EPA-560/1-76-005
     CHEMICALS WHICH HAVE BEEN
              TESTED FOR
          NEUROTOXIC  EFFECTS
                   MAY 1976
                FINAL REPORT
             ENVIRONMENTAL PROTECTION AGENCY
               OFFICE OF TOXIC SUBSTANCES
                 WASHINGTON, D.C.

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EPA-560/1-76-005
                  CHEMICALS WHICH HAVE BEEN TESTED
                       FOR NEUROTOXIC EFFECTS
                            Final Report
                              May 1976
                     Contract 68-01-3255, Task 4
                     Office of Toxic Substances
                    Invironmental Protection Agency
                       Washington, D.C.  20460
                          Frank Letkiewicz
                           Project Officer

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                 NOTICE

   This report has been reviewed by the
Office of Toxic Substances, EPA, and
approved for publication.  Approval does
not signify that the contents necessarily
reflect the views and policies of the
Environmental Protection Agency, nor does
mention of trade names or commercial pro-
ducts constitute indorsement or recommen-
dation for use.

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                                PREFACE

     This document presents information obtained from the literature on
substances that have been tested for neurotoxic effects.  Damage to the
central and/or peripheral nervous systems is an important category of
hazards from chemicals that enter the human environment.  A variety of
chemicals are known to be neurotoxic and there are many reported incidents
of chemically induced neurotoxicity in humans.  However, this category of
hazards has received far less attention than other hazards such as cancer
and birth defects.
     Recognizing this, the office of Toxic Substances (OTS) initiated a
task to collect reports of chemicals tested for neurotoxic activity
published in the scientific literature.  One intention of this task was to
develop a data base which could be utilized by the Office of Toxic Substances
in developing techniques for correlating reported effects (in this case neuro-
toxic effects) of substances with their chemical and/or physical properties.
At the same time, it was recognized that the data base developed would be
the first such compilation of information, and, as such, could find use
an.ong other persons or organizations concerned with adverse health effects
induced by chemicals.  Therefore, it was decided that the collected data
should be made available through publication.  It should be noted that
reports of tests for neurotoxic effects yielding both positive and negative
findings were extracted for this document.
     For the purpose of this task, neurotoxic effects are defined as
structural or functional damage to the nervous system, such as, histological
changes in nerve tissue, grossly observable dysfunction (e.g., paralysis),
ir.strumentally detectable dysfunction (e.g. electroencephalographic changes),
and performance dysfunction (e.g., using the rotating rod test for balance).
Qualitative effects such as hallucinations or mental depression were also
included in the case of reports on humans.  Teratological findings affecting
the offspring of pregnant females exposed to chemical substances were included.
Biochemical disturbances in the nervous systems produced by chemical
substances were generally not included; some exceptions are:  inhibition of
the enzyme cholinesterase and other esterases present in the nervous system,
GABA levels, and serotonin levels.

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     Problems of terminology were met in the literature at every stage of
the task.  Technical terms were found to be used in different senses, often
imprecisely, so that the degree and often the type of dysfunction was dif-
ficult to infer from many of the reports.  In such cases it was impossible
to modify the terms to conform to a meaningful, consistent nomenclature.
Thus, the descriptive medical terms used in the extracts are generally the
authors' own.
     This problem was most apparent in the literature search.  Most of the
secondary sources are not indexed by general terms for neurotoxicity.
It was necessary, therefore, to perform much of the literature searching
by scanning primary publications directly.  Practical constraints resulted
in the ability to scan only select journals, and many of those only for
select years of publication.  However, the selection of journals and other
sources searched provided for a reasonably thorough coverage of the subject.
The sources employed in the literature search are listed in the appendix.
                                   ii

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                      Table of Contents




                                                        Page




Preface   	  i






Introduction	 .  . iv
Extracts
Index   	1231
Appendix	1330
                              iii

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                             Introduction

     The text of this document consists of a series of brief extracts of
studies in which chemicals were tested for neurotoxic effects.  A separate
extract was prepared for each chemical reported in each article.  The
extracts, which are arranged in alphabetical order by subject chemical,
are a structured arrangement of data as presented in the original articles.
Each review contains, if it was available, the following information:

Compound;  the subject chemical of the study.  The chemical nomenclature
     used is that established by the Chemical Abstracts Service for
     their 8th Collective Index.
Reference;  a complete bibliographic citation, consisting of author(s),
     journal, volume, issue, pages and year of publication.
Observed neurotoxic effects;  reported dysfunctions and structural changes
     of the nervous system effected by exposure to the subject compounds.
Animals;  species,  variety, age, sex, and weight of the test animals.
Preparation and Dose or History of Patient;  preliminary treatment of test
     animals, quantity of compound administered, and duration of exposure.
Route and Site;   method and location of administration of the compound.
Control Information;  preparation and treatment of control animals.
Duration of experiment;   period of time during which the test animals
     were observed.
Exam. Type;  general technical procedures employed in the study.
                                  iv

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     The following is a list of  the abbreviations  used  in the extracts.
atm - atmosphere
av - average
CD,.. - the dose which was calculated
  ''    to cause convulsions in 50%
       of the animals
cmpd - compound
CN!> - central nervous system
d •• day
ED,.. - the dose which was calculated
  '     to be effective for 50% of the
       animals for the test employed
F -• female
g -• gram
GAM - gamma-aminobutyric acid
grp - group
in;i - injection
I.]'. - intraperitoneal
I.Tub. - intubation
IU - international unit
I.V. - intravenous
kg - kilogram
LDrn - the dose which was calculated
       to be lethal to 50% of the
       animals
M -• male; mole
MA(! - Maximum acceptable concentration
mcCi - microcurie
meg - microgram
mEq - milliequivalent
mg - milligram
min - minute
ml - milliliter
mM - millimole
mo - month
ns - not stated
PNS - peripheral nervous system
P.O. - per os
ppm - parts per million
sacr. - sacrificed
S.C. - subcutaneous
sec - second
soln - solution
TLV - threshold limit value
trtd - treated
untrtd - untreated
wk - week
w/v - weight/volume
yr - year
     An index has been prepared to facilitate  the use  of  this  document.   To
loc:ate a compound in the text, one should first look it up in  the  index.
The. index will identify the page(s) of the text dealing with the compound.
It will also identify the class of chemical, selected  neurotoxic effects
induced by the chemical, and reported human exposure to the chemical.  The
ind.ex can also be used to identify the chemicals in a  given class,  chemicals
which induce selected neurotoxic effects, and  chemicals for which  incidents or
studies involving humans have been reported.

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 COMPOUND:       Acetaldehyde

                000075070

 REFERENCE:      Schneider,  F.H.
                Biochem.  Pharm.  23:223-229,  1974.
OBSERVED NEUROTOXIC EFFECTS:
Total catecholamines expressed as micromoles of
epinephrine.  Rate of release Increased with time of
exposure to acetaldehyde; concentration-
response curve shifted to left with acetaldehyde
but not with carbachol.  When cone, of acetaldehyde
was lowered below 2 x 10"  M, delay of peak
response increased.  Withdrawal of acetaldehyde
returned catecholamine levels to normal.
COMPOUND:    Acetaldehyde, chloro-, (2,4-dinitrophenyl) hydrazone

            005135808

REFERENCE:   Ambrose, A.M.,  Borzelleca,  J.F.,  Larson,  P.S., Smith, R.B., Jr.,
            and Hennigar, G.R.
            Tox.  Appl.  Pharm.  8:472-481,  1966.

OBSERVED NEUROTOXIC EFFECTS:  Subacute:   1500  and higher levels, hindlimb rigidity.
                              Chronic:   1000 ppm, at 15th mo. episodic hindlimb
                                        ataxia,  later convulsions, no lesions
                                        reported at autopsy.
ANIMALS:   Bovine adrenals.in vitro.
                                                                                          ANIMALS:     Dogs, purebred beagle, 2 M and 2 F, age  6 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          Adrenals  10-20  g perfused with  Tyrode  soln at
                          37°  containing  acetaldehyde  at  1.5 x 10   to 2.5
                          x 10  M.  Perfusate was analyzed for  total catecholamines.
                                                            PREPARATION AND DOSE
                                                            or HISTORY OF PATIENT:  0,  100,  400,  1000 ppm in diet for 2 yr (chronic toxicity);
                                                                                   Subacute studies 0-3000 ppm.
ROUTE AND SITE:  Perfusion was  retrograde  via  adrenal vein, at  10 ml/min.

CONTROL INFORMATION:      Some adrenals were  perfused with carbachol.
                                                            ROUTE AND SITE:   oral

                                                            CONTROL INFORMATION:    Zero treatment
DURATION OF EXPERIMENT:    About  2  hr.

EXAM. TYPE:  Biochemical
                                                            DURATION OF EXPERIMENT:   2 yr

                                                            EXAM.  TYPE:  Behavior, biochemistry (clinical), autopsy

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COMPOUND:    Acetamide, 2-fluoro-N-methyl-N-l-napthyl

             005903139

REFERENCE:   Hashimoto, Y., Noguchi, T., Mori, T. and Kltagawa, H.
             Tox.  Appl. Pharm. 13:174-188, 1968.
                                                                                              COMPOUND:    Acetanilide,  2'-(2-bromo-3-thienyl)thio-
REFERENCE:
               Grol, C.J. and  Rollema,  H.
               J. Med. Chem. 18:857-861,  1975.
OBSERVED NEUROTOXIC EFFECTS:Toxic or lethal doses produced EEC's with no evidence
                           of convusive pattern, but a flat wave pattern before death
                           indicated severe brain impairment.  Toxicity, judged small,
                           was attributed to the metabolite, monofluoroacetic
                           acid.
OBSERVED NEUROTOXIC EFFECTS:   This compound gave positive results  in  a
                               neurotoxicity screening test in which the
                               criteria were ptos'is, sedation and catalepsy.
ANIMALS:      Eats,  albino, M, 150 g                       Rabbits
             10  Mice,  M,  20  g                             Cats
             10  Guinea-pigs, albino, M, 350 g             Dogs
             In  vitro                        •             Monkeys
PREPARATION AND  DOSE
or HISTORY OF PATIENT: Manyschedules and dosages, acute and chronic; some animals
                      prepared surgically.
                                                                                              ANIMALS:
                                                                                                             Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    40 mg/kg.
ROUTE AND SITE:  Various

CONTROL INFORMATION:   Various
ROUTE AND SITE:      I.P.

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:  Many:   EEC relevant  here.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:     Behavior screening tests

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COMPOUND:    Acetanllide,  4'-(4-(3-dimethyl amino)propyl)-l-piperazinyl)-
                                                                                              COMPOUNO:    Acetanilide,  2'-(3-thienyl)thio-
REFERENCE:  Benitz, K.F.  and Kramer,  A.W.
            Fd. Cosmet.  Toxicol.    6:   125-133,  1968.
                                                                                              REFERENCE:
               Grol, C.J. and Rollema,  H.
               J. Med. Chem. 18:857-861,  1975.
OBSERVED NEUROTOXIC EFFECTS:    Hydrocephalus,  oedema,  hyperaemla and  lesions  of  the
                               brain.   Vacuolization of the  choroid plexus.
OBSERVED NEUROTOXIC EFFECTS:  This  compound gave positive results in a
                              neurotoxiclty screening test in which the
                              criteria were ptosis, sedation and catalepsy.
ANIMALS:    Rats (CFN and Sherman),  Mongolian Gerbils,  Swiss  Albino Mice,
            African Green Monkeys  and  Miniature  Pigs  (Pitman-Moore strain)
                                                                                              ANIMALS:
               Rats and mice, no  details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    60-488  mg/kg/d
PREPARATION AND DOSE
or HISTORY OF PATIENT:   40 mg/kg.
ROUTE AND SITE:   Oral,  gavage

CONTROL INFORMATION:    ns
ROUTE AND SITE:     I.P.

CONTROL INFORMATION:     ns.
DURATION OF EXPERIMENT:    Serial Sacr.  2 d  to  50  wk

EXAM. TYPE:   Histology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:     Behavior  screening tests

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COMPOUND:    Acethydrazide

            001068571

REFERENCE:   Jenney,  E.H.  and Pfeiffer,  C.C.
             J.  Pharm.  Exp.  Ther.  122:   110-123,  1958.


OBSERVED NEUROTOXIC EFFECTS:    Convulsions
COMPOUND:
Acetic acid, bis(p-chlorophenyl)-    (DDA, a metabolite of DDT)
REFERENCE:   Bleiberg,  M.J.,  Cefaratti, M.,  Klinman, N. and Kornblith, P.
             Tox.  Appl. Pharm.  4:292-312, 1962.
                                                                                          OBSERVED  NEUROTOXIC  EFFECTS:
                                 Blocked patellar reflex at doses over 2 mg/rabbit;
                                 in vitro block on choline acetylase, probably at
                                 the acetate activating .step, in brain, and blocked
                                 in vitro peristalsis of gut preparations.
                                 Interpreted in terms of mode of action of toxicity
                                 of DDT.
ANIMALS:    Mice, Harlan, 19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    2.1 mM/kgm
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:   ns
ANIMALS:     (1) Rabbits,  white, 2.5-3.5 kg, surgically prepared.
             (2) Rabbit small intestine in vitro.
             (3) Guinea-pig ileum in vitro.
             (4) Rabbit brains, powdered and acetone-dried.
PREPARATION AND DOSE
or HISTORY OF PATIENT:       Sodium salt of DDA used.
                            (1) In vivo single or successive doses 0.4-2.3 mg/rabbit,
                          (2&3) 10"^ to 10"-* M in medium, various schedules and
                                combinations.
                            (4) AChE inhibition by 10 mcgM DDA in vitro.

ROUTE AND SITE:   In vivo:  intra-arterial, lumbar.

CONTROL INFORMATION:   Yes
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:      Various

EXAM. TYPE:  Biochemistry, electrophysiology

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COMPOUND:   Acetic acid,  cyano-,  hydrazide
REFERENCE:   Jenney,  E.H.  and  Pfeiffer,  C.C.
             J. Phann.  Exp. Ther.  122:   110-123,  1958.
OBSERVED NEUROTOXIC EFFECTS:    Convulsions
COMPOUND:   Acetic acid,  (2,3-dichloro-4-(2-methylenebutryl) phenoxy)-

            000058548

REFERENCE:  Schneider, W.J. and Becker, E.L.
            Arch.  Inter. Med. 117:715-717,  1966.



OBSERVED NEUROTOXIC EFFECTS:     Acute  deafness.
ANIMALS:    Mice, Harlan, 19-21 g
                                                                                          ANIMALS:      5 Humans:  4 F,  1M, age  20-76
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1.8 mM/kgm
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                      150-700 mg.
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:  ns
ROUTE AND SITE:   I.V.  and oral

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:  Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:     ns.

EXAM. TYPE:  Clinical,  behavior,  urinalysis
                                                                                                                                       10

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COMPOUND:   Acetic acid, 2,4-dichlorophenoxy-
                                                                                            COMPOUND:
             Acetic acid,  2,4-dichlorophenoxy-
REFERENCE: Desi, I. and Sos.J.
           Acta Med. Acad. Sci.  Hung. 18:   429-433,  1962.
REFERENCE:   Desi,  I.,  Sos,  J.  and Nikolits, I.
            Acta  Physiol. Acad.  Sci.  Hung.  22:  73-80, 1962.
OBSERVED NEUROTOXIC EFFECTS:   Acute studies:   reversible EEC inhibition.   Chronic:
                              gradual slowing of EEC and shortening of  desynchron-
                              ization times;  disordered conditioned reflexes
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                               EEC:   Lower frequency and greater amplitude at
                               24 hr; after 5 d, big, slow, toxic waves predominated.
                               Little or no desynchronization response to reticular
                               formation stimuli.  The authors concluded that  DCPA
                               acted first on the cortex; the thyroid and cardiac
                               disturbances being attributed to secondary subcor-
                               tical lesions.
ANIMALS:    24 rats, white, M, 240-250 g
           4 cats
           2 dogs

PREPARATION AND DOSE
or HISTORY OF PATIENT:   200 mg/kg/d (rat I.P. LD5Q reported as 640 mg/kg)
ANIMALS:    15  cats,  2.5-3.5 kg,  11 treated, all surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:   100 mg/kg/d 11 d
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:  Untreated
ROUTE AND SITE:   ns

CONTROL INFORMATION:    4 cats
DURATION OF EXPERIMENT:  Up to 6 d

EXAM. TYPE:  Behavior, electrophysiology
DURATION OF EXPERIMENT:    15 d

EXAM. TYPE:    EEC
                                         11
                                                                                                                                       12

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COMPOUND:  Acetic acid,  (2,4-dichlorophenoxy)-

           OOOOQA7S7

REFERENCE:  Goldstein,  N.P., Jones,  P.H.  and Brown, J.R.
            J. Am. Med.  Assn. 171:1306-1309, 1959.
OBSERVED NEUROTOXIC EFFECTS:
       Peripheral neuropathy.  Delayed and prolonged
       polyneuritis, especially of lower limbs, slow
       nerve conduction, incomplete recovery.
ANIMALS:    3 Humans
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Exposure during horticulture.
ROUTE AND SITE:     Skin absorption

CONTROL INFORMATION:       ns.



DURATION OF EXPERIMENT:    3 yr.

EXAM.. TYPE:   Clinical,  electophysiology
                                          13
COMPOUND:  Acetic acid, (2,4-dichlorophenoxy)-, compound with dimethylamine  (1:1)

           002008391

REFERENCE:  Berkley,  M.C. and  Magee,  K.R.
           Arch.  Int.  Med.  111:351-352,  1963.


OBSERVED NEUROTOXIC EFFECTS:   Peripheral neuropathy, mainly sensory, gradual
     imporvement  after "several weeks".
                                                                                               ANIMALS:'   1  Human, M,  age  39
                                                                     PREPARATION AND DOSE
                                                                     or HISTORY OF PATIENT:   Exposure to agricultural spray
                                                                     ROUTE AND SITE:   skin contact, probable inhalation

                                                                     CONTROL INFORMATION:     None
                                                                     DURATION OF EXPERIMENT:      Follow-up for 9 mo.

                                                                     EXAM.  TYPE:  Physical; clinical laboratory; electromyography

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COMPOUND:  Acetic acid, (ethylene-dinitrilo)  tetra-

           000060004
REFERENCE:
              Swenerton,  H.  and Hurley,  L.S.
              Science 173:62-63, 1971.
COMPOUND:  Acetic acid, fluoro-, sodium salt
           000062748
REFERENCE:
             Corsi,  A.  and Granata,  A.L.
             Biochem.  Pharmacol.  16:1083-1089, 1967.
OBSERVED NEUROTOXIC EFFECTS:  Hydrocephalus,  anencephalus,  hydranencephalus,
                              exencephalus,  prevented by 1000  ppm of  zinc  in  diet
                              but not by 100 ppm.   Author  suggests the congenital
                              anomalies caused,  may be due to zinc deficiency.
OBSERVED NEUROTOXIC EFFECTS:    No effect on respiration of brain mitochondria
    with any substrate.   No effect on oxidation of glucose.  Citrate found
    higher in brain homogenates from trtd rats, but this could not be reproduced
    in vitro.
ANIMALS:   Rats,.S-D, F, 210 g.
                                                                                             ANIMALS:
             Rats, Uistar
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                              (1)   2% or 3% in diet throughout.
                              (2)   3% in diet from d 6 to 21,  or  d  6-14  of
                                   pregnancy, followed by control diet until
                                   term.
                              (3)   3% in diet, plus 1000 ppm of zinc  from d 6-21.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   Rats fed control diet,  without compound.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20 mg/kg one dose, rats killed after 1 hr, brain  mitochondria
    incubated in vitro with various substrates, slices and homogenates  of  brain
    cortex incubated with/without glucose.
ROUTE AND SITE:  i.p., incubation In vitro.

CONTROL INFORMATION:   Laboratory controls
DURATION OF EXPERIMENT:   Pregnancy

EXAM. TYPE:  Teratology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry
                                        15
                                                                                                                                     16

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COMPOUND:  Acetic acid, imlnodi

           000142734

REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment  caused  excitation  or  depression of
                               neuronal activity.   Excitatory  ranking:   glutamic,
                               S-aminoglutaric,  aspartic, cysteic,  cysteine-
                               sulfinic acids, 8-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic  acids.
                               Depressant ranking:   B-alanine,  GABA,  taurine,
                               N-methyl-B-alanine,  6-amino-B-hydroxybutyric,
                               glycine, a-alanine,  6-aminovaleric,  B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
ANIMALS:    Cats, surgically prepared  to  exposed motoneurones,  Renshaw cells or
            dorsal horn interneurones  in  lumbar cord.


PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
COMPOUND:   Acetic acid,  lead  (2+)  salt

            000301042

REFERENCE:  Brown, S., Dragann, N. and Vogel, K.H.
            Arch. Env. Hlth. 22:370-372, 1971.
OBSERVED NEUROTOXIC EFFECTS:  No significant effects on learning or memory
     of rats as tested in water-filled T-maze.
                                                                                                ANIMALS:   Rats, S-D, M, aged 8 d to 5 wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   100 mg/kg/d, 3-4 in. most cases.
ROUTE AND SITE:   Topical,  iontophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:        I.P.

CONTROL INFORMATION:     Rats sodium acetate treated.
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:  Behavior
                                            17
                                                                                                                                        18

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COMPOUND:      Acetic acid,  lead  (2+) salt

               000301042

REFERENCE:     Carson, T.L.,  Van Gelder, G.A. Karas, G.C. and Buck, W.B.
               Env.  Hlth. Persp. 7:233-237, 1974.
OBSERVED NEUROTOXIC EFFECTS:
      Poor performance of auditory discrimination task
      by adults, no change in reinforcement behavioral
      task.  Lambs, no change in closed-field maze task,
      slow learning of nonspatial two-choice visual
      discrimination tasks at 10-15 mo.  of age after
      prenatal exposure.
ANIMALS;.   .    Sheeps,  3  grps. of  5 adults and 5 grps of 4 lambs.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Adults:  100 mg/kg/d for 9 wk,  120 and 230 mg/sheep/d
         for 27 wk.
 Lambs:  Exposed prenatally, 16 or 34 mcl/100 ml of blood,
         postnatal 2-16 mg/kg/d in diet.
ROUTE AND SITE:   Oral,  transplacental

CONTROL INFORMATION:  Untreated  controls



DURATION OF EXPERIMENT:   Up  to  15 mo.

EXAM. TYPE:   Behavior
                                            19
                                                                       COMPOUND:  Acetic acid,  lead  (2+)  salt
                                                                                  000301042
                                                                       REFERENCE:   Goiter,  M.  and  Michaelson,  I.A.
                                                                                    Science  187:359-360,  1975.
OBSERVED NEUROTOXIC EFFECTS:   More active than controls; more norepinephrine,
     no change of dopamine in brains (opposite findings to previous report,
     see under Lead carbonate, Sauerhoff and Michaelson.
                                                                                                ANIMALS:   Rats, S-D, F, pregnant 16 d
PREPARATION AND DOSE
or HISTORY OF PATIENT:  (B)  Neonates 1 mg of Pb in 0.1 ml  for  15  d,  then 40 ppm
     Pb in diet.
     (C)  Dams 5% Pb-acetate in diet till neonates 16 d old,  then  40  ppm Pb
     in diet;  neonates 40 ppm in diet from d 16, weaning.


ROUTE AND SITE:   oral

CONTROL INFORMATION:  (A)  Dams untrtd; neonates 0.1 ml of  2% Na-acetate d 1-15,
     then weaned onto normal diet.


DURATION OF EXPERIMENT: Serial sacr to 81 d of age of neonates.

EXAM. TYPE:  Behavior, biochemistry
                                                                                                                                         20

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 COMPOUND:
 REFERENCE:
Acetic acid, lead (2+) salt

000301042

Michaelson, I.A. and Sauerhoff, M.W.
Env. Hlth. Persp. 7:201-225, 1974.
COMPOUND:   Acetic acid,  lead  (2+)  salt

           000301042

REFERENCE:  Michaelson,  I.A. and Sauerhoff, M.W.
            Toxicol. Appl.  Pharin.  28:88-96, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                 30% less food eaten by lactating dams, offspring
                 had 85% more lead than controls in cerebellum and
                 cerebral cortex with 10-20% less DNA in cerebellum at
                 3 wk of age, paraplegia and cerebellar damage after
                 eating lead diet.  After 25 ppm lead in diet
                 encephalopathy less severe:  hyperactivity,
                 tremors, stereotype behavior, 15-20% decrease of .
                 dopamine but no change in 5-HT, GABA or NE, no
                 "debilitating histopathology."
OBSERVED NEUROTOXIC EFFECTS:   Histological lesions in the cerebellum  and
                               paraplegia.  Hyperactivity, aggressiveness
                               and tremors.
ANIMALS:
               Rats,  Forton,  newborn with dams.
                                                                                                ANIMALS:    Rats, S-D pregnant and offspring.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
           4.5 or 5% in diet fed to dams and, at weaning, to litters.
           Diet gave 2.73% Pb, and produced milk containing 25 ppm
           Pb.  Some diets adjusted to contain 25 ppm Pb.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5% in diet to mothers immediately after birth, when
                         offspring were 16 d old, mother's diet was changed  to
                         25 ppm lead to compare to that in maternal milk.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:
           Diets without lead, pair-feeding controls
                                                                                  ROUTE AND  SITE:    Oral

                                                                                  CONTROL  INFORMATION:  Control  sucklings,  no  treatment to mothers
DURATION OF EXPERIMENT:    30 d

EXAM. TYPE:     Behavior,  biochemistry
                                                                                  DURATION OF  EXPERIMENT:   Sucklings  sacr  at 25 d age.

                                                                                  EXAM. TYPE:  Histology
                                            21
                                                                                                                                         22

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COMPOUND:  Acetic acid, lead (2+) salt

           000301042

REFERENCE:  Schlaepfer, W.W.
            J. Neuropath. Exp.  Neurol. 28(3):  401-418,  1969.


OBSERVED NEUROTOXIC EFFECTS: Segmental demyelination and remyelination in peripheral
                             nervous system and spinal nerve roots.   Wallerian degen-
                             eration present in distal peripheral nervous system and
                             in posterior nerve roots.
                                PNS:  6/14 axonal or Wallerian degeneration and
                                      9/14 segmental demyelination and remyelination.
                                Spinal cord:  Wallerian and segmental change.
COMPOUND:  Acetic  acid,  lead  (2+)  salt

           000301042

REFERENCE:   Silbergeld,  E.K.  and  Goldberg,  A.M.
             Life Sci.  13:1275-1283,  1973.


OBSERVED NEUROTOXIC EFFECTS:     Induced hyperactivity (not dose-related), peripheral
                                 ataxia  ar.d  splayed gait.  10 mg/ml for 90 days
                                 produced convulsions and death.
ANIMALS:    18 Rats, S-D, 200-250 gm.
ANIMALS:     Mice,  age 12 hr
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1% soln., avg. 60 cc/rat/d.
PREPARATION AND DOSE
or HISTORY OF PATIENT: 2, 5, or 10 mg/ml in drinking water
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   3 Rats untreated.
ROUTE AND SITE:   Oral

CONTROL  INFORMATION:   Age and dose matched with sodium acetate
DURATION OF EXPERIMENT:   Serial sacr 3-18 mo.

EXAM. TYPE:  Ultrastructural, histochemistry
DURATION OF  EXPERIMENT:  90 d

EXAM. TYPE:  Behavior
                                            23
                                                                                                                                         24

-------
 COMPOUND:  Acetic acid, mercaptophenyl-, ethyl ester,  S-ester with 0,0-dimethyl
            phosphorodithioate
 REFERENCE:   Sherman, M., Ross, E. and Chang, M.T.Y.
             Tox. Appl. Pharm. 6:147-153, 1964.


 OBSERVED NEUROTOXIC  EFFECTS:  (D   Convulsions  followed  in many by death within
                              18 hr.   Survivors were lethargic for 6-19 hrs.
                              post treatment.   (2)  50% cholinesterase inhibition
                              by dose <50 ppm.
COMPOUND:  Acetic acid, thallium (1) salt

           000563688

REFERENCE:  Spencer, P.S., Peterson, t.K.,  Madrid,  R.  and Raiiie,  C.3.
            J. Cell Biol. 58:  79-95,  1973.
OBSERVED NEUROTOXIC EFFECTS: Mitochondria  in  axons of peripheral nerve fibers were
                             enlarged  after 2 hours,  then mitochondria swelled to
                             become axonal vacuoles,  which coalesced, and the
                             outer membranes  had affinity for thallium which is
                             electron-dense.   Swelling made myelin retract from
                             nodes of  Ranvier,  but there was no degeneration, and
                             conduction was not lost.  There were similar changes,
                             but less  severe, in dorsal root ganglia and central
                             fibers, but not  in other cell types.
ANIMALS:     Cockerels, White Leghorn, single-comb, 10-50/grp, 12 d old
ANIMALS:    In vitro cross-sections  of  fetal  mouse spinal cord with dorsal root
            ganglia, 14 d  in utero
PREPARATION'AND DOSE
or HISTORY OF PATIENT: (i)  Acute:   LD   (56.6 mg/kg)  in  gelatin  capsule.
                       (2)  Subacute:    50-800 ppm in  feed.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   10 meg/ml
2 x 10~5M
ROUTE AND SITE:    Oral

CONTROL INFORMATION:     Untreated diet.
ROUTE AND SITE:  in vitro

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:  1 wk

EXAM.  TYPE:   Mortality,  behavior,  blood ChE
DURATION OF EXPERIMENT:    Cultures  grown  for 12 wk,  exposed to thallium for up to 4  d

EXAM.  TYPE:   Histology
                                         25
                                                                                                                                     26

-------
 COMPOUND:  Acetic acid, p-tolyl-, 3-alpha-tropanyl ester
 REFERENCE:    Friess,  S.L. and Anderson, J.B.
              Tox. Appl. Pharm. 22:   208-212, 1972.
                                                            COMPOUND:    Acetic acid,  zinc  salt
                                                                         000557346

                                                            REFERENCE:       Prakash,  N.J.,  Fontana,  J.  and Henkin, R.I.
                                                                             Life Sci.  12(1):249-259, 1973.
OBSERVED NEUROTOXIC EFFECTS:
  With the above compound   or its quaternary methiodide
separately, there was reversibility of induced blockade
on washing depending on the extent of N-substitution,
quaternary methiodide being more reversible than the
tertiary ester.  But 1 mM of tropine-£-tolylacetate
added to 5mM of its quaternary methiodide halved the
reversibility of quaternary methiodide blockade.  More
than 1 mM of tropine-2.-t°lylacetate had no more effect.
OBSERVED NEUROTOXIC EFFECTS:     At  concentrations over 0.1 mM, Zn"1"1" completely
                                 inhibited (Na+ + K+) ATPase.  Inhibition involved
                                 blockage of norepinephrine and choline uptake.
ANIMALS:      In vitro  excitable nodes of Ranvier  in single  fibers  of frog  sciatic
              nerve.
                                                            ANIMALS:
                                                                              Rat brain synaptosomes in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:    5mM for separate  incubations with  tropine-p_-tolylacetate and
                         its quaternary methiodide;  tropine-£-tolylacetate:the quater-
                         nary methiodide ratios  in  mixed incubations 1:5,  2:5, and
                         3:5 in mM.
                                                            PREPARATION AND DOSE
                                                            or HISTORY OF PATIENT:
                            Zn acetate added to medium in various expts.
ROUTE AND SITE:   in vitro

CONTROL INFORMATION: Laboratory
                                                            ROUTE AND SITE:   in vitro

                                                            CONTROL INFORMATION:   Lab
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:   Incubation,  removal, washing, observing by electrophysiology
                                                            DURATION OF EXPERIMENT:     Minutes

                                                            EXAM. TYPE:       Biochemistry
                                          27
                                                                                                                                       28

-------
COMPOUND:  Acetone

           000067641
REFERENCE:
                Ross, D.S.
                Ann. Occup. Hyg.  16:73-75, 1973.
OBSERVED NEUROTOXIC EFFECTS:   Urine level at least 4.6-7.15 mg% after exposure,
                              0.39-1.29 mg% 7 d later.  Dizziness, unconsciousness,
                              with recovery.
                                                                                            COMPOUND:   Acetone,  allophanylhydrazone
REFERENCE:  Jenney, E.H.  and Pfeiffer, C.C.
            J. Pharm.  Exp.  Ther.  122:  110-123, 1958.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:    7 Human   cases  of  industrial exposure
                                                                                            ANIMALS:    Mice, Harlan,  19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:     900-12,000 ppm  2 min - 4 hr  (acute exposure).
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2.5  mM/kgm
ROUTE AND SITE:  inhalation

CONTROL INFORMATION:      None
ROUTE AND SITE:  i.p.

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:    7  d  ttmt  afterwards

EXAM.  TYPE:Clinical,  urinalysis
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:   Clinical
                                          29
                                                                                                                                       30

-------
COMPOUND:   Acetone semicarbazone

            000110203

REFERENCE:  Jenney, E.H. and Pfeiffer, C.C.
            J. Pharm. Exp. Ther. 122:  110-123, 1958.


OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:    Mice, Harlan, 19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.78 mM/kgm
ROUTE AND SITE:   i.v.

CONTROL INFORMATION:   ns



DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
                                          31
COMPOUND: Acetone, thiocarbohydrazone
REFERENCE:   Jenney,  E.H.  and Pfeiffer, C.C.
             J.  Pharm.  Exp.  Ther. 122:  110-123, 1958.
OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:     Mice,  Harlan,  19-21 g
PREPARATION AND DOSE
or HISTORY Of PATIENT:    0.27mM/kgm
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:   ns



DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:   Clinical
                                                                                                                                      32

-------
COMPGUiiD:
            Acetone, thiocarbohydrazonodi-
REFERENCE:   Jenney,  E.H.  r,nd Ffeiffer,  C.C.
             J.  Pharra.  Exp.  Thor.  122:   110-123, 1958.
OBSERVED KEUROTOXIC EFFECTS:    Convulsions
ANIMALS:    Mice, Harlan,  19-21  g
PREPARATION AND DOSE
or HISTORY Of PATIENT:   0.55
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:  ns



DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Cllulr.al
                                           33
COMPOUND:    Acetone  thiosemicarbazone

             001752303

REFERENCE:   Jenney,  E.H.  and Pfeiffer, C.C.
             J.  Pharm.  Exp.  Ther.  122:  110-123, 1958.


OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:    Mice, Harlan,  19-21  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.18 mM/kgm
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical

-------
COMPOUND:  Acetophenone, 2-chloro

           000532274

REFERENCE:    Rutledge,  C.O. and Dietrich, R.A.
              Biochem. Pharmacol. 20:193-201, 1971.
OBSERVED NEUROTOXIC EFFECTS:   Inhibited norepinephrine catabolism.  Inhibited
                              formation of phenolic acids and enhanced that of
                              phenolic glycols.  In vitro aldehyde dehydrogenase
                              was inhibited  (prevented with glutathione, reversed
                              with sulfhydryl reagents).
                                                                                           COMPOUND:
            Acetophenone, thiocarbohydrazone
REFERENCE:   Jenney,  E.H. and Pfeiffer, C.C.
             J.  Phartn.  Exp. Ther. 122:  110-123,  1958.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:.   Rabbits,  adult M,  2.0-2.5 kg.
ANIMALS:     Mice,  Harlan,  19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:     In vivo pretreatment:   300 mg/kg in 100% EtOH  (1.33 g/kg) .
                          In vitro  incubation of  brain cortex xlices  (150 mg)
                          with  and  without 2-chloroacetophenone.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    1.2 tnM/kgm
ROUTE AND SITE:    I.P.;  addition  to medium.

CONTROL INFORMATION:   Pretreatment:   ethanol  only.   In vitro:  HC1.
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:    In vitro:   30-40 min.

EXAM. TYPE:    Biochemical
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
                                        35
                                                                                                                                     36

-------
COMPOUND:  Acrylamlde

           000079061

REFERENCE:   Auld,  R.B.  and  Bedwell,  S.F.
             Can. Med. Assn.  J.  96:652-654,  1967.
                                                                                             COMPOUND:
                                                                        Acrylamide
                                                                        000079061
                                                              REFERENCE:
                                                                              Barnes, J.M.
                                                                              Erie.  J.  Indust.  Med.  27:147-149, 1970.
OBSERVED NEUROTOXIC EFFECTS:
Contact dermatitis with polyneuropathy of extremities
attributed to sympathetic overactivity.  Complete
recovery in 3 mo. "Believed" to have resulted
from acrylamide, and claimed as the first human
case-report.
                                                                                             OBSERVED  NEUROTOXIC  EFFECTS:
(1) Most rats died within a few days.   The
rest had signs of gross general weakness.
(2) Within four weeks, signs of disability
appeared; marked by eight weeks.
ANIMALS:   Human:   1  case-report, M aged  21 yr.
                                                              ANIMALS:   Rats> Porton(  albino
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Industrial  exposure  to  10%  aqueous  solution  35 hr/wk,
                          signs  after 2 wk, hospitalized  after  3 mo.
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:
                                                                                        (1)  Two doses,  100 mg/kg
                                                                                        (2)  400 ppm
ROUTE AND SITE:    Skin  contact,  especially  face  and  forearms

CONTROL INFORMATION:       None
                                                              ROUTE AND SITE:    Oral

                                                              CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:    Observations  total  6.5 mo.

EXAM. TYPE:     Clinical,  hospital  laboratory
                                                              DURATION OF EXPERIMENT:    10 wk

                                                              EXAM.  TYPE:   Behavior, physiology
                                          37
                                                                                                                                       38

-------
 COMPOUND:  Acrylamide

           000079061

 REFERENCE:   Edwards,  P.M.
             Br.  J.  Ind.  Med.  32:31-38,  1975.
                                                   COMPOUND:  Acrylamide

                                                             000079061
                                                   REFERENCE:
                                                                  Fullerton, P.M. and Barnes, J.M.
                                                                  Br. J. Indust. Med. 23:210-221, 1966.
OBSERVED NEUROTOXIC EFFECTS:
                                 (1)   Rats:  Ataxia, waddling  gait, hindlitnb weakness.
                                 (2)   Hens:  Slight ataxia; degeneration  of sciatic
                                            and peroneal nerve  fibers and medullary
                                            and  cervical spinocerebellar tracts.
                                 (3,4)   Frogs,  goldfish:  sublethel effects varying
                                                         with dosage-.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
                                                                                 Ataxia and limb weaknesses at  single  or repeated
                                                                                 doses of 25-100 mg/kg  (gavage)  or  100-400 ppm
                                                                                 (diet).  Severe cases  20%.slower nerve  conduction.
                                                                                 Degeneration of myelin and axis cylinders in
                                                                                 long fibers of peripheral nervous  system.   On
                                                                                 stopping treatment, clinical recovery,  normalized
                                                                                 conduction, and some histological regeneration.
ANIMALS:     (i)   Rats,  Porton, M,  200  g
             (2)   Hens,  Star  Cross,  adult,  3  leg
             (3)   Frogs,  R. Temporaria, M
             (4)   Goldfish
PREPARATION AND DOSE
or HISTORY OF PATIENT:      Dose varied with  species
                                                                                             ANIMALS:   Rats, Porton, M and F, various ages.
                                                  PREPARATION AND DOSE
                                                  or HISTORY OF PATIENT:
ROUTE AND SITE:  (1)  Oral,  I.P.
                 (2)  Oral
CONTROL INFORMATION:  „  u.  ,
                     Vehicles only
                          (1) 100 mg/kg, one dose, or two doses on successive days.
                          (2) 50 mg/kg/d, 12 doses in 15 d.
                          (3) 25 mg/kg/d, 5 d/wk.
                          (4) 10 mg/kg/d for 55 or 116 doses.
                          (5) 100 mg/kg twice/wk, once/wk, once/10 d, once/14 d.
                          (6) Diets with 0-400 ppm (greatest intake 30 mg/kg/d).
(3)  Dorsal sac injection or via exposure
(4)  Through natural habitat
ROUTE AND SITE: Gavage or oral (diet).

CONTROL INFORMATION:  only in (6), diet alone.
DURATION OF EXPERIMENT:   Up  to  13 wk

EXAM., TYPE:  Behavior, histology
                                                  DURATION OF EXPERIMENT:   up to 52 wk.

                                                  EXAM. TYPE:    Behavior, electrophysiology, histology
                                          39
                                                                                                                                       40

-------
COMPOUND:  Acrylamide

           000079061

REFERENCE:      Fullerton,  P.M.
                J.  Neurol.  Neurosurg.  Psychiat.  32:186-192,  1969.
COMPOUND:  Acrylamide

           000079061

REFERENCE:   Hashimoto, K. and Ando, K.
             Biochera. Pharm 22:1057-1066, 1973.
OBSERVED NEUROTOXIC EFFECTS:    Sural nerve biopsies  from  the  lateral malleolus
                               (ankle), showed degeneration and regeneration
                               thought to have begun before onset of symptoms.
                               Sensory nerve action  potentials were weak or absent;
                               motor conduction was  slow.
OBSERVED NEUROTOXIC EFFECTS:   Hindlimb weakness at 2 wk, paralysis at  4 wk,
                               clinical recovery 5-6 wk after ttmt ended.   In-
                               corporation of labeled lysine and methionine into
                               proteins of sciatic nerve and spinal cord altered
                               by compound.
ANIMALS:  Human:   3  cases, M  (already reported by Garland & Patterson 1967).
ANIMALS:   Rats, SD, M, 8 wk old.   Groups of 3, 5, or 15.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:   ns.

CONTROL INFORMATION:
                          (1) Exposure for 1 mo, symptoms then progressive for
                             2 mo.
                          (2) Exposure for 6 wk, then severely disabled after 6 wk.
                          (3) Exposure for 18 mo,  then symptoms progressive for
                             2 mo and recovery incomplete 10 wk later.
                         None
PREPARATION AND DOSE
or HISTORY OF PATIENT:    500 ppm in "Oriental M" powder diet for 4 wk,  followed
                          by 4 wk control diet.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:      Groups fed powder diet only.
DURATION OF EXPERIMENT:   Up to 2-1/2 yr

EXAM. TYPE:  Electrophysiology, histology
DURATION OF EXPERIMENT:    Up to 6 wk after ttmt, sacr

EXAM. TYPE:     Behavior; radioautography; biochemistry.
                                         41

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COMPOUND: Acrylamide

          000079061

REFERENCE:      Igisu, H., Goto, I., Kawamura, Y., Kato, M., Izumi, K. and
                Kuroiwa, Y.
                J. Neurol. Neurosurg, Psychiat. 38:581-584, 1975.

OBSERVED NEUROTOXIC EFFECTS:   Signs appeared 3 wk after act of contamination,
                              subacute mental confusion and/or truncal ataxia;
                              good recovery within 4 mo.
ANIMALS:    Human:   1  family of 5  (F 65, M 42, F 40, M 13, F 10)
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Well-water found to contain 400 ppm, from roadworks
                         performed 1 mo. before sampling; exposure max 4 wk.
ROUTE AND SITE:    oral,  skin  contact

CONTROL INFORMATION:      None



DURATION OF EXPERIMENT:   l mo., plus  follow-up 4 mo.

EXAM. TYPE:  Clinical,  electrophysiology
                                         43
COMPOUND: Acrylamide

           000079061

REFERENCE:      Kaplan,  M.L.,  Murphy,  S.D.  and Gilles, F.H.
                Tox. Appl.  Pharm.  24:564-579, 1973.
OBSERVED NEUROTOXIC EFFECTS:
     Cumulative total to produce neurologic deficit
     was 360 mg/kg in controls, to 600 mg/kg  in Pheno-
     barbital-premedicated.  The latter and young  rats
     had severe peripheral nerve damage; unpretreated
     adults did not.  Rotarod appratus used to measure
     neurologic deficit.
ANIMALS:   Rats,  Holtzman,  M,  200-300 g or 5 wk old.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Daily aq soln, various compounds given  to modify
the "neurologic deficit."  Complex schedules.   Some
rats adrenalectomized.
ROUTE AND SITE: I.p., in vitro

CONTROL INFORMATION:



DURATION OF EXPERIMENT:

EXAM. TYPE:     Behavior, histology, in-vitro.
                                                                                                                                      44

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COMPOUND:  Acrylamide

          000079061
REFERENCE:
                Kuperman, A.S.
                J.  Pharm. Exp.  Ther.  123:180-192,  1958.
OBSERVED NEUROTOXIC EFFECTS:
                              Lethal doses produced convulsions; sublethal
                              doses produced ataxia and tremors like cerebellar
                              asynergia.  No other biological effects, no
                              histological alterations.  Primary site of non-
                              convulsive action was subcortical, diffuse; author
                              infers the mesencephalic tegmentum as the primary
                              site of intoxication.
COMPOUND:  Acrylamide

           000079061

REFERENCE:   Leswing, R.J. and Ribelin, W.E.
             Arch. Env. Hlth. 18: 22-29, 1969

OBSERVED NEUROTOXIC EFFECTS:    Paralysis, especially hindlimbs, at higher dosage
     in monkeys.  Conduction in sciatic nerves 28% slower in cats, 22%  in monkeys,
     20% in ulnar nerve of monkeys,  with longer latencies.  Degeneration of myelin
     and axons in affected nerves.  When treatment stopped, signs improved.
ANIMALS:    Cats,  intact  and surgically prepared:  spinal cord transection,
           decerebellation, decortication, or decerebration.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Nonconvulsive doses of  1-50 mg/kg/d.  Convulsive single
                         doses of  75-1000 mg/kg.  Many schedules used, acrylamide
                         99.2% pure  in water.
ANIMALS:   (1)   11 cats,  unselected young adults
           (2)   4 Cebus  albifrons monkeys
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)   Cats:   20 mg/kg/d
                          (2)   Monkeys:   20 mg/kg/d for 8 wk, then 30 mg/kg/d
ROUTE AND SITE:  z.v.  Or  I.P.

CONTROL INFORMATION:   None
ROUTE AND SITE:  oral

CONTROL INFORMATION:  ns.
DURATION OF EXPERIMENT:    Different  schedules.

EXAM.  TYPE:      Behavior,  EEC,  histology.
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:   Behavior, electrophysiology, histology
                                            45

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 COMPOUND:  Acrylamlde

           000079061

 REFERENCE:      McCollister, D.D., Oyen, F. and Rowe, V.K.
                Tox. Appl. Pharm. 6:172-181, 1964.
                                                            COMPOUND:      Acrylamide

                                                                          000079061

                                                            REFERENCE:     Morgan-Hughes, J.A.,  Sinclair,  S.  and Durston,  J.H.J.
                                                                          Brain 97:235-250,  1974.
OBSERVED NEUROTOXIC EFFECTS:
Weakness and ataxia, starting in hindlimbs.  Re-
covery of survivors prolonged according to dose(s);
"no nerve tissue pathology has been found in the
affected animals, not even in those severely
intoxicated to the point of death."
                                                                                          OBSERVED NEUROTOXIC EFFECTS:
                 Peripheral neuropathy, flacid weakness of  the
                 hindlimbs, retarded nerve growth.  Axonal  degeneration
                 Crush injury healed in 8 wk in controls, healing
                 delayed or inhibited in those treated.  Less
                 regeneration and when regeneration occured it was  less
                 than usual.
            Monkeys,  F  (no  other details)
ANIMALS:   Rats,  Dow-Wistar, M and F, about  60 d old
           Guinea-pigs, M
           Rabbits, M and F
           Cats  (no details)
PREPARATION AND DOSE
or HISTORY OF PATIENT:      Various schedules
                                                            ANIMALS:
20 Rats, Wistar, 300-440 g.
                                                            PREPARATION AND DOSE
                                                            or HISTORY OF PATIENT:     200  ppm (12 rats)  or 300 ppm (2 rats) in diet. Right
                                                                                      sciatic crush injury 7-22 wk after start of experiment.
ROUTE AND SITE:    Gavage (one  dose);  skin  contact;  eye contact; I.P.; I.V.; diet
                  (oral)
CONTROL INFORMATION:      Zero  dosage
                                                            ROUTE AND SITE:   Oral

                                                            CONTROL INFORMATION:
                                                                                                                    14 matched rats, untreated.
DURATION OF EXPERIMENT:     Up  to 1 yr  (diet,  cats and monkeys)

EXAM. TYPE:   Clinical, pathology
                                                            DURATION OF EXPERIMENT:    Up to 30 wk after sciatic crush

                                                            EXAM.  TYPE:     Electrophysiology,  histology, clinical
                                         47
                                                                                                                                      48

-------
COMPOUND:     Acrylamide

              000079061

REFERENCE:    Prineas, J.
              J.  Neuropath.  Exp.  Neurol  28(4):598-621, 1969.
COMPOUND:   Acrylamide

           000079061

REFERENCE:    Schaumberg,  H.H., Wlsniewski,  H.M.,and Spencer, P.S.
              J.  Neuropathol.  Exp.  Neurol 33:260-284, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                 Left  tibial nerve and right anterior horn
                                 cells of  cord showed "dying-back changes"
                                 of  axons.  Subcellular changes differed from
                                 those due  to TOCP.  Behavior "was very similar
                                 to  that seen in TOCP intoxication," progressive
                                 weakness of limbs starting with hind limbs.
OBSERVED NEUROTOXIC EFFECTS:  Unsteady gait,  head tremor and distal muscle
                              weakness.   Loss of peripheral myelinated fibers,
                              unmyelinated were preserved.   Degeneration of Pacinian
                              corpuscles, muscle spindles,  and some neuromuscular
                              junctions,  consistent with dying back.
ANIMALS:    6  Cats, M and  F,  2.5-4.0 kg.
ANIMALS:  12. Cats,  3 aged 1 yr  or  more,  9 aged less.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                             (1)   5  cats:  10 mg/kg/d in 2 ml water.
                             (2)   1  cat:  150 mg/kg in 2 doses, 21 hr apart.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
(1)   10 mg/kg/d.
(2)   10 mg/kg alternating with 20-40 mg/kg.
(3)   3 mg/kg/d in drinking water.
ROUTE AND SITE:     s.C.

CONTROL INFORMATION:     4  Cats  from another study.
ROUTE AND SITE:  (1)   I.P.      (2)   I.P.    (3)   Oral

CONTROL INFORMATION:   6 control cats.
DURATION OF EXPERIMENT:   Serial  sacr  up  to 49 d

EXAM.  TYPE:  Behavior, histology
DURATION OF EXPERIMENT:   7-294 d,  irregular schedules.

EXAM.  TYPE:  Behavior,  histology (biopsy and autopsy)
                                        49
                                                                                                                                    50

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COMPOUND:  Acrylamide

           000079061

REFERENCE:   Suzuki,  K.  and Pfaff,  L.D.
             Acta Neuropath 24:197-213,  1973.
OBSERVED NEUROTOXIC EFFECTS:   Weakness  of  limb muscles, recovered after 1-2 mo.,
                              some adults  had hindlimb paralyzed.  Axonal
                              degeneration,  demyelination in  sciatic nerve,
                              regeneration observed.
                                                          COMPOUND:    Acrylamide,  N,N-diethyl-
                                                          REFERENCE:   Edwards,  P.M.
                                                                       Br.  J.  Ind.  Med.  32:31-38,  1975.
                                                          OBSERVED NEUROTOXIC EFFECTS:
                                 (1)   Rats:   Ataxia,"waddling gait, hindlimb weakness.
                                 (2)   Hens:   Slight ataxia; degeneration of sciatic
                                             and peroneal. nerve fibers and medullary
                                             and cervical spinocerebellar tracts.
                                 (3,4)  Frogs,  goldfish:  sublethel effects varying
                                                          with dosage..
ANIMALS:    Rats,  Osborn-Mendel,  30 suckling-5  to  8  g,  28 adults  150-300  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
50 mg/kg in saline,  3/wk to 18 doses,  2 adults had
26 doses.
ANIMALS:      (i)   Rats,  Porton,  M,  200 g
             (2)   Hens,  Star Cross, adult, 3 leg
             (3)-  Frogs,  R.  Temporaria, M
             (4)  Goldfish
PREPARATION AND DOSE
or HISTORY OF PATIENT:      Dose varied with species
ROUTE AND SITE:     I.P.

CONTROL INFORMATION:   12 rats saline only



DURATION OF EXPERIMENT:   Up to about 4 mo.

EXAM. TYPE:   Histology of sciatic nerve
                                                          ROUTE AND SITE:  (1) Oral, I.P.
                                                                           (2) Oral
                                                          CONTROL INFORMATION: .. , . ,     ,
                                                                               Vehicles only
                                                          DURATION OF EXPERIMENT:  Up to 13 wk

                                                          EXAM/TYPE:  Behavior, histology
                                           (3) Dorsal sac injection  or  via exposure
                                           (4) Through natural habitat
                                        51
                                                                                                                                     52

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 COMPOUND:   Acrylamide,  N-hydroxymethyl-
                                                                 COMPOUND:    Acrylamide,  N-hydroxymethyl-
 REFERENCE:   Barnes,  J.M.
             Brit.  J.  Industr.  Med.  27:147-149,  1970.
                                                                 REFERENCE:   Edwards,  P.M.
                                                                              Br.  J.  Ind.  Med.  32:31-38,  1975.
OBSERVED NEUROTOXIC EFFECTS:    "Fine tremors  and  were generally affected."  No
                                 gross signs of weakness.
                                                                 OBSERVED NEUROTOXIC EFFECTS:
                                                                                                  (1)   Rats:   Ataxia, waddling gait, hindlimb weakness.
                                                                                                  (2)   Hens:   Slight ataxia; degeneration of sciatic
                                                                                                              and peroneal nerve fibers and medullary
                                                                                                              and cervical spinocerebellar tracts.
                                                                                                  (3,4)  Frogs, goldfish:  sublethel effects varying
                                                                                                                           with dosage.
ANIMALS:     6 .young Adult  rats,  Po.rton Strain,  M
PREPARATION AND DOSE
or HISTORY OF PATIENT:
7 doses of 100 mg/kg in 12 d.
2 doses of 200 mg/kg on day 23 and 24.
ANIMALS:     (i)  Rats,  Porton, M,  200  g
             (2)  Hens,  Star Cross, adult,  3 leg
             (3)  Frogs,  R. Temporaria,  M
             (4)  Goldfish
PREPARATION AND DOSE
or HISTORY OF PATIENT:      Dose varied with species
ROUTE AND SITE:    Oral

CONTROL INFORMATION:    ns.
                                                                 ROUTE AND SITE:  (1)  Oral,  I.P.
                                                                                  (2)  Oral
                                                                 CONTROL INFORMATION:  „ . .  ,      ,
                                                                                      Vehicles  only
                                           (3)  Dorsal sac injection or via exposure
                                           (4)  Through natural habitat
DURATION OF EXPERIMENT:      37 d.

EXAM. TYPE:  Behavior,  physiology
                                                                 DURATION OF EXPERIMENT:  Up to 13 wk

                                                                 EXAM. TYPE:  Behavior, histology
                                            53
                                                                                                                                         54

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COMPOUND:
Acrylamide, N-methyl
                                                                                             COMPOUND:  Acrylamide,  N-methyl
REFERENCE:   Barnes, J.M.
            Brit. J. Industr. Med. 27:147-149,  1970.
                                                                                REFERENCE:  Edwards, P.M.
                                                                                            Br. J.  Ind.  Med.  32:31-38,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                   2 of the 3 had definite weakness like mild
                   acrylamide poisoning.   One rat died after
                   second series of doses.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
                                 (1)  Rats:  Ataxia, waddling  gait,  hindlimb weakness
                                 (2)  Hens:  Slight ataxia; degeneration of sciatic
                                             and peroneal. nerve  fibers  and medullary
                                             and cervical spinocerebellar tracts.
                                 (3,4)  Frogs, goldfish:  sublethel  effects varying
                                                          with dosage.
ANIMALS:      (1) 6 Rats, Porton, Albino, M
             (2) 4 Rats, Porton, Albino, M
             (3) 3 Rats, Porton, Albino, M
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               (1) 400 ppm for 10 wks followed by 3 wks at 800 ppm.
               (2) 7 doses of 100 mg/kg for 2 wks.
               (3) 10 doses of 50 mg/kg, then 11 doses of 100 mg/kg for 3  wks.
ANIMALS:     (i)   Rats,  Porton, M, 200 g
             (2)   Hens,  Star Cross, adult, 3 leg
             (3)   Frogs, R.  Temporaria, M
             (4)   Goldfish
PREPARATION AND DOSE
or HISTORY OF PATIENT:      Dose varied with species
ROUTE AND SITE:    (1) diet     (2) —  (3) oral dose

CONTROL INFORMATION:    2 animals, not described.
                                                                                ROUTE AND SITE:  (1)  Oral,  I.P.
                                                                                                 (2)  Oral
                                                                                CONTROL INFORMATION:  ......     ,
                                                                                                     Vehicles only
                                            (3) Dorsal  sac  injection or via exposure
                                            (4) Through natural habitat
DURATION OF EXPERIMENT:     Approximately 18 wks

EXAM. TYPE:  Behavior, physiology
                                                                                DURATION OF EXPERIMENT:  Up to 13 wk

                                                                                EXAM.. TYPE:  Behavior,  histology
                                            55
                                                                                                                                        56

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COMPOUND:  Acrylamide monomer
REFERENCE:   Garland,  T.O. and Patterson, M.W.H.
             Br. Med.  J.  iv:134-138, 1967.
                                                                                            COMPOUND:
                                                                                                        Acrylic acid, 2-cyano-, methyl ester

                                                                                                        000137053
REFERENCE:  Dutton, J. and Yates, P.O
            J. Neurosurg. 24:  876-882, 1966.
OBSERVED NEUROTOXIC EFFECTS:   Limb numbness and paresthesias, weakness,
                              sweating and peeling, ataxia, lethargy, tremors,
                              slurred speech, wt loss, bladder dysfunction;
                              authors infer peripheral neuropathy and midbrain
                              disturbance.  Recovery 2-12 mo., not always complete.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                             The dura matter in the brain of  13  cats was  incised
                             and then closed with a fascial graft and  coated with
                             the compound.  9 reacted and later  healed, with no
                             underlying damage and no damage  to  controls.   Vertical
                             incisions in the brain of 5 cats  showed the  death of
                             neurons and glial response.  Saphenous nerves  were
                             coated (30 cats) with 8 showing  perineural inflammation
                             and some damage to neurolemmaand  axons.   All specimens
                             showed inflammatory or granulomatous response,  and
                             fibrin proliferated between glue  and tissues.
ANIMALS:    Human:   6  cases, M, aged 19-59
                                                                                            ANIMALS:
            Cats, M & F, 2-2.5 kg, surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Exposure to process of polymerization in manufacturing of
                         flocculators.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Experimental brain incisions (unilateral) were coated with
compound.
ROUTE AND SITE:    skin of hands and inhalation of dust.

CONTROL INFORMATION:    None
ROUTE AND SITE:    Topical

CONTROL INFORMATION:   Saline contralaterally
DURATION OF EXPERIMENT:   Exposure of 4 wk to over 1 yr.

EXAM.  TYPE:   clinical
DURATION OF EXPERIMENT:   3 d to 8 wk

EXAM.  TYPE:   Autopsy, histology
                                         57
                                                                                                                                      58

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COMPOUND:   Acrylic acid, 2-cyano-, methyl ester

            000137053

REFERENCE:  Kline, D.G. and Hayes, G.J.
            J. Neurosurg. 20:  647-654, 1963.
                                                               COMPOUND:    Actinomycin D

                                                                            000050760

                                                               REFERENCE:    Torvik,  A., and Heding,  A.
                                                                             Acta Neuropath. 9:  146-157, 1967.
OBSERVED NEUROTOXIC EFFECTS:
The compound caused inflammation in all cases,  tubular
and axonal damage in most,  and necrosis of neurons (no
damage in any controls).  In monkeys,  inflammation,
necrosis, demyelination and loss of axons  were  observed.
The authors commented that  the compound was not well
tolerated by nerve tissues.
OBSERVED NEUROTOXIC EFFECTS:  Animals  treated  i.p. had no histologic brain
     changes.  After intracerebral  treatment changes  in  all  neurons from the
     anterior part of the brain to  sacral  segments of spinal cord.   Control
     animals:  changes at injection site only.  Neurons  nucleoli disintegrated
     rapidly.  Retrograde reactions due to sectioning are blocked by Actinomycin D
     when injection given at time of operation.
ANIMALS:    Dogs, mongrel, M & F, 30-45 Ibs, 2 grps of 10, surgically prepared.
            Monkeys, no details
                                                                                              ANIMALS:   75 mice, albino, 60-75 d old, 20-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Dogs:  Part-isolated peroneal nerves of both hindlegs,  one
                              coated with compound, the other with saline.
                              Bilateral trephination, 5 drops of compound applied
                              to cortex; same of saline to other side.
                       Monkeys:  Optic-chiasm implants.

ROUTE AND SITE:  Topical

CONTROL INFORMATION:  Saline
                                                               PREPARATION AND  DOSE
                                                               or HISTORY OF PATIENT:   (1) 3 mice:  1.5 meg in 0.07 ml water, every 3hr  for  48hr,
                                                                                            Vllth (facial) nerve sectioned.
                                                                                        (2) 14 mice:  1.5 meg in 0.03 ml water or 0.9%  saline,
                                                                                            every 3-4 hr for 2-48 hr.
                                                                                        (3) 14 mice:  as above, first inj given at time of operation
                                                                                            to facial nerve.
                                                               ROUTE AND SITE: !-p-     (4) 12 mice:  as above, except doses begun 48hr after operat
                                                                        and Intracerebral.
                                                               CONTROL  INFORMATION:   control groups:  vehicle alone, operation only, vehicle and
                                                                                      operation.
DURATION OF EXPERIMENT:   Serial 2-12 wk

EXAM. TYPE:  Autopsy, histology
                                                               DURATION OF  EXPERIMENT:  Serial sacr to 4d

                                                               EXAM. TYPE:   Histology
                                         59
                                                                                                                                      60

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COMPOUND: Adenosine, 3'-(alpha-amino-p-methoxy hydrocennamamido)-3'-deoxy-N,N-
          dimethyl    (Puromycin)
          000053792

REFERENCE:  Moss,  E.E.,  Moss,  D.R.  and Fahrney,  D.
            Pharm. Biochem.  Behav.  2:   271-275,  1974 6
COMPOUND:  Adenosine, 3'-(alpha-amlno-p-methoxy hydrocennamamido)-3'-deoxy-N,N-
           dimethyl    ("vrc—*=ir.)
           000053792

REFERENCE:   Zech,  R.  and Domagk,  G.F.
             Brain  Res. 86:339-342,  1975.
OBSERVED NEUROTOXIC EFFECTS:  Puromycin gave 50% inhibition of  the cholinesterase
                              at O.SraM with  SOtnM substrate.   The  authors  inferred
                              that puromycin binds at two enzyme  sites, one  of
                              which is allosteric.
OBSERVED NEUROTOXIC EFFECTS:
     Puromycin inhibited the activity of  the  enzyme,
     noncompetitively and reversibly.
ANIMALS:    In  vitro  rat brain  cholinesterase  preparation.
ANIMALS:     In vitro human brain acetylcholinesterase
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Various
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Chemical enzyme inhibition system
ROUTE AND SITE:   in vitro

CONTROL INFORMATION:    ns
ROUTE AND SITE:   In vitro

CONTROL INFORMATION:   Lab
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Biochemistry
DURATION OF EXPERIMENT:     ns.

EXAM. TYPE:  Biochemistry
                                            61
                                                                                                                                         62

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COMPOUND:  Alanlne,  3-(3,4-dihydroxyphenyl)-, L-

           000059927

REFERENCE:   Narotzky, R., Griffith, D., Stahl,  S., Bondareff,  W.  and Zeller,  E.A.
            Exp. Neurol. 38:218-230, 1973.
                                                                 COMPOUND:
             Alanine, 3-mercapto-, hydrogen sulfate  (ester)
                                                                 REFERENCE:   Olney, J.W., Misra, C.H., De Gubareff, T.
                                                                             J. Neuropath. Exp. Neurol 34(2):167-177, 1975.
OBSERVED NEUROTOXIC EFFECTS:     Increased spontaneous motor activity and pain
                                responses with decrease of norepinephrine, inter-
                                preted with respect to psychiatric side-effects of
                                parkinsonism therapy.
                                                                OBSERVED  NEUROTOXIC  EFFECTS:
                                                                                                 Induction of glutamate  type of neuropathology in
                                                                                                 rat central nervous system.
                                                                                                 (1) Lesions in retina and arcuate nucleus  of
                                                                                                 hypothalamus.
                                                                                                 (2) Neuron-necrotizing  lesion in brain,  acute
                                                                                                 neuronal degeneration.
ANIMAIS:     Rats, S-D, M, 1.5-2 yr old, 3-4 per group
                                                                                            ANIMALS:
                                                                             (1) 18 Rats, Wistar albino, 5 days old
                                                                             (2) Rats, Holtzman, adult
PREPARATION AND DOSE
or HISTORY OF PATIENT:
12.5-62.5 mg/kg,  or 250-1000 rag/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            (1)  1 injection at one of 3 doses (0.04, 0.4 and 4.0
                            m moles/kg) aqueous, pH 7.0 + 0.1.
                            (2)  2 mcl of 77 mM soln, total dose 0.15 me moles.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:  Vehicle only; untrtd.



DURATION OF EXPERIMENT:     1-20 hr.

EXAM. TYPE: Behavior, biochemistry, histology
                                                                ROUTE AND SITE:    (i) s.C.  (2) Intracerebral
                                                                CONTROL  INFORMATION:



                                                                DURATION OF EXPERIMENT:

                                                                EXAM. TYPE:  Histology.
                            (1) 6 litter-mate injected subcut. with NaCl, 4 m moles/kg.
                            (2) 3 rats:  2 mcl inj 154 mM NaCl, 3 rats:  cannulated  no
                            other treatment.

                            Sacr after 3 hrs following injections.
                                            63

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  COMPOUND:
               Alanine,  N-methyl-3-sulfo-, L-    (N-methyl-L-cysteic  acid)
 COMPOUND:   Alanine, phenyl-, L-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
           J. Physiol. 166:1-14, 1963.
 REFERENCE:   Adelman,  L.S., Mann,  J.D.,  Caley,  D.W.  and Bass,  N.H.
              J.  Neuropath. Exp. Neurol.  33(2):380-393,  1974.
 OBSERVED NEUROTOXIC EFFECTS:  N-methyl-D-aspartic and D-homocysteic acids were
                               stronger excitants of depolarization than all
                               others.  With some compounds the action was
                               prolonged for many seconds after the stimulus
                               was terminated, notably N-n_-propyl-D-aspartic
                               acid.  There were no differences among types of
                               neurons tested; structure-activity relationship
                               was observed.
 OBSERVED NEUROTOXIC EFFECTS:     Neuropathic  lesions  in  the  cerebellum.   Axonal
                                 swelling.
 ANIMALS:   Cats prepared for electrophoretlc application of chemicals to single
           central nervous system neurons.
 ANIMALS:     12 Rats, CDR, 14-16 days gestation
             108 Weanling rats.
 PREPARATION AND  DOSE
 or  HISTORY OF  PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                          glutamic and cysteic acids listed in order of
                          potency of results.
 PREPARATION AND DOSE
 or  HISTORY OF PATIENT:
                            0.9 mg/kg/d.
ROUTE AND SITE:      Electrophoretic application,  various sites in central nervous
                     system.
CONTROL INFORMATION:      „
                          None
ROUTE AND SITE:   s.C.

CONTROL INFORMATION:        18,  dose  and  age matched.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophyslological
DURATION OF EXPERIMENT:      Serial  sacr.  8,  13,  15,  20,  30,  and 50

EXAM. TYPE: Microscopy, neuropathology
                                         65
                                                                                                                                     66

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COMPOUND:   Alanine, phenyl-, L-
                                                                                      COMPOUND:
             Alanine, 3-sulflno-
REFERENCE:    Shah, S.N., Peterson, N.A. and McKean,  C.M.
              J. Neurochem. 19:479-485, 1972.


OBSERVED NEUROTOXIC EFFECTS:  Reduced cholesterol,  glycollpids, and myelin
                             in brains; DNA and protein unchanged, myelin
                             composition unchanged.  Authors inferred cholesterol
                             reduction as the mechanism.
REFERENCE:  Curtis, D.R.  and  Watkins,  J.C.
            J. Neurochem.  6:117-141,  1960.
OBSERVED NEUROTOXIC EFFECTS:
                                Treatment caused excitation or depression  of
                                neuronal activity.  Excitatory ranking:  glutamic,
                                B-aminoglutaric, aspartic, cysteic, sulfino-
                                alanfnes, B-hydroxyglutamic, N-methylaspartic,
                                N-formiminoaspartic acids.
                                Depressant ranking:  6-alanine, GABA,  taurine,
                                N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                acids.
                                Structure-activity relationships established.
ANIMALS:    Rats,  S-D, aged 5 d
ANIMALS:     Cats,  surgically prepared to exposed motoneurones,  Renshaw cells or
             dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  3 mg/g/d in 3 doses for 5,  10, 15 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:   I.M.

CONTROL INFORMATION:  Controls:  saline only
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:    Serial sacr to 30 d

EXAM.  TYPE:    Biochemistry
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry, electrophysiology
                                       67
                                                                                                                                  68

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COMPOUND:   Alanine,  3-sulfino-
                                                                                           COMPOUND:  Alanine, 3-sulfo-, D-
                            u~  r\ T
                                     --- 1  ni ---
               Exp.  Brain Res.  14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:   The compound was equipotent  to monosodium
                              glutamate in necrosing neurons in  the retina
                              and brain.   This compound  is a powerful neuro-
                              excitant and the neurotoxic  properties may be
                              governed by similar mechanisms.
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocysteic acids were
stronger excitants of depolarization than all
others.  With some compounds  the action was
prolonged for many seconds  after the stimulus
was terminated, notably N-n_-propyl-D-aspartic
acid.  There were no differences among types of
neurons tested; structure-activity relationship
was observed.
ANIMALS:   Mice, Swiss-webster  age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                         each compound.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5 M  of  31 compounds mainly of aspartic,
                         glutamic and  cysteic acids listed in order of
                         potency of results.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM.  TYPE:     Histology
ROUTE AND SITE:     Electrophoretic application,  various sites in central nervous
                    system.
CONTROL INFORMATION:      „             '                '
                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                         69
                                                                                                                                    70

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COMPOUND:
             Alanine, 3-sulfo-, L-
COMPOUND:  Alanine, 3-sulfo-, L-
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of.
                               neuronal activity.  Excitatory ranking:  glutamic,
                               6-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  B-alanine, GABA, taurine,
                               N-methyl-8-alanine, S-amino-B-hydroxybutyric,
                               glycine, a-alanine, S-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
OBSERVED NEUROTOXIC EFFECTS:
          N-methyl-D-aspartic and D-homocysteic acids were
          stronger excitants of depolarization than all
          others.   With some compounds the action was
          prolonged for many seconds after the stimulus
          was terminated, notably N-ii-propyl-D-aspartic
          acid.  There were no differences among types of
          neurons tested; structure-activity relationship
          was observed.
ANIMALS:    Cats, surgically prepared to exposed motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
ANIMALS:  Cats prepared  for electrophoretic  application of chemicals to single
          central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions  0.1-0.5  M of 31 compounds mainly of aspartic,
                         glutamic and  cysteic acids listed in order of
                         potency of results.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:

CONTROL INFORMATION:
Electrophoretic application, various sites  in central nervous
system.
     None
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:     Electrophysiological
                                          71
                                                                                                                                       72

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COMPOUND:   Alanine, 3-sulfo-, L-
                                                                                            COMPOUND:
                                                                                                            Alanine,  3-(2-thienyl)-
Dcccorwrc.
               Exp. Brain Res. 14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:  The compound was equlpotent to monosodium glutamate
                              in necrosing neurons in the retina and brain.
                              This compound is a powerful neuroexcitant
                              and the neurotoxic properties may be governed by
                              similar mechanisms.
                                                                                            REFERENCE:
                                                                                                            Capobianco,  J.O.  and Beck,  S.L.
                                                                                                            Teratology 4:295-302,  1971.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
Prenatal treatment during "period of accelerated
neural growth and differentiation" resulted in
decreased brain weight and increased body wt
compared to controls.  Treated offspring had
more sound-induced seizures than untreated controls,
but not more than solvent-treated.  Sound-
stressed mice had lower brain catecholamine levels.
ANIMALS:  Mice, Swiss-webster age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established  for
                         each compound.
                                                                                            ANIMALS:
                                                                                                            Mice,  12th-13th  generations  of  4-way outcross of C3H/HeH,
                                                                                                            CBA/Gr,  A/Gr,  and  C57BL/Gr strains,  pregnant females.   Tot
                                                                                                            480 animals.
                                                                                            PREPARATION AND DOSE
                                                                                            or HISTORY OF PATIENT:
                                                                                                                      40,  60  or  70 mg in 1 ml saline,  0.1 N HC1 and 0.1
                                                                                                                      N NaOH  (18:1:1) per d,  on d 10-12 of gestation.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:     Compounds compared with monosodium L-glutamate  (MSG)
                         potency for selectively necrosing  neurons  in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals  including 5  hr.

EXAM. TYPE:    Histology
                                                                                            ROUTE AND  SITE:  i.p.

                                                                                            CONTROL  INFORMATION:
                                                                                                                      Groups  of  solvent  ttd and unttd animals.
                                                                                            DURATION OF EXPERIMENT:    Sacr  23  d  postnatal

                                                                                            EXAM. TYPE:      Sound-stress, and  biochemistry
                                          73
                                                                                                                                    74

-------
 COMPOUND:   Alanine.  2.4,5-trihvrtroxyphenyl-
REFERENCE:   Richardson, J.S., Cowan,N.,  Hartman, R. and Jacobowitz, D.M.
             Res. Comm. Chem. Path. Pharm.. 8(l):29-44, 1974.
OBSERVED NEUROTOXIC EFFECTS:    Lowered norepinephrine 25-50%; in combination
         with 5,6-dihydroxytryptamine (I) lowered norepinephrine and serotonin;
         no effect on dopamine.  Alone or in combination with  I, lowered food
         and water intakes.  Alone, but not in combination with I, lowered
         spontaneous locomotion.  Increased emotionality scores; I attenuated
         the increase.  Other complex effects reported, and the causes speculated
         to be selective destruction of noradrenergic and/or serotonergic nerve
         terminals.
ANIMALS:     Rats, S-D, M, 180-200 g, 5-12/group
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           90 meg/rat
ROUTE AND SITE:   Intraventricular

CONTROL INFORMATION:    Vehicle



DURATION OF EXPERIMENT:      14 d

EXAM. TYPE:  Behavior
                                          75
COMPOUND:  Alanine, 2,4,5-trihydroxyphenyl-
REFERENCE:   Sachs, C. and Jonsson,  G.
             J. Neurochem. 19:1561-1575,  1972.
OBSERVED NEUROTOXIC EFFECTS:  Doses (1)  lethal, (2) MTD.   Degeneration of central
                              and peripheral norepinephrine neurons, mediated by
                              decarboxylation of 6-OH-DOPA to 6-OH-Da.  Neither
                              5-HT neurons nor dopamine neurons were affected.
                                                                                                ANIMALS:   Mice, N.M.R.I., M, 25-30 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)   250 or 400 mg/kg, one dose.
                         (2)   100 mg/kg, 1-6 doses at intervals.
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:   Controls untreated.



DURATION OF EXPERIMENT:   Up to 42 d

EXAM. TYPE:   Biochemistry, fluorescence histochemistry
                                                                                                                                       76

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COMPOUND:  Alanine,  2,4,5-trihydroxyphenyl-, hydrobromide
COMPOUND:   Alkyl mercury
REFERENCE:  Bonagura,  V.,  Cassebaum,  L.,  Dangman,  K.,  Freund,  J.,  Cabbat,  F., Dembiec,
               D.,  Helkkila,  R.  and  Cohrn,  G.
            Res.  Comm.  Chem.  Path. Pharm. 4:   163-171,  1972,

OBSERVED NEUROTOXIC EFFECTS:   Treatment  caused diminished  uptake of norepinephrine,
                              resulting  from destruction of adrenergic nerve terminals.
                              Accumulation  of  the  compound at  site needed  for these
                              effects.   Desipramine, 25 mg/kg, protected under conditions
                              of this experiment.
                                                                                             REFERENCE:
             Charlton,  K.M.
             Can.  J.  Comp. Med.  38(1):75-81,  1974.
OBSERVED NEUROTOXIC EFFECTS:
     Weakness of gait, blindness in affected pigs,
     aimless walking, reflexes minimally altered,
     death.  Peripheral nervous system:  Wallerian
     degeneration of sensory fibers, neuronal degeneral
     of dorsal root ganglia.  Central nervous system:
     degeneration of neurons and glia.
ANIMALS:    Mice,  Swiss-Webster, M,  25g
                                                                                            ANIMALS:     20 Pigs, Yorkshire,  7 M and 13 F, aged approx. 10 wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  100 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
0.24-5.76 mg/kg/d of mercury for 11-199 d.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:  Saline
ROUTE AND SITE:   ns.

CONTROL INFORMATION:   4 of above kept as controls, untreated
DURATION OF EXPERIMENT:   72 hr

EXAM.  TYPE:    Biochemistry of heart slices
DURATION OF EXPERIMENT:      Killed on d 13-205.

EXAM. TYPE:  Behavior, histology
                                          77
                                                                                                                                       78

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COMPOUND:
            Allophanic acid, hydrazide
                                                                                            COMPOUND:
                                                                                                           Aloes
REFERENCE:  Jenney, E.H.  and Pfeiffer, C.C.
            J. Pharm. Exp. Ther.  122:  110-123,  1958.
REFERENCE:
Steer, H.W. and Colin-Jones, D.G.
J. Path. 115:199-205, 1975.
OBSERVED NEUROTOXIC EFFECTS:    Convulsions
                                                                                            OBSERVED NEUROTOXIC EFFECTS:    More lysosomal activity and lysosotnes in Schwann
                                                                                                                           cells and neurons of submucosal plexus of colonic
                                                                                                                           mucosa.
ANIMALS:    Mice, Harlan, 19-21 g
ANIMALS:         Human:  7 aged 24-80 with melanosia coli who took purgatives;
                        1 who had taken purgatives for only 1 m.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2.5 mM/kgm
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Rectal biopsy before and 3-7 m after stopping medication
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:  ns
ROUTE AND SITE:  Oral

CONTROL INFORMATION:
                                                                                                                      7 aged 27-70 with other gut disorders who had  taken no
                                                                                                                      purgatives for 3 m.
DURATION OF EXPERIMENT:  Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:    About 7 m.

EXAM. TYPE:     Histology, histochemistry
                                        79
                                                                                                                                     80

-------
COMPOUND:   Aluminum hydroxide
COMPOUND:  Ammonium, (O-b-romobenzyl)ethyldimethyl-, p-toluenesulfonate

           000061756

             Acta  Neuropath. 11:311-329, 1968.
               Quinton, R.M.
               Br. J. Pharmac. 21:51-66,  1963.
OBSERVED NEUROTOXIC EFFECTS:    No effect in nonmyelinated white-matter of
    juveniles;  severe  demyelination and gliosis of white-matter in adults,
    with added  effects on  grey-matter.
OBSERVED NEUROTOXIC EFFECTS:  The compound  enhanced the effect of Yohimbine
                              and lowered its  lethal dosage.
ANIMALS:     10  cats, various ages, in 3 grps.
ANIMALS:
               Mice, TT, M, 18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.03-0.12 ml, one dose.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q  >40 mg/kg

                         ED__ = dose  producing a 50% mortality of mice injected
                                S.C.  with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:   intracerebral

CONTROL INFORMATION:    None
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   Serial  sacr:   7  d,  40  d,  3 mo.

EXAM. TYPE:  Histology.
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology,  biochemistry
                                       81
                                                                                                                                   82

-------
COMPOUND:   Ammonium,  (3-carboxypropyl)  trimethyl-, carboxylate
                                                                                          COMPOUND:
               Ammonium, dibutyl(2-hydroxyethyl)methyl-
REFERENCE:   Curtis, D.R. and Watkins, J.C.
             J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               B-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  6-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-amlnoisobutyric
                               acids.
                               Structure-activity relationships established.
             Cats, surgically prepared to expose- motoneurones, Renshaw  cells or
             dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
REFERENCE:   Hartung, R. and^Cornish, H.H.
             Tox.  Appl.  Pharm. 12:486-494, 1968.
                                                                                          OBSERVED NEUROTOXIC EFFECTS:
                                 This compound was tested with a group of other amino-
                                 ethanols and choline analogs, all of which inhibited
                                 cholinesterase in vitro.  In vitro inhibition
                                 increases as the number of carbon atoms attached
                                 on the nitrogenous head of the 2-amino-ethanol moledule.
                                 In the in vivo tests the oral LDj-'s were uniformly
                                 higher than the i.p. LD . values.  When given i.p.,
                                 compound reduced brain cnolinesterase.
                                                                                          ANIMALS:      Rats,  S-D,  M
PREPARATION AND DOSE
or HISTORY OF PATIENT:   In vitro:  10 4 to 10"1.
                                                                                                                   In vivo:

                                                                                                                                   and lower doses.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:   Oral, i.p., in vitro

CONTROL INFORMATION:  ns.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry
                                          83
                                                                                                                                      84

-------
 COMPOUND:
              Ammonium,  diethyl(2-hydroxyethyl)methyl-
                                                                                              COMPOUND:  Ammonium,  (2-hydroxyethyl)triethyl-
 REFERENCE:
             Hartung, R. and Cornish, H.H.
             Tox. Appl. Pharm. 12:486-494, 1968.
 OBSERVED  NEUROTOXIC  EFFECTS:
This compound was tested with a group of other
aminoethanols and choline analogs,  all of which
inhibited cholinesterase in vitro.   In vitro
inhibition increases as the number  of carbon atoms
attached on the nitrogenous head of the 2-amino-
ethanol molecule.  In the in vivo tests the oral
LD   were uniformly higher than the i.p. LD   values.
                                                              REFERENCE:   Bhatnagar, S.P., Lam, A. and McColl, J.D.
                                                                          Blochem. Pharm. 14:  421-434, 1965.
OBSERVED NEUROTOXIC EFFECTS:  Muscular weakness,  respiratory paralysis, failure
                              of transmission at  cholinergic synapses; inhibition
                              of acetylcholine synthesis.
ANIMALS:     Rats, S-D, M
PREPARATION AND DOSE
or HISTORY OF PATIENT:   In vitro:   10~4 to 10.
                         In vivo:    LD   anc^ l°wer doses.
                                                              ANIMALS:     Mice, CFW, F, 15-20 g and mouse brain tissues  in vitro
                                                                          Cats, M & F, 2-3 kg, surgically prepared
                                                                          In vitro reaction mixtures
                                                              PREPARATION  AND DOSE
                                                              or  HISTORY OF  PATIENT:
                                                                                        Various doses
ROUTE AND SITE:    Oral,  i.p.,  in vitro

CONTROL INFORMATION:   ns.
                                                              ROUTE AND  SITE:   Various routes

                                                              CONTROL  INFORMATION:   Various controls
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:   Biochemistry
                                                              DURATION OF  EXPERIMENT:  various

                                                              EXAM.  TYPE:    Chemistry, electrophysiology
                                          85
                                                                                                                                       86

-------
COMPOUND:  Ammonium,  (2-hydroxyethyl)  triethyl-,  p-toluenesulfonate,  3,4,5-
           trimethoxybenzoate
                                                            COMPOUND:   Ammonium, (m-hydroxyphenyl)trimethyl-, bromide,  dimethylcarbamate

                                                                        000114807
REFERENCE:  Bhatnagar, S.P., Lam, A. and McColl, J.D.
            Biochem. Pharm. 14:  421-434, 1965
                                                            REFERENCE:  Tang, A.H. and  Schroeder,  L.A.
                                                                        Tox. Appl. Pharm.  12:44-47,  1968.
OBSERVED NEUROTOXIC EFFECTS:
Muscular weakness, respiratory paralysis, failure
of transmission at cholinergic synapses; inhibition
of acetylcholine synthesis.
OBSERVED NEUROTOXIC EFFECTS: Produced variable results, ranging from reversal to
                             enhancement of neuromuscular blockade.
ANIMALS:    Mice, CFW, F, 15-20 g and mouse brain tissues in vitro
            Cats, M & F, 2-3 kg, surgically prepared
            In vitro reaction mixtures
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          Various doses
                                                                                          ANIMALS:
                                                                         4  Rabbits
                                                            PREPARATION AND DOSE
                                                            or HISTORY OF PATIENT:  25-100 meg/kg administered at peak of the neuromuscular
                                                                                   blockade from lincomycin (50 mg/kg).
ROUTE AND SITE:   Various routes

CONTROL INFORMATION:   Various controls
                                                            ROUTE AND SITE:  I.V.

                                                            CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:  Various

EXAM.  TYPE:   Chemistry, electrophysiology
                                                            DURATION OF EXPERIMENT:   ns.

                                                            EXAM.  TYPE:  Electrophysiology
                                        87
                                                                                                                                     88

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COMPOUND:   Ammonium ion (+1)
COMPOUND:   Andros t-5-en-3-beta-ol,  17-beta-((3-(dlmethylamino)propyl)methylamino)-
REFERENCE:  Lux, H.D., Loracher, C. and Neher, E.
            Exp. Brain Res. 11:  431-447, 1970.
REFERENCE:   Suzuki, K., Zagoren, J.C., Chen, S.M. and  Suzuki, K.
            Acta Neuropath. 29:141-156, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                              Treatment caused reversible reductions of IPSP-
                              equilibrium potential which were more sensitive to
                              extracellular and systemic ammonium than to intra-
                              cellular ammonium.  The authors suggest that slow
                              release from inside the cells explains the long
                              duration effects after intracellular applications.
                              The effective extracellular doses corresponded to
                              intracerebral concentrations of compound reported
                              for preconvulsive states of epilepsies induced
                              metabolically.
ANIMALS:
            45  Cats, adult, 1.5-2.5 kg, surgically prepared
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
     Scattered intracytoplasmic osmiophilic inclusions
     in central nervous system (far fewer than with
     Triparanol, q.v.) at higher dose-level only.
     No degeneration of oligodendroglia.  Massive
     accumulations of desmosterol and less of A->»'«'''-
     cholestatriene-36-ol.  Authors argue that as a
     A -reductase inhibitor causes massive accumulations
     of 7-dehydrocholesterol (provitamin D3), as
     A7'   and A5' '   sterols produce Triparanol-like
     lesions, and as diazacholesterol produces few
     such lesions, the lesions may be due to a double
     bond at the 7-position.
                                                                                                      Rats, Wistar, M and F, newborn
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                        Compound applied by iontophoresis to exposed neurons, both
                        intra- and extra-cellularly
PREPARATION AND DOSE
or HISTORY OF PATIENT:
30 or 60 mg/kg/d in saline, from d 5 of age.
ROUTE AND SITE:   See above

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:    Saline only
DURATION OF EXPERIMENT:    Various to 120 min

EXAM.  TYPE:      Electrophysiology
DURATION OF EXPERIMENT:      Serial,  15-32  d

EXAM.  TYPE:  Histology,  biochemistry
                                        89
                                                                                                                                     90

-------
COMPOUND:  Androst-5-en-17-one,  3-beta-hydroxy-,  succinate,  sodtum salt
REFERENCE:
Heuser, G., Ling, G.M.  and Buchwald, N.A.
Arch. Neurol 13:195-203, 1965.
OBSERVED NEUROTOXIC EFFECTS:
                 Doses of 40-70 mg/kg produced sedation and slow
                 wave activity.  Doses of 100-150 mg/kg (high)
                 resulted in repeated tonic seizures and intermittent
                 falling spells.
                                                                                 COMPOUND:   Aniline,  4,4'-sulfonyldi-

                                                                                            000080080
                                                                                                REFERENCE:
             duVivier, A. and Fowler, T.
             Proc. Royal Soc. Med. 67:439-440, 1974.
OBSERVED NEUROTOXIC EFFECTS:   Wasting of hand muscles and of some  feet muscles.
     Sensorimotor neuropathy with denervation of small hand muscles with pro-
     longed distal latency.  Axonal degeneration and denervation atrophy.   4 mo.
     after withdrawal of dapsone, no recovery.
ANIMALS:
Monkeys, Squirrel, surgically prepared
                                                                                                ANIMALS:    1 Human,  M,  age 57 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
          Varying doses approx 5-200 mg/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   200-300 mg/d for 18 yr for dermatitis herpetiformis.
     Complained of tingling of hands and feet and weakness of hands,  starting
     1 yr. before.
ROUTE AND SITE:
                  I.V.  or  I.P.
CONTROL INFORMATION:
          Sham inj as well as saline and sodium bicarbonate soln
          were used as controls.  Control injections did not
          produce sedative or convulsion effects.
DURATION OF EXPERIMENT:      Up  to approx  30 min/test

EXAM. TYPE:     Electrophysiology, behavior
ROUTE AND SITE:   oral

CONTROL INFORMATION:  ns.



DURATION OF EXPERIMENT:  18 yr. drug treatment, follow-up 4 mo.

EXAM. TYPE:  Clinical, electromyography, nerve and muscle biopsy.
                                          91
                                                                                                                                       92

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COMPOUND:   o-Anisamide, 4-amino-5-chloro-N-(2-diethylamino)ethyl)-
REFERENCE:  DeSilva, K.L., Muller, P.J. and Pearce, J.
            Practitioner 211:  316-320, 1973.
COMPOUND:   Anthraquinone, dihydroxy-

            001322607

REFERENCE:  Steer, H.W. and Colin-Jones, D.G.
            J. Path. 115:  199-205, 1975
OBSERVED NEUROTOXIC EFFECTS: Extrapyramidal signs, spasms especially of face, tongue
                             and jaws, torticollis, opisthotonus, trismus; onset in
                             2-60 hrs. commonest in young.  No dose relationship,
                             recovery after withdrawal.  One case had added dienceph-
                             alic features.  Authors comment that etiology still
                             unknown, and suggest idiosyncracy to class of drugs
                             (phenothiazines).
OBSERVED NEUROTOXIC EFFECTS: More lysosomal activity and lysosomes  in  Schwann
                             cells and neurons of submucosal plexus of colonic
                             mucosa.
ANIMALS:    Human:  10 cases, M & F, 14-30, selected from 20 cases treated at a
                    hospital serving 500,000 population, over 2 yrs
ANIMALS:    Human:  7 aged 24-80 with melanosis coli who took purgatives;
                    1 who had taken purgatives for only 1 m.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    4 cases:  10 mg t.d.s.,  P.O.
                         Adverse drug reaction.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Rectal biopsy before and 3-7 m after stopping medication
ROUTE AND SITE:  t.d.s., P.O. (see above)

CONTROL INFORMATION:    None
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   7 aged 27-70 with other gut disorders who had taken no
                      purgatives for 3 m
DURATION OF EXPERIMENT:    12-48 hrs.

EXAM. TYPE:   Clinical
DURATION OF EXPERIMENT:   About 7 m.

EXAM. TYPE:  Histology, histochemistry
                                        93
                                                                                                                                    94

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COMPOUND:
             Arsenic

             007440382
REFERENCE:   Chhuttani, P.N.,  Chawla, L.A. and  Sharma, T.D.
             Neurology 17:269-274,  1967.


OBSERVED NEUROTOXIC EFFECTS:     Mainly  sensory polyneuropathy, degeneration
    correlating in severity with clinical data, no  specific pattern.
ANIMALS:     Human:   34  M,  6  F  aged  20-65  yr  (av.  34.2)  seen over  12 yr.  in  a
    series of 708  neuropathies  (these were the  cases due to As).


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Unknown amts.   Sources:   prescription  27, homicide  5,
    culinary 3,  accident 3, injection 2.
ROUTE AND SITE:   30 Oral,  2  parenteral

CONTROL INFORMATION:   None



DURATION OF EXPERIMENT:  12yr

EXAM. TYPE:  Behavior,  biochemistry,  histology
                                       95
COMPOUND:    Arsenic

             007440382

REFERENCE:   Hassin, G.B.
             J.  Nerv.  Ment.  Dis.  72:628-636, 1930.


OBSERVED NEUROTOXIC EFFECTS:  Paralysis or polyneuritis of sudden  onset
     deposits of arsenic seen as bands in nails, high arsenic content in hair.
ANIMALS:   6 Human case-reports
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Source, type and amount of arsenic  intake not  discovered.
ROUTE AND SITE:  N.S.

CONTROL INFORMATION:    None



DURATION OF EXPERIMENT:     weeks to years

EXAM. TYPE: clinical and laboratory
                                                                                                                                    96

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COMPOUND:
Aspartic acid
                                                                                             COMPOUND:    Aspartic acid,  D-
REFERENCE:   Olney,  J.W.  and  Ho., 0.
             Nature  227:609-610,  1970.
OBSERVED NEUROTOXIC EFFECTS:
                   Necrosis of hypothalamic  neurons  in mice given
                   glutamate,  compound    or  cysteine, dose-related;
                   zero damage from other compounds
ANIMALS:
             75 Mice,  Swiss Webster, age 10 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
              One of 10 amino acids  and various  other compounds, 2.5 or 10%
              in water, 0.25-2 g/kg.
                                                                               REFERENCE:   Curtis, D.R. and Watkins,  J.C.
                                                                                            J. Neurochem. 6:117-141, 1960.
                                                                                             OBSERVED  NEUROTOXIC  EFFECTS:
                                                                                             ANIMALS:
                                                                                                                            Treatment caused excitation or depression  of
                                                                                                                            neuronal activity.  Excitatory ranking:  glutamic,
                                                                                                                            6-aminoglutaric, aspartic, cysteic, cysteine-
                                                                                                                            sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                                                                                                                            N-formiminoaspartic acids.
                                                                                                                            Depressant ranking:  6-alanine, GABA,  taurine,
                                                                                                                            N-methyl-B-alanine, 6-amino-S-hydroxybutyric,
                                                                                                                            glycine, a-alanine, 6-aminovaleric, S-aminoisobutyric
                                                                                                                            acids.
                                                                                                                            Structure-activity relationships established.
                                                                                                         Cats, surgically prepared to expose  motoneurones, Renshaw cells  or
                                                                                                         dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:    Gavage

CONTROL INFORMATION:    Intubated, no  treatment, 10 mice
                                                                               ROUTE AND SITE:   Topical, ionophoresis

                                                                               CONTROL INFORMATION:    Laboratory
DURATION OF EXPERIMENT:     5 hr.

EXAM.  TYPE:   Histology
                                                                               DURATION OF EXPERIMENT:   ns.

                                                                               EXAM.  TYPE: Biochemistry, electrophysiology
                                            97
                                                                                                                                       98

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 COMPOUND:  Aspartlc acid, D-
                                                                                            COMPOUND:   Aspartlc acid,  D-
 REFERENCE.'Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
          N-methyl-D-aspartic and D-homocysteic acids were
          stronger excitants of depolarization than all
          others.   With some compounds the action was
          prolonged for many seconds after the stimulus
          was terminated, notably N-nj-propyl-D-aspartic
          acid.  There were no differences among types of
          neurons tested; structure-activity relationship
          was observed.
                                                                                            REFERENCE:
                                                                                      Olney,  J.W.,  Ho,  O.L.  and Rhee,  V.
                                                                                      Exp.  Brain  Res.  14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:   The  compound  was  equipotent  to monosodium
                               glutamate  in  necrosing  neurons in the retina
                               and  brain.  This  compound  is a powerful neuro-
                               excitant and  the  neurotoxic  properties may be
                               governed by similar  mechanisms.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                            ANIMALS:   Mice, Swiss-webster  age 10 d, total 250
                                                                       PREPARATION AND DOSE
                                                                       or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                                                                                                 each compound.
ROUTE AND SITE:

CONTROL INFORMATION:
Electrophoretic application, various sites in central nervous
system.
     None
                                                                                            ROUTE AND SITE:
                                                                                                                B.C.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
CONTROL INFORMATION:     Compounds  compared with monosodium L-glutamate (MSG)
                         potency  for  selectively necrosing neurons in retina
                         and brain  (hypothalamus)

DURATION OF EXPERIMENT:  5 hr  or  serial intervals including 5 hr.

EXAM. TYPE:    Histology
                                        99
                                                                                                                                    100

-------
COMPOUND:   Aspartic acid, DL-
COMPOUND:   Aspartic acid, L-
REFERENCE:   Curtis, D.R. and Watkins, J.C.
             J. Neurochem. 6:117-141, 1960.
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               8-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, 8-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  B-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused  excitation  or  depression of
                               neuronal activity.   Excitatory  ranking:   glutamic,
                               g-aminoglutaric,  aspartic, cysteic,  cysteine-
                               sulflnic acids, B-hydroxyglutamic,  N-methylaspartic,
                               N-formiminoaspartic  acids.
                               Depressant ranking:   B-alanine,  GABA,  taurine,
                               N-methyl-B-alanine,  6-amino-B-hydroxybutyric,
                               glycine, a-alanine,  6-aminovaleric,  B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
ANIMALS:
             Cats, surgically prepared to expose  motoneurones, Renshaw cells or
             dorsal horn interneurones in lumbar cord.
ANIMALS:
            Cats, surgically prepared  to  expose  motoneurones,  Renshaw cells or
            dorsal horn  interneurones  in  lumbar  cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:    Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE: Biochemistry,  electrophysiology
                                          101
                                                                                                                                     102

-------
COMPOUND:  Aspartic acid, L-
                                                                                            COMPOUND:   Aspartic acid,  L-
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-ti-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
                                                                                            REFERENCE:
               Olney, J.W., Ho, O.L. and Rhee, V.
               Exp. Brain Res. 14:61-76, 1971.
                                                                                            OBSERVED  NEUROTOXIC  EFFECTS:
                               The  compound was  equipotent  to monosodium
                               glutamate  in necrosing neurons in the retina
                               and  brain.  This  compound is a powerful neuroexcitant
                               and  the neurotoxic  properties may be governed
                               by similar mechanisms.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                           ANIMALS:  Mice, Swlss-webster  age 10 d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Initially  12 mmoles/kg,  then range established for
                         each compound.
ROUTE AND SITE:      Electrophoretic application, various sites in central nervous
                    system.
CONTROL INFORMATION:      „             '               '
                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                                           ROUTE AND SITE:
                                                                                                                S.C.
CONTROL INFORMATION:     Compounds  compared  with monosodium L-glutamate (MSG)
                         potency  for  selectively necrosing neurons in retina
                         and brain  (hypothalamus)

DURATION OF EXPERIMENT:   5 hr  or  serial  intervals including 5 hr.

EXAM. TYPE:    Histology
                                        103
                                                                                                                                    104

-------
COMPOUND:
            Aspartic acid, N-acetyl-, L-
                                                                                              COMPOUND:    Aspartic acid,  N-acetyl-,  L-
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
                                                                                              REFERENCE:
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               8-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:   6-alanine, GABA, taurine,
                               N-methyl-B-alanine, S-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
            Cats, surgically prepared to expose  motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE-
or HISTORY OF PATIENT: Qualitative doses.
               Olney, J.W., Ho, O.L. and Rhee,  V.
               Exp. Brain Res. 14:61-76, 1971.
                                                                                              OBSERVED NEUROTOXIC  EFFECTS:   No cytotoxicity was observed.
                                                                                             ANIMALS:  Mice, Swiss-webster  age  10  d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Initially 12 mmoles/kg,  then range established for
                         each compound.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE: Biochemistry, electrophysiology
                                                                                             ROUTE AND SITE:
                                                                                                                  S.C.
CONTROL INFORMATION:      Compounds compared with  monosodium L-glutamate (MSG)
                         potency  for selectively  necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or  serial  intervals including 5 hr.

EXAM. TYPE:    Histology
                                          105
                                                                                                                                      106

-------
COMPOUND:  Aspartic acid, N-carbamoyl-,  DL-
                                                                                             COMPOUND:  Aspartic acid, N,N-dimethyl-, D-
REFERENCE:   Curtis, D.R. and Watkins, J.C.
             J. Neurochem. 6:117-141, 1960.
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               6-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, 8-hydroxyglutamic,  N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  g-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-8-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, £-aminolsobutyric
                               acids.
                               Structure-activity relationships established.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocysteic  acids  were
stronger excitants of depolarization than all
others.  With some compounds  the  action was
prolonged for many seconds after  the stimulus
was terminated, notably N-n-propyl-D-aspartic
acid.  There were no differences  among types of
neurons tested; structure-activity  relationship
was observed.
ANIMALS'.    Cats, surgically prepared to exposed motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
ANIMALS:  Cats prepared for electrophoretic  application of chemicals to single
          central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5  M of 31 compounds mainly of aspartic,
                         glutamic and  cysteic acids listed in order of
                         potency of  results.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:     Electrophoretic  application,  various sites in central nervous
                    system.
CONTROL INFORMATION:     „
                         None
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:    Electrophysiological
                                          107
                                                                                                                                      108

-------
COMPOUND:   Aspartic acid,  N.N-dimethyl-,  DL-
                                                                                             COMPOUND:
            Aspartic acid, N,N-dimethyl-, DL-
REFERENCE:   Curtis,  D.R.  and  Watkins,  J.C.
             J. Neurochem.  6:117-141, 1960.
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               6-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:   g-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic  and  D-homocysteic acids were
                              stronger excitants of  depolarization than all
                              others.  With  some compounds  the action was
                              prolonged  for  many seconds  after the stimulus
                              was  terminated,  notably  N-n-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested;  structure-activity relationship
                              was  observed.
ANIMALS:
             Cats,  surgically prepared  to  exposed motoneurones, Renshaw cells or
             dorsal horn  interneurones  in  lumbar cord.
ANIMALS:  Cats prepared  for electrophoretic  application of chemicals to single
          central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5 M of  31  compounds mainly of aspartic,
                         glutamic and  cysteic acids listed in order of
                         potency of results.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:

CONTROL INFORMATION:
                    Electrophoretic application,  various  sites in central nervous
                    system.
                         None
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE: Biochemistry, electrophysiology
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                          109
                                                                                                                                        110

-------
 COMPOUND: .  Aspartlc acid, N-ethyl,  D-
                                                                                           COMPOUND:   Aspartic  acid, N-ethyl-, DL-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
                                                                                           REFERENCE:Curtis, D.R. and Watkins, J.C.
                                                                                                     J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-ii-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                         N-methyl-D-aspartic and D-homocysteic acids were
                                                                                                                         stronger excitants of depolarization than all
                                                                                                                         others.  With some compounds  the action was
                                                                                                                         prolonged  for many seconds  after the stimulus
                                                                                                                         was terminated, notably N-ii-propyl-D-aspartic
                                                                                                                         acid.  There were no differences among types of
                                                                                                                         neurons tested; structure-activity relationship
                                                                                                                         was observed.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
                                                                                           ANIMALS:  Cats prepared for electrophoretic  application of chemicals to single
                                                                                                     central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                           PREPARATION AND DOSE
                                                                                           or HISTORY OF PATIENT:   Dilutions 0.1-0.5 M of  31 compounds mainly of aspartic,
                                                                                                                    glutamic and  cysteic acids listed in order of
                                                                                                                    potency of results.
ROUTE AND SITE:

CONTROL INFORMATION:
                    Electrophoretic application, various sites in central nervous
                    system.
                         None
ROUTE AND SITE:

CONTROL INFORMATION:
Electrophoretic application, various sites in central  nervous
system.
     None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                                           DURATION OF EXPERIMENT:   ns.

                                                                                           EXAM. TYPE:    Electrophysiological
                                        111
                                                                                                                                    112

-------
 COMPOUND:    Aspartic  acid, N-ethyl, L-
                                                                      COMPOUND-
                                                                                                      Aspartic  acid,  N-formimino-, L-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
                                                                     REFERENCE:   Curtis,  D.R.  and Watkins,  J.C.
                                                                                  J.  Neurochem.  6:117-141,  1960.
 OBSERVED NEUROTOXIC EFFECTS:
          N-methyl-D-aspartic and D-homocysteic acids were
          stronger excitants of depolarization than all
          others.  With some compounds the action was
          prolonged for many seconds after the stimulus
          was terminated, notably N-ii-propyl-D-aspartic
          acid.  There were no differences among types of
          neurons tested; structure-activity relationship
          was observed.
OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                         Treatment caused excitation or depression of
                                                                                                                         neuronal activity.  Excitatory ranking:  glutamic,
                                                                                                                         6-aminoglutaric, aspartic, cysteic, cysteine-
                                                                                                                         sulfihic acids, B-hydroxyglutamic, N-methylaspartic,
                                                                                                                         N-formiminoaspartic acids.
                                                                                                                         Depressant ranking:  6-alanine, GABA, taurine,
                                                                                                                         N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                                                                                                         glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                                                                                                         acids.
                                                                                                                         Structure-activity relationships established.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
                                                                     ANIMALS:
                                                                                  Cats,  surgically prepared  to exposed motoneurones, Renshaw cells or
                                                                                  dorsal horn interneurones  in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                     PREPARATION AND DOSE
                                                                     or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:

CONTROL INFORMATION:
Electrophoretic application, various sites in central nervous
system.
     None
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                     DURATION OF EXPERIMENT:  ns.

                                                                     EXAM. TYPE:  Biochemistry,  electrophysiology
                                         113
                                                                                                                                    114

-------
 COMPOUND:  Aspartic acid, N-iminomethyl-, D-
                                                             COMPOUND'  Aspartic acid, N-iminomethyl-, L-
 REFERENCE:Curtis, D.R. and Watklns, J.C.
          J. Physiol. 166:1-14, 1963.
                                                             REFERENCE:Curtls, D.R. and Watkins, J.C.
                                                                       J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocysteic acids were
stronger excitants of depolarization than all
others.  With some compounds the action was
prolonged for many seconds after the stimulus
was terminated, notably N-nj-propyl-D-aspartic
acid.  There were no differences among types of
neurons tested; structure-activity relationship
was observed.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:  N-methyl-D-aspartic and D-homocysteic  acids were
                                                                                                                         stronger excitants of depolarization than all
                                                                                                                         others.  With some compounds  the  action was
                                                                                                                         prolonged for many seconds after  the stimulus
                                                                                                                         was terminated, notably N-n^propyl-D-aspartic
                                                                                                                         acid.  There were no differences  among types of
                                                                                                                         neurons tested; structure-activity relationship
                                                                                                                         was observed.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
                                                             ANIMALS:  Cats prepared for electrophoretic  application of chemicals to single
                                                                       central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                             PREPARATION AND DOSE
                                                             or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of  31  compounds mainly of aspartic,
                                                                                      glutamic and cysteic acids listed in order of
                                                                                      potency of results.
ROUTE AND SITE:      Electrophoretic application, various sites in central nervous
                    system.
CONTROL INFORMATION:      „
                         None
                                                             ROUTE AND SITE:     Electrophoretic application,  various sites In central nervous
                                                                                 system.
                                                             CONTROL INFORMATION:
                                                                                      None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                             DURATION OF EXPERIMENT:   ns.

                                                             EXAM. TYPE:    Electrophysiological
                                        115
                                                                                                      116

-------
 COMPOUND:
           Aspartic acid, N-methyl-, D-
COMPOUND:  Aspartic acid, N-methyl, DL-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Phyaiol. 166:1-14, 1963.
REFERENCE:  Curtis, D.R.  and Watkins,  J.C.
            J. Neurochem.  6:117-141,  1960.
OBSERVED NEUROTOXIC EFFECTS:. Aspartic acid,  N-methyl-, Dr and.D-homocysteic acid wer
                              stronger excitants of depolarization than all
                              others.  With some compounds  the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-n-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:
                               Treatment  caused excitation or depression of
                               neuronal activity.   Excitatory ranking:  glutamic,
                               6-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                               N-fonniminoaspartic acids.
                               Depressant ranking:  S-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity  relationships established.
ANIMALS:  Cats prepared for electrophoretic application of chemicals  to single
          central nervous system neurons.
ANIMALS:
             Cats,  surgically  prepared to expose-  motoneurones, Renshaw cells or
             dorsal horn  interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:

CONTROL INFORMATION:
Electrophoretic application,  various  sites  in central  nervous
system.
     None
ROUTE AND SITE:    Topical,  ionophoresis

CONTROL INFORMATION:    Laboratory
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:     Electrophysiological
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE:  Biochemistry,  electrophysiology
                                        117
                                                                                                                                    118

-------
 COMPOUND"  Aspartic acid, N-methyl-, DL-
                                                                                            COMPOUND:
                                                                              Aspartic  acid,  alpha-methyl-,  DL-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocysteic acids were
stronger excitants of depolarization than all
others.  With some compounds the action was
prolonged for many seconds after the stimulus
was terminated, notably N-ir-propyl-D-aspartic
acid.  There were no differences among types of
neurons tested; structure-activity relationship
was observed.
                                                                                            REFERENCE:
                                                                             Olney,  J.W.,  Ho, O.L. and Rhee, V.
                                                                             Exp.  Brain Res.  14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:   The compound was toxic to non-neurol components
                              (glia, etc.), but not to neurons.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                            ANIMALS:   Mice, Swiss-webster  age 10 d, total 250
                                                              PREPARATION  AND DOSE
                                                              or HISTORY OF  PATIENT:    Initially 12 mmoles/kg, then range established for
                                                                                       each compound.
ROUTE AND SITE:      Electrophoretic application, various sites in central nervous
                    system.
CONTROL INFORMATION:
                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                                            ROUTE  AND  SITE:
                                                                                                                S.C.
                                                              CONTROL  INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                                                                                       potency for selectively necrosing  neurons  in retina
                                                                                       and brain (hypothalamus)

                                                              DURATION OF  EXPERIMENT:   5 hr or serial intervals including 5  hr.

                                                              EXAM.  TYPE:     Histology
                                         119
                                                                                                                                    120

-------
 COMPOUND:
                Aspartic acid, N-methyl-,  DL-
REFERENCE:
               Olney, J.W., Ho, O.L. and Rhee, V.
               Exp. Brain Res. 14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:  The compound was more potent than monosodlum
                              glutamate in necrosing neurons in the retina
                              and brain.  This compound is a powerful neuro-
                              excitant and the neurotoxic properties may  be
                              governed by similar mechanisms.
ANIMALS:  Mice, Swiss-webster age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                         each compound.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM.  TYPE:    Histology
                                        121
                                                                                            COMPOUND:
                                                                                                            Aspartic  acid,  N-methyl-,  DL-
REFERENCE:     Olney, J.W., Ho, O.L.  and Rhee,  V.
               Exp. Brain  Res. 14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:   The compound was more potent than monosodium
                               glutamate in necrosing neurons in the retina
                               and brain.   This compound is a powerful neuro-
                               excitant and the neurotoxic properties may be
                               governed by similar mechanisms.
ANIMALS:  Mice, Swiss-webster  age  10  d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially  12 mmoles/kg, then range established  for
                          each  compound.
ROUTE AND SITE:
                                                                                                                S.C.
CONTROL INFORMATION:      Compounds  compared with monosodium L-glutamate  (MSG)
                          potency  for  selectively necrosing neurons in retina
                          and  brain  (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or  serial intervals including 5 hr.

EXAM. TYPE:    Histology
                                                                                                                                  122

-------
 COMPOUND: Aspartic acid, N-methyl-, L-
                                                                                           COMPOUND:   Aspartic acid, N-propyl-, D-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
                                                                                           REFERENCE:Curtis, D.R. and Watkins, J.C.
                                                                                                     J. Physiol. 166:1-14, 1963.
 OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartlc and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-n-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic and D-homocysteic  acids  were
                              stronger excitants of depolarization than all
                              others.  With some compounds  the  action was
                              prolonged for many seconds after  the stimulus
                              was terminated, notably N-nj-propyl-D-aspartic
                              acid.  There were no differences  among types of
                              neurons tested; structure—activity relationship
                              was observed.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
                                                                                           ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
                                                                                                     central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                           PREPARATION AND DOSE
                                                                                           or HISTORY OF PATIENT:   Dilutions  0.1-0.5  M of 31 compounds mainly of aspartic,
                                                                                                                    glutamic and  cysteic acids listed in order of
                                                                                                                    potency of results.
ROUTE AND SITE:

CONTROL INFORMATION:
                    Electrophoretic application, various sites in central nervous
                    system.
                         None
ROUTE AND SITE:     Electrophoretic application,  various sites in central nervous
                    system.
CONTROL INFORMATION:                    '                '
                         None
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:     Electrophysiological
                                                                                           DURATION OF EXPERIMENT:   ns.

                                                                                           EXAM. TYPE:     Electrophysiological
                                         123
                                                                                                                                    124

-------
 COMPOUND:  Aspartic acid,  N-propyl-,  L-
                                                                                         COMPOUND:
                                                                                                      Atropine
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-ii-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
REFERENCE: pfeiffer,  C.C., Murphree, H.B.,  Jenney,  E.H.,  Robertson, M.G.,
           Randall, A.H.  and Bryan, L.
           Neurology  9:   249-250, 1959.

OBSERVED NEUROTOXIC EFFECTS:  The authors  concluded  that synthetic atropines are more
                 j            active hallucinogens than atropine or scopolamine, pro-
                             ducing effects lasting 24-48 hr.   Synthetic antltremor
                             drugs had  fewer peripheral nervous system side-effects,
                             but central  nervous system side-effects (hallucinations)
                             may have been  exaggerated.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
                                                                                         ANIMALS:    Human:  prison volunteers,  drug-sophisticated,  no other details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                         PREPARATION AND DOSE
                                                                                         or HISTORY OF PATIENT:    2 mg/man
ROUTE AND SITE:      Electrophoretic application, various sites in central nervous
                    system.
                         None
CONTROL INFORMATION:
                                                                                         ROUTE AND SITE:   Oral

                                                                                         CONTROL  INFORMATION:  LSD-25:  0, 25, 50,  100 meg/man
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                                         DURATION  OF EXPERIMENT:  Up  to 3 d

                                                                                         EXAM.  TYPE:   Opinion of volunteers
                                         125
                                                                                                                                    126

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COMPOUND:  Atropinium,  8-methyl-, nitrate

           000052880

REFERENCE:     Qulnton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:   The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
COMPOUND: Atropinium, 8-methyl-, nitrate

          000052880

REFERENCE:  Spooner,  C.E. and Winters, W.D.
            Int.  J.  Neuropharmacol. 5:  217-236, 1966


OBSERVED NEUROTOXIC EFFECTS:  Compound produced  locomotor ataxia and arousal EEGs.
ANIMALS:
               Mice, TT, M, 18-25 g.
ANIMALS:    200 Cockerels,  White Leghorn, ages 5-14 d, 45-100  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q   15 mg/kg

                              = dose producing a 50% mortality of mice injected
                          "50
                                S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2 mg/kg
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:      Various
ROUTE AND SITE:   S.C.  near axillary vein; I.P. for doses over 0.05 ml

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Behavior,  EEC
                                         127
                                                                                                                                     128

-------
COMPOUND: Atroplne SO^ (2:1)

          000055481

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.
                                                                 COMPOUND:   Atropine S04 (2:1)

                                                                            000055481

                                                                 REFERENCE:  Spooner, C.E. and Winters, W.D.
                                                                            Int. J. Nr.uropharmacol.  5:   217-236,  1966
OBSERVED NEUROTOXIC EFFECTS:   The compound enhanced the effect of Yohimblne
                              and lowered its lethal dosage.
                                                                 OBSERVED  NEUROTOXIC  EFFECTS:  Compound produced locomotor  ataxia  and  arousal  EEGs.
ANIMALS:
               Mice, TT, M, 18-25 g.
                                                                ANIMALS:    200 Cockerels, White Leghorn, ages  5-14  d,  45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ED5Q   40 mg/kg

ED,- = dose producing a 50% mortality of mice injected
       S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2-10 mg/kg
ROUTE AND SITE:      S.C., Oral

CONTROL INFORMATION:      Various
                                                                ROUTE AND SITE:   S.C. near axillary vein; I.P.'for doses  over  0.05 ml

                                                                CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
                                                                DURATION OF EXPERIMENT:   ns

                                                                EXAM. TYPE:   Behavior, EEC
                                         129
                                                                                                                                     130

-------
COMPOUND:   Barbituric acid, 5-allyl-5-(l-Methylbutyl)-

            000076733

REFERENCE:Melville, K., Jordon, G., Douglas, D.
          Toxicology and Applied Pharmacology 9:363-375, 1966.


OBSERVED NEUROTOXIC EFFECTS:   Ataxia or "no  spontaneous movement" as compared to
                               intense central nervous system depression by
                               synergistic action with alcohol.
COMPOUND:     Barbituric acid,  5-allyl-l-methyl-5-(l-methyl-2-pentynyl)-,
              sodium salt
              000309364

REFERENCE:  Spooner, C.E. and Winters,  W.D.
            Int. J. Neurophannacol.  5:   217-236,  1966


OBSERVED NEUROTOXIC  EFFECTS:  Compound  produced depression  and  associated slow-
                              wave EEGs.
ANIMALS:  Mongrel dogs, 7.0-12.0 kg, M and F.
ANIMALS:    200 Cockerels, White Leghorn, ages  5-14  d,  45-100 g
PREPARATION AND DOSE
Or HISTORY OF PATIENT:    25 mg/kg in total volume of 60 ml water
PREPARATION AND DOSE
or HISTORY OF PATIENT:   10-30 mg/kg
ROUTE AND SITE:          Stomach tube

CONTROL INFORMATION:      ns.
ROUTE AND SITE:   s.C.  near axillary vein; I.P. for doses over  0.05 ml

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   More  than 1 wk.

EXAM. TYPE Behavior
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Behavior,  EEC
                                          131
                                                                                                                                      132

-------
COMPOUND:    Barbituric acid, 5,5-Diethyl-, sodium salt

             000144025

REFERENCE:  Essig,  C.F. and Flanary, H.G.
            Exp. Neurol.  3:   149-159,  1961f
COMPOUND:  Barbituric acid, 5-ethyl-5-(l-methylbutyl)-, sodium salt  (Nembutal)
REFERENCE:   Becker,  R.F.,  Flannagan,  E.  and King,  J.E.
            Neurology  8:   776-782,  1958.
OBSERVED NEUROTOXIC EFFECTS:  Withdrawal  caused major and minor seizures with bi-
                             laterally symmetrical inter-seizure EEC abnormalities.
                             The cerebral cortex appeared to be involved, but only
                             as secondary brainstern involvement.
OBSERVED NEUROTOXIC EFFECTS:   Nembutal sedation of mother followed by Cesarian
                              delivery resulted in severe neural damage.  Of spontan-
                              eous  deliveries  after treatment with Nembutal on day
                              22, 42,  or 63 of gestation, birth mortality was high;
                              surviving young  showed only mild signs of brain
                              damage.   Heavy anesthetization of newborn caused
                              severe neuropathy.
ANIMALS:   Cats, surgically prepared, 6
ANIMALS:     Guinea-pigs,  pregnant
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Increasing doses, 95-335 mg/kg/d up to 267 d; then abrupt
                           withdrawal
PREPARATION AND DOSE
or HISTORY OF PATIENT:   30 or  38 mg/kg before  spontaneous delivery
ROUTE AND SITE:   Oral  (capsules)

CONTROL INFORMATION:    3 cats prepared but untreated
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:   Saline;  Cesarian section.
DURATION OF EXPERIMENT:    106-267 d

EXAM. TYPE:   Electrophysiological, behavioral
DURATION OF EXPERIMENT:    term  (average  66.5  d)

EXAM.  TYPE:     Teratology
                                           133
                                                                                                                                       134

-------
COMPOUND:    Barbituric acid,  5-ethyl-5-(l-methylbutyl)-, sodium salt

             000057330

REFERENCE:  Spooner,  C.E.  and  Winters,  W.D.
            Int.  J. Neuropharmacol.  5:   217-236,  1966.


OBSERVED NEUROTOXIC EFFECTS:   Compound  produced depression and associated slow-wave
                              EEGs.
COMPOUND:    Barbituric acid, 5-ethyl-5-(l-methylbutyl)-2-thio-, sodium salt

             000071738

REFERENCE:  Spooner, C.E.  and Winters, W.D.
            Int.  J.  Neuropharmacol. 5:  217-236, 1966


OBSERVED NEUROTOXIC EFFECTS:   Compound produced depression and associated slow-
                               wave EEGs.
ANIMALS:     200  Cockerels, White Leghorn,  ages  5-14 d, 45-100 g
                                                                                           ANIMALS:    200 Cockerels, White Leghorn, ages 5-14 d, 45-100  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2-100 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   io-30 mg/kg
ROUTE AND SITE:    s.C. near axillary vein;  I.P.  for doses over 0.05 ml

CONTROL INFORMATION:  ns
ROUTE AND SITE:   S.C.  near axillary vein; I.P. for doses over 0.05 ml

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:  Behavior, EEC
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Behavior,  EEC
                                           135
                                                                                                                                       136

-------
COMPOUND:   Barbituric acid, 5-ethyl-5-phenyl-

            000050066

REFERENCE:   Schain, R.J. and Watanabe, K.
             Exp. Neurol. 47:509-515,  1975.
OBSERVED NEUROTOXIC EFFECTS: Body and brain growth retarded, not due only
     to  impaired  nutrition.   In  cerebellum, accumulation of cholesterol
     was retarded more  than  of DNA, RNA  or protein, interpreted by authors
     as  interference with myelination.
COMPOUND:  Benzamide, p-amino-n-(2-(dlethylamino)ethyl))-
REFERENCE:
Drachman, D.A. and Skom, J.H.
Arch. Weurol. 13:316-320, 1965.
OBSERVED NEUROTOXIC EFFECTS:    Muscle weakness attributed to acetylcholine
                                inhibition,  recovered after withdrawal of compound
                                on two occasions.
ANIMALS:   Rats, Wistar, newborn M pups
                                                                                        ANIMALS:
                                                                                                       1 Human, M aged 78 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   30-60 mg/kg/d,  from d 3-d  21, vehicle ns.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                  Myasthenia gravis with myocardial  infarction  on many
                                                                                                                  drugs in hospital; single doses of 500  and  250  mg of
                                                                                                                  compound, then 6 hourly doses of 250 mg for 14  doses.
ROUTE AND SITE:   s.C.

CONTROL INFORMATION:    Littermate  controls, vehicle only
ROUTE AND SITE:   Oral

CONTROL INFORMATION:
                                                                                                                  None
DURATION OF EXPERIMENT:      Sacr at  21 d age

EXAM.  TYPE: Biochemical
DURATION OF EXPERIMENT:    About 1 mo.

EXAM.  TYPE:    Clinical
                                      137
                                                                                                                                    138

-------
COMPOUND:     Benzenearsonic  acid, 4-hydroxy-3-nitro-

             000121197
                                                          COMPOUND:   Benzilic acid, l-methyl-3-piperidyl ester, hydrochloride
REFERENCE:   Wise, D.R., Hartley, W.J. and Fowler, N.G.
            Res. Vet. Sci. 16:  336-340, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                                          REFERENCE:  Pfeiffer,  C.C.,  Murphree,  H.B., Jenney, E.H., Robertson, M.G.,
                                                                      Randall, A.H.  and Bryan,  L.
                                                                      Neurology  9:   249-250,  1959.
Those fed over SOppm exhibited ataxic and leg weakness.    nDCcm.rn urnon-rAvr,- rr-rr^-rc-
No damage was found in the central nervous system,  but    OBbtRVED NEUROTOXIC EFFECTS:  The authors concluded that synthetic atropines  are  more
distal peripheral nervous system degeneration (wallerian)                               active hallucinogens than atropine or scopolamine,  pro-
of myelin and axons was observed.                                                       ducing effects lasting 24-48 hr.  Synthetic antitremor
                                                                                        drugs had  fewer peripheral nervous system  side-effects,
                                                                                        but central nervous system side-effects  (hallucinations)
                                                                                        may have been exaggerated.
ANIMALS:    75 Turkey hens, 1 d old, in 5 groups of 15
                                                                                        ANIMALS:    Human:   prison volunteers, drug-sophisticated, no  other  details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    0-547 PPm in diet
                                                          PREPARATION AND DOSE
                                                          or HISTORY OF PATIENT:   6 mg/man  (experimental)
                                                                                   9 mg/man  (hallucinogens)
ROUTE AND SITE:     oral

CONTROL INFORMATION:   untreated
                                                          ROUTE AND SITE:   Oral

                                                          CONTROL INFORMATION:  LSD-25:  0, 25, 50, 100 meg/man
DURATION OF EXPERIMENT:   35 d

EXAM. TYPE:   Behavior,  histology
                                                          DURATION OF EXPERIMENT:  Up to 3 d

                                                          EXAM. TYPE:   Opinion of volunteers
                                         139
                                                                                                                                    140

-------
COMPOUND:  2-Benzimidazolinone,  l-(l-(3-(p-fluorobenzoyl)propyl)-l,2,3,6-
           tetrahydro-4-pyridyl)-
REFERENCE:  DeSilva, K.L., Muller, P.J. and Pearce, J.
            Practitioner 211:  316-320, 1973.
                                                                 COMPOUND:    3H-l,4-Benzodiazepine,  7-chloro-2-(methylamlno)-5-phenyl-,  4-oxide
                                                                 REFERENCE:
                                                                                                      UUUU30Z3J
               Pearlman,  C.  and  Becker, M.
               Psychopharmacologia A2:63-66,  1975.
OBSERVED NEUROTOXIC EFFECTS:
    Extrapyramidal signs, spasms especially of face, tongue
    and jaws, torticollis, opisthotonus, trismus; onset in
    2-60 hrs. commonest in young.  No dose relationship,
    recovery after withdrawal.  One case had added dienceph-
    alic features.  Authors comment that etiology still
    unknown, and suggest idiosyncracy to class of drugs
    (phenothiazines).
                                                                                          OBSERVED  NEUROTOXIC  EFFECTS:
                                Cooperative behavior  training  and  performance pre-
                                vented when compound  administered  a few minutes
                                after feeding  session,  no  effects  if given 3 hr
                                afterwards.  Authors  concluded mechanism was pre-
                                vention of REM sleep  during  this time.
ANIMALS:     Human:  10 cases, M & F, 14-30, selected from 20 cases treated at a
                    hospital serving 500,000 population, over 2 yrs
                                                                ANIMALS:       Rats:  Long-Evans, F, 3 mo. age.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1 case:  10 mg.  I.V.
Adverse drug reaction.
PREPARATION AND DOSE
Or HISTORY OF PATIENT:     4 mg/kg  on  alternate  days  a few minutes  after session
                          or  after 3  hrs.  of  rest.
ROUTE AND SITE:   I.V. (see above)

CONTROL INFORMATION:    None
                                                                ROUTE AND SITE:  I.P.

                                                                CONTROL INFORMATION:      6 Controls undistrubed sleep, 6 had saline inj. followed
                                                                                          by normal sleep.
DURATION OF EXPERIMENT:   3 hrs.

EXAM.  TYPE:   Clinical
                                                                DURATION OF EXPERIMENT:   Approx. 10 d

                                                                EXAM. TYPE:    Behavior
                                        141
                                                                                                                                    142

-------
COMPOUND:    3H-l,4-Benzodiazepine, 7-chloro-2-(methylamino)-5-phenyl-,  4-oxide

            000058253

REFERENCE:  Zbtnden,  G., Bagdon, R.E., Keith, E.F., Phillips, R.D., and Randall, L.O.
            Toxicol.  Appl. Pharmacol. 3:  619-637, 1961.
COMPOUND:  2H-l,4-Benzodiazepin-2-one,7_chloro-l,3-dihydro-l-methyl-5-phenyl-

           006613850

REFERENCE:  Greenblatt, D.J. and Kock-Weser, J.
            Am. J. Med. Sci. 266:  261-266, 1973.
OBSERVED NEUROTOXIC EFFECTS:   (D  Ingestion caused sedation, often ataxia and dysarthria,
                                  and  in rare instances sleep and coma
                            „ (2 and 3)  Symptoms similar to (1)
OBSERVED NEUROTOXIC EFFECTS:  Apnea and coma, hypotension and coma,  confusion and
                              obtundation were observed in patients  with  contributory
                              complications or other drug therapy.
ANIMALS:    (D  Human,  6 M and  16  F,  15  to  59 yr  (attempted  suicides)
            (2)  Rats,  CFN
            (3)  Dogs

PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  200 to 2250 mg/kg
                         (2)  20, 40,  or  80  mg/kg/day  for  52  wk
                         (3)  5  to  80 mg/kg/day  for 6  mo
ANIMALS:    Human:  6 patients  ages 40-91, 3.5% of 173 subjects  given  compound  I.V.,
            who were 1.2% of 2,623 patients receiving compound,  who were  18.3%  of
            14,344 patients studied in a drug surveillance program.

PREPARATION AND DOSE
or HISTORY OF PATIENT:  Doses 5-30 mg/patient, one dose
ROUTE AND SITE:  Oral

CONTROL INFORMATION:  ns
 ROUTE AND  SITE:   I.v.

 CONTROL  INFORMATION:   None
DURATION OF EXPERIMENT:  52 wk

EXAM. TYPE:  Clinical
 DURATION OF  EXPERIMENT:  Up to 19 d

 EXAM. TYPE:   Clinical
                                           143
                                                                                                                                        144

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COMPOUND:  Benzole acid
           000065850
REFERENCE: Krels, H., Frese, K., and Wilmes,  G.
           Fd. Cosmet. Toxicol., 5:   505-511, 1967.
                                                                 COMPOUND:   Benzole acid, p-amino-,  2-(diethylamino)ethyl ester    (Procalne)

                                                                             O00059':61

                                                                 REFERENCE:  Hirst, G.D.S. and Wood, D.R.
                                                                             Br. J. Pharmac. 41:  94-104, 1971.
OBSERVED NEUROTOXIC EFFECTS:
Retarded growth,  irritation, ataxia,tonic-clonic
convulsions.  Necrosis of parenchymal cells of
stratum granulosum of fascia dentata and cortex
of lobus plriformis.  Feeding of 1.1% failed to
induce any neurotoxic signs or pathological changes
in the brain.
OBSERVED NEUROTOXIC EFFECTS:   Procaine caused paralysis resembling  that  produced
                              by tubocurarine.  At low stimulation  rates,  it produced
                              no depression of transmitter release  but at  high rates,
                              a distinctive prejunctional failure was observed.
ANIMALS:   Rats, Weanling, M.
                                                                 ANIMALS:     Phrenic nerve-diaphragm preparations from rats, Wistar, M,  150-250 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
(1)  3% dietary level for 5 d.
(2)  1.1% in diet for 35 d.
                                                                 PREPARATION AND DOSE
                                                                 or HISTORY OF  PATIENT:  0.025-0.1 mM
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   ns.
                                                                 ROUTE  AND  SITE:    m vitro

                                                                 CONTROL  INFORMATION:   Laboratory
DURATION OF EXPERIMENT:   5 d

EXAM.  TYPE:   Pathology, behavior
                                                                 DURATION OF  EXPERIMENT:    various

                                                                 EXAM. TYPE:    Electrophysiology
                                          145
                                                                                                                                       146

-------
COMPOUND:
             Benzole acid, hydrazide

             00613945
REFERENCE:   Jenney,  E.H.  and Pfeiffer,  C.C.
             J.  Pharm.  Exp.  Ther.  122:   110-123,  1958.


OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:    Mice, Harlan,  19-21  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.9 mM/kgm
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:  ns



DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
                                        147
COMPOUND: Benzoxazole,  2-amino-5-chloro-

          000061803

REFERENCE:    Fujii, K., Jaffe, H. and Epstein, S.S.
              Tox. Appl. Pharm. 13:431-438, 1968.


OBSERVED NEUROTOXIC EFFECTS: Temporary paralysis
ANIMALS:      Mice, ICR Swiss Albino, A/J,  and  BALB/c
PREPARATION AND DOSE
or HISTORY OF PATIENT:   80 mg/kg  as  part of a larger study.
ROUTE AND SITE:  i.p.

CONTROL  INFORMATION:     Various



DURATION OF EXPERIMENT:  5 hr.

EXAM. TYPE:    clinical
                                                                                                                                     148

-------
COMPOUND:  Benzyl alcohol, 3,4-dichloro-alpha-((isopropylamino)methyl)-,
           hydrochloride
REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66,  1963.
 COMPOUND:   Benzyl alcohol, m-hydroxy-alpha-(methylamino)methyl)-, hydrochloride,  (-)-
 REFERENCE:   Ceilings,  H.
             Arch.  Neurol.  3:656-660,  1960.
OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced  the  effect of Yohimbine
                              and lowered its  lethal dosage.
 OBSERVED NEUROTOXIC EFFECTS:     Polyneuropathy, severe disintegration of myelin in
                                 peripheral nerves and nerve roots.
ANIMALS:
               Mice, TT, M, 18-25 g.
ANIMALS:
             Human:   4 case reports;  1 case in addendum.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q   >50 mg/kg

                         ED,. = dose producing a  50% mortality of mice injected
                                S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:     Various
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:   Oral

CONTROL INFORMATION:
Furacin 0.5 g three times daily for 2 d, then  four  times
daily for a total of 30.5 g; furadantin 100 mg
four times daily for a total 24 g in 59 d; furandantin 100
mg four times daily for total of 18 g in 45 d  (intermittent
therapy).  Addendum:  furaltadone 250 mg four  times daily
for a total of 52 g in 26 d. (Furacin = Nitrofurazone;
furadantin = nitrofurantoin)

None
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:      Months of follow-up

EXAM.  TYPE:   Behavior,  autopsy
                                         149
                                                                                                                                     150

-------
COMPOUND:  Benzylamine, N-(2-chloroethyl)-N-(l-methyl-2-phenoxyethyl)-

           000059961

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
COMPOUND:  Benzylamine, N-methyl-N-2-propynyl-, hydrochloride

           000306070

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound  enhanced the effect of Yohimbine
                              and lowered its  lethal dosage.
ANIMALS:
               Mice, TT, M, 18-25 g.
                                                                                           ANIMALS:
               Mice, TT, M, 18-25  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q   33 mg/kg
                         EDen = dose producing a 50% mortality of mice injected
                          "50
                                S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q    80 mg/kg
                         ED_n =  dose  producing a 50% mortality of mice injected
                                 S.C.  with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:      s.c., Oral

CONTROL INFORMATION:      Various
ROUTE AND SITE:     S.C.,  Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology,  biochemistry
                                         151
                                                                                                                                    152

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COMPOUND:   Bicuculline

            nnn/.os/.o/.


REFERENCE:  Davidoff, R.A.
            Science 175:   331-333,  1972,


OBSERVED NEUROTOXIC EFFECTS:  The compound blocked the normal actions of GABA (gamma-
                              aminobutyric acid).
COMPOUND:    Bicuculline

             000485494

REFERENCE:  Hill, E.G., Simmonds, M.A.  and  Straughan,  D.W.
            Br. J. Pharmac. 45:  176P-177P,  1972  (Abstract  of proceedings).
OBSERVED NEUROTOXIC EFFECTS:  The  convulsive  threshold was reached in 20 min;
                              abnormal  electrographs were seen before GABA antagon-
                              ism,  and  were related with seizures.  GABA was
                              ineffective  in  preventing convulsions.
ANIMALS:    Frog spinal cord preparation,  in vitro
ANIMALS:    Cats, surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:     5  to  20  meg/ml
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20 mcg/min/kg
ROUTE AND SITE:    in vitro

CONTROL INFORMATION:  ns
ROUTE AND SITE:    i.v.  infusion

CONTROL INFORMATION: Leptazol  (6 mg)  used as control
DURATION OF EXPERIMENT:      10 hr

EXAM.  TYPE: Electrophysiology
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:  Biochemistry, behavior
                                           153
                                                                                                                                        154

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COMPOUND:   Bicuculline (Biculline)
REFERENCE:
                 Johnston, G.A.R. and Mitchell, J.F.
                 J. Neurochem. 18:2441-2446, 1971.
OBSERVED NEUROTOXIC EFFECTS:
COMPOUND:  Biphenyl   (Diphenyl)

           000092524

REFERENCE:  Hakkinen, I., Siltanen, E., Hernberg,  S.,  Seppalainen,  A.M.
            Karli,  P. and Vikkula, E.
            Arch. Env. Hlth. 26:  70-74,  1973.
                                All four compounds influenced the release of GABA,
                                but not its uptake.  Biculline, at 10~5 M (not
                                more or less) potentiated evoked release of GABA
                                but not the resting release.   Metrazol inhibited
                                the electrically resting release but not the
                                electrically evoked release.   Strychnine and
                                picrotoxin inhibited the electrically evoked
                                release of GABA.
                                                                                              OBSERVED NEUROTOXIC EFFECTS:
                              There was  evidence  of  central and  peripheral nervous
                              system  damage.  The damage to the  peripheral nervous
                              system  was judged to be  demyelination,  while that of
                              central nervous system appeared  in an uncertain site
                              affecting  memory and temper as well as  sensorimotor
                              functions.   The damage was progressive, with minor
                              function recoveries, for observed  6-7 month follow-u
                              after stopping exposure  and the  authors state that
                              prognosis  must await longer follow-ups.
ANIMALS:     In vitro slices of rat cerebral cortex
                                                                                              ANIMALS:
            Human:  32 M, IF
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:    in vitro

CONTROL INFORMATION:  Lab
                           Preincubated with compounds for 15 min, then with labeled
                           GABA for 10 min.
PREPARATION AND DOSE
or HISTORY OF PATIENT
                                                                                              ROUTE AND SITE:
      History of exposure for various times to diphenyl in  fruit
      paper manufacture.  Case-reports of 1 fatal, 9 nonfatal ca
      exposed 5-15 yr to 4-128 mg/m  (measured in 1959) or  0.6-1
      mg/m (measured in 1970).  TLV of 1 mg/m  was set in 1968,
      manufacturers claimed no dangers in paper-making in 1965.
      process involved 800-840 hr/yr exposure to 128 (1959) or 6
      (1970) mg/ni
Inhalation and skin contact
CONTROL INFORMATION:   None, and  few  data  found  in literature
DURATION OF EXPERIMENT:     25 min

EXAM. TYPE:      Biochemistry
DURATION OF EXPERIMENT:    5-15 yr with  6-7 mo  follow-ups

EXAM. TYPE:   History (ethanol  and  tri-  and tetrachlorethylene solvents were
              eliminated), electromyography,  EEC
                                          155
                                                                                                                                       156

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 COMPOUND:   Biphenyl  (Diphenyl)
           000092524


 REFERENCE:   Seppalainen, A.M. and Hakkinen, I.
             J. Neurol. Neurosurg, Psychiat. 38:248-252, 1975.
COMPOUND:   Biphenyl,  chloro-
REFERENCE:   Mural,  Y.  and Kuroiwa,  Y.
             Neurology  21:1173-1176, 1971.
OBSERVED NEUROTOXIC EFFECTS: Abnormal EEC in 10, no recovery in 7 after 2 yr.
     Abnormal electromyographs in 9, fibrillation in 7.  Reduced nerve conductions.
     These signs also persisted.  Thus both central nervous system and peripheral
     nervous system were affected.
OBSERVED NEUROTOXIC EFFECTS:    Sensory neuropathy (symptoms and reduced
    conduction velocity)  found in about one-half of the cases.  Only one case
    of reduced motor conduction.
ANIMALS:   Human:  23 M and 1 F selected from a larger group with industrial
     exposure.
ANIMALS:
             21 Humans,  ages 7-60 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Chronic, long term, to concentrations well over the
     TLV of 1 mg/m-'.  Exposure ceased at start of study (after 1 fatality).
PREPARATION AND DOSE
or HISTORY OF PATIENT: 21 consecutive cases seen at a hospital, in a mass  outbreak
    of tetrachlorobiphenyl poisoning (total about 350 cases).  Contaminated  rice
    oil used for cooking.
ROUTE AND SITE:     Inhalation, skin contact, perhaps oral too.

CONTROL INFORMATION:   ns.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   Normal subjects were measured.
DURATION OF EXPERIMENT:   2 yr.

EXAM. TYPE:  Clinical, electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Clinical, electrophysiological
                                       157
                                                                                                                                     158

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COMPOUND:     Bis(p-aminophenoxy)  alkane  series
                                                                                           COMPOUND:  Biuret, diamino-
REFERENCE:   Udall, V.
            Proc. Roy. Soc. Med. 65:   197-199,  1972.
OBSERVED NEUROTOXIC EFFECTS:   Retinal damage to pigmented epithelium,  no pupil
                              reflexes, perception deficits.
REFERENCE:   Jenney,  E.H.  and Pfeiffer, C.C.
             J.  Pharm.  Exp.  Ther. 122:  110-123, 1958.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:     Convulsions
ANIMALS:    Cats and Rabbits
                                                                                            ANIMALS:     Mice, Harlan,  19-21  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    ns
PREPARATION AND DOSE
or HISTORY OF PATIENT:    3.0 mM/kgm
ROUTE AND SITE:  oral

CONTROL INFORMATION:   ns
ROUTE AND SITE:  i.p.

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Fundoscopy and histology
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:   Clinical
                                         159
                                                                                                                                      160

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 COMPOUND:
REFERENCE:
               Boric acid
               ni r\r\/. one o
Pfeiffer, C.C., Hallman, L.F. and Bersh, I.
J. Am. Med. Assn. 128:266-274, 1945.
COMPOUND:   Boric acid

           010043353

REFERENCE:  Watson, E.H.
            J. Am. Med. Assn. 129:332-333, 1945.
OBSERVED NEUROTOXIC EFFECTS:
               Acute:  antemortem rigidity of legs.  The largest amount of
               boric acid was found in the brain:  whole brain
               214 mg/100 cc, cortex 231, corpus callosum
               142 mg/100 cc.  There was an increase of microglia,
               and a shrinkage of cord neurons.  Cortex lesions
              "were distributed through grey-matter in some, and
               concentrated around blood vessels in others.
               There was an accumulation in the brain after
               repeated doses.
OBSERVED NEUROTOXIC EFFECTS:   Fatai in 3 wk.  convulsions and coma, blindness,
                               deafness.  At autopsy "irreparable damage  to the
                               central nervous system" but brain not reported
                               as examined.
ANIMALS:
               Dogs
                                                                                              ANIMALS:    Human:  M, age 4 1/2 mo., fatal case.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
          Acute:  1.5-2 g/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Eczema, treated with whole-body applications of  compound,
                         total estimated 60-100 g.
ROUTE AND SITE:      Acute:  S.C.

CONTROL INFORMATION:      ns.
                                                                               ROUTE AND SITE:   Topical

                                                                               CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:    Behavior, biochemistry, histology
                                                                               DURATION OF EXPERIMENT:  3 wk.

                                                                               EXAM. TYPE: Clinical
                                         161
                                                                                                                                     162

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COMPOUND:    Boric acid, tri-o-tolyl ester
                                                                                              COMPOUND:   Botulinum toxin type A
REFERENCE:      Hine,  C.H., Dunlap, M.K., Rice, E.G., Coursey, M.M., Gross, R.M.
                and Anderson, H.H.
                J. Pharm. Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC EFFECTS:      (1) All had paralysis.  (2) All died.
                                                                                              REFERENCE:  Duchen, L.W.
                                                                                                          Proc. Roy. Soc. Med. 65:  196-197, 1972.
                                                                                              OBSERVED NEUROTOXIC EFFECTS:
                              The leg muscles were paralysed  in  24  hours and
                              recovered after 1 week.  Progress  and abnormalities
                              in axonal regenerating sprouts  were observed
                              sequentially in time.  The  author  concluded that
                              the toxin binds either to the presynaptic axolemma
                              or to a component of the motor  nerve  terminal
                              axoplasm to block neuromuscular transmission; only
                              new axonal tissue can transmit.  Also concluded that
                              the compound can induce the observed  regeneration.
ANIMALS:
                22  Chickens, White Leghorn, M, 0.75-1.3 kg
ANIMALS:    Mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:     (1)  0.5 gm/kg
                          (2)  1.0 gm/kg
                                                                                              PREPARATION AND DOSE
                                                                                              or HISTORY OF PATIENT:   "Sublethal" doses
ROUTE AND SITE:    (1)  S.C.,    (2) Oral

CONTROL INFORMATION:    One group of 5 per experimental group.
                                                                                              ROUTE AND SITE:   LM., one hindleg

                                                                                              CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   14-36 d after treatment.

EXAM. TYPE:      Behavior, histology
                                                                                              DURATION OF EXPERIMENT:   Probably 6-7 d

                                                                                              EXAM.  TYPE:   Histology
                                          163
                                                                                                                                       164

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COMPOUND:  Botulinum toxin type A
COMPOUND:
              Botulinum toxin type A
REFERENCE: Holman, M.E. and Spitzer, N.C.
           Br. J. Pharmac. 47:  431-433, 1973.
                                                                                          REFERENCE:
             Simpson,  L.L.  and Rapport,  M.M.
             J.  Neurochem.  18:1341-1343,  1971.
OBSERVED NEUROTOXIC EFFECTS:   The toxin depressed or abolished transmission from
                              postganglionic nerves to smooth-muscle, less rapidly
                              than in rat diaphragm reported elsewhere.
                                                                                          OBSERVED NEUROTOXIC EFFECTS:
                                 (1)  Trisialoganglioside G± produced the solution
                                with the  least residual toxicity.  (2) Survival
                                time was  prolonged in ratio to the amount of
                                G^;  asialo-G^-ganglioside was ineffective in vitro
                                and  in  vivo as were sialic acid, glucose, galactose,
                                galactosamine, or ceramide.  (3) Potency for
                                paralysing synaptic transmission was similarly
                                diminished.  Authors' conclusion:  first
                                demonstration of direct interaction of a compound
                                with a  natural constituent of nerve tissue.
ANIMALS:   Isolated vas deferens preparations from mice and guinea-pigs
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Concentrations of compound ns
ANIMALS:     (1)  In vitro  incubation of  toxin with test substances
             (2)  Residual  toxicity  tested in mice in vivo.
             (3)  Residual  toxicity  measured in vitro in rat phrenic nerve-diaphragm
                 preparations.
PREPARATION AND DOSE
or HISTORY OF PATIENT:      (1)  Brain gangliosides singly or mixed 0.1-100 meg
                                incubation with compound type A at 103 or 10^ MLD/ml.
                            (2)  10  4 MLD incubation, 0.1 ml of solution.
                            (3)  as  for (2).
ROUTE AND SITE:    Incubations in vitro

CONTROL INFORMATION:   ns



DURATION OF EXPERIMENT:   Up to 6 hr

EXAM. TYPE:   Electrophysiology
ROUTE AND SITE:   (1)  In vitro   (2)  I.V.   (3)  Added to incubation mix in vitro.
CONTROL INFORMATION:
(1)  Without ganglioside.
(2)  Without ganglioside,  103 MLD.
(3)  Similar.
DURATION OF EXPERIMENT:     (1)  ns.   (2)  Over 300 min.   (3) ns.

EXAM.  TYPE:  (1)  Chemistry   (2)  Survival  time  (3) Physiology
                                        165
                                                                                                                                     166

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COMPOUND:       Brisacodyl
REFERENCE:      Steer,  H.W.  and Colin-Jones,  D.G.
                J.  Path.  115:199-205,  1975.
COMPOUND:     a-Bungarotoxin

              11032794

REFERENCE:    Katz,  B. and Miledl, R.
              Br.  J. Pharmac. 49:  138-139, 1973.
OBSERVED NEUROTOXIC EFFECTS:    More lysosomal activity  and  lysosomes  in Schwann
                               cells and neurons  of  submucosal  plexus of colonic
OBSERVED NEUROTOXIC EFFECTS:   The toxin inhibited acetylcholine sensitivity
                               irreversibly but not the amplitude nor  time-
                               course of "elementary" potential changes.
ANIMALS:
                Human:   7 aged 24-80 with melanosis coli who took purgatives;
                        1 who had taken purgatives for  only 1 m.
ANIMALS:      in vitro endplates of frog muscle fibers
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Rectal biopsy before and 3-7  m after stopping medication
PREPARATION AND DOSE
or HISTORY OF PATIENT:   lontophoretic application
ROUTE AND SITE:

CONTROL INFORMATION:
                          7 aged 27-70 with other gut disorders who had taken no
                          purgatives for 3 m.
ROUTE AND SITE:    m vitro

CONTROL INFORMATION:  Laboratory
DURATION OF EXPERIMENT:    About 7 m.

EXAM.  TYPE:     Histology, histochemistry
DURATION OF EXPERIMENT:    About 30 min

EXAM. TYPE:    Electrophysiology
                                        167
                                                                                                                                      168

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COMPOUND:
1,3-Butanediamine,  N,N,N',N'-tetramethyl-

000097647
REFERENCE:  Goldberg, M.E. and Johnson, H.E.
            Tox. Appl. Pharm. 4:522-545, 1962.
COMPOUND:   1,4-Butanediol

            0001110634

REFERENCE:  Zabik, J.E., Van Dam, D.P.  and Maickel,  R.P.
            Res. Conm. Chem. Path. Pharm. 8(1):83-90,  1974.
OBSERVED NEUROTOXIC EFFECTS:   This compound selectively blocked autonomic ganglia,  and
                              produced ocular disturbances.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                Loss of righting reflex, assumed  to  show toxicity.
                                                                                                                This reflex was reduced, dose-dependent,  from
                                                                                                                50 mg/kg on up, with complete loss at  300 and 400
                                                                                                                mg/kg.  No increase in triglycerides (metabolic).
ANIMALS:     Rats, CFE, M, 5-6 wk old, 90-120 g, 5 rats/grp or 6/grp  (inhalation)
            Rabbits, NZ white, 2.5-3.5 kg, M, 4 rabbits/grp, and isolated ileum.
            Mice, white, F, 20^28 g.
            41 mongrel dogs (8.5-12.5 kg) M and F.  10 cats, F, 2.2-3.8 kg.
PREPARATION AND DOSE
or HISTORY OF  PATIENT:      Various schedules
                                                                               ANIMALS:     Rats, S-D, M, 300-350 g
                                                                               PREPARATION AND DOSE
                                                                               or HISTORY OF PATIENT:
                                                                                                           50-1600 mg/kg/d, 1-14 doses.  1600 mg/kg was  LD,QO»
                                                                                                           1328 mg/kg was U>50,  «° deaths below  1000  mg/kg.
ROUTE AND SITE:   Topical, shaved skin  (rabbits); inhalation  (rats, mice);
                 intra-arterial  (carotid)  (dogs, cats) and I.V.  femoral  (dogs, cats)
CONTROL INFORMATION:   Varied.
                                                                                ROUTE AND SITE:   i.p.

                                                                                CONTROL  INFORMATION:   Mentioned, not described
DURATION OF EXPERIMENT:     Various

EXAM. TYPE: Physiology, biochemistry
                                                                                DURATION OF  EXPERIMENT:     ns.

                                                                                EXAM. TYPE:  Behavior, metabolism
                                           169
                                                                                                                                        170

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COMPOUND:    2-Butanol,4-(dlmethylamino)-3-methyl-l,2-diphenyl-,  propionate  (ester),
             hydrochloride (-•-)-

             001639607

REFERENCE:   Chapman,  J.E.  and  Walaszek,  E.J.
             Tox.  Appl.  Pharm.  4:752-758, 1962.


OBSERVED NEUROTOXIC EFFECTS:  The LD    of this compound, when given  i.p., was
                             68-105  mg/kg.  Convulsions produced and shown
                             to  be of  cerebral origin.
COMPOUND:   2-Butanol, 4-(dimethylamino)-3-methyl-l,2-diphenyl-,  propionate (ester).
            hydrochloride  (+)-
            001639607

REFERENCE:  Young,  D.J.
            Arch.  Int. Med.  129:62-66,  1972.


OBSERVED NEUROTOXIC EFFECTS:  Tissue levels reached 130 mg/kg in brain where
                              measured.  Convulsions and respiratory arrest.
                              Blood levels miniscule.  Death resulted from anoxia
                              and complications.  Central nervous system stimulation
                              hypothesized by author.
ANIMALS:      Rats,  Holtzman,  F,  200  g
                                                                                                ANIMALS:   Human:   10 cases,  9 suicides and 1 survival (3M, 7 F)
PREPARATION AND DOSE
or HISTORY OF PATIENT:  10-160 mg/kg with/without nalorphine; Some rats were
                       prepared surgically-spinal cord  sectioned.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Doses of 1-2 g where known.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:    Antagonist or no controls.
ROUTE AND SITE:   Oral None

CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:   Observed until death or  recovery.

EXAM.  TYPE:  Behavior, mortality.
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:   Pathology (gross), behavior
                                          171
                                                                                                                                        172

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COMPOUND:    Butyl alcohol
             onnrmifii

REFERENCE:  Roach, M.K., Davis, D.L. Pennlngton, W. and Nordyke, E.
            Life Sci. 12(1):433-441, 1973.
OBSERVED NEUROTOXIC EFFECTS:
                                Butanol inhibited active transport of probable
                                neurotransmitters of the central nervous system
                                by synaptosomes.  Authors conclude that alcohol
                                interacts with membrane lipids of synaptosome.
COMPOUND:     Butyric acid, 4-amino

              000056122

REFERENCE:     Olney, J.W. , Ho, O.L. and Rhee, V..
               Exp. Brain Res. 14:61-76, 1971.


OBSERVED NEUROTOXIC EFFECTS:   N°  cytotoxicity was  observed.
ANIMALS:     Rats, S-D, M, 200-250 g, brains removed and homogenates incubated in vitro.
                                                                                              ANIMALS:  Mice, Swiss-webster  age  10 d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT: Butanol added as 25% soln, at start of preincubation period.
                      Butanol cone 5-30 mg/ml.  Incubated in vitro with labeled
                      norepinephrine, GABA and glutamate.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Initially 12 mmoles/kg,  then range established for
                         each compound.
ROUTE AND SITE:   in vitro

CONTROL INFORMATION:   Control:  incubation in medium with no alcohol.



DURATION OF EXPERIMENT:  Laboratory procedure

EXAM. TYPE: Biochemistry
                                                                                              ROUTE AND SITE:
                                                                                                                   S.C.
CONTROL INFORMATION:     Compounds  compared with monosodium L-glutamate  (MSG)
                         potency  for  selectively necrosing neurons in retina
                         and brain  (hypothalamus)

DURATION OF EXPERIMENT:  5 hr  or  serial intervals including 5 hr.

EXAM. TYPE:    Histology
                                           173
                                                                                                                                        174

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COMPOUND:    Butyric acid, 2-amino-4-hydroxy-,  phosphonate,  (ester)
                                                                                           COMPOUND:  Butyric acid,  2-amino-A-sulfino-,  DL-
REFERENCE:     Olney, J.W.,  Ho,  O.L.  and Rhee,  V.
               Exp.  Brain Res.  14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:   The compound was  toxic to  non-neurol components
                              (glia, etc.), but not to neurons.
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:  N-methyl-D-aspartic and D-homocysteic acids were
                              stronger  excitants of depolarization than all
                              others.   With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was  terminated,  notably N-n_-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested;  structure-activity relationship
                              was  observed.
ANIMALS:   Mice, Swiss-webster  age 10 d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg,  then range established for
                         each compound.
ANIMALS:  Cats prepared  for  electrophoretic application of chemicals to single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions  0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals .including 5 hr.

EXAM. TYPE:    Histology
ROUTE AND SITE:      Electrophoretic  application, various sites in central nervous
                     system.
CONTROL INFORMATION:
                          None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:     Electrophysiological
                                        175
                                                                                                                                   176

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 COMPOUND:     Butyric acid, 2-hydrazino-2-methyl-
                                                                                           COMPOUND:   Butyric acid, 2-(methylamino)-4-sulfo-,  DL-
 REFERENCE:   Jenney,  E.H.  and  Pfeiffer,  C.C.
             J.  Pharm.  Exp.  Ther.  122:   110-123,  1958.


 OBSERVED NEUROTOXIC EFFECTS:   Convulsions
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:   N-methyl-D-aspartic and D-homocysteic acids were
                                                                                                                         stronger excitants of depolarization than  all
                                                                                                                         others.  With some compounds the action was
                                                                                                                         prolonged for many seconds after the stimulus
                                                                                                                         was terminated, notably N-n-propyl-D-aspartic
                                                                                                                         acid.  There were no differences among types of
                                                                                                                         neurons tested; structure-activity relationship
                                                                                                                         was observed.
ANIMALS:    Mice, Harlan, 19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1.52 mM/kgm
ANIMALS:  Cats prepared for electrophoretic application of chemicals  to single
          central nervous system neurons.


PREPARATION AND DOSE
Or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of  31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in  order of
                         potency of results.
ROUTE AND SITE:   I.p.

CONTROL INFORMATION:   ns
ROUTE AND SITE:      Electrophoretic application, various  sites  in central nervous
                    system.
CONTROL INFORMATION:
                         None
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:   ns.   '

EXAM. TYPE:    Electrophysiological
                                        177
                                                                                                                                    178

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COMPOUND:   Cadmium chloride

            010108642

REFERENCE:  Gabbiani, G., Bale, D. and Deziel, C.
            Exp. Neurol. 18:154-160, 1967..
OBSERVED NEUROTOXIC EFFECTS:     Hemorrhagic damage, especially to granular layer
                                of cerebellum, also cerebrum, but only in young rats
                                and rabbits.
                                                                     COMPOUND:  Cadium chloride

                                                                                010108642

                                                                     REFERENCE: Gabbiani, G., Gregory,  A.  and  Baic,  D.
                                                                               J. Neuropath. Exp. Neurol.  26(3):498-506,  1967.
                                                                     OBSERVED NEUROTOXIC EFFECTS:   Acute hemorrhagic lesions of Gasserian and
                                                                          sensory  spinal ganglia in all species.   Nuclear pyknosis, PAS - and
                                                                          H-positive masses  in nerve fibers.   Pretreatment with zinc acetate or
                                                                          glutathione  protected the animals.
ANIMALS:     Rats,  aged  1-30 d, 5 groups of 10  (S-D)
             Rabbits,  43, aged 1-30 d
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Rats:  10 mg/kg
Rabbits:  20 mg/kg
ANIMALS:   Guinea-pigs, golden hamsters, and mice in grps of 10; 260 rats:
           S-D, 205 g, in grps of 15.  3 grps of rats also had surgical transection
           of the spinal cord, right sciatic and femoral nerves.

PREPARATION AND DOSE
Or HISTORY OF PATIENT:  10 mg/kg in water (1 ml/inj); rats given 2 mg/rat  in 1 ml
     of water.
ROUTE AND SITE:   S.C.

CONTROL INFORMATION:   2 rats/1 rabbit per  group untreated.
                                                                     ROUTE AND SITE:   S.C.,  interscapular region

                                                                     CONTROL INFORMATION:     20 rats untreated
DURATION OF EXPERIMENT:     30 d mentioned, real duration ns.

EXAM. TYPE:  Histology
                                                                     DURATION OF EXPERIMENT:  1-96 hr

                                                                     EXAM.  TYPE:  Behavior, histology
                                           179
                                                                                                                                        180

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COMPOUND:   Cadmium chloride
REFERENCE:   Tischner, K.H. and  Schroder, J.M.
             J. Neurol. Sci. 16:383-399, 1972.
OBSERVED NEUROTOXIC EFFECTS:    Glycogen deposits in periphery of neuronal
    perikarya,  dose-related.  Other ultrastructural changes including mitochondria
    and  unmyelinated  axons  (degeneration).  Authors conclude that cadmium ions
    are  direct  pathogens  for nerve tissues.
                                                                                        COMPOUND:   Caffeine
REFERENCE:  Scott, C.C., Anderson, R.C.  and  Chen,  K.K.
            J. Pharm. Exp. Ther. 86:   113-119,  1946.


OBSERVED NEUROTOXIC  EFFECTS:   Produced  tetanic convulsions.
ANIMALS:     Dorsal root  ganglia  from 19-21  d Wistar rat embryos in culture.
                                                                                        ANIMALS:   Mice
PREPARATION AND DOSE            ,
or HISTORY OF PATIENT:    4 x  10   M  in medium, replenished every 3 d, exposures
                         1 d  to  3 wk.
                                                                                        PREPARATION AND DOSE
                                                                                        or HISTORY OF PATIENT:
                          84.4 mg/kg (median convulsive dose)
ROUTE AND SITE:   In vitro

CONTROL INFORMATION:   ns.
ROUTE AND SITE:    I.V.,  tail vein

CONTROL INFORMATION: ns
DURATION OF EXPERIMENT:   Cultures maintained up  to  2  mo.

EXAM. TYPE:  Histology,  chemistry
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:  Clinical
                                       181
                                                                                                                                       182

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 COMPOUND:
             Calcium chloride

             010043524
 REFERENCE:   Tang,  A.H.  and Schroeder,  L.A.
             Tox. Appl.  Pharm.  12:44-47,  1968.
COMPOUND:
                                                                                                          Carbamic acid,  diethylthio-,  sodium salt
REFERENCE:  Edington,  N.  and Howell,  J.  McC.
            Nature 210:1060-1062,  1966.
OBSERVED NEUROTOXIC EFFECTS:  The  compound  did not antagonize the effects of
                              lincomycin.
OBSERVED NEUROTOXIC EFFECTS:
Copper level in the CNS  was increased by  compound,
not by saline.  Cord white matter had Wallerian
degeneration throughout, loss of structure in
some grey-matter neurons.  Corpus striatum
not damaged.  Some sciatic nerves also contained
Wallerian degeneration.
ANIMALS:     3 rabbits
ANIMALS:    18 Rabbits,  Dutch and NZ
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.1-50 mg/kg during the neuromuscular blockade produced by
                       lincomycin.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dose ns., but after 5 mo. it was 10 ml/kg/d, in 15
                          rabbits for a further 2.5 mo.
ROUTE AND SITE:   i.v.

CONTROL INFORMATION:    ns.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:      3 given saline, 5 ml/kg/d.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Electrophysiology
DURATION OF EXPERIMENT:   Approx 7.5 mo.

EXAM. TYPE:   Histology, biochemistry
                                          183
                                                                                                                                        184

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COMPOUND:
           Carbamic acid, diethyldithio-, sodium salt
COMPOUND:  Carbamic acid, diethylthio-, sodium salt
REFERENCE:   Edington,  N.  and Howell,  J.  McC.
             Acta Neuropath.  12:339-347,  1969.
REFERENCE:   Howell, J. McC. and Edington, N.
             J. Neuropath. Exp. Neurol. 27:464-472, 1968.
OBSERVED NEUROTOXIC EFFECTS:    Degeneration:   at  6 wk in accessory cuneate
    nucleus and Clarke's column,  at 18 wk in spinocerebellar tracts of  cerebellum
    and in medulla,  at 24 wk in peripheral white-matter of cord.   Peripheral
    Nervous System effects "minimal."
OBSERVED NEUROTOXIC EFFECTS:     Wallerian nerve fiber degeneration  in -cerebellum,
    medulla, cord, and peripheral nerves.
ANIMALS:     25 Rabbits,  (Dutch x NZ),  M and  F,  2.6-3.3 kg  in  5  grps of  5.
                                                                                            ANIMALS:   13 Hens, Thornber's 404  strain,  age 6 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   330 mg/kg/d,  6  d/wk,  in buffer  to  all  5  grps.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  330 mg/kg/d, 5 d/wk, as 10% solution  in phosphate buffer
    pH 7.2-7.4  (7 hens).
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:   None
ROUTE AND SITE:  Deposited in crop

CONTROL INFORMATION:   4 hens given saline in buffer
DURATION OF EXPERIMENT:   Serial  sacr  6-30 wk.

EXAM. TYPE: Histology
DURATION OF EXPERIMENT:   19 wk

EXAM. TYPE:  Histology
                                       185
                                                                                                                                    186

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COMPOUND:  Carbamic acid,  diethylthio-,  sodium  salt
                                                                                            COMPOUND:
           Carbamic acid, diethylthio-,  sodium salt
REFERENCE:  Howell, J. McC.,  Ishmael, J., Ewbank, R. and Blakemore, W.F.
            Acta Neuropath. 15:197-207,  1970.
REFERENCE:  Rasul,  A.R. and Howell, J.McC.
            Acta Neuropath. 24:68-75, 1973.
OBSERVED NEUROTOXIC EFFECTS:  No signs of incoordination.  All lambs had
     peritonitis.   Microscopic lesions in medulla and spinal cord:  swollen
     axons  but  no  nerve  fiber degeneration.  High copper levels found in spinal
     cord.
OBSERVED NEUROTOXIC EFFECTS:  Degeneration of the long tracts of the spinal
     cord:  fragmented axons and ballooned myelin sheaths.  Lesions could  be
     traced into cerebellum.  Lesions were first seen after 18 wk in chicks and
     4 wk in adults.  Ataxia was observed after 25 wk in chicks and 5 wk in adults.
     Degeneration characterized as a "dying back process" and an "organophosphorous
     pattern."
ANIMALS:    Sheep,  20  Clun Forest purebreds or crosses, 5 aged 2 d, 11 aged 1 mo.
                                                                                            ANIMALS: Cockerels, Thornber's 909, aged 1 wk or 6 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   165  or  330 mg/kg in phosphate buffer pH 7.0, daily 5 d/wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  330 mg/kg/d, 6 d/wk, in phosphate buffer
ROUTE AND SITE:  i.P.

CONTROL INFORMATION:   2 aged  2  d, vehicle only
ROUTE AND SITE:  Oral

CONTROL INFORMATION:  Untreated birds
DURATION OF EXPERIMENT:   one survivor  arid  the controls sacr at 16 wk.

EXAM. TYPE: Histology, behavior,  biochemistry.
DURATION OF EXPERIMENT:  Serial to 35 wk

EXAM. TYPE:  Behavior, histology
                                      187
                                                                                                                                    188

-------
 COMPOUND:       Carbamic acid, diethyldithio-, sodium salt

                UUUJL4B103


 REFERENCE:      Rasul, A.R. and Howell, J. McC.
                Acta Neuropath. 24:161-173, 1973.
                                                                           COMPOUND:    Carbamic acid, ethyl ester
                                                                           REFERENCE:  Fern.,  V.H.
                                                                                       Arch.  Path.  81:   174-177,  1966.
 OBSERVED NEUROTOXIC EFFECTS:   No effects on neuromuscular endplates, peripheral
                               nerves, or "teased" nerve fibers.  Treatment
                               for 9 wk, fewer large-diameter fibers.  In central
                               nervous system:  Wallerian degeneration and
                               eosinophilic bodies seen after 4 wk of treatment;
                               long spinal tracts involved, initial lesions
                               inferred in thoracic cord. •
                                                                           OBSERVED NEUROTOXIC EFFECTS:   Exencephaly and failure of neural tube to close after
                                                                                                         administration of compound, more so after I.V. treatment.
ANIMALS:
20 Rabbits, Dutch, M, 12 wk, 1.88-2.48 kg.
                                                                                           ANIMALS:    Golden hamsters, F,  pregnant, 100-125 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    330 mg/kg/d, 5-d/wk as 10% soln in NaPO
                          buffer pH 7.2-7.4
                                                                           PREPARATION AND DOSE
                                                                           Or HISTORY  OF PATIENT:   25-150 rag/hamster on d 9,  10 or 11
ROUTE AND SITE:  Oral

CONTROL INFORMATION:       10 rabbits NaPO buffer only.
                                                                           ROUTE  AND SITE:   t.V.  lingual vein  or  I.P.

                                                                           CONTROL  INFORMATION: ns
DURATION OF EXPERIMENT:    Serial sacr 4,6,9 wk.

EXAM. TYPE:     Histology
                                                                           DURATION OF  EXPERIMENT:    24-72 hr. after  treatment.

                                                                           EXAM. TYPE:    Teratological
                                        189
                                                                                                                                     190

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COMPOUND:
            Carbamic  acid,  dimethyl-6-methyl-2-propyl-4-pyrimidnyl ester

            002532492
REFERENCE:   Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm. 11:  49-67, 1967.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
                                                                    COMPOUND:   Carbamic acid, methyl-, benzo(b)thien-4-yl-ester

                                                                                0010793310

                                                                    .-EFERENCE:  Galnes, T.B.
                                                                                Tox. Appl. Pharm.  14:   515-534,  1969.


                                                                    OBSERVED  NEUROTOXIC EFFECTS:    400 mg/kg produced leg weakness
ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
                                                                                             ANIMALS:    Chickens, White Leghorn, F
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute:  LD - 60.0 mg/kg
                         	     2:  50-8C-
(2)  Subacute:   50-800  ppm in  diet,  20 chicks/grp, for 2 wk
                                                                     PREPARATION AND DOSE
                                                                     or HISTORY OF PATIENT:    15 mg/kg atropine sulfate orally 15 min prior  to compound;
                                                                                               graded doses compound in peanut oil
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
                                                                     ROUTE AND SITE:   S.C.,  under right wing

                                                                     CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:  Behavior, mortality
                                                                     DURATION OF EXPERIMENT:   1 yr

                                                                     EXAM. TYPE:    Clinical
                                            191
                                                                                                                                         192

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COMPOUND:      Carbamic Acid, methyl-, benzo(b)thien-4-yl-ester

               001079330


REFERENCE:  Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
            Toxicol. Appl. Pharm. 11:  49-67, 1967.


OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
              Carbamic acid,  methyl-, S-sec-butyl-2-chlorophenyl ester
                                                                                             COMPOUND:
REFERENCE:   Sherman, M.,  Herrick,  R.B.,  Ross,  E.  and Chang, M.T.Y.
             Toxicol. Appl. Pharm.  11:   49-67,  1967.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia,  paralysis,  convulsions.
ANIMALS:  Cockerels, Single Comb White Leghorn, 10-12 d old
                                                                                            ANIMALS:   Cockerels,  Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD5Q 85.4 mg/kg
                         (2) Subacute:  50-800 ppm in diet, 20 chicks/grp, for 2 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute: LD    19.4 mg/kg
                         (2) Subacute:   50-800  ppm in diet,  20 chicks/grp, for 2 wk
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  Untreated  control grps
DURATION OF EXPERIMENT:    1-3 wk

EXAM. TYPE:  Behavior, mortality
DURATION OF EXPERIMENT:    1-3 wk

EXAM.  TYPE:   Behavior,  mortality
                                             193
                                                                                                                                         194

-------
COMPOUND:
             Carbamic acid,  methyl-m-sec-butylphenyl ester
REFERENCE:   Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm. 11:  49-67, 1967.
OBSERVED NEUROTOXIC EFFECTS:  Ataxia, paralysis, convulsions.
COMPOUND:   Carbamic acid, methyl-, m-cumenyl ester

            000064006

REFERENCE:  Sherman, M.,  Herrick,  R.B.,  Ross,  E.  and Chang, M.T.Y.
            Toxicol. Appl. Pharm.  11:   49-67,  1967.


OBSERVED NEUROTOXIC EFFECTS:   Ataxia,  paralysis,  convulsions.
ANIMALS:  Cockerels,  Single Comb White Leghorn, 10-12 d old
                                                                                             ANIMALS:   Cockerels, Single Comb White  Leghorn,  10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD5Q 13.6 mg/kg
                         (2) Subacute:  50-800 ppm in diet, 20 chicks/grp, for 1 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  Acute:  LI>50  12.0 mg/kg
                         (2)  Subacute:   50-800 ppm in diet, 20 chicks/grp, for 2 wk
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
DURATION OF EXPERIMENT:   1-3 wk

EXAM.  TYPE:   Behavior, mortality
DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:   Behavior, mortality
                                            195
                                                                                                                                          196

-------
 COMPOUND:    Carbamic acid, methyl-,2,3-dlhydro-2,2-dimethyl-7-benzofuranyl ester

             001563662

 REFERENCE:   Sherman, M., Herrick, R.B.,  Ross,  E.  and Chang,  M.T.Y.
             Toxicol. Appl. Pharm. 11:  49-67,  1967.


 OBSERVED NEUROTOXIC  EFFECTS:   Ataxia, paralysis,  convulsions.
ANIMALS:   Cockerels,  Single Comb White  Leghorn,  10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute: LD,,. 6.3 mg/kg
                         (2) Subacute:  50-800 ppm in diet, 20 chicks/grp, for 2  wk
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   Untreated control grps



DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:  Behavior, mortality
                                            197
 COMPOUND-  Carbamlc acld'  methyl-,4-dimethyl-amino-3,5-xylyl ester

           000315184

 REFERENCE:Tucker, R.K. and Crabtree, D.G.
          J. Econ. Entomol. 62:1307-1310, 1969.
                                                                                                 OBSERVED NEUROTOXIC EFFECTS:
                              Varying with the species the following symptoms
                              were observed:  Tachypnea, ataxia, tremors,
                              salivation, lachrimation, plloerection, clonic
                              or tonic convulsions, opisthotonus, phonation,
                              anorexia, nystagmus.  Death tended to follow
                              respiratory paralysis.  Birds were generally
                              more susceptible than mammals; cumulative
                              effects were not marked; teratology was not
                              demonstrated; the authors concluded that practical
                              exposures would be far below toxic levels.
ANIMALS:  Rats (S-D), Rabbits (NZ White), Lesser sandhill cranes, Canada  geese,
          Mourning doves, Mallard ducks, Coturnix quails, Ring-necked pheasants,
          House finches, Chukar partridges, Domestic pigeons, Sharp-tailed
          grouse, Domestic goats, Mule deer, House sparrows, Bullfrogs.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Acute oral U),Q varied from 1 mg/kg in cranes to
                         800 mg/kg in bullfrogs.  Subacute feeding  tests
                         at various doses.  Acute dermal toxicity tests
                         in rabbits, 2 g/kg.


ROUTE AND SITE: oral; dermal

CONTROL INFORMATION:      ns.



DURATION OF EXPERIMENT:   Subacute, 30 d.

EXAM. TYPE Behavior, mortality
                                                                                                                                         198

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COMPOUND:
               Carbamic acid, methyl-, m-(l-methylbutyl)phenyl ester
REFERENCE:  Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
            Toxicol. Appl. Pharm. 11:  49-67, 1967.
COMPOUND:  Carbamic acid, methyl-,  1-naphthyl  ester

           000063252

REFERENCE:  Gaines, T.B.
            Tox. Appl. Pharm. 14:   515-534,  1969.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
OBSERVED NEUROTOXIC EFFECTS:   800 mg/kg produced  leg weakness
ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
ANIMALS:    Chickens, White Leghorn, F
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute:  LD Q 44.3 mg/kg
                        (2) Subacute:  50-800 ppm in diet,  20 chicks/grp,  .for 2  wk
PREPARATION AND  DOSE
or HISTORY OF  PATIENT:    15 mg/kg atropine  sulfate orally 15 min prior to compound
                          graded doses  compound in peanut oil
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
 ROUTE  AND  SITE:   S.C., under right wing

 CONTROL  INFORMATION:   ns
DURATION OF EXPERIMENT:   1-3 wk

EXAM.  TYPE:  Behavior, mortality
 DURATION  OF EXPERIMENT:   1 yr

 EXAM.  TYPE:    Clinical
                                            199
                                                                                                                                         200

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COMPOUND:   Carbamic acid, methyl-, 1-naphthyl ester
REFERENCE:   Smalley,  H.E.,  O'Hara,  P.J.,  Bridges,  C.H.  and  Radeleff,  R.D.
             Tox.  Appl.  Pharm.  14:409-419,  1969.


OBSERVED NEUROTOXIC EFFECTS: Myasthenia,  incoordination,  ataxia,  tremor,
                             clonic contractions,  paraplegia.   Compound
                             inhibits  cholinesterase.   Central  nervous
                             system lesions:   edema of  tnyelinated tracts of
                             cerebellum,  brain stem,  and  upper  cord,  with  vascular
                             degeneration.

                                                                                                       Carbamic acid, methyl-, 3,4-5-trimethylphenyl  ester
REFERENCE:  Gaines, T.B.
            Tox. Appl. Pharm. 14:  515-534, 1969,


OBSERVED NEUROTOXIC EFFECTS:   400 mg/kg produced  leg weakness
ANIMALS:     Pigs,  Yorkshire,  litter of 4 M and 4 F,  in 2  groups.
                                                                                            ANIMALS:    Chickens, White Leghorn, F
PREPARATION AND DOSE
or HISTORY OF PATIENT:  150 and 300 mg/kg/d in diet.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    15 mg/kg atropine sulfate orally  15 min prior to compound;
                          graded doses compound in peanut oil
ROUTE AND SITE:     Oral,  incidental inhalation

CONTROL INFORMATION:    2  pigs of litter
ROUTE AND SITE:   S.C.,  under right wing

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   Up to 85 d

EXAM. TYPE:  Clinical,  histology
DURATION OF EXPERIMENT:   1 yr

EXAM. TYPE:    Clinical
                                           201
                                                                                                                                       202

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COMPOUND:
               Carbonic add, methyl-,3,4-5-trioethylphenyl ester

               002686999

            Sbenam, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
                        l. Fharo. 11:  49-67, 1967.
                              Ataxia, paralysis, convulsions.
                                                                                                COMPOUND:    Carbohydrazlde

                                                                                                             000497187

                                                                                                REFERENCE:   Jenney, E.H. and Pfelffer, C.C.
                                                                                                             J, Pharm. Ezp. Ther. 122:  110-123,  1958.


                                                                                                OBSERVED NEUROTOXIC tfFtCTS:    Convulsions
AJHIWLS:  Cockerels, Single Comb White Leghorn, 10-12 d old
                                                                                                ANIMALS:     Mice. Bar Ian, 19-21 g
PREPARATION MID MSE
or HISTORY OF PATIENT:   (1) Acute: LD^ 50.3 ng/kg
                         (2) Snbacute:  50-800 ppm in diet, 20 chicks/grp, for 2 wk
                                                                                                 PREPARATION AND DOSE
                                                                                                 or HISTORY Of PATIENT:    1.3 nM/kgm
pROMTE Mm SITE:  Oral

        ' IJtFOJMftTIOSI:   Untreated control grps
                                                                                                ROUTE AND SITE:   i.v.

                                                                                                CONTROL INFORMATION:  ns
        I OF EXPERINENT:  1-3 sk

EXAM. TYPE:  Behavior, mortality
                                                                                                 DURATION OF EXPERIMENT:  Acute

                                                                                                 EXAM. TYPE:  Clinical
                                            203
                                                                                                                                         204

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 COMPOUND:
           Carbohydrazide, thio-
           002231574
 REFERENCE:   Jenney,  E.H.  and Pfelffer, C.C.
             J.  Fhann.  Exp. Ther. 122:  110-123, 1958.


 OBSERVED NEUROTOXIC EFFECTS:    Convulsions
COMPOUND:   Carbon dioxide
REFERENCE:  Walker,  J.L.,  Jr. and  Brown, A.M.
            Science  167:1502-1504, 1970.
                                                                                          OBSERVED NEUROTOXIC EFFECTS:
                                 Some neurons  were depolarized,  others hyperpolarized,
                                 others  unaffected.   Mechanism:  acidosis that
                                 increased  membrane chloride conductance of responsive
                                 cells.
ANIMALS:    Mice, Harlan,  19-21  g
                                                                                          ANIMALS:     Aplysia californica surgically prepared.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.04 mM/kgm
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                      Abdominal ganglion exposed to 5% CO
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:   ns
ROUTE AND SITE:   Laboratory methods  described.

CONTROL INFORMATION:   Described
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:     About.1 min.

EXAM. TYPE:  Electrophysiology
                                         205
                                                                                                                                     206

-------
COMPOUND:   Carbon disulfide

             000075150

REFERENCE:  Alpers, B.J. and Lewy, F.H.
            Arch. Neurol. Psychiat. 44:725-739, 1940.
COMPOUND:    Carbon disulfide

             000075150

REFERENCE:   Ferraro, A., Jervis, G.A.,  & Flicker,  D.J.
             Arch. Pathol. 32:  723-738, 1941.
OBSERVED NEUROTOXIC EFFECTS:    Apathy, hostility.  Damage to cortex, basal
    ganglia, cerebellum; moderate involvement of cord; little involvement of brainstem
    and peripheral nervous system.
OBSERVED NEUROTOXIC EFFECTS:   Cerebrovascular  proliferation with diffuse nerve
      cell changes  (from chrolatolysis  to  severe  degeneration)  scattered through
      brain and cerebellum.   Salivation, dyspnea,  restlessness, rarely vomiting,
      progressing to  tremors, apathy, and  occasionally coma.
ANIMALS:     9 Dogs
ANIMALS:    5  cats.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposure 8 hr/d, 5 d/wk, for 2-6 wk.  Concentration ns.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  8-10 mg/liter of air,  0.5-2.5 hr/d, total exposures 19-65
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   None
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   Serial  sacr  2-6 wk.

EXAM. TYPE:  Behavior, Histology
DURATION OF EXPERIMENT:   Serial sacr to 92 d

EXAM. TYPE:   Behavior,  histology
                                       207
                                                                                                                                    208

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COMPOUND:
             Carbon disulfide
REFERENCE:   Juntunen,  J.,  Haltia,  M. arid Linnoila, I.
             Acta Neuropath.  29:361-366,  1974.
COMPOUND:  Carbon disulfide

            000075150

REFERENCE: Lewey, F.H.
           Ann. Int. Med. 15:  869-883, 1941.
OBSERVED NEUROTOXIC EFFECTS:   Slight weakness,  progressing to severe  in hindlimbs.
     Only intramuscular nerves examined:   axonal degeneration.   Intense
     nonspecific cholinesterase activity  correlated with degeneration.   Authors
     suggest that non-specific cholinesterase activity could  be used  as an
     indicator of early axonal degeneration in  progressive polyneuropathy.
OBSERVED NEUROTOXIC EFFECTS:
Any part of the central or peripheral nervous system
can be affected.  In general,  the  first  signs were
psychic with peripheral neuropathy, progressing to
cranial nerve involvement, eye muscle control,  pyra-
midal and extra-pyramidal signs.   Parkinsonism and
a thalamic syndrome were seen.  The author  concluded
that some neuropathy was secondary to induced thiamine
deficiency.
ANIMALS:      21 Eats,  S-D,  age 3 mo.
ANIMALS:    Human:  120 viscose rayon workers
PREPARATION AND DOSE
or HISTORY OF PATIENT:   750 ppm in air,  6 hr/d for 5  d/wk or  (later)  3/d/wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Long-term chronic exposures
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:     5 rats untreated
ROUTE AND SITE:     Inhalation

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:  5 wk to 5 mo.

EXAM. TYPE:  Behavior, histology, histochemistry
DURATION OF EXPERIMENT:   ns

EXAM.  TYPE:   Clinical, biochemistry, statistics
                                       209
                                                                                                                                    210

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COMPOUND:   Carbon disulfide

           000075150


REFERENCE:  Lukas, E., Kotas, P. and Obrusnik,  I.
           Br. J. Indust. Med.  31:   288-291,  1974.


OBSERVED NEUROTOXIC EFFECTS:   Slow conduction measured In lumbar plexus-tibial nerves.
                              Copper levels increased, while zinc did not.
COMPOUND:    Carbon disulfide

            000075150

REFERENCE:   Richter,  R.
             J.  Neuropath.  Exp.  Neurol.  4:324-353, 1945.


OBSERVED NEUROTOXIC EFFECTS:    Grey-metter necrosis especially in globus pallidus
    and substantia nigra,  thought to have developed acutely after long cumulative
    exposures;  other changes such as gliosis in nonnecrotic parts of Central
    Nervous System thought to have developed gradually.
ANIMALS:    Rats, SPF, M, 300 g, 18/gp, 2 gps trtd.
                                                                                                ANIMALS:      4  Rhesus monkeys (M.  mulatta),  healthy, young.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2.4 or 3.6 mg/liter  of air, 6 hr/d,  5 d/wk.
PREPARATION AND DOSE
Or HISTORY OF PATIENT:   Exposure to vapor, concentration not measured,  for  about
    6 hr/d, 5 d/wk, for 1-2 yr.
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION:   Same numbers of rats.
ROUTE AND SITE:  inhalation

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   Sacrifice when neuropathy obvious (13 or 37 wk).

EXAM. TYPE:  Electrophysiology, biochemistry.
DURATION OF EXPERIMENT:  1-2 yr.

EXAM. TYPE:  Behavior, histology
                                           211
                                                                                                                                          212

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COMPOUND:      Carbon disulfide

              000075150

REFERENCE:      Tarkowski,  S.  and  Cramer, J.E.
               J.  Neurochem.  19:2631-2640,  1972.
OBSERVED NEUROTOXIC EFFECTS:
                               Ataxia,  tremors, some convulsions; brain glutamine
                               rose,  glutamate and GABA  fell, interpreted as  due
                               to  increased removal of ammonia and  interference
                               with pyridoxal-PO,-dependent enzymes.
                                                                                           COMPOUND:
                                                                                                         Carbonic acid, dithio-, cyclic S,S-(6-methyl-2,3-quinoxalinediyl) ester
REFERENCE:   Sherman, M.,  Herrick,  R.B.,  Ross, E.  and Chang, M.T.Y.
             Toxicol. Appl.  Pharm.  11:   49-67, 1967.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:   Ataxia,  paralysis, convulsions.
ANIMALS:
               Rats,  Forton,  M,  8-10 wk,  180-200  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     2.5 mg/liter of  air  for  15 hr.
                                                                                           ANIMALS:   Cockerels,  Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  Acute: LD5Q  979.6 mg/kg
                         (2)  Subacute:   50-800 ppm in diet, 20 chicks/grp, for 2 wk
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:       Same,  no compound



DURATION OF EXPERIMENT:    15 hr.

EXAM. TYPE:    Behavior,  biochemistry
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated  control grps



DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:   Behavior,  mortality
                                           213
                                                                                                                                        214

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COMPOUND:
             Carbon monoxide

             000630080
COMPOUND:
REFERENCE:    Bogusz, M.,  Cholewa, L. Pach, J. and Mlodkowska, K.
             Arch.  Toxicol.  33:141-149, 1975.
            Carbon monoxide

            000630080
REFERENCE:  Einhorn,  I.N.
            Env. Hlth. Persp.  11:163-189,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                               Lactate, pyruvate, aspartate aminotransferase,
                               LDH, all increased; muscle twitching to convulsions.
                               A  triple-normal lactate was considered reason for
                               hospitalization, and  triple-normal Asp-At signified
                               complications.
OBSERVED NEUROTOXIC EFFECTS:
                                 Level  3 (motor collapse) :   no changes observable
                                 in  central or peripheral nervous system by light
                                 microscopy in 10 rats exposed 30 d, but on
                                 electron microscope changes seen in Ranvier nodes
                                 in  peripheral nervous system.  Demyelination apparent
                                 at  level 4, especially of large fibers in central
                                 nervous systems white-matter.
ANIMALS:      47  patients:   28 F,  19 M, ages  14-88 yr.
ANIMALS:
             Rats
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposure  to  coal-stove  gas  or  lighting  gas  for  1-16
                        hr,  hospitalized  1-5 hr after  onset of  symptoms.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Levels 2-5 of toxicity produced by various exposures.
ROUTE AND SITE:          Inhalation

CONTROL INFORMATION:     None
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Clinical, biochemistry
DURATION OF EXPERIMENT:     ns.

EXAM. TYPE: Electrophysiology,  histology, behavior
                                          215
                                                                                                                                        216

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COMPOUND:   Carbon monoxide

            000630080

REFERENCE:  Shillito, F.H., Drinker, C.K. and  Shaughnessy, T.J.
            J. Am. Med. Assn.  106:  669-674, 1936.
OBSERVED NEUROTOXIC EFFECTS:
43 cases had sequelae sufficient for admission to mental
institutions; confusion psychosis, disorientation,
amnesia, parkinsonism, increased deep reflexes, skin
anesthesia and peripheral neuropathy.  All such cases
had unconsciousness during acute phase, none had low-
level chronic exposures.  Of the 43, 23 recovered com-
pletely, 9 had permanent nerve or mental damage, and
11 died.
                                                                   COMPOUND:    Carbon monoxide

                                                                                000630080

                                                                   REFERENCE:   Snyder, R.D.
                                                                                Neurology 20:177-180,  1970.
OBSERVED NEUROTOXIC EFFECTS:    Symmetrical peripheral neuropathy not due only
    to  hypoxia,  additional to Central Nervous system involvement, suspected of
    "toxic or ischemic basis."
ANIMALS:   Human:  43 cases abstracted from 10-yr records of 21,143 cases in
                   New York metropolitan area
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                        Various exposures
                                                                                                ANIMALS:     Human:  family of 4 (M 25 yr, F 29 yr, M 5 yr, F 3 yr).
                                                                   PREPARATION AND DOSE
                                                                   or HISTORY OF PATIENT:  Exposure to malfunctioning gas heaters in closed house, for
                                                                       approx.  2 d.
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:  None
                                                                   ROUTE AND SITE:   Inhalation

                                                                   CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    clinical
                                                                   DURATION OF EXPERIMENT:   About 2 d

                                                                   EXAM.  TYPE:  Autopsy (F,  29),  electrophysiology, blood chemistry, behavior
                                          217
                                                                                                                                       218

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COMPOUND:   Carbon  tetrachloride

           000056235

REFERENCE:  Cohen,  M.M.
            Neurology 7:   238-244,  1957.
OBSERVED NEUROTOXIC EFFECTS:   The  compound  caused patchy pontine necrosis and demyelin-
                              ation and Purkinje cell  damage; other effects were  con-
                              sidered secondary to vascular, hepatic or renal damage.
COMPOUND:   Carbon tetrachloride

            000056235

REFERENCE:  Hasson, J. and Leech. R.W.
            Arch. Path. 84:286-289,  1967.
OBSERVED NEUROTOXIC EFFECTS:     Globus  pallidus  was examined;  Alzheimer glia cell
                                 changes were not found,  but astrocytic nuclear
                                 size was  increased significantly in cirrhotic
                                 vs. control rats.
ANIMALS:    Human:   2 fatal  cases, M,  24  and  40
ANIMALS:    Rats,  S-D, M,  150  g,  2  groups of 18
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) A suicide;  history  of  alcohol, drugs  and  liver  damage.
                         (2) Accidental  inhalation;  history of  alcohol
PREPARATION AND DOSE
or HISTORY OF PATIENT: i ml/kg twice/wk for 5 wk (10 doses), 1 group, to produce
                       liver cirrhosis.
ROUTE AND SITE:  (1)  Oral  (2)  Inhalation

CONTROL INFORMATION:    None
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:   1 group untrtd
DURATION OF EXPERIMENT:  (1)  Survived 13 d;  (2)  survived  less  than 24  hr

EXAM. TYPE:   Histology (autopsy)
DURATION OF EXPERIMENT:  Sacrifice 1 d after 10th dose.

EXAM. TYPE: Histology
                                           219
                                                                                                                                        220

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COMPOUND:     Carbon tetrachloride

              000056235

REFERENCE:    Knoct. P..T.  and Curzcn,  G.
              Biochem.  Pharmacol.  24:963-966,  1975.
COMPOUND:     Carbon tetrachloride

              000056235

REFERENCE:    Luse, S.A.. and Wood, W.G.
              Arch. Neurol. 17:304-312, 1967.
OBSERVED NEUROTOXIC EFFECTS:  Brain tryptophan,  tyrosine,  5-HIAA and (less)
                              5-HT increased;  related decrease of food intake.
                              Brain changes not  seen with  restricted intake  alone.
                              Interpreted with reference to appetite control and
                              liver failure.
                                                                                            OBSERVED  NEUROTOXIC  EFFECTS:
                               Mental stupor, confusion, convulsion.   Edema
                               and spongiform lesions through pons, cerebellum,
                               cerebrum.  No demyelination by electronmicroscopy,
                               though appearance of it by photomicroscopy.
                               Edema was extracellular.
ANIMALS:      Rats,  S-D,  M,  140-150 g.
ANIMALS:
              Human:  one case, M, 32
PREPARATION AND DOSE
or HISTORY OF PATIENT:     10% in arachis oil,  13 ml/kg when mean wt was 200 g,
                          one dose.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           Used a CC14 extinguisher for a fire  in a  closed  room.
                           Died 7 d later, without reporting  this.
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:    Arachis oil vehicle only;  restricted diet 48 hr.
ROUTE AND SITE:   inhalation

CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:   48 hr.

EXAM. TYPE:  Biochemical
DURATION OF EXPERIMENT:    7 d

EXAM. TYPE:   Behavior, clinical, histology
                                          221
                                                                                                                                    222

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COMPOUND:
Cardiotoxin
                                                                             COMPOUND:
                                                                                                            Gascara
REFERENCE:
Chang, C.C., Chuang, S-T.,  Lee,  C.Y. ,  Wei,  J.W.
Br. J. Pharmac. 44:752-764,  1972.
                                                                                            REFERENCE:
                Steer, H.W.  and Colin-Jones, D.G.
                J.  Path. 115:199-205, 1975.
OBSERVED NEUROTOXIC EFFECTS:
               Affected axonal conduction,  but less potent
               than crude cobra venom.   Blocking action
               accelerated by addition  of PhA, the minimum
               effective concentration  being 100 meg/ml.   3 meg/ml
               completely depolarized superficial muscle  fibers
               within 60 min, this dose being three times more
               potent than crude venom.  CaCl2 antogonized nerve
               blocking and depolarizing effect.
OBSERVED NEUROTOXIC EFFECTS:   More lysosomal activity and lysosomes in Schwann
                               cells and neurons of submucosal plexus of colonic
                               mucosa.
ANIMALS:
               Phrenic nerve-diaphragm preparation from Long-Evans rats.
                                                                             ANIMALS:        Human:   7 aged  24-80 with melanosls coli who took purgatives;
                                                                                                      1 who had  taken  purgatives for only 1 m.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         Various doses in vitro.
                                                                             PREPARATION AND DOSE
                                                                             or HISTORY OF PATIENT:    Rectal biopsy  before and 3-7 m after stopping medication
ROUTE AND SITE:      in vitro

CONTROL INFORMATION:      Laboratory
                                                                             ROUTE AND SITE: Oral

                                                                             CONTROL INFORMATION:
                                                                                                        7  aged  27-70 with other gut disorders who had taken no
                                                                                                        purgatives for 3 m.
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Electrophysiology, chemistry
                                                                             DURATION OF EXPERIMENT:    About 7  m.

                                                                             EXAM. TYPE:     Histology, histochemistry
                                        223
                                                                                                                                     224

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COMPOUND:
            beta-Chloroethylamine, ethyl-n-propyl-, hydrochloride
REFERENCE:   Goldin.  A..  Now.  H.A..  ^Mins,  B.H.,
             J.  Phann.  Exp.  Ther.  94:249-261, 1958.

OBSERVED NEUROTOXIC EFFECTS:
     Waltzing syndrome was produced by dialkyl and hetero-
     cyclic B-chloroethylamines but not when (a) OH
     or bromine replaced the S chlorine, (b) a 6-phenyl
     group replaced one of the 8 hydrogens in the
     chlorinated chain, or (c) phenyl groups were introduced
     into the dialkyl carbons.  No effect from primary/
    .secondary B-chloroethylamines, related quaternary
     compounds, or bis-, tris-, or tetrakis-B-chloro-
     ethylamines.  Piperidine and morpholine analogs and
     arsacetin produced waltzing.  Cerebellar and
     axial lesions found consistent with behavior.
ANIMALS:
             Mice,  CF1,  M,  2-3m,  18-25  g;  also  CF1 F and C3H M.
                                                                 COMPOUND:   Choralose, alpha

                                                                            015879933

                                                                 REFERENCE:  Spooner, C.E. and Winters, W.D.
                                                                            Int. J. Neuropharmacol. 5:   217-236,  1966
                                                                                            OBSERVED NEUROTOXIC EFFECTS:   Compound produced depression and associated slow-
                                                                                                             i              wave EEGs.
                                                                                            ANIMALS:     200  Cockerels, White  Leghorn,  ages 5-14 d, 45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1-625 mg/kg in saline or (insolubles) 10% acacia,
various schedules.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     20-50 mg/kg
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:    Vehicle alone
                                                                ROUTE AND SITE:   s.C.  near axillary vein; I.P. for doses over 0.05 ml

                                                                CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:      At  least  10  d after treatment.

EXAM. TYPE:  Behavior, histology.
                                                                DURATION OF EXPERIMENT:   ns

                                                                EXAM. TYPE:   Behavior,  EEC
                                           225
                                                                                                                                       226

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COMPOUND:  Citric acid, fluoro-
                                                                                          COMPOUND:    Citric acid,  fluoro-
REFERENCE:  Koenig, H.
            Science 164:310-312, 1969.
OBSERVED NEUROTOXIC EFFECTS:  Convulsions.  Cord neurons expelled lysosomes,
     mitochondria,  other cytoplasmic structures into their axons.  Axons and
     mitochondria swelled.
REFERENCE:  Patel, A. and Koenig, H.
            J. Neurochem. 18:  621-628, 1971.
OBSERVED NEUROTOXIC EFFECTS:
      Fluorocitrate blocks citrate (isocitrate) hydrolyase
      (EC A.2.1.3); before and during convulsions, rat brair
      and cat spinal cord alanine rose, and free aspartate,
      glutamate and glutamine fell; GABA rose, then  fell;
      citrate rose markedly; glycogen fell; ammonia  and ATP
      remained constant; incorporation of glucose and lysint
      into nerve proteins fell sharply.  The authors proposi
      that convulsions follow complexing of excess citrate
      with Mg   and consequent chemical reactions.
ANIMALS:   Cats
PREPARATION AND DOSE
or HISTORY OF PATIENT:   3-50 meg of active isomer in 0.003-0.05 ml water, one
     dose.
                                                                                          ANIMALS:    Rats, S-D, F,  180-200  g
                                                                                                      Cats, adult, 2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1.5 meg/rat
10 meg/cat
ROUTE AND SITE:   Inj.  into lumbar  subarachnoid space

CONTROL INFORMATION:   None
ROUTE AND SITE:  Rats, intracerebral;  cats,  into lumbar subarachnoid space

CONTROL INFORMATION:  Compound omitted  from treatment
DURATION OF EXPERIMENT:   Serial  sacr  up  to  24 hr, av 1-6 hr.

EXAM. TYPE:  Behavior, histology
DURATION OF EXPERIMENT:   Rats  20 min,  cats  30 min

EXAM.  TYPE:   Biochemistry
                                       227
                                                                                                                                   228

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COMPOUND:    Cobalt  ion  (+2)
REFERENCE:  Nichols,  R.A.  and Nakajima,  Y.
            Brain Res.  86:   493-498,  1975
OBSERVED NEUROTOXIC EFFECTS:   Cobalt inhibited the generation of  the  IPSP  (sic) of
                              the stretch receptor neuron and had some depolarizing
                              action on the soma.
                                                                                           COMPOUND:         Cobalt ion (+2)
REFERENCE:        Prakash,  N.J.,  Fontana, J. and Henkin, R.I.
                  Life Sci. 12(1):249-259, 1973.


OBSERVED NEUROTOXIC EFFECTS:     Inhibited (Na+ + K+) ATPase, although never  more
                                 than 20%, even at 0.2 mM.  Inhibition involved
                                 blockage of norepinephrine and choline uptake.
ANIMALS:    In vitro:   slow adapting stretch  receptors  from 8th  thoracic  segment
                       of lobster  (I!,  americanus)  and crayfish  (Oronectes),  or  from
                       the 2nd-3rd abdominal  segment of crayfish.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         Co at 0-5 mM
                                                                                           ANIMALS:
                                                                                                            Rat brain synaptosomes in vitro
                                                                                           PREPARATION AND DOSE
                                                                                           or HISTORY OF PATIENT:
                            Co   chloride added to medium in various  expts.
ROUTE AND SITE:   In vitro

CONTROL INFORMATION:   Zero  treatment
ROUTE AND SITE:   in vitro

CONTROL INFORMATION:   Lab
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Biochemistry, electrophyslology
DURATION OF EXPERIMENT:     Minutes

EXAM. TYPE:       Biochemistry
                                           229
                                                                                                                                       230

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COMPOUND:    Cobra  toxin
                                                                                            COMPOUND:
              Colchicine
              000064868
REFERENCE:      Chang,  C.C.,  Chuang,  S-T., Lee, C.Y., Wei, J.W.
               Br.  J.  Pharmac. 44:752-764, 1972.
OBSERVED NEUROTOXIC EFFECTS:   Ineffective on axonal conduction and on membrane
                              potentials.
REFERENCE:   Daniels,  M.P.
             J.  Cell Biol.  58:   463-470,  1973.
OBSERVED NEUROTOXIC EFFECTS:   Reversible inhibition of neurite elongation and
                               reversible neurite retraction was seen within 6 hr.
                               Assembly of the microtubules was interrupted and
                               disassembly started.  Neurite outgrowth involves
                               assembly.
ANIMALS:
               Phrenic nerve-diaphragm preparation  from Long-Evans rats.
ANIMALS:     In  vitro  cultures of chick dorsal-root ganglia
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Various doses in vitro.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.05  meg/ml
ROUTE AND SITE:      in vltro

CONTROL INFORMATION:      Laboratory
ROUTE AND SITE:   In medium

CONTROL  INFORMATION:   Laboratory
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Electrophysiology, chemistry
DURATION OF EXPERIMENT:    Up  to 62 hr

EXAM. TYPE:   Biochemistry, histology
                                        231
                                                                                                                                     232

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COMPOUND:   Colchicine

            000064868

REFERENCE:   Wisnlewski, H. and Terry, R.D.
             Lab.  Invest. 17:577-587, 1967.
COMPOUND:
             Copper (II) chloride
             rtrtl tf./.C to
REFERENCE:   Borchard,  U.  and Schneider,  K.U.
             Arch.  Toxicol.  33:17-30,  1974.
OBSERVED NEUROTOXIC EFFECTS:  After 2 mg died in 2 hr in status epilepticus;
     others mild paresis by 6 hr quadriparesis by 1 d, died or were killed
     within 6 d.  Large neurons of brainstem and cord altered structurally,
     and axons distended.
OBSERVED NEUROTOXIC EFFECTSJAmplitude of b-wave of ERG decreased reversibly at Cu
                            6 x 10"^ m/liter and irreversibly above that, during 30 min
                            of testing.   Complexing agents suggested that intoxication
                            might be caused by blocking of enzymes containing
                            sulfhydryl groups.
ANIMALS:   15 rabbits,  M and F, 3-4 kg.
                                                                                        ANIMALS:     Frog retina in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.01-2.0 mg in 0.1 ml H20 (one dose)
PREPARATION AND DOSE
                                -6
or HISTORY OF PATIENT:  3-60 x 10   m/liter of medium
ROUTE AND SITE:   Injection  into cisterna magna

CONTROL INFORMATION:     None
ROUTE AND SITE:    Incubation

CONTROL INFORMATION:    Laboratory
DURATION OF EXPERIMENT:   Serial to 6 d

EXAM. TYPE:  Behavior,  histology
DURATION OF EXPERIMENT:About 1 hr.

EXAM. TYPE:  Electrophysiology (ERG)
                                      233
                                                                                                                                   234

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COMPOUND:
Copper Ion (+2)
REFERENCE:
    Prakash, N.J., Fontana, J. and Henkin, R.I.
    Life Sci. 12(1):249-259, 1973.
OBSERVED NEUROTOXIC EFFECTS:     At  concentrations over 0.01 mM, Cu
                                 completely inhibited  (Na+ + K+) ATPase.
                                 Inhibition involved blockage of norepinephrine
                                 and choline uptake.
ANIMALS:
                  Rat  brain  synaptosomes  in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Cu   chloride  added  to medium in various expts.
ROUTE AND SITE:   in vitro

CONTROL INFORMATION:   Lab



DURATION OF EXPERIMENT:     Minutes

EXAM. TYPE:       Biochemistry
                                           235
COMPOUND: Copper  II  sulphate
          007758987


REFERENCE:   Howell,  J. McC.,  Blakemore, W.F., Gopinath, C., Hall, G.A. and
             Parker,  J.H.
             Acta Neuropath.  29:9-24, 1974.

OBSERVED NEUROTOXIC  EFFECTS:  Central Nervous System examined:  astrocytic
changes, vacuoles in white-matter, swollen astrocytes accumulated glycogen,
mitrochondria and endoplasmic reticulum.  Authors conclude brain changes in
chronic copper poisoning may arise as result of altered glial transport mechanisms.
                                                                                   ANIMALS: Sheep:   39 (Clun Forest x Sussex)  and 3 Welsh halfbred, 6-12 mo.  old.
                                                                                   PREPARATION AND DOSE
                                                                                   Or HISTORY OF PATIENT:    Av.  7 ppm copper in feed.   29 sheep given 0.5% aqueous
                                                                                   soln of copper sulphate daily:  22 at rate of 20 mg/kg, 7 at rate of 30 mg/kg.
                                                                                   ROUTE AND SITE:  oral

                                                                                   CONTROL INFORMATION: 13 sheep untreated
                                                                                   DURATION OF EXPERIMENT:  Serial sacr to 37 wk.  9 sacr before, 11 sacr during
                                                                                                            and 9 died after hemolysis.
                                                                                   EXAM. TYPE: Blood chemistry, histology.
                                                                                                                                       236

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COMPOUND:
             Copper(II)  sulfate pentahydrate  (1:1:5)
             \J I I JO77O
REFERENCE:  Morgan, K.T.
            Res. Vet. Sci. 15:  88-95, 1973.
                                                            COMPOUND:    Cortlsol

                                                                        ouuuso^av

                                                            REFERENCE:
Heuser, G., Ling, G.M. and Buchwald, N.A.
Arch. Neurol. 13:195-203, 1965.
OBSERVED NEUROTOXIC EFFECTS:
The treatment caused a spongy transformation of
the white matter.  Vacuoles were seen in the myelin
and lamellae split, but neurones and glia were not
involved and there was no extracellular edema.
                                                                                          OBSERVED NEUROTOXIC EFFECTS:
                 Compound produced neither sedation nor  seizures
                 in these monkeys.
ANIMALS:
            Lambs, 6 mo total 8
                                                                                          ANIMALS:
                                                                           Monkeys, Squirrel, surgically prepared
PREPARATION AND DOSE                                                                      PREPARATION AND DOSE
or HISTORY OF PATIENT:   Diet had 5 ppm of copper; 5 lambs drenched with 1 g compound/d    or HISTORY  OF  PATIENT:     Varying doses,  exact amts not given, however comparable
                          5 d/wk  11 wk                                                                             to doses of  5-200 mg/kg of other steroid sodium succinate
                                                                                                                    salts.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:    3 untreated



DURATION OF EXPERIMENT:   11 wk

EXAM. TYPE:  Histology
                                                                                          ROUTE AND  SITE:
                                                                              I.V. or  I.P.
                                                           CONTROL  INFORMATION:       Sham  inj  as well  as  saline and sodium bicarbonate soln
                                                                                      were  used as  controls.   Control inj did not produce
                                                                                      sedative  or convulsion  effects.

                                                           DURATION OF EXPERIMENT:    Up  to approx.  30  min/test

                                                           EXAM. TYPE:      Electrophysiology,  behavior
                                        237
                                                                                                                                     238

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COMPOUND:
              Cortisol, 21-acetate
                                                                                            COMPOUND:
                                                                                                         Cottonseed  oil
REFERENCE:
Cotterrell, M.,  Balazs,  R.  and Johnson,  A.L.
J. Neurochem. 19:2151-2167, 1972.
REFERENCE:   Boyd,  E.M.  and Boulanger,  M.A.
             Tox. Appl.  Pharm.  14:432-438,  1969.
OBSERVED NEUROTOXIC EFFECTS:
                 By 35 d body wt reduced by 50%,  brain wt by 30%
                 of norms;  20% fewer cells  in cerebrum, 30% in
                 cerebellum;  cell size not  affected as judged by DNA;
                 cell destruction not affected.   Thus growth retardation
                 in terms of  new cell divisions was inferred.
OBSERVED NEUROTOXIC EFFECTS:  The clinical signs included:  listlessness, epistaxis,
                              ataxia,  and anorexia.  Autopsy showed congestion of
                              the brain associated with generalized capillary-
                              venous congestion.
ANIMALS:       Rats, Porton, M, newborn
                                                                              ANIMALS:     (1) 20 Rats:  Wlstar, young, M.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     0.125-0.4 mg/rat/d, various periods; most rats got 0.2
                          mg/d  for 4 d.
                                                                              PREPARATION AND DOSE
                                                                              or HISTORY OF PATIENT: 5-110 rag/kg for 4 d, cumulative  amounts  of  200-440  ml/kg.
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:       Saline  treated  controls
                                                                              ROUTE AND SITE:  i.e.

                                                                              CONTROL INFORMATION:  66 control rats
DURATION OF EXPERIMENT:    Serial  sacr  to  35  d.

EXAM. TYPE:    Biochemistry.
                                                                              DURATION OF EXPERIMENT:  5 d.

                                                                              EXAM. TYPE:  Behavior, autopsy, histopathological
                                           239
                                                                                                                                        240

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COMPOUND:   Coumarin,  3-chloro-7-hydroxy-4-methyl-, bis(2-chloroethyl) phosphate
              (Haloxon)
REFERENCE:  Malone, J.C.
            Res. Vet. Sci. 5:  17-31, 1964.
OBSERVED NEUROTOXIC EFFECTS:
                              At high doses, haloxon produced hindleg ataxia in
                              sheep and in poultry.  Histological examination
                              revealed axonal degeneration.  There was no apparent
                              relationship of the effects with cholinesterase.
                                                                                          COMPOUND:
                                                                                                     Coumarin,3-Chloro-7-hydroxy-4-methyl,0-ester with 0,0-diethyl phosphorothioate
                                                                                                     000056724
REFERENCE:  Gaines, T.B.
            Tox. Appl. Pharm. 14:  515-534, 1969.
                                                                                          OBSERVED NEUROTOXIC EFFECTS:    100  mg/kg produced leg weakness
            Mice, M, 20-25 g
ANIMALS:    Rats, S-D, F, 110-150 g
            Guinea-pigs, F, 400-600 g
            Rats, S-D, weanling, M & F
            Cats, adult, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:         c
                         Many formulations and doses, from
                                             Dogs, adult, no details
                                             Monkeys, adult, no details
                                             Hens, 18 mo, 16 groups of 10
                                             Sheep, lambs 1-8 mo, ewes & wethers 1 )
                                                    ewes over 4 yr, rams 1-5 yr
                                                             .-
                                                                down.
ANIMALS:    Chickens,  White Leghorn, F
PREPARATION AND DOSE
or HISTORY OF PATIENT:    15 mg/kg atropine sulfate orally 15 min  prior to compound;
                          graded doses compound in peanut oil
ROUTE AND SITE:   Oral, in diet; I.P.; dermal.

CONTROL INFORMATION:  Various
ROUTE AND SITE:   S.C.,  under right wing

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   Various

EXAM.  TYPE:  Behavior, biochemistry, histology
DURATION OF EXPERIMENT:   1 yr

EXAM. TYPE:    Clinical
                                         241
                                                                                                                                     242

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COMPOUND:  Coumarin, 7-hydroxy-4-methyl-, bis(2-chloropropyl)phosphate
REFERENCE:  Aldridge, W.N. and Barnes, J.M.
            Biochemical Pharm. 15:541-548, 1966.
COMPOUND:  0-Cresol, 4,6-dinitro-   (DNOC)

           000534521

REFERENCE:  Burkatskaya, E.N.
            Hygiene and Sanitation 30:  197-201, 1965. (Russ.) (Translated)
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histological changes in the
                              spinal cord and sciatic nerves.  Inhibition of
                              CNS esterase.
OBSERVED NEUROTOXIC EFFECTS:  Cats (2 of 4) exhibited twitching, tremor, dyspnea
                              and ataxia, with a blood DNOC level of 6-15 mg%;
                              DNOC gradually disappeared from the blood in  6-8
                              days.
                              Humans (indoors):  changes in central and autonomic
                              nervous systems (sic); (outdoors):  only slight changes
ANIMALS:
                Hens,  grps  of  2-4, RIR x Light  Sussex, 2-3
ANIMALS:
            Cats.
            Humans (exposed industrially)
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly  1  dose,  amount varied by compound
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Cats:  4 exposed to dust containing 0.036-0.06 mg/liter
                        Humans:  exposed to av. 0.9mcg/liter in breathing zone
                                 indoors; 0.7 in agriculture
ROUTE AND SITE:    oral,  s.c.,  or i.p.

CONTROL INFORMATION:      ns.
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:    u-21 d

EXAM.  TYPE:     Biochemistry,  histology
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:    Clinical
                                        243
                                                                                                                                     244

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COMPOUND:
Crotonic acid,3-hydroxy-,alpha-methylbenzylester, dimethyl phosphate,  (E)-

007700176
                                                                                            COMPOUND:  Cyanic acid
REFERENCE:  Gaines,  T.B.
            Tox.  Appl.  Pharm.  14:   515-534,  1969.
OBSERVED NEUROTOXJC EFFECTS:    200  mg/kg produced leg weakness
                                                                               REFERENCE:   Papayannopoulou, T., Stamatoyannopoulos, G,, Giblett, E.R. and
                                                                                           Anderson, J.
                                                                                           Life Sci. 12(2):127-133, 1973.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                            In vitro electrophoretic changes  in  25  enzymes.
                                                                                                                            In vivo changes in 10 of these enzymes  in 5  tissues
                                                                                                                            including brain homogenates, dose-related; in
                                                                                                                            LDjO survivors no changes detected.   Changes
                                                                                                                            reversible.  Interpreted by authors  to  show  tissue
                                                                                                                            protein carbamylation independent of effects on
                                                                                                                            blood.
ANIMALS:     Chickens, White  Leghorn,  F
PREPARATION AND. DOSE
Or HISTORY OF PATIENT:     15 mg/kg atropine  sulfate  orally  15 min prior  to compound;
                          graded doses  compound  in peanut oil
ROUTE AND SITE:   S.C., under right wing

CONTROL INFORMATION:   ns
                                                                                            ANIMALS:     In vitro  tissues from "animals";
                                                                                                         C3H mice, aged 12-14 wk, 4 groups  total 42 mice.
                                                                               PREPARATION AND DOSE
                                                                               or HISTORY  OF  PATIENT:
80 mg/kg, 12 doses in 3 wk; 100 mg/kg, 5 doses in 1 wk;
22 mg/kg, 17 doses in 3 wk; 250 mg/kg, one dose of the
sodium salt (equal to LD50), survivors used.
In vitro:  0.05 M cyanate added to medium incubating
blood.
                                                                               ROUTE  AND  SITE:   i.p. Or I.V.

                                                                               CONTROL  INFORMATION:   ns.
DURATION OF EXPERIMENT:   1 yr

EXAM. TYPE:   Clinical
                                                                               DURATION  OF  EXPERIMENT:

                                                                               EXAM.  TYPE:  Biochemical
20-24 hr after last injection.
                                           245
                                                                                                                                       246

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COMPOUND:   Cyanide

            000057125
REFERENCE:
             Bass,  N.H.
             Neurology 18:167-177,  1968.
COMPOUND:  Cyanide

           000057125

REFERENCE:  Hirano, A., Leving,  S.  and  Zimmerman,  H.M.
            J. Neuropath. Exp. Neurol.  27(2) :234-245,  1968.
OBSERVED NEUROTOXIC EFFECTS:   Myelin  lesions  in  somatosensory cortex and
    subcortical white-matter.   At  5 hr  after  1 dose white-matter DNA lower by
    29%,  residue protein up by 28%, cortex gangliosides  down by 27%.  At
    30 d  chronic-treated rats  had  no  cortical lesions but white-matter demyelination
    with  28% gain in residue protein, and  losses of DNA  (37%) and  cerebrosides
    .(65%).
OBSERVED NEUROTOXIC EFFECTS:  Corpus  callosum and callosal radiation (the only
                              tissues reported on)  had distortions of remyelination
                              shown at 4 mo.  after intoxication.  Observations,
                              not fully reported, imply that demyelination had
                              occurred on intoxication.
ANIMALS:-   (1)   30 Rats,  COBS,  M,  adult  300 g.
           (2)   10 Rats,  COBS,  M,  adult  300 g.
ANIMALS:
Rats, young albino.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)   Chronic:   8  mg/kg/d stepped  up  during 25  d  in  survivor
                        (2)   Acute:     2  mg/rat/10 min  for 3 doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                     Deep intoxication for  30, min  (ref.  Leving,  S.
                     and Stypulkowski, W. Arch. Path.  67:306  (1959)).
ROUTE AND SITE:   S.C.,  abdominal wall

CONTROL INFORMATION:  10 rats untreated
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   30 d

EXAM. TYPE:  Chemistry,  Histology
DURATION OF EXPERIMENT:    1 wk to 6 mo. after intoxication, serial sacr.

EXAM. TYPE:      Electronmicroscopy
                                       247
                                                                                                                                       248

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COMPOUND:    Cyanide

            000057125

REFERENCE:   Van Houten, W.H. and Friede, R.L.
             Exp. Neurology 4:402-412, 1961.
COMPOUND:    1,3,5-Cycloheptatriene
             000544252

REFERENCE:  Brown, V.K.H., Kerrigan, L.W. and  Stevenson,  D.E.
            Ann. Occup. Hyg. 10:123-126,  1967.
OBSERVED NEUROTOXIC EFFECTS:
                                Increase of oxidative enzymatic activity in white
                                matter; increase of enzyme activity in neuroglia
                                cell perikarya-astrocytes.  Edema, anoxia.
OBSERVED NEUROTOXIC EFFECTS:     Clonic  convulsions  preceded death.  (LD50 dosages).
ANIMALS:
            45 Rats, Albino, 200-300 mg.
ANIMALS:     Rats, Hooded Lister, 4 M and  4  F/group,  150-250 g Mice, CF No. 1,
            4 M and 4 F, 21-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           Inhalation of air bubbled through 10% soln of potassium
                           cyanide in a 1 gallon jar until animal became unconscious
                           and remained so  for 20 mins.  Few given additional
                           exposures at 24 hr intervals.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Rats:  Oral 57 mg/kg  percutaneous 442-884 rag/kg
                      Mice:  Oral 171 mg/kg
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:        ns.
ROUTE AND SITE:   Gavage,  topical  (dorso-lumbar skin)

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:     Animals killed 24 hrs or more after last exposure

EXAM. TYPE: Histochemical.
DURATION OF EXPERIMENT: Death  in  24 hr,  usually in'minutes

EXAM. TYPE: Behavior,  histopathological
                                           249
                                                                                                                                        250

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COMPOUND:   Cyclohexane,  1,2,3,4,5,6-hexachloro-, gamma-isomer

           000058899

REFERENCE:  Czegledl-Janko, G. and Avar,  P.
           Br. J. Indust. Med. 27:  283-286,  1970.


OBSERVED NEUROTOXIC  EFFECTS:  EEC and clinical findings  increased with blood
                             concentration over 0.02 ppm.
COMPOUND:   Cyclohexane,  1,2,3,4,5,6-hexachloro-,  gamma  isomer  (Lindane)
            000058899

REFERENCE:  St. Omer, V.
            J. Neurochem. 18:  365-374, 1971,
OBSERVED NEUROTOXIC EFFECTS:
Convulsions, starting  in  some cases  during injection.
Intensity and other signs were directly related to
Increases of brain ammonia.   Toxicity ranking:
lindane > dieldrin > heptachlor >  DDT.   Brain gluta-
mlne increases resulting  from conversion of ammonia
to glutamine were related to  the toxicity ranking,
suggesting that  the 4  compounds produced convulsions by
one mechanism involving interference with the production
and/or utilization of  ammonia.
ANIMALS:    -37  men, working in a fertilizer factory.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Final product'contained 1.5% lindane;  no other toxic  agent,
                       but 22 subjects had previous exposure  to aldrin,  3  acute
                       histories  (convulsions), another 3 EEC disorders.   Lindane
                       not measured, exposure lasted 0.5-2 yr.  Blood levels
                       0.002-0.340 ppm.

ROUTE AND SITE:   Inhalation, skin contact

CONTROL INFORMATION:   Blood levels in 20 of general population 0.003-0.017  ppm.
ANIMALS:    Rats, adult F, Wistar, 250-300 g, surgically  prepared.
            Cockerels, White Leghorn or Barred Plymouth Rock,  12 wk,  1.4-1.6 kg,
               surgically prepared.

PREPARATION AND  DOSE
or HISTORY OF PATIENT:  Rats:  mg/kg — lindane  11.5,  DDT 50,  dieldrin 6,  heptachlor 13
                        Cockerels:  mg/kg — lindane  6.3,  DDT  30, dieldrin 6, heptachlo
                        The compounds stated to  be  structurally unrelated.
ROUTE AND SITE:  Intra-arteriai (carotid) at 1 ml/min

CONTROL  INFORMATION:  Vehicle only
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Blood lindane,  EEC,  clinical.
DURATION OF  EXPERIMENT:   Up to 60 min, in controls  7  d

EXAM. TYPE:    Behavior, biochemistry
                                           251
                                                                                                                                      252

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COMPOUND:  5H-Cyclooct(b)indole, 5-(3-(dimethylamino)propyl)-6,7,8,9,10,ll-
           hexahydro-
           UU5560725

REFERENCE:  Lullmann-Rauch,  R.
            Acta Neuropath.  (Berl.)  29:   237-249,  1974.


OBSERVED NEUROTOXIC EFFECTS:  Significant ultrastructural alterations of nerve
     cells, both in spinal cord and  in cerebellar  cortex.
COMPOUND: Cyclopentanecarboxylic acid,  1-amino

          000052528

REFERENCE:  Ross, R.B., Noll, C.I., Ross, W.C.J., Nadkarni, M.V., Morrison,
            B.H., Jr., and Bond, H.W.
            J. Med. Pharm. Chem. 3:1-23, 1961.

OBSERVED NEUROTOXIC EFFECTS:  Dogs:  Slight derayelination of cerebellum.
                              Mice:  Slight demyelination of central nervous system.
                              Nerve effects not mentioned for other species.
ANIMALS:    Rats,  Wistar,  M,  young adult
ANIMALS:    Dogs, rats, mice, cats, monkeys, humans
PREPARATION AND DOSE
or HISTORY OF PATIENT:   125 mg/kg bw,  5d/wk in water,  0.5 ml/100  g  bw,  for  5  wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         Dogs:  31.6 mg/kg/d for 30 d  (lower doses no  effect;
                                LD,Q one dose was 300 mg/kg).

                         Mice:  200-1259 mg/kg.
ROUTE AND SITE:   I.  Tub.

CONTROL INFORMATION:   Force-fed  pure water.
ROUTE AND SITE:   Dogs:  Oral (capsule)  Mice:  Gavage

CONTROL INFORMATION:  ns.
DURATION OF EXPERIMENT:   5 wk

EXAM. TYPE:   Histology
DURATION OF EXPERIMENT:

EXAM. TYPE: clinical, autopsy
                                       253
                                                                                                                                    254

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COMPOUND:   Cyclopentane carboxylic acid, 1-phenyl-, 2-(diethylamino)ethyl  ester,
            hydrochloride
            000125859

REFERENCE:  pfeiffer, C.C., Murphree, H.B., Jenney, E.H., Robertson, M.G.,
            Randall, A.H. and Bryan, L.
            Neurology 9:  249-250, 1959.

OBSERVED NEUROTOXIC EFFECTS:  The authors concluded that synthetic atropines are more
                             active hallucinogens  than atropine or scopolamine, pro-
                             ducing effects lasting 24-48 hr.  Synthetic  antitremor
                             drugs had  fewer peripheral nervous system side-effects,
                             but.central nervous system side-effects  (hallucinations)
                             may have been exaggerated.
                                                                                              COMPOUND:  Cyclopropylamine, 2-phenyl-, sulfate trans- (+,-)-, (2:1)
REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66,  1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect of Yohimbine
                              and lowered its  lethal dosage.
ANIMALS:    Human:   prison volunteers,  drug-sophisticated, no other details
                                                                                              ANIMALS:
               Mice, TT, M,  18-25  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    25 mg/man
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           »5o     4 mg/kg
                                                                                                                       ED50 " dose producing a 50% mortality of mice injected
                                                                                                                              S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   LSD-25:   0,  25,  50,  100 meg/man
ROUTE AND SITE:      S.C., Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   Up  to 3  d

EXAM. TYPE:   Opinion of volunteers
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology,  biochemistry
                                           255
                                                                                                                                       256

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 COMPOUND:
Cysteine,  L-
                                                                                               COMPOUND:
                                                                                                            Cysteine, L-
 REFERENCE:   Olney,  J.W.  and  Ho.,  0.
             Nature  227:609-610, 1970.
                                                                                 REFERENCE:      Olney, J.W., Ho,  O.L.  and  Rhee,  V.
                                                                                                Exp. Brain  Res.  14:61-76,  1971.
OBSERVED NEUROTOXIC EFFECTS:     Necrosis of hypothalamic neurons in mice given
                                 glutamate, aspartate, or cysteine, dose-related;
                                 zero damage from other compounds
                                                                                 OBSERVED  NEUROTOXIC  EFFECTS:   The compound was equipotent to monosodium
                                                                                                               glutamate in necrosing neurons in the retina
                                                                                                               and brain.  This compound is a powerful neuro-
                                                                                                               excitant and the neurotoxic properties may be
                                                                                                               governed by similar mechanisms.
ANIMALS:     75  Mice,  Swiss Webster, age 10 d.
                                                                                ANIMALS:  Mice, Swiss-webster  age  10 d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            One of  10 amino acids and various other compounds, 2.5 or 10%
                            in water, 0.25-2 g/kg.
                                                                                PREPARATION AND DOSE
                                                                                or HISTORY OF  PATIENT:    Initially 12 mmoles/kg, then range established for
                                                                                                          each compound.
ROUTE AND SITE:    Gavage

CONTROL INFORMATION:    Intubated, no  treatment, 10 mice



DURATION OF EXPERIMENT:     5 hr.

EXAM. TYPE: Histology
                                                                                 ROUTE AND SITE:      s.C.

                                                                                 CONTROL  INFORMATION:      Compounds compared with monosodium L-glutamate  (MSG)
                                                                                                          potency for selectively necrosing neurons in retina
                                                                                                          and brain (hypothalamus)

                                                                                 DURATION OF EXPERIMENT:   s.hr or serial intervals including 5 hr.

                                                                                 EXAM. TYPE:     Histology
                                           257
                                                                                                                                        258

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COMPOUND:   Cysteine, N-acetyl-, L-

            000616911

REFERENCE:     Olney,  J.W.,  Ho,  0.1.  and Rhee,  V.
               Exp.  Brain Res.  14:61-76, 1971.


OBSERVED NEUROTOXIC EFFECTS:   No cytotoxicity was observed.
COMPOUND:
              Decaborane

              017702419
REFERENCE:  Feinsilver, L., Lawson, L.H., Yevich, P.P. and  Jacobson,  K.H.
            U.S. Army CWL Report CWLR 2367, 1960.


OBSERVED NEUROTOXIC EFFECTS:  LC5Q under conditions were:
                              Rats - 46ppm; mice - 12ppm.  Signs included ataxia,
                              depression, prostration, tremors, clonic convulsions,
                              interpreted as "marked effects upon" the central
                              nervous system.
ANIMALS:   Mice, Swiss-webster  age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                         each compound.
ANIMALS:    Rats, ages 8-10 wk, M
            Mice, 8-10 wk, F
            Dogs, beagle, M.

PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposed to vapors of  compounds  in LC5Q study, 2-4 hr
ROUTE AND SITE:      s.C.

CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM. TYPE:    Histology
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION: None



DURATION OF EXPERIMENT:  Observation to 7 d after  exposure

EXAM. TYPE:  Behavior, pathology
                                        259
                                                                                                                                       260

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COMPOUND:   Decaborane,  ethyl
                                                                                             COMPOUND:
             1,4-Diazabicyclo(2.2.2.)octane
REFERENCE:  Feinsilver, L., Lawson, L.H., Yevich, P.P. and Jacobson, K.H.
            U.S. Army CWL Report CWLR 2367, 1960.
REFERENCE:   Goldberg, M.E. and Johnson,  H.E.
             Tox. Appl. Pharm. 4:522-545,  1962.
OBSERVED NEUROTOXIC EFFECTS:  LC5Q under conditions were:
                              Rats - 23ppm; mice - 6ppm; dogs - approximately •
                              6ppm.  Signs included ataxia, depression, prostration,
                              tremors, clonic convulsions, interpreted as "marked
                              effects upon" the central nervous system.
OBSERVED NEUROTOXIC EFFECTS:     Treatment apparently stimulated sympathetic  ganglia.
ANIMALS:    Rats, ages 8-10 wk, M
            Mice, 8-10 wk, F
            Dogs, beagle, M.

PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposed to vapors of compounds in LC5Q study, 2-4 hr
ANIMALS:     Rats,  CFE, M,  5-6 wk old,  90-120 g,  5 rats/grp or 6/grp (inhalation)
             Rabbits,  NZ white,  2.5-3.5 kg,  M,  4  rabbits/grp, and isolated ileum.
             Mice,  white, F,  20-28 g.
             41  mongrel dogs  (8.5-12.5  kg) M and  F.  10 cats, F, 2.2-3.8 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Various schedules
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:  None
ROUTE AND SITE:    Topical,  shaved skin (rabbits); inhalation (rats, mice);
                  intra-arterial (carotid)  (dogs, cats) and I.V. femoral  (dogs, cats)
CONTROL INFORMATION:    Varied
DURATION OF EXPERIMENT:  Observation to 7 d after exposure

EXAM. TYPE:  Behavior, pathology
DURATION OF EXPERIMENT:      Various

EXAM. TYPE:  Physiology,  biochemistry
                                           261
                                                                                                                                        262

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COMPOUND:   5H-Dibenz(b,f)azepine, 3-chloro-5-(3-(dimethylamlnopropyl)-10,
            11-dihydro-

              Lullmann-Rauch, R.
REFERENCE:    Acts Neuropath.  (Berl.)  29:  237-249, 1974.
OBSERVED NEUROTOXIC EFFECTS:   Very mild changes in the fine structure of neuronal
      lysosomes,  in  cord and cerebellar cortex.
COMPOUND:    5H-Dibenz(b,f) azepine,  5-(3-(dimethylamino)propyl)-10,ll-dlhydro-

             000050497

REFERENCE:     Pearlman,  C.  and Becker,  M.
               Psychopharmacologia 42:63-66,  1975.
OBSERVED NEUROTOXIC EFFECTS:
Cooperative behavior training and performance
prevented when compound administered a few minutes
after feeding session, no effects if given 3
hr afterwards.  Authors concluded mechanism was
prevention of REM sleep during this time.
ANIMALS:   Rats, Wistar, M, young adult
                                                                                        ANIMALS:       Rats, Long-Evans, F, 3 mo. age.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   150 mg/kg bw, 5d/wk, in water 0.5 ml/100 g bw for 4 wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    5 mg/kg on alternate days a few minutes after session or
                          after 3 hrs of rest.
ROUTE AND SITE:   I. Tub.

CONTROL INFORMATION:   Controls force-fed pure water
ROUTE AND SITE:  !•?•

CONTROL INFORMATION:      6 controls:  undisturbed sleep, 6 had saline inj  followed
                          by normal sleep.
DURATION OF EXPERIMENT:   4 wk.

EXAM. TYPE:  Histology
DURATION OF EXPERIMENT:   Approx. 10 d

EXAM. TYPE:    Behavior
                                       263
                                                                                                                                    264

-------
COMPOUND:  : 5H-Dibenz(b,f)  azeplne,  5-(3-(dimethylamino)propyl)-10,ll-
-------
COMPOUND:   5H-Dibenzo(a,d) cycloheptene-delta (Sup 5),  gamma-propylamine,  10,11-
           dihydro-M.N-dimethyl-
           000050486
            Lullmann-Rauch, R.
REFERENCE:   Acta Neuropath. (Berl.)29: 237-249, 1974
OBSERVED NEUROTOXIC EFFECTS:   Administration  for  lOwk did not  induce alterations
     in the nerve cells of spinal  cord  and  cerebellar cortex cells examined.
COMPOUND:  5H-Dibenzo(a,d) cycloheptene-delta (sup5), gamma-propylamine,  10,11-dihydi
           N,N-dimethyl-, hydrochloride
           000549188

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac.  21:51-66,  1963.


OBSERVED NEUROTOXIC EFFECTS:   The  compound enhanced the effect of Yohimbine
                               and  lowered its lethal dosage.
ANIMALS:   Rats,  Wistar,  M,  young adult.
                                                                                          ANIMALS:
               Mice,  TT,  M,  18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   150 mg/kg bw,  5d/wk  in water, 0.5 ml/100 g bw, for 8 wk.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          ED,
                                                                                                                     '50
mg/kg
                                                                                                                   ED,.- = dose  producing a 50% mortality of mice injected
                                                                                                                    "50
                                                                                                                          S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:  I.  Tub.

CONTROL INFORMATION:    Controls force-fed  pure water.
ROUTE AND SITE:      S.C.,  Oral

CONTROL INFORMATION:      Various
DURATION OF EXPERIMENT:   8 wk.

EXAM. TYPE:    Histology
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:     Behavior, electrophysiology, biochemistry
                                       267
                                                                                                                                   268

-------
COMPOUND:    5H-Dibenzo(a,d)cyclohepten-5-one, 10,ll-dihydro-,o-(2-(dimethyl
             amino)e thy1)oxime
COMPOUND:
 Dibenzo-p-dioxin,2,3,7,8-tetrachloro

 001746016
REFERENCE:    Lullmann-Rauch, R.
              Acta Neuropath. 29:   237-249,  1974.
REFERENCE:
                Oliver, R.M.
                Br.  J.  Indust, Med.  32:49-53,  1975.
OBSERVED NEUROTOXIC EFFECTS:    Administration for 10 wk did not  induce alterations
     in the nerve cells of spinal cord and cerebellar cortex cells examined.
OBSERVED NEUROTOXIC EFFECTS:    Personality disorders, emotional instability,
                                loss of hearing, sense of smell or taste.
                                Headaches and blurred vision.  Neuropathy recovered
                                over approx. 6 mo.
ANIMALS:   Rats, Wistar, M, young adult.
ANIMALS:
3 Humans:  M, age 45, 33, 35  yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   150 mg/kg bw, 5d/wk, in water 0.5 ml/100g bw for 8 wk
PREPARATION AND.DOSE
or HISTORY OF PATIENT:  Scientists in the same lab, extent of exposure unknown.
ROUTE AND SITE:   i. Tub.

CONTROL INFORMATION:   Controls force fed pure water
ROUTE AND SITE:    Unknown

CONTROL INFORMATION:   3 other scientists in same lab with no known  exposure to
                       dioxin.
DURATION OF EXPERIMENT:    8 wk

EXAM. TYPE:    Histology
DURATION OF EXPERIMENT:  3 yr.

EXAM. TYPE:  Clinical,"biochemical
                                       269
                                                                                                                                    270

-------
 COMPOUND:    6H-Dibenzo(b,d)pyran-l-01,3-(l'2'-dimethylheptyl)-7,8,9,10-tetrahydro-
             f-, 1,3-tr imethyl-                  (Dimethylheptylpyran)
 REFERENCE:   Karler, R., Cely, W. and Turkanis, S.A.
             Res. Comm. Chem. Path. Pharm.  7(2):353-358,  1974.
 OBSERVED  NEUROTOXIC EFFECTS:
                                 Bar-walk test gave decreasing order  of  toxicity
                                 as dimethylheptylpyran,  A'-tetrahydrocannabinol,
                                 cannabidiol; anticonvulsant  and "toxic" actions
                                 concluded to be separable.
ANIMALS:     Mice, ICR, 4-5 wk old
PREPARATION AND DOSE
or HISTORY OF PATIENT:
3-20 mg/kg
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:
                            Own controls
DURATION OF EXPERIMENT:

EXAM.  TYPE:   Behavior
                                            271
                                                                     COMPOUND:   6H-Dibenzo(b,d)pyran-l-ol, 6a,7,10,10a-tetrahydro-7-alpha, 11-
                                                                                 d ihydroxy-6,6,9-trimethyl-3-pentyl-


                                                                     REFERENCE: Christensen, H.D., Freudenthal, R.I., Gidley, J.T., Rosenfeld, R.,
                                                                                Boegli, G., Testino, L., Brine, D.R., Pitt, C.G. and Wall,  M.E.
                                                                                Science 172:  165-167, 1971.

                                                                     OBSERVED NEUROTOXIC EFFECTS: The biological activity of the above  compound,  and
                                                                          other cannabinoids was compared to that of A9-Tetrahydrocannabinol.  Similar
                                                                          neurological and behavioral responses were found for all, provided  that high
                                                                          concentrations were given.  The potency of the compounds varied depending on
                                                                          structure and route of administration.  Behavioral pattern was character-
                                                                          ized by irritability, decrease in activity, reduced sensorimotor  responses.
                                                                          This compound was approx. seven times more potent by intracerebral  admin.
                                                                          than by I.V.
                                                                                                   ANIMALS:    Mice
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Amount ns., table included comparing  relative  potency of
                        A9THC to compound tested.
                                                                     ROUTE AND SITE:  I.V. or Intracerebral

                                                                     CONTROL INFORMATION:   ns.



                                                                     DURATION OF EXPERIMENT:  ns.

                                                                     EXAM. TYPE:   Behavior
                                                                                                                                        272

-------
COMPOUND-   6H-Dibenzo(b,d)pyran-l-ol,  6a,7,10,10a-tetrahydro-7-beta,ll-dihydroxy-
            e, fi q_fviifi-?-^er-tvl-
REFERENCE: Christensen, H.D., Freudenthal, R.I., Gldley, J.T., Rosenfeld, R.,
           Boegli, G., Testino, L., Brine, D.R., Pitt, C.G. and Wall, M.E.
           Science 172:  165-167, 1971.

OBSERVED NEUROTOXIC EFFECTS:  The biological activity of the above compound, and
     other cannabinoids was compared to that of A9-Tetrahydrocannabinol.   Similar
     neurological and behavioral responses were found for all, provided that high
     concentrations were given.  The potency of the compounds varied depending on
     structure and route of administration.  Behavioral pattern was character-
     ized by irritability,  decrease in activity, reduced sensorimotor responses.
     This compound was approx. seven times more potent by intracerebral admin.
     than by I.V.
COMPOUND:  6H-Dibenzo(b,d)pyran-1-ol, 6a, 7,8,lOa-tetrahydro-8,11-dihydroxy-
           6,6,9-trimethvl-3-oentyl-


REFERENCE: Christensen, H.D., Freudenthal, R.I., Gidley,  J.T.,  Rosenfeld,  R.,
           Boegli, G., Testino, L., Brine, D.R., Pitt,  C.G.  and Wall,  M.E.
           Science 172:   165-167, 1971.

OBSERVED NEUROTOXIC EFFECTS: The biological activity of the  above  compound,  and
     other cannabinoids was compared to that of A9-Tetrahydrocannabinol.   Similar
     neurological and behavioral responses were found for all,  provided that high
     concentrations were  given.  The potency of the compounds varied depending on
     structure and route  of administration.  Behavioral pattern was character-
     ized by irritability, decrease in activity, reduced  sensorimotor  responses.
     This compound was significantly more potent by intracerebral admin, than by  I.V.
ANIMALS:    Mice
                                                                                            ANIMALS:   Mice
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Amount ns.,  table included comparing relative potency of
                        A9THC to compound tested.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Amount ns., table included comparing relative potency of
                        A9THC to compound tested.
ROUTE AND SITE:   i.V.  or Intracerebral

CONTROL INFORMATION:    ns.
ROUTE AND SITE:   i.V. or Intracerebral

CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:   Behavior
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:   Behavior
                                      273
                                                                                                                                  274

-------
COMPOUND:  6H-Dibenzo(b,d)pyran-l-ol,  6a,  7,10,10a-tetrahydro-ll-hydroxy-
           6,6,9-trimethyl-3-pentyl-


REFERENCE: Christensen, H.D., Freudenthal, R.I.,  Gidley,  J.T.,  Rosenfeld,  R.,
           Boegli, G., Testino, L., Brine, D.R.,  Pitt,  C.G.  and Wall,  M.E.
           Science 172:  165-167,  1971.

OBSERVED NEUROTOXIC EFFECTS:  The biological activity of the  above  compound,  and
     other cannabinoids was compared to  that of A -Tetrahydrocannabinol.   Similar
     neurological and behavioral responses were found for all,  provided  that high
     concentrations were given.  The potency of the compounds varied depending on
     structure and route of administration.  Behavioral pattern was character-
     ized by irritability, decrease in activity,  reduced  sensorimotor  responses.
     This compound  was  approx.  seven times more potent by intracerebral admin.
     than by  I.V.
COMPOUND:   6H-Dibenzo(b,d)pyran-1-ol,  6a,7,10,10a-tetrahydro-6,6,9-
           trimethyl-3-pentyl-


REFERENCE: Christensen, H.D., Freudenthal, R.I., Gidley, J.T., Rosenfeld,  R.,
           Boegli, G., Testino, L., Brine, D.R., Pitt, C.G. and  Wall, M.E.
           Science 172:  165-167, 1971.

OBSERVED NEUROTOXIC EFFECTS: The biological  activity of  the above  compound,  and
     other cannabinoids was compared to that of A^-Tetrahydrocannabinol.   Similar
     neurological and behavioral responses were found  for  all, provided that high
     concentrations were given.  The potency of the compounds varied  depending on
     structure and route of administration.  Behavioral  pattern  was character-
     ized by irritability, decrease in activity, reduced sensorimotor responses.
     Immobility was more pronounced with  the A° THC compounds.   Equipotent by
     either method of admin, faster onset of activity  after intracerebral.
     Activity after I.V. may be due to conversion to 11-hydroxy  metabolite.
ANIMALS:    Mice
                                                                                            ANIMALS:    Mice
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Amount ns.,  table included  comparing relative potency  of
                        A9THC to compound tested.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Amount ns., table included comparing relative  potency of
A9THC to compound tested.
ROUTE AND SITE:   i.v. Or Intracerebral

CONTROL INFORMATION:    ns.
ROUTE AND SITE:  i.v. or Intracerebral

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:   Behavior
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:   Behavior
                                     275
                                                                                                                                  276

-------
COMPOUND:
6H-Dibenzo(b,d)pyran-l-ol,  6a,7,10,lOa-tetrahydro-6,6,9-trimethy1-3-
pentyl-
REFERENCE: McCaughran, J.A., Jr.,  Corcoran, M.E.  and Wada,  J.A.
           Pharm.  Biochem. Behav.  2:   227-233,  1974.
COMPOUND:  6H-Dibenzo(b,d)pyran-l-ol,  6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-
              •-"-  r'  -"  trans1-

           1972083
REFERENCE:  Carlini, E.A., Karniol, I.G., Renault, P.F. and Schuster, C.R.
           Br. J. Pharmac. 50:  299-309, 1974.
OBSERVED NEUROTOXIC EFFECTS:  The rats  exhibited  flaccid muscles,  ataxla,  catalepsy,
                             hyperreactivity,  and  loss  of  righting.   These symptoms
                             were dose-related from 0  (1 mg/kg)  to  100% (9 mg/kg).
                             A TD5_  of 4.3 mg/kg was determined.  Protection against
                             metrazol  induced  seizures  was provided by far higher
                             doses.
                                                                                 OBSERVED NEUROTOXIC EFFECTS:     ^ compound dlsrupted time production tasks,
                                                                                                                 Increased pulse rate and provoked psychic
                                                                                                                 reactions in humans.  The different animals
                                                                                                                 responded similarly.
ANIMALS:    Rats, hooded, M,  300-480  g,  total  over  200  in  groups  of  4
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1-9 mg/kg, one  dose  (toxicity)
                        15-200 mg/kg  (protection against  induced seizures)
                                                                                 ANIMAIS-    Rabbits, .albino, adult M, 2.5-3.5 kg
                                                                                            Mice, albino, M, 3 mo, 25-30 g
                                                                                            Rats, no details
                                                                                            Human:  11 physicians and 22 medical students, all M, 18-42 yr,  51-80 kg
                                                                                 PREPARATION AND DOSE
                                                                                 or HISTORY OF PATIENT:   Rabbits:  continuous infusions
                                                                                                         Rats:  0-40 mg/kg
                                                                                                         Mice:  0-80 mg/kg
                                                                                                         Humans:  1-20 mg/man
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:  ns
                                                                                 ROUTE AND SITE:   Rabbits:  I.V.; rats:  ns; mice:  I.P.; humans:  inhalation.

                                                                                 CONTROL INFORMATION:    Zero treatment, placebo
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:    Behavior
                                                                                 DURATION OF EXPERIMENT:   Various

                                                                                 EXAM.  TYPE:  Behavior
                                           277
                                                                                                                                        278

-------
COMPOUND:       6H-Dibenzo(b,d)pyran-l-ol,  6a,7,8,10a-tetrahydro-6,6,9-
                trimethyl-3-pentyl-,(6 afl^trans)-

                1972083

REFERENCE:   Christensen, H.D., Freudenthal, R.I., Gldley, J.T., Rosenfeld, R.,
             Boegli,  G., Testlno, L.,  Brine, D.R., Pitt, C.G. and Wall, M.E.
             Science  172:  165-167, 1971.

OBSERVED NEUROTOXIC EFFECTS: The biological activity of the above compound, was
      compared  to other cannabinoids.   Similar neurological and behavioral responses
      were  found for  all provided that  high concentrations were given.  Behavioral
      pattern was characterized by irritability, decrease in spontaneous activity,
      reduced sensorimotor responses.   The potency of the compounds varied depending
    .  on structure and route of administration.  Measurable behavioral alterations
      after intracerebral 0.05 mg.  Compound is approximately equipotent by
      either  method of administration,  however, faster onset of activity after
      intracerebral.
COMPOUND:  6H-Dibenzo(b,d) pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-
           pentyl-, (6 aR-trans)-

           1972083

REFERENCE:    Fried,  P.A.  and Husband, C.A.
              Life Sci.  12(1):289-295, 1973.


OBSERVED NEUROTOXIC EFFECTS:   Visual cliff test.  No differences in depth
     perception in treated vs control groups.  Acute group took significantly
     longer than other groups to perform the tests.
ANIMALS:
          Mice.  Also in vitro study of metabolism.
                                                                                           ANIMALS:    43 Rats, hooded, M, Aged 2 mo, 6 grps of 7-8 rats
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.05 mg, 0.2 mg or 0:.| mg.
                        Relative potency of A THC to related compounds given in table.
                        In vitro:  1.0 mg labeled/g tissue for 1 hr in 0.1M potassium
                                   phosphate buffer.


ROUTE AND SITE:  1.7., or Intracerebral

CONTROL INFORMATION:  ns.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Chronic: 0.5 or 4 mg/kg in propylene glycol,  1/2  d
                                  for 44 d prior to testing.
                         Acute: 0.5 or 4 mg/kg once, preceded by  21  inj  0.5
                                 cc propylene glycol 1/2 d.

ROUTE AND SITE: i.p.

CONTROL INFORMATION:  1 group vehicle only, 1 group sham inj.
DURATION OF EXPERIMENT:    ns.

EXAM. TYPE:   Behavior, biochemistry
DURATION OF EXPERIMENT:   44 d plus testing time.

EXAM. TYPE:  Behavior
                                      279
                                                                                                                                   280

-------
COMPOUND:  6H-Dibenzo(b,d) pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-
           pentyl-,  (6 aR-trans)-

           1972083
REFERENCE:  Fujimori, M.,  Trusty,  D.M. and Himwich,  H.E.
            Life Sci. 12(1):553-563,  1973.
COMPOUND-    6H-Dibenzo(b, d)p-yran-l-ol, 6a, 7,8,10a-tetrahydro-6,6,9-trimethyl-
             3-pentyl-, (6aR-trans)-
REFERENCE:   Hockman,  C.H.,  Perrin, R.G. and Kalant, H.
             Science 172:968-970,  1971.
OBSERVED NEUROTOXIC EFFECTS:    Simultaneous EEC changes,  hypotension,  slow
                               EKG,  all dose-dependent.   Authors suggest mechanism
                               of action may be different from that of other
                               psychotomimetrics.
OBSERVED NEUROTOXIC EFFECTS:   Doses at all levels produced disruption of both
                               behavior and electroencephalogram.
ANIMALS:   46 Rabbits,  white,  3.1-3.7 kg,  tracheotomized,  10-12/grp
ANIMALS:   6 Cats,  surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:    4 different doses:   0.1,  0.5,  1.0 and 2.0 mg/kg as
                         1 mg/ml in soln of  10% propylene glycol.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.5,  1 and 4 mg/kg to each cat in successive trials,
                         4-7 d intervals.
ROUTE AND SITE:   I.V.  rate 1 ml/min.

CONTROL INFORMATION:  Control measurements taken prior to testing of compound.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:   Self-controls
DURATION OF EXPERIMENT:    Serial sacr 0-90 min after dose.

EXAM. TYPE:   Electrophysiological
DURATION OF EXPERIMENT:  60-min sessions

EXAM. TYPE:    Electrophysiology, behavior
                                       281
                                                                                                                                    282

-------
COMPOUND'     6H-Dibenzo(b,d)  pyran-1-ol,  6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-
             pentyl-, (6 aR-trans)-

             1972083

REFERENCE:   Karler,  R., Cely, W. and Turkanis, S.A.
            Res. Comm. Chem. Path. Pharm. 7(2):353-358, 1974.
                                                                                             COMPOUND:     6H-Dibenzo(b,d)  pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-
                                                                                                          pentyl-,  (6 aR-trans)-
                                                                                                          1972083
                                                                                             REFERENCE:  McCaughran, J.A.,  Jr., Corcoran, M.E. and Wada, J.A.
                                                                                                        Pharm. Biochem. Behav. 2:  227-233, 1974,
OBSERVED NEUROTOXIC EFFECTS:
                                Bar-walk test gave decreasing order of toxicity
                                as dimethylheptylpyran, the above compound,
                                cannabidiol; anticonvulsant and "toxic" actions
                                concluded to be separable.
OBSERVED NEUROTOXIC EFFECTS:  The rats exhibited flaccid muscles, ataxia, catalepsy,
                              hyperreactivity,  and loss of righting.  These symptoms
                              were dose-related from 0 (1 mg/kg) to 100% (9 mg/kg).
                              A TD5_  of 3.4 mg/kg was determined.  Protection against
                              metrazol induced  seizures was provided by far higher
                              doses.
ANIMALS:     Mice, ICR,  4-5 wk old
                                                                                            ANIMALS:    Rats,  hooded, M,  300-480 g, total over 200 in groups of 4
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           40-130 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1-9 mg/kg,  one dose (toxicity)
                        15-200 mg/kg (protection against induced seizures)
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:
                            Own controls
                                                                                            ROUTE AND SITE:  I.P.

                                                                                            CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:

EXAM. TYPE:  Behavior
                                                                                            DURATION OF EXPERIMENT:  ns

                                                                                            EXAM. TYPE:    Behavior
                                           283
                                                                                                                                        284

-------
COMPOUND.  Dibenzylamine, N-(2-chloroethyl)-

           UUUU313UJ

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.
COMPOUND:    Diethylamine, 2,2'-dichloro-N-methyl-
             nnnnci-750
REFERENCE:    McDonald,  T.P.  and Asano, M.
              Am.  J. Path.  38:695-702, 1964.
OBSERVED NEUROTOXIC EFFECTS:   The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
                                Severe, dose-related, neuronal  shrinkage with later
                                focal necrosis, peak on  d  6-8.  Most  affected:
                                neocortex,  pyriform cortex,  hippocampus,
                                cerebellum, medulla oblongata.  Signs:   inactivity,
                                incoordination, irritability, convulsions,
                                lacrimation.
ANIMALS:
               Mice, TT, M, 18-25 g.
ANIMALS:    Mice,  RF,  F aged  10 wk,  21-26  g,  total  189  used  in  an  acute  toxicity
            study.
PREPARATION AND uoSE
or HISTORY OF PATIENT:
                                50 mg/kg

                                dose producing a 50% mortality of mice injected
                                S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:        0.05-0.4 mg/mouse  in 0.9% NaCl  at pH 4.2-4.6.
ROUTE AND SITE:      S.C., Oral

CONTROL INFORMATION:      Various
ROUTE AND SITE:    i.v.,  dorsal  caudal  vein

CONTROL INFORMATION:      None
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:     Serial  sacr  1-28 d

EXAM. TYPE:    Histology,  behavior
                                         285
                                                                                                                                    286

-------
COMPOUND:   6,7-Dihydrodipyrido[l,2-a:2',l'-c] pyrazidllnium dibromide
               COMPOUND:   1,4:5,8-Dimethanonaphthalene,  acetoxy-1,2,3,4,10,10-hexachloro-
                           l,4,4a,5,8,8a-hexahydro-,  exo-
REFERENCE:   Clark, D.G. and Hurst, E.W.
            Brit. J.  Industr. Med. 27:  51-55, 1970.


OBSERVED NEUROTOXIC  EFFECTS:  Large doses (4 or 5 times LD5Q) produced signs indicative
                             of an action on the central nervous system:  lethargy,
                             labored respiration, muscular twitching, generalized
                             convulsions.
               REFERENCE:   Ryan,  W.H.  and  Shankland,  D.L.
                            Life  Sci.  10(1):193-200,  1971.
               OBSERVED NEUROTOXIC EFFECTS:
                                                Instability and block of activity of giant fibers;
                                                no direct action on axonal membrane.  Exo-acetoxy
                                                analog of aldrin was nontoxic.
ANIMALS:    Rats, Alderly Park (albino), 180-200 g
               ANIMALS:     Cockroach (Perlo^angta americana),  surgically prepared
                            Housefiles,  NAIDM strain
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Compound given as dichloride or dibromide, 99% pure, LD,
                          10-11 mg/kg
50'
PREPARATION AND DOSE
or HISTORY OF PATIENT: DDT 10   M,  other compounds (aldrin, dieldrin, endrin,
                       heptachlor)  2 x 10~6 to 5 x 10   M (cockroaches).  Up to
                       300 mcg/g (houseflies).
ROUTE AND SITE:   S.c.

CONTROL INFORMATION:  ns
               ROUTE AND SITE:   Irrigation of exposed nerves (cockroaches), topical  (houseflies)

               CONTROL INFORMATION:   Three types (described)
DURATION OF EXPERIMENT:  13 d

EXAM.  TYPE:     Clinical
               DURATION OF EXPERIMENT:  Several hours

               EXAM., TYPE:  Electrophysiology
                                          287
                                                                                                                                       288

-------
COMPOUND:  1,4:5,8- Dimethanonapthalene,  1,2,3,4,10,10-hexachloro-6,7-epoxy-
           1,4, Aa, 5, fi, 7.8, 8a-octahydro-, endo, endo-
           000072208

REFERENCE:  Ryan,  W.H. and  Shankland, D.L.
            Life Sci.  10(1):193-200, 1971.
COMPOUND:   1,4:5,8-Dimethanonapthalene, 1,2,3,4,10,10-hexachloro-6,7,epoxy-1,4,4a,
            5,6,7,8,8a-octahydro, endo, exo-  (Dieldrin)
            000060571
REFERENCE:  Ryan, W.H.  and  Shankland,  D.L.
            Life  Sci.  10(1):193-200,  1971.
OBSERVED NEUROTOXIC EFFECTS:
                                 Instability and block of activity of giant  fibers;
                                 no direct action on axonal membrane.  Exo-acetoxy
                                 analog of aldrin was nontoxic.  DDT with other
                                 compounds produced effects not seen with any compound
                                 alone.
OBSERVED NEUROTOXIC EFFECTS:
                                 Instability  and block of activity of giant fibers;
                                 no  direct  action on axonal membrane.  Exo-acetoxy
                                 analog  of  aldrin was nontoxic.   DDT with other
                                 compounds  produced effects not  seen with any compound
                                 alone.
ANIMALS:     Cockroach  (Perjplaneta americana). surgically prepared
            Housefiles, NAIDM strain
ANIMALS:
            Cockroach  (Pe_riplaneta ag
            Housefiles,  NAIDM strain
icana),  surgically prepared
PREPARATION AND DOSE
                           ,,-4
or HISTORY OF PATIENT: DDT 10   M, other compounds  (aldrin, dieldrin, endrin,
                      heptachlor) 2 x 10~6 to 5 x  10   M  (cockroaches).  Up to
                      300 mcg/g  (houseflies).
PREPARATION AND DOSE
or HISTORY OF PATIENT: DDT  10   M,  other  compounds  (aldrin,  dieldrin, endrin,
                      heptachlor)  2 x  10"^  to 5  x  10   M (cockroaches).  Up to
                      300  mcg/g  (houseflies).
ROUTE AND SITE:   Irrigation of exposed nerves  (cockroaches), topical  (houseflies)

CONTROL INFORMATION:   Three types  (described)
ROUTE AND SITE:    Irrigation  of  exposed  nerves (cockroaches), topical (houseflies)

CONTROL INFORMATION:    Three  types  (described)
DURATION OF EXPERIMENT:  Several hours

EXAM.. TYPE:  Electrophysiology
DURATION OF EXPERIMENT:   Several  hours

EXAM..TYPE:  Electrophysiology
                                         289
                                                                                                                                      290

-------
COMPOUND:   l,4:5,8-Dimethanonapthalene, l,2,3,4,10,10-hexachloro-6,7,epoxy-l,4,4a,
            5,6,7,8,8a-octahydro, endo, exo-  (Dieldrin)

            000060571
REFERENCE:  St.  Omer,  V.
            J.  Neurochem.  18:   365-374,  1971.
                                                                 COMPOUND:   1,4:5,8-Dlmethanonapthalene,  1,2,3,4,10,10-hexachloro-6,7,epoxy-1,4,4a,
                                                                            5,e,7,?,«a-octahydro, endo, exo-  (Dieldrin)

                                                                            000060571
                                                                 REFERENCE:   Schaffer,  C.H. and Sun, Y.P.
                                                                             J.  Econ. Entomol. 60:   1580-1583, 1967.
OBSERVED NEUROTOXIC EFFECTS:
Convulsions, starting in some cases during injection.
Intensity and other signs were directly related to
increases of brain ammonia.  Toxicity ranking:
lindane > dieldrin > heptachlor > DDT.  Brain gluta-
mine increases resulting from conversion of ammonia
to glutamine were related to the toxicity ranking,
suggesting that the 4 compounds produced convulsions by
one mechanism involving interference with the production
and/or utilization of ammonia.
                                                                                              OBSERVED NEUROTOXIC EFFECTS:
     No evidence found that binding within the fly central
     nervous system is a factor in resistance; no metabolism
     of dieldrin in central nervous system tissues was detected
     in resistant or susceptible flies.  The authors concluded
     that resistance might be due to insensltivity at the
     receptor site.
ANIMALS:    Rats,  adult  F, Wistar,  250-300  g,  surgically  prepared.
            Cockerels, White Leghorn or  Barred Plymouth Rock,  12 wk,  1.4-1.6 kg,
               surgically prepared.

PREPARATION AND DOSE
or HISTORY OF PATIENT:   Rats:  rag/kg —  lindane 11.5,  DDT 50,  dieldrin 6,  heptachlor 13.
                        Cockerels:   mg/kg —  lindane  6.3, DDT  30,  dieldrin 6, heptachlor  6.3.
                        The  compounds stated  to be  structurally unrelated.
                                                                 ANIMALS:    Houseflies  (Musca domestica)
                                                                 PREPARATION AND DOSE
                                                                 or HISTORY OF PATIENT:
In most cases, 0.02 meg/fly; 25 meg/fly to resistant flies
ROUTE AND SITE:  Intra-arterial (carotid)  at  1  ml/min

CONTROL INFORMATION:  Vehicle  only
                                                                 ROUTE AND SITE:   Injection or  infusion

                                                                 CONTROL INFORMATION:    ns
DURATION OF EXPERIMENT:  Up  to  60 min,  in  controls  7  d

EXAM. TYPE:    Behavior, biochemistry
                                                                 DURATION OF EXPERIMENT:    Up  to  24 hr

                                                                 EXAM.  TYPE:     Biochemistry, behavior
                                           291
                                                                                                                                          292

-------
COMPOUND:   1,4:5,8-Dimethanonapthalene, 1,2,3,4,10,10-hexachloro-l,4,4a,5,8,8a-hexa-
            nydro-, enao, enao-
            000309002

REFERENCE:  Avar, P., Czegledi-Janko, G.
            Brit. J. Industr. Med. 27:279-282, 1970.
                                                                   COMPOUND:   1,4:5,8-Dimethanonapthalene,  1,2,3,4,10,10-hexachloro-l,4 ,4a,5,8,8a-hexa-
                                                                              000309002

                                                                   REFERENCE:   Ryan, W.H. and Shnnkland, D.L.
                                                                               Life Sr.i. 10(1) : 193-200,
OBSERVED NEUROTOXIC EFFECTS:     Three had epileptiform fits.
                                                                   OBSERVED NEUROTOXIC  EFFECTS:
                                                                                                                               Instability and block of activity of giant  fibers;
                                                                                                                               no direct action on axonal membrane.  Exo-acetoxy
                                                                                                                               analog of aldrin was nontoxic.  DDT with other
                                                                                                                               compounds produced effects not seen with any compound
                                                                                                                               alone.
ANIMALS:       15, humans from plant manufacturing aldrin and lindane, M.
                                                                   ANIMALS:
                                                                                                           Cockroach (Peri£lan.eta americana) ,  surgically prepared
                                                                                                           Housefiles,  NAIDK strain
PREPARATION AND DOSE
or HISTORY OF PATIENT:
.02,  .039,  .014,  .006 ppm HEOD in whole blood.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  DDT  10~* M,  other  compounds  (aldrin,  dieldrin, endrin,
                       Iieptachlor)  2  x  10~6 to
                       300  mcg/g  (houseflies).
                                                                                                                              M,  other 	.
                                                                                                                     Iieptachlor)  2 x 10~° to 5 x 10   M (cockroaches).  Up to
ROUTE AND SITE:    ns.

CONTROL INFORMATION:         12  Humans
                                                                  ROUTE AND SITE:   Irrigation of exposed nerves (cockroaches), topical  (houseflies)

                                                                  CONTROL INFORMATION:   Three types (described)
DURATION OF EXPERIMENTS  yrs.

EXAM. TYPE:   EEC,  biochemistry,  neurology
                                                                  DURATION OF EXPERIMENT:  Several hours

                                                                  EXAM..TYPE:  niectrophysiology
                                           293
                                                                                                                                       294

-------
COMPOUND:   4-Dimethylamino-3,5 xylyl methylcarbamate, 22.3% emulsifiable concentrate
REFERENCE:   Shennan, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm. U:  49-67, 1967.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
COMPOUND:    Distannoxane,  hexabutyl-

             000056359

REFERENCE:  Robinson, I.M.
            Fd. Cosmet. Toxicol. 7:  45-52, 1969
OBSERVED NEUROTOXIC EFFECTS:  Treatment lowered brain epinephrine, norepinephrine.
                              and serotonin for 48 hours.
ANIMALS:  Cockerels, Single Comb White Leghorn, 10-12 d old
                                                                                             ANIMALS:    Rats, Osborne-Mendel,  F,  190-220 g, 18/group
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD,.. 4.4 mg/kg
                         (2) Subacute:  50-800 ppm in diet, 20 chicks/grp, for 3 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:   10 mg/kg in corn oil
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
ROUTE AND SITE:  i.P.

CONTROL INFORMATION:  Equivalent corn  oil
DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:   Behavior, mortality
DURATION OF EXPERIMENT:  Serial  to  48 hr

EXAM. TYPE:   Behavior, biochemistry
                                            295
                                                                                                                                         296

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COMPOUND:  Disulfide, bis (diethylthiocarbamoyl)

           uuuuy////a

REFERENCE:   Gardner-Thorpe,  C.  and  Benjamin,  S.
             J.  Neurol.  Neurosurg, Paychiat. 34:253-259, 1971.
OBSERVED
NEUROTOXIC EFFECTS:   Peripheral neuropathy and optic neuritis.
                                                                                 COMPOUND:  Ephedrine HC1
REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66,  1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound  enhanced the effect of Yohimbine
                              and lowered its  lethal dosage.
ANIMALS:    Human:   7  case-reports
                                                                                 ANIMALS:
                                                                                                Mice, TT, M, 18-25  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    250-1500 mg/d  for alcoholism, long term.
                                                                                 PREPARATION AND DOSE
                                                                                 or HISTORY OF PATIENT:
                         ED
                                                                                                                     5Q
                                                                                                                   4 rag/kg
                                                                                                                   ED,,. =  dose  producing a 50% mortality of mice  injected
                                                                                                                           S.C.  with yohimbine hydrochloride  (20 mg/kg) .
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   None
                                                                                 ROUTE AND SITE:      S.C.,  Oral

                                                                                 CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:    Follow-up  to  2  yr  after  discontinuing  drug

EXAM.  TYPE:  Clinical chemistry,  behavior, nerve-conduction  tests
                                                                                 DURATION OF EXPERIMENT:  Various

                                                                                 EXAM. TYPE:    Behavior, electrophysiology, biochemistry
                                       297
                                                                                                                                   29.8

-------
COMPOUND:    Ergoline-8-beta-carboxamide, 2-bromo-9,10-didehydro-N,N-diethyl-6-methyl

             000050373

REFERENCE:     Brown,  I.R. and Liew, C.C.
               Science 188:1122-1123, 1975.


OBSERVED NEUROTOXIC EFFECTS:    LSD stimulated acetylation of specific histones
                               in cerebral hemispheres and midbrain 30 min
                               after injection.
COMPOUND:   Ergoline-8-beta-carboxamide, 2-bromo-9,10-didehydro-N,N-diethyl-6-metl

            000050373

REFERENCE:   Diaz,  J-L. and Huttunen, M.O.
             Science 174:62-63, 1971.


OBSERVED NEUROTOXIC EFFECTS:  Chronic oral intake raised synthesis and  turnover
                              of 5-HT by 25-30%, and levels of  5-HT  (13%)  and
                              tryptophan (18%).  No "grossly" evident behavioral
                              changes in treated rats.
ANIMALS:        Rabbits, young NZ White, M, 1 kg
                                                                                                ANIMALS:   Rats, S-D, M, 150-160 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:     10  and  100 meg/kg in 0.1 ml saline.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20 mcg/kg/d in 1.0 ml water  for  1  mo.   The dose was
                         increased daily according  to weight  gain.
ROUTE AND SITE:   l.v.,  ear vein

CONTROL INFORMATION:      Vehicle only
ROUTE AND SITE:  Gavage

CONTROL INFORMATION:  Controls treated water  only.
DURATION OF EXPERIMENT:    15  and  30 min

EXAM. TYPE:    Biochemistry
DURATION OF EXPERIMENT: 1 mo.

EXAM. TYPE:   Biochemistry
                                          299
                                                                                                                                        300

-------
COMPOUND:   Ergoline-8-beta-carboxamide,  2-bromo-9,10-diehydro-N,N-diethyl-6-methyl

            000050373

REFERENCE:   Farrow,  J.T.  and Van Vunakis,  H.
             Blochem. Pharmacol.  22:1103-1113,  1973.
OBSERVED NEUROTOXIC EFFECTS:
     Synaptosomes of cortical grey-matter contained low
     concentrations of high- and medium- affinity
     binding-sites for LSD.  Synaptic membranes had
     2.2 times more high-affinity sites/mg protein
     but only 1.8 times more medium-affinity sites than
     synaptosomes.  These sites are not found elsewhere
     in the brain.  Binding inhibited by chlorpromazine
     or any of 10 other hallucinogens; enhanced by cAMP
     or prostaglandin E .
COMPOUND:    Ergoline-8-beta-carboxamide,   2-bromo-9,10-didehydro-N,N-diethyl-6-methyl

            000050373

REFERENCE:     Idanpaan-Heikkila, J.E. and  Schoolar,  J.C.
               Science  164:1295-1297,  1969.


OBSERVED NEUROTOXIC EFFECTS:   Brain  uptake  higher than blood concentration.
                              Part of  dose  (2.5% early in pregnancy,  0.5% late)
                              passed into the fetuses in 5 min,  over  70%
                              being  unmetabolized LSD.  For 30 min LSD in
                              cortex higher than in white-matter.  Related
                              behavior started at 3-4 min and lasted  40-60 min.
ANIMALS:
             Rat  cerebral cortex fractions  in  vitro.
                                                                                                ANIMALS:  Mice, Yale Swiss, 4 M and 6 F pregnant
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Myelin, synaptosomes, mitochondria obtained by centrimga-
tion and verifeid by electronmicroscopy.   Binding of
3H-LSD studied.
                                                                     PREPARATION AND DOSE
                                                                     or HISTORY OF PATIENT:   19.8 and  9.9  mcg/g of labeled compound.
ROUTE AND SITE:    In vitro

CONTROL INFORMATION:   Laboratory  controls
                                                                     ROUTE AND SITE:     I.V.,  tailvein

                                                                     CONTROL  INFORMATION:  ns.
DURATION OF EXPERIMENT:      Various

EXAM.  TYPE:  Biochemical
                                                                     DURATION OF EXPERIMENT:    Serial  sacr 5 min to 24 hr.

                                                                     EXAM.  TYPE:   Autoradiography
                                           301
                                                                                                                                       302

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COMPOUND:  Ergollne-8-beta-carboxamlde,  2-bromo-9,10-didehydro-N,N-diethyl-6-methyl

           000050373
REFERENCE:
             Peters, D.A.
             Biochem.  Pharmacol. 23:231-237, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                Brainstem:  norepinephine and tyrosine hydroxylase
                                lower after 20 mcg/kg/d for 14 d, more so after 100
                                mcg/kg/d.  Mixed results with serotonin and
                                5-hydroxyindoleacetic acid.
                                                                   COMPOUND:  Ergoline-8-beta-carboxamide,   2-bromo-9,10-didehydro-N,N-diethyl-6-methyl

                                                                             000050373

                                                                   REFERENCE:      Quinton,  R.M.
                                                                                  Br.  J.  Pharmac. 21:51-66, 1963.


                                                                   OBSERVED NEUROTOXIC EFFECTS:   The compound enhanced the effect  of Yohimbine
                                                                                                 and lowered its lethal dosage.
ANIMALS:
             Eats,  S-D,  M,  160-180 g
                                                                                              ANIMALS:
                                                                                                             Mice, TT, M, 18-25  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:    i.p.

CONTROL INFORMATION:
500 meg/kg in saline 2 ml/kg.   One dose,  or 5 x 100
meg/kg half-hourly for 5 doses (acute).   500 mcg/kg/d
(chronic).  Sacrifice 24 hr after last  dose.  Chronic
rats also given lower daily amounts (from 20 meg)  ns.
under Methods.
                            Saline only, all studies.
                                                                   PREPARATION  AND DOSE
                                                                   or  HISTORY OF  PATIENT:
                          ED5Q  >10  mg/kg
                          ED,_  = dose producing a 50% mortality of mice  injected
                                 S.C. with yohimbine hydrochloride  (20 mg/kg).
                                                                   ROUTE  AND  SITE:      S.C., Oral

                                                                   CONTROL  INFORMATION:      Various
DURATION OF EXPERIMENT:

EXAM.  TYPE:  Biochemical
14 d (chronic)
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior,  electrophysiology, biochemistry
                                          303
                                                                                                                                       304

-------
COMPOUND:   Ergoline-8-beta-carboxamide,  2-bromo-9,10-didehydro-N,N-diethyl-6-methyl

            000050373

REFERENCE:  Spooner,  C.E.  and Winters, W.D.
            Int.  J.  Neuropharmacol.  5:  217-236, 1966
COMPOUND'   Ergollne-8-beta-Carboxylic acid,  9,10-didehydro-6-methyl-,morpholide
REFERENCE:  Gogerty, J.H. and Dille, J.M.
            J. Pharm. Exp. Ther. 120:  340-348, 1957.
OBSERVED NEUROTOXIC EFFECTS:  Compound produced  excitement, abnormal postures,
                              arousal EEGs,  then depression.
OBSERVED NEUROTOXIC EFFECTS:   The compound induced behavior changes  like  those from
                              LSD, the equivalent dose being one-third  more than LSD
                              and the duration of effects half as  long.
ANIMALS:    200  Cockerels,  White Leghorn,  ages 5-14 d,  45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.025-0.1 mg/kg
ANIMALS:    Mice, albino, 25 g
            Cats
            Rabbits
Rats, F
Human:  2 volunteers
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Various schedules and doses
ROUTE AND SITE:    s.C.  near  axillary  vein;  I.P.  for doses over 0.05 ml

CONTROL INFORMATION:  ns
ROUTE AND SITE:   i.v. (mice, cats, rabbits); S.C.  (rats); oral  (humans)

CONTROL INFORMATION:    Various
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:  Behavior, EEC
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:  Behavior, clinical
                                           305
                                                                                                                                        306

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COMPOUND:  Ergotamine, dihydro-,  monomethanesulfonate

           001381028

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
                                                           COMPOUND:   D-Erythro-D-galacto-octo pyranoside, methyl 6,8-dideoxy-6-(l-methyl-4-
                                                                      propyl-2-pvrrolidine carbox.amido)-l-thio-


                                                           REFERENCE:   Tang, A.H. and Schroeder, L.A.
                                                                       Tox. Appl. Pharm. 12:44-47, 1968.


                                                           OBSERVED  NEUROTOXIC  EFFECTS:   (1 and 2) Depressed neuromuscular  transmission at
                                                                                         doses of 25 and 50 mg/kg.   (3)  Immediate ataxia,
                                                                                         higher doses were lethal.
ANIMALS:.
               Mice, TT, M, 18-25 g.
                                                           ANIMALS:    (1 and  2)  6 Rabbits
                                                                      (3)  3 Chickens
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED
                           ...
>20 mg/kg

 dose producing a 50% mortality of mice injected
 S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT: (D 25 mg/kg followed by 50 mg/kg, in saline.
                       (2) 50 mg/kg during each of four stimulation frequencies
                           in a latin-square design.
                       (3) 200 mg/kg or 300-500 mg/kg.
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:      Various
                                                           ROUTE AND  SITE:   I.V.

                                                           CONTROL  INFORMATION:    ns.
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
                                                           DURATION OF  EXPERIMENT:   ns.

                                                           EXAM.  TYPE:   Electrophysiology,  behavior
                                         307
                                                                                                                                     308

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            Ethanamine
COMPOUND:
REFERENCE:   Curtis,  0.R.  and  Watkins,  J.C.
             J.  Neurochem.  6:117-141,  1960.
COMPOUND:   Ethane,  2-bromo-2-chloro-l,l,l-trifluoro-
REFERENCE:  Chang, L.W., Dudley, A.W., Jr., Lee, Y.K. and Katz, J.
            Exp. Neurol. 45: 209-219, 1974.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                                Treatment  caused excitation or depression of
                                neuronal activity.   Excitatory ranking:   glutamic,
                                (3-aminoglutaric, aspartic,  cysteic,  cysteine-
                                sulfinic acids,  B-hydroxyglutamic,  N-methylaspartic,
                                N-formiminoaspartic  acids.
                                Depressant ranking:   6-alanine, GABA,  taurine,
                                N-methyl-B-alanine,  (5-amino-B-hydroxybutyric,
                                glycine, a-alanine,  6-aminovaleric,  6-aminoisobutyric
                                acids.
                                Structure-activity  relationships established.
             Cats,  surgically  prepared  to  exposed motoneurones,  Renshaw cells or
             dorsal horn interneurones  in  lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
OBSERVED NEUROTOXIC EFFECTS:  Superior parasagittal cerebral cortex showed
     collapses of neuronal rough endoplasmic reticulum, dilated.Golgi complex,
     and some vacuoles in cytoplasm.  After higher dose, effects more severe:
     loss of mitochondrial membranes, coagulative necrosis of cortical neurons,
     and edematous glial cells.
                                                                                                ANIMALS:   Rats,  young M and F
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                        (1) 5 rats:  10 ppm 8 hr/d, 5d/wk for 8 wk.
                        (2) 5 rats: 500 ppm 8 hr/d, 5d/wk for 4 wk.
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:  Inhaiation

CONTROL INFORMATION:  6 control rats
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
DURATION OF EXPERIMENT:   (i) 8 wk, (2) 4 wk

EXAM. TYPE: Histology
                                           309
                                                                                                                                       310

-------
COMPOUND:   Ethann, 2-bromo-2-chloro-l,l,1-trifluoro-
REFERENCE:    Chang,  L.W., Dudley, A.W., Jr., Katz, J. and Martin, A.H.
              Teratology  9:A-15,  1974.   (Abstract)
OBSERVED NEUROTOXIC EFFECTS:
No gross fetal anomalies.   Brain ultrastructure
of newborn focal weakness/disruption of cortical
neurons, vacuolation,  myelin anomalies, abnormal
synapses.
                                                        COMPOUND:   Ethane, l,l'-oxybis-

                                                                    000060297

                                                        REFERENCE:  Denst, J.
                                                                    Neurology 3:  239-249, 1959.
                                                                                         OBSERVED NEUROTOXIC  EFFECTS:
                                                                                                                      Coma  from 8  hours  to  35  days.   Cerebral lesions charac-
                                                                                                                      terized  by:   anemic infarction,  loss of Purkinje cells,
                                                                                                                      and severe gliosis of the molecular layer of the cere-
                                                                                                                      bellum;  neuronal degeneration  and focal necrosis of corte:
                                                                                                                      degeneration of basal nuclei;  necrosis of cerebral white
                                                                                                                      matter with  giant-cell granulomas.   This damage was not
                                                                                                                      attributed to anoxemia or circulatory stagnation.
ANIMALS:    Rats,  S-D,  pregnant  F
                                                                                        ANIMALS:    Human:  3 cases  (M,  8; M,  72;  F,  33)
PREPARATION AND DOSE
or HISTORY OF PATIENT:     10  ppm,  40  hr/wk  thru pregnancy.
                                                        PREPARATION AND DOSE
                                                        or HISTORY OF PATIENT:  Anesthesia by open-drip or closed system
ROUTE AND SITE:    Inhalation

CONTROL INFORMATION:     ns.
                                                        ROUTE AND SITE:    Inhalation

                                                        CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:     Gestation

EXAM. TYPE:  Histology
                                                        DURATION OF EXPERIMENT:  Up to 35 d

                                                        EXAM. TYPE:   Clinical; autopsy
                                       311
                                                                                                                                    312

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COMPOUND:   Ethane,  l,l'-oxybis-(ether)

            000060297

REFERENCE:  Owens, G.
            Neurology 8:   827-831,  1958.
COMPOUND:    Ethane, l,l,l-trichloro-2,2-bis (p-chlorophenyl)-   (DDT)

            000050293

REFERENCE:  Dale,  W.E.,  Gaines,  T.B.  and Hayes, W.J., Jr.
            Tox.  Appl.  Pharm.  4:   89-106, 1962,
OBSERVED NEUROTOXIC EFFECTS:  Convulsions were recorded by EEC  in dogs subjected
                             to hyperthermia and  ether anesthesia, probably due
                             to fat  embolisms.  Prior heparinization protected
                             the animals.
OBSERVED NEUROTOXIC EFFECTS:   Signs correlated with increases of DDT concentration
                              in brain induced by starvation; this concentration was
                              not parallel with concentrations of metabolites DDE
                              (plasma metabolite) and DDA (urinary metabolite).
                              Tremors developed during the 12th week.
ANIMALS:     Dogs,  2  groups  of  10
ANIMALS:    Rats,  Sherman,  22-28 d old weanlings, M & F
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Closed  gas  system,  dose ns
PREPARATION AND DOSE
or HISTORY OF PATIENT:  200 ppm DDT in diet
ROUTE AND SITE:    Inhalation

CONTROL INFORMATION:   ns
ROUTE AND SITE:  Oral

CONTROL INFORMATION:  Untreated rats
DURATION OF EXPERIMENT:    Up to 2 wk

EXAM. TYPE:   Clinical,  biochemistry,  histology
DURATION OF EXPERIMENT:   Up to 140 d

EXAM. TYPE: Behavior,  biochemistry
                                           313
                                                                                                                                        314

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COMPOUND:    Ethane, l,l,l-trichloro-2,2-bis (p-chlorophenyl)-

             000050293

REFERENCE:  Dvorchik,  B.H. and Maren, T.H.
            Comp. Gen. Pharm. 5:  37-49, 1974.
                                                            COMPOUND:    Ethane,  l,l,l-trichloro-2,2-bls  (p-chlorophenyl)-

                                                                        000050293

                                                            REFERENCE:  Eaton, J.L. and Sternburg, J.G.
                                                                       J. Econ. Entomol.  60:  1699-1703, 1967.
                                                                                                                                                          (DDT)
OBSERVED NEUROTOXIC EFFECTS:
The compound was taken up by all tissues and stored
mainly in the liver and muscle with no significant
storage in red cells nor excretion.  Metabolism was
slow (after 17 d 95% of liver store was intact).
The brain level at autopsy after receiving the LD
suggested that the brain was more sensitive to the
compound than that of mammals.
                                                                                         OBSERVED NEUROTOXIC  EFFECTS:
 The frequency of DDT-induced  trains in  the abdominal
central nervous system was not directly  related  to  the
DDT content of the central nervous system.  More trains
appeared after topical application than  after  injection,
although less DDT was found in the abdominal central
nervous system.  Injection into the 6th  abdominal ganglion
produced dose-related trains indicating  that high afferent
(sensory) activity was needed.  Therefore, the synaptic
block following DDT was secondary to some more direct
action of DDT or a metabolite.
ANIMALS:     Dogfish, M, 1-3 kg (Squalus acanthias)
                                                           ANIMALS:    American cockroach (Periplaneta americana), adult M.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1-20 mg/kg, or 60 meg/kg of labeled compound
                                                            PREPARATION AND  DOSE
                                                            or HISTORY OF  PATIENT:
                                                                                     (a) 120 meg/cockroach
                                                                                     (b) 1 meg/cockroach
ROUTE AND SITE:  I.V.

CONTROL INFORMATION:   Sham injections
                                                           ROUTE AND  SITE:  (a)  Topical,  on both cerci; (b) Injected into the 6th abdominal ganglion

                                                           CONTROL  INFORMATION:   ns
DURATION OF EXPERIMENT:   1 hr to 15 d (serial), or longer (1 mo)

EXAM. TYPE:  Biochemistry
                                                           DURATION OF  EXPERIMENT:  Probably 24 hr

                                                           EXAM. TYPE:   Electrophysiology,  biochemistry
                                        315
                                                                                                                                     316

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COMPOUND:   Ethane, l,l,l-trichloro-2,2-bis (p-chlorophenyl)-   (DDT)

            000050293
REFERENCE:
                  Peters,  D.A.V.,  Hrdina,  P.D.,  Singhal,  R.L.  and  Ling,  G.M.
                  J.  Neurochem.  19:1131-1136,  1972.
                                                                                 COMPOUND:    Ethane,  l,l,l-trichloro-2,2-bis  (p-chlorophenyl)-
                                                                 (DDT)
                                                                                 REFERENCE:   Ryan,  W.H.  and Shankland, D.L.
                                                                                             Life Set.  10(1):193-200,  1971.
OBSERVED NEUROTOXIC EFFECTS
ANIMALS:
                    A single dose raised the brainstem 5-hydroxy-
                    indoleacetic acid but not 5-hydroxytryptamine.
                    Pretreatment with Pargyline allowed 5-hydroxy-
                    tryptamine to increase.  Administration of
                    DL-£-chlorophenylalanine with DDT blocked the
                    rise of 5-hydroxyindoleacetic acid and neuropathy
                    signs (pyrexia, tremors, convulsions) from DDT.
                    DL-6-fluorotryptophan (serotonin inhibitor)
                    blocked the rise of 5-hydroxyindoleacetic acid
                    and pyrexia but not tremors and convulsions.
                    The authors infer that 5-hydroxytryptamine turnover
                    is connected with pyrexia.
Rats, Wistar, M, 190-220 g, at least 4/grp.
OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                             Instability  and block of  activity of giant fibers;
                                                                                                                             no  direct  action  on axonal membrane.  Exo-acetoxy
                                                                                                                             analog  of  aldrin  was nontoxic.   DDT with other
                                                                                                                             compounds  produced effects not  seen with any compound
                                                                                                                             alone.
                                                                                             ANIMALS:     Cockroach  (PerjLplanepa  flrogi-l|c,aina') -  surgically prepared
                                                                                                          Housefiles, NAIDM strain
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               600 mg/kg in corn oil with/without other compounds.
PREPARATION AND DOSE
or HISTORY OF PATIENT: DDT  10   M,  other  compounds  (aldrin,  dieldrin,  endrin,
                      heptachlor)  2  x 10~6  to 5  x  10   M (cockroaches).  Up to
                      300  mcg/g  (houseflies).
ROUTE AND SITE:    Oral;  other  compounds  given I.P.

CONTROL INFORMATION:    One group,  vehicle
                                                                                ROUTE AND  SITE:   Irrigation of exposed nerves  (cockroaches), topical  (houseflies)

                                                                                CONTROL  INFORMATION:   Three types (described)
DURATION OF EXPERIMENT:      Serial  to 5  hr.

EXAM. TYPE:       Biochemistry
                                                                                 DURATION OF  EXPERIMENT:  Several hours

                                                                                 EXAM.  TYPE:  Electrophysiology
                                           317
                                                                                                                                        318

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COMPOUND:    Ethane, l,l,l-trichloro-2,2-bis (p-chlorophenyl)-  (DDT)

             000050293

REFERENCE:  St.  Omer,  V.
            J.  Neurochem.  18:   365-374,  1971,
OBSERVED NEUROTOXIC EFFECTS:
Convulsions, starting in some cases during injection.
Intensity and other signs were directly related to
increases of brain ammonia.  Toxlcity ranking:
lindane > dieldrin > heptachlor > DDT.  Brain  gluta-
mine increases resulting from conversion of ammonia
to glutamine were related to the toxicity ranking,
suggesting that the 4 compounds produced convulsions by
one mechanism involving interference with the  production
and/or utilization of ammonia.
                                                               COMPOUND:    Ethane, l,l,l-trichloro-2,2-bis (p-chlorophenyl)-  (DDT)

                                                                            000050293

                                                               REFERENCE:  Shankland, D.L.
                                                                           Tox. Appl. Pharm. 6:197-213, 1964.
                                                                                             OBSERVED NEUROTOXIC  EFFECTS:
                    Symptoms  in hindlimbs  if  spinal  reflexes
                    functioned, then excised  tibial  nerves  responded
                    to electrostimulation.  Without  reflexes,  neither
                    symptoms  arose,  nor did excised'nerves  respond.
                    Course of DDT-tremors  similar to that in the American
                    cockroach.
ANIMALS:    Rats,  adult F,  Wistar,  250-300 g,  surgically prepared.
            Cockerels,  White Leghorn or Barred Plymouth Rock, 12 wk, 1.4-1.6 kg,
               surgically prepared.
                                                               ANIMALS:
Rats, Purdue-Wistar (sic), M and F, 150-400 g
PREPARATION AND DOSE                                                                         PREPARATION AND DOSE
or HISTORY OF PATIENT:  Rats:   mg/kg ~ lindane 11.5,  DDT 50,  dieldrin 6, heptachlor 13.     or HISTORY OF PATIENT:
                        Cockerels:   mg/kg — lindane 6.3, DDT 30,  dieldrin 6, heptachlor 6.3.
                        The compounds stated to be structurally unrelated.
                                                                                           50-300 mg/kg in oil,  100 mg/ml
ROUTE AND SITE:  Intra-arterial (carotid)  at 1 ml/min

CONTROL INFORMATION:  Vehicle only
                                                               ROUTE AND SITE:   Gavage or instillation into throat

                                                               CONTROL INFORMATION:   Untrtd rats
DURATION OF EXPERIMENT:   Up to 60 min,  in controls 7 d

EXAM. TYPE:    Behavior,  biochemistry
                                                               DURATION OF EXPERIMENT:     ns., apparently up to about 1 wk

                                                               EXAM. TYPE:  Electrophysiology, behavior
                                            319
                                                                                                                                        320

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 COMPOUND:   Ethane, l,l,l-trichloro-2,2-bis  (p-chlorophenyl)-

            000050293
          .  Wooiey,  D.t.  and  Barren,  B.A.
            Tox.  Appl.  Pharm.  12:   440-454,  1968.
COMPOUND:   Ethane, l,l,l-trlchloro-2,2-bis (p-chlorophenyl)-

            000050293
REFERENCE:
            Woolley, D.E. and Runnells, A.L.
            Tox. Appi. Pharm. 11:389-395, 1967.
OBSERVED NEUROTOXIC EFFECTS:   Hyperexcitability and tremors.   Mild clonic
                               convulsions occurred only rarely,  but seen in
                               rats which died.   Spontaneous electric activity
                               changed before onset of tremors (10 areas measured),
                               most in cerebellum.
OBSERVED NEUROTOXIC EFFECTS:
                                High peak concentration of compound  in  central
                                nervous system grey-matter by  6-12 hr,  slower
                                uptake and lower concentration in myelinated
                                tissues, e.g. brainstem and cord.  Hyperirritability
                                and tremor more intense at 6-12 hr than at  24 hr,
                                corresponding with peak concentrations  in neocortex
                                and cerebellum.  Fine  tremor thought related to
                                brain peak, coarse tremor to cord peak.
ANIMALS:    22 Rats,  S-D,  F,  200-250 g,  surgically prepared.
ANIMALS:     RatS)  s-D, F, 200-250 g, total 24.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    50 and  100  mg/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT: 100 mg/kg after 24-hr fast.
ROUTE AND SITE:   oral

CONTROL INFORMATION:  ns.
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:   4 rats untrtd
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE: Electrophysiology
DURATION OF EXPERIMENT: 6, 12, 24 hr

EXAM. TYPE:  Biochemistry
                                           321
                                                                                                                                        322

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COMPOUND:      Ethanol,  2-butylamino
               000111751


REFERENCE:   Hartung,  R. and  Cornish,  H.H.
             Tox.  Appl.  Pharm.  12:486-494,  1968,
OBSERVED NEUROTOXIC EFFECTS:
                                                              COMPOUND:     Ethanol, 2-(p-chlorophenyl)-l-(p-(2-(diethylamino)ethoxy)phenyl)-
                                                                           1-p-tolyl-
                                                                           000078411
                                                              REFERENCE:   Suzuki,  K., Zagoren, J.C., Chen, S.M.  and  Suzuki,  K.
                                                                          Acta Neuropath. 29:141-156, 1974.
This compound was tested with a group of other
aminoethanols and choline analogs,  all of which
inhibited cholinesterase in vitro.   In vitro
inhibition increases as the number  of carbon atoms
attached on the nitrogenous head of the 2-amino-
ethanol molecule.  In the in vivo tests the oral
                                                                                              OBSERVED NEUROTOXIC EFFECTS:
                                LD   's were uniformly higher than the i.p.
                                values .

Intracytoplasmic osmiophilic inclusions throughout
central nervous system in all treated rats, dose-
related, followed by degeneration especially of
oligodendroglia, and demyelination.  Large
accumulations of A7>2^-cholestadiene-36-ol and
(less) of desmosterol.  Authors state that the former
produces identical lesions and attribute  them  (see
also under 20, 25-diazacholesterol)  to the presence
of a double bond at the 7-position.
ANIMALS:     Rats,  S-D,  M
                                                                                              ANIMALS:     Rats,  Wistar,  M and F,  newborn
PREPARATION AND DOSE
or HISTORY OF PATIENT:    In vitro:   10   to  10   .
                         In vivo:    LD   and lower  doses.
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:
                                                                                          250 mg/kg/d  in olive oil,  from d 5 of age.
ROUTE AND SITE:    Oral,  i.p.,  in vitro

CONTROL INFORMATION:   ns.
                                                              ROUTE AND SITE:   oral or  I.P.

                                                              CONTROL INFORMATION:        Olive  oil only,  or (biochemistry) untreated
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:  Biochemistry
                                                              DURATION OF EXPERIMENT:     Serial,  3-9 d

                                                              EXAM. TYPE:  Histology, biochemistry
                                            323
                                                                                                                                          324

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COMPOUND:   Ethanol,  2-(dibutylamino)-

            000102818

REFERENCE:   Hartung, R.  and  Cornish, H.H.
             Tox.  Appl.  Pharm.  12:486-494, 1968.
                                                                                             COMPOUND:     Ethanol,  2-(diethylamino)-
                                                             REFERENCE:   Hartung, R. and.: Cornish, H.H.
                                                                         Tox. Appl. Pharm. 12:486-494, 1968.
3BSERVED NEUROTOXIC EFFECTS:
This compound was tested with a group of other
aminoethanols, all of which inhibited cholinesterase
in vitro.  In vitro inhibition increases as the
number of carbon atoms attached on the nitrogenous
head of the 2-aminoethanol molecule.  In the in vivo!
tests the oral LD,. 's were uniformly higher than the
i.p. LDqn values.  When given i.p., compound reduced
brain
                                       cholinesterase.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
This compound was tested with a group of other amino-
ethanols, all of which inhibited cholinesterase  in
vitro.  In vitro inhibition increases as the number
of carbon atoms attached on the nitrogenous head of
the 2-aminoethanol molecule.  In the in vivo tests I
the oral LD  's were uniformly higher than the i.p.
LD5Q values.
ANIMALS:     Rats,  S-D,  M
                                                            ANIMALS:     Rats, S-D, M
PREPARATION AND DOSE
or HISTORY OF PATIENT:   In vitro:   10   to 10  .
                         In vivo:

                                         and lower doses.
                                                            PREPARATION AND  DOSE
                                                            or HISTORY OF  PATIENT:   In vitro:  10~^  to 10  i.
                                                                                     In vivo:   LD5g  and l°wer  doses.
ROUTE AND SITE:    Oral,  i.p.,  in vitro

CONTROL INFORMATION:   ns.
                                                            ROUTE AND SITE:   Oral, i.p., in vitro

                                                            CONTROL INFORMATION:  ns.
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:  Biochemistry
                                                            DURATION OF EXPERIMENT:  ns.

                                                            EXAM. TYPE:  Biochemistry
                                            325
                                                                                                                                         326

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 COMPOUND:     Ethanol, 2-dimethylamino-

              000108010

 REFERENCE:   Hartung, R. and  Cornish, H.H.
             Tox. Appl. Pharm.  12:486-494, 1968.
                                                             COMPOUND:     Ethanol, 2-(ethylamino)-

                                                                          000110736

                                                             REFERENCE:   Hartung, R. and Cornish, H.H.
                                                                         Tox. Appl. Pharm. 12:486-494, 1968.
OBSERVED NEUROTOXIC EFFECTS:
This compound was tested with a group of other  .
aminoethanols, all of which inhibited cholinesterase
in vitro.  In vitro inhibition increases as the
number of carbon atoms attached on the nitrogenous
head of the 2-aminoethanol molecule.  In the in vivo
tests the oral ID  's were uniformly higher than the
i.p. l^rn values.  When given i.p., compound reduced
brain cRolinesterase.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
This compound was tested with a group of other
aminoethanols, all of which inhibited cholinesterase
in vitro.  In vitro inhibition increases as  the
number of carbon atoms attached on  the nitrogenous
head of the 2-aminoethanol molecule.  In the in vivo'
tests the oral ID  's were uniformly higher  than
the I.P. U>5Q values.  When given i.p., compound
reduced brain cholinesterase.
ANIMALS:     Rats, S-D, M
                                                            ANIMALS:     Rats, S-D, M
PREPARATION AND DOSE                   .        .
or HISTORY OF PATIENT:   In vitro:   10 *  to 10 i.
                         In vivo:    ^cn  an<^ l°wer doses.
                                                            PREPARATION AND  DOSE
                                                            or HISTORY OF  PATIENT:   In vitro:   10    to  10   .
                                                                                     In vivo:
                                                                                                      and lower doses.
ROUTE AND SITE:   Oral,  i.p.,  in vitro

CONTROL INFORMATION:   ns.
                                                            ROUTE AND  SITE:   Oral, i.p.,  in  vitro

                                                            CONTROL  INFORMATION:  ns.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Biochemistry
                                                            DURATION OF  EXPERIMENT:  ns.

                                                            EXAM. TYPE:  Biochemistry
                                             327
                                                                                                                                          328

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COMPOUND:   Ethanol,  2-methoxy-
REFERENCE:   Goldberg,  M.E.,  Haun,  C.  and Smyth,  H.F.
             Tox.  Appl.  Pharm.  4:148-164, 1962.
OBSERVED NEUROTOXIC EFFECTS:   Specific Inhibition  of  conditioned  avoidance  -
                              escape behavior without motor  imbalance.   Given
                              i.p.,  barbiturate hypnosis was potentiated, same  if
                              inhaled; pretreatment with LSD antagonized this effect.
COMPOUND:  Ethanol, 2-methoxy-

           000109864

REFERENCE:   Greenburg,  L.,  Mayers,  M.R.,  Goldwater, L.J. Burke, W.J. and
             Moskowitz,  S.
             J. Ind. Hyg.  Toxicol.  20:134-147, 1938.

OBSERVED NEUROTOXIC EFFECTS:  Abnormal reflexes, tremor, mental retardation,
                              lethargy; abnormal blood picutre.  Compound only
                              the probable cause of the neuropathy.
ANIMALS:      Rats:   DW or CFE,  F,  130 g
             Mice:   White,  F,  22 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:  (1)  0.5-2 mg/kg
                       (2)  125-32,000 ppm in air
                                                                                                ANIMALS:    Humans 19 M 16-26 yr (av. 20)
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Industrial exposure 25-76 ppm, occasionally more;
other compounds in mix EtOH, MeOH, ethylacetate,
petroleum naptha.  Exposures of 1-3 mo.
ROUTE AND SITE:   (1)  I.P.   (2)  Inhalation

CONTROL INFORMATION:    Untreated groups
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   Various schedules

EXAM.  TYPE:  Behavior
DURATION OF EXPERIMENT:     1 yr of follow-up

EXAM. TYPE:    Hematology, Behavior
                                           329
                                                                                                                                        330

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COMPOUND:      Ethanol, 2-(methylamino)-

               00019831

REFERENCE:   Hartung,  R. and  Cornish,  H.H.
             Tox.  Appl. Pharm.  12:486-494, 1968.
OBSERVED NEUROTOXIC EFFECTS:
This compound was tested with a group of other amino-
ethanols, all of which inhibited cholinesterase
in vitro.  In vitro inhibition increases as the
number of carbon atoms attached on the nitrogenous
head of the  compounds     molecule.  In the in     !
vivo tests the oral LD  's were uniformly higher
than the i.p. LD.-Q values.
COMPOUND:     Ether,  chloromethyl methyl

              000107302

REFERENCE:     Laskin,  S.,  Drew, R.T., Cappiello, V., Kuschner, M. and Nelson, N.
               Arch.  Env.  Hlth.  30:70-72, 1975.


OBSERVED NEUROTOXIC EFFECTS:    One rat developed esthioneuroepithelioma of olfactory
                                epithelium after exposure; one rat developed undif-
                                ferentiated pituitary tumor considered "coincidental."
ANIMALS:     Rats,  S-D,  M
                                                                                               ANIMALS:       74 Rats,  90 hamsters
PREPARATION AND DOSE
or HISTORY OF PATIENT:   In vitro:   10"4 to 10  .
                         In vivo:    ^D   an<* lower doses.
                                                               PREPARATION  AND DOSE
                                                               or  HISTORY OF  PATIENT:    i ppln,  6  hr/d,  5  d/wk,  565 exposures in 852 d.
ROUTE AND SITE:    Oral,  i.p.,  in vitro

CONTROL INFORMATION:   ns.
                                                               ROUTE  AND  SITE:     inhalation

                                                               CONTROL  INFORMATION:      74  Rats,  88 hamsters
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Biochemistry
                                                               DURATION  OF  EXPERIMENT:   128 wk after 1st exposure

                                                               EXAM.  TYPE:     Carcinogenesis bioassay
                                            331
                                                                                                                                          332

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COMPOUND:  "-thy! alcohol

           000064175

REFERENCE:   Ahtee,  L.  and Svartstrom-Fraser,  M.
             Acta Pharmacol.  Toxicol.  36:289-298,  1975.
COMPOUND:  Ethyl alcohol

           000064175

REFERENCE:   Bauer-Moffett,  C.  and Altaian,  J.
             Exp.  Neurol.  48:378-382,  1975.
OBSERVED NEUROTOXIC EFFECTS:    Rigidity,  convulsions.   Rapid disappearance
    and  low levels  of  noradrenaline in brain.
OBSERVED NEUROTOXIC EFFECTS: Histology on 2 rats/litter.   Dry and wet wt of
     cerebellum reduced by 26%,  of rest of brain by about 14%.  Reduction of
     Purkinje cells averaged 27.4%.   Bodyweights, livers, lungs all found normal;
     thiamine 10 mcg/d did not relieve damage.
ANIMALS:     Rats,  M,  S-D,  250-300 g.
                                                                                             ANIMALS:    Rats,  Purdue-Wistar,  cross-fostered,  8/litter.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   8-11 g/kg/d,  7-10 d,  then withdrawal.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  3.5-4.0% in air, inhaled for 2 x 90 min/d for 3-20 d.
     Cardiac blood after 2nd exposure averaged 268 mg EtOH/ 100 ml; all
     rats remained conscious.   Experiment started at day 3 of age.
ROUTE AND SITE:  Gavage

CONTROL INFORMATION:   Untreated controls
ROUTE AND SITE:       Inhalation

CONTROL INFORMATION:  Air only
DURATION OF EXPERIMENT:  Maximum lid

EXAM. TYPE:  Behavior,  biochemistry
DURATION OF EXPERIMENT:

EXAM. TYPE:  Histology
                                                                                                                          20  d
                                       333
                                                                                                                                    334

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COMPOUND:  Ethyl alcohol

           000064175

REFERENCE:    Blum,  K.,  Wallace,  J.E.  and Geller,  I.
              Science 176:292-294,  1972.
COMPOUND:  Ethyl alcohol

           000064175

REFERENCE:   Davis, V.E. and Walsh, M.J.
             Science 167:1005-1007, 1970.
OBSERVED NEUROTOXIC EFFECTS:   Glycine or serine enhanced ethanol-induced sleeptime;
                              authors inferred interaction in the central nervous
                              system.
OBSERVED NEUROTOXIC EFFECTS: Ethanol indirectly augmented  formation of  tetrahydro-
                             papaveroline, a morphine-like compound.
ANIMALS:   Mice
                                                                                             ANIMALS:   Rat brainstem homogenates  in vitro.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    10 mmoles/100 g and/or 0.45-0.9 mmole/100 g of glycine.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Incubation mixture with dopamine  and  added EtOH 100
                        mM, or acetaldehyde 0.5-2 mM.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:  Saline
ROUTE AND SITE:  In vitro

CONTROL INFORMATION:  Laboratory
DURATION OF EXPERIMENT: Up to 140 min.

EXAM. TYPE:  Behavior, biochemistry
DURATION OF EXPERIMENT: 30 min

EXAM. TYPE:  Biochemistry
                                       335
                                                                                                                                    336

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COMPOUND:   Ethyl alcohol

            000064175

REFERENCE:  Decker,  J.B., Wells, C.E.  and McDowell,  F.
            Neurology  9:  361-366, 1959.
COMPOUND:  Ethyl alcohol

           nnnn £. /.tic

REFERENCE:  Goldberg, M.E., Haun, C. and  Smyth,  H.F.
            Tox. Appi. Pharm. 4:148-164,  1962.
OBSERVED NEUROTOXIC EFFECTS:  Leg function of  the patients suggested cerebellar dys-
                             function, which  responded to diet and supplements.  The
                             authors concluded that ethanol rather than diet deficits
                             had been the cause.
OBSERVED NEUROTOXIC EFFECTS:  Treatment did not  produce  inhibition of conditioned
                             avoidance—escape behavior  without motor imbalance
                             separately  from ataxia.
ANIMALS:    Human:  10 patients aged 33-68, all M
                                                                                             ANIMALS:
             Rats:   DW or  CFE,  F,  130
             Mice:   White,  F,  22  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   History of prolonged alcoholism with poor diet
PREPARATION AND DOSE
or HISTORY OF PATIENT: 2,000-32,000 ppm in air.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   None
ROUTE AND SITE:    Inhalation

CONTROL INFORMATION:   Untreated groups
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Clinical
DURATION OF EXPERIMENT:  Various schedules.

EXAM. TYPE:  Behavior
                                           337
                                                                                                                                        338

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COMPOUND:  Ethyl alcohol

           000064175

REFERENCE:   Israel, M.A. and Kuriyama, K.
             Life  Sci.  lOf2):591-599, 1971.
                                                            COMPOUND:  Ethyl alcohol

                                                                       000064175

                                                            REFERENCE:
              Jarlstedt, J. and Hamberger,  A.
              J. Neurochem. 19:2299-2306,  1972.
OBSERVED NEUROTOXIC EFFECTS:
Mitochondrial ATPase rose after acute and chronic
ethanol.  The increase was mainly Mg  -dependent,
ouabain-insensitive, and not DNP-activated.  No
effect on ATPase in synaptosomes or microsomes.
OBSERVED NEUROTOXIC EFFECTS:    Ethanol diminshed incorporation of leucine into
                                glial but not neuronal proteins.
ANIMALS:    Mice,  Siss albino, M, 25-28  g.
                                                            ANIMALS:
               Eats,  S-D,  M,  100-110 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:      Acute:  4  g/kg as  20% w/v in saline.
                         Chronic:  6% w/v cf  diet.
                                                            PREPARATION AND  DOSE
                                                            or HISTORY OF  PATIENT. 1. 3.2 g/kg, preceded by  15 hr  fast.
                                                                                   2. 0.1-5% in medium to brain  cortex  slices.
ROUTE AND SITE:   Acute:   I.P.     Chronic:   Oral

CONTROL INFORMATION:     Sucrose  instead  of  compound.
                                                             ROUTE  AND  SITE:  I.P.; in vitro

                                                             CONTROL  INFORMATION:      Saline  treated  controls
DURATION OF EXPERIMENT:      2 wk.

EXAM.  TYPE:  Biochemistry
                                                             DURATION  OF  EXPERIMENT:    3 hr.

                                                             EXAM.  TYPE:    Biochemistry
                                              339
                                                                                                                                        340

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COMPOUND:  Ethyl alcohol

           000064175

REFERENCE:   Kurlyama,  K.  and Israel,  M.A.
             Biochem.  Pharmacol.  22:2919-2922,  1973.
COMPOUND:  Ethyl alcohol

           000064175

REFERENCE:    Kuriyama,  K.,  Sze,  P.Y. and Rauscher, G.E.
              Life Sci.  10(2):181-189, 1971.
OBSERVED NEUROTOXIC EFFECTS:   Adenyl cyclase activity in homogenates of cerebral
     cortex declined after 10 min incubation of controls but  not  of  ethanol
     groups;  no change of  phosphodiesterase activity.   No effect  of  in vitro.
     additions of ethanol; nevertheless cAMP content  increased  significantly,
     all groups.
OBSERVED NEUROTOXIC EFFECTS:  Protein synthesis by brain ribosomes was inhibited
                              acutely (3 hr) and increased chronically (7-14 d)
                              in vivo.   Not related to blood ethanol levels, or to
                              observed central nervous system depression.
ANIMALS:   Mouse,  Swiss albino,  F,  25-30 g.
ANIMALS:   Mice,  Swiss ablino,  M,  25-28 g.
PRF.PARATION AND DOSE
or HISTORY OF PATIENT:   6% in liquid diet,  av.  intake 7-9 ml/d,  dose of ethanol
     16-21 g/kg.   Acute study:   4 g/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Acute:   4 g/kg as 20% w/v in saline, 1 dose.
                       Chronic:   liquid died 6% ethanol.
ROUTE AND SITE:        Oral.   Acute study:   I.P.

CONTROL INFORMATION:   Control group treated isocaloric sucrose diet.
ROUTE AND SITE:   Acute:   I.P.    Chronic:   Oral

CONTROL INFORMATION:  Control group sucrose treated.
DURATION OF EXPERIMENT:   3 wk.

EXAM. TYPE:  Biochemical
DURATION OF EXPERIMENT:  Serial sacr to 14 d

EXAM. TYPE:   Biochemistry
                                       341
                                                                                                                                   342

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COMPOUND:   Ethyl  alcohol

            000064175

REF£RENCE:Melvllle, K., Jordon, G., Douglas, D.
          Toxicology and Applied Pharmacology 9:363-375, 1966.
                                                                     COMPOUND:   Ethyl alcohol

                                                                                000064175

                                                                     REFERENCE:    Novak,  D.J.  and Victor, M.
                                                                                  Arch.  Neuirol.  30:  273-284, 1974.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia with depression; maximal effects occurred
                               during 1st hr.  Synergistic action with glutethimide
                               increased central nervous system depression and
                               produced surgical anesthesia.
                                                                     OBSERVED NEUROTOXIC  EFFECTS:   Non-inflammatory degeneration of myelinated nerve
                                                                          fibers affecting peripheral nerves (legs more than arms).  Denervation atrophy.
                                                                          Primary degeneration of the vagus nerves, lesions acute and extended throughout
                                                                          all portions of the nerve.
ANIMALS:  Mongrel dogs, 7.0-12.0 kg, M and F.
                                                                                               ANIMALS:   4 human alcoholics.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
50% soln of EtOH in water.   Dose  of  1  ml/kg hourly,
3 or 5 times.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Alcoholic neuropathy with hoarseness and weakness  of
                          the voice, dysphagia, and derangements of the  autonomic
                          nervous functions.
ROUTE AND SITE:           Stomach tube

CONTROL INFORMATION:      ns.
                                                                     ROUTE  AND SITE:   Oral.

                                                                     CONTROL  INFORMATION:    ns.
DURATION OF EXPERIMENT:   More  than  1 wk.

EXAM. TYPE Behavior
                                                                     DURATION OF EXPERIMENT:   "Many years"

                                                                     EXAM.  TYPE:   Histology
                                          343
                                                                                                                                       344

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COMPOUND:   Ethyl alcohol

            000064175

REFERENCE:   Roach, M.K., Davis, D.L., Pennlngton, W. and Nordyke, E.
            Life Sci. 12(1):433-441, 1973.
                                                                                   COMPOUND:       Ethyl alcohol
                                                                                                  000064175


                                                                                   REFERENCE:      Skillicorn, S.A.
                                                                                                  Neurology 5:524-534, 1955.
OBSERVED NEUROTOXIC EFFECTS:
                    Ethanol inhibited active active transport of probable
                    neurotransmitters of the central nervous system by
                    synaptosomes.  Authors conclude that alcohol interacts
                    with membrane lipids of synaptosome.
OBSERVED NEUROTOXIC EFFECTS:    Ataxia of legs;  no nystagmus; pneumoencephalograms
                               suggested diffuse degenerative disease of the
                               cerebrum as well as cerebellar atrophy of a
                               presenile type.
ANIMALS:
Rats, S-D, M, 200-250 g, brains removed and homogenates incubated in
vitro.
                                                                                               ANIMALS:
                                                                                                  Human:  6 cases, 39-55 at onset
PREPARATION AND DOSE
or HISTORY OF PATIENT: Ethanol added as 25% soln, at start of preincubation period.
                      Ethanol cone 5-30 mg/ml.  Incubated in vitro with labeled
                      norepinephrine, GABA and glutamate.
                                                                                  PREPARATION AND DOSE
                                                                                  Or HISTORY OF PATIENT:    History of prolonged  chronic  alcoholism and gait
                                                                                                            disorder lasting  1-15 yr
ROUTE AND SITE:   In vitro

CONTROL INFORMATION:   Control:  incubation in medium with no alcohol.
                                                                                  ROUTE AND SITE:  Oral

                                                                                  CONTROL INFORMATION:      None
DURATION OF EXPERIMENT:  Laboratory procedure.

EXAM. TYPE: Biochemistry.
                                                                                  DURATION OF EXPERIMENT:    6  mo

                                                                                  EXAM. TYPE:      Clinical,  neurological
                                           345
                                                                                                                                       346

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COMPOUND:  Ethyl alcohol

           000064175
COMPOUND:  Ethyl alcohol

           000064175
REFERENCE:
             Sutton,  I.  and Simmonds,  M.A.
             Biochem.  Pharmacol.  22:1685-1692,  1973.
REFERENCE:
Tytell, M. and Myers, R.D.
Biochem. Pharmacol. 22:361-372, 1973.
OBSERVED NEUROTOXIC EFFECTS:  Endogenous  y-aminobutyric acid  (GABA) no change
     after acute ethanol but  increased 48%  after chronic  treatment.  Exogenous
     GABA disappeared at same rate  throughout,  The enzyme GAD increased after
     acute ethanol treatment,  and  the  enzyme GABA-T increased after chronic ethanol.
OBSERVED NEUROTOXIC EFFECTS:
                    Acute  (see below) rats converted more  5-hydroxy-
                    tryptamine to 5-hydroxyindoleacetic  acid than
                    chronic or controls in caudate nucleus;  chronics
                    no different from controls; no differences in
                    production of 5-hydroxytrytophol.  In  this, "some
                    parts" of central nervous system differ  from
                    peripheral nervous system, according to  the authors.
ANIMALS:   Rats,  Wistar,  M.,  160-200 g (acute),  130  g  (chronic)
                                                                                        ANIMALS:     Rats, adult Royal Victoria hooded  (sex ns.), 3 per group  (acute,
                                                                                                     chronic, control)
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)  Acute:   4g/kg as  20%  soln  in  saline, preceded
     by 24 hr fast and  followed 30 min by  admin, of  labeled GABA.
     (2) Chronic:   14%  in water as only drink  for  3  wk, followed by  24 hr
     fast and admin labeled  GABA.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               All rats prepared surgically  for brain perfusion,  3 sites,
               with labeled serotonin.
               Acute:  6 g/kg EtOH in 20% v/v solution intragastric
             Chronic:  Sole drink 8% v/v EtOH plus  2% malt extract.
             Control:  Water ad lib, no treatment.
ROUTE AND SITE:
                      Acute:   I.P.,  Chronic:   Oral
CONTROL INFORMATION-   Acute:   saline treated only,   Chronic:  water  treated only.
     All:   GABA or no GABA.
ROUTE AND SITE:   Oral or intragastric

CONTROL INFORMATION:   3 Rats, as stated above.
DURATION OF EXPERIMENT:   3 wk.

EXAM. TYPE:  Biochemical
DURATION OF EXPERIMENT:

EXAM. TYPE:  Biochemical
               130-147 d
                                       347
                                                                                                                                    348

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COMPOUND:  Ethyl alcohol
REFERENCE:
                Veloso,  D.,  Passoneau,  J.V.  and Veech,  R.L.
                J.  Neurochem.  19:2679-2686,  1972.
OBSERVED NEUROTOXIC EFFECTS:     (1)   Rats  lost their  righting reflex within 6-7
      min.  after  injection,  general anesthesia within  8 min.   Rises  of  brain glucose,
      G6P and  citrate,  no  change  in arterial pCO-.
      (2)   General anesthesia,  rises  of  glucose,  G6P,  glycogen,  arterial pCO.,
      falls of lactate,  pyruvate,  a-oxoglutarate, malate,  glutamate,  aspartate.
      Interpreted as  effects on nerve cell  membrane, contrasted with liver where
      ADH is "primary target."
COMPOUND:   Ethyl alcohol

            000064175

REFERENCE:   Walsh,  J.C.  and McLeod,  J.G.
             J. Neurol.  Sci. 10:457-469, 1970.
OBSERVED NEUROTOXIC EFFECTS:    Slow sensory and motor conduction; sural nerves
    (myelinated fibers) axonal or Wallerian degeneration and regeneration.
ANIMALS:    Rats,  S-D,  M,  390-400  g
ANIMALS:     11 Humans with alcoholic peripheral neuropathy, ages 41-73 yr
    (av 58 yr).
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          Rats  starved  for  72  hr  prior  to  treatment.
                      1.   Acute:   3.5 ml  of 7M ethanol  in  0.15M NaCl.
                      2.   Chronic:   3 ml  at 13 and  5  hr and  1  ml  at  3  and 1 hr.
                                    prior to brain  removal.  7 M  ethanol in 0.15
                                    m NaCl.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:  Controls  treated with  0.15M NaCl.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Studied within 3 wk of admission to hospital.
ROUTE AND SITE:

CONTROL INFORMATION:   20 control subjects aged 38-73 yr  (av 54).
DURATION OF EXPERIMENT:    Acute:   8  min;   Chronic:   13 hr.

EXAM.  TYPE:     Behavior,  biochemistry
DURATION OF EXPERIMENT:

EXAM. TYPE:  Electrophysiology, histology (biopsy)
                                             349
                                                                                                                                              350

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COMPOUND:   Ethylamine, 2-chloro-N,N-dimethyl-,  hydrochloride
                                                                               COMPOUND:    Ethylamine, 2-chloro-N,N-dipropyl-
REFERENCE:  Goldin, A., Now, H.A., Landing, B.H., Shapiro, D.M. and Goldberg, B.
            J. Pharm. Exp. Ther. 94:249-261, 1958.
                                                                               REFERENCE:   Goldin, A., Now, H.A., Landing, B.H., Shapiro,  D.M.  and  Goldberg,  B.
                                                                                           J. Pharm. Exp. Ther. 94:249-261, 1958.
OBSERVED NEUROTOXIC EFFECTS:
                    Waltzing syndrome was  produced by dialkyl and hetero-
                    cyclic B-chloroethylamines but not when (a)  OH
                    or bromine replaced the $ chlorine, (b) a B-phenyl
                    group replaced one of  the B hydrogens in the
                    chlorinated chain, or  (c) phenyl groups were introduced
                    into the dialkyl carbons.  No effect from primary/
                    secondary B-chloroethylamines, related quaternary
                    compounds, or bis-, tris-, or tetrakis-B-chloro-
                    ethylamines.  Piperidine and morpholine analogs and
                    arsacetin produced waltzing.  Cerebellar and
                    axial lesions found consistent with behavior.
OBSERVED NEUROTOXIC EFFECTS:
     Waltzing syndrome was produced by dialkyl and hetero-
     cyclic B-chloroethylamines but not when  (a) OH
     or bromine replaced the B chlorine,  (b)  a B-phenyl
     group replaced one of the B hydrogens in the
     chlorinated chain, or (c) phenyl groups  were introduce
     into the dialkyl carbons.  No effect from primary/
     secondary B-chloroethylamines, related quaternary
     compounds, or bis-, tris-, or tetrakis-B-chloro-
     ethylamines.  Piperidine and morpholine  analogs and
     arsacetin produced waltzing.  Cerebellar and
     axial lesions found consistent with behavior.
ANIMALS:
Mice, CF1, M, 2-3m, 18-25 g; also CF1 F and C3H M.
                                                                               ANIMALS:
                                                                                                        Mice,  CF1,  M,  2-3m,  18-25 g;  also CF1 F and C3H M.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               1-625 mg/kg in saline or (insolubles)  10% acacia,
               various schedules.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1-625 mg/kg in saline or  (insolubles) 10% acacia,
various schedules.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:    Vehicle  alone
                                                                               ROUTE  AND  SITE:   I.P.

                                                                               CONTROL  INFORMATION:   Vehicle alone
DURATION OF EXPERIMENT:     At  least  10 d after treatment.

EXAM. TYPE:  Behavior, histology.
                                                                               DURATION  OF  EXPERIMENT:     At least  10  d  after  treatment.

                                                                               EXAM.  TYPE:  Behavior, histology.
                                            351
                                                                                                                                      352

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COMPOUND:   Ethylamine, 2-chloro-N-ethyl-N-methyl-, hydrochloride
                                                                                            COMPOUND:
                                                                                                         Ethylamine,  N-chloro-methyl-N-propyl-2-, hydrochloride
REFERENCE:   Goldin,  A.,  Now,  H.A.,  Landing,  B.H.,  Shapiro,  D.M.  and  Goldberg,  B.
             J.  Pharm.  Exp.  Ther.  94:249-261,  1958.
OBSERVED NEUROTOXIC EFFECTS:
     Waltzing syndrome was produced by dialkyl and hetero-
     cyclic B-chloroethylamines but not when (a) OH
     or bromine replaced the 8 chlorine, (b) a B-phenyl
     group replaced one of the B hydrogens in the
     chlorinated chain, or (c) phenyl groups were introduced
     into the dialkyl carbons.  No effect from primary/
     secondary B-chloroethylamines, related quaternary
     compounds, or bis-, tris-, or tetrakis-8-chloro-
     ethylamines.  Piperidine and morpholine analogs and
     arsacetin produced waltzing.  Cerebellar and
     axial lesions found consistent with behavior.
                                                                REFERENCE:   Goldin, A., Now, H.A., Landing, B.H., Shapiro, D.M. and Goldberg,  B.
                                                                            J. Pharm. Exp. Ther. 94:249-261, 1958.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
     Waltzing syndrome was produced by dialkyl and hetero-
     cyclic B-chloroethylamines but not when  (a) OH
     or bromine replaced the B chlorine,  (b)  a B-phenyl
     group replaced one of the B hydrogens in the
     chlorinated chain, or (c) phenyl groups  were introduced
     into the dialkyl carbons.  No effect from primary/
     secondary B-chloroethylamines, related quaternary
     compounds, or bis-, tris-, or tetrakis-B-chloro-
     ethylamines.  Piperidine and morpholine  analogs and
     arsacetin produced waltzing.  Cerebellar and
     axial lesions found consistent with behavior.
ANIMALS:
             Mice,  CF1, M,  2-3m,  18-25  g; also  CF1  F and C3H M.
                                                                                           ANIMALS:
                                                                            Mice, CF1, M, 2-3m, 18-25 g; also CF1 F and C3H M.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1-625 mg/kg in saline or (insolubles) 10% acacia,
various schedules.
                                                                PREPARATION  AND  DOSE
                                                                or  HISTORY OF  PATIENT:
1-625 mg/kg in saline or (insolubles) 10% acacia,
various schedules.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:    Vehicle alone
                                                                ROUTE AND  SITE:   I.P.

                                                                CONTROL  INFORMATION:   Vehicle alone
DURATION OF EXPERIMENT:     At  least  10 d after  treatment.

EXAM.  TYPE:   Behavior, histology.
                                                                DURATION OF  EXPERIMENT:     At least 10 d after treatment.

                                                                EXAM. TYPE:  Behavior, histology.
                                           353
                                                                                                                                      354

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COMPOUND:  Ethylamine, N,N-dimethyl-2-(o-methyl-alpha-pheriylbenzyl-oxy)-
REFERENCE: pfeiffer, C.C., Murphree, H.B., Jenney, E.H., Robertson,  M.G.,
           Randall, A.H.  and Bryan, L.
           Neurology 9:   249-250,  1959.

OBSERVED NEUROTOXIC EFFECTS:  The  authors  concluded that synthetic  atroplnes  are more
                 i            active hallucinogens  than atropine or scopolamine, pro-
                             ducing effects  lasting  24-48 hr.   Synthetic antitremor
                             drugs had  fewer peripheral nervous system side-effects,
                             but  central  nervous system side-effects (hallucinations)
                             may  have been exaggerated.
COMPOUND:  Ethylamine,  N,N-dimethyl-2-((o-methyl-alpha-phenylbenzyl)  oxy)-, hydro-
           chloride
           000341695

REFERENCE: Gill, D.G. and Sowerby, H.A.
           Practitioner 214:  542-544, 1975.


OBSERVED NEUROTOXIC EFFECTS:   Epileptiform seizures, status epilepticus.   Plasma
                              compound level was 12.3 and 5.1 meg/ml.  Both cases
                              recovered.  The authors reviewed fatal cases with
                              lower plasma levels.
ANIMALS:    Human:   prison volunteers,  drug-sophisticated,  no other details
ANIMALS:   Human:  2 cases, F, 23 mo 12 kg; F, 52 mo 17.1 kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   100 rag/man
PREPARATION AND DOSE
or HISTORY OF PATIENT:   In both cases, compound was prescribed for iatrogenic
                        illness and was swallowed accidentally by children"
                        300 mg, unknown amount.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  LSD-25:  0, 25, 50, 100 meg/man
ROUTE AND SITE:   Oral

CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:  Up to 3 d

EXAM. TYPE:   Opinion of volunteers
DURATION OF EXPERIMENT:    3 d, 4 d

EXAM. TYPE:   Clinical,  biochemistry
                                           155
                                                                                                                                       356

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COMPOUND:     Ethylamine, 2-(diphenylmethoxy)-N,N-dimethyl-

              000058731


REFERENCE: pfeiffer,  C.C.,  Murphree, H.B.,  Jenney,  E.H.,  Robertson,  M.G.,
           Randall, A.H. and  Bryan, L.
           Neurology  9:  249-250,  1959.

OBSERVED NEUROTOXIC EFFECTS:  The  authors  concluded  that synthetic atroplnes are more
                              active hallucinogens  than atropine or scopolamine, pro-
                              ducing effects lasting 24-48 hr.   Synthetic antltremor
                              drugs had  fewer peripheral nervous system side-effects,
                              but  central  nervous system side-effects (hallucinations)
                              may  have been  exaggerated.
COMPOUND:    Ethylene, tetrachloro-
             000127184
REFERENCE:  Haerer,  A.F.  and Udelman,  H.D.
            Am.  J.  Psychiat. 121:   78-79,  1964.
OBSERVED NEUROTOXIC EFFECTS:   The  subject  developed  amnesia  within  2  hours,  suffering
                              confusion, irritation,  hallucinations,  distorted color-
                              vision,  and  speech  difficulty.   All symptoms cleared
                              within 3 hours  of the  dose with  no sequelae.
ANIMALS:    Human:   prison volunteers,  drug-sophisticated,  no other details
ANIMALS:     Human:   one  isolated case, M,  21
PREPARATION AND DOSE
or HISTORY OF PATIENT:    100 mg/man
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5 ml, one dose, prescribed as anthelmintic; history
                           noncontributory.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   iSD-25:   0,  25,  50,  100 meg/man
ROUTE AND SITE:    Oral

CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:   Up to 3 d

EXAM. TYPE:   Opinion of volunteers
DURATION OF EXPERIMENT:   3 hr with follow-up

EXAM.  TYPE:     Clinical
                                           357
                                                                                                                                       358

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COMPOUND:   Ethylene,  trichloro-

            000070916

REFERENCE:   Buxton, P.H. and Hayward, M.
             J. Neurol. Neurosurg,  Psychiat.  30:511-518,  1967.
COMPOUND:   Ethylene,  trichloro-

            000079016

REFERENCE:   Feldman,  R.G., Mayer, R.M. and Taub, A.
             Neurology 20:599-606, 1970.
OBSERVED NEUROTOXIC EFFECTS:     Exposure-related:   after 10 min,  headache and
    nausea for 48 hr; after 30 min,  vomiting and numbness for 15  d;  after 2.5 hr,
    dizziness progressing to facial diplegia by d 9,  residual visual and trigeminal
    motor signs present after 2.5 yr,  4 hr,  facial diplegia by d  6,  tracheostomy
    needed by d 12, continual vomiting and emaciation,  died after 51 d.   Damage
    most severe in brainstem and Vth-nerves; changes  in cerebral  and cerebellar
    cortexes attributed to secondary hypoxemia.  Peripheral nervous  system and
    cord, where examined, showed little damage.
OBSERVED NEUROTOXIC EFFECTS:    Peripheral neuropathy, trigeminal sensory  loss,
    authors infer demyelination.
ANIMALS:     Human:  4 case-reports including 1 autopsy.
                                                                                             ANIMALS:
                                                                                                          Human:   one case
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Industrial accident, exposure for 10 min.  to 4 hr.  while
    cleaning tanks without respirators.
PREPARATION AND DOSE
Or HISTORY OF PATIENT:   Industrial exposure to vapor for 5 min and  indirect
    exposure via closed-circuit gasmask for 1.5 hr.
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION:    Other operators wearing fresh-air respirators had no
    effects.
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   51 d, 2 1/2 yr.

EXAM. TYPE:  History, clinical observation, autopsy
DURATION OF EXPERIMENT:  Follow-up period, more than one month.

EXAM. TYPE:  Behavior, electrophysiology, clinical tests
                                                                                                                                    360

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 COMPOUND:   Ethyl (beta-hydroxy ethyl)trimethylaramonium hydroxide
                                                                                               COMPOUND:   Ethyl (m-hydroxyphenyl)  dimethylammonivnn chloride
 REFERENCE:   Hartung, R. and Cornish, H.H.
             Tox. Appl. Pharm. 12:486-494, 1968.
OBSERVED  NEUROTOXIC  EFFECTS:
This compound was tested with a group of other
aminoethanols and choline analogs, all of which
inhibited cholinesterase in vitro.  In vitro
inhibition increases as the number of carbon atoms
attached on the nitrogenous head of the 2-amino-    i
ethanol molecule.  In the in vivo tests the oral
LD  's were uniformly higher than the i.p. U>CQ values.
                                                              REFERENCE:  Tang, A.H. and Schroeder, L.A.
                                                                          Tox. Appl. Pharm. 12:44-47,  1968.
                                                                                               OBSERVED NEUROTOXIC EFFECTS:  Produced consistent partial  antagonism,  the effects
                                                                                                                            of lincomycin were never  completely reversed by
                                                                                                                            edrophonium.
ANIMALS:     Rats, S-D, M
                                                                                               ANIMALS:     4 Rabbits
PREPARATION AND DOSE
or HISTORY OF PATIENT:   In vitro:  10   to 10  .
                         In vivo:   LD   and lower doses.
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT: 10-100 meg/kg administered at peak of the neuromuscular
                                                                                     blockade  from lincomycin (50 mg/kg).
ROUTE AND SITE:   Oral, i.p., in vitro

CONTROL INFORMATION:  ns.
                                                              ROUTE AND SITE:   l.V.

                                                              CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE:  Biochemistry
                                                              DURATION OF EXPERIMENT:   ns.

                                                              EXAM. TYPE:  Electrophysiology
                                             361
                                                                                                                                          362

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COMPOUND:   Follc acid

            000059303

REFERENCE:  Baxter,  M.G.,  Miller, A.A. and Webster, R.A.
            Br.  J.  Pharmac.  49:   350P-351P, 1973  (abstract of proceedings).
OBSERVED NEUROTOXIC EFFECTS:
Convulsive doses (ED,-,,)  reported by three routes  and
compared with those or six other compounds (leptazol,
picrotoxin, strychnine,  bicuculline,  glutamate,
ouabain).   Folic acid produces a flexor-extensor
convulsion pattern.
                                                                                              COMPOUND:    Folic acid, sodium salt
                                                               REFERENCE:  Hill, R.G. and Miller, A.A.
                                                                           Br. J. Pharmac. 50:  425-427,  1974.
OBSERVED NEUROTOXIC EFFECTS:  The compound reduced  presynaptic inhibition produced
                              by peripheral  stimulation,  and is a known convulsant.
                              The authors infer  that  both folic acid and picrotoxin
                              act by the same mechanism.
ANIMALS:     Mice,  no  details
                                                                                              ANIMALS:     6  piebald Lister rats,  adult, surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:   17-1024 meg/mouse
                                                               PREPARATION AND DOSE
                                                               or HISTORY OF PATIENT:   Concentrations:   0.1-1% w/v (1 to 10 mM)
ROUTE AND SITE:   I.V.  and intracerebroventricular; also oral.

CONTROL INFORMATION:   ns
                                                               ROUTE AND SITE:  Cannulated onto  the  surface of the cuneate nucleus

                                                               CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:   Behavior
                                                               DURATION OF EXPERIMENT:  About  2 hr  per test

                                                               EXAM. TYPE:    Electrophysiology
                                           363
                                                                                                                                       364

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 COMPOUND:      Formaldehyde

               000050000

 REFERENCE:     Kulle,  T.J.  and Cooper,  G.P.
               Arch.  Env. Hlth.  30:237-243,  1975.
OBSERVED NEUROTOXIC EFFECTS:
Examined effects of prolonged exposure.  Formaldehyde
decreased response to amyl alcohol directly according
to concentration; perfusion with air for 1 hr. partly
restored response.
                                                                                              COMPOUND:   Formanilide, 2'-(3-bromo-2-thienyl)thio-
                                                               REFERENCE:
                                                                              Grol,  C.J.  and Rollema, H.
                                                                              J.  Med.  Chem.  18:857-861, 1975.
OBSERVED NEUROTOXIC EFFECTS:  This compound  gave positive results in a
                              neurotoxicity  screening test in which the
                              criteria were  ptosls,  sedation and catalepsy.
ANIMALS:
               Rats,  S-D,  M,  250-400 g,  surgically prepared  for  testing of  nasopalatine
               nerve  twigs.
                                                                                              ANIMALS:
                                                                              Rats  and mice,  no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:     0.5,  1.0,  1.5,  or 2.0  ppm for  continuously  for  1 hr.
                          Repeated  tests  in many animals,  for  total exposure
                          of  4  hr.
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:    40  mg/kg.
ROUTE AND SITE:   Gas  drawn through nasal  cavities  by  vacuum pump.

CONTROL INFORMATION:    Pre-exposure  control  responsiveness determined by  test  series
                       of  amyl  alcohol  (0.3,  0.7,  1.0,  3.3, 6.7, 10.0 pph) and then
                       repeated after exposure  to  test  compound.  Air controls also run.

DURATION OF EXPERIMENT:    Several hr.

EXAM. TYPE:    Electrophysiology.
                                                              ROUTE AND SITE:      I.P.

                                                              CONTROL  INFORMATION:      ns.



                                                              DURATION OF EXPERIMENT:   ns.

                                                              EXAM. TYPE:     Behavior screening tests
                                          365
                                                                                                                                       366

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COMPOUND:   Formanilide,  2'-(3-bromo-4-thienyl)thio-
REFERENCE:
               Grol, C.J.  and Rollema, H.
               J.  Med.  Chem.  18:857-861, 1975.
OBSERVED NEUROTOXIC EFFECTS:   This compound gave positive results in a
                              neurotoxicity screening test in which the
                              criteria were ptosis, sedation and catalepsy.
ANIMALS:
               Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    40 mg/kg.
ROUTE AND SITE:      I.P.

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Behavior screening tests
COMPOUND:
                                                                                                       Formanilide, 2'(2-bromo-3-thienyl)thio-5'-chloro-
REFERENCE:
               Grol, C.J. and Rollema, H.
               J. Med. Chem. 18:857-861,  1975.
OBSERVED NEUROTOXIC EFFECTS:  This compound  gave positive results in a
                              neurotoxicity  screening test in which the
                              criteria were  ptosis,  sedation and catalepsy.
ANIMALS:
               Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:   40 mg/kg.
ROUTE AND SITE:     I.P.

CONTROL INFORMATION:     ns.



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:    Behavior screening  tests
                                                                                                                                     368

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COMPOUND:   Foraanllide,  2'-(3-bromo-2-thienyl)thio-5'-chloro
REFERENCE:
               C-rol, C.J. and Rollema, H.
               J. Med. Chem. 18:857-861, 1975.
OBSERVED NEUROTOXIC EFFECTS:   This compound gave positive results in a
                              neurotoxicity screening test in which the
                              criteria were ptosis, sedation and catalepsy.
ANIMALS:
               Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    40 mg/kg.
ROUTE AND SITE:     i.P.

CONTROL INFORMATION:      ns.



DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Behavior screening tests
                                         369
COMPOUND:   Formanilide, 2'-(3-bromo-4-thienyl)thio-5'-chloro
REFERENCE:
               Grol, C.J. and Rollema, H.
               J. Med. Chem. 18:857-861, 1975.
OBSERVED NEUROTOXIC EFFECTS:  This compound  gave  positive results in a
                              neurotoxicity  screening test in which the
                              criteria were  ptosis,  sedation and catalepsy.
ANIMALS:       Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:   40 mg/kg.
ROUTE AND SITE:     i.P.

CONTROL INFORMATION:     ns.



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:    Behavior screening tests
                                                                                                                                     370

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COMPOUND:   Formanilide,  2'-(2-bromo-3-thienyl)thio-5'-(trifluoromethyl)-
REFERENCE:
               Grol, C.J. and Rollema, H.
               J. Med. Chem. 18:857-861, 1975.
OBSERVED NEUROTOXIC EFFECTS:   This compound gave positive results in a
                              neurotoxicity screening test in which the
                              criteria were ptosis, sedation and catalepsy.
ANIMALS:
               Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    40 mg/kg.
ROUTE AND SITE:      i.P.

CONTROL INFORMATION:      ns.



DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Behavior screening tests
COMPOUND:
Formanilide,  5'-chloro-2'-(3-thienyl)thio-
REFERENCE:
               Grol, C.J. and Rollema, H.
               J. Med. Chem. 18:857-861,  1975.
OBSERVED NEUROTOXIC EFFECTS:  This  compound gave positive results in a
                              neurotoxicity screening test in which the
                              criteria were ptosis,  sedation and catalepsy.
                                                                                            ANIMALS:
                                                                                                           Rats and mice, no details
PREPARATION AND DOSE
or HISTORY OF PATIENT:    40 mg/kg.
ROUTE AND SITE:      I.P.

CONTROL INFORMATION:      ns.



DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:     Behavior screening tests
                                                                                                                                     372

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COMPOUND:
                Formanilide,  2'-(3-thienyl)thio-5'-(trifluoromethyl)-
                                                                                             COMPOUND:    Furoyl hydrazide
REFERENCE:
               Grol, C.J. and Rollema, H.
               J. Med. Chem. 18:857-861, 1975.
OBSERVED NEUROTOXIC EFFECTS:   This compound gave positive results in a
                              neurotoxicity screening test in which the
                              criteria were ptosis, sedation and catalepsy.
REFERENCE:   Jenney,  E.H.  and Pfeiffer,  C.C.
             J.-Phann.  Exp.  Ther.  122:   110-123, 1958.


OBSERVED NEUROTOXIC EFFECTS:    Convulsions
ANIMALS:
               Rats and mice, no details
                                                                                            ANIMALS:     Mice, Harlan, 19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    40 mg/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  o.48 nM/kgm
ROUTE AND SITE:     I.P.

CONTROL INFORMATION:      ns.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Behavior screening tests
DURATION OF EXPERIMENT:  Acute

EXAM. TYPE:  Clinical
                                         373
                                                                                                                                     374

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COMPOUND:  Galactose
                                                                                        COMPOUND:    D-Galactose
REFERENCE:   Malone,  J.I.,  Wells,  H.J.  and  Segal, S.
             Science  174:952-954,  1971.
REFERENCE:  Blosser, J.C. and Wells, W.W.
            J. Neurochem. 19:1539-1547,  1972.
OBSERVED NEUROTOXIC EFFECTS:   Severe  hyperosmolar dehydration which, according
                              to  authors,  could account for  toxic changes in
                              brain chemistry.
OBSERVED NEUROTOXIC EFFECTS:
     Neurotoxicity was produced, and neural lysosomes
     were studied.  Fragility higher than controls.
     Enzyme studies indicated a role of galactitol
     as  well as of galactose.
ANIMALS:    Chicks,  Rhode Island  Red,  day-old
                                                                                        ANIMALS:     Cockerels, Leghorn, day-old
PREPARATION AND DOSE
or HISTORY OF PATIENT:     10% w/v in drinking water  for  2 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
40% (w/w) in diet.
ROUTE AND SITE:      Oral

CONTROL INFORMATION: Controls water  alone
ROUTE AND SITE:   Oral

CONTROL INFORMATION:
DURATION OF EXPERIMENT:    2 d

EXAM. TYPE:  Biochemistry
DURATION OF EXPERIMENT:     Up to 64 hr.

EXAM. TYPE:  Biochemistry
                                       375
                                                                                                                                    376

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COMPOUND:   D-Galactose
REFERENCE:
Granett, S.E., Kozak, L.P., Mclntyre, J.P. abd Wells, W.W.
J. Heurochera. 19:1659-1670, 1972.
OBSERVED NEUROTOXIC EFFECTS:
                 Levels of ATP, G6P (down by 9 hr),  FDP, 3PG,
                 a-GP, lactate (not down till 18 hr),  and glucose
                 and glycogen (later stages; G1P, citrate and
                 cAMP not altered) suggested that compound
                 interfered with brain uptake of glucose.
ANIMALS:    Chicks,  White Leghorn,  M,  1-2 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:     40% D-galactose w/w in place of glucose in diet.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:       Glucose treated controls



DURATION OF EXPERIMENT:    Up to 50 hr.

EXAM. TYPE:    Biochemistry
                                           377
                                                                                               COMPOUND:
                                                                                              Galactosiduronic acid, methyl-, methyl ester, polymer of  sulfated

                                                                                              sodium salt
REFERENCE:   Joseph, A.D.
             Br. J. Pharmacol. 17:  533-538,  1961.
OBSERVED NEUROTOXIC EFFECTS:   5-10 tog of mepesulfate  produced  tremor,  salivation,
                              tachypnea, loud  calling,  seizures,  blind charging,
                              and then  somnolence within minutes.   Complete re-
                              covery in 24 hours.   2.5  mg produced few or no such
                              effects.
                                                                                ANIMALS:     Cats,  no  details,  surgically prepared
                                                                                PREPARATION AND DOSE
                                                                                or HISTORY OF PATIENT:   5-10 mg
                                                                                                         2.5 mg
                                                                                ROUTE AND SITE:   Cannulated into left  lateral  ventricle of brain

                                                                                CONTROL INFORMATION:  None



                                                                                DURATION OF EXPERIMENT:  Weeks

                                                                                EXAM. TYPE:    Behavior
                                                                                                                                       378

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COMPOUND:  Gallium Fluoride
REFERENCE:  Melgs, J.W.
            J. Occup. Med. 14:  225-226, 1972.
OBSERVED NEUROTOXIC EFFECTS:   Pain, motor weakness of extensor muscles (localized),
                              blood negative for lead and mercury, recovery after 3 mo,
                              neurology attributed to gallium.
COMPOUND:   Gasoline

             MX8006619

REFERENCE:  saito, K.
            Brit. J.  Indust. Med.  30:352-358,  1973.
OBSERVED NEUROTOXIC EFFECTS:
     Evidence of tension and excitement after 6-7 d in rats
     given lead; after 1-3 d EEC showed decreased 6,6
     and a waves for both types of gasoline; cortex
     showed marked a and 6 activity after 6-7 d
     in lead rats.  Lead content and cortical re-
     cordings correlated.
ANIMALS:    1 Human, F. 43, research chemist.
ANIMALS:     19  rats, Wistar, M,  330-453 g,  aged 7 mo.,  surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Lab exposure to fumes from crystals +
PREPARATION AND DOSE
or HISTORY OF PATIENT:
10 ml/kg; from leaded gasoline rats received  16.5 mg/kg
of tetraethyl lead (LD,  13.2-18 mg/kg); one  dose.
ROUTE AND SITE:   Skin  contact, hands and arms  (despite use of fume hood), inhalation.

CONTROL INFORMATION:     None
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:     3 mo.

EXAM. TYPE:   Clinical,  blood  chemistry
DURATION OF EXPERIMENT:     Follow-up for 10 d

EXAM. TYPE:  Electrophysiology (EEC)
                                           379
                                                                                                                                        380

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COMPOUND:  beta-D-Glucopyranoside, (methyl-ONN-azoxy)methyl)-
REFERENCE: Hirano, A.,  Dembitzer, H.M. , and Jones, M.
           J.  Neuropath.  Exp. Neurol.  31(1):  113-125,  1972,
OBSERVED NEUROTOXIC EFFECTS:
                             Severe ataxia.  Granule cells absent, but postsynaptic
                             Purkinje cell dendritic spines present, surrounded by
                             astrocytic cytoplasm, resembling post-synaptic endings.
                             Membranous thickening apposed dense material in inter-
                             cellular cleft.  Possible development of Purkinje cell
                             dendritic spines, independent of presynaptic ending.
COMPOUND:  beta-D-Glucopyranoside,(methyl-ONN-azoxy)methyl)-

           014901087

REFERENCE:  Jones, M.
            Am. J. Path. 62:69, 1971.  (Abstract)
                                                                                                OBSERVED NEUROTOXIC EFFECTS:
                               Ataxia, abnormal gait, diminished cerebellum
                               with diminutive granule cells, disarrangement
                               of layers.  Clinical signs did not persist in
                               less severe cases.  No lesions in cord.
ANIMALS:   Mice, Swiss albino, newborn
                                                                                                ANIMALS:
            Mice, Swiss albino
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.5 mg/g
PREPARATION AND DOSE
or HISTORY OF PATIENT:  ns.
ROUTE AND SITE:   S.C.

CONTROL INFORMATION:  Saline only
ROUTE AND SITE:   ns.

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:  25 d

EXAM. TYPE:  Electron microscopy
DURATION OF EXPERIMENT:  ns. but at least 90 d

EXAM. TYPE:    Clinical, histology
                                          381
                                                                                                                                       382

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COMPOUND:  beta-D-Glucopyranoside,(methyl-ONN-azoxy )methyl)-

           014901087
REFERENCE:
Hirono, I. and Shlbuya, C.
Nature 216:1311-1312,  1967.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, posterior paralysis,  many deaths;  nerve
                              histology (incomplete at time of writing)  negative.
                              In acute study (2) death occurred without
                              neurological signs.
ANIMALS:    (1)  60 newborn mice from 11 C57BL/6 F mice.
           (2)  58 mice, C57BL/6, aged 2 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)  0.5 mg/g one dose,  in saline.
                         (2)  0.3/0.5/1 mg/g, one dose in saline.
ROUTE AND SITE:     (1) S.C., dorsal         (2) Gavage

CONTROL INFORMATION:  (1) 21 newborn to 3 dams, saline only      (2) ns.



DURATION OF EXPERIMENT:,  Over 8 mo. follow-up of 34 survivors.

EXAM. TYPE:   Behavior,  histology
                                       383
COMPOUND:   beta-D-Glucopyranoside,  (methyl-ONN-azoxy)methyl)-

            014901087

REFERENCE:   Hirono, I., Shibuya, C. and Hayashi, K.
             Proc. Soc. Exp. Biol. Med.  131:593-599, 1969.


OBSERVED NEUROTOXIC EFFECTS:    Ataxia, disturbed gait; necrosis  of  granular
    layer of cerebellum in newborn, persisting as developmental defect  in mature
    animals.  These in mice and hamsters; rats not affected.
                                                                                ANIMALS:   18 Golden hamsters,  F,  their 150 newborn, and 23 mature hamsters
                                                                                    29 rats, Moriyamaso,  F,  their 276 newborn
                                                                                    3 similar rats, their 21 newborn
                                                                                    72 C57BL/6 mice, F,  their 415 newborn; 10 dd mice, their 64 newborn.
                                                                                PREPARATION AND DOSE
                                                                                or HISTORY OF PATIENT:    Mice:  0.5 or 1 mg/g one dose at various times.
                                                                                    Hamsters:  0.15-0.6  mg/g one dose at various times.
                                                                                    Rats:   0.5 mg/g or  250 mg/kg, various times.
                                                                                ROUTE AND SITE:   Oral or S.C.

                                                                                CONTROL INFORMATION:    ns.



                                                                                DURATION OF EXPERIMENT:  Serial sacr up to 72 hr, some animals to maturity.

                                                                                EXAM. TYPE:  Behavior, histology
                                                                                                                                    384

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COMPOUND:  Glue vapors
                                                                                        COMPOUND:   Glutaconic acid, 3-hydroxy-, dimethyl ester, dimethyl phosphate
REFERENCE:   Shirabe, T., Tsuda, T., Terao, A. and Araki, S.
             J. Neurol.  Sci. 21:  101-113, 1974.
OBSERVED NEUROTOXIC EFFECTS:  Polyneuropathy after 2.5-3 yr exposure, mainly
      motor with limb weakness and muscle-wasting, progressing after exposure
      ceased.  Sural nerve extensive axonal degeneration, no regeneration 3 mo.
      after exposure ceased.  Neurogenic atrophy of skeletal muscle.  Deep
      sensation stimuli retarded, superficial sensation stimuli less affected.
 REFERENCE:   Sherman,  M.,  Herrick,  R.B.,  Ross, E. and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:   49-67, 1967.
                                                                                        OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
ANIMALS:    Human:  M, 20: M, 19, both painters.
                                                                                        ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Glue-sniffing for 3 and 2 yr respectively.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute: LD    9.45 mg/kg
                         (2) Subacute:   50-800  ppm in diet, 20 chicks/grp, for 2 wk
ROUTE AND SITE:    Inhalation

CONTROL INFORMATION:   None
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated  control  grps
DURATION OF EXPERIMENT:    Follow-up 3 mo.

EXAM. TYPE:  Histology (biopsy), clinical
DURATION OF EXPERIMENT:    1-3 wk

EXAM. TYPE:   Behavior,  mortality
                                       385
                                                                                                                                    386

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COMPOUND:   Glutamic acid
COMPOUND:   Glutamic acid
REFERENCE:   Van Harreveld, A.  and Fifkova, E.
             Exp.  Mel.  Path.  15:61-81, 1971.
REFERENCE:   Zarzecki, P., Blum, P.S.,  Cordingley,  G.E.  and Somjen,  G.G.
             Brain  Reo.  89:187-191,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                                 Compound damage to cortex distinguished from
                                 method-artifacts, dose-related.  Edema, destruction
                                 and removal of "dark" nerve cells.
OBSERVED NEUROTOXIC EFFECTS:
     Excitation of cells by compound  was never
     enhanced by proline in the cortex, was occasionally
     potentiated in the cord, no effect in the cuneate
     nucleus.  Authors conclude that proline may block
     compound  as a synaptic transmitter but not as an
     excitant.
ANIMALS:     Rats,  surgically prepared
ANIMALS:     Cats,  surgically  prepared.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           Qualitative dosage
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Proline 0.5-2 M at pH 7.5-9.0.
ROUTE AND SITE:    Electrophoretic injection

CONTROL INFORMATION:    Microelectrodes  filled with Ringer's soln were used
                       controls.
ROUTE AND SITE:   Microinontophoresis,  to neurons in 3 central nervous system areas;
                  cortex,  cord,  and cuneate nucleus.
CONTROL INFORMATION:
                       Laboratory controls.
DURATION OF EXPERIMENT:      1 hr  to  15 d.

EXAM. TYPE:  Histology
DURATION OF EXPERIMENT:     ns.

EXAM. TYPE:  Biochemical
                                          287
                                                                                                                                       388

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COMPOUND:   Glutamic acid,  D-
                                                                                             COMPOUND:
                                                                                                          Glutamic acid,  D-
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               B-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  6-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-8-hydroxybutyric,
                               glycine, o-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocystelc  acids were
stronger excitants of depolarization than all
others.  With some compounds the action  was
prolonged for many seconds after the stimulus
was terminated, notably N-nj-propyl-D-aspartic
acid.  There were no differences among types of
neurons tested; structure-activity relationship
was observed.
ANIMALS:
            Cats, surgically prepared to expose* motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
ANIMALS:  Cats prepared for electrophoretic application of  chemicals  to single
          central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5 M of 31 compounds  mainly  of aspartic,
                         glutamic and cysteic acids  listed  in order  of
                         potency of results.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:     Electrophoretic application, various  sites  in central nervous
                    system.
CONTROL INFORMATION:
                         None
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                          3S9
                                                                                                                                        390

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 COMPOUND:   Glutamic acid,  D-
COMPOUND:   Glutamic acid, DL-
 REFEREHCE:
               Olnoy,  J.W.,  Ho,  O.L.  and  Rhee, V.
               Exp.  Brain Res.  14:61-76,  1971.
REFERENCE:   Curtis,  D.R.  and  Watkins,  J.C.
             J. Neurochem.  6:117-141,  1960.
OBSERVED NEUROTOXIC EFFECTS:   The compound was equipotent to monosodium
                              glutaraate in necrosing neurons in the retina
                              and brain.  This compound is a powerful neuro-
                              excltant and the neurotoxic properties may be
                              governed by similar mechanisms.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:   Mice,  Swiss-webster  age 10  d,  total  250
ANIMALS:
                                Treatment caused excitation or depression  of
                                neuronal activity.  Excitatory ranking:  glutamic,
                                B-aminoglutaric, aspartic, cysteic, cysteine-
                                sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                                N-fonaiminoaspartic acids.
                                Depressant ranking:  6-alanine, GABA,  taurine,
                                N-methyl-f5-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, 6-aminoisobutyric
                                acids.
                                Structure-activity relationships established.
             Cats,  surgically prepared to expose  motoneurones, Renshaw cells or
             dorsal horn interneurones in lumbar cord.
PREPARATION AMD DOSE
or HISTORY OF PATIENT:    Initially 12  mmoles/kg,  then range established for
                         each compound.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds  compared with monosodium L-glutamate  (MSG)
                         potency for  selectively necrosing neurons in retina
                         and brain  (hypothalamus)

DURATION OF  EXPERIMENT:   5 hr or serlai intervals  including 5 hr.

EXAM.  TYPE:     Histology
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry, eleetrophysiology
                                        391
                                                                                                                                  392

-------
 COMPOUND:
                Glutamic acid, L-
 COMPOUND:   Glutamic acid, L-
 REFERENCE:
                Curtis, D.R.  and Watkins,  J.C.
                J. Neurochem. 6:117-141, 1960.
REFERENCE:Curtls, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
 OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or  depression of
                               neuronal activity.   Excitatory  ranking:   glutamic,
                               g-aminoglutaric, aspartic,  cysteic,  cysteine-
                               sulfinic acids,  B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  S-alanine,  GABA,  taurine,
                               N-methyl-B-alanine, 5-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric,  B-amino-
                               isobutyric acids.
                               Structure-activity  relationships established.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocysteic acids were
stronger excitants of depolarization than all
others.  With some compounds  the action was
prolonged for many seconds  after the stimulus
was terminated, notably N-ii-propyl-D-aspartic
acid.  There were no differences among types of
neurons tested; structure-activity relationship
was observed.
ANIMALS:
                Cats, surgically prepared to exposed motoneurones,  Renshaw
                cells or dorsal horn interneurones in lumbar cord.
ANIMALS:   Cats prepared  for electrophoretic  application of chemicals to single
           central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5  M of 31 compounds mainly of aspartic,
                         glutamic and  cysteic acids listed in order of
                         potency of  results.
ROUTE AND SITE:  Topical, ionophoresis

CONTROL INFORMATION:       Laboratory
ROUTE AND SITE:      Electrophoretic  application,  various sites in central nervous
                     system.
CONTROL INFORMATION:
                          None
DURATION OF EXPERIMENT:    ns.

EXAM.  TYPE:      Biochemistry, electrophysiology
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:     Electrophysiological
                                        393
                                                                                                                                    394

-------
COMPOUND:  Glutamic acid, L-
                                                                                         COMPOUND:   Glutamic  acid, N-acetyl
REFERENCE:
               Olney,  J.W.,  Ho,  O.L.  and  Rhee, V.
               Exp.  Brain Res.  14:61-76,  1971.
OBSERVED NEUROTOXIC EFFECTS:
                              The compound was  equipotent to monosodium
                              glutamate in necrosing neurons in the retina
                              and brain.   This  compound is a powerful neuro-
                              excitant and the  neurotoxic properties may be
                              governed by similar mechanisms.
REFERENCE:  Curtis, D.R. and Watkins,  J.C.
            J. Neurochem. 6:117-141, 1960.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:
                                Treatment  caused excitation or depression of
                                neuronal activity.   Excitatory ranking:  glutamic,
                                B-aminoglutaric, aspartic, cysteic, cysteine-
                                sulfinic acids,  8-hydroxyglutamic, N-methylaspartic,
                                N-formiminoaspartic acids.
                                Depressant ranking:  6-alanine, GABA, taurine,
                                N-methyl-6-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                acids.
                                Structure-activity relationships established.
ANIMALS:   Mice, Swiss-webster  age 10  d,  total  250
                                                                                         ANIMALS:
             Cats,  surgically  prepared to expose  motoneurones, Renshaw cells or
             dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg,  then range established for
                         each compound.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:      s.C.

CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate  (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals  including 5 hr.

EXAM. TYPE:     Histology
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                        395
                                                                                                                                    396

-------
 COMPOUND:    Glutamic acid, N-acetyl, L~
                                                                                         COMPOUND:   Glutamic acid,  3-amino-
REFERENCE:
               Olney, J.W., Ho, O.L. and Rhee, V.
               Exp. Brain Res. 14:61-76, 1971.
OBSERVED NEUROTOX1C EFFECTS:   No cytotoxicity was observed.
ANIMALS:  Mice, Swiss-webster  age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                         each compound.
REFERENCE:   Curtis,  D.R.  and Watkins, J.C.
             J. Neurochem.  6:117-141, 1960.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:
                                                                                         ANIMALS:
                                                                                                                         Treatment caused excitation or depression of
                                                                                                                         neuronal activity.  Excitatory ranking:  glutamic,
                                                                                                                         B-aminoglutaric, aspartic, cysteic, cysteine-
                                                                                                                         sulfinic acids,  6-hydroxyglutamic, N-methylaspartic,
                                                                                                                         N-formiminoaspartic acids.
                                                                                                                         Depressant ranking:  B-alanine, GABA, taurine,
                                                                                                                         N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                                                                                                         glycine, a-alanine, 6-aminovaleric, 6-aminoisobutyric
                                                                                                                         acids.
                                                                                                                         Structure-activity relationships established.
                                                                                                      Cats,  surgically prepared to expose  motoneurones, Renshaw cells or
                                                                                                      dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalainus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM.  TYPE:     Histology
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                        397
                                                                                                                                    398

-------
COMPOUND:
Glutamic acid,  N-carbamoyl-,  L-
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment  caused  excitation  or  depression of
                               neuronal activity.   Excitatory  ranking:   glutamic,
                               S-aminoglutaric,  aspartic, cysteic,  cysteine-
                               sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic  acids.
                               Depressant ranking:   g-alanine,  GABA,  taurine,
                               N-methyl-g-alanine,  6-amino-8-hydroxybutyric,
                               glycine, a-alanine,  6-aminovaleric,  B-aminoispbutyric
                               acids.
                               Structure-activity relationships established.
                                                                                            COMPOUND:     Glutamic acid, N-(p-(((2,4-diamino-6-pteridnyl)methyl)methylamino)
                                                                                                          t>enzoyl)-,L-
                                                                                                          000059052
                                                                               REFERENCE:
                                                                                             Greenhouse, A.H., Neubuerger, K.T. and Bowerman, D.L.
                                                                                             Arch. Seurol. 11:618-625, 1964.
                                                                               OBSERVED NEUROTOXIC  EFFECTS:    Aphasia, right hemiparesis, convulsions;
                                                                                                              inflammatory lesions in left cerebral hemisphere
                                                                                                              attributed to direct toxic action of compound.
ANIMALS:
             Cats,  surgically prepared  to  exposed motoneurones,  Renshaw cells or
             dorsal horn  interneurones  in  lumbar cord.
                                                                               ANIMALS:
1 Human, F aged 36 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
                                                                               PREPARATION AND DOSE
                                                                               or HISTORY  OF  PATIENT:    Active lymphosarcoma; 30 mg given, further doses not
                                                                                                        quantified.
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory
                                                                               ROUTE AND SITE:   Intra-arterial, carotid

                                                                               CONTROL INFORMATION:      None
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                                                               DURATION OF EXPERIMENT:   About  3 wk.

                                                                               EXAM.  TYPE:    Behavior, histology  (autopsy)
                                          399
                                                                                                                                      400

-------
 COMPOUND:   Glutamic acid, N-(p-(((2,4-diamino-6- pteridny])methyl)methylamino)
            benzoyl),-L-

            000059052
 REFERENCE:    Smith,  B.
              J.  Neurol.  Neurosurg.  Psychiat.   38:810-815,  1975.
COMPOUND:   Glutamic acid, N.N-dimethyl-,  L-
REFERENCE:   Curtis,  D.R.  and Watkins, J.C.
             J.  Neurochem.  6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:  Destruction  of  oligodendrites and severe
                              astrocytosis leading  to death from therapy.
ANIMALS:     Human autopsy material:   10  brains  from  treated leukemics.
OBSERVED NEUROTOXIC EFFECTS:
                                                                                        ANIMALS:
                               Treatment  caused  excitation or depression of
                               neuronal activity.   Excitatory ranking:  glutamic,
                               6-aminoglutaric,  aspartic,  cysteic, cysteine-
                               sulfinic acids,  6-hydroxyglutamic, N-tnethylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  6-alanine, GABA, taurine,
                               N-methyl-B-alanlne, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity  relationships established.
                                                                                                    Cats, surgically prepared to exposed motoneurones,  Renshaw cells or
                                                                                                    dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    10,  12, or 12.5 mg/wk in addition to other drugs and
                         radiotherapy.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:   Intrathecal

CONTROL INFORMATION:   Human autopsy material from 10 untreated leukemics.
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:    Laboratory
DURATION OF EXPERIMENT:   Therapy.

EXAM. TYPE:    Histology
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                      401
                                                                                                                                  402

-------
COMPOUND:   Glutamlc acid,  hydrazide, L-
COMPOUND:   Glutamlc acid, beta-hydroxy
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
REFERENCE:   Curtis, D.R. and Watkins,  J.C.
             J. Neurochem. 6:117-141,  1960.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               8-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, B-hydroxyglutamic,  N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  6-alanine, GABA, taurine,
                               N-methyl-8-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
OBSERVED NEUROTOXIC EFFECTS:
                                Treatment  caused  excitation or depression of
                                neuronal activity.   Excitatory ranking:   glutamic,
                                B-aminoglutaric,  aspartic,  cysteic,  cysteine-
                                sulfinic acids, 8-hydroxyglutamic,  N-methylaspartic,
                                N-formiminoaspartic acids.
                                Depressant ranking:  B-alanine, GABA, taurine,
                                N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric,  B-aminoisobutyric
                                acids.
                                Structure-activity  relationships established.
ANIMALS:
            Cats, surgically prepared to expose  motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
                                                                                           ANIMALS:
             Cats,  surgically prepared to expose  motoneurones, Renshaw cells or
             dorsal horn  interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                                                                                                                      404

-------
 COMPOUND:   Glutamic acid, N-methyl-, D-
                                                                                          COMPOUND:
                                                                                                       Glutamic  acid, alpha-methyl-, DL-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
                                                                                          REFERENCE:   Curtis,  D.R.  and Watkins,  J.C.
                                                                                                      J.  Neuror.hem. 6:117-141,  1960.
 OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-ri-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                         Treatment caused excitation or depression of
                                                                                                                         neuronal activity.  Excitatory ranking:  glutamic,
                                                                                                                         B-aminoglutaric, aspartic, cysteic, cysteine-
                                                                                                                         sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                                                                                                                         N-formiminoaspartic acids.
                                                                                                                         Depressant ranking:  B-alanine, GABA, taurine,
                                                                                                                         N-methyl-6-alanine, 6-amino-S-hydroxybutyric,
                                                                                                                         glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                                                                                                         acids.
                                                                                                                         Structure-activity relationships established.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
                                                                                         ANIMALS:
                                                                                                      Cats,  surgically prepared to exposed motoneurones, Renshaw cells or
                                                                                                      dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed In order of
                         potency of results.
                                                                                         PREPARATION AND DOSE
                                                                                         or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:      Electrophoretic application, various sites in central nervous
                    system.
CONTROL INFORMATION:
                         None
                                                                                          ROUTE AND  SITE:   Topical, ionophoresis

                                                                                          CONTROL  INFORMATION:   Laboratory
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                                         DURATION OF EXPERIMENT:  ns.

                                                                                         EXAM. TYPE:  Biochemistry, electrophysiology
                                        4C5
                                                                                                                                    406

-------
COMPOUND:  Glutamic acid, alpha-methyl-,  DL-
COMPOUND:
Glutamic acid,  N-methyl-,  DL-
REFERENCE:     Olney,  J.W.,  Ho,  O.L.  and  Rhee, V.
               Exp.  Brain Res.  14:61-76,  1971.
REFERENCE:   Curtis,  D.R.  and  Watkins,  J.C.
             J.  Neurochem.  6:117-141,  1960.
OBSERVED NEUROTOXIC EFFECTS:   The compound  was  toxic to non-neurol components
                              (glia,  etc.), but not to neurons.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:   Mice, Swiss-webster  age  10  d,  total  250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12  mmoles/kg,  then range established for
                         each compound.
ANIMALS:
                                Treatment caused excitation or depression of
                                neuronal activity.  Excitatory ranking:  glutamic,
                                6-aminoglutaric, aspartic, cysteic, cysteine-
                                sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                                N-formiminoaspartic acids.
                                Depressant ranking:  6-alanine, GABA, taurine,
                                N-methyl-6-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                acids.
                                Structure-activity relationships established.
                                                                                                     Cats,  surgically prepared  to  exposed motoneurones, Renshaw cells or
                                                                                                     dorsal horn  interneurones  in  lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:      s.C.

CONTROL INFORMATION:      Compounds compared with  monosodium L-glutamate  (MSG)
                         potency for selectively  necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM. TYPE:     Histology
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                       407
                                                                                                                                  408

-------
 COMPOUND*   Glutamic acid,  N-methyl-, DL-
                                                                                            COMPOUND:  Glutamic acid, N-methyl-, DL-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:  N-methyl^D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than  all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-n_-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
REFERENCE:     Olney, J.W., Ho, O.L. and Rhee, V.
               Exp. Brain Res. 14:61-76, 1971.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                               The  compound was more  potent  than monosodium
                               glutamate  in necrosing neurons  in the  retina
                               and  brain.  This compound .is  a  powerful  neuro-
                               excitant and the neurotoxic properties may  be
                               governed by similar mechanisms.
ANIMALS:  Cats prepared for electrophoretic application of  chemicals  to  single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:   Dilutions 0.1-0.5 M of  31 compounds  mainly of aspartic,
                         glutamic and cysteic acids listed  in order of
                         potency of results.
                                                                                            ANIMALS:  Mice, Swiss-webster  age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range  established  for
                         each compound.
ROUTE AND SITE:     Electrophoretic application, various sites  in central nervous
                    system.
CONTROL INFORMATION:
                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                                                                            ROUTE AND SITE:
                                                                                                                S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing  neurons  in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5  hr.

EXAM. TYPE:    Histology
                                        409
                                                                                                                                    410

-------
COMPOUND:
Glutamic acid,  alpha-methyl ester, L-
COMPOUND:
                                                                                                       Glutamic acid, gamma-methyl ester, L-
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
                                                                               REFERENCE:   Curtis,  D.R.  and  Watkins,  J.C.
                                                                                            J.  Neurochem.  6:117-141,  1960.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               6-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  B-alanine, GABA, taurine,
                               N-methyl-S-alanine, 6-amlno-8-hydroxybutyric,
                               glycine, a-alanine', 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
                                                                               OBSERVED NEUROTOXIC EFFECTS:
                                                                                                               Treatment  caused excitation or depression of
                                                                                                               neuronal activity.   Excitatory ranking:  glutamic,
                                                                                                               B-aminoglutaric, aspartic, cysteic, cysteine-
                                                                                                               sulfinic acids,  B-hydroxyglutamic,  N-methylaspartic,
                                                                                                               N-formiminoaspartic acids.
                                                                                                               Depressant ranking:  B-alanine, GABA, taurine,
                                                                                                               N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                                                                                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                                                                                               acids.
                                                                                                               Structure-activity  relationships established.
ANIMALS:
             Cats, surgically prepared to expose  motoneurones, Renshaw cells or
             dorsal horn interneurones in lumbar cord.
                                                                               ANIMALS:
                                                                                            Cats,  surgically  prepared to expose  motoneurones, Renshaw cells or
                                                                                            dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
                                                                               PREPARATION AND DOSE
                                                                               or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE: •  Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
                                                                               ROUTE AND SITE:   Topical,  ionophoresis

                                                                               CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                                                               DURATION OF EXPERIMENT:  ns.

                                                                               EXAM. TYPE:  Biochemistry,  electrophysiology
                                          411
                                                                                                                                      412

-------
 COMPOUND:    Glutamic acid, monosodlum salt, L-(+)_

             000142472


 REFERENCE:   Knaape, H.H. and Wlechert, P. (In Ger.)
             J. Neurochem. 17:  1171-1175, 1970.
 OBSERVED NEUROTOXIC EFFECTS:   EEC seizures followed injection into the hippocampus;
                               other sites are  ranked in order of decreasing
                               sensitivity to compound,  the ventricle being insen-
                               sitive at doses used.  The authors discuss the metab-
                               olism of compound as producing releasing factors for
                               EEC seizures.
COMPOUND:  Glutamic acid, monosodium salt, L-(+)-

           000142472

REFERENCE:    Lemkey-Johnston,  N.  and Reynolds, W.A.
              J. Neuropath.  Exp,  Neurol. 33(l):74-97, 1974.
OBSERVED NEUROTOXIC EFFECTS:  Tremors, and damage to dentate-hippocampal
                              gyrl surfaces.  Involvement of retina and in the
                              arcuate nucleus.  Lesions in the tectum, habenular
                              nuclei, subfornical organ, dorsolateral surface of
                              the thalamus,cerebral cortex, area postrema, cuneatus
                              and the nuclei gracilis.  Death.
ANIMALS:     45  cats,  2.5-5  kg,  surgically prepared
ANIMALS:   3 strains of Mice,  Swiss-Albino - 7-10 days, and 1 mouse - A/Jax
           ICR hybrid.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   50-250 microliter  in  10-15  sec
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1,  2,  or 4 mg/gm in 20% soln.
ROUTE AND SITE:     Stereotactlc injection into various cerebral regions

CONTROL INFORMATION:  ns
ROUTE AND SITE:   I.P.  and S.C.

CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:    Each up to about 30 min

EXAM. TYPE:    Behavior, EEC
DURATION OF EXPERIMENT:   Serial Sacr.  10 min to 48 hr.

EXAM. TYPE:   Histology,  Ultrastructural.
                                        413
                                                                                                                                    414

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COMPOUND:   Glutamlc acid, monosodium salt, L-(+)-
            000142472
REFERENCE:
            Lemkey-Johnston, N., Butler, V. and Reynolds, W.A.
            Expl. Neurol.  48:292-309, 1975.
                                                                                  COMPOUND:    Glutamic acid, monosodium salt, L-(+)-

                                                                                               000142472

                                                                                  REFERENCE:  Olney,  J.W.
                                                                                              J. Neuropath.  Exp.  Neurol.  28:   455-474, 1969.
OBSERVED NEUROTOXIC EFFECTS:
                    Glutamic acid HC1 at 2 mg/g produced lesions  in
                    arcuate nucleus (10 of 11 mice),  also preoptic
                    nucleus, tectum and pretectal area,  subconmissural
                    and subfornical organs and cerebellum (neuronal
                    damage like that from MSG).  Higher  equivalency
                    NaCl damaged mainly caudate-putamen, cerebellum,
                    cortex, and habenula, related apparently to vascular
                    changes.  Sucrose produced vascular  changes but
                    no brain lesions.
                                                                                               OBSERVED NEUROTOXIC  EFFECTS:
                              A single injection caused degeneration of the inner
                              retinal cells of mice aged 9-10 days.  There was
                              evidence of edema of dendrites and cell bodies, mito-
                              chondria and several patterns of degeneration leading
                              to necrosis.
ANIMALS:
Mice, ICR or A/JAX-ICR hybrids, aged 4-12 d.
                                                                                               ANIMALS:     Over 200 mice, Swiss albino
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               Glutamic acid HC1 2 and 4 mg/g as 20% solution;  NaCl
               equimolar for Na to 1-10 mg/g MSG (0.31-3.12 mg/g);
               sucrose 14.6-36.5 mg/g as 80% solution, also equimolar
               to 4-10 mg/g MSG.  Purpose:  to test the components of
               MSG separately.
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:    None other  than sucrose..
PREPARATION AND DOSE
or HISTORY OF PATIENT:  4 g/kg and  other  schedules
                                                                                  ROUTE AND SITE:   s.C.

                                                                                  CONTROL INFORMATION:  Various
DURATION OF EXPERIMENT^.

EXAM. TYPE:  Histology,  but timings  and  preparations are not  described,  though
             they reportedly influence the findings.
                                                                                  DURATION OF EXPERIMENT:   30 min  to  48 hr

                                                                                  EXAM. TYPE:   Histology
                                             415
                                                                                                                                       416

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COMPOUND:  Glutamic acid, monosodlum salt, L-(+)-

           000142472

REFERENCE:  oiney,  J.W.
            Science 164:719-721,  1969.
OBSERVED NEUROTOXIC EFFECTS:  (1)  Selective destruction of:   proptic and arcuate
     nuclei,  some neurons in median eminence,  subcommissural and subfornical
     organs,  medial habenular nuclei,  dentate  gyrus.   (2 and 3)  Brain lesions
     found, not described.   Chronic dosage: mainly non-neural studies,  but stunting
     found  in adenohypophysis.
COMPOUND:  Glutamic acid, monosodium salt, L-(+)-

           000142472

REFERENCE:  Olney, J.W.  and Ho., 0.
            Nature 227:609-610, 1970.
OBSERVED NEUROTOXIC EFFECTS:    Necrosis  of hypothalamic neurons in mice given
                                glutamate,  aspartate,  or cysteine, dose-related;
                                zero  damage from other compounds
ANIMALS:   (i)  Mice,  Swiss albino,  10 litters aged 2-9 d
           (2)  Adult  mice
           (3)  Neonatal C57BL/6  mice and albino rats

PREPARATION AND DOSE
or HISTORY OF PATIENT:  (1)  0.5-4 mg/g,  one dose;  20 dosed daily,  for d 1-10
                            of age.
                        (2)  5-7  mg/g.
                        (3)  ns.
ANIMALS:      75 Mice,  Swiss  Webster,  age 10 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
One of 10 amino acids and various other compounds,  2.5  or 10%
in water, 0.25-2 g/kg.
ROUTE AND SITE:  S.C.

CONTROL INFORMATION:   (1)  18 mice untreated.
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:   Intubated,  no treatment, 10 mice
DURATION OF EXPERIMENT:   1.9 mo.

EXAM. TYPE: Histology
DURATION OF EXPERIMENT:     5 hr.

EXAM. TYPE:  Histology
                                         417
                                                                                                                                   418

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COMPOUND'   Glutamic acid,  monosodium salt,  L-(+)-
            000142472
REFERENCE: Olney, J.W.
           J. Neuropath. Exp. Neurol. 30(1):75-90, 1971.
OBSERVED NEUROTOXIC EFFECTS:   Hypothalamic lesions.  Involvement of glial and
                              ependymal cells.  Arcuate (infundibular) nucleus
                              and inner retinal neurons were destroyed.  An
                              identical pattern of neuronal necrosis can be
                              induced by certain other amino acids, which have
                              neuroexcitatory properties.
ANIMALS:.    27  Mice, Webster  Swiss, albino, 10 d post natal.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    IS m mole/kg  in  10% aq soln.
ROUTE AND SITE:   S.C.

CONTROL INFORMATION:  3 mice untreated,  3 mice:  18 m mole/kg  sodium  chloride.



DURATION OF EXPERIMENT:  Sacr.  15  min to 8  d.

EXAM. TYPE:   Histology,  ultrastructure.
                                      419
COMPOUND:   Glutamic acid, monosodium salt, L-(+)-

            000142472

REFERENCE:  Olney,  J.W.,  Sharpe, L.G.,  and Feigin, R.D.
            J.  Neuropath.  Exp.  Neurol.  31(3):  464-488, 1972.


OBSERVED NEUROTOXIC EFFECTS:   Cyanosis, vomiting, convulsions, neuron-necrotized
      hypothalamus,  and  brain lesions.   Arcuate nucleus, medial habenular nucleus
      neurons,  subfornical organ, cingulate cortex midline, anterior hippocamus
      (denate gyrus) and superior colliculus destroyed.
ANIMALS:  9 Rhesus Monkeys,  (Macaca Mulatta),  Infants.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1-4 g/kg admin,  as 20cc/kg of skim milk water soln.
ROUTE AND SITE:   Oral and S.C.

CONTROL INFORMATION:  3 monkeys  treated with NaCl



DURATION OF EXPERIMENT:   Serial sacr 3-5 hrs.

EXAM. TYPE:   Ultrastructural, histology, cytopathology
                                                                                                                                  420

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COMPOUND"   Glutamic acid, monosodium salt, L-(+)-
            000142472
REFERENCE:  Olney,  J.W., Ho, O.L., Rhee, V. and DeGubareff, T.
            New Eng. J. Med. 289:1374-1375, 1973.
OBSERVED NEUROTOXIC EFFECTS: Brain lesions at junction of median eminence and
     arcuate-periventricular nucleus.
COMPOUND:    Glutamic acid, monosodium salt, L-(+)-
REFERENCE:
                Perez,  V.J.  and Olney,  J.W.
                J.  Neurochem.  19:1777-1782,  1972.
OBSERVED NEUROTOXIC EFFECTS:
Arcuate nucleus, ventromedial hypothalamus
and lateral thalamus were examined:
control MSG level 25 mmol/kg dry weight, rose  to  111
mmol in arcuat nucleus, 42 in ventromedial hypothalamus
and lateral thalamus, at 3 hr, back to normal  in
12-15 hr, blood (normal <1 mM) rose to 40 mM in 15
min, back to normal in 1-3 hr.
ANIMALS:   Guinea-pigs, age  3 d
                                                                                        ANIMALS:   124 Mice, 18 litters, M and F, Swiss-Webster, aged 4 d
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1 mg/g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    2 mg/g
ROUTE AND SITE:    s.C.

CONTROL INFORMATION:  Guinea-pigs  sodium  chloride  treated.
ROUTE AND SITE:   s.C.

CONTROL INFORMATION:       Untreated mice, also zero time treated.
DURATION OF EXPERIMENT:   5 hr

EXAM. TYPE: Histology
DURATION OF EXPERIMENT:    7.5 min to 18 hr, serial sacr.

EXAM.  TYPE:     Biochemistry
                                      421
                                                                                                                                  422

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COMPOUND:  Glutamic acid,  monosodium salt,  L-(+)-

           000142472


REFERENCE:  Reynolds, W.A., Lemkey-Johnston, N.,  Filer,  L.J.,  Jr. and Pitkin,  R.M.
            Science 172:  1342-1345, 1971.
COMPOUND: Glutamic acid, monosodium salt, L-(+)-

          000142472


REFERENCE:  Snapir, N., Robinzon, B.  and  Perek, M.
            Poulr.ry Sci. 50:1511-1514,  1971.
OBSERVED NEUROTOXIC EFFECTS:   No morphological differences between treated and
                              control hypothalami,  but some tissue fixed inadequately
                              resembled brain lesions.
OBSERVED NEUROTOXIC EFFECTS: Compound  induced brain damage in the hypothalamus
    region surrounding  the  ventromedial  area, leaving the hypothalamus itself
    unaffected.
ANIMALS:  16 Monkeys (M. mulatta and M. irus),  infants
                                                                                             ANIMALS:   84 Chicks, New Hampshire x White Leghorn, M, aged  5 d,  in  6  grps.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1, 2, 4 g/kg, 50% soln in water.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1  and  4  mg/g bw,  one dose or daily
ROUTE AND SHE:  Nasogastric tube

CONTROL INFORMATION:  5 additional monkeys, water only.
ROUTE AND SITE:  S.C.,  back of neck

CONTROL INFORMATION:    2 grps saline
DURATION OF EXPERIMENT:  6 hr

EXAM. TYPE:   Histology
DURATION OF EXPERIMENT:     40 d after first dose

EXAM. TYPE: Histology
                                                                                                                                   424

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COMPOUND:   Glutamic acid,  sodium salt
                                                                                            COMPOUND:   Glutamine, L-
REFERENCE:  Fifkova, E., Van Harreveld, A.
            Exp. Neurology 28:286-298, 1970.
OBSERVED NEUROTOXIC EFFECTS:
     (1) Transient arrest of electrogram of  corpus
         striatum
     (2) No noticeable effect on EEC.

     Depolarizes neurons when app.  electrophoretically
     may arrest all activity.
                                                                REFERENCE:   Curtis,  D.R.  and  Watkins,  J.C.
                                                                             J.  Neurochem.  6:117-141,  1960.
                                                                                            OBSERVED NEUROTOXIC  EFFECTS:
                               Treatment  caused excitation or depression of
                               neuronal activity.   Excitatory ranking:  glutamic,
                               g-aminoglutaric,  aspartic,  cysteic, cysteine-
                               sulfinic acids,  6-hydroxyglutamic,  N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:   B-alanine, GABA, taurine,
                               N-methyl-B-alanine,  6-amino-8-hydroxybutyric,
                               glycine, ct-alanine,  6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity  relationships established.
ANIMALS:      (1) Chicks, Leghorn, 16 d incubation to hatching time.
             (2) Chicks, 5 d after hatching.
                                                                                            ANIMALS:
                                                                             Cats,  surgically  prepared to expose  motoneurones, Renshaw cells or
                                                                             dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
100 mM soln.  of 1 sodium-glutamate,  pH 7.2.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:   I.V. at rate 1.2 ml/min for 1-5-2 min.

CONTROL INFORMATION:   ns.
                                                                ROUTE AND SITE:   Topical, ionophoresis

                                                                CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:16 d incubation-5 d old chicks.

EXAM.  TYPE: Neurological.
                                                                DURATION OF EXPERIMENT:  ns.

                                                                EXAM. TYPE:  Biochemistry, electrophysiology
                                         425
                                                                                                                                     426

-------
 COMPOUND:   Glutamine,  L-
                                                                                         COMPOUND:   Glutamine, N,N-dimethyl-, L-
 REFERENCE:     Olney, J.V?. , Ho, O.L. and Rhee, V.
               Exp. Erain Res. 14:61-76, 1971.
OBSERVED NEUROTOXIC EFFECTS:  Go cytotoxicity was observed.
ANIMALS:  Mice, Swiss-webster  age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                         each compound.
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141,  1960.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:
                                                                                         ANIMALS:
                                                                                                                         Treatment caused excitation or depression of
                                                                                                                         neuronal activity.  Excitatory ranking:  glutamic,
                                                                                                                         B-aminoglutaric, aspartic, cysteic, cysteine-
                                                                                                                         sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                                                                                                                         N-forroiminoaspartlc acids.
                                                                                                                         Depressant ranking:  6-alanine, GABA, taurine,
                                                                                                                         N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                                                                                                         glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                                                                                                         acids.
                                                                                                                         Structure-activity relationships established.
                                                                                                      Cats,  surgically prepared to expose . motoneurones, Renshaw cells or
                                                                                                      dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamstn (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM.  TYPE:     Histology
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                       427
                                                                                                                                   428

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COMPOUND: •  Glutamine, N-methyl-,  L-
REFERENCE:   Curtis,  D.R.  and Watkins,  J.C.
             J. Neurochem.  6:117-141, 1960.
COMPOUND:  Glutaramide, 3-(2-(3,5-dimethyl-2-oxocvclohexyl)-?.-hyHroxy=ethyl)-

           000066819

REFERENCE:    Segal, D.S.,  Squire,  L.R.  and Barondes,  S.H.
              Science 172:82-83,  1971.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                               Treatment  caused  excitation  or  depression of
                               neuronal activity.   Excitatory  ranking:   glutamic,
                               6-aminoglutaric,  aspartic, cysteic,  cysteine-
                               sulfinic acids, B-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic  acids.
                               Depressant ranking:   6-alanine,  GABA,  taurine,
                               N-methyl-B-alanine,  6-amino-B-hydroxybutyric,
                               glycine, a-alanine,  6-aminovaleric,  B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
             Cats,  surgically prepared  to  expose"  motoneurones,  Renshaw cells or
             dorsal horn  interneurones  in  lumbar cord.
                                                                                               OBSERVED NEUROTOXIC EFFECTS:
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
                                                                                               ANIMALS:   Mice
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                              The compound  inhibits protein synthesis (trans-
                              lation)  and long term memory, and produces initial
                              hyperactivity.   The effect of amphetamine on
                              memory in the compound  treated mice is not correlated
                              with a measurable increase in activity.  Studies
                              using other compounds lead the authors to conclude
                              that the block on memory was separate from the hyper-
                              activity and was due to inhibition of protein synthesis.
                          (1)   120 mg/kg
                          (2)   200 meg
                          (3)   Amt ns. follwoed 3 hr 45 min by amphetamine, 1 mg/kg,
                               or saline.
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:    Laboratory
ROUTE AND SITE:   s.C. or Intracerebral

CONTROL INFORMATION:    Controls saline treated.
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
DURATION OF EXPERIMENT:    3 hr

EXAM. TYPE:   Behavior
                                         429
                                                                                                                                     430

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COMPOUND:    Glutaramide, 3-(2-(3,5-dimethyl-2-oxocyclohexyl)-2-hydroxymethyl)

             000066819

REFERENCE:   Zech, R. and Domagk, G.F.
             Brain Res. 86:339-342, 1975.
COMPOUND:   Glutaric acid
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:      The compound inhibited the activity of the
                                 enzyme, noncompetitively and reversibly.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                               Treatment  caused  excitation or depression of
                               neuronal activity.   Excitatory ranking:   glutamic,
                               B-aminoglutaric,  aspartic,  cysteic,  cysteine-
                               sulfinic acids, B-hydroxyglutamic,  N-methylaspartic,
                               N-fonniminoaspartic acids.
                               Depressant ranking:   B-alanine, GABA, taurine,
                               N-methyl-8-alanine,  6-amino-g-hydroxybutyric,
                               glycine, a-alanine,  6-aminovaleric,  B-aminoisobutyric
                               acids.
                               Structure-activity  relationships established.
ANIMALS:     In.vitro  human brain acetylcholinesterase
                                                                                            ANIMALS:
             Cats,  surgically prepared  to expose  motoneurones,  Renshaw cells or
             dorsal horn  interneurones  in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Chemical  enzyme inhibition system
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:    In vitro

CONTROL INFORMATION:   Lab
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:      ns.

EXAM. TYPE:  Biochemistry
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                         431
                                                                                                                                      432

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COMPOUND:
Glutaric acid,  2-oxo-
                                                                                              COMPOUND:   Glutarimide,  3-(2-(3,5-dimethyl-2-oxocyclohexyl)-2-hvdroxyethy1)
REFERENCE:     Olney, J.W.,  Ho,  O.L. and Rhee, V.
               Exp.  Brain Res.  14:61-76, 1971.
                                                                                REFERENCE:    Segal,  D.S.,  Squire,  L.R. and Barondes, S.H.
                                                                                             Science 172:62-83,  1971.
OBSERVED NEUROTOXIC EFFECTS:   No cytotoxicity was observed.
                                                                                              OBSERVED NEUROTOXIC EFFECTS:   Depression in activity from 1-4 hr after injection.
                                                                                                                            Depression did not differ significantly from that
                                                                                                                            produced by cycloheximide.  No amnesic effect.
                                                                                                                            Compound does not markedly inhibit cerebral protein
                                                                                                                            synthesis.  Authors conclude depression activity
                                                                                                                            is unrealted to either amnesic action or to inhibition
                                                                                                                            of cerebral protein synthesis.
ANIMALS:  Mice, Swiss-webster  age 10 d, total 250
                                                                                              ANIMALS:   Mice
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg, then range established for
                         each compound.
                                                                                PREPARATION AND DOSE
                                                                                or HISTORY OF PATIENT:   200 meg
ROUTE AND SITE:      s.C.

CONTROL INFORMATION:      Compounds compared with monosodium L-glutarcate  (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM. TYPE:    Histology
                                                                                ROUTE AND SITE:    Intracerebrally

                                                                                CONTROL INFORMATION:    Controls saline treated



                                                                                DURATION OF EXPERIMENT:   At least 4 d.

                                                                                EXAM. TYPE:   Behavior,  light discrimination tests.
                                       433
                                                                                                                                   434

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COMPOUND:
             Glutarimlde, 3-ethyl-3-methyl-
REFERENCE:  Cohen,  B.,  Rey-Bellet,  J.  and Bergman,  P.S.
            Neurology 10:   1024-1030,  1960.
COMPOUND:   Gluterimide,  2-ethyl-2-phenyl-

            000077214

REFERENCE:  Ambre,  J.J. and Fischer,  L.J.
            Res.  Comm.  Chem.  Path.  Pharm.  4:   307-326,  1972*
OBSERVED NEUROTOXIC EFFECTS:   Grand  mal  seizures  were  induced  33  times  in  26  patients,
                              psychomotor  seizures  in  2.   The  authors concluded  that
                              the  compound was  safe for EEC  activation.
OBSERVED NEUROTOXIC EFFECTS:   Treatment with compound     resulted in a coma lasting
                              about 36 hours.   The intensity of the coma appeared to
                              correlate to the plasma level of an unidentified major
                              metabolite.
ANIMALS:    63 patients with definite  brain disease
PREPARATION AND DOSE
or HISTORY OF PATIENT:   10-915  mg,  no  other  details
ANIMALS:    Humans:   6 patients
            Dogs:     4 healthy mongrels, 20 kg
            Rats:     M, S-D,  400 g

PREPARATION AND DOSE
or HISTORY OF PATIENT:  Humans:  intoxicated by overdoses (1 case of 10 g reported)
                        Dogs:     400 mg/kg
                        Rats:   400 mg/kg
ROUTE AND SITE:   ns

CONTROL INFORMATION:   ns
ROUTE AND SITE:  Oral (humans);  gavage (dogs, rats)

CONTROL INFORMATION:  Humans,  3  healthy M, 70-84 kg, 1 g/subject orally
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:   clinical, EEC
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:  Behavior, biochemistry
                                          435
                                                                                                                                       436

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COMPOUND:   Glur.erimide.  2-ethyl-2-phenyl-

            000077214

REFERENCE: Haas, D.C. and Maraslgan, A.
           J. Neurol. Neurosurg. Psychiat. 31:  561-564, 1968.
COMPQJJND:  Gluterimlde, 2-ethyl-2-phenyl-

           000077214

REFERENCE:Melville, K., Jordon, G., Douglas,  D.
          Toxicology and Applied Pharmacology 9:363-375, 1966.
OBSERVED NEUROTOXIC EFFECTS:  Cerebellar ataxla, organic mental changes, peripheral
                             neuropathy
OBSERVED NEUROTOXIC EFFECTS:    Ataxia,  complete surgical anesthesia in 3-6 hrs.
                                Synergistic action with alcohol increased and
                                hastened central nervous system depression and
                                with increased dose produced surgical anesthesia.
ANIMALS:    Human:  3 F, 41-45
ANIMALS:  Mongrel  dogs,  7.0-12.0  kg,  M and F.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   History of alcohol treated, replaced or supplemented with
                            compound 1-4 g/d
PREPARATION AND DOSE
or HISTORY OF PATIENT:     100-300 mg/kg in total volumes of 50-8 ml water.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  None
ROUTE AND SITE:           Stomach tube

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:  2 mo to 8 yr (according to histories)

EXAM. TYPE: Clinical, electrophysiology
DURATION OF EXPERIMENT:   More than 1 wk.

EXAM. TYPE Behavior
                                         437
                                                                                                                                      438

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COMPOUND:  Glycine, N-sllyl-
                                                            COMPOUND:    Glycine, N-allyl-
REFERENCE:   Horton,  R.W.  and Meldrum,  S.S.
             Br.  J.  Pharmac.  49:   52-63,  1973-
                                                            REFERENCE:   Meldrum, B.S., Horton, R.W.  and  Brierley,  J.B.
                                                                        Brain 97:407-418,  1974.
OBSERVED NEUROTOXIC EFFECTS:
Seizures, photic stimulation,  EEC changes, inhibition
of brain glutamate carboxylase were caused by 3-mer-
captopropionic acid more strongly than by allylglycine
or 4-deoxypryidoxine HC1.   Thus the authors concluded
that seizures were due to  depletion of glycine and j-
aminobutyric acid (GABA).
OBSERVED NEUROTOXIC EFFECTS:    Tonic-clonic seizures in varying degrees.  Eventual
                                brain damage in some.  Selective changes in
                                hippocampus and neocortex, later neuronal loss
                                and gliosis; authors inferred medial temporal sclerosis.
ANIMALS:      Mice, CFW or BALB/C,  M, 20-30 g
             10 Baboons (Papio papio),  adolescent,  from Senegal,  3-6 kg
                                                            ANIMALS:      13 Baboons:   9 _P_.  papio and 4 P. cynocephalus, 3.4-6.6 kg, surgically
                                                                         prepared.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Mice:   ED5Q  and latency 1.0 mmol/kg,  160 min.
                         Baboons:   ED.-  and  latency 4 mmol/kg,  100 min.
                                                            PREPARATION AND DOSE
                                                            or HISTORY OF PATIENT:   350-630 mg/kg in saline
ROUTE AND SITE:    Mice I.P.,  Baboons I.V.

CONTROL INFORMATION:   Timed studies
                                                            ROUTE AND SITE:   I.V.

                                                            CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:   Various

EXAM.  TYPE:   Mice:  behavior, biochemistry; baboons:   polygraph.
                                                            DURATION OF EXPERIMENT: 42 d

                                                            EXAM. TYPE:  EEC, histology, pathology
                                       439
                                                                                                                                    440

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COMPOUND:   Glycine,  N-(gamma-glutamyl)-, L-
                                                                                              COMPOUND:   Glycolic  acid, hydrazide
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                               Treatment caused excitation or depression  of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               B-aminoglutaric, aspartic, cysteic,  cysteine-
                               sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:   B-alanine, GABA,  taurine,
                               N-methyl-8-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric,  B-aminoisobutyric
                               acids.
                               Structure-activity relationships  established.
            Cats, surgically prepared  to  expose  motoneurones,  Renshaw cells  or
            dorsal horn interneurones  in  lumbar  cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative  doses.
 REFERENCE:   Jenney, E.H. and Pfeiffer, C.C.
             J. Pharm. Exp.  Ther.  122:  110-123, 1958.


 OBSERVED NEUROTOXIC EFFECTS:    Convulsions
                                                                                              ANIMALS:     Mice, Harlan, 19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   8.9 mM/kgm
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:    Laboratory
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
DURATION OF EXPERIMENT:  Acute

EXAM. TYPE:  Clinical
                                         441
                                                                                                                                     442

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COMPOUND:
REFERENCE:    Walsh,  J.C.
             Neurology  20:455-458, 1970.
COMPOUND:   Guanidine, (2-(hexahydro-l(2H)azocinyl)ethyl)-, sulphate (2:1)

            000060026

REFERENCE:     Quinton, R.M.
               Br. J. Phannac.  21:51-66,  1963.
OBSERVED NEUROTOXIC  EFFECTS:    Acute peripheral neuropathy, mainly sensory
    impairment,  severe  axonal degeneration in sural nerve.
OBSERVED NEUROTOXIC EFFECTS:  The  compound enhanced the effect of Yohimbine
                              and  lowered its lethal dosage.
ANIMALS:      Human:   one case,  F,  63 yr.
                                                                                          ANIMALS:
               Mice, TT, M,  18-25  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  3 doses  in 2 wk of  sodium aurothiomalate  (44.5-46% Au)
    total 85 mg Au,  for osteoarthritis.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q   >50 mg/kg

                         ED._  = dose producing a 50% mortality of mice injected
                                 S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:   Inj.

CONTROL INFORMATION:    None
ROUTE AND SITE:      S.C.,  Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   2 wk with follow-up,  period ns.

EXAM. TYPE:  Behavior,  electrophysiology,  histology  (biopsy)
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior,  electrophysiology, biochemistry
                                      443
                                                                                                                                  444

-------
COMPOUND:  Harrisite
COMPOUND:    HEF-2  (mix of alkylpentaborane  derivatives)
REFERENCE:  Satran,  R.
            Neurology 11:   928-932,  1961
REFERENCE:   Feinsilver,  L., Lawson,  L.H.,  Berntson,  L.G.,  Yevich,  P.P.  and Groff, W.A.
             U.S.  Arm-/ report CRDLR  3035,  1960.
OBSERVED NEUROTOXIC EFFECTS:  Grand mal seizures,  EEC paroxysmal bursts of moderate
                             voltage spikes followed by high voltage waves, residual
                             on overbreathing throughout test period.  Inferred from
                             review of  literature to result from major component.
OBSERVED NEUROTOXIC EFFECTS:
                                Acute:   ataxia,  tremors,  convulsions,  hyperactivity
                                on  recovery;  no  lesions  found in brain (dogs).
                                Subacute:   similar  but less severe,  guinea-pigs
                                least severe;  no lesions  found (but  dogs had increase
                                of  CSF).   Concluded:  Compound highly  neurotoxic to
                                central  nervous  system,  speculatively  inhibiting
                                vital enzymes  (but  no ultrastructure was studied).
ANIMALS:   Human:   3  cases, M,  ages  22-32
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Chewed for 30 sec  to 10 min
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   None
ANIMALS:     Acute:   dogs,  beagle, M and  F.
             Subacute:   rats, M,  ages 8-10 wk;  mice,  F,  8-10 wk;  dogs, beagle, M;
                        guinea-pigs  (no details) .
             Odor detection:  15  volunteers,  human
PREPARATION AND DOSE
or HISTORY OF PATIENT:       Acute:   6 or  9.5  ppm  for  4 hr (dogs,  grps of 3).
                         Subacute:     1.9 ppm  6  hr/d, 5 d/wk,  30 d (25 rats);
                                      same for 22 d  (3  dogs);  same for 31 d
                                       (10 guinea-pigs).
            Odor detection:  0.41-26.1 ppm,  time  ns,  median threshold 6.4 ppm.

ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   Subacute:  equal numbers untreated
DURATION OF EXPERIMENT:   Up to 5 mo

EXAM.  TYPE:  EEC, clinical
DURATION OF EXPERIMENT:      ns.

EXAM.  TYPE:  Biochemistry,  behavior,  histology
                                          445
                                                                                                                                       446

-------
COMPOUND:    ct-Hemolysin from Staphylococcus  aureus
REFERENCE:   Edelwejn,  Z.,  Jeljaszewicz,  J.,  Szmlgielski,  S.  and  Zak,  C.
             Tox.  Appl.  Phann.  13:133-145,  1968.


OBSERVED NEUROTOXIC EFFECTS:"Collapse of  the  brain bioelectric activity"  (EEC
                            tracings),  partly prevented  by antagonist.  Compound
                            interpreted to  disturb  repolarization of stimulated
                            neurons.
COMPOUND:   (-)-Heptadeca-trans-8,10,12-Trlene-4,6-Diyne-l,14-Diol

            000505759

REFERENCE:  Starreveld, E. and Hope, C.E.
            Neurology 25:730-734, 1975.


OBSERVED NEUROTOXIC EFFECTS:   Muscarinic effects, convulsions,  "diffusely
                               abnormal"  EEC, hypoxia, metabolic  acidosis.
ANIMALS:     20 Rabbits,  Polish lowland,  M,  3 kg,  surgically prepared
                                                                                                ANIMALS:  Human:  1 case-report, M, age 54.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  10 meg/kg of purified compound with/without an antagonist
                       Cp_-chlorophenoxyacetic acid-dimethylaminoethyl chlorohydrate,
                       centrophenoxine)  on various schedules.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Ate 2 bites of root,  thinking  plant  to  be type of parsnip.
ROUTE AND SITE:    i.v.

CONTROL INFORMATION:    Recordings before test
ROUTE AND SITE:    oral

CONTROL INFORMATION:      None
DURATION OF EXPERIMENT:      About 6 d.

EXAM.  TYPE:  EEC-
DURATION OF EXPERIMENT:  n d

EXAM. TYPE:   Clinical, EEC, hospital  laboratory
                                                                                                                                       448

-------
COMPOUND:   Hepcanedioic acid, 4-amino-
COMPOUND:   Heptanedioic acid, 2-amino-, DL-
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
REFERENCE:   Curtis, D.R. and Watkins, J.C.
             J.  Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               6-aminoglutaric, aspartic, cystelc, cysteine-
                               sulfinic acids, 8-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  S-alanine, GABA, taurine,
                               N-methyl-B-alanine, S-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, S-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
OBSERVED NEUROTOXIC EFFECTS:
                               Treatment  caused  excitation  or  depression of
                               neuronal activity.   Excitatory  ranking:   glutamic,
                               6-aminoglutaric,  aspartic, cysteic,  cysteine-
                               sulfinic acids, 8-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic  acids.
                               Depressant ranking:   6-alanine,  GABA,  taurine,
                               N-methyl-B-alanine,  6-amino-B-hydroxybutyric,
                               glycine, a-alanine,  6-aminovaleric,  B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
ANIMALS:
            Cats, surgically prepared to expose  motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
                                                                                           ANIMALS:
             Cats,  surgically prepared to expose  motoneurones,  Renshaw cells or
             dorsal horn interneurones in lumbar  cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE: Biochemistry, electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry, electrophysiology
                                                                                                                                     450

-------
COMPOUND:   Heptanedioic acid,  2-amino-,  DL-
                                                                                         COMPOUND:  Heptanedioic acid, 2,5-diamino-, L-
P.EFERENCE:     Olney,  J.W. ,  Ko,  O.L.  ,-nd  Rhee,  V.
               Exp.  Brain Res.  14:61-76,  1971.
OBSERVED NEUROTOXIC EFFECTS:   Ko cytotoxicity was observed.
ANIMALS:  Mice, Swiss-webster  age 10 d,  total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 mmoles/kg,  then range established for
                         each compound.
REFERENCE:  Curtis, D.R. and Watkins,  J.C.
            J. Neurochem. 6:117-141,  1960.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:
                                                                                         ANIMALS:
                                                                                                                         Treatment  caused excitation or depression of
                                                                                                                         neuronal activity.   Excitatory ranking:  glutamic,
                                                                                                                         B-aminoglutaric, aspartic,  cysteic, cysteine-
                                                                                                                         sulfinic acids,  6-hydroxyglutamic, N-methylaspartic,
                                                                                                                         N-fortniminoaspartic acids.
                                                                                                                         Depressant ranking:  6-alanine, GABA, taurine,
                                                                                                                         N-methyl-B-alanine, 6-amino-6-hydroxybutyric,
                                                                                                                         glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                                                                                                         acids.
                                                                                                                         Structure-activity  relationships established.
                                                                                                      Cats,  surgically  prepared to exposed inotoneurones,  Renshaw cells or
                                                                                                      dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:
                    S.C.
CONTROL INFORMATION:      Compounds compared with monosodium L-glutamate (MSG)
                         potency for selectively necrosing neurons in retina
                         and brain (hypcthalamus)

DURATION OF EXPERIMENT:   5 hr or serial intervals including 5 hr.

EXAM.  TYPE:    Histology
ROUTE AND SITE:   Topical,  ionophoresis

CONTROL INFORMATION:   Laboratory



DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                                                                                                                    452

-------
 COMPOUND:
Hexane

 000110543
 REFERENCE:  Herskowitz, A., Ishl,  N.  and Schaumberg,  H.
            New Eng. J. Med. 285:82-85,  1971.
OBSERVED NEUROTOXIC EFFECTS:  Weakness and sensory loss  after  2-4 mo., dose-
     related, peripheral nervous system demyelination and  axonal degeneration,
     denervation of muscles, slow clinical recovery.   Authors  recommend  that
     current safety limit of 500 ppm be reduced to 100 ppm as  in Japan.
ANIMALS:   Human:  3 cases,  F,  age 27-47.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposure to  650-1300 ppm in  air,  industrially.
                                                                                        COMPOUND:   Hexanedioic acid,  2-amino-,  DL-
                                                                           REFERENCE:  Curtis, D.R. and Watkins, J.C.
                                                                                       J. Neurochem. 6:117-141, 1960.
                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                                                                        ANIMALS:
                                                                                                          Treatment  caused  excitation or depression of
                                                                                                          neuronal activity.   Excitatory ranking:  glutamic,
                                                                                                          B-aminoglutaric,  aspartic,  cysteic,  cysteine-
                                                                                                          sulfinic acids,  B-hydroxyglutamic,  N-methylaspartic,
                                                                                                          N-formiminoaspartic  acids.
                                                                                                          Depressant ranking:   6-alanine, GABA, taurine,
                                                                                                          N-methyl-B-alanine,  6-amino-B-hydroxybutyric,
                                                                                                          glycine, a-alanine,  6-aminovaleric,  8-aminoisobutyric
                                                                                                          acids.
                                                                                                          Structure-activity  relationships established.
                                                                                                     Cats,  surgically prepared  to  expose  motoneurones, Renshaw cells or
                                                                                                     dorsal horn interneurones  in  lumbar cord.
                                                                           PREPARATION AND DOSE
                                                                           or HISTORY OF PATIENT: Qualitative  doses.
ROUTE AND SITE:    Inhalation,  cutaneous,  oral

CONTROL INFORMATION:   None
                                                                           ROUTE AND SITE:   Topical,  ionophoresis

                                                                           CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:   Over  6 mo.

EXAM. TYPE: Clinical,  electrophysiology, histology  (biopsy), biochemistry
                                                                           DURATION OF EXPERIMENT:  ns.

                                                                           EXAM. TYPE:  Biochemistry,  electrophysiology
                                      453
                                                                                                                                   454

-------
 COMPOUND:   Hexanedioic acid, 2-amino-, DL-
                                                                                            COMPOUND:  Hexanedioic acid,  2-amino-,  DL-
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:  N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-n-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
 REFERENCE:     Olney, J.W., Ho,  O.L.  and  Rhee,  V.
               Exp. Brain  Res. 14:61-76,  1971.
OBSERVED  NEUROTOXIC EFFECTS:   The compound was toxic to non-neurol components
                               (glia,  etc.), but not to neurons.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                            ANIMALS:   Mice, Swlss-webster  age 10 d, total 250
PREPARATION AND DOSE
Or HISTORY OF PATIENT:   Initially  12 nmoles/kg,  then range established for
                         each compound.
ROUTE AND SITE:     Electrophoretic application, various sites in central nervous
                    system.
CONTROL INFORMATION:
                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
ROUTE AND SITE:     s.C.

CONTROL INFORMATION:     Compounds  compared  with monosodium L-glutamate (MSG)
                         potency  for  selectively necrosing neurons in retina
                         and brain  (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or  serial  intervals including 5 hr.

EXAM. TYPE:    Histology
                                        455
                                                                                                                                    456

-------
COMPOUND:   2,5-Sexanedione
                                                                                                 COMPOUND:    2,5-Hexanedione
REFERENCE:  Raleigh, R.L.,  Spencer,  P.S.  and  Schaumburg,  H.H.
            J. Occup. Med.  17:286,  1975.  (Letter  to  Editor)
OBSERVED NEUROTOXIC EFFECTS:  Peripheral  neuropathy  observed in both groups.
                                                                                                 REFERENCE:    Spencer,  P.S.  and Schaumburg, H.H.
                                                                                                              J.  Neurol.  Neurosurg.  Psychiat. 38:771-775, 1975.


                                                                                                 OBSERVED NEUROTOXIC EFFECTS:   Peripheral neuropathy with dying-back peripheral an.
                                                                                                      central nervous system degeneration; giant axonal swelling and massed
                                                                                                      neurofilaments.
ANIMALS:   Rats
                                                                                                 ANIMALS:    6 rats,  S-D,  400 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          (1)  Av.  dose 340 mg/kg/d,  5d/wk for 19 wk.
                          (2)  Av.  25  mi of 0.5% soln,  520 mg/kg/d for 2 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  (1) 0.1 ml/rat/d, 5 d/wk for 13 wk or
                        (2) 0.2 or 0.4 ml/rat/d for 6-10 wk,
                        Mean total was equivalent to 340 mg/kg/d.
ROUTE AND SITE:    (1)  E.G.     (2)  Oral

CONTROL INFORMATION:    ns,
                                                                                                 ROUTE AND SITE:   S.C.

                                                                                                 CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:      (1)  19 wk  (2)  2 mo.

EXAM.  TYPE:  ns.
                                                                                                 DURATION OF EXPERIMENT:   Up to 13 wk

                                                                                                 EXAM.  TYPE: Behavior, histology
                                           45 /
                                                                                                                                        458

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COMPOUND:   2-Hexanone

            000591786

REFERENCE:   Allen,  N.,  Mendell, J.R.,  Billmaier,  D.J.,  Fontaine,  R.E.  and  O'Neill,  J.
             Arch.  Neurol 32:209-218,  1975.


OBSERVED NEUROTOXIC EFFECTS:     Peripheral neuropathy:   distal, motor,  and
    sensory disorder with minimal reflex loss.   Muscle weakness and  sensory
    loss most common in  hands and feet.   No evidence  of  autonomic  dysfunction
    observed.
COMPOUND:
               2-Hexanone
               000591786
REFERENCE:     Billmaier, D., Yee, H.T., Allen, N.,  Craft,  B.,  Williams,  N.,
               Epstein,  S. and Fontaine, R.
               J. Occup. Med. 16:665-671, 1974.
OBSERVED NEUROTOXIC EFFECTS:
      All workers screened for nerve conduction and
      electromyography, 192 referred for study, 68 with
      definite peripheral neuropathy, 28 more suspected,
      6 severe.  Sural nerve biopsies normal.  Part-
      recovery in 6 mo. or more, severe cases.
ANIMALS:
             86 cases in 1,157 employees screened  at  a  factory  in Ohio.
                                                                                         ANIMALS:
              Human:   1157 workers  at  a coated fabrics plant.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Workers in plant producting  plastic-coated  and color-
    printed fabrics.  Methyl n-butyl Ketone was implicated  as  causative agent on the
    basis of correlation with exposure,  with incidence and  severity  of  disease,
    and temporal course of out break.   Exposure to  36 ppm in air  for over
    42 hr/wk.  Synergistic effect with methyl ethyl ketone  or  other  chemicals
    possible.
ROUTE AND SITE:  inhalation, skin contact

CONTROL INFORMATION:   Investigative (questions and answers),  retrospective
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Of approx 275 chemicals MBK was suspected  (timing of use  and
of cases) but methyl ethyl ketone and phthalate  esters
were not ruled out.  Cases centered on print-shop, were
related to work-load and to eating at work.
ROUTE AND SITE:  Inhalation,  skin contact,  ingestion considered.

CONTROL INFORMATION:      Sought but not rigorously established.
DURATION OF EXPERIMENT:   Approx.  1 yr.

EXAM. TYPE:  clinical and electrodiagnostic
DURATION OF EXPERIMENT:   Ongoing

EXAM. TYPE:    Electrophysiology, behavior, biopsy, clinical, laboratory.
                                      459
                                                                                                                                    460

-------
COMPOUND:   2-Hexanone

            000591786

REFERENCE:   Duckett, S., Williams,  N.  and Francis, S.
             New Eng. J. Med.  290:1264, 1974.
OBSERVED NEUROTOXIC EFFECTS:   Sciatic nerves axonal edema, degeneration associated
     with secondary myelin breakdown.
COMPOUND:
             2-Hexanone

             000591786
REFERENCE:     McDonough, J.R.
               New Eng. J. Med. 290:695, 1974.   (Letter to Editor)


OBSERVED NEUROTOXIC EFFECTS:    Peripheral neuropathy
ANIMALS:   (1)  9 rats, (2) 8 rats
                                                                                         ANIMALS:
                                                                                                        6 rats
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  200 ppm in air,  8 hr/d,  5 d/wk, for 6 wk.
     (2)  same plus methyl-ethyl ketone 2000 ppm.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1300 ppm in air, 6 hr/d, 5 d/wk, 4 mo.  (TLV  is  100 ppm
410 mg/m ).
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:  ns.
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:  6 wk

EXAM. TYPE:  Histology
DURATION OF EXPERIMENT:   4 ">o-

EXAM.  TYPE:    ns.
                                       461
                                                                                                                                    462

-------
COMPOUND:       2-Hexanone

                000591786

REFERENCE:     Mendell,  J.R.,
               New Eng.  J.  Med  290:  1263-1264, 1974.
OBSERVED NEUROTOXIC EFFECTS:
182 employees with abnormal electrophyslology, 79
with clinical polyneuropathy, peripheral, related
epidemiologically to exposure.  Chickens had signs
of nerve damage after 35 d at 200 ppm, cats at
33 d and rats at 60 d of 400-600 ppm.  Limb weakness,
slow conduction, swollen axons, demyellnation.  Rat
and human exposures were seen as "remarkably close"
in duration.
                                                             COMPOUND:
                                                             REFERENCE:
                                                                             2-Hexanone

                                                                             000591786
              Mendell,  J.R.,  Salda,  K.,  Ganansia,  M.F., Jackson, D.B.,
              Weiss,  H.,  Gardner,  R.W.,  Chrisman,  C., Allen, N.,
              Couri,  D.,  O'Neill,  J.
              Science 185:787-789, 1974.
OBSERVED NEUROTOXIC EFFECTS:    Hindlimb  then forelimb weakness in animals, increased
                                water intake, slow nerve conduction in cats, with disturbed
                                patterns, demyelination and axonal degeneration in
                                animals.
ANIMALS:       1.   Human:   1161  industrial employees
               2.   Rats,  cats, chickens
PREPARATION AND DOSE
or HISTORY OF PATIENT:    1.   Exposure,  8-12 hr/d  22-24 d/mo for 9 mo.  total 1584-2592
                              hr.
                          2.   200-600  ppm 24 hr/d,  7  d/wk, 60 d for .total 1440
                              hr exposures.
                                                             ANIMALS:   5 chickens, domestic
                                                                        4 Rats, S-D
                                                                        4 Cats, domestic

                                                             PREPARATION AND DOSE
                                                             or HISTORY OF PATIENT:   All groups exposed 24 hr/d for 2 mo.,  total 1440 hr.
                                                                                      Chickens:  200 ppm in air, reduced to  100 ppm.
                                                                                          Rats:  600 ppm reduced to 400 ppm.
                                                                                          Cats:  600 ppm reduced to 400 ppm.
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION:      ns
                                                             ROUTE AND SITE:  Inhalatlon

                                                             CONTROL INFORMATION:  Pair-fed matched controls
DURATION OF EXPERIMENT:    ns.

EXAM. TYPE:    Electrophysiology,  behavior,  histology
                                                             DURATION OF EXPERIMENT:  2 mo., on going

                                                             EXAM. TYPE:    Behavior, electorphysiology, histology.
                                           463
                                                                                                                                        464

-------
 COMPOUND:      2-Hexanone

               000591786

 REFERENCE:   Raleigh, R.L.,  Spencer,  P.S.  and Schaumburg,  H.H.
             J. Occup. Med.  17:286,  1975 (Letter to Editor)
OBSERVED NEUROTOXIC EFFECTS:  (1)  No evidence of clinical neuropathy.   Minimal
                            " histologic changes in nerve fibers in cats treated
                              with 330 ppm for 4.5 months, not seen in 100 ppm
                              group.  Histological exam of rats incomplete to
                              date.   (2) Clinical neuropathy seen.   (3)  Clinical
                              neuropathy was not produced.
                                                                                            COMPOUND:   HiCal-2
REFERENCE:  Feinsilver, L., Lawson,  L.H.,  Yevich, P.P. and Jacobson, K.H.
            D.S. Army  CWL  Report  CWLR 2367,  1960.


OBSERVED NEUROTOXIC EFFECTS:  LC«.n under conditions were:
                                50         3               3
                              Rats-103 mg/m  ; mice-96  mg/m .   Signs  included  •
                              ataxia, depression,  prostration,  tremors,  clonic
                              convulsions, interpreted as "marked  effect upon"
                              the central nervous  system.
ANIMALS: (1) Cats,  rats  (2)  Cats and dogs  (3)  Guinea pigs
PREPARATION AND DOSE
or HISTORY OF PATIENT:  (D  330 ppm and 100 ppm for 6 hr/d,  5d/wk for 5 mo.
                       (2)  150 rag/kg, 2/d, 5d/wk for 2 mo(cat)  2-4 mo dogs.
                       (3)  Amt ns., repeated applications over period of 8 mo.
ANIMALS:    Rats, ages 8-10 wk, M
            Mice, 8-10 wk, F
            Dogs, beagle, M.

PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposed to vapors  of  compounds in LC5Q study, 2-4 hr
ROUTE AND SITE:    (1) Inhalation  (2) S.C.   (3)  Top.  Sk.

CONTROL INFORMATION:    ns.
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION: None
DURATION OF EXPERIMENT: ns.

EXAM.  TYPE:  Clinical, histological
DURATION OF EXPERIMENT:  Observation to  7  d after exposure

EXAM. TYPE:  Behavior, pathology
                                          465
                                                                                                                                       466

-------
COMPOUND:
             Holothurin A
COMPOUND: D-Homocysteic acid
REFERENCE:   Thron,  C.D., Durant, R.C. and Friess, S.L.
             Tox. Appl. Pharm. 6:182-196, 1964.
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:
                               Lower concentrations produced tissue responses that
                               were "largely irreversible," loss of excitability,
                               and blocks of nerve conduction.  Interaction
                               of this animal saponin with chemoreceptors in nerve
                               and neuromuscular tissues is discussed.
OBSERVED NEUROTOXIC EFFECTS:
N-methyl-D-aspartic and D-homocysteic acids were
stronger excitants of depolarization than all
others.  With some compounds  the action was
prolonged for many seconds  after the stimulus
was terminated, notably N-n-propyl-D-aspartic
acid.  There were no differences among types of
neurons tested; structure-activity relationship
was observed.
ANIMALS:
             In vitro nodes of Ranvier from desheather sciatic nerves of frog
             (R.  pipiens), and rat phrenic nerve-diaphragm preparations
ANIMALS:  Cats prepared  for electrophoretic application of chemicals to single
          central nervous  system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5.54 x 10~10 to 10~4 M in medium, applied for brief periods.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions  0.1-0.5 M of 31 compounds mainly of aspartic,
                          glutamic and cysteic acids listed in order of
                          potency of results.
ROUTE AND SITE:    In  vitro

CONTROL INFORMATION:     Zero application.
ROUTE AND SITE:      Electrophoretic application, various sites in central nervous
                     system.
CONTROL INFORMATION:
                          None
DURATION OF EXPERIMENT:  Up  to about x hr.
EXAM.  TYPE:
             Electrophysiology
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:     Electrophysiological
                                          467
                                                                                                                                      468

-------
 COMPOUND:  DL-Homocystelc  acid
                                                                                            COMPOUND:
                                                                                                           DL-Homocysteic acid
 REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
 OBSERVED NEUROTOXIC EFFECTS:
                              N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-ii-propyl-D-aspartic
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
                                                                                            REFtRENCE:
                                                                                                           Olney, J.W.,  Ho, O.L. and Rhee, V.
                                                                                                           Exp.  Brain Res.  14:61-76, 1971.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                               The  compound was  more  potent  than monosodium
                               glutamate  in necrosing neurons  in the retina
                               and  brain.  This  compound  is  a  powerful neuro-
                               excitant and the  neurotoxic properties may be
                               governed by similar  mechanisms.
ANIMALS:  Cats prepared for electrophoretic application of chemicals to single
          central nervous system neurons.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic
                         glutamic and cysteic acids listed in order of
                         potency of results.
                                                                                            ANIMALS:   Mice, Swiss-webster  age 10 d, total 250
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Initially 12 mmoles/kg,  then range established for
                         each compound.
ROUTE AND SITE:

CONTROL INFORMATION:
                    Electrophoretic application, various sites in central nervous
                    system.

                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
ROUTE AND SITE:     s.C.

CONTROL INFORMATION:     Compounds compared  with moncsodium L-glutamate (MSG)
                         potency for  selectively necrosing neurons in retina
                         and brain  (hypothalamus)

DURATION OF EXPERIMENT:   5 hr or serial  intervals including 5 hr.

EXAM. TYPE:     Histology
                                        469
                                                                                                                                    470

-------
COMPOUND: L-Homocysteic acid
REFERENCE:Curtis, D.R. and Watkins, J.C.
          J. Physiol. 166:1-14, 1963.
OBSERVED NEUROTOXIC EFFECTS:  N-methyl-D-aspartic and D-homocysteic acids were
                              stronger excitants of depolarization than all
                              others.  With some compounds the action was
                              prolonged for many seconds after the stimulus
                              was terminated, notably N-n_-propyl-D-aspartlc
                              acid.  There were no differences among types of
                              neurons tested; structure-activity relationship
                              was observed.
ANIMALS:  Cats prepared for electrophoretic application of chemicals  to  single
          central nervous system neurons.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dilutions 0.1-0.5 M of 31 compounds mainly of aspartic,
                         glutamic and cysteic acids listed in order of
                         potency of results.
ROUTE AND SITE:     Electrophoretic application, various sites  in central nervous
                    system.
CONTROL INFORMATION:
                         None
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiological
                                         471
COMPOUND:  Hydantoin,  5,5-diphenyl-      (Phenytoin)

           000057410

REFERENCE:   Ahmad,  S., Laidlaw,  J.,  Houghton,  G.W.  and Richens,  A.
             J.  Neurol. Neurosurg,  Psychiat.  38:225-231, 1975.


OBSERVED NEUROTOXIC EFFECTS:   Intoxication confirmed by serum phenytoin levels.
     Choreoathetoid  movements typical.   In 3 cases intoxication resulted from
     drug interactions.
                                                                                              ANIMALS:   Human:  4 cases (m 19, F 34, F 28, F 61) epileptics
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Usual dose 300 g/d long term
ROUTE AND SITE:       Oral

CONTROL INFORMATION:  None



DURATION OF EXPERIMENT:  Years

EXAM. TYPE:  Clinical, EEC, blood chemistry
                                                                                                                                     472

-------
COMPOUND:     Hydanm-tn.  5,5-diphenyl-

              000057410

REFERENCE:   Dam,  M.
             Acta  Neurol.  Scand.  42:491-494,  1966.
                                                                                                           H..J ._..-.*-
OBSERVED NEUROTOXIC EFFECTS:
                                Severe ataxia,  uncertain gait,  difficulty in turning,
                                falling.   Attacks recalled brain stem attacks with
                                tonic convulsions in legs in one pig.  One showed
                                nystagmus.  Cerebellum had altered Purkinje cells
                                swollen in 1 pig, shrunken and  swollen in other.
                                Loss of ganglion cells with empty synapses.
REFERENCE:   del Cerro, M.P. and Snider, R.S.
             Neurology 17:452-466, 1967.
OBSERVED NEUROTOXIC EFFECTS:    Severely ataxic at time of sacrafice.  infrastructure
    study.   Lamellar concentric bodies typical of lipoidoses throughout  cerebellar
    cortex but most affecting Purkinje cells.  Some myelinated axons were  altered.
ANIMALS:     3 Pigs,  20 kg,  litter-mates
                                                                                                ANIMALS:     30 Rats, Wistar, adult M, 200 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  10 mg/kg followed by increasing doses for 3 mo.
                        (2)  As above,  except starting with 20 mg/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT: 10 mg/d, 5 d/wk for 1 wk, then 20 mg/d, then 30 mg/d,
    then 40 mg/d for 5 d/wk till death or sacrifice.  Elsewhere authors  state
    drug discontinued after 10 wk in animals kept for 6 mo.
ROUTE AND SITE:    oral

CONTROL INFORMATION:     i pig untreated
ROUTE AND SITE:  I.M.

CONTROL INFORMATION:   2 Control groups:  solvent only and no treatment.
DURATION OF EXPERIMENT:  Approx.  3 mo.

EXAM.  TYPE:   Histological and chemical
DURATION OF EXPERIMENT:  Serial sacr to 6 mo.

EXAM. TYPE:  Histology
                                          473
                                                                                                                                       474

-------
COMPOUND:   Hydantoin, 5,5-diphenyl
                                                                                            COMPOUND:  Hydantoin,  5,5-diphenyl
REFERENCE:   Hofmann,  W.W.
             Neurology 8:210-214,  1958.
REFERENCE:  Kooiker, J.C. and Sumi, S.M.
            Neurology 1:68-71, 1974.
OBSERVED NEUROTOXIC EFFECTS:     Cerebellum:  Purkinje cells "virtually disappeared,"
    attributed by author  partly  to  the drug.  But cause of seizures was not
    found.
OBSERVED NEUROTOXIC EFFECTS:  Choreoathetold symptoms that disappeared with falling
     serum levels of drug and did not recur when patients took  the prescribed
     intake (300 mg/d) and no more.
ANIMALS:     Human:   1 F,  28  yr,  with multiple  seizures of sudden onset.
ANIMALS:   Humans:  2 case-reports of adverse drug reaction
PREPARATION AND DOSE
or HISTORY OF PATIENT:    250 mg/4 hr for  4  d,  then  taper off, but  seizures
    recurred,  and 250 mg/4-6 hr reinstituted,  Patient died after  16 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  (1) prescribed 300 mg/d, sometimes  took more;  serum level
     was 40 meg/ml.
     (2) prescribed 300 mg/d; serum level was 64-68 meg/ml.
ROUTE AND SITE:   I.V.  1 dose,  then I.M.

CONTROL INFORMATION:    None
ROUTE AND SITE:  Oral

CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:    16 d

EXAM. TYPE:  Autopsy
DURATION OF EXPERIMENT: Follow-up reported:   (1)  21 mo;  (2)  12 d

EXAM. TYPE: Clinical, laboratory, EEC
                                       475
                                                                                                                                    476

-------
COMPOUND:  Hydantoln, 5,5-diphenyl
                                                                                             COMPOUND:
REFERENCE:
Kutt, H., Winters, W.,  Kokenge,  R.  and McDowell,  F.
Arch. Neurol. 11:642-648, 1964.
REFERENCE: Kutt, H., Wolk, M., Scherman, R.  and  McDowell,  F.
           Neurology 14:  542-548, 1964.
OBSERVED NEUROTOXIC EFFECTS:
                 Diphenylhydantoin blood levels (thus ability to
                 metabolize) related to side-effects:  nystagmus at
                 20, ataxia at 30 mental changes at 40 meg/ml of blood.
                 Extent of mental changes varied widely,  with lethargy
                 and inability to concentrate were the most frequent
                 manifes tations.
OBSERVED NEUROTOXIC EFFECTS:  Nystagmus, ataxia  and  other  signs  correlated with
                             accumulations of unmetabolized compound owing to low
                             activity of liver  production of metabolite,  which appeared
                             to the authors  to  be a genetically determined deficiency.
ANIMALS:
Human, 32 patients
                                                                              ANIMALS:
                                                                                                       Human:   2  of  4 siblings  and a mother of a healthy family
PREPARATION AND DOSE
or HISTORY OF PATIENT:     4-10  mg/kg/d.
                                                                              PREPARATION AND DOSE
                                                                              or HISTORY OF PATIENT:
                         Usual dosage of about 4 mg/kg  and  smaller dosages.
                         Experimentation with an important  parahydroxylated
                         metabolite, 5-phenyl-5'-parahydroxyphenylhydantoin,  normally
                         resulting from enzymatic reaction  in  liver.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:       None
                                                                              ROUTE AND SITE:   Oral

                                                                              CONTROL INFORMATION:   Described
DURATION OF EXPERIMENT:    Long-term,  not described

EXAM.  TYPE:     Clinical
                                                                              DURATION OF EXPERIMENT:    About 5 wk

                                                                              EXAM.  TYPE:   Metabolic,  genetic, clinical
                                           477
                                                                                                                                        478

-------
COMPOUND:  Hydantoin, 5,5-diphenyl
                                                                                            COMPOUND'  Hydantoin, 5,5-diphenyl
REFERENCE:
               Lovelace,  R.E. and Horwitz, S.J.
               Arch.  Neurol.  18:69-77, 1968.
REFERENCE:  Morrell, F., Bradley, W. and Ptashne, M.
            Neurology 8:  140-144, 1958.
OBSERVED NEUROTOXIC EFFECTS:
                               Peripheral neuropathy in 26, absent deep tendon
                               reflexes in legs  (both knee and ankle in 19),
                               related slow nerve conduction.  More frequent in those
                               treated>10 yr, but amount of dose no guide.  Slow
                               conduction considered an early-warning of neuropathy
                               from  compound.
OBSERVED NEUROTOXIC EFFECTS:  The compound raised the threshold  for response  to electrical
                              stimulus, decreased the spike amplitude  in A fibers,  abolish-
                              ed "nerve repetition" and reversed the effects  of oxalate.
ANIMALS:       Humans:   50  selected  epileptics age-range 12-50 yr.
                                                                                            ANIMALS:     48 Rabbits, 2-3.5 kg, prepared surgically.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     200-600 mg  for  5-26 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Peripheral nerve preparation  in  situ,  doses  ns.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:       None
ROUTE AND SITE:  i.V. or I.P.

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:    ns.

EXAM.  TYPE:    Clinical,  electrophysiology
DURATION OF EXPERIMENT:  ns.but in one test 90 rain.

EXAM. TYPE:    Electrophysiology
                                          479
                                                                                                                                       480

-------
COMPOUND:   Hydantoin, 5,5-diphenyl
REFERENCE: Norris, F.H., Colella, J. and McFarlin, D.
           Neurology 14:  869-876, 1964,
OBSERVED NEUROTOXIC EFFECTS: Of human cases, 2 took massive doses, and 1 had BIZ
                             deficiency; neuromuscular transmission was disordered.
                             Competitive neuromuscular blockade appeared to result
                             from either end-plate depolarization or anticholin-
                             esterase activity.
ANIMALS:   (1)  Human:  3 cases
           (2)  Rats:  150-360 g, sciatic nerve and anterior tibial and peroneus
                       longus preparations

PREPARATION AND DOSE
or HISTORY OF PATIENT: (D  Up to 26 mg/kg
                       (2)  10 mg/kg
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  Various



DURATION OF EXPERIMENT:  Various

EXAM. TYPE:  Electromyography, clinical chemistry
                                          481
                                                                                                 COMPOUND:   Hydantoin,  5,5-diphenyl
REFERENCE:  Riehl, J-L.  and Mclntyre, H.B.
            Neurology 18:1107-1112, 1968.
OBSERVED NEUROTOXIC EFFECTS:   EEC:  slowing and/or increased amplitude  only
                               in zone(s) of abnormalities, not in unaffected
                               zones nor in control subjects.
                                                                                                ANIMALS:    Humans:  5F, 3 M, ages 18-60 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Epileptics with abnormal EEC and no history  of  drug use.
                         50 mg/2 min to total 250 mg.
ROUTE AND SITE: i.v.

CONTROL INFORMATION:  Added:  3 volunteers, M 25, F 48, 55, not  epileptics yr.



DURATION OF EXPERIMENT:   ns.

EXAM. TYPE: EEC
                                                                                                                                       482

-------
COMPOUND:   Hydantoln,  5,5-diphenyl
                                                                                                COMPOUND:   Hydantoin, 5,5-diphenyl
REFERENCE: Roseman, E.
           Neurology 11:  912-920, 1961


OBSERVED NEUROTOXIC EFFECTS:  Toxlcity manifested by Dilantin "drunkenness"
                             accompanied by EEC changes illustrated in detail, from
                             slow alpha to marked delta activity.  Author suggests
                             these as index for managing dosage of Dilantin in
                             difficult cases.
REFERENCE:   Selhorst,  J.B.,  Kaufman,  B. and Horwitz, S.J.
             Arch.  Neurol.  27:453-455, 1972.


OBSERVED NEUROTOXIC EFFECTS: Peripheral neuropathy, cerebellar damage.  Not
     reversed after discontinuation of drug for up to 4 yr.
ANIMALS:   Human:  4 cases, 2-24 yr old
                                                                                                ANIMALS:   2 Humans, F aged 16, M aged 11 with epilepsy.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.1 g (infants) to 0.4-0.6 g (adults) per d, judged by
                       results to be maximal effective dosage (not minimal).
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Histories of 300-1000 mg/d for 28 mo. and  9.5 yr.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:  None
ROUTE AND SITE:       Oral

CONTROL INFORMATION:  No controls
DURATION OF EXPERIMENT:  Up  to about 3 mo

EXAM. TYPE:   Clinical, EEC
DURATION OF EXPERIMENT:      28 mo; 9.5 yr  (histories)

EXAM. TYPE:  Electrophysiologlcal, radiological
                                           483
                                                                                                                                       484

-------
COMPOUND:  Hydantoin, 5,5-diphenyl
COMPOUND:  Hydantoin,  5,5-diphenyl
REFERENCE: Theil, G.B.,  Richter,  R.W.,  Powell,  M.R.  and  Doolan,  P.D.
           Neurology 11:   138-142,  1961.
REFERENCE:  Wstepne, D.
           Neur. Neurochir. Pol. 8:  427-431, 1974.
OBSERVED NEUROTOXIC EFFECTS:  Prolonged restless coma with cycles  of  responsiveness.
                             Hemodialysis after 138 hr thought  to have  prevented
                             worse damage.  Residual frontal-lobe damage  suspected
                             after 1 yr.   Male infant born during treatment  appeared
                             normal at birth and after 1  yr.
OBSERVED NEUROTOXIC EFFECTS:  Disseminated changes in neurons, and demyelination
                             of white matter of cerebral hemispheres.   EEC showed
                             modified spindles in frontal leads, interpreted as
                             nonpathological.  Chronic dose produced blood level
                             of 10-20 meg/ml.
ANIMALS:   Human:   one  F,  age  18, pregnant  8
ANIMALS:   8 cats
PREPARATION AND DOSE
or HISTORY OF PATIENT:   21.5 g one dose  (attempted suicide)
                       History of grand-mal, schizophrenia
PREPARATION AND DOSE
or HISTORY OF PATIENT:   15-20 mg/kg  for  "several months  to  1 year"
                        2 cats:  10-15 mg/kg  I.V.  one  dose
ROUTE AND SITE:    oral

CONTROL INFORMATION:   None
ROUTE AND SITE:  Oral,  I.V.

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:  1 yr

EXAM.  TYPE:   Behavior, EEC, clinical
DURATION OF EXPERIMENT:   Up  to  1  yr

EXAM. TYPE:   EEC and  evoked potentials,  histology
                                           485
                                                                                                                                       486

-------
COMPOUND:   Hydantoin,  5,5-diphenyl
REFERENCE:    Yanaglhara, T. and Hamberger,  A.
              Exp. Neurol. 32:152-162,  1971.
OBSERVED NEUROTOXIC EFFECTS:  Amino acid incorporation into  proteins  of  cerebral
                              cortex:  in neurons inhibited quickly with  recovery,
                              in neuroglia prolonged inhibition;  perikarya
                              (mainly  nuclei)  responded sensitively and  neuro-
                              suppressively.
COMPOUND:   Hydantoin, 5,5-diphenyl-monosodium salt  (Dilantin)

            000630933

REFERENCE:  Kokenge,  R., Kutt, H., McDowell,  F.
            Neurology 15:823-829,  1965.
OBSERVED NEUROTOXIC EFFECTS:
(1)  Nystagmus  ataxia, stuporous, disoriented.
(2)  High blood 6. tissue levels of Dilatin which can
    damage neural tissues, loss of Purkinje
    cells & occurrence of edema of Bergmann's
    glial layer.
ANIMALS:     Rats, S-D, F,  150-170 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    80-300 mg/kg/d,  various schedules.
ROUTE AND SITE:     I.P.

CONTROL INFORMATION:   None
                                                                                         ANIMALS:     (1) Human, 18 yrs, 66 kg.
                                                                                                     (2) 36 rats, Albino, 200 gm
                                                                                                     (3) Cats
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                     (1) 300 mg Dilantin,  90  mg phenobarbital,  500 mg
                                                                                                                        primidone,  20 mg  Librium daily. Dilantin may have
                                                                                                                        been  increased  to 900-1000 mg and phenobarbital 300 mg.
                                                                                                                     (2) 10, 20,  30,  50, 75,  100,  150 mg/kg daily for 15-30 d.
ROUTE AND SITE:   (i)  oral  (2)  I.M.

CONTROL INFORMATION: (3)  Cats
DURATION OF EXPERIMENT:      Up to 12 d

EXAM. TYPE: Biochemistry
DURATION OF EXPERIMENT:     (i)  15 yr  (2) 15 d

EXAM. TYPE: Neurological
                                      487
                                                                                                                                    488

-------
COMPOUND:   Hydantoin, l-((5-nitrofurfurylidene)amino)-

            000067209
REFERENCE:   Asbury,  A.K.
             Lancet 1:334-335,  1963.
                               (Nitrofurantoin)
COMPOUND:      Hydantoin,  l-((5-nitrofurfurylidene)amino)-

               000067209


REFERENCE:     Behar,  A.,  Rachmilewltz, E., Rahamimoff, R. and Denman, M.
               Arch.  JJeurol.  13:160-163, 1965.
OBSERVED NEUROTOXIC EFFECTS:    Polyneuropathy  reported  after nitrofurantoln
                                In  presence  of  renal  impairment  claimed  to  be
                                secondary  to renal  impairment, as here,  where
                                no  nitrofurantoin was given.
                                                                 OBSERVED NEUROTOXIC EFFECTS:    Sciatic and brachial nerves showed axonal  dystrophy
                                                                                                 in all treated rats, sciatic showed increased  chronaxis
                                                                                                 and decreased conduction.velocity; all related to
                                                                                                 amount and duration of treatment.
ANIMALS:     Human:   4  cases, M,  details ns.
                                                                 ANIMALS:       83 Rats, Sabra,  M and F
PREPARATION AND DOSE
or HISTORY OF PATIENT:
No treatment with compound.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20,  50,  100 mg/kg/d in divided doses (2/d) for 2, 4, 6, 8 d.
ROUTE AND SITE:   Nil

CONTROL INFORMATION:    This  group
                                                                 ROUTE AND SITE:  oral

                                                                 CONTROL INFORMATION:     20 Rats
DURATION OF EXPERIMENT:      ns.

EXAM. TYPE:  Autopsy (pathology)
                                                                 DURATION OF EXPERIMENT:  Serial sacr to 8 d.

                                                                 EXAM. TYPE:   Blood chemistry, electrophysiology, histology
                                           489
                                                                                                                                        490

-------
COMPOUND:  Hydantoin, l-((5-nitrofurfurylidene)amino)-

           000067209


REFERENCE:    Ellis,  F.G., Lond, M.S.
              Lancet  11:1136-1138, 1962.
                                                              COMPOUND:   Hydantoin,  l-((5-nitrofurfurylidene)amino)-
                                                                         000067209
                                                              REFERENCE:  Honet, J.C.
                                                                         Arch. Phys. Med. Rehab.  48:   209-212,  1967.
OBSERVED NEUROTOXIC EFFECTS:   Peripheral  (limb) polyneuritis progressive till
                              'death or cessation of compound; part-recovery
                              over long time.  No histology performed.
                                                             OBSERVED  NEUROTOXIC  EFFECTS:  Peripheral neuropathy with denervatlon of limb
                                                                                           extremities.
ANIMALS:      6 Humans,  M,  53-79 years with  renal  impairment.
                                                                                        ANIMALS:    Human:  one F, 43, 32.2 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
300-400 mg/d for 4 wk to 7 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  800 mg/d for 1 wk and then 400 mg/d for  3 wk
ROUTE AND SITE:   Oral

CONTROL INFORMATION:    None
                                                              ROUTE  AND  SITE:  Oral

                                                              CONTROL  INFORMATION:  None
DURATION OF EXPERIMENT:     ns.

EXAM. TYPE:   Clinical
                                                             DURATION OF  EXPERIMENT:  Hospital stay 9 d

                                                             EXAM. TYPE:   Clinical,  electromyography
                                       491
                                                                                                                                    492

-------
             Hydantoin.  l-((5-nltrofurfurylldene)aTn1nn)-

             000067209
REFERENCE:   Llndholm, T.
             Neurology 17:1017-1020, 1967.
OBSERVED NEUROTOXIC EFFECTS:    Electromyographical signs of peripheral muscle
    denervation in 23 (62%)  treated,  2 (18%) controls; only 5 treated subjects
    had behavioral (clinical) signs.
COMPOUND:   Hydantoin, l-((5-nitrofurfurylidene)amino)-

            000067209

REFERENCE:  Loughridge,  L.W.
            Lancet 11:1133-1135,  1962.
OBSERVED NEUROTOXIC EFFECTS:
                                 Blood level 5.1-6.5 meg/ml vs. normal 1.8
                                 in similarly treated patients.  Peripheral
                                 neuropathy (limbs) diagnosed during life;
                                 Median nerves swollen, atrophic, with Wallerian
                                 degeneration.
ANIMALS:     Human:   43 F,  5 M with urinary infections but not uremia.   Treated
    group:   33 F,  4  M (ages 12-70 yr,  av.  43).
ANIMALS:  1 Human:   M,  54,  with renal failure
PREPARATION AND DOSE
or HISTORY OF PATIENT:    50-300 (av.  115)  mg/d, total 0.7-77.1 (av. 15.8) g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    100 mg, 3/d for 6 wk.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:    10 F,  1M (ages 20-64 yr,  av.  46) untreated.
ROUTE AND SITE:    oral

CONTROL INFORMATION:      None
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:  Electrophysiology,  behavior
DURATION OF EXPERIMENT:   Approx. 7 wk.

EXAM. TYPE:   Clinical, blood-chemistry, histology (autopsy)
                                       493
                                                                                                                                    494

-------
COMPOUND:   Hydantoin, l-((5-nitrofurfurylidene)amino)-

            000067209

REFERENCE: Morris, J.S.
           J. Neurol. Neurosurg. Psychiat. 29:  224-228,  1966,


OBSERVED NEUROTOXIC EFFECTS:   Signs of peripheral neuropathy (paralysis,  muscle-
                             wasting) that were only partly reversible after
                             discontinuing medication.
COMPOUND:     Hydantoin, l-(5-nitrofurfurylidene)amino)-

              000067209

REFERENCE:    Rubensteln,  C.J.
              J.  Am.  Med.  Assn  187:647-649,  1964.
OBSERVED NEUROTOXIC EFFECTS:    Peripheral neuropathy, mainly of lower limbs, expecially
                                in presence of renal impairment; recovery if
                                muscle weakness not severe.  Wallerian degeneration
                                in myelin sheaths.
ANIMALS:   Human:  4 cases aged 36-75, M and F
ANIMALS:
               5 Humans,  M,  F
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Total doses:  8-1000 g over time
PREPARATION AND DOSE
or HISTORY OF PATIENT:    300-600 mg/d for 10 d to several yr.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  None
ROUTE AND SITE:  Oral

CONTROL INFORMATION:      None
DURATION OF EXPERIMENT:   About 2-6 mo

EXAM. TYPE:   Clinical
DURATION OF EXPERIMENT:   10 d to several yr.

EXAM. TYPE:    Clinical,  histology
                                          495
                                                                                                                                       496

-------
rnunnimn.   Kydantoin.  l-((5-nitrofurfurylidene')amino)-

            000067209
L'OHPOUNU:  Kyuaufcoiu, i-((5-nicrofurfuryIidene;aminoj-

           000067209
REFERENCE:  Toole, J.F. and Parrish, M.L.
            Neurology 23:554-559, 1973.
REFERENCE:   Toole, J.F., Gergen, J.A., Hayes, D.M., and Felts, J.H.
             Arch.  Neurol. 18:680-687, 1968.
OBSERVED NEUROTOXIC EFFECTS:   Symptoms began usually within 45 d, progressed in
    pattern of ascending sensorimotor polyneuropathy.  Degree of recovery related
    to symptoms severity but not to dose, nor to continuance of drug despite
    symptoms.  Recovery took days to 7 mo., deaths were not drug-related.  20%
    of lumbar punctures showed high protein.  Demyelination, axonal chromatolysis,
    but no inflammation.
OBSERVED NEUROTOXIC EFFECTS:  Changes in sensory and motor nerve conduction
     velocities;  no related changes in blood or urine.
ANIMALS:  Humans
ANIMALS:   Human healthy volunteers, 7 M, 7F, ages 22-58 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.0-100+ g during 7-196 d.  137 patients in world literature,
                        reports assembled and analyzed.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  100 mg with meals and at bedtime for 14 d
ROUTE AND SITE:    Oral (I.V. in one, instilled into bladder in two, into pleura
                  in one).
CONTROL INFORMATION:     None
ROUTE AND SITE:  Oral

CONTROL INFORMATION:    Placebo, double-blind
DURATION OF EXPERIMENT:   Up to 196 d

EXAM. TYPE:  Behavior, laboratory, histology
DURATION OF EXPERIMENT: 6 wk

EXAM. TYPE:  Physical;  bloods and urine
                                       497
                                                                                                                                    498

-------
COMPOUND:   Hydrazine, 1,1-dlmethyl-

            000057147

REFERENCE:   Cornish,  H.H.  and  Earth, M.L.
             Tox.  Appl.  Pharm.  6:568-575, 1964.


OBSERVED NEUROTOXIC EFFECTS:     Tremors  followed by  tonlc-clonic convulsions;
                                increased urinary amino acid excretion, no change
                                of brain sulfhydryl  levels, no observed tissue
                                pathology.
COMPOUND:  Hydrazine, 1,1-dimethyl-

           000057147

REFERENCE:   Rinehart, W.E.,  Donati,  E.  and Greene,  E.A.
             U.S. Army CCRDC  Report CRDLR 3047,  1961.
OBSERVED NEUROTOXIC EFFECTS:
                                 Compound used in guided-missile systems, known
                                 central nervous system stimulant; aim of study
                                 was  to learn MAC for prolonged exposure.  Toxic
                                 effects seen included tremors, convulsions, death.
                                 Mild signs seen in dogs exposed to 5 ppm 26 wk.
                                 No lesions in central nervous system reported.
                                 Conclusion:  MAC for man should be "well below 5 ppm"
                                 and  0.5 ppm was suggested.
ANIMALS:     Rats,  S-D,  M,  225-275 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   60-120 mg/kg; 100 mg/kg was LD   80 mg/kg was dose most
                        used.
ANIMALS:     (1)  60 Mice,  CS1,  F,  20-30 g
             (2)  50 Rats,  Wistar CRDL,  M, 200 g
             (3)  6  Dogs, beagle, M,  11.4 kg

PREPARATION AND DOSE
or HISTORY OF PATIENT:      5-140 ppm of air (12.2-342 mg/ni ) for 6-26 wk
                      (1&2)  140 ppm 6 wk and 75 ppm 7 wk
                      (3)    25  ppm 13 wk and 5 ppm 26 wk.
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:     Mentioned, not described.
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:   Untrtd animals in all experiments
DURATION OF EXPERIMENT:  Up  to  10 d

EXAM.  TYPE:  Behavior, biochemistry, histology
DURATION OF EXPERIMENT:     At least 9 mo.

EXAM. TYPE:  Behavior,  pathology-histology
                                          499
                                                                                                                                       500

-------
COMPOUND:  Hydrazine,  hydrochlorlde
           uydrazine, (aipha-methyiphenethyi;-, hydrochioride
REFERENCE:  Jenney, E.H.  and Pfeiffer, C.C.
            J. Pharm. Exp. Ther.  122:  110-123,  1958.
OBSERVED NEUROTOXIC EFFECTS:     Convulsions
REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced  the effect of Yohimbine
                              and lowered its  lethal dosage.
ANIMALS:    Mice, Harlan, 19-21 g
ANIMALS:
               Mice, IT, M, 18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    2.5 mM/kgm
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q  20  mg/kg
                                                                                                                    ED,n = dose producing a 50% mortality of mice injected
                                                                                                                       S    S.C. with  yohimbine hydrochioride (20 mg/kg).
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:   ns
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
                                        501
                                                                                                                                    502

-------
COMPOUND:  Hydrazine, phenethyl-, hydrochloride
REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
ANIMALS:       Mice, XT, M, 18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q   20 mg/kg
                         ED
                           '50
dose producing a 50% mortality of nice injected
S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:      Various



DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
                                        503
                                                              COMPOUND: Hydrazoic acid

                                                                        007782798

                                                              REFERENCE:   Graham, J.D.P., Rogan,  J.M.  and Robertson,  D.G.
                                                                           J.  Indust. Hyg. Toxicol.  30(2):98-102,  1948.
                                                              OBSERVED NEUROTOXIC EFFECTS:   Respiratory stimulation followed by depression;
                                                                                             generalized convulsion with or without recovery.
                                                                                             Central nervous  system not examined.
                                                                                              ANIMALS:    Mice, Rats, Guinea-pigs, Rabbits (no details)
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:   Lethal and sublethal doses mentioned, no details.
                                                              ROUTE AND SITE:   Inj.,  inhalation.

                                                              CONTROL INFORMATION:    ns.



                                                              DURATION OF EXPERIMENT:   ns.

                                                              EXAM. TYPE: Behavior, body-counts
                                                                                                                                     504

-------
COMPOUND:   Hydrocyanic acid

            000074908

REFERENCE: Ibrahim, M.Z.M. and Levine, S.
           J. Neurol. Neurosurg. Psychiat. 30:  545-555, 1967,
COMPOUND:    Hydrocyanic acid

             000074908

REFERENCE:  Levine, S. and Stypulkowski, W.
            Neurology 9:  407-411, 1959.
OBSERVED NEUROTOXIC EFFECTS: As a result of studies of fixation-artifacts, differ-
                             ences among artifacts were found when rats had been
                             intoxicated with cyanide.  Authors concluded that
                             oligodendroglial proliferation in central nervous
                             system was closely related in time to earliest detectable
                             photomicroscopic changes in myelin produced by the
                             compound.
OBSERVED NEUROTOXIC EFFECTS:   The distribution of hydrogen cyanide lesions  could  be
                              reproduced by ligation alone.  The authors concluded
                              that ischemia was the mechanism of cyanide encephalopathy.
ANIMALS:   27 rats, Lewis, young adult, M & F
ANIMALS:    Rats,  Wistar,  F,  160 or 225 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Exposure to compound for 20-30 min, sacrificed by overdose
                       of same
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposure for 25-35 min in inhalation jars; half of each
                            group given unilateral ligation of common carotid.
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:  7 other rats, untrtd, killed by other methods
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:    Ligation  or  no
DURATION OF EXPERIMENT:   Serial to 80 d

EXAM.  TYPE:  Histology, histochemistry
DURATION OF EXPERIMENT:  About 4 d after exposure

EXAM.  TYPE:   Histology
                                           505
                                                                                                                                       506

-------
COMPOUND:  Hydrogen selenide
           007783075

REFERENCE:   Buchan,  R.F.
             Occup.  Med.  3:439-456,  1947.
                                                           COMPOUND:    Hydrogen sulfide

                                                                        007783064

                                                           REFERENCE:   Adelson,  L.  and Sunshine,  I.
                                                                        Arch.  Path.  81:375-380,  1966.
OBSERVED NEUROTOXIC EFFECTS:   Nausea,  vomiting,  dysgeusia,  dizziness,  lethargy;
                              gradual  recovery over  6 mo. after  removal  of
                              selenium source.
                                                           OBSERVED NEUROTOXIC EFFECTS:     Rapid and complete central nervous system  paralysis,
                                                                                            fatal.
ANIMALS:    Human:   5 case who complained,  selected from 25 exposed industrially
                                                                                         ANIMALS:     Human:   3 M,  ages 21-32
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Exposure not measurable (below 0.2 ppm) because methods
admitted to be insensitive.  Urine av 6.16 meg/100
ml (range 0-13.1).  Source (ink) contained 52 mg/liter
as selenious acid.  Odor identified by investigators.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Industrial exposure to high concentrations of  gas,  probably over
                       0.1-0.2%.
ROUTE AND SITE:   Inhalation,  perhpas other routes too.

CONTROL INFORMATION:  Yes,  but  later found to have been exposed.
                                                           ROUTE AND SITE:   Inhalation

                                                           CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:    About 1 mo.

EXAM. TYPE:   Urinalysis,  clinical
                                                           DURATION OF EXPERIMENT:  Minutes

                                                           EXAM. TYPE:  Autopsy
                                       507
                                                                                                                                    508

-------
 COMPOUND:      Imldazole

               000288324

 REFERENCE:     Nishie, K. , Walss, A.C. and Keyl, A.C.
               Tox. Appl. Pharm. 41:301-307, 1969.
                                                                              COMPOUND:    Imldazole, 1-methyl-

                                                                                          000616477
                                                                             REFERENCE:
               Nishie, K., Waiss, A.C., and Keyl, A.C.
               Tox. Appl. Pharm. 41:301-307, 1969.
OBSERVED NEUROTOXIC EFFECTS:  Convulsions, varying degrees of tremor, opisthotonus
                              and tonic extensor seizures.  Authors note higher
                              pH correspond to lower CD - values.
                                                                             OBSERVED NEUROTOXIC EFFECTS:  Convulsions, varying  degrees  of tremor,  opisthotonus
                                                                                                           and tonic extensor  seizures.   Authors note higher
                                                                                                           pH correspond  to  lower  CD  - values.
ANIMALS:
Mice, albino, M, 20-25 g.
ANIMALS:       Mice, albino, M, 20-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Data reported:
                         CD -- 560 mg/kg I.p., 1880 mg/kg P.O.
                         LD- 610 rag/kg I.P., 1880 mg/kg P.O.
                                                                             PREPARATION AND DOSE
                                                                             or HISTORY OF PATIENT:   Data reported:
                                                                                                      CD   - 380 mg/kg  I.P.,  1400  mg/kg P.O.
                                                                                                      LD " - 380 mg/kg  I.P.,  1400  mg/kg P.O.
ROUTE AND SITE: I.P. and P.O.

CONTROL INFORMATION:      Saline or other parameter
                                                                             ROUTE AND SITE:      I.P.,  P.O.

                                                                             CONTROL INFORMATION:      Saline or other parameter
DURATION OF EXPERIMENT:   Various

EXAM.  TYPE:     Behavior, electrophysiology
                                                                             DURATION OF EXPERIMENT:   Various

                                                                             EXAM.  TYPE:     Behavior, electrophysiology.
                                        509
                                                                                                                                     510

-------
COMPOUND:    Imidazole, 2-methyl-

             000693981

REFERENCE:     Nishie, K., Waiss, A.C. and Keyl, A.C.
               Tox. Appl. Pharm. 41:301-307, 1969.
COMPOUND:     Imidazole, 4-methyl-

              000822366

REFERENCE:     Nishie, K., Waiss, A.C.,  and Keyl,  A.C.
               Tox. Appl. Pharm. 41:301-307,  1969.
OBSERVED NEUROTOXIC EFFECTS:   Convulsions, varying degrees of tremor, opisthotonus
                              and tonic extensor seizures.  Authors note higher
                              pH correspond to lower CD,- values.
OBSERVED NEUROTOXIC EFFECTS:
     (1) Produced convulsions, tremors, opisthotonus
     and tonic extensor seizure.  Authors  report  that
     high pH values correspond to lower  CD,.^  values.
     (2) Tremors at dosages of 100 rag/kg to opisthotonus,
     terminal tonic extensor  seizures at dosages  of
     150 mg/kg.  (3) Produced convulsions.
ANIMALS:
               Mice, albino, M, 20-25 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Data reported:
                         CD   - 500 mg/kg I.P., 1300 mg/kg P.O.
                         IK" - 480 mg/kg I.P., 1400 mg/kg P.O.
ANIMALS:        (1) Mice, albino, M,  20-25  g.
                (2) Chicks,  10  day  old
                (3) Rabbits,  2.3-3  kg,  surgically prepared.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Data reported:
(1) LD50 - 165 mg/kg I.P., 370 mg/kg P.O.
    CD5Q - 155 mg/kg I.P., 360 mg/kg P.O.
(2) LD50 - 210 mg/kg I.P., 174 mg/kg P.O.
(3) 50 - 180 mg/kg I.P. for anticonvulsant  testing
ROUTE AND SITE:      l.p. and P.O.

CONTROL INFORMATION:      Saline or other parameter.
ROUTE AND SITE:      (1) I.P., P.O.   (2)  I.P.,  P.O.   (3)  I.P.

CONTROL INFORMATION:     Saline or other parameter
DURATION OF EXPERIMENT:   Various

EXAM.  TYPE:     Behavior, electrophysiology.
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology
                                        511
                                                                                                                                     512

-------
 COMPOUND:   2-Imidazoline-2-bentyl-hydrochloride
REFERENCE:     Quinton,  R.M.
               Br. J. Pharmac.  21:51-66,  1963.


OBSERVED NEUROTOXIC EFFECTS:  The  compound  enhanced the effect of Yohlmbine
                              and  lowered its lethal dosage.
COMPOUND:    1H -Indazole, l-benzyl-3(3-(dimethylamino)propoxy)-

             000642728

REFERENCE:   Silvestrini,  B., Barcellona, P.S.,  Gabau,  A.  and Catanese,  B.
             Tox. Appl. Pharm. 10:148-159,  1967.
OBSERVED NEUROTOXIC EFFECTS:
                                Therapeutic effects  of muscle  relaxation and sedation
                                at 0.7-1 mg/kg  in man.  Ataxia and  convulsions
                                in mice, rats,  rabbits,.cats near LDso levels (33
                                mg/kg  I.V. to >1000  mg/kg orally);  dogs vomited
                                at lower dosages.
ANIMALS:
               Mice, TT, M, 18-25 g.
                                                                                          ANIMALS:
                                                                                                       (1)  Mice and Rats
                                                                                                       (2)  Mice,  rats,  rabbits,  cats,  dogs
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED
                           '5Q    27 mg/kg

                          D,- •»  dose producing a  50% mortality  of  mice injected
                                 S.C. with yohimbine hydrochloride  (20  mg/kg).
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:      Various
PRFPARATTflN AND
or HlS OF PAENT:
                            (1) A<=«te:  Mouse LD5Q  -  33  mg/kg for  I.V.,  110 mg/kg for

                       "" ™ ^  f°*  *£•'  «£  5" mg/kf f°r °^   Rat
                       100 mg/kg for I. P.,  1050 mg/kg for  oral.
                            (2) General effects  (convulsions, incoordination) :
                               Mouse:  100 mg/kg I. P.,  400  mg/kg  oral.
 Cat:   25-50 mg/kg  I. P.         Rat:    50  mg/kg  I. P., 400-800 mg/kg oral.
 Dog:   50 mg/kg oral.          Rabbit:  5 mg/kg I.V.
ROUTE AND SITE:  Diet,  oral  dosage, gavage, I. P., I.V.

CONTROL INFORMATION:    Various
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:     Varied

EXAM.  TYPE:   Clinical, pathological, immunological,  reproductive.
                                         513
                                                                                                                                     514

-------
COMPOUND:   Indole, 3-(2-aminobutyl)-,  monoacetate

            000118683

REFERENCE:  Gray,  J.E., McWade, D.H., Johnston, R.L., Larson, E.J. and Freyburger, W.A.
            Tox. Appl. Pharm. 4:547-560, 1962.
OBSERVED NEUROTOXIC EFFECTS:
                                Stimulated central nervous system of dogs when
                                dose is greater than 100 mg/kg.  LD5Q value in
                                mice following intraperitoneal administration is
                                72 mg/kg and 49 mg/kg orally in rats.
ANIMALS:    Rats,  S-D and Wistar, M and F.
            Mice
            Dogs,  beagle
            Rabbits
PREPARATION AND DOSE
or HISTORY OF  PATIENT:      Acute, subacute and reproductive studies various levels
                           and schedules.
COMPOUND:   Indole, 3-(2-aminoethyl)-5,6-dihydroxy-
REFERENCE:   Baumgarten,  H.G.,  Evetts,  K.D.,  Holman,  R.B.,  Iversen, L.L.,
             Vogt,  M.  and Wilson,  G.  and Vogt and Wilson,  ibid. 19:1599-1600, 1972.
             J.  Neurochem.  19:1587-1597, 1972.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                 Serotonin (5-HT)  depleted for several d but normal
                                 after  2 mo.   Most effect near injection site and
                                 in cord; some permanent atrophy of septum and
                                 caudate.  No loss of noreplnephrine, dopamine,
                                 or tyrosine  hydroxylase activity.  5,6-HT inhibited
                                 uptake of 5-HT by brain slices more than of catecholamines
                                 Severely toxic doses caused losses of tyrosine
                                 hydroxylase  and catecholamines.
                                 The second paper gives normal levels of 5-HT and
                                 5-hydroxyindoleacetic acid.
ANIMALS:     (1)  Rats,  Wistar,  M and F,  200 g
             (2)  Rats,  Wistar,  F, 180-250 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            50 meg by one of two methods
ROUTE AND SITE:    Oral,  gavage,  I.P., I.M.

CONTROL INFORMATION:        Various
ROUTE AND SITE:   Injected into lateral ventricle

CONTROL INFORMATION:   Vehicle given
DURATION OF EXPERIMENT:     Various

EXAM.  TYPE:  Biochemistry,  physiology
DURATION OF EXPERIMENT:     68 d

EXAM. TYPE:  Biochemistry
                                          515
                                                                                                                                       516

-------
COMPOUND:   Indole,  3-(2-aminoethyl)-5,6-dihydroxy-
                                                                                        COMPOUND:   Indole, 3-(2-aminoethyl)-5,6-dihydroxy-
REFERENCE:   Baumgarten, H.G., Lachenmayer, L., Bjorklund, A., Nobin, A., and
             Rosengren, E.
             Life Sci. 12(1): 357-364, 1973.

OBSERVED NEUROTOXIC EFFECTS:   SHT in brain and cord depleted for 2 wk, brain
     5HT gradually recovered by 2-4 mo., some overshoots in septum hypothamalmus;
     no recovery within 6 mo in cord.  Cited literature to interpret regeneration
     of serotonin axon lesions by treatment (authors).
REFERENCE'   Richardson,  J.S.,  Cowan,N.,  Hartman,  R.  and Jacobowitz, D.M.
             Res.  Comm.  Chem. Path.  Pharm.  8(l):29-44, 1974.
OBSERVED NEUROTOXIC EFFECTS:
     Lowered serotonin; in combination with 6-hydroxydopa
     lowered norepinephrine and serotonin; no effect
     on dopamine.   Other complex effects reported, and
     the causes speculated to be selective destruction
     of noradrenergic and/or serotonergic nerve
     terminals.
ANIMALS:   Rats, Wistar AF HAN, M, 180-200 g
                                                                                        ANIMALS:     Rats, S-D, M, 180-220 g, 5-12/group
PREPARATION AND DOSE
or HISTORY OF PATIENT:   75 meg/rat of free base (creatinine sulfate -H20
                        complex) one dose.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
50 meg/rat
ROUTE AND SITE:    Inj, lateral ventricle

CONTROL INFORMATION:    Age-matched controls
ROUTE AND SITE:    Intraventricular

CONTROL INFORMATION:    Vehicle
DURATION OF EXPERIMENT:   Serial sacr 10 d to 6 mo after injection.

EXAM.  TYPE:   Biochemical
DURATION OF EXPERIMENT:      14 d

EXAM.  TYPE:  Behavior
                                       517
                                                                                                                                   518

-------
COMPOUND:
            Ir.dole, 3-(2-aminoethyl)-5,7-dihydroxy-
                                                                                              COMPOUND:
                                                                                                          Indole,  3-(2-aminoethyl)-5-methoxy-
REFERENCE:     Baumgarten, H.G., Victor, S.J. and Lovenberg,  W.
              J. Neurochem. 21:251-253, 1973.
OBSERVED NEUROTOXIC EFFECTS:
Progressive depletion of tryptophan hydroxylase
in brain and cord.   Degeneration of serotonergic
neurons.  Less potent than 5,6-DDT, but damage
apparently greater  and more specific.   Animals
sedated for a few hr but then became
hyperactive and pugnacious.
                                                              REFERENCE:   Rivier, L. and Lindgren, J-E.
                                                                           Econ. Bot. 26:  101-129, 1972.
                                                                                              OBSERVED NEUROTOXIC EFFECTS:   Hallucinatory (visual)
ANIMALS:       Rats, Wistar, M, 150-200 g.
                                                                                              ANIMALS:
                                                                                                          Humans:  anecdotal and  personal experiences
PREPARATION AND DOSE
or HISTORY OF PATIENT:     150 meg/rat of free base equivalent in saline and
                          ascorbic acid.
ROUTE AND SITE:   Intraventricular

CONTROL INFORMATION:       Vehicle only
                                                              PREPARATION AND  DOSE
                                                              or HISTORY OF  PATIENT:
                                                                                       Identification and quantisation analyses, still not complete
                                                                                       as reported, indicate  that  200 ml of drink (normal dose)
                                                                                       includes 30 mg hannine,  10  mg TH-harmine and 25 mg DMT
                                                                                       (relative amounts in separate ingredients found to be
                                                                                       different), taken up to  10  times/mo or more.
                                                              ROUTE AND SITE:   oral

                                                              CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:    2  and  12 d

EXAM. TYPE:    Behavior,  biochemistry
                                                              DURATION OF EXPERIMENT:   Expedition, duration ns

                                                              EXAM. TYPE:    Behavior, analytical chemistry
                                           519
                                                                                                                                      520

-------
COMPOUND:
             Indole, 3-(2-aminoethyl)-6-methoxy-
COMPOUND:
                                                                                                      Indole,  3-(2-aminopropyl)-,  acetate
REFERENCE:  Rivier, L. and Lindgren, J-E.
            Econ. Bot. 26:  101-129, 1972.
REFERENCE:   Gray, J.E., McWade, D.H., Johnston,  R.L.,  Larson, E.J. and Freyburger, W.A.
            Tox. Appl. Pharm. 4:547-560,  1962.
OBSERVED NEUROTOXIC EFFECTS:   Hallucinatory (visual)
OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                          Stimulated central nervous system of dogs when dose
                                                                                                                          is greater than 100 mg/kg.  Signs of intoxication
                                                                                                                          subsided after second day.  U>50 value in mice is
                                                                                                                          38 mg/kg I.P. and 22 mg/kg orally in rats.
ANIMALS:
            Humans:  anecdotal and personal experiences
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                        Identification and quantitation analyses, still not  complete
                        as reported, indicate that  200 ml of drink  (normal dose)
                        includes 30 mg harmine, 10  mg TH-harmine and  25 mg DMT
                        (relative amounts in separate ingredients found to be
                        different), taken up to 10  times/mo or more.
ROUTE AND SITE:   oral

CONTROL INFORMATION:   None
ANIMALS:      Bats,  S-D  and Wistar,  M and F.
             Mice
             Dogs,  beagle
             Rabbits
PREPARATION AND DOSE
or HISTORY OF PATIENT:       Acute,  subacute and reproductive studies various levels
                            and schedules.
ROUTE AND SITE:    Oral,  gavage,  I.P.,  I.M.

CONTROL INFORMATION:        Various
DURATION OF EXPERIMENT:   Expedition, duration ns

EXAM. TYPE:   Behavior, analytical chemistry
DURATION OF EXPERIMENT:     Various

EXAM. TYPE:  Biochemistry, physiology
                                         521
                                                                                                                                     522

-------
COMPOUND:
             Indole, 3-(2-(dibutylamino)ethyl)-
REFERENCE:   Szara,  S.
            Biochem. Pharm.  8:   32,  1961.
                                                                                            COMPOUND:   Indole, 3-(2-(diethylamino)  ethyl)-

                                                                                                        000061518

                                                                                            REFERENCE:  Szara,  S.
                                                                                                        Biochem.  Pharm.  8:   32,  1961.
OBSERVED NEUROTOXIC EFFECTS:
                              Treatment  caused  disturbances of  the autonomlc,  emotional
                              perceptual and  thinking  systems,  dependent  on  the  6-
                              hydroxylation rate  in  liver; dealkylation,  for instance,
                              produced inactive metabolites.  Thus diethyl,  dimethyl,
                              and  dlpropyl homologs  were active, while dibutyl was
                              barely active,  and  dihexyl was inactive.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                          Treatment caused disturbances of the autonotnic, emotional,
                                                                                                                          perceptual and thinking systems, dependent on the 6-
                                                                                                                          hydroxylation rate in liver; dealkylation, for instance,
                                                                                                                          produced inactive metabolites.  Thus diethyl, dimethyl,
                                                                                                                          and dipropyl homologs were active, while dibutyl was
                                                                                                                          barely active, and dihexyl was inactive.
ANIMALS:    Human
                                                                                            ANIMALS:    Human
PREPARATION AND DC'E
or HISTORY OF PATIENT:    1 mg/kg
                                                                                            PREPARATION AND DOSE
                                                                                            or HISTORY OF PATIENT:   1 mg/kg
ROUTE AND SITE:   ns

CONTROL INFORMATION:   ns
                                                                                            ROUTE AND SITE:   ns

                                                                                            CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:      ns
                                                                                            DURATION OF EXPERIMENT:    ns

                                                                                            EXAM. TYPE:      ns
                                           523
                                                                                                                                       524

-------
COMPOUND:   Indole,  3-(2-dihexylaminoethyl)-
REFERENCE:  Szara,  S.
            Biochem.  Pharm.  8:   32,  1961.
COMPOUND:    Indole, 3-(2-dimethylaminoethyl)-

            000061507

REFERENCE:   Gallagher,  C.H.,  Koch, J.H. and Hoffman,  H.
            Int.  J.  Neuropharmacol.  6:  223-228,  1967.
OBSERVED NEUROTOXIC EFFECTS:
                              Treatment  caused  disturbances of  the autonomic,  emotional,
                              perceptual and  thinking  systems,  dependent  on  the  6-
                              hydroxylation rate  in  liver; dealkylation,  for instance,
                              produced inactive metabolites.  Thus diethyl,  dimethyl,
                              and dipropyl homologs  were active, while dibutyl was
                              barely active,  and  dihexyl was inactive.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                              Convulsions,  spasms.   The authors showed that the
                              convulsions originated in the brain and that the
                              spasms  originated in  the spinal cord.
ANIMALS:   Human
ANIMALS:     Sheep,  surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1 mg/kg
ROUTE AND SITE:   ns

CONTROL INFORMATION:   ns
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Dimethyl tryptamine (1) and 5-methoxydimethyltryptamine (2)
were administered as HC1 derivatives; 5-hydroxydimethyltrypt-
amine (3) as a bioxalate derivative.  0.05-0.1 mg/kg of each,
mixed, or 0.05-0.1 mg/kg of"^(2), or 0.25-0.5 mg/kg of (3)
were equivalent doses.  One sheep that was poisoned while
grazing was obtained.
ROUTE AND SITE:    I.V.,  jugular; oral.

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:    ns

EXAM. TYPE:     ns
DURATION OF EXPERIMENT:    Various

EXAM.  TYPE:   Electrophysiology, pharmacology
                                          525
                                                                                                                                      526

-------
COMPOUND:   Indole, 3-(2-dimethylaminoethyl)-

            000061507

REFERENCE:  Rivier, L. and Lindgren,  J-E.
            Econ. Bot. 26:  101-129,  1972.


OBSERVED NEUROTOXIC EFFECTS:   Hallucinatory (visual)
COMPOUND:   Indole,  3-(2-dimethylaminoethyl)-

            000061507

REFERENCE:  Szara, S.
            Biochem. Pharm. 8:  32, 1961.
OBSERVED NEUROTOXIC EFFECTS:
Treatment caused disturbances  of  the autonomic, emotional,
perceptual and thinking  systems,  dependent on the 6-
hydroxylation rate in  liver; dealkylation, for instance,
produced inactive metabolites.  Thus diethyl, dimethyl,
and dipropyl homologs  were  active,  while dibutyl was
barely active, and dihexyl  was inactive.
ANIMALS:
            Humans:  anecdotal and personal experiences
                                                                                        ANIMALS:    Human
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                        Identification and quantitation analyses,  still  not  complete
                        as reported, indicate that 200  ml  of  drink (normal dose)
                        includes 30 mg harmine,  10 mg TH-harmine and  25  mg DMT
                        (relative amounts in separate ingredients  found  to be
                        different), taken up to  10 times/mo or more.
ROUTE AND SITE:   oral

CONTROL INFORMATION:   None
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1 mg/kg
ROUTE AND SITE:   ns

CONTROL  INFORMATION:   ns
DURATION OF EXPERIMENT:   Expedition, duration ns

EXAM. TYPE:   Behavior, analytical chemistry
DURATION OF  EXPERIMENT:    ns

EXAM. TYPE:      ns
                                        527
                                                                                                                                    528

-------
COMPOUND:  Indole,  3-(2-(dimethylamino)ethyl)-5-methoxy-

                 (5-methoxydimethyltryptamlne)


REFERENCE:   Gallagher,  C.H.,  Koch,  J.H. and Hoffman, H.
            Int.  J. Neuropharmacol.  6:  223-228, 1967.
                                                                  COMPOUND:  Indole, 3-(2-dlpropyl amlno)ethyl)-

                                                                             000061529

                                                                  REFERENCE:  Szara, S.
                                                                              Biochem.  Pharm. 8:   32,  1961,
OBSERVED NEUROTOXIC EFFECTS:
    Convulsions, spasms.  The authors showed that the
    convulsions originated in the brain and that the
    spasms originated in the spinal cord.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                         Treatment caused disturbances  of  the autonomic,  emotional,
                                                                                                                         perceptual and thinking systems,  dependent on the 6-
                                                                                                                         hydroxylation rate in  liver; dealkylation, for instance,
                                                                                                                         produced inactive metabolites.  Thus diethyl, dimethyl,
                                                                                                                         and dipropyl homologs were active,  while dibutyl was
                                                                                                                         barely active, and dihexyl was inactive.
ANIMALS:    Sheep,  surgically prepared
                                                                                           ANIMALS:    Human
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Dimethyl tryptamine (1) and 5-methoxydimethyltryptamine (2)
were administered as HC1 derivatives; 5-hydroxydimethy1trypt-
amine (3) as a bioxalate derivative.  0.05-0:1 mg/kg of each,
mixed, or 0.05-0.1 mg/kg of (2), or 0.25-0.5 mg/kg of (3)
were equivalent doses.  One sheep that was poisoned while
grazing was obtained.
ROUTE AND SITE:    I.V.,  jugular; oral.

CONTROL INFORMATION:  ns
PREPARATION AND DOSE
or HISTORY OF PATIENT:   l mg/kg
                                                                  ROUTE AND SITE:  ns

                                                                  CONTROL INFORMATION:    ns
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:   Electrophysiology, pharmacology
                                                                  DURATION OF EXPERIMENT:   ns

                                                                  EXAM. TYPE:     ns
                                           529
                                                                                                                                      530

-------
COMPOUND:
            Indol-5-ol-3-02-(dimethylamino)ethylo-

             0000487934
REFERENCE:   Gallagher,  C.H., Koch, J.H. and Hoffman, H.
            Int.  J.  Neuropharmacol. 6:  223-228, 1967.
                                                                 COMPOUND:   Indol-4-ol,  3(2-(dimethyl amino)ethyl)-
                                                                             000520536
                                                                 REFERENCE:  Horita,  A.  and Weber,  L.J.
                                                                             Tox.  Appl.  Phann.  4:   730-737, 1962.
                                                     (Psylocin)
OBSERVED NEUROTOXIC EFFECTS:  Convulsions, spasms.  The authors showed that the
                             convulsions originated in the brain and that the
                             spasms originated in the spinal cord.
                                                                 OBSERVED NEUROTOXIC EFFECTS:
                             After administration  of psilocybin,  psylocin (4-hydroxy
                             analog of  psilocybin)  appeared in tissues including
                             brain, brain  peak 25-30 min after dose.  Piloerection,
                             exophthalmos,  motor incoordination followed brain levels
                             of psylocin.   Pretreatment with B-glycerophosphate did
                             not  alter  distribution of psylocin nor behavior.
                             Interpreted  to mean that psilocybin was rapidly dephos-
                             phorylated,  and central nervous system effects exerted
                             by the psylocin metabolite.
ANIMALS:    Sheep, surgically prepared
                                                                 ANIMALS:    Mice,  albino, 25-35g, 6/group
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Dimethyl tryptamine (1) and 5-methoxydimethyltryptamine (2)
were administered as HC1 derivatives;  5-hydroxydimethyltrypt-
amine (3) as a bioxalate derivative.  0.05-0.1 mg/kg of each,
mixed, or 0.05-0.1 mg/kg of (2),  or 0.25-0.5 mg/kg of (3)
were equivalent doses.   One sheep that was poisoned while
grazing was obtained.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                   100 mg/kg, equalling 0.35 mmole/kg
ROUTE AND SITE:   I.V., jugular; oral.

CONTROL INFORMATION:  ns
                                                                 ROUTE AND  SITE:   I.P.

                                                                 CONTROL  INFORMATION:  "Normal mice", details ns
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:   Electrophysiology, pharmacology
                                                                 DURATION OF  EXPERIMENT:   Serial to 30 min

                                                                 EXAM. TYPE:   Biochemistry, behavior
                                          531
                                                                                                                                      532

-------
COMPOUND'   Indol-4-ol, 3-(2-(dimethylamino)ethyl)-, dihydrogen phosphate  (Psilocybln)

            000520525


REFERENCE: Horita, A. and Weber, L.J.
           Tox. Appl. Pharm. 4:  730-737, 1962.


OBSERVED NEUROTOXIC EFFECTS:  After administration of psilocybin, psylocin (4-hydroxy
                             analog of psilocybin) appeared in tissues including
                             brain, brain peak 25-30 min after dose.  Piloerection,
                             exophthalmos, motor incoordination followed brain levels
                             of psylocin.  Pretreatment with B-glycerophosphate did
                             not alter distribution of psylocin nor behavior.
                             Interpreted to mean that psilocybin was rapidly dephos-
                             phorylated, and central nervous system effects exerted
                             by the psylocin metabolite.
COMPOUND:    Indol-4-ol,  3-(2-(dimethylamino)ethyl)-, dihydrogen phosphate

             000520525


REFERENCE:  Spooner, C.E. and Winters, W.D.
            Int. J. Neuropharmacol. 5:   217-236,  1966


OBSERVED NEUROTOXIC EFFECTS:  compound produced excitement, abnormal postures,
                 :             arousal EEGs, then depression.
ANIMALS:   Mice, albino, 25-35g, 6/group
                                                                                            ANIMALS:    200 Cockerels, White Leghorn,  ages 5-14 d, 45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   72 mg/kg, equalling 0.35 mmole/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1-50 mg/kg
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:  "Normal mice", details ns
ROUTE AND SITE:   s.C.  near axillary vein; I.P. for doses over  0.05  ml

CONTROL INFORMATION: ns
DURATION OF EXPERIMENT:   Serial to 30 min

EXAM. TYPE:   Biochemistry, behavior
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Behavior,  EEC
                                           533
                                                                                                                                       534

-------
COMPOUND:
             Isocyanic acid,  p-bromophenyl ester
                                                                                           COMPOUND:  Isoglutamlne, L-
REFERENCE:  Lessel, B. and Towlerton, R.G.
            Fd. Cosmet. Toxicol. 5:741-743,  1967.
                                                                REFERENCE:   Curtis, D.R. and Watkins, J.C.
                                                                            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
     Swaying gait,  ataxia, weak hindlimbs, and swelling-
     degeneration of  the axons.  Demyelination of spinal
     cord.   Neuronal  degeneration.  Death.  Spinal
     cord lesions.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                Treatment  caused excitation or depression of
                                neuronal activity.   Excitatory ranking:  glutamic,
                                B-aminoglutaric, aspartic, cysteic, cysteine-
                                sulfinic acids,  B-hydroxyglutamic, N-methylaspartic,
                                N-formiminoaspartlc acids.
                                Depressant ranking:  6-alanine, GABA, taurine,
                                N-methyl-6-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, jJ-aminoisobutyric
                                acids.
                                Structure-activity  relationships established.
ANIMALS:    16 Lambs, 8 wk, 19-24 kg.
                                                                                           ANIMALS:
                                                                            Cats, surgically prepared to exposed motoneurones,  Renshaw cells or
                                                                            dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
150-200 mg/kg/d.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:
                                                                ROUTE AND  SITE:   Topical, ionophoresis

                                                                CONTROL  INFORMATION:   Laboratory
DURATION OF EXPERIMENT:

EXAM.  TYPE:  Dissection
Sacr.
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry,  electrophysiology
                                          535
                                                                                                                                      536

-------
COMPOUND:  Isonicotinic acid,  2-(2-(benzylcarbamoyl)ethyl)hydrazide

           Q00051127

REFERENCE:     Quinton, R.M.
               Br. J. Phannac. 21:51-66, 1963.
                                                         COMPOUND:  Isonicotinic acid, hydrazlde

                                                                    000054853

                                                         REFERENCE: Alder,  S.  and  Zbinden,  G.
                                                                    Agents  and Actions  3/4:   233-243,  1973,
OBSERVED NEUROTOXIC EFFECTS:   The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
                                                         OBSERVED NEUROTOXIC EFFECTS:
Water intake increased at weekends  (no dose given),
normal during treatment.  In Hot Plate Test, delayed
response; in Foot Print Test, gait not altered;  in
Rotating Rod Test performance impaired in some rats.
All rats had peripheral neuropathy after 5 d, all
doses:  degenerative changes, especially of myelin.
Brain and cord no changes.  Thymus moderate atrophy
with 600 mg/kg.
ANIMALS:
               Mice, TT, M, 18-25 g.
                                                                                          ANIMALS:    Rats,  CFN Zu, F.  38-53g,  6 groups of 8-10 each.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q    9 mg/kg
                         ED
                           50
dose producing a 50% mortality of mice injected
S.C. with yohimbine hydrochloride (20 mg/kg).
                                                         PREPARATION AND DOSE
                                                         or HISTORY OF PATIENT:  200,  400,  600  mg/kg,  5d/wk,  for 5-26 doses.
ROUTE AND SITE:      S.C., Oral

CONTROL INFORMATION:      Various
                                                          ROUTE AND SITE:   Oral

                                                          CONTROL  INFORMATION:   6  groups  given water orally.
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
                                                          DURATION OF EXPERIMENT:   Serial  sacr  1-5 wk.

                                                          EXAM. TYPE:   Behavior,  histology
                                         537
                                                                                                                                     538

-------
COMPOUND:   Isonicotinic  acid, hydrazlde

            000054853

REFERENCE:    Botta,  J.A.,  Jr. and Carlton, W.W.
              Tox.  Appl.  Pharm.  11:35-48,  1967.
OBSERVED NEUROTOXIC EFFECTS:  Excitement,  ataxia,  convulsions;  cerebellar  lesions.
                             Dose-relationships with  symptoms  and  pathology
                             are explored.
ANIMALS:      Drakes, Pekin and Rouen, 30-36 hr old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.1-6.3% in diet; 40-1250 mg/kg/d i.p.  7 d;  0.001-0.1%
                        in diet.
ROUTE AND SITE:   Oral, I.P.

CONTROL INFORMATION:     Untreated



DURATION OF EXPERIMENT: Up to 3 mo. or more.

EXAM. TYPE:   Mortality, behavior, pathology
                                       539
COMPOUND:  Isonicotinic acid,  hydrazide

           000054853

REFERENCE:   Carlton,  W.W.  and Kreutzberg, G.
             Am.  J.  Path.  48:91-98, 1966.


OBSERVED NEUROTOXIC EFFECTS:   Tremors, ataxia.  Spongy degeneration  (vacuoles,
     demyelination)  in cerebellar white matter, also in optic lobe, hemispheres,
     cord.   Local axonal degeneration, proliferation of glia, edema of astrocytes.
     No protection from pyridoxal.
ANIMALS:     Drakes, Pekin, day-old, 4 grps of 10, 3 grps treated.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1 g/kg in diet with 0, 0.2, 1 g/kg of pyridoxal hydro-
     chloride.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:     1 group untreated.



DURATION OF EXPERIMENT:  4 wk.

EXAM. TYPE:  Behavior, histology
                                                                                                                                   540

-------
COMPOUND:  Isonicotinic  acid, hydrazide

           000054853

REFERENCE:   Carlton,  W.W.
             Avian Dis.  11:241-254,  1967.
COMPOUND:  Isonicotinic  acid, hydrazide

           000054853

REFERENCE:   Cavanagh, J.B.
             J.  Neurol.  Neurosurg.  Psychiat.  30:26-33,  1967.
OBSERVED NEUROTOXIC EFFECTS:   Neuropathy (taxia,  tremor,  convulsions)  severe
     only with 0.15 and 0.30% feeding.   Central Nervous  System spongy  degeneration
     especially in cerebellar medulla,  less  in medulla oblongata, optic  lobes
     and cord.   No protection if  0.2% pyridoxine  was  fed.   Growth depressed in  all,
     mortality 25-85% dose-related.
OBSERVED NEUROTOXIC EFFECTS:    Weakness and wasting of hindlimb muscles, varying
    degrees.   Denervation  of mainly motor,  also sensory nerves in distal muscles,
    medium  sized fibers specially.   Pattern like that in acute intermittent
    porphyria  in man,  unlike that from organophosphourses.
ANIMALS:   Chicks:   broiler stock,  M,  day-old,  grps of  20.
ANIMALS:     Rats,  Wistar, M,  270-300 g (12), av.  68 g (12), av. 73 g (8).
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.05-0.30% of diet.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   250 mg/kg/d in diet or in two doses B.C.
ROUTE AND SITE:  oral

CONTROL INFORMATION:     Diet only
ROUTE AND SITE:  Oral or s.c.

CONTROL INFORMATION:   None  reported
DURATION OF EXPERIMENT:  8 wk

EXAM. TYPE:  Behavior,  histology
DURATION OF EXPERIMENT:  Serial sacr to 12 wk

EXAM. TYPE:  Behavior,  histology
                                       541
                                                                                                                                   542

-------
COMPOUND:   Isonicotinlc acid, hydrazide

           000054853

REFERENCE:    Gammon,  G.D.,  Burge, F.W. and King, G.
             Arch.  Neurol.  Psychiat.  70:64-69, 1953.


OBSERVED NEUROTOXIC EFFECTS:    Signs  of peripheral neuropathy, regressed on
     stopping the drug.   Inducing dose 4.5-13.5 mg/kg, "in the range in which
     toxicity is to be excepted."
ANIMALS:     Human:   14 cases  selected  from 46  "with similar complaints" in
     a series of 408 treated with isoniazid.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    300-700 mg/d,  duration ns.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:      ns.



DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  Clinical
                                       543
COMPOUND:  Isonicotinic acid,  hydrazide

           000054853

REFERENCE:  Hildebrand, J., Joffroy, A. and Goers, C.
            Arch. Neurol. 19:60-70, 1968.


OBSERVED NEUROTOXIC EFFECTS:  At 3 d, 10% of sciatic nerve  fibers  damaged and
     conduction reduced; at 7 d myelin disruped  in 32% of fibers,  axonal
     fragmentation, collateral sprouting of subterminal  fibers,  altered
     muscle action potentials; at 13 d 76% of  fibers damaged,  slower  motor
     condution, large group atrophy of muscles.  After 37 d of no  treatment
     much nerve damage persisted, no recovery  of muscles.   Collateral
     branching explained continued motor activity.
ANIMALS:  19 Rats, S-D, M, Age 3 mo.  260-300  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:  90 mg/rat/d,  3-13  d
ROUTE AND SITE:    i.e.

CONTROL INFORMATION:  23 Matched rats,  280-320 g



DURATION OF EXPERIMENT:   Sacr after  4-50 d observation

EXAM. TYPE:  Electrophysiology, histology
                                                                                                                                   544

-------
COMPOUND:    Isonicotinic  acid, hydrazide

             000054853

REFERENCE:   Jenney,  E.H.  and Pfeiffer, C.C.
             J.  Pharm.  Exp.  Ther.  122:  110-123, 1958.
COMPOUND:  Isonicotinic  acid, hydrazide

           000054853

REFERENCE:  Jones, W.A.  and Jones, G.P.
            Lancet:1073-1074,  1953.
OBSERVED NEUROTOXIC EFFECTS:    Convulsions
                                                                                              OBSERVED NEUROTOXIC EFFECTS:   Polyneuropathy of limbs,  resembling pellagra and
                                                                                                  attributed to competitive inhibition of nicotinic acid and perhaps other
                                                                                                  B-vitamins by the drug.
ANIMALS:    Mice, Harlan,  19-21  g
ANIMALS:   Human:  2 case-reports, M aged 23 and F aged 18
PREPARATION AND DOSE
or HISTORY OF PATIENT:   l.i mM/kgm
PREPARATION AND DOSE
or HISTORY OF PATIENT:  (1) 300 mg/d (5 mg/kg/d) for over 6 wk, admitted to
                            hospital 4 wk after treatment ended.
                        (2) 450 mg/d (12 mg/kg/d) for 3 mo., repeated after
                            4 mo. interval, admitted 2 wk later.
ROUTE AND SITE:   I.P., i.v.

CONTROL INFORMATION:  ns
ROUTE AND SITE:   Oral

CONTROL INFORMATION: None
DURATION OF EXPERIMENT:  Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:  (1) 1 mo. observation, (2) 3 wk.

EXAM. TYPE:  clinical
                                         545
                                                                                                                                     546

-------
COMPOUND:       Isonicotinic acid, hydrazlde

                000054853

REFERENCE:   Noel,  P.R.B.,  Worden,  A.N.  and Palmer,  A.C.
             Tox.  Appl.  Pharm.  10:183-198,  1967.
OBSERVED NEUROTOXIC EFFECTS:  No constant evidence of peripheral  nervous  system
                              damage.   Brain damage mainly  due to subcortical
                              myelin of hemispheres, considered edematous.
COMPOUND: Isonicotinic acid, hydrazide

          000054853

REFERENCE:  Ochoa, J.
            Brain 93:831-850, 1970.
OBSERVED NEUROTOXIC EFFECTS:  Peripheral neuropathy;  sural  nerves  myelinated
    and unmyelinated fibers were damaged, with differences;  regeneration and
    degeneration of regenerated fibers were seen.
ANIMALS:
             12 Dogs, Pembroke Corgi, 6M,  6F
                                                                                                 ANIMALS:     9  Humans,  M and F,  aged 35-70 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  25 or 50 mg/kg/d in gelatin capsules,  6d/wk.
                       High dose reduced to 40 mg/kg due to convulsions,  and
                       then both groups reduced to 5 or 25  mg.   Continued
                       treatment resulted in death, so 25 mg/kg reduced to 15 mg/kg.


ROUTE AND SITE:  Oral

CONTROL INFORMATION:   6 undosed controls.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  300-500 mg/d; 1 patient  given 2  g/d for 5 d in error.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:   195 d

EXAM. TYPE:   Clinical, biochemistry, autopsy
DURATION OF EXPERIMENT:  Up to about  3 yr.

EXAM. TYPE:   Clinical and lab, histology  (biopsy)
                                           547
                                                                                                                                        548

-------
COMPOUND:  Isonicotinic acid, hydrazide

           000054853

REFERENCE: Palmer, A.C. and Noel, P.R.B.
           Nature 205:506-507, 1965.
OBSERVED NEUROTOXIC EFFECTS:     Seperation of fibers  in subcortical rayelin,
                                ballooning, but axons intact, activation of
                                microglia and hypertrophy of astrocytes.
                                                                       COMPOUND:  Isonicotinic acid, hydrazide

                                                                                 000054853

                                                                       REFERENCE:   Ramakrishna,  T.  and  Smith,  B.H.
                                                                                   Neurology  20:1142-1145,  1970.


                                                                       OBSERVED NEUROTOXIC EFFECTS:  Generalized  convulsions, abnormal EEC.
ANIMALS:    Dogs
                                                                                                ANIMALS:   Human:  2 case-reports  (F, 14 yr; F,  22 yr)
PREPARATION AND DOSE
or HISTORY OF PATIENT:
5 or 15 mg/kg/d for up to 6 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Two attempted suicides:  2.4 g and about  5  g,  single doses
     (50 and 93 mg/kg)
ROUTE AND SITE:   Oral

CONTROL INFORMATION:       Control dogs,  no details.
                                                                       ROUTE AND SITE:      Oral

                                                                       CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:    Up to 6 mo.

EXAM. TYPE:   Histology
                                                                       DURATION OF EXPERIMENT:    ns.

                                                                       EXAM.  TYPE:     Clinical,  EEC
                                           549
                                                                                                                                       550

-------
COMPOUND:  Isonicotinic acid, hydrazide

           000054853

REFERENCE:   Schlaepfer, W.W. and Hager, H.
             Am.  J.  Path.  45:209-216, 1964.


OBSERVED NEUROTOXIC EFFECTS:   Primary axonal degeneration with swelled mitochon-
     dria in  peripheral nerves;  changes  in axoplasm.
COMPOUND:   Isonicotinic acid,  hydrazide

            000054853

REFERENCE:   Schlaepfer, W.W. and Hager, H.
             Am. J. Path. 45:423-430, 1964.
OBSERVED NEUROTOXIC EFFECTS:   Specific report on breakdown of myelin.   Collapse
     of cylinder, myelin globules formed within Schwann cell cytoplasm with reactive
     changes and phagosome-like vacuoles; products transferred to  macrophages.
ANIMALS:     20 rats,  S-D,  F,  250-400  g
                                                                                            ANIMALS:      20 rats, S-D, F
PREPARATION AND DOSE
or HISTORY OF PATIENT:    250 mg/kg/d  for  6-16 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   350 mg/kg/d for 6-16 d.
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:      "Normal rats" number  and treatment ns.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:     4 "normal rats" as control.
DURATION OF EXPERIMENT:   Serial sacr to 16 d

EXAM. TYPE:  Histology
DURATION OF EXPERIMENT:  Serial sacr to 154 d.

EXAM. TYPE:  Histology
                                       551
                                                                                                                                   552

-------
COMPOUND:    Isonicotinic acid, hydrazide

            000054853

REFERENCE:    Schlaepfer, W.W. and Hager, H.
             Am.  J. Path. 45:679-686, 1964.
COMPOUND:   Isonicotinic acid,  hydrazide

            000054853

REFERENCE:   Sea,  C.P.  and Peterson,  E.G.
             Exp.  Neurol. 48:.252-260,  1975.
OBSERVED NEUROTOXIC EFFECTS:    Focal disruption of axons and myelin sheaths.
     Regeneration  studied: mild fibrosis of endoneurium, shcwann-cell pro-
     liferation, regeneration  of axons  interacting with schwann-cell processes and
     remyelinat ion.
OBSERVED NEUROTOXIC EFFECTS:  Portions  of  both sciatic nerves (one for histology,
      the other  for biochemistry); neuropathy varied axon to axon and rat to rat.
      Degeneration of myelin;  Schwann cells appeared to transform into macro-
      phages.  Loss of  the main protein band (electrophoresis).
ANIMALS:      20 rats,  S-D,  F
ANIMALS:   30 Rats,  S-D, M, 200-300 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    350 mg/kg/d  for  6-15  d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  270 mg/kg/d  till hyperactivity seen (usually 6 d),  then
                        200 mg/kg/d  to  day  14.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:      4 "Normal rats"  as  control.
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:    2 Controls, saline  treated.
DURATION OF EXPERIMENT:   Serial sacr to 154 d

EXAM. TYPE:  Histology
DURATION OF EXPERIMENT:  Serial sacr to 14 d

EXAM. TYPE:   Histology, biochemistry
                                       553
                                                                                                                                    554

-------
COMPOUND:  Isonicotinic acid, hydra-ide

           100054653

REFERENCE:  Smith, B.
            J. Neurol. Neurosurg. Psychiat. 30:  506-510, 1967.
COMPOUND:   Isonicotinic acid,  hydrazide

            000054853
REFERENCE:
                Terman,  D.S.  and Teitelbaum,  D.T.
                Neurology 20:299-304,  1970.
OBSERVED NEUROTOXIC EFFECTS:  The myenteric plexus was examined, and histological
                             changes were found.  The author suggests her method
                             for screening for neurotoxicity by looking for damage
                             to the myenteric plexus in the large intestine.
OBSERVED NEUROTOXIC EFFECTS:  Intractable convulsions, metabolic acidosis.
     All recovered eventually.
ANIMALS:    45 Mice, TO, CFW and Porton strains, 20-25 g
ANIMALS:   Human:   4 cases (M, 35; M, 21; F, 16; F, 20)
PREPARATION AND DOSE
or HISTORY OF PATIENT:   f, r.g twice weekly fcr 5-20  doses, 9 mice
                        Acute study:  10 mg  I.P. or 2 mg I.V. one dose
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Single doses:  (1) amt unknown, (2) 30 g,  (3) approx  10  g
     plus pyridoxine, (4) amt unknown.  In each case self-administered,  thought
     to 'be over 7 g.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:   ns
ROUTE AND SITE:   oral

CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:   2 d to 3 mo after last dose.  Acute:  20 min.

EXAM. TYPE:   Histology
DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:  clinical, hospital lab.
                                                                                                                                     556

-------
COMPOUND:   Isonicotinic  acid, hydrazide

            000054853

REFERENCE: Tomkin, G.H.
           Practitioner  211:773-777,  1973.
COMPOUND:    Isonicotinic  acid  2-lsopropyl  hydrazide phosphate
REFERENCE:     Quinton,  R.M.
               Br. J. Pharnac.  21:51-66,  1963.
OBSERVED NEUROTOXIC EFFECTS:   Loss of strength in arms  and  legs,  absent
     tendon reflexes,  plantar responses flexor, impaired sensation to pinpricks.
     Complication:   sideroblastic anemia.   After all drugs were discontinued and
     blood and pyridoxlne given,  patient began recovery.  In 3 wk  patient walked
     unaided,  in 4  mo.  sensations and tendon reflexes except ankle-jerk were
     normal.
OBSERVED NEUROTOXIC EFFECTS:   The  compound enhanced the effect of Yohimbine
                               and  lowered its lethal dosage.
ANIMALS:   1 Human, M, aged 67 yr.
ANIMALS:
                                                                                                          Mice,  XT,  M,  18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Dose 300 mg/d as antituberculosis  therapy, after  2 yr
     complained of limb numbness; was found unable  to  walk  unaided.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          ED5Q   200 mg/kg

                          ED,n  - dose producing a 50% mortality of mice  injected
                                                                                                                     "50
                                                                                                                           S.C. with yohimbine hydrochloride  (20 mg/kg).
ROUTE AND SITE:        ns.

CONTROL INFORMATION:   ns.
ROUTE AND SITE:      S.C.,  Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   2 yr of drug  therapy,  follow up.

EXAM. TYPE:  Hospital
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior,  electrophysiology, biochemistry
                                       557
                                                                                                                                    558

-------
COMPOUND:     Isonicotinic acid, 2-(sulfomethyl)hydrazide,  sodium salt

              003804895


REFERENCE:  Noel, P.R.B., Worden, A.N. and Palmer, A.C.
            Tox. Appl. Pharm. 10:183-198, 1967.
COMPOUND:    Isonicotinic  acid,  2-(sulfomethvl)  hvdraziHe,  sodium salt

           003804895

REFERENCE: Palmer,  A.C.  and Noel,  P.R.B.
           Nature 205:506-507,  1965.
OBSERVED NEUROTOXIC EFFECTS:  No constant evidence of peripheral nervous system
                             damage.  Brain damage mainly due to subcortical
                             myelin of hemispheres, considered edematous.
OBSERVED NEUROTOXIC EFFECTS:
                                 Seperation of fibers in subcortical myelin, ballooning,
                                 but axons Intact, activation of microglia and
                                 hypertrophy of astrocytes.  Severe laminar necrosis
                                 of cerebral cortex.
ANIMALS:
             18 Dogs, Pembroke Corgi, 9 M, 9 F
ANIMALS:    Dogs
PREPARATION AND DOSE
or HISTORY OF PATIENT:  6,  30 or 60 mg/kg/d in gelatin capsules, 6d/wk.  High
                       dose reduced to 48 mg/kg due to convulsions, and then to
                .   ••   40  mg/kg.  Deaths caused further reduction to 20 or 10
                       mg/kg/d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
6, 10, or 20 mg/kg/d.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:    6  undosed controls.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:      Control dogs, no details
DURATION OF EXPERIMENT:   195  d

EXAM. TYPE:  Clinical, biochemistry,  autopsy
DURATION OF EXPERIMENT:   Up to 6 mo.

EXAM. TYPE:   Histology
                                           559
                                                                                                                                        560

-------
COMPOUND:
            Lactic acid,  hydrazide
REFERENCE:   Jenney,  E.H.  and Pfeiffer,  C.C.
             J.  Pharm.  Exp.  Ther.  122:   110-123,  1958.
COMPOUND:    Lead

             007439921

REFERENCE:   Anku,  V.D.  and  Harris,  J.W.
             J.  of  Pediatrics  85(3):337-340,  1974.
OBSERVED NEUROTOXIC EFFECTS:    Convulsions
                                                                                              OBSERVED NEUROTOXIC EFFECTS:   Peripheral neuropathy,  fatigue,  headache,
                                                                                                                            epistaxis, clumsiness and  limb weakness.
ANIMALS:    Mice, Harlan,  19-21  g
ANIMALS:   1 Human,  M,  6 yrs.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   9.6 nM/kgm
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Ingestion of lead-base paint chips.
ROUTE AND SITE:   i.P.

CONTROL INFORMATION:   ns
ROUTE AND SITE:    Oral

CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:   5 mo.

EXAM. TYPE:   Clinical,  hematology.
                                        561
                                                                                                                                     562

-------
COMPOUND:    Lead

             007439921

REFERENCE:   Baloh, R.,  Sturm, R., Green, B. and Gleser, G.
             Arch. Neurol.  32:326-330, 1975.
OBSERVED NEUROTOXIC EFFECTS:
                                All subjects asymptomatic when evaluated.  Hyper-
                                activity correlated with increased lead levels, but
                                quantitative tests did not.  Authors comment
                                about "uncontrolled variables."
COMPOUND:   Lead

            007439921

REFERENCE:  Beattie, A.D., Briggs,  J.D.,  Canavan,  J.S.F.,  Doyle, D., Mullin, P.J.
            and Watson, A.A.
            Quart. J. Med. 44(174):   275-284,  1975.

OBSERVED NEUROTOXIC EFFECTS:   Two  of  the  cases showed severe neuropathy character-
                               ized by sudden flaccid paralysis 15 days after the
                               dose, with  quadriplegia and  respiratory paralysis.
                               Peripheral  nervous system motor end plates lacked
                               innervation and  showed degenerated axons and myelin.
ANIMALS:     Human children aged over 3 1/2 yr with 2 blood tests over 50 mcg/Pb/100
ANIMALS:    Human:  5 cases,  all  associated
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           History, physical exam, blood Pb determination, and
                           psychological tests  (motor, perceptual-motor, verbal-
                           cognitive, memory, quantitative).
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Self-administration of lead-opium pills obtained by
                        burglary,  ground,  suspended,  and injected (3-712 pills)
                        one dose.
ROUTE AND SITE:    N/A

CONTROL INFORMATION:    Controls matched from files  (m of age, sex, race, background)
                       and  screened at under 30 meg Pb/100 ml blood.
ROUTE AND SITE:  I.V.

CONTROL INFORMATION:  Absent
DURATION OF EXPERIMENT:      as.

EXAM. TYPE:  History,  physical, hematological, behavioral
DURATION OF EXPERIMENT:  About 2 wk

EXAM. TYPE:   Clinical, biochemistry, histology (autopsy)
                                           563
                                                                                                                                       564

-------
COMPOUND:    Lead

             007439921

REFERENCE:   Carson, T.L., Van Gelder, G.A., Karas, G.C. and Buck, W.B.
             Arch.  Env. Hlth. 29:154-156, 1974.
COMPOUND:    Lead

             007439921

REFERENCE:   David,  O.J.
             Lancet  i, 866, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                Blood lead of controls 4.7, lows 18.6, highs 34.8
                                meg/100 ml; of lambs at 2-4 wk of age controls 6.0,
                                lows 17.0, highs 25.0 meg/100 ml; of lambs
                                at 10-12 wk controls 4.0, lows 9.0, highs 14.0
                                meg/100 ml.  Rate of learning six visual discrimination
                                problems:  highs but not lows significantly slower
                                than controls.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:     Lambs  born  to  ewes fed high or low lead diets:
             7  in high group, 8 in low group.
             Used eventually:  4 control, 8 low, and 6 high lambs.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           High:  dams fed 4.5 mg/kg/d.
                            Low:  dams fed 2.3 mg/kg/d.
                          Lambs weaned at 3 mo.-exposure ceased.
ANIMALS:  Humans
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Criticisms of paper by Lansdown et al.,  Lancet  i_,
538, 1974.  (1) Blood lead does not signify  lead
burden, without lead mobilization tests.
(2) Behaviorial controls should be outside the
affected area, and methods should be justified
for purpose (lead-free population, and scale
intended to measure hyperkinesis).  (3)  Sex
imbalance in expected frequencies of behavior
disturbance (boys more than girls) should be
considered in selecting the study sample and
in data-processing; same with age-imbalance
(omission of cases under 6 yr old).  Therefore,
conclusions are not proved by data (may  still be
correct, but issue unresolved).
                            Industrial exposure to emissions from a lead smelter
ROUTE AND SITE:        Diet

CONTROL INFORMATION:   Lambs  from ewes  fed normal diet:  9 lambs.
ROUTE AND SITE:    ns.

CONTROL INFORMATION:    Subject of argument
DURATION OF EXPERIMENT:     About 15 mo.

EXAM.  TYPE:  Behavioral, blood chemistry
DURATION OF EXPERIMENT:      ns.

EXAM.  TYPE:  Subject of  argument
                                          565
                                                                                                                                       566

-------
COMPOUND:      Lead

              007439921

REFERENCE:     Krigman, M.R.
              Env. Hlth. Persp. 4:98, 1973.  (Abstracts).
                                                                                             COMPOUND:    Lead

                                                                                                         007439921

                                                                                             REFERENCE:   Lansdown, R.G.,  Shepherd, J., Clayton, B.E., Delves, H.T., Graham, P.J.
                                                                                                         and Turner,  W.C.
                                                                                                         Lancet 1:538-541, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                Thinner cortical mantle, smaller neurons, less
                                developed neuropil, fewer synapses but larger.
                                Lead retarded neuronal growth but not maturation,
                                whereas undernourishment affected both growth and
                                maturation.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
Weak positive correlation of blood lead with distance
of home from source of pollution.  No relationship
between blood lead and level of mental functioning
by any of several measurements  (dysfunction was
found to be related to social factors).
ANIMALS:       Rats,  Long-Evans, age  30 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Amt ns;,  to undernourished litters.
                                                                                            ANIMALS:     Human:  whole population  under 17  in working-class area,  317; 275
                                                                                                        of  these available  for  testing,  232 (84%)  were tested, 215 (78%) had
                                                                                                        blood  tests, 227  (82%)  were  behavior-rated,  social-worker data were
                                                                                                        obtained on  218  (79%);  1% did  not  take part  (parents refused).
                                                                                            PREPARATION AND DOSE
                                                                                            or HISTORY OF  PATIENT:      Exposure to airborne emissions and dust from a smelting
                                                                                                                       factory  for whole life, gauged by distance of home from
                                                                                                            .           source in  steps of  100 m from 0-500 and 500+.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:      Mentioned, not described
                                                                                            ROUTE AND SITE:    Inhalation of  airborne emissions and of dusts in homes and on
                                                                                                              roads,  ingestion of  dusts.
                                                                                            CONTROL  INFORMATION:       '.               .       ,  .
                                                                                                                  Another,  non-exposed,  population
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE:    Histology
                                                                                            DURATION  OF EXPERIMENT:     ns.

                                                                                            EXAM.  TYPE:   Behavior, blood  chemistry
                                              567
                                                                                                                                       568

-------
COMPOUND:    Lead

             007439921

REFERENCE:   Moore,  J.F., Mushak, P. and Krigman, M.R.
             Env.  Hlth.  Persp.  10:266,  1975  (Abstract).
                                                                 COMPOUND:   Lead

                                                                             007439921

                                                                 REFERENCE:  O'Tuama, L.A., Howard, J.L., Kim,  C.S.  Mushak,  P.M.  and Krigman, M.R.
                                                                             Env. Hlth. Persp. 10:266,  1975  (Abstract).
OBSERVED NEUROTOXIC EFFECTS:
                                Level of lead In cerebrum increased just before onset
                                of convulsions, in nuclei and mitochondria more
                                than in other organelles.
                                                                 OBSERVED NEUROTOXIC EFFECTS:
                                                                                                 At 5 min  lead was  strongly concentrated in choroid
                                                                                                 plexus and meninges;  low concentration in brain;
                                                                                                 ouabain reduced  choroid plexus level to 2%,
                                                                                                 meninges  to  13%, brain to 70% of controls.  At
                                                                                                 240 min these tissue-to-blood ratios had fallen
                                                                                                 and ouabain  had  no effect.  Interpreted in terms
                                                                                                 of lead transport  and its importance in lead encephalopathy.
ANIMALS:     Guinea-pigs
                                                                 ANIMALS:     Guinea-pigs
PREPARATION AND DOSE
or HISTORY OF PATIENT:
"large doses"
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                        0.01 mcCi/kg with/without ouabain
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   ns.
                                                                 ROUTE  AND SITE:   ns.

                                                                 CONTROL  INFORMATION:   Lead regarded as control
DURATION OF EXPERIMENT:     5 d

iXAM. TYPE:  Biochemistry
                                                                 DURATION OF  EXPERIMENT:     240 min

                                                                 EXAM.  TYPE:  Biochemistry
                                          569
                                                                                                                                       570

-------
COMPOUND:    Lead

             007439921

REFERENCE:   Popoff, N., Keinberg, S. and Feigin, I.
             Neurology  13:101-112, 1963.
                                                                 COMPOUND:      Lead

                                                                                007439921

                                                                 REFERENCE:     Pueschel,  S.M.
                                                                                Env.  Hlth.  Persp.  7:13-16,  1974.
OBSERVED NEUROTOXIC EFFECTS:
     Clinically:  vomiting, headache,  stupor,
     papilledema, coma, convulsions.   Edema of brain,  petechial
     hemorrhages in cortex, demyelination and  astrocytic
     and nicroglial reactions.   Authors concluded
     that vascular damage contributed  to the encephalopathy.
                                                                                            OBSERVED NEUROTOXIC  EFFECTS:
                                23-27% found to have neurological dysfunction
                                and motor impairment; assessed as low average
                                mental abilities at first examination, some
                                improvement reported at reexamination 1 1/2 -
                                3 yr later.
ANIMALS:    Human:  6 cases aged 1 1/2-3
                                                                                            ANIMALS:
                                                                                Human:   58 children diagnosed as lead-poisoned in a survey of 705
                                                                                        children in Boston.  Analysis of hair, then blood.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
History of eating paint for 4-6 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Evaluation, then reexamination 11/2-3 yr later.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   ns.
                                                                 ROUTE AND SITE:  ns.

                                                                 CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:     5 died in 9 hr to 8 d of hospitalization, one lived
                           39 d.
EXAM. TYPE: Autopsy, histology
                                                                 DURATION OF EXPERIMENT:   ns.

                                                                 EXAM. TYPE:    Clinical, behavior
                                          571
                                                                                                                                       572

-------
 COMPOUND:      Lead

               007439921

 REFERENCE:     Roberts,  T.M.,  Hutchlnson,  T.C.,  Paciga,  J.,  Chattopadhyayt,  A.,
               Jervis, R.E.  and Van Loon,  J.
               Science 186:1120-1123,  1974.
                                                                            COMPOUND:    Lead

                                                                                         007439921
                                                                            REFERENCE:
                                                                                         Rosenblaum,  W.I.
                                                                                         Acta Neuropathologlca.  5:54-60, 1965.
OBSERVED NEUROTOXIC EFFECTS:
                                2  cases  of  neuropathy,  3  of  slow nerve  conduction;
                                increased absorption  not  enough to  cause  clear-cut
                                symptoms but  "may cause metabolic and subtle neurological
                                changes, "found  in  10-15% of 21 selected  children
                                with excessive lead loads.
                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                                                                                             Lead caused dilation of pial arteries and
                                                                                                             inhibited the contractile response to barium.
                                                                                                             At lower doses, the responses were reversible,
                                                                                                             but at concentrations of 2%  or higher the
                                                                                                             arteries never regained their responsiveness
                                                                                                             to barium.
ANIMALS:
               Humans:
                        286  residents  of  zone  contaminated by lead  smelter A,  1425
                        close  to  smelter  B.
                                                                            ANIMALS:    Mice,  Swiss-Webster,  Male,  20 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:
         Emissions estimated from A:  15,000 kg/yr, from B:
         30,000 kg/yr.  Soil near A contained 40 mg lead/g, soil near
         B contained 16 mg/g.  More dust than fumes.  Blood lead
         levels near source A:  27 meg/100 ml, near B:  28 meg/100 ml,
         but levels over 40 occured in <1% of controls, in 28%
         near source A (summer) and 13% near source B (winter).

Inhalation, skin contact, ingestion
CONTROL INFORMATION:
                          1232  socioeconomically matched urbanites not  exposed.
                          Urban control  soil  content 0.1-0.5 mg/g.  Mean blood lead
                          level of  control  children was 19 meg/100 ml.
DURATION OF EXPERIMENT:    ns.

EXAM.  TYPE:     Clinical, biochemistry
PREPARATION AND DOSE
or HISTORY OF PATIENT:      7.0 mg/100 g
ROUTE AND SITE:   Injection

CONTROL INFORMATION:        ns.



DURATION OF EXPERIMENT:     ns.

EXAM. TYPE:  Dissection
                                          573
                                                                                                                                       574

-------
COMPOUND:      Lead

               007439921

REFERENCE:     Sachs,  H.K.
               Env.  Hlth. Persp.  7:41-45, 1974.
COMPOUND:     Lead

              007439921

REFERENCE:    SeppalHinen,  A.M.,  Tola,  S.,  Hernberg,  S.  and Kock,  B.
              Arch.  Env. Hlth.  30:180-183,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                                Symptoms found in 12.2% of subjects in year 1,
                                falling to 4.2% in year 5 of study:  drowsiness,
                                vomiting, irritability, g-i, behavior, ataxia,
                                convulsions, stupor peripheral neuropathy; only one
                                death.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                Blood lead regularly monitored and never above 70 meg/
                                100 ml (accepted safety norm).  Yet nerve-conduction
                                in selected muscles was slower (P<0.001) than in
                                controls.   As no complaints were involved, authors
                                term findings "subclinical neuropathy" and suggest
                                that safety norms be reconsidered.
ANIMALS:
               Human:  -6804  (3.2%) of 213,598 screened who had ^50 meg/100 ml of
               blood,  in Chicago.
                                                                                            ANIMALS:
               Human:   26 workers (18 M, 8 F) at a battery factory in Finland.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    History of eating paint or plaster 80%, x-ray finding
                         of  paint  chips in abdomen in another 10%.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    No previous exposure, current exposures (4.6 yr range 13 mo.-
                          17 yr. slight or moderate.  Clinical exam, and electromyography
ROUTE AND SITE:   Oral mainly

CONTROL INFORMATION:       ns.



DURATION OF EXPERIMENT:    Several yr.

EXAM. TYPE:     Clinical,  blood chemistry
ROUTE AND SITE:    Occupational exposure, inhalation.

CONTROL INFORMATION:      Age-sex-matched data from normals  (blue-collar) assembled
                          at Inst. Occupational Hlth., Helesinki, about 200; Blood
                          lead estimated 10-13 meg/100 ml.

DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:    Electrophysiology
                                          575
                                                                                                                                       576

-------
COMPOUND:
Lead (Pb210)
REFERENCE:    Thomas,  J.A.,  Dallenbach,  F.D.  and  Thomas, M.
              J.  Path.  109:45-50,  1973.
COMPOUND: Lead

          007439921
                                                                                             REFERENCE:
                                                                                              Zaworskl, R.E. and Oyasu, R.
                                                                                              Arch. Env. Hlth. 27:383-386,  1973.
OBSERVED NEUROTOXIC EFFECTS:  study to localize  lead  In developing  cerebellum:
                              in cytoplasm of  capillary endothelial cells,  later
                              in astrocyte foot-processes.  After 72 hr  lead
                              associated with  edema.
                                                                                 OBSERVED NEUROTOXIC EFFECTS:  By atomic absorption:   0.5 + .68 ppm in wet
                                                                                                              tissue of normals;  increase in first two decades
                                                                                                              of life.  0.34 + 0.03  ppm in tumor brains,
                                                                                                              statistically non-significant.
ANIMALS:      t> Rats,  Wistar,  F,  each with  litter  aged  1  d;  2  grps  trtd.
                                                                                 ANIMALS:    Humans:  Autopsy material  (brains)  from 4 hospitals,  only R frontal
                                                                                                     lobes  studied:  191 normal brains,  9 with tumors.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     5 or 10 mcCi.
                                                                                 PREPARATION AND DOSE
                                                                                 or  HISTORY OF  PATIENT:
                              No  known industrial exposure to lead, childhood exposure
                              unknown.  Samples obtained from ten patient with
                              brain tumors  and 191 normals.
ROUTE AND SITE:   I.p.

CONTROL INFORMATION:   2 grps
                                                                                 ROUTE AND  SITE:  ns.

                                                                                 CONTROL  INFORMATION:   191 Control brains,  lead content undetectable to 7.9 ppm
DURATION OF EXPERIMENT:     Serial sacr to  168 hr.

EXAM.  TYPE:   Autoradiography after histology
                                                                                 DURATION OF EXPERIMENT:   ns.

                                                                                 EXAM. TYPE:   Chemistry
                                       577
                                                                                                                                   578

-------
COMPOUND:   Lead acetate,  trihydrate
REFERENCE:  Roy> s., Hirano, A., Kochen, J.A. and Zimmerman, H.M.
            Acta Neuropath. 30: 287-294, 1974.


OBSERVED NEUROTOXIC EFFECTS: Attenuated endothelial cells of cerebral vessels
     with altered ultrastrueture.
COMPOUND:   Lead, bis (acetato)tetrahydrooxytri
            001335326

REFERENCE:     Clasen, R.A.,  Hartmann,  J.F.,  Coogan,  P.S., Pandolfi, S., Laing, I.
               and Decker,  R.
               Env.  Hlth.  Persp.  7:175-185,  1974.
OBSERVED NEUROTOXIC EFFECTS:
At 6-18 wk onset of ataxia, nystagmus, weakness,
convulsions; rise of blood Pb and urinary ALA,
fall of Hb.  Central nervous system edema of white matter
of hemispheres and cerebellum; granular precipitate
with expanded extracellular space; axonal swelling
in cortex only.
ANIMALS:   Chick eggs
                                                                                        ANIMALS:       4 Rhesus monkeys (3 M, 1 F) age 5-6 mo. newly weaned.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   50-75 meg inj  into yolksac  on d 4  of  incubation.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    0.5 g with 1000 IU vitamin D in corn oil 3 doses/wk.
ROUTE AND SITE:     Ini,  yolksac

CONTROL INFORMATION:   ns.
ROUTE AND SITE:  Gavage

CONTROL INFORMATION:      2 animals given vitamin D alone.
DURATION OF EXPERIMENT:   Living  embryos  sacrificed serially 5-18 d of incubation

EXAM.  TYPE:   Histology.
DURATION OF EXPERIMENT:   Up to 18 wk.

EXAM. TYPE:    Behavior, histology
                                      579
                                                                                                                                   580

-------
COMPOUND:
Lead carbonate

000598630
COMPOUND:   Lead carbonate
            000598630
REFERENCE:
               Hopkins, A.
               Br.  J.  Indust. Med.  27:130-140,  1970.
                                                                             REFERENCE:  Hopkins, A.P. and Dayan, A.D.
                                                                                         Br. J. Indust. Med. 31:128-133, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                Ten  adults  died,  2 were killed;  2  infants  died,  1
                                was  killed;  8  convulsed,  3 had limb weakness;
                                no peripheral  nervous  system abnormality found,
                                nor  anemia  nor punctate basophilia.   Central nervous
                                system findings to be  given elesewhere; author
                                discusses species differences.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
                                                                                                              Seizures, widespread cerebral  edema,  focal
                                                                                                              cortical necroses.
ANIMALS:       Baboons,  3 M,  9  F,  7.2-13.6  kg,  F adult, M not  full-grown;  and
               3  infant  F,  2.8-3.3 kg.
                                                                             ANIMALS:    3 Baboons:  1 F, 11.7 kg; 1 F, 10.7 kg; 1 F,  2.8 kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     50-135 mg/kg  for  39-362  d,  single  and multiple  doses.
                                                                             PREPARATION AND DOSE
                                                                             or HISTORY OF PATIENT:    1.  86 mg/kg, 5 doses in 122 d and  1  dose  on d 137.
                                                                                                       2.  94 mg/kg, 8 doses in 234 d.
                                                                                                       3.  54 mg/kg, 1 dose and 2 larger doses  in 84 d.
ROUTE AND SITE:    Intratracheal

CONTROL INFORMATION:       Starting data and  12 healthy baboons  used  in other
                          studies
                                                                             ROUTE AND SITE:   Intratracheal

                                                                             CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:    up  to  362  d.

EXAM.  TYPE:    Behavior,  electrophysiology, histology
                                                                             DURATION OF EXPERIMENT:   Death on d 156, 265 and 117 respectively.

                                                                             EXAM. TYPE:   Behavior, histology
                                           581
                                                                                                                                       582

-------
COMPOUND:     Lead carbonate
              000598630


REFERENCE:       Krigman, K.R., Druse, M.J., Traylor, T.D., Wilson, M.H., Newell, L.R.
                and Hogan, E.L.
                J. Neuropath. Exp. Neurol. 33(l):58-73, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                                Neural tissue growth retarded.  Myelin formation
                                altered and its cerebral content reduced.  Axons
                                and number of myelin lamellae in the sheaths
                                were reduced.  Hypomyelination.  Caudal paraplegia
                                and medullary  cysts.  Abnormally small brains.
                                                                             COMPOUND:   Lead carbonate

                                                                                        000598630

                                                                             REFERENCE:     Krigman, M.R. and Hogan, E.L.
                                                                                           Env. Hlth. Persp. 7:187-199, 1974.


                                                                             OBSERVED  NEUROTOXIC  EFFECTS:    Brain growth  retarded (mass,  not cell numbers),
                                                                                                            with slow maturation, fewer synapses, hypomyelination,
                                                                                                            but essentially  normal chemistry.
ANIMALS:
Rats, Long-Evan newborns
ANIMALS:       Rats,  Long-Evans, neonates with dams.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     4% lead carbonate to nursing mothers and then to weanlings
                          via diet.
                                                                             PREPARATION  AND DOSE
                                                                             or  HISTORY OF  PATIENT:    4% in diet  fed  to  dams and,  at weaning, to litters.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:        8 pups - no lead as controls.
                                                                             ROUTE  AND  SITE:  oral

                                                                             CONTROL  INFORMATION:       Controls  similarly treated, no lead.
DURATION OF EXPERIMENT:     Sacr. after  30 d post-natal.

EXAM. TYPE:     Biochemical,  Histology, Ultra structural.
                                                                             DURATION  OF  EXPERIMENT:    30  d

                                                                             EXAM.  TYPE:    Histology,  biochemistry
                                          583
                                                                                                                                       584

-------
COMPOUND:  Lead carbonate

           000598630

REFERENCE:  Lampert, P.W. and Schochet, S.S.
            J. Neuropath. Exp. Neurol. 27: 527-545, 1968.


OBSERVED NEUROTOXIC EFFECTS:  Proliferation and degeneration of Schwann cells,
     with disintegration of myelin lamellae, new lamellae are formed and
     disintegrate, leaving remnants of basement membrane.  Schwann cells
     proliferate along this membrane.
COMPOUND:  Lead carbonate

           000598630

REFERENCE:  Rosenblum, W.I. and Johnson, M.G.
            Arch. Path. 85:  640-648, 1968.
OBSERVED NEUROTOXIC EFFECTS:
Neonates exhibited an altered gait and  loss  of
righting reflex.  Neuropathologic findings  induced
excesses of fibrous intercapillary strands  in
cerebral sites, astrocytosis in the hippocampus,  and
altered properties of glia and/or cerebral  tissues.
ANIMALS:   26 Long-Evans rats average 100 g
                                                                                           ANIMALS:   Mice,  Balb/c, pregnant F.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   4% in chow diet.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Diet contained 1%  (in 3 cases  0.5%)  lead  carbonate after
                       delivery.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:  Chow only, "parallel groups"
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   No lead carbonate
DURATION OF EXPERIMENT:    Serial sacr 2-12 mo.

EXAM. TYPE:  Histology
DURATION OF EXPERIMENT:  Suckling neonates were killed at  14,  17,  20,  23d of age.

EXAM. TYPE:  Clinical, histology
                                       585
                                                                                                                                    586

-------
COMPOUND:   Lead carbonate

            000598630

REFERENCE:  Sauerhoff, M.W.  and Michaelson,  I.A.
            Science 182:1022-1024,   1973.


OBSERVED NEUROTOXIC EFFECTS:   Hyperactivity, aggression,  stereotype-behavior  in
     neonates exposed via dam, starting at 4 wk of age; brain lead increased
     8-fold, 20% less dopamine, no  change  in norepinephrine.   Authors infer
     relationship of lead,  dopamine, and behavior.  (This report retracted in
     1975 by Goiter and Michaelson, see under Lead acetate).
ANIMALS:   Rats, S-D, F, pregnant 16 d
PREPARATION AND DOSE
or HISTORY OF PATIENT:   4% in diet for 16 d, then 40 ppm.
ROUTE AND SITE:   oral

CONTROL INFORMATION:     Pair-fed, matched controls



DURATION OF EXPERIMENT:  Neonates serially sacr up to 29 d of age.

EXAM. TYPE:  Behavior, biochemistry
                                       587
                                                                                             COMPOUND:   Lead (II) nitrate (1:2)

                                                                                                       010099748

                                                                                             REFERENCE:   Markov,  D.V.  and Dimova,  R.N.
                                                                                                         Acta  Neuropath. 28:25-35, 1974.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:   Ultrastructural changes seen only in microglial
                                                                                                 cells  of  parietal  cortex:   hypertrophy especially of endoplasmic reticulum,
                                                                                                 lipid  inculsions.
                                                                                            ANIMALS:   Rats,  11 littermates M and F,  newborn.
                                                                                             PREPARATION AND  DOSE
                                                                                             or HISTORY OF  PATIENT:   0.4% in drinking water from birth.
                                                                                            ROUTE AND  SITE:   Oral

                                                                                            CONTROL  INFORMATION:   Mentioned-not described



                                                                                            DURATION OF  EXPERIMENT:   9 mo.

                                                                                            EXAM. TYPE:   Histology
                                                                                                                                    588

-------
COMPOUND: Leurocristine

          000057227

REFERENCE:   Anderson,  P.J.  Song,  S.K.  and Slotwlner,  P.
             J.  Neuropath.  Exp.  Neurol.  26(1):15-24, 1967.
OBSERVED NEUROTOXIC EFFECTS:  Peripheral and  terminal  motor  endplates were  de-
     generated when paralysis  was maximal;  interpretation  uncertain  according  to
     authors.   Other wise  no peripheral  nervous  system abnormalities.
ANIMALS:   20 Rats,  S-D,  M,  150-250 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.3-0.4 mg/kg/d  up  to  4  d
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:   Matched controls  untreated.



DURATION OF EXPERIMENT:   4  d

EXAM. TYPE:  Histology
                                      589
COMPOUND:    Leurocristine

             000057227

REFERENCE:   Bradley, W.G.
             J.  Neurol. Sci. 10:133-162, 1970.


OBSERVED NEUROTOXIC  EFFECTS:    Acute:  axonal degeneration in sciatic, posterior
    tibial,  digital and intramuscular nerves; minor changes in dorsal  root
    ganglia  and  anterior horn and in motor endplate axons.  Chronic:   Similar
    changes  with denervation and terminal regeneration.  Sciatic nerve conduction
    reduced  to 81%.
ANIMALS:     27 Guinea-pigs, M, young (200-300 g), and old (>500 g) , outbred.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) 1 mg/kg one dose to 10 animals.
    (2)  0.03 mg/kg,  2/wk to 17 animals.
ROUTE AND SITE:  I>P.

CONTROL INFORMATION:   25 untreated controls.



DURATION OF EXPERIMENT:  Up to 14 wk.

EXAM. TYPE:  Electrophysiology, histology
                                                                                                                                   590

-------
COMPOUND:   Leurocristine
            000057227


REFERENCE:  Bradley, W.G., Lassman, L.P., Pearce, G.W. and Walton, J.N.
            J.  Neurol.  Sci.  10:107-131, 1970.


OBSERVED NEUROTOXIC EFFECTS:    All treated over  2 mo. had mixed sensorimotor
    peripheral neuropathy, children less sensitive.  Distal nerve conduction:
    increased latency to complete block.  Main nerve trunks unaffected.  Sural
    nerve biopsy:   axonal degeneration.  In 5 autopsies, distal muscles denervated.
    No  signs of  CNS damage, but ultrastructure not studied.
COMPOUND:    Leurocristine
             000057227


REFERENCE: Gottschalk, P.G., Dyck,  P.J.  and Kiely,  J.M.
           Neurol. 18:  875-882,  1968.
OBSERVED NEUROTOXIC EFFECTS:  During third  week of vincristine therapy, paresthesias
                              in  the fingers  and toes appeared.   Mild generalized
                              muscle weakness and absence of muscle stretch reflexes
                              noted  at  the  end of seven weeks.
ANIMALS:     Human:   Cancer  patients  -  23  adults aged  26-63 year,  14 children  aged
    14 mo.  to 13 yr.   Follow-up  data.   Studied personally:  2 adults,  3 children.
ANIMALS:   1 Human, F, age  63 yr
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.05 mg/kg/wk (one  dose/wk)  for up  to  20 mo.
PREPARATION AND DOSE
or HISTORY OF PATIENT: 12 mg  in  7 wk
ROUTE AND SITE:   I.V.

CONTROL INFORMATION:    ns.
ROUTE AND SITE:  I.V.   .          .

CONTROL INFORMATION: Group of rats,  not  described
DURATION OF EXPERIMENT:   20 mo.

EXAM. TYPE:  Clinical,  electrophysiology,  histology (biopsy)
DURATION OF EXPERIMENT:  7 wk

EXAM. TYPE:  Neurological, physiological
                                       591
                                                                                                                                    592

-------
COMPOUND:     Leurocristine

              000057227

REFERENCE:   Joneja, M.  and Ungthavorn, S.
             Teratology 2:235-240, 1969.
COMPOUND:     Leurocristine

              000057227

REFERENCE:   Levitt,  L.P.  and Prager,  D.
             Neurology 25:894-895,  1975.
OBSERVED NEUROTOXIC EFFECTS:  Of 222 surviving fetuses, 36 had exencephaly,
     encephalocele, anopthalmia especially in C3H mice.  115/222 abnormal in some
     way.
OBSERVED NEUROTOXIC EFFECTS:    "Mononeuropathy," acute, followed each of the
    last 2 single doses.   Different nerve on each occasion.  Claimed first
    report of an additional neurotoxic manifestation of vincristine.
ANIMALS:     Mice:   Inbred C3H/HeJ and DBA/2J and randombred Swiss ICR/Ha,  F,
             pregnant.
ANIMALS:     Human:   one case,  leukemic M aged 3 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.01% in saline on d 9 of gestation.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2 mg/28 d for 9 mo. with no ill effect; 18 mo. later
    one dose of 2 mg,  repeated after 6 mo.
ROUTE AND SITE:   i.P.

CONTROL INFORMATION:     Saline only
ROUTE AND SITE:  i.v.

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:  8 d

EXAM. TYPE:  Teratological
DURATION OF EXPERIMENT:  Over 3 mo.  from last dose.

EXAM. TYPE:  Behavior,  electrophysiology
                                       593
                                                                                                                                    594

-------
COMPOUND:    Leurocristine

             000057227

REFERENCE:  McLeod,  J.G.  and  Penny,  R.
            J.  Neurol.  Neurosurg.  Psychlat.  32:   297-304, 1969.
COMPOUND:    Leurocristine

             000057227

REFERENCE:    Moress, G.R.,  D'Agostino, A.N. and Jarcho, L.W.
              Arch. Neurol.  16:377-384, 1967.
OBSERVED NEUROTOXIC EFFECTS:   The  patients  suffered paresthesias, areflexias  (ankle)
                              and  slow motor  and  impaired sensory conduction  in per-
                              ipheral  nerves  which progressed or reversed after ex-
                              posure stopped.  Biopsy revealed demyelination  and
                              axonal degeneration in sural nerves; regeneration
                              occurred after  exposure stopped.
OBSERVED NEUROTOXIC EFFECTS:   Clinical neuropathy, mainly lower extremities,
                               progressing to quadriparesis,  time-related  to
                               compound.  Necropsy:  demyelination  and  axonal
                               degeneration.
ANIMALS:  .  Human:   9  patients, M &  F,  18-79
                                                                                                ANIMALS:      Human:   3  cases  of  acute  lymphoblastic leukemia
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5-15.5 mg (total)  in  0.02-0.05 mg doses, no more  than
                          5  doses/course
PREPARATION AND DOSE
or HISTORY OF PATIENT:
0.05 mg/kg, 0.1 mg/kg, 2 or more doses.
ROUTE AND SITE:   I.V. •

CONTROL INFORMATION:    None
ROUTE AND SITE:   I.V.

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:    ns

EXAM. TYPE:    Clinical,  electrophysiology, histology
DURATION OF EXPERIMENT:    Lifetime of patients

EXAM. TYPE:   Clinical, histology  (necropsy)
                                           595
                                                                                                                                        596

-------
COMPOUND:    Leurocristine
             000057227


REFERENCE:  Shelanski, M.L.  and Wisniewski, H.
            Arch. Neurol  20:199-206,  1969.
OBSERVED NEUROTOXIC EFFECTS:
                                Neurofibrillary proliferation found in all  3
                                cases.  Authors feel effects were due to leurocristine
                                and not the other chemotherapeutic agents administered.
COMPOUND: Leurocristine

         000057227


REFERENCE:   Uy, Q.L., Moen, T.H., Johns, R.J. and Owens, A.H., Jr.
            Johns Hopkins Med. J. 121:349-360, 1967.


OBSERVED NEUROTOXIC EFFECTS:  Mice and rats:  hindlimb paralysis; chromoatolysis
     of dorsal root ganglia; later, degeneration of myelin and axis cylinders
     of sciatic nerves.   No Impairment of neuromuscular transmission or nerve
     conduction.
ANIMALS:
            3  Humans,  acute  leukemics, M 7 yr.,  F  13 yr and M 17 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                             Dosage varied  1.0 mg-0.5 mg  from Feg and Aug.
                             1.7 mg,  3 doses, plus mercaptopurine 150 mg by
                             mouth for 3 d  and 75 mg after.
                          3.  2.7 mg,  preceded by treatment with prednisone,
                             mercaptopurine, and cyclophosphamide.

ROUTE AND SITE:     1.   I.V.,  2.  ns.,  3.   I.V.

CONTROL INFORMATION:       Control specimens  mentioned, no  details
ANIMALS:   Mice:  BDF  (C57BL/6 x DBA/2), F, 20-25 g.
           Rats:  Lewis,  F, 180-200 g.


PREPARATION AND DOSE
or HISTORY OF PATIENT:  Mice:  1-8 rag/kg, one dose.
                        Rats:  0.25-1 mg/kg, one dose.
                                                                                                 ROUTE AND SITE:   Mice I.P.,  rats I.V.

                                                                                                 CONTROL INFORMATION:   starved untreated animals.
DURATION OF EXPERIMENT:    Weeks

EXAM. TYPE:   Clinical exam, histopathology  at  autopsy.
                                                                                                 DURATION OF  EXPERIMENT:  serial sacr to 30 d

                                                                                                 EXAM.  TYPE:  Behavior,  histology,  electrophysiology
                                           597
                                                                                                                                        598

-------
COMPOUND:     Leurocristine, sulfate (1:1)  (salt)

             2068782

REFERENCE:   Clarke, J.T.R., Karpati.G., Carpenter, S. and Wolfe, L.E.
            J. Neuropath.  Exp. Neurol 31(2):247-266, 1972.
                                                                                            COMPOUND:    Leurocristine,  sulfate  (1:1)  (salt)

                                                                                                         2068782

                                                                                            REFERENCE:  Gottschalk,  P.G., Dyck, P.J. and Kiely, J.M.
                                                                                                        Neurol.  18:   875-882, 1968.
OBSERVED NEUROTOXIC EFFECTS:     Lethargy, ataxia, paraplegia and quadriplegia
                                after 24 hrs.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:  Peripheral neurophathy was produced.  Axonal  type
                                                                                                                          degeneration of myelinated fibers.  Most rats receiving
                                                                                                                          more than 0.15 mg/kg/d died within four days.  Those
                                                                                                                          receiving 0.1 mg/kg/d died between eight and  thirty days
                                                                                                                          after initial injection.
ANIMALS:     Rats, Wistar, M,  100-150 gm.
                                                                                            ANIMALS:    70 Rats,  S-D,  M,  10-12 wk old, 174-300 gm
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            (1)  0.4 mg/kg  for  chemistry study.
                            (2)  0.3-0.4 mg/kg/d  for  3  d as  0.1  mg/'ml  saline  soln
                                for histochemical  studies.
                                                                                            PREPARATION AND  DOSE
                                                                                            or HISTORY OF PATIENT:  2 doses 2/wk which equal 0.05-0.5 mg/kg/d
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:
                                                                                            ROUTE AND SITE:  ns

                                                                                            CONTROL  INFORMATION:   Untreated controls
DURATION OF EXPERIMENT:     (1)  Sacr after 28 hr.     (2)  4 d

EXAM. TYPE:  Histochemistry,  ultrastructural, chemistry
                                                                                            DURATION OF EXPERIMENT:  5-6d after admin to time of disorder manifestation

                                                                                            EXAM. TYPE:   Behavior,  histology
                                           599
                                                                                                                                        60C

-------
 COMPOUND:    Leurocristine, sulfate  (1:1)  (salt)

             2068782

 REFERENCE:  Schlaepfer, W.W.
            .1.  Neuropath. Exp. Neurol. 30(3):  488-505, 1971.
COMPOUND:  Leurocristine, sulfate (1:1)  (salt)
           2068782
REFERENCE: Schochet,  S.S.,  Jr.,  Lampert,  P.W. and Earle, K.M.
           J.  Neuropath.  Exp.  Neurol.  27:645-658, 1968.
OBSERVED NEUROTOXIC EFFECTS: Axonal alterations of peripheral nerve.  Axonal neuro-
                             tubular disruption.  Wallerian degeneration in the distal
                             segment of nerve fibers.
OBSERVED NEUROTOXIC EFFECTS:  1.   Human:   seizures, neuronal changes  (clumped
     Nissl substance,  clear areas, acidophilic rhombohedral crystals)
     2.   Rabbits:   similar effects:  the clear areas were skeins of neurofilaments
ANIMALS:    Rats, Albino, M, 300-350 gm.
ANIMALS:   1.   Human:   1 case,  F,  Aged 2 1/2, acute leukemia, ending in autopsy.
           2.   20 Rabbits,  NZ White,  2.5 kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1 x 10~3 M, 1 x 10   M or 1 x 10   M in saline solution.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1.   Human:  15 mo. history of cytotoxic drugs including
     vincristine i.v.; then 3 mg given intrathecally, and 200 ml of cerebrospinal
     fluid exchanged for 200 ml saline.
     2.   Rabbits:   0.001-0.2 mg/kg one dose intracisternally.
ROUTE AND SITE:    Endoneural inj.

CONTROL INFORMATION:   None
ROUTE AND SITE:  See above

CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:   Serial sacr 0.5-72 hr

EXAM.  TYPE:  Histochemistry, cytochemistry, ultrastructural
DURATION OF EXPERIMENT: Rabbits:  1-4 d

EXAM. TYPE:  Autopsy, histology
                                           601
                                                                                                                                        602

-------
COMPOUND:   Leurocristine sulfate
REFERENCE:  Sell, F.J. and Lampert, P.W.
           Exp. Neurol. 21:  219-230, 1968
COMPOUND:  Leurocristine,  sulfate (1:1) (salt)

           2068782

REFERENCE:  Sell, F.J., Lampert, P.W.  and Klatzo, I.
            J. Neuropath. Exp. Neurol. 28:  74-85,  1969.
OBSERVED NEUROTOXIC EFFECTS:  Neurofibrillary  tangles and neuronal degeneration;
                             starting with clumping of argentophilic neurofilaments
                             around the nucleus.   Persistent after withdrawal of
                             compound.
OBSERVED NEUROTOXIC EFFECTS:  Induced neurofibrillary  spheroids  filled  the cytoplasm
                             of the cells exposed  to  aluminum phosphate,  and the
                             nuclei were displaced.   The  spheroids  were compared
                             with those induced hy vincristine  sulfate.  The author
                             claimed the former were  like those of  postencephalitic
                             parkinsonism and  the  latter  like those of Alzheimer's
                             disease.
ANIMALS:    In vitro cultures of fetal rabbit spinal cord and dorsal root ganglia
ANIMALS:    In vitro cultures of  spinal  cord and  dorsal  root  ganglia from fetal
            NZ White rabbits.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.5-20 ng/drop of medium, changed twice a week,  starting
                       serially at 17-26 d in vitro.  Exposures lasted  in all 31 hr
                       to 14 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.5-20 ng/drop of medium for  31hr to  14  d, medium
                         renewed twice weekly
ROUTE AND SITE:   in vitro

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE: In vitro

CONTROL INFORMATION:   Untreated  cultures
DURATION OF EXPERIMENT:   ns

EXAM. TYPE: Histology
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:  Light and electron microscopy
                                          603
                                                                                                                                       604

-------
COMPOUND:    Lithium carbonate

             000554132

REFERENCE: Vacaflor, L., Lehmann, H.E. and Ban, T.A.
           J. Clin. Pharm. 10:  387-389, 1970.
                                                            COMPOUND:    Lithium  chloride
                                                                        007447418
                                                            REFERENCE:   Benowitz, L.J. and  Sperry,  R.W.
                                                                        Exp.  Neurol.  40:540-546,  1973.
OBSERVED NEUROTOXIC EFFECTS:
The patients experienced toxic confusion within 2 wk
of treatment (impaired consciousness, clonic limb
movements), which reversed in 1 wk after treatment was
stopped and did not reappear after treatment was
reinstituted.  One case (gravida 7 mo, history of
mania) given 900-1200 mg/d developed hand tremor,
whereupon treatment was stopped; after delivery she
took unknown amount of unprescribed compound (serum
SmEq/liter) and had 5 d of coma, spasticity of limbs,
and convulsions.
                                                                                          OBSERVED NEUROTOXIC EFFECTS:
     No effect on memory 20 min after treatment, but
     amnesia 24 hr afterwards, if treated 4 min before
     training (less so if treated 2 min before, and no
     effect if treated 10 min after training).  Delayed
     effect on development of long term memory in chicks.
ANIMALS:    Human:  5 cases of side-effects attributed to compound, all over 50 yr old     ANIMALS:     Cockerels,  White  Leghorn,  1  d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:  600 mg/d increasing to 900-1200 mg/d, producing only serum
                       0.97-1.53 mEq/liter
                                                            PREPARATION  AND DOSE
                                                            or HISTORY OF  PATIENT:
0.245 mg/chick, before or after memory-training
ROUTE AND SITE:     Oral

CONTROL INFORMATION:   None
                                                            ROUTE  AND SITE:    Injected into 2 cerebral hemispheres, 1/2-dose to each

                                                            CONTROL  INFORMATION:    Vehicle only (some), sham training (others)
DURATION OF EXPERIMENT:   ns

EXAM.  TYPE:  Clinical
                                                            DURATION  OF  EXPERIMENT:      10 sec to 2 hr.

                                                            EXAM.  TYPE:   Behavior
                                        605
                                                                                                                                     606

-------
COMPOUND:   D-Lyseramide, N-N-diethyl ester,  tartrate  (LSD)
                                                                                           COMPOUND:   Malic acid, L(+)-
REFERENCE:  Diab,  I.M., Freedman, D.X. and Roth, L.J.
            Science 173:1022-1024, 1971.
                                                                REFERENCE:   Curtis, D.R. and Watkins, J.C.
                                                                            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
     Free LSD generally distributed in pituitary,
     pineal,  cerebellum, hippocampus, choroid plexus.
     Bound LSD localized in  cortical neurons, caudate
     nucleus, midbrain, medulla, epithelium of choroid
     plexus.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                Treatment caused excitation or depression of
                                neuronal activity.   Excitatory ranking:  glutamic,
                                g-aminoglutaric, aspartic, cysteic, cysteine-
                                sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                                N-formiminoaspartic acids.
                                Depressant ranking:  6-alanine, GABA, taurine,
                                N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                                acids.
                                Structure-activity relationships established.
ANIMALS:     Rats, S-D, M, 100-125 g
                                                                ANIMALS:     Cats, surgically prepared  to  expose,  motoneurones,  Renshaw cells or
                                                                            dorsal horn interneurones  in  lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1 mcg/g,  or 1.7 mcg/g of  labeled compound.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
ROUTE AND SITE:    i.V.

CONTROL INFORMATION:   None
                                                                ROUTE AND SITE:   Topical,  ionophoresis

                                                                CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:     Serial sacr 5-60 min.

EXAM.  TYPE:  Autoradiography
                                                                DURATION OF EXPERIMENT:   ns.

                                                                EXAM.  TYPE: Biochemistry,  electrophysiology
                                          607
                                                                                                                                      608

-------
 COMPOUND:   Maicmic acid

             000141822

 REFERENCE:  Curtis, D.R. and Watkins, J.C.
             J. Neurochem. 6:117-141, I960.
 OBSERVED NEUROTOXIC EFFECTS:
'ANIMALS:
                                Treatment caused excitation or depression of
                                neuronal activity.  Excitatory ranking:  glutamic,
                                8-aminoglutaric, aspartic, cysteic, cysteins-
                                sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                                N-formiminoaspartic acids.
                                Depressant ranking:  8-alanine, GABA, taurine,
                                N-methyl-3-alanine, 6-amino-6-hydroxybutyric,
                                glycine, a-alanine, 6-aminovaleric, 6-amirioisobutyric
                                acids.
                                Structure-activity relationships established.
             Cats, surgically prepared to expose;., motoneurones, Renshaw cells or
             dorsal horn interneurones in lumbar cord.
COMPOUND:  Malonic acid, amino-
REFERENCE:
             Curtis,  D.R.  and Watkins, J.C.
             J.  Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                               Treatment caused  excitation  or  depressicn of
                               neuronal activity.  Excitatory  ranking:   glutamic,
                               B-amiaoglutaric,  aspartic, cysteic,  cysteine-
                               sulfinic acids, S-hydroxyglutamic, N-methylaspartic,
                               N-fonniminoaspartic acids.
                               Depressant ranking:   B-alanine,  GABA,  taurine,
                               N-methyl-S-alanine, 6-amino-S-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric,  6-aininoisQbutyric
                               acids.
                               Structure-activity relationships established.
            Cats, surgically prepared to expose  motoneurones, Renshaw  cells  or
            dorsal horn  interneurones in lumbar cord.
 PREPARATION AND DOSE
 or HISTORY OF  PATIENT: Qualitative doses.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
 ROUTE AND SITE:   Topical, ionophoresis

 CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
 DURATION OF EXPERIMENT:  ns.

 EXAM.  TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:  ns.

EXAM.  TYPE: Biochemistry, electrophysiology
                                           609
                                                                                                                                       610

-------
COMPOUND:  Malonic acid,  aminoethyl-
                                                                                              COMPOUND:    Mandelic acid, hydrazide
REFERENCE:  Curtis, D.R. and Watkins, J.C.
            J. Neurochem. 6:117-141, 1960.
OBSERVED NEUROTOXIC EFFECTS:
ANIMALS:
                               Treatment caused excitation or depression of
                               neuronal activity.  Excitatory ranking:  glutamic,
                               B-aminoglutaric, aspartic, cysteic, cysteine-
                               sulfinic acids, 6-hydroxyglutamic, N-methylaspartic,
                               N-formiminoaspartic acids.
                               Depressant ranking:  6-alanine, GABA, taurine,
                               N-methyl-B-alanine, 6-amino-B-hydroxybutyric,
                               glycine, a-alanine, 6-aminovaleric, B-aminoisobutyric
                               acids.
                               Structure-activity relationships established.
            Cats, surgically prepared to expose  motoneurones, Renshaw cells or
            dorsal horn interneurones in lumbar cord.
PREPARATION AND DOSE
or HISTORY OF PATIENT: Qualitative doses.
REFERENCE:   Jenney, E.H. and Pfeiffer, C.C.
             J.  Pharm.  Exp. Ther. 122:  110-123, 1958.


OBSERVED NEUROTOXIC EFFECTS:    Convulsions
                                                                                              ANIMALS:     nice, Harlan, 19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   6.0  mM/kgm
ROUTE AND SITE:   Topical, ionophoresis

CONTROL INFORMATION:   Laboratory
ROUTE AND SITE:  i.p.

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:  ns.

EXAM. TYPE:  Biochemistry, electrophysiology
DURATION OF EXPERIMENT:  Acute

EXAM. TYPE:  Clinical
                                                                                                                                      612

-------
COMPOUND:     Manganese

              007439965

REFERENCE:    Cotzias,  G.C., Horiuchi,  K.,  Fuenzalida,  S.  and Mena,  I.
              Neurology 18:376-382,  1968.
OBSERVED NEUROTOXIC EFFECTS:
                                 "Healthy" miners had more  tissue manganese
                                 and  cleared Manganese  faster  than  controls  or
                                 chronic-poisoned grps  from tissues,  although
                                 clearance from bloodstream was slower.  Neuropathy
                                 continued in  poisoned  grp.  Authors  conclude that higl
                                 tissue  Manganese not needed for neuropathy
                                 to continue;  thus  chelation therapy  logically
                                 useless.
COMPOUND:  Manganese
           007439965

REFERENCE:  Mena, I., Marin, 0., Fuenzallda, S. and Cotzias, G.C.
            Neurology 17:  128-136, 1967.


OBSERVED NEUROTOXIC EFFECTS: Transient psychiatric symptoms  (long list)
     followed by permanent neurologic (partly extrapyramidal) changes, only
     in the poisoned group.  "Healthy" miners eliminated labeled Mn faster than
     either poisoned or non-exposed control groups.
ANIMALS:      Humans:   20 healthy miners  M,  aged  23-60 yr.
                       18 patients with chronic Manganese poisoning M,  aged  18-56  yr.
                       19 hospital staff, M  and F,  aged  20-30  yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         (1)  1-20 yr  industrial exposure  continuing.
                         (2)  Exposure terminated 2-27 yr  before  study.
                         (3)  No  exposure.
                     All given    Manganese  for clearance studies.
ROUTE AND SITE:  1%v.f  antecubital

CONTROL INFORMATION:      Grps  (1) and (3)  treated  as  controls.
ANIMALS:  Human:  114 Mn miners, clinically "healthy", of whom 14 were selected
                  for isotope studies:  M ages 20-60  (av. 37 yr).
                  13 in-patients with chronic Mn poisoning; ages 18-56 yr (av. 50)

PREPARATION AND DOSE
or HISTORY OF PATIENT:  Industrial exposure; clinical histories and lab studies
                        performed.
ROUTE AND SITE:  Mainly inhalation of dusts

CONTROL INFORMATION:  Medical workers, 4 M, 4 F, aged 20-30.
DURATION OF EXPERIMENT:   About 1 mo.

EXAM. TYPE:   Biochemical
DURATION OF EXPERIMENT:  20-30 d for each case

EXAM. TYPE:    Behavior, laboratory, isotope studies.
                                          613
                                                                                                                                       614

-------
COMPOUND:    Manganese

             007439965

REFERENCE:  Nichols,  R.A.  and Nakajima,  Y.
            Brain Res.  86:  493-498,  1975.
                                                              COMPOUND:          Manganese

                                                                                007439965

                                                              REFERENCE-        Prakash, N.J., Fontana, J.  and  Henkin,  R.I.
                                                                               Life Sci. 12(1):249-259,  1973.
OBSERVED NEUROTOXIC EFFECTS:
Manganese inhibited the generation of the IPSP (sic)
of the stretch receptor neuron but did not affect  the
action potential of the soma and had no effect on  GABA-
induced increase of conductance.  Manganese was inter-
preted to affect coupling of excitation with GABA
secretion at the presynaptic site of the inhibitory
synapse.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
     Inhibited (Na+ + K+)  ATPase, although never more
     than 20%, even at 0.2 mM.   Inhibition involved
     blockage of norepinephrine.
ANIMALS:    In vitro:   slow adapting stretch receptors from 8th thoracic segment
                       of lobster (II.  americanus)  and crayfish (Oronectes) , or from
                       the 2nd-3rd abdominal segment of crayfish.

PREPARATION AND DOSE
or HISTORY OF PATIENT:   Mn at 0-5 mM
                                                              ANIMALS:
                                                                               Rat brain synaptosomes in vitro
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:
Mn   chloride added to medium in various expts.
ROUTE AND SITE:   In vitro

CONTROL INFORMATION:   Zero treatment
                                                              ROUTE AND SITE:   in vitro

                                                              CONTROL INFORMATION:   Lab
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Biochemistry,  electrophysiology
                                                              DURATION OF EXPERIMENT:     Minutes

                                                              EXAM. TYPE:       Biochemistry
                                           615
                                                                                                                                        616

-------
COMPOUND:   Manganese
            007439965

REFERENCE:   Prasad, K.N.
             Exp. Neurol. 45:554-557, 1974.
OBSERVED NEUROTOXIC EFFECTS:  Adenyl cyclase inhibited, cAMP phosphodiesterase
                             stimulated by manganese.  Differentiated cells more
                             sensitive to manganese than undifferentiated.
COMPOUND:       Manganese

                007439965

REFERENCE:     Rosenstock, H.A.,  Simons,  D.G.  and Meyer,  J.S.
               J.  Am.  Med. Assn.  217:1354-1358,  1971.
OBSERVED NEUROTOXIC EFFECTS:
Impairment of gait and station, dysarthric  speech
and deterioration of fine motor coordination.
Headaches, anxiety and irritability.
ANIMALS:   In  vitro  cultured mouse neuroblastoma cells
                                                                                         ANIMALS:
                Human:   one, M,  22  yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1  or  10 mM in medium
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                   Exposure to fumes present in a  steel  foundry over a two
                                                                                                                   year period.  After that too disabled to  work,  14 yr
                                                                                                                   later was confined to wheelchair.
ROUTE AND SITE:     In vitro

CONTROL INFORMATION:     Mentioned,  no  details.
ROUTE AND SITE: Inhalation

CONTROL INFORMATION:        None
DURATION OF EXPERIMENT:     3 or  more d

EXAM.  TYPE:  Biochemistry
DURATION OF EXPERIMENT:     14 mo.  of exposure

EXAM. TYPE:     Clinical
                                       617
                                                                                                                                   618

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COMPOUND:     Manganese
              007439965

REFERENCE:     Smyth,  L.T.,  Ruhf,  R.C., Whitman, N.E.  and Dugan, T.
               J.  Occup.  Med.  15:101-109,  1973.
OBSERVED NEUROTOXIC EFFECTS:
       5 Subjects with signs of Parkinsonism were examined,
       removed from exposure, and reexamined after 3 mo.
       Reversible manifestations (loss of associated
       arm movements) had disappeared, irreversible
       ones had not progressed.  Authors concluded that
       Manganese exposure was the cause, although urine
       values were not high (but bile is the main route
       of excretion of Manganese).  Blood chemistry was
       inconclusive.
ANIMALS:   Human:   142 employees  of  a  steelworks  producing  ferromanganese  alloy,
           71 directly exposed,  71 not directly exposed.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Exposure to fume and dust, 0.12-13.3 mg/m  (TLV = 5
mg/m3) up to 26 yr.   Fume was mainly Mn,0,  <2 me in s
Dust was mainly FeMn, also MnO, Mn.O, and Fe~0, , 95%
                                                                             size.
                         <5 me in size,  and  respirable.
ROUTE AND SITE:    Inhalation,  skin contact

CONTROL INFORMATION:      The 71 not exposed were carefully  matched.



DURATION OF EXPERIMENT:   Over 3 mo.

EXAM. TYPE:    Clinical
                                          619
COMPOUND:   Manganese

            007439965

REFERENCE:    Tanaka, S. and Lieben,
              J. Arch.  Env. Hlth. 19:674-684, 1969.


OBSERVED NEUROTOXIC EFFECTS:   Weakness, tremors, disturbed gait, motor  impairment
                               of extremities.  Recovery, none  to partial.
                                                                                                ANIMALS:    Human,  3  selected  cases  of industrial exposure
                                                                        PREPARATION AND DOSE
                                                                        or HISTORY OF PATIENT:   Up to >100 mg/m  in air (dust) for 1-17 yr.
                                                                        ROUTE AND SITE:   Inhalation and skin contact

                                                                        CONTROL INFORMATION: None
                                                                                                     -X


                                                                        DURATION OF EXPERIMENT:  Years

                                                                        EXAM. TYPE: Clinical, clinicochemical
                                                                                                                                        620

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COMPOUND:  Manganese (II) chloride (1:2)
           0096250


REFERENCE:   Chandra,  S.V.  and  Sur,  R.N.
             Env.  Res.  3:417-424,  1970.
OBSERVED NEUROTOXIC EFFECTS:   Convulsions,  EEC changes,  scattered  degeneration
                              of neurons  in cerebral  and cerebellar  cortex.
                                                             COMPOUND:    Manganese (II) chloride (1:2)
                                                                          0096250


                                                             REFERENCE:  Meiri, U. and  Rahamimoff,  R.
                                                                         Science  176:308-309,  1972.
                                                             OBSERVED NEUROTOXIC EFFECTS:    Managanese ions blocked synaptic transmission at
                                                                                             the  neuromuscular junction.  The inhibition
                                                                                             produced  is reversible.
ANIMALS:    40 Rabbits,  M,  av.  1.5  kg.   30  had  surgical  impl  of  brain  cannulae.
                                                                                         ANIMALS:     In vitro preparation of frog sartorius muscle.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
0.5 mg in 0.1 ml saline/2 d for 15 d
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                    1 mM MnCl  ; 0.07-1 mM Mn
                                                                                                                 2+
ROUTE AND SITE:     intravehtricular

CONTROL INFORMATION:   10  normal  controls,  10  had  cannula  impl and  0.1 ml
                      saline inj.
                                                             ROUTE AND SITE:   In vitro

                                                             CONTROL INFORMATION:   Laboratory
DURATION OF EXPERIMENT:    Serial  sacr  0  hr  to  15  d

EXAM. TYPE:   Behavior,  autopsy,  histology
                                                             DURATION OF EXPERIMENT:     Minutes

                                                             EXAM. TYPE:  Electrophysiology
                                       621
                                                                                                                                    622

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 COMPOUND:    Manganese,  cyclopentadienyltricarbonyl
             012079651


 REFERENCE:  Arkhipova, O.G.
            Fed. Proc. 23:  T51-T54,  1964.
OBSERVED NEUROTOXIC EFFECTS:  Damage to nervous  system indicated  by  trembling, paresis
                              of limbs and reduced neuromuscular  excitability.
                                                                                                COMPOUND:
                                                                                                            3-Mercaptopropionic acid
REFERENCE:   Arnaiz,  G.R.  deL.,  de Canal, M.A. and DeRobertis, E.
             J.  Neurochem. 19:1379-1385, 1972.


OBSERVED NEUROTOXIC EFFECTS:  Dose-related convulsant properties studied in
                              cerebellum.  Glutamate decarboxylase and GABA fell,
                              GABA-aminotransferase rose, and dose-related changes
                              were seen in Purkinje cells.  From these and other
                              enzyme and amino-acid changes the authors inferred
                              that the compound causes imbalance among the excitatory-
                              inhibitory amino acids.
ANIMALS:    Rats, white; Mice, white;  Rabbits;  Guinea-pigs
                                                                                                ANIMALS:    Rats, Wistar, 100-150 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Rats:  LD,n was 80 mg/kg,  MLD 40 mg/kg
                        Mice:  LD^ was 150 mg/kg, MLD 80-100 mg/kg

                        Rats, rabbits,  guinea-pigs:  Exposed to 0.0007-0.001 mg/liter
                                                     of air for 10 mo


ROUTE AND SITE:   Inhalation.  Route of  LD and MLD doses ns  (but not inhalation).

CONTROL INFORMATION:   Yes, but not described
PREPARATION AND DOSE
or HISTORY OF PATIENT:  35-150 mg/kg
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:  Controls no treatment.
DURATION OF EXPERIMENT:   10 mo

EXAM.  TYPE:  Clinical
DURATION OF EXPERIMENT:   60 min

EXAM. TYPE:   Biochemistry, histology, behavior
                                           623
                                                                                                                                        624

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COMPOUND:   Manganese dioxide
            001313139

REFERENCE:  Abd el  Naby,  S.  and Hassanein, M.
            J.  Neurol. Neurosurg, Psychiat. 28:
                   282-288, 1965.
OBSERVED NEUROTOXIC EFFECTS:
The subjects experienced insidious onset with fatigue
and inertia; then weak, stiff gait, parkinsonian-type
imbalance, motor signs cerebellar, pyramidal, and/or
extrapyramidal; sleep disturbances, psychoses and
emotional lability.  Permanent disabilities included
the use of legs, and neurological signs continued to
progress after exposure stopped;  only psychic changes
regressed.
                                                                                               COMPOUND:
                                                                                                           3-Mercaptopropionic acid
REFERENCE:    Horton,  R.W.  and Meldrum, B.S.
             Br.  J.  Pharmac.  49:   52-63, 1973.


OBSERVED NEUROTOXIC  EFFECTS:   Seizures, photic stimulation, EEC changes,  inhibition
                              of  brain glutamate carboxylase were caused  by  3-mer-
                              captopropionic acid more strongly than by allylglycine
                              or  4-deoxypryidoxine HC1.  Thus the authors concluded
                              that seizures were due to depletion of glycine and Y-
                              aminobutyric acid (GABA).
ANIMALS:    Human:   45 miners, M, 21-54
                                                                 ANIMALS:      Mice, CFW or BALB/C, M, 20-30 g
                                                                              10 Baboons (Papio papio) , adolescent, from Senegal,  3-6  kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                       Exposure to dust for 5 mo to 25 yr
                                                                 PREPARATION AND DOSE
                                                                 or HISTORY OF PATIENT:   Mice:  EP5Q and  latency  0.27 mmol/kg,  4.5  min.
                                                                                         Baboons:  ED   and  latency  0.28 mmol/kg, 4 min.
ROUTE AND SITE:  Dermal,  inhalation, possibly ingestion too.

CONTROL INFORMATION:   None
                                                                 .ROUJE AND SITE:    Mice I.*., Baboons I.V.

                                                                 .CONTROL INFORMATION:   Timed studies
DURATION OF EXPERIMENT:   ns

EXAM.  TYPE:    Clinical
                                                                 .DURATION OF .EXPERIMENT:   Various

                                                                 EXAM. TYPE:   Mice:  behavior, biochemistry; baboons:   polygraph.
                                          625
                                                                                                                                        626

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                   3-Mercaptopropionic acid
 RL!'LntNCC:      Olnoy,  J.W. ,  Ho,  0.1..  nm! iilicc, V.
                Exp.  lir.-iin Kcs.  1';: i?l-'/(i, 19V.I.


 OBSERVED NEURCTOX1C  EFFECTS:    No cytotoxicity was  observed.
COMPOUND:   Mercuric bichloride

            007487947

REFERENCE:  Chang, L.W., Desnoyers,  P.A.,  and Hartmann,  H.A.
            J. Neuropath. Exp. Neurol.  31(3):489-501,  1972.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                 Poisoning produced initial decrease in RKA content
                                 followed by partial increase of RNA after prolonged
                                 intoxication.   Cell volume decreased.  Moderate
                                 increase in RNA was noted in anterior horn
                                 motoneurons.
ANIMALS:  Rice, Swiss-wcbster  a^c 10 d,  total 250
                                                                                           ANIMALS:     18 Rats
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Initially 12 iimiolcs/kg, then range established Cor
                          each coinpound.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Daily dosage of 1.2 mg/kg body weight.
ROUTE AND SITE:      s.C.

CONTROL INFORMATION:      Compounds compared with monosodium L-plutnnate  (MSG)
                          potency for selectively necrosing neurons in retina
                          and  brain (hypothalamus)

DURATION OF EXPERIMENT:   5  hr or serial intervals including 5 hr.

EXAM. TYPE:     Histology
ROUTE AND SITE:   Oral,  stomach tube, S.C.

CONTROL INFORMATION:        6 Rats



DURATION OF EXPERIMENT:      Serial sacr 1 wk, 2 wks, 6 wks

EXAM. TYPE:  Histology,  quantitative, cytochemical
                                          627
                                                                                                                                       628

-------
COMPOUND:    Mercuric bichloride

             007487947

REFERENCE:   Chang, L.W. and Hartmann, H.A.
             Exp. Neurol. 35:122-137, 1972.
                                                                 COMPOUND:
                                                                                                        Mercuric bichloride
                                                                             007487947
                                                                 REFERENCE:   Takeda,  Y.,  Kunugi,  T.,  Hoshino, 0. and Ukita, T.
                                                                             Tox.  Appl.  Pharm.  13:   156-164, 1968.
OBSERVED NEUROTOXIC EFFECTS:
     General distribution of mercury parallel to
     gross neuropathology; intracellular binding
     to membraneous structures in cytoplasm,  minimally
     in nucleus.
OBSERVED NEUROTOXIC EFFECTS:   Alkyl mercury compounds excreted more slowly  than  inorganic
                              or aryl compounds.  Metabolism varied with C-chain length.
                              Distribution in brain and reported neurotoxlcity were  re-
                              lated to structure of compound.
ANIMALS:     Rats,  S-D, adult M
                                                                 ANIMALS:     Rats,  Donryu,  aged 7 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1 mg/kg/d
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Compounds labeled with iuJHg; mercuric chloride 3 mg/kg,
                        others 10 mg/kg (one dose).
                                                                                                                203,,
ROUTE AND SITE:    Gavage  or S.C.

CONTROL INFORMATION:   Mentioned,  not  described
                                                                 ROUTE AND SITE:   S.C.

                                                                 CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:      1 d  to 11 wk,  serial

EXAM.  TYPE:  Histochemistry
                                                                 DURATION OF EXPERIMENT:   Serial 1-8 d

                                                                 EXAM. TYPE:  Biochemistry
                                           629
                                                                                                                                       630

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COMPOUND:  Mecuric (II) nitrate
           010045940
REFERENCE:   Fox, J.H.,  Patel-Mandlik,  K.  and Cohen,  M.M.
             J. Neurochem 24:757-762,  1975.
OBSERVED NEUROTOXIC EFFECTS:   No effect on respiration  or metabolism.
COMPOUND    Mercury

            007439976

REFERENCE:   Chang,  L.W.,  Optiz,  J.M.,  Pallister, P.D.,  Gilbert, E.F. and Viseskul, C.
             Acta  Neuropath.  (Berl.)  26:275-284,  1973.
                                                                                        OBSERVED NEUROTOXIC EFFECTS:
                                 Disintegration of granular layer, disapperance of
                                 Purkinje cells with Bergmann's fiber proliferation
                                 and demyelination of fiber tracts observed in
                                 cerebellum.   Extensive proliferation of astrocyte
                                 fibers and characteristic focal demyelination and
                                 loosening of tayelin sheaths in many nerve fibers.
ANIMALS:   Guinea-pig brain slices,  in vitro.
                                                                                        ANIMALS:     1  case  study  of 21 yr female.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.1-1.0 mM in medium.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                    Accidental exposure to mercury-containing herbicide
                                                                                                                    during childhood.
ROUTE AND SITE:   In vitro incubation

CONTROL INFORMATION:   Mercury-free medium used for control.
ROUTE AND SITE:   Ingestion

CONTROL INFORMATION:   Experimental rat poisoned with mercury.
DURATION OF EXPERIMENT:  1 hr in some cases

EXAM. TYPE:  Biochemistry
DURATION OF EXPERIMENT:     19 yrs.

EXAM. TYPE:  Light and election microscopy.
                                       631
                                                                                                                                   632

-------
 COMPOUND    Mercury

             007439976

 REFERENCE:   Danziger,  S.J.  and Fossick,  P.A.
             J.  Occup.  Med.  15:15-20,  1973.
 OBSERVED NEUROTOXIC EFFECTS:
                                 Symptoms:   6  insomnia,  5  hard-of-hearing,  4  oral
                                 phenomena,  3  peripheral neuropathy,  2  depression,
                                 1 severe oral and sensory disturbance  with tremors
                                 and  irritability.   Signs:   59 myopia,  12 dermograph-
                                 ism,  9  hearing loss,  2  hyperesthesia,  1 dental
                                 oral and ocular disorders.  High  urine Hg  and 6
                                 cases of proteinuria.
                                                                                            COMPOUND:
 REFERENCE:
             Mercury

             00743996
                  Prakash, N.J., Fontana, J.  and  Henkin,  R.I.
                  Life Sci. 12(1):249-259,  1973.
                                                                                            OBSERVED NEUROTOXIC  EFFECTS:
                                 At concentrations  over  0.01  mM,  Hg"*"1" completely
                                 inhibited  (Na+ + K+)  ATPase.  Inhibition
                                 involved blockage  of  norepinephrine and choline
                                 uptake.
ANIMALS:     Human:   75  workers  (gender  ns)  calibrating  lab  glassware  in  13
                     factories in  New Jersey,  ages  20-60+
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Exposure from 0.5  to  40+ y,  skin  contact;  vapor  0-0.3
                            Kg/m3  in breathing zone, tc  1.03  elsewhere.   (TLV  is
                            0.1, 0.05 proposed).
                                                                                            ANIMALS:
                                                                                                              Rat brain synaptosomes in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Hg   chloride added to medium  in  various  expts.
ROUTE AND SITE:    skin,  inhalation,  perhaps  ingestion

CONTROL INFORMATION:    4 foremen claiming to work in uncontaminated  areas,  and  the
                       research team.


DURATION OF EXPERIMENT:      ns.

EXAM. TYPE:   Clinical,  behavior,  blood  and urinalysis.  environmental
ROUTE AND SITE:   Xn vitro

CONTROL INFORMATION:   Lab



DURATION OF EXPERIMENT:     Minutes

EXAM. TYPE:       Biochemistry
                                                                                                                                       634

-------
COMPOUND:
                 Mercury

                 007439976
REFERENCE:     Smith, E.G., Vorwald, A.J., Patll, L.S. and Mooney, T.F.
               Am. Indust. Hyg. Assn. J. 31:687-700, 1970.


OBSERVED NEUROTOXIC EFFECTS:     Anorexia, insomina, tremors, other signs.
COMPOUND    Mercury

            007439976

REFERENCE:  Vroom,  F.Q.  and Greer, M.
            Brain 95:  305-318,  1972.
OBSERVED NEUROTOXIC EFFECTS:  Irritability and poor concentration (transient), memory
                              defects (permanent), suggesting temporal lobe lesions;
                              neuropsychology suggesting general cortical dysfunction;
                              abnormal EEG; parkinsonianism; severe tremors in all;
                              peripheral nervous system involvement; electromyography
                              indicating denervation.
ANIMALS:
               Human:  642 workers from 21 chloralkali plants in U.S. and Canada.
ANIMALS:    Human:   9 selected employees of a thermometer factory where industrial
                    negligence had produced an epidemic of signs.
PREPARATION AND DOSE                                                     , 3
or HISTORY OF PATIENT:     Time-weighted av exposures approx. 0 to 0.27 mg/m , 85%
                          _< 0.1 mg/m3.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  About 3 yr exposure, less in some cases.
ROUTE AND SITE:  Inhalation, skin contact

CONTROL INFORMATION:       382 non-exposed workers
ROUTE AND SITE:  Inhalation, skin contact, ingestion

CONTROL INFORMATION:  Up to 40 normal subjects for various tests
DURATION OF EXPERIMENT:    1 vr-

EXAM.  TYPE:     Full medical.
DURATION OF EXPERIMENT:  Up to 20 mo after diagnosis

EXAM. TYPE: Electrophysiology, neuropsychology, behavior, chemistry
                                          635
                                                                                                                                       636

-------
COMPOUND:    Mercury,  (acetato)methyl-
                                                              COMPOUND:     Mercury, (acetato)methyl-
REFERENCE:  Carraichael, N., Cavanagh, J.B. and Rodda, R.A.
            Acta. Neuropath. 32(2):115-125, 1975.
                                                              REFERENCE:    Kim,  S.U.
                                                                           Exp.  Neurol.  32:237-246,  1971.
OBSERVED NEUROTOXIC EFFECTS:
Severe ataxia. Degenerative changes seen in
primary sensory ganglion cells, in both Purkinje
and granule cells of the cerebellum, and in cells
of the forebrain.  Wallerian degeneration of
sensory neurones, widespread pyknosis of cerebellum,
symmetrical changes in cerebral cortex.
OBSERVED NEUROTOXIC EFFECTS:  Vacuolar degeneration especially in granule  and
                              Purkinje cells.  Axonx and melin sheaths degen-
                              erated, cytoplasmic organelles affected but  not
                              nuclear structures.
ANIMALS:    Rabbits, New Zealand, White, M and F, young 1.0-2.5 kg.
                                                              ANIMALS:    Slices of newborn mouse cerebellum in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:    7.5 mg/kg/d for 3-4 d, total 22.5 or 30 mg/kg.
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:    10 mM in medium
ROUTE AND SITE:    I. Tub.

CONTROL INFORMATION:  2 rabbits.
                                                              ROUTE AND SITE:   In vitro

                                                              CONTROL INFORMATION:  Laboratory
DURATION OF EXPERIMENT:   Serial sacr:  1, 2, 8 d

EXAM.  TYPE:   Histology, vascular
                                                              DURATION OF EXPERIMENT:   5 h to 24 d

                                                              EXAM.  TYPE:  Histology
                                       637
                                                                                                                                    638

-------
COMPOUND:   Mercury, butyl-chloro-

            000543635.    ,

REFERENCE:  Takeda, Y., Kunugi, T.,  Hoshino, 0. and Uklta, T.
            Tox.  Appl. Pharm.  13:  156-164, 1968«
                                                 COMPOUND:    Mercury (I)  chloride

                                                              007546307


                                                 REFERENCE:   Davis,  L.E.,  Wands, J.R., Weiss, S.A.,  Price, D.L. and Girling, E.F.
                                                              Arch. Neurol. 30:428-431, 1974
OBSERVED NEUROTOXIC EFFECTS:   Alkyl mercury compounds excreted more slowly than inorganic
                 l             or aryl compounds.  Metabolism varied with C-chain length.
                 '             Distribution in brain and reported neurotoxlcity were re-
                              lated to structure of compound.
                                                 OBSERVED NEUROTOXIC EFFECTS:    Dementia, recent memory loss, sensorineural loss,
                                                     ataxia,  coarse tremors.   Autopsy revealed small brains, loss of cerebellar
                                                     granular cells, Hg in neuronal cytoplasm (especially choroid plexus).
ANIMALS:    Rats,  Donryu, aged 7 wk
                                                                                                ANIMALS:     2 Human patients:  (1) F, 63 yr and (2) F, 56 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Compounds labeled with iuJHg; mercuric chloride 3 mg/kg,
                        others 10 mg/kg (one dose).
203.,
PREPARATION AND DOSE
or HISTORY OF PATIENT:    120 mg as laxative tablet, twice daily for:  (1) 25 yr,
    (2)  6 yr prior to death.
ROUTE AND SITE:  S.C.

CONTROL INFORMATION:   ns
                                                 ROUTE AND SITE:  Oral

                                                 CONTROL INFORMATION:   No controls
DURATION OF EXPERIMENT:   Serial 1-8 d

EXAM. TYPE:  Biochemistry
                                                 DURATION OF EXPERIMENT:   (1) 25 yr,   (2) 6 yr

                                                 EXAM. TYPE:  Behavior, Hospital investigations.
                                           639
                                                                                                                                       640

-------
COMPOUND:     Mercury  (II) chloride

              007487947

REFERENCE:   Chang,  L.W.  and  Hartmann,  H.A.
             Acta Neuropath.  20:316-334,  1972.
OBSERVED NEUROTOXIC EFFECTS:
     Pathological manifestations in dorsal and ventral
     root fibers and sciatic nerve.  Axonal degeneration.
     Disoriented myelin layers.
                                                                 COMPOUND:   Mercury, chloroethyl-

                                                                             000107277
                                                                 REFERENCE:  Hay,  W.J.,  Rickards,  A.G.,  McMenemey,  W.H.  and  Cumings,  J.N.
                                                                             J.  Neuro. Neurosurg.  Psychiat.  26:   199-202,  1963.
                                                                                             OBSERVED NEUROTOXIC EFFECTS:
                             The brain cortex was selectively damaged, especially  the
                             calcarine, parastriate, motor and sensory areas and the
                             caudal part of first temporal gyrus.  A loss of neurons,
                             a porous underlying white matter, swollen oligodendro-
                             cytes were observed.  There was a high concentration  of
                             mercury in the corpus callosum.  The patient experienced
                             blurred vision, deafness, ataxic dysarthria, incoordin-
                             ation and weakness of arms and legs.
ANIMALS:     Rats,  Adult,  M
                                                                                             ANIMALS:    Human:   M,  29  (one case)
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1.0 mg/kg/d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Occupational exposure of 7 wk before onset of  symptoms,  died
                           25 wk after  first exposure
ROUTE AND SITE:   Oral and injections

CONTROL INFORMATION:   ns.
                                                                 ROUTE AND SITE:  ns

                                                                 CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:Serial  sacr.  5 hr,  12 hr,  1 d,  4 d,  1 wk,  6 wk,  11 wk.

EXAM. TYPE:  Ultrastructural,  histology
                                                                 DURATION OF EXPERIMENT:   25 wk

                                                                 EXAM. TYPE:   Clinical, histology
                                            641
                                                                                                                                        642

-------
COMPOUND:   Mercury,  chloroethyl-

            000107277

REFERENCE:  Kasuya, M.
            Tox. Appl. Pharm. 32:347-354, 1975.
OBSERVED NEUROTOXIC EFFECTS:
Compound inhibited outgrowth.  Vitamin E pro-
tected against toxicity,  less  potently against
ethylmercuric chloride than methylmercuric chloride.
Interpreted that alkyl mercurials interact with
membranes to produce nerve degeneration.
COMPOUND:   Mercury, chloroethyl-

            000107277

REFERENCE:  Takeda, Y., Kunugi, T., Hoshino,  0.  and  Ukita,  T.
            Tox. Appl. Pharm. 13:  156-164,  1968.


OBSERVED NEUROTOXIC EFFECTS:  Alkyl mercury  compounds  excreted more slowly than inorganic
                              or aryl compounds.   Metabolism varied with C-chain length.
                              Distribution in brain  and reported neurotoxicity were re-
                              lated to structure of  compound.
ANIMALS:     In vitro slices of newborn rat cerebella
                                                                                           ANIMALS:    Rats, Donryu,  aged 7 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           6 x 10   to 2 x 10   M; in presence of ethanol 0.1-0.4%,
                           glucose 550 mg/100 ml, and vitamin E (DL-a-tocopherol
                           acetate) 0-2 x 10~5 M.
                                                           PREPARATION AND  DOSE
                                                           or HISTORY OF  PATIENT:  Compounds  labeled with ^UJHg; mercuric chloride 3 mg/kg,
                                                                                   others  10  mg/kg (one dose).
                                                203.,
ROUTE AND SITE:   Culture medium

CONTROL INFORMATION:   Zero levels of various additives to medium
                                                           ROUTE AND SITE:  S.C.

                                                           CONTROL  INFORMATION:  ns
DURATION OF EXPERIMENT:     4 d

EXAM.  TYPE:  Microscopic outgrowth of neurons and fibroblasts
                                                           DURATION OF EXPERIMENT:  Serial  1-8  d

                                                           EXAM. TYPE:  Biochemistry
                                          643
                                                                                                                                       644

-------
COMPOUND:       Mercury, chloromethyl-

                000115093

REFERENCE:     Carmichael, N.,  Cavanagh, J.B., and Rodda, R.A.
               Acta Neuropath.  32(2):115-125, 1975.
                                                           COMPOUND:    Mercury,  chloromethyl-

                                                                       000115093

                                                           REFERENCE:   Chang, L.W. Desnoyers,  P.A., and Hartmann, H.A.
                                                                       J. Neuropath. Exp. Neurol. 31(3):489-501, 1972.
OBSERVED NEUROTOXIC EFFECTS:
Severe ataxia.  Primary sensory ganglion cells,
cerebellar Purkinje and granule cell and forebrain
cell degeneration.  Wallerian degeneration of
sensory neurones, widespread pyknosis of cerebellum,
symmetrical changes in cerebral cortex.
                                                           OBSERVED NEUROTOXIC  EFFECTS:
     Continuous decrease in RNA content in spinal
     ganglion neurons.  Except for cell swelling
     during first week of methylmercury poisoning,
     cell volume decreased after poisoning.  Moderate
     increase in RNA after poisoning was noted in
     anterior horn motoneurons.
ANIMALS:
                Rabbits, New Zealand, White, M and F, young 1.0-2.5 kg.
                                                           ANIMALS:     9 Rats, S-D (Holtzman), 150 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    7.5 mg/kg/d for 3-4 d, as suspension  (5 mg/tnl)
                          in 50% polyethylene glycol 400.  Total 22.5 or 30 mg/kg.
                                                           PREPARATION  AND  DOSE
                                                           or HISTORY OF  PATIENT:
Daily dosage of 1.0 mg/kg body weight
ROUTE AND SITE: s.C., neck

CONTROL INFORMATION:       2 rabbits
                                                           ROUTE  AND SITE:   Orally, stomach tube, S.C.

                                                           CONTROL  INFORMATION:   6 Rats
DURATION OF EXPERIMENT:    Serial sacr:  l,2,8d.

EXAM. TYPE:     Histology, vascular.
                                                           DURATION OF EXPERIMENT:     Serial sacr 1 wk, 2 wks, 6 wks, 11 wks.

                                                           EXAM.  TYPE:  Histology, quantitative, cytochemical studies.
                                        645
                                                                                                                                    646

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COMPOUND:     Mercury,  chloromethyl-

              000115093

REFERENCE:   Chang,  L.W.  and Hartmann,  H.A.
             Exp. Neurol.  35:122-137, 1972.
OBSERVED NEUROTOXIC EFFECTS:
     General distribution of mercury parallel to
     gross neuropathology;  intracellular binding
     to membraneous structures in cytoplasm, minimally
     in nucleus.
ANIMALS:     Rats,  S-D,  adult  M
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1 mg/kg/d
ROUTE AND SITE:    Gavage or S.C.

CONTROL INFORMATION:    Mentioned,  not described



DURATION OF EXPERIMENT:     1 d to 11 wk,  serial

EXAM. TYPE:  Histochemistry
                                            647
                                                                    COMPOUND:       Mercury, chloromethyl-

                                                                                   000115093

                                                                    REFERENCE:      Chang, L.W. and Hartmann, H.A.
                                                                                   Acta Neuropath. 20:316-334, 1972.
                                                                                               OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                              After 4 days, mercury apparent in axoplasm.  Dorsal
                                                                                                                              root fiber pathology after 1 wk.  Axonal de-
                                                                                                                              generation with destruction of myelin.  Limited
                                                                                                                              damage to ventral root fibers and extensive damage
                                                                                                                              to sciatic nerve in 2nd wk.  Phagocytosis by
                                                                                                                              Schwann cells observed.
                                                                                               ANIMALS:
                                                                                                               Rats, adult M
PREPARATION AND DOSE
or HISTORY OF PATIENT:     1 mg/kg/d
                                                                   ROUTE AND SITE:  oral  or  I.P.

                                                                   CONTROL INFORMATION:      ns.
                                                                   DURATION OF EXPERIMENT:    Serial to 11 wk.
                                                                   EXAM. TYPE:
                                                                                                               Histology
                                                                                                                                        648

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COMPOUND:  Mercury, chloromethyl-
                                                                                         COMPOUND:    Mercury, chloromethyl-

                                                                                                      000115093
 REFERENCE:  Fehling, C., Abdulla, M.,  Brun,  A.,  Dictor,  M.,  Schutz,  A.  and Skerfving,  S.
            Toxicol. Appl. Pharm. 33:27-37,  1975.


 OBSERVED NEUROTOXIC EFFECTS:  Waddling gait, cross of hindlimbs and  severe
                              involvement of righting reflexes.  Wallerian
                              degeneration and edema and degeneration of
                              sensory ganglia.  Partial reversible peripheral
                              neuropathy.
REFERENCE:   Carman,  R.H.,  Weiss,  B.  and Evans,  H.L.
             Acta Neuropath.  32:61-74,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                                 Neuronal damage in cerebral cortex, eosimophilic
                                 neuron degeneration, loss of Nissl substance,
                                 impairment of touch and vision.  Loss of pro-
                                 prioceptive sense, incoordination, astereognosis.
'ANIMALS:   30 Rats,  Wistar,  M,  135-170 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20 or 40 mg Hg/kg/d as soln with dilute sodium hydroxide
                         and 20% (w/w)  egg albumin.
                                                                                         ANIMALS:      14  Squirrel Monkeys,  Saimiri sciureus,  Male
                                                                                                      6   Monkeys, Macaca, Male
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            0.4-4  mg Hg/kg/wk.
ROUTE AND SITE:  I.  Tub.

CONTROL INFORMATION:  10  controls mercury-free albumin soln.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:   15 d

EXAM. TYPE:  Neurological,  chemical,  nerve conduction velocity,  histopathology.
DURATION OF EXPERIMENT:      Sacr.  at various intervals.

EXAM.  TYPE:  Clinicopathology,  autoradiography,  necropsy, histology
                                       649
                                                                                                                                   650

-------
COMPOUND:   Mercury, chloromethyl-

            000115093


REFERENCE:   Harris,  S.B., Wilson, J.G. and  Printz, R.H.
             Teratology  6:139-142, 1972.
OBSERVED NEUROTOXIC EFFECTS:  Hydrocephalus among surviving fetuses.  Compound
     produced  significant amounts of embryotoxicity, and also produced some maternal
     toxicity.
COMPOUND:     Mercury, chloromethyl-

              000115093

REFERENCE:     Iverson,  F.,  Downie, H.,  Paul, C. and Trenholm, H.L.
               Tox.  Appl.  Pharm.  24:545-554, 1973.
OBSERVED NEUROTOXIC EFFECTS:
Loss of muscular control  (neurotoxiclty)  1-2
wk after treatment, some  cases.  In Central nervous
system levels ranked cerebrum, cerebellum, cord,
dose-related; decay (elimination) rate not dose-
related but biphasic.
ANIMALS:   Golden hamsters,  F,  pregnant, at least 134
                                                                                         ANIMALS:
                                                                                                        Guinea-pigs,  English, F, 400-500 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)  2-8 mg/kg  in  carboxymethylcellulose  (0.2%) one time,
     d 5-10 of  pregnancy;
     (2)  Groups of  20 given 8 mg/kg  on  d 5,  8 or  9.
     (3)  10 animals given  4 mg/kg  on d  8.
     (4)  Chronic: 1,  4,  or 2 mg/kg/d for 14  d.

ROUTE AND SITE:  i.p.

CONTROL INFORMATION:  Control group  vehicle  only.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Acute toxicity
                         I.P.:  1.5-9.1 mg Hg/kg
                         P.O.:  4-30 mg Hg/kg
                         in 5mM sodium carbonated at 0.5 ml/100  g  to  10 animals each dose.


ROUTE AND SITE:  Oral, i.p.

CONTROL INFORMATION:     Controls:  sodium carbonate treatment.
DURATION OF EXPERIMENT:    Sacr  on  d  15  of pregnancy

EXAM. TYPE:  Teratological
DURATION OF EXPERIMENT:  Serial sacr, 1-49 d after dose.

EXAM. TYPE:    Mortality, biochemistry
                                      651
                                                                                                                                    652

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COMPOUND:     Mercury,  chloromethyl-

              000115093

REFERENCE:   Kasuya,  M.
             Tox.  Appl. Pharm. 32:347-354, 1975.
                                                                                                 COMPOUND:
                                                                            Mercury, chloromethyl-

                                                                            000115093
                                                                REFERENCE:   Khera, K.S.
                                                                            Teratology 8:293-304, 1973.
OBSERVED NEUROTOXIC EFFECTS:
Compound Inhibited outgrowth. Vitamin E pro-
tected against toxicity, less potently against
ethylmercuric chloride than methylmercuric chloride.
Interpreted that alkyl mercurials interact with
membranes to produce nerve degeneration.
OBSERVED NEUROTOXIC EFFECTS: Mercury  6.6  ppm  in  maternal brain.   Fetal cerebellum:
     transient  external granular  layer  thinner than  in  controls;  cell aggregates
     in incipient molecular layer more  common than in controls, changes dose-
     related, mainly  in 0.25 mg/kg  grp.
ANIMALS:     In vitro slices of newborn rat cerebella
                                                                                                ANIMALS:   Cats of random origin, 2.2-3.5 kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            10   M;  in presence of ethanol 0.1-0.4%,  glucose
                            550 mg/100 ml,  and vitamin E (DL-o-tocopherol  acetate)
                            0-2 x 10~5 H.
                                                                PREPARATION AND  DOSE
                                                                or HISTORY OF  PATIENT:  0.03-0.75 mg/kg/d in corn oil d 10-58 of pregnancy.
ROUTE AND SITE:   Culture medium

CONTROL INFORMATION:    Zero levels of various additives to medium
                                                                ROUTE  AND  SITE:   Oral in gelatin capsules

                                                                CONTROL  INFORMATION:  Controls treated corn oil alone
DURATION OF EXPERIMENT:      4 d

EXAM. TYPE:  Microscopic outgrowth of neurons and fibroblasts
                                                                DURATION OF  EXPERIMENT:      Sacr on d  59 of pregnancy

                                                                EXAM. TYPE:   Teratological
                                           653
                                                                                                                                       654

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COMPOUND:  Mercury, chloromethyl-

           000115093

REFERENCE: Khera,  K.S.,  Iverson,  F.,  Hierlihy, L., Tanner, R. and Trivett, G.
           Teratology 10:69-76,  1974.


OBSERVED NEUROTOXIC EFFECTS:   Clinical:   0.5 mg/d and over, ataxia, visual,
     sensory  and righting-reflex  losses.   High brain levels of mercury.
     Cerebral degeneration,  especially in white matter of cortex and internal
     granular layer of cerebellum.
ANIMALS:   Cats,  age 4-9 d
PREPARATION AND DOSE
or HISTORY. OF PATIENT:
     up to 184 d.
0.25-1.0 mg/kg dissolved in 0.05%,  NaHCO-,  daily,
ROUTE AND SITE:        Gavage

CONTROL INFORMATION:   Control treatment  vehicle  only



DURATION OF EXPERIMENT:       Maximum  184 d.

EXAM. TYPE:  Biochemistry,  histology
                                      655
                                                                  COMPOUND:     Mercury,  chloromethyl-
                                                                               000115093


                                                                  REFERENCE:    Ware,  R.A.,  Chang,  L.W.  and Burkholder, P.M.
                                                                               Acta Neuropath 30:211-224, 1974.
                                                                  OBSERVED  NEUROTOXIC  EFFECTS:   infrastructure damage and subsequent dysfunction
                                                                      of blood-brain barrier induced 4-6 hr after administration.  Horseradish
                                                                      peroxidase demonstrated:   tracer extravasation into brain parenchyma after
                                                                      4 hr  and,  tracer permeation into neurons and axons after 10-12 hr.
                                                                  ANIMALS:    72 Rats, S-D, M, adult, av 200 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT: 10 mg/kg,  followed  10  min prior to sacr by Horseradish
    peroxidase:  10 mg in 0.25 ml saline,  i.v.
                                                                  ROUTE AND SITE:   I.P.

                                                                  CONTROL INFORMATION:    18 rats, 1 ml saline as controls.



                                                                  DURATION OF EXPERIMENT:   Serial sacr 0.5-24 hr.

                                                                  EXAM. TYPE:  Histochemistry, Histology
                                                                                                                                    656

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COMPOUND:     Mercury,  chlorophenyl

              000100561 •

REFERENCE:  Takeda, Y., Kunugl, T.,  Hoshino, 0. and Ukita, T.
            Tox.  Appl.  Pharm. 13:  156-164, 1968.


OBSERVED NEUROTOXIC EFFECTS:  Alkyl mercury compounds excreted more slowly than  Inorganic
                 I             or aryl compounds.  Metabolism varied with C-chain length.
                              Distribution in brain and reported neurotoxicity were  re-
                              lated to structure of compound.
COMPOUND:  Mercury,  (3-cyanoguanidino)methyl-
           000502396


REFERENCE:   Cavanagh,  J.B.  and Chen,  F.C.K.
             Acta Neuropath.  19:208-215,  1971.
OBSERVED NEUROTOXIC EFFECTS:   Early loss of hindlimb control,  recovery complete
     5 wk after stopping doses (5 mg/kg).  Gross ataxia of all limbs at 14-16
     d, recovery always incomplete,  some died (7.5 mg/kg).  By 10th-12th d
     Wallerian degeneration in peripheral nerves,  then spinal ganglion cells,
     then axonal degeneration in cord,   then discrete degeneration in cerebellum
     (Purkinje cells normal, no other brain findings).
ANIMALS:    Rats, Donryu, aged 7 wk
                                                                                                ANIMALS:   Rats,  WAG/C,  S-D,  and Porton,  M and F
PREPARATION AND DOSE
                                               203,,
or HISTORY OF PATIENT:  Compounds labeled with    Hg; mercuric chloride 3 mg/kg,
                        others 10 mg/kg (one dose).
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.25 mg/ml,  in 50% polyethyleneglycol 400
     (1)   5 mg/kg/d for 8 d.
     (2)   7.5 mg/kg/d for 8 d.
ROUTE AND SITE:  S.C.

CONTROL INFORMATION:  ns
ROUTE AND SITE:       Gavage

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:   Serial 1-8 d

EXAM. TYPE:  Biochemistry
DURATION OF EXPERIMENT:   "Many months"

EXAM. TYPE:  Histology,  behavior
                                           657
                                                                                                                                       658

-------
COMPOUND:   Mercury, (3-cyanoguanidino)methyl-
           000502396


REFERENCE:     Diamond, S.S. and Sleight, S.D.
              Tox.  Appl. Pharm. 23:197-207, 1972.
                                                                 COMPOUND:  Mercury,  (3-cyanoguanidino)  methyl-

                                                                           000502396

                                                                 REFERENCE:   Magos, L. and  Butler, W.H.
                                                                             Fd. Cosmet. Toxicol. 10:   513-517,  1972.
OBSERVED NEUROTOXIC EFFECTS:  Demyelination of sciatic nerve, atrophy of
                             cerebellum granular cells,  Neuronal degeneration
                             in cerebrum, hippocampus and cervical spinal
                             cord.  Peripheral nervous system and cerebellum
                             lesions.
                                                                 OBSERVED NEUROTOXIC EFFECTS:
                                                                                               Dose-time-related  linear  accumulation of methyl
                                                                                               mercury  in  the  brain .   Granular-layer necrosis was
                                                                                               observed in the cerebellum with white-matter edema.
                                                                                               Ataxia was  apparent.
ANIMALS:    84 Fats,  S-D,  M,  lOOg
                                                                 ANIMALS:
                                                                                                       Rats, Porton, F, 200 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
(1)   0.5-25.0 mg/100 g bw,  single  dose.
(2)   20 rats given U>50>  1.:

(3)   1.0 mg/100 g bw,  1/wk.
                          (2)   20 rats  given U>50>  1.335 mg/100  g bw.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.84 mg Hg/kg/d,  5  d/wk for up to 59 doses
                        1.68 mg Hg/kg/d,  5  d/wk for up to 34 doses
                        3.36 mg Hg/kg/d,  5  d/wk for up to 16 doses
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:   (2)   6 rats distilled water
                                                                 ROUTE AND SITE:   Oral

                                                                 CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   (1)   1 wk,

EXAM. TYPE:    Clinical,  histology
                                                                 DURATION OF EXPERIMENT:   Sacrificed after last dose  if  surviving

                                                                 EXAM.  TYPE:    Behavior,  histology, chemistry
                                       659
                                                                                                                                    660

-------
 COMPOUND:  Mercury, (3-cyanoguanldino) methyl-
           000502396
 REFERENCE:Spyker, J.M.
          Federation Proc. 34:1835-1844, 1975.
OBSERVED NEUROTOXIC EFFECTS:  Offspring of 6 mo-yr whose mothers were exposed to
                              8 mg/kg displayed tremors, ataxia, difficulty
                              righting.  Those of mothers exposed to a smaller
                              dose underwent retarded growth and development.
                              Mothers unaffected.
                                                                                              COMPOUND:  Mercury,  cysteinylethyl-
REFERENCE:   Mukai, N.
             Acta Neuropath.  22:102-109, 1972.


OBSERVED NEUROTOXIC EFFECTS:   Accretion in central nervous; predicatable selective
     necrosis of small granular neurons in koniocortex and neostriatum.  Astroglial
     cell compartment believed to transport mercury protein complex into neurons.
ANIMALS:  Mice, Strain 129/SvSl:  nulliparous, F, offspring
                                                                                              ANIMALS:   Mice:  24 C3H and 27 CD-I, 20-25 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    0.5-8 mg/kg in saline.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.3 mg/d in 0.5 ml saline x 8 d, labeled with tritium.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:     Females with saline gave birth to offspring which developed
                         normally.
DURATION OF EXPERIMENT:   1 yr.

EXAM.  TYPE:    Behavior, neurochemical analysis
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:  None



DURATION OF EXPERIMENT:  15 d

EXAM. TYPE:  Histology, autoradiography
                                         661
                                                                                                                                     662

-------
COMPOUND:
Mercury,  ((2,3-dihydroxypropyl)thio)methyl-
REFERENCE:    Charlton,  K.M.
              Can.  J.  Comp. Med.  38:75-81,  Jan.  1974.
                                                                              COMPOUND:     •  Mercury, hydroxymethyl-

                                                                                              001184572

                                                                              REFERENCE:    Berlin,  M.,  Grant,  C.A.,  Hellberg,  J.  and SchUtz, A.
                                                                                            Arch.  Env. Hlth.  30:340-348,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                                 Gait  disturbance.  Peripheral nervous system:
                                 Wallerian  degeneration in sensory  fibers and
                                 neuronal degeneration in dorsal root ganglia.
                                 Lesions caused by neuronal-axonal  degeneration.
                                 Central nervous  system:  Ischemic  neuronal
                                 degeneration  glial degeneration,and gliosis.
                                                                              OBSERVED NEUROTOXIC EFFECTS:
                                                                                                              Operant behavior tests,  filmed.  As blood mercury was
                                                                                                              increased,  sudden visual disorder was seen, suggesting
                                                                                                              tissue threshold for mercury toxicity.  Typical cerebral
                                                                                                              cortical lesions always  involved visual cortex, and the
                                                                                                              tissue methylmercury level was claimed to be the
                                                                                                              lowest associated with such lesions yet seen.
ANIMALS:      20 Pigs,  Yorkshire,  7  M and 13 F,  10  wk old.
                                                                              ANIMALS:
                                                                                                           Squirrel monkeys, M and F, 500-1000 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    0.24-5.76  mg Hg/kg/d.
                                                                              PREPARATION AND DOSE
                                                                              or HISTORY OF PATIENT:    0.2-0.8 mg/monkey/wk, adjusted to produce desired level
                                                                                                        in blood; 4 levels apparently aimed at (0.6-1.8 mcg/g);
                                                                                                        in some expts labeled methylmercury given.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:      4 untreated controls.
                                                                              ROUTE AND SITE:  Gavage

                                                                              CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:   2 sacr at 1 d,  others  left to  die.

EXAM.  TYPE:    Histology,  necropsy.
                                                                              DURATION OF EXPERIMENT:   Approx 9 mo.

                                                                              EXAM. TYPE:    Behavior, biochemistry, histology
                                           663
                                                                                                                                       664

-------
COMPOUND:   Mercury, hydroxymethyl-

            001184572

REFERENCE:   Falk,  S.A., Klein, R., Baseman, J.K., Sanders, G.M., Talley F.A.
             and Lira, D.J.
             Arch.  Path. 97:297-305, 1974.

OBSERVED NEUROTOXIC EFFECTS:    Only wt. loss, lethargy clinically; slow
    increase of brain mercury; pyknotic neurons in cerebellum.
COMPOUND:   Mercury, hydroxymethyl-

            001184572


REFERENCE:    Herman,  S.P., Klein,  R.,  Talley,  F.A.  and Krigman, M.R.
              Lab.  Invest.  28(1):104-118,  1973.


OBSERVED NEUROTOXIC EFFECTS:   Ataxic hindlimb gait,  selective Wallerian-like
                              degeneration in sensory fibers in dorsal root, sciatic
                              nerve, brachial plexus and sural nerve.  Sensory
                              polyneuropathy in peripheral nerves, spinal
                              ganglia and  cord.   Wallerian degeneration in
                              peripheral sensory axons and central nervous
                              system neuronal necrosis.
ANIMALS:   Guinea-pigs, Hartley, M, 250-300 g
ANIMALS:   16  Rats,  albino,  C-D,  M
PREPARATION AND DOSE
or HISTORY OF PATIENT:  2 mg/kg/d, 5 d/wk, for 1-6 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2 mg Hg/kg/d,  5 d/wk for 1-3 wk.
ROUTE AND SITE:   s.C.

CONTROL INFORMATION:    Uttermates, total 55, no details.
ROUTE AND SITE:   S.C.

CONTROL INFORMATION:   6 Rats treated sterile water.
DURATION OF EXPERIMENT:   Serial sacr to 11 wk.

EXAM.  TYPE:  Clinical, biochemical, histology
DURATION OF EXPERIMENT:    Sacr 1-24 d

EXAM.  TYPE:   Ultrastructural, histology, clinical
                                       665
                                                                                                                                    666

-------
COMPOUND: Mercury,  hydroxymethyl-

          001184572

REFERENCE:   Null,  D.H.,  Gartside,  P.S.  and Wei,  E.
             Life Sci.  12(2):65-72, 1973.
OBSERVED NEUROTOXIC EFFECTS:    Mercury cone in fetal brains  "at  least  twice"
     that in dams or nonpregnant adults.   Interpreted by authors to  explain
     greater susceptibility of fetus to compound.
COMPOUND:   Mercury, mercaptomethyl-
REFERENCE:  Miyakawa, T., Deshimaru, M.,  Sumiyoshi,  S.,  Teraoka, A., Udo, N.,
            Hattori, E.  and Tatetsu,  S.
            Acta Neuropath.  15:45-55,  1970.
OBSERVED NEUROTOXIC EFFECTS:
Pathological changes in peripheral sensory  nerve
fibers:  swelling and degeneration of  Schwann cells;
changes in both myelin sheaths and axons  (beginning
at nodes of Ranvier).
ANIMALS:   20 Rats, F, 200-220 g,  pregnant and non-pregnant.
                                                                                        ANIMALS:     Rats, adult, M, 100-115 g, 4 x 3  (rats & groups)
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5-40 mg Hg/kg to pregnant (d 13  gestation)  and non-
     pregnant rats.   Preliminary tests showed highest mercury concentration
     in brain found  5-9 d after treatment.
PREPARATION AND DOSE
or HISTORY OF PATIENT: 1 mg/rat/d
ROUTE AND SITE:    S.c.

CONTROL INFORMATION:  Control:   saline only.
ROUTE AND SITE:        Oral

CONTROL INFORMATION:   4 Rats
DURATION OF EXPERIMENT:   7 d after treatment

EXAM. TYPE:    Chemistry
DURATION OF EXPERIMENT:  Sacrifice on d 4, 8, 12, 20.

EXAM. TYPE:  Histology
                                       667
                                                                                                                                    668

-------
COMPOUND:   Mercury, mercaptomethyl-
COMPOUND:   Mercury, methjl-
REFERENCE:   Mlkayawa,  T.,  Deshimaru,  M.,  Sumiyoshl,  S.,  Teraoka,  A.  and  Tatetsu,  S.
             Acta  Neuropath.  17:6-13,  1971.
                                                                                             REFERENCE:
                Abe, T., Haga, T. and Kurokawa, M.
                Brain Res. 86:504-508, 1975.
OBSERVED NEUROTOXIC EFFECTS:
                                 Day  7:  Mitosis  of  Schwann cells.   Day  250:   Decreased
                                 number  of myelinated  fibers;  some  regeneration
                                 (peripheral nervous system).   Posterior nerve root
                                 ganglion cells intact.
OBSERVED NEUROTOXIC EFFECTS:     Blockage of axoplasmic transport.  Depolymerized
                                 cerebral microtubules in vitro.
ANIMALS:     6  Rats,  adult,  M,  100-115  g
ANIMALS:   Frogs, R. catesbeiana
PREPARATION AND DOSE
or HISTORY OF PATIENT: 1 mg/rat/d  for  20  d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           (1) 5 mcl of 5mM methyl mercury  2 hr after  labeled leucine.
                           (2) 108.5 mcM to purified microtubule  protein from pig brain.
ROUTE AND SITE:   oral

CONTROL INFORMATION:    2  Rats
ROUTE AND SITE: Inj., 9th dorsal root ganglion; In vitro

CONTROL INFORMATION:       Vehicle only
DURATION OF EXPERIMENT^ Rats  sacrificed  7  d  after  last  dose,  3  sacrificed  250  d
                       afterwards.   1  rat/gp  control.
EXAM. TYPE: Histology
DURATION OF EXPERIMENT:     38 hr.

EXAM. TYPE:     Biochemistry
                                          669
                                                                                                                                        670

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COMPOUND:  Mercury, methyl-
                                                                                           COMPOUND:
                                                                                                          Mercury,  methyl-
REFERENCE:    Albanus,  L.,  Frankenberg,  L.,  Grant,  C., von Haartman, U.,
              Jernelov,  A.,  Nordberg,  G.,  Rydalv, M., Schutz, A. and Skerfving, S.
              Env.  Res.  5:425-442,  1972.
OBSERVED NEUROTOXIC EFFECTS:
Gait and visual field impairment, convulsions.
Over 90% of mercury was absorbed, 20% found in hair,
1% of remainder in brain (18 meg/kg, all as
methyl-mercury, comparable with compound as
administered in lab experiments.
                                                             REFERENCE:
                                                                             Fox, H.H., Patel-Mandlik, K. and Cohen, M.M.
                                                                             J. Neurochem. 24:757-762, 1975.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                          Decreased oxygen uptake and carbon dioxide
                                                                                                                          production, increased production of pyruvate
                                                                                                                          and lactate.  Authors propose inhibition of
                                                                                                                          tricarboxylic acid cycle as basis of organomercury
                                                                                                                          neurotoxicity.
ANIMALS:    Pike (Esox lucius)  from contaminated  and uncontaminated waters;
           Cats,  European short-haired,  9  F  and  6  M in  3  grps  of  3 F and  2 M.
                                                             ANIMALS:
                                                                             Guinea-pig brain slices  in  vitro.
PREPARATION AND DOSE
Or HISTORY OF PATIENT:   The pike were  fed  to  the  cats.   Contaminated  fish had
                        been exposed to  phenyl mercury  acetate.  Trace  amounts
                        of methylmercury hydroxide sprayed  on  homogenized
                        contaminated and uncontaminated fish.  Amount added
                        corresponded to  0.6%  of mercury present  originally.

ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Noncontaminated fish,  homogenized and frozen without
                       further treatment.
                                                             PREPARATION AND DOSE
                                                             or HISTORY OF PATIENT:    0.01-0.5 mM in medium
                                                             ROUTE AND SITE: In vitro  incubation

                                                             CONTROL INFORMATION:       Mercury-free medium used for control.
DURATION OF EXPERIMENT:   Up to 82 d

EXAM. TYPE:    Behavior,  biochemistry
                                                             DURATION OF EXPERIMENT:    1 hr in some cases.

                                                             EXAM. TYPE:      Biochemistry
                                       671
                                                                                                                                    672

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COMPOUND:   Mercury,  methyl-
                                                                                         COMPOUND:   Mercury, methyl-
REFERENCE:    Ganther, H.E.,  Goudie, C.,  Sunde, M.L., Kopecky,  M.J.,  Wagner,  P.
              Oh, S-H. and Hoekstra, W.G.
              Science 175:1122-1124, 1972.

OBSERVED NEUROTOXIC EFFECTS:  Death rate from mercury diminished by selenium
                              in amounts reported.
REFERENCE:  Iwata, H., Okamoto, H. and  Ohsawa,  Y.
            Res. Comn. Chem. Path. Pharm.  5(3):673-680,  1973.
OBSERVED NEUROTOXIC EFFECTS:
     A dose of 0.5 mg/kg sodium selenite  given  S.C.
     with the compound increased immediate accumulation
     of mercury in the brain but not in other organs;
     after 1 wk this accumulation was decreased.   The
     authors concluded that selenium complexing with
     mercury hastened excretion of mercury.
ANIMALS:  360 Japanese quail (Coturnix coturnix japonica).  day-old, in 8 grps of 45.
                                                                                         ANIMALS:     Rats,  Wistar,  M,  140-160 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:    0-20 ppm Hg as methylmercury in diets (various)
                          with/without natural Se or Se supplement 0.5 ppm as
PREPARATION AND DOSE
or HISTORY OF PATIENT:
10 mg/kg/d 8-10 d
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Yes
ROUTE AND SITE:    Oral

CONTROL INFORMATION:
DURATION OF EXPERIMENT:   Serial sacr to 7 wk

EXAM.  TYPE:   Epidemiology, behavior
DURATION OF EXPERIMENT:      24 hr  or  1 wk

EXAM.  TYPE:  Behavior, mortality,  biochemistry
                                       673
                                                                                                                                   674

-------
COMPOUND: Mercury, methyl-
                                                                                COMPOUND:  Mercury, methyl-
REFERENCE:   Klein,  R., Herman, S.P. Brubaker, P.E., Lucier, G.W. and
             Krigman, M.R.
             Arch. Path.  93:408-418, 1972.

OBSERVED NEUROTOXIC EFFECTS:    Ataxia, hindlimb-crossing; advanced peripheral
    neuropathy,  vacuoles  and neurophagia in anterior horns, fewer neurons in
    parts of  brainstem,   pyknotic nuclei in internal granular layer of cerebellum.
                                                                                REFERENCE:   Matsumoto, H.,  Koya,  G.  and Takeuchi,  T.
                                                                                            J. Neuropath. Exp.  Neurol.  24(4):563-574, 1965.


                                                                                OBSERVED NEUROTOXIC EFFECTS:   Small  brains (650 g vs normal 960 g at 2.5 yr;
                                                                                     630 g vs  1125  g normal  at  6 yr.   Disorganized cellular structure of cortex,
                                                                                     no  active demyleination but poor corpora callosa, atrophy of cerebellum;
                                                                                     no  great  changes in brain  stem,  few in cord, retina intact.  However,
                                                                                     pyramidal tracts were demyelinated, in brain and cord.  Picture claimed
                                                                                     typical of Minamata disease.
ANIMALS:
Rats, Chalres Rvier,  M,  280-365 g,  total 28 in 4 grps
                                                                                             ANIMALS:   2 Human autopsies
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)   6 rats,  20 mg/kg in 2 doses  1/d,  killed  on  d  3.
    (2)  6 rats, 50 mg/kg in  5 doses 1/d, killed on d  6.
    (3)  6 rats, 70 mg/kg in  7 doses 1/d, killed on d  8.
    (4) 10 rats, 70 mg/kg in  7 doses 1/d, killed on d  15.
                                                                                PREPARATION AND DOSE
                                                                                or HISTORY OF PATIENT:     2 F human children inferred to have been exposed in utero.
                                                                                     Autopsy findings at  2.5 and 6 yr respectively.  Families had histories of
                                                                                     Minamata disease,  no exposure of subjects.
ROUTE AND SITE:  s.C.

CONTROL INFORMATION:   26 in 4 grps,  paired with above.
                                                                                ROUTE AND SITE:        Transplacental

                                                                                CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   Serial sacr to 15 d

EXAM. TYPE:  Behavior, histology
                                                                                DURATION OF EXPERIMENT:

                                                                                EXAM.  TYPE:  Histopathology
                                       675
                                                                                                                                    676

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COMPOUND:    Mercury,  methyl-
COMPOUND:  Mercury, methyl-
REFERENCE:
                Rustam,  H.  and Hamdi,  T.
                Brain 97:499-510,  1974.
REFERENCE:     Rustam,  H.,  Von Burg,  R.,  Amin-Zaki,  L.  and El Haasani, S.
               Arch.  Env. Hlth.  30:190-195,  1975.
OBSERVED NEUROTOXIC EFFECTS:
                                 Multiple system involvement in most cases,
                                 severity varied within families.   In coordination,
                                 ataxic gait,  dysarthria and nystagmus.   Reduced
                                 visual acuity,  blindness and some speech
                                 disturbance.   Sensory changes like peripheral
                                 neuropathy were not confirmed electrophysiologically.
OBSERVED NEUROTOXIC EFFECTS:    Selective muscle weakness was uncovered; neostigmine
                                produced clinical improvement that was transient, suggesting
                                direct/indirect action of methyl mercury on transmitter
                                release.
ANIMALS:
                53 Humans,  30 F,  23 M,  5-60 yr.
ANIMALS:
               Human:   3 cases (F 25,  M 10,  F 10)  from the 1972 outbreak with
               delayed recovery.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           Consumption of bread made from wheat  treated with
                           compound.   Grain eaten within 1-3 mo,  and 2-8 wk
                           intervened between last poisoned  meal  and onset  of
                           symptoms.   Patients selected from 6,530  admitted to
                           hospital.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   ns.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Effects of neostigmine therapy on electromyography were
                         tested.  0.25-0.5 mg neostigmine and 0.3-0.6 mg atropine
                         sulfate were given.
ROUTE AND SITE:   i.M.

CONTROL INFORMATION:      Alternate drug and placebo periods in each case.
DURATION OF EXPERIMENT:
EXAM.  TYPE:
                           Cases  occured between  1956-1962.
                Clinical, physiological,  clinical  laboratory.
DURATION OF EXPERIMENT:   Months

EXAM. TYPE:    Electrophysiology,  behavior
                                          677
                                                                                                                                       678

-------
COMPOUND:  Mercury, methyl-
                                                               COMPOUND:   Mercury,  methyl-
REFERENCE: Salvaterra,  P.,  Lown,  B.,  Morganti,  J.  and  Massaro,  E.J.
           Acta Pharmacol.  Toxicol.  33:   177-190,  1973.


OBSERVED NEUROTOXIC EFFECTS:  Open field  tests and  alterations of selected glycolytic
                             pathway intermediates corresponded and  were dose-related,
                             at 1 and 3  hr after doses;  by 72 hr all normal.
                                                               REFERENCE:     Somjen,  G.G., Herman, S.P., Klein, R. and Krigman, M.R.
                                                                              Env.  Hlth. Persp. 4:99, 1973.  (Abstract).
                                                               OBSERVED NEUROTOXIC EFFECTS:
                                Sensory neurons of dorsal root ganglia damaged
                                first and most, accumulate methyl mercury more
                                avidly.  Neurons held more mercury than glia,
                                satellite cells or Schwann cells.
ANIMALS:   Mice,  Swiss-Webster,  M,  25-32 g,  6/grp.
                                                               ANIMALS:
                                                                              Rats
PREPARATION AND DOSE
or HISTORY OF PATIENT:
(1)  1,  5,  10 mg Hg/kg as  chloride salt.
(2)  10  mg  Hg/kg (single doses).
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:   NaCl treated controls.
                                                                ROUTE AND SITE:  ns.

                                                                CONTROL  INFORMATION:      ns.
DURATION OF EXPERIMENT:  (1) Serial sacr to 74 hr.   (2)  Serial sacr to 7 d.

EXAM. TYPE:  Behavior, biochemistry
                                                                DURATION OF  EXPERIMENT:   ns.

                                                                EXAM.  TYPE:    Behavior, electrophysiology,  radlosotope studies
                                           679
                                                                                                                                        680

-------
COMPOUND:
Mercury, methyl(methylthio)-
                                                                                         COMPOUND:
                                                                                        Mercury, Methyl(thioacetamido)-
REFERENCE'    Miyakawa,  T.,  Sumiyoshi,  S. and Deshimaru, M.
              Acta Neuropath.   30:33-41,  1974.
OBSERVED NEUROTOXIC EFFECTS:   Destruction of myelin sheath, slight ataxia in
                              hindlimbs, slight  involvement of dorsal root
                              ganglia  fibers, morphological changes in nodes of
                              Ranvier  axons and  Wallerian or segmental degeneration
                              of nerve fibers.   Involvement of the sural nerve.
                                                                            REFERENCE:  Okinaka, S., Yoshikawa, M., Mozai, T., Mizuno, Y., Terao,  T., Watanabe,  H.,
                                                                                       Ogihara, Y.., Hirai.'S., Yoshino, Y., Inose, T., Anzai, S.  and Tsuda,  M.
                                                                                       Neurology 14:  69-76, 1964.

                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                                                                       Clinical effects:  numbness, speech disturbances, ataxia,  paralysis,
                                                                                       restriction of visual fields.   Levels of Hg in blood, hair, liver, kidney,
                                                                                       brain increased up to 40-fold.   Widespread denervation of  cerebral cortex
                                                                                       granular layers,  especially calcarine and superior temporal convolution,
                                                                                       in cerebellar cortex (layer adjacent to Purkinje cells, but not Golgi
                                                                                       cells),  and in anterior horn of cord.
ANIMALS:   10  Rats,  Wistar, M,  100-110  g.
                                                                                        ANIMALS:    Human:   3 cases,  M,  17-35
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1  mg/kg/d  x 10.
                                                                           PREPARATION AND DOSE
                                                                           or HISTORY OF PATIENT:  skin application for  widespread fungal infection
ROUTE AND SITE:     Oral

CONTROL INFORMATION:   5 control rats
                                                                           ROUTE AND SITE: Topical, limbs and trunk

                                                                           CONTROL INFORMATION:  None
DURATION OF EXPERIMENT:   Sacr  600 d

EXAM. TYPE:   Ultrastructural,  histology
                                   \
                                                                           DURATION OF EXPERIMENT:  2 mo (fatal cases), 8 mo  (surviving  case)

                                                                           EXAM. TYPE: Autopsy (histology), clinical
                                      681
                                                                                                                                   682

-------
COMPOUND:
Mercury, methyl (thioacetamido)-
                                                                                            COMPOUND:
                                                                                            Mercury, methyl  (thioacetamido)-
REFERENCE:   Yoshlno, Y., Mozai, T. and Nakao, K.
            J.  Neurochem.  13:   397-406, 1966.
                                                                               REFERENCE:  Yoshino,  Y.,  Mozai,  T.  and Nakao,  K.
                                                                                           J.  Neurochem.  13:   1223-1230,  1966.
OBSERVED NEUROTOXIC EFFECTS:
                 (1) The highest mercury level and the greatest histo-
                 logical changes occurred in the calcarine area.
                 (2) Almost all label was found in the protein fraction
                 of the brain; little in the lipid or nucleic acid fractions.
                 Subcellular distribution:  mitochondrias > microsomes >
                 supernatant.  A lag time was noted from peak concentra-
                 tions to onset of nervous symptoms.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                             Protein synthesis in brain cortex  slices  was  markedly
                             inhibited before the onset of neurological  signs;
                             oxygen consumption, glycolysis,  and  sulfhydryl-enzyme
                             activities were unchanged.  After  the  onset of  neurological
                             signs, oxygen and aerobic glycolysis decreased.  At
                             advanced stages, activity of succinate dehydrogenase de-
                             creased.  Thus, the compound exerted selective  inhibition
                             of enzyme synthesis.
ANIMALS:     (1)  Dogs,  adult,  6.1-16 kg
            (2)  Rats,  Wistar,  120  g
                                                                                            ANIMALS:   Rats, Wistar,  M,  120 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  30-60 mg/kg
                        (2)  ns  rUJHg)
                                                                               PREPARATION AND DOSE
                                                                               or HISTORY OF PATIENT:   75 mg/kg
ROUTE AND SITE:   I.v.

CONTROL INFORMATION: ns
                                                                               ROUTE AND SITE:    i.p.

                                                                               CONTROL INFORMATION:  Untreated.
DURATION OF EXPERIMENT:

EXAM. TYPE:
            Dogs:  2-19 d
            Rats:  48 hr or 6hr to 16 d
            Histology,  biochemistry
DURATION OF EXPERIMENT:   up to 5-7 d

EXAM. TYPE:   Biochemistry in vitro
                                           683
                                                                                                                                        684

-------
COMPOUND:   Methane, bromo-

            000074839


REFERENCE:  Collins, R.P.
            California Med.  103:   112-116,  1965.
OBSERVED NEUROTOXIC EFFECTS:   Exposure caused progressive sensorimotor weakness  of
                              the fingers  and toes.   Nine months  after exposure
                              ceased,  a slight residual weakness  of  muscles  persisted.
COMPOUND:     Methane,  bromo-

             000074839

REFERENCE:  Kantarjian, A.D., and Shaheen, A.S.
            Neurologj 13:1054-1058, 1963.


OBSERVED NEUROTOXIC EFFECTS:    Numbness of  extremeties,  unsteadiness on walking,
                                some with ataxia.   Deep  reflexes absent or sluggish.
ANIMALS:     Human:   1 case,  M,  22,  a fumigator
ANIMALS:     8 humans, M,  18-43 years.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposures  possible  over  18  mo before medical  consultation
                        and  progressed  for  4  mo  until exposure  ceased
PREPARATION AND DOSE
or HISTORY OF PATIENT:
6-8 hrs daily, 6 d/wk, for 3 mo., dose believed  to be low.
ROUTE AND SITE:    Probably  dermal

CONTROL INFORMATION:    None
ROUTE AND SITE:   Exposure by  date fumigation process.

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:   13  mo

EXAM.  TYPE:   Clinical
DURATION OF EXPERIMENT:     6-8 mo.

EXAM. TYPE:  Behavioral,  biochemistry
                                           685
                                                                                                                                        686

-------
COMPOUND:    Methane, chloro-

             000074873

REFERENCE:     Scharnweber, B.C., Spears, G.N. and Cowles, S.R.
               J. Occup. Med. 16:112-113, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                               Ataxia, disorientatlon, combativeness, lethargy,
                               loss of short-term memory, blurred vision, stated
                               to be nonspecific signs, with progression only in
                               Central Nervous System.  Recovery in 6 wk to 3 mo.
                               Physical and neurologic examination and laboratory
                               studies "usually completely normal."
COMPOUND:  Methane, dichloro-
REFERENCE: Steward, R.D., Fisher, T.N., Hosko,  M.J.,  Peterson,  J.E., Baretta, E.D.,
           and Dodd, B.C.
           Arch. Env. Hlth.  25:  342-348,  1972.

OBSERVED NEUROTOXIC EFFECTS:   Sustained elevation of  carboxyhemoglobin in all subjects,
                               altered  Visual Evoked Responses and other Central Nervous
                               System signs in 2 subjects.
ANIMALS:   Human:   6  cases, M,  24-58 yr.
ANIMALS:    11 Humans, healthy M,  23-43 yr old, nonsmokers
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Workers with  foam plastics, exposed to 200-400 ppm for
                        2-3 wk or more before onset of symptoms  (TLV is 100 ppm).
PREPARATION AND DOSE
or HISTORY OF PATIENT:  986  ppm in air for 2 hr.
ROUTE AND SITE:   Inhalation,  possibly  skin  contact

CONTROL INFORMATION:     None
ROUTE AND SITE:   Inhalation

CONTROL INFORMATION:  Previous tests.
DURATION OF EXPERIMENT:   6 wk to  3 mo. per  case.

EXAM.  TYPE:    Clinical
DURATION OF EXPERIMENT:  2 hr.

EXAM. TYPE:  Biochemistry
                                           687
                                                                                                                                       688

-------
COMPOUND:  Methane, dichloro-
REFERENCE:  Weiss, G.
           Abstr. Hyg. 43:  1123, 1968, abstracting from
           Zentbl. Arbmed. Arbschutz. 17:  282-285, 1967 (Ger.).

OBSERVED NEUROTOXIC  EFFECTS:  Disturbed cerebral functions and hallucinations (optic
                             and acoustic) attributed to toxic encephalitis caused by
                             the compound.
                                                                                              COMPOUND:   4,7-Methanoindene, l,4,5,6,7,8,8-heptachloro-3a,  4,7,7a-tetrahydro-

                                                                                                          000076448
REFERENCE:
             Ryan,  W.H.  and  Shankland,  D.L.
             Life  Sci.  10(1):193-200, 1971.
OBSERVED NEUROTOXIC EFFECTS:
                                 Instability and block of activity •"•. ;;i.ant  fibers;
                                 no direct action on axonal membrane.  Exo-acetoxy
                                 analog of aldrin was nontoxic.  DDT with other
                                 compounds produced effects not seen with any compound
                                 alone.
ANIMALS:    Human:  1 case, a distiller of compound
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Vapor 900-3600 ppm in air, "several" hr/d for 3 yr before
                          symptoms and then 2 yr more.  Compound was 98-100% pure.
                                                                                              ANIMALS:
                                                                                                           Cockroach  (Periplaneta  ame_ricana),  surgically prepared
                                                                                                           Housefiles,  NAIDM strain	
PREPARATION AND DOSE
or HISTORY OF PATIENT: DDT 10~   M,  other compounds (aldrin, dieldrin, endrin,
                       heptachlor)  2 x iO~6 to 5 x 10~4 M  (cockroaches).  Up  to
                       300 mcg/g (houseflies).
ROUTE AND SITE:   Inhalation, skin contact

CONTROL INFORMATION:  None
ROUTE AND SITE:   Irrigation  of  exposed nerves (cockroaches), topical  (houseflies)

CONTROL INFORMATION:   Three  types  (described)
DURATION OF EXPERIMENT:   ns

EXAM.  TYPE:   Clinical
DURATION OF EXPERIMENT:  Several  hours

EXAM.. TYPE:  Electrophysiology
                                           689
                                                                                                                                       690

-------
COMPOUND:     4,7-Methanoindene,  l,4,5,6,7,8,8-heptachloro-3a, 4,7,7a- tetrahydro-
              (heptachlor)
              000076448

REFERENCE:  St.  Omer, V.
            J. Neurochem.  18:   365-374,  1971U
OBSERVED NEUROTOXIC EFFECTS:
      Convulsions, starting in some cases during injection.
      Intensity and other signs were directly related to
      increases of brain ammonia.  Toxicity ranking:
      llndane > dieldrin > heptachlor > DDT.  Brain gluta-
      mlne increases resulting from conversion of ammonia
      to glutamine were related to the toxicity ranking,
      suggesting that the 4 compounds produced convulsions by
      one mechanism involving interference with the production
      and/or utilization of ammonia.
                                                                      COMPOUND:
                                                                      REFERENCE:
 4,7-Methanoisobenzofuran,  1,3,4,5,6,7,8,8-octachloro-l,3,3a,4,7,7a-
 hexahydro

 000297789
Worden, A.N.
Tox. Appl. Pharm. 14:556-573, 1969.
                                                                                              OBSERVED  NEUROTOXIC  EFFECTS:
                    LD50 between 1.6 and 10 mg/kg for single oral dose,
                    with central nervous system symptoms like  those
                    from other chlorinated hydrocarbons.  Chronic
                    toxicity for rats less than that of endrin or of
                    1,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4a,5,6,
                    7,8,8a-octahydro-l,4-endo-5,8-endodlmethanonaphthalene.
                    Symptoms:  twitching, frothing, opisthotonus,
                    convulsions.
ANIMALS:    Rats,  adult  F,  Wistar,  250-300  g,  surgically  prepared.
            Cockerels, White Leghorn  or  Barred Plymouth Rock,  12  wk,  1.4-1.6  kg,
               surgically prepared.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Rats:  mg/kg — lindane 11.5, DDT 50, dieldrin 6, heptachlor 13.
Cockerels:  mg/kg — lindane 6.3, DDT 30, dieldrin 6, heptachlor 6.3.
The compounds stated to be structurally unrelated.
                                                                      ANIMALS:     Rats,  Hooded  Lister  and S-D
                                                                                   Mice,  Schofield
                                                                                   Guinea-pigs,  albino
                                                                                   Hamsters,  golden
                                                                      PREPARATION AND DOSE
                                                                                              or  HISTORY  OF  PATIENT:
                                        Rabbits, Dutch
                                        Cats,  mongrel
                                        Dogs,  mongrel
                                        Chickens,  Light  Sussex
               Acute:   single  dose by  gavage to find U>50
                        single  dose S.C.  (mice and rats,  M and F,  10 each)
             Chronic:   dermal  2 mg/kg  1  dose to 0.3 mg/kg/d 30 d  (rats,
                        rabbits, guinea-pigs); 25-100 ppm in diet  up to
                        78  d  (rats),  5-30 ppm for 2 yr (rats), 0.025 and 0.1
                        mg/kg/d by gavage (dogs).
ROUTE AND SITE:   Intra-arteriai  (carotid) at  1 ml/min

CONTROL INFORMATION:  Vehicle only
                                                                      ROUTE AND SITE:   Gavage,  S.C.  left flank.

                                                                      CONTROL INFORMATION:   Various  including endrin equivalent
DURATION OF EXPERIMENT:   Up to 60 min, in controls  7 d

EXAM. TYPE:   Behavior, biochemistry
                                                                      DURATION OF EXPERIMENT:     Up to 2 yr.

                                                                      EXAM. TYPE:  Clinical, behavior, mortality, biochemistry
                                           691
                                                                                                                                        692

-------
COMPOUND:  Methanol
           000067561
REFERENCE:   Bennett,  I.L.,  Jr.,  Gary,  F.H.,  Mitchell,  G.L.,  Jr.  and  Cooper, M.N.
             Medicine  32:431-463,  1953.


OBSERVED NEUROTOXIC EFFECTS:   Cerebral  edema, optic  tracts ganglia  degenerated
                              but  not optic nerves.
COMPOUND:   Methanol

            000067561

REFERENCE:   Erlanson, P., Fritz, H., Hagstam, K-E., Liljenberg,  B.,  Tryding,  N.
             and Voigt, G.
             Acta Med. Scand. 177:393-408, 1965.
OBSERVED NEUROTOXIC EFFECTS:
                                Acidosis, blindness,  cerebral  damage  (massive
                                necrosis).  Hemorrhages  into putamen.   No reaction of glia.
                                4th case below:  symmetrical slit-shaped
                                cysts in putamina, residual damage; cerebellar
                                loss of Purkinje cells could not  be definitely
                                attributed  to  the methanol.
ANIMALS:    Humans:   323 cases (308 Black,  15 White;  210 M,  113  F)  ages  10-78 yr.
ANIMALS:  Human:  4 cases of accidental poisoning.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Bootleg "whiskey" ingested in a 5-d period,  October  1951,
     Atlanta, Ga.   90 gall distributed,  35-40% MeOH,  under 4% EtOH in composition.
     Patients presented selves to hospitals.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                Accidental poisoning.   All treated within
                                29-44 hr with  alkali,  ethanol,  dialysis;
                                3 cases fatal,  4th  died later;  all were autopsied.
ROUTE AND SITE:   oral

CONTROL INFORMATION:    None
ROUTE AND SITE:    oral

CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:   5 d

EXAM.  TYPE:    Clinical,  autopsy (10 of  41  deaths)
DURATION OF EXPERIMENT:   Up  to 1.5 yr.

EXAM. TYPE:   Behavior,  chemistry, histology
                                      693
                                                                                                                                    694

-------
 COMPOUND:    Methanol

              000067561

 REFERENCE:   Guggenheim, M.A., Couch, J.R. and Welnberg, W.
             Arch. Neurol. 24:550-554, 1971.


 OBSERVED NEUROTOXIC EFFECTS:    Immediate and permanent nervous system damage:
    bilateral optic atrophy, rigidity, spasticity, hypokinesis.  Administration
    of levodopa improved condition.
 COMPOUND:
             Methanol

              000067561
 REFERENCE:   Riegel, H., and Wolf,  G.
             Food and  Cosmet.  Tox.  5:828-829,  1967.
 OBSERVED NEUROTOXIC EFFECTS:
Unconscious for 3 days, unable  to  swallow or speak.
Eyesight permanently and severely  damaged.
Brain damage involving movement and walking distur-
bances still seen 20 years  later.  Symptoms similar
to those of Parkinson's syndrome.
ANIMALS:     One Human, F, age 13 yr, 10 no.
                                                                                         ANIMALS:     1 Human,  F
PREPARATION AND DOSE      ...             •       .
or HISTORY OF PATIENT:   ,-Ingeati.on of 90 and 240 .ml antifreeze contg 60Z
•  -  methanol, no* heavy metals, as suicide atteapt.
• PREPARATION AND DOSE
 or HISTORY OF PATIENT:  Intake of "spirit" at a party.
ROUTE AND SITE:  oral

CONTROL INFORMATION:   None
 ROUTE AND SITE:    Oral

 CONTROL INFORMATION:    ns.
DURATION OF EXPERIMENT:  Approx. 1 yr follow-up and therapy.

EXAM. TYPE:  Hospital neurological exam.
 DURATION OF EXPERIMENT:   Appears follow-up of 2 yr.

 EXAM.  TYPE:  Clinical
                                       695
                                                                                                                                    696

-------
COMPOUND:   Methanol

             000067561

REFERENCE:  Roach, M.K., Davis. D.L., Pennington, W. and Nordyke, E.
            Life Sci.  12(1):433-441, 1973.
                                                                                             COMPOUND:     16-Methylpregna-l,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy
REFERENCE:  Miyakawa, T.,  Sumiyoshi,  S.  and Deshimaru,  M.
            Acta Neuropath.  30:85-89,  1974.
OBSERVED NEUROTOXIC EFFECTS:
                                Methanol inhibited active transport of probable
                                neurotransmitters of the central nervous systems
                                by synaptosomes.  Authors conclude that alcohol inter-
                                acts with membrane lipids of synaptosome.
OBSERVED NEUROTOXIC EFFECTS:    Dose-related changes both groups: thalamus and
                                hypothalamus vacuolar degeneration, hypertrophic
                                mitochondria,  astrocyte edema, more free ribosomes;
                                Group  (1)  rats but not group (2) became restless.
ANIMALS:     Rats, S-D, M, 200-250 g; brains removed and homogenates
            incubated in vitro.
                                                                                             ANIMALS:     Rats, Wistar, M, 100-120 g
PREPARATION AND DOSE
Or HISTORY OF PATIENT: Graded amounts added to incubation medium; concentration not
                      specified.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (D  0.5  mg/kg for 30 d.
                         (2)  0.05 mg/kg for 130 d.
ROUTE AND SITE:   in vitro

CONTROL INFORMATION:   Control:  incubation in medium with no alcohol.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:    Controls mentioned, no details
DURATION OF EXPERIMENT:  Laboratory procedure

EXAM.  TYPE: Biochemistry.
DURATION OF EXPERIMENT:      ns.

EXAM.  TYPE:  Behavior,  histology
                                          697
                                                                                                                                        698

-------
COMPOUND:    2-Methyoxyacridine,  6-chloro-9-[[4-(diethylamino)-l-methylbutyl]amino]-,
             dimethane sulfonate


REFERENCE:  Smith,  B.
            J.  Neurol. Neurosurg. Psychlat.  30:   506-510,  1967.


OBSERVED NEUROTOX1C EFFECTS:  The  myenteric plexus was examined,  and hlstologlcal
                             changes were found.   The author suggests her method
                             for  screening for neurotoxicity by  looking for damage
                             to the myenteric plexus in the large intestine.
COMPOUND:   Morphinan-3,6-alpha-diol  17-allyl-7,8  didehydro-4,5-alpha-epoxy-, HC1

            000062679

REFERENCE:  Spooner, C.E. and Winters, W.D.
            Int. J. Neuropharmacol. 5:  217-236, 1966


OBSERVED NEUROTOXIC EFFECTS:  Compound produced depression and associated slow-wave
                              EEGs.
ANIMALS:     45 Mice, TO, CFW and Porton strains, 20-25 g
                                                                                         ANIMALS:    200 Cockerels, White Leghorn, ages  5-14 d,  45-100  g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   3 mg/d for 5 d, 18 mice
                        Acute study:  10 mg I.P. or 2 mg I.V. one dose
PREPARATION AND DOSE
or HISTORY OF PATIENT:  10 mg/kg
ROUTE AND SITE:   I.p.

CONTROL INFORMATION:   ns
ROUTE AND SITE:   s.C.  near axillary vein; I.P. for doses over 0.05 ml

CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:   2 d to 3 mo after last dose.  Acute:  20 min.

EXAM. TYPE:   Histology
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:  Behavior,  EEC
                                        699
                                                                                                                                     700

-------
 COMPOUND:   Morphinan-3,6-alpha-diol, 7,8-didehydro-4,5-alpha-epoxy-17-methy1-

            000057272

 REFERENCE:  Davis,  W.M. and  Khalsa, J.H.
            Res.  Comm.  Chem.  Path. Pharm. 6:  867-872, 1973,


 OBSERVED NEUROTOXIC EFFECTS:  Tropolone, which inhibits catecholamine-0-methyltrans-
                              ferase, reduced the morphine LD5Q to 54 mg/kg.  The
                              authors concluded that the release of brain catecholamines
                              was a strong factor in morphine toxicity.
COMPOUND:   Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-, hydrochloride,
            (5-alpha-6-alpha)-
            000052266

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66,  1963.


OBSERVED NEUROTOXIC EFFECTS:   The  compound enhanced the effect of Yohimbine
                               and  lowered its lethal dosage.
ANIMALS:    Rats,  Holtzman, M,  350-450 g
                                                                                             ANIMALS:
               Mice, TT, M,  18-25  g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   10-640 mg/kg; LD5Q 292 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                          ED5() >80  mg/kg
                          ED_n =  dose producing a 50% mortality of mice injected
                                 S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:     I.P.

CONTROL INFORMATION:   The LD.  served as control for tests of modifying drugs
ROUTE AND SITE:      S.C.,  Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:  Up  to  24 hr.

EXAM.  TYPE:   Mortality
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:     Behavior,  electrophysiology, biochemistry
                                          701
                                                                                                                                      702

-------
COMPOUND:  Morphinan-3,6-alpha-diol, 7,8-didehydro-4,5-alpha epoxy-17-methyl-,  sulfate

          000064313

REFERENCE:   Ross, D.H., Medina, M.A. and Cardenas, H.L.
            Science 186:63-65, 1974.
OBSERVED NEUROTOXIC EFFECTS:
     Regional Ca depletion (from 55-60  to  33-39 mcg/g)
     in hypothalamus,  hippocampus,  corpus  striatum,
     and cortex; antagonized by naloxone.   Ca  considered
     important in release of transmitters  and  neuron
     stimulation.
COMPOUND:   Morphinan-3,6-alpha-diol, 7,8-didehydro-4,5-alpha epoxy-17-methyl-, sulfate

            000064313

REFERENCE:  Spooner, C.E. and Winters, W.D.
            Int.  J. Neuropharmacol.  5:  217-236,  1966


OBSERVED NEUROTOXIC EFFECTS:  Compound produced depression and associated  slow-wave
                              EEGs.
ANIMALS:     Rats, S-D, M, 150-200 g, groups of 3
                                                                                            ANIMALS:     200 Cockerels,  White Leghorn, ages 5-14 d, 45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Morphine sulfate 25 mg/kg, 30 min antemortem
Ethanol 1.5 mg/kg 120 min antemortem
Other treatments also given.
                                                                PREPARATION AND  DOSE
                                                                or HISTORY OF  PATIENT:  5-20 mg/kg
ROUTE AND SITE:    i.p.

CONTROL INFORMATION:   Untreated, 1:1, each expt replicated 3 or more times
                                                                ROUTE AND SITE:   s.C. near axillary vein;  I.P.  for doses over 0.05 ml

                                                                CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:     ns.

EXAM. TYPE:  Biochemistry
                                                                DURATION OF EXPERIMENT:   ns

                                                                EXAM. TYPE:   Behavior, EEC
                                           703
                                                                                                                                        704

-------
COMPOUND:   Morphinan-6-one, 4-5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, hydrochloride,
            (5-alpha)-
            000357084
REFERENCE:   Tseng, L.F., Menon, M.K. and Loh, H.H.
            Neuropharmacology 14:  247-250, 1975.


OBSERVED NEUROTOXIC  EFFECTS:  Naloxone precipitated abstinence signs, teeth chatter-
                             ing, myoclonic twitch, and repetitive shaking.  Bilateral
                             transverse lesions suggested that the different signs
                             originated in different brain areas.
                                                                                           COMPOUND:   Morpholine,  2-chloroethyl-,  hydrochloride
                                                                                           REFERENCE:   Goldin,  A.,  Now,  H.A.,  Landing,  B.H.,  Shapiro, D.M. and Goldberg, B.
                                                                                                        J.  Pharm.  Exp.  Ther.  94:249-261, 1958.
                                                                                           OBSERVED NEUROTOXIC EFFECTS:
                                 Waltzing syndrome was produced by dialkyl and hetero-
                                 cyclic B-chloroethylamines but not when (a) OH
                                 or  bromine replaced the B chlorine, (b) a 8-phenyl
                                 group replaced one of the 6 hydrogens in the
                                 chlorinated chain, or (c) phenyl groups were introduced
                                 into the dialkyl carbons.  No effect from primary/
                                 secondary B-chloroethylamines, related quaternary
                                 compounds, or bis-, tris-, or tetrakis-B-chloro-
                                 ethylamines.  Piperidine and morpholine analogs and
                                 arsacetin produced waltzing.  Cerebellar and
                                 axial lesions found consistent with behavior.
ANIMALS:     Rats,  S-D, M, 350-400 g, morphine-dependent and surgically prepared
                                                                                           ANIMALS:
             Mice,  CF1,  M,  2-3m,  18-25 g;  also CF1 F and C3H M.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  4 mg/kg
                                                                                           PREPARATION AND DOSE
                                                                                           or HISTORY OF PATIENT:
                            1-625 mg/kg in saline or (insolubles) 10% acacia,
                            various schedules.
ROUTE AND SITE:    i.p.

CONTROL INFORMATION:    Sham-operated rats
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:    Vehicle alone
DURATION OF EXPERIMENT:  30 min each test

EXAM.  TYPE:    Behavior
DURATION OF EXPERIMENT:      At least 10 d after treatment.

EXAM. TYPE:  Behavior, histology.
                                          705
                                                                                                                                       706

-------
COMPOUND:  Morphollnium,  2,2'-(4,4'-biphenylylene)bis(2-hydroxy-4,4-dimethyl-,  dibromide)
COMPOUND:
              stilus  edulis  toxins
REFERENCE:  Shellenberger,  M.K.  and Domino, E.F.
            Int.  J.  Neuropharmacol. 6:   283-291,  1967f
REFERENCE:  Evans, M.H.
            Br. J. Pharmac. 40:   847-865,  1970.
OBSERVED NEUROTOXIC EFFECTS:   Treatment produced seizures with a 20 min latency.
                              The  authors  inferred  that the compound exerted direct
                              action  on possible cholinergic receptors, rather than
                              acting  by way of acetylcholinesterase inhibition.
                                                                                               OBSERVED  NEUROTOXIC  EFFECTS:
                              Outbreak  of  paralytic  poisoning in about 80 subjects
                              in NW  England  in May,  1968.   Assays and signs in
                              animals and  nerve preparations were used to try to
                              identify  the toxins.
ANIMALS:    Dogs, beagle-like mongrel, M and F, 8-12 kg, surgically prepared
PREPARATION AND DOSE
or HISTORY OF PATIENT:  5 mg  (basis not given)
ANIMALS:     Humans:   about  80 who  suffered  paralytic shellfish poisoning
            Mice,  rabbits,  and  desheathed sciatic nerves from rat, frog and newt,
               and  rat cauda equina nerves.

PREPARATION AND DOSE
or HISTORY OF PATIENT:   Humans:   unwitting ingestion.
                         Animals and in vitro preparations:   assay of crude extracts
                                                              and part-purified toxins.
ROUTE AND SITE:  Intraventricular

CONTROL INFORMATION:   None
ROUTE AND SITE:   Various

CONTROL INFORMATION:  Various
DURATION OF EXPERIMENT:   At peak response, duration ns

EXAM. TYPE:    EEC, biochemistry
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:   Behavior, electrophysiology,  chemistry
                                          707
                                                                                                                                        708

-------
COMPOUND:  Naphthalene methanol, alpha-(isopropylamino) methyl-, hydrochloride

           001722516

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect  of Yohimbine
                              and lowered its lethal dosage.
 COMPOUND:    Napthalimlde, N-hvdroxy-.diethyl phosphate

             001491414

 REFERENCE:   Sherman,  M.,  Herrick,  R.B.,  Ross,  E. and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:   49-67,  1967.


 OBSERVED NEUROTOXIC EFFECTS:   Ataxia,  paralysis, convulsions.
ANIMALS:
               Mice, IT, M, 18-25 g.
                                                                                         ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q  >40  mg/kg

                         ED,. = dose producing a 50% mortality  of mice  injected
                                S.C. with yohimbine hydrochloride  (20 mg/kg).
ROUTE AND SITE:      s.C., Oral

CONTROL INFORMATION:      Various
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute: LD   43.3 mg/kg
                         (2) Subacute:   50-800 ppm in diet,  20 chicks/grp, for 2 wk
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control  grps
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:    1-3 wk

EXAM.  TYPE:   Behavior, mortality
                                         709
                                                                                                                                     710

-------
 COMPOUND:
              Neomycin
              001404042
 REFERENCE:   Tang, A.H.  and Schroeder,  L.A.
             Tox.  Appl.  Pharm.  12:44-47,  1968.
 OBSERVED  NEUROTOXIC EFFECTS:  (1)  Depressed neuromuscular  transmission of doses of
                              25 and 50 mg/kg.   (2)  Immediate  ataxia  in  chicks.
                                                                                            COMPOUND:
                                                                                            REFERENCE:
               Nickel
               007440020
                 Prakash,  N.J.,  Fontana, J. and Henkin, R.I.
                 Life  Sci.  12(1):249-259, 1973.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                 Inhibited (Na+ + K ) ATPase, although never
                                 more than 20%, even at 0.2 mM.  Inhibition
                                 involved blockage of norepinephrine and
                                 choline uptake.
 ANIMALS:
             (1) 6 Rabbits
             (2) Chickens
•PREPARATION AND DOSE
 or  HISTORY OF PATIENT: (1) 25 mg/kg followed by 50 mg/kg,  in saline.
                       (2) 50-100 mg/kg
                                                                                            ANIMALS:
                                                                                                              Rat brain synaptosomes in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Ni   chloride added to medium in various expts.
 ROUTE AND SITE:    l.v.

 CONTROL  INFORMATION:   ns.
ROUTE AND SITE:   Jn vitro

CONTROL INFORMATION:   Lab
 DURATION OF EXPERIMENT: ns.

 EXAM. TYPE:  Electrophysiology, behavior
DURATION OF EXPERIMENT:     Minutes

EXAM. TYPE:       Biochemistry
                                           711
                                                                                                                                        712

-------
COMPOUND:    Nitrous acid, pentyl ester

            000463047

REFERENCE:   Dewey, W.L., Tucker, L.S., Prange, A., Spaulding, T. and Chau, T.T.
            Res. Comm. Chem. Path. Pharm. 5(3):889-892, 1973.
OBSERVED NEUROTOXIC EFFECTS:
     Inhalation:   tremors, ataxia,  short duration.
     I.V.:   generalized convulsion in 30 sec,  died  in
     1 min.   Vomiting, defecation and other "unpleasant"
     effects reported.
                                                                                           COMPOUND:  2.Norbornene, 1,2,3,4,7,7-hexachloro-5,6-bis(chloromethyl)-
REFERENCE:   Sherman,  M.,  Herrick,  R.B.,  Ross,  E.  and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:   49-67,  1967.


OBSERVED NEUROTOXIC EFFECTS:   Ataxia,  paralysis,  convulsions.
                               Acute:   No mortality at highest dose level (5000 mg/kg),
                               and  no signs  of  intoxication.
ANIMALS:    Mice  for ID    studies
            Dogs,  5-10.5  kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Various doses, I.V. or by inhalation (dogs)
                                                                                           ANIMALS:   Cockerels,  Single  Comb White  Leghorn,  10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD5Q >  5000 mg/kg
                         (2) Subacute:  50-800 ppm in diet,  20 chicks/grp, for 2 wk
ROUTE AND SITE:   I.V.,  inhalation

CONTROL INFORMATION:   No  controls
                                                               ROUTE AND SITE:   Oral

                                                               CONTROL INFORMATION:   Untreated control grps
DURATION OF EXPERIMENT:     i d

EXAM. TYPE:  Behavior
                                                               DURATION OF EXPERIMENT:   1-3 wk

                                                               EXAM. TYPE:   Behavior, mortality
                                           713
                                                                                                                                        714

-------
COMPOUND:
            Notechis scutatus scutatus  venom
                                                                                            COMPOUND:
                                                                                                        Notechis scutatus scutatus venom,  toxin  from
REFERENCE:   Datyner, M.E. and Gage, P.W.
            Br.  J. Pharmac. 49:  340-354, 1973.
                                                              REFERENCE:  Harris,  J.B.,  Karlsson,  E.  and Thesleff, S.
                                                                         Brit.  J.  Pharmac.  47:   141-146, 1973.
OBSERVED NEUROTOXIC EFFECTS:
50 meg/ml blocked elicited twitches without affecting
compound action potentials.   1-10 meg/ml reduced
amplitude of endplate potentials and inhibited depolar-
izations by carbachol.  The authors concluded that  a
venom fraction was bound to acetylcholine.   Other in
vitro effects were observed.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
The resting membrane potentials and  action  potentials
were normal.  There was a low frequency  of  miniature
endplate potentials (amplitude unchanged).   The toxin
was almost ineffective in vitro.  In vivo,  adminis-
tration caused deaths by respiratory paralysis.
ANIMALS:     Isolated  sciatic-sartorius nerve-muscle preparations from Queensland
            cane  toads  (Bufo marinus)
                                                              ANIMALS:     Mice,  NMR1,  M,  25-30 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1-200 meg/ml of Ringer solution
                                                              PREPARATION AND DOSE
                                                              or HISTORY OF PATIENT:   10 meg/mouse
ROUTE AND SITE:   in  vitro

CONTROL INFORMATION:  Laboratory
                                                              ROUTE AND SITE:  i.V.,  tail vein

                                                              CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:  Minutes to 6 hr

EXAM. TYPE:    Electrophysiology
                                                                                            DURATION OF EXPERIMENT:   Various
                                                              EXAM. TYPE:
                                                                             In vitro studies on hemidiaphragm and digitorum longus nerve-muscle
                                                                             preparations dissected from mice intoxicated in vivo
                                           715
                                                                                                                                       716

-------
COMPOUND:  Organophosphate pesticides
REFERENCE:
               Rodnitzky,  R.L., Levin, H.S., Mick, D.L.
               Arch.  Env.  Hlth. 30:98-103,  1975.
COMPOUND:  Ouabain

           000036066

REFERENCE:   Doggett,  N.S.
             Life Sci.  12(1):121-129,  1973.
OBSERVED NEUROTOXIC EFFECTS:
                                Behavior  tasks performed as well as by controls,
                                blood  ChE in normal range  though lower in some
                                subjects  than control values.  Conclusion:  that
                                "higher nervous system  functions" have "relative
                                resistance" to mild chronic exposures.
OBSERVED NEUROTOXIC EFFECTS:  Hypothermia did not involve brain noradrenergic
                              systems but possible direct action on thermoregulation
                              including interference with amine function.
ANIMALS:
               23  Humans  (12  farmers,  11  commercial applicators)
ANIMALS:     Mice, TO,  M, 16-20 g
PREPARATION AND DOSE
Or HISTORY OF PATIENT:    Regularly used  organophosphates, had applied them personally
                         to at  least  500 acres  and who had used  them in  the previous
                         2 wk every working  day.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.1-0.25 meg/mouse with one or more of:  noradrenaline,
                       phentolamine, a-methylmetatyrosine, (+)-amphetamine.
ROUTE AND SITE:   Inhalation, skin  contact

CONTROL INFORMATION:      Age-education-matched  farmers whose pesticides, if any,
                         were  applied  for  them  by  contractors.
ROUTE AND SITE:   Intracerebroventricular

CONTROL INFORMATION:    Controls saline treated
DURATION OF EXPERIMENT:    ns.

EXAM.  TYPE:    Behavior  tasks, blood  chemistry
DURATION OF EXPERIMENT:   Hours

EXAM.  TYPE:  Biochemistry
                                          717
                                                                                                                                        718

-------
 COMPOUND:
Ouabain

000036066
 REFERENCE:  Grasso,  A.  and Majorl,  G.
            J.  Econ.  Entomol.  62:   944-945,  1969.
COMPOUND:    Ouabain

            000036066

REFERENCE:   Towfighi,  J.  and Gonatas,  N.K.
            Lab.  Invest.  28:170-180,  1973.
OBSERVED NEUROTOXIC EFFECTS:   Ouabain  is known  to inhibit the Na+/K+-dependent
                              ATPase found  in the ventral nerve cord of cockroaches.
                              By  inference,  such was presumed to be the basis of
                              ouabain  toxicity  in the housefly.
                                                                                OBSERVED NEUROTOXIC EFFECTS:
                                 Edema corresponding to spread of labeled
                                 more in adults than juveniles, central zone of
                                 swollen dendrites, Golgi, and rough endoplasmic
                                 reticulum,  marginal zone of swollen astrocytes,
                                 presynaptic terminals, and dark neurons.  Central
                                 zone interpreted as primary effect, marginal as
                                 secondary to pressure or ischemia.
ANIMALS:    Houseflies  (Musca domestica), adult, 22 mg
                                                                                ANIMALS:     129  Rats,  Osborne-Mendel,  M and F, adult and juvenile.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   LD5Q  found to be:   Feeding 270-690 rag/kg
                                            Topical 292-1600 mg/kg
                                            Injected 0.9-2.25 mg/kg
                        Ranges of averages of three groups:  susceptible to resistant.
                                                                                PREPARATION AND DOSE
                                                                                or HISTORY OF PATIENT:     0.0006-0.00125 mg/rat (1-5 d old); 0.0025 mg/rat  (older);
                                                                                                          in buffered saline pH 7.2.
ROUTE AND SITE:   Injection  into thorax; dermal to dorsal surface; feeding in sucrose
                   by  calibrated micropipet method.
CONTROL INFORMATION:  ......
                     Vehicles
                                                                                ROUTE AND SITE:     Intracerebral

                                                                                CONTROL INFORMATION:   Vehicle only.
DURATION OF EXPERIMENT:  24 hr

EXAM.  TYPE:   Count of knocked-down insects
                                                                                DURATION OF EXPERIMENT:    2 hr.

                                                                                EXAM.  TYPE:   Histology,  histochemistry
                                          719
                                                                                                                                        720

-------
COMPOUND:    Oxalic acid, bis(cyclohexylidenehydrazide)

             000370810

REFERENCE:    Carlton,  W.W.
              Life Sci  6:11-19,  1967.
                                                                                 COMPOUND:  Oxalic acid, Bis(Cyclohexylidenehydrazide)
                                                                                 REFERENCE:  Pattison,  I.H., Clarke, M.C.,  Haig,  D.A.  and Jebbett, J.N.
                                                                                             Res. Vet.  Sci.  12:   478-480,  1971.
OBSERVED NEUROTOXIC EFFECTS:
                   Hydrocephalus and spongy degeneration of brain,
                   cord and sciatic nerve.  Copper reduced hydrocephalus
                   but not edema, spongy degeneration or astrogliosis.
                   Liability to hydrocephalus decreased with age.
                   Myelin loss occurred late, spongy degeneration
                   early, glial proliferation in-between.
OBSERVED NEUROTOXIC EFFECTS:  Cultured brain  cells  from mice treated with the
                              compound or with  scrapie but not controls tended to
                              adhere  to  glass.
ANIMALS:
Mice, M, albino, weanling aged 21-28 d (groups of 10)
ANIMALS:    Mice, BSVS, aged 4-6 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:  Oral

CONTROL INFORMATION:
           (1) 0.5% in diet of Cuprizone precursors:   cyclohexanone
           and oxaldihydrazide.
           (2) 0.5% in diet, plus vitamins at lOOOx the recommended
           requirements.
           (3) 0.5% in diet, plus diuretic, Diurill,  0.5 and 1 gm/kg.
           (4) 0.2% in diet, plus copper 130 and 260  ppm.
           (5) 0.5% in diet for 8 wk.
           (3) Diurill treatment only
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.5% of diet
                                                                                 ROUTE AND SITE:  Oral

                                                                                 CONTROL INFORMATION:  Untreated, treated with  scrapie  agent
DURATION OF EXPERIMENT:   Maximum 9 wk

EXAM.  TYPE:   Histology,  hematology
                                                                                 DURATION OF EXPERIMENT:  Over 16 d

                                                                                 EXAM. TYPE:   Biophysics in vitro
                                           721
                                                                                                                                       722

-------
COMPOUND:    Oxalic acid,  bis(cyclohexylidenehydrazide)

            000370810

REFERENCE:      Pattison, I.H. and Jebbett, J.N.
               J. Path. 109:245-250, 1973.
                                                                                COMPOUND:    Oxalic acid, bis(cyclohexylidenehydrazide)

                                                                                            000370810

                                                                                REFERENCE:   Suzuki,  K.  and Kikkawa, Y.
                                                                                            Am.  J.  Path. 54:307-325, 1969.
OBSERVED NEUROTOXIC EFFECTS:
                    Scrapie-like spongiform encephalopathy;  functional
                    recovery in "a few days,"  histological  recovery
                    in 34 d; apparent correlation with microglial
                    proliferation.
OBSERVED NEUROTOXIC EFFECTS:    Inactive  at  1-2 wk,  hindlimb weakness, most died
                                at  3 wk.   Spongy  degeneration in CNS:  brainstem
                                and cerebellar white matter.  Vacuoles in myelin
                                and glia.
ANIMALS:
Mice, BSVS, F aged 3-6 wk, weaned.
                                                                                            ANIMALS:   30 Mice, Swiss-Webster, M
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   None
                    (1)   0.5% in diet, up to 15 mg/mouse/d,  for 7,  14,
                         21 d then 60 d untrtd.:  3 grps of  12
                         clinically abnormals.
                    (2)   Similar test, adding 28 and 35 d trtmts.
                    (3)   37 d trtmt (max), 52 d no trtmt, 38 d (max)  trtmt,
                         and then 52 d no treatment.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.5  g/100 g diet.
                                                                                ROUTE AND SITE:   Oral

                                                                                CONTROL INFORMATION:    10 untreated  controls
DURATION OF EXPERIMENT:   Serial sacr  to 179 d

EXAM. TYPE:    Histology, behavior
                                                                                DURATION OF EXPERIMENT:  About  3 wk

                                                                                EXAM. TYPE:   Behavior, histology
                                       723
                                                                                                                                    724

-------
COMPOUND:
            Oxalic acid, dihydrazide
 REFERENCE:   Jenney,  E.H. and Pfeiffer, C.C.
             J.  Phann.  Exp.  Ther.  122:  110-123, 1958.


 OBSERVED NEUROTOXIC EFFECTS:    Convulsions
COMPOUND:  2H-l,3,2-oxazaphosphorine,  2-(bis(2-chloroethyl)amino) tetrahydro-, 2-oxide

           000050180

REFERENCE:Levine, S. , and Sowinski, R.
          J. Neuropath. Exp.  Neurol 32(3), 365-370, 1973.


OBSERVED NEUROTOXIC EFFECTS:   Lesions of the choroid plexus were well developled
                              after 24-48 hours and were characterized by
                              severe edema, hemorrhage, and focal leukocytic
                              infiltration.   Progressed to necrosis of individual
                              villi and hemorrhage infarction of an entire
                              plexus after 4-6 days.  Plexitis was greatest in
                              plexus of 4th ventricle.
ANIMALS:    Mice, Harlan,  19-21 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1.7 mM/kgm
ANIMALS:   Rats, Lewis strain:  (1) 38 rats, 100-300 g.
                               (2) 8 rats, 100-175 g.


PREPARATION AND DOSE
or HISTORY OF PATIENT:    125-500 mg/kg in saline.
ROUTE AND SITE:  I.P.

CONTROL INFORMATION:  ns
ROUTE AND SITE:      S.C. or I.P.

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:   Acute

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:   7 d.

EXAM.  TYPE:   Histology
                                        725
                                                                                                                                     726

-------
COMPOUND:
2-Oxazolidinone, 5-((0-methoxyphenoxy)methyl)

000070075
REFERENCE:    Benitz,  K-F.,  Moraski,  R.,  Roepke,  R.R.  and Wozniak,  L.A.
             Tox.  Appl.  Pharm.  4:220-237,  1962.
OBSERVED NEUROTOXIC EFFECTS:
                     (1)  Dogs,  ataxia  and emesis on  480 or  600 mg/kg/d.
                     (2)  Rats,  no  neural  signs.
ANIMALS:     (1)  6 Dogs,  beagle,  1 M and 1 F/group,  3 groups.
             (2)  80 Rats,  Sherman, 10 M and 10 F/group,  4 groups.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            (1)  Short term - 70,  200,  600 mg/kg/d for 30 d.
                                Long term - 30,  120,  480 mg/kg/d for 6 mo.
                            (2)  0.0625,  0.25,  1% in diet.
ROUTE AND SITE:   oral (dogs and rats)

CONTROL INFORMATION:    i Group untreated (dogs and rats)
DURATION OF EXPERIMENT:      (i)  30 d and 6 mo.
                            (2)  30 d
EXAM. TYPE:  Behavior,  pathology (at sacrifice)
                                           727
COMPOUND:  2-Oxazoline,  2-amino-5-phenyl-

           002207503

REFERENCE:  Borbely, F., Past, A. and Velvart, J.
            Arch. Toxikol. 26:117-124, 1970.


OBSERVED NEUROTOXIC EFFECTS:   Ataxia, cramps, convulsions;  transient.
                                                                                                 ANIMALS:     30  human cases
                                                                                     PREPARATION  AND DOSE
                                                                                     or  HISTORY OF  PATIENT:    1-2 mg/kg estimated as toxic for central nervous  system.
                                                                                     ROUTE AND SITE:    oral

                                                                                     CONTROL  INFORMATION:   ns.



                                                                                     DURATION OF EXPERIMENT:   2 hr.

                                                                                     EXAM. TYPE:  Clinical
                                                                                                                                         728

-------
COMPOUND:  Oxygen
REFERENCE:  Barnard, E.E.P.
            Proc. Roy. Soc. Med. 64:  874-876, 1971.
OBSERVED NEUROTOXIC EFFECTS:
                             Men:  convulsions, susceptibility (threshold, taken
                             as 1.7 atm) varied day-to-day.  Mice:  Time course
                             of minor convulsions, slow onset, duration 5-10 sec;
                             major convulsions, rapid onset, preceded by spinning,
                             duration 30-60 sec followed by tonic spasm for
                             15-30 sec; normal movements then till next convul-
                             sion.  Dose-response (atm) and major-minor relation-
                             ships reported.
ANIMALS:    Human:  Naval volunteers
            Mice:  unspecified.


PREPARATION AND DOSE
or HISTORY OF PATIENT:   Diving experiments, no details
                        Mice:  chamber experiments, no details
ROUTE AND SITE:   inhalation

CONTROL INFORMATION:   ns



DURATION OF EXPERIMENT:  ns

EXAM. TYPE:    clinical
                                        729
                                                                                              COMPOUND:   Oxygen
REFERENCE:   Joanny,  P.,  Corriol,  J.  and  Brue,  F.
             Science  167:1508-1510,  1970.
OBSERVED NEUROTOXIC EFFECTS:  Less  oxidation by tissues, fall of phosphocreatine
                              and ATP,  and rise of lipid peroxides.  The increased
                              lipid peroxides is attributed to the toxic
                              effects of hyperbaric oxygen.
                                                                                              ANIMALS:   Guinea-pig, brain cortex slices in vitro.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Incubation in presence of 1-10 atm of pure
                        and labeled substrates.
ROUTE AND SITE:   In vitro

CONTROL INFORMATION:  Laboratory methods



DURATION OF EXPERIMENT:   60 min

EXAM. TYPE:    Biochemistry
                                                                                                                                     730

-------
COMPOUND:   Oxygen
COMPOUND:   Oxygen.
REFERENCE:  Walter, D.C., Underwood, B.C. and Nelson, S.R.
            Comp. Gen. Pharm. 5:  165-167, 1974.
REFERENCE:  Wood,  J.D.
            J.  Neurochem.  17:   573-579,  1970.
OBSERVED NEUROTOXIC EFFECTS:   Tremors, loss of righting reflex,  6 hr survival
                              limit.  The authors report much variation among
                              species.
OBSERVED NEUROTOXIC EFFECTS:
                               Susceptibility to 0- convulsions rose with age at
                               exposure (1-23 d),   and brain y-aminobutyric acid
                               (GABA)  changed less with age.  The rate of GABA deple-
                               tion was related to the time of convulsions.  Injected
                               GABA protected young chicks more than old, consistent
                               with decreasing permeability of blood-brain barrier
                               to GABA with age.
ANIMALS:    Cockroach (Periplaneta americana), adult M & F
ANIMALS:    Cockerels,  White Leghorn, age 1 d
PREPARATION AND DOSE
or HISTORY OF PATIENT:   6 atm (75 psi), 0-6 hr
PREPARATION AND DOSE
or HISTORY OF PATIENT:   C>2:  exposure to 60 psi for 5-38 min
                         GABA:  1-20 mmoles/kg 30 min before exposure  to 0. or  sacrifice
ROUTE AND SITE:    Inhalation

CONTROL INFORMATION:   Untreated
ROUTE AND SITE:   02> inhalation; GABA, I.P.

CONTROL INFORMATION:   One or other treatment omitted
DURATION OF EXPERIMENT:   Serial to 6 hr.

EXAM. TYPE:   Behavior, physiology
DURATION OF EXPERIMENT:   About 1 hr

EXAM. TYPE:    Behavior, biochemistry
                                        731
                                                                                                                                     732

-------
COMPOUND:      Ozone

               010028156

REFERENCE:     Kulle,  T.J.  and  Cooper,  G.P.
               Arch.  Env. Hlth  30:237-243,  1975.
                                                                                            COMPOUND:
OBSERVED NEUROTOXIC EFFECTS:
Examined effects of prolonged exposure.   Ozone
increased response to amyl alcohol; perfuslon
with air for 1 hr. partly normalized the response.
                                                                         Pentaborane (9)

                                                                         019624227
REFERENCE:  Feinsilver, L., Lawson, L.H., Yevich,  P.P.  and Jacobson, K.H.
            U.S. Army CWL Report CWLR  2367,  1960.


OBSERVED NEUROTOXIC EFFECTS:  LC5Q under conditions were:

                 j             Rats - 6ppm;  mice - 3ppm.   Signs included ataxia;
                              depression,  prostration, tremors, clonic convulsions,
                              interpreted as "marked effects upon" the central
                              nervous system.
ANIMALS:       Rats,  S-D,  M,  250-400  g,  surgically prepared for testing of nasopalatine
               nerve  twigs.


PREPARATION AND DOSE
or HISTORY OF PATIENT:     5 ppm for 1 hr.   Repeated  tests  in many animals, for
                          total exposure of 5 hr.
                                                            ANIMALS:    Rats, ages 8-10 wk, M
                                                                        Mice, 8-10 wk, F
                                                                        Dogs, beagle, M.

                                                            PREPARATION AND DOSE
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposed to vapors of compounds  in LC5Q study, 2-4 hr
ROUTE AND SITE:   Gas  drawn through  nasal  cavities by vacuum pump.
CONTROL INFORMATION:
DURATION OF EXPERIMENT:
                          Several hr.
EXAM.  TYPE:     Electrophysiology
                          Pre-exposure  control  responsiveness determined by test
                          series  of  amyl alcohol  (0.3, 0.7, 1.0, 3.3, 6.7, 10.0 pph)
                          and  then test repeated  after exposure to test compound.  Air
                          controls also run.
                                                            ROUTE AND SITE:  Inhalation

                                                            CONTROL INFORMATION: None



                                                            DURATION OF EXPERIMENT:  Observation to 7 d after exposure

                                                            EXAM. TYPE:  Behavior, pathology
                                           733
                                                                                                                                      734

-------
COMPOUND:    Pentaborane (9)

             019624227

REFERENCE:  Schoettlin, C.E., Clanko, G.M., Walter, R.D. and Freedman, T.
            ASD Tech. Report 61-438 (DSAF), 1961.
OBSERVED NEUROTOXIC EFFECTS:
     Mental confusion,  lack of  coordination; EEC changes
     reversible  about  1 yr after exposure.  One or more
     expsoures produced abnormalities.  EEC's not
     specific for boranes.
ANIMALS:    Humans:  119 rocket fuel handlers
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Symptoms and signs recorded,  plus  a total  333  EEC's.
Composition of fuels ns.
ROUTE AND SITE:  Inhalation, skin contact

CONTROL INFORMATION:   22 controls



DURATION OF EXPERIMENT:     Over 1 yr

EXAM. TYPE:  Behavior, EEC
                                          735
COMPOUND:    2-Pentanone, 4-methyl-

             000108101

REFERENCE:  Spencer, P.S.,  Schaumburg,  H.H.,  Raleigh,  R.L.  and Terhaar, C.J.
            Arch. Neurol. 32:   219-222,  1975.


OBSERVED NEUROTOXIC EFFECTS: Compound produced  no clinical  signs,  no histological
     damage except  in distal tibial  and  ulnar nerves,  which were not degenerated.
                                                                                                ANIMALS:    6 Rats,  young adult
PREPARATION AND DOSE
or HISTORY OF PATIENT:  1,500 ppm commercial grade in air,  exposed 6 hr/d,
                        5  d/wk for up to 5 mo.   Approx. 3% MBK contaminant.
                                                                     ROUTE AND SITE:   inhalation

                                                                     CONTROL INFORMATION:    Normal  control rats



                                                                     DURATION OF EXPERIMENT:   5 mo.

                                                                     EXAM. TYPE:    Behavior, histology
                                                                                                                                       736

-------
COMPOUND:  Pesticides  (unspecified)
REFERENCE:  Drenth, H.J., Ensberg, I.F.G., Roberts, D.V. & Wilson, A.
            Arch. Env. Hlth. 25:395-398, 1972.


OBSERVED NEUROTOXIC EFFECTS:    Abnormal electromyographic (EMG) exam in 40%
                                indicating disturbed peripheral nervous system
                                function.  No abnormal blood cholinesterase or
                                other biological data.
ANIMALS:
Human:  102 agric.  workers with pesticides,  M,  aged 17-59.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               Exposure varied from 1 compound daily for 7 d to
               several compounds/d.  Screening study for blood
               cholinesterase and EMG function.
ROUTE AND SITE:    Skin, inhalation, oral

CONTROL INFORMATION:   130  industrial workers not exposed to pesticides



DURATION OF EXPERIMENT:   2 screenings 2 mo apart.

EXAM. TYPE:   Electomyography, blood chemistry
                                          737
                                                                                    COMPOUND:    Phenethylamine, p-chloro-alpha, alpha-dimethyl

                                                                                                000461789

                                                                                    REFERENCE:   Lullmann-Rauch, R.
                                                                                                Acta Neuropath. (Berl)29: 237-249, 1974.
                                                                                    OBSERVED NEUROTOXIC EFFECTS:  Significant ultrastructural alterations  of  nerve
                                                                                         cells, both in spinal cord and in cerebellar cortex.
                                                                                                ANIMALS:   Rats, Wistar, M., Young Adult.
                                                                                    PREPARATION  AND  DOSE
                                                                                    or  HISTORY OF  PATIENT:    40 mg/kg b.w., 5d/wk in saline 0.5ml/100g bw,  for 5  wk.
                                                                                    ROUTE AND  SITE:    I.P.

                                                                                    CONTROL  INFORMATION:   Controls inj. saline



                                                                                    DURATION OF  EXPERIMENT:   5 wk

                                                                                    EXAM. TYPE:   Histology
                                                                                                                                       738

-------
COMPOUND:
Phenethylamine,  4-chloro-2-methyl-,  DL-
COMPOUND:
Phenethylamine, 4-chloro-alpha-methyl-
REFERENCE:    Harvey, J.A., McMaster, S.E. and Yunger, L.M.
              Science 187:841-843, 1975.
                                                                               REFERENCE:   Sanders-Bush, E.,  Bushing,  J.A.  and Sulser,  F.
                                                                                           Biochetn. Pharmacol.  21:1501-1510,  1972.
OBSERVED NEUROTOXIC EFFECTS:
                               Dissolution of neurons in ventral midbrain
                               tegmentum (B-9 serotonergic cell group) and in
                               substantla nigra, starting at 1 d and progressing
                               to 30 d.  Damage interpreted to explain effects
                               of compound on 5-HT and tryptophan-5-hydroxylase.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                                                                                                                Dose-related inhibition of tryptophan hydroxylase.
                                                                                                                Authors claim that this explains the prolonged
                                                                                                                reductions of 5-hydroxytrptamine and 5-hydroxy-
                                                                                                                indoleacetic acid produced by this compound.
ANIMALS:       25  Rats, Holtzman, M, 150-200 g
                                                                                            ANIMALS:
                                                                                            Rats,  S-D,  M,  180-220 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    2.5-20 mg/kg in saline to 1 ml.
                                                                               PREPARATION AND DOSE
                                                                               or HISTORY OF PATIENT:
                            Pretreatment (some experiments) 2-10 mg/kg 16 hr before
                            sacrifice (2i rats) , in one expt 6 d.
                            In vitro:  homogenized brainstems used to assay tryptophan
                            hydroxylase activity with/without £-chloroamphetamine.
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:      Vehicle only
                                                                               ROUTE AND SITE:   Pretreatment:  I.P.

                                                                               CONTROL INFORMATION:   Pretreatment:  5 rats no dose.
DURATION OF EXPERIMENT:    Serial sacr to 30 d

EXAM. TYPE:    Histology
                                                                               DURATION OF EXPERIMENT:

                                                                               EXAM. TYPE:  Biochemical
                            Pretreatment 16 hr., or less, one expt.  6  d.
                                          739
                                                                                                                                       740

-------
COMPOUND:    Phenethylamlne,  2-chloro-2-methyl-,  (±)-
COMPOUND:   Phenethylamlne, 3-chloro-2-methyl-,  (±)-
REFERENCE:   Wong,  D.T.,  Horng,  J-S.,  and  Fuller,  R.W.
             Biochem.  Phannacol.  22:311-322,  1973.
REFERENCE:  Wong, D.T.,  Horng,  J-S.,  and Fuller,  R.W.
            Biochem. Pharmacol.  22:311-322,  1973.
OBSERVED NEUROTOXIC EFFECTS:     Synaptosomes  accumulated  serotonin  by  (a) high-
                                 affinity  and  (b)  low-affinity processes.
                                 2-chloroamphetamine  inhibited both  processes.
OBSERVED NEUROTOXIC EFFECTS:
     Synaptosomes accumulated serotonin by  (a)  high-
     affinity and (b) low-affinity processes.
     3-chloroamphetamine inhibited both processes.
ANIMALS:
             Rat  brain in vitro
ANIMALS:
                                                                                                         Rat brain in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Synaptosomes  isolated  from homogenized whole brains,
                            and  uptake  of labeled  serotonin  or norepinephin measured
                            in presence/absence  of the amphetamine.   Some  rats
                            pretreated  with  the  amphetamine.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            Synaptosomes  insolated from homogenized whole brains,
                            and  uptake of- labeled serotonin or norepinephin measured
                            in presence/absence of the amphetamine.  Some rats
                            pretreated with the amphetamine.
ROUTE AND SITE:    Addition to  incubation medium

CONTROL INFORMATION:    Laboratory  controls
ROUTE AND SITE:   Addition to  incubation medium.

CONTROL INFORMATION:    Laboratory controls.
DURATION OF EXPERIMENT:      Pretreatment  up  to  22.5 hr;  in  vitro  5  sec  to  30 min.

EXAM.  TYPE:  Biochemical
DURATION OF EXPERIMENT:

EXAM.  TYPE:  Biochemical
Pretreatment up to 22.5 hr; in vitro 5 sec  to  30  min.
                                          741
                                                                                                                                       742

-------
COMPOUND:   Phenethylamine, 4-chloro-2-methyl-,  (±)-
REFERENCE:  Wong, D.T., Horng, J-S., and Fuller, R.W.
            Biochem. Pharmacol. 22:311-322, 1973.
OBSERVED NEUROTOXIC EFFECTS:
     Synaptosomes accumulated serotonin by (a)  high-
     affinity and (b)  low-affinity processes.
     4-chloroamphetamine strongly  inhibited (a)
     and inhibited (b) to a lesser extent.
ANIMALS:
            Rat brain in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                           Synaptosomes isolated from homogenized whole brains,
                           and uptake of labeled serotonin or norepinephin
                           measured in presence/absence of the amphetamine.  Some
                           rats pretreated with the amphetamine.
ROUTE AND SITE:   Addition  to  incubation medium

CONTROL INFORMATION:   Laboratory  controls
DURATION OF EXPERIMENT:

EXAM. TYPE:  Biochemical
Pretreatment up to 22.5 hr; in vitro 5 sec to 30 min.
                                          743
                                                                                                COMPOUND' Phenethylamine, N-alpha-dimethyl-, hydrochloride,  (-)-
                                                                     REFERENCE:    Kasirsky,  G.  and  Tansy,  M.F.
                                                                                  Teratology 4:131-134,  1971.
OBSERVED NEUROTOXIC EFFECTS:    Both mice and rabbits showed excitement within
    5 min after ttmt,  continuing for 6-7 hr.  Fetal anomalies:  exencephaly,
    anophthalmia,  microphthalmia greater in all treated litters of mice; exencephaly
    and microphthalmia in rabbits litters.
                                                                     ANIMALS:    Mice,  CF1,  pregnant;  Rabbits,  New Zealand white, F, pregnant
                                                                         and M,  sires.


                                                                     PREPARATION AND DOSE
                                                                     or HISTORY  OF PATIENT:   Mice:   5 or 10 mg/kg/d for 3, 4, or 7 d during d 9-15
                                                                         of gestation.
                                                                         Rabbits:  1.5 mg/kg for 4,  6, or "18 d during d 12-30 of gestation.  Males:   1.5,
                                                                         3.0,  or 5.0 mg/kg/d for 3 mo. prior mating.


                                                                     ROUTE AND SITE:  I.V.  Mice:  tail,   Rabbits:  ear.

                                                                     CONTROL INFORMATION:   Untreated and saline ttd groups for mice and rabbits.
DURATION OF EXPERIMENT:   Mice sacr day 19, Rabbits  (F)  sacr  day 30.

EXAM. TYPE:  Teratological
                                                                                                                                       744

-------
 COMPOUND:  Phenethylamine, N-alpha-dimethyl-, hydrochloride,  (-)-
                                                                                          COMPOUND:  Phenethylamlne, alpha-methyl-(+)-amphetamine
REFERENCE:Schuster, C.R., and Fischmann, M.W.
          Federation Proceedings 34:1845-1451, 1975.
REFERENCE:  Wong, D.T.,  Horng,  J-S.,  and  Fuller,  R.W.
            Biochem. Pharmacol.  22:311-322,  1973.
OBSERVED NEUROTOXIC EFFECTS:  Dose of 9.0 and 5.0 mg/kg caused collapse with no
                              sympathomimetic symptoms in contrast to the dose
                              of 2.5 and 3.0 mg/kg which brought on piloerection,
                              pupillary dilation, salvation, tremors in
                              extremities.
OBSERVED NEUROTOXIC EFFECTS:
                                 Synaptosomes  accumulated serotonin by (a) high-
                                 affinity  and  (b)  low-affinity processes.  Compound
                                 weakly  inhibited  both processes.
ANIMALS:  19 Monkeys, Rhesus, M
ANIMALS:
                                                                                                      Rat brain in vitro
PREPARATION AND DOSE
or HISTORY OF PATIENT:    1 ml I.V. over 10 sec.  Dose range 9.0-1.0 mg/kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                     Synaptosomes  isolated  from homogenized whole brains,
                                                                                                                     and uptake of- labeled  serotonin or norepinephin measured
                                                                                                                     in presence/absence  of the amphetamine.  Some rats
                                                                                                                     pretreated with  the  amphetamine.
ROUTE AND SITE:      i.v.

CONTROL INFORMATION:      ns.
ROUTE AND SITE:   Addition to  incubation  medium.

CONTROL INFORMATION:    Laboratory  controls
DURATION OF EXPERIMENT:   ns.

EXAM.  TYPE Behavioral
DURATION OF EXPERIMENT:

EXAM.  TYPE:  Biochemical
Pretreatment up to 22.5 hr; in vitro 5 sec  to  30  min.
                                        745
                                                                                                                                    746

-------
COMPOUND:  Phenethylamine,  alpha-methyl-sulphate (2:1),(+,-)-

           000060139

REFERENCE:     Quinton, R.M.
               Br.  J.  Pharmac.  21:51-66, 1963.
COMPOUND:   Phenethylamine, alpha-methyl-, sulphate  (2:1),  (+-)-
REFERENCE:  Spooner,  C.E. and Winters, W.D.
            Int.  J.  Neuropharmacol.  5:  217-236, 1966
OBSERVED NEUROTOXIC EFFECTS:   The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
OBSERVED NEUROTOXIC EFFECTS:  Compound produced increased locomotion,  abnormal
                              postures and arousal EEGs.   Atropine sulfate and atropine
                              methylnitrate potentiated the effects of this compound.
                              Chlorpromazine HC1,  reserpine phosphate, diphenhydramine
                              HC1,  cycllzine,  chlorpheniramine maleate,  promethazine
                              HC1,  meprobamate, phenoxybenzamine HC1 blocked the effects
                              of this compound.
ANIMALS:
               Mice, IT, M, 18-25 g.
ANIMALS:    200 Cockerels,  White Leghorn, ages 5-14 d, 45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ED,
                                 2 mg/kg
                         ED,- = dose producing a 50% mortality of mice injected
                                S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1-50  mg/kg
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:      Various
ROUTE AND SITE:   S.C.  near axillary vein; I.P. for doses over 0.05 ml

CONTROL INFORMATION: ns
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Behavior,  EEC
                                        747
                                                                                                                                    748

-------
COMPOUND:    Phenethylamine,  3,4,5,-trimethoxy-
             000054046

REFERENCE: Dill, R.E.  and  Campbell, K.M.
           Res. Comm.  Chem.  Path. Pharm.  6:   975-982,  1973.
COMPOUND:     Phenethylamine, 3,4,5,-trimethoxy-
             000054046
REFERENCE:   Seller, N. and Demisch, L.
             Biochem. Pharmacol. 23:273-287, 1974.
OBSERVED NEUROTOXIC EFFECTS:  Treatment produced  tremors  in the  contralateral limbs
                             lasting 1/2-hour.
OBSERVED NEUROTOXIC EFFECTS:
     Probable formation of trimethoxyphenylacetic acids
     in the brain.
ANIMALS:   Squirrel monkeys
           Rats (details ns)
ANIMALS:     Mice,  NMR1,  M,  30-35  g  (groups  of  10)
PREPARATION AND DOSE
Of HISTORY OF PATIENT:   161 or 540 nMoles/monkey
                         About 200-800 nMoles/rat
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Various labeled compounds including 2,6-mescaline HC1
120 mg/kg.
ROUTE AND SITE:   Monkeys:  direct application to putamen
                  Rats:  intrastriatal
CONTROL INFORMATION:   „
                      Homovanillic acid or saline
ROUTE AND SITE:   I.P.

CONTROL INFORMATION:   Laboratory controls
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:   Clinical (behavior)
DURATION OF EXPERIMENT:     1-24 hr.  serial

EXAM. TYPE:  Biochemical
                                           749
                                                                                                                                       750

-------
COMPOUND:    Phenethylamine, 3,4,5,-trimethoxy-
            000054046
REFERENCE:   Shah, N.S. and Neely, A.E.
            Biochem. Phannacol. 22:1535-1538, 1973.
                                                                                            COMPOUND:    Phenethylamine, 3,4,5rtrimethoxy-, hemlsulfate
                                                                REFERENCE:  Spooner, C.E. and Winters, W.D.
                                                                            Int. J. Neuropharmacol. 5:   217-236,  1966
OBSERVED NEUROTOXIC EFFECTS:     Nontoxic doses of chlorpromazine caused "marked
                                and prolonged retention" of compound   blocking its
                                disappearance from brain of both mother and fetuses.
                                                                OBSERVED NEUROTOXIC EFFECTS:   Compound produced excitement, abnormal  postures,
                                                                                               arousal EEGs, then depression.
ANIMALS:     Mouse, Swiss-Webster, pregnant F (number ns.)
                                                                ANIMALS:    200 Cockerels, White Leghorn, ages  5-14  d,  45-100 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Labeled mescaline 8.33 micromoles/kg.   Chlorpromazine
up to 15 mg/kg,  serially.   Various schedules.   Days
15-18 of gestation.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5-100 mg/kg
ROUTE AND SITE:    I.P.

CONTROL INFORMATION:    Incorporated into schedules
                                                                ROUTE AND SITE:   s.C.  near axillary vein; I.P.  for  doses  over 0.05 ml

                                                                CONTROL INFORMATION:  ns
DURATION OF EXPERIMENT:      4 hr after mescaline, sacrifice

EXAM. TYPE:  Biochemical
                                                                DURATION OF EXPERIMENT:   ns

                                                                EXAM. TYPE:   Behavior, EEC
                                          751
                                                                                                                                       752

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COMPOUND:   Phenol

            000108952

REFERENCE:  Berry, K. and Olszewski, J.
            Neurology 13:  152-154, 1963.


OBSERVED NEUROTOXIC EFFECTS:   The treatment gave scant relief of pain, but caused
                              severe demyelination, especially in the outer zone
                              of the posterior roots, affecting fibers of all sizes.
                                                                                                  .  Phenol, p-(2-aminoethyl)-3-methoxy-
                                                                                          COMPOUND:
REFERENCE: Dill, R.E.  and Campbell, K.M.
           Res. Comm.  Chem. Path. Pharm.  6:   975-982,  1973.


OBSERVED NEUROTOXIC EFFECTS:  Treatment  produced tremors in the contralateral limbs
                             lasting  1/2-hour.
ANIMALS:     Human:  3 terminal cancer patients with intractable pain.
ANIMALS:   Squirrel monkeys
           Rats (details ns)
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.5-0.6 ml of 5% compound
PREPARATION AND DOSE
or HISTORY OF PATIENT:   161 or 540 nMoles/monkey
                         About 200-800 nMoles/rat
ROUTE AND SITE:   Intrathecal

CONTROL INFORMATION:    None
ROUTE AND SITE:   Monkeys:  direct application to putamen
                  Rats:  intrastriatal
CONTROL INFORMATION:  „      ,,,_,
                      Homovanillic acid or saline
DURATION OF EXPERIMENT:   12 d to 1°-1/2 wk

EXAM. TYPE:   Clinical, autopsy (histology)
DURATION OF EXPERIMENT:  ns

EXAM. TYPE:   Clinical (behavior)
                                        753
                                                                                                                                     754

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COMPOUND:   Phenol, m-(N-(2-imidazolin-2-ylmethyl)-p-toluidino)-,
            monoethanesulfonate  (salt)
            000065281

REFERENCE:     Qulnton, R.M.
               Br..J. Pharmac.  21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
COMPOUND:   Phenol,  2,2' -methylenebis (3,4,6-trichloro)-

           000070304

REFERENCE: Alder, S. and Zbinden, G.
           Agents and Actions 3/4:  233-243, 1973.-


OBSERVED NEUROTOXIC EFFECTS:  Spongiform encephalopathy of brain and cord after 5 doses
                             (10 and 15mg levels), severe after 9 doses; occasional
                             degeneration of sciatic nerve.  Mild atrophy of pancreas
                             at 5 mg level.  Hind leg paresis at 10 and 15mg levels.
                             Slight delay on Hot Plate Test, no effects on Foot Print
                             Test, failures of Rotating Rod Test after 4 (15mg level)
                             and 10 (lOmg level) days.
ANIMALS:
               Mice, TT, M, 18-25 g.
                                                                                          ANIMALS:   Rats:  CFN  Zu, F,  38-53g,  8  groups  10-12  each
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q   46 mg/kg
                         ED,- = dose producing a 50% mortality of mice  injected
                                S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:  5, 10, 15 mg/kg, 5 d/wk, 2 groups/level,  5-50  doses
ROUTE AND SITE:      S.C., Oral

CONTROL INFORMATION:      Various
ROUTE AND SITE: Oral

CONTROL INFORMATION: 2 groups water orally
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT: Serial sacr 1-10 wk

EXAM. TYPE:    Behavior, histology
                                        755
                                                                                                                                     756

-------
 COMPOUND:   Phenol, 2,2'-methylenebis (3,4,6-trichloro)
             (Hexachlorophene)

             000070304

 REFERENCE:    DeJesus, P.V., Jr. and Pleasure, D.E.
              Arch. Neurol. 29:180-182, 1973.
OBSERVED NEUROTOXIC EFFECTS:
Low-Hexachlorophene rats few signs but motor
nerve conduction velocity (MNCV) diminished,
and yield of myelin sulfatide was low.
High-Hexachlorophene  rats had hind limb
weakness and muscle-wasting (recovered in 1-2
wk),MNCV 72% diminished, and still lower yield
of myelin sulfatide.
ANIMALS:   Rats, Osborne-Mendel, adult, 3 grps
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Low-Hexachlorophene fed diet giving 25-35
mg/kg/d.  High-Hexachlorophene diet gave
50-75 mg/kg/d.  Sciatic nerves extracted,
on termination.
ROUTE AND SITE:    Oral

CONTROL INFORMATION:    Untreated group.



DURATION OF EXPERIMENT:   About 2 mo.

EXAM. TYPE:     Behavior; nerve-conduction; biochemistry
                                      757
                                                            COMPOUND:    Phenol,  2,2'-methylenebis  (3,4,6-trichloro)-

                                                                         000070304

                                                            REFERENCE:   Hall, G.A.  and Reid, I.M.
                                                                         J. Path. 114:241-246, 1974.
OBSERVED NEUROTOXIC EFFECTS:    Incoordination, varied extent(none to fatal).
    White-matter vacuolation in Central and Peripheral Nervous System, rapid
    onset, severe in some clinically normal animals.
                                                            ANIMALS:     Sheep,  Herdwick or (Suffolk x Clun Forest), F and castrated M
                                                                yearlings, 3 studies with 9, 6, and 11 sheep.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  20 mg/kg/d as 5% w/v in paraffin.
                                                            ROUTE AND SITE:   Oral (1,2); injection into rumen (3).

                                                            CONTROL INFORMATION:    Paraffin only



                                                            DURATION OF EXPERIMENT:   Serial sacr to 12 d

                                                            EXAM. TYPE:   Behavior, histology
                                                                                                                                  758

-------
COMPOUND:   Phenol, 2,2'-methylenebis (3,4,6-trichloro)-(hexachlorophene)

            000070304

REFERENCE:    Herter, W.B.
              Kaiser Fdn. Hosp.  Bull. 7:59, 1959.
                                                              COMPOUND: .  Phenol, 2,2'-methylenebis  (3,4,6-trichloro)-

                                                                          000070304

                                                              REFERENCE:  Kimbrough, R.D. and Gaines,  T.B.
                                                                          Arch. Env. Hlth.  23:114-118,  1971.
OBSERVED NEUROTOXIC EFFECTS:  Twitching, nystagmus,  convulsions;  recovery started
                              on d 4 of hospital stay.   On d 6,  left facial
                              paralysis; recovered by d 16.  Author stated that
                              no similar case of hexachlorophene poisoning
                              was found in published reports.
                                                              OBSERVED NEUROTOXIC  EFFECTS:  Leg weakness  at  2 wk,  paralysis at 3-5 wk, recovery
                                                                   in 6 wk.  Brain wt  increased and returned to normal.   Cerebral white-matter
                                                                   edema, diffuse  spongy degeneration.
ANIMALS:  Human:  baby, 5 d old
                                                               ANIMALS:  Rats,  Sherman,  adult  F
PREPARATION AND DOSE
or HISTORY OF PATIENT:
3% lotion applied and left there daily for 4 d.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  500 ppm in diet (25 mg/kg/d)
ROUTE AND SITE:   Topical, after bath,  all over skin.

CONTROL INFORMATION:    None
                                                               ROUTE AND SITE:  oral

                                                               CONTROL INFORMATION:   Matched untreated controls
DURATION OF EXPERIMENT:   11

EXAM.  TYPE:  Clinical
                                                               DURATION OF EXPERIMENT:  serial sacr to 14 wk

                                                               EXAM.  TYPE: Behavior,  histology
                                       759
                                                                                                                                    760

-------
 COMPOUND:   Phenol, 2,21-methvlenebis (3,4,6-trichloro)-

            000070304

 REFERENCE:   Lampert,  P.,  O'Brien,  J.  and Garrett,  R.
             Acta Neuropath.  23:326-333,  1973.
COMPOUND:   Phenol,  2,2'-methylenebis  (3,4,6-trichloro)-

            000070304

REFERENCE:  Martinez,  A.J.,  Boehm,  R.  and Hadfield, M.G.
            Acta Neuropath.  28:93-103, 1974.
OBSERVED NEUROTOXIC EFFECTS:   Lethargy,  dragging hindlegs  after  2 wk.   Gross
     cerebral edema,  especially white-matter (corpus callosum).   Widely-
     spaced myelinated axons.   Wide clear spaces  within myelin  sheaths  (between
     lamellae).   Spaces disappeared on recovery.   Water content of brain had
     been increased,  as had proportion of ganglioside GM  .   Little axonal
    . degeneration.
OBSERVED NEUROTOXIC EFFECTS:  Anorexia,  nausea,  vomiting; blurred vision,
     blindness;  later  somnolence,  disorientation.   Decerebrate posturing,
     respiratory and cardiac arrest.   EEG slowed at 40 hr after admission,
     isoelectric at  71 hr.   Demyelination and axonal degeneration throughout
     optic  pathways, considered secondary to edema.  Optic tract localization
     shown  dependent on oral route,  as in animal models.
ANIMALS:   10 Rats (Sherman)  and  40 mice
ANIMALS:     1 Human:   M,  aged 7 yr
PREPARATION AND DOSE
or HISTORY OF PATIENT:   700-1000  ppm respectively in diet
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Accidental administration of 6 doses totaling approx. 45 ml
     67-21 hr before admission to hospital.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   20  mice  transferred  to  normal  diet  after  2 wk and  so  fed
     for up to 12  wk.   Some  normal-diet  controls.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:    14  wk

EXAM.  TYPE:  Behavior, histology, biochemistry
DURATION OF EXPERIMENT:  Death 83 hr after admission

EXAM.  TYPE:  Behavior; Histology
                                      761
                                                                                                                                   762

-------
COMPOUND:   Phenol. 2,2'-methylenebis (3,4,6-trichloro)-
            (Hexachlorophene)
            000070304

REFERENCE:    Matthieu, J-M., Zimmerman, A.W., Webster, H.deF.,  Ulsamer,  A.G.,
              Brady, R.O. and Quarles, R.H.
              Exp. Neurol. 45:558-575, 1974.
OBSERVED NEUROTOXIC EFFECTS:
                     500  ppm fed  d  1-10 had proved lethal.  Now,
                     lethargy,  incontinence of urine, and spastic
                     paraplegia in  pups and dams, but pups placed
                     on control diet  at d  18 recovered in 4 wk.
                     Central Nervous  System white-matter was
                     demyelinated,  apparently following degradation
                     of a myelin  glycoprotein.
ANIMALS:
Rats, S-D, 16 litters (9-10/litter)  aged  2  d,  randomized.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:   Oral
                     300 ppm in SPF diet  (15 mg/kg/d)  days  2-10,
                     then 500.ppm (25 mg/kg/d)  days  11-18,  fed
                     to dams; same fed  to pups  days  19-21.  On d
                     21 pups were injected intracerebrally with
                     labeled fucose and sacrificed 16  hr  later
                     (d 22) .
CONTROL INFORMATION:    Fed SPF diet without hexachlorophene.



DURATION OF EXPERIMENT:   22 d

EXAM. TYPE:  Histology and biochemistry; behavior.
                                      763
                                                                                COMPOUND:   Phenol, 2,2'-methylenebis  (3,4,6-trichloro)-

                                                                                            000070304

                                                                                REFERENCE:  NaKaue, H.S., Dost, F.N. andBuhler, D.R.
                                                                                            Tox. Appl.  Pharm. 24:239-249, 1973.
OBSERVED NEUROTOXIC EFFECTS:   Lethargy, posterior paralysis, histopathological
                               change in the brain, characterized by extensive
                               vacuolization and edema of myelinated areas.  Hind
                               limb weakness, brain lesions and death.
ANIMALS:    Rats, albino, Wistar, M and F, 4 wk old.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    I.P.:  21.8-39.9 mg/kg/d.
                          Oral:  63.0-87.0 mg/kg/d.
                                                                                ROUTE AND SITE:    I.P. and oral

                                                                                CONTROL INFORMATION:  ns.


                                                                                DURATION OF EXPERIMENT:   Sacr 16 weeks,  others  demised.

                                                                                EXAM. TYPE:  Histology, hematology.
                                                                                                                                   764

-------
COMPOUND:   Phenol,  2,2'-methylenebls  (3,4,6-trichloro)-

            000070304

REFERENCE:   Pilapil, v.R.
             Am. J. Dis. Child. 11:333-336, 1966.
COMPOUND:   Phenol,  2,2'-methylenebis  (3,4,6-trichloro)-
            (Hexachlorophene)
            00007034
REFERENCE:  Pleasure, D.,  Towfighi,  J.,Silberberg,  D.  and Parris, J.
            Neurology 24:1068-1075,  1974.
OBSERVED NEUROTOXIC EFFECTS:   Neuromuscular signs by d 3-4, progressing to
     seizures.  After correction of error, spastic flexion of extremities persisted
     at 1 wk, slight at 1 mo. (EEC normal at 2 wk, no observed residual signs at
     6 mo.
OBSERVED NEUROTOXIC EFFECTS:  (1)  In vivo:   hindlimb weakness in 2-3 wk, sciatic
     nerve demyelination,  loss of  about 40% of myelin.
     (2)   In vitro (rat brain):  disruption of myelin within 12 hr.
     (3)   Chick embryo sciatic nerves:   hexachlorophene was bound rapidly,
     inhibited protein and lipid synthesis  after 1 hr and depleted the nerves of
     ATP.
ANIMALS:     Human:  one case, neonate, M
PREPARATION AND DOSE
or HISTORY OF PATIENT:   3% prep, 20 drops 4/d for 2 d, 25 drops 4/d, for 5 d,
     by mistake for sulfisoxazole (misbottling).
ROUTE AND SITE:  Oral, gavage

CONTROL INFORMATION:     None
ANIMALS:   (1)  Rats, Osborne-Mendel,  adult,  30 including controls.
           (2)  Cultures of newborn rat cerebellum, 47 including control cultures.
           (3)  Sciatic nerves from chick embryos, 18 d old.

PREPARATION AND DOSE
or HISTORY OF PATIENT:  (1) 0.1% in diet (w/w).
                        (2) Selected cultures exposed to 0.3-10 meg/ml of medium
     for 48 hr  on d 14-19 in vitro.  x
     (3) Incubated for 2 hr with labeled myelin precursors and "sufficient"
     HCP, or with labeled HCP.

ROUTE AND SITE:  (1) oral (2 and 3) in medium in vitro.

CONTROL INFORMATION:  Controls as above without hexachlorophene.
DURATION OF EXPERIMENT:  7 d plus 6 mo. follow-up

EXAM. TYPE:  Clinical
DURATION OF EXPERIMENT:   (1)  up to 4 wk,  (2)  48 hr (3) 2 hr.

EXAM.  TYPE:  Behavior,  biochemistry, histology
                                      765
                                                                                                                                  766

-------
COMPOUND:   Phenol, 2,2'-methylenebis (3,4,6-trichloro)-
            (Hexachlorophene)

             000070304
REFERENCE:   Rose,  A.L., Wisniewski,  H.M., and Cannner, W.
             J.  Neurol.  Sci. 24:425-435,  1975.
COMPOUND:   Phenol,  2,2'-methylenebis (3,4,6-trichloro)-
            (Hexachlorophene)
            000070304
REFERENCE:  Shuman,  R.M., Leech, R.W., and Alvord, B.C.
            Arch. Neurol.  32:  315-319, 1975.
OBSERVED NEUROTOXIC EFFECTS:    Paralysis of hindlimbs.  Survivor's vision
    was impaired.   Myelin was vacuolated in central and peripheral nervous system
    with axonal  degeneration, especially in optic nerves.  After treatment stopped,
    poisoned  infants  had hydrocephalus, optic nerve atrophy.  50% of dams
    and 75% infants died.  Hexachlorophene in blood:  dams 4.7-6 meg/ml,
    infants 2-2.5  meg/ml.
OBSERVED NEUROTOXIC EFFECTS:  Inactivity decreased feeding, weakness,  coarse
     tremor;  "extremely susceptible" at age 6-22 d, not susceptible after
     d 26, or before d 2.  Vacuolar encephalopathy was produced by  2 washes
     only between d 13 and 22.  Vacuolization and disruption of myelin,  no
     damage to nonmyelinated nuclear areas.  "Age-dose-response curves are
    . similar to those in humans."
ANIMALS:     23 Rats,  S-D,  F with nursing   litters  (20 were ttd).
ANIMALS:   Rats aged 0-33 d kept with dams
PREPARATION AND DOSE
or HISTORY OF PATIENT:    500 ppm in dams'  diet  (50 mg/kg/d)  from  9th d postpartum.
    Young received same diet from weaning.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Daily wash with 3% hexachlorophene  in detergent,  2-3 ml.
ROUTE AND SITE:   oral

CONTROL INFORMATION:    3 dams and litters  untreated, diet  alone.
ROUTE AND SITE:   Topical

CONTROL INFORMATION:   2 litters washed with detergent only, one  litter unwashed.
DURATION OF EXPERIMENT:   Serial sacr  to 180 d.

EXAM. TYPE:  Behavior,  biochemistry,  histology
DURATION OF EXPERIMENT:    33 d, serial termination.

EXAM. TYPE:   Behavior, histology
                                      767
                                                                                                                                   768

-------
COMPOUND:    Phenol.  2,2'-methylenebis  (3,4,6-trichloro)-
            (Hexachlorophene)

             000070304
REFERENCE:   Shuman,  R.M., Leech, R.W.  and Alvord, E.G.
            Arch. Neurol. 32:  320-325, 1975.


OBSERVED NEUROTOXIC EFFECTS:   whole-body bathing repeatedly in 3% hexachloro-
    phene  (history) significantly associated with vacuolar encephalopathy of
    brainstera reticular formation; prevalence related to number of exposures,
    concentration of  hexachlorophene, thoroughness of rinsing, and exposure
    to UV.
                                                               COMPOUND:   Phenol, 2.2'-methvlenebis (3.4.6-trichloro)-

                                                                           000070304

                                                               REFERENCE:     StenbHck,  F.
                                                                              Arch.  Env.  Hlth.  30:32-35,  1975.
                                                               OBSERVED NEUROTOXIC EFFECTS:
                               Hindlimb  tremor, paralysis,  convulsions,  death
                               (22% in 2 wk,  thereafter  mortality unremarkable).
                               Symptoms  vanished  after  2-6  wk,  epidermis at site
                               thickened.  Autopsies  showed edema and cystic lesions
                               in Central Nervous System white-matter; some of the
                               lesions persisted  after  symptoms had vanished.
ANIMALS:    Human neonates under 1.4 kg birthweight that survived 4 or more d
           and were autopsied from 1/1/66 through 6/30/73; total of 46, in
           2 hospitals.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
Available brain sections, with 2 or more brainstem
levels (medulla and either pons or midbrain).   Histories
examined independently and then matched with histology
data.
                                                               ANIMALS:       Mice, random-bred Swiss, F, age 8 wk.
PREPARATION AND DOSE                                            ,         c   fn
or HISTORY OF PATIENT:    5,  25 or  50% in 0.2 ml acetone, 2 doses/wk for life, 50
                         mice/cone.      -.
ROUTE AND SITE:   Topical (washing)

CONTROL INFORMATION:   Blind review of 2 sets of data.
                                                               ROUTE AND SITE:  Topical, dorsal skin between flanks, shaved regularly

                                                               CONTROL INFORMATION:     One control group.
DURATION OF EXPERIMENT:    18 mo.

EXAM. TYPE:   Histology and history
                                                               DURATION OF EXPERIMENT:  Lifetime

                                                               EXAM. TYPE:    Behavior, clinical, autopsy, histology
                                      769
                                                                                                                                  770

-------
COMPOUND:   Phenol,  2,2'-methvlenebis  (3,4,6-trichloro)-

            000070304

REFERENCE:  Udall, V.
            Proc. Roy. Soc. Med. 65:  197-199,  1972
COMPOUND:   Phenol, 2,2'-methylenebis (3,4,6-trichloro)-

            000070304

REFERENCE'  Webster, Henry DeF., Ulsamer,  A.G.  and O'Connell,  M.F.
            J. Neuropath. Exp. Neurol.  33(1):144-170,  1970.
OBSERVED NEUROTOXIC EFFECTS:   Signs 12-30 hours after dose included loss of visual
                              acuity and pupil response (no recovery after 4 mo),
                              transient optic disc edema,  no retino-EEG action
                              potentials, exophthalmos, cerebral edema.
OBSERVED NEUROTOXIC EFFECTS:
Large optical lesions, myelin sheath splitting
at axonal and extracellular surfaces, vacuolation
in myelin sheaths, ventral tail nerve fibers exhibited
focal splitting and lesions on peripheral myelin sheath.
Loss of some motor activity.
ANIMALS:     Sheep and Cattle
ANIMALS:     25-40 groups Tadpoles,  Xenopus, 45-55th development stage.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20-80 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT: Immersed in 0.1-0.2 meg Compound/ml.
ROUTE AND SITE:   Oral, abomasal, or ruminal

CONTROL INFORMATION:  ns
ROUTE AND SITE:   Absorption via immersion

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:   ns

EXAM.  TYPE:    Behavior, physiology
DURATION OF EXPERIMENT:Sacr 1, 3, 5, 6 or 7 d.

EXAM. TYPE:  Ultrastruetural, histology
                                       771
                                                                                                                                     772

-------
 COMPOUND:
                Phenolphthalein
COMPOUND:   Phenothiazine drugs (unspecified)
REFERENCE:
                Steer, H.W.  and Colin-Jones,  D.G.
                J. Path. 115:199-205, 1975
REFERENCE: Myrianthopoulos, N.C., Kurland, A.A. and  Kurland,  L.T.
           Arch. Neurol. 6: 19-23, 1962.
OBSERVED NEUROTOXIC EFFECTS:   More lysosomal activity and lysosomes in Schwann
                               cells and neurons of submucosal plexus in colonic
OBSERVED NEUROTOXIC EFFECTS:  13 cases of parkinsonism found among relatives of
                             propositi, 3 among relatives  of controls;  numbers too
                             small for analysis but  suggested some hereditary
                             susceptibility  to parkinsonian side-effects of
                             ataractic drugs.
ANIMALS:        Human:  7 aged 24-80 with melanosis coli who took purgatives;
                        1 who had taken purgatives for only 1 m.
ANIMALS:   Human:  728 relatives of 59 propositi
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Rectal biopsy before and 3-7 m after stopping medication
PREPARATION AND DOSE
or HISTORY OF PATIENT:   History of high doses of compounds with  parkinsonian
                        side-effects
ROUTE AND SITE:  oral

CONTROL INFORMATION:
                          7 aged 27-70 with other gut disorders who had taken no
                          purgatives for 3 m.
ROUTE AND SITE:  oral

CONTROL INFORMATION:   777 relatives of 67 controls
DURATION OF EXPERIMENT:    About 7 m.

EXAM.  TYPE:      Histology, histochemistry
DURATION OF EXPERIMENT:   ns

EXAM.  TYPE:  Epidemiology
                                        773
                                                                                                                                     774

-------
COMPOUND:     Phenothiazine,  2-chloro-10-3(3-dimethylamino)propyl)-  (chloropromazine)

             000050533


REFERENCE:   Brosnan, C.F.,  Bunge,  M.B.  and Murray, M.R.
            J. Neuopath. Exp. Neurol.  24(3):337-353, 1970.


OBSERVED NEUROTOXIC EFFECTS:   Chlorpromazine affected the lysosomal system,
    inducing acid Pase activity; compound appeared to be concentrated within
    the multilaminated dense bodies of  the lysosomal system.  The purpose of
    the study was to explore the mode  of action of chloropromazine.
                                                                                         COMPOUND:   Phenothiazine, 2-c'hloro-10-3(3-dimethylamino)propyl)-

                                                                                                     000050533

                                                                                         REFERENCE:   Shah,  N.S.  and Neely, A.E.
                                                                                                      Biochem.  Pharmacol.  22:1535-1538, 1973.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:
Nontoxic doses of Chlorpromazine caused "marked
and prolonged retention"  of mescaline, blocking its
disappearance from brain  of both mother and fetuses.
ANIMALS:   Rat ganglia from 18-19 d fetuses, cultured in vitro.
                                                                                         ANIMALS:     Mouse,  Swiss-Webster,  pregnant F (number ns.)
PREPARATION AND DOSE             _.              _4
or HISTORY OF PATIENT:   7-0 x 10   M or 1.4 x 10   M in salt  solution, 74
     cultures  examined.
                                                                                         PREPARATION AND DOSE
                                                                                         or  HISTORY  OF PATIENT:
                                                                                                                     Labeled mescaline.8.33 micromoles/kg.   Chlorpromazine
                                                                                                                     up  to 15 mgVkg, serially.  Various  schedules.   Days
                                                                                                                     15-18 of gestation.
ROUTE AND SITE:       In vitro

CONTROL INFORMATION:  Controls with substrate alone,  or no substrate.
                                                                                        ROUTE AND  SITE:    I.P.

                                                                                        CONTROL  INFORMATION:    Incorporated into schedules
DURATION OF EXPERIMENT:  Weeks

EXAM.  TYPE:  Cytology, biochemistry
                                                                                        DURATION  OF  EXPERIMENT:      4  hr after mescaline. sacrifice

                                                                                        EXAM.|  TYPE:  Biochemical
                                      775
                                                                                                                                 776

-------
 COMPOUND:   Phenothiazine,  2-chloro-10-3(3-dimethylamino)propyl)-

            000050533

 REFERENCE:  Stunnan, G.
            Br. J. Pharmac. 50:  153-155, 1974.
                                                        COMPOUND:  Phenothiazine, 2-chloro-10-(3-(dlmethylamlno)propyl)-,mono-hydrochlorlde

                                                                   000069090

                                                        REFERENCE:     Qulnton,  R.M.
                                                                       Br. J. Pharmac.  21:51-66, 1963.
OBSERVED NEUROTOXIC EFFECTS:
Mice:  Pretreatment 1 hour beforehand with  piperazine
enhanced the acute toxicity of chlorpromazine  but not
of prochlorperazine.   Rats:  Pretreatment with piper-
azine enhanced catatonia from chlorpromazine but not
from prochlorperazine.  Piperazine did not  alter the
EEC changes induced by chlorpromazine or prochlor-
perazine.  In sum:  piperazine potentiated  the central
nervous system effects of chlorpromazine but not of
prochlorperazine.
OBSERVED NEUROTOXIC EFFECTS:
The compound  enhanced the effect of Tohimbine
and lowered its  lethal dosage.
ANIMALS:    Mice, no details
            Rats, F, no other details
                                                        ANIMALS:
                Mice, TT, M, 18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Piperazine:   0,  1,  2.5  or 5  g/kg~i  followed after 1 or 24
                       hr by various doses of  chlorpromazine  or prochlorperazine
                         -1
ROUTE AND SITE:    Piperazine:   S.C.;  chlorpromazine and prochlorperazine:  I.P.

CONTROL INFORMATION:   No piperazine given
                                                        PREPARATION AND DOSE
                                                        or HISTORY OF PATIENT:
                                 7  mg/kg
                                                                                                                ED-- «• dose producing  a 50% mortality of mice  injected
                                                                                                                  50   S.C. with yohimbine hydrochloride  (20 mg/kg).
                                                        ROUTE AND SITE:      s.C., Oral

                                                        CONTROL  INFORMATION:      Various
DURATION OF EXPERIMENT:   Hours

EXAM. TYPE:    Behavior
                                                        DURATION OF EXPERIMENT:   Various

                                                        EXAM.  TYPE:    Behavior, electrophysiology, biochemistry
                                       777
                                                                                                                               778

-------
COMPOUND:   Phenothiazine,  2-chloro-10-(3-(dimethylamino)propyl)-,  mono-hydrochloride

            000069090


REFERENCE:  Spooner,  C.E.  and Winters, W.D.
            Int.  J.  Neuropharmacol.  5:  217-236, 1966.


OBSERVED NEUROTOXIC EFFECTS:   Compound produced depression and associated slow-
                               wave  EEGs.
COMPOUND:   Phenothiazine,  2-chloro-10-(3-(4-methyl-l-piperazinyl)  propyl

            000058388

REFERENCE:  DeSilva, K.L.,  Muller, P.J. and Pearce, J.
            Practitioner 211:   316-320, 1973.


OBSERVED NEUROTOXIC EFFECTS:  Extrapyramidal signs, spasms especially of face, tongue
                             and jaws, torticollis, opisthotonus, trismus; onset in
                             2-60 hrs. commonest in young.  No dose relationship,
                             recovery after withdrawal.  One case had added dienceph-
                             alic features.  Authors comment that etiology still
                             unknown, and suggest idlosyncracy to class of drugs
                             (phenothiazines).
ANIMALS:    200 Cockerels,  White Leghorn, ages 5-14 d, 45-100 g
ANIMALS:    Human:  10 cases, M & F, 14-30, selected from 20 cases treated at a
                    hospital serving 500,000 population, over 2 yrs
PREPARATION AND DOSE
or HISTORY OF PATIENT:   2.5-50 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   3 cases:  15 mg P.O., 12.5  to 25 mg I.M.
                         Adverse drug reaction.
ROUTE AND SITE:   s.C.  near axillary vela; I.P. for doses over 0.05 ml

CONTROL INFORMATION:  ns
ROUTE AND SITE:    I.M. and P.O.  (see above)

CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:   Behavior,  EEC
DURATION OF EXPERIMENT:   2-24 hrs.

EXAM.  TYPE:   Clinical
                                           779.
                                                                                                                                     780

-------
 COMPOUND:   Phenothiazlne, 2-chloro-10-(3-(4-methyl-l-piperazinyl)propyl- (prochlorperazine)

            OOOOS8388

 REFERENCE:  Stunnan, G.
            Br. J. Phannac. 50:  153-155, 1974.
OBSERVED NEUROTOXIC EFFECTS:
Mice:  Pretreatment 1 hour beforehand with piperazine
enhanced the acute toxicity of chlorpromazine but  not
of prochlorperazine.  Rats:  Pretreatment with  piper-
azine enhanced catatonia from chlorpromazine but not
from prochlorperazine.  Piperazine did not alter the
EEC changes induced by chlorpromazine or prochlor-
perazine.  In sum:  piperazine potentiated the  central
nervous system effects of chlorpromazine but not of
prochlorperazine.
                                                              COMPOUND:   Phenothiazine,  10-(2-diethylamino)  propyl)-

                                                                          000522009

                                                              REFERENCE:  pfeiffer,  C.C.,  Murphree,  H.B., Jenney, E.H., Robertson, M.G.,
                                                                          Randall,  A.H.  and Bryan,  L.
                                                                          Neurology 9:   249-250,  1959.
                                                                                            OBSERVED NEUROTOXIC EFFECTS:
                              The authors concluded that synthetic atropines  are more
                              active hallucinogens than atropine or scopolamine, pro-
                              ducing effects lasting 24-48 hr.  Synthetic  antitremor
                              drugs had fewer peripheral nervous system  side-effects,
                              but central nervous system side-effects  (hallucinations)
                              may have been exaggerated.
ANIMALS:    Mice, no details
            Rats, F, no other details
                                                              ANIMALS:   Human:   prison volunteers,  drug-sophisticated, no other details
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Piperazine:  0, 1,  2.5 or 5 g/kg"-1 followed  after  1 or  24
                       hr by various doses of chlorpromazine or prochlorperazine
                         -1
PREPARATION AND DOSE
or HISTORY OF PATIENT:   50 mg/man
ROUTE AND SITE:    Piperazine:  S.C.; chlorpromazine and prochlorperazine:   I.P.

CONTROL INFORMATION:   No piperazine given
                                                              ROUTE AND SITE:    Oral

                                                              CONTROL INFORMATION:   LSD-25:   0,  25,  50, 100 meg/man
DURATION OF EXPERIMENT:   Hours

EXAM.  TYPE:    Behavior
                                                              DURATION OF EXPERIMENT:   Up to 3 d

                                                              EXAM.  TYPE:   Opinion of volunteers
                                       781
                                                                                                                                      782

-------
COMPOUND:  Phenothiazlne, 10-(2-dimethylamino propyl)

           000060877

REFERENCE:     Qulnton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  the compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
COMPOUND:  Phenothiazine, 10-(3-(dimethylamino)propyl)-, monohydrochloride   (promazine)

           000053601

REFERENCE: Barsa, J.A. and Kline, N.S.
           Am. J. Psychiatry 113:  654, 1957.


OBSERVED NEUROTOXIC EFFECTS:  "A few" developed mild rigidity;  2 patients had grand
                             mal seizures.  When the dose was  reduced  to  200 mg
                             four times per day, there were no adverse reactions.   An
                             EEC taken in 1 case was normal.
ANIMALS:
               Mice, TT, M, 18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED50   16 mg/kg

                         ED,n = dose producing a 50% mortality of mice injected
                                S.C. with yohimbine hydrochloride  (20 mg/kg).
ANIMALS:    Human:  schizophrenics, subjects of a  clinical pharmacology  trial,
                   ages 25-68, hospitalized 2-24  yr,  total  21  subjects


PREPARATION AND DOSE
or HISTORY OF PATIENT:   All had been  receiving chlorpromazine  for 6 mo  or more.
                        Promazine  given  25-300 mg four times per day.
ROUTE AND SITE:     s.C., Oral

CONTROL INFORMATION:     Various
ROUTE AND SITE:   Oral

CONTROL INFORMATION: ns
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:  3 mo or more

EXAM. TYPE:   Clinical
                                        783
                                                                                                                                     784

-------
COMPOUND:  Phenothiazine, 10-(3-(dimethylamino)propyl)-, monohydrochloride

           000053601

REFERENCE:     Quinton, R.M.
               Br. J. Phannac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced the effect of Yohimbine
                              and lowered its lethal dosage.
COMPOUND:   Phenothiazine,  10-(2-(dimethylamino) propyl)-, monohydrochloride

            000058333

REFERENCE:     Quinton, R.M.
               Br. J. Pharmac. 21:51-66, 1963.


OBSERVED NEUROTOXIC EFFECTS:  The compound enhanced  the effect of Yohimbine
                              and lowered its lethal dosage.
ANIMALS:       Mice, TT, M, 18-25 g.
                                                                                           ANIMALS:
               Mice, TT, M, 18-25 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ^50
                         ED_. ° dose producing a 50% mortality of mice injected
                                S.C. with yohimbine hydrochloride (20 mg/kg).
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                         ED5Q >50  mg/kg
                         ED   = dose producing a 50% mortality of mice injected
                                S.C. with yohimbine hydrochloride (20 mg/kg).
ROUTE AND SITE:      S.C., Oral

CONTROL INFORMATION:      Various
ROUTE AND SITE:     S.C., Oral

CONTROL INFORMATION:     Various
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:    Behavior, electrophysiology, biochemistry
DURATION OF EXPERIMENT:  Various

EXAM. TYPE:    Behavior, electrophysiology,  biochemistry
                                        785
                                                                                                                                    786

-------
COMPOUND:  Phenothiazine,  2-(ethylthio)-10-(3-(4-methyl-l-piperazinyl)propyl)-'
COMPOUND:    Phenothiazine,  10-(3-(4-methyl-l-piperazinyl)propyl)-2-(trifluoromethyl)-
REFERENCE:  DeSilva, K.L.,  Muller,  P.J.  and Pearce,  J.
            Practitioner 211:   316-320,  1973.
REFERENCE:  DeSilva, K.L., Muller, P.J. and Pearce, J.
            Practitioner 211:  316-320, 1973.
OBSERVED NEUROTOXIC EFFECTS:  Extrapyramidal signs,  spasms  especially of  face,  tongue
                             and jaws,  torticollis,  opisthotonus,  trismus;  onset  in
                             2-60 hrs.  commonest in young.   No dose relationship,
                             recovery after withdrawal.  One case  had added dienceph-
                             alic features.  Authors comment that  etiology  still
                             unknown, and suggest idiosyncracy to  class  of  drugs
                             (phenothiazines).
OBSERVED NEUROTOXIC EFFECTS:
Extrapyramidal signs, spasms especially  of  face,  tongue
and Jaws, torticollis, opisthotonus,  trismus;  onset in
2-60 hrs. commonest in young.  No  dose relationship,
recovery after withdrawal.  One  case  had added dienceph-
alic features.  Authors comment  that  etiology still
unknown, and suggest idiosyncracy  to  class  of drugs
(phenothiazines).
ANIMALS:    Human:  10 cases,  M & F,  14-30,  selected from 20 cases treated at
                    hospital serving  500,000 population,  over 2 yrs
ANIMALS:    Human:  10 cases, M & F, 14-30,  selected  from 20  cases treated at a
                    hospital serving 500,000 population,  over 2 yrs
PREPARATION AND DOSE
or HISTORY OF PATIENT:    1 case:  10 mg,  t.d.s.,  P.O.
                         Adverse drug reaction.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1 case:  1 mg, b.d., P.O.
                         Adverse drug reaction.
ROUTE AND SITE:   T.d.s., P.O. (see above)

CONTROL INFORMATION:    None
ROUTE AND SITE:  B.d., P.O. (see above)

CONTROL INFORMATION:   None
DURATION OF EXPERIMENT:   60 hrs.

EXAM. TYPE:   Clinical
DURATION OF EXPERIMENT:  60 hrs.

EXAM. TYPE:   Clinical
                                        787
                                                                                                                                   788

-------
COMPOUND:  Phenothiazine, 10-(3-(4-methyl-l-piperazinyl)propyl)-2-trifluoromethyl)-.
                                                                                        COMPOUND:   /
                                                                                                    3-Phosphabicyclo(4.4.0) decane, p-chloro-2,4-dioxa-5-methyl-p-thiono-
REFERENCE:   Romasenko,  V.A.  and Jacobson,  I.S.
             Acta Neuropath.  12:23-32,  1969.
OBSERVED NEUROTOXIC EFFECTS:   "Sluggishness,  motor inhibition,  and  catalepsy"
     reversed on stopping the drug.   Vascular changes and hyperchromic  and
     "wrinkled"  nerve cells  in cerebral  cortex.   Increased RNA,  proteins,
     SH-groups,  and polysaccharides.   Diminished activities  of  acid phosphatase
     and succinic dehydrogenase.   Some Purkinje  cells affected  in cerebellum.
     Author concluded changes are very slight and reversible.
 REFERENCE:   Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm. 11:  49-67, 1967.


 OBSERVED NEUROTOXIC  EFFECTS:   Ataxia, paralysis, convulsions.
                               Acute:  Significant growth depression even at  levels
                                       lower than the LD....
ANIMALS:   96 Rats,  white,  M,  150-250 g
                                                                                       ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   1-   Chronic:   1,  5,  or 20-25 mg/kg for 1-5 wk.
                        2.   Acute and subacute:   50-250 mg/kg, one dose.
                        3.   Observational only.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  Acute: LD5Q  25.6 mg/kg
                         (2)  Subacute:   50-800 ppm in diet, 20 chicks/grp,  for 2 wk
ROUTE AND SITE:   1-   Oral:   gavage or in diet.   2.   I.M.

CONTROL INFORMATION:     Mentioned, not described.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
DURATION OF EXPERIMENT:  1.  about 2 mo.   2.   30 min.   3.   1 mo.  after (1)

EXAM. TYPE: Behavior,  biochemistry, histology
DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:   Behavior,  mortality
                                      789
                                                                                                                                   790

-------
 COMPOUND:     Phosphine oxide,  tri-o-tolyl-
REFERENCE:      Hine,  C.H.,  Dunlap,  M.K.,  Rice,  E.G.  Coursey, M.M.,  Gross,  R.M.
                and Anderson,  H.H.
                J.  Pharm.  Exp.  Ther.  116:227,  1956.


OBSERVED NEUROTOXIC EFFECTS:     None had  paralysis.
ANIMALS:
                22 Chickens,  White Leghorn,  M,  0.75-1.3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     (1)  0.5 gm/kg.
                          (2)  1.0 gm/kg
ROUTE AND SITE:  (i) s.C.     (2) Oral

CONTROL INFORMATION:    One group of 5 per experimental group.




DURATION OF EXPERIMENT: 14-36 d after treatment.

EXAM. TYPE:     Behavior, histology
                                          791
COMPOUND:  Phosphofluoridic acid,  methyl-,  isopropyl ester

           000107448


REFERENCE:  Bajgar, J.
            Tox.  and  App.  Pharm.  22:93-96, 1972.
OBSERVED NEUROTOXIC EFFECTS:     Acetylcholinesterase inhibition in blood  and
                                 subcellular fractions of medulla oblong gata.
ANIMALS:     Rats,  Wistar/Mezno, F, 150-170 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
0.2 mg/kg (approxamating LD,-).
ROUTE AND SITE:   I.M.

CONTROL INFORMATION:   ns.



DURATION OF EXPERIMENT:     Immediately

EXAM. TYPE:  Histological, biochemical
                                                                                                                                       792

-------
 COMPOUND:
Phosphollpase A
 REFERENCE:
Chang, C.C., Chuang, S-T., Lee, C.Y., Wei, J.W.
Br. J. Pharmac. 44:752-764, 1972.
OBSERVED NEUROTOXIC EFFECTS:   Ineffective on axonal conduction.  Synergistic
                              effect on cardiotoxin's blocking action due to
                              aceleration rather than potentiation of its
                              action.  90 meg/ml completely depolarized
                              superficial muscle fibers.  High concentrations
                             ' of CaCl2 enhanced the depolarizing effect.
ANIMALS:
               Phrenic nerve-diaphragm preparation from Long-Evans rats.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Various doses in vitro.
ROUTE AND SITE:      in vitro.

CONTROL INFORMATION:      Laboratory



DURATION OF .EXPERIMENT:   Various

EXAM. TYPE:    Electrophysiology, chemistry.
                                        793
COMPOUND:
                                                                                                             Fhosphonic acid, decyl-, ethyl p-nitrophenyl ester
REFERENCE:
                                                                                                             Aldridge, W.N.  and Barnes, J.M.
                                                                                                             Biochemical Pharm. 15:541-548, 1966.
                                                                              OBSERVED NEUROTOXIC EFFECTS:   Weakened  limbs.   Histological changes in the
                                                                                                            spinal  cord and  sciatic nerves.  Inhibition of
                                                                                                            CNS  esterase.
                                                                              ANIMALS:
                                                                                             Hens,  grps  of  2-4,  RIR x Light Sussex, 2-3 kg
                                                                              PREPARATION AND DOSE
                                                                              or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied by compound
                                                                             ROUTE AND SITE:  oral,  s.c.,  or  l.p.

                                                                             CONTROL INFORMATION:       ns.



                                                                             DURATION OF EXPERIMENT:    14-21 d

                                                                             EXAM. TYPE:      Biochemistry, histology
                                                                                                                                     794

-------
COMPOUND:
Phosphonic acid, ethyl-,  2-chloroethyl 2,2-dichlorovinyl ester
COMPOUND:  Phosphonic acid, 0-ethy1-0-(4-nitrophenyl)-ethyl ester
REFERENCE:
                Aldridge,  W.N.  and  Barnes, J.M.
                Biochemical  Pharm.  15:541-548, 1966.
                                                                             REFERENCE:   Rosic, N.,  Lonax, P. and Kovacevic, N.
                                                                                         Comp. Gen.  Pharm. 5:  187-189, 1974.
OBSERVED NEUROTOXIC EFFECTS:    Weakened  limbs.  Histological changes in the
                               spinal  cord  and  sciatic nerves.  Inhibition of
                               CNS  esterase.
                                                                             OBSERVED  NEUROTOXIC  EFFECTS:   Avoidance behavior was depressed up  to  6  hr after
                                                                                                           treatment with recovery by  24 hr.  Brain  cholinesterase
                                                                                                           was down 20% by 2 hr, returning after 6 hr, and re-
                                                                                                           covered by 24 hr.  The authors suggest  these findings
                                                                                                           are related.
ANIMALS:
                Hens,  grps of 2-4,  RIR x Light  Sussex,  2-3 kg
                                                                            ANIMALS:     Fish (Serranus scriba). 15-25 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied  by  compound
                                                                             PREPARATION AND  DOSE
                                                                             or HISTORY OF  PATIENT:   60 meg/kg after avoidance training  (half LD5Q)
ROUTE AND SITE:    Oral, s.c., or i.p.

CONTROL INFORMATION:       ns.
                                                                             ROUTE AND  SITE:   S. C.

                                                                             CONTROL  INFORMATION:   ns
DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:     Biochemistry, histology
                                                                             DURATION OF  EXPERIMENT:   Serial to 24 hr

                                                                             EXAM. TYPE:  Behavior, biochemistry
                                        795
                                                                                                                                     796

-------
COMPOUND:
Phosphonic acid, pentyl-, ethyl p-nitrophenyl ester
COMPOUND:      Phosphonic  acid,  2-phenylethyl-,  ethyl p-nitrophenyl ester
REFERENCE:
Aldridge, W.N. and Barnes, J.M.
Biochemical Pharm. 15:541-548, 1966.
                                                                                             REFERENCE:
               Aldridge,  W.N.  and Barnes,  J.M.
               Biochemical Pharm.  15:541-548
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.   Histological changes in the
                               spinal cord and  sciatic nerves.   Inhibition
                               of CNS esterase.
                                                                             OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histological changes  in  the  spinal
                                                                                                            cord and sciatic nerves.  Inhibition of CNS
                                                                                                            esterase.
ANIMALS:         Hens,  grps of 2-4,  RIR x Light Sussex,  2-3 kg
                                                                                             ANIMALS:
                                                                                             Hens, grps of 2-4, RIR x Light Sussex, 2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied by compound
                                                                             PREPARATION AND DOSE
                                                                             or HISTORY OF PATIENT:    Mostly 1 dose, amount varied by compound
ROUTE AND SITE:  Oral, s.c., or i.p.

CONTROL INFORMATION:       ns.
                                                                             ROUTE AND SITE:    oral, s.c., or i.p.

                                                                             CONTROL INFORMATION:       ns.
DURATION OF EXPERIMENT:    14-21 d

EXAM.  TYPE:      Biochemistry, histology
                                                                             DURATION OF EXPERIMENT:    14-21 d

                                                                             EXAM.  TYPE:      Biochemistry, histology
                                        797
                                                                                                                                    798

-------
COMPOUND:   Phosphonic acid, phenylmethyl-, ethyl p-nitrophenyl ester
                                                                                           COMPOUND:
                                                                                                           Phosphonic acid,  3-phenylpropyl-,  ethyl p-nitrpphenyl ester
REFERENCE:   Aldridge, W.N. and Barnes,  J.M.
             Biochemical Pharm. 15:  541-548,  1966.
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.   Histological  changes  in the
     spinal cord and sciatic  nerves.   Inhibition of  CNS  esterase.
REFERENCE:
                Aldridge,  W.N.  and Barnes,  J.M.
                Biochemical Pharm.  15:541-548,  1966.
OBSERVED NEUROTOXIC EFFECTS:    Weakened limbs.   Histological changes in the spinal
                               cord and sciatic nerves.   Inhibition of CNS
                               esterase.
ANIMALS:  Hens,  grps of 2-4,  RIR x Light  Sussex,  2-3 kg
                                                                                           ANIMALS:
                                                                                                           Hens, grps of 2-4, RIR x Light Sussex, 2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Mostly  1  dose,  amount varied by compound
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Mostly 1 dose, amount varied by compound
ROUTE AND SITE:   oral,  B.C.,  or  i.p,

CONTROL INFORMATION:  ns.
ROUTE AND SITE:   Oral, B.C.. or i.p.

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:  14-21 d

EXAM. TYPE:   Biochemistry, histology.
DURATION OF EXPERIMENT:   14-21 d

EXAM. TYPE:     Biochemistry, histology
                                       799
                                                                                                                                    800

-------
COMPOUND:   Phosphonic acid,  (2,2,2-trichloro-l-hydroxyethyl)-, dimethyl ester

            000052686

REFERENCE:  Rayner,  M.D.,  Popper,  J.S.,  Carvalho, E.W. and Hurov, R.
            Res.  Comm. Chem.  Path.  Phann.  4:   595-606, 1972.


OBSERVED NEUROTOXIC EFFECTS:    The  force generated by the achilles tendon reflex was
                              subnormal  in exposed subjects.  The authors suggest
                 !             that  this  hyporeflexia may be a sensitive indicator of
                              chronic exposure to organophosphates.
COMPOUND:   Phosphonodithioic acid, chloromethyl-, S-(p-chlorophenyl)0-isopropyl  ester

            001713979

REFERENCE:   Sherman,  M.,  Herrick,  R.B.,  Ross,  E.  and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:   49-67,  1967.


OBSERVED NEUROTOXIC EFFECTS:  Ataxia,  paralysis,  convulsions.
ANIMALS:    Humans,  Japanese ancestry,  M,  ages 22-59 (orchid farmers)
                                                                                           ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposure of  more than 4 hr/d,  2 d/wk,  52 wk/yr for 5 yr except
                        one case (2  yr).  Other types  of pesticide also used, but
                        authors  judged organophosphates exposures to be primary.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD   30.9 mg/kg
                         (2) Subacute:  50-800 ppm in diet,  20  chicks/grp,  for 2 wk
ROUTE AND SITE:    Skin contact,  inhalation

CONTROL INFORMATION:   Matched non-exposed subjects,  so far as could be ascertained
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
DURATION OF EXPERIMENT:   ns

EXAM. TYPE:     Physiological
DURATION OF EXPERIMENT:   1-3 wk

EXAM.  TYPE:   Behavior, mortality
                                           801
                                                                                                                                      802

-------
COMPOUND:   Phosphonodithiotic  acid,  0-isopropyl-S-p-tolyl chloromethyl ester
                                                                                            COMPOUND:    Phcisphonofluoridic acid,  methyl-, isopropyl ester
REFERENCE:  Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
            Toxicol. Appl. Pharm. 11:  49-67, 1967.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
REFERENCE:   Loomis,  T.A.
             Tox.  Appl.  Pharm.  5:489-499, 1963.


OBSERVED NEUROTOXIC EFFECTS:     Motor activity in activity-cage decreased.
ANIMALS:  Cockerels, Single Comb White Leghorn, 10-12 d old
                                                                                            ANIMALS:     Mice, white, 25-30 g, and  2 dogs  (no  details)
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD   34.1 mg/kg
                         (2) Subacute:  50-800 ppm in diet, 20 chicks/grp, for 2 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT: 40 meg/kg.
ROUTE AND SITE:  Oral

CONTROL INFORMATION:  Untreated  control grps
ROUTE AND SITE:   i.p.

CONTROL INFORMATION:   Saline treated  controls.
DURATION OF EXPERIMENT:    1-3 wk

EXAM. TYPE:   Behavior, mortality
DURATION OF EXPERIMENT:Serial sacr  to  25  min.

EXAM. TYPE:  Biochemistry, behavior
                                            803
                                                                                                                                       804

-------
COMPOUND:    Phosphonofluoridic acid, methyl-, isopropyl ester
REFERENCE:  Loomls, T.A. and Salafsky, B.
            Tox. Appl. Pharm. 5:685-701, 1963.
OBSERVED NEUROTOXIC EFFECTS:     Acetylcholinesterase inhibition.
COMPOUND:    Phosphonofluoridic  acid, methyl-,  1,2,2-trimethylpropyl ester

             000096640

REFERENCE:   Loomis,  T.A.  and  Salafsky,  B.
             Tox.  Appl.  Pharm.  5:685-701, 1963.



OBSERVED NEUROTOXIC EFFECTS:     Acetylcholinesterase inhibition
ANIMALS:    Mice, C^B,  25-35 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            0.01 ml
                                                                                           ANIMALS:     Mice, CJl, 25-35 g
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            0.01 ml
ROUTE AND SITE:   Dermal

CONTROL INFORMATION:    ns.
ROUTE AND SITE:   Dermal

CONTROL INFORMATION:   ns.
DURATION OF EXPERIMENT:      Various

EXAM. TYPE: Mortality,  electrophysiology
DURATION OF EXPERIMENT:     Various

EXAM. TYPE:  Mortality, electrophysiology
                                          805
                                                                                                                                      806

-------
COMPOUND:       Phosphonothioic acid,  ethyl-,  di(2-chloroethyl)  ester.
REFERENCE:      Aldridge, W.N.  and Barnes,  J.M.
                Biochemical Pharra. 15:541-548,  1966.
COMPOUND:       Phosphonothioic acid, ethyl-, 0-ethyl 0-(2,4,5-trichlorophenyl)
                ester
                000327980
REFERENCE:
                Aldridge, W.N. and Barnes, J.M.
                Biochemical Pharm. 15:541-548, 1966.
OBSERVED NEUROTOXIC EFFECTS:    Weakened limbs.   Histological  changes in the
                               spinal cord and  sciatic nerves.   Inhibition
                               of CNS esterase.
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histological changes  in  the  spinal
                               cord and sciatic nerves.  Inhibition of CNS
                               of esterase.
ANIMALS:        Hens, grps of 2-4,  RIR x Light Sussex,  2-3  kg
ANIMALS:
                Hens, grps of 2-4, RIR x Light Sussex, 2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose,  amount  varied  by  compound
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose, amount varied by compound
ROUTE AND SITE:    oral,  B.C.,  or i.p.

CONTROL INFORMATION:       ns.
ROUTE AND SITE:   Oral, s.c., or i.p.

CONTROL INFORMATION:       ns.
DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:     Biochemistry,  histology
DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:     Biochemistry, histology.
                                        807
                                                                                                                                    808

-------
COMPOUND:    Phosphonothioic acid,  ethyl-,  0-ethyl 0-(2,4,5-trichlorophenyl)  ester

             000327980

REFERENCE:   Sherman,  M.,  Herrick,  R.B.,  Ross,  E.  and  Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:  49-67,  1967.


OBSERVED NEUROTOXIC EFFECTS:  Ataxia,  paralysis,  convulsions.
COMPOUND:       Phosphonothioic acid,  methyl-, 2,4-dichlorphenyl methyl ester
REFERENCE:      Aldridge,  W.N.  and Barnes, J.M.
                Biochemical Pharm. 15:541-548, 1966.
                                                                                                 OBSERVED NEUROTOXIC EFFECTS:    Weakened limbs.   Histological changes in the
                                                                                                                                spinal cord and sciatic nerves.  Inhibition of
                                                                                                                                CNS esterase.
ANIMALS:  Cockerels,  Single Comb White Leghorn,  10-12 d old
                                                                                                 ANIMALS:
                                                                                                                 Hens,  grps of 2-4, RIR x Light Sussex, 2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD5Q 12.3 mg/kg
                         (2) Subacute:  50-800 ppm in diet,'  20 chicks/grp, for 2 wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose, amount varied by compound
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
ROUTE AND SITE:    Oral, B.C.,'or l.p.

CONTROL INFORMATION:       ns.
DURATION OF EXPERIMENT:   1-3 wk

EXAM.  TYPE:  Behavior, mortality
DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:     Biochemistry, histology
                                            809
                                                                                                                                         810

-------
COMPOUND:   Phosphonothioic  acid, phenyl.-0-ethyl ester, 0-ester with p-hydroxybenzonitrile   COMPOUND:   '  Phosphonothioic  acid,  phenyl-,0-ethyl  0-  (p-nitrophenyl)ester

            013067931                                                                                      002104645
REFERENCE:   Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm. 11:  49-67, 1967.
REFERENCE:  Gaines, T.B.
            Tox.  Appl. Pharm. 14:  515-534, 1969.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
OBSERVED NEUROTOXIC EFFECTS:    80 mg/kg produced  leg weakness
ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
ANIMALS:    Chickens, White Leghorn, F
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute: LD   20.3 mg/kg
                        (2) Subacute:  50-800 ppm in diet, 20 chicks/grp,  for 2  wk
PREPARATION AND DOSE
or HISTORY OF PATIENT:    15 mg/kg atropine  sulfate orally 15 min prior to compound;
                          graded doses compound  in peanut oil
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
ROUTE AND SITE:   S.C., under right wing

CONTROL  INFORMATION:   ns
DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:  Behavior, mortality
DURATION OF  EXPERIMENT:   1 yr

EXAM. TYPE:    Clinical
                                            811
                                                                                                                                         812

-------
COMPOUND:   Phosphonothiooic acid, 0-ethyl S-(2-dimethyl amino ethyl  methyl ester
                                                                                         COMPOUND:    Phosphonotrithioic acid, S,S-dlpropyl methyl
REFERENCE:   Bajgar, J.
            Br. J. Pharmac. 45:  368-371, 1972.
OBSERVED NEUROTOXIC EFFECTS:   Acetylcholinesterase Inhibition in 3 parts of the
                              medulla oblongata proceeded at different rates.
                              The author concluded that.penetration of the compound
                              through corresponding parts of the blood-brain
                              barrier was not uniform.
REFERENCE:   Sherman,  M., Herrick,  R.B.,  Ross,  E.  and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:   49-67,  1967.
                                                                                         OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
ANIMALS:     Rats, Wistar, F, 150-170 g
                                                                                         ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.035 mg/kg
PREPARATION AND DOSE      •                                                 -      .
or HISTORY OF PATIENT:   (1) Acute: LD5Q 11.6 mg/kg
                         (2) Subacute:   50-800 ppm in diet, 20 chicks/grp, for 2 wk
ROUTE AND SITE:   I.M.

CONTROL INFORMATION:   None
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated  control grps
DURATION OF EXPERIMENT:  1-30 min

EXAM. TYPE:  Biochemistry
DURATION OF EXPERIMENT:   1-3  wk

EXAM. TYPE:   Behavior,  mortality
                                        813
                                                                                                                                     814

-------
 COMPOUND:
            Phosphonotrithiolc  acid, methyl-, S-propyl-S-diethy1.
-------
COMPOUND:
             Phosphoramldic acid, methyl-4-tert-butyl-2-chlorophenyl methyl-ester

             000299865
REFERENCE:  Khan, M.A.
            Res. Vet. Sci. 15:  180-185, 1973.
OBSERVED NEUROTOXIC EFFECTS:   The animals exhibited dullness, ataxia and muscular
                              fasciculation, with recovery in 72 hr (1 case 1 wk).
                              The signs were related to inhibition of whole-blood
                              cholinesterases.
COMPOUND:   Phosphoramidothioic acid, isopropyl-,0-2,4-dichlorophenyl 0-methyl ester

            000299854

REFERENCE:   Sherman, M., Ross, E. and Chang, M.T.Y.
             Tox. Appl. Pharm. 6:147-153, 1964.


OBSERVED NEUROTOXIC  EFFECTS:  
-------
COMPOUND:  Phosphoric  acid, aluminum salt
                                                                                           COMPOUND:    Phosphoric acid, bis(2-ethylhexyl) o-tolyl ester
REFERENCE:  Seil, F.J., Lampert, P.W. and Klatzo, I.
            J. Neuropath. Exp. Neurol. 28:  74-85, 1969.
OBSERVED NEUROTOXIC EFFECTS:  Induced neurofibrillary spheroids filled  the cytoplasm
                             of the cells exposed to aluminum phosphate, and the
                             nuclei were displaced.  The spheroids were compared
                             with those induced by vincristine sulfate.  The author
                             claimed the former were like those of postencephalitic
                             parkinsonism and the latter like those of Alzheimer's
                             disease.
                                                                  REFERENCE:      Hine,  C.H.,  Dunlap,  M.K.,  Rice,  E.G.,  Coursey, M.M., Gross, R.M.
                                                                                  and Anderson,  H.H.
                                                                                  J.  Pharm.  Exp.  Ther. 116:227,  1956.

                                                                  OBSERVED NEUROTOXIC EFFECTS:    No  paralysis reported.
ANIMALS:    In vitro cultures of spinal cord and dorsal root ganglia from  fetal
            NZ White rabbits.
                                                                  ANIMALS:   * Chickens, White  Leghorn,  M,  0.75-1.3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
1:100 suspension every 4  d  after  20-22 d  in vitro:
time of exposure 6-11 d in  each cycle of  20 d
PREPARATION AND DOSE
or HISTORY OF PATIENT: (1)  0.5 gm/kg
                       (2)  1.0 gm/kg
ROUTE AND SITE:  In vitro

CONTROL INFORMATION:   Untreated cultures
                                                                  ROUTE AND SITE: (i) s.C.    (2) Oral

                                                                  CONTROL INFORMATION:   one group of 5 per experimental group.
DURATION OF EXPERIMENT:   Various

EXAM. TYPE:  Light and electron microscopy
                                                                  DURATION OF EXPERIMENT:  14-36 d after treatment. .

                                                                  EXAM. TYPE:     Behavior, histology
                                         819
                                                                                                                                     820

-------
COMPOUND:  Phosphoric acid,  bis(p-ethylphenyl)  ester
COMPOUND:  Phosphoric acid, bis(4-ethylphenyl) 2-propylphenyl  ester
REFERENCE:  Bondy,  H.F.,  Field,  E.J.,  Worden,  A.N.  and Hughes,  J.P.W.
            Brit.  J.  Indust.  Med.  17:   190-200,  1960.
REFERENCE:  Aldridge, W.N. and Barnes, J.M.
            Biochem. Pharm. 6:  177-188, 1961.
OBSERVED NEUROTOXIC EFFECTS:   (D  All birds were severely paralyzed.
                              (2)  All birds developed ataxia within 12 days.
                              (3)  All birds developed ataxia within 10 days.
OBSERVED NEUROTOXIC EFFECTS:   Neurotoxicity independent of cholinesterase inhibition
                              in vivo; the latter was found and  attributed to some
                              metabolite (unidentified).  Little structure-activity
                              relationship seen between triaryl  phosphates.   Most
                              common sign of toxicity was ataxia.
ANIMALS:     (D  12 Chickens
            (2)  3 Chickens
            (3)  3 Chickens

PREPARATION AND  DOSE
or HISTORY OF PATIENT:   (1) 1,000 mg/kg
                        (2) 500 mg/kg
                        (3) 100 mg/kg
ANIMALS:    Chickens, F, aged over 4 mo, usually 6-12 mo, various breeds
PREPARATION AND DOSE
or HISTORY OF PATIENT:   50-5000 mg/kg
ROUTE AND SITE:    Gavage

CONTROL INFORMATION:   Controls mentioned but not described
ROUTE AND SITE:   Oral

CONTROL INFORMATION:    ns
DURATION OF EXPERIMENT:   Up to 1 yr

EXAM.  TYPE:  Behavior,  histology
DURATION OF EXPERIMENT:   24 hr to 21 d

EXAM. TYPE:   Behavior
                                          821
                                                                                                                                       822

-------
COMPOUND:   Phosphoric acid, bis(2-ethylphenyl) p-tolyl ester
                                                                                            COMPOUND:  Phosphoric acid, bis(o-propylphenyl) p-tolyl ester
REFERENCE:  Aldridge, W.N. and Barnes, J.M.
            Biochem. Pharm. 6:  177-188, 1961.
REFERENCE:  Bondy,  H.F.,  Field, E.J., Worden, A.N. and Hughes, J.P.W.
            Brit.  J.  Tndust.  Med. 17:  190-200, 1960.
OBSERVED NEUROTOXIC EFFECTS:   Neurotoxicity independent of cholinesterase inhibition
                 i             in vivo; the latter was found and attributed to some
                 !             metabolite (unidentified).   Little structure-activity
                              relationship seen between triaryl phosphates.  Most
                              common sign of toxicity was ataxia.
OBSERVED NEUROTOXIC EFFECTS:  All birds developed ataxia within 10 days.
ANIMALS:    Chickens, F, aged over 4 mo, usually 6-12 mo, various breeds
ANIMALS:    6 Chickens
PREPARATION AND DOSE
or HISTORY OF PATIENT:  50-5000 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   500 mg/kg
ROUTE AND SITE:  Oral

CONTROL INFORMATION:   ns
ROUTE AND SITE:  Gavage

CONTROL INFORMATION:  Controls mentioned but not described
DURATION OF EXPERIMENT:   24 hr to 21 d

EXAM. TYPE:   Behavior
DURATION OF EXPERIMENT:  Up to 1 yr

EXAM. TYPE:  Behavior, histology
                                          823
                                                                                                                                       824

-------
COMPOUND:   Phosphoric acid, bis (3,5-xylyl) 2-ethylphenyl ester
                                                                                             COMPOUND:    Phosphoric acid, 2-chloro-l-(2,4-dibromophenyl) vinyl dimethyl ester
REFERENCE:  Aldridge, W.N. and Barnes, J.M.
            Biochem. Pharm. 6:  177-188, 1961.


OBSERVED NEUROTOXIC EFFECTS:   Neurotoxicity independent of cholinesterase inhibition
                              in vivo; the latter was found and attributed to some
                              metabolite (unidentified).   Little structure-activity
                              relationship seen between triaryl phosphates.  Most
                              common sign of toxicity was ataxia.
                                                                                             REFERENCE:
               Morallo, B.D. and Sherman, M.
               J. Econ. Entomol. 60:509-515, 1967.
OBSERVED NEUROTOXIC EFFECTS:
The order of resistance to the insecticide was:
fleshfly > house fly > anthomyiid fly > blow fly.
This insecticide caused 50% mortality in the
anthomyiid fly within one hour, but was much slower
with the other species.  It caused a low level of
inhibition of cholinesterase in house flies, but
caused high levels in the other species, with maximum
inhibition occurring within 30 minutes.  Recovery
was not very complete in anthomyiid flies and flesh
flies.
ANIMALS:    Chickens, F, aged over 4 mo,  usually 6-12 mo, various breeds
PREPARATION AND DOSE
or HISTORY OF PATIENT:   50-5000 mg/kg
ROUTE AND SITE:   Oral

CONTROL INFORMATION:    ns
ANIMALS:       Housefly, Musca domestica, adult F,  3-4 d  old
               Anthomyiid fly, Fannia pusio, adult  F, 3-4 d old
               Blowfly, Chrysoma megacephala, adult F, 3-4 d  old
               Flesh fly, parasarcophaga argyrostoma, adult F, 3-4  d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    In vitro:  The LD50  (0.26-21.6 mcg/g), 10-20 flies/
                                    group or dose-level,  each test  replicated
                                    3 or more times.
                         In vivo:   10 groups of  50 each  of houseflies and
                                    anthomyiid flies, and 10  groups of 20 each
                                    of blowflies  and  flesh flies.
ROUTE AND SITE: Applied topically, venter of thorax.
CONTROL INFORMATION:
                         Untreated fly heads
DURATION OF EXPERIMENT:    24 hr to 21 d

EXAM. TYPE:   Behavior
DURATION OF EXPERIMENT:  Serial to 24 hr.

EXAM. TYPE:    Biochemistry, mortality
                                          825
                                                                                                                                     826

-------
 COMPOUND:    Phosphoric acid,  2-chloro-l-(2,4-dichlorophenyl) vinyl diethyl ester

             00047096

 REFERENCE:   Sherman,  M.,  Herrick,  R.B., Ross, E. and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:  49-67, 1967.


 OBSERVED NEUROTOXIC EFFECTS:  Ataxia, paralysis, convulsions.
ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD   29.1 mg/kg
                         (2) Subacute:5050-800 ppm in diet, 20 chicks/grp,  for 2  wk
ROUTE AND SITE:   oral

CONTROL INFORMATION:   Untreated control grps



DURATION OF EXPERIMENT:   1-3 wk

EXAM. TYPE:   Behavior, mortality
                                           827
COMPOUND:   Phosphoric acid, 2-chloro-l-(2,4-dichlorophenyl) vinyl dimethyl ester

            002274671
REFERENCE:
Morallo, B.D. and Sherman, M.
J. Econ. Entomol. 60:509-515, 1967.
                                                                                               OBSERVED NEUROTOXIC EFFECTS:
                               The  order  of  resistance  to  the  insecticide was
                               flesh  fly  >house  fly  >anthomyiid  fly >blow fly.  This
                               insecticide is  a  relatively rapid toxicant, with
                               50%  mortality occurring within one hour.   100%
                               inhibition of cholinesterase occurred in the flesh
                               fly  within 5  minutes.  Inhibition was higher and
                               recovery less complete in dead  flies than in living
                               flies.
ANIMALS:       Housefly, Muaca domestica,  adult  F,  3-4 d old
               Anthomyiid fly, Fannia pusio,  adult  F,  3-4 d old
               Blowfly, Chrysoma mcgacephala,  adult F, 3-4 d old
               Flesh fly, parasarcophaga argyrostoma,  adult F, 3-4 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    In vitro:  The LD50  (0.26-21.6 mcg/g), 10-20 flies/
                                    group  or  dose-level, each test replicated
                                    3 or more times.
                         In vivo:   10 groups of 50 each of houseflies and
                                    anthornylid flies,  and 10 groups of 20 each
                                    of blowflies and flesh flies.
ROUTE AND SITE: Applied topically, venter of thorax.
CONTROL INFORMATION:
                         Untreated  fly heads
DURATION OF EXPERIMENT:  Serial to  24 hr.

EXAM. TYPE:    Biochemistry, mortality
                                                                                                                                       828

-------
COMPOUND:   Phosphoric acid, 2-chloro-l-(2,5-dichlorophenyl) vinyl dimethyl ester
                                                                                             COMPOUND:
                Phosphoric acid, 2-chloroethyl 2,2-dichlorovinyl methyl ester
REFERENCE:
               Morallo, B.D. and Sherman, M.
               J. Econ. Entomol. 60:509-515, 1967.
 REFERENCE:
Aldridge, W.N. and Barnes, J.M.
Biochemical Pharm. 15:541-548, 1966.
OBSERVED NEUROTOXIC EFFECTS:
                             The order of resistance to the insecticide was:
                             flesh fly > house fly > anthomyiid fly > blow fly.
                             This toxicant caused 50% mortality in all flies
                             within 2 hours.  Within 5 minutes, 90% inhibition
                             of cholinesterase occurred in both house flies and
                             flesh flies.  Anthomyiid flies took 2 hours to reach
                             maximum inhibition (49%).  The recovery of the flesh
                             fly was very slow with 50% inhibition after 24 hours.
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histological changes in the
                               spinal cord and sciatic nerves.  Inhibition of
                               CNS esterase.
ANIMALS:       Housefly, Musca domestica, adult F, 3-4 d old
               Anthomyiid fly, Fannia pusio, adult F, 3-4  d old
               Blowfly, Chrysoma megacephala, adult F, 3-4 d  old
               Flesh fly, parasareophaga argyrostoma, adult F, 3-4  d  old
PREPARATION AND DOSE
or HISTORY OF PATIENT:    In vitro:  The LD50 (0.26-21.6 mcg/g), 10-20 flies/
                                    group or dose-level, each test  replicated
                                    3 or more times.
                         In vivo:   10 groups of 50 each of houseflies and
                                    anthomyiid flies, and  10  groups of 20 each
                                    of blowflies and flesh flies.
ROUTE AND SITE: Applied topically, venter of thorax.
CONTROL INFORMATION:
ANIMALS:
                Hens, grps of 2-4, RIR x Light Sussex, 2-3 kg
                         Untreated fly heads
PREPARATION AND DOSE            '
or HISTORY OF PATIENT:    Mostly 1 dose, amount varied by compound
ROUTE AND SITE:  Oral, s.c., or i.p.

CONTROL INFORMATION:       ns.
DURATION OF EXPERIMENT:   Serial to 24 hr.

EXAM.  TYPE:    Biochemistry, mortality
DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:     Biochemistry, histology
                                        829
                                                                                                                                    830

-------
 COMPOUND:    Phosphoric  acid,  2-chloroethyl 2-dichlorovinyl methyl ester
COMPOUND:
Phosphoric acid, 2-chloroethyl ethyl p-nitrophenyl  ester
 REFERENCE:   Sherman, M., Ross, E. and Chang, M.T.Y.
             Tox. Appl. Pharm. 6:147-153, 1964.
REFERENCE:
                Aldridge,  W.N. and Barnes, J.M.
                Biochemical Pharm. 15:541-548, 1966.
OBSERVED NEUROTOXIC EFFECTS:    (1) Convulsions and death within 18 hrs.  Survivors
                               were lethargic for 6-19 hrs. post treatment.
                                (2) 50% Cholinesterase inhibited by doses of >800 ppm
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histologlcal changes in the
                               spinal cord and sciatic nerves.  Inhibition of
                               CNS esterase.
ANIMALS:     Cockerels, White Leghorn, single-comb, 10-50/grp, 12 d old
ANIMALS:
Hens, grps of 2-4, RIR x Light  Sussex,  2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)   Acute:  LD    (37.8 mg/kg) as gelatin  capsule.
                         (2)   Subacute:   50-800 ppm in feed.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    Mostly 1 dose, amount varied by  compound
ROUTE AND SITE:    Oral

CONTROL INFORMATION:     Untreated diet.
ROUTE AND SITE: oral, s.c., or i.p.

CONTROL INFORMATION:      ns.
DURATION OF EXPERIMENT:  1 wk

EXAM.  TYPE:  Mortality,  behavior, blood ChE
DURATION OF EXPERIMENT:   14-21 d

EXAM. TYPE:     Biochemistry, histology
                                        831
                                                                                                                                      832

-------
COMPOUND:
            Phosphoric acid,  o-chlorophenyl diphenyl ester
REFERENCE:      Hine, C.H., Dunlap, M.K., Rice, E.G., Coursey, M.M., Gross, R.M.
               and Anderson, H.H.
               J. Pharm.  Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC  EFFECTS:     NO paralysis.
COMPOUND:   Phosphoric acid,  l-((p-chlorophenyl)thio) vinyl dimethyl ester

            002595531

REFERENCE:   Sherman, M.,  Herrick,  R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm.  11:   49-67, 1967.


OBSERVED NEUROTOXIC  EFFECTS:    Ataxia,  paralysis, convulsions.
ANIMALS:   4  Chickens, White Leghorn, M, 0.75-1.3 kg
                                                                                           ANIMALS:  Cockerels,  Single Comb White Leghorn,  10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:     (i)  o.5  gm/kg
                          (2)  1.0  gm/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1) Acute: LD    51.3 mg/kg
                         (2) Subacute:   50-800 ppm in diet, 20 chicks/grp, for 2 wk
ROUTE AND SITE:   (1)  S.C.   (2)  Oral

CONTROL INFORMATION:    One group of 5 per experimental group.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:    Untreated  control grps
DURATION OF EXPERIMENT:   14-36 d after treatment.

EXAM. TYPE:     Behavior, histology
DURATION OF EXPERIMENT:    1-3 wk

EXAM.  TYPE:  Behavior,  mortality
                                          833
                                                                                                                                       834

-------
COMPOUND:
Phosphoric acid,  2-chloro-l-(2,4,5-trichloro-phenyl)vinyl dimethyl ester

000961115
                                                                                              COMPOUND:   Phosphoric acid,  o-cresyl diphenyl ester
REFERENCE:   Sherman, M., Herrick, R.B., Ross, E. and Chang, M.T.Y.
             Toxicol. Appl. Pharm. 11:  49-67, 1967.
                                                                                 REFERENCE:  Johnson, M.K. and Barnes, J.M.
                                                                                             Biochem. Pharm. 19:3045-3047,  1970.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia, paralysis, convulsions.
                                                                                              OBSERVED  NEUROTOXIC  EFFECTS:
                                                                                                                 Toxic  to  adult  hens at 0.1 rag/kg.   Repeated doses
                                                                                                                 produced  ataxia and "characteristic" lesions in
                                                                                                                 cord and  peripheral nerves.
ANIMALS:   Cockerels, Single Comb White Leghorn, 10-12 d old
                                                                                              ANIMALS:     Chickens, various breeds, sex not  stated.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1) Acute: LD,. 2528 mg/kg
                         (2) Subacute:  50-800 ppm in diet, 20 chicks/grp, for 2 wk
                                                                                 PREPARATION AND DOSE
                                                                                 or HISTORY OF PATIENT:
                                                                                                             0.5  ml/kg,  then 0.1 ml/kg up to 6 doses.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated control grps
                                                                                 ROUTE AND SITE:    Oral

                                                                                 CONTROL INFORMATION:    Mentioned,  not described
DURATION OF EXPERIMENT:   1-3 wk

EXAM.  TYPE:  Behavior, mortality
                                                                                 DURATION OF EXPERIMENT:      Up to 63 d

                                                                                 EXAM.  TYPE:  Behavior,  then histology.  Also, in vitro bioassay.
                                           835
                                                                                                                                        836

-------
COMPOUND:
            Phosphoric acid, cyclic methylene-o-phenylene o-tolyl  ester
REFERENCE:   Baron,  R.L.  and  Casida,  J.E.
            Biochem.  Pharm.  11:   1129-1136,  1962.
OBSERVED NEUROTOXIC  EFFECTS:  Ataxic doses inhibited  selectively nerve esterases
                             hydrolyzing butyryl  esters  of  choline, glycerol and
                             phenols.   TOCP  more  persistent than metabolite.
                             Oxidation of succinate^  pyruvate, a-ketoglutarate
                             by nerve  and brain preparations was not affected.
ANIMALS:     Chickens,  White Leghorn,  1-2 y,  1.5-2.5  kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   20mg/kg
ROUTE AND SITE:    TOCP:   gavage;  DFP and metabolite:   I.P.

CONTROL INFORMATION:  ns



DURATION OF EXPERIMENT:   ns

EXAM. TYPE:    Biochemistry
                                        837
                                                                                             COMPOUND:  Phosphoric acid, cyclic methylene-o-phenylene tolyl ester
REFERENCE:   Baron, R.L.,-Bennett, D.R. and Casida, J.E.
             Br. 3. Pharmacol. 18:465-474, 1962.


OBSERVED NEUROTOXIC EFFECTS:  clinical and neurological comparison was made
                              between this compound and tri-ortho-cresyl phosphate.
                              Ataxia was present with both,  higher doses increased
                              the degree of peripheral neuropathy.  Demyelination
                              of the spinal cord occurred at doses below those
                              effecting peripheral nerve degeneration.  Axon
                              and myelin damage was prominent with both agents.
                                                                                             ANIMALS:     24 Chickens,  White Leghorn,  aged 12-18 mo, av 2 kg.
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                                                                                                                           8-400 mg/kg in corn oil, single dose.
ROUTE AND SITE:     I.P.

CONTROL INFORMATION: ns.



DURATION OF EXPERIMENT:   ns.

EXAM. TYPE:   Histology
                                                                                                                                   838

-------
COMPOUND:
Phosphoric acid,  cyclic methylene-o-phenylene o-tolyl ester
COMPOUND:    Phosphoric acid,  l,2-dibromo-2,2-dichloroethyl  dimethyl  ester
             000300765
REFERENCE:   Taylor, J.D.
            Tox. Appl. Pharmac.  11:538-545,  1967.
OBSERVED NEUROTOXIC  EFFECTS:
                   (1) Paralysis as from TOCP in 21  d.   (2)  Doses over
                   75 mg/kg to adults produced ataxia and  an abnormal
                   reflex; no effect on kittens.   Axonal degeneration
                   in cord, as from TOCP, found in cats.
REFERENCE:  Rayner, M.D., Popper, J.S., Carvalho, E.W.  and Hurov,  R.
            Res.  Comm. Chem. Path. Pharm. 4:  595-606,  1972.


OBSERVED NEUROTOXIC EFFECTS:   The force generated by  the achllles tendon reflex was
                              subnormal in exposed subjects.   The  authors suggest
                              that this hyporeflexia may be  a sensitive indicator of
                              chronic exposure to organophosphates.
ANIMALS:      (1) One White Leghorn chicken
             (2) 18 Cats, adult M, random-bred, castrated,  and 8 kittens
                                                                                           ANIMALS:    Humans,  Japanese ancestry, M, ages 22-59  (orchid  farmers)
PREPARATION AND DOSE
or HISTORY OF PATIENT:
               (1) 10 mg/kg, one dose.
               (2) 15-200 mg/kg, one dose.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  Exposure of more than 4 hr/d,  2  d/wk,  52 wk/yr for 5 yr except
                        one case (2 yr).  Other types  of pesticide also used, but
                        authors judged organophosphates  exposures to be primary.
ROUTE AND SITE:(l)ns.

CONTROL INFORMATION:
            (2) I.M. in shoulder

          (1) One control chicken
          (2) 4 of the 8 kittens.
ROUTE AND SITE:   Skin contact, inhalation

CONTROL INFORMATION:  Matched non-exposed subjects, so  far  as  could be ascertained
DURATION OF EXPERIMENT:     Up to 190 d.

EXAM. TYPE:  Behavior, histology
                                                                              DURATION OF EXPERIMENT:  ns

                                                                              EXAM. TYPE:   .  Physiological
                                          839
                                                                                                                                      840

-------
COMPOUND:
Phosphoric acid, di(2-chloroethyl) 2,2-dichlorovlnyl ester
REFERENCE:
                Aldridge,  W.N.  and  Barnes,  J.M.
                Biochemical Pharm.  15:541-548,  1966.
OBSERVED NEUROTOXIC EFFECTS:    Weakened  limbs.   Histological  changes  in the
                               spinal  cord  and  sciatic  nerves.   Inhibition of
                               CNS  esterase.
ANIMALS:         Hens,  grps of 2-4,  RIR x Light Sussex,  2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied by compound
ROUTE AND SITE:  oral,  B.C.,  or i.p.

CONTROL INFORMATION:   ns.



DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:      Biochemistry,  histology
                                        841
                                                                             COMPOUND:
Phosphoric acid, di(2-chloroethyl) p-nitrophenyl ester
                                                                             REFERENCE:
                                                                                             Aldridge, W.N.  and  Barnes,  J.M.
                                                                                             Biochemical  Pharm.  15:541-548,  1966.
                                                                             OBSERVED NEUROTOXIC EFFECTS:    Weakened limbs.   Histological changes in the
                                                                                                            spinal cord and  sciatic nerves.  Inhibition of
                                                                                                            CNS esterase.
                                                                             ANIMALS:
Hens, grps of 2-4 RIR x Light Sussex, 2-3 kg
                                                                             PREPARATION AND DOSE
                                                                             or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied by compound
                                                                             ROUTE AND SITE:    Oral,  s.c.,  or i.p.

                                                                             CONTROL INFORMATION:       ns.



                                                                             DURATION OF EXPERIMENT:    14-21 d

                                                                             EXAM. TYPE:      Biochemistry,  histology
                                                                                                                                     842

-------
 COMPOUND:       Phosphoric acid, di(2-chloroethyl)  2,3,5-trichlorophenyl ester
 REFERENCE:
                Aldridge, W.N. and Barnes, J.M.
                Biochemical Pharm. 15:541-548,  1966.
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histological changes in the
                               spinal cord and  sciatic nerves.   Inhibition
                               of CNS esterase.
ANIMALS:
                Hens, grps of 2-4, RIR x Light Sussex,  2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose, amount varied by compound
ROUTE AND SITE:    oral, s.c., or i.p.

CONTROL INFORMATION:       ns.



DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:     Biochemistry, histology
                                        843
COMPOUND:    Phosphoric acid, di-o-chlorophenyl  phenyl  ester
REFERENCE:      Hine,  C.H.,  Dunlap, M.K., Rice, E.G., Coursey, M.M.,  Gross,  R.M.
                and Anderson, H.H.
                J.  Pharm.  Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC EFFECTS:     No paralysis.
ANIMALS:   4  Chickens,  White Leghorn, M, 0.75-1.3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)  0.5 gin/kg
                          (2)  1.0 gm/kg
ROUTE AND SITE: (i) s.C.  (2) Oral

CONTROL INFORMATION:   One group of 5 per  experimental group.



DURATION OF EXPERIMENT:14-36 d after  treatment.

EXAM. TYPE:     Behavior, histology
                                                                                                                                     844

-------
 COMPOUND:       Phosphoric acid, 2-2-dichlorovinyl dimethyl ester

                000062737

 REFERENCE:      Aldridge, W.N. and Barnes,  J.M.
                Biochemical Pharm. 15:541-548,  1966.
 COMPOUND:   Phosphoric  acid,  diethyl  p-nitrophenyl  ester

            000311455

 REFERENCE:  Murphy,  S.D., Lauwerys, R.R.  and  Cheever,  K.L.
            Tox. Appl.  Pharm.  12:   22-35,  1968.
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.   Histological changes  in the
                               spinal cord and  sciatic nerves.   Inhibition of
                               CNS esterase.
OBSERVED NEUROTOXIC EFFECTS:  Inhibits brain cholinesterase.
                              Sensitivities:  birds> mammals > fish.
ANIMALS:        Hens, grps of 2-4,  RIR x Light Sussex,  2-3  kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied by  compound
                                                              In vitro brains of rats,
                                                              guinea pigs, sparrows, small-
                                                              mouth bass, flounder, sculpin
                                                              and monkey.
ANIMALS-   Mlce> Swiss-Webster, M, 25-30g
           Chickens, White Rock X N.H. Red, M, 5BO-700g
           Sunfish, M and F, 40-80g
           Bullfish, M and F, 40-80g
PREPARATION AND DOSE
or HISTORY OF PATIENT:   0.1-1500 mg/kg, various schedules  (I.P.)  in mice, chickens,
                        sunfish and bullheads; 0.1-200  mg/kg (orally)  in sunfish;
                        0.001-4 picomoles of malaoxon in vitro.
ROUTE AND SITE:  oral,  B.C..  or i.p.

CONTROL INFORMATION:       ns.
ROUTE AND SITE:  See above

CONTROL INFORMATION:  Brain cholinesterase determined  in controls
DURATION OF EXPERIMENT:    u_2i a

EXAM. TYPE:      Biochemistry,  histology
DURATION OF EXPERIMENT: Various

EXAM. TYPE:   Biochemistry
                                        845
                                                                                                                                    846

-------
COMPOUND:   Phosphoric acid,  di(o-ethylphenyl)  p-tolyl ester
COMPOUND:   Phosphoric acid, diethyl o-tolyl ester
REFERENCE:  Bondy,  H.F.,  Field,  E.J.,  Worden,  A.N.  and Hughes,  J.P.W.
            Brit.  J.  Indust.  Med.  17:   190-200,  1960.
OBSERVED NEUROTOXIC EFFECTS:   Three out  of four  birds became  paralyzed.
REFERENCE:      Hine,  C.H.,  Dunlap, M.K., Rice, E.G., Coursey, M.M., Gross,  R.M.
                and Anderson, H.H.
                J.  Pharm. Exp. Ther. 116:227, 1956.


OBSERVED NEUROTOXIC EFFECTS:     No paralysis
ANIMALS:     4 Chickens
                                                                                            ANIMALS:
                It  Chickens, White Leghorn, M, 0.75-1.3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:   5 x 500 mg/kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:
(1)   0.5 gm/kg.
(2)   1.0 gm/kg.
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:   Controls  mentioned but not described
ROUTE AND SITE:   (1)  S.C.   (2)  Oral

CONTROL INFORMATION:   One group of  5 per  experimental group.
DURATION OF EXPERIMENT:   Up  to 1  yr

EXAM. TYPE:    Behavior,  histology
DURATION OF EXPERIMENT:  14-36 d  after  treatment.

EXAM. TYPE:     Behavior, histology
                                          847
                                                                                                                                       848

-------
 COMPOUND:    Phosphoric acid, dimethyl (l-(dimethylphosphonyl)vinyl)  ester
 REFERENCE:   Sherman, M., Ross, E. and Chang, M.T.Y.
             Tox. Appl. Pharm. 6:147-153, 1964.


 OBSERVED NEUROTOXIC  EFFECTS:     (i) Convulsions and death within 18 hrs.
                                    Survivors were lethargic for 6-19 hrs. post
                                    treatment.
                                 (2) 50%  Cholinesterase inhibited by doses of 45 ppm.
COMPOUND:    Phosphoric acid, dimethyl ester, ester with  (E)-3hydroxy-N-methyl
             crotonamide
             000919448

REFERENCE:   Sherman,  M.,  Herrick,  R.B.,  Ross,  E. and Chang, M.T.Y.
             Toxicol.  Appl.  Pharm.  11:   49-67,  1967.
OBSERVED NEUROTOXIC EFFECTS:   Ataxia,  paralysis, convulsions.
ANIMALS:     Cockerels, White Leghorn, single-comb, 10-50/grp, 12 d old
                                                                                          ANIMALS:   Cockerels, Single Comb White  Leghorn,  10-12 d old
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (i)  Acute:   LD    (43.9 rag/kg)  as  gelatin  capsule.
                         (2)  Subacute:    50-800 ppm in  feed.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   (1)  Acute:  LD5_  3.54 mg/kg
                         (2)  Subacute:   50-800 ppm in diet, 20 chicks/grp, for 3 wk
ROUTE AND SITE:    Oral

CONTROL INFORMATION:     Untreated diet.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   Untreated  control grps
DURATION OF EXPERIMENT:  1 wk

EXAM.  TYPE:  Mortality,  behavior, blood ChE
DURATION OF EXPERIMENT:    1-3 wk

EXAM.  TYPE:  Behavior,  mortality
                                         849
                                                                                                                                      850

-------
COMPOUND:       Phosphoric acid,  diphenyl o-tolyl ester
COMPOUND:    Phosphoric  acid,  diphenyl o-tolyl ester
REFERENCE:
                Aldridge, W.N.  and Barnes,  J.M.
                Biochemical Pharm. 15:541-548,  1966.
OBSERVED NEUROTOXIC EFFECTS:    Weakened limbs.   Histological  changes  in the
                               spinal cord and  sciatic nerves.   Inhibition
                               of CNS esterase.
REFERENCE:      Hine,  C.H.,  Dunlap, M.K., Rice, E.G., Coursey, M.M.,  Gross,  R.M.
                and Anderson,  H.H.
                J.  Pharm.  Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC EFFECTS:     All had paralysis.
ANIMALS:
                Hens, grps of 2-4,  RIR x Light Sussex,  2-3 kg
ANIMALS:        4  Chickens,  White Leghorn, M, 0.75-1.3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose,  amount varied by compound
PREPARATION AND DOSE
or HISTORY OF PATIENT:    (1)  0.5 gin/kg.
                          (2)  1.0 gm/kg.
ROUTE AND SITE:    Oral, s.c., or i.p.

CONTROL INFORMATION:       ns.
ROUTE AND SITE:     (1)  S.C.    (2)  Oral

CONTROL INFORMATION:   One group of 5 per experimental  group.
DURATION OF EXPERIMENT:    14-21 d

EXAM.  TYPE:     Biochemistry, histology
DURATION OF EXPERIMENT:  14-36 d after treatment.

EXAM. TYPE:     Behavior, histology
                                        851
                                                                                                                                     852

-------
COMPOUND:     Phosphoric  acid, di-o-tolyl ester
                                                                                           COMPOUND:  Phosphoric acid, di-p-tolyl 2-ethylphenyl ester
REFERENCE:      Hine, C.H., Dunlap, M.K., Rice. E.G., Coursey, M.M., Gross, R.M.
               and Anderson, H.H.
               J. Pharm. Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC  EFFECTS:     No paralysis.
                                                                            REFERENCE:   Aldridge, W.N. and Barnes, J.M.
                                                                                        Biochem. Pharm. 6:  177-188, 1961.


                                                                            OBSERVED NEUROTOXIC EFFECTS:   Neurotoxicity independent of  cholinesterase inhibition
                                                                                                          in vivo; the latter was found and  attributed to some
                                                                                                          metabolite (unidentified).  Little structure-activity
                                                                                                          relationship seen between triaryl  phosphates.   Most
                                                                                                          common sign of toxicity was ataxia.
ANIMALS:
4  Chickens,  White  Leghorn, M, 0.75-1.3
                                                                                           ANIMALS:    'Chickens, F, aged over A mo,  usually 6-12 mo, various breeds
PREPARATION AND DOSE
or HISTORY OF PATIENT:     (1)  1.0 gm/kg
                          (2)  2.5 gm/kg in 5 aliquots over 10 d period.
                                                                            PREPARATION AND DOSE
                                                                            or HISTORY OF PATIENT:   50-5000 mg/kg
ROUTE AND SITE:    (1)   Oral

CONTROL INFORMATION:    One group  of  5 per experimental group.
                                                                            ROUTE AND SITE:   Oral

                                                                            CONTROL INFORMATION:    ns
DURATION OF EXPERIMENT:   14-36  d  after  treatment.

EXAM. TYPE:     Behavior, histology
                                                                            DURATION OF EXPERIMENT:   24 hr to 21 d

                                                                            EXAM.  TYPE:   Behavior
                                          853
                                                                                                                                      854

-------
COMPOUND:   Phosphoric acid, di-p-tolyl o-ethylphenyl ester
COMPOUND:   Phosphoric acid, di-o-tolyl m-tolyl ester
REFERENCE:  Bondy, H.F.,  Field,  E.J.,  Worden, A.M.  and Hughes, J.P.W.
            Brit.  J.  Indust.  Med.  17:   190-200,  1960.
REFERENCE:  Aldridge, W.N. and Barnes,  J.M.
            Biochem. Pharm. 6:  177-188,  1961.
OBSERVED NEUROTOXIC EFFECTS:   All chickens were  .paralyzed.
OBSERVED NEUROTOXIC EFFECTS:  Neurotoxicity independent of cholinesterase inhibition
                              in vivo;  the  latter was found and attributed to  some
                              metabolite  (unidentified).   Little structure-activity
                              relationship  seen between triaryl phosphates.  Most
                              common  sign of toxicity was ataxia.
ANIMALS:    (l)  5 Chickens
            (2)  3 Chickens
ANIMALS:    Chickens, F, aged over  4 mo,  usually 6-12 mo, various breeds
PREPARATION AND DOSE
or HISTORY OF PATIENT:     
-------
COMPOUND:   Phosphoric acid, di-p-tolyl o-tolyl ester
COMPOUND:    Phosphoric acid, di-o-tolyl p-tolyl ester
REFERENCE:  Aldridge, W.N. and Barnes, J.M.
            Biochem. Pharm. 6:  177-188, 1961.
OBSERVED NEUROTOXIC EFFECTS:  Neurotoxicity independent of cholinesterase inhibition
                 I             in vivo; the latter was found and attributed  to some
                              metabolite (unidentified).  Little structure-activity
                              relationship seen between triaryl phosphates.  Most
                              common sign of toxicity was ataxia.
REFERENCE:      Hine,  C.H.,  Dunlap,  M.K.,  Rice,  E.G.,  Coursey, M.M.,  Gross, R.M.
                and Anderson,  H.H.
                J.  Pharm.  Exp.  Ther. 116:227,  1956.

OBSERVED NEUROTOXIC EFFECTS:     Paralysis seen  in all groups.
ANIMALS:    Chickens, F, aged over 4 mo, usually 6-12 mo, various breeds
                                                                                            ANIMALS:
                                                                                                            22 Chickens,  White Leghorn, M, 0.75-1.3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:  5075000 mg/kg
ROUTE AND SITE:  Oral

CONTROL INFORMATION:    ns
PREPARATION AND DOSE      (1)  0.4 gm/kg
or HISTORY OF PATIENT:    (2)  0.2 gm/kg
                          (3)  0.1 gm/kg
                          (4)  0.05 gm/kg
                          (5)  0.025 gm/kg
                          (6)  2.5 gm/kg in 5 aliquots over 10 d period.

ROUTE AND SITE:   Oral

CONTRfll INFORMATION:     One group of 5 per experimental group.
DURATION OF EXPERIMENT:   24 hr to 21 d

EXAM. TYPE:   Behavior
DURATION OF EXPERIMENT:   14-36 d after treatment.

EXAM. TYPE:     Behavior, histology
                                          857
                                                                                                                                      858

-------
COMPOUND:    Phosphoric acid, di-p-tolyl o-tolyl ester
                                                                                           COMPOUND:    Phosphoric acid,  di(3,5-xylyl)  o-tolyl ester
REFERENCE:     Hine, C.H., Dunlap, M.K., Rice, E.G., Coursey, M.M., Gross, R.M.
               and Anderson, H.H.
               J. Pharm.  Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC  EFFECTS:     (1, 2 and 5) All had paralysis, (3) 1 had paralysis
                                (A) None had paralysis.
                                                                  REFERENCE:   Aldridge, W.N. and Barnes, J.M.
                                                                              Biochem. Pharm. 6:  177-188,  1961.
                                                                  OBSERVED NEUROTOXIC EFFECTS:  Neurotoxicity  independent of cholinesterase inhibition
                                                                                                in vivo;  the latter was found and attributed to some
                                                                                                metabolite  (unidentified).  Little structure-activity
                                                                                                relationship seen between triaryl phosphates.  Most
                                                                                                common sign of toxicity was ataxia.
ANIMALS:         18  Chickens, White Leghorn, M, 0.75-1.3 kg
                                                                                            ANIMALS:     Chickens,  F,  aged over 4 mo, usually 6-12 mo,  various breeds
PREPARATION AND DOSE
or HISTORY OF PATIENT:
(1)  0.2  gin/kg
(2)  0.1  gm/kg
(3)  0.05 gm/kg
(4)  0.025 gm/kg
(5)  2.5  gm/kg  in 5  aliquots over 10 d period.
PREPARATION AND DOSE
or HISTORY OF PATIENT:  50-5000 mg/kg
ROUTE AND SITE:    Oral

CONTROL INFORMATION:   One group of 5 per experimental group.
                                                                  ROUTE AND SITE:  Oral

                                                                  CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT:   14-36 d after treatment.

EXAM. TYPE:     Behavior, histology
                                                                  DURATION OF EXPERIMENT:   24 hr to 21 d

                                                                  EXAM. TYPE:   Behavior
                                          859
                                                                                                                                      860

-------
 COMPOUND:
                Phosphoric acid, o-hydroxyphenyl phenyl ester
 REFERENCE:
                Aldridge, W.N. and Barnes, J.M.
                Biochemical Pharm. 15:541-548, 1966.
OBSERVED NEUROTOXIC EFFECTS:   Weakened limbs.  Histological changes in the
                               spinal cord and sciatic nerves.   Inhibition of
                               CNS esterase.
ANIMALS:
                Hens, grps of 2-4, RIR x Light Sussex, 2-3 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:     Mostly 1 dose, amount varied by compound
ROUTE AND SITE:    Oral, s.c., or i.p.

CONTROL INFORMATION:       ns.



DURATION OF EXPERIMENT:    14-21 d

EXAM. TYPE:      Biochemistry, histology
                                        861
                                                                                               COMPOUND:    Phosphoric acid, tolyl ester
REFERENCE:   Smith,  H.V.  and  Spalding,  J.M.K,
             Lancet  2:   1019-21,  1959.
OBSERVED NEUROTOXIC EFFECTS:   Distal weakness and paresthesias.  No deaths
                               reported,  most patients were expected to recover.
                                                                                              ANIMALS:  Humans, more than 2,000 cases.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   Exposure via "olive oil" used in food preparation.
                         Later exam,  of sample showed oil to contain 3% mixed
                         cresyl phosphates, mainly meta and para compounds.
ROUTE AND SITE:   Oral

CONTROL INFORMATION:   None



DURATION OF EXPERIMENT:    Weeks

EXAM. TYPE:   Behavior
                                                                                                                                     862

-------
COMPOUND:  phosphoric acid, o-tolyl ester
                                                                                            COMPOUND:   Phosphoric acid, triaryl ester
REFERENCE:  Vora, D.D., Dastur, D.K., Braganca, B.M., Parihar, L.M., Iyer, C.G.S.,
           Fodekar, R.B. and Prabhakaran, K.
           J. Neurol. Neurosurg. Psychiat. 25:  234-242, 1962.

OBSERVED NEUROTOXIC EFFECTS:  Glove-and-stocking type sensory impairment, distal
                             muscle paralysis with characteristic gait;  degeneration
                             of intramuscular and intradermal nerve twigs, increased
                             plasma cholinesterase.
REFERENCE: Siegel, J., Rudolph, H.S.,  Getzkin,  A.J.  and Jones, R.A.
           Tox. Appl. Pharm.  7:   543-549,  1965.


OBSERVED NEUROTOXIC EFFECTS:   Neurotoxic signs  in chickens over 23 mg/m , in rabbits
                               at  102 mg/m ,  but none in rats, dogs or monkeys at
                               levels tested.
ANIMALS:   Human:  32 of 58 reported cases in Bombay in 1960.
PREPARATION AND DOSE
or HISTORY OF PATIENT:   History noncontributory.  Later investigation showed that
                        oil from some sources was contaminated with 0.65-32.5 mg
                        OCP/100 g oil or with 2-12% of mineral oil containing OCP.
ANIMALS:    53 hens,  White Vantress, 6 mo, 2-2 1/2 kg     21 squirrel monkeys,  0.5-1  kg
            50 rats,  Long-Evans,  200-250 g
            31 rabbits,  NZ White, 3-4 kg
            18 dogs,  beagle,  6-10 kg
PREPARATION AND DOSE
or HISTORY OF PATIENT:      ,
            (1) 1.8-110  mg/m  of air, 24 hr/d, 36-163 d
            (2) 25 and 50 mg/m  of air, 8 hr/d, 5 d/wk, total 30 exposures.
ROUTE AND SITE:  Oral or skin contact (oil used for massaging body).

CONTROL INFORMATION:   Epidemiological data
ROUTE AND SITE:  Inhalation

CONTROL INFORMATION:   24 chickens, 30 rabbits, 10 monkeys
DURATION OF EXPERIMENT:  Admissions over a 5-mo period

EXAM. TYPE:   Clinical, lab, and histology of biopsy specimens.
DURATION OF EXPERIMENT:  Up to 1 yr after exposures

EXAM. TYPE:    Behavior, autopsy (gross and histological)
                                          863
                                                                                                                                       864

-------
COMPOUND:    Phosphoric acid, tri(o-biphenylyl) ester
REFERENCE:      Hine, C.H., Dunlap, M.K., Rice, E.G., Coursey, M.M., Gross, R.M.
               and Anderson, H.H.
               J. Pharm. Exp. Ther. 116:227, 1956.

OBSERVED NEUROTOXIC  EFFECTS:     No paralysis.
COMPOUND:   Phosphoric  acid, tributyl  ester

            000126738

REFERENCE:  Chambers, H.W.  and  Casida,  J.E.
            Tox.  Appl.  Pharm. 10:105-118,  1967.
OBSERVED NEUROTOXIC EFFECTS:
                                 Ataxia,  paralysis; protection interpreted in terms
                                 of structure-activity relationships.
ANIMALS:     4  Chickens, White Leghorn, M, 0.75-1.3 kg
ANIMALS:
             Mice,  Swiss  albino,  M,  14-17 g.
PREPARATION AND DOSE
or HISTORY OF PATIENT:     (1)  0.5 gm/kg
                          (2)  1.0
PREPARATION AND DOSE
or HISTORY OF PATIENT:
                            850-1000 mg/kg
                            Study  tested 21 nicotinic acid analogs for protection
                            against neurotoxicity of compound.
ROUTE AND SITE:    (1)  S.C.     (2) Oral

CONTROL INFORMATION:    One  group  of  5 per  experimental  group.
ROUTE AND SITE:   Mice:   I.P.

CONTROL INFORMATION:   Various  parameters
DURATION OF EXPERIMENT:   14-36 d after  treatment.

EXAM. TYPE:     Behavior,  histology
DURATION OF EXPERIMENT:     Up to 10 d

EXAM. TYPE:  Clinical,  biochemistry
                                          865
                                                                                                                                       866

-------
COMPOUND:
Phosphoric acid,  triethyl  ester
                                                                                           COMPOUND:
                                                                                           Phosphoric acid, tri-p-ethylphenyl ester
REFERENCE:   Gumbmann, M.R., Gagne, W.E. and Williams,  S.N.
            Tox. Appl. Pharm. 12:360-371, 1968.
OBSERVED NEUROTOXIC EFFECTS:
                               Adverse effects on growth (at 5%)  and reproduction
                               (at 1%), minimal changes in blood  or brain
                               cholinesterase (10% grp was excluded for anorexia),
                               no brain changes reported.
                                                                              REFERENCE:   Aldridge, W.N. and Barnes, J.M.
                                                                                          Biochem.  Pharm. 6:  177-188, 1961.


                                                                              OBSERVED NEUROTOXIC EFFECTS:   Neurotoxicity independent  of  cholinesterase inhibition
                                                                                               i             in vivo; the latter was  found and  attributed to some
                                                                                                            metabolite (unidentified).  Little structure-activity
                                                                                                            relationship seen between  triaryl  phosphates.  Most
                                                                                                            common sign of toxicity .was ataxia.
ANIMALS:
                  S-D, 5 M and 5 F/grp, initially 71-79 g,  and their litters
                                                                                           ANIMALS:    Chickens, F, aged over A mo, usually 6-12 mo,  various breeds
PREPARATION AND DOSE
or HISTORY OF PATIENT:  0.1-10% in diet.
                                                                              PREPARATION AND DOSE
                                                                              or HISTORY OF PATIENT:   50-5000 mg/kg
ROUTE AND SITE:         oral

CONTROL INFORMATION:    ns.
                                                                              ROUTE AND SITE:  Oral

                                                                              CONTROL INFORMATION:   ns
DURATION OF EXPERIMENT: Original M killed at 120 d, F at 150 d.

EXAM. TYPE:  Behavior, biochemistry, necropsy
                                                                              DURATION OF EXPERIMENT:   24 hr to 21 d

                                                                              EXAM. TYPE:   Behavior
                                          867
                                                                                                                                      868

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 COMPOUND:    Phosphoric acid, tri-p-ethylphenyl ester
                                                                                            COMPOUND:   Phosphoric  acid, tri-4-ethyl nhenyl  ester
REFERENCE:  Bondy, H.F., Field, E.J.,  Worden,  A.M.  and Hughes,  J.P.W.
            Brit. J. Indust.  Med.  17:   190-200,  1960.
REFERENCE:  Cavanagh, J.B., Davies, D.R., Holland, P. and  Lancaster,  M.
            Porton Tech. Paper #760, 1961.
OBSERVED NEUROTOXIC EFFECTS:   Birds paralyzed with significant  demyelination.
OBSERVED NEUROTOXIC EFFECTS:
         Threshold dose was "about" 150 mg/kg; between 150
         and 500 mg/kg, signs were delayed till 20-30
         d and preceded by typical "high stepping gait,"
         followed by ataxla.  Sciatic nerves always
         damaged severely, but ventral cord little.  Relative
         absence of anticholinesterase.
ANIMALS:    30 chickens
                                                                                            ANIMALS:
                                                                                                         Hens,  White Leghorn,  ages 1-2 yr.
PREPARATION AND DOSE
or HISTORY OF PATIENT:    200 mg/kg -  5  x 500 mg/kg
ROUTE AND SITE:   Gavage

CONTROL INFORMATION:   Controls  mentioned but not described
PREPARATION AND DOSE
or HISTORY OF PATIENT:
ROUTE AND SITE:    I.M.
    Triparethylphenylphosphate, TOCP, or diisopropyl-
    fluoridate at:  (1) 150-750 mg/kg, (2) 30-400 mg/kg,
    (3) 0.3-1 mg/kg.  (With Triparaethylphenylphosphate
    500-1000 mg/kg ataxia and paralysis occur after 10-20
    d and signs and results resemble those of TOCF and
    diisopropylfluoridate; aim of present study was to
    find threshold dose).
breast muscle; oral
CONTROL INFORMATION:    None
DURATION OF EXPERIMENT:   Up to  1 yr

EXAM.  TYPE:   Behavior, histology
DURATION OF EXPERIMENT:   1 mo.

EXAM. TYPE: Behavior, histology
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