CLINICAL
HANDBOOK
ON
ECONOMIC
POISONS
ENVIRONMENTAL
PROTECTION AGENCY
PESTICIDES PROGRAMS
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The Environmental Protection Agency and the U. S. Department of
Health, Education, and Welfare have a vital interest in the entire field
of poison control including, but not limited to, the toxicology of pesti-
cides.
The Division of Hazardous Substances and Poison Control, Bureau
of Product Safety, Food and Drug Administration, provides interchange
of information for poison contra/ centers throughout the country as a
part of its broad poison control activities.
A "Directory of Poison Control Centers," PHS Publication No. 7278
(Revised March 1971), compiled by the Division of Hazardous Substances
and Poison Control, can be purchased for 35 cents through the Superin-
tendent of Documents, U. S. Government Printing Office, Washington,
D. C. 20402.
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CLINICAL HANDBOOK ON ECONOMIC POISONS
Emergency Information
for Treating Poisoning
WAYLAND J. HAYES, JR., M.D., Ph.D.*
ENVIRONMENTAL PROTECTION AGENCY
PESTICIDES PROGRAMS
Division of Pesticide Community Studies
4770 Buford Highway
Chamblee, Georgia 30341
*Now with the Center in Toxicology, Department of Biochemistry, Vanderbilt University School of
Medicine, Nashville, Tenn. 37203.
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Names of commercial manufacturers and trade names of pesticides
are provided for identification only.
This handbook is a revision of Public Health Service Publication
No. 476 originally published in 1956 under the title "Clinical
Memoranda of Economic Poisons."
Revised 1963
Reprinted October 1971
U. S. Government Printing Office, Washington: 1963
For sale by the Superintendent of Documents
U. S. Government Printing Office, Washington, D. C. 20402
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CONTENTS
INTRODUCTION 1
Form of the Handbook 2
Interpretation of Toxicity 3
Suggestions for Clinical Study 4
General Suggestions for Treatment 7
Reporting 10
Prevention of Poisoning ] 1
ORGANIC PHOSPHORUS INSECTICIDES 12
Chlorthion 24
Co-Ral 24
DDVP 25
D erne ton 27
Diazinon 29
Guthion 30
Malathion 31
Methyl parathion 34
Parathion 35
Phorate 37
Phosdrin 38
Schradan 39
TEPP 40
Trichlorofon 42
CARBAMATE INSECTICIDES 44
Carbaryl 44
CHLORINATED HYDROCARBON INSECTICIDES 47
BHC 50
Ch lord one 55
DDT 58
Dieldrin 62
Dilan 67
Endrin 68
Heptachlor 70
Toxaphene 71
BOTANICAL INSECTICIDES 74
Pyrethrum and Allethrin 74
RODENTICIDES 77
Phosphorus 77
Sodium fIuoroacetate 79
Thallium 82
Warfarin 85
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FUNGICIDES 90
Dithiocarbamates 90
Organic mercury compounds 91
Pentachlorophenol 97
HERBICIDES 101
Arsenic 101
Chlorophenoxy herbicides 106
Din Itrophenol s 109
SOLVENTS 114
Kerosene 114
Xylene 118
APPENDIX A (Case History Form) 121
APPENDIX B (Instructions for Obtaining and Shipping a Fat
Biopsy for Analysis for Fat Soluble Compounds) 124
APPENDIX C (Instructions for Drawing, Preparing, and
Shipping Blood Samples for Cholinesterase Determinations) 126
APPENDIX D (Instructions for Shipping Stomach Contents, Urine,
Tissues, or Certain Other Materials for Toxicological
Examination) 128
APPENDIX E (Artificial Respiration) 129
LIST OF MANUFACTURERS 133
INDEX 135
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INTRODUCTION
The Environmental Protection Agency conducts laboratory, field
and clinical studies to determine the toxic hazards to man that are
involved in the use of economic poisons in public health, agriculture,
and the home. The subjects of clinical study include: (1) persons
with occupational exposure—including malaria-control spraymen,
farmers, orchardists, spray pilots, pest control operators, formula-
tors, and others with heavy occupational exposure; (2) volunteers
who take part in strictly experimental investigations of pesticides
under controlled conditions; and (3) patients who are sick as a result
of accidental over-exposure to pesticides. Facilities available for this
work include the Chamblee Toxicology Laboratory in Chamblee, Ga.,
the Pesticides Research Laboratories in Perrine, Fla. and Wenatchee,
Wash., plus 14 contract laboratories at various locations throughout
the country. Special study cases may be admitted to Public Health
Service Hospitals in accordance with Division of Hospitals Operations
Manual Part B, Chapter 1, Section 21.1, which was issued under
authority of Section 301 (f), Public Law 410. Additional facilities for
the study of volunteers have been made available generously by other
institutions.
This Handbook replaces the "Clinical Memoranda on Economic
Poisons," which were first issued in March 1950 as separate releases
on several new insecticides. Additional compounds were discussed in
subsequent editions. No attempt has been made in the Memoranda or
in the Handbook to cover a large number of compounds. Attention
has been given to those materials that are manufactured in large
amounts, that are known to have caused poisoning relatively fre-
quently, or that are of special interest for some other reason. In gen-
eral, the pesticides introduced before DDT have been omitted because
information on them is readily available in textbooks of pharma-
cology. However, sections have been devoted to arsenic, thallium,
phosphorus, and kerosene, because they are leading causes of deaths
associated with pesticides.
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The Handbook is based on research of the Environmental Pro-
tection Agency as well as reports from other sources. No credit or
reference is given unless it is felt that such a reference is reasonably
available to most readers and would be of some real use to the physi-
cian in the management of his patient. The Handbook is prepared
primarily for the guidance of physicians in the diagnosis and treat-
ment of persons who may have had extensive or intensive exposure
to economic poisons; however, it contains general information that
may be of interest to others also.
Form of the Ha
This Handbook is arranged under several main headings such
as "Organic Phosphorus Insecticides," "Chlorinated Hydrocarbon
Insecticides," and "Rodenticides." In order to conserve space,
statements that apply to all members of a class of pesticides have
been placed immediately under the main heading for that class and
have not been repeated in the sections on the individual com-
pounds. Synonyms for the different pesticides have not been listed
in the text, but some are given in the index.
A part of each section is devoted to a description of the
chemical nature, formulations, and uses of the compound under
consideration. This portion is intentionally a very brief resume of
the subject matter and is intended to guide the attending physician
in questioning the patient on his exposure to economic poisons or
their solvents. It must be understood clearly that, especially for
the newer organic poisons, very much more is known now regarding
their chemical nature, formulations, and uses than is known about
treatment or even the diagnosis of acute or chronic poisoning by
them in man.
The remainder of each section is devoted to medical consider-
ations including mode of action, diagnosis, and treatment. This
part is developed in greater detail than the first, although it is on
these medical considerations that research is most urgently
needed. In many instances, the suggestions for treatment are based
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on general medical principles and on animal experimentation
because many of the forms of poisoning have never been observed
in man.
Attention is called to the analytical services offered to physi-
cians in connection with cases of poisoning. Directions for the
collection and shipping of samples are given as appendices to
this Handbook. (Only those samples that cannot be processed
adequately by local or State laboratories should be submitted.)
Other appendices contain a convenient form for the collection of
data in cases of suspected poisoning and directions for giving
artificial respiration.
nternrefcihon of To,
Any compound may be toxic if it is absorbed to an excessive
degree. The simplest way of expressing the toxicity of a compound
is by means of an LD5Q -value. Such a value is a statistical esti-
mate of the dosage necessary to kill 50 percent of a very large
population of the test species under stated conditions (e.g., single
oral dose of aqueous solution).
Caution is necessary in the interpretation of LD --values.
First, hazards presented by any compound depend more on how
it is used than on how toxic it is. In this country, the majority of
the fatal and nonfatal accidents caused by solid or liquid sub-
stances involve relatively nonpoisonous materials, available to a
great number of people and sometimes used with reckless care-
lessness. This fact does not reduce the tragedy of needless injury.
Also, highly toxic substances do present a relatively greater
hazard if used under comparable conditions.
Second, it is known that toxicity may vary with species, age,
sex, nutritional state, and formulation of poison, as well as with
the route of administration. By necessity, LD -values are given
for animals. They can be applied only with reservation to man.
Third, an LD -value is a statistic which, in itself, gives no
50
information on the dosage that will be fatal to a very small pro-
portion of a large group of animals. Although values such as the
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LD5 or LDj may be determined for laboratory animals, they are
(for statistical reasons) less precise than the corresponding LDgo-
value and, therefore, even more difficult to apply to man.
Fourth, LD^Q -values are usually expressed in terms of single
dosages only. Thus, these values give little or no information
about the possible cumulative effects of a compound.
In spite of these necessary qualifications, LD50-values are
useful in making an objective comparison of the inherent toxicity
of different compounds. Some materials are so poisonous that
known exposure to a few drops on the skin is reasonable justifica-
tion for diagnosing consistent illness as poisoning. On the con-
trary, other compounds are so relatively harmless that a small dose
maybe ingested without causing any harm. As a very general guide,
the probable lethal oral dose for a grown person may be estimated
as follows:
Acute oral LD-. for
any animal (mg./kg.)
Less than 5
5 to 50
50 to 500
500 to 5,000
5,000 to 15,000
Probable lethal oral dose of
technical material for a human adult
a few drops
"a pinch" to 1 teaspoonful
1 teaspoonful to 2 tablespoonsful
1 ounce to 1 pint (1 pound)
1 pint to 1 quart (2 pounds)
It has been found that occupational poisoning with nonfumi-
gant pesticides shows a very much closer correlation with acute
dermal LD50-values than with oral toxicity.
Suggestions
Study
In certain cases, the life of the patient has been saved
because the physician suspected poisoning and began vigorous
treatment promptly. Response to therapy may help to establish the
diagnosis. However, proof of adequate exposure to a poison should
be obtained after the crisis if not before. The compound or a me-
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tabolite may be present in the excreta. For at least 24 hours
after onset, all vomitus, urine, and feces should be saved
systematically.
The history of each case is of the greatest importance. If the
fact of exposure to a toxicant is clearly established, it is then neces-
sary to know what poison or poisons were involved (including the
solvents and other adjuvants); the concentration and amount of the
contaminating material; the type, duration and frequency of ex-
posure; and the period from exposure to the onset of symptoms. Not
only is the most recent exposure important, but all preceding known
instances should be listed. To facilitate the taking and recording of
an adequate toxicologic history, a form (Appendix A) has been de-
vised and copies are available upon request from the Chamblee Toxi-
cology Laboratory, EPA, 4770 Buford Highway, Chamblee. Ga. 30341
A careful neurologic examination is essential because the
syndromes associated with many pesticides are predominantly
neurologic.
The physician will perform only those tests and administer
only those treatments that he believes are indicated. On the other
hand, to learn more about poisoning and treatment, it is desirable
to collect comparable data from a number of patients. To that end,
it is respectfully requested that the tests listed below be con-
sidered and performed if there is no medical or administrative
contraindication. Tests that are abnormal should be rechecked to
rule out laboratory error. Confirmed abnormalities should be studied
in detail. Reports of all tests should include a statement of the
method and of the normal range for that test in the laboratory where
it was made. Most of the tests suggested are nonspecific in regard
to any particular toxicant. Although the clinical manifestations of
poisoning in man with many of the newer groups of pesticides are
primarily neurologic in origin, repeated dosages of the chlorinated
hydrocarbon insecticides may produce pathologic changes in the
liver and kidney without signs referable to these organs (as they
do under appropriate conditions in experimental animals). For this
reason, special attention should be given to liver and kidney
function tests in man in order that urgently needed data may be
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collected with reference to the possible effects of pesticides on
these organs in man. The following clinical and laboratory tests
are suggested:
Complete blood count including:
Red cell count
Reticulocyte count
White cell count
Differential count
Hemoglobin (in grams percent)
Hematocrit
Urinalysis
Serologic test for syphilis
Lumbar puncture with cerebrospinal fluid analysis if there
is any neurosymptomatology
Phenolsulfonphthalein kidney test
Qnject 1.0 ml. (6 mg.) of dye intravenously and
collect a specimen of urine every 15 minutes for
2 hoursJ
Mosenthal test
Nonprotein nitrogen of the blood
Icterus index
Urobilin in the urine (Schlesinger's test)
Bromsulfalein liver function test (inject 5 mg./kg. and
make a reading at 45 minutes).
Cephalin flocculation
Blood pressure (at least daily)
X-ray of chest
Basal metabolic rate (BMR)
Electrocardiogram
Electroencephalogram, if equipment is available
Certain other specific tests (including tissue biopsy or
examination of stomach contents, excreta, or blood)
listed under "Laboratory Findings" for each particu-
lar economic poison. (Directions for taking and
shipping biopsy specimens form Appendix B. Direc-
tions for preparing and shipping blood samples for
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cholinesterase determination form Appendix C.
Directions for shipping stomach contents form
Appendix D.)
General Suggestions for Treatment
In many cases of poisoning, the nature of the toxic agent is
not known. The treatment is, therefore, symptomatic and may
include:
(1) Removal of the toxic agent.
(a) Emesis or gastric lavage if poison has been taken
internally. As a first aid measure after ingestion of a
nonirritant poison, vomiting may be produced by put-
ting a finger down the patient's throat or by giving a
child 20 ml. of syrup of ipecac plus water to mobilize
the poison. Do not repeat the dose of ipecac as a
first aid measure. Never try to make a stuperous or
unconscious person vomit. Never use fluid extract
of ipecac.
(b) Evacuation of the gut (avoiding oily laxatives where
it is possible that an organic solvent or a halogenated
insecticide is involved).
(c) Thorough washing of the eyes or body if there has
been external contact with the poison.
(d) Removal of the patient to fresh air if poisoning has
resulted from exposure to a contaminated atmosphere.
(2) Supportive therapy.
(a) Sedatives. Sodium pentobarbital is preferred for acute
poisoning because of its rapidity of action. Phenobar-
bital is useful in maintaining a prolonged level of
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sedation to combat persisting hyperexcitability or
recurring convulsions.
(b) Stimulants. In treating vascular collapse, substances
such as adrenalin should be used only after careful
consideration; these stimulants are contraindicated in
poisoning by the halogenated hydrocarbon insecti-
cides, even though the patient may be in severe de-
pression or coma.
(c) Transfusions. Patients in shock, for whatever reason,
may be helped by transfusion unless pulmonary edema
or some other contraindication is present. If blood is
not readily available or if simple dehydration is
present, 5% glucose or normal saline infusions are
indicated. Intravenous fluids should not be continued
long without a careful laboratory evaluation of the
acid-base balance.
(d) Artificial Respiration. (For a suggested method see
Appendix E.) It is more important to provide a free
respiratory passage and, if necessary, artificial respi-
ration to an anoxic patient than it is to move him to a
doctor or hospital. Frequently, the physician is in
telephone contact with the patient's family or associ-
ates quite early. The physician should inquire about
the victim's breathing and color. If anoxia seems to be
present or imminent, a warning should be given against
moving the patient, and someone trained and equipped
for giving emergency mechanical artificial respiration
(usually the fire department) should be called. If
necessary, the person initiating the telephone call
should be instructed in artificial mouth-to-mouth
respiration to be carried out while the physician goes
to the patient.
(e) Oxygen therapy. Oxygen should be administered to
patients showing cyanosis or severe respiratory diffi-
culty. Patients with pulmonary edema require oxygen
under positive pressure as well as postural drainage
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and dehydration therapy until the condition is
corrected.
These suggestions for symptomatic treatment are intentionally
brief and emphasize early treatment. More detailed information may
be found in the following recommended books:
von Oettingen, W.F.: Poisoning, A Guide to Clin-
ical Diagnosis and Treatment, Second Edition,
Philadelphia, W.B. Saunders Co., 1958.
Gleason, M.N.; Gosselin, R.E.; and Hodge, H.C.;
Clinical Toxicology of Commercial Products, Acute
Poisoning (Home and Farm), Baltimore, Williams
and Wilkins Co., 1969.
It is understood that, if the nature of the toxic agent is known,
the physician may be able to use a specific antidote to supplement
the general treatment. Where an antidote is known, it is described
in the section on "Treatment" dealing with each pesticide. In any
event, the importance of general medical care in cases of poisoning
should not be underestimated. Even when a recognized antidote is
properly administered, the general care of the patient may do as
much or more to insure his survival.
Additional information on a pesticide frequently may be obtained
from the medical department of the company which manufactures the
compound in question. For emergency consultation, physicians or hos-
pital representatives may also call the nearer of the following medical
officers:
Dr. Wayland J. Hayes, Jr. Dr. George A. Reich
Nashville, Tennessee 37203 Chamblee, Georgia 30341
Office: (AC: 615) 322-3315 Office: (AC: 404) 633-3311
Home: 269-9792 Home: 938-4357
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Reporting
In cases of pesticide poisoning, no matter how mild, physi-
cians and others are urged to notify promptly the nearest of the
following laboratories:
Chamblee Toxicology Laboratory, Wenatchee, Kesearch Station,
EPA EPA
4770 Buford Highway P. 0. Box 73
Chamblee, Georgia 30341 Wenatchee, Washington 98801
This direct notification is not to be confused with or intended to
be a substitute for the morbidity reports usually sent local and
State departments of health or poison control centers.
Reports are solicited not only on cases that involve clearly
established poisoning but also on cases that present a diagnostic
problem, even after thorough study. However, past experience has
shown that the following caution is necessary: Before chronic
poisoning is reported, be sure that exposure to a pesticide has
occurred.
The narrative report that is requested for each case of poison-
ing should be more complete than the average clinical summary,
for it will frequently be impossible to refer to the original chart.
These case histories form one important source of information for
this booklet, so that the experience of one person may help many.
All information received will be kept confidential so far as the
identity of the patient is concerned.
10
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Prevention of Poisoning
In the United States pesticides kill more children than adults.
It is probable that nonfatal poisoning also occurs predominantly in
children. These cases in children could be virtually eliminated if
(a) pesticides were always stored under lock and key, (b) care
were taken that children could not reach the poisons while they are
in use, and (c) empty containers were disposed of safely. Some of
the compounds are extremely persistent. Poisoning has occurred
from contact with a cup used a year before for measuring a
pesticide.
Strangely enough most deaths caused by pesticides are still
associated with arsenic, phosphorus, and other poisons that were
available before the introduction of DDT and newer materials.
Great care should be used with all poisons — including those that
are so familiar that some people forget their undiminished danger.
11
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ORGANIC PHOSPHORUS INSECTICIDES
Introduction: The organic phosphorus insecticides are character-
ized by (1) similar chemical structure (they may all be considered
derivatives of phosphoric acid) and (2) similar primary mode of
action. These insecticides differ widely in their inherent toxicity
and differ at least to some extent in their rate of absorption, point
of maximal action following absorption, and rate of destruction or
excretion. The acute oral and dermal LD5Q-values to rats of certain
organic phosphorus insecticides including those mentioned in this
Handbook are given in the table on page 13.
Routes of Absorption: Organic phosphorus insecticides are ab-
sorbed by the skin as well as by the respiratory and gastrointesti-
nal tracts. Absorption by the skin tends to be slow, but, because
the insecticides are difficult to remove, such absorption is fre-
quently prolonged. Skin absorption is somewhat greater at higher
temperatures and is much greater in the presence of dermatitis.
Thus, dermatitis may lead to serious poisoning following exposure
that would ordinarily cause no inconvenience.
Phormacologic Action: The organic phosphorus poisons act as
more or less irreversible inhibitors of the enzyme cholinesterase
and thus allow the accumulation of large amounts of acetylcholine.
The cholinesterase content of various tissues is not equally af-
fected in the same poisoned animal, and the level in all tissues
including even the brain can be lowered markedly from the pre-
poisoning level without seriously affecting normal function, espe-
cially if the reduction is gradual. Almost as important as the
degree of cholinesterase depression is the rate at which it occurs.
A sudden slight depression resulting from a small dose that is
rapidly absorbed may lead to incapacitating acute illness, though
not to fatal illness. A sudden marked depression from a sufficient
dose leads to critical and frequently fatal poisoning. However, the
blood cholinesterase of men and animals maybe gradually depressed
12
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ACUTE ORAL AND DERMAL LD50-VALUES OF
ORGANIC PHOSPHORUS INSECTICIDES FOR
MALE AND FEMALE WHITE RATS*
COMPOUND
Carbophenothion
Chlorthion
Co-Ral
DDVP
Del no v
Demeton
Diazinon
Dicapthon
Dimethoate
Di-Syston
EPN
Ethion
Fenthion
Guthion
Malathion
Methyl para th ion
Methyl Trithion
NPD
Parathion
Phorote
Phosdrin
Phosphamidon
Ronnel
Schradan
TEPP
Trichlorofon
ORAL LDSO (MG./KG.)
MALES
30
880
41
80
43
6.2
108
400
215
6.8
36
65
215
13
1375
14
98
—
13
2.3
6.1
23.5
1250
9.1
1.05
630
FEMALES
10.0
980
15.5
56
23
2.5
76
330
-
2.3
7.7
27
245
11
1000
24
120
-
3.6
1.1
3.7
23.5
2630
42
—
560
DERMAL LD50 (MG./KG.)
MALES
54
<4500
860
107
235
14
900
790
400
15
230
245
330
220
> 4444
67
215
2100
21
6.2
4.7
143
-
15
2.4
> 2000
FEMALES
27
4100
_
75
63
8.2
455
1250
-
6
25
62
330
220
>4444
67
190
1800
6.8
2.5
4.2
107
-
44
—
> 2000
*With the exception of the dermal LD» for dimethoate, these values were determined by the
Chamblee Toxicology Laboratory under standardized conditions.
13
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to a very low level (<0.2Aph/hr in man) by repeated small ex-
posures to organic phosphorus compounds without necessarily
producing serious symptoms or even any symptoms whatever. Thus,
a very low blood cholinesterase is not always proof that a clinical
illness represents poisoning, but critical poisoning usually does
not occur in man or laboratory animals in the absence of such
enzyme levels. In every case, the exposure history, symptoms, and
clinical findings must be considered carefully, no matter what the
cholinesterase level may be.
It is known now that some effects of organic phosphorus
insecticides (e.g., headache and irritation of the urinary tract both
caused by paranitrophenol) are not always related directly to the
inhibition of cholinesterase, but the relative importance of differ-
ent processes in determining the clinical outcome is not estab-
lished. In any event, recovery is apparently complete if a poisoned
animal or man has time to re-form his critical quota of cholinester-
ase. Experiments with rats show that gradual depression of the
blood cholinesterase by repeated, small, tolerated doses does not
make the animals significantly more susceptible to a challenge
dose. Field experience suggests that the same is true of man.
Thus, there is a physiological adjustment to the stress of repeated,
small, tolerated doses that is at least partially independent of the
blood cholinesterase per se. On the contrary, repeated doses which
produce any detectable clinical injury in rats tend not only to
reduce cholinesterase levels progressively but to produce cumula-
tive clinical injury also. Thus, if a small second dose of poison is
administered before physiological adjustment is complete, the
effect is partially additive. Following clinical recovery after
illness caused by one or a few doses, physiological adjustment
may be safely presumed complete only after the activity of the
blood cholinesterases has returned to normal. Depending on the
degree of depression and other factors, the recovery may require
about three months. This does not mean that workers who have
been poisoned may not return to work much sooner than three
months providing the attending physician is satisfied that his
patient is clinically normal and able to carry out all safety meas-
ures under the conditions of his employment.
14
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Some unmetabolized organic phosphorus insecticides are able
to inhibit cholinesterase and are said to have a direct action;
many other compounds are not active until they have been altered
either by chemical or enzymatic change, and, therefore, are called
indirect inhibitors. Direct inhibitors tend to have more prominent
local effects and to produce systemic poisoning more rapidly.
Signs and Symptoms of Poisoning in Man: Signs and symptoms are,
at least to a very great extent, secondary to cholinesterase inhibi-
tion. The usual symptoms include: headache, giddiness, nervous-
ness, blurred vision, weakness, nausea, cramps, diarrhea, and
discomfort in the chest. Signs include: sweating, miosis, tearing,
salivation and other excessive respiratory tract secretion, vom-
iting, cyanosis, papilledema, uncontrollable muscle twitches,
convulsions, coma, loss of reflexes, and loss of sphincter control.
The last four signs are seen only in advanced cases but do not
preclude a favorable outcome if energetic treatment is continued.
Poisoned animals show various degrees of heart block, and cardiac
arrest may occur. Following a massive oral dose associated with
murder or suicide, death has occurred in 5 minutes or less after
ingestion. Following smaller doses swallowed accidentally, onset
of illness was sometimes delayed an hour or more. In occupational
cases, illness is frequently delayed several hours so that the
worker may first become sick at home after supper. (However, if
symptoms begin more than 12 hours after the last known exposure
to insecticide, illness is probably due to some other cause.)
Furthermore, in occupational cases, relatively incapacitating symp-
toms of nausea, cramps, discomfort in the chest, muscular twitch-
ing, etc., often follow the initial giddiness, blurred vision, and
headache only after a period of 2 to 8 hours, but the onset of
serious symptoms may be more rapid. It seems that in the past
undue emphasis has been given to miosis as a diagnostic sign.
Miosis may appear late; in fact, the opposite condition, mydriasis,
may be present, perhaps as a nonspecific reaction to the discom-
fort and apprehension associated with poisoning. Treatment of
significant illness following excessive exposure to these com-
pounds should not be delayed merely because miosis is absent.
15
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There have been at least 3 cases in which artificial respira-
tion was required but was inadequate, so that the patient survived
temporarily but showed severe brain injury as a result of the
anoxia. The reason for inadequacy of artificial respiration in
different instances was delay in reaching the victim or resistance
of the airway or other difficulty that could not be overcome by well-
trained and well-equipped physicians. The patients gradually re-
covered from the specific signs of poisoning but remained comatose
and tended to continue to have inadequate spontaneous respira-
tion. Two of them showed temporary hyperthermia after the acute
episode presumably as a result rather than a cause of brain injury.
Death occurred 6 days to 4 weeks after onset. Extensive necrosis
of the brain was present in those cases that came to autopsy.
Laboratory Findings: Leukocytosis and moderate albuminuria, ace-
tonuria, and glycosuria are frequent and hemoconcentration may
occur.
By special techniques, the cholinesterase level of the blood
or serum may be shown to be greatly reduced. At autopsy, the
same may be demonstrated for the cholinesterase level cf the
brain or other tissues provided fresh unfixed tissue is employed.
Blood is usually adequate for examination if taken within a few
days of death. Directions for collecting and shipping blood sam-
ples form Appendix C.
The most extensive single study of cholinesterase values of
normal persons without exposure to organic phosphorus insecti-
cides employed the Michel method (J. Lab. Clin. Med. 34:1564;
1949) and revealed the following values:
Cholinesterase Activity (ApH/hr) of Normal Human Blood*
Men Women
Red cells - range 0.39 - 1.02 0.34 - 1.10
mean ± s.d. 0.766± 0.081 0.750± 0.082
Plasma - range 0.44 - 1.6.3 0.24 - 1.54
mean ± s.d. 0.953± 0.187 0.817± 0.187
*The means (but not the ranges) are for people 40 years old. On the average, the plasma
cholinesterase of men Increases about 0.02 per decade and that of women increases about
0.04 per decade. The enzyme activity of red cells does not change with age.
16
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Other studies have shown that values exceeding the ranges
in the table are encountered in normal people, but only very
rarely.
It is believed that cholinesterase values of 0.5 or less for
either cells or plasma represent abnormal depressions for most
individuals. Nevertheless, people may experience far greater
depressions (to 0.2 or less) without the onset of clinical signs
or symptoms; this situation is especially true of workers who are
exposed daily over a period of weeks but whose exposure at any
one time is kept at a minimum. On the contrary, a considerable
absorption of an organic phosphorus insecticide may occur in one
or a few exposures without producing any measurable reduction of
blood cholinesterase. For practical purposes, exposure to organic
phosphorus or carbamate insecticides is the only cause of signifi-
cant depression of cholinesterase activity. Certain diseases of the
liver cause a reduction of the enzyme in the plasma, but these
diseases are not consistent with active work.
It is also possible to estimate absorption of some of the or-
ganic phosphorus insecticides by analysis for their metabolic
products in urine. Urinary levels of paranitrophenol have been
used in this way to provide an estimate of parathion exposure.
Other methods are available for other compounds. There is a broad
correlation between the excretion of biotransformation products
and the occurrence of illness. However, there are great individual
differences in susceptibility.
Bradycardia, A-V block and dissociation, exaggeration and
inversion of the T wave, and disappearance of the P wave have
been observed in experimental animals poisoned by TEPP, and are
likely to be encountered with other organic phosphorus insecticides
under suitable conditions.
Pathology: No significant gross or microscopic pathology is to be
expected except that associated with pulmonary or cerebral con-
gestion or changes secondary to convulsions.
17
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Differential Diagnosis: In the absence of laboratory facilities for
cholinesterase determinations, brain hemorrhage, heat stroke, heat
exhaustion, hypoglycemia, gastroenteritis, and pneumonia or other
severe respiratory infection have been confused at times with
poisoning by these compounds. Mild poisoning must frequently be
distinguished from asthma and from simple fright with various
psychosomatic manifestations, particularly among the associates
of known poisoning cases. In recent years, a number of cases have
been provisionally diagnosed as poisoning by one of the less toxic
organic phosphorus insecticides before a complete investigation
of the exposure history and clinical course changed the diagnosis
to poisoning by more toxic insecticides, mercury fungicides, or
solvents, or even to disease unrelated to pesticides.
Treatment:
I. In very severe cases, the order of treatment should be as
follows:
(1) ARTIFICIAL RESPIRATION, if required, preferably by
mechanical means. See Appendix E.
(2) ATROPINE SULFATE, 2 to 4 mg. (i/so to 1/15 grain)
intravenously as soon as cyanosis is overcome. Repeat
at 5- to 10-minute intervals until signs of atropinization
appear (dry, flushed skin and tachycardia as high as 140
per minute).
(3) 2-PAM, SLOWLY, intravenously, 1 g. for adults and 0.25 g.
for infants.
(4) DECONTAMINATION of the skin, stomach, and eyes
as indicated.
(5) SYMPTOMATIC TREATMENT.
n. In the more usual case, proceed as follows:
(1) ATROPINE SULFATE, 1 to 2 mg. (1/60 to 1/30 grain),
if symptoms appear. If excessive secretions occur, keep
18
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the patient fully atropinized. Give atropine sulfate every
hour up to 25 to 50 mg. in a day.
(2) DECONTAMINATION of the skin, stomach, and eyes as
indicated.
(3) 2-PAM, SLOWLY, intravenously, if the patient fails to
respond satisfactorily to atropine sulfate. Dose of 1 g. for
adults, 0.25 g. for infants.
(4) SYMPTOMATIC TREATMENT.
It will be noted that the recommended dosage of atropine sulfate is
greater than that conventionally employed for other purposes but is
within safe limits. Atropine sulfate relieves many of the distress-
ing symptoms, reduces heart block, and dries secretions of the
respiratory tract. People poisoned by anticholinesterase organic
phosphorus compounds have an increased tolerance for atropine
sulfate. Furthermore, a single dose of as much as 10 mg. of atropine
sulfate has been inadvertently administered intravenously to normal
adults without endangering life, although it has, of course, pro-
duced very marked signs of overdosage. In the presence of severe
anticholinesterase poisoning, 40 mg. of atropine sulfate may be
given in a day without producing symptoms attributable to atropine
sulfate. The effects of intravenous atropine sulfate begin in 1 to 4
minutes and are maximal within 8 minutes. A mild degree of atro-
pinization should be maintained in all cases for 24 hours, and in
severe cases for at least 48 hours.
The tenacity of the chemical bond between cholinesterase and
one of the various organic phosphorus compounds depends on the
compound. For some, the bond is irreversible under ordinary condi-
tions. However, it has been found that certain derivatives of hy-
droxamic acid or oximes may promote release of the enzyme even
when the bond is otherwise practically irreversible.
Three derivatives (one available in at least 3 forms) have
proved outstanding:
(a) 2-Pyridine aldoxime methiodide (2-PAM iodide or
19
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pralidoxime iodide).
2-Pyridine aldoxime methochloride (2-PAM chloride or
pralidoxime chloride)
2-Pyridine aldoxime methyl methanesulfonate (P2S)
(b) Diacetyl monoxime (DAM)
(c) l,l-Trimethylene-5t's-(4-formyl pyridinium bromide)
dioxime. (TMB-4).
One of these drugs, used in conjunction with atropine sulfate, will
protect experimental animals from much larger doses of organic
phosphorus compounds than is possible by the use of the drug or
atropine sulfate alone. Of the three drugs, the first is best known.
Tests carried out with 2-PAM on more than 40 people accidentally
poisoned by parathion are most encouraging. The dosage used has
usually been 1 g. for adults with proportionally smaller doses for
infants. However, one patient severely poisoned by parathion re-
ceived 40.5 g. of 2-PAM over a period of 6 days. In most cases, a
single dose was sufficient to produce dramatic improvement within
30 minutes. In poisoning resulting from one or a few large doses of
parathion, 2-PAM causes a marked reactivation of red cell cholin-
esterase but much less effect on the plasma enzyme. Side effects
have been minimal in normal subjects and practically nonexistent
in people who were poisoned. A few patients given the iodine
preparation complained of a taste that no doubt resulted from the
iodine moiety of the molecule. The other salts have the advantage
of being more soluble and producing no taste. 2-PAM is rapidly ex-
creted, chiefly in the urine. The half-life in the blood is about
1 hour.
2-PAM chloride is available from Ayerst Laboratories, Inc.,
685 Third Avenue, New York, N. Y. 10017.
Miosis and headache may persist after recovery from poisoning
20
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by organic phosphorus insecticides is otherwise largely complete.
In some cases, the systemic administration of atropine sulfate is
followed by partial or temporary dilatation of the pupils. Miosis re-
sponds more dependably to 2-PAM. If further systemic treatment is
not necessary, the miosis and associated headache will respond to
the instillation of 1/2% to 1% atropine sulfate solution or 1/2%
atropine sulfate ointment into the eyes.
Never give morphine, theophylline, or theophylline-ethylene-
diamine (Aminophylline). Do not give atropine to a cyanotic patient;
give artificial respiration first and then give atropine sulfate. Large
amounts of intravenous fluids are generally contraindicated be-
cause of excessive fluid in the respiratory tract.
Tranquilizers should be used with great caution; they are
seldom indicated at all. In fact, there are some indications that use
of a phenothiazine-substituted drug to overcome anxiety and rest-
lessness may have been a contributing cause in the fatal outcome
of a case in which the side effects of the drug were apparently
mistaken for persisting signs of poisoning by organic phosphorus
insecticides. Promazine and chlorpromazine increase mortality in
experimental animals poisoned by parathion.
If pulmonary secretions have accumulated before atropine
sulfate has become effective, they should be removed by suction
and a catheter. If the stomach is distended, empty it with a Levin
tube.
If the patient has not yet shown symptoms or they have been
allayed by treatment, he must be completely and quickly decontami-
nated. Remove the patient's clothing, and, with due regard for his
condition at the moment, bathe him thoroughly. Remove any visible
insecticide gently with lots of water and soap or other detergent, if
available. Avoid abrasion. When the skin appears clear, bathe or
swab with ethyl alcohol. Parathion and many of the other organic
phosphorus insecticides are very much more soluble in alcohol
than in water, and significant amounts can be washed from skin
that has been scrubbed several times with soap and water.
If there is any suspicion that the poison has been ingested or
21
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inhaled and if the patient is still responsive, induce vomiting, give
some neutral material such as milk or water, and induce vomiting
again. The reason for mentioning inhaled material is, of course,
that a large portion of such material may be deposited in the upper
respiratory tract and subsequently carried to the pharynx and
swallowed. Nausea may be anticipated, of course, on the basis of
the systemic action of organic phosphorus compounds, but if vomit-
ing is not profuse, gastric lavage may be used. Experiments have
indicated that vomiting induced immediately or even 1.5 hours after
ingestion is more effective than gastric lavage in removing poison.
Atropine sulfate does not protect against muscular weakness.
The usual mechanism of death appears to be respiratory failure.
The use of an oxygen tent or even the use of oxygen under slight
positive pressure is advisable and should be started early. Watch
the patient constantly, since the need for artificial respiration may
appear suddenly. Equipment for oxygen therapy and for artificial
respiration should be placed by the patient's bed in readiness
while the patient is on his way to the hospital. Cyanosis should be
prevented by the most suitable means, since continued anoxia
aggravates the depression of the respiratory center caused directly
by the poison. Complete recovery may occur even after many hours
of artificial respiration have been necessary.
If there is any reason to think that the eyes may have been
contaminated, irrigate them with physiological saline or water. The
absorption of some of the organic phosphorus insecticides by the
eye is remarkably rapid.
The acute emergency lasts 24 to 48 hours, and the patient
must be watched continuously during that time. Favorable response
to one or more doses of atropine sulfate, frequently given as a
first aid measure, does not guarantee against sudden and fatal
relapse. Medication must be continued during the entire emergency.
Any person who is ill enough to receive a single dose of atropine
sulfate should remain under medical observation for 24 hours,
because the atropine sulfate may produce only a temporary relief of
symptoms in what may prove to be a serious case of poisoning.
22
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Atropine sulfate should never be administered for preventive pur-
poses to persons who have not become sick. 2-PAM is not used as
first aid, and one dose of it is frequently adequate. However, re-
peated administration may be required in severe cases, and the
patient always must have continuous observation.
Following exposure heavy enough to produce symptoms, further
organic phosphorus insecticide exposure of any sort should be
avoided. The patient may remain susceptible to relatively small
exposures to the same or any other organic phosphorus compound
until regeneration of cholinesterase is nearly complete.
Prevention: Poisoning in those who work with the more toxic
organic phosphorus insecticides may be prevented in three general
ways: (1) constant, thoughtful care on the part of every worker;
(2) mechanical aids such as protective clothing, masks, and factory
safety ventilation; and (3) regular inspection of working condi-
tions. It is practical to test routinely the plasma and erythrocyte
cholinesterase levels of factory or agricultural workers who may
be subject to significant exposure to organic phosphorus com-
pounds. The interpretation of individual values in asymptomatic
persons is difficult. It is clear, however, that a single very low
enzyme value for one worker or a low average value for a group of
exposed workers is an indication of the need for improved personal
care or better mechanical protection or both. In a similar way,
poisoning may be minimized by proper evaluation of the amount of
urinary excretion of biotransformation products, such as para-
nitrophenol.
23
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Chlorthion
Chemical Name: 0,0-dimethyl 0-(ffz-chloro-/?-nitrophenyl)
phosphorothioate:
Chemical Formula:
CH3-0NS /=\
Formulations: Chlorthion is available as an approximately 50%
emulsifiable concentrate, 25% water-wettable powder, and 3% dust.
Uses: Chlorthion is used in control of roaches and adult and larval
mosquitoes. It is approved for use in dairy barns for fly control.
Toxicology: No cases of human poisoning are known. Studies of
the acute oral and dermal toxicity of Chlorthion to experimental
animals indicate a low toxic hazard. By both oral and dermal
routes, the toxicity of Chlorthion is less than that of DDT and much
less than that of certain other of the organic phosphorus group of
insecticides. From animal studies, one might expect some cholin-
esterase depletion in persons having very heavy repeated expo-
sures to Chlorthion. Taking dosage into account, the toxicology of
Chlorthion is similar to that of the organic phosphorus insecticides
generally. See pages 12 to 23-
Co-Ra
Chemical Name: 0,0-diethyl 0-(3-chloro-4-methyl-2-oxo-2H-l-
benzopyran-7-yl)phosphorothioate.
ru • i c I c*H'-°x§
Chemical Formula: ^j>j
C2H,-0X
^^x'
CH}
24
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Formulations: Co-Ral is available in the form of a 25% wettable
powder and 0.5% dust.
Uses: Co-Ral is a systemic insecticide for control of arthropod
parasites of animals by external application. Sprays and dips of
0.25% and 0.5% concentration are used to control cattle grubs as
well as external parasites of cattle, sheep, goats, dogs, and
chickens.
Routes of Absorption: Co-Ral can be absorbed through the skin as
well as by other routes.
Pharmacologic Action: See page 12. Co-Ral differs from manyother
organic phosphates in that the toxicity as a result of oral adminis-
tration is delayed and more prolonged.
Toxicology: The dermal toxicity of Co-Ral is low. No toxic symp-
toms due to the use of Co-Ral have been observed in man. How-
ever, excessive exposure has been shown in a few cases to lower
blood cholinesterase values. The ingestion of significant quanti-
ties would be expected to produce poisoning. Taking dosage into
account, and with the possible exception of its delayed action, the
toxicology of Co-Ral is similar to that of the organic phosphorus
insecticides generally. See pages 12 to 23.
DDVP
Chemical Name: 0,0-dimethyl 2,2-dichlorovinyl phosphate.
Chemical Formula: CH3-O^(j)
yP-O-CH=CC!2
CHj-O
Formulations: Technical, baits, concentrates, and aerosols are
available.
25
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Uses: DDVP is used for control of houseflies, phorid flies (in
mushroom cultures), Mediterranean fruit flies, and cigarette beetles
(in warehouses).
Routes of Absorption: DDVP is easily absorbed by the skin as
well as by other routes. Although inherently less poisonous than
parathion or TEPP, it has a much greater vapor pressure, and toxic
concentrations of DDVP may be produced in special chambers in
the laboratory. Measurements show that dangerous concentrations
of vapor are not produced under practical conditions of use in
warehouses, but fogs or aerosols may be dangerous.
Phormocologic Action: In general, the action is similar to that of
other organic phosphorus insecticides, but the compound is a
direct inhibitor of cholinesterase, and it is detoxicated relatively
quickly. At least in animals, recovery from acute poisoning is
rapid and the range of tolerated dosage is wide. Although a dietary
concentration of DDVP as low as 50 ppm produces definite lower-
ing of the plasma and red cell cholinesterase levels of rats, yet
these animals withstand a dietary level of 1,000 ppm for 90 days
without showing any signs of intoxication.
Dangerous Single and Repeated Doses to Man: Two laborers in
another country died after spilling concentrated DDVP on their
arms. No details are available.
In another instance, the spillage of only about 4 ounces of a
3% oil solution of DDVP on a man's lap resulted in poisoning
which apparently would have been fatal had it not been for unusu-
ally vigorous treatment. There was no previous exposure and no
effort to remove the poison until the man noticed a burning of the
skin about half an hour after the accident. Even then, washing was
very superficial and a bath was delayed another hour.
In still another case, a man spilled a smaller amount of the
same 3% formulation on his arm. He removed his shirt at once and
washed with soap and water as soon as possible, about 15 minutes
later. He developed dizziness and nausea as the only symptoms.
26
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Tests have shown that men can withstand brief exposure to
air concentrations at least as high as 6.9 |ig./l- without clinical
effect or depression of blood cholinesterase; intermittent exposure
totaling 5 hours daily at a concentration of 0.5 ug./l- produces no
clinical effect and no effect on red cell cholinesterase, but does
cause a gradual, moderate reduction of plasma cholinesterase.
Signs and Symptoms of Poisoning in Man: In the serious, nonfatal
case mentioned above, the victim developed slurred speech and
drowsiness slightly more than an hour and a half after the acci-
dent. He collapsed suddenly after reaching a hospital. Prompt
use of oxygen, a total of 15 mg. of atropine sulfate (mostly intra-
venously), and supportive treatment saved him. He appeared to be
recovering uneventfully when he developed periodic hallucinations
and violent combativeness during the fourth and fifth day after the
accident. Because of certain factors peculiar to this case, it was
not possible to tell whether these complications were related
directly to DDVP. In any event, the patient finally recovered
completely.
Laboratory Findings and Other Toxicology: See page 16. , The first
sample of blood for cholinesterase determination in the serious,
nonfatal case mentioned above was taken the day after the acci-
dent. The enzyme activity, though reduced, was surprisingly high
in view of the near-fatal outcome. Animals show a rapid recovery
of cholinesterase activity, especially of the plasma, following
poisoning with DDVP. The same may occur in man. For other
points of toxicology, see pages 12 to 23.
Demeton
Chemical Name: 0,0-diethyl 0-[2-(ethylthio)ethyl2]phosphorothioate
(I) and 0,0-diethyl S-[j-(ethylthio)ethyQphos-
phorothioate(II) in a ratio of approximately 2 to 1.
27
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Chemical Formulae:
C2H,-0NS
/P-O-C2H4-S-C2H, P-S-C2H4-S-C2H,
v. 2 ** 5 "v v> 2 ** 5 "
I. Thiono Isomer II. Thiol Isomer
Formulations: Demeton is available as an approximately 24%
emulsifiable concentrate.
Uses: Demeton is a systemic insecticide in plants; that is, the
compound is translocatable from one part of a living plant to
another. Thus, demeton will control certain plant pests on all
parts of the plant, even though it may be applied to only one part.
The compound is used on cotton, ornamentals, seed crops, and
some food plants.
Routes of Absorption: Demeton is -readily absorbed through the
skin, as well as by other portals.
Pharmacologic Action: See page 12.
Dangerous Single and Repeated Doses to Man: Little is known
regarding the acute and repeated dosages that would be dangerous
to man. However, the minimum acute lethal oral dose for man is
believed to be approximately equal to that of parathion. The com-
pound is only slightly less toxic by the dermal route. In the female
rat, a dietary intake at the rate of 0.16 mg./kg./day produced slight
cholinesterase depression. An intake of 2.6 mg./kg./day caused
signs of poisoning that tended to diminish as feeding continued.
Men tolerated 3.75 mg. daily for 24 days (approximately 0.05 mg./
kg./day) with only about 15% depression of plasma cholinesterase
and no significant change of red cell enzyme.
Signs and Symptoms of Poisoning in Man: At least four fatal,
several severe nonfatal, and a number of mild cases of demeton
poisoning have been reported. Persons poisoned with demeton
28
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have shown the typical symptoms of organic phosphorus poisoning
described on page 15.
Pathology: One autopsy revealed congestion in the viscera, a
bloody exudate in the lungs, and a unique odor of the contents of
the peritoneal cavity.
Treatment and Other Toxicology: See pages 12 to 23.
Diazinon
Chemical Name: 0,0-diethyl 0-(2-isopropyl-4-methyl-6-pyrimidinyl)
phosphorothioate.
Chemical Formula: C2H,-O S
-OiS
C2H5-0X
CH5
Formulations: Diazinon is available in the technical form (about
90% pure), as a 25% wettable powder, 2% to 4% dust, 25% emulsifi-
able concentrate, 20% solution, and as a poison bait. For fly
control, the addition of sugar (2.5 parts sugar to 1 part of toxicant)
has been used.
Uses: Diazinon is effective against flies and roaches as well as
many insect pests of fruits and vegetables. In addition to the more
usual formulations, it may be used to impregnate cords for fly
control.
Routes of Absorption: Diazinon is readily absorbed through the
skin as well as through other portals.
Dangerous Single and Repeated Doses to Man: Eight men drank
only part of a bottle of Diazinon dissolved in xylene or a xylene-
29
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like material in the belief that the liquid was wine. Three of them,
with an average age of 73 years, died.
Diazinon, formulated as an ointment, caused sweating, abdomi-
nal pain, nausea, and, in one instance, coma when 80 mg. of active
ingredient was applied experimentally twice to the skin of each of
two men for the treatment of creeping eruption. It is not possible
at this time to state whether the unexpectedly great dermal absorp-
tion was caused by the formulation or the dermatitis, or both.
The spraying of an oil formulation on floors and bedclothing
caused near-fatal poisoning of 3 children.
Slight asymptomatic cholinesterase depletion occurs in spray-
men as a result of extensive occupational exposure to Diazinon.
This fact and the cases mentioned show that Diazinon must be
used with care even though its toxicity is relatively low in com-
parison with many other organic phosphorus insecticides.
Signs and Symptoms of Poisoning in Man: Typical symptoms (listed
on page 15 ) occurred in the cases of Diazinon poisoning. Miosis,
bradycardia, diarrhea, increased respiratory tract secretions, coma,
and convulsions were seen in one or more cases, including those
that survived. The illness tends to be somewhat more protracted
than poisoning by most other organic phosphorus compounds.
Laboratory Findings and Other Toxicology: Serious illness is
associated with very marked inhibition of blood cholinesterase. For
treatment and other aspects of toxicology, see pages 18 to 23.
Guthion
Chemical Name: 0,0-dimethyl S-(4-oxo-l,2,3-benzotriazin-3
(4H)-ylmethyl)phosphorodithioate.
Chemical Formula: CH3"°\J
30
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Formulations: Guthion is available as an approximately 18% emul-
sifiable concentrate, as 25% wettable powder, and as 3% dust.
Uses: Guthion is currently used in controlling a wide variety of
insects on fruit, nuts, cotton, and some vegetables.
Routes of Absorption: Guthion can be absorbed through any body
portal.
Dangerous Acute and Repeated Doses to Man: There is little
direct knowledge of the acute and chronic dosages that would be
dangerous to man. Although the acute oral toxicity is similar to
that of parathion, the dermal toxicity is considerably lower than
that of most other highly toxic organophosphorus pesticides. This
difference may account for the better safety record of Guthion.
Dogs that were fed diets containing 20 ppm of Guthion for 12
weeks exhibited no toxic symptoms, although their red blood cell
cholinesterase was depressed to about 80% of normal.
Signs and Symptoms of Poisoning in Man: No fatal cases of poison-
ing with Guthion are known. People with occupational exposure
have an excellent safety record similar to that of people using
malathion.
Other Toxicology: The toxicology of Guthion is similar to that of
the organic phosphorus compounds generally. See pages 12 to 23.
Chemical Name: 0,0-dimethyl S-(l,2-dicarbethoxyethyl)
phosphorodithioate.
Chemical Formula: CH3^X§
P-
/P-S-CH-C-O- C2H$
| g
CH2-C-O- C2H5
31
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Formulations: Malathion is available as technical grade material,
wettable powder (25%), dusts, solutions, poison baits, and emulsi-
fiable concentrates.
Uses: Malathion is used in the control of certain pests of fruits,
vegetables, and ornamentals. As a public health pesticide, it has
been employed for the control of house flies, mosquitoes, and lice.
For fly control, malathion is used in liquid and dry baits.
Routes of Absorption: Malathion is absorbed by all portals, but
skin absorption is inefficient (see below).
Pharmacologic Action: Much of the malathion taken into the mam-
malian body is broken down, chiefly in the liver, into harmless
materials, but some is converted into compounds that inhibit cho-
linesterase and, therefore, may produce the characteristic signs
and symptoms caused by other organic phosphorus compounds (see
page 15). Massive doses of malathion produce temporary muscular
weakness in chickens, which, like man, are susceptible to this
kind of effect. Affected chickens continue to show this paresis for
up to three weeks after full recovery from the ordinary signs of
malathion poisoning. Moderate doses produce no such effect, and
the compound is practical for the control of ectoparasites of
chickens. The mechanism by which the muscular weakness is pro-
duced is not known, but it is clearly not identical to that responsi-
ble for other poisoning. The muscular weakness, such as that seen
in chickens, has not been seen in human cases (perhaps because of
dosage); its relationship to the coma and flaccidity seen in some
human cases is not known.
Dangerous Single and Repeated Doses to Man: A dose of only about
4 g. of malathion produced severe but nonfatal illness in a child
who drank it, and a dose of 14 g. had a similar effect on a woman.
On the contrary, an amount estimated at 5 g. led to the death of a
75-year-old man about 1.5 hours after ingestion. A second fatality
resulted from an estimated 56.7 g. of malathion. All confirmed
cases, whether fatal or not, have involved proved or possible in-
32
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gestion as determined by history or the finding of malathion in
stomach washings, or both. Five cases reported as malathion
poisoning presumably involved dermal or respiratory exposure.
These cases show little clinical resemblance to confirmed cases
or to one another. An oral dose of 58 mg. taken experimentally
produced no clinical effect and 23% of the dose was recovered in
the urine. A total of 1106 mg. was recovered from the urine of a
man who barely recovered following attempted suicide.
The repeated dosage of malathion necessary to produce clini-
cal illness in man is unknown. Experiments have shown that people
can eat 16 mg. of malathion daily without significant depression
of cholinesterase or any clinical effect. A dosage of 24 mg. per
day for 56 days produced a maximal reduction of 25% in both plasma
and red blood cell cholinesterase. Ten percent malathion powder
was applied daily to essentially all the human skin, and an average
of 2% of the available dose was recovered in the urine. When this
dosage was repeated daily, an average daily excretion of 51.5 mg.
of malathion-equivalent was recovered. The maximal rate of ex-
cretion measured in this way with no clinical side effects was
229 mg. per day. The rate of malathion absorption was undoubtedly
somewhat greater than the rate of recovery of malathion-equivalent
in the urine. Very extensive use of malathion has not led to de-
pletion of blood cholinesterase in applicators. The threshold limit
value for malathion in air is 15 mg./M3.
Signs and Symptoms of Poisoning in Man: Broadly speaking, the
signs and symptoms observed in poisoning by other organic phos-
phorus compounds have been seen in poisoning by malathion.
However, sudden coma (characterized by unconsciousness and
marked flaccidity of the limbs, but without cardiovascular collapse
and with minimal interference with respiration) occurred in several
cases that went on to uneventful recovery. (A similar flaccidity
with minimal interference with respiration has been reported more
rarely in people poisoned by parathion.) In at least one case of
malathion poisoning, coma was recurrent. Involuntary defecation
and urination occurred during coma in several instances. Some
33
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patients seemed to respond promptly to atropine sulfate, while
others showed less response than might be expected. Cholinester-
ase was only moderately depressed when illness was severe, but
was severely depressed in a fatal case in which the measurement
was made. Thus, there is more than a hint that poisoning by mala-
thion is characterized in man by "side effects" not seen in poison-
ing by inherently more toxic organic phosphorus compounds. In any
event, it is clear that a relatively large dose of malathion is re-
quired to produce illness and that the chances of recovery from
this illness are better than might be judged from the clinical ap-
pearance of the patient.
Laboratory Findings: In the few cases in which blood cholinester-
ase was measured, the red cell and plasma enzymes were about
40% to 50% of normal, which was higher than the clinical severity
of the cases would have led one to predict.
Treotmenf ond Other Toxicology: See pages 18 to 23.
Methyl parathion
Chemical Name: 0,0-dimethyl O-(p-nitrophenyl) phosphorothioate.
ff
Chemical Formula: CH3-O S
CHj-O
Formulations: Methyl parathion is available as 70% solution, 24%
to 51% emulsifiable concentrates, and 25% dust concentrate. It is
applied in the form of dilute sprays or dusts (1.5% to 5%).
Uses: Control of agricultural pests.
Routes of Absorption: Methyl parathion may be absorbed by any
route.
34
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Toxicology: The dangerous dose is not known. An oral dosage of
7.0 mg. daily for 24 days (approximately 0.1 mg./kg./day) produced
no significant effect on red cell cholinesterase and only about 15%
inhibition of the plasma enzyme of volunteers. All confirmed cases
of human poisoning have had substantial exposure. In what may
have been the only fatal case, the compound was recovered from
the stomach and must have been ingested. Animal experiments
indicate a somewhat lower dermal toxicity than that for parathion.
This finding may be a factor in explaining the relatively good
occupational safety record of methyl parathion. For treatment and
other aspects of toxicology, see pages 18 to 23.
Parafhion
Chemical Name: 0,O-diethyl O-(p-nitrophenyl) phosphorothioate.
Chemical Formula; C2H,-Ox
C2H,-0'
Formulations: Parathion is currently used as dilute sprays, which
are prepared by the operator from 15% or 25% wettable powders or
from emulsifiable concentrates of 50% or less. Dusts are used also.
They may be purchased ready mixed in concentrations of 5% or
less. Technical parathion, which is a deep brown to yellow liquid
and approximately 98% pure, may be encountered under industrial
conditions and in formulating establishments. Aerosol formulations
containing up to 10% parathion may be used in greenhouses. Cords
impregnated with parathion for fly control contain about 100 mg. per
linear foot.
Uses: Parathion finds almost its entire use in agriculture including
nurseries, greenhouses, etc. Persons exposed occupationally to
parathion may be engaged in synthesizing the compound, formula-
35
-------
ting and packaging it, applying it, or working among residues. Even
those workers whose only contact has been with fresh residues
have occasionally been poisoned. This has been noted among such
crop workers as thinners, harvesters, and irrigators. Accidental ex-
posure of children to open or even "empty" containers has been a
major and dramatic source of fatal poisonings.
Under practical field conditions, agricultural workers may have
approximately concurrent exposure to two or more organic phos-
phorus pesticides. The patient may recall only the most recent use
of the most advertised formulation; a careful history is necessary
to reveal the facts.
Routes of Absorption: Absorption takes place readily through any
portal. Fatal human poisoning has followed ingestion, skin ex-
posure, and also inhalation with varying degrees of skin exposure.
The vapor pressure of parathion is so low that respiratory exposure
alone is not considered important as a cause of serious poisoning
from wet sprays. Respiratory exposure to finely particulate dust is
hazardous; complete respiratory protection has reduced illness
among formulating plant workers. Aerosol preparations are known
to be highly dangerous.
Pharmacologic Action: See page 12.
Dangerous Single and Repeated Doses to Man: Death has followed
splashing of the body and clothing of one worker with technical
parathion (approximately 95% pure). The amount was sufficiently
small that the worker was not soaked or at any rate did not follow
the simple instructions for changing clothes and bathing. Several
operators have died after rather extensive skin contact with -dilute
agricultural sprays or dusts. Children 7 to 9 years old were killed
by bathing in a tub in a house that had been sprayed several days
earlier with 10% parathion intended for ornamental plants in a
greenhouse. Other children died after swinging on a parathion con-
taminated bag suspended by a rope. Both children and adults have
been poisoned by parathion applied with the intention of controlling
head lice or other lice.
36
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In a number of fatal cases of human poisoning by parathion,
the dosage which the victim received orally was known to be
exactly 900 mg. In one carefully studied case, the ingestion of
120 mg. led rapidly to death of a man. Children 5 to 6 years old
were killed by eating 2 mg. of parathion, a dosage of about 0.1
mg./kg. In instances in which parathion contaminated food eaten
by people of different ages, death occurred mainly or exclusively
among children.
A daily oral dose of 7.2 mg. produced a 33% fall in whole
blood cholinesterase of adult volunteers in 42 days. A dose of
3 mg./day produced no effect. The established threshold limit for
parathion in air is 0.1 mg./M3.
Laboratory Findings: See page 16. Under certain circumstances,
parathion may be isolated from exhumed bodies as well as fresh
necropsy specimens.
Treatment and Other Toxicology: See pages 18 to 23.
Phorate
Chemical Name: 0,0-diethyl S-(methylthio-ethyl)phosphorodithioate.
Chemical Formula: C2H5-O S
/P-S-CH2-S-C2H5
C2H5-0
Formulations: Carbon impregnated with 44% phorate.
Uses: Seed treatment of cotton and legumes.
Dangerous Single and Repeated Doses to Man: The dangerous dose
of phorate for man is unknown but obviously small.
Signs and Symptoms of Poisoning in Man: The signs and symptoms
described on page 15 have occurred in cases associated with
37
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phorate. One patient suffered occasional convulsions and a severe
fall in blood pressure. He required artificial respiration but ulti-
mately recovered.
Treatment and Other Toxicology: See pages 18 to 23.
Phosdrin
Chemical Name: alpha isomer of 2-carbomethoxy-l-methylvinyl
dimethyl phosphate.
Chemical Formula: CH3-O O CH3 fl
/P-O-C = CH-C-O-CHj
CHj-O
Formulations: Technical Phosdrin contains not less than 60% of
the alpha isomer listed above, the remainder being insecticidally
active related compounds. It is available as approximately 25%
and 50% concentrates, 25% water-soluble solutions, 1% and 2%
dusts, 1% and 2% granules, and 20% to 25% wettable powders.
Pharmacologic Action: Phosdrin is a direct inhibitor of cholines-
terase. It, therefore, shares with TEPP the unusual property of
causing miosis in the presence of mild or even no systemic illness.
It is also distinguished by its ability to cause other local effects
and by its high toxicity and rapid onset of systemic symptoms.
Dangerous Acute and Repeated Doses to Man: The dangerous dose
of Phosdrin for man is unknown. However, animal experiments and
human cases show that it is very small. The tentative threshold
limit value for Phosdrin in air is 0.1 mg./M3.
Signs ond Symptoms of Poisoning in Man: Most observed cases
have been occupational in origin. In general, the signs and symp-
38
-------
toms described on page 15 have been seen, but presence of visual
disturbance and rapidity of onset have been noteworthy and are
probably associated with direct inhibition of cholinesterase. Illness
has begun within 15 minutes of spillage of the insecticide and
within 45 minutes of first exposure.
Treatment and Other Toxicology: See pages 18 to 23.
Schradai
Chemical Name: octamethylpyrophosphoramide
Chemical Formula: CH3^
Formulations: Sprays and aerosol bombs (7%). Concentrations as
high as 42% are available.
Uses: Schradan is a systemic insecticide absorbed by plants and
translocated to all parts for the control of sucking insects.
Dangerous Single and Repeated Doses to Man: Apparently, human
illness as the result of exposure to schradan has not been re-
ported. The ingestion of Img. of schradan per day caused a gradual,
asymptomatic depression of blood cholinesterase (especially red
cell enzyme) in 24 volunteers. The depression was maximal (25%
in whole blood) after about 40 days. The ingestion of 4.2 mg. of
schradan per day by one subject caused a maximal depression of
whole blood cholinesterase (67%) after about 60 days of the 74-day
exposure period. Patients with myasthenia gravis have been main-
tained on doses of 7 mg. every 12 hours for months with apparent
39
-------
benefit and on doses of 15 mg. every 12 hours with some signs of
intoxication.
Treatment and Other Toxicology: See pages 18 to 23.
TEPP
Chemical Name: tetraethyl pyrophosphate.
Chemical Formula: C2H,-O. o o x°-C2Hs
\» n/
P-O-P
C
--
2H5-
-------
lessness, such as taking the compound by mouth or spilling a
concentrate of it on the skin. The dosages in such cases are, of
course, unknown. Several persons, including children, have died
after spilling the concentrated material on their skin. A number of
nonfatal accidents have been reported among agricultural workers
and airplane pilots who were making agricultural application of the
insecticide. Some experience has been had in man in connection
with the treatment of myasthenia gravis. A single dose of 5 mg., or
3.6 mg. daily for 2 days, or 2.4 mg. daily for 3 days parenterally;
or 7.2 mg. every 3 hours orally for S to 5 doses, produced symptoms
in normal subjects as did slightly larger doses in myasthenia
gravis patients receiving atropine sulfate. Symptoms at these
relatively low dosages included localized fasciculations, anorexia,
nausea, sweating, abdominal cramps, salivation, giddiness, rest-
lessness, insomnia, paresthesias, and dreaming. Symptoms ap-
peared suddenly about 30 minutes after the final dose.
Evidence has been obtained that 5 mg. intramuscularly or 25
mg. orally would cause severe symptoms. Likewise, it is believed
that 20 mg. intramuscularly or 100 mg. orally would cause death.
It will be noted that the single oral dose of 25 mg. per man men-
tioned above represents a dosage of only about 0.35 mg./kg.
The threshold limit value for TEPP in air is 0.05 mg./M3.
Signs and Symptoms of Poisoning in Man: In addition to the sys-
temic poisoning effects listed on page 15, the following local
effects should be mentioned. Since TEPP is a direct inhibitor of
cholinesterase, it may produce ophthalmic and possibly pulmonary
signs and symptoms without accompanying systemic illness. The
picture produced by ophthalmic instillation of 0.1% technical TEPP
in peanut oil consisted of excess lacrimation, rhinitis, burning,
mild blurring of vision, mild headaches, sensations of pressure in
the eyeballs or over the frons and, within 20-30 minutes, pin-point
pupils with accompanying increased accommodation and diminished
light perception. Most of these signs and symptoms disappeared in
a few hours, but considerable miosis persisted for 24 hours and the
effects were not all gone after 48 hours. When instillation was
limited to one eye, resulting in unilateral miosis, the volunteers
41
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complained of disturbance of depth perception even though they
passed standard tests of static depth perception. This complaint
was due to the production of the Pulfrich phenomenon brought on by
the unequal light in the two eyes. Similar effects, especially
miosis, have occurred in agricultural workers, including pilots, who
were exposed in the course of their work.
There is evidence, especially with dusts, that there may be
signs of TEPP poisoning restricted to the respiratory system.
Rhinitis and a sensation of tightness in the chest may be due
entirely to the localized effect of the TEPP. Local effects from
parathion or demeton are less apparent.
Laboratory Findings: See page 16.
Treatment and Other Toxicology: See pages 18 to 23.
Trichlorofon
Chemical Name: 0,0-dimethyl,2,2,2-trichloro-l-hydroxyethyl
phosphonate.
Chemical Formula: CH3-OO OH
P- CH-CC1,
CH3-O
Formulations: Trichlorofon is available as a 1% dry bait for fly
control. Other formulations are 50% wettable powder, 5% dusts and
granules, and fly disks each of which contains 0.1 g.
Uses: This material is used in dairy barns and milk processing
rooms as a poison bait for fly control. It is also used for control of
roaches and a variety of insect pests of field crops and ornamen-
tals. More recently the compound has been used, either as an oral
dose or spray for control of cattle grubs, horse bots, screw worms,
various arthropod ectoparasites, and several nematode worms.
42
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Routes of Absorption: Trichlorofon is readily absorbed through the
skin as well as by other routes.
Pharmacologic Action: See page 12. Trichlorofon is a weak direct
inhibitor of cholinesterase. It differs from other compounds in this
group with respect to the very rapid recovery from symptoms of sub-
lethal poisoning noted in experimental animals.
Dangerous Single and Repeated Doses to Man: A highly purified
trichlorofon formulation given in two doses of 7.5 mg./kg. on suc-
ceeding days to 15 volunteers (a total dose of 1,050 mg. for a 70
kg. man) produced nausea, colic, and sweating in one and no ill-
ness in the others. The affected person recovered after a single
dose of atropine sulfate. The plasma cholinesterase level fell to
below 10% of normal, and the red cell cholinesterase fell to about
50% in all the subjects. Later, this same dosage was used ex-
tensively for the treatment of intestinal worms with infrequent
and mild side effects.
Other Toxicology: Taking into account the high dosage of tri-
chlorofon necessary to produce poisoning in man or animals, and
also taking into account the rapidity of recovery, the toxicology of
trichlorofon is otherwise similar to that of the organic phosphorus
insecticides generally. For treatment and other aspects of toxi-
cology, see pages 18 to 23.
-------
CARBAMATE INSECTICIDES
Carbary!
Chemical Name: 1-naphthyl-N-methylcarbamate
Chemical Formula: O ,H
Formulations: Carbaryl is manufactured as a 98% concentrate which
is formulated for use as dusts (1.75% to 10%), wettable powders
(50% to 80%), and flowable formulations (40% to 50%).
Uses: Carbaryl is a wide spectrum insecticide effective against
insect pests of fruits and nuts, vegetables, forage crops and cotton,
and forest and range land.
Routes of Absorption: Carbaryl is absorbed by all portals including
the skin.
Pharmacologic Action: The carbamates are reversible inhibitors
of cholinesterase. The reversal is so rapid that, unless special
precautions are taken, measurements of blood cholinesterase of
people or animals exposed to carbamates are likely to be inaccurate
and always in the direction of appearing to be normal. The com-
pound is rapidly metabolized. The naphthalene moiety is excreted
as 1-naphthol, largely in a conjugated form. Concentrates may
cause skin irritation as well as systemic poisoning.
Dangerous Acute and Repeated Doses to Man: A single, carefully-
measured oral dose of 250 mg. (approximately 2.8 mg./kg.) resulted
44
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in moderately severe poisoning of an adult. The smallest dosage
that will produce illness in man following prolonged exposure is
not known. Because of the rapid metabolism, the dangerous re-
peated dose may be only slightly smaller than the dangerous single
dose. Workers exposed to carbaryl dust, sometimes at concentra-
tions as high as 40 mg./M 3 under abnormal conditions but usually
at lower concentrations, showed a slight depression of blood
cholinesterase but no illness. Dogs were acutely poisoned when
exposed in a chamber at a concentration of 75 mg./M 3 for 5 hours.
In the male rat, the oral LD is 850 mg./kg. and the dermal
LD is >4,000 mg./kg. Carbaryl was fed to'male and female rats
5 0
for 92 days at levels as high as 225 to 237 mg./kg./day without
significant effect on food consumption, rate of growth, or level of
plasma or red cell cholinesterase. Single oral doses at the highest
level depressed the plasma and red cell cholinesterases but the
activities of these enzymes came back to normal within 16 hours.
Signs and Symptoms of Poisoning in Man: A 19-month old infant
developed constriction of the pupils, salivation, and muscular in-
coordination in spite of gastric lavage within half an hour after
ingestion of an unknown amount of carbaryl. A single 0.3 mg. dose
of atropine sulfate was effective, and recovery was apparently
complete in 12 hours. The man who swallowed 250 mg. of carbaryl
had a very sudden onset of violent epigastric pain 20 minutes after
the dose. A little later he began to sweat profusely. A 1 mg. dose
of atropine sulfate produced little improvement although he was
still able to continue work. He gradually developed great lassitude
and vomited twice. One hour after ingesting carbaryl, and following
a total of 3 mg. of atropine sulfate, he was feeling better. After one
more hour he was completely recovered and enjoyed lunch.
Laboratory Findings: Blood cholinesterase is inhibited; it should
be measured by a technique that minimizes reactivation. 1-Naph-
thol, a compound normally present only in traces, is excreted in
the urine following absorption of carbaryl. A specimen collected 18
hours after poisoning from the infant mentioned above contained a
45
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concentration of 31.4 ppm. Healthy men with occupational ex-
posure have been found to excrete conjugated plus free 1-naphthol
at a rate of 10 ppm or slightly higher, while unexposed men excrete
1.5 to 4.0 ppm.
Treatment: Depending on the severity of the case, all the methods
used for treating poisoning by organic phosphorus compounds are
useful with one exception: 2-PAM and other oximes are not recom-
mended for routine use. Animal studies indicate that the use of 2-
PAM might be harmful. Although people might not show the same
reaction, no oxime should be used for treating poisoning by a
carbamate insecticide except on an investigational basis.
46
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CHLORINATED HYDROCARBON INSECTICIDES
Introduction: The chlorinated hydrocarbon insecticides have in
common the chemical composition implied in the group name.
However, beyond this broad similarity, the compounds vary widely
in chemical structure and activity. Although much is known about
the pharmacology of these materials, the basic mode of action is
not known for a single one of them. It is entirely possible that
chlorinated hydrocarbon insecticides of significantly different
chemical structure have different modes of action; it is certain
that there are qualitative as well as quantitative differences in
their pharmacologic action.
The acute oral and dermal LD -values to rats of certain
so
chlorinated hydrocarbon insecticides and derivatives including
those treated in this Handbook are given in the table (page 48).
The following description, based largely on DDT, is appli-
cable to the chlorinated hydrocarbon insecticides as a group. The
actions known to be peculiar to specific compounds are described
in the separate sections.
.Pharmacologic Action: The chlorinated hydrocarbon insecticides
act on the central nervous system, but the exact mechanism of
this action either in man or in animals has not been elucidated.
Large doses also induce nausea and/or diarrhea. On repeated dos-
age, the compounds produce microscopic changes in the liver and
kidneys in some experimental animals. This has not been demon-
strated clearly in man in connection with uncomplicated poisoning.
Somewhat different lesions may be produced in man or animals by a
single fatal dose.
The compounds and/or certain degradation products are stored
in fat. Such storage results either from a single large dose or from
repeated small doses. The materials stored in the fat appear to be
largely inactive, since the total amount stored in an experimental
animal often may be greater than the lethal dose if given at one
time. The insecticides (or their derivatives) usually may be demon-
47
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ACUTE ORAL AND DERMAL LD5()-VALUES OF
CHLORINATED HYDROCARBON INSECTICIDES FOR
MALE AND FEMALE WHITE RATS
COMPOUND
Aldrin
Chtordane
Chlorobenzilate
DDA +
DDE +
DDT
Dieldrin
Dilan
Endrin
Heptachlor
Isodrin
Keif hone
Lindane
Methoxychlor
Perthane
TDE (ODD)
Thiodon
Toxophene
ORAL LD50 (MG./KG.)
MALES
39*
335*
1040*
740*
880*
113*
46*
-
17.8*
100
15.5*
1100*
88
(6000.0)**
> 4000*
(3400)**
43*
90*
FEMALES
60*
430*
1220
600
1240*
118*
46*
_
7.5*
162
7.0*
1000*
91
-
> 4000*
_
18*
80*
DERMAL LD50 (MG./KG.)
MALES
98*
840*
—
_
_
-
90*
6900*
_
195
35*
1230*
1000
-
-
-
130*
1075
FEMALES
98*
690*
_
_
_
2510*
60*
5900*
15*
250
23*
1000*
900
>6000*
—
_
74*
780
*These values were determined by the Chamblee Toxicology Laboratory under standardized
conditions.
**Sex not specified.
^Metabolite of DDT.
strated in milk and urine. The compounds stored in the fat are
eliminated only very gradually when further dosage is discontinued.
Laboratory Findings: Laboratory findings are usually negative and
always nonspecific except that the insecticide or its derivatives
may be demonstrated in stomach contents, urine, or tissues, es-
pecially fat. See Appendices B and D.
Pathology: In experimental animals killed by large doses of chlori-
nated hydrocarbon insecticides, dilatation of blood vessels and
48
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even small petechial hemorrhages secondary to convulsions may be
encountered. The outstanding changes following repeated DDT
feeding in rodents are found in the liver. These changes consist of
centrolobular hypertrophy, margination of cytoplasmic granules,
fatty infiltration, and iipospheres formed by proliferation of smooth-
contoured endoplasmic reticulum. Similar changes occur in combi-
nation following exposure to other chlorinated hydrocarbon insecti-
cides and occur separately following a wide variety of toxicants.
These changes have not been found in the higher animals nor in
man. All species show liver cell necrosis but only at very high
levels of dosage. Here again the changes are in no way specific.
Differential Diagnosis: Nervous symptoms and convulsions entirely
similar to those of chlorinated hydrocarbon insecticide poisoning
may be induced by a variety of economic poisons as well as by
even less specific neurologic disease. If maximal symptoms are
not reached within a matter of a few hours after acute exposure,
then another diagnosis or some complicating factor should be
sought. Even if it is known that an insecticide has been taken, the
effect of the solvent should be carefully considered. (See section
on solvents, page 114.)
Treatment: Depending on the condition of the patient, attention
should first be given to sedation or to the removal of poison which
may have been taken internally. Syrup of ipecac, gastric lavage,
and saline laxatives may be used. Oil laxatives should be avoided,
for they promote absorption of these insecticides and of many
organic solvents. Removal of poison from the skin is important
also; it is done best with soap and water.
While antidotes discovered in animal tests can be expected to
provide protection-for poisoned human beings, it is not always easy
to draw conclusions regarding human dosage from such tests. In
general, the dosage of antidotes employed successfully in animals
exceeds that considered safe in human practice. The following
recommendations are necessarily based on the results obtained
from the administration of likely antidotes to warm-blooded animals
49
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(including monkeys) previously dosed with lethal amounts of
insecticide:
Phenobarbital, which has been used in doses up to 0.7
g. per day in epilepsy, and pentobarbital (0.25 to 0.5 g.)
are the barbiturates known to control convulsions of
central origin. The object of sedation is not to induce
sleep but to restore a relative calm; however, the proper
dosage in the presence of poisoning may be so large that
it would induce anesthesia if poisoning were not present.
Calcium gluconate has been used iess than the other
antidotes. It is reported to control convulsions caused by
chlorinated hydrocarbon insecticides in experimental
animals, and it has seemed helpful in a few human cases.
Since its mechanism of action is entirely different, it may
be used in addition to sedatives.
Epinephrine is contraindicated. It sensitizes the heart,
predisposing to serious arrhythmias and th.us to death.
BHC
Chemical Name: 1,2,3,4,5,6-hexachlorocyclohexane.*
Chemical Formula:
Formulations: In addition to the technical grade material,* solu-
tions, emulsions, wettable powders, dusts, and poison baits are
* The commercial product has about the following isomeric composition: alpha, 65% to
70%; beta. 6% to 8%; gamma, 12% to 15%; delta, 2% to 5%; epsilon, 3% to 7%; other
isomers and related compounds, 2% to 3%.
50
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available. Lindane* is used in many formulations, especially
those for household use.
Uses: BHC is widely used in the control of cotton insects. As a
1% powder lindane is used for the control of body lice which are
resistant to DDT. BHC has been used for the control of other
insects of public health importance particularly in the countries
under British influence, and it has found some use for this purpose
in the United States. Some household preparations contain BHC or
lindane, and it has been used to some extent for the control of
DDT-resistant flies and mosquitoes. In some areas, lindane is
extensively used for termite control.
Routes of Absorption: BHC may be absorbed through any portal
including the skin. The material is a local irritant, but this property
is inversely proportional to the purity of the sample.
Pharmacologic Action: The several isomers of BHC have different
actions. The gamma and alpha isomers are stimulants to the cen-
tral nervous system, the principal symptom being convulsions. The
beta and delta isomers are depressants of the central nervous
system.
Dangerous Single Dose to Man: The dangerous single dose of the
technical mixture has been estimated at about 30 g. and the danger-
ous dose of lindane at about 7 to 15 g. These estimates may be too
high, for a young man suffered serious illness including a convul-
sion following a single carefully-measured dose of 45 mg. of lin-
dane intended as a vermifuge. He was one of 15 patients treated
with a highly dispersed emulsion at an intended dosage of 45 mg.
(30 mg. for the last of the series) three times a day for 3 days. Of
the 15 patients, 6 showed some toxic symptoms. It is true, that in
similar studies of the potential use of benzene hexachloride as a
drug, other persons have withstood larger doses, especially of
* Lindane is the accepted common name for essentially pure gamma isomer of benzene
hexachloride.
51
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undissolved or poorly dispersed material, apparently without seri-
ous effect. These observations are summarized in the table be-
low. In these studies, it was found that a mixture of isomers
burned the tongue and the unpurified mixtures were highly irritative.
The fatal poisoning of a 5-year-old girl weighing about 55
pounds was caused by the accidental ingestion of 4.5 g. of BHC as
a 30% solution in an unspecified organic solvent. This represents
a dosage of 180 mg./kg. In spite of evacuation of her stomach and
therapy to restore failing circulation, she died.
Formulation
(Percent Gamma
Isomer)
Dosage
Effect
10-30
60-85
100
40 mg./day,
10 days
40 mg./day,
14 days
110 mg./day,
repeated
40 mg./day,
14 days
45 mg. t.i.d., 3 days.
Diarrhea after 8th day.
No effect observed.
Diarrhea after 6th day.
No effect observed.
No effect observed.
(20 patients)
180 mg./day,
repeated
Dizziness and diarrhea
after several days.
A number of children have been poisoned by eating as little as
a part of one (0.33 g.) tablet of lindane intended for use in thermal
vaporizers. At least three 1.4 to 1.5-year-old children have been
killed by eating larger amounts of lindane intended for this purpose.
The dosage in one case was thought to be 7 g. In one other case, it
was an unknown multiple of 0.8 g. (the weight of one tablet).
52
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The use of thermal vaporizers with Lindane has caused some
clear-cut instances of respiratory poisoning. For example, two
refreshment stand operators suffered severe headache; nausea; and
irritation of eyes, nose, and throat shortly after exposure to lindane
vapors from a dispenser in which the insecticide apparently became
overheated. The symptoms abated 2 hours after the device was
removed. Overheated lindane is more apt to cause respiratory dis-
tress than is lindane vaporized at lower temperatures. This is true
because the greater heat releases more of the compound and also
causes some splitting of the molecule into highly irritating decom-
position products.
It is interesting to note that lindane shows a marked difference
in toxicity to different species. Its toxicity to laboratory animals
is less than that of DDT, but for several domestic animals, notably
calves, lindane is more toxic than DDT or even dieldrin.
Dangerous Repeated Dose to Man: There are no confirmed cases of
systemic poisoning in man as a result of repeated exposure to BHC.
It is interesting to note that in laboratory animals the gamma
isomer has by far the greatest acute toxicity, but its relatively
rapid excretion by the kidneys does not permit extensive accumu-
lation in the body, and the gamma isomer shows the lowest toxicity
on repeated exposure. The highest toxicity following repeated
dosage and the lowest acute toxicity are shown by the beta isomer,
which has no insecticidal importance but forms a part of those
formulations prepared from technical grade BHC. The use of lin-
dane, therefore, is favored not only because it is the most effective
form of BHC for killing insects, but also because it probably pre-
sents a relatively low toxicity to workers who have long, intensive
exposure.
Dermatitis and perhaps other manifestations based on sensi-
tivity have been observed in human beings. Dermatitis has been
reported in workers who came in contact with BHC and its pre-
cursors during manufacture without proper hygienic precautions.
Shortly after a lindane vaporizer was installed in her place of
employment, a 35-year-old woman developed urticaria. The dermati-
-------
tis improved during weekends, but recurred when she returned to
work. Patch tests were positive. Complete elimination of exposure
resulted in permanent recovery. For a more extended discussion
see articles by the A.M.A. Committee on Pesticides: Health haz-
ards of electric vaporizing devices for insecticides. J.A.M.A. 149:
367-369, May 1952; Health problems of vaporizing and fumigating
devices for insecticides; a supplementary report. J.A.M.A. 152;
1232-1234, July 1953; and Abuse of insecticide fumigating devices,
J.A.M.A. 156:607, October 1954.
The threshold limit value for lindane in air is 0.5 mg./M3.
Signs and Symptoms of Poisoning in Man: In 3 of the fatal cases,
symptoms began 1 to 2 hours and death followed 12 hours or less
after BHC was ingested.In another case, symptoms began 3.3 hours
and death occurred 80 hours after ingestion. Illness was character-
ized by repeated, violent, clonic convulsions, sometimes super-
imposed on a continuous tonic spasm. Respiratory difficulty and
cyanosis secondary to the convulsions were common. In some
cases, the victim screamed during convulsions as if in terrible
pain. In at least one case, the rectal temperature reached 103° F.
Insofar as records are available, heart and respiratory failure ap-
peared to be simultaneous. In the nonfatal cases, signs of hyper-
irritability have differed only in degree.
Men acutely exposed to high air concentrations of lindane
and its decomposition products show headache, nausea, and irrita-
tion of eyes, nose, and throat.
Urticaria has followed exposure to lindane vapor in rare in-
stances. Unlike the signs and symptoms already mentioned, this
allergic manifestation occurs only in susceptible individuals,
apparently only after a period of sensitization.
Blood dyscrasias have been attributed to BHC rarely. How-
ever, they probably have been attributed more frequently to it than
to any other modern pesticide including those used in greater
tonnage. About half the reported cases happened in one European
country. It is possible that the occurrence of traces of impurities
or some other differences of formulation account for the peculiar
distribution of alleged cases. The same may be said about cases of
54
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nervous disorder in men working with BHC in another European
country. The relationship between these disorders of the blood and
the nervous system and BHC is not fully established even in con-
nection with large doses.
Laboratory Findings: In one case, the following concentrations of
lindane were found at autopsy: fat, 343 ppm; liver, 88 ppm; stool,
478 ppm; and stomach contents, 105,000 ppm.
Pathology: In the case of a 1.5-year-old boy who ingested lindane
with no solvent or other toxicant present, the gross findings in-
cluded congestion of the lungs and kidneys, distention of the
intestinal tract, and a reddish yellow appearance of the liver.
Microscopically, the lungs showed edema, congestion, and broncho-
pneumonia. The liver exhibited fatty metamorphosis, and the kid-
ney tubules revealed degenerative changes. There were tiny
hemorrhages in the brain associated, at least in some instances,
with necrosis in the walls of the small blood vessels. The change
in the lung appeared to be consistent with aspiration pneumonia.
The liver changes were more prominent than those seen in labora-
tory animals under similar conditions. The findings were similar
in two other cases in which pathology was reported.
Chlordane
Chemical Name: l,2,4,5,6,7,8,8-octachloro-3a,4,7,7a-tetrahydro-4,7-
methanoindane.*
Chemical Formula:
H
Cl
Cl
* The technical grade chlordane consists of the A and B chlordsne, heptachlor, and trlchlor
in addition to related materials and a small percentage of hexachlorocyclopentadiene.
55
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Formulations: Chlordane is commercially available as wettable
powders, emulsifiable concentrates, oil solutions, low percentage
dusts, and technical chlordane. Technical chlordane is available in
two grades — refined and agricultural. Both grades appear essen-
tially equal in their insecticidal properties. The agricultural grade
may be used wherever the staining of treated surfaces is not a
problem. The refined grade is generally used for the control of
household insect pests.
Uses: Chlordane has been found useful in agriculture. It was used
rather extensively for control of flies and mosquitoes in Italy,
Sardinia, and Greece until resistance developed. It is found in a
number of household formulations sold in this country, either alone
or in combination with other insecticides.
Routes of Absorption: Chlordane is readily absorbed through the
skin as well as through other portals.
Pharmacologic Action: Chlordane is a stimulant to the central
nervous system; its exact mode of action is unknown. Animals
poisoned by this and related compounds show an extremely marked
loss of appetite about the same time that they show neurological
symptoms. See also page 47.
Dangerous Single and Repeated Doses to Man: Convulsions fol-
lowed by recovery occurred in an infant following a dosage of about
10 mg./kg. and in an adult following 32 mg./kg. The fatal dose for
man has been estimated to be between 6 and 60 g., and clinical
experience indicates that this is essentially correct. One person
receiving an accidental skin application of 25% solution amounting
to something over 30 g. of technical chlordane developed symp-
toms within about 40 minutes and died before medical attention was
obtained. In one patient known to be an alcoholic, death followed
exposure to a low oral dosage of chlordane (2-4 g.). Microscopic
examination of the tissues revealed severe chronic fatty degenera-
tion of the liver, characteristic of chronic alcoholism. Although
56
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this fatality cannot be attributed exclusively to chlordane, it is
consistent with previous observations that the toxicity of some
chlorinated hydrocarbons is much enhanced in the presence of
chronic liver damage.
A woman who ingested 6 g. (104 mg./kg.) of chlordane in talc
with suicidal intent suffered chemical burns of the mouth, severe
gastritis, enteritis, diffuse pneumonia, lower nephron syndrome,
and central nervous system excitation with terminal mania and
convulsions. Death occurred after 9.5 days. The most important
autopsy findings were those of severe necrotizing bronchopneu-
monia, and desquamation and degeneration of the renal tubular
epithelium. The dangerous repeated dose is unknown. The thresh-
old limit value for chlordane in air is 2.0 mg./M3.
Signs and Symptoms of Poisoning in Man: One person poisoned by
chlordane developed convulsions within 40 minutes of gross skin
contamination and died, apparently of respiratory failure, before
medical aid could be obtained. Convulsions and coma may begin
as little as 30 minutes after ingestion, but these signs do not
preclude complete recovery.
Acutely poisoned experimental animals show similar signs.
Experimental animals exposed to repeated small doses exhibit
hyperexcitability, tremors, and convulsions, and those which sur-
vive long enough show marked anorexia and loss of weight. Symp-
toms in animals frequently occur within an hour of the administra-
tion of a large dose, but death often is delayed for several days
depending on the dosage and route of administration. In any event,
symptoms are of longer duration with chlordane than with DDT
under similar conditions.
Laboratory Findings: See page 48.
Pathology: See page 48.
5T
-------
DDT
Chemical Name: 2,2,&zs(p-chlorophenyl)l,l,l-trichloroethane.
Chemical Formula:
Formulations: DDT is available as a technical grade material, as
emulsifiable concentrates of 50% or less, as wettable powders of
25% to 75%, as aerosol bombs, as solutions, as emulsions, and as
dusts of various concentrations. Emulsions and wettable powder
suspensions of 5% are commonly used in residual spray operations.
Dusts frequently contain 10% of DDT. Many commercially avail-
able formulations contain, in addition to DDT, a variety of other
insecticides and one or more solvents or carriers. Increasing use is
being made of various synergists in combination with DDT to over-
come the resistance developed to it by some insects. Many house-
hold insecticide sprays consist of a 5% solution of DDT in purified
kerosene. All the ingredients of these preparations contribute to
their toxicity.
Uses: DDT is probably the most widely used insecticide now avail-
able. It is used for a variety of purposes in agriculture, for the
control of insects of public health and pest significance, and for
various household uses. A 10% dust is employed for the control of
human lice. Because of its very wide use, DDT is more likely to
be encountered than any other single insecticide.
Routes of Absorption: DDT is absorbed from the intestinal tract
and, if it occurs in the air in the form of a very fine aerosol or
dust, it may be taken into the alveoli of the lung from which it is
absorbed readily. DDT is not, however, absorbed through the skin
unless it is in solution. Solutions are absorbed through the skin
and, by the same token, emulsions are absorbed to some extent.
58
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Likewise, fats and oils from whatever source increase the absorp-
tion of DDT by the intestine.
Pharmacologic Action: See page 47.
Dangerous Single Dose to Man: The oral dosage of DDT necessary
to produce illness in man has become rather accurately known. A
single ingestion of 10 mg./kg. produces illness in some but not all
subjects, even though no vomiting occurs. Smaller dosages gener-
ally produce no illness, although a dosage of 6 mg./kg. produced
perspiration, headache, and nausea in a man who was already
sickly and who was hungry at the time of eating the compound.
Those who have shown illness following ingestion of 10 mg./kg.
have not shown convulsions. Convulsions have frequently occurred
when the dosage level was 16 mg./kg. or greater. Dosages at least
as high as 285 mg./kg. have been taken without fatal result. How-
ever, even somewhat smaller dosage levels lead to prompt vomiting,
so that the amount retained is not determinable. After a single
dose, the excretion of DDA in the urine reaches its height within a
day or two and continues at a lower level for several days
thereafter.
Animal studies indicate that DDD and Perthane are somewhat
less toxic than DDT. Methoxychlor is significantly • less toxic
than DDT.
Dangerous Repeated Dose to Man: The minimal daily dosage pro-
ducing illness in man is not known. Experiments with the most
susceptible animals would suggest that some individuals might
show mild illness at a dosage ranging from 2.5 to 5 mg./kg./day.
Although dogs withstand 10 mg./kg./day for years without any
adverse effect, the fact that some human subjects are made ill by
a single dose at this rate shows that man is more susceptible to
DDT than the dog. In studies of volunteers, 40 ate 35 mg. per man
per day (about 0.5 mg./kg./day), 17 for as long as 21 months,
without producing any adverse effect. A dosage of 0.5 mg./kg./day
is about 200 times the daily rate at which the average citizen in
the United States receives DDT in his diet. These volunteers on
59
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the higher dosage level stored from 101 to 466 ppm of DDT after 12
months and 105 to 659 ppm after 21 months. Periodic physical and
laboratory examinations revealed no indication of any clinical
effect of the DDT. An average concentration of about 50 ppm of
DDT in the total dry diet would be required to produce a dosage of
0.5 mg./kg./day. The actual concentration of DDT in prepared
meals is in the order of 0.25 ppm (dry basis), and the consequent
dosage is calculated to be about 0.0026 mg./kg./day.
This dietary DDT is undoubtedly the major source of DDT and
DDE stored in the fat of persons in the general population. Essen-
tially all samples from people in the United States show some
storage. The highest concentrations of DDT-derived material stored
in anyone in recent years with no known occupational exposure
were: DDT, 16 ppm; DDE, 31 ppm. The average storage level for
DDT is less than 10 ppm and for DDE less than 15 ppm.
A higher content of DDT and its derivatives was found in
workers who had occupational exposure. Even concentrations of
DDT as high as 648 ppm and of DDE as high as 434 ppm in the fat
of a man who had formulated DDT for 5 years were not associated
with any detectable injury from DDT. Careful hospital examination
of the workers who had very extensive exposure and who volun-
teered for examination revealed no abnormality which could be
attributed to DDT. Much higher levels than have been found in man
have been observed in the fat of experimental animals which were
apparently asymptomatic.
DDT stored in the fat is eliminated only very gradually when
further dosage is discontinued.
The threshold limit value for DDT in air is 1.0 mg./M3.
Signs and Symptoms of Poisoning in Man: In acute poisoning, the
time of onset depends on the dose; it maybe as little as 30 minutes
after a dose of 20 grams, but is usually 2 to 3 hours, and may be
even longer. The onset is characterized by paresthesia of the
tongue, lip, and part of the face. In more severe poisoning, the
paresthesia may also be detected in the extremities, the proximal
extent of the involvement depending on dosage. The patient soon
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suffers from a sense of apprehension, a disturbance of equilibrium,
dizziness, confusion, and — most characteristic — tremor. In severe
poisoning, convulsions may intervene, and there may be paresis of
the hands. General symptoms include malaise, headache, and
fatigue. Very large doses are followed promptly by vomiting, which
apparently depends on an irritant action of the compound. Delayed
vomiting with or without diarrhea may also follow, but the mecha-
nisms of these actions are not clear. Careful medical examination
during the period of severe symptoms indicates that the pupils are
dilated. Except in severe poisoning the pupils react normally to
light and accommodation, ana the eyes show no nystagmus. Sensi-
tivity to touch and pain are exaggerated in the areas in which the
patient feels paresthesia, and proprioception and vibratory sensa-
tion may be lost in the fingers and toes but not in the more proxi-
mal portions of the arms and legs. Tests to demonstrate coordina-
tion are performed poorly, but the reflexes are normal except when
the dosage has been very large. The pulse may be quickened in
mild poisoning, probably as a nonspecific reaction to discomfort
and apprehension. The pulse is irregular or abnormally slowed
(45-60/min.), or both, in severe poisoning. Blood pressure and
temperature remain essentially normal. Transient jaundice following
a dosage of about 70 mg./kg. was reported by one observer but has
not been seen by others even with higher dosage levels. Except in
the most serious cases, recovery has always been well advanced or
complete in 24 hours. Three persons, who were estimated to have
eaten 20 g. of DDT each, still showed a residual weakness of the
hands after 5 weeks.
There is no well-described case of fatal, uncomplicated DDT
poisoning. In one instance, death followed the taking of an unstated
amount of DDT powder with suicidal intent, but the possible in-
volvement of other poisons was not excluded. A number of deaths
have been reported following the ingestion of DDT solutions. In
these instances, the clinical picture has frequently been character-
istic of solvent poisoning.
Signs and symptoms of chronic poisoning in man are unknown,
although, judging from experimental animals, liver and kidney dys-
61
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functions should be looked for as possible complications of a
disease entirely similar to acute poisoning.
The primary irritancy of DDT to the skin is practically nil,
and it has little or no tendency to produce allergy. Dermatitis
associated with DDT has occasionally been reported. Some cases
involved physical irritation by flying chips, but local or systemic
allergy should be expected to occur in rare instances, and the
possibility should be considered and carefully studied. In no case
should a dermatitis or other disease of allergic origin be ascribed
to DDT without a careful effort to rule out other causes and without
some direct demonstration that DDT is, in fact, involved.
Laboratory Findings: Laboratory findings are essentially negative
except for the presence of DDT and its metabolites, which may be
quantitatively measured by special methods. In any cases of acute
DDT poisoning, the urine should be examined for the presence of
DDA Qfris-(p-chlorophenyl) acetic acidj (See Appendix D). Follow-
ing the ingestion of a single dose of DDT at the rate of 11 mg./kg.,
the highest concentration of DDA reached in the urine of a volun-
teer was 2.24 ppm. Daily ingestion of DDT at the rate of 0.05
mg./kg./day for 270 or more days produced concentrations of 0.02
to 1.98 ppm, while 0.5 mg./kg./day gave 0.36 to 10.56 ppm of DDA.
The single available report indicates a high concentration of DDT
in human organs (but not necessarily fat) following fatal poisoning.
Pathology: See page 48.
Dieldi
Chemical Name:
l,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4a,5,6,7,8,
8a-octahydro-l,4-en<20,ea;0-5,8-dimethanonaphthalene.
62
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Chemical Formula:
H
Formulations: Dieldrin formulations are available as wettable pow-
ders (25% to 75%), dust coventrates (25% to 50%), emulsifiable
concentrates (18%), solutions (0.5%), impregnated pellets (1% to
15%) and as low percentage dusts (alone or in combination with
other insecticides).
Uses: Dieldrin has been used extensively since 1952 for the con-
trol of a variety of agricultural insects and forest pests, especially
in situations where a long-lasting residual effect is advantageous.
It also has been used in several foreign countries as a residual
house spray for control of disease vectors, but has been registered
for limited treatment only of homes in this country to control some
household pests. Dieldrin also is of value in the control of several
species of mosquitoes, ticks, chiggers, and sand flies.
Routes of Absorption: Dieldrin is absorbed readily through the skin
as well as through other portals.
Pharmacologic Action: Dieldrin like many other chlorinated hydro-
carbons acts as a stimulant to the central nervous system; see
page 47. Three syndromes (determined largely by the size and
number of doses) may be recognized: (1) A few large doses produce
increasing stimulation of the central nervous system culminating,
if the dosage is sufficiently high, in one or more convulsions. If
death does not occur, there is relatively prompt recovery without
significant weight loss or other permanent injury. (2) A larger
number of moderate-sized doses may produce without warning a
condition marked by complete loss of appetite, weight loss, and
63
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convulsions. Without treatment, death is apparently inevitable.
(3) Many relatively small doses may produce one or a few convul-
sions with lesser accompanying symptoms that may recur even
though exposure is discontinued. Types 1 and 3 have been observed
repeatedly in man; the occurrence of type 2 in man is unconfirmed,
although it is easily produced in animals. Electroencephalograms
indicate injury to the brain stem.
Dangerous Single Dose to Man: Those persons with the greatest
opportunity for exposure to dieldrin may also have contact with
related compounds, notably aldrin. The effects of dieldrin and
aldrin are similar both quantitatively and qualitatively in animals,
and this appears to be true for man also. Persons exposed to oral
dosages which exceed 10 mg./kg. frequently become acutely ill.
A dosage of about 44 mg./kg. led to convulsions in a child. Symp-
toms may appear within 20 minutes, and in no instance has a latent
period of more than 12 hours been confirmed in connection with a
single exposure.
The most thoroughly described related case involved an at-
tempted suicide by ingesting aldrin at an estimated dosage of
25.6 mg./kg. There have been at least two deaths caused by the
ingestion of undissolved dieldrin and several caused by drinking
emulsions or solutions. The dosage in these cases is unknown.
In animals, the acute dermal toxicity of dieldrin in xylene is
roughly 40 times that of DDT. Tests with certain other solvents
indicate a factor of only about six. An important difference is that
undissolved DDT is not absorbed from the skin but undissolved
dieldrin is readily absorbed.
Dangerous Repeated Dose to Man: Little is known quantitatively
about the toxicity of repeated doses of dieldrin for man. However,
in different countries 2% to 40% of men applying 0.5% to 2.5% sus-
pensions or emulsions at the rate of about 1 g./M 2 have developed
poisoning within 2 weeks to 24 months after first exposure. Most
of the cases were not complicated by contact with insecticides
closely related to dieldrin. Some of the men were exposed to no
other insecticide while some were previously exposed to DDT,
64
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BHC, or chlordane. However, no relevant disease has been re-
ported following similar exposure to these latter three compounds
alone or in combination.
Animals have shown convulsions as much as 120 days follow-
ing the last dermal dose of dieldrin, indicating that dieldrin or its
derivatives and/or residual toxicant-induced injury may persist in
the body for a long time once severe poisoning has occurred.
Entirely similar recurrent illness has been observed repeatedly in
man.
The threshold limit values for aldrin and dieldrin in air are
each 0.25 mg./M3.
Signs and Symptoms of Poisoning in Man: Early symptoms of acute
poisoning include headache, nausea, vomiting, general malaise,
and dizziness. With more severe poisoning, clonic and tonic con-
vulsions ensue or they may appear without the premonitory symp-
toms just mentioned. Coma may or may not follow the convulsions.
Hyperexcitability and hyperirritability are common findings. Follow-
ing repeated exposure some spraymen developed a condition in-
distinguishable from epilepsy — the number of cases being much
greater than could be explained on the basis of idiopathic disease.
Seizures recurred in some men even though they were removed from
exposure. Poisoning characterized by a combination of convulsions,
complete loss of appetite, and severe weight loss has not been
confirmed in man but would probably occur under certain conditions
of exposure. About 6 hours after ingesting dieldrin, a baby suddenly
lost consciousness, became dyspneic and then convulsed. Finally
the convulsions were stopped by treatment, but she remained un-
conscious; the temperature rose to 104° F., cyanosis and tachycar-
dia increased, and the child died 20 hours after exposure.
Aldrin is reported to have caused erythemato-bullous dermati-
tis in a single case.
Laboratory Findings: Findings may be essentially normal except
for the EEC, the presence of insecticide in the tissues, and the
excretion of dieldrin-derived material in the urine. However, the
65
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mere finding of insecticide is not proof of poisoning, for the com-
pound or derivatives have been demonstrated in the blood and
urine of spraymen who were asymptomatic. To be sure, there was a
general parallelism in the results of bioassays on blood and the
presence of poisoning; workers who had had convulsions tended
to show high concentrations of dieldrin in their blood.
Aldrin absorbed into the body is converted to dieldrin and
stored in that form. In one case of acute aldrin poisoning with
complete recovery, dieldrin was found in the fat in a concentration
of 40 ppm. Earlier reports based on older analytical methods indi-
cated lower concentrations in other cases.
In the case in which aldrin was ingested at the estimated rate
of 25.6 mg./kg., laboratory tests indicated transient kidney damage
and questionable liver involvement. The patient responded well to
supportive therapy and showed no residual effects except for.
border-line abnormalities of the electroencephalogram. Later elec-
troencephalographic studies of a series of patients showed specific
changes: bilateral synchronous spikes, spike and wave complexes,
and slow theta waves.
Treatment: In addition to the information on page 49, the following
is of importance. Animal experiments indicate that it maybe neces-
sary to give phenobarbital in large doses over a period of 2 weeks
or more in connection with the syndrome characterized by complete
loss of appetite and severe weight loss. The dosage required to
keep poisoned animals from showing hyperexcitability or convul-
sions and to enable them to eat and behave normally is often a
dosage that would induce sleep or even anaesthesia in a normal
animal of the same species. In human beings the dosage should be
adjusted to the symptoms.
Prevention: Workers applying dieldrin residual sprays indoors or
workers who are otherwise exposed extensively to dieldrin for
relatively long periods of time should be told clearly about the
danger which carelessness may involve. They should be thoroughly
trained in proper methods of handling dieldrin, and they should be
provided with industrial safeguards or protective clothing suitable
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to the conditions of work. Work should be limited to 40 hours per
week. Periodic electroencephalographic examinations may offer a
valuable method for detecting subclinical intoxication.
Dilan
Chemical Name: mixture of 2-nitro-l,l-6es (p-chlorophenyl)
propane (1 part) plus 2-nitro-l,l-5es (p-
chlorophenyl) butane (2 parts).
Chemical Formula:
2-nitro-l,l-&is
(p-chlorophenyl) propane
Prolan (1 Part)
=/NO2-C-H
CH2
CH}
2-nitro-l,l-6is
(p-chlorophenyl) butane
Bulan (2 Parts)
Formulations: Dilan is available as an 80% liquid concentrate,
and as dusts.
Uses: Dilan has been recommended for use in fly control for strains
resistant to other chlorinated hydrocarbons. (Following spraying
directly on skin of cattle, Dilan is excreted in milk in amounts
intermediate between DDT and methoxychlor and, therefore, is not
recommended for use on dairy cattle.)
Dilan is used to some extent as a substitute for pyrethrum
powder in control of agricultural pests.
Routes of Absorption: Toxicity tests in lower animals indicate
that it can be absorbed from the digestive tract. Dilan does not
seem to be absorbed to an appreciable extent through the skin.
6T
-------
Toxicology: In the absence of reported poisoning, the dangerous
dose to man is unknown. Results with animals indicate that the
mixture is considerably less toxic than DDT. In animals, the
signs and symptoms resemble those caused by the other chlorinated
hydrocarbons.
Laboratory Findings: None available.
Treatment: See page 49.
Endrin
Identity: 1,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4:a,5,6,7,8,8a-
octahydro-l,4-tf7u/0-enflfo-5,8-dimethanonaphthalene.
Formulations: Endrin is available as dusts (1.5%), granules (1%),
water-wettable powders (as high as 75%), emulsifiable concentrates
(19.5%) and baits (0.75%).
Uses: Endrin is used for soil insects and foliage insects (with
limitations to prevent residues in the food of man or animals); it
is also used for seed treatments and for the control of mice in
orchards.
Pharmacologic Action: See dieldrin, which has the same action.
Routes of Absorption: Endrin is absorbed by the skin as well as
by the respiratory and gastrointestinal systems.
68
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Dangerous Single and Repeated Doses to Man: An outbreak of
poisoning was caused by the contamination of sacked flour during
shipment in a railway car in which endrin had leaked two months
earlier. Endrin in a concentration of 150 ppm was found in the re-
mains of a loaf of bread that had caused illness in one person.
The severity of illness was proportional to the amount of bread
eaten; 3 or 4 slices or 2 or 3 rolls were usually sufficient to pro-
duce a convulsion, and a man who ate nearly a vthole loaf had
repeated convulsions in quick succession for about an hour. Com-
putations based on these observations indicate that the dosage
necessary to produce a single convulsion in man is about 0.20 to
0.25 mg./kg., and the dosage necessary to produce repeated fits
probably is about 1 mg./kg. A child who died an hour and 10
minutes after ingesting endrin is estimated to have taken about 30
mg./kg. Animal experiments suggest that a much smaller dosage
also could be fatal.
There is no direct evidence on the repeated dosage that must
be absorbed in order to produce illness. Endrin poisoning has oc-
curred among formulators and applicators. Endrin is more toxic
than dieldrin and, by analogy, endrin would be expected to require
somewhat smaller dosages to produce poisoning following daily
exposure.
The tentative threshold Limit value for endrin in air is 0.25
mg./M3.
Signs and Symptoms of Poisoning in Man: In the contaminated
bread episode, mild illness involved dizziness, weakness of the
legs, abdominal discomfort, and nausea but usually not vomiting.
Several patients were temporarily deaf, and some were slightly
disoriented or aggressive. Insomnia was common. More serious
illness involved convulsions and occurred in about 30 people. The
time of onset was irregular, but usually 2 to 4 hours in those who
ate contaminated bread only once. People who ate 2 or more meals
frequently showed no acceleration of onset after the last dose, but
in some instances onset was as little as half an hour after the
meal. The fits were sudden and without warning. They were epi-
69
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leptiform in character with frothing at the mouth, facial congestion,
and violent convulsive movements of the limbs, sometimes leading
to dislocation of the shoulder or other injury. The fits lasting
several minutes were followed by semiconsciousness for 15 to 30
minutes. Recovery was well advanced by the next day in most
patients but a few complained of headache, dizziness, lethargy,
weakness, and anorexia for 2 to 4 weeks. Except for abnormal
electroencephalograms, neurological findings were normal soon
after a convulsion.
In fatal cases, the onset may be as little as 20 minutes, and
death about an hour after ingestion. Convulsions may become
almost continuous. Hyperthermia (107°F. or more) was associated
with endrin poisoning in two children, 1 and 2.5 years old. The
high fever was followed by decerebrate rigidity in both instances.
The hyperthermia may have been a specific effect of endrin. Other
findings in one of the cases strongly suggested injury to the brain
stem. The same conclusion is justified by electroencephalographic
studies.
Laboratory Findings: The insecticide has been found in the fat of
man (as high as 400 ppm by bioassay) and other tissues (as high
as 10 ppm). The concentrations consistent with health or disease
in man are not yet established. Electroencephalograms may show
bilateral synchronous spikes, spike and wave complexes, and
slow theta waves. The EEG usually returns to normal within 3 to 6
months after exposure is stopped.
Treatment: See dieldrin, page 66.
Preventions: See dieldrin, page 66.
Heptachlor
Chemical Name: 1,4,5,6,7,8,8-heptachloro-3a,4,7,7a-tetrahydro-
4,7-methanoindane.
70
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Chemical Formula:
Cl
Formulations: Heptachlor is available as emulsifiable concentrates
(24%), 2.5% dusts, 25% wettable powders, and granular formula-
tions containing from 2.5% to 25% heptachlor. Heptachlor is also
formulated with some fertilizer mixtures for the control of soil
pests.
Uses: Heptachlor is used against flies, mosquitoes, and a variety
of household pests. It is also used in controlling agricultural pests,
especially soil insects.
Toxicology: It has been estimated that the minimal dermal dose
required to produce symptoms in man is 46 g. for a single dose and
1.2 g. per day for repeated exposure. In animals, heptachlor causes
signs of poisoning similar to those caused by aldrin and dieldrin
(see page 62). Just as aldrin is converted in the body to its
epoxide (dieldrin), so heptachlor is converted to its epoxide and
stored largely in that form.
The threshold limit value for heptachlor in air is 0.5 mg./M3.
Laboratory Findings: See page 48.
Treatment: See dieldrin, page 66.
Toxaphene
Identity: A chlorinated camphene whose approximate empirical
71
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formula is C10H10Clg, representing a chlorine content of between
67% and 69%.
Formulations: Toxaphene is marketed as the technical grade mate-
rial; as a 40% dust concentrate; as dilute dusts; as a wettable
powder; as impregnated pellets; as 42% to 73% emulsifiable con-
centrates; as 44% to 80% concentrates in oil; as a 5% bran bait;
and as a cotton dusting formula (toxaphene 20%, sulfur 40%, inert
material 40%).
Uses: Toxaphene is used for the control of grasshoppers, soil
pests, and many insects that attack forage crops, cotton, and
certain vegetables. It is also used to control the ectoparasites of
livestock.
Routes of Absorption: Toxic and in some instances lethal amounts
of toxaphene can enter the body through the mouth, lungs, and
skin. Enteric absorption of the insecticide is increased by the
presence of digestible oils, and liquid preparations of the insecti-
cide penetrate the skin more readily than do dusts and wettable
powders.
Pharmacologic Action: In general, toxaphene resembles chlordane
and to some extent camphor in its physiological action. Toxaphene
causes diffuse stimulation of the brain and spinal cord resulting
in generalized convulsions of a tonic or clonic character. Death
usually results from respiratory failure. Detoxification appears
to occur in the liver.
Dangerous Single and Repeated Doses to Man: Toxaphene has an
irregular range of toxicity with the minimal acute lethal oral dose
for man estimated to be 2 to 7 g. Its chronic oral toxicity in the
dog (an animal susceptible to toxaphene) is some 10 times that of
DDT. In man a single dermal application of 46 g. or daily applica-
tions of 2.4 g. over a period of days is very dangerous. Toxaphene
causes moderate irritation of the skin but little or no sensitization.
At least 7 human deaths have been reported as due to toxa-
phene. All 7 cases were children. In 5 instances the poison was
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swallowed and may have been swallowed in the other cases also;
the dosage could not be determined. From other cases, it appears
that 10 mg./kg. or less leads to nonfatal convulsions in some per-
sons but to no disease at all in other persons.
Signs and Symptoms of Poisoning in Man: Nonfatal poisoning
generally begins in 4 hours or less after toxaphene is ingested. In
fatal cases, severe symptoms have begun as early as half an hour
after exposure, and death occurred in one instance in less than 4
hours from the time of exposure. In all reported cases, death has
occurred or recovery has begun and been essentially complete in a
period of 12 hours or less. However, control of convulsions is not
necessarily decisive. In one case, convulsions had been controlled
for some hours, and there were hopeful signs of improvement for a
time, followed by a sudden rise in temperature, respiratory collapse,
and death. Nonfatal poisoning has been characterized by nausea,
mental confusion, jerking of the arms and legs, and by convulsions.
In some instances convulsions have begun suddenly without any
warning signs or symptoms. Fatal poisoning has been characterized
by frequent, repeated, violent convulsions and by cyanosis. In some
instances the cyanosis may result from mechanical interference of
the convulsions with respiration. However, in one carefully ob-
served case, cyanosis appeared before convulsions.
Laboratory Findings: The only significant finding is the storage of
compounds related to toxaphene. This complex can be specifically
identified.
Pathology: See page 48.
Treatment: See page 49.
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BOTANICAL INSECTICIDES
Pyrethrum and Allethrin
Chemical Nome: The active ingredients in pyrethrum extract con-
sist of a mixture of four compounds, pyrethrin I and H, and cinerin
I and n. Pyrethrin I, the constituent possessing the greatest insec-
ticidal activity, is represented by the chemical formula shown
below. Allethrin is a synthetic pyrethrin analogue.
Chemical Formula:
CH,
CH,
CH}_C
9
H
\ /
CH
I
CH
n
C
,-CH2 -CH=CH-CH=CH2
CH} CH}
Formulations: Pyrethrum and allethrin are available commercially
in powder or dust form, in a variety of solvent extracts, and in
emulsifiable preparations of various concentrations. The usual
household spray contains about 0.5% active pyrethrum principles.
Uses: Pyrethrum and allethrin, alone or combined with synergists,
are used extensively in dusts, sprays, and aerosols against a wide
variety of insects. Allethrin has also been used in vaporizers.
Routes of Absorption: Pyrethrum and allethrin may be absorbed
from the gastrointestinal tract and by the respiratory route. They
are not absorbed to a significant degree through the skin; however,
allergic reactions may result from this route of exposure.
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Pharmocologic Action: The nervous symptoms produced by pyre-
thrum and allethrin poisoning resemble those of veratrin intoxica-
tion, proceeding from excitation to convulsions to tetanic paralysis,
except that pyrethrins cause muscular fibrillation as well.Death is
due to respiratory failure. If recovery occurs, it is usually complete.
Injury to man from pyrethrum has most frequently resulted from the
allergenic properties of the material rather than its direct toxicity.
Dangerous Single and Repeated Doses to Man: Under practical
conditions, pyrethrum and allethrin are probably the least toxic to
mammals of all the insecticides currently in use. Pyrethrum has
been used orally as an anthelmintic in some areas for many years
with no apparent ill effects. The approximate oral LDSO to white
rats of pyrethrum is 200 mg./kg. and of allethrin, 680 mg./kg.
The occurrence of a rare individual hypersensitive reaction,
especially following a previous sensitizing exposure, is a possi-
bility. The death of a two-year-old child following the eating of
one half ounce (15 g.) of pyrethrum concentrate was attributed to
pyrethrum poisoning. The esters constituting allethrin and pyre-
thrum mixtures are rapidly detoxified by hydrolysis in the gastro-
intestinal tract and to some extent in other tissues of warm-blooded
animals. The chrysanthemum monocarboxylic acid formed is ex-
creted in the urine. Because of their ready excretion, these com-
pounds exhibit little or no toxicity following repeated exposure.
The threshold limit value for pyrethrum in air is 5 mg./M3.
Signs and Symptoms of Poisoning in Man: Pyrethrum toxicity may
manifest itself in several forms in man. Contact dermatitis is by
far the most common. The usual picture is a mild erythematous,
vesicular dermatitis with papules in moist areas, and Intense
pruritus. A bullous dermatitis may develop. Some individuals show
manifestations of pyrethrum sensitivity similar to those seen in
pollinosis, including sneezing, serous nasal discharge, and nasal
stuffiness. A few cases of extrinsic asthma due to pyrethrum mix-
tures have been reported. Some of the individuals involved had a
previous history of asthma with a very broad allergic background.
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A severe anaphylactic reaction, including peripheral vascular col-
lapse and respiratory difficulty, is a rare accompaniment of the
dermatologic reaction.
Laboratory Findings: Positive patch tests with pyrethrum are help-
ful in diagnosis. Eosinophilia may accompany the acute allergic
reaction. Examination of mucous nasal smears from individuals
with vasomotor rhinitis reveals numerous eosinophils following
exposure.
Treatment: The treatment for the various reactions to allethrin and
pyrethrum is symptomatic. Antihistimines are of value. If sufficient
pyrethrum has been ingested to cause nervous manifestations,
pentobarbital should be used. The diarrhea that occurs may be
controlled with atropine sulfate.
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RODENTICIDES
Introduction: The rodenticides differ widely in their chemical
nature. Strange to say, they also differ widely in the hazard which
they offer under practical conditions, even though all of them are
used to kill animals that are physiologically similar to man. Sodium
fluoroacetate is one of the most hazardous rodenticides available.
Warfarin is the most thoroughly studied of a group of new rodenti-
cides which present a minimal hazard.
With the exception of arsenic, thallium, and phosphorus, the
older rodenticides are not covered in this handbook, but their
properties are listed in standard texts on pharmacology. (Arsenic
is discussed under "Herbicides" because of its relative impor-
tance as an eradicative weed killer.)
Phosphorus
Identity: Elementary phosphorus occurs in two common forms: the
relatively harmless red and the highly toxic white or yellow.
Formulations and Uses: White phosphorus is formulated as a 2%
to 5% paste for use against rats and roaches.
Routes of Absorption: Poisoning results from ingestion. Contact
of yellow phosphorus with the skin causes burns, but dermal absorp-
tion is not known to lead to systemic poisoning.
Dangerous Single and Repeated Doses to Man: A dose of 15 mg.
may be severely toxic and 50 mg. may be fatal. The element is
more toxic when ingested in solution or in a finely divided state
than when taken in lumps. A daily dosage of 1 mg. given with
therapeutic intent sometimes produced gastrointestinal disturbance,
necrosis of the jaw, and rarely typical phosphorus poisoning. The
threshold limit value for yellow phosphorus in air is 0.1 mg./M3.
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Signs and Symptoms of Poisoning in Man: Acute phosphorus poison-
ing is peculiar because symptoms appear in two stages. During the
first 24 hours, symptoms of severe gastrointestinal irritation occur
as soon as one-half hour after ingestion. The victim may die of
cardiovascular failure within 12 hours. This first stage may be fol-
lowed by a latent period lasting from a few hours to a few days
depending upon the amount ingested. The systemic stage is charac-
terized by abdominal pain, nausea, vomiting, hematemesis and
other hemorrhagic manifestations, jaundice, hepatomegaly, oliguria,
toxic psychosis, convulsions, coma, and shock. There may be
severe damage to the liver, heart, and kidney, and death may ensue
at any time. Cirrhosis of the liver has been reported after recovery
from the acute state.
Formerly, chronic poisoning, characterized by necrosis of the
mandible and maxillary bone, was caused by prolonged inhalation
of phosphorus in industry.
Pathology: Fatty degeneration is striking in the liver, heart and
kidney but may be found in all organs. Hepatic necrosis may be
extensive with changes occurring first in the periphery of lobules.
Differential Diagnosis: If history of phosphorus exposure is un-
available, the initial symptoms may be confused with the gastro-
enteritis caused by agents such as arsenic. There is a charac-
teristic odor of garlic to the breath and vomitus in phosphorus
poisoning. Luminescence in a darkened room of the gastric con-
tents, feces, or urine is pathognomonic.
Laboratory Findings: Urinalysis may show albuminuria, cylindruria,
and hematuria. Liver function tests, including prothrombin time, are
abnormal. Hypoglycemia may be severe; blood urea nitrogen and
creatinine may be elevated. The phosphorus content of the blood
is usually normal. EKG changes may be present with myocarditis.
Analysis for phosphorus may be done on tissue or gastric contents.
Treatment: Since there is no specific therapy, the removal of
phosphorus by vomiting or gastric lav age with large volumes of
fluid is of utmost importance. Potassium permanganate, 0.1% solu-
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tion, or 2% hydrogen peroxide are used in preference to water since
they may oxidize phosphorus to harmless phosphates. Two hundred
ml. of mineral oil or 100 to 200 ml. of petrolatum, which prevents
phosphorus absorption, can then be administered. However, absorp-
tion can be increased by other fats and oils. The treatment of shock
and acute hepatic or renal failure is instituted when necessary. Ade-
quate carbohydrate intake is important. Shock has responded to
vasopressor agents. The use of steroids resulted in dramatic im-
provement in one case of severe poisoning after the ingestion of
825 mg. of phosphorus.
Sodium fluoroacetate
Chemical Name: sodium mono fluoroacetate.
Chemical Formula: H o
I '/
H ONa
Formulations: Sodium fluoroacetate is a colorless, odorless, water-
soluble salt having a purity of about 95%. An extremely dilute solu-
tion has a vinegar-like taste, at least to some people. The salt is
dissolved in water in the proportion of 12 g./gal. (1:300). This
solution is used against rats by filling %-ounce squat souffle cups
(70 mg./cup) and by placing these at strategic locations in rat-
infested areas. This solution is often colored with a black dye.
Sodium fluoroacetate is also mixed with common rat baits at the
rate of 1 oz. of poison to 28 Ibs. of bait (1:500).
Uses: Sodium fluoroacetate is a nonspecific poison which is used
to kill rats, mice, other rodents, and predators in general.
Routes of Absorption: Sodium fluoroacetate is rapidly absorbed
from the gastrointestinal tract. Oral doses of sodium fluoroacetate
have approximately the same toxicity as those given subcutan-
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eously, intramuscularly, intraperitoneally, or intravenously, dodium
fluoroacetate is not readily absorbed through the intact skin, but it
may be absorbed in the presence of cuts or dermatitis. Dusts of the
poison are efficiently absorbed in the pulmonary system. The poi-
son appears to be uniformly distributed in the tissues, including
the brain, heart, liver, and kidney.
Pharmacologic Action: Following absorption, sodium fluoroacetate
appears to act without being chemically changed. Through a direct
interference with acetate metabolism by an ill-defined mechanism,
sodium fluoroacetate has a strong effect on either the cardiovascu-
lar or nervous system, or both, in all species and on the skeletal
muscles in some species. Man gives a mixed type response with
the cardiac feature predominating. By a direct action on the
heart, notably in the rabbit, contractile power is lost, which leads
to declining blood pressure. Premature ventricular contractions are
seen in all species and arrhythmias are marked in some species
including man. The central nervous system, notably that of the dog,
is directly attacked by sodium fluoroacetate. In man, the action on
the central nervous system produces epileptiform convulsive sei-
zures followed by severe depression. Cumulation of sodium fluoro-
acetate occurs to some extent, and some tolerance can be demon-
strated in the mouse and rat, and possibly in the rhesus monkey.
Dangerous Single Dose to Man: Judging from fatal and near-fatal
cases, the dangerous dose for man is 0.5 to 2 mg./kg. Other
species vary considerably in their response to sodium fluoroace-
tate with primates and birds being the most resistant and carnivora
and rodents being the most susceptible. Most domestic animals
show a susceptibility falling between the two extremes.
The threshold limit value for sodium fluoroacetate in air is
0.05mg./M3.
Signs and Symptoms of Poisoning in Man: In all species, there is a
variable latent period ranging from 30 minutes to 2 hours or more
between dosing and the appearance of symptoms. This period is
shortened but not eliminated by large amounts of sodium bicarbo-
nate, fumarate, or chloride. Both man and rhesus monkeys give a
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"mixed response" to fluoroacetate poisoning. In both fatal and
nonfatal cases in man, the first indication of poisoning was nausea
and mental apprehension, generally followed by epileptiform convul-
sions. After a period of several hours, pulsus alternans may exist
followed by ventricular fibrillation and death. Children appear to
be more subject to cardiac arrest than to ventricular fibrillation.
In rhesus monkeys convulsive seizures pass from the facial
muscles to the ear and masseter muscles and then over the entire
body, ending in violent jerks. Recovery from the seizure may occur
only to be followed by a sudden attack of ventricular fibrillation
and cardiac failure.
Laboratory Findings: In animals, increases in the blood levels of
certain constituents have been observed as follows: (1) glucose in
rabbits and goats, (2) lactic and pyruvic acids in the rabbit, (3) ace-
tate in the dog. Serum inorganic phosphate levels (probably from
muscle) are increased in goats and rabbits; the concentration of
plasma potassium is also increased (from control levels of 17 mg./
100 ml. to 25 mg./lOO ml.) in poisoned animals. Analyses for fluo-
rine content of the organs of a fatally poisoned patient showed
elevated values.
Pathology: The histopathologic changes in poisoning by fluoro-
acetate appear to contribute little to the elucidation of its action.
Congestion of abdominal viscera and lungs, resulting from cardiac
failure is seen in animals, with focal lung hemorrhage and gen-
eralized hemorrhage occurring in the rat and chicken, respectively.
Differential Diagnosis: In general, poisoning with sodium mono-
fluoroacetate is so acute and so violent that it has only to be
distinguished from poisoning with other convulsant poisons.
Treatment: The treatment for sodium fluoroacetate poisoning is
mainly symptomatic. Immediate emesis and gastric lavage followed
by oral doses of magnesium sulfate may be useful. Administration
of certain compounds capable of supplying acetate ions have shown
antidotal effects in animals including monkeys; the choice drugs
being monoacetin (glycerol monoacetate) (0.1 to 0.5 ml./kg. by
deep intramuscular injection). A single dose of magnesium sulfate
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(800 mg./kg.) given intramuscularly as a 50% solution has saved
the life of rats dosed with lethal amounts of sodium fluoroacetate.
Complete quiet and rest are indicated, but barbiturates to the point
of anesthesia have proved disappointing when used as antidotes
against this poison.
Prevention: Sodium fluoroacetate should be used by competent
specialists and then only under very strict limitations.
Thallium
Identify and Formula: thallium sulfate, T1S04.
Formulation and Use: Thallium sulfate is sold as the salt, as
prepared rodenticides (0.5% to 3% food baits and 1.5% liquid baits)
and as ant and roach poisons (0.05% to 3% baits). Some States and
cities ban the general sale of formulations containing more than
1% or 2% thallium sulfate.
Routes of Absorption: The oral route is the most important in cases
of poisoning, although dermal absorption may also occur. Formerly,
intoxication but no known deaths resulted from the application of
ointment containing 3% to 7% thallium acetate for depilation.
Pharmacologic Action: Thallium is a cellular toxin and resembles
arsenic in its effects. However, sulfhydryl-containing enzymes are
only slightly inhibited by thallium. Thallium is distributed to all
the tissues of the body; there is no tendency to accumulate in bone.
Excretion is mainly by the kidney and to some extent into the in-
testine. In humans, only about 3.2% of the thallium in the body is
excreted each day.
Dangerous Single and Repeated Doses to Man: Thallium acetate was
formerly used as a depilatory in children at a single oral dose of
8 mg./kg. Lower dosages were unreliable in causing hair loss.
Depilation is, of course, a toxic effect. Even though dosage was
carefully regulated, serious poisoning, including 6 deaths was
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found in 5.5% of 8,006 cases. No deaths were reported at lower
dosages, but poisoning occurred in 1 case from a dose of 4 mg./kg.
of thallium acetate. Adults are susceptible to lower dosages than
children and thallium was administered therapeutically only to
children under 10 or 12. Thallium acetate and sulfate are equiva-
lent in toxicity; both compounds are water-soluble and contain
about 80% thallium.
Thallium is a cumulative poison. The repeated dose necessary
to produce toxicity is not so well known. The daily oral admini-
stration of thallium acetate to rats at less than 1/50 of the single
LD -dose caused depilation in 6 weeks and death in rats within
4 months. The threshold limit for thallium in air in 0.1 mg./M3.
Signs and Symptoms of Poisoning in Man: The clinical picture re-
sembles arsenic intoxication. Signs and symptoms are referable
mainly to the gastrointestinal tract and nervous system. After large
doses, gastroenteritis is evident in about 12 to 14 hours, while
neurological symptoms may be delayed 2 to 5 days. Gastrointestinal
manifestations include severe paroxysmal abdominal pain, vomiting,
diarrhea, anorexia, stomatitis, salivation, and weight loss. Neuro-
logical manifestations during the first days of illness may include
paresthesias, headache, cranial nerve damage, convulsions, deli-
rium, and coma. Vascular collapse and death may occur in 24 to
48 hours, but the course is usually more prolonged. Death may be
caused by respiratory paralysis, pneumonia, or circulatory dis-
turbances. Peripheral neuropathy, particularly in the legs, is com-
mon with severe pain, paresthesias, muscle weakness, and atrophy.
Loss of hair begins after 1 to 2 weeks have elapsed. In the more
protracted cases, ataxia, choreiform movements, dementia, depres-
sion, and psychosis may be prominent. A blue gingival line and
dermatological abnormalities, including white bands in the nails
may appear. Neurologic damage may be permanent. Liver damage
occurs but is not prominent clinically. Kidney damage is mani-
fested by proteinuria, cylindruria, and sometime oliguria and
hematuria.
With the continued administration of smaller doses, symptoms
may first be apparent in a week with progression for several more
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weeks. In chronic poisoning, symptoms can be nonspecific and
thallium intoxication may not be suspected unless depilation occurs.
Although characteristic of thallium toxicity, hair loss also can re-
sult from poisoning with other metals and certain drugs.
Laboratory Findings: Diagnosis can be confirmed by analysis for
thallium in urine, blood, or hair. Thallium does not occur normally
in body fluids or tissue; however, its presence in urine does not
necessarily mean intoxication. In fatal, acute and subacute cases,
the concentration of thallium in tissue ranges from 5 to 100 ppm.
Thallium can be found in the urine for as long as 2 months after
intoxication. Other laboratory determinations are not specific.
The blood picture and the cerebrospinal fluid are usually normal.
Tests of liver function have been abnormal in a few instances.
Pathology: Only hyperemia and punctate hemorrhages of the gastro-
intestinal tract and visceral congestion may be found if death is
soon after exposure. There may be fatty degeneration of the heart
and liver, degeneration of kidney tubules, and edema and conges-
tion of the lungs. Degeneration occurs in peripheral nerves, and
cortical vessels are engorged. Chromatolysis in neurones is prom-
inent in the pyramidal tracts, basal ganglia, and third nucleus.
Treatment: Gastric lavage should be done in. acute cases. Acti-
vated charcoal and potassium iodide can be given orally to reduce
thallium absorption. Sodium thiosulfate may be given intravenously
to inactivate any thallium in the blood, but its usefulness has not
been proved. In one study, dithizon, a chelating agent, was effec-
tive in 5 out of 6 severely ill children in an oral dosage of 10 mg.
kg. twice a day for 4 days or longer. The mechanism of action was
unknown. It is generally felt that EDTA or BAL are not useful in
the treatment of thallium intoxication. However, there are reports
of improvement after the administration of BAL. In animals BAL
has not been effective, while dithizon (diphenylthiocarbazone) was
protective in rats after thallium administration. In one report, tri-
hexyphenidyl (Artane) caused a striking reduction of tremors.
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Warfai
Chemical Name: 3-(a-phenyl-(3-acetylethyl)-4:-hydroxycoumarin.
The compound is also available as the sodium
salt.
Chemical Formula:
Formulations: Warfarin is available in the form of a 0.5% powder.
The diluent is cornstarch suitable for mixing with additional bait
such as corn meal, bread crumbs, meat, etc. A final concentration
of 0.025% or less is recommended for bait, depending on the spe-
cies of rodent to be controlled and upon other conditions. In addi-
tion to the concentrate, finished baits containing 0.025% warfarin
are available commercially. Warfarin sodium is available pharma-
ceutically in capsules and tablets.
Uses: As a rodenticide, warfarin is used both for commensal rats
and mice and for wild forms. It has proved to be very effective.
Routes of Absorption: Warfarin is readily bsorbed by the gastro-
intestinal tract; absorption of the sodium salt in man requires about
3 hours as indicated by a comparison of the rate of action of oral
and intravenous doses. Warfarin is not significantly absorbed
through the skin.Its absorption by the respiratory tract is unknown,
but there need be no circumstance in which small particles of dust
could be inhaled, even in manufacture.
Pharmacologic Action: Warfarin has two actions: inhibition of
prothrombin formation and capillary damage. There is unconfirmed
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evidence that these two actions are produced by the two moieties
of the molecule. Thus, 4-hydroxycoumarin inhibits the formation of
prothrombin and reduces the clotting power of the blood, while
there is some evidence that at sufficient dosage benzalacetone
produces capillary damage and leads to bleeding upon the very
slightest trauma. Significantly enough, vitamin K has an antidotal
action against both actions of warfarin up to a certain point.
A single intravenous, therapeutic, dose of the sodium deriva-
tive (70-75 mg. or about 1 mg./kg.) in man may produce some in-
crease in prothrombin time within 2 hours, and usually produces a
substantial increase within 14 hours. The average maximum re-
sponse is on the fourth day. Spontaneous recovery to normal occurs
about 8 days after a single therapeutic dose. Thus, significant
clinical depression of prothrombin level is maintained for 3-6 days.
In the treatment of thromboembolie disease, a maintenance dose of
about 10 mg./day or 50 mg. every 5 days is required to keep the
prothrombin level between 10% and 30% of normal. Patients have
been thus maintained for years.
Ail the pathology induced by warfarin is reversible up to a
certain point (See below).
Warfarin and some other anticoagulants are derived from cou-
marin while others as well as the drug phenindione are indandione
derivatives. The occurrence of agranulocytosis and hepatitis in
some patients treated with phenindione suggests the possibility
that phenindione compounds may have effects entirely unrelated to
their anticoagulant properties.
Dangerous Single and Repeated Doses to Man: Serious illness was
induced by the ingestion of 1.7 mg. of warfarin per kg. per day for
six consecutive days with suicidal intent. This would correspond
to eating almost 1 pound of bait (0.025% warfarin) each day for 6
days. All signs and symptoms were caused by hemorrhage and,
following multiple small transfusions and massive doses of vitamin
K, recovery was complete.
In Korea, a family of 14 persons lived for a period of 15 days
on a diet consisting almost entirely of corn meal containing war-
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farin. The dosage of the different individuals was determined to
vary from about 1 to 2 mg. of warfarin per kilogram per day. As a
result of this exposure and without benefit of treatment, 2 of the 14
persons died. A 19-year-old girl who was in a state of shock and
severe hemorrhage 2 days after the warfarin diet was discontinued
recovered following a blood transfusion and small daily doses of
vitamin K. The remaining 11 members of the family recovered
within a week after exposure, although only small daily doses of
vitamin K were given, and although they all had shown marked
signs of poisoning when they first accepted treatment. Recovery of
the 12 survivors was complete. The entire episode was made pos-
sible only by a series of unusual events and by the extraordinary
apathy of the family, resulting in their totally ignoring unmistak-
able signs of illness.
The possibility of human poisoning by warfarin must be kept
in mind. In spite of one reported case which suggests the possi-
bility of hypersensitivity, the safety factors and experience with
use of the sodium salt in medical treatment make it appear un-
likely that poisoning with this pesticide will occur except with
suicidal intent or as the result of gross carelessness and igno-
rance. Although numerous accidental ingestions by children and
adults have been reported to the New York Poison Control Center,
no known injury from these ingestions has been observed.
The threshold limit value for warfarin in air is 0.1 mg./M3.
Signs and Symptoms of Poisoning in Man: The initial symptoms in
an attempted suicide using warfarin were back pain and abdominal
pain. The onset occurred one day after the sixth daily dose. A day
after onset, vomiting and attacks of nose bleeding occurred. On the
second day of illness, when admitted to the hospital, the patient
was observed to have a generalized petechial rash. The prothrombin
time was greatly prolonged. The coagulation time was definitely
increased by the Lee-White method and slightly increased by the
capillary tube method. Bleeding time was normal. Urine was normal
in appearance but contained many red cells on microscopic exami-
nation.
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In the Korean cases, the first symptoms appeared 7 to 10 days
after the eating of warfarin was begun. Massive bruises or hema-
tomata developed at the knee and elbow joints and on the buttocks
in all cases. Extensive gum and nasal hemorrhage usually appeared
about a day later and by the 15th day blood loss was extensive.
Animals intoxicated with the compound exhibit increasing
pallor and weakness reflecting blood loss. Appetite and body weight
are not specifically affected. The blood loss may be evident in the
form of bloody sputum, bloody or tarry stools, petechiae, or ex-
ternally visible hematomata. Hematoma formation is more common
than free hemorrhage. If the hematoma is superficial, it will be
marked by swelling and discoloration. However, in laboratory
animals, hematomata are frequently so large in muscle septa that
the entire upper or lower leg is grossly swollen, even though the
lesion is so deep that no color is evident beneath the skin. There
is no typical location for hematoma formation, the location of
bleeding being apparently a matter of chance. Bleeding associated
with the central nervous system may be of such location and ex-
tent as to cause paralysis of the hindquarters several days before
death occurs.
Laboratory Findings: Of greatest specific significance is the
markedly reduced prothrombin activity of the blood plasma as
measured by the method of Quick or its modifications. More deli-
cate tests may be made using both dilute and whole plasma. How-
ever, a clinical case should show marked increase of the pro-
thrombin time of whole plasma.
A less specific test that will be abnormal in the presence
of poisoning is the clotting time. The red count and hemoglobin
gradually fall if bleeding continues. In terminal cases, a state
of shock develops.
A chemical method for detecting the presence of warfarin is
available but not practical for the hospital laboratory. Specimens of
the stomach contents suspected of containing warfarin should be
shipped refrigerated to the Chamblee Toxicology Laboratory for
chemical analysis. See Appendix D.
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Pathology: Animals killed by warfarin show most extreme pallor
of the skin, muscles, and all the viscera. In addition, evidence
of hemorrhage maybe found in any part of the body but usually only
in one location in a single autopsy. Such blood as remains in the
heart and vessels is grossly thin and forms a poor clot or no clot.
Treatment: After blood has been taken for prothrombin and other
differential diagnostic tests, vitamin K in a dose of 65 mg. should
be given three times on the first day of treatment irrespective of
symptoms. Smaller doses should be continued until the prothrombin
time has reached normal. In a seriously ill patient, a small trans-
fusion of carefully matched whole blood should be given initially
and repeated daily until the patient has returned to normal. Such
a patient should be given vitamin K also. If it were ever necessary
to treat a patient in shock from blood loss resulting from warfarin
poisoning, frequent small transfusions and a complete consider-
ation of the blood chemistry would be in order. Any large hema-
tomata should be the subject of a surgical consultation, but any
surgical action should be taken only after the clotting power of
the blood is restored to normal.
The progress of the patient should be followed by the pro-
thrombin test. Tests should be made at least twice daily until a
return to normal is clearly established.
It will be noted that the suggested dosage of vitamin K is far
in excess of the 1.0 mg. dose recommended in the Pharmacopoeia.
It is, however, a safe dosage and is based on that already used
successfully for some years in the treatment of excessive hypo-
prothrombinemia in the course of medication with coumarin drugs.
-------
FUNGICIDES
Dithiocarbamates
Identity, ferbam — ferric dimethyldithiocarbamate; ziram — zinc
dimethyl dithiocarbamate; maneb — manganese ethylene bisdithio-
carbamate; zineb — zinc ethylene bisdithiocarbamate; and nabam —
disodium ethylene bisdithiocarbamate.
Chemical Formulae:
CH3
^v
_>X
CH3^
N— C— S
H
S
Fe
3
ferbam
CH,
CHj'
5N-C-S
ii
S
Zn
ziram
CH,-N-C-SN
i
H
CH2-N-C-S
i ii
H S
maneb
Mn
H,-N-C-Sv
H I \
CH,-N-C-S
A S
zineb
Na-S-C-N-CH, -CH2 _N-C-S-Na
n I I ii
S H
nabam
H S
Formulations: The several compounds are available as solutions up
to 76%,as dusts up to 20%, and as wettable powders.
Uses: All the dithiocarbamates are fungicides used mostly on fruit
crops and tobacco but also on vegetables and ornamentals.
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Toxicology: The acute oral toxicity of dithiocarbamates to rats
is as follows:
Compound
Ferbam
Ziram
Maneb
Zineb
No bam
LD50 -Value
(mg./kg.)
17,000
1,400
7,500
> 5,200
395
The exact dosage necessary to produce poisoning in man is
not known for any of these compounds. Most applicators have con-
sidered the dithiocarbamates to be harmless and acted accordingly
without experiencing anything more serious than mild dermatitis,
pharyngitis, rhinitis, bronchitis, and conjunctivitis as a result of
the rather heavy exposure. There is some evidence that much of
the primary irritancy of formulations of these compounds may be
due to the vehicle as well as to the active ingredients.
Organic mercury compounds
Identity: Mercury is bivalent in the organic compounds used as
fungicides. As a rule, an alkyl (methyl, ethyl, methoxyethyl, etc.)
or an aryl (phenyl, tolyl, etc.) mercury group is combined with
an inorganic or organic acid or amide. Typical examples are: ethyl
mercury phosphate, phenyl mercury acetate.
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Most methyl mercury compounds appear to be more effective
than other organic mercury compounds as fungicides. Some of the
methyl compounds present a greater hazard to the user partly be-
cause of their higher volatility, although by simple LD5Q teets the
methyl mercury salts are not more toxic than the phenyl mercury
salts.
Formulations: Both dusts and sprays are available. In some areas,
there has been a trend to the use of sprays. Commercially treated
seed generally are colored with a bright dye as a warning.
Users: The organic mercury compounds are used as seed dressings
for the prevention of seed-borne diseases of grains, vegetables,
cotton, peanuts, soybeans, sugar beets, and ornamentals. They
may be used for the control of fungus diseases of turf, fruits, cere-
als, and vegetables but not under conditions that will leave any
measurable residue in the food of man or animals. At least in other
countries, organic mercury compounds have been used for the pres-
ervation of wood and in the paper, plastics, and fabric industries.
Routes of Absorption: These compounds are absorbed by the skin
and by the respiratory and gastrointestinal tracts. Some of the alkyl
compounds are highly volatile, thus increasing the hazard of inhala-
tion.
Pharmacologic Action: Mercury, in whatever form, is a general
protoplasmic poison. Differences in toxic manifestations of the
organic mercury compounds and the better known inorganic com-
pounds are seen particularly in chronic poisoning and are correlated
with the greater storage of the organic compounds in the liver,
kidneys, and brain. Storage in the brain may indicate a greater
ability of some of the organic compounds to pass the blood-brain
barrier but may represent only an equilibrium between blood and
brain levels. At equivalent dosages of mercury, more is excreted
in the urine after repeated feeding with phenylmercuric acetate
than after similar feeding with mercuric acetate, but after injection
more is excreted with the inorganic form. With repeated dosage, the
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organic compounds are more toxic. These facts have been offered
as evidence of a greater initial absorption of the organic compounds
(mercuric acetate vs. phenylmercuric acetate) from the gastroin-
testinal tract. Thus, the greater toxicity of the organic compounds,
especially the alkyl ones is largely explained by their greater
absorption and lesser excretion resulting in greater storage.
Following daily oral dosage at the same rate, rats stored
only traces of mercuric chloride or mercuric nitrate in the blood
and brain; they stored more phenylmercuric acetate and much more
cyano (methyl-mercuric) guanidine and methyl mercuric hydroxide
in these tissues. A similar relationship was true for the liver and
kidneys (inorganic < aryl < alkyl), but the concentrations were
larger so that the storage of even inorganic mercury was easily
detected. The concentration of all three classes in the different
tissues increased in the order: brain < blood < liver < kidneys.
Inorganic mercury is transported mainly in the plasma while both
alkyl and aryl mercury are largely bound to the erythrocytes. The
excretion of mercury in man exhibits two phases following ces-
sation of exposure to ethyl mercury chloride, ethyl mercury phos-
phate or ethyl or phenyl mercury acetate. The first phase shows a
slight rise in urinary mercury concentration, which reaches a peak
that is variable in both magnitude and the interval of time after
exposure ceases. Following the peak level, a second uniformly
downward trend occurs.
All compounds of mercury can damage the kidney. Mercury
vapor, its inorganic salts, and the lower alkyl compounds produce
damage to the central nervous system. In the case of the methyl
and ethyl mercury compounds, this damage can take the form of
irreversible brain cell injury. Such changes may continue to pro-
gress for some time after the exposure to mercury has ceased.
Dangerous Single and Repeated Doses to Man: The exact
amount of any organic mercury compound necessary to produce
poisoning in man is not known but is obviously small. The acute
oral LDgQ-value for representative compounds in rats is approxi-
mately 30 mg./kg. The total dose of an organic mercury compound
necessary to produce chronic poisoning in cats is about the same,
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that is 6 to 24 mg./kg. expressed as mercury. Acute poisoning by
organic mercury has been reported infrequently in man, although
such poisoning by methyl and other alkyl compounds has occurred.
There have been many cases of chronic poisoning involving both
inorganic and organic mercury. Most chronic cases caused by known
organic chemicals were associated with repeated exposure in con-
nection with the manufacture of alkyl compounds, their use for
treating seed, or the eating of treated seed. Other cases were asso-
ciated with the ingestion of seafood contaminated by industrial
waste. The threshold limit value for organic mercury compounds
in air is 0.01 mg./M^.
Signs and Symptoms of Poisoning in Man: The acute symptoms
associated with irritation of the gastrointestinal system and renal
failure caused by inorganic mercury compounds are seldom observed
in poisoning by organic mercury compounds and then almost exclu-
sively in acute poisoning. Even the mild digestive disturbances
and sore mouth seen in moderate, chronic, occupational poisoning
by inorganic mercury are relatively rare. Instead, the nervous symp-
toms appear first, sometimes after relatively slight exposure and
after months of latency. The patient may complain of headache;
paresthesia of the tongue, lips, fingers, and toes; and other non-
specific dysfunction.
Early signs include fine tremors of the extended hands, loss
of side vision, and slight loss of coordination, especially with the
eyes closed as in the finger-to-nose-test. Incoordination is espec-
illy notable in speech, writing, and gait. Incoordination may pro-
gress to the point of inability to stand or to carry out other volun-
tary movements. Occasionally there is muscle atrophy and flexure
contractures. In other cases, there are generalized myoclonic
movements.
There may be difficulty in understanding ordinary speech
although hearing and the understanding of slow deliberate speech
often remain unaffected. Irritability and bad temper are frequently
present and may progress to mania. Occasionally the mental picture
deteriorates to stupor or coma. Especially in children, mental
retardation may be added to the symptoms of poisoning already
mentioned.
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Patients frequently become gradually much worse after their
illness is recognized and exposure is stopped. Even in those cases
in which recovery occurs in the course of months or years, there
may be little or no real neurological improvement, only an adapta-
tion and reeducation. The duration of illness in fatal cases has
ranged from about a month to 15 years. Intercurrent infection, aspi-
ration pneumonia, or inanition are the immediate causes of death.
The organic mercury compounds are strong irritants of the skin
and may cause blisters or other dermatitis with or without asso-
ciated systemic illness.
Laboratory Findings: The average excretion of mercury by normal
people is 0.5 |J.g. daily in the urine and 10 |ig. daily in the feces.
Although there is some disagreement about the concentration of
mercury that can be excreted safely, there is general agreement
about the value of making the measurement. The most conservative
view is that the concentration in the urine should not exceed 15
micrograms per liter (ug./l.) or slightly higher following exposure
to alkyl mercury. Somewhat higher excretion can be tolerated fol-
lowing exposure to inorganic mercury, because any given level of
excretion represents less absorption as compared with an organic
compound. Other investigators, who have presumably used more
sensitive chemical methods (although they failed to recognize the
possibility of exposure to inorganic mercury in association with
organic compounds), indicate that any operator exposed chiefly to
alkyl compounds excreting more than 50 |j.g. of mercury per liter of
urine should be placed on a "watch list" requiring weekly urinaly-
sis and that any operator excreting more than 100 p.g./l. should be
removed from exposure. Hospitalized cases may excrete 600 or more
micrograms per 24 hours (300 to 400 |ig./!.).
Pathology: Extensive and relatively characteristic pathology has
been reported in man and experimental animals. The most common
findings are: (1) bilateral cortical atrophy around the anterior end
of the calcarine tissue with disappearances of the striation of
Gennari (associated with constriction of the visual fields) and (2)
gross atrophy of the folia in the depths of the sulci of the lateral
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lobes and the declive of the cerebellum involving the granule cell
layer (associated with ataxia). The hypothalamus, midbrain, and
basal ganglia may be involved. The changes in the brain involve
gliosis as well as the abnormality and loss of specific neurones.
The bodies of the Purkinje cells are spared although the axones
are affected. Changes in the peripheral nerve and the posterior
columns have been reported in animals. Decrease in anterior horn
cells with demyelination of the lateral columns of the spinal cord
(associated with a case said to resemble amyotrophic sclerosis)
has been reported; the difference may be related to the fact that
a phenyl mercury compound was involved.
In fatal cases, the concentration of mercury in the organs has
been in the following ranges: brain, 4.0 to 10.0 ppm; spinal cord,
3.5 to 40 ppm; liver, 14.0 to 20.0 ppm; kidney, 3.0 to 30.0 ppm;
and lung, 2.0 to 4.0 ppm. More recent investigations have shown
higher maximal values perhaps as a result of better analytical
methods: brain, 21 ppm; liver, 71 ppm; kidney, 144 ppm. Excessive
mercury may be found in the hair also. Comparable values obtained
by modern techniques do not seem to be available in connection
with chronic poisoning by inorganic mercury.
Differential Diagnosis: Viral encephalitis, poisoning by certain
other metals, and some neurological disorders of unknown or here-
ditary cause must be considered. Diagnosis depends on a history
of exposure and the measurement of mercury in urine and tissues.
Treatment: In poisoning by alkyl mercury compounds, BAL is
considered of doubtful value or even harmful. It may be useful in
treating sequelae of alkyl mercury poisoning perhaps because in-
organic mercury may be left in the tissues. EDTA has also been
used as an antidote but its value is not established.
Prevention of Poisoning: If mercury compounds must be used in-
stead of less poisonous fungicides, then the use of masks, rubber
gloves, and separate work clothing is necessary. More elaborate
protective devices are recommended under manufacturing condi-
tions. Special closed machinery is available for applying dressing
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to seed and should be used if possible. Even if the best equipment
is available, all clothing, including shoes, must be changed after
work. Smoking, chewing gum or tobacco, drinking, or eating are
prohibited during work. Tobacco, gum, or candy must not be carried
in work clothing. Scrupulous personal hygiene is required. Workers
should receive preemployment medical examination to exclude
those with neurasthenia, nervous disease, dermatitis, liver disorder,
hypertension, or defective kidney function. Persons with repeated
exposure should have periodical medical examination and frequent,
regular analysis of the urine for mercury.
Pentachlorophenol
Chemical Name: pentachlorophenol
Chemical Formula:
Formulations: Pentachlorophenol, a crystalline solid, is soluble in
various organic solvents, including the petroleum oils in which it
is applied. It is frequently used as the sodium salt, which is freely
soluble in water.
Uses: Pentachlorophenol is an insecticide, moluscicide, herbicide,
fungicide, and bactericide. It is used to control termites and other
wood insects and various snails, including those that carry schisto-
somiasis. It is used as a weed killer, cotton defoliant, and preserv-
ative for timber.
Routes of Absorption: Pentachlorophenol is absorbed by the skin
as well as after inhalation or ingestion.
Pharmacologic Action: The action of pentachlorophenol is similar
to that of the dinitrophenols (which see) and consists of an in-
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crease in the metabolic rate leading to a marked increase in body
temperature, collapse, and death. The main action of the chemical
is a rapid uncoupling of oxidation and phosphorylation cycles.
Although illness may be produced by the cumulative action of
several doses, the onset of critical illness tends to be sudden and
the course of the disease rapid. In 19 cases for which the informa-
tion is available, the time from first symptoms to death ranged
from 3 to 30 hours and averaged 14 hours.
Excretion occurs largely in the urine. In certain fatal cases,
it seemed that the victim was unusually susceptible by virtue of
renal deficiency. This hypothesis was supported by experiments
which showed that rabbits made nephritic experimentally were very
much more easily poisoned by pentachlorophenol than were normal
animals.
Dangerous Single and Repeated Doses to Man: The exact dosage
necessary to produce illness is not known. It is clear that the
largest dosage that produces no illness whatever is little less
than the fatal dosage. It is claimed that one man drank a glassful
of 2% solution of the sodium salt with no effect except a hangover.
One man died after working 6 days as a mixer preparing 2.1% cotton
defoliant from 40% concentrate. Nine died after dipping timber by
hand and without any protection in 1.5% to 2% solution for periods
varying from 3 to 30 days with an average of 13 days; this is typ-
ical of several other situations in which accidents have occurred.
The threshold limit value for pentachlorophenol in air is 0.5
mg./M3.
Signs and Symptoms of Poisoning in Man: Nonfatal systemic poi.-
soning is characterized by weakness, by more or less marked loss
of appetite and weight, sometimes by a feeling of constriction in
the chest and dyspnea on moderate exercise, and almost always by
excessive sweating. Headache, dizziness, nausea, and vomiting
may be present.
In fatal cases the temperature is frequently extremely high
[jip to 108°F (42.2°C)J, but may be only moderately elevated.
Sweating, dehydration, and dyspnea are present and there may be
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pain in the chest or abdomen. The pulse is rapid. Coma appears
early. There is frequently a terminal spasm.
Under some conditions of use, pentachlorophenoi causes
irritation of the skin, conjunctiva, and upper respiratory tract even
at dosages that do not produce systemic disease. Dermatitis may
be acneform or eczematous.
Pathology and Laboratory Findings: The pathology is not charac-
teristic except that the high temperature of the body may be noted
if autopsy is performed within a few hours after death. The organs
frequently show some congestion and there may be some cerebral
edema. Degenerative changes in the liver and kidneys have been
observed in a few cases. In one case of fatal occupational poison-
ing, with autopsy three days after death, pentachlorophenoi was
found in the following concentrations: lung, 76 ppm; blood from
lung, 97 ppm; liver, 62 ppm; blood from liver, 46 ppm; and kidney,
84 ppm. A child who ingested the material showed the following
concentrations: liver, 59 ppm; blood from liver, 53 ppm;kidney,
41 ppm; and urine (post mortem), 28 ppm.
Nonfatal cases have shown 3 to 10 ppm of pentachlorophenoi
in the urine and sometimes traces of albumin. Concentrations were
55 and 96 ppm in urine taken at autopsy from adults. Early reports
of concentrations as low as 7 ppm in fatal cases may be in error.
Differential Diagnosis: The greatest danger is that poisoning by
pentachlorophenoi will be mistaken for poisoning by an organic
phosphorus insecticide, which is also characterized by sweating,
difficulty in breathing, and pain in the chest and abdomen.
Treatment: The use of atropine sulfate is absolutely contraindicated.
Treatment is symptomatic and difficult. An effort must be made to
maintain the fluid and electrolyte balance and to keep the body
temperature within tolerable limits.
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Prevention: The first rule of prevention is good general hygiene
with emphasis on protection of the skin of wbrkers. At least under
field conditions, it is wise to alternate workers so that repeated
exposure is for a maximum of two weeks. During the preemployment
examination, careful measurement of renal function should be made
in order to exclude applicants with deficient function.
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HERBICIDES
Arsenic
Identity and Formulae: Elementary arsenic forms two oxides: the
trioxide, As203, and the pentoxide, As205- Arsenic trioxide (tri-
valent) reacts with water to form arsenous acid, H AsO , which
is known only in solution and forms three series of salts: ortho-
arsenites (e.g., Na AsO ), metaarsenites (e.g., NaAsO ), and
pyroarsenites (e.g., Na As 0 ). Arsenic pentoxide (pentavalent)
reacts with water to form three acids that may be isolated: ortho-
arsenic acid, H AsO ; metaarsenic acid, HAsO,; and pyroarsenic
34 3
acid, H As 0 . These acids form the corresponding salts: ortho-
arsenates, metaarsenates, and pyroarsenates. A few organic arsenic
compounds are also used as pesticides.
Although & great many arsenicals have had some use, the fol-
lowing are of most importance:
Nome
Arsenic trioxide
Sodium arsenite
Paris green
Lead arsenate
Basic lead arsenate
Calcium arsenate
Dimethylarsinic acid
Disodium methyl
arsenate
Synonym
white arsenic
copper aceto-meta-
arsenite
acid lead arsenate
standard lead arsenate
dilead arsenate
lead hydroxy-
arsenate
Arsan
cacodylic acid
Formula
AS2°3
Mixture, see above
Cu(CH COO) . 3Cu(AsO )
2'2
PbHAsO.
Pb4(PbOH)(As04)3.H20
a complex mixture
(CH3)2AsO(OH)
Na2CH3As03.6H20
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Formulations and Uses: Arsenic trioxide in the form of a powder is
used as a rodenticide. Arsenites are more soluble and more rapidly
toxic than corresponding arsenates; therefore, arsenites are used
as rodenticides and herbicides, and in insecticidal baits. Sodium
arsenite is usually sold as a solution. Dimethylarsinic acid and
disodium methyl arsenate are herbicides. In some countries sodium
arsenite was used to dry up potato tops in preparation for me-
chanical harvesting, but the practice is very dangerous. Paris
green, although an arsenite, may be applied to foliage but the
arsenates are less phytotoxic and, therefore, preferred. Lead ar-
senate is usually used as a wettable powder, calcium arsenate as
a dust. Paris green impregnated on vermiculite is used to an in-
creasing degree as a mosquito larvicide. The use of arsenical
insecticides in agriculture has decreased greatly since the intro-
duction of DDT and later poisons, but the use of arsenical
herbicides has increased.
Route of Absorption: Arsenic is absorbed chiefly by the respira-
tory and gastrointestinal tracts. However, some is absorbed by the
intact skin, and systemic illness may follow application of arseni-
cal ointment to eczematous skin.
Pharmacologic Action: Arsenic in whatever form is a general pro-
toplasmic poison. It binds organic sulfhydryl groups, thus inhibit-
ing a number of enzymes, notably pryuvate oxidase and the phospha-
tases, so that tissue respiration is reduced. The chief pharmaco-
dynamic action is dilatation and increased permeability of the
capillaries. This action is strongest in the intestines regardless
of route of absorption. Arsine (hydrogen arsenite), is a powerful
hemolytic agent but it is unlikely to be found in connection with
pesticides. Most commercial arsenic formulations are irritant, at
least in part because of their impurities. Pure compounds are
only weakly irritant but they slowly kill cells on prolonged con-
tact, and by local action on capillaries they cause congestion,
stasis, thrombosis, ischemia and necrosis. Such necrosis extends
into the bone in some instances. It is generally stated that arsenic
can cause cancer, especially of the skin, but the epidemiology is
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not clear. No cases have been clearly traced to occupational or
accidental contact with pesticides.
Dangerous Single and Repeated Doses to Man: A dose of 5 to 50 mg.
of arsenic trioxide is toxic. A dosage of 128 mg. has proved fatal
but recovery has occurred after much larger doses. The effective-
ness of arsenical rat poisons varies greatly with the grind of the
powder; very fine powders approach the toxicity of solutions con-
taining an equivalent amount of arsenic. Thus the ease of absorp-
tion influences the toxicity to a marked degree. The repeated dose
necessary to produce poisoning is less well known. The "thera-
peutic" dose of arsenic trioxide (1 to 2 mg. three times daily) that
used to be employed as a tonic frequently led to mild poisoning.
The threshold limit for arsenic is 0.5 mg./M3, a value higher than
that for lead because arsenic is more efficiently excreted.
Signs and Symptoms of Poisoning in Man: For many years, arsenic
has been the most important single cause of accidental deaths
associated with pesticides. In 1956, it caused 35% of such cases.
Accidental poisoning by arsenic pesticides is almost always acute
and often involves children (74% of these cases in 1956 involved
children 5 years old or younger). Abdominal pain and vomiting often
start within an hour of ingestion, although the onset may be de-
layed particularly if foul play is involved and the dosage is con-
trolled. Death may result from a severe fall in blood pressure and
collapse as in "dry" cholera. Generally death is delayed for 1.5
to 3 days after onset and sometimes as much as 14 days. In this
event, death follows vomiting and profuse, painful diarrhea; the
clinical picture is similar to cholera because of the character of
the stools and the great dehydration of the patient. If the patient
survives the acute phase, exfoliative dermatitis or neuritis may
appear. People with this polyneuritis have pain, burning, and ten-
derness of the affected limbs and trouble in walking. Chronic
poisoning has not been a significant problem in pesticide appli-
cators; cases reported in vineyard workers in Germany may have
involved the drinking of contaminated wine. Chronic poisoning is
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well known from other sources. It usually involves the frequently
insidious onset of loss of appetite, weight loss, weakness, nausea,
alternating diarrhea and constipation, colic, peripheral neuritis,
dermatitis, some loss of hair, giddiness, and headache. Cyanosis
of the face may be present. The dermatitis may be erythematous,
pustular, or even ulcerative. Burning and itching may be present
and there may be serous discharge. \Vith most arsenic compounds,
the skin lesions tend to be most marked in the area of greatest
contact. They are considered mainly the result of direct toxic
action. The action may involve the face, eyelids, conjunctivae, or
even cornea. There may be irritation of the nose, pharynx, and
trachea. Perforation of the nasal septum has occurred. In less
acute cases, hyperkeratosis, hyperhidrosis, or melanosis may oc-
cur. White transverse bands in the nails frequently accompany
polyneuritis. The bands gradually migrate to the free edge of the
nails as the result of growth of the nails. A highly characteristic
dermatitis confined to the scrotum, inguinal area, and nasolabial
folds may follow moderate occupational exposure to Paris green.
The lesions begin with erythema, frequently become eczematous
and weeping, and may start to heal with the formation of a black
scab. A sensitization reaction may be involved because the dis-
tribution does not correspond to the distribution of insecticide on
the skin, and the dermatitis generally occurs in the absence of
typical poisoning.
Laboratory Findings: Normal people may excrete arsenic in the
urine at rates as high as 0.17 ppm (as As2 03 ). Blood levels as high
as 1 ppm have been reported in normal people as the result of arse-
nic in ordinary food and water. Concentrations in other soft tissues
may be as high as 7.6 ppm; the hair may have 10 to 15 ppm. Asymp-
tomatic chemical workers may show arsenic at a concentration of
100 ppm in the hair and 0.82 ppm or more in the urine. Serious but
nonfatal cases showed urinary excretion as high as 6.2 mg. per
24 hours or between 4 and 6 ppm. Victims of acute poisoning
showed 148 and 150 ppm of arsenic in the liver. Values from the
kidneys in fatal cases have ranged from 9.2 to 91 ppm.
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Electrocardiographic changes may be present. In arsine poi-
soning (unlikely in connection with pesticides), severe anemia is
found in the presence of a normal bone marrow; the urine shows
hemoglobin and sometimes albumin.
Autopsy Findings: In acute poisoning, erosion and inflammation
of the stomach and upper intestinal tract may be marked. The liver
may show degenerative lesions and in chronic poisoning these can
lead to cirrhosis. Unless death is very rapid, the severe dehydra-
tion produced by acute poisoning gives the body an emaciated
appearance even though a normal amount of fat remains. The ali-
mentary canal shows a large amount of fluid, shreds of mucous,
and false membrane in the absence of marked corrosion — a picture
similar to that in cholera. The body may decay more slowly than
would be expected in the same amount of time at the same
temperature.
Treatmentrlf ingestion is suspected, the stomach should be emptied
by vomiting and lavage with warm water followed by a saline ca-
thartic. BAL (Dimercaprol) is a specific antidote; it should be
given intramuscularly at the rate of 3 mg./kg. every four hours for
the first two days, every six hours on the third day, and twice daily
thereafter until recovery is complete. The drug is available as a
10% solution in peanut oil with 20% benzyl alcohol. Dehydration
should be combatted with saline infusions guided, where possible,
by laboratory studies. The diet should be liquid. BAL is indicated
in the various forms of chronic poisoning as well as in acute
poisoning.
Prevention: Most accidental cases of poisoning by arsenical pesti-
cides would be prevented if formulations were always kept in the
original, labeled containers and the containers were stored so that
they were absolutely inaccessible to children.
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Chlorophenoxy herbicides
Identity: 2,4-D — 2,4-dichlorophenoxyacetic acid
2,4,5-T — 2,4,5-trichlorophenoxyacetic acid
MCPA - 2-methyl-4-chIorophenoxyacetic acid
Chemical Formulae:
O-CH2 -COOH
O-CH2_COOH
O-CH2 -COOH
1
Formulations: The acids themselves are sometimes used but the
salts or esters are more widely applied as weed killers. The
alkyl amine salts of 2,4-dichlorophenoxyacetic acid (e.g., tri-
ethylamine, triethanolamine) have largely replaced the inorganic
salts (sodium or ammonium) as herbicides. A wide range of simple
alkyl esters (e.g., isopropyl and butyl) are used when relatively
high volatility is desired: other esters (e.g., butoxyethanol, tetra-
hydrofurfuryl) are used when low volatility is required. A similar
array of derivatives of 2,4,5-T and of MCPA are available. Other
related hormone-type herbicides include 3,4-D,^-chlorophenoxy-
acetic acid, various phenoxyproprionic acids and various phenoxy-
butyric acids. In general, each of these may be prepared as the
acid, inorganic salts, amine salts, or esters. These compounds are
sold as dry salts, pastes, emulsifiable concentrates, water-
wettable powders, and dusts varying in strength of active ingred-
ients from 2% to 98%. A wide variety of solvents have been used
with them including kerosene, Stoddard's solvent, xylene, and
106
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methylated naphthalenes. The active ingredients are applied at
final dilutions as low as 3 ppm and as high as 25% (250,000 ppm)
depending on the use.
Uses: As herbicides, 2,4-D-type compounds are used for selective
weed control in many crops on over 50 million acres. These com-
pounds are used widely as eradicative herbicides in industrial
weed control. They are also used in very high dilutions as hor-
mone sprays to prevent the early dropping of fruit.
Routes of Absorption: These compounds may be absorbed if taken
by mouth or presumably if inhaled. Skin absorption is slight.
Pharmacologic Action: 2,4-D and related compounds act as
growth hormones in plants. They have no hormonal action in ani-
mals, but the mechanism of their toxic action is poorly understood.
Dangerous Single and Repeated Doses to Man: The acute oral
toxicity of representative compounds to the rat is as follows:
Compound LPsQ-Volue (mg./kg.)
2,4 D- acid 375
- sodium salt 666 - 805
- mixed butyl esters 620
— isopropyl ester 700
2,4,5-T - acid 500
— mixed butyl esters 481
— isopropyl ester 495
MCPA - acid 700
- amine salt 1,200
The oral dose required to produce symptoms in man is probably
3 to 4 g. One man consumed 500 mg. of purified 2,4-D per day for
21 days without ill effect. When 2,4-D acid was investigated as a
possible treatment for disseminated coccidiodomycosis, the patient
had no side effects from 18 intravenous doses during 33 days; each
of the last 12 doses in this series was 800 mg. or more; the last
107
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being 2,000 mg. (about 37 mg./kg.). A nineteenth and final dose of
3,600 mg. produced acute illness described below. An oral dose of
not less than 6,500 mg. led to death in a case of suicide.
Animals fed 2,4-D or 2,4,5-T tolerate for months daily doses
only slightly smaller than those which cause toxic effects when
given only once. Thus, cumulative effect is minimal. Recovery
from poisoning is complete.
The threshold limit value for 2,4-D in air is 10 mg./M3, and
the tentative value for 2,4,5-T is the same.
Signs and Symptoms of Poisoning in Man: The patient given 3,600
mg. of 2,4-D acid intravenously suffered coma, fibrillary twitching
of some muscles, hyporeflexia, and urinary incontinence. Seven
hours after infusion the patient could be roused but lapsed back
into deep sleep. Twenty-four hours after dosage he was eating well
but still complained of profound muscular weakness; within an ad-
ditional 24 hours he had apparently recovered from all effects of
the plant hormone. In what was presumably attempted suicide,
ingestion of an unknown amount of 2,4-D resulted in "prolonged
stupor" followed by recovery. The body of the man who committed
suicide showed signs of convulsions prior to death.
Animals killed quickly by large doses of 2,4-D are thought to
die of ventricular fibrillation. If death is delayed, myotonia, stiff-
ness of the extremities, ataxia, paralysis, and coma are seen.
Repeated doses that may or may not eventually lead to death pro-
duce loss of appetite, loss of weight, vomiting, depression, rough-
ness of coat, and general tenseness and muscular weakness. It
may be significant that the myotonia characteristic of poisoning
by 2,4-D in animals has not been reported in man.
Three cases of "peripheral neuritis" among men very recently
exposed to 2,4-D were seen at one clinic in a single month. No
valid toxicological or epidemiological evidence was given to sup-
port a causal relationship. Although more than 700,000,000 pounds
of 2,4-D and related compounds have been manufactured and used,
no similar cases have been reported.
As with other chemicals, 2,4-D may be a cause of contact
108
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dermatitis, but this effect in man is neither so common nor so
severe as animal experiments would suggest.
Laboratory Findings: Animal studies have not indicated any use-
ful laboratory tests.
Pathology: Experimental animals killed by 2,4-D show irritation
of the stomach (or the abomasum of ruminants), minor liver and
kidney injury, and sometimes congestion of the lungs. Nonspecific
hyperemia of the lungs, liver, and brain were found in the case of
suicide.
Differential Diagnosis: The occurrence of myotonia soon after
heavy exposure to 2,4-D would be suggestive of poisoning. 2,4,5-T
produces only mild spasticity but may produce difficulty in swal-
lowing. In the absence of myotonia, poisoning by solvents and the
possibility of neurological disease unrelated to chemicals must be
considered in view of the low toxicity and good safety record of
the hormone-type herbicides.
Treatment: If poisoning were to occur, for example in attempted
suicide, treatment would be symptomatic.
Dinitrophenols
Identity: A number of substituted dinitrophenols, alone or as salts
of aliphatic amines (triethanolamine or isopropanolamine) or alka-
lies (sodium or ammonium hydroxide), are sold under many trade
names, frequently with a suffix to indicate the formulation. Repre-
sentative materials are as follows:
OH
^*^
_H-CH2-CHj
CH3
So2
2-sec-butyl-4,6-dinitrophenol
NO>
4,6-dinitro-o-cresol (DNOC)
(2-methyl-4,6-dinitrophenol)
109
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O,N
OH C^C2 ° NHj-CH2-CHOH-CH3
CH CH, °* Nrl^H-CH2 ~CH2 -CH §
W~
H2 H2
•2
N02
isopropanolamine
2-cyclohexyl-4,6-dinitrophenol salt of 2-«£c-amyl-4,6-dinitro-
phenol
Formulations: Dinitrophenols are marketed as 1.5% to 2.5% solu-
tions in oil and up to 53% water-wettable powders. They are also
available in the form of 20% salts in 14/2 oxidized oil. Frequently
2% sodium chromate is included in liquid concentrates as a cor-
rosion inhibitor.
Uses: The substituted dinitrophenols are used, in different formu-
lations, as fungicides, insecticides, miticides, or herbicides. They
are used extensively in dormant sprays for the control of mites,
aphids, scale insects, and other pests in overwintering stages.
They are useful as acaricides in greenhouse, field, and orchard.
In other countries, DNOC has been released by aircraft against
airborne swarms of grasshoppers. The compounds may be used as
eradicant herbicides in such locations as roadsides and right-of-
ways, or as selective weed killers in fields or pastures, or as
blossom thinners for tree fruits.
Routes of Absorption: All of the compounds listed may be ab-
sorbed in toxic amounts by inhalation or ingestion. DNOC and the
secondary butyl derivative may be absorbed through the skin to a
dangerous degree while the cyclohexyl derivative is not absorbed
to an appreciable extent by this route.
Pharmacologic Action: All of the compounds increase the oxidative
metabolism and therefore the heat production of the body chiefly
by direct peripheral action.
Dangerous Single and Repeated Doses to Man: The dangerous
single dose of DNOC has been estimated to be 2 g. (about 29 mg.
kg.). No toxic effects were noted by any of five volunteers after
110
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the ingestion of the first of 5 or more doses of 75 mg. of DNOC
leading to blood levels of 10 ppm or slightly less. Two volunteers
who ingested doses of 75 mg. of DNOC per day for 5 and 7 days,
respectively, experienced lassitude, headache, and malaise.
Because DNOC is a cumulative poison and is excreted very
slowly by human beings, persons who have suffered any symptoms
of poisoning should be removed from risk of further absorption for
a period of at least 6 weeks. Less is known of the toxicity of the
other compounds to man but their toxicity to the rat is similar, as
shown in the table below.
The threshold limit value for DNOC in air has been set at
0.2 mg./M3.
ORAL TOXICITY OF SELECTED SUBSTITUTED
DINITROPHENOLS TO THE RAT
Compound
(R = 4,6-dinitrophenol)
2-Methyl-R (DNOC)
2-sec-Butyl-R
2-Cyclohexyl-R
Tolerated
Acute
Dosage
(mg./kg.)
10
5
30
Acute
LD50
(mg./kg.)
30
37
80
Tolerated
Concentration
in Diet
(ppm)
100
100
500
Signs and Symptoms of Poisoning in Man: The signs and symptoms
of confirmed acute DNOC poisoning in man have closely paralleled
those of experimental animals and include nausea, gastric distress,
restlessness, sensation of heat, flushed skin, sweating, deep and
rapid respiration, tachycardia, fever, cyanosis, collapse, and coma.
Acute poisoning with DNOC usually runs a rapid course; death or
almost complete recovery within 24 to 48 hours is the general rule.
The increase in metabolic rate is proportional to the dose of
the toxicant absorbed, and very high levels (up to 4 times normal)
may be reached temporarily. However, with high metabolic rates,
heat production so exceeds the physiologic capabilities of heat
111
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dissipation that fatal hyperthermia may result. DNOC is much more
effective in raising the body temperature if the temperature of the
surroundings is 22°C. (72°F.) or over. If the external temperature
is 16°C. (61°F.) or below, increased oxidation and pyrexia are not
produced. On the contrary, in this situation, DNOC lowers oxida-
tion by greatly diminishing or abolishing shivering, and eventually
causes rapid cooling of the animals. Beat regulation is, therefore,
disturbed in both directions, so as to exaggerate the detrimental
effects of external temperature.
The signs and symptoms of chronic DNOC intoxication may
include fatigue, restlessness, anxiety, excessive sweating, un-
usual thirst, and loss of weight. Yellow staining of the conjunc-
tivae may be noted though staining of skin is not necessarily in-
dicative of poisoning. Cataract formation is another possible
sequela of chronic DNOC poisoning.
Laboratory Findings: The most striking laboratory finding is the
increased basal metabolic rate (BMR). A test is available for
determining the blood and urinary content of DNOC. Repeated daily
oral doses of 75 mg. gives rise, after 3 days, to a blood level of
about 20 ppm. Symptoms appear when the concentration in the blood
reaches 40 ppm, or more. A case with a blood level of 70 ppm, termi-
nated fatally. In very cool weather, blood levels as high as 50 ppm
may be tolerated without symptoms.
Pathology: In persons who have died from the effect of DNOC,
yellow staining of the organs, tissues, and fluids due to the pres-
ence of the sodium salt of DNOC may be noted. The lungs are con-
gested and there is usually some edema and a few petechial hemor-
rhages. There may be similar hemorrhagic changes in the brain and
gastric mucosa.
Differential Diagnosis: The symptoms of chronic poisoning from
substituted dinitrophenols resemble those of hyperthyroidism rather
closely. BMR determination, of course, is of no value in differentia-
ting between these two conditions. An exposure history should pro-
vide some basis for making a distinction. In doubtful cases, this
may be supplemented by urine and blood determinations for DNOC
112
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content, and by the use of other tests for thyroid function such as
blood protein-bound iodine, and rate of uptake of radioactive iodine
by the thyroid gland.
Acute poisoning is so rapid in onset that it will not be con-
fused with hyperthyroidism. It may be confused with other forms of
poisoning merely because of rapidity and severity. Confusion with
poisoning by an organic phosphorous compound would be disastrous.
Treatment: Atropine sulfate is absolutely contraindicated. The
poison should be promptly removed from the skin and/or gastro-
intestinal tract with an appropriate alkaline agent. No attempt
beyond ordinary washing should be made to remove the deeply-
penetrated, persistent stain from the skin or hair.
Treatment consists of an ice bath to reduce the patient's fever,
the administration of oxygen to assure maximal oxygenation of the
blood, and the infusion of large quantities of isotonic saline to
replace the fluid and electrolyte lost by sweating.
It has been claimed that the intravenous injection of 10 ml.
of a 2.5% solution of sodium methyl thiouracil rapidly reduces the
BMR in persons in whom the rate of metabolism has been increased
by DNOC.
Prevention: Applicators should observe all necessary precautions
in using dinitrophenols and should have routine periodic checks of
blood levels. The significance of different concentrations of DNOC
in whole blood is as follows:
0-10 ppm trivial
11 - 20 appreciable absorption
21-30 unsafe
31 - 40 likely to cause some toxicity
41 - 50 dangerous
> 50 critically dangerous
Corresponding values for plasma or serum are approximately twice
as high.
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SOLVENTS
Introduction: Solvents and other carriers may contribute to the
danger of insecticidal formulations either through their inherent
toxicity or through their solubilizing action on the so-called active
ingredients. In some instances, cases of poisoning by solutions of
insecticides have been characterized by symptoms and clinical
course indistinguishable from those caused by the solvent alone.
On the other hand, a clinical course characteristic of the active
ingredient has been present in other cases.
Kerosene
Identity: Kerosene, or coal oil, is a mixture of principally aliphatic
hydrocarbons distilled from petroleum in the temperature range of
204° to 315°C. The empirical formula is CnH2n+ 2 (Where n ranges
from approximately 10 to 16). Other petroleum fractions such as
diesel fuels Nos. 1 and 2 are closely related chemically, and much
of this section pertains to such fractions also.
Formulations: Kerosene is one of the most common solvents in
insecticidal solutions and emulsions, especially in sprays of the
household type, which may contain up to 98% kerosene. This sol-
vent is usually highly refined and — unlike fuel grade kerosene —
essentially odorless. Other toxic solvents are often included in
formulations of insecticides.
Uses: Kerosene is used as a solvent, diluent, and vehicle in
sprays for household, agricultural, and public health use. Kerosene
is also commonly used alone as an herbicide, as a fuel, as an in-
dustrial solvent, and for many other purposes.
Routes of Absorption: Kerosene may be absorbed orally or through
the respiratory tract. Its dermal absorption is not significant for
systemic poisoning under ordinary conditions of exposure
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Pharmacologic Action: Systemically, kerosene acts as a narcotic
producing depression that may or may not be preceded by an excite-
ment phase. At least in connection with ingestion, depression
per se is apparently never fatal although it may be alarming. Liver
and kidney damage may occur in severe cases. Coma and other
major central nervous system effects are frequently present in
cases that result from fumes and are serious enough to come to
medical attention. However, such serious effects are reported in
only 3% to 6% of cases involving ingestion. In one series of 204
cases, 4% of the children were semiconscious but none had con-
vulsions, 40% were lethargic and 28% had gastrointestinal symp-
toms; however, all had respiratory symptoms and 3% died. Ingestion
of kerosene has been known to produce rapid death by gross aspira-
tion and occlusion of the respiratory system. Even when death does
not occur promptly, there is abundant evidence that the pneumonia
commonly seen in children who swallow kerosene usually results
from aspiration. The aspiration usually occurs at the moment of
ingestion or as the result of vomiting within the first hour. The
ratio of the oral to the intratracheal LD5Q for kerosene is approxi-
mately 140:1. Animal experiments prove that kerosene is absorbed
from the gastrointestinal tract. Concentrations of aromatics as high
as 140 ppm and of aliphatics as high as 917 ppm were found in
blood or tissues. In spite of this absorption, the lungs of animals
receiving dosages of 13 ml./kg. or less with precautions to prevent
aspiration were normal histologically when the animals were sacri-
ficed. The lungs of rats dosed at 18 ml./kg. showed moderate
changes on sacrifice, and rats killed by 30 to 40 ml./kg. showed
more marked pathology of the lungs as well as liver and kidney
changes. Fatal aspiration leads to gross hemorrhagic pneumonitis
most severe in the hilar and dependent portion of the lung in con-
trast to the even distribution of hemorrhage following rapid intra-
venous injection or pulmonary edema following slow intravenous
injection. It would appear that, in the absence of aspiration, the
dosage of kerosene necessary to produce pneumonitis or other
serious effects is greater than that likely to be ingested. Evidence
on the effect of mineral oil and vegetable oil on absorption of
kerosene is conflicting.
115
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Like many other oils, kerosene is a local irritant and may
cause a maculopapular eruption of the exposed skin. The irritation
tends to increase and later decrease with repeated exposure over a
long period.
Dangerous Single Dose to Man: Although kerosene is a common
cause of poisoning especially in children, the amount taken is
seldom known. Survival has been reported following the ingestion
of one liter, but death has followed the ingestion of doses as small
as 30 ml., especially after kerosene was aspirated. The air con-
centration capable of producing acute symptoms by inhalation is
not known.
Dangerous Repeated Dose to Man: Chronic intoxication has not
been reported.
Signs and Symptoms of Poisoning of Man: The use of kerosene
sprays in closed or poorly ventilated spaces may lead to fullness
of the head, headache, blurred vision, dizziness, unsteady gait, and
nausea. More massive exposure may cause collapse, nervous twitch-
ing; and coma before the victim is apparently aware of overexposure
and before he seeks fresh air.
Ingestion frequently results in immediate gagging and coughing
and thus leads to aspiration of the oil. The initial symptoms are
followed by deep drowsiness. In the more serious cases, broncho-
pneumonia may develop in 24 to 36 hours. Chest signs are likely to
be few or absent even when X-ray of the chest reveals an extensive
bronchopneumonia. Liver and kidney damage may be manifest by
hepatomegaly and by albumin, cells, and casts in the urine.
Laboratory Findings: Leukocytosis and albuminuria or casts
(generally in severe cases, only) may be present. It may be pos-
sible to recognize kerosene in stomach contents by its characteris-
tic odor. This odor will be negligible or absent in poisoning by
deodorized kerosene. X-ray and liver and kidney function tests
should be used to follow the progress of visceral damage.
116
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Pathology: Bronchopneumonia, visceral congestion, acute pul-
monary edema, and hemorrhage. Evidence of inflammation of the
upper gastrointestinal tract may be seen in cases that die early.
Differentia! Diagnosis: The case history will usually establish the
diagnosis. The characteristic odor may or may not be present.
Where there is doubt, poisoning by alcohol and other solvents and
by a wide range of narcotic agents may be considered as well as
diabetic coma.
Treatment: The injury caused by inhalation of kerosene fumes
seldom requires any treatment except prompt removal from exposure.
If kerosene containing no insecticide has been ingested, gas-
tric lavage may be done mainly as a precaution against regurgitation
and aspiration from the gastrointestinal tract. A recent study has
shown that gastric lav age was not harmful to patients but there
was no conclusive evidence that it was beneficial. This is en-
couraging in connection with cases in which the ingested kerosene
was the solvent for an insecticide that should be removed rapidly
and thoroughly. If attempted, the gastric lavage should be done very
early before narcosis sets in and every other possible precaution,
including use of an intratracheal tube with inflated balloon, should
be taken so that the lavage itself does not lead to aspiration of the
kerosene. Emetics are contraindicated. Oil laxatives should be
avoided, especially if the kerosene was the vehicle for an insecti-
cide. A saline laxative may be helpful. Sedatives and stimulants
may be used symptomatically in moderation. Antibiotic therapy
does not benefit kerosene pneumonia as such, but it may be of some
benefit in preventing bacterial invasion. Oxygen should be used
promptly if the patient shows any respiratory difficulty or the
slightest cyanosis. Cortisone and related drugs have been used for
treating chemical pneumonitis caused by kerosene and other oils,
but the value of this treatment remains to be determined. There
seems to be no doubt that the inflammatory reaction is suppressed
and symptoms are relieved, but there is some indication that this
merely postpones the removal of oil from the lung and healing of
the injury. Thus, the value of adrenocortical steroids for the treat-
117
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ment of kerosene pneumonitis can be decided only after further
carefully-controlled study. Liver damage may be minimized by the
use of a diet low in fat and adequate in carbohydrate. The useful-
ness of lipotrophic drugs has not been investigated in this con-
nection. Kidney involvement is rarely sufficient to merit special
treatment and for those rare cases where the kidneys are seriously
involved the treatment should be the same as for toxic nephritis
of other etiology.
Kerosene dermatitis requires no special treatment and will
regress spontaneously if exposure is discontinued. Cleanliness
will help to prevent its occurrence.
Xylei
Chemical Name: A mixture of o—, m—, and p-xylene. (The ortho
isomer is predominant in percentage.)
Chemical Formulae:
CHj
ortho
isomer
CHj
meta
isomer
isomer
Formulations and Uses: Xylene is a common solvent in insecti-
cidal solutions, emulsifiable concentrates, and emulsions. It is
extensively used in industry especially as the main constituent
of "solvent naphtha."
Routes of Absorption: Xylene is absorbed when taken orally or
inhaled by the respiratory tract. Its dermal absorption is not sig-
nificant under ordinary conditions of exposure.
118
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Phormacologic Action: Undiluted xylene is a severe irritant to
mucous membranes and delicate skin. Xylene can cause a local
dermatitis on any type of skin if used repeatedly. When absorbed,
it acts as a narcotic and affects the circulating red blood cells.
Dangerous Single and Repeated Doses to Man: The smallest oral
dose which may prove fatal is unknown. The threshold limit value
for xylene in air has been set at 870 mg./M3.
Signs and Symptoms of Poisoning in Man: Local application to
tender skin or to the eyes results in intense burning. Exposure to
vapors in a poorly ventilated room results in headache, disturbed
vision, dizziness, poor coordination, and nausea. Severe exposure
may lead to collapse and coma. Repeated exposure may lead to
moderate anemia as well as headache, dizziness, malaise, loss of
appetite, ready fatigue and later nausea, chilliness, and hemorrhage
from the nasal mucosae. It should be pointed out that commercial
grades of xylene may be contaminated by appreciable amounts of
benzene, so that the inhalation of the vapor may affect the hemat-
opoietic system.
Laboratory Findings: Complete blood studies.including, if neces-
sary, sternal puncture should be done if chronic xylene poisoning
is suspected. Macrocytosis, moderate decrease of the red cells,
and lymphocytosis are suggestive but not diagnostic.
Differential Diagnosis: Diagnosis is usually established by the
history. If in doubt, alcohol and a wide variety of narcotic agents
must be considered. Changes in the blood picture must be distin-
guished from similar changes caused by other materials and from
acute leukemia.
Treatment: If the eyes or skin are contaminated, they should be
thoroughly washed. Two percent butyn sulfate ophthalmic ointment
may be placed in the eyes immediately after washing to allay pain;
119
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later cortisone ophthalmic ointment may be used to reduce inflam-
mation. Any analgesic ointment may be applied to the skin.
If xylene has been taken by mouth, an effort should be made to
remove it by induced vomiting and by gastric lavage. Oi! laxatives
should be avoided if the xylene served as a vehicle for an insecti-
cide. Saline laxatives may be used. General care of the patient is
symptomatic.
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APPENDIX A
CASE HISTORY FORM*
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NSM: DO MOT URITE IK THIS BOX
Address: Case No.:
Phone: Code:
An: Sex: Race: Mar. Status: Diagnosis:
Occupation: Investigator: Date:
EsBloyer: Address:
Referred by: Address:
CHIEF COHPIAW with date and tlsK of onset:
PRESENT ILUBSS:
GEM: Fever .Weight change, Ueakn««., Fat igability, Sweating, Sleep, Skin, Allergy
Cj: n*uaea,VoaltlnglAppetite, Taste, Gas, Pain, Stools, Sialorrhea
MM: Ketdacha,Dl«lne»s,IrritabiUty,Paresthesla, Pains, Twitching, Tremors,
Fasciculatlons, Convulsions, Hallucinations, Unconsciousness
CR: Nasal dlscharge.Wheexe^Cough, Expectoration, Pain, Tightness, Dyspnea,
Palpitation, Heart consciousness, Tachycardia, Hypertension, Fainting, Cyanosis
OT: Urination
EYE: Miosls, Acuity, Depth perception, Double vision, Intensity, Tearing
PSY: TesKieranent , Judgment .Affect, Memory, Nervousness, Drowsiness, Insomnia
PAST HLMESS (Especially that caused by poisons or of unknown origin):
FAMILY HISTORY:
DOCTOR'S ORIGINAL CLINICAL IMPRESSION:
"" 'i'.Vi(Ca:' TOXICOLOGY CAM MISTOdt sZ.r.wS ... SS..M
•The form is shown In reduced size. Full-sized copies will be sent to collabo-
rating physician! who request them from the following addresses.
Chamblee Toxicology Laboratory, EPA
4770 Buford Highway
Chamblee, Georgia 30341
Wenatchee Research Station, EPA
P. O. Box 73
Wenatchee, Washington 98801
121
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CASE HISTORY FORM (Continued)
PREVIOUS EXPOSURE: Compou
ads
No. Seasons No. days this season.
DVfM?1JT 17WOCITPV.
REICH i EXrUaUKC:
Compounds
Date and tine began
ended
Duration exposure (hours)
Strength of poison as
sold? Ytettable powder,
solution, or dust? Final
strength used? How appl.?
Crop or other use
Route exposure: oral
dermal
respiratory
mixed
pT^lve comple"
clothing:
partial
gloves
shoes or boots
Respirator: type
Ablutions: washing
bathing
clothes changed
Habits: smoking
alcohol
Temp, and humidity
Sweating
Describe any known spill-
age or accident, and sub-
sequent clean up, if any.
Immediate or Last
Other Recent
Remarks:
122
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CASE HISTORY FORM (Continued)
LABORATORY ANALYSES:
Lab No. SAMPLE
DATE HOUR ANALYSIS FOR
RESULTS
BY
TREATMENT AND CLINICAL COURSE:
FIRST AID
ATTENDED BY_
M.D. of
Address
Home, Office, Hospital.
ADMITTED: Date
DISCHARGED: Date
DETAILS:
Hour
Condition
Condition
CONVALESCENCE RECOMMENDATIONS AND RETURN TO WORK:
123
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APPENDIX B
Instructions for obtaining and shipping a fat biopsy for analysis
for fat soluble compounds.
1. Fat from any portion of the body is suitable. However, when
performing an operation primarily for the purpose of obtaining a
biopsy, it is convenient to obtain the fat from the subcutaneous
tissue of the anterior part of the abdomen. It is more comfortable
for the patient if the belt line is avoided for the site of incision.
The minor surgical procedure may be done on an outpatient basis.
2. The amount of fat should be about 2.5 g. This is a piece about
the size of the tip of a man's thumb. The fat should be separated
from any attached skin or other nonfatty tissue, blotted with paper
toweling, and then weighed carefully on a pharmacist's balance (or
one more accurate).
3. Immediately after weighing, the biopsy should be placed into a
small, wide-mouth bottle and frozen. No preservative should be
used because of interference with certain tests, except that 10%
formalin may be used if chlorinated hydrocarbons are the only com-
pounds for which analysis is desired. The container should be
tightly closed and taped and the label filled in with the following
information:
(a) Name of patient
(b) Weight of sample in grams
(accurate to at least two decimal places)
(c) Date sample taken
(d) Name of referring physician
124
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Frozen samples should be shipped in dry ice by air. Samples pre-
served with formalin may be shipped by surface mail. Specimens
should be sent to the nearer of the following addresses:
Chamblee Toxicology Laboratory, EPA
4770 Buf ord Highway
Chamblee, Georgia 30341
Wenatchee Research Station, EPA
P. 0. Box 73
Wenatchee, Washington 98801
125
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APPENDIX C
Instructions for drawing, preparing, and shipping blood samples
for cholinesterase determinations.
Blood should be taken by venipuncture in the usual way, using
sterile equipment. Heparin is the anticoagulant of choice, and the
minimal amount to prevent clotting should be used, so as to dilute
the blood sample as little as possible. Merely wetting the inside
of the syringe with heparin as supplied in the ampule (1,000 units
per milliliter) is sufficient. Sodium citrate may be used if heparin
is unavailable. The blood should be carefully transferred from
the syringe to a clean, dry 15-ml. graduated centrifuge tube by
gentle pressure on the plunger. The needle should be removed, and
the aperture of the syringe should be placed in contact with the
side of the tube before the blood is forced out. These precautions
are helpful in preventing hemolysis. Ideally, ten milliliters of blood
should be drawn and processed to insure adequate amounts of
material for cholinesterase analysis and other tests that may be
indicated.
The collected blood is centrifuged for 15 minutes at 2,000 rpm,
and the plasma thus separated. The plasma may now be placed in a
clean, dry, glass or polyethylene test tube of suitable size, closed
with a tight-fitting, rubber or polyethylene stopper, and plainly
labeled. The white cells and any remaining plasma at the interface
in the centrifuge tube are discarded. The remaining red cells are
transferred to a test tube, stoppered, and labeled in a manner simi-
lar to that suggested for plasma.
The samples must be kept refrigerated. For shipment, the
tubes should be wrapped to prevent breakage. Refrigeration may
be provided by placing the samples between plastic bags filled
with chips of ice. Refrigeration may also be provided by "refreez-
ants" (water or silica gel packaged in plastic or metal) sold for
keeping picnic lunches and drinks cold. Before use, refreezants
must be thoroughly frozen.
126
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It is just as important that the shipping containers be carefully
insulated and sealed as that the samples be surrounded by ice.
Never use dry ice for cholinesterase samples because the
samples will freeze and the red cell sample will be ruined.
It is recommended that shipments be made by the fastest avail-
able means of transportation in order to insure adequate refrigera-
tion for the samples during the entire period of shipment. Please
mark all packages "PERISHABLE," "RUSH," and "REFRIGE-
RATE UPON ARRIVAL - DO NOT FREEZE."
Samples for analysis should be sent to the closest of the fol-
lowing laboratories:
Chamblee Toxicology Laboratory, Wenatchee Research Station,
EPA EPA
4770 Buford Highway P. O. Box 73
Chamblee, Georgia 30341 Wenatchee, Washington 98801
127
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APPENDIX D
Instructions for shipping stomach contents, urine, tissues, or cer-
tain other materials for toxicological examination.
If the nature of the toxicant is unknown, it may be expedient
to do a bioassay, and formalin or other preservatives (even volatile
ones) may interfere with the procedure. In such instances, speci-
mens for routine toxicological study may be frozen and shipped with
dry ice. Packages should be marked "PERISHABLE," "RUSH,"
and "FREEZE ON ARRIVAL." They should be shipped by the
fastest means of transportation available to one of the addresses
given below.
Each sample of an organ or tissue should be in a separate
jar.
It is usually satisfactory to preserve urine with a few drops
of 10% formalin and ship the specimen by ordinary mail. In case of
doubt, urine too may be shipped under refrigeration. (Of course,
liquid in glass cannot be shipped with dry ice because freezing of
the liquid may break the glass.)
Samples of insecticides suspected of being the cause of poi-
soning should be shipped in a completely separate package from
blood, tissue, or other biological specimens because of the possi-
bility of vapor contamination. If clothing or other objects suspected
of being contaminated by insecticides are to be shipped, they should
be put in a third package; if there is any possible difference be-
tween the samples, they should be sealed in glass jars. Ordinary
plastic wrapping may not be sufficient to prevent cross-contamina-
tion.
Chamblee Toxicology Laboratory, EPA
4770 Buford Highway
Chamblee, Georgia 30341
Wenatchee Research Station, EPA
P. O. Box 73
Wentachee, Washington 98801
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APPENDIX E
ARTIFICIAL RESPIRATION
Unless the apneic victim is in a toxic atmosphere, do not
waste time moving him. Start artificial respiration at once. The
mouth-to-mouth (or mouth-to-nose) technique of artificial respiration
is the only one that requires no equipment and will still overcome
the airway resistance that may be present in poisoning by organic
phosphorus insecticides as a result of bronchial constriction and
excessive secretion. No matter why breathing has stopped, this
technique allows the rescuer to get a better idea of the volume and
pressure needed to inflate the victim's lungs than can be gotten
by other methods. Timing tends to be correct automatically with
the mouth-to-mouth method, because the nonbreathing adult needs
about the same volume of air as the rescuer breathes at the normal
rate (12 to 16 per minute), while the infant or very young child
requires a smaller volume delivered at a slightly higher rate (about
20 per minute).
When a person is unconscious and stops breathing, the base
of the tongue tends to press against the back of the pharynx and
block the passage of air from either the nose or mouth into the
lungs. To clear the upper airway, wipe out the mouth with your
finger covered by your handkerchief or your shirt. Roll the victim
onto his back. Place both your hands at the angles of his lower
jaw and lift it so that it juts out and the head tilts back (Fig. 1).
You may do the same thing by putting your thumb in his mouth,
grasping the jaw, and pulling it forward.
Having cleared the airway, pinch the victim's finger so that
your fingernail is driven in hard enough to cause sharp pain in a
normal person. This may cause the victim to gasp and start breath-
ing again. If this maneuver fails and if the victim is a child, place
your mouth over his mouth and nose and blow into him gently so
that the chest is inflated to about the normal degree (Fig. 2).
Remove your mouth to take fresh air and to let the victim breath
out. As you remove your mouth, turn your ear to listen for air being
129
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passively exhaled by the victim. Repeat the active inflation and
passive deflation of the victim 20 times per minute.
If the victim is adult, place your mouth over either his nose
or mouth and pinch the other opening closed with the fingers of
one hand. (You can blow between his teeth even though his jaws
are closed.) You will have to blow harder to get enough air into
an adult, especially a heavily muscled one. Insofar as possible,
keep the jaw jutting out while artificial respiration progresses.
If there seems to be resistance to your blowing, recheck the
position of the jaw. A child may be held up by the ankles (Fig. 3)
or hung with his abdomen over one of your arms (Fig. 4) while
you pat him sharply on the back in the hope of dislodging any
obstructing matter. This effort should last only a moment. Wipe
out the mouth again and continue artificial respiration.
If obstruction is still present after the jaw has been rechecked
and if the victim is too heavy to lift, he may be rolled onto his
side and struck several times between the shoulder blades in the
hope of dislodging foreign matter. Clean out the mouth and continue
artificial respiration.
If the victim vomits, turn the head quickly to the side. Clear
out the mouth and continue artificial respiration as soon as pos-
sible. Those who do not wish to contact the victim directly may
cover his mouth with a cloth. This will not interfere very much
with the exchange of air.
If someone comes to help, send him to call the police for an
ambulance equipped for mechanical artificial respiration.
If the victim begins to breathe for himself, try to time your
blowing to match his rate of breathing and help his natural inspira-
tion. As his breathing becomes stronger, stop helping but watch
very closely lest he stop again. Keep the person as quiet as
possible.
If the victim does not start to breath promptly, do not despair.
Remember that some poisoned people who required artificial respira-
tion for many hours survived without permanent injury.
130
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FIGURE 1. Tilt the head back and
lift the jaw forward before giving
artificial respiration.
FIGURE 2. Blow into the child's
mouth and nose about 20 times a
minute (12-16 for adults) holding the
head back and the chin up.
FIGURE 3. Invert the infant and pat
him on the back if there is something
caught in the windpipe.
FIGURE 4. Hold an older child over
your arm to dislodge an obstruction
to breathing.
Figures on artificial respiration by courtesy of the American Red Cross.
131
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SUMMARY
1. Don't waste time moving the victim unless he is actually in a
toxic atmosphere.
2. Quickly clear the mouth and throat.
3. Tilt head back as far as possible.
4. Lift lower jaw forward.
5. Pinch the patient sharply to see if he will gasp and breathe.
If this fails,
6. open your mouth wide and blow into the victim's mouth and
nose (or one of them with the other squeezed shut) until you
see the chest rise.
7. Listen for exhalation.
8. Repeat (No. 6 and 7) 12 to 16 times per minute for adults or
20 per minute for small children.
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LIST OF MANUFACTURERS
1. Agricultural Chemical Company, Phoenix, Arizona.
2. Amchem Products, Inc., Agricultural Chemicals Division,
Ambler, Pennsylvania.
3. American Cyanamid Company, Agricultural Chemicals Division,
30 Rockefeller Plaza, New York 20, New York.
4. American Potash and Chemical Corporation, Agricultural Chem-
icals Division, 3000 West 6th Street, Los Angeles 54, Cali-
fornia.
5. Bayer Farbenfabriken, Bayerwork, Leverkusen, Germany.
6. California Chemical Company, Ortho Division, Lucas and Ortho
Way, Richmond, California.
7. Chemagro Corporation, Hawthorn Road, Kansas City 20, Mis-
souri.
8. Chipman Chemical Company, Bound Brook, New Jersey.
9. Ciba, Ltd., Basel, Switzerland.
10. Commercial Solvents Corporation, 260 Madison Avenue, New
York 16, New York.
11. Dow Chemical Company, Midland, Michigan.
12. E I. du Pont de Nemours and Company, Inc., Grasselli Chemi-
cals Department, Wilmington 98, Delaware.
13. Fisons Pest Control Ltd., Harston, Cambridge, England.
14. Geigy Agricultural Chemicals, Post Office Box 430, Yonkers,
New York.
15. Hercules Powder Company, Inc., Agricultural Chemicals Divi-
sion, Wilmington 99, Delaware.
16. Imperial Chemicals Industries Ltd., Curzon Street, London Wl,
England.
17. Monsanto Chemicals Company, Organics Division, 800 North
Lindberg Blvd., St. Louis 24, Missouri.
18. Montecatini, Via F. Turati 18, Milan, Italy..
19. Motomco, Inc., 89 Terminal Avenue, Clark, New Jersey.
20. Norda Essential Oil and Chemical Company, 601 West 26th
Street, New York, New York.
133
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21. Rohm and Haas Company, Washington Square, Philadelphia 5,
Pennsylvania.
22. Shell Chemical Corporation, Agricultural Chemicals Division,
110 West 51st Street, New York 20, New York.
23. Standard Agricultural Chemicals, Inc., Hoboken, New Jersey.
24. Stauffer Chemical Company, 380 Madison Avenue, New York 17,
New York.
25. Thompson Hayward Chemical Company, Kansas City, Missouri.
26. Union Carbide Chemicals Company, 30 East 42nd Street, New
York 17, New York.
27. Velsicol Chemical Corporation, 330 East Grand Avenue, Chi-
cago 11, Illinois.
Names and addresses of manufacturers whose trade name
products are mentioned in this Handbook are provided for the con-
venience of the physician. Manufacturers are often good sources of
recent and detailed information on the toxicology of their products.
It may sometimes be necessary for a physician to get in touch with
one of them without delay.
134
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INDEX
Insofar as possible, common or standard names have been
used in the text of this Handbook. However, some containers for
pesticides are so labeled that only the chemical name or the trade
name of the principal active ingredient is given. Chemical names and
important trade names of compounds mentioned in the text are
listed in the following index so the Handbook will be of use to
physicians in emergencies. In most instances, the form of chemical
name favored by Chemical Abstracts has been used. Unfortunately,
limitation of space makes it impossible to include all relevant trade
names or all important variants of chemical names. A number assoc-
iated with each trade name below indicates a company in the pre-
ceding list that is concerned. Main headings in the text are printed
in bold type in the index.
Aldrin (see related compound dieldrin) 62
Allethrin 74
3-Allyl-2-methyl-4-oxo-2-cyclopenten-l-yl
chrysanthemumate (allethrin) 74
2-sec-Amyl-4-6-dinitrophenol (isopropanolamine) 109
Arsenic 101
Artificial respiration (appendix E) 129
Azinphos-methyl (Guthion ®.7) 30
Bayer L 13/59 (trichlorofon) 42
Bayer 21/199 (Co-Ral ®-7) 24
Bayer 22/190 (Chorthion 24
Bayer 8169 (demeton) 27
Bayer 17147 (Guthion <§>-?) 30
Baytex ®-7 (fenthion) 13
Benzahex (BHC) 50
Benzene hexachloride (BHC) 50
BHC 50
2,2,Bis-(p-chlorophenyl)-l,l,l-trichloroethane (DDT) 58
135
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Botanical insecticides 74
Bulan ®-io (see Dilan ®-io) 67
2-sec-Butyl-4,6-dinitrophenol (dinitrobutylphenol) 109
Carbamate insecticides 44
Carbaryl 44
2-Carbomethoxy-l-methylvinyl dimethyl phosphate
(Phosdrin ©-22) 38
Carbophenothion (see organic phosphorus insecticides) 13
Case history form (appendix A) 121
CD-68 (chlordane) 55
Chlordan (chlordane) 55
Chlordane 55
Chlorinated camphene (toxaphene) 71
Chlorinated hydrocarbon insecticides 47
Chlorobenzilate ®-M (see related compound DDT) 58
2-Chloro-2-diethylcarbamoyl-l-methylvinyl dimethyl
phosphate (phosphamidon) 13
Chlorophenothane (DDT) 58
Chlorophenoxy herbicides 106
Chlorothion (Chlorthion ® -?) 24
Chlorthion <§) -7 24
Clinical tests 6
Coal oil (kerosene) 114
Compound 42 (warfarin) 85
Compound 269 (endrin) 68
Compound 497 (dieldrin) 62
Compound 1080 (sodium fluoroacetate) 79
Compound 3422 (parathion) 35
Compound 3911 (phorate) 37
Compound 3956 (toxaphene) 71
Compound 4049 (malathion) 31
Compound 4124 (dicapthon) 13
Co-Ral ®-7 24
Coumachlor (see related compound warfarin) - 85
Coumafene (warfarin) 85
136
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Coumafuryl (see related compound warfarin) 85
2-Cyclohexyl-4,6-dinitrophenol (dinitrocyclo-
hexylphenol) 109
2,4-D (see chlorophenoxy herbicides) 106
Dalmatian insect flowers (pyrethrum) 74
DBD (Guthion®-7) 30
DDA (see related compound DDT) 58
ODD (TDE) 58
DDE (see related compound DDT) 58
DDT 58
DDVP 25
Delnav ®-is (see organic phosphorus insecticides) 13
Demeton 27
Deobase (kerosene) 114
Oiazinon <§)-i4 29
Dibrom ®-6 (naled) 25
l,2-Dibromo-2,2-dichloroethyl dimethyl phosphate
(naled) 25
Dicapthon (see organic phosphorus insecticides) 13
l,l-Dichloro-2,2-bis(p-chlorophenyl) ethane
tetrachlorodiphenylethane (TDE) 58
2,4-Dichlorophenoxyacetic acid (2,4-D) 106
Dichlorvos (DDVP) 25
Dicophane (DDT) 58
Dieldrin 62
Diesel oil (see related kerosene) 114
0,0-Diethyl 0-(3-chloro-4-methyl-2-oxo-2H-l- benzopyran-
7-yl)phosphorothioate (Co-Ral®-?) 24
0,0-Diethyl p-chlorophenylmercaptomethyl dithio-
phosphate (carbophenothion) 13
0,0-Diethyl 0-[2-(ethylthio)ethylJphosphorothioate plus
0,0-diethyl S-[j-(ethylthio)ethyl_]phosphorothioate
(demeton) 27
0,0-Diethyl 0-(2-isopropyl-4-methyl-6-pyrimidinyI)
phosphorothioate (Diazinon®-!.*) 29
137
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0,0-Diethyl S-(methylthio-ethyl) phosphorodithioate
(phorate) 37
0,0-Diethyl O-(p-nitrophenyl) phosphorothioate
(parathion) 35
Dilan ®-io 67
Dimecron ®.p (phosphamidon) 13
Dimethoate (see organic phosphorus insecticides) 13
Dimethylbenzene (xylene) 118
0,0-Dimethyl O-(m-chloro-p-nitrophenyl) phosphorothioate
(Chlorthion <§>-?) 24
0,0-Dimethyl 0-(2-chloro-4-nitrophenyl) thiophosphate
(dicapthon) 13
0,0-Dimethyl S-(l,2-dicarbethoxyethyl) phosphoro-
dithioate (malathion) 31
0,0-Dimethyl 2,2-dichlorovinyl phosphate (DDVP) 25
0,0-Dimethyl S-(N-methylcarbamoylmethyl) phosphoro-
dithioate (dimethoate) 13
0,0-Dimethyl O-(p-nitrophenyl) phosphorothioate
(methyl parathion) 34
0,0-Dimethyl S-(4-oxo-l,2,3-benzotriazin-3 (4H)-ylmethyl
phosphorodithioate (Guthion ®-T) 30
Dimethyl parathion (methyl parathion) 34
0,0-Dimethyl-2,2,2-trichloro-l-hydroxyethyl phosphonate
(trichlorofon) ; 42
0,0-Dimethyl 0-(2,4,5-trichlorophenyl) phosphorothioate
(ronnel) 13
Dinitrobutylphenol (see dinitrophenols) 109
Dinitrocresol (DNOC) 109
Dinitrocyclohexylphenol (see dinitrophenols) 109
4,6-Dinitro-o-cresol (DNOC) 109
Dinitrophenols 109
Dinoseb (dinitrobutylphenol) 109
Dipterex <§)-? (trichlorofon) 42
Disodium ethylene bisdithiocarbamate (nabam) 90
Di-Syston ®-? (sulfur analog of demeton) 27
Dithane D-14 ®-2i (nabam) 90
138
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Dithane-Manganese ®-2i (maneb) 90
Dithane Z-78 ®-2i (zineb) 90
Dithiocarbamates _ 90
DNBP (dinitrobutylphenol) 109
DNC (DNOC) 109
DNOC (see dinitrophenols) 109
DNOCHP (dinitrocyclohexylphenol) 109
DNOSBP (dinitrobutylphenol) 109
DNSBP (dinitrobutylphenol) 109
DNTP (parathion) 35
DSE (nabam) 90
Dylox ®-7 (trichlorofon) 42
E-600 (paraoxon) 35
E-601 (methyl parathion) 34
E-605 (parathion) 35
E-1059 (demeton) 27
E-3314 (heptachlor) 70
Elgetol 30 ®-23 (DNOC) 109
Endrin 68
EPN (see organic phosphorus insecticides) 13
Ethion (see organic phosphorus insecticides) 13
Ethyl 4,4'-dichlorobenzilate (Chlorobenzilate ®-i4) 58
0-Ethyl 0-p-nitrophenyl phenyl phosphonothioate
(EPN) 13
Fenthion (see organic phosphorus insecticides) 13
Ferbam (see dithiocarbamates) 90
Fermate ®-i2 (ferbam) 90
Ferric dimethyldithiocarbamate (ferbam) 90
Folidol <§) -s (parathion) 35
Fuel oil (see related kerosene) 114
Fumarin ®-2 (coumafuryl) 85
Fungicides 90
G-24480 (Diazinon ®-i4) 29
Gammexane ®-ie (BHC) 50
Gesapon ®-i4 (DDT) 58
Gesarex ®-J4 (DDT) 58
Gesarol ®-i4 (DDT) 58
139
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Guesarol ®-i4 (DDT) 58
Gusathion ®-? (Guthion ®-T) 30
Guthion ®-? 30
HCH(BHC) , 50
HEOD (dieldrin) 62
Heptachlor 70
l,4,5,6,7,8,8-Heptachloro-3a,4,7,7a-tetrahydro-4,7-
methanoindane (heptachlor) 70
Herbicides 101
Herkol ®-20 (DDVP) 25
HETP (see related compound TEPP) 40
1,2,3,4,5,6-Hexachlorocyclohexane (BHC) 50
1,2,3,4,10,10-Hexachloro-6,7-epoxy-l,4,4a,5,6,7,8,8a-
octahydro-l,4-era?o-end0-5,8-dimethanonaphthalene
(endrin) 68
1,2,3,4,10,10-Hexachloro-6,7-epoxy-l,4,4a,5,6,7,8,8a-
octahydro-l,4-en«?o-earo-5,8-diraethanonaphthalene
(dieldrin) 62
l,2,3,4,10,10-Hexachloro-l,4,4&,5,8,8a-hexahydro-l,4-
enJo-ea!o-5,8-dimethanonaphthalene (aldrin) 62
Hexaethyl tetraphosphate (HETP) 40
Insect powder (pyrethrum) 74
Introduction 1
Isodrin (see related compounds dieldrin and
endrin) 62,68
Isopropanolamine (see dinitrophenols) 109
Kelthane ®-zi (see related compound DDT) 58
Kerosene 114
Korlan ®-n (ronnel) 13
L-ll/6 (phorate) 37
Lindane (gamma isomer of BHC) 50
Mai a th ion 31
Malathon (malathion) 31
Maneb (see dithiocarbamates) 90
Manganese ethylene bisdithiocarbamate (maneb) 90
Manzate ®-i2 (maneb) 90
140
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MCP (MCPA) 106
MCPA (see chlorophenoxy herbicides) 106
MEB (maneb) 90
Mephanac (MCPA) 106
Mercury (see organic mercury compounds) 91
Methoxone ®-ie (MCPA) 106
Methoxychlor (see related compound DDT) 58
2-Methyl-4-chlorophenoxyacetic acid (MCPA) 106
2-Methyl-4,6-dinitrophenol (DNOC) 109
Methyl parathion 34
Methyl Trithion ®-24 (see organic phosphorus
insecticides) 13
Milbam ®-i2 (ziram) 90
MnEBD (maneb) 90
Muscotox ®-?(Co-Ral ®-v) 24
Nabam (see dithiocarbamates) 90
Naled (see closely related compound DDVP) 25
Neguvon ®-7 (trichlorofon) 42
Neocid ®-i4 (DDT) 58
Neocidol ®-i4 (DDT) 58
Niran ® -17 (parathion) 35
2-Nitro-l,l-bis (p-chlorophenyl) propane plus 2-nitro-
1,1-bis (p-chlorophenyl) butane (Dilan ®-io) 67
Nitrox 80 ®-7 (methyl parathion) 34
NPD (see organic phosphorus insecticides) 13
Octachlorocamphene (toxaphene) 71
1,2,4,5,6,7,8.8-OctachIoro-3a,4,7,7a-tetrahydro-4,
7-methanoindane (chlordane) 55
Octalox ®-22 (dieldrin) 62
Octamethylpyrophosphoramide (schradan) , 39
OMPA (schradan) 39
Organic mercury compounds 91
Organic phosphorus insecticides 12
Paraoxon (see related compound parathion) 35
Parathion 35
Parathion methyl (methyl parathion) 34
141
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Paris green (see arsenic) 101
Parzate ®-i2 (nabam) 90
Parzate zineb®-i2 (zineb) 90
PCP (pentachlorophenol) 97
Penchlorol (pentachlorophenol) 97
Penta (pentachlorophenol) 97
Pentachlorin (DDT) 58
Pentachlorophenol 97
Perthane ®-2i (see related compound DDT) 58
Pestox 3 ®-i3 (schradan) 39
Phenacide ®-2s (toxaphene) 71
Phenatox ®-i (toxaphene) 71
3-(a-Phenyl- (3 - acetylethyl)-4-hydroxycoumarin
(warfarin) 85
Phorate 37
Phosdrin ®-22 38
Phosphamidon (see organic phosphorus insecticides) 13
Phosphorus 77
Pindone (see related compound warfarin) 85
Pival ®-i9 (pindone) 85
Prolan ®-io (see Dilan ®-io) 67
Pyrethrum 74
Reporting of cases 10
Rhothane ®-2i (TDE) 58
Rodenticides 77
Rogor ® -1 s (dimethoate) 13
Ronnel (see organic phosphorus insecticides) 13
666 (BHC) 50
Schradan •..-• 39
Sevin ®-26 (carbaryl) 44
Sinox ®-23 (DNOC) 109
SNP (parathion) 35
Sodium fluoroacetate 79
Sodium monofluoroacetate (sodium fluoroacetate) 79
Solvents 114
Suggestions for clinical study 4
142
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Systox ®-7 (demeton) 27
Synthetic pyrethrins (allethrin) 74
Sytam (schradan) 39
2,4,5-T (see chlorophenoxy herbicides) 106
1080 (sodium fluoroacetate) 79
TDE (see closely related compound DDT) 58
Ten eighty (sodium fluoroacetate) 79
TEP (TEPP) 40
TEPP 40
0,0,0',O'-Tetraethyl S,S'-methylene bisphosphoro-
dithioate (ethion) 13
Tetraethyl pyrophosphate (TEPP) 40
Tetron ®-4 (TEPP) 40
Thallium 82
Thimet ®-s (phorate) 37
Thiophos ®-3 (parathion) 35
Tomarin ®-i9 (coumachlor) 85
Toxaphene 71
Treatment — general suggestions 7
l,l,l-Trichloro-2,2-bis (/>-methoxyphenyl) ethane
(methoxychlor) 58
Trichlorofon 42
2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) 106
Trichlorophon (trichlorofon) 42
Trieste flowers (pyrethrum) 74
Trithion ®-24 (carbophenothion) 13
Trolene ®-n (ronnel) 13
Vapona ® -22 (DDVP) 25
Vapotone ®-6 (TEPP) 40
Velsicol 104 ®-2? (heptachlor) 70
Velsicol 1068 ®-2? (chlordane) 55
Warfarin 85
WARF-42 (warfarin) 85
Xylene 118
Xylol (xylene) 118
Z-78 (zineb) 90
143
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Zerlate <§>-i2 (ziram) 90
Zinc dimethyl dithiocarbamate (ziram) 90
Zinc ethylene bisdithiocarbamate (zineb) 90
Zineb (see dithiocarbamates) 90
Ziram (see dithiocarbamates) 90
144
U.S. GOVERNMENT PRINTING OFFICE : 1971 O - 74O-352
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