Historical Contributions To The Human Toxicology of Atrompine

GOODMAN
HISTORICAL CONTRIBUTIONS
TO THE HUMAN TOXICOLOGY
OF ATROPINE
Behavioral Effects of High Doses of Atropine
and Military Uses of Atropine to Produce Intoxication
HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE
This monograph reviews selected aspects of the clinical syndrome

produced by atropine intoxication, with particular reference to behavioral
disturbances manifested therein. A human LD50 dose is estimated to be
453 mg, with 95% confidence limits of 335 - 612 mg (probit slope 1.8), for
orally ingested atropine. The range of individual differences in behavioral
toxicity and in lethality is described. Routes of administration of atropine
are discussed, and some attempt is made to correlate dose-response data
for the various routes. Finally, an historical summary of the military
applications of the behavioral toxicology of atropine is presented with an
Afterword on later research on atropine-related military incapacitants,.
viz. the chemical warfare agent BZ.
OH
O
O
By Ephraim Goodman
Edited with Foreword & Afterword by
COL James S. Ketchum, MD USAMC (ret.)
Mr. Reid Kirby
OF ATROPINE
Behavioral Eects of High Doses of Atropine and Military Uses of Atropine to Produce
Intoxication
By Ephraim Goodman
OH
O
O

Mr. Reid Kirby
Published by
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2010 by eximdyne - all rights reserved.
The original manuscript by Ephraim Goodman (1962) was made for hire
and is in the public domain as a publication of the United States government. Copyright is claimed only on the Foreword, Afterword, and editorial comments.
This book is printed on acid-free paper
Printed in the United States
Library of Congress Control Number: 2010925351
Goodman, Ephraim
Historical Contributions to the Human Toxicology of Atropine:
Behavioral Effects of High Doses of Atropine and Military Uses of Atropine to Produce Intoxication / Edited by James S. Ketchum, and Reid
Kirby
Illustrated, includes bibliography
1. Medicine. 2) Toxicology. 3) Chemical Warfare. 4) Histroy.
ISBN: 978-0-9677264-3-4
Abstract
produced by atropine intoxication, with particular reference to behavioral disturbances manifested therein. A human LD50 dose is
estimated to be 453 mg, with 95% confidence limits of 335 - 612
mg (probit slope 1.8), for orally ingested atropine. The range of individual differences in behavioral toxicity and in lethality is described.
Routes of administration of atropine are discussed, and some attempt
is made to correlate dose-response data for the various routes. Finally,
an historical summary of the military applications of the behavioral
toxicology of atropine is presented with an Afterword on later research on atropine-related military incapacitants.
Acknowledgements
The editors are especially grateful for the suggestion to publish this
work by Dr. Frederick Sidell, MD (deceased), and encouragement
from Drs. Margaret Filbert, PhD and Harry Salem, PhD.
Contents
Foreword..................................................................................................1
Introduction.............................................................................................3
Behavioral Toxicity Atropine Scopolamine
The Atropine Intoxication Syndrome............................................19

General Clinical Description of the Toxicity of Atropine
Clinical Description of the Specific Toxicity of Atropine
Other Forms of Poisoning and Various Routes of
Administration for Scopolamine
Military Applications of Atropine Toxicity...................................53

Poisoned Weapons Other Methods of Poisoning
Chemical Weapons
Afterword...............................................................................................61
Therapies
Differential Effects of Various Routes of Administration
Incapacitation Lethality Chemical Warfare
References..............................................................................................85
Illustrations
Figures
1. Atropine.............................................................................4
2. Scopolamine.......................................................................4
3. 3-Quinuclidinyl benzilate................................................ 62
4. Coverage of M43 (CBU-5/B) 750-lb BZ Cluster Bomb.....80
Illustrations
1. Atropa Belladonna..............................................................7
2. Hyoscyanus niger...............................................................8
3. Datura stramonium............................................................9
4. M43 (CBU-5/B) 750-lb BZ Cluster Bomb........................ 79
5. M138 BZ Bomb............................................................... 79
Tables
1. Incidence of Intoxication by Route & Age........................ 17
2. Route & Mortality Rate................................................... 31
3. Age & Mortality Rate....................................................... 32
4. Deaths Following Known Oral Doses of Atropine........... 35
5A. Recoveries Following Large Doses of Atropine............... 37
5B. Recoveries Following Large Oral Doses of Scopolamine 37
6. Adjusted Atropine Lethal Doses.......................................38
7. Human Lethal Estimates for Atropine.............................. 39
8. Atropine Composite Per Oral Dosemetric Effects............. 47
9. Atropine Specific Oral Dosimetric Effects.........................48

10. Response to Intramuscular Doses of Atropine................. 49
11. Responses to Intramuscular Doses of Scopolamine.........50
12. Atropine Composite Intramuscular Dosimetric Effects... 51
13A. Responses to Oral Scopolamine................................... 52
13B. Responses to Subcutaneous Scopolamine..................... 52
14. Generic and BZ Administration Route Comparison.......66
15. BZ Signs & Symptoms at Equivalent i.v. Doses...............68
16. Total Response Index (TRI) Incapacitation Criteria....... 69
17. Incapacitation Course of BZ............................................ 70
Abbreviations

2-PAM
-

BZ
-

CAS
-

CNS
-

CS
-

Eqv
-

GB
-

GD
-

ICt50
-

ID50
-

i.h.
-

i.m.
-

i.v.
-

K
-

LCt50
-

LD50
-

NF
-

PNS
-

p.c.
-

p.o.
-
-

Q30

QMR
-

s.c.
-

SN
-

THA
-

THC
-

VX
-
pralidoxime chloride (nerve agent antidote)

3-quinuclidinyl benzilate
(an incapacitating chemical agent)
Chemical Abstract Number
Central Nervous System
2-chlorobenzalmalononitrile
(a riot control agent)
Equivallence
Sarin (a nerve agent)
Soman (a nerve agent)
Dosage in concentration (mg/m3) x time (min) to
incapacitate 50% of exposed population
Dose (mg/kg of body weight) to incapacitate
50% of exposed population
Inhalation route
Intramuscular route
Intravenous route
Lysergic Acid Diethylamide (LSD-25) and other
psychochemical warfare agents
Dosage in concentration (mg/m3) x time (min)
lethal to 50% of exposed population
Dose (mg/kg of body weight) for lethal to 50%
of exposed population
Number Facility Test
Peripheral Nervous System
Percutaneous
Per Oral
30% Casualty Quantity (munition expenditure)
Qualitative Military Requirement
Subcutaneous
Sernyl (PCP)
Tetrahydroaminoacridine
Tetrahydrocannabinol
(a nerve agent)
Foreword
This monograph was first written in 1962, at the Clinical Research
Department, Medical Research Laboratories, Edgewood Arsenal,
Maryland. When first presented to the acting department chief,
Major Claude McClure, the manuscript was not approved for
publication on the grounds of length and tangential relavence to
existing military research goals. Instead, it languished in a file
drawer until it was recently discovered and considered too valuable to ignore.
Ephraim E. Goodman was a psychologist, who served as an enlisted psychology technician (Specialist 5) at Edgewood Arsenal in
1960. As a two-year draftee he did not seek officer status though
he possessed a Masters Degree in psychology. After completion
of military service he returned to civilian life as a teacher.
By nature, Goodman was a meticulous reader of literature and
had compiled reference lists as numerous as 1,500 while assisting
a civilian researcher prior to his military induction. One of the
current editors, James Ketchum, requested in 1961 that he perform an extensive search of the medical literature pertaining to
atropine and scopolamine, two naturally occuring anticholinergic substances, widely used for centuries for numerous purposes,
both medical and otherwise. At the time, the United States Army
Chemical Corps had an active program to develop psychochemical incapacitating weapons, wherein substances with pharmacology comperable to antropine played an important role.
This monograph is only slightly modified from the original manuscript authored by Goodman. The original was highly regarded
as a valuable addition, to the existing data concerning atropine in

particular. It provided a standard for estimating the safety and
profile of effects of military psychochemical agents such as BZ
(3-quinuclidinyl benzilate), to which it bears a strong similiarty
in the nature and course of clinical effects.
At the time compiled, Goodman did not have the advantage
of later data gathered in the course of following years in which
systematic studies of atropine and scopolamine were conducted.
The results showed that some of the dose-response estimates contained herein were imprecise understandably so, since they were
derived from calculations based on the then available literature.
Nevertheless, they are included in this revision since they represent date-appropriate approximations supported, for the most
part, by subsequent systematic studies at Edgewood Arsenal.
Goodmans monograph is remarkable for its scholarship and
thoroughness of library research by a single author, organized
into a comprehensive review. Students of pharmacology and the
history of drugs will value it for its completeness and objectivity.
The editors have added and subtracted very little from the original version. It is regrettable that it was not published in 1962, as
even 47 years later, it remains a model of academic effort and it is
relevant to present concerns about nonlethal chemical weapons,
the most well studied of which are belladonna alkaloids similar
to atropine and scopolamine. Much can be learned, therefore,
from this documentation of historical incidents of the use of belladonna substances on the battlefield, extending through more
than two millennia of history.
Introduction
Behavioral Toxicity
This monograph is concerned with the descriptive toxicology
of substances similar to or containing atropine, with particular
emphasis on behavioral toxicology. The concept of behavioral
toxicity has long concerned physicians, psychiatrists and psychologists, although the phrase itself was first used in 1956 by
Brady (Cole, 1960). As opposed to the classical use of toxicity in
reference to side effects endangering life, behavioral toxicity refers
to maladaptive or decremental behavior induced by a drug or a
chemical. Behavioral toxicity may be tolerated in order to receive
the benefits of the therapeutic action of the drug, or may be of
sufficient degree to warrant discarding the drug.
Behavioral toxicity may fall in one or more of the following areas,
which have been held to include the majority if not all of human behavioral functions such as motor response, sensation and
perception, cognition and emotional response (Clovis, 1960). Interference with the adequacy of function of one or more of these
areas should impair performance in a wide variety of situations.
These functions are clearly disrupted in delirium (Wolff & Curran, 1935).
Atropine
Reasons for Studying It Atropine was chosen in this monograph
because it has been widely used in official and folk medicine
(Wolff & Curran, 1935). It has been a substance of interest in
military medicine in the treatment of anticholinesterase intoxication*; and associated with the production of delirium.
* Commercial organic phosphorous based pesticides (e.g., Malathion) and chemical
warfare nerve agents (e.g., GB, GD, and VX) [Ed.].
Chemical warfare psychochemical agents (e.g., BZ) [Ed.].
Figure 1
Atropine (CAS 51-55-8)
(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate
OH
O
O
Figure 2
Scopolamine (CAS 51-34-3)
(-)-(S)-3-hydroxy-2-phenyl-propionic acid (1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
H3C
N
O
OH
O
O
In 1867, Headland differentiated three classes of narcotics (1) Inebriants, which bewilder and impair the powers of the mind and
senses; (2) Soporifics, which subdue and extinguish for a while
both volition and the senses, but may leave the mind alone and
(3) Deliriants, which excite the mind and the volition, and delude or derange the senses. In delirium, the mind, volition and
the senses are thus not impaired and held in subjection, but they
are led astray. The mind is occupied intently upon imaginary
fancies; unreal objects and hallucinations that are presented to
the senses.
Almost forty years later, Smith (1905) described a class of Deliriants which caused spectral illusions, delirium and incoordination. More recently, Lewin (1931) presented a class of Drugs of Illusion, which bring about exident cerebral excitation in the form
of hallucinations, illusions and visions. These phenomena may be
accompanied or followed by unconsciousness or other symptoms
of altered cerebral function
Sources of Atropine The drugs most commonly related to these
three classes (Inebriants, Soporifics, and Deliriants) are derived
from the sources of atropine. The authorities cited above disagreed about the proper placement of other drugs that bring
about behavioral change, although they agreed about sources of
atropine as deliriogenic substances.
Atropine-like substances are ordinarily derived from several
members of the potato family, Solanaceae, including the potato,
tomato, eggplant, certain ornamental plants and the botanical
sources of the mydriatic alkaloids atropine, hyocyamine and
scopolamine. Common sources are Atropa belladonna (Deadly
Nightshade), Hyoscyamus niger (Henbane) and Datura stramoni-
um (Jimson Weed). Other species are known, but these three are
of greatest relevance to this monograph (Nelson, 1951).
Solanaceous plants comprise a large family in the tropics and are
also found widely dispersed in the temperate regions. As a result
of the widespread distribution of the Solanaceae, many cultures
have employed these plants and their derivatives for medicinal
purposes (Dragendorff, 1898). Solanaceae have been used for such
non-medicinal purposes as: robbery (Overbeck-Wright, 1921), seduction (Christian, 1832), Satanism (Lewin, 1931), primitive religion (Wooton, 1910), initiation into adulthood (Gordon, 1949),
tribal justice by ordeal (Watt and Brey-Brandwijk, 1932), location
of precious objects and stolen articles (Kilmer, 1930), individual
thrill-seeking (Jacobinzzer and Raybin, 1961), and practical joking (De Orta, 1913; Fuhneer, 1919).
Scope
This paper will discuss the clinical syndrome associated with atropine poisoning, and will also review accidental mass intoxications. The use of the intoxication produced by atropine for
military purposes will then be sketched.
Discussion of the clinical syndrome will include data derived
from an extensive survey of the literature since 1861. In order
to obtain dose-response data, four journals were surveyed since
1861 or date of inception of publication. These included: The
Journal of the American Medical Association, Boston Medical
and Surgical Journal (continued as The New England Journal of
Medicine), Lancet, and The British Medical Journal. Specialized
sources included Fhner-Wielands Smmlung von Vergiftungsfallen continued as Archiv fur Toxikologie (from 1930 through
1962), and Deutsche Zeitschrift fur die Gesamte Gerichtliche
Illustration 1
Atropa Belladonna (Klher, 1887)
Illustration 2
Hyoscyanus niger (Klher, 1887)
Illustration 3
Datura stramonium (Klher, 1887)
10 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE
Medizin (1922 through 1939). The journals were examined individually for short communications of case reports which might
otherwise have escaped notice. Major reports in other sources
were discovered by examining standard medical literature indices
from 1880 through 1962.
Historical material reviewed in this monograph was also derived
from works on medical jurisprudence, toxicology, and materia
medica and therapeutics since the early part of the 19th century.
Cautions in Interpretation of Data A few prefatory words are
necessary in the interpretation of toxicity data presented in this
monograph.
Among the sources of difficulty are variations in alkaloidal content found in the Solanaceae with age of the plants, geographical
locale and the season of the year due to which the plants were harvested (Henry, 1949; Barthe, 1918). Another difficulty, particularly in the older reports, is that previously discovered alkaloids
have been rediscovered and renamed. An additional difficulty is
the naming of what have been referred to as the solanaceous or
mydriatic alkaloids (Henry, 1949).
The term hyoscyamus refers to the ability of the plant, from which
atropine is derived, to poison hogs. Henbane has a similar connotation. It has also been suggested that bean of the hogs refers
not to the poisoning of hogs, but to the state in which the victims
of the witch Circe found themselves (Locket, 1957).
The founder of medical botany, Dioscordes, wrote a materia
medica which was the standard authority in one form or another
through early modern times. According to him, the older name
for the plant was dioskyamos, or bean of the gods (Griffith & Gor-
HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 11
don-Smith, 1960). This name may be traced to the delirious state

which imbued the frenzy of some religious ceremonies. Fuehner
translates a Baltic folk name for one kind of hyoscyamus as Gotteskraut, or herb of the gods (Blancard, 1888). Some interpret
this as evidence for the widespread tendency to attribute divine
characteristics to those under the influence of Solanaceous poisoning.
Scribonius Largus referred to henbane as altercum, since the delirium which it produced was often accompanied by fighting.
Another Roman name for the plant was insane (Grossier, 1991).
In Anglo-Saxon medicine henbane was referred to as belenan or
beolone. This might be related to belenountiam, which Dioscordes gives as the Gaulish equivalent for henbane (Jones, 1995).
There was a presumptive reference to belladonna as solatrum
furiale by Saladinus of Arcoli in 1450 (Atkinson, 1899). The
Grand Herbier of Paris, published about 1504, contained the
first definite reference to belladonna as opposed to mandragora
and hyoscyamus, (Fried, 1927). In the same period of time, Hieronymus Brunschwyg called belladonna solatrum mortale, while
some forty years later, Leonhard Fuchs referred to the plant as
solanum somniferum (Fuchs, 1542).
In 1544, Matthiolus published a commentary on Dioscorides
work. In this volume, the term Solanum somniferum altercum
was used to encompass the belligerence or frenzy of Saladinus
term, as well as the sleep of Fuchs word. Matthiolus noted that
belladonna was used for cosmetic purposes, and also suggested
that the unwelcomed guests be mildly poisoned to discourage
sponging (Daly, 1959).
Despite the variety of names given to the various members of

the Solanaceae family of plants, the uses of each compound were
quite similar. Celsus, who flourished in the early part of the first
century C.E., used various Solanaceae to relieve pain, as many
physicians before him had done. Wine of mandragora or morion
was also used in those early years to allay the pain of persons being executed (Desiderio and Brignola, 1959). Pliny, the Roman
author of the middle of the first century, recommended mandragora for surgical anesthesia.
When the mandrake is used as a sleeping draught, the
quantity administered should be proportioned to the
strength of the patient . It is also taken in drink for
snake bite, and before surgical operations and punctures
to produce anesthesia. For this purpose, some find it
enough to put themselves asleep by the smell (Starr,
1911).
In the second century, Galen, who was said to have prescribed in
an intelligent manner (Firth and Bentley, 1921), recommended
the following:
We narcotizewith opium, mandragora, and hyoscyamus, for as Hippocrates teaches, moderate narcotism
relieves pain. Yet it is not to be forgotten that too powerful narcoticsmay cause death (Seelye, 1894).
In the ninth century, Rhazes treated insomnia with mandragora,
and directed that poisoning by mandragora should be treated
with cold water to the head and by the induction of emesis (Windon and Manley, 1936).
Throughout the following centuries, the use of the Solanaceae as

an anesthetic became widely accepted. In Anglo-Saxon times,
the narcotic effect of these compounds was employed in the treatment of mental illness, as the following indicates:
For witlessness, that is, for devil sickness, take from the
body of the same wort mandragora by weight of three
pennies, administerin warm water, as he may find most
convenient: so he will be healed (Binz, 1895).
As will be described later in this review, atropine was used for
similar purposes in the 20th century.
Throughout the period of the late medieval and early modern
eras, it was common practice to immerse sponges in anesthetic
mixtures of opium and solanaceae. In the ninth century, the
Bamburg and Mone Cassino Manuscripts gave recipes for the
preparation of such sponges (Beyer, 1898). The effects of the anesthesia were to be terminated by inhalation of vinegar. It is
possible that some of the ingredients of these sponges were swallowed rather than inhaled (Starr, 1911).
Contemporary surgeons were not satisfied with sponges. On
the one hand, some patients were quite inebriated and had to
be bound. On the other hand, certain sponges must have been
toxic to an impractical extent. Perhaps due to variations in the
strength of the ingredients, the use of such sponges was followed
by madness, convulsions and death in many cases (Abrahams,
1898). It should be noted, however, that authorities who were
modern enough to stress wound cleanliness and healing through
primary intention (skin closure without sutures) often used these
sponges.
The concern of early modern physicians with the behavioral toxicity of the solanaceae may be seen in Gerardes Herbal of 1597. According to the 1633 edition, there seemed to be a differential toxicity among the Solanaceae. The most dangerous of all the plants
was belladonna, which Gerarde called Sleepy Nightshade (Krber,
1948). Other names were Solanum lethale and the French term
Morelle mortelle. Gerarde gave the following caution:
If you will follow my counsel, deale not with the same
in any case, and banish it from your gardens and the
use of it also, being a plant so furious and deadly: for it
bringeth such as have eaten thereof into a deade sleepe
wherein many have died, as hath often been seen and
proved by experience both in England and else where
(Krber, 1948).
The course of the intoxication was given as follows:
This kind of Nightshade causeth sleep, troubleth the
minde, bringeth madnesse if a few of the berries be inwardly taken, but if more be given they also kill and bring
present death (Krber, 1948).
Although Gerarde did not recommend the internal use of belladonna, a narcotic effect was to be obtained from external application:
The leaves hereof laid unto the temples cause sleep, especially if they be imbibed or moistened in wine vinegar.
It easeth the intolerable paines of the head-ache proceeding of heat in furious agues, causing rest being applied as
aforesaid (Krber, 1948).
Gerarde believed that henbane caused drowsiness. Mandragora

was recommended for insomnia by rectal administration (Potter,
1947). It was also said that the wine wherein the root hath beene
boyled of infused provoketh sleepe and asswageth paine.
It is thus evident that issues of nomenclature and dose-response
relationship, as well as the beneficial versus toxic effects of belladonna containing plants created some confusion through the
ages. The same problems in defining the properties of atropine
exist today.
These difficulties must be considered as additional to an almost
necessary inexactness of the estimate of the alkaloidal content
of any medicinal preparation containing such preparations as
extracts and the powdered leaves and roots themselves. The
amounts of belladonna alkaloids present in galenical preparations
were calculated from standards for the United States Pharmacopeia and the British Pharmacopeia (Gunn, Berry & Hoyle, 1937;
Wilcox, 1929).
It has been reported that the total alkaloids present in a medicinal preparation or raw material possess greater physiological activity than expected from the atropine content alone (Starkenstein, Rost, & Pohl, 1929; Garcia, 1937). It is recognized that
the various alkaloids differ in relative strength (Berthalow, 1890).
However, consistent with the practice in the literature, calculated
amounts of belladonna alkaloids were considered to be doses of
atropine.
Sample Composition A total of 576 cases were collected (Table
1). This total does not include instances of mass intoxication, but
does include members of small groups such as families, since it
seemed probable that the risk of exposure to the toxic substances

would be relatively equal in small groups.
Distributions by Age and Route As may be expected, certain
age groups appear to be more susceptible to intoxication by the
several routes than other age groups. For purposes of chi-square
analysis, the last Other route-classes were grouped due to their
small numbers. There is less than one chance in one thousand
that the distribution of reported cases of intoxication by routes,
distributed by age of victim, arose by chance. It is not unreasonable that children under the age of five years are more susceptible
to poisoning through ingestion of leaves and berries, and that
they are less likely to be poisoned by oral ingestion of medicinal
products, in addition to the decreased probability of intoxication
through percutaneous and parenteral application of atropine containing substances.
From simple inspection of the distribution of routes and age
classes in Table 1, certain tendencies can be noted. Persons in the
age group 16 to 40 years seem to be more resistant to the effects
of atropine in eye drops and also less resistant to the effects of
percutaneous and other routes of administration. Persons in the
age group 41-50 years of age are similarly resistant to the effects
of atropine eye drops. They seem to be more likely to be poisoned
by injections of atropine. Persons 51-60 years of age seem likely
to be poisoned by percutaneous and other routes of administration. The oldest group, 61 years of age and above, are least likely
to be poisoned by oral ingestion of plants and most likely to be
poisoned by percutaneous routes. Older people also appear to be
more susceptible to the action of atropine eye drops, in common
with children.
15
22
61
0
0
0
98
17.0
Oral (medicinal)
Oral (plant)
Parenteral
Percutaneous
Other
Totals
% For Age Group
0-5
Ophthamological
Route of
Administration
14.9
86
43
32
6-15
33.7
194
11
19
23
79
47
15
14.9
86
17
28
26
13.5
86
36
17
10
16-40 41-50 51-60
Age of Intoxicated Person
Table 1
Incidence of Intoxication by Route & Age
5.9
34
13
10
61+
576
19
45
49
249
126
88
Total
3.3
7.8
8.5
43.2
21.9
15.3
% of
Total

The apparent differential susceptibility of various age groups to

various routes of administration of atropine may be an artifact.
The base rate in the various age groups of administration of belladonna plasters to reduce mammary inflammation and secretion, as well as to relieve aches and pains of rheumatism, is not
known. It is, on the other hand, entirely reasonable that children
would be more susceptible to intoxication through ingestion of
raw plant materials.
The Atropine Intoxication

Syndrome
General Clinical Description of the Toxicity of Atropine
Incidence Although intoxication with atropine-containing
substances is less frequently reported, and is not as important
a cause of death as it once was, solanaceous intoxication is still
encountered, although mostly in children (Polson and Tattersall,
1959; Gonzales, Vance, Halpern & Umberger, 1954). During
the period 1950-1955 it represented four percent of the pediatric
poisoning cases admitted to a hospital servicing a large southern
rural area (Mitchell & Mitchell, 1955). Solanaceous intoxication up through 1962 accounted for over ten percent of the live
admissions under five years of age admitted to hospitals in Scotland and the outskirts of London. Two-thirds of the pediatric
patients admitted to a South African hospital for poisoning by
plants were victims of solanaceae.
Methods of Intoxication Medicinal overdose and accidental ingestion appear to account for the majority of reported cases.
Persons have been intoxicated through the use of atropine administered in a variety of forms, including inhalation (Blankard,
1888), nose drops (Daly, 1959), or suppositories (Atkinson, 1899)
applied within the body orifices, as well as through the use of
plasters (Fried, 1927), injections (Welbourne & Buxton, 1948)
and eye drops (Daly, 1959).* Some cases of poisoning have occurred through the use of contaminated food ( Desiderio & Brignola, 1959; Wright, 1944), The consumptions of animal flesh
* And ointments (Jones, 1995). [Ed.]
has enabled intoxication to take place (Firth & Bentley, 1921;

Seelye, 1894). Persons making use of liver extract from cows feeding on solanaceae have been affected (Daly, 1959).
Confusing Nature of Signs and Symptoms Numerous works
describing the signs and symptoms of Solanaceae poisoning or
intoxication have come down to us. Nicander of Colophon, a
physician and hereditary priest of Apollo, dealt with poisonous
minerals and vegetables in the Alexipharmica. The exhaustion
and motor excitement from intoxication with Solanaceae, together with the aversion to water which is sometimes noted, were
mentioned by Nicander in the following quotation concerning
Stramonium poisoning:
Sometimes worn out with the parching struggle his limbs
give way and he falls to the ground, yet has no wish to
moisten his dry mouth.
The problem of addiction was mentioned by Avieux. He noted
that:
Confection arabum, called benge, prepared from a species of hyosyamus is inebriating and those who are in the
habit of taking it cannot do without it; that it eventually
produces great disability of the nervous system, irritability, and terror at the least noise (De Orta, 1913).
Superstitions concerning the various members of the Solanaceae
family were especially prevalent during the medieval era. Some
believed that the presence of mandragora would guard a home
against misfortune (Henry, 1949). Late medieval and early modern Germans dressed mandrake roots in clothes and venerated
them as household oracles. Mandrake was mentioned in the
twelfth century book of magic, Picatrix (Barthe, 1918).
Another belief, popular in England during the Anglo-Saxon period, has been handed down from the days of Flavius Josephus of
the first century (Henry, 1949). This belief, which was apparently
of Syrian origin, stated that anyone digging up the mandrake
would die, having been driven mad by the shrieking spirit of the
plant. A hungry, black dog was to be tied to the plant and then
lured away with food. After the dog had uprooted the plant, the
mandragora was believed to be harmless.
These superstitions, as well as the variability of response, were
possibly related to the use of the Solanaceae for legitimate medicinal purposes after the thirteenth century (Henry, 1949). As
McKenzie wrote in 1925:
The nugget of truth was thus thrown away with the
washings, and we may well wonder today as Adams did
sixty-three years ago, why the enterprise of modern pharmacology has passed over the old remedy, without making any attempt, as far as I am aware, to investigate its
therapeutic actions (Gunn, Berry & Hoyle, 1937).
McKenzie overlooked the experiments of which Sir Benjamin
Ward Richardson published accounts in 1874. After replicating
classical prescriptions, it was possible to produce in human and
animal subjects excitement, uneasiness, delirium, and deep and
prolonged sleep (Wilcod, 1929).
Those who preceded Richardson by a century also experimented
with these drugs. The behavioral effects of narcosis were used
in excitement by Baron von Stoerck (Starkenstein, Rost & Pahol,
1929). In 1797, Cooper recommended Datura for titanic fever
(Garcia, 1937). Cullen noted that Solanaceae caused restlessness
in sleep (Bertholow, 1890). He also recommended belladonna as

an anodyne (Polson & Tattersall, 1959). In 1861, Pitha induced
twelve hours of complete and placid narcosis by the rectal administration of belladonna (Gonzales, Vance, Halpern & Umberger, 1954). In 1900, Schneiderlin employed morphine and
scopolamine for surgical anesthesia. Chloroform was required,
however, for the patients who awoke excited and delirious (Mitchell & Mitchell, 1955).
Many antidotes for Solanaceae poisoning have been developed
through the centuries. Several points may be noted in the following quotations:
One can also be deceived with Schukran and Bendsch;
these are species of Hyoscyamus. If one is cognizant of
having take some, heat the bark of the mulberry tree in
vinegar, and take as an emetic, then take milk.
Datura metel (stramonium)is extremely poisonous in
the weight of one siculus; it is a poison which is commonly found, and with which one can easily be deceived,
for it change neither the taste nor the odor, hence it is
highly unnoticeable. If one is aware he has taken some,
then saltpeter must promptly be taken as an emetic, and
warm water and oil; then much butter and much wine in
white pepper and spices have been put.
Mandragorin (sic) can be sucked out of a wound without
harm; but its shell and grain are harmful. I have seen
many women and children partake the same unknowingly with the customary symptoms of redness and swelling of the body, itching, and a sort of intoxication. Treatment is the same as for datura metel. (Schneider, 1929).
It is not surprising that modern physicians have often been misled by the confusing nature of the signs and symptoms exhibited
in cases of intoxication by atropine (Binz, 1895). The most common incorrect diagnosis has been that of a psychosis (Beyer, 1898).
Not that such a diagnosis was at the time absolutely incorrect, but
the existing state usually did not require more than supportive
care for a short period, whereas the more persistent forms of psychosis entertained have included paresis (Starr, 911), post-partum
psychosis (Abrahams, 1898), dementia praecox (Krber, 1948),
and acute manic-depressive psychosis (Dameshak and Feinsilver,
1937).
Other erroneous diagnoses have included intoxication with alcohol (Potter, 1947; Schneider, 1929), meningitis (Sims, 1954)
or cerebral hemorrhage (Morgan, 1866), and poliomyelitis (Leffkowitz, 1933). Scarlet fever (Page, 1955) has also been suggested
by the manifestations of the intoxications. Therapy considered or
administered has included further administration of solanaceae
for sedation (Krber, 1948), electric shock treatment (Jacobinzzer
& Raybin, 1961), penicillin (Sims, 1954), and care in a mental
hospital (Fleming, 1866) or by psychiatric attendants (Brown,
1866). In one case a person who was actually in a mental hospital
as a result of atropine intoxication was examined by a consultant
who rejected a diagnosis of toxic delirium (Baker & Farley, 1958).
In another case a person who was under observation in a hospital
developed a severe reaction thirty minutes after it was decided to
release her (Todd, 1958).
Clinical Manifestations The signs and symptoms produced by
intoxication with atropine have been summarized by Morton
(1939) as follows:
Hot as a hare, caused by an increase in body temperature

because of lack of perspiration. Blind as a bat, caused
by dilation of the pupils, making normal sight difficult.
Dry as a bone from blocking of glandular secretions and
Red as a beet from heat flush, and Mad as a hen.
The first four similies refer to the peripheral action and the last
to the behavioral toxicity of atropine. A condition of impaired
motor control is also seen in many cases. Even in mild cases, the
onset is usually within a few hours of ingestion.
The course of atropine intoxication, as employed therapeutically
in psychiatry has been summarized in two sequences, neurological and behavioral. The neurological sequence is as follows (Miller, Schwarz & Forrer, 1958):
1. Progressive muscular incoordination;
2. Decreased pain sensitivity; and,
3. Hyperreflexia with development of the Babinski sign.
The behavioral sequence is as follows:
1. Clouding of the sensorium;
2. Disorientation;
3. Loss of time-space relationships;
4. Distortion of perception with illusions and hallucinations;
5. Confusion; and,
6. Coma.
General Behavioral Manifestations: The onset of the intoxicated state may be accompanied by great anxiety.
I felt as though I were mad; a terrible sensation of insecurity came over me; I could not retain my ideas; I did
not know whether I was dreaming or awake, whether the
horrid visions before me were real or phantasies (Binz,
1895).
Not all cases of oncoming delirium, however, have been marked
by such terror. In a personal account, a physician who was poisoned at a dinner party to facilitate robbery described his condition as follows: mouth very dry, thirst unquenchable, swallowing
painful, speech thick and difficult, some deafness; also, eyelids
heavy but no desire for sleep, hallucinations of vision, a stone
appearing like a bunch of beautiful flowers, delusions of seeing
familiar facts. The motor disturbances may be so extreme as to
result in actual convulsions, or else a violent tossing about on the
ground or bed (Mehta, 1904). Thus, post mortem examination
of two persons poisoned by a passing stranger revealed the presence of large superficial wounds, with blood spread beneath the
scalp (Saunders, 1876).
The phrase Mad as a hen arises from a state of mental impairment characterized by the presence of an inability to concentrate,
confusion, disorientation and coma (Parks, 1878; Ismael, 1915).
There may be violent purposeful struggling (Crawford, 1917), as
opposed to the motor unrest noted above, and there usually is
occupational delirium, in which habitual activities may be repeated for long periods of time (Wood, 1860). At times very
little overt gross activity may be expected, even though the affected persons may not be in a coma. There is usually, but not
always, some degree of amnesia for events during the period of

intoxication (Meggendorfer, 1928). Communication is generally
greatly impaired (Wood, 1860).
The following mental status examination, performed by a Portuguese physician in India in the sixteenth century, in the case
of a woman who was poisoned for criminal purposes, illustrates
(from information given in the account) the inability to communicate (De Orta, 1913). It should be noted that one can not
differentiate inability to utter meaningful words from inability to
understand or formulate a reply.
Physician: God preserve you, lady.
Patient: Im, Im, Im.
Physician: Have you no answer to give me? How is
this?
Patient: Im, Im, Im.
Dangerous Behavioral Manifestations: Among the behavioral
effects of particular consequence arising from the poor orientation
and comprehension, with resultant fear and lack of judgment, are
those which bring about danger to life (Gautier, 1814; Osetsky,
1931, Philippi & Mhle, 1910). Patients poisoned by solanaceae
may require restraint to prevent self-injury and to permit transportation to the hospital (Roland, 1906; Hoffman & Gay, 1959).
They have tried to escape from hospitals (Wilson, 1878), and have
jumped from windows (Silk, 1881). Several authors have stressed
the presence of delusional beliefs to the effect that harm was to be
done (Oknesorge-Voigt, 1943; Collins, 1887; Rodger, 1903). Patients have been assaultive (Polisch, 1928), have brandished dan-
gerous weapons (Anderson, Begg & McNaughton, 1867), and

have tried to commit acts which would have endangered their
own lives (Gaultier, 1814). In other cases, the relatively minor
disruptive actions have included going to work with insufficient
clothing (Tyrrell, 1867), and issuing inappropriate orders (Fleming, 1866). These people then caused difficulties when the orders
were not carried out.
Phenomena Seen in Mass Intoxications: The accidental intoxication of groups of varying age, cultural level, and geographical
location has been reported covering two thousand years. The
syndrome produced by intoxication with the solanaceae is quite
constant and may be reproduced, depending probably on the
amount of alkaloid ingested (Polisch, 1928), in any group.
The most severe cases of intoxication involved deaths. This occurred in Anthonys army in the last half-century BCE (Plutarch,
no date), and in a company of French Infantry poisoned on 14
September 1813 while on the march (Gaultier, 1814).
Protective confinement was apparently required for the Colonial
troops poisoned in Virginia in 1676 (Beverly, 1947). The eleven day period does seem rather long and has been questioned
(Schauenstein, 1882).
Well-learned and habitual behavior was quite disrupted in the
case of the poisoning of monks in a monastery. The date of the
intoxication is not known, although it was referred to in a work
published in 1679 (Beck & Beck, 1863; Stille, 1860).
A group of sailors intoxicated while on board a French corvette
in April 1792 was able to call for help by firing cannon and by
running up signal flags (Fodere, 1813).
The delirious condition is clearly described in the case of eight

Indian troops poisoned in 1895:
Most of them were unable to answer when spoken to, and
those who could had forgotten their own names. Some
lay on the ground in a dazed condition, others sat up
constantly making fidgety movements with their fingers,
picking up small particles of sand or pebbles from the
ground or appearing to be searching for something they
had lost and occasionally looking up with a half vacant,
half wild expression (MacNab, 1895).
A similar state was described by Plutarch, who recorded the intoxication of Anthonys army:
They chanced upon an herb that was mortal, first taking
away all sense and understanding. He that had eaten
of it remembered nothing in the world, and employed
himself only in moving great stones from one place to
another, which he did with as much earnestness and industry as if it had been a business of the greatest consequence. Through all the camp there was nothing to be
seen but men grubbing upon the ground at stones, which
they carried from place to place.
The French soldiers poisoned in 1813 were In continual agitation. Their knees sank under the
weight of the body, inclining them forwards, and carrying their trembling hands towards the earth, endeavoring to collect little stones and bits of wood, which they
always let fall or threw away, to recommence the same
pursuit (Gaultier, 1814).
This grubbing on the ground seems to be a constant finding in

cases of intoxication.
Some group intoxications have been characterized by very slight
degrees of illness. In the epidemic of twelve outbreaks, involving
1,524 African troops, only four medically severe and dangerously
affected were seen. In this small minority of cases there were visual hallucinations, temporary lapse of memory and purposeless
actions as well as mental excitement of acute maniacal proportions (Anderson, Begg & McNaughton, 1867).
The intoxication of groups of children does not seem to differ
in character from that observed when groups of adults are affected. In one situation, eight school-aged children each received
eye drops containing thirteen milligrams. All children exhibited
thirst, flushing, rapid feeble pulses and difficulty in talking, with
some motor incoordination. Two became delirious and hallucinated mice and worms (Jonec, 1921). In another situation, thirty
boys, aged from six to eight, ate seeds of Datura stramonium
(Jimson Weed). Several hours later the children began crawling
around, making noise, trying to pull imaginary objects from the
air, crying out, or just moaning (Garvon & Ruh, 1921).
Lethality Considerations The mortality rate in any series would
depend upon the sampling of cases included. This involves to
some degree the propensity of physicians to publish or otherwise
report cases, the editorial policies of the journals, and the question
as to what constitutes a case of poisoning. Some authors reported
poisoning from extremely small doses of atropine. Hospital admissions data may not be representative of incidence. Locket
(1957) suggests that admissions to teaching hospitals cannot be
utilized for obtaining true incidence, mortality or cure figures.
In the present series, where all cases found were included in data
determining the over-all mortality rate, a lower estimate would
be obtained than in a series where more stringent criteria for inclusion prevailed.
Mortality Rate of Present Series: The present series yielded an
over-all mortality rate of 6.94%. There are ninety-nine chances
out of one hundred that the true value falls between 4.21% and
9.67%.
Mortality Rates of Series From the Literature: The published
mortality rates vary to a considerable extent. In four independent series of Datura poisoning in India in the last half of the
nineteenth century, a weighted mortality rate based on 241 cases
was 14.9% (Taylor, 1875; Banerjee, 1885; Wilthaus, 1911). One
would expect that these cases occurred under comparable standards of medical care and administrative development. However,
there were some differences either in severity of intoxication or
adequacy of treatment, all other factors being equal, since the
mortality rates for the individual series varied from 1.96% of 51
cases to 22.8% of 92 cases.
The scholarly work by Wilthaus (1911) is marred by internal inconsistencies in his tabular case data, so that his collection of
1,087 cases does not yield a useful mortality estimate. Two series which overlap with each other, and which appear to overlap
with that of Wilthaus, are that of 973 cases with a mortality rate
of 9.46% cited by Peterson and associates (Peterson, Haines, &
Webster, 1923), and that of 1,063 cases, with a mortality rate of
10.54%, cited by Webster (1930).
In a series of 103 cases of atropine poisoning collected before

1882 there was a mortality rate of 11.6% (Kunkel, 1901). In a
series of 63 cases collected in Hungary between 1900 and 1905,
3.2% died. There were no deaths in a series of 35 Hungarian
cases treated between 1930 and 1932 (Balazs, 1933). Gordon
and Frye (1955) found in a series of 110 cases reviewed in 1955 a
mortality rate of 8.2%.
Mortality by Route of Administration and Age: Tables 2 and
3 present descriptive statistics of cases of intoxication with solanaceae. Table 2 summarizes the cases by route of administration
and mortality rate. Table 3 summarizes the cases by age and
mortality rate. Analysis by chi-square test does not indicate the
presence of statistically significant differences in the susceptibility
of the extremes of life to fatal atropine poisoning in this sample
when considered apart from route of administration. Statistically significant differences in the mortality rates of the several
routes of administration, when considered apart from age, were
Table 2
Route & Mortality Rate
Route of Administration
Number of Cases
Mortality Rate (%)
Opthalmological
88
5.68
Oral Medicinal Products
126
10.32
Oral Plant Material
249
7.63
Parenteral
49
4.08
Percutaneous
45
2.22
19
0.00
576
6.94
Other
Overall:
Table 3
Age & Mortality Rate
Age (Years)
Number of Cases
Mortality Rate (%)
0-5
98
11.22
6 - 15
86
5.81
16 - 40
194
6.70
41 - 50
86
4.65
51 - 60
78
5.13
61 and Over
34
8.82
576
6.97
Overall:
not demonstrated by the chi-square test.

It has been suggested that children are more susceptible to fatal
outcome in cases of solanaceous intoxication (Gimlette, 1939),
and that there is greater sensitivity in the case of applications to
the eye (Gordon and Frye, 1955). In the present series all of the
ophthalmological deaths occurred in children less than five years
of age. The modal age for deaths from orally administered medicinal products was 41-50 years, while fatalities from ingestion
of plant materials were most common in the age group 16-40
years.
Turning from a classification in terms of routes of administration
to that of age of victims, almost half of the fatalities in children
less than five years of age were due to ophthalmological administration, all of the deaths in children 6-15 were due to ingestion of
plant materials, almost seventy percent of the deaths in the age
group 16 to 40 were due to ingestion of plant materials, and all
of the four deaths in the 41-50 age group were due to orally ad-
ministered medicinal products. Oral administration accounted

for two of the four deaths in the 51 to 60 age group, and for two
of the deaths in the 60 years and over group.
The tolerance of children to atropine has been a subject of controversy (Unna, Glasser, Lipton & Patterson, 1950). The generally
accepted tolerance of children to solanaceae has been thought to
be a function of the criteria for determining presence of intoxication. Harley (1869) suggests that peripheral indications are readiliy induced in children, while central effects are developed after
very large doses. Pilcher (1934) notes that not only does the effective dose vary between children, but that the same child might
at times exhibit differential susceptibility. Unna, Glaser, Lipton,
& Patterson (1950) found variations in susceptibility to atropine
with age. In general, these investigators failed to find evidence
that children were more resistant to the effects of atropine, using
changes in salivation as a criterion. They recommend administration of atropine in accordance with body weight.
Environmental warmth has been accounted a factor in lessening
resistance to atropine. A relatively hot summer, for Scandinavia, contributed to the death of a person taking large daily doses
of atropine for the treatment of Parkinsonism (Segerdahl, 1935).
Death from heat stroke after atropine eye medication in young
children was recorded by a physician in Baghdad (Jahnke, 1957)
Adults in the hot dry Iraqi climate seemed to be more susceptible to atropine intoxication after instillation of eye drops, while
military performance tests in Iraq demonstrated the potentially
dangerous effects of extreme heat. However, warm moist climate
is less deleterious (Collumbine, Adrian, & Muir, C. 1954). A
physician in Australia ascribed psychotic reactions to atropine
eye drops to the hot weather (Daly, 1959).
Hyperpyrexia may be considered an important cause of death

in intoxication with the solanaceae (Black, 1916). However, the
fact that a victims temperature has been brought down does not
mean that he is out of danger (Konar, 1937).
Among other conditions leading to greater susceptibility to intoxication with atropine may be debilitating conditions such as tuberculosis and hypoglycemia (Williamson, 1878). This occurred
in fifty percent of a series of insulin experiments in which prior
administration of atropine alone did not result in any mental
disturbances (Quigley, 1937).
The question of susceptibility to atropine can not be adequately
resolved. One would have to stratify a sample by age, sex and
general health, and then give graded amounts per unit of body
weight. The comparability of age has to be determined; Banerjees Indian patients of 50 were apparently older physiologically
than persons of similar age elsewhere (Banerjee, 1885). The most
important consideration is that the lethality of compounds can
not be definitely and empirically determined on humans.
Differences in Susceptibility to Atropine: It has not been considered possible to assign a definite lethal dose of atropine (von
Jaksch, 1910). It has been stated that the surely fatal dose for
humans is from 15 to 20 mg/kg (Hauschild, 1956). This dose is
almost ten times as great as noted by Moeschlin (1952). Polson
and Tattersall (1959) state the usual textbook estimate of somewhat more than 100 mg as a dose able to cause death and that
death following less than 2 grains (128 mg) in our opinion is
probably due, presumably, to disease in circumstances where the
part played by atropine is only as an accelerating factor.
Lethal Dose: Table 4 presents cases of death following known

oral doses of atropine. In some of the cases death appeared to be
due to intercurrent infection, most commonly pneumonia. OverTable 4
Deaths Following Known Oral Doses of Atropine
Age Range
Dose (mg)
Remarks
0 - 5 years
3 weeks
3 years
3
98
Death in 10.5 hrs
39
77
Died in 4 hrs
Died in 3.5 hrs
222
32
192
Died in 18 hrs
Died in 84 hrs from pneumonia
Died in 15 hrs (possible morphine
reaction)
39
Daily dose with up to 39 mg - died of

hyperpyrexia (summer)
Died in 15 hrs
Died in 7 hrs
Received divided dosage during
night (possible illness)
16 - 40 years
41 - 50 years
51 - 60 years
61 and Over
Unstated Age
(Adult)
390
56
6
14
6
>230
112
Died in 16 hrs
Died in 2 hrs
3
4
Circumstances unkown
Died in 41 hrs - circumstances unknown
Died in 12 hrs - circumstances unknown
Died in 27 hrs (highest 24 hr survival
known)
120
3200
enthusiastic treatment with opium and pilocarpine probably contributed to lethality to a certain extent. Exhausting attempts
at resuscitation probably did not help matters much (Bartholow,
1881). Persons who appeared from fragmentary reports to be
physically ill died from small doses of atropine. One such person
was administered atropine in place of strychnine; presumably the
person might have been in a state requiring strong stimulation.
Table 5A and 5B presents survivals reported after large oral doses
of atropine or scopolamine, with age and sex data when available. Table 6 presents lethal doses in the case of children when
the corrections for estimated body weight are introduced, so that
all doses are adjusted in terms of a 70 kg subject. Normal weight
standards for the time period of the most frequent incidents of
intoxication were taken from L. Emmett Holts (1898) classical
text on pediatrics.
It should be noted that these survivals are not nearly as remarkable as they once would have been thought to be, in light of the
large parenteral doses administered in the Forrer atropine toxicity
treatment in psychiatry (Miller, 1958) In general, doses lethal to
some persons have been survived by others.
In tables 4, 5A, 5B and 6, not all of the cases are represented in
the data presented in Tables 2 and 3. The latter data represent
only those cases found by the present writer (Goodman) in his
search of the journal literature. The former data include cases
found in secondary sources. These cases were not included in the
overall mortality rate in order to prevent distortion thereof, since
they were derived from an unknown sample of cases of fatal and
nonfatal outcome.
Table 5A
Recoveries Following Large Doses of Atropine
Sex
Age
Dose (mg)
192
225
225
30
225
228
250
250
14
256
21
260
26
267
324
324
20
500
20
1,000
500
500
1,000
Table 5B
Recoveries Following Large Oral Doses of Scopolamine
Sex
Age
Dose (mg)
24
350
52
500
Table 6
Adjusted Atropine Lethal Doses*
Age
Sex
Weight (kg)
Dose (mg)
Dose (Adult
Equivalent)
7 wks
70
1190
1.25
10
16
112
2.0
12
32
186
2.0
12
65
377
2.5
13
32
173
2.5
13
130
702
15
65
306
16
32
141
15
60
282
19
64
237
22
50
160
26
128
346
27
65
176
In the course of another project of the Edgewood Arsenal Medical

Research Laboratories, data based on 86 case reports of persons
who had received known oral doses of 30 mg or more, including
15 children with a dose adjusted to a body weight of 154 lbs were
submitted to Captain James Ketchum, USAMC and Dr. John
Atkinson (Human Estimates Committee, 1962) The data were
otherwise unselected. They were grouped by the Reed-Muench
Method and a Bliss Probit analysis was performed. The following
results (Table 7) were obtained.
Thirteen deaths occurred in this group of 86 persons, yielding
* Weight estimated according to normal standards for time of intoxication.
LD50 453 mg/person (p.o.) with a probit slope of 1.8 [Ed].
Table 7
Human Lethal Dose Estimates for Atropine (oral equivalent)
% Mortality
Total Dose (mg)
95% Confidence
Limits (mg)
23
13 - 40
16
127
96 - 167
30
232
181 - 297
50
453
335 - 612
84
1,621
963 - 2,729
an overall mortality rate of 15.1%. This illustrates the point that

increasing the stringency for classification of a case as one of
poisoning can increase the mortality rate; including all overdose
cases would yield a lower number (and percentages) of deaths and
would produce a lower estimate of mortality rate.
The lower limit of 30 mg was therefore chosen in order to avoid
deaths from lesser amounts. Some of these lower dose deaths
seemed grossly idiosyncratic. Eliminating these from the analysis, this procedure decreased the numbers of survivals relative to
the number of deaths.
Sequelae and the Role of Stress and Predisposition: There are
apparently very few known instances of long term sequelae in
solanaceous intoxication (Lendle, 1954). Five definite statements
are known to the writer (Goodman) to have been made in the literature (Polson and Tottersall, 1959). In one case, a man abused
his family for a month following intoxication (Ismael, 1915) In
another instance, known only by title, there was impairment for
an unknown period of time. Three cases were reported by a
physician at a French penal colony in 1908, who found insanity

after use of Datura.
The duration of disability resulting from intoxication with solanaceous material has entered into legal medicine in a judgment of
damages or compensation awarded (Meissner, 1922). Some case
notes describing sequelae of varying duration are in the following
paragraphs.
An unusual instance of sequelae of moderate duration is that of
a soldier in Burma who smoked and chewed stramonium leaves.
He felt sick, and was amnesic. He had been observed to be exhibiting unusual behavior, laughing and crying. Then he disappeared after about a week, and was found unconscious near a
well. Thirty-six hours later he awoke in the hospital and became
violent. After treatment with potassium bromide, he fell asleep
and then awoke in his usual state. This person apparently was ill
for nine or so days after smoking and chewing the Datura leaves.
No information was given with regard to his mental state before
the intoxication (Blancard, 1888).
Prolonged psychiatric disturbances as sequelae have been found
in individuals with presumed predisposition in some respect to
be susceptible to stress. Lundquist (1935) described the case of
a twenty-six year old male described as psychically healthy but
of a schizothymic character who sustained a skull fracture and
contusion in an automobile accident, followed by three convulsive seizures and bronchopneumonia. One month after the accident he experienced a transitory hallucinatory episode of a weeks
duration. Four and one-half months after the accident he was
admitted to a neurological institute in an encephalitic state resulting from the accident.
He was treated with gradually increasing doses of atropine. Some

improvement was observed and five and a half months after
the accident, he was receiving daily doses of 8 mg of atropine.
Suddenly his condition deteriorated and he exhibited confused
thinking. A left hemiparesis appeared, in addition to dilatation
of the pupils and dryness of the mucous membranes. After one
week, his condition improved and there were no neurological
abnormalities except for some muscle weakness on the left side.
However, he was disoriented and appeared to hallucinate. Nine
and one-quarter months after the accident he was transferred to
a psychiatric hospital.
At this time he was responding to auditory and visual hallucinations and believed that his thoughts were subject to control by
external influences. Upon mental status examination at this time,
there were no defects in orientation, grasp, insight or memory.
There were disturbances in mood. He heard voices during the
interview, but could exclude them from awareness. After two
months of general, non-medicinal care, he was considered to
have recovered.
Lundquist (1935) suggests that a diagnosis, made without detailed knowledge of the history, would have been schizophrenia
and that a diagnosis with a more complete history might have included traumatic epilepsy. The final diagnosis was symptomatic
schizophrenia (in accordance with the diagnostic system used at
that time). Lundquist referred to the intolerance exhibited by
encephalopathic patients to various poisons. It would seem to
the present writer (Goodman) that the role of atropine in this
case was only to precipitate the illness; in any stress situation, a
schizophrenic psychosis might have come about.
A second case was that of a prudent, sensitive individual of forty

who was intolerant of alcohol received standard therapeutic doses
of atropine over an eight week period, minus two interruptions
totaling twenty-four days (Fickler, 1910). In the sixth week, there
were visual disturbances, dryness of the mouth and disorders of
movement. He received no atropine in the seventh week. In
the eighth week he exhibited difficulties in swallowing, loss of
appetite, vomiting, increase in pulse and maximally dilated pupils which did not react to light. He exhibited manic behavior
such as great joviality and excitement for a short period, which
was then followed by visual hallucinations, ideas of reference and
thought of impending doom, resembling an alcoholic delirium.
The visual hallucinations disappeared, but hallucinations in other
modalities persisted. He was removed to a psychiatric hospital
twenty-four days after the onset of the acute psychotic state. His
heart rate was 132; his pupils were unequal and moderately dilated, reacting well to light and accommodation. Upon mental
status examination he appeared to be a shy, dejected and anxious
individual who exhibited no defects in orientation or comprehension. Insight was limited and he continued to express the belief
that he had been, and was going to be, interfered with in some
way. He believed he was being harmed by X-rays, electricity and
heat. He fasted for a day to avoid being poisoned. There was little affect displayed with respect to his delusional beliefs and hallucinations. By the eleventh week after the onset of the psychotic
state, the patients condition had improved and he was considered
well except for some mild neurasthenic symptoms.
In this case, as in the preceding one, it is important to note that
the auditory hallucinations more characteristic of schizophrenia than visual hallucinations predominated. It seems clear to
the present writer (Goodman) that these two cases of atropine

psychosis well illustrate the possibility that mental disturbances
may follow from predisposition to schizophrenic reactions to
stress. The first case exhibited a hallucinatory state after trauma
and before administration of atropine.
The second patient could not tolerate alcohol, and by analogy,
other toxic substances, and was described as sensitive. The
good memory and orientation exhibited by these patients, except
for amnesic periods of short duration, is more consistent with
schizophrenic psychosis than with organic brain syndromes. The
retention of memory is important in differential diagnosis.
Cooper (1936) described subacute confusional reactions in
chronic encephalitics treated with solanaceae. Of five cases exhibiting confusion with terrifying hallucinations, one recovered,
two developed antisocial tendencies, and two developed paranoid
schizophrenic states. In contrast to the good memory exhibited
by his other patients, Cooper noted an amnesic state for the acute
confusional reaction. It seems clear that these reactions were
simply atropine toxic states, with sequelae reflecting predisposition.
Collins (1939) reported a fatal case of a psychotic state marked by
over-activity in a twenty-nine year old male being treated for myasthenia gravis with atropine and other drugs. The present writer
(Goodman) agrees with Smith (1939), who thought that this was
a case of atropine intoxication, and suggests that this is another
example of stress influencing the reaction to atropine.
That defective memory (and not schizophrenic manifestations) is
characteristic of the atropine intoxication, is well illustrated by
the following case:

A fifty-two year old poorly nourished unemotional and
industrious woman was treated for iritis by thrice daily
instillations of atropine eye drops. After nine weeks the
manifestations of intoxication appeared suddenly. She
required restraint for twenty-four hours. Two days after
admission she was less excited and had no insight. Several days later she was able to give a personal history, except
that she had a retrograde confusion for the seven weeks
preceding admission in spite of the fact that symptoms
were said to have come on suddenly. There was difficulty
in attention and concentration, and fabrication of memory. After two weeks in the hospital she had transient
momentary hallucinations only, and was discharged as
recovered after six weeks.
The clinical picture here probably represents atropine intoxication without superimposed schizophrenic or other symptomatology (Burr, 1913). This case contrasts with that of an anxious
forty-two year old woman who receive small continued doses of
approximately 0.4 mg daily of belladonna alkaloid for treatment
of nephritis. She was exalted, hallucinated, and had religious
delusions for eight days. The functional or predispositional component here seems to have been much more important than in
the preceding case (Starr, 1911).
The importance of predisposition is further brought out in the following case in which marked psychotic symptoms and signs were
not manifest (Tyrrell, 1906). A veterinary surgeon employed atropine eye drops for a fourteen year period, and exhibited cardiac
and respiratory irregularities and restlessness, mild delirium and
even hallucinations at times. However, after withdrawal of the

drug for three months, considerable improvement was evident.
There appeared to be a residual weakness and tremor. Tyrrell, the
author reporting this case, makes the following remarks, which
are worth quoting:
In atropine poisoning, and especially from its continued
use over so long a time, the prognosis is not good. The
patient may rally by proper treatment on the withdrawal of the drug, but there seems to result a derangement
of the circulatory and digestive apparatus from which
they never recover, and are subject to occasional attacks
of delirium, all of which contribute to make the patient
mentally non compos mentis and physically a true morbid
asthenici. The alienation in these cases is a loss of retentive accuracy in memory. Improvement is very slow and
is marked by great irritability of temper. These patients
may live and appear apparently well for a few years and
then die of some intercurrent trouble; or, in a few instances, they have landed in asylums, only to live a few
years (Tyrrell, 1906).
The writer was unable to find information supporting Tyrrells
generalizations. It is true that memory failure is characteristic.
However, there is very little information, if any, based on long
term follow-up studies of persons with chronic intoxications.
The discussion of two series of cases terminates this section of the
paper. The importance of concomitant physical and psychological stress in atypical atropine poisoning is brought out in Parfills
(1947) report of fifteen Royal Air Force (RAF) personnel, mainly
in their twenties, being treated by prolonged narcosis therapy,
with atropine to control side effects of the paraldehyde and barbiturate medication. No case received as much as sixty-four milligrams in ten days.
The results of this study led Parfill (1947) to suggest that approximately 4 mg of atropine can be given daily from ten to fourteen
days safely, but that a dose of six mg daily for ten days can endanger life. Parfills cases exhibited undeniable evidence of atropine
intoxication. There was certainly a potentiation of the effect of
the atropine, since the doses employed, though large in comparison with the usual recommendations, were not large enough to
produce such distressing results.
Welbourn and Buxton (1948) describe thirteen cases of a dispensing error, in which nine persons are known to have received 6 mg
of atropine preoperatively. Of five who had no toxic signs, three
received additional anesthesia, while two had large collections of
pus. It would appear that concomitant chemical states in this
case influenced the reaction of the subjects of atropine.
Specific Clinical Description of the Toxicity of Atropine
Tables 8 and 9 show the general dose-response characteristics of
atropine in human subjects. An important indicator of the level
of intoxication is the measure of heart rate (not shown).
Comparison Data for Other Routes and for Scopolamine
Tables 11 through 13B demonstrate the dose-response relationship by different routes of administration, and includes figures
on scopolamine for comparison. Table 11 presents data from
experimental per oral (p.o.) and subcutaneous (s.c.) administration of scopolamine as given by previously cited authors and by
Table 8
Atropine Composite Dosimetric Effects After Oral Ingestion
Dose
(mg)
Clinical Description of
Observed Signs and Symptoms
0.25
May cause effects to be seen.
0.50
Slowing of the pulse to some extent; dryness of the

throat to some extent.
1.00
Definite dryness of the throat and mouth; mild papillary dilatation.
2.00
Mydriasis; palpitation and rapid heart rate; pupil not

quite immobile, blurring of near vision.
3.00
Stimulation of cells of cerebral cortex; headache;

dysphagia; malaise; muscular weakness.
5.00
Speech disturbed; restlessness; dry, hot skin.
7.00
Wide mydriasis; visual disturbances.
8.00
Excitation; marked muscular incoordination.
10.00
Severe poisoning in a healthy person; symptoms

may cause concern. Apathy; hallucination; delirium;
unconsciousness; iris practically obliterated; ataxia;
skin flushed and scarlet in hue.
50.00
Condition dangerous.
100.00
May be lethal dose.
Table 9
Atropine Specific Dosimetric Effects After Oral Ingestion
Dose
(mg)
Specific Responses
1.8
Felt tired, would have liked to have gone to sleep;

able to carry on, however, as physicians on duty.
2-3
Slight dizziness, tachycardia, mydriasis, dry mouth.
4-5
Medical student subjects could perform arithmetic problems. Tried to read or converse with other subjects.
6.75
Diminution of recent memory in five of ten subjects.
10
Medical student subjects exhibited no hallucinations, illusions or disorientation. There was a diminution of recent
memory. They were unable to perform arithmetic. They
were able to answer simple questions and to perform
simple automatic acts upon command. They preferred
to lie quietly or sleep. The duration of sluggishness, lassitude and poor memory was from 7 to 10 hours.
Table 10
Specific Responses to Intramuscular Doses of Atropine
Equivalent
Intramuscular
Oral Doses
Dose (mg)
(mg)
Response
0.5
1.0 - 1.5
May have slight giddiness.
1.0
2.0 - 3.0
Considerable giddiness and waviness

of vision; walks cautiously, inclined to
ataxia.
1.3
2.6 - 3.9
Moderate drowsiness, some restlessness, may be some dreaminess, unable

to read or thread a needle.
1.6
3.2 - 4.8
Lethargic, fitful sleep disturbances by

dreams, fancied noises cause awakening.
2.0
4.0 - 6.0
A weakened person may have a busy,

meddlesome delirium, and require supervision. A stronger person would
have restless sleep, as main symptom.
2.6
5.2 - 7.8
Illusions and hallucinations when eyes

are closed, but not when open.
3.0
6.0 - 9.0
Inclined to sleep. After walking home,

he was unable to fit his key in the lock.
5.0
10.0 - 15.0
Restless, moaning, delirium.
Table 11
Specific Responses to Intramuscular Doses of Scopolamine
s.c.
1.0
2.0
3.0
5.0
p.o.
Eqv.
2-3
4-6
6-9
10 - 15
Dizzy, giddy,
lightheaded
42
18
56
100
Clouded
sensorium
10
12
10
Incoordinated
10
13
82
10
26
70
40
46
70
68
10
11
30
38
96
100
100
Dysuria
10
36
83
Reading
difficulty
24
15
40
100
Headache
26
19
35
13.6
Symptoms
Required extra
sleep
Lassitude
Fatigue
Dysphoric
Dryness of
mouth
Dose
(mg)
Percent Responding
N.B. Different subjects or combinations thereof were used at the four dose
levels. The irregular progression in incidence of symptoms may be ascribed
to differential sensitivity or suggestibility of the subject groups. Symptoms
exhibiting a regular progression with increasing dose may thus be considered
to be more reliably due to the drug per se.
Wangeman and Hawk (1942). The oral doses may be multiplied

by a potency factor (not shown) to obtain equivalents for oral
atropine.
It should be emphasized that relative potency factors are rough es-
Table 12
Atropine Composite Intramuscular Dosimetric Effects
Dose (mg)
Specific Responses
2.0
No effect on marksmanship. Minimal effect on general

condition. Did not impair intelligence test results (no
speed criterion) in intellectually superior subjects.
3.0 - 8.0
Dryness, tachycardia. Various degrees of intensity, not

perfectly consistent with dose/kg: Drowsiness, ataxia, attention loss, malaise, headache and vertigo. Doses of this
magnitude were said to cause impairment of judgment
and loss of power of concentration. Subjects became out
of touch with their environment. It became difficult to
keep their eyes open. The effects were not dangerous
as much as irritating. In other studies, 4 and 5 mg doses
caused fatigue, lassitude, reading difficulty.
10.0
Subject considered disturbed. Tachycardia in one or two

minutes. Active dreaming. Loss of ability to fix attention. Visual hallucinations, euphoria, slurring of speech,
acute anxiety in test situation, ataxia and drowsiness.
timates and are not based upon exact experimental comparisons,

but are based on an examination of data from various sources.
Adequate determinations would require experimentation involving clinical observation and extensive serial psychological testing,
which has not been done, to plot the course of impairment.
Table 13A
Responses to Oral Scopolamine
Dose
(mg)
Responses
2.0
Recent memory impairment, sleep.
3.0
Slight drowsiness in some subjects. Some jerking of muscles. Dryness. Some excitement resembling alcoholic intoxication in older subjects.
4.5
Illusions and hallucinations in half of a group of medical

student subjects.
Table 13B
Responses to Subcutaneous Scopolamine
Dose
(mg)
Responses
0.2
Drowsiness.
0.4
Drowsiness.
0.5
Difficult to keep on feet, drowsy, sleepy, dizzy, excitation,

confusion.
0.6
Restless, drowsy,
incoordination.
0.8
Confused, visual and auditory hallucinations in some,

disorientation equal to or greater than 10 mg of atropine
p.o.
1.3
Irrational, belligerent.
amnesic,
euphoric,
fine
motor
Military Applications of
Atropine Toxicity
The final section of this monograph concerns the use of solanaceous substances to influence behavior on a group basis for military purposes. There are three routes of administration which
have been employed for the delivery of atropine.
Poisoned Weapons
The first and least important of these has been by means of sharppointed weapons (Lewin, 1923; Millspaugh, 1892). Several authors mention the use of solanaceae by people in various parts of
Africa as arrow and spear poisons. However, the use of solanaceae
for this purpose is rather limited.*
Other Methods of Poisoning
The second and most profitable form of military use of these substances has been through the contamination of food or drink.
This has been known and practiced since the period of classical
antiquity.
According to Sextus Julius Frontinius (1925), who presented in his
Strategematicon of approximately 90 A.D. schemes reminiscent
of contemporary practices (Meyer, 1925) an officer in Hannibals
Army, about 200 B.C.E., used atropa mandragora (mandrake) as
a chemical weapon:
Maharbal, sent by the Carthaginians against the rebellious Africans, knowing that the tribe was passionately
* Jones, D. (2007), demonstrates scant evidence of solanaceae being of importance in
North American arrows. However, Mayor (2003) notes that the Romans referred
to Belladonna as Dorycnion, or spear drug, and Pliny commented that before battle
spear tips were dipped in dorycnion and retained toxicity for 30 years. [Ed].
fond of wine, mixed a large quantity of it with mandragora, which in potency is something between a poison and a
soporific. Then, after an insignificant skirmish, he deliberately withdrew. At dead of night, leaving in his camp
some of his baggage and all the drugged wine, he feigned
flight. When the barbarians captured the camp and in
frenzy of delight greedily drank the drugged wine, Maharbal returned and either took them prisoners or slaughtered them while they lay stretched out as if dead.
Two incidents in the life of Julius Caesar involving solanaceae
are recorded. In the first case, Sicilian pirates who captured him
were thought to have been drugged with mandragora (Ellis,
1946). In the second case, during the struggle for power between
Pompey and Caesar in approximately 50 B.C.E., troops in Africa
were poisoned by drinking water in such a way that their vision
became hazy, as in a fog, and an invincible sleep overtook them.
Then followed vomiting and jerking of the whole body. Lewin
(1923) believes that the ocular accommodation difficulties, the
muscular excitation and the desire for sleep point to intoxication
by solanaceae. It seems likely that Hyoscyamus falezlez and Hyoscyamus muticus, which are indigenous to North Africa may have
been used to drug the troops.
The next example of the use of solanaceae for military purposes
occurred nearly eleven hundred years later. In the reign of Duncan (1034-1040 A.D.) the eighty-fourth King of Scotland, Swain
(or Sweno), King of Norway, landed his army in Fife. The Scots
retreated to Perth after a battle near Culross. Duncan sent messengers to Sweno to negotiate surrender and, during the discussions, supplied the Norwegians with provisions. As expected,
this was looked upon as a sign of weakness. The Scottish forces
under Bancho entered Swenos camp while the invaders were intoxicated with wine dosed with sleepy nightshade (Buchanan,
1831; Lewin, 1920; Mitchell, 1857).
In the Bacon Rebellion British soldiers were sent to put down an
uprising in Williamsburg, Virginia in 1676. The local inhabitants prepared a salad for the soldiers containing Jamestown Weed
(Datura). As Robert Beverly recorded in 1705:
The soldiers presented a very pleasant comedy, for they
turned natural fools upon it for several days: one would
blow up a feather in the air; another would dart straws
at it with much fury; another, stark naked, was sitting in
a corner like a monkey, grinning and making mows at
them; a fourth would fondly kiss and paw his companions, and sneer in their faces with a countenance more
antic than any in a Dutch droll. In this frantic condition they were confined, lest they should, in their folly,
destroy themselves - though it was observed that all their
actions were full of innocense and good nature. Indeed
they were not very cleanly; for they would have wallowed
in their own excrements, if they had not been prevented. A thousand such simple tricks they played, and after
eleven days returned themsleves again, not remembering
anything that had passed (Beverly, 1947).
The historical evidence of the oral use of the solanaceae for military purposes exhibits another gap of two hundred years. In
1861, a peaceful railway surveying expedition under LieutenantColonel Paul Flatters was proceeding through the territory of the
Touareg (Leder, 1954). These Berbers who, unlike other North
Africans, veil the men and not the women, are a raider people
who did not completely surrender to French authorities until

1943 (Skolle, 1952).
The Touareg call themselves The Blue Men and The People of
the Veil; the other inhabitants, however, call them The Abandoned of God. Flatters ignored a warning letter and marched
into an ambush on 16 February 1881, losing approximately half
of his force, or all of the personnel in the area where the ambush
took place. On the next day, the five French and fifty-one indigenous survivors started to march to a French outpost. This party
was trailed by a force of approximately two hundred Touareg.
On 8 March 1881, their supplies having been observed to be low,
they were approached by three men who claimed to be members
of another tribe and offered to sell the party provisions. On the
next day, three bundles of dried dates were thrown into the camp
and varying quantities were consumed. The French members of
the party apparently ate more than the indigenous soldiers.
Shortly thereafter, signs and symptoms of solanaceous intoxication were manifested (Leder, 1954). Five of the fifty-six men
disappeared in the confusion of the first few minutes. Thirty-one
of the remainder were so sick that they were unable to look after
themselves. In the evening some attempted to crawl away into
the desert. The Frenchmen had been tied down by the senior
indigenous soldier to prevent injury.
There was some improvement by morning. And so they set off,
half mad, bent double under excruciating pain, their legs crumbling, their voices shrill, their words unintelligible. On the second day after the poisoning they reached an oasis, where a force
of Touareg awaited them. By this time, however, the survivors
were able to function as an effective fighting force, and thus the

attack was repulsed. Two of the French, said to be under the
influence of the drug, rose and marched forward to death. After
more difficulties, the party evaded the Touareg and found water.
They resorted to cannibalism to sustain life. On 29 March 1881
twelve Algerian soldiers reported to a French outpost. The poison used has been identified as Hyoscyamus falezlez (Cornevin,
1893).
The next recorded oral use of solanaceae in a military situation occurred in Hanoi, Tanking Province, French Indo-China, in what
is now known as Vietnam (Hammer, 1954).* On 27 June 1908,
some two hundred French soldiers were poisoned by Datura in
the evening meal. They were soon discovered and all recovered
after medical attention. Two indigenous non-commissioned officers and an artilleryman were convicted by courts-martial of
plotting with numbers of ex-river pirates under the influence of
what was called Chinese reformer agitation. They had incited a
theft of weapons and a general rising against the French. One of
the intoxicated soldiers saw ants on his bed, a second fled to a tree
to escape from an hallucinated tiger, and a third took aim at birds
in the sky. After the initial excitement and delirium there was
a period of fatigue and intellectual sluggishness (Lewin, 1929;
Times London , 1908).
The most recent attempt at oral employment of the solanaceae in
a group military situation was the abortive attempt to poison
the staff of Radio Free Europe in Munich in 1959. Through the
person of a double agent it was discovered that salt shakers in a
cafeteria serving 1,248 employees had been dosed with atropine.
Analysis of the contents of two shakers revealed the presence of
2.36 per cent by weight of atropine (Newsweek, 1959; Time,
* North Vietnam in 1962 [Ed.].
1959; U.S. News and World Reports, 1959).

Chemical Weapons
The third route of administration of solanaceae for military purposes is that of inhalation. In the third century A.D. Sextus
Julius Africanus described magical methods for poisoning air
(Meyer, 1925). In the last quarter of the thirteenth century, Assan Alrammah suggested that arsenic and opium be burned to
produce lethal and soporific fumes (Meyer, 1925). In about 1450,
Paulus Santinus suggested the sleep-producing and narcotic substances for delivery by inhalation. In other contemporary works
the enemy was to have been rendered defenceless by the use of
soporific roots (Meyer, 1925).
The foregoing remarks present indications that although solanaceae were not known by the present writer (Goodman) to have
been delivered through the air prior to modern times, such a
method would have been consistent with the knowledge of the
era. As presented by Lewin (1920), from whose discussion the
following paragraphs were adapted, there was in the seventeenth
century abundant use of chemical shells.
The accelerated development in technology resulted in new
gadgetry and put into practice some of the ideas advanced in
earlier periods. An example of this is the assault by the troops
of the Bishop of Muenster on the city of Groningen on 29 July
1672. Some buildings were damaged, but casualties were few, if
any. The historian comments that the fruitlessness of the clever
though impractical scheme was often demonstrated. It was difficult to achieve an adequate concentration, since in open spaces
the fumes rose in the air and were dispersed. It was thought that
the use of such weapon systems would be most effective in foggy
or rainy weather, or in confined spaces. A shift in the wind direction was considered dangerous. The heat of combustion probably destroyed active principles of vegetable poisons employed in
shells.
According to such military manuals as von Flemings Der volkonne teutsche Soldat (1726), chemical shells might contain arsenic trioxide and trisulfide, of each fifteen hundred grams along
with quantities of hyoscyamus and other vegetable substances.
Other recipes included solanaceae along with hemlock and mineral poisons.
Hand grenades for close fighting are also described (Meyer, 1925).
These were supposed to contain 180 grams each of several mineral poisons, such as arsenic trisulfide, antimony, or basic copper
acetate along with 120 each of the juice of such plants (Meyer,
1925). The whole mass was to be formed into a ball with linseed
oil. The smoke of such a hand-fire-work was supposed to be
deadly. In exceptional cases, notes Lewin (1920), this would have
been true.
Whether or not these were effective, it should be noted that the
French and Germans negotiated a treaty at Strasbourg on 27 August 1675 and outlawed the use of poisoned shells (Lewin, 1920).
The method described herein is a shot-gun approach in that
the mineral poisons would cause death if the solanaceae did not
incapacitate the enemy by causing intoxication.
Clinical research at Edgewood Arsenal was focused on BZ, until
the early 1960s, a belladonnoid substance which is pharmacologically very similar to solanaceous substances such as atropine and
scopolamine. BZ (3-quinuclidinyl benzilate) differs from atro-
pine in that it is about 30 as effective and produces delirium

that lasts several times as long as atropine. Qualitatively, its clinical effects are identical.
Afterword
Goodman wrote this monograph in 1962 when employed by
the US Army. At the time the United States Army Chemical
Corps was responsible for developing chemical weapons, and was
making significant investments into psychochemicals, following
the nascent revolution in psychiatric pharmacology of the 1950s.
Starting in 1955, research efforts centered around Agent K (lysergic acid diethylamide),* whose effects were popularized in a
film showing a cat becoming scared of a mouse after receiving an
aerosolized dose of K.
Debate as to what incapacitation meant necessitated human trials, without which the military establishment would not have
confidence in such weapons. Hallucinating, for example, did not
necessarily mean incapable of fighting. The Chemical Corps
thereby initiated a program in 1955 for human trails using 6,700
volunteers. By 1975, when the program was terminated, 3,200
volunteers had been exposed to chemical agents while the remainder were involved in other chemical defense studies. One
of the editors (Ketchum), wrote a book on his experience as a
psychiatrist helping to develop these projects (2005).
Partly due to the high cost of manufacturing and a foreign-owned
patent, the Chemical Corps passed on standardizing Agent K.
By 1958 interest had moved instead to centrally active anticholinergic compounds related to atropine (i.e., CNS depressants).
Hoffmann-LaRoche synthesized a series of new antispasmodics
resembling tropine, the basic byicyclic basic alcohol moiety of
atropine, in 1951. Of these, Ro 2-3308 had the highest potency
* Also known as LSD, the Chemical Corps referred to it as EA1729. K agent also refers
to incapacitants as a class of chemical warfare agents (i.e., knockout).
A potent discoordinating CNS stimulant with a human ICt50 of 55 mgmin/m3,
rate-of-action of 0.5 hrs and a duration-of-action of 4 hours (Witten, 1969).
Stoll, A. & Hofmann, A. (1948). U.S. Pat. 2,438,259 - assignor Sandoz, Ltd.,
Switzerland.
Figure 3
3-Quinuclidinyl benzilate (CAS 6581-06-2)
-hydroxy--phenyl-1-azabicyclo[2.2.2]oct-3-yl ester
O
N
HO
O
(Sternbach & Kaiser, 1952). Its potency and psychogenic properties made it unsuitable as a pharmaceutical. Later a screening
program at the University of Chicago proposed it as a candidate
for the Armys psychochemical program in 1958. This compound,
3-quinuclidnyl benzilate (Agent BZ), was judged able to fulfill the
Qualitative Military Requirements (QMR) for an incapacitating
psychochemical agent (Fig. 3).
It should be noted that following preliminary studies of the effects of phencyclidine in volunteers, there had also been a temporary, ultimately abortive, attempt to weaponize this agent (Agent
SN) by 1960 due to difficulties in finding a manufacturing process for BZ.* Once the manufacturing process problem had been
resolved, BZ was standardized in 1962 and filled into chemical
weapons (Kirby, 2006).
* Also known as PCP, the Chemical Corps referred to it as EA2148. Due to variable
effects the necessary ICt50 was believed to be 1,000 mgmin/m3 for ataxia, a logistically improbable dosage in the field.
Assigned the symbol TK before standardization as BZ, the Chemical Corps initially referred to it as CS4030, then later as EA2277.
Research with BZ continued for several years after the completion

of Goodmans manuscript. At least a dozen other anticholinergic
belladonnoids were also tested in volunteers. They were found to
be similar in their actions to BZ, but had durations that varied
from a few hours to several days. Several exceeded it in potency.
When the Army adopted BZ in 1962 it was type classified Standard B to rush it into inventories. This was prior to comparative studies of these other agents. Although BZ is estimated to
have a safety margin (LD50/ID50) of approximately 40, some
of these other related compounds were estimated to have even
higher safety margins, some of them close to 100-fold (Ketchum,
& Sidell, 1998).
A detailed comparison of atropine with BZ puts its intoxicating
effects into perspective. When the therapeutic uses of atropine,
as well as its ability to produce incapacitation and lethality (including its historical chemical warfare aspects), are compared
with BZ, it is easier to reach a dosimetric understanding of the
toxicology of atropine and related compounds.
Therapies
Merrell (a major pharmaceutical company from 1950 to 1996) in
1952 advertised Bentyl (dicyclomine) claiming it did not have a
belladonna backfire (blurred vision, dry mouth, etc.), which was
a reference to the unpleasant side effects of atropine. In Goodmans manuscript, intoxicating doses of atropine only occurred
after administration of doses several times greater than the doses
typically prescribed for medical purposes.
Medically, atropine is a useful antisialogogic, antispasmodic, cycloplegic, chronotropic, and antidotal agent. Prior to the use of
more effective drugs, it was also used as a anodyne, and to immobilize agitated neuropsychiatric patients. Except when higher
doses are used to antagonize the effects of nerve agents (which
inhibit acetylcholinesterase), therapeutic doses of atropine have a
safety margin in the order of several hundred-fold.
Antisialogogic When administered in doses of 0.5 to 1.0 mg per
person, by the intravenous route (or in adjusted oral or inhalation
route), atropine relieves most secretions associated with disease,
infection, and allergies. In Parkinsons disease it reduces excessive salivation and perspiration. It also relieves excessive stomach
acid and pancreatic excretions.
Antispasmodic Atropine can relieve gastrointestinal spasms associated with colitis, peptic ulcer, colic, irritable bowel syndrome,
and for spastic bladder. In Parkinsons disease, it reduces tremors
and rigidity. For such uses it is often taken nightly in 0.6 to 1.2
mg per person doses orally.
Cycloplegic Atropine may be administered as 1% ophthalmic
drops which enables it to serve as a cycloplegic agent. It is used
to treat iridocyclitis and malignant glaucoma by producing prolonged pupilary dilation. Its use as a mydriatic agent (as in eye
examinations) has now been superseded by drugs with far shorter
duration, such as tropicamide.
Chronotropic In bradycardia with associated hypotension,
atropine (at doses of 0.008 mg/kg intravenous) is administered in
order to restore a normal heart rate.
Antidote Contemporary treatment of nerve agent poisoning
makes use of a combination of autoinjectable atropine with an
oxime, such as pralidoxime chloride (2-PAM), and a benzodiazepine such as diazepam (an anticonvulsant).* Treatment with
atropine alone is effective, but in treating high doses of nerve
agents, the oximes have a complex synergistic-like effect. Typically, atropine is administered in 2 mg intramuscular injections
doses, using an autoinjector, and repeated every 10 to 15 minutes
until reversal of bradycardia (restoration of heart rate to over 90
beats per second) is achieved, as well as the drying of salivation
(Marrs, Maynard, & Sidell, 1996).
In a land engagement the maximum exposure to a nerve agent on
a battalion-sized target, without using strategic delivery systems
(e.g., bombers, large caliber missiles), is predicted to be no greater
than 5 LD50. Half the target would be covered by 1 LD50 or less,
25% by 2 LD50 or less, and 12.5% by 3 LD50 or less (Lindstrom,
1980). Under these battlefield conditions, the treatment of nerve
agent poisoning will usually require atropine doses less than 30
mg per person.
In the case of attempted suicides involving, for example, the ingestion of a large quantity of an organic phosphorous pesticide,
it may be necessary to give atropine in divided dosages, up to a
cumulative dose of 1,000 mg or more, over an extended course
of intensive care (e.g., Chew, Chee, Yeo, & Jayaratnam, 1971).
Overdosing with atropine, should it occur, is less of a concern
than the immediate lethality of the nerve agents or pesticides.
Differential Effects of Various Routes of Administration
Goodman assumed the potency of atropine by the oral route to
be only a third to half the intramuscular route (see Table 10).
Experiments with BZ demonstrated, using the intravenous route
as a reference, that the intramuscular route was equally effective,
* At first the US Army distributed atropine syrettes for self administration, then later
ampins (See Gordon, Kalser, Silber, & Frye, 1952). Finally there was ACE, that later
became the atropen (US Pat. 2,832,339), a spring-loaded autoinjector and progenitor
of the autoinjectors now commonly used in medicine.
Other authors have noted that heart rate alone is insufficient an indicator of reversal
and that clinicians must consider restored respiration as the true indicator of adequate
dosing.
Table 14
Generic and BZ Administration Route Comparison
Route
Generic
BZ
intravenous
1.0
1.0
intramuscular
1.0
oral
10
1.1
inhalation
1.0 - 1.5
1.6
percutaneous
100
the oral route 90% as effective (with a delay in onset of about 1

hour) and inhalation is only 60% as effective (Ketchum, 1963).
With the exception of oral administration, these figures agree
fairly well with the comparative route administration values provided by Salem (1987) in Table 14.
Goodman also describes some early uses of atropine by the percutaneous route. Ketchum (1963) similarly describes an inconclussive preliminary human assessment of BZ by the percutaneous
route (using cresol and N-ethylmorpholine as a carrier). The effectiveness appeared to be an order of magnitude less than when
given by the intravenous or intramuscular routes, and were delayed by 24 to 36 hrs (most evident at the highest doses).
It is interesting to note that the effects produced by nebulized
atropine usually require 2.0 - 2.5 the intravenous dosage. This

does not indicate the amount absorbable by the lungs, only the
decreased efficacy of the nebulizer. Ketchum (1963) has similarly
estimated that when given as an aerosol, only 80% of the BZ dose
is retained, and only 80% of that quantity is actually absorbed by
the lungs, resulting in a total of 64% of the inspired aerosol crossing the alveolar membrane into the bloodstream.
The probit slopes of the dose-response regression line calculated
from inhalation studies in wind tunnels was approximately 7,
most of the variability being attributed to inconsistencies in individual breathing rates. Test subjects could be taught to breathe
in conformity with an idealized curve inscribed on the face of
an oscilloscope. Actual breathing depth was monitored by the
subject, who could deflect the trace as it swept across the screen
every four seconds. With this feedback of his own breathing, the
subject could more easily produce the desired respiratory pattern,
significantly reducing the previously observed variability (Ketchum, 1963).
Incapacitation
Initially, the definition of incapacitation was subjective, rather
than operational. Gradually, to measure the degree of incapacitation, US Army investigators used a variety of performance tests,
such as obstacle courses, shooting ranges, and repeated measures
of cognitive abilities. Eventually, the Number Facility (NF) subtest of the Texas Battery (Moran, Kimble, & Mefford, 1964)
was found to be the most valid and reliable. This exam involves
adding up a series of three rows of numbers over a 3 minute
period. The average of the five highest scores out of 20 tests,
administered over a 24-hour period prior to dosing, was used as
Table 15
BZ Signs & Symptoms at Equivalent i.v. Doses
ED50
(mg/kg)
0.00460
0.00524
0.00616
0.00837
Probit
Slope
Signs & Symptoms
9.84
Mild incapacitation - peak heart rate 80 to

85, elevated systolic blood pressure under
10 mmHg, moderate pupil dilation and slight
blurring of vision, sleepiness, slight dryness
of mouth, minimal incoordination, some
mental retardation, without loss of contact
with reality. Average score of 3 low NF scores
<75%.
8.59
Moderate Incapacitation - peak heart rate

85 to 95, elevated systolic blood pressure under 20 mmHg, increased severity over mild
effects with fleeting illusions, hallucinations,
brief lapses in concentration, and transient
confusion. At least 2 consecutive NF scores
<75%.
9.20
Severe Incapacitation - peak heart rate 95 to

110, hallucinations, confusion, hyperactive
disorganized behavior, incoherent speech,
and disturbances in mentality and attention
characteristically following an early period of
sleep or stupor. Militarily incapacitated with
at least 2 consecutive NF scores <25%.
6.15
Maximal Incapacitation - peak heart rate 110

to 140, elevated systolic blood pressure 20
to 60 mmHg, rapid onset of stupor, often followed by agitation, then protracted period
of sleeplessness, disorganized behavior, hallucinations, periodic impulsive outbursts of
fear or anger from misinterpretation of surroundings. Militarily incapacitated with at
least 2 consecutive NF scores <10%.
the baseline for evaluating subsequent performance decrements

produced by any particular psychochemical (Ketchum, 2005).
In combination with the signs and symptoms of BZ intoxication,
the NF score reflected the degree of incapacitation (Table 15).
If scores fell below 10% of baseline, the subject was considered
to be fully incapacitated. Two consecutive scores below 25% of
baseline, severe incapacitation, were considered to constitute a
desired degree of militarily significant incapacitation. (Deseret
Test Center, 1972).
An early approach to quantifying the degree of delirium produced by BZ was named the Total Response Index (TRI), which
combined cognitive (arithmetic ability) with physiological (heart
rate and blood pressure) changes into an indexed weighted average. This Edgewood TRI was inspired by similar weighted
average of responses, developed by Pincus and Hoagland at the
Woods Hole Institute (c. 1960). Their TRI was calculated from
the diverse physiological indicators of adrenocortical function
in schizophrenia. Ketchum (1963) found the Edgewood TRI
Table 16
Total Response Index (TRI) Incapaciation Criteria
TRI
Degree of
ED50
Incapacitation (mg/kg)
Onset
(hrs)
Partial
Recovery
(hrs)
Complete
Recovery
(hrs)
4.0 Mild
0.004
4-5
20-25
50-60
5.0 Moderate
0.005
2.5-3.5
25-35
70-80
6.0 Severe
0.006
1.5-2.5
35-45
90-100
7.0 Maximal
0.007
1-2
50-60
100-140
Table 17
Time Course of Symptoms when Incapacitated by BZ
Time
(hrs)
Symptoms
0.5 - 3
Dizziness, extreme drowsiness, dryness of the mouth,

tachycardia.
3-5
Restlessness, involuntary muscular movement, near vision impairment, and physical incapacitation.
6 - 10
Hallucinations, lack of muscular coordination, disorientation, and difficulty in memory recall.
10 - 96
Increasing activity, random unpredictable behavior,

gradual return to normal 48 to 96 hours after exposure.
to have good correlation with the degree of incapacitation, with

peak effects at 8 - 12 hrs (Table 16).
After testing more than 100 subjects, the incapacitating dose of
BZ (the ID50) by the intravenous route was estimated to be 6.16
g/kg i.v. with a very steep probit slope of 9.20. This dose corresponds to a respiratory ICt50 (mgmin/m3) of 110 for a mildly
active individual breathing at a rate of 15 l/min. At this dose the
onset time of severe incapacitation is typically about four hours
with a duration of severe effects lasting 20 hrs (peak effects occurring at 8 to 10 hrs).
In small doses, BZ produces sleepiness, decreased alertness, elevated hear rate, dry warm skin, and mydriasis. Table 17 presents
a composite of the severity of various symptoms at the militarily incapacitating dosage. Peripheral nervous system (PNS) effects proceed CNS effects, a relative lag that is also observed with
atropine. Lilliputian hallucinations (objects seeming to be tiny
transformations of real ones) are common for both atropine and

BZ intoxication. The mechanism is unknown and may be optical
or central in origin. As observed from BZ trials, the termination
of delirium is often proceeded by a deep restful sleep.
For atropine the ID50 was found to be 150 g/kg i.v. (about 10 mg
total dose per person). Incapacitation has an onset of about two
hours and a duration of four to six hours (Witten, 1969). The
performance of complex tasks is particularly impaired by atropine intoxication. In aviators tested with total doses of 2.0 or 4.0
mg of atropine by injection, a definite reduction of such abilities
was encountered at doses of 2 mg/person, and a substantial decrement was evident at 4 mg/person. Either dose would create an
unacceptable risk of error by a pilot (Taylor, Dellinger, Richardson, Weller, Porges, et al., 1985).
Violent behavior Rather than causing excitement and increased
activity, the incapacitating effects of atropine typically include
temporary physical disability, profound sedation and confusion.
Similarly, BZ and related compounds are soporific rather than
stimulating, causing sleep or even stupor. Interestingly, aggressive behavior directed toward the enemy by the victims was never
observed in the historical cases cited by Goodman. Escape from
a perceived enemy seems to have been the goal of victims of atropine intoxication, rather than an inclination to fight back.
It is evident that when it does occur, violence arises from the
subjects misinterpretation of the environment (delusional state)
and is dose-dependent. Only 5 of 116 test subjects exposed to
BZ (4%) exhibited any violent behavior. None of these cases were
observed below a TRI of 6.9, but tended to increase in frequency
as the TRI went over 8 (Ketchum, 1963). As noted, none of these
(usually brief) outbursts were deliberately directed at staff members or other personnel.
Treatment Doubling the ID50 of atropine adds an additional 4
hours (or more) to the duration of incapacitation. In the case of
BZ, doubling the ID50 appears to increases the duration of effect
by another 40 hours.* In military situations, there is an obvious
need to negate incapacitation and return soldiers to fighting form.
Accordingly, the investigators at the Medical Research Laboratories studied several agents thought to be able to counteract the
central actions of BZ.
Tetrahydroaminoacridine (THA) was the first compound investigated as an antidote to BZ intoxication. Published studies had
indicated its effectiveness in reversing toxic therapeutic deliria
caused by the administration of Ditran (JB238/239) and other JB
compounds. In a limited number of human trials at the Clinical
Research Division (Edgewood Arsenal), THA was indeed found
to reverse the effects of BZ within minutes. Temporary, reversible liver abnormalities, however, were also noted in some test
subjects, and work on THA was discontinued. Physostigmine,
one of the only other anticholinesterases that can cross the bloodbrain barrier, did not produce such changes (Deseret Test Center,
1972; Ketchum, 2005).
Physostigmine (eserine) is considered the most effective antidote
for the symptoms of belladonnoid intoxication. It is recommended, however, that a test dose of 1 to 2 mg by the intramuscular
route be given initially to assess its efficacy in any suspected case
of belladonnoid intoxication. If effective, physostigmine should
then be administered by the oral route at doses of 2 to 4 mg every
40 to 60 minutes. This dosage should be maintained to prevent
* This is a nonlinear relationship, i.e., three-times the ID50 does not increase the duration-of-effect by another 40 hours.
relapse since its use does not shorten the course of intoxication.
With BZ intoxication (and also with atropine), even if administered immediately after exposure, physostigmine was noted to be
of limited effectiveness until peak effects developed, but could restore normal behavior when given after the peak. With BZ, continual administration of 3 to 5 mg of physostigmine by mouth
every hour for two to four days was also shown to be capable
of maintaining nearly normal performance scores and behavior
until spontaneous recovery occurred. The dose of phsyostigmine
is to be adjusted downward progressively as recovery from BZ
proceeds (Ketchum, & Sidell, 1998).
The Soviet Union also investigated the medical management of
psychochemical casualties and concluded that a corpsman would
be unable to distinguish between chemical intoxication and a
psychological reaction to combat.* They developed an alternate
approach to treating these casualties. The initial Soviet regimen
was to restrain the casualty and treat with Russian equivalent
of the American antipsychotic drug Stelazine (trifluoroperazine)
which they found could keep the patient conscious and not exasperate any other conditions. George Aghajanian concluded in
1964, however, that another antipsychotic drug (thorazine) was
sedating; producing slight improvements in performance, and
actually prolonged the time of recovery.
Specifically for BZ, the Soviet Union devised a drug called Bugafen
as a treatment - a mixture of butyroxan, galanthamine, and phenomene (galanthamine is a therapeutic with similar activity to
physostigmine). Bugafen was apparently never adopted due to
shortages; thus the final treatment regimen was galanthamine,
sodium oxybutyrate, and a beta blocker to alleviate tachycardia
* In contrast with the Soviet Union, incidentally, the United States did not find it
difficult to train corpsmen to distinguish between toxic delirium and other combat
related neuropsychiatric disorders.
(Peymer, 1992). Amphetamines were also believed to be useful.

With the exception of galanthamine (a physostigmine-like anticholinesterase) the treatment cocktail suggested by the Soviet
Union would have been contradictory in treating BZ casualties.
If used, antipsychotics, amphetamines and beta-blockers would
have resulted in a myriad of other intoxications that would delay
recovery.
Lethality
Based on more than 500 case reports of accidental atropine overdose and deliberate poisoning, Goodman estimated the median
lethal oral dose to be approximately 450 mg (with a shallow probit slope of 1.8). A figure strikingly higher than estimates given
in many textbooks of pharmacology.
Some estimates of lethality with BZ have been grossly erroneous,
apparently due to the use of other erroneous data. For example,
an LCt50 value of 200,000 mgmin/m3 is sometimes quoted in
literature (e.g., US Army, 1990). Other authors, however, have
estimated the human intravenous LD50 (extrapolated from animal data) to be only 0.5 to 3.0 mg/kg, and an LD01 is 0.2 to 1.4
mg/kg (Rosenblatt, Dacre, Shiotsuka, & Rowlett, 1977). From
these figures an LCt50 was estimated to be about 4,000 mgmin/
m3 (probit slope of 5.9). If this LCt50 is adjusted to apply to the
general population (cf. Cosier, 2003), then the LCt50 for BZ may
be as low as 3,000 mgmin/m3 (probit slope of 3.8). Another
estimate of the ICt50/LCt01 may be ~40, with a possible range
of 32 to 384 (Rosenblatt, Dacre, Shiotsuka & Rowlett, 1977).
This is in good agreement with Goodmans calculate values for
atropine.
For atropine, the cause of death is probably of cardiac origin, rather than respiratory, as was suggested by most contemporaneous
textbooks. This conclusion is supported by the observed strong
correlation between LD50 in animals and the peripheral rather
than central potency of several belladonnoids. Compared with
the CNS effects of scopolamine, atropine is only 1/th as potent,
while BZ is about four times as potent. Compared with atropine,
BZ is 5.4 to 6.2 as potent in its effects on the peripheral nervous system (PNS). The larger relative central effect of BZ versus
atropine indicates a potentially larger safety margin for BZ, if the
lethal mechanism should indeed prove to be cardiac in nature.*
Ultimately, the estimated safety margin for BZ is inconclusive
due to a lack of actual human data at the higher ranges of dosage.
It may be noted, however, that atropine coma therapy demonstrated doses of up to 200 mg by injection could be safely used in
the treatment of psychiatric patients, even when repeated over a
period of weeks (Miller, Schwarz, & Forrer, 1958).
Age-dependent susceptibility Adverse reactions following low
doses of atropine (2 to 3 mg) may occur in patients with preexisting conditions such as glaucoma and in those individuals over
the age of 40 who are at risk of cardiovascular disease.
Children are often believed to be more susceptible than adults to
atropine poisoning. Goodman, however, did not find evidence
to support this assumption. Likewise, in the Gulf War there
were 249 Israeli pediatric cases of accidental injection from government issued atropine autoinjectors. Some doses as high as 17
the age-weight adjusted dosage. Of these cases, none required
supportive treatment nor had signs and symptoms of gross intoxication (Epstein & Seidman, 1994). Overall, the relationship of
* The tachycardia produced by BZ rarely exceeds 150 beats per minute. The degree
of cardiocirculatory effect is dependent on the specific agent. For example, EA3167,
which is chemically identical to BZ with the exception of replacing a benzyl-group
with a cyclopentyl ring, produces incapacitation with practically no peripheral effects
(Ketchum, 2006).
atropine toxicity to body weight is linear (Hart, 1967). Pediatric

subjects accordingly would require weight-adjusted doses in the
range of 0.01 to 0.03 mg/kg for therapeutic purposes.
Hyperthermia The strikingly warm dry skin resulting from
anticholinergic intoxication raises concern that life-threatening
hyperthermia (i.e., core body temperature >40 C) may develop.
The antimuscarinic blockage of sweat glands by 2 mg of atropine
reduces sweating by an average of 60%, which in turn reduces
evaporative heat loss by about half. Atropine also increases cutaneous vasodilation by about 60%, enhancing radiant and convective heat loss and partially offsetting the thermoregulatory effects
of reduced evaporative heat loss (Kolka, Stepnenson & Gonzalez,
1994).
While testing the effects on visual acuity, Kobrick, Johnson &
McMenemy (1989) found that 2 mg per person of atropine combined with 600 mg per person of 2-PAM under severe heat and
humidity (i.e., 35 C, 60% relative humidity) did not prevent subjects from completing six hours of military tasks, while wearing
US Army battle dress uniforms. Stamina, however, while wearing
chemical protective gear, was limited to only about two hours.
For BZ the disturbances in thermoregulation at doses of 0.002
to 0.006 mg/kg i.m. (up to the ID50) and an elevated ambient
temperature of 41 C were not found to be hazardous. The peak
thermoregulatory imbalances were noted to occur about 6 hours
after injection with recovery occurring within 24 hours (Rosenblatt, Dacre, Shiotsuka & Rowlett, 1977).
Historical records of the military use of solanaceae provide useful
anecdotal insight into the potential thermoregulatory effects of
atropine and BZ at high doses. For example, in the 19th centurty,

the troops of Lieutenant Colonel Flatters were induced to ingest
dates impregnated with Hyoscyamus falezlez. Their unwitting
consumption of large amounts of these dates led to a totally crippling of their fighting ability, rendering them helpless to resist an
ambush by the Touareg. Nevertheless, the survivors were able to
regain most of their fighting strength by the third day after poisoning. In spite of equatorial conditions that would surely compromise the bodys thermoregulatory mechanisms, and without
immediate access to food or water, many of the troops somehow
managed, ten days later, to reach safety alive.
Under more favorable conditions, it is also noteworthy that all of
the 200 French soldiers, who were covertly poisoned with Datura
provided by the Chinese during the Indo-China war in 1908,
were reported to have recovered (Hammer, 1954; Lewin, 1929;
Barthe, 1918; The Times, 1908 ). This lack of fatalities suggests
that military incapacitation might be achieved by substances like
BZ without loss of life (contra Klotz, Furmanski, Wheelis, 2003).
Chemical Warfare
Goodman divided the use of belladonna in military conflicts by
its route of delivery, comparing poisoned weapons, other forms of
poisoning, and chemical weapons. The first two routes of administration are not permitted in modern combat due to the prohibition against poisoning and other acts of perfidy in Article 23 of
Hague II (1899). Until the prohibition of the Chemical Weapons
Convention of 1993, the use of chemical weapons was governed
mostly by wide-spread accession to non-first use pledges.
The 18th century artillery dissemination of solanaceae as a toxic
smoke was attempted, but would have been of negligible efficacy
for logistical reasons. Given the ID50 of atropine, the respiratory

ICt50 would be around 2,400 mgmin/m3. To attack a nominal
artillery square, or hectare (100 m 100 m area), for a 30% casualty rate in open terrain under neutral atmospheric stability and
five knot winds would require a Q 30 of 50 kg/ha; a quantity that
would barely produce any casualties at all within a city. Since
purified atropine was not known until 1831, this combat effect
would have been unattainable in previous centuries. Accounting
for dissemination loss, such a scheme would have required an
unimaginable quantity of dried solanaceae matter in the order of
7,100 kg/ha.*
Within the art of chemical warfare as it developed in the 1960s,
dissemination parameters in the production of casualties by inhalation were well understood. In the case of BZ, the United
States developed a variety of clustered munitions for aerosol delivery (Kirby, 2006). One of the prominent weapons was the M43,
which was also the largest weapon for disseminating BZ.
The M43 750-lb BZ Cluster Bomb (Ill. 4), known as the CBU5/B when used with tail faring for high-performance aircraft,
contained 57 M138 pyrotechnic bomblets (Ill. 5). Each 10-lb
M138 held four M7 canisters with a 50/50 BZ-pyrotechnic mixture. The M43 thus contained a total of 39 kg of BZ, and with
a dissemination efficiency of 70%, it delivered about 27.3 kg as a
1.0 to 1.6 m (mass median diameter) aerosol.
The US Army Field Manual FM 3-10B Employment of Chemical
Agents (1966B) stated the coverage of the M43 as 1.2 hectares
under neutral atmospheric stability, relatively insensitive to wind
speed or direction. Under stable atmospheric conditions the coverage increased to 1.5 to 2.0 hectares and under unstable condi* Estimates are after an integrated adaptation of a posological theorem of dose-dosage-quantity (cf. Kirby, 2007).
The naming of BZ munitions was in accordance with Federal systems, except that
Gas was dropped as a modifier for Bomb and Generator so the clusters may be identified as conventional types (Chemical Corps Technical Committee, 1962). The CBU5/B also had an optional M30E1 blunted nose dome.
Illustration 4
M43 (CBU-5/B) 750-lb BZ Cluster Bomb
Illustration 5
M138 BZ Bomb
10
Figure 4
Coverage of M43 (CBU-5/B) 750-lb BZ Cluster Bomb
DOCTRINAL MAX COVERAGE
IMPACT AREA
DOCTRINAL MIN COVERAGE
0.01
Area (Ha)
0.1
rate-of-action (hrs):
13
7 4
0.5
duration-of-action (hrs):
37
45 51
60
75
incapacitation (%):
1 10
50 99
lethality (%):
0.001
123
10
100
Dosage ( mgmin/m3)
1000
tions, this reduced to somewhat less than 1.2 hectares. Aircraft

were to release the M43 above 6,200 feet so that it would open at
4,500 feet and scatter its bomblets over a 100 200 meter elliptical area (1.57 ha). The area of casualty effects was mostly within
this impact area.
Figure 4 shows the area-dosage ranges of five field trials of the
M43 with a trend line of geometric means (Deseret Test Center,
1972). Superimposed on this figure is the range of expected target coverages and impact area of bomblets, along with the casualty effects relative to the dosages indicated.
The integrated casualty rate from the M43 over its doctrinal
range of coverage may have been as high as 94%. Excepting
the throw-weight of its 10-lb bomblets descending at 500 knot
speeds, assuming an LCt50 of 3,000 mgmin/m3 with a probit
slope of 3.8, the integrated fatality rate might approach 2%, satisfying the Qualitative Military Requirement for incapacitating
munitions described in Chemical Corps Technical Committee
CCTC Item 3960 (1962).*
In US Army planning, BZ was to be used on carefully selected
targets where lethality and physical destruction were militarily or
politically undesirable. The agent was expected to attain delayed
(3 to 6 hrs onset) and relatively long-term (1 - 5 days duration)
neutralization. At the time of its standardization the concept of
use was for coverage from 900 m2 to up to a square mile for either
a Berlin-type or Algerian-type action.
In a Berlin-type action BZ would be used with CS against rioting civilians possibly intermingled with enemy forces. Repeated
use of CS would contain the targeted population to permit BZ
* Over an urban area the lethality would be negligible at 0.4 ; and if the LCt50 is
assumed at 4,000 mgmin/m3 with a probit slope of 5.9, the lethality in an open area
would be a negligible 5 .
time to neutralize resistance without escalated physical violence,

a scenario requiring perhaps as few as 10% BZ casualties. In
an Algerian-type action BZ would be used to immobilize paramilitary forces sighted by air reconnaissance within 2 to 4 hours,
thereby permitting time to amass available forces to a remote area
and increase the probability of taking prisoners (Chemical Corps
Technical Committee, 1962).
The eventual doctrine for employing BZ proposed its use against
hard targets for delayed exploitation or capture (including hostage rescue). It advocated use against intermingled military units
or mixed military/civilian populations for follow-up physical separation, and against selected high-value targets for collection of
intelligence or to disrupt enemy use (US Army, 1966A).
As Goodman noted, some people are unusually sensitive to the
behavioral effects of atropine. Work with BZ also demonstrated
that some people can be relatively insensitive, and therefore a sizable variability in results is to be expected. Friendly forces could
enter the area after the aerosol cloud had passed, but predicting casualty effects was difficult due to the numerous variables
involved. Best estimates suggest that 5% of a target would be
incapacitated within 2 hrs, 50% in 4.5 hrs, and 95% in 9.5 hrs
(US Army, 1966B).
Operationally, BZ had obvious limitations. Its white agent cloud
from pyrotechnic dissemination served as a visible alarm, possibly leading to it being defeated by use of improvised respiratory
protection (e.g., folded damp cloth over nose and mouth). The
possibility of fatalities among the very young, aged, or infirmed
could be counter-productive in a counter-insurgency role without
adequate psychological preparation, and the erratic behavioral ef-
fects of casualties would require physical control to prevent secondary hazards, especially in built-up areas (US Army, 1966B).
During a national security review of chemical biological weapons,
Morton Halperin sent a 28 August 1969 memorandum to Dr.
Henry Kissenger on US policy, programs and issues on CBW that
included a summarized opinion on BZ. It advanced the notion
that chemical incapacitants such as BZ tended towards a first use
concept and doctrine and held no deterrent nor retaliatory value.
The uncertainty surrounding BZ effects and duration - its general
unreliability and limitations of weapon systems - made its use
highly questionable. While the Joint Chiefs of Staff wished to
retain a first use policy for such chemical incapacitants, the State
Department maintained a policy recommendation of research
and development (R&D) only.
BZ was to be replaced by a quicker-acting belladonnoid with a
shorter duration-of-action, but due to approaching disestablishment of the Chemical Corps in 1973 it never received standardization.* The United States never used BZ in combat; declaring
BZ obsolete in 1977, and by 1990 the entire holding of BZ was
incinerated (Kirby, 2006).
* The replacement candidate was 1-methyl-4-piperidyl isopropylphenylglycolate

(EA3834). At an ICt50 of 73.4 mgmin/m3 it would have a rate-of-action of 35 minutes and a duration-of-action of 10 to 15 hours. It could be used interchangeably in
CS munitions and was unlikely to produce incapacitation exceeding 24 hours.
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GOODMAN
OF ATROPINE
Behavioral Effects of High Doses of Atropine
and Military Uses of Atropine to Produce Intoxication

produced by atropine intoxication, with particular reference to behavioral
disturbances manifested therein. A human LD50 dose is estimated to be
453 mg, with 95% confidence limits of 335 - 612 mg (probit slope 1.8), for
orally ingested atropine. The range of individual differences in behavioral
toxicity and in lethality is described. Routes of administration of atropine
are discussed, and some attempt is made to correlate dose-response data
for the various routes. Finally, an historical summary of the military
applications of the behavioral toxicology of atropine is presented with an
Afterword on later research on atropine-related military incapacitants,.
viz. the chemical warfare agent BZ.
OH
O
O
By Ephraim Goodman
Mr. Reid Kirby

Historical Contributions To The Human Toxicology of Atrompine

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GOODMAN

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

This monograph reviews selected aspects of the clinical syndrome

Edited with Foreword & Afterword by

2208 Autumn Trace parkway

The Atropine Intoxication Syndrome............................................19

Military Applications of Atropine Toxicity...................................53

9. Atropine Specific Oral Dosimetric Effects.........................48

pralidoxime chloride (nerve agent antidote)

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 

 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

as a valuable addition, to the existing data concerning atropine in

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 

 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

(-)-(S)-3-hydroxy-2-phenyl-propionic acid (1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 

 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 

 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 

10 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 11

don-Smith, 1960). This name may be traced to the delirious state

12 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

Despite the variety of names given to the various members of

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 13

Throughout the following centuries, the use of the Solanaceae as

14 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 15

Gerarde believed that henbane caused drowsiness. Mandragora

16 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

seemed probable that the risk of exposure to the toxic substances

% For Age Group

16-40 41-50 51-60

Age of Intoxicated Person

18 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

The apparent differential susceptibility of various age groups to

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 19

The Atropine Intoxication

20 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

has enabled intoxication to take place (Firth & Bentley, 1921;

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 21

22 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

in sleep (Bertholow, 1890). He also recommended belladonna as

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 23

24 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

Hot as a hare, caused by an increase in body temperature

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 25

26 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

always, some degree of amnesia for events during the period of

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 27

gerous weapons (Anderson, Begg & McNaughton, 1867), and

28 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

The delirious condition is clearly described in the case of eight

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 29

This grubbing on the ground seems to be a constant finding in

30 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE 31

In a series of 103 cases of atropine poisoning collected before

Mortality Rate (%)

Oral Medicinal Products

Oral Plant Material

32 HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE

HISTORICAL CONTRIBUTIONS TO THE HUMAN TOXICOLOGY OF ATROPINE