demonstrate the sensitivity of the procedure being used. Historical control

data can be critical in the interpretation of study findings. We require submission of such data to facilitate the rapid review of the significance of

the observed effects.

(ii) Procedures for calibrating the stimulation and recording equipment and balancing the groups.

(2) Results. The following must be arranged by test group (dose

level).

(i) In tabular form, data must be provided showing for each animal:

(A) Its identification number.

(B) Body weight for each day tested.

(C) Values of each evoked potential dependent measure
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(D) Body temperature of the animal at the time of acquisition of each

evoked potential.

(iii) Group summary data should also be reported. Data reporting

should include in tabular form measures of central tendency and variability

for each combination of stimulus conditions and treatment with the test

compound, and the statistical significance level for effects of treatment

with the test compound associated with each set of values. The final sample size should be reported along with reasons for excluded or missing

data. The noise level should be reported. Graphic presentation of the data,

or portions thereof, may also be included. Also, samples of typical individual animal evoked potential waveforms illustrating all stimulus conditions

and the noise level, or preferably group mean waveforms of the same,

should be included.

(3) Evaluations of the data—(i) Data analysis. (A) Numerical data

analysis should include a measure of central tendency, such as mean, and

a measure of variability, such as standard error of the mean, for each stimulus and dose treatment combination, and for each dependent variable.

(B) Statistical analysis should test the null hypothesis of no statistically significant overall effect of treatment with the test compound across

stimulus conditions for each type of sensory evoked potential. In addition,

statistical tests for interactions between treatment with the test compound

and the manipulation of the stimulus parameters should be performed and

the results reported. The choice of statistical analysis should consider the

experimental design and address the problem of adjustments for multiple

statistical analyses.

(ii) Interpretation. The report should include an interpretation of the

neurotoxicological significance of the findings, and relate the

neurophysiological results to those of other neurotoxicological results, and

to other data to the extent possible.

(g) References. The following references should be consulted for additional background information on this guideline.

(1) Boyes, W. K. and R. S. Dyer. Pattern reversal visual evoked potentials in awake rats. Brain Research Bulletin 10:817–823 (1983).

(2) Conlee J.W. et al. Differential susceptibility to noise-induced permanent threshold shift between albino and pigmented guinea pigs. Hearing

Research 23:81–91 (1986).

(3) Conlee J.W. et al. Differential susceptibility to gentamicin

ototoxicity between albino and pigmented guinea pigs. Hearing Research

41:43–52 (1989).

(4) Creel, D. Inappropriate use of albino animals in research. Pharmacology and Bioochemical Behavior 12:969–977 (1980).
11

(5) Creel, D. Albinism and evoked potentials: Factors in the selection

of infrahuman models in predicting the human response to neurotoxic

agents. Neurobehavioral Toxicology and Teratology 6:447–453 (1984).

(6) Dyer, R. S. and H. S. Swartzwelder. Sex and strain differences

in the visual evoked potentials of albino and hooded rats. Pharmacology

and Biochemical Behavior 9:301–306 (1978).

(7) Heywood, R. and C. Gopinath. Morphological assessment of visual dysfunction. Toxicology and Pathology 18:204–217 (1990).

(8) International Federation of Societies for Electroencephalography

and Clinical Neurophysiology. Recommendations for the Practice of Clinical Neurophysiology. Elsevier Science, Amsterdam, The Netherlands

(1983).

(9) Mattsson, J. L. and R. R. Albee. Sensory evoked potentials in

neurotoxicology. Neurotoxicology and Teratology 10:435–443 (1988).

(10) Myers, R.D. Methods in Psychobiology. Academic Press, NY

(1971).

(11) Paxinos, G. and Watson, C. The Rat Brain in Stereotaxic Coordinates. Academic Press, Sydney (1982).

(12) Pelligrino, L. J. et al. A Stereotaxic Atlas of the Rat Brain, 2nd

ed., Plenum, NY (1979).

(13) Prieur, D. J. Albino animals: Their use and misuse in biomedical

research. Comparative Pathology Bulletin XIV(3):1–4 (1982).

(14) Rebert, C. S. Multisensory evoked potentials in experimental and

applied neurotoxicology. Neurobehavioral Toxicology and Teratology

5:659–671 (1983).

(15) Thompson, R.F. Methods in Physiological Psychology, Vol 1:

Bioelectric Recording Techniques; Parts A, B and C. Academic Press, NY

(1973 and 1974).

(16) U.S. Department of Health and Human Services, Public Health

Service, National Institutes of Health, Publication No. 85–23, Guide for

the care and use of laboratory animals, Revised 1985.

(17) Witkop, C. J. et al. (eds), The Metabolic Basis of Inherited Diseases, McGraw-Hill, NY, pp. 301–346 (1983).