UnTed Slates Environmental
Protection Agwey
EPA 735K13001
Recognition and
Management of
Pesticide Poisonings
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RECOGNITION AND
MANAGEMENT OF
PESTICIDE POISONINGS
Sixth Edition 2013
James R. Roberts, M.D., M.P.H.
Professor of Pediatrics, Medical University of South Carolina
J. Routt Reigart, M.D.
Professor Emeritus, Medical University of South Carolina
Support for this publication was provided by:
Office of Pesticide Programs
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW (7506P)
Washington, DC 20460
To access the electronic version of this manual please visit:
http://www2.epa.gov/pesticide-worker-safety
This manual was developed under Cooperative Agreement No. X8-83384201, awarded by the U.S. Environmental
Protection Agency (EPA) to the Medical University of South Carolina. The design and printing of this manual was
facilitated by the National Association of State Departments of Agriculture Research Foundation (NASDARF) under the
NASDARF Cooperative Agreement with EPA, No. X8-83456201. The information in this publication does not in any
way replace or supersede the restrictions, precautions, directions or other information on the pesticide label or any other
regulatory requirements, nor does it necessarily reflect the position of the EPA.
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Acknowledgments
We would like to thank the Environmental Protection Agency's Office of Pesticide Programs for providing
the opportunity to collaborate on this sixth edition of Recognition and Management of Pesticide Poison-
ings. We are particularly grateful to Kevin Keaney, Chief of Hie Pesticide Worker Safety Program, who
provided the vision and support for the continuation of this manual. Elizabeth Evans. M.P.H., Environmental
Protection Specialist in the Pesticide Worker Safety Program, was our project officer and provided constant
oversight and assistance. We thank Khin Swe Oo, M.D., D.A.B.T., from the Toxicology and Epidemiology
Branch of OPP's Health Effects Division for serving as the lead EPA final technical reviewer for all chapters.
Dian D. Overbey, Environmental Protection Specialist in (lie Communication Services Branch, provided
copy editing.
Amy K. Liebman, M.P. A.. M. A., Director of Environmental and Occupational Health, Migrant Clinicians
Network; Geoffrey M. Calvert, M.D., M.P.H., Senior Medical Officer with the National Institute for Occupa-
tional Safety & Health's Division of Surveillance, Hazard Evaluations, and Field Studies; and Elizabeth Evans
from EPA served as co-authors on Chapter 1, Introduction and Chapter 2, Making the Diagnosis.
This edition was peer reviewed by experts in clinical toxicology. We greatly appreciate the efforts of
the following reviewers:
Alvin C. Bronstein M.D., F. A.C.E.P.
Medical and Managing Director
Rocky Mountain Poison and Drug Center
Denver Health and Hospital Authority
Associate Professor
Department of Emergency Medicine
University of Colorado School of Medicine
Denver, Colorado
Catherine J. Karr, M.D., Ph.D.
Associate Professor
Departments of Pediatrics and Environmental
& Occupational Health Sciences
University of Washington
Director, NW Pediatric Environmental
Health Specialty Unit
Seattle, Washington
Caroline Cox, M.S.
Research Director
Center for Environmental Health
Oakland, California
Matthew C. Keifer, M.D., M.P.H.
Director, National Farm Medicine Center
Marshficld Clinic Research Foundation
Marshfield, Wisconsin
Tammi H. Schaeffer, D.O., F.A.C.M.T.
Medical Toxicologist
Rocky Mountain Poison and Drug Center
Denver Health and Hospital Authority
Assistant Professor
Department of Emergency Medicine
University of Colorado School of Medicine
Denver, Colorado
We are extremely grateful for the assistance of Katie Chamberlain, R.N., in developing this new edition.
Ms. Chamberlain was instrumental in cataloguing electronic versions of all of the references from the previous
edition, securing and organizing the new references, communicating with reviewers and providing editorial
review. It is an understatement to say that she made this process easier than anticipated.
Sally D. O'Neal was responsible for additional editing, graphic design and formatting of this manual.
Carol Black and the National Association of State Departments of Agriculture Research Foundation
(NASDARF) provided financial support for the design and printing of this manual.
Bottom color photo on the cover (clinician and worker) © earldotter.com, courtesy1 Migrant Clinicians Network.
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of
Section I. General Information
1. Introduction 2
2. Making the Diagnosis 13
a. Data Collection on Acute Pesticide Exposed Patient 26
3. General Principles in the Management of Acute Pesticide Poisonings 29
Section II. Insecticides
4. Pyrethrins and Pyrethroids 38
5. Organophosphate Insecticides 43
6. N-Methyl Carbamate Insecticides 56
7. Organochlorincs 63
8. Biologicals and Insecticides of Biological Origin 70
9. Other Insecticides and Acaricides 80
Section III. Herbicides
10. Chlorophenoxy Herbicides 98
11. Pentachlorophenol and Dinitrophenolic Pesticides 103
12. Paraquat and Diquat 110
13. Other Herbicides 118
Section IV. Other Pesticides
14. Insect Repellents 128
15. Arsenical Pesticides 135
16. Fungicides 143
17. Fumigants 161
18. Rodenticides 173
19. Miscellaneous Pesticides, Synergists, Solvents and Adjuvants 188
20. Disinfectants 200
Section V. Chronic Effects
21. Chronic Effects 212
Section VI. Appendixes
Appendix A: Detailed Occupational/Environmental Exposure History 240
Appendix B: Key Competencies for Clinicians 242
Section VII. Indexes
Index of Signs and Symptoms of Acute Poisoning 244
Index of Pesticide Products 257
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and
Dosage Tables (in alphabetical order) Figures (in order of appearance)
Activated Charcoal 32 Pesticide Label Organization, Front 19
Atr°Pme 48' 58 Pesticide Label Organization, Back 20
Atropine Sulfate 75, 77
National Poison Data System Human
BAL 138 Pesticide Exposure Cases 2000-2010 29
Bentonite 114
Calcitonin 183
Calcium Chloride 87 Tables (in order of appearance)
CalciumDisodiumEDTA 156 _, . ., ., , _rj T .. ^ , .
Pesticides Most Often Implicated in
Calcium Gluconate 86, 181 Acute Occupational Pesticide-Related
Cliolcstryaminc Resin 67 lllness 2005-2009 6
D-peniciiianiine 139 Pesticide Exposures Most Commonly
DMSA (Succimer) 139 Reported to National Poison
Data System 7
Diazepam 34,66. 168
Dimercaprol (BAL) 138 Summary of California Pesticide
Exposures 2005-2009 8
Fuller's Earth 114
Glucocorticoids 183 Data Collection on an Acute
Pesticide Exposed Patient 26
Lorazepam 33
Magnesium Sulfate 169 Gastric Lavage Contraindications 31
Methylene Blue 88, 125, 152, 191, 195 Potential Effects of Various Herbicides 120
Morphine Sulfate 116
Mucomyst 168
Phenobarbitol 34
Pralidoxime 50
Prednisone 183
Propofol 34
Prussian Blue 179
Sodium Thiosulfate 194
Succimer 139
Vitamin K 176
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Section I
GENERAL INFORMATION
Introduction 2
Making the Diagnosis 13
Data Collection on Acute Pesticide Exposed Patient 26
General Principles in the Management of Acute Pesticide Poisonings 29
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CHAPTER 1
Introduction
The purpose of this manual is to provide healthcare professionals with current consensus
recommendations for treating patients with pesticide-related illnesses or injuries. The
Office of Pesticide Programs of the U.S. Environmental Protection Agency has spon-
sored the series since 1973. The 5th edition of this manual was published in 1999;
since then, much has changed with regard to the pesticide products on the market.
Most indoor uses of organophosphates have been eliminated, and a combination of
EPA risk mitigation actions has limited their use on food crops. Pyrethroids have
largely replaced organophosphates for residential pest control. While this conversion
is beneficial in that the risk to human health is lower with this relatively less acutely
toxic class of pesticide, it introduces a new set of health issues for consideration. Many
new pesticide products have been registered and are not necessarily widely known
among health professionals. This 6th edition includes a chapter that explores potential
association between low-level exposure to pesticides over time and chronic diseases.
Treatments for pesticide
exposure carry health risks of
their own.
There is general agreement that prevention of pesticide poisoning remains a
much surer path to safety and health than reliance on treatment. In addition to the
inherent toxicity of pesticides, none of the medical procedures or drugs used in treating
poisonings is risk free. In fact, many antidotes are toxic in their own right, and such
apparently simple procedures as gastric intubation involve substantial risk. The clini-
cian must weigh the hazards of various courses of action (including no treatment at all)
against the risks of various interventions, such as gastric emptying, catharsis, admin-
istration of intravenous fluids or administration of an antidote, if available. Clinical
management decisions have to be made promptly and, as often as not, on the basis
of limited scientific and medical information. The complex circumstances of human
poisonings rarely allow for precise comparisons of alternative management strategies.
Therefore, it is important for the reader to keep in mind that the treatment recommen-
dations in this book do not guarantee successful outcomes. They are merely consensus
judgments of the best available clinical management options. Clinical toxicology is
a dynamic field of medicine; new treatment methods are developed regularly, and the
effectiveness of old as well as new modalities is subject to constant critical review.
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CHAPTER 1
Introduction
Key Principles
General methods of managing pesticide poisonings are presented in Chapter 3 and
reflect a broad base of clinical experience. Several key points deserve emphasis. The
need to protect the airway from aspiration of vomitus cannot be overstated. Death has
resulted from aspiration, even following ingestion of substances having relatively low
toxic potential. In poisonings by agents that depress central nervous system functions
or cause convulsions, airway protection by early placement of a cuffed endotracheal
tube (even when this requires light general anesthesia) may be life saving. Mainte-
nance of adequate pulmonary gas exchange is another essential element of poisoning
management that deserves constant reemphasis.
The amount of pesticide absorbed is a critical factor in making treatment deci-
sions, and estimation of dosage in many circumstances of pesticide exposure remains
difficult. The terms "small amount" and "large amount" used in
this book are obviously ambiguous, but the quality of expo-
sure information obtained rarely justifies more specific
terminology. Sometimes the circumstances of exposure
are a rough guide to the amount absorbed. Spray drift
from a pesticide properly diluted for field application is
not likely to convey a large dose unless exposure has
been prolonged. However, drift is the leading cause of
incidents among agricultural workers reported to the
Sentinel Event Notification System for Occupational Risk
(SENSOR)-Pesticides.1 Farmworkers and pesticide applica-
tors working with pesticides on a regular basis are at risk for acute
pesticide poisonings. Spills of a concentrated chemical onto the skin or clothing may
well represent a large dose of pesticide unless the contamination is promptly removed.
Brief dermal exposure to foliage residues of cholinesterase-inhibiting pesticides is not
likely to lead to poisoning, but prolonged exposures may.
Suicidal ingestions almost always involve "large amounts," requiring the most
aggressive management. Except in children, accidental pesticide ingestions are likely
to be spat out or vomited. Ingestions of pesticides by children are the most difficult
to evaluate. The clinician usually must base clinical management decisions on "worst
case" assumptions of dosage. Childhood poisonings are further complicated by the
greater vulnerability of the very young, not only to the pesticides, but also to the
drugs and treatment procedures. Children ingest a greater amount per body weight
than adults. The nature of neurological development in children entails an additional
level of risk that is not present in adults.
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CHAPTER 1
Introduction
Underreporting
Pesticide incidents are
underreported for several
reasons. According to the
OPP Report on Incident
Information (EPA, 2007),
these include:
Lack of a universal,
mandatory legal duty to report
incidents
Lack of a central reporting
point for all incidents
Similarity of symptoms
associated with pesticide
poisonings to other causes
Misdiagnosis by physicians
because of a lack of familiarity
with pesticide effects
Inadequate investigation
of incidents to identify the
pesticide that caused the
effects
Difficulty in identifying and
tracking chronic effects
Reluctance or inability of
physicians to report incidents
Limited geographic coverage
of individual poisoning
databases
Barriers to Proper Recognition and Management
of Pesticide Poisonings
Pesticide-related illnesses are one example of a myriad of existing Environmental
and Occupational Health (EOH) exposures of concern. For many reasons, accurate
diagnosis and treatment of pesticide poisonings present a challenge to the clinician.
Like many illnesses linked to environmental exposures, pesticide poisonings remain
commonly under-diagnosed due in large part to barriers in seeking care and diagnosis
of pesticide poisonings.
Seeking Care
One important factor contributing to under-diagnosis occurs if the exposed person
does not, or is unable to, seek medical attention. A pesticide applicator, for example.
may not perceive the incident as significant enough to seek care, particularly if he or
she has been accustomed to low-level exposure scenarios on the job. Some agricul-
tural workers are unable to readily address a pesticide poisoning because of a complex
set of socioeconomic factors including inability to take off from work, transportation
problems, language and cultural barriers, lack of health insurance, scarcity of avail-
able community health services and fear of losing employment. Another scenario is
the exposed person may simply not recognize his or her symptoms as pesticide related.
Diagnosis
When an individual exposed to pesticides does seek care, diagnosis has its own
set of challenges. Differential diagnosis is difficult because signs and symptoms of
pesticide-related illnesses are often nonspecific and may be confused with common
illnesses unrelated to pesticide exposure. The clinician may neglect to take an envi-
ronmental and occupational exposure history,2 a key to proper diagnosis, and thereby
miss the opportunity to uncover a pesticide poisoning. Even when pesticide poisoning
is suspected, few diagnostic tools are available. Chapter 2 of this manual, entitled
Making the Diagnosis, is intended to guide clinicians in determining whether the
patient may be experiencing symptoms of a pesticide poisoning, with an emphasis on
taking an environmental and occupational exposure history.
Institutional
The 1999 edition of this manual stated, "Despite recommendations by the Institute of
Medicine and others urging the integration of environmental medicine into medical
education, healthcare providers generally receive a very limited amount of training
in occupational and environmental health, and in pesticide-related illnesses, in partic-
ular."3 Migrant Clinicians Network surveyed clinicians in 2000 and found that more
than 80% reported little or no EOH training.4 This reality remains largely unchanged.
"...environmental medicine education is largely omitted in the
continuum of U.S. medical education, leaving future physicians
and current practitioners without expertise in environmental
medicine to provide or facilitate environmental preventative or
curative patient care." (Gehel, et al, 2011)
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CHAPTER 1
Introduction
Few healthcare providers are adequately trained in environmental medicine
despite widespread recognition of a need to better prepare the nation's frontline in
public health to respond to EOH issues.5 There is growing interest in environmental
medicine among practicing clinicians6 and medical and nursing students, but the
existing education system does little to address this demand.5 Institutional change to
expand an already stressed medical curriculum has proven to be a major obstacle to
inserting EOH training.
Assessing the Relationship of Work
or Environment to Disease
Pesticides and other chemical and physical hazards are often associated with nonspe-
cific medical complaints so it is very important to link the symptoms with the timing of
suspected exposure to the hazardous agent. The Index of Signs and Symptoms, begin-
ning on page 244, provides a quick reference to symptoms and medical conditions
associated with specific pesticides. Further details on the toxicology, confirmatory
tests and treatment of illnesses related to pesticides are provided in each chapter of this
manual. A general understanding of pesticide classes and some of the more common
pesticide agents is helpful in making a pesticide-related disease diagnosis. A concur-
rent non-pesticide exposure can have no health effect, exacerbate an existing pesticide
health effect or solely cause the health effect in a patient. In the more complicated
exposure scenarios, assistance should be sought from environmental and occupational
medicine (EOM) specialists.
Common Pesticide Poisonings
Following are three pesticide incident data tables created for this manual to illustrate
which pesticides are most frequently implicated in incident reports to SENSOR-
Pesticides, National Poison Data System (NPDS) and California's Pesticide Illness
Surveillance Program (PISP). These tables cannot be considered representative of all
incidents because they only show those that were reported to these three databases.
The relative frequency of cases generally reflects how widely a product is used in
the environment. Organophosphate (OP) insecticides have historically topped the list
of most commonly reported exposures. EPA risk mitigation measures have greatly
diminished the use of organophosphates for residential, particularly indoor, use. In
the United States, pyrethroids have largely replaced the OPs in terms of widespread
usage. As such, they now account for the most human case reports in the United States.
Although they are relatively less acutely toxic than their predecessors, some severe
poisonings have similar presenting signs and symptoms as that of OP poisoning, thus
complicating the process of making the correct diagnosis.
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CHAPTER 1
Introduction
Data Sources for
Poisoning Incidents
Table 1.SENSOR-
Pesticides Program
Table 2. National Poison
Data System
Table 3. California Pesticide
Illness and Surveillance
Program
TABLE 1
PESTICIDES MOST OFTEN IMPLICATED IN ACUTE OCCUPATIONAL
PESTICIDE-RELATED ILLNESS AND INJURY CASES AND NUMBER
OF CASES, SENSOR-PESTICIDES PROGRAM, 2005-2009 (N=9,906)
Rank
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pesticide Category
Pyrethroids
Chlorinated
compounds
Organophosphorous
compounds
Pyrethrins
Glyphosate
Ammonium/ammonia
N-methyl carbamates
DEET
Sulfur compounds
Triazines
Fipronil
Naphthalene
Imidacloprid
Thiocarbamates/
Dithiocarbamates
Glutaraldehyde
All other
TOTAL INDIVIDUALS
Number of Exposed Cases
Exposed
to Single
Substance
(n=6,187
individuals)
n
1,368
1,174
600
358
274
32
249
292
145
168
26
113
1
67
51
1,269
6,187
%
22.10
19.00
9.70
5.80
4.40
0.50
4.00
4.70
2.30
2.70
0.40
1.80
0.00
1.10
0.80
20.50
100.00
Exposed
to Multiple
Substances*
(n=3,719
individuals)
n
1,479
387
429
620
203
361
112
59
143
60
135
22
118
31
15
1,287
3,719
%
39.80
10.40
11.50
16.70
5.50
9.70
3.00
1.60
3.80
1.60
3.60
0.60
3.20
0.80
0.40
34.60
100.00
Sum of Single
+ Multiple
Exposure
Cases*
(n=9,906
individuals)
n
2,847
1,561
1,029
978
477
393
361
351
288
228
161
135
119
98
66
2,556
9,906
%
28.70
15.80
10.40
9.90
4.80
4.00
3.60
3.50
2.90
2.30
1.60
1.40
1.20
1.00
0.70
25.80
100.00
"Because some of the individuals exposed to multiple substances appear in the totals of
more than one pesticide category, the sum of the pesticide categories exceeds the number of
individuals.
Source: Edward J. Kasner, MPH and Geoffrey M. Calvert, MD, National Institute for Occupational Safety
and Health, Centers for Disease Control and Prevention.
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CHAPTER 1
Introduction
TABLE 2
Pesticide or Pesticide Class
Child
<5
years
6-12
years
13-19
years
>20
years
Unknown
age
Total
Pyrethrins and pyrethroids
7,717
1,672
1,222
14,800
2,706
28,117
Disinfectants
Rodenticides
Insect repellents
Hypochlorite
disinfectants
5,024
563
837
5,471
Other disinfectants
(e.g., pine oil and
phenols)
6,994
619
433
2,435
Anticoagulant
rodenticides
9,176
204
95
796
Other rodenticides
1,785
89
67
250
DEET
3,194
685
251
934
Others (e.g.,
naphthalene moth
repellent)
3,178
328
130
1,338
1,355
537
225
183
189
491
13,250
11,018
10,496
2,374
5,253
5,465
Herbicides (e.g., glyphosate,
chlorophenoxy herbicides)
2,019
362
246
4,593
817
8,037
Borates and boric acid pesticides
4,270
92
62
466
110
5,000
Qrganophosphates
OPs alone
722
171
107
1,331
OP + carbamate
and OP + non-
carbamate
insecticides
158
47
49
495
321
83
2,652
832
Carbamate insecticides
804
119
83
1,027
221
2,254
Fungicides
171
25
21
414
73
704
Organochlorine insecticides
182
30
15
245
Fumigants
48
19
14
213
AN other insecticides (including unknown)
5,526
615
387
5,264
58
56
1,371
530
350
13,163
TOTAL PESTICIDES/DISINFECTANTS
50,968
5,640
4,019
40,072
8,796
109,495
The pesticides most commonly reported to Poison Control Centers, according to the
2010 Annual Report data from the American Association of Poison Control Centers'
(AAPCC) National Poison Data System (NPDS) are listed in Table 2, above. Cases
listed as organophosphates (and the other categories as well) may also include other
insecticides such as carbamates and organochlorines in a single product. Asymptom-
atic cases are included in Table 2 only.
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CHAPTER 1
Introduction
TABLE 3
SUMMARY OF PESTICIDE EXPOSURES AMONG CASES IDENTIFIED
BY THE CALIFORNIA PESTICIDE ILLNESS SURVEILLANCE
PROGRAM FROM 2005-2009 AND EVALUATED, AFTER
INVESTIGATION, AS DEFINITELY, PROBABLY OR POSSIBLY
RELATED TO PESTICIDE EXPOSURE, BY PESTICIDE CATEGORY
Pesticide category
Occupational
Only
pesticide
implicated
Two or more
pesticides
involved
Non-Occupational
Only
pesticide
implicated
Two or more
pesticides
involved
Antimicrobials
Hypochlorite
Quaternary
Ammonium
Glutaraldehyde
Other/Unknown
422
227
69
197
69
106
3
297
98
15
0
92
81
14
0
88
Insecticides/ Miticides/lnsect Growth Regulators
Organophosphates
Carbamates
Pyrethrins/
Pyrethroids
Organochlorines
Other/Unknown
Herbicides/Defoliants
Fungicides
Fumigants
Other/unknown*
TOTAL EXPOSURES
162
13
56
0
61
80
81
228
41
1,637
227
16
425
1
612
184
548
106
568
3,162
52
12
134
0
124
28
29
366
83
1,033
91
4
294
2
136
44
62
134
97
1,047
The majority of other/unknown pesticides are adjuvants, which are registered in California but not
necessarily identified by active ingredients. Additionally, this category includes a molluscicide, a
nematicide and several pheromones, plant growth regulators, preservatives, repellents, rodenticides,
synergists, pesticides with multiple functions and products that never were identified.
Table 3 shows the numbers of occupational and non-occupational exposures from
2005-2009 that the California Pesticide Illness Surveillance Program associated
with various categories of pesticides. All exposures that occurred while the affected
person was at work are considered occupational. Occupational exposures probably
continue to be more fully reported than non-occupational exposures. A case repre-
sents one individual's exposure to pesticide(s). Cases in which only one exposure was
credibly implicated are distinguished from those to which any or all of two or more
pesticides may have contributed. This table illustrates exposures; when more than one
pesticide active ingredient is implicated, an exposure is counted for each person/pesti-
cide combination. Multiple pesticide active ingredients were implicated in the cases
of 2,657 people exposed occupationally and 432 exposed non-occupationally. These
cases are counted in each pesticide category forwhichthey qualify, fortotals of 3,162
occupational exposures and 1,047 non-occupational exposures.
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CHAPTER 1
Introduction
Special Populations and Environmental Justice
Environmental justice strives to ensure that no population is forced to shoulder a
disproportionate burden of the negative human health and environmental impacts of
pollution or other environmental hazards.8 EPA seeks to ensure the fair treatment and
meaningful involvement of all people regardless of race, color, national origin, educa-
tional level or income with respect to the development, implementation and enforce-
ment of environmental laws, regulations and policies.9
With regard to pesticide exposure and environmental justice, the farmworker
population is of particular concern. The majority of farmworkers and their family
members in the United States are Latinos living in poverty. Farmworkers are the popu-
lation most often affected by pesticide overexposure. Children represent another popu-
lation of concern as they may be at greater risk from pesticide exposures because they
are growing and developing. Women of reproductive age and pregnant and nursing
women may also be more vulnerable because of the effects of pesticide exposures on
fetuses and infants. These three populations face higher risk of harmful pesticide expo-
sure because of occupation or developmental susceptibility, or combination thereof.
Each is discussed in more detail below.
Agricultural Workers
In the United States, between 1 million and 2.5 million hired farmworkers earn their
living from agriculture.10'11 Farmworkers are the working population most often
affected by pesticide overexposure, especially Latino farmworkers.12 Farmworker
patients should be considered to be at high risk for pesticide exposure; their screening
or exposure history should include specific questions about any agricultural work
being done. For example:
Are pesticides being used at home or at work?
Do you mix or apply pesticides?
Are the fields or orchards wet when you pick, prune or harvest?
Was spraying taking place in or near the fields or orchards while you
were working?
Do you get sick during or after working in the fields or orchards?
Do you use agricultural pesticides in your home?
Did you learn about adverse health effects of pesticides and how to
protect yourself from exposure while using pesticides?
Farmworkers often reside in agricultural communities where they and their
family members may be further exposed in their homes because of pesticide drift
from spraying of nearby fields or orchards and drinking contaminated water. Para-
occupational exposure factors such as pesticide residue on workers and their clothing,
shoes and vehicles and lack of adequate facilities to clean pesticide-contaminated
work clothes may increase the risk of pesticide exposure for other household members
as well.
Children
Children face particular risks from pesticides, as their physical makeup, behavior and
physiology may make them more susceptible than adults.13'14'15 As such, it is important
to assess pesticide exposures by asking about where pediatric patients live, the occu-
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CHAPTER 1
Introduction
pation of their parents and whether pesticides are used in the home, childcare facility.
school and play areas. It is also important to remind parents to store pesticides out of
the reach of children.
Children from agricultural families and those living in close proximity to agri-
cultural areas are exposed to higher levels of pesticides than those whose parents do
not work in agriculture and who do not live close to farms.16'17'18 The higher pesticide
levels may result from parents' tracking pesticides from the workplace into the home
or by pesticide drift.19'20
Adolescents working in agriculture are also at risk of exposure to pesticides-21'22
The incidence rate of acute occupational pesticide-related illness in adolescents is
significantly higher compared to adolescents not working in agriculture.23 This is a
particular concern for young farmworkers since adolescents are permitted to work in
agriculture at younger ages than in other industries. While the research examining the
impact of neurotoxicants on the central nervous system of adolescents is limited,24'25'26
there is strong evidence of neural remodeling and brain development during adoles-
cence.25'26'27'28 Dose responses, metabolic rates and routes of exposure may vary by age.
gender and maturation.21'22'28 Extra caution is merited as consideration is given to acute
and chronic pesticide exposures of adolescents.21'22
Women of Reproductive Age and Pregnant Women
Pesticides may cause the most damage in humans during periods of rapid development.
especially in utero through transplacental absorption.29'30 Even prior to fetal periods
of increased sensitivity, studies have found that preconception exposure of either the
mother or father may have an effect on reproductive outcome and offspring.31'32'33'34
Maternal exposure to pesticides should be minimized during pregnancy and during
the preconception period. The period of maximal sensitivity to a teratogen varies
depending on the birth defect, but is almost always within the first 10 weeks of the
pregnancy. However, the central nervous system, eyes, teeth and external genitalia
may be susceptible to teratogenic exposures throughout the pregnancy.35 Although
no pesticides have been proven to be human teratogens, several studies have shown
associations between pesticide exposures and reproductive toxicity in humans. For
example, in utero exposure to organophosphates has been associated with low birth
weight, mental and motor delay, attention deficit hyperactivity disorder (ADHD), and
reduced IQ.36'37 Women who are pregnant or planning a pregnancy, especially those
currently engaging in agricultural activities, should be informed of the implications of
exposure before conception and during the pre- and peri-natal periods, and assisted in
making decisions that are appropriate for their individual work and home situations.38
See Chapter 21, Chronic Effects, for further information and examples.
10
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CHAPTER 1
Introduction
References
1. Calvert GM, Kamik J, Mehler L, Beckman J, Morrissey B, Sievert J, Barrett R, Lackovic
M, Mabee L, Schwartz A, Mitchell Y, Moraga-McHaley S. Acute pesticide poisoning
among agricultural workers in the United States, 1998-2005. Am JIndMed. 2008;883-898.
2. Trasande, et al. Pediatrician Attitudes, Clinical Activities, and Knowledge of Environ-
mental Health in Wisconsin. Wisconsin MedJ. 2006; 105(2).
3. Institute of Medicine. Role of the Primary Care Physician in Occupational and Environ-
mental Medicine, Washington, DC: Institute of Medicine, 1988.
4. Liebman A., Harper S. Environmental Health Perceptions Among Clinicians and Adminis-
trators Caring for Migrants. MCN Streamline. 2001;7(1).
5. Gehle, et al. Integrating Environmental Health Into Medical Education. Am JPrev Med.
2011;41(4S3):S296-S301.
6. Trasande, et al. Pediatrician Attitudes, Clinical Activities, and Knowledge of Environ-
mental Health in Wisconsin. Wisconsin Med J. 2006; 105(2).
7. 2010 Annual Report of the American Association of Poison Control Centers' National
Poison Data System (NPDS): 28th Annual Report. Table A. "Demographic profile of
Single Substance Nonpharmaceuticals exposure cases by generic category."
8. U.S. Department of Health and Human Services. Subcommittee on Environmental Justice,
Environmental Health Policy Committee. Strategic elements for environmental justice.
Environ Health Perspect. 1995 Sep; 103(9): 796- 801.
9. Environmental Protection Agency. Environmental Justice, http://www.epa.gov/environ-
mentaljustice/index.html.
10. Kandel W Profile of Hired Farmworkers, A 2008 Update. Economic Research Report No.
60. Economic Research Service, U.S. Department of Agriculture. 2008.
11. Martin P. Immigration reform: implications for agriculture. Agricultural and Resource
Economics Update. Davis, CA: University of California, Giannini Foundation. 2006.
12. Calvert GM, Kamik J, Mehler L et al. Acute pesticide poisoning among agricultural
workers in the United States, 1998-2005. Am JIndMed. 2008;51(12):883-98.
13. Landrigan, P. Pesticides and PCBs: Does the evidence show that they threaten children's
health? Contemp Pediatr. 2001;18(2):110-124.
14. Faustman EM, Silbemagel SM, Fenske RA, Burbacher TM, Ponce RA. Mechanisms
underlying children's susceptibility to environmental toxicants. Environ Health Perspect.
2001;108 suppl 1:13-21.
15. Reigart JR, Roberts JR. Pesticides in children. PediatrClinNorthAm. 2001 Oct;48(5):1185-
98, ix.
16. Simcox NJ, Fenske RA, Wolz SA, Lee 1C, Kalman DA. Pesticides in household dust and
soil: exposure pathways for children in agricultural families. Environ Health Perspect.
1995;103(12):1126-34.
17. Fenske RA, Kissel JC, Lu C, Kalman DA, Simcox NJ, Allen EH, Keifer MC. Biologically
based pesticide dose estimates for children in an agricultural community. Environ Health
Perspect. 2000;108(6):515-20.
18. Curl C, Fenske RA, Kissel JC, Shirai JH, Moate TF, Griffith W. Evaluation of take-home
organophosphorus pesticide exposure among agricultural workers and their children.
Environ Health Perspect. 2002;110:A787-A792.
19. Thompson B, Coronado GD, Grossman JE, Puschel K, Solomon CC, Mas I, Curl CL,
Shirai JH, Kissel JC. Pesticide take-home pathway among children of agricultural workers:
Study design, methods, and baseline findings. J Occup Environ Med. 2003;45:43-53.
20. Eskenai B, Bradman A, Castorina R. Exposures of children to organophosphate pesticides
and their potential adverse health effects. Environ Health Perspect. 1999;107 Suppl 3:409-19.
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Introduction
21. Rohlman DS, Nuwayhid I, Ismail A, Saddik B. Using epidemiology and neurotoxicology
to reduce risks to young workers. Neurotoxicology. 2012 Aug;33(4):817-22.
22. Rohlman DS, Lasarev M, Anger WK, Scherer J, Stupfel J, McCauley L. Neurobehav-
ioral performance of adult and adolescent agricultural workers. Neurotoxicology. 2007
Mar;28(2): 374-80.
23. Calvert GM, Mehler LN, Resales R, Baum L, Thomsen C, Male D, Shafey O, Das R,
Lackovic M, Arvizu E. Acute pesticide-related illnesses among working youths, 1988-
1999. Am J Public Health. 2003 Apr;93(4):605-10.
24. Adams J, Barone S Jr, LaMantia A, Philen R, Rice DC, Spear L, Susser E. Workshop to
identify critical windows of exposure for children's health: neurobehavioral work group
summary. Environ Health Perspect. 2000 Jun;108 Suppl 3:535-44.
25. Brown SA, Tapert SF, Granholm E, Delis DC. Neurocognitvie functioning of adolescents:
effects of protracted alcohol use. Alcohol Clin Exp Res. 2000;24:164-71.
26. Spear LR Alcohol's effect on adolescents. Alcohol Res Health. 2002;26: 287-91.
27. Andersen SL. Trajectories of brain development: point of vulnerability or window of
opportunity. Neurosci Biobehav Rev. 2003;27:3-18.
28. Spear LR Assessment of adolescent neurotoxicity: rationale and methodological consider-
ations. Neurotoxicol Teratol. 2007 Jan-Feb;29(l):l-9.
29. Jurewicz J, Hanke W, Johansson C, Lundquist C, Ceccatelli S, Van Den Hazel P, Saunders
M, Zetterstrom R. Adverse health effects of children's exposure to pesticides: What do we
really know and what can be done about it. Acta Pcediatrica. 2006;95 Suppl 453:71.
30. Committee on Pesticides in the Diets of Infants and Children: Pesticides in the Diets of
Infants and Children. National Academy Press, Washington, DC, 1993. 408 pp.
31. Arbuckle TE, Lin Z, Mery LS. An exploratory analysis of the effect of pesticide expo-
sure on the risk of spontaneous abortion in an Ontario farm population. Environ Health
Perspect. 2001 Aug; 109(8):851-7. PubMed PMD: 11564623; PubMed Central PMCID:
PMC1240415.
32. Vinson F, Merhi M, Baldi I, Raynal H, Gamet-Payrastre L. Exposure to pesticides and risk
of childhood cancer: a meta-analysis of recent epidemiological studies. Occup Environ
Med. 2011 Sep;68(9):694-702. Epub2011 May 23. PubMed PMID: 21606468.
33. Abadi-Korek I, Stark B, Zaizov R, Shaham J. Parental occupational exposure and the
risk of acute lymphoblastic leukemia in offspring in Israel. J Occup Environ Med. 2006
Feb;48(2): 165-74. PubMed PMID: 16474265.
34. Murphy LE, Gollenberg AL, Buck Louis GM, Kostyniak PJ, Sundaram R. Maternal serum
preconception polychlorinated biphenyl concentrations and infant birth weight. Environ
Health Perspect. 2010 Feb;118(2):297-302. PubMed PMID: 20123616; PubMed Central
PMCID: PMC2831933.
35. Moore KL, Persaud TVN. The developing human: clinically oriented embryology. 7th
edition. Sauders, Philadelphia, Pennsylvania. 2003. 544 pp.
36. Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, Whyatt R. Seven-year
neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural
pesticide. Environ Health Perspect. 2001 Aug;119(8):1196-1201.
37. Bouchard MF, Chevrier J, Harley KG, Kogut K, Vedar M, Calderon N, Trujillo C, Johnson
C, Bradman A, Barr DB, Eskanazi B. Prenatal exposure to organophosphate pesticides and
IQ in 7-year old children. Environ Health Perspect. 2011 Aug; 119(8): 1189-1195.
38. McDiarmid MA, Gehle K: Preconception Brief: Occupational/Environmental Exposures.
Maternal and Child Health J. 2006;10:S123-S128.
12
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CHAPTER 2
Making the Diagnosis
Tools for Clinicians to Ascertain Environmental and
Occupational Health Exposures
OVERVIEW
Accurate identification of the patient's exposure can lead to improved diagnostic.
therapeutic and rehabilitative decisions by the clinician and result in improved patient
outcomes. Without an accurate diagnosis, the clinician may decide upon a symptom-
based treatment that may be less effective.
Once identified, a pesticide exposure incident should be considered a poten-
tial sentinel health event that may require follow-up efforts to locate the source and
any additional cases. By identifying the source of exposure, the clinician can avert
further exposure in the initial patient and other exposed individuals. Post-diagnostic
activities are important to support a systems approach to pesticide exposure cases.
including reporting the incident, filing a workers' compensation claim, and conducting
specialty care referrals. The clinician must also be aware of several ethical and public
health considerations. Lastly, there are key resources available to assist clinicians and
patients in dealing with pesticide-related illnesses or injuries.
TAKE INITIAL SCREENING FOR PESTICIDE EXPOSURE
Asking the patient a few initial screening questions is critical for making an accurate
diagnosis and may flag the need to take a more extensive exposure history. Given that
time constraints in a primary care setting compete with the need to identify a patient's
potential EOH exposures, it is highly recommended that a few short screening
questions be incorporated into the routine patient intake procedure in order to
identify relevant EOH exposures.1 See the Sample Screening Questions in the sidebar.
OBTAIN DETAILED EXPOSURE HISTORY
If the initial screening suggests a potential EOH exposure concern, a detailed exposure
interview is often needed. An extensive exposure history can take up to an hour and
provides a more complete picture of pertinent exposure factors. The detailed interview
includes questions on occupational exposure, environmental exposure, symptoms and
medical conditions. Data collection guidelines specific to patients with confirmed acute
pesticide illnesses or injuries is provided at the end of this chapter, on pages 26-27.
Although the focus is on pesticide exposures and related health effects, concurrent
non-pesticide exposures need to be considered in the overall patient health assessment.
Questions typical of a detailed EOH history are provided in Appendix A,
Detailed Occupational and Environmental Exposure History Questions, on page
240. For further information on taking a history for all types of occupational and
environmental hazards, consult a general occupational and environmental medicine
reference text2 or Agency for Toxic Substances and Disease Registry's Case Study in
Environmental Medicine: Taking an Exposure History?
SAMPLE SCREENING
QUESTIONS
For an adult patient
After establishing the chief
complaint and history of
present illness:
What kind of work do you
do?
(If unemployed) Do you
think your health problems
are related to your home or
other location?
(If employed) Do you think
your health problems are
related to your work? Are
your symptoms better or
worse when you are at
home or at work?
Are you now or have you
previously been exposed to
pesticides, solvents or other
chemicals, dusts, fumes,
radiation or loud noise?
For a pediatric patient
Questions asked of parent
or guardian
Do you think the patient's
health problems are related
to the home, child care
setting, school or other
location?
Has there been any
exposure to pesticides,
solvents or other chemicals,
dusts, fumes, radiation or
loud noise?
In what kind of work are the
parents and other household
members engaged?
13
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CHAPTER 2
Making the Diagnosis
DEALING WITH A SUSPECTED PESTICIDE EXPOSURE
After conducting exposure screening and possibly a detailed exposure history, the
clinician should take the following steps once they suspect a pesticide poisoning.4 It
should be noted that each pesticide incident is a unique situation with varying levels
of severity and urgency; therefore, these steps are not always achieved in the order
they are presented. It is, however, crucial to obtain and preserve any evidence of the
exposure as soon as possible.
1. Collect Information on the Pesticide
When you suspect a pesticide poisoning, try to get as much information about the
pesticide(s) as possible, including: the name of the pesticide used, the EPA pesticide
registration number, and the pesticide label and/or the Material Safety Data Sheet
(MSDS) for the pesticide(s). If this is a case involving agricultural workers or residents
in an agricultural area, try to talk directly to the farm manager, safety coordinator
or the pesticide applicator to get this information in addition to a description of the
incident itself. Often application records will be made available if requested. Under
EPA's Worker Protection Standard (40 CFR 170), agricultural employers are required
to make the name of the pesticide and the label available to healthcare providers and
workers if it is requested. Refer to the material entitled Data Collection on an Acutely
Pesticide Exposed Patient found on pages 26-27 at the end of this chapter.
2. Follow Decontamination Procedures
Follow the decontamination procedures as outlined in Chapter 3, General Principles,
beginning on page 29.
3. Collect Evidence of Contamination
Obtain an unlaundered sample of clothing that the patient was wearing at the time
of the incident, if available. Put it in a plastic bag to prevent further exposure and to
preserve the specimens for subsequent analysis; freezing is optimal. It can be difficult
to find appropriate clothing to sample if the worker has been instructed to go home and
thoroughly wash his/her clothing. If most clothing has been washed or is not available.
it is likely the patient's hat or shoes would still be contaminated and could be analyzed.
4. Obtain a Urine Sample
If an exposure seems likely, either based on the history or the clinical exam, obtain a
urine sample and freeze it. If more than one patient is exposed, obtain a urine sample
for each patient. Freezing the urine allows you extra time to determine if the sample
needs to be analyzed and to which laboratory it should be sent.
5. Order Laboratory Tests
The National Pesticide Information Center (NPIC) provides a list of pesticides that can
be analyzed by clinical laboratories. This list and a list of accredited laboratories can
be accessed at: http://npic.orst.edu/mcapro/PesticidesTestingForExposure.pdf.
If the patient appears to have been exposed to an organophosphate or N-methyl
carbamate insecticide, order cholinesterase blood tests, both plasma and red blood cell.
to determine the clinical level of cholinesterase activity. Some experts recommend
blood testing if a clinician believes any significant exposure has occurred regardless
of a baseline test. Unless a dramatic depression is present, the results of post-exposure
testing are likely to be difficult to interpret in the absence of baseline cholinesterase
testing. In this instance, it is advisable to conduct periodic re-tests, until it appears
14
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CHAPTER 2
Making the Diagnosis
that the cholinesterase level has returned to normal. A "negative" cholinesterase (i.e.,
results within the "reference range") does not rule out the possibility that the patient's
symptoms are due to pesticides if the patient was reacting to a pesticide other than
an organophosphate or N-methyl carbamate or if s/he was reacting to other ingre-
dients in the organophosphate or carbamate formulation (e.g., the solvents, propel-
lents and carriers in the pesticide product formulation). However, negative results
could be misinterpreted by an employer or insurer to mean that no exposure occurred.
Post-exposure cholinesterase tests need to be compared to baseline pre-exposure test
results or re-testing of cholinesterase several weeks post-exposure. The recovery rate
for depressed cholinesterase can be estimated to be 0.8% per day for red blood cells
and 1.2% per day for plasma.
6. Consult with the Appropriate Specialists
You may need to consult with others, such as lexicologists, occupational and environ-
mental medicine specialists, and industrial hygienists, who have expertise in dealing
with chemical exposures. Pesticide Information Resources including the Association
of Occupational and Environmental Clinics (p. 25) are listed later in this chapter, be-
ginning on page 23.
7. Schedule/Conduct Patient Follow-up
Make arrangements with the patient(s) for follow-up appointments and for reporting
test results. Once the patient has been cared for, inform everyone else who needs to
know about the incident - the workers' compensation case manager and the employer,
in particular. The healthcare provider must obtain the employee's permission before
notifying the employer.
While a diagnosis can be based on a group exposure for the purpose of treatment,
workers' compensation systems generally deal with workers one at a time. Therefore
the clinician must collect the information needed to document the exposure, symp-
tomatology and confirmatory data for each individual involved in a multiple-patient
poisoning. While illness consistent with other members in a clearly sick group may be
sufficient for the clinician facing an outbreak, it may not be sufficient objective infor-
mation to establish causality for a worker compensation claim.
8. Report the Pesticide Incident
a. Contact the Appropriate State Health Agency
Pesticide exposures are reportable as health incidents and occupational incidents may
also be reportable as a violation of the Agricultural Worker Protection Standard. Both
of these important reporting requirements are discussed here.
If a healthcare professional suspects that a patient has a pesticide-related illness,
the clinician should report it to the appropriate state health agency. If the healthcare
professional is in one of the 30 states that mandate these reports, than s/he should send
the report to the appropriate state health agency.
More information about state-specific reporting requirements can be found at
http://www.migrantclinician.org/exposurereportingmap. The healthcare professional
can notify the local poison control center (PCC) by calling (800) 222-1222.
The National Institute for Occupational Safety and Health (NIOSH), Centers for
Disease Control and Prevention (CDC) and EPA support surveillance for pesticide-
related illness and injury through the SENSOR-Pesticides program that aggregates pesti-
cide incident data from 11 states (California, Florida, Iowa, Louisiana, Michigan, New
Mexico, New York, North Carolina, Oregon, Texas and Washington) and has an occu-
pational focus. The California Department of Pesticide Regulation (DPR) maintains the
15
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CHAPTER 2
Making the Diagnosis
Pesticide Incident Surveillance System (PISP). These surveillance systems collect case
reports on pesticide-related illnesses and injuries from clinicians and other sources (e.g.,
poison control centers, workers' compensation agencies and state agencies that regulate
pesticides); conduct selected interviews, field investigations and research projects; and
function as a resource for pesticide information within their state.
The impacts of these surveillance programs extend beyond the participant states
by identifying emerging pesticide exposure issues that steer intervention efforts to
prevent future incidents with similar exposure scenarios nationwide. However, there
remains a need for systematic reporting of pesticide poisonings in all states into a
central agency in order to compile accurate statistics on the frequency and circum-
stances of poisoning and facilitate efforts to limit these occurrences.
b. Contact Pesticide State Lead Agency
Before sending the patient(s) home, call the appropriate EPA-recognized pesticide
State Lead Agency (SLA), which can investigate pesticide poisoning incidents. To
find your SLA contact, go to http://aapco.org/officials.html.
The SLA will help determine if there was any violation of the Agricultural
Worker Protection Standard. It can also tell you if additional action or information is
needed.
9. Discuss Workers' Compensation with the Patient
If the case involves an occupational exposure, each patient's chart should document it
as such. A workers' compensation report must be completed for each exposed worker.
To achieve a successful workers' compensation claim, the healthcare provider
must document evidence of the exposure and the illness and conclude that it is more
likely than not that the illness was caused or aggravated by a workplace pesticide
exposure. The legal standard for a workers' compensation case is that there must be
a "preponderance of evidence" that the disease is work related. A preponderance
of evidence is defined as meaning that it is more likely than not (i.e., greater than 50%
probability) that the poisoning was caused or aggravated by a workplace pesticide
exposure.
Workers' compensation laws exist in all states, but benefit levels vary across
states and not all states require coverage for agricultural workers. In the realm of
workers' compensation, the worker is responsible for proving that his/her disease
is occupational in origin. It is not the employer's responsibility. Workers' compen-
sation claims for minor ailments or for injuries that are obviously work related are
rarely contested by the compensation insurance companies.5 This tends to be true for
many acute pesticide poisoning cases where the illness is consistent with the known
toxicology of the pesticide, where there is objective evidence that the patient expe-
rienced a pesticide exposure, and where the dose was sufficient to produce illness.
Costly claims, such as death claims or claims involving permanent total disability are
often contested by the workers' compensation insurance company. The proportion of
workers' compensation claims for acute pesticide poisoning that are contested is not
known. However, in those cases with little or no objective evidence that a pesticide
exposure occurred (i.e., lack of biological or residue evidence of exposure), especially
when the poisoning signs and symptoms resemble a common respiratory or gastroin-
testinal illness, achieving a successful workers' compensation claim may be difficult.
Finally, clinicians should be aware that reporting a workers' compensation case can
have substantial deleterious implications for the worker being evaluated (e.g., job loss
or disciplinary action).
16
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SPECIAL CONCERNS
Ethical Considerations
Ethical guidelines and codes of conduct have been established that can guide health-
care professionals who are dealing with dilemmas involving pesticide poisoning.6'7
Three fundamental values underpin these guidelines and codes of conduct: (1) it is
the duty of the healthcare professional to do good for the patient and to place the
patient's interests above those of the healthcare professional, (2) the individual is
the best judge of his or her own best interests and (3) social justice promotion of a
fair and equitable distribution of finite health resources. Among the codes of ethics
most relevant to the realm of pesticide poisoning is the need to keep confidential
all individual medical information, only releasing such information "with proper
authorization when required by law, for overriding public health considerations, to
other healthcare professionals according to accepted medical practice, to others at
the request of the individual, or when there is reasonable concern about potential
endangerment of third parties."6
Investigation of a suspected occupational pesticide illness may necessitate
obtaining further information from the worksite manager or owner. Any contact with
the worksite should be taken in consultation with the patient because of the potential
for retaliatory actions against the patient (such as job loss or other disciplinary action).
Similarly, a request for a workplace visit or more information about pesticide exposure
at the workplace should occur only after gaining the patient's permission. Even when
investigating non-occupational pesticide illnesses, the patient's permission should be
obtained before calling the patient's neighbors or others potentially responsible for the
pesticide exposure. The discovery of pesticide contamination in a residence, school.
childcare setting, food product or other environmental site or product can have public
health, financial and legal consequences for the patient and other individuals (e.g.,
building owner, school district, food producer). It is prudent to discuss these poten-
tial adverse consequences and follow-up options with the patient before pursuing an
investigation.
In situations where the pesticide hazard is substantial and many individuals
might be affected, a request can be made to the state health department to obtain the
assistance needed for a disease outbreak investigation. If an outbreak investigation
demands more resources than the state health department can provide, the state health
department can request assistance from the Centers for Disease Control and Preven-
tion. In such a situation, even if the initial case patient objects to disclosing the pesti-
cide hazard to public health authorities, state reporting requirements and overriding
public health considerations may require this notification.
Public Health Considerations
Healthcare providers must recognize and diagnose cases of pesticide poisoning to
ensure that pesticides are not producing unreasonable harm to human health. Cases of
suspected pesticide poisoning can lead to detection of new pesticide hazards. Health-
care professionals are often the first to see a poisoned patient who may represent
evidence of a new or re-emerging pesticide hazard. Such patients may also represent
a full-blown disease outbreak.
A disease outbreak is defined as a statistically elevated rate of disease among a
well-defined population as compared to a standard population. For example, in 2010.
two workers were diagnosed with methyl bromide poisoning after being exposed
to methyl bromide over several months while inspecting produce in a California
cold storage facility. Methyl bromide was being used to fumigate grapes imported
from Chile. Both workers had profound neurologic symptoms and elevated serum
CHAPTER 2
Making the Diagnosis
Steps in Investigating
a Disease Outbreak
Confirm diagnosis of initial
case reports (the "index"
cases)
Identify other unrecognized
cases
Establish a case definition
Characterize cases by
person, place, and time
characteristics (e.g., age,
race, ethnicity, gender and
location within a company or
a neighborhood, timeline of
exposure and health events)
Create plot of case
incidence by time (an
epidemic curve)
Determine if a dose-
response relationship
exists (i.e., more severe
clinical case presentation
for individuals with higher
exposures)
Derive an attack rate and
determine if statistical
significance is achieved
(divide number of incident
cases by number of exposed
individuals and multiply by
100 to obtain attack rate
percentage)
17
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CHAPTER 2
Making the Diagnosis
Items Contained in a
Material Safety Data
Sheet (MSDS)
Material identification
Ingredients and occupational
exposure limits
Physical data
Fire and explosion data
Reactivity data
Health hazard data
Spill, leak and disposal
procedures
Special protection data
Special precautions and
comments
bromide levels. The physician for one of these workers notified the local poison
control center, which notified the California DPR. The California DPR conducted
an investigation and found that methyl bromide reached unsafe concentrations in
enclosed areas during the transportation and storage of fumigated grapes. Stake-
holders (e.g., commodity groups, warehouse operators, USD A, EPA and the Chilean
produce industry) were notified of these findings, and measures were adopted to
reduce methyl bromide exposures.8
Disease outbreak investigations are conducted for many types of exposures and
health events, not only those in the occupational and environmental areas. Usually.
assistance from government or university experts is needed because the investigation
may require access to information, expertise and resources beyond those available
to the average clinician. The steps involved in such an investigation and the types of
information typically gathered in the preliminary clinical stages are outlined in the
Steps in Investigating a Disease Outbreak list in the margin on the previous page. The
clinician must be aware that an outbreak investigation may be needed when severe
and widespread exposure and disease scenarios exist. For more information on disease
outbreak investigations, consult the literature.9'10
Clinicians are typically prohibited from sharing identifiable health data without
the consent of the patient. However, an exception is made when the clinician disclo-
sure is for public health purposes. The Health Insurance Portability and Accountability
(HIPAA) Privacy Rule balances the protection of individual privacy with the need to
protect public health. This privacy rule permits identifiable health data disclosures
without patient consent to public health authorities authorized by law to collect or
receive the information for the purpose of preventing or controlling disease, injury or
disability [45 CFR 164.512(b)].u In other words, when state public health authorities
need identifiable health data to address a public health need, this need overrides the
HIPAA privacy rule requirements for patient consent before sharing.
RESOURCES
Material Safety Data Sheets and Pesticide Labels
In addition to the patient history, it is often helpful to obtain further information on
suspect pesticide products. Two documents are useful starting points in the identifica-
tion and evaluation of the pesticide exposure: the Material Safety Data Sheet (MSDS)
and the pesticide label.
Material Safety Data Sheet (MSDS)
Under OSHA's Hazard Communications Standard (29 CFR 1910.1200), all chem-
ical manufacturers are required to provide an MSDS for each hazardous chemical
they produce or import. Employers are required to keep copies of the MSDS for all
chemicals used at the workplace and make them available to the workers. The items
contained in an MSDS are shown in the margin.
These documents tend to provide very limited information on health effects, and
some of the chemical ingredients may be omitted because of trade secret consider-
ations. One cannot rely solely on an MSDS when making medical determinations.
Pesticide Label
EPA requires that all pesticide products bear labels that provide certain information.
This information can help in evaluating pesticide health effects and necessary precau-
tions. Pesticide labels must include the information listed on the next page. The general
18
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organization of a pesticide label is illustrated in the front panel schematic below and
the back panel schematic on the following page.
Note that for some products with multiple uses (typically agricultural products)
or products with very small containers, EPA allows some information, such as direc-
tions for use or worker protection requirements, to be contained in an accompanying
booklet rather than affixed on the container. The booklet is part of the legal label.
which is reviewed and approved by EPA. The most important safety-related elements
of the label, such as the signal word, ingredients, hazard statements, treatment state-
ment and EPA registration number, must be on the container itself.
The EPA registration number is very useful when contacting EPA for informa-
tion or when calling the National Pesticide Information Center hotline (see page 24).
Pesticide product labels may differ from one state to another based on marketing or
other area-specific considerations. Also, different formulations of the same active
ingredients may result in different label information. The pesticide label generally
lists information only for active ingredients (not for inert/other components) and rarely
Front Panel
Organization
This diagram illustrates the order in
which front panel label parts usually
appear. Note that not all of the
elements must appear on every label.
1 . Restricted use pesticide
statement (if applicable)
2. Product name, brand or
trademark
3. Ingredient statement
panel if inadequate space
on front panel)
5. Child hazard warning
6. Sienal word (if
applicable); skull and
crossbones symbol and
the word "Poison" (if
applicable)
7. First aid statement ^
(may appear on back '
panel if there is a note
indicating this on
front panel)
t
RESTRICTED USE PESTICIDE
Due to (insert reason)
For retail sale to and use only by Certified
Applicators or persons under their direct
supervision and only for those uses covered by
^ the Certified Applicator's certification.
^> DDfim IfT NIAIWIC
^ KUUUlr 1 INAIVIt
ACTIVE INGREDIENT(S) 90 00%
OTHER INGREDIENT(S) 10.00%
TOTAL 10000%
This product contains XX Ibs of [a.i.] per gallon.
^ Product Information (what product is used for)
^^ KEEP OUT OF REACH OF CHILDREN
^ SIGNAL WORD
^ (ENGLISH/SPANISH)
Poison
I
Si usted no entiende la etiqueta, busque a alguien para que se la
explique a usted en detail e. (If you do not understand the label,
find someone to explain it to you in detail.)
FIRST AID
If Swallowed -If Inhaled
If on Skin If in Eyes
Reminder to have label with you when
calling emergency phone number or going
for treatment. Emergency phone number.
Note to Physician:
SEE OTHER PANEL FOR
PRECAUTIONARY STATEMENTS
CHAPTER 2
Making the Diagnosis
Items Required on
Pesticide Labels
Product name
Manufacturer name and
address
EPA registration number
Active ingredients
Precautionary statements:
Human hazard signal
words "Danger" (most
hazardous), "Warning,"
and "Caution" (least
hazardous)
"Poison" and symbol, if
applicable
Child hazard warning
Statement of practical
treatment (signs and
symptoms of poisoning,
first aid, antidotes and
note to physicians in the
event of a poisoning)
Hazards to humans and
domestic animals
Environmental hazards
Physical or chemical
hazards
Directions for use
Net contents
EPA establishment number
Worker Protection Standard
(WPS) designation,
including restricted entry
interval and personal
protection equipment
required (agricultural
products only) (see WPS
description on page 21)
19
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CHAPTER 2
Making the Diagnosis
contains information on chronic health effects (e.g., cancer and neurologic, reproduc-
tive and respiratory diseases). Although further information is often needed, pesticide
labels and labeling should be considered as the first step in identifying and under-
standing the health effects of a given pesticide. The Agricultural Worker Protection
Standard provides the legal basis for the healthcare provider(s) to obtain from the
employer the name of the pesticide product to which the patient was exposed. When
requesting this information, the clinician should keep the patient's name confidential
whenever possible.
Back Panel
Organization
This diagram illustrates the
order in which back panel
label (or labeling booklet)
parts usually appear.
Note that not all of these
elements must appear on
every label. For products
subject to the Agricultural
Worker Protection Standard
(WPS), the precautionary
statements and directions
for use sections contain
additional pertinent statements.
1 . Precautionary statements
2. Directions for use ^^^
3. Storage and disposal ^ ^~
4. Warranty statement
(if the registrant chooses ^^
to include one)
^^^m
1
^^^m
~*
-J
-*
'
> PRECAUTIONARY STATEMENTS
HAZARDS TO HUMANS AND
DOMESTIC ANIMALS
Signal Word
Avoid contact with skin, eyes or clothing. Wash thoroughly
with soap and water after handling and before eating,
drinking, chewing gum, using tobacco or using the toilet.
Causes moderate eye irritation. Wear goggles. Harmful if
swallowed. Harmful if absorbed through skin.
ENVIRONMENTAL HAZARDS
Xxxxx xx xxxxxxx x xxx xxxxxxxxx xxxxx xxxx xxx xxxxx.
PHYSICAL OR CHEMICAL
HAZARDS
Xxxxx xx xxxxxxx x xxx xxxxxxxxx xxxxx xxxx xxx. Xxxxx
XX XXXXXXX X XXX XXXXXXXXX XXXXX XXXX XXX XXXXX.
>
> DIRECTIONS FOR USE
It is a violation of Federal law to use this product in a
manner inconsistent with its labeling.
GENERAL INSTRUCTIONS AND
INFORMATION
General Information (non-site-specific):
General Precautions and Restrictions
(non-site-specific):
Non-Crop Site/Pest:
Non-Crop Site/Pest:
Crop/Pest:
> Crop/Pest:
+ STORAGE AND DISPOSAL
PESTICIDE STORAGE
PESTICIDE DISPOSAL
» CONTAINER DISPOSAL
i A i A n n A ik i ^r\f o T A T t n A t k i T
WARRANTY STATEMENT
Xxxxx xx xxxxxxx x xxx xxxxxxxxx xxxxx xxxx xxx. Xxxxx xx
xxxxxxx x xxx xxxxxxxxx xxxxx xxxx xxx xxxxx. Xxxxx
| XXXXXXX X XXX XXXXXXXXX XXXXX XXXX XXX XXXXX
20
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CHAPTER 2
Making the Diagnosis
Federal Regulatory Agencies
U.S. Environmental Protection Agency
a. Office of Pesticide Programs
Since its formation in 1970, EPA has been the lead agency for the regulation of
pesticide use under the Federal Insecticide, Fungicide, and Rodenticide Act. EPA's
mandates include the registration of all pesticides used in the United States, setting
restricted entry intervals (i.e., the time interval during which individuals should not
enter or be present in a pesticide-treated area, unless the individual is using appro-
priate personal protective equipment), specification and approval of label information
and setting acceptable food and water tolerance (i.e., residue) levels. In addition, EPA
works in partnership with state, territorial, and tribal agencies to implement two field
programs. First, the certification and training program for pesticide applicators sets
national standards for those who apply restricted use pesticides, currently just under 1
million people. Second, the Agricultural Worker Protection Standard protects agricul-
tural workers and pesticide handlers from pesticide exposures through training, field
posting, requirements for protective equipment and decontamination protocols.
The authority to enforce EPA pesticide regulations is delegated to the states.
Concerns about non-compliance with these regulations can typically be directed
to your pesticide State Lead Agency (SLA). The EPA-recognized pesticide SLA is
typically the state agriculture department but in some states and territories it can be
another state agency (e.g., the state environmental protection agency). To identify
the pesticide SLA in your state, visit the Association of American Pesticide Control
Officials (AAPCO) website at http://aapco.org/. If a worker would like to report a
pesticide violation to the SLA but fears possible retaliatory action by management
(e.g. , job loss or disciplinary action), the worker can make an anonymous call to the
SLA. Note that not all state departments of agriculture have identical regulations. For
instance, only California and Washington State require employers to obtain cholin-
esterase testing of agricultural pesticide handlers who apply pesticides containing
cholinesterase-inhibiting compounds.
For pesticide contamination in water, EPA sets enforceable maximum contain-
ment levels. EPA also works jointly with the Food and Drug Administration (FDA)
and the U.S. Department of Agriculture (USDA) to monitor and regulate pesticide
residues and their metabolites in food and drugs. Tolerance limits are established by
EPA for pesticides and their metabolites in raw agricultural commodities.
b. Agricultural Worker Protection Standard (WPS)
Recognizing that agricultural employees needed increased protection from pesti-
cide exposures, EPA promulgated 40 CFR 170, the Agricultural Worker Protection
Standard (WPS). The intent of the regulation is to protect agricultural employees
by eliminating or reducing pesticide exposure, mitigating exposures that occur and
informing agricultural employees about the hazards of pesticides. The WPS applies
to two types of employees in the farm, greenhouse, nursery and forest industries:
(1) agricultural pesticide handlers (mixer, loader, applicator, equipment cleaner
or repair person, and nagger) and (2) field workers performing hand labor tasks
(cultivator or harvester). The regulation does not cover agricultural employees in
livestock production. The WPS includes requirements that agricultural employers
notify employees about pesticide applications in advance, offer basic pesticide
safety training, provide necessary personal protective equipment for direct work
21
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CHAPTER 2
Making the Diagnosis
with pesticides and observe restricted entry interval (REI) times. Of special interest
to healthcare providers, the WPS also requires agricultural employers to:
Post an emergency medical facility address and phone number in a
central location.
Arrange immediate transport from the agricultural establishment to a
medical facility for field workers or pesticide handlers who become ill
or injured after an acute work-related pesticide exposure.
Provide the exposed worker or handler and medical personnel with the
pesticide product name, EPA registration number, active ingredient(s).
medical information from the label, a description of how the pesticide
was used, and any other relevant exposure information.
Occupational Safety and Health Administration
The Occupational Safety and Health Administration (OSHA) plays a less substantial
role than EPA in pesticide regulation. Whereas EPA has authority over pesticides in the
home, environment and workplace, OSHA has authority only in the workplace. Like
EPA, OSHA allows states to enforce federal OSHA regulations or their own adaption
of the federal regulations (which must be approved by federal OSHA and be at least
as stringent as the federal regulations). A total of 25 states, Puerto Rico and the Virgin
Islands have such OSHA-approved state plans. In the other 25 states, regulations are
enforced by federal OSHA.
OSHA has fewer responsibilities in agricultural workplaces compared to non-
agricultural workplaces. For example, small farms (employing 10 or fewer non-family
workers and having no temporary labor camps within the last 12 months) are exempt
from enforcement of all OSHA rules, regulations and standards (http://www.osha.
gov/pls/oshaweb/owadisp.show_document?p_table=DIRECTIVES&p_id=1519). The
only exceptions to this are in California, Oregon and Washington, where the OSHA-
approved state plans enforce OSHA rules, regulations and standards on farms of all
sizes. OSHA is authorized to inspect farms with 11 or more employees but generally
defers to EPA-delegated state agencies for enforcement of all pesticide-related activi-
ties in crop-based agriculture. The pesticide enforcement activities deferred to these
EPA-delegated state agencies include the Worker Protection Standard, compliance
with language on the pesticide label and compliance with pesticide registration, clas-
sification and labeling requirements.
In the non-agricultural setting, OSHA has greater jurisdiction over workplace
pesticide exposures. All workers involved in pesticide manufacturing are covered by
OSHA, which has established permissible exposure levels for selected pesticides (e.g.,
captan, carbaryl, carbofuran, chlorpyrifos, chloropicrin, 2,4-D, diazinon, propoxur
and pyrethrum). Similar to the option of anonymous reporting of suspected pesticide
exposures or violations in agriculture to EPA or the State Lead Agency, a worker in a
non-agricultural setting who fears possible retaliatory action can anonymously report
a suspected pesticide violation to OSHA.
22
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CHAPTER 2
Making the Diagnosis
Pesticide Information Resources
EPA Office of Pesticide Programs
EPA's Office of Pesticide Programs (OPP) is responsible for registering pesticide
products and regulating their use.
a. Pesticide Worker Safety Program. Within OPP, the Pesticide Worker Safety
Program conducts a variety of regulatory and outreach activities aimed at protecting the
pesticide workforce, including agricultural workers, handlers and pesticide applicators.
EPA/OPP also leads the National Strategies for Health Care Providers: Pesticides Initiative
with the goal of improving the training of healthcare providers in the recognition,
diagnosis, treatment and prevention of pesticide poisonings among those who work with
pesticides. See Appendix B, Key Competencies for Clinicians to learn more. Pesticide
safety materials developed through the Pesticide Worker Safety Program, including this
manual, can be ordered online at no charge from the National Agricultural Center at:
http://www.epa.gov/agriculture/awor.html
Further information on Pesticide Worker Safety Program activities is available at:
http://www2.epa.gov/pesticide-worker-safety
b. Pesticide Chemical Search. Pesticide Chemical Search was created by EPA/OPP to
allow users to easily find information such as Reregistration Eligibility Decisions (REDs),
factsheets, science reviews and regulatory actions on the chemical of interest. The site is
searchable by chemical name or active ingredient (CAS number or pc code) and is located on
the EPAPesticides website at http://iaspub.epa.gov/apex/pesticides/f?p=chemicalsearch: 1
or click on the Chemical Search icon on the EPAPesticides homepage.
National Institute for Occupational Safety and Health (NIOSH)
Centers for Disease Control and Prevention
NIOSH is the federal agency responsible for conducting research on occupational
disease and injury. NIOSH investigates potentially hazardous working conditions
upon request, makes recommendations on preventing workplace disease and injury,
and provides training to occupational safety and health professionals.
(800) 356-4674 or http://www.cdc.gov/niosh/homepage.html
a. Centers for Agricultural Disease and Injury Research, Education, and
Prevention. NIOSH has funded eight Agricultural Health and Safety Centers throughout
the country. These centers conduct research and develop intervention programs aimed
at preventing occupational disease and injury of agricultural workers and their families.
http://www.cdc.gov/niosh/agctrhom.html
b. Sentinel Event Notification System for Occupational Risk (SENSOR)-
Pesticides. Surveillance for pesticide-related illness and injury is designed to protect
the public by determining the magnitude and underlying causes of over-exposure to
pesticides. Surveillance also serves as an early warning system of any harmful effects not
detected by manufacturer testing of pesticides. The NIOSH Centers for Disease Control
and Prevention (CDC) and EPA support surveillance for pesticide-related illness and
injury through the SENSOR-Pesticides program. In2012,11 states were participating in
the SENSOR-Pesticides program. The success of these state-based pesticide poisoning
surveillance systems relies on healthcare providers to report cases of suspected pesticide
poisoning. Further information about SENSOR-Pesticides is available at the website.
http://www.cdc.gov/niosh/topics/pesticides/
23
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CHAPTER 2
Making the Diagnosis
National Pesticide Information Center
The National Pesticide Information Center (NPIC) is based at Oregon State University
and is cooperatively sponsored by the university and EPA. NPIC serves as a source
of objective, science-based pesticide information on a wide range of pesticide-related
topics, such as recognition and management of pesticide poisonings, safety informa-
tion, health and environmental effects, referrals for investigation of pesticide inci-
dents, emergency treatment for both humans and animals and cleanup and disposal
procedures. NPIC also provides a rapid response in the form of skilled technical assis-
tance to persons suspected of being adversely affected by pesticide exposures. Highly
qualified pesticide specialists and a physician with extensive experience in pesticide
toxicology provide and deliver appropriate information to all inquiries. Atoll-free tele-
phone service provides pesticide information in both English and Spanish to callers in
the continental United States, Puerto Rico and the Virgin Islands. Additionally, pesti-
cide questions and comments can be sent to an email address. The website (in both
English and Spanish) has links to other sites and databases for further information.
(800) 858-7378
(Hotline hours of operation: 6:30 am - 3:30 pm PST,
Monday through Friday, except holidays)
http ://www.npic.orstedu
Migrant Clinicians Network
The Migrant Clinicians Network strengthens healthcare services and infrastructure for
migrants and other mobile poor through training and technical assistance to clinicians
and communities. As a partner to EPA's Health Care Provider Initiative, MCN assists
primary care providers in recognizing, managing and preventing pesticide exposures and
provides critically needed referral to occupational and environmental specialists. MCN's
pesticide website provides clinical tools and resources and patient educational materials
as part of its comprehensive pesticide exposure prevention and response efforts.
(512) 327-2017 or http://www.migrantclinician.org
http://www.migr antclinician.org/clinical_topics/pesticides.html
http://www.migrantclinician.org/clinical_topics/environmental-
and-occupational-health.html
American Association of Poison Control Centers
The American Association of Poison Control Centers (AAPCC) is a non-profit.
national organization founded in 1958. AAPCC represents the poison control centers
of the United States and the interests of poison prevention and treatment of poisoning.
Emergencies
Local Poison
Control
1-800-222-1222
(800) 222-1212
(local Poison Control Center access)
http://www.aapcc.org
24
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CHAPTER 2
Making the Diagnosis
Association of Occupational and Environmental Clinics
The Association of Occupational and Environmental Clinics (AOEC) is a network of
more than 60 clinics and more than 250 specialists that facilitates the prevention and
treatment of occupational and environmental illnesses and injuries.
(202) 347-4976 or http://www.aoec.org
Farmworker Justice
The Farmworker Justice Fund can provide an appropriate referral to a network of legal
services and nonprofit groups which represent farmworkers for free.
(202) 776-1757 or http://www.farmworkerjustice.org
Pesticide Information Databases
California Department of Pesticide Regulation
Pesticide Illness Surveillance Program
Since 1971, California law has required doctors to report any disease or condition that
they know or have reason to believe resulted from pesticide exposure. The California
Department of Pesticide Regulation (DPR) collects these reports in its Pesticide Illness
Surveillance Program. To supplement physician reporting, DPR cooperates with the
California Department of Public Health and California Department of Industrial Rela-
tions to search workers' compensation documents for pesticide-related disability. More
recently, DPR has contracted with the California Poison Control System to help doctors
fulfill their responsibility to report. As of 2011, a law requires clinical laboratories to
send DPR the results of cholinesterase tests done to evaluate pesticide exposure. County
agricultural commissioners (CACs) investigate every case identified and send reports of
their findings to DPR. Scientists of the Pesticide Illness Surveillance Program review,
evaluate and abstract all reports received from CACs and are working to integrate cholin-
esterase reports. Data from this program and others (including pesticide use, product
label, enforcement, school IPM and more) can be retrieved from the website.
http://www.cdpr.ca.gov/dprdatabase.htm
National Pesticide Information Retrieval Service (NPIRS)
The National Pesticide Information Retrieval System (NPIRS) receives funding from
EPA to maintain a pesticide information database. NPIRS provides publicly available
registration information on approximately 90,000 EPA-registered pesticides. The data
include: product number and name, company number and name, registration date,
cancellation date and reason, existing stocks date and product manager name and
phone number. NPIRS is administered by the Center for Environmental and Regula-
tory Information Systems at Purdue University in West Lafayette, Indiana.
http://ppis.ceris.purdue.edu/
Agency for Toxic Substances and Disease Registry
The Agency for Toxic Substances and Disease Registry (ATSDR), part of the Depart-
ment of Human Health and Services, publishes fact sheets and information on pesti-
cides and other toxic substances.
http ://www. atsdr.cdc. gov/
25
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CHAPTER 2
Making the Diagnosis
Data Collection on an Acute Pesticide Exposed Patient
When patients present with an identified pesticide poisoning, the following
data collection format has been recommended to guide the clinician on the
appropriate information to obtain as well as an evaluation of appropriate
samples and other materials.
1. PT ID: Name/Age/Sex/Occupation
2. Initial and subsequent symptoms and signs*
3. Name of pesticide product and active ingredients, their concentration
and EPA registration number
4. Date and time when exposure occurred
5. How the pesticide was applied, when applied and on what crop or for
what use
6. Route(s) of exposure: dermal, ocular, oral, respiratory
7. How much of the product was ingested, if ingested
8. Circumstances of exposure - intentional or accidental, occupational or
non-occupational
9. A detailed description of how the exposure happened
10. Treatment already received
a. Skin exposure:
i. Was affected area washed? If so, when? If not, proceed with
skin decontamination procedures
ii. Was any clothing contaminated?
ill. If so did they change clothes?
b. Ocular exposure:
i. Were the eyes irrigated?
ii. If so, with what and for how long?
c. Gl exposure:
i. Were any emetics used?
ii. Were any absorbents used?
ill. Were any home remedies (e.g., water, milk, lemon juice)
used?
iv. Was there any emesis before arrival?
26
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CHAPTER 2
Making the Diagnosis
Data Collection on an Acute Pesticide Exposed Patient, continued
Materials to be Gathered:
1. A copy of the pesticide label and/or a copy of the Material Safety Data
Sheet (MSDS).
2. A copy of the pesticide application record (tank mix, concentration, etc.)
if applicable. This should be available from the pesticide applicator or
the grower.
3. 10 cc whole blood, anticoagulated with sodium heparin (refrigerate).
4. 5 cc plasma anticoagulated with sodium heparin (refrigerate).
5. Afresh urine sample (label and freeze).
6. Any contaminated clothing, hats, foliage from the site. Place in clean
scalable plastic bag; label, seal and freeze.
7. Other options:
a. Fingernail residue. If the worker handled the pesticide or materials
with pesticide residue, some pesticide may be lodged under the
fingernails. Clean under the nails. Place in clean scalable plastic
bag, label, seal and freeze.
b. Saliva sample. Some pesticides can be detected in saliva. Have the
patient spit repeatedly into a clean glass or plastic container. Seal
the container, label and freeze.
c. Hair sample, if the head was exposed. Place in clean scalable
plastic bag, label, seal and freeze.
d. A skin wipe with ethanol-impregnated swab
i. Wipe skin that was contaminated if possible. Use a newly
opened alcohol wipe. Wipe an area of skin and if possible
estimate the size of the area wiped and record this on the
sample label. Try to focus on an area that is likely to have been
contaminated in the exposure.
ii. Place wipe in clean scalable plastic bag, label, seal and freeze.
*For the pediatric patient, note parents'occupations and child's
appearance compared to his/her usual baseline. It is important to ask
if the child is acting normally, if there is an abnormal gait, stumbling or
ataxia; and if the child has experienced excessive sleepiness, irritability
or other personality changes.
Developed by Matthew C. Keifer MD, MPH
National Farm Medicine Center
27
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CHAPTER 2
Making the Diagnosis
References
1. Liebman AK, Rowland MM. To ask or not ask: The critical role of the primary care
provider in screening for occupational injuries and exposures. J Public Health Manag
Pract. 2009:15(2):173-5.
2. Levy BS, Wegman DH (eds). Occupational and Environmental Health, 5th ed. Lippincott
Williams and Wilkins, Phila. 2006. 847 pp.
3. Agency for Toxic Substances and Disease Registry. Case studies in environmental medi-
cine: taking an exposure history. 2008, 2011. Accessed 10/12/12: http://www.atsdr.cdc.
go v/csem/exphistory/docs/exposure_hi story.pdf.
4. Rowland MM, Liebman AK, Sudakin DL, Keifer MC. Learning Opportunities from the
Reported Incident of Pesticide Poisoning. Streamline. 2006,12(5):6.
5. Ashford NA. Workers' compensation. In: Rom WN, editor. Environmental and Occupa-
tional Medicine. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams and Wilkins.
2007. pp 1712-19.
6. ACOEM. The seven ethical principals of occupational and environmental medicine.
ACOEM: Elk Grove Village, IL. 2010. Available at http://www.acoem.org/codeofconduct.
aspx.
7. Blank L, Kimball H, McDonald W, Merino J; ABIM Foundation; ACP Foundation; Euro-
pean Federation of Internal Medicine. Medical professionalism in the new millennium: a
physician charter 15 months later. Ann InternMed. 2003;138:839-41.
8. Centers for Disease Control and Prevention. Illnesses associated with exposure to methyl
bromide-fumigated produce California, 2010. MMWR. 2011;60:923-26.
9. Brooks SM, Gochfield M, Herzstein J, et al. Environmental Medicine. St. Louis, MO:
Mosby Yearbook. 1995.
10. Steenland K. Case Studies in Occupational Epidemiology. New York: Oxford University
Press. 1993.
11. Centers for Disease Control and Prevention. FflPAA Privacy Rule and Public Health: Guid-
ance from the CDC and the U.S. Department of Health and Human Services. Available at
http://www.cdc.gov/mmwr/preview/mmwrhtml/m2e41 lal .htm.
Other References
Blondell, J. Epidemiology of pesticide poisonings in the United States, with special reference to
occupational cases. OccupMed-C. 1997; 12(2):209-20.
McCauley LA, Lazarev MR, Higgins G, Rothlein J, Muniz J, Ebbert C, et al. Work character-
istics and pesticide exposures among migrant agricultural families: A community based
research approach. Environ Health Perspect. 2001;109:533-538.
Stanbury M, Anderson H, Rogers P, Bonauto D, Davis L, Materna B, Rosenman K. Guidelines
for Minimum and Comprehensive State-Based Public Health Activities in Occupational
Safety and Health, DHHS Publication No. 2008-148. National Institute for Occupational
Safety and Health, Cincinnati, OH. 2008. Online at http://www.cdc.gov/niosh/docs/2008-
148.
28
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CHAPTER 3
General Principles in the Management
of Acute Pesticide Poisonings
Introduction
This chapter describes basic management techniques applicable to most acute pesti-
cide exposures. Where special considerations and treatments are required for a partic-
ular pesticide, they are addressed separately in the appropriate chapter.
Remember: Treat the patient, not the poison. Symptomatic and supportive care
is the mainstay of therapy. Severe poisoning should be treated in an intensive care unit
setting, preferably with lexicological consultation, if available. Consultation with the
regional poison control center is highly advisable. Its staff can assist with treatment
recommendations or advise when no treatment is needed, helping to avoid unneces-
sary and possibly harmful interventions.
The American Association of Poison Control Centers (AAPCC) maintains the
National Poison Data System (NPDS). NPDS records data from the 57 U.S. poison
centers in near real-time. In 2010, 2.4 million human exposures were reported to
NPDS. Of these, 90,037 (3.8%) were exposed to some type of pesticide. The chart
below demonstrates the seasonal variation for 2000-2010, with peak exposures in July
of each year.
NPDS Human Pesticide Exposure Cases 2000 - 2010
» Human Pesticide Exposures
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Skin Decontamination
Decontamination must proceed concurrently with whatever resuscitative and antidotal
measures are necessary to preserve life. Be careful not to expose yourself or other care
providers to potentially contaminating substances. Wear protective gear (gloves, gown
and goggles) and wash exposed areas promptly. Persons attending the victim should
avoid direct contact with heavily contaminated clothing and bodily fluids.
29
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CHAPTER 3
General Principles
Place all contaminated clothing and personal effects in an appropriate container.
While no glove will provide complete protection to all possible chemical contamina-
tion, butyl rubber gloves generally provide the best protection compared to latex and
other surgical or precautionary gloves. If butyl rubber gloves are not available, nitrile
gloves may be an option. A double layer of gloves will increase protection, but will
decrease manual dexterity.1
Flush exposed areas with copious amounts of water. Wash carefully behind ears.
under nails and in skin folds. Use soap and shampoo for oily substances. If the patient
exhibits any signs of weakness, ataxia or other neurologic impairment, clothing should
be removed and a complete bath and shampoo given while the victim is recumbent.
Eye Decontamination
Ocular exposures should be treated by irrigating the exposed eyes with copious
amounts of clean water for at least 15 minutes. Remove contact lenses if present prior
to irrigation. If irritation persists after irrigation, patients should be referred to a health-
care facility for an ophthalmic exam.
Airway Protection
Support airway, breathing and circulation. Suction any oral secretions using a large
bore suction device if necessary. Intubate and ventilate as needed, especially if the
patient has respiratory depression or if the patient appears obtunded or otherwise
neurologically impaired. Administer oxygen as necessary to maintain adequate tissue
perfusion. In severe poisonings, it may be necessary to mechanically support pulmo-
nary ventilation for several days.
There are a couple of special considerations with regard to certain pesticides. In
organophosphate and carbamate poisoning, adequate tissue oxygenation is essential
prior to administering atropine. In paraquat and diquat poisoning, oxygen is contra-
indicated early in the poisoning because of progressive oxygen toxicity to the lung
tissue. See specific chapters for more details.
Gastrointestinal Decontamination
Control seizures before attempting any method of GI decontamination.2
Gastric lavage should NOT be routinely used in pesticide exposure manage-
ment and is contraindicated in poisonings due to hydrocarbon ingestion. Lavage is
indicated only when a patient has ingested a potentially life-threatening amount of
poison and the procedure can be done within 60 minutes of ingestion. Even then, clin-
ical benefit has not been confirmed in controlled studies.2'3 Studies of poison recovery
have been performed mainly with solid material such as pills. Reported recovery of
material at 60 minutes in several studies was 8%-32%.4'5 There is further evidence
that lavage may propel the material into the small bowel, thus increasing absorption.6
There are no controlled studies of pesticide recovery by these methods.
For gastric lavage, a large bore (36-40 French for adult, 24-28 French for chil-
dren) orogastric tube is passed through the mouth into the stomach followed by
administration of small volumes (200-300 mL adults, lOmL/kg child) warmed saline
or water (avoid water in children, use saline instead), which is then allowed to drain
back out with the hope of removing poisons in the stomach. Patient must be able to
maintain airway or be intubated prior to lavage. Do not attempt to lavage a patient with
ingestion of poisons that may cause seizures or rapid CNS depression, unless intu-
bated. Measure the patient for the correct placement of tube; place in left-lateral decu-
bitus position. Place on cardiac monitor and pulse oximetry. Have suction equipment
30
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CHAPTER 3
General Principles
GASTRIC LAVAGE CONTRAINDICATIONS2
1
2
3
4
5
6
Patients with unprotected airway
Patients with decreased level of
consciousness without intubation
Patients who have ingested drugs that
may cause abrupt CMS depression
or seizures and who have not been
intu bated
Patients who have Ingested corrosive
substances: acid or alkali
Patients who have ingested
hydrocarbon and have high risk of
aspiration
Patients at risk of bleeding or GI
perforation because of recent surgery
or medical conditions such as
coagulopathy
nearby. Continue lavage process
until returns are clear. Volume of
fluid returned should be the same
as the amount instilled to avoid
fluid and electrolyte imbalance.
Negative or poor lavage does not
rule out significant ingestion.
Complications of gastric
lavage may include aspiration.
fluid and electrolyte imbal-
ance, mechanical injury to the
throat-esophagus-stomach and
hypoxia. Lavage is contraindi-
cated in hydrocarbon ingestion.
a common solvent used in many
pesticide formulations. There-
fore, for most pesticide expo-
sures, gastric lavage should not
be performed. Contraindications
to gastric lavage are listed in the
adjacent table.
Cathartics have NO role in management of poisoned patients and are NOT
recommended as a way to decontaminate the GI tract. Repeat doses of cathartics may
result in fluid and electrolyte imbalances, particularly in children.7
Saline cathartics include magnesium citrate, magnesium sulfate, sodium sulfate
and magnesium hydroxide. Osmotic cathartics increase the water content and weight
of the stool. Sorbitol is a sugar alcohol that functions as an osmotic cathartic and is
slowly metabolized in humans. Sorbitol is often combined with charcoal to improve
the taste and mask the grittiness of charcoal. Previously given along with charcoal.
cathartics were intended to decrease the absorption of poisons by speeding movement
of the charcoal-poison complex through the gut resulting in bowel evacuation. The use
of sorbitol is not recommended in poisonings with organophosphates, carbamates or
arsenicals, which generally result in profuse diarrhea, or in poisonings with diquat or
paraquat, which may result in an ileus.
Contraindications to cathartic use include absent bowel sounds, abdominal
trauma or surgery, or intestinal perforation or obstruction. Cathartics are also contra-
indicated in volume depletion, hypotension, electrolyte imbalance or the ingestion of
a corrosive substance.7 A 2004 revision of a 1997 position paper on cathartics deter-
mined that there was no new evidence that required a change in the 1997 conclusions.8
Activated charcoal is an effective adsorbent for many poisonings. Volun-
teer studies suggest that it reduces the amount of poison absorbed if given within
60 minutes of ingestion.9 There are insufficient data to support or exclude its use if
time from ingestion is prolonged, although some poisons that are less soluble may be
adsorbed beyond 60 minutes.
Nearly all clinical trials with charcoal have been conducted with poisons other
than pesticides. There is evidence that paraquat is well adsorbed by activated char-
coal.10'11'12'13 In vitro data demonstrated that boric acid is well adsorbed by charcoal.14
Charcoal has been anecdotally successful in cases of poisoning from other pesticides.
There are in vitro data that evaluated the effect of the herbicide 2,4-D, although the
purpose of the study was to evaluate charcoal for environmental adsorption. It was
not simulated in a gastric environment, so the data do not strictly reflect an effect in
human poisoning.15
31
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CHAPTER 3
General Principles
Dosage of Activated Charcoal
It is difficult to determine the precise dosage, as clinical studies are either
conducted in animals or in humans with a known quantity of ingestant. The
following dosages are recommended.16
Infants up to 1 year of age: 10-25 g or 0.5-1.0 g/kg
Children 1 to 12 years of age: 25-50 g or 0.5-1.0 g/kg
Adolescents and adults: 25-100 g
Administer charcoal as an aqueous slurry. Encourage the victim to swallow the
adsorbent. Antiemetic therapy may help control vomiting in adults or older children.
As an alternative, activated charcoal may be administered through an orogastric tube
or diluted with water and administered slowly through a nasogastric tube. Repeated
administration of charcoal or other absorbent every 2-4 hours may be beneficial in
both children and adults. Repeated doses of activated charcoal should not be adminis-
tered if the gut is atonic. The use of charcoal without airway protection is contraindi-
cated in the neurologically impaired patient.
Charcoal should be used with caution in cases of poisoning from organophos-
phates, carbamates and organochlorines if they are prepared in a hydrocarbon solution
as this will increase the risk for aspiration.
Single-dose activated charcoal should not be used routinely in the management
of poisoned patients. Charcoal appears to be most effective within 60 minutes of inges-
tion and may be considered for use for this time period. Although it may be considered
60 minutes after ingestion, there is insufficient evidence to support or exclude its use
for this time period. Despite improved binding of poisons within 60 minutes, only one
study exists to suggest that there is improved clinical outcome.17
Activated charcoal is contraindicated in an unprotected airway, a GI tract not
anatomically intact, and when charcoal therapy may increase the risk of aspiration.
such as when a hydrocarbon-based pesticide has been ingested.9 A 2004 position paper
by the American Academy of Clinical Toxicology (AACT) reviewed data since its
1997 statement was published and essentially reiterated the position of those guide-
lines.8 A randomized controlled trial of multiple dose charcoal conducted in Sri Lanka
was published after the 2004 AACT position paper. This study did not find a difference
in mortality between the two groups, and the researchers concluded that routine use
of multiple-dose activated charcoal could not be recommended in rural Asia Pacific.18
Syrup of ipecac was historically given to patients to induce emesis, both prior
to emergency department referral and on emergency department arrival. Ipecac syrup
was used as an intervention in order to prevent healthcare facility referral in minor
ingestions. Ipecac has been used as an emetic since the 1950s. In a pediatric study.
administration of syrup of ipecac resulted in emesis within 30 minutes in 88% of chil-
dren.19 Most clinical trials involve the use of pill form ingestants, such as aspirin,5'20
acetaminophen,21 ampicillin22 and multiple types of tablets.23 No clinical trials have
been done with pesticides. In 2010, the National Poison Data System of the Amer-
ican Association of Poison Control Centers (AAPCC) reported more than 2.4 million
human exposures, and syrup of ipecac was administered in only 359 (0.02%).24 This
was a significant decrease from 2009, when syrup of ipecac was administered for
decontamination in only 658 (0.03%) of all human exposures.25
In 1993, the American Academy of Clinical Toxicology (AACT) advised that
ipecac syrup should not be routinely administered to poison patients in a healthcare
setting. In the 1997 AACT guidelines, syrup of ipecac was not considered first-line
32
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CHAPTER 3
General Principles
therapy. The guidelines acknowledged that clinical studies have demonstrated no
benefit from its use.26 A subsequent revised position statement in 2004 acknowledged
that no changes to the 1997 statement recommendations were required.27
In 2003, the American Academy of Pediatrics recommended that ipecac syrup
not be used as home treatment in a child who ingested any toxic substance. The policy
statement also recommended that existing ipecac in homes should be disposed of
safely.28 This recommendation was reinforced in 2005 when the AAPCC issued guide-
lines on syrup of ipecac use. The AAPCC concluded that there were only rare circum-
stances in which use of ipecac syrup should be considered. All of the following would
have to be true:
1. syrup of ipecac is not contraindicated.
2. the poisoning in question will give substantial risk of toxicity to the patient.
3. there is no available alternative gastrointestinal decontamination therapy.
4. there will be a delay of greater than 1 hour to get to an emergency medical
facility, and
5. ipecac syrup would not adversely affect definitive treatment available at the
hospital or other medical facility.29
It is unlikely that syrup of ipecac would ever be indicated for home or pre-
hospital gastric decontamination.
Seizure Management
Lorazepam is increasingly being recognized as the benzodiazepine of choice for toxi-
cological induced single or multiple seizures, although there are few reports of its use
with certain pesticides. With any benzodiazepine or other seizure control medication.
one must be prepared to assist ventilation.
Dosage of Lorazepam for Seizure Control
Adults: 2-4 mg/dose given IV over 2-5 minutes. Repeat if
necessary to a maximum of 8 mg in a 12-hour period.
Adolescents: Same as adult dose, except maximum dose
is 4 mg.
Children under 12 years: 0.05-0.10 mg/kg IV over 2-5
minutes. Repeat if necessary 0.05 mg/kg 10-15 minutes after
first dose, with a maximum dose of 4 mg.
CAUTION: Be prepared to assist pulmonary ventilation mechanically and
endotracheally intubate the patient if laryngospasm or respiratory depres-
sion occurs and hypoxia is possible. Monitor for hypotension and cardiac
dysrhythmias. Also remember to evaluate for hypoglycemia, electrolyte
disturbances and hypoxia.
33
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CHAPTER 3
General Principles
For organochlorine compounds, use of lorazepam has not been reported in the
literature. Diazepam is often used for this and other pesticide poisonings.
Dosage of Diazepam
Adults: 5-10 mg IV and repeat every 5-10 minutes to
maximum of 30 mg.
Children: 0.2 to 0.5 mg/kg IV every 5 minutes to maximum
of 10 mg in children over 5 years and 5 mg in children under
5 years.
Phenobarbital is an additional treatment option for seizure control.
Dosage of Phenobarbital
Infants, children and adults: 15-20 mg/kg as an IV loading
dose. Give an additional 5 mg/kg IV every 15-30 minutes to a
maximum of 30 mg/kg. The drug should be pushed no faster
than 1 mg/kg/minute.
For seizure management, most patients respond well to usual management
consisting of benzodiazepines and phenobarbital.
Management of Refractory Seizures
These patients require intensive care management and should be referred to a tertiary
center.
Consider an infusion of propofol in patients who continue to experience seizures
despite adequate benzodiazepine and/or phenobarbital dosing. Monitor closely for
propofol infusion syndrome, cardiac failure, rhabdomyolysis, metabolic acidosis and
renal failure, which may be fatal.30
Dosage of Propofol
Infants, children, and adults: Start with a bolus dose of 1
to 2 mg/kg IV. Follow with an infusion of 2 mg/kg/hour IV and
titrate up as needed for sedation and control of seizures.
34
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CHAPTER 3
General Principles
References
1. OSHA. Hospital-Based Receivers of Victims from Mass Casualty Incidents Involving the
Release of Hazardous Substances. 2005; http://www.osha.gov/dts/osta/bestpractices/first-
receivers_ho spital. pdf.
2. Vale JA, Kulig K. Position paper: gastric lavage. J Toxicol Clin Toxicol. 2004 ;42(7): 933-
943.
3. Vale JA. Position statement: gastric lavage. American Academy of Clinical Toxicology;
European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin
Toxicol. 1997;35(7):711-719.
4. Tenenbein M, Cohen S, Sitar DS. Efficacy of ipecac-induced emesis, orogastric lavage.
and activated charcoal for acute drug overdose. AnnEmergMed. Aug 1987;16(8):838-841.
5. Danel V, Henry JA, Glucksman E. Activated charcoal, emesis, and gastric lavage in aspirin
overdose. BrMed J (Clin Res Ed). May 28 1988;296(6635): 1507.
6. Saetta JP, March S, Gaunt ME, Quintan DN. Gastric emptying procedures in the self-
poisoned patient: are we forcing gastric content beyond the pylorus? J R Soc Med. May
1991;84(5):274-276.
7. Barceloux D, McGuigan M, Hartigan-Go K. Position statement: cathartics. American
Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical
Toxicologists. J Toxicol Clin Toxicol. 1997;35(7):743-752.
8. Position paper: cathartics. J Toxicol Clin Toxicol. 2004;42(3):243-253.
9. Chyka PA, Seger D. Position statement: single-dose activated charcoal. American Academy
of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicolo-
gists. J Toxicol Clin Toxicol. 1997;35(7):721-741.
10. Idid SZ, Lee CY. Effects of Fuller's Earth and activated charcoal on oral absorption of
paraquat in rabbits. Clin Exp PharmacolPhysiol. Aug 1996;23(8):679-681.
11. Nakamura T, Kawasaki N, Tamura T, Tanada S. In vitro adsorption characteristics of
paraquat and diquat with activated carbon varying in particle size. Bull Environ Contam
Toxicol. Mar2000;64(3):377-382.
12. Gaudreault P, Friedman PA, Lo vej oy FH, Jr. Efficacy of activated charcoal and magnesium
citrate in the treatment of oral paraquat intoxication. Ann EmergMed. Feb 1985; 14(2): 123-
125.
13. Terada H, Miyoshi T, Imaki M, Nakamura T, Tanada S. Studies on in vitro paraquat and
diquat removal by activated carbon. Tokushima JExpMed. Jun 1994;41(1-2):31-40.
14. Oderda GM, Klein-Schwartz W, Insley BM. In vitro study of boric acid and activated char-
coal. J Toxicol Clin Toxicol. 1987;25(1-2):13-19.
15. Belmouden M, Assabbane A, Ichou YA. Adsorption characteristics of a phenoxy acetic
acid herbicide on activated carbon. J Environ Monit. Jun 2000;2(3):257-260.
16. Chyka PA, Seger D, Krenzelok EP, Vale JA. Position paper: Single-dose activated char-
coal. Clin Toxicol (Phila). 2005;43(2):61-87.
17. Merigian KS, Woodard M, Hedges JR, Roberts JR, Stuebing R, Rashkin MC. Prospec-
tive evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med. Nov
1990;8(6):479-483.
18. Eddleston M, Juszczak E, Buckley NA, et al. Multiple-dose activated charcoal in acute
self-poisoning: a randomised controlled trial. Lancet. Feb 16 2008;371(9612):579-587.
19. Robertson WO. Syrup of ipecaca slow or fast emetic? Am J Dis Child. Feb 1962;103:136-
139.
20. Curtis RA, Barone J, Giacona N. Efficacy of ipecac and activated charcoal/cathartic.
Prevention of salicylate absorption in a simulated overdose. Arch Intern Med. Jan
1984;144(l):48-52.
35
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CHAPTER 3
General Principles
21. McNamara RM, Aaron CK, Gemborys M, Davidheiser S. Efficacy of charcoal cathartic
versus ipecac in reducing serum acetaminophen in a simulated overdose. Ann EmergMed.
Sep 1989;18(9):934-938.
22. Tenenbein M, Cohen S, and Sitar DS. Efficacy of ipecac-induced emesis, orogastric lavage.
and activated charcoal for acute drug overdose. Ann EmergMed. 1987; 16:838-41.
23. Neuvonen PJ, Vartiainen M, Toko la O. Comparison of activated charcoal and ipecac syrup
in prevention of drug absorption. Eur J Clin Pharmacol. 1983;24(4): 557-562.
24. Bronstein AC, Spyker DA, Cantilena LR, Jr., Green JL, Rumack BH, Dart RC. 2010
Annual Report of the American Association of Poison Control Centers' National Poison
Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila). Dec 2011; 49(10):910-
941.
25. Bronstein AC, Spyker DA, Cantilena LR, Jr., Green JL, Rumack BH, Giffin SL. 2009
Annual Report of the American Association of Poison Control Centers' National Poison
Data System (NPDS): 27th Annual Report. Clin Toxicol (Phila). Dec 2010;48(10):979-
1178.
26. Krenzelok EP, McGuigan M, Lheur P. Position statement: ipecac syrup. American Academy
of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicolo-
gists. J Toxicol Clin Toxicol. 1997;35(7):699-709.
27. Position paper: Ipecac syrup. J Toxicol Clin Toxicol. 2004;42(2): 133-143.
28. Poison treatment in the home. American Academy of Pediatrics Committee on Injury,
Violence, and Poison Prevention. Pediatrics. Nov 2003;112(5): 1182-1185.
29. Manoguerra AS, Cobaugh DJ. Guideline on the use of ipecac syrup in the out-of-hospital
management of ingested poisons. Clin Toxicol (Phila). 2005;43(1):1-10.
30. Abend NS, Dlugos DJ. Treatment of refractory status epilepticus: literature review and a
proposed protocol. Pediatr Neural. Jun2008;38(6):377-390.
36
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Section II
INSECTICIDES
Pyrethrins and Pyrethroids 38
Organophosphate Insecticides 43
N-Methyl Carbamate Insecticides 56
Organochlorines 63
Biologicals and Insecticides of Biological Origin 70
Other Insecticides and Acaricides 80
-------
Pyrethrins
HIGHLIGHTS
Strongly lipophilic
Crude pyrethrum is a dermal
& respiratory allergen
Easily absorbed by Gl tract
& pulmonary membranes
Relatively low mammalian
toxicity
SIGNS & SYMPTOMS
Contact dermatitis
Rhinitis, asthma
TREATMENT
Antihistamines
Epinephrine for anaphylaxis
as required
Topical corticosteroid for
contact dermatitis
Flush eyes as necessary
Consider gastric emptying or
charcoal adsorption
CHAPTER 4
Pyrethrins and Pyrethroids
PYRETHRINS
Pyrethrum is the oleoresin extract of dried chrysanthemum flowers. The extract
contains about 50% active insecticidal ingredients known as pyrethrins. The ketoalco-
holic esters of chrysanthemic and pyrethroic acids are known as pyrethrins, cinerins
and jasmolins. These strongly lipophilic esters rapidly penetrate many insects and
paralyze their nervous systems. Both crude pyrethrum extract and purified pyrethrins
are contained in various commercial products, commonly dissolved in petroleum
distillates. Some are packaged in pressurized containers ("bug bombs"), usually in
combination with the synergists piperonyl butoxide and n-octyl bicycloheptene dicar-
boximide. The synergists retard enzymatic degradation of pyrethrins. Pyrethrum and
pyrethrin products are used mainly for indoor pest control. They are not sufficiently
stable in light and heat to remain as active residues on crops. The synthetic insecticides
known as pyrethroids (chemically similar to pyrethrins) have the stability needed for
agricultural applications. Pyrethroids are discussed separately below.
Toxicology
Crude pyrethrum is a dermal and respiratory allergen, probably due mainly to non-
insecticidal ingredients. Contact dermatitis and allergic respiratory reactions (rhinitis
and asthma) have occurred following exposures.1'2 Single cases exhibiting anaphy-
lactic3 and pneumonitic manifestations4 have also been reported. Pulmonary symp-
toms may be due to inhalation of the hydrocarbon vehicle(s) of the insecticides. The
refined pyrethrins are probably less allergenic but appear to retain some irritant and/
or sensitizing properties.
Pyrethrins are absorbed across the gastrointestinal tract and pulmonary
membranes, but only slightly across intact skin. They are very effectively hydrolyzed
to inert products by mammalian liver enzymes. This rapid degradation, combined
with relatively poor bioavailability, probably accounts in large part for their relatively
low mammalian toxicity. Dogs fed extraordinary doses exhibit tremor, ataxia, labored
breathing and salivation. Similar neurotoxicity has been rarely observed in humans.
even in individuals who have had extensive contact from using pyrethrins for body
lice control or have ingested pyrethrum as an anthelmintic.
In cases of human exposure to commercial products, the possible role of other
toxicants in the products should be kept in mind. The synergists piperonyl butoxide
and n-octyl bicycloheptene dicarboximide have low toxic potential in humans, which
is further discussed in Chapter 19, Miscellaneous Pesticides, Solvents and Adju-
vants. However, the hydrocarbon vehicle(s) may have significant toxicity. Pyrethrins
themselves do not inhibit the cholinesterase enzymes.
Confirmation of Poisoning
No practical tests for pyrethrin metabolites or pyrethrin effects on human enzymes or
tissues are currently available.
38
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Treatment of Pyrethrin or Pyrethrum Toxicosis
1. Use antihistamines, which are effective in controlling most allergic reactions.
Severe asthmatic reactions, particularly in predisposed persons, may require
administration of inhaled p-agonists and/or systemic corticosteroids. Inhalation
exposure should be carefully avoided in the future.
2. For anaphylaxis-type reactions, use subcutaneous epinephrine, epinephrine and
respiratory support as necessary.3
3. In cases of contact dermatitis, administer topical corticosteroid preparations for
an extended period, as necessary, under the supervision of a physician. Future
contact with the allergen must be avoided.
4. Remove eye contamination by flushing the eye with copious amounts of clean
water or saline. Specialized ophthalmologic care should be obtained if irritation
persists.
5. Treat toxic manifestations caused by other ingredients according to their respec-
tive toxic actions, independent of pyrethrin-related effects.
6. Even though most ingestions of pyrethrin products present little risk, if a large
amount of pyrethrin-containing material has been ingested and the patient is seen
within 1 hour, consider gastric emptying. If seen later, or if gastric emptying is
performed, consider administration of activated charcoal as described in Chapter
3, General Principles.
CHAPTER 4
Pyrethrins & Pyrethroids
Pyrethrins
COMMERCIAL
PRODUCTS
Aquacide
Black Flag
Chemsico
Evercide
Hot Shot Flea Killer
Prentox
Purge
Pyrocide Fogging
Concentrate
Raid Ant & Roach Killer
Raid Fogger
Supra-Quick Flea & Tick
Mist
PYRETHROIDS
These modern synthetic insecticides are similar chemically to natural pyrethrins, but
pyrethroids are modified to increase stability in the natural environment. They are now
widely used in agriculture, in homes and gardens, and for treatment of ectoparasitic
disease. There has been increasing use of these agents as use of organophosphate pesti-
cides becomes more restricted.5
Toxicology
Although certain pyrethroids exhibit striking neurotoxicity in laboratory animals
when administered by intravenous injection and some are toxic by the oral route.
systemic toxicity by inhalation and dermal absorption is low. While limited absorp-
tion may account for the low toxicity of some pyrethroids, rapid biodegradation by
mammalian liver enzymes (ester hydrolysis and oxidation) is probably the major
factor responsible for this phenomenon.6'7 Neonatal rats have been demonstrated to
have decreased ability to metabolize and excrete pyrethroids. The LD50 for weanling
rats with deltamethrin has been reported at 12 rng/kg, while the adult LD50 is about 80
mg/kg. At these doses, the brain levels of deltamethrin at death are equivalent in both
weanling and adult rats.8 Most pyrethroid metabolites are promptly excreted, at least
in part, by the kidneys.
Multiple mechanisms and targets have been evaluated for mammalian toxicity.
At concentrations as low as 10~10M in in vitro systems, pyrethroids alter sodium and
chloride channels and result in norepinephrine release. At concentrations around 10~7
M, membrane depolarization and apoptosis occur, as well as other cellular effects. In
laboratory animal studies, this results in a state of hyperexcitability at lower expo-
39
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CHAPTER 4
Pyrethrins & Pyrethroids
Pyrethroids
HIGHLIGHTS
Low systemic toxicity via
inhalation and dermal route
Sites of action: sodium &
chloride channels; GABA,
nicotinic acetylcholine,
peripheral benzodiazepine
receptors
Type I (e.g., permethrin)
usually do not contain a
cyano group
Type II (e.g., cypermethrin,
fenvalerate) always contain
a cyano group
Type II acute poisonings are
generally more severe
SIGNS & SYMPTOMS
Type I: fine tremor, reflex
hyperexcitability
Type II: severe salivation,
hyperexcitability,
choreoathetosis
May include dizziness,
headache, fatigue, vomiting,
diarrhea
Stinging, burning, itching,
tingling, numb skin may be
reported
Severe cases: pulmonary
edema, seizures, coma
TREATMENT
Decontaminate skin, eyes
Consider Gl
decontamination
Treat seizures as necessary
sures, followed by depolarization, conduction block and cell death at very high levels
of exposure.7 In addition to the calcium and sodium channel sites of action, multiple
other sites described include GABA receptors (for Type II effects, see following).
nicotinic acetylcholine receptors and peripheral benzodiazepine receptors. They have
also been shown to alter mitochondrial electron transport.9
These discrete effects at differing levels and the relative resistance of mammals
to these agents explain the typical syndromes of human poisoning. However, the possi-
bility of neuronal death with prenatal exposure or with repeated dosing in adults has
been raised.7 The potential decreased ability of the fetus to metabolize these agents
could result in higher levels in the developing brain, with resulting neurotoxicity.
Pyrethroids have been divided into two types based on clinical findings with
overdosing. Type I pyrethroids, such as permethrin, usually do not contain a cyano
group, while most Type II pyrethroids, such as cypermethrin and fenvalerate, always
do.10 Both of these types show marked stimulus of catecholamine release from the
adrenals with overdosing. This release of epinephrine and norepinephrine results in
marked sympathetic symptoms.
There have been recent reports of illnesses due to these agents. A report of 466
episodes of illnesses and injuries related to total release foggers notes that eight of
the ten most commonly reported active ingredients in these episodes are pyrethroid
compounds, representing 86% of all reported episodes.11 In these cases, 18% were
reported as moderate severity and 2% were classified as high severity.
Signs and Symptoms of Poisoning
Type II acute poisonings are generally more severe than Type I.10 Type I poisoning
has been described as characterized by fine tremor and reflex hyperexcitability. Type
II poisoning has typically shown severe salivation, hyperexcitability and choreoath-
etosis. Other signs and symptoms of toxicity include abnormal facial sensation, dizzi-
ness, headache, fatigue, vomiting, diarrhea and irritability to sound and touch. In more
severe cases, pulmonary edema, muscle fasiculations, seizures and coma can develop.
A large ingestion (200 to 500 mL) of concentrated formulations may cause coma and
seizures within 20 minutes. Initial symptoms following ingestion include gastrointes-
tinal events (i.e., abdominal pain, vomiting and diarrhea) generally within 10 to 60
minutes. Of 573 cases reviewed in China, 51 included disturbed consciousness and 34
included seizures. Of those 85 symptomatic cases, only five were from occupational
exposure.12
A report of illnesses in 27 farmworkers and 4 emergency responders was related
to pesticide drift of the pyrethroid cyfluthrin.13 In this episode, the most commonly
reported symptoms were headache (96%), nausea (89%), eye irritation (70%), muscle
weakness (70%), anxiety (67%) and shortness of breath (64%).n
Apart from central nervous system toxicity, some pyrethroids do cause distressing
paresthesias when liquid or volatilized materials contact human skin. These symptoms
are more common with exposure to the Type II pyrethroids than the Type 1.6 Sensations
are described as stinging, burning, itching and tingling, progressing to numbness.12'14'15
The skin of the face seems to be most commonly affected, but the hands, forearms and
neck are sometimes involved. Sweating, exposure to sun or heat and application of
water enhance the disagreeable sensations. Sometimes the paresthetic effect is noted
within minutes of exposure, but a 1-2 hour delay in appearance of symptoms is more
common.14'16 Sensations rarely persist more than 24 hours.7 Little or no inflammatory
reaction is apparent where the paresthesias are reported; the effect is presumed to
result from pyrethroid contact with sensory nerve endings in the skin. The paresthetic
reaction is not allergic in nature, though sensitization and allergic responses have been
40
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reported as an independent phenomenon with pyrethroid exposure. However, allergic
responses are less likely with pyrethroids than with pyrethrins. Race, skin type and
disposition to allergic disease do not affect the likelihood or severity of the reaction.
Persons treated with permethrin for lice or flea infestations sometimes experi-
ence itching and burning at the site of application, but this is chiefly an exacerbation
of sensations caused by the parasites themselves and is not typical of the paresthetic
reaction described above.
Pyrethroids are not cholinesterase inhibitors. However, there have been some
cases in which pyrethroid poisoning has been misdiagnosed as organophosphate
poisoning, due to similar presenting signs.7'12 There are also reports of mixed poisoning
where the initial diagnosis of organophosphate poisoning had to be reconsidered when
the response to atropine was more prompt and complete than expected.16
Confirmation of Poisoning
Pyrethroid metabolites can be measured in the urine; however, this is not routinely
available for the acutely poisoned patient. The following metabolites have been
detected in occupationally exposed workers: cis- and trans-3-(2,2-dichlorovinyl)-
2,2-dimethylcyclopropanecarboxylic acid, cis-3-(2,2-dibromovinyl)-2,2-dimethylcy-
clopropanecarboxylic acid, 3-phenoxybenzoic acid and 4-fluoro-3-phenoxybenzoic
acid.17
Treatment of Pyrethroid Toxicosis
Decontaminate the skin promptly with soap and water as outlined in Chapter 3,
General Principles. If irritant or paresthetic effects occur, obtain treatment by a
physician. Because volatilization of pyrethroids apparently accounts for pares-
thesia affecting the face, strenuous measures should be taken (ventilation, protec-
tive face mask and hood) to avoid vapor contact with the face and eyes. Vitamin E
oil preparations (dl-alpha tocopheryl acetate) are uniquely effective in preventing
and stopping the paresthetic reaction.14'18 They are safe for application to the skin
under field conditions. Corn oil is somewhat effective, but possible side effects
with continued use make it less suitable. Vaseline is less effective than corn oil,
and zinc oxide actually worsens the reaction.
Treat eye contamination immediately by prolonged flushing with copious amounts
of clean water or saline. Some pyrethroid compounds can be very corrosive to the
eyes, so extraordinary measures should be taken to avoid eye contamination. If
irritation persists, professional ophthalmologic care should be obtained.
If large amounts of pyrethroids, especially the cyano-pyrethroids, have been
ingested and the patient is seen soon after exposure, consider gastrointestinal
decontamination as outlined in Chapter 3. Based on observations in labora-
tory animals6 and humans,12 large ingestions of allethrin, cismethrin, fluvalinate,
fenvalerate or deltamethrin would be the most likely to generate neurotoxic mani-
festations.
If only small amounts of pyrethroid have been ingested, or if treatment has been
delayed, administer activated charcoal and a cathartic orally as this probably
represents optimal management. Do not give cathartic if patient has diarrhea or
an ileus.
CHAPTER 4
Pyrethrins & Pyrethroids
Pyrethroids
COMMERCIAL
PRODUCTS
This list includes the names
of several pyrethroids
that are not currently in
commercial production.
These are included because
they may be marketed in the
future, if not in the United
States, then possibly in
other countries,
allethrin (Pynamin)
barthrin*
bioallethrin (D-trans)
bioresmethrin*
biopermethrin*
cismethrin*
cyfluthrin (Baythroid)
cypermethrin (Ammo,
Barricade, CCN52,
Cymbush, Cymperator,
Cynoff, Cyperkill, Demon,
Folcord, KafilSuper, NRDC
149, Polytrin, Siperin,
Ripcord, Flectron, Ustadd,
Cyrux, many others)
deltamethrin (DeltaDust,
DeltaGard, Suspend, Deltex,
Decis)
dimethrin
fenothrin*
fenpropanate*
fenpropathrin (Danitol,
Herald, Meothrin, Rody)
fenvalerate (Belmark,
Sumicidin, Fenkill)
flucythrinate (Cybolt, Payoff,
Fluent)
fluvalinate*
furethrin*
continued next page
41
-------
CHAPTER 4
Pyrethrins & Pyrethroids
Pyrethroids
COMMERCIAL
PRODUCTS
continued
permethrin (Ambush,
Dragnet, Eksmin, Kafil,
Permasect, Perthrine,
Pounce, Pramex, Outflank,
Talcord and others)
phthalthrin*
resmethrin (Benzofuroline,
Chrysron, Pynosect)
tetramethrin (Neopynamin)
tralomethrin (Tralex, SAGA)
Nix and Elimite - permethrin
creams applied to control
human ectoparasites
*Not registered in the U.S.
Treat seizures as outlined in Chapter 3. Several drugs are effective in relieving
the pyrethroid neurotoxic manifestations observed in deliberately poisoned
laboratory animals, but none has been tested in human poisonings. Therefore,
neither efficacy nor safety under these circumstances is known. Furthermore,
moderate neurotoxic symptoms and signs are likely to resolve spontaneously.
References
i.
2.
Moretto A. Indoor spraying with the pyrethroid insecticide lambda-cyhalothrin: effects on
spraymen and inhabitants of sprayed houses. Bull World Health Organ. 1991;69(5):591-
594.
Newton JG, Breslin AB. Asthmatic reactions to a commonly used aerosol insect killer. Med
JAust. Apr 16 1983;1(8):378-380.
3. Culver CA, Malina JJ, Talbert RL. Probable anaphylactoid reaction to a pyrethrin pedicu-
locide shampoo. ClinPharm. Nov 1988;7(ll):846-849.
4. Carlson JE, Villaveces JW. Hypersensitivity pneumonitis due to pyrethrum. Report of a
case. JAMA. Apr 18 1977;237(16):1718-1719.
5. Williams MK, Rundle A, Holmes D, et al. Changes in pest infestation levels, self-reported
pesticide use, and permethrin exposure during pregnancy after the 2000-2001 U.S. Envi-
ronmental Protection Agency restriction of organophosphates. Environ Health Perspect.
Dec2008;116(12):1681-1688.
6. Dorman DC, Beasley VR. Neurotoxicology of pyrethrin and the pyrethroid insecticides.
Vet Hum Toxicol. Jun 1991;33(3):238-243.
7. Ray DE, Fry JR. A reassessment of the neurotoxicity of pyrethroid insecticides. Pharmacol
Ther. M2006;lll(l):174-193.
8. Sheets LP, Doherty ID, Law MW, Reiter LW, Crofton KM. Age-dependent differences in the
susceptibility of rats to deltamethrin. Toxicol Appl Pharmacol. May 1994;126(1):186-190.
9. Soderlund DM, Clark JM, Sheets LP, et al. Mechanisms of pyrethroid neurotoxicity: impli-
cations for cumulative risk assessment. Toxicology. Feb 1 2002;171(l):3-59.
10. Ray DE, Forshaw PJ. Pyrethroid insecticides: poisoning syndromes, synergies, and therapy.
J Toxicol Clin Toxicol. 2000;38(2):95-101.
11. Illnesses and injuries related to total release foggerseight states, 2001-2006. MMWR
Morb Mortal Wkly Rep. Oct 17 2008;57(41):1125-1129. Available on-line: http://www.
cdc.gov/mmwr/preview/mmwrhtml/mm5741a3.htm, accessed 12-27-12.
12. He F, Wang S, Liu L, Chen S, Zhang Z, Sun J. Clinical manifestations and diagnosis of
acute pyrethroid poisoning. Arch Toxicol. 1989;63(l):54-58.
13. Worker illness related to ground application of pesticideKern County, California, 2005.
MMWR Morb Mortal Wkly Rep. May 5 2006;55(17):486-488.
14. Flarmigan SA, Tucker SB, Key MM, et al. Synthetic pyrethroid insecticides: a dermato-
logical evaluation. BrJIndMed. Jun 1985;42(6):363-372.
15. Tucker SB, Flarmigan SA. Cutaneous effects from occupational exposure to fenvalerate.
Arch Toxicol. Nov 1983;54(3):195-202.
16. Tripathi M, Pandey R, Ambesh SP, Pandey M. A mixture of organophosphate and pyre-
throid intoxication requiring intensive care unit admission: a diagnostic dilemma and ther-
apeutic approach. Anesth Analg. Aug 2006;103(2):410-412, table of contents.
17. Leng G, Kuhn KH, Idel H. Biological monitoring of pyrethroid metabolites in urine of pest
control operators. Toxicol Lett. Nov 1996;88(1-3):215-220.
18. Tucker SB, Flarmigan SA, Ross CE. Inhibition of cutaneous paresthesia resulting from
synthetic pyrethroid exposure. Int JDermatol. Dec 1984;23(10):686-689.
42
-------
CHAPTER 5
HIGHLIGHTS
Organophosphate Insecticides
Organophosphates (OPs) are a class of insecticides, several of which are highly toxic.
Until the 21st century, they were among the most widely used insecticides available.
Thirty-six of them are presently registered for use in the United States, and all can
potentially cause acute and subacute toxicity. Organophosphates are used in agricul-
ture, homes, gardens and veterinary practices; however, in the past decade, several
notable OPs have been discontinued for use, including parathion, which is no longer
registered for any use, and chlorpyrifos, which is no longer registered for home use.
All share a common mechanism of cholinesterase inhibition and can cause similar
symptoms, although there are some differences within the class. Since they share this
mechanism, exposure to the same organophosphate by multiple routes or to multiple
Organophosphates by multiple routes may lead to serious additive toxicity. It is impor-
tant to understand, however, that there is a wide range of toxicity in these agents and
wide variation in dermal absorption, making specific identification of the agent and
individualized management quite important.
Toxicology
Organophosphates poison insects and other animals, including birds, amphibians and
mammals, primarily by phosphorylation of the acetylcholinesterase enzyme (AChE)
at nerve endings. The result is a loss of available AChE so that the effector organ
becomes overstimulated by the excess acetylcholine (ACh, the impulse-transmitting
substance) in the nerve ending. The enzyme is critical to normal control of nerve
impulse transmission from nerve fibers to smooth and skeletal muscle cells, secretory
cells and autonomic ganglia, and within the central nervous system (CNS). Once a
critical proportion of the tissue enzyme mass is inactivated by phosphorylation, symp-
toms and signs of cholinergic poisoning become manifest.
At sufficient dosage, loss of enzyme function allows accumulation of ACh
peripherally at cholinergic neuroeffector junctions (muscarinic effects), skeletal nerve-
muscle junctions and autonomic ganglia (nicotinic effects), as well as centrally. At
cholinergic nerve junctions with smooth muscle and secretory cells, high ACh concen-
tration causes muscle contraction and secretion, respectively. At skeletal muscle junc-
tions, excess ACh may be excitatory (cause muscle twitching) but may also weaken
or paralyze the cell by depolarizing the end plate. Impairment of the diaphragm and
thoracic skeletal muscles can cause respiratory paralysis. In the CNS, high ACh
concentrations cause sensory and behavioral disturbances, incoordination, depressed
motor function and respiratory depression. Increased pulmonary secretions coupled
with respiratory failure are the usual causes of death from organophosphate poisoning.
Recovery depends ultimately on generation of new enzyme in critical tissues.
Organophosphates are efficiently absorbed by inhalation and ingestion. Dermal
penetration and subsequent systemic absorption varies with the specific agents.
There is considerable variation in the relative absorption by these various routes. For
instance, the oral LD50 of parathion in rats is between 3-8 mg/kg, which is quite
toxic,1'2 and essentially equivalent to dermal absorption with an LD50 of 8 mg/kg.2
On the other hand, the toxicity of phosalone is much lower from the dermal route
than the oral route, with rat LD50s of 1,500 mg/kg and 120 mg/kg, respectively.2 In
general, the highly toxic agents are more likely to have higher-order dermal toxicity
Acts through
phosphorylation of the
acetylcholinesterase
enzyme at nerve endings
Efficiently absorbed by
inhalation and ingestion
Dermal penetration/
absorption varies
Muscarinic, nicotinic, CNS
effects
SIGNS & SYMPTOMS
Headache, hypersecretion,
muscle twitching, nausea,
diarrhea, vomiting
Tachycardia/bradycardia,
bronchospasm/
bronchorrhea
Respiratory depression,
seizures (esp. pediatric),
loss of consciousness
Miosis is often a helpful
diagnostic sign
Depressed RBC AChE and/
or butyrylcholinesterase
levels
TREATMENT
Ensure a clear airway
Administer atropine sulfate
or glycopyrolate
Pralidoxime may be
indicated
Decontaminate concurrently
CONTRAINDICATED
Morphine, succinylcholine,
theophylline,
phenothiazines, reserpine
43
-------
CHAPTER 5
Organophosphates
COMMERCIAL
PRODUCTS
Highly Toxic1
azinphos-methyl (Guthion,
Gusathion)
bomyl2 (Swat)
carbophenothion (Trithion)
chlorfenvinphos (Apachlor,
Birlane)
chlormephos2 (Dotan)
chlorthiophos2 (Celathion)
coumaphos (Co-Ral, Asuntol)
cyanofenphos2 (Surecide)
demeton3(Syntox)
dialifor(Torak)
dicrotophos (Bidrin)
dimefos2 (Hanane, Pestox
XIV)
dioxathion (Delnav)
disulfoton3 (Disyston)
endothion2
EPN
ethyl parathion (E605,
Parathion, thiophos)
famphur2 (Famfos, Bo-Ana,
Bash)
fenamiphos (Nemacur)
fenophosphon2 (trichloronate,
Agritox)
continued next page
Compounds are listed
approximately in order of
descending toxicity. "Highly toxic"
organophosphates have listed oral
LD50 values (rat) less than 50 mg/
kg; "moderately toxic" agents have
LD50 values in excess of 50 mg/kg
and less than 500 mg/kg.
'Products no longer registered in
the United States.
3These organophosphates are
systemic: they are taken up by the
plant and translocated into foliage
and sometimes into the fruit.
than the moderately toxic agents. To a degree, the occurrence of poisoning depends on
the rate at which the pesticide is absorbed. Breakdown occurs chiefly by hydrolysis
in the liver, and rates of hydrolysis vary widely from one compound to another. In
those organophosphates for which breakdown is relatively slow, significant temporary
storage in body fat may occur. Some organophosphates, such as diazinon, fenthion
and methyl parathion, have significant lipid solubility, allowing fat storage with
delayed toxicity due to late release.3'4 Delayed toxicity may also occur atypically with
other organophosphates, specifically dichlorofenthion and demton-methyl.5 Many
organothiophosphates readily undergo conversion from thions (P=S) to oxons (P=O).
Conversion occurs in the environment under the influence of oxygen and light and, in
the body, chiefly by the action of liver microsomal enzymes. Oxons are much more
toxic than thions, but oxons break down more readily than thions. Ultimately, both
thions and oxons are hydrolyzed at the ester linkage, yielding alkyl phosphates and
leaving groups, both of which are of relatively low toxicity. They are either excreted
or further transformed in the body before excretion.
After the initial exposure of the effector junction and the organophosphate, the
enzyme-phosphoryl bond is strengthened by loss of one alkyl group from the phos-
phoryl adduct. This process is known as aging. The bond is then essentially perma-
nent. Time of aging varies by agent and can occur within minutes to days. Depending
on the time of aging of the agent, some phosphorylated acetylcholinesterase enzyme
can be de-phosphorylated (reactivated) by a compound known as an oxime. The only
currently FDA-approved oxime in the United States is pralidoxime. Other oximes
include obidoxime and HI-6, which have been used in Europe and Asia. Depending on
the agent, pralidoxime reactivation may be no longer possible after a couple of days,6
although in some cases, improvement has still been seen with pralidoxime administra-
tion days after exposure.7 Oximes have been used for OP poisoning for more than 50
years.8 However, controversy remains as to the effectiveness of oximes because of
conflicting and limited evidence of efficacy.4'9'10
Rarely, certain organophosphates have caused a different kind of neurotoxicity
consisting of damage to the afferent fibers of peripheral and central nerves and associ-
ated with inhibition of "neuropathy target esterase" (NTE). Certain organophosphates
are exceptionally prone to storage in fat tissue, prolonging the need for antidote for
several days as stored pesticide is released back into the circulation.3'4'11 This delayed
syndrome has been termed organophosphate-induced delayed neuropathy (OPIDN)
and is manifested chiefly by weakness or paralysis and paresthesia of the extremities.12
OPIDN predominantly affects the legs and may persist for weeks to years. Only a
few of the many organophosphates used as pesticides have been implicated as causes
of delayed neuropathy in humans. EPA guidelines require that organophosphate and
carbamate compounds that are candidate pesticides be tested in susceptible animal
species for this neurotoxic property.
In addition to acute poisoning episodes and OPIDN, an intermediate syndrome
has been described. This syndrome occurs after resolution of the acute cholinergic
crisis, generally 24-96 hours after exposure. It is characterized by acute respira-
tory paresis and muscular weakness, primarily in the facial, neck and proximal limb
muscles. In addition, it is often accompanied by cranial nerve palsies and depressed
tendon reflexes. Like OPIDN, this syndrome lacks muscarinic symptoms and appears
to result from a combined pre- and post-synaptic dysfunction of neuromuscular trans-
mission. Symptoms do not respond well to atropine and oximes; therefore, treatment
is mainly supportive.13'14 The most common compounds involved in this syndrome are
methyl parathion, fenthion and dimethoate, although one case with ethyl-parathion
was also observed.4'13
44
-------
CHAPTER 5
Organophosphates
Other specific properties of individual Organophosphates may render them more
hazardous than basic toxicity data suggest. Certain Organophosphates are exception-
ally prone to storage in fat tissue, prolonging the need for antidote for several days as
stored pesticide is released back into the circulation. In vitro and animal studies have
demonstrated potentiation or additive effects when two or more Organophosphates are
absorbed simultaneously, thereby creating a cumulative effect.15>16 Animal studies have
also demonstrated additive effects when orgranophosphates are combined with other
pesticides including herbicides, carbamates and pyrethroids.17'18'19 Animal studies have
demonstrated a protective effect of toxicity from phenobarbital, which induces hepatic
degradation of the pesticide.1 Degradation of some compounds to a trimethyl phos-
phate can cause restrictive lung disease.20
In the late 1950s and 1960s, several reports appeared suggesting that long-term
effects have occurred following acute and often massive exposures. Symptoms that
are consistently reported from exposed persons include depression, memory and
concentration problems, irritability, persistent headaches and motor weakness.21'22'23
In these rare, anecdotal cases, symptoms have persisted for months to years. These
hypothesis-generating cases eventually led to larger epidemiological studies with an
exposed group and a control group that also supported the hypothesis that a propor-
tion of patients acutely poisoned from any organophosphate can experience some
long-term neuropsychiatric sequelae. The findings included significantly impaired
performance on a battery of neuro-behavioral tests and compound-specific peripheral
neuropathy, in some cases. Specific functions included impaired memory and concen-
tration, depressed mood and peripheral neuropathy. These findings were subtle and, in
some cases, picked up only on neuropsychologic testing rather than during neurologic
exam.24'25'26 For information on chronic and long-term effects from OPs, including
subacute effects and long-term exposure without acute poisoning, see Chapter 21,
Chronic Effects.
Signs and Symptoms of Poisoning
Symptoms of acute organophosphate poisoning develop during or after exposure.
within minutes to hours, depending on method of exposure. Exposure by inhalation
results in the fastest appearance of toxic symptoms, followed by the oral route and
finally the dermal route. All signs and symptoms are cholinergic in nature and affect
muscarinic, nicotinic and central nervous system receptors.6 The critical symptoms
in initial management are the respiratory symptoms. Sufficient muscular fascicula-
tions and weakness are often observed and require respiratory support, as respira-
tory arrest can occur suddenly. Bronchospasm and bronchorrhea can occur, producing
chest tightness, wheezing, productive cough and pulmonary edema. These can impede
efforts at adequate oxygenation of the patient. A life-threatening severity of poisoning
is signified by loss of consciousness, incontinence, seizures and respiratory depres-
sion. The primary cause of death is respiratory failure.
There usually is a secondary cardiovascular component to the respiratory symp-
toms. The classic cardiovascular sign is bradycardia, which can progress to sinus
arrest. However, this may be superseded by tachycardia and hypertension from nico-
tinic (sympathetic ganglia) stimulation.27 Toxic cardiomyopathy has been reported
after severe poisoning due to sarin, a weaponized organophosphate compound struc-
turally similar to the insecticides.28
Some of the most commonly reported early symptoms include headache, nausea.
dizziness and hypersecretion, the latter of which is manifested by sweating, saliva-
tion, lacrimation and rhinorrhea. Muscle twitching, weakness, tremor, incoordination.
vomiting, abdominal cramps and diarrhea all signal worsening of the poisoned state.
Highly Toxic
Commercial Products
continued
fensulfothion (Dasanit)
fonofos (Dyfonate, N-2790)
fosthietan (Nem-A-Tak)
isofenphos (Amaze, Oftanol)
mephosfolan2'3 (Cytrolane)
methamidophos (Monitor)
methidathion (Supracide,
Ultracide)
methyl parathion (E601,
Penncap-M)
mevinphos (Phosdrin,
Duraphos)
mipafox2 (Isopestox, Pestox
XV)
monocrotophos (Azodrin)
phorate (Thimet, Rampart,
AASTAR)
phosfolan2'3 (Cyolane,
Cylan)
phosphamidon (Dimecron)
prothoate2'3 (Fac)
schradan2 (OMPA)
sulfotep (Thiotepp,
Bladafum, Dithione)
terbufos (Counter,
Contraven)
tetraethyl pyrophosphate2
(TEPP)
Moderately Toxic1
acephate (Orthene)
bensulide (Betasan, Prefar)
bromophos-ethyl2 (Nexagan)
bromophos2 (Nexion)
chlorphoxim2 (Baythion-C)
chlorpyrifos (Dursban,
Lorsban, Brodan)
continued next page
45
-------
CHAPTER 5
Organophosphates
Moderately Toxic
Commercial Products
continued
crotoxyphos (Ciodrin, Cypona)
crufomate2 (Ruelene)
cyanophos2(Cyanox)
cythioate2 (Proban, Cyflee)
DEF (De-Green, E-Z-Off D)
demeton-S-methyl3 (Duratox,
Metasystox-R)
diazinon (Spectracide)
dichlofenthion (VC-13
Nemacide)
dichlorvos (DDVP, Vapona)
edifenphos2
EPBP2 (S-Seven)
ethion (Ethanox)
ethoprop (Mocap)
etrimfos2 (Ekamet)
fenitrothion (Accothion,
Agrothion, Sumithion)
fenthion (mercaptophos,
Entex, Baytex, Tiguvon)
formothion2 (Anthio)
heptenophos2 (Hostaquick)
IBP (Kitazin)
iodofenphos2 (Nuvanol-N)
isoxathion2 (E-48, Karphos)
leptophos2 (Phosvel)
continued next page
'Compounds are listed
approximately in order of
descending toxicity. "Highly toxic"
organophosphates have listed oral
LD50 values (rat) less than 50 mg/
kg; "moderately toxic" agents have
LD50 values in excess of 50 mg/kg
and less than 500 mg/kg.
Products no longer registered in
the United States.
3These organophosphates are
systemic: they are taken up by the
plant and translocated into foliage
and sometimes into the fruit.
46
Miosis is often a helpful diagnostic sign, and the patient may report blurred and/or
dark vision. Anxiety and restlessness are prominent. There are a few reports of chorei-
form movements.29'30 Psychiatric symptoms including depression, memory loss and
confusion have been reported. Toxic psychosis, manifested as confusion or bizarre
behavior, has been misdiagnosed as alcohol intoxication.
Children often present with a slightly different clinical picture from adults. Four
series have been published that describe children with poisoning from cholinesterase-
inhibiting insecticides. Some of the more typical cholinergic signs of bradycardia.
muscular fasciculations, lacrimation and sweating were less common. Seizures (range
8%-39%) and mental status changes, including lethargy and coma (range 55%-100%)
were common in children.31'32'33'34 In comparison, only around 2%-3% of adults present
with seizures.35'36 Other common presenting signs in children include flaccid muscle
weakness, miosis and excessive salivation. In one of the studies, 80% of all cases were
transferred with the wrong preliminary diagnosis.33 In another study, 88% of parents
initially denied a history of organophosphate exposure.32 See the preceding section for
information regarding the features of the intermediate syndrome and OPIDN.
Confirmation of Poisoning
CAUTION: If strong clinical indications of acute organophosphate
poisoning are present, treat patient immediately. Do not wait for laboratory
confirmation, which can take days. Initial medical care should be based on
clinical presentations.
Blood samples can measure plasma butyrylcholinesterase (pseudocholinesterase)
and red blood cell (RBC) AChE levels.37 Depressions of plasma pseudocholines-
terase and/or RBC acetylcholinersterase enzyme activities are generally available
biochemical indicators of excessive organophosphate absorption. Rarely, there have
been reports of cases of symptomatic organophosphate toxicity in which the initial
red blood cell cholinesterase levels were not depressed. Subsequent testing eventu-
ally demonstrated depressed cholinesterase levels. Certain organophosphates may
selectively inhibit either plasma pseudocholinesterase or RBC acetylcholinesterase.38
A minimum amount of organophosphate must be absorbed to depress blood cholin-
esterase activities, but enzyme activities, especially plasma pseudocholinesterase.
may be lowered by dosages considerably less than are required to cause symptomatic
poisoning. A 20%-30% depression of AChE may indicate a significant OP poisoning
that, even without symptoms, needs antidotal treatment. In severe cases, the enzyme
is usually depressed by 80%-90% of normal levels. The latter group typically requires
significantly high doses of atropine.4'37 Enzyme depression is usually apparent within
a few minutes or hours of significant absorption of organophosphate. Depression of
the plasma enzyme generally persists several days to a few weeks; the RBC enzyme
activity may not reach its minimum for several days, and usually remains depressed
longer, sometimes 1-3 months, until new enzyme replaces that inactivated by organo-
phosphate. Lower limits of cholinesterase levels vary among laboratories and methods.
so clinicians should interpret levels based on the given reference ranges. Patients with
clinical signs of toxicity and accompanied by AChE levels depressed by 20%-50%
should be managed as outlined in the treatment section.
In certain conditions, the activities of plasma and RBC cholinesterase are
depressed in the absence of chemical inhibition. About 3% of individuals have a
genetically determined low level of plasma pseudocholinesterase. These persons
are particularly vulnerable to the action of the muscle-paralyzing drug succinylcho-
-------
CHAPTER 5
Organophosphates
line, often administered to surgical patients, but not organophosphates. Patients with
hepatitis, cirrhosis, malnutrition, chronic alcoholism and dermatomyositis exhibit
low plasma cholinesterase activities. A number of toxicants, notably cocaine, carbon
disulfide, benzalkonium salts, organic mercury compounds, ciguatoxins and sola-
nines may reduce plasma pseudocholinesterase activity. Early pregnancy, oral contra-
ception and metoclopramide may also cause some depression. The RBC acetylcho-
linesterase is less likely than the plasma enzyme to be affected by factors other than
organophosphates. It is reduced, however, in certain rare conditions that damage the
red cell membrane, such as hemolytic anemia.
The alkyl phosphates and phenols to which organophosphates are hydrolyzed in
the body can often be detected in the urine during pesticide absorption and up to about
48 hours thereafter. These analyses are sometimes useful in identifying and quantifying
the actual pesticide to which workers have been exposed. Urinary alkyl phosphate and
phenol analyses can demonstrate organophosphate absorption at lower dosages than
those required to depress cholinesterase activities and at much lower dosages than
those required to produce symptoms and signs. Their presence may simply be a result
of organophosphates in the food chain. These metabolites are among the numerous
chemical metabolites measured in a U.S. sample via the National Health and Nutrition
Education Survey (NHANES) and can be found in CDC's National Report on Human
Exposure to Environmental Chemicals.39
Detection of intact organophosphates in the blood usually is not possible except
during or soon after absorption of a substantial amount. In general, organophosphates
do not remain unhydrolyzed in the blood more than a few minutes or hours, unless
the quantity absorbed is large or the hydrolyzing liver enzymes are inhibited. Blood
should be obtained for cholinesterase testing as described above, but it is not feasible
or practical to attempt to test for specific compounds. It may be useful to obtain a urine
sample from the poisoned patient and send it for metabolite detection as discussed in
the preceding paragraph. For a patient with an unknown poisoning, a frozen sample of
urine for later testing may be useful.
Treatment of Organophosphate Toxicosis
CAUTION: Persons attending the victim should avoid direct contact with
heavily contaminated clothing and vomitus. All caregivers should have appro-
priate protective gear when in contact with a patient poisoned by organophos-
phates. Wear rubber gloves while washing pesticide from skin and hair.
1. Ensure that a clear airway exists. Intubate the patient and aspirate the secretions
with a large bore suction device if necessary. Administer oxygen by mechanically
assisted pulmonary ventilation if respiration is depressed and keep patient on a
high FiO2. In severe poisonings, patients should be treated in an intensive care
unit setting.
2. Administer atropine sulfate intravenously, or intramuscularly if intravenous
injection is not possible. Remember that atropine can be administered through
an endotracheal tube if initial IV access is difficult to obtain. Depending on the
severity of poisoning, doses of atropine ranging from very low to as high as 300
mg per day or more may be required,40 or even continuous infusion.41'42 (See
dosage on following page.)
Moderately Toxic
Commercial Products
continued
malathion (Cythion)
merphos (Folex, Easy Off-D)
methyl trithion2, dimethoate
(Cygon, DeFend)
naled (Dibrom)
oxydemeton-methyl3
(Metasystox-R)
oxydeprofos2'3 (Metasystox-S)
phencapton2 (G 28029)
phenthoate2
(dimephenthoate,
Phenthoate)
phosalone (Zolone)
phosmet (Imidan, Prolate)
phoxim2 (Baythion)
pirimiphos-ethyl2 (Primicid)
pirimiphos-methyl (Actellic)
profenofos (Curacron)
propetamphos (Safrotin)
propyl thiopyrophosphate2
(Aspon)
pyrazophos2 (Afugan,
Curamil)
pyridaphenthion2 (Ofunack)
quinalphos2 (Bayrusil)
ronnel (Fenchlorphos,
Korlan)
sulprofos2 (Bolstar,
Helothion)
temephos (Abate, Abathion).
tetrachlorvinphos (Gardona,
Apex, Stirofos)
thiometon2 (Ekatin)
triazophos2 (Hostathion)
trichlorfon (Dylox, Dipterex,
Proxol, Neguvon)
47
-------
CHAPTER 5
Organophosphates
The objective of atropine antidotal therapy is to antagonize the effects of exces-
sive concentrations of acetylcholine at end-organs having muscarinic receptors.
Atropine does not reactivate the cholinesterase enzyme or accelerate disposition of
organophosphate. Recrudescence of poisoning may occur if tissue concentrations
of organophosphate remain high when the effect of atropine wears off, and multiple
doses will be required. Atropine is effective against muscarinic manifestations, but it is
ineffective against nicotinic actions, specifically muscle weakness and twitching, and
respiratory depression. Despite these limitations, atropine is often a life-saving agent
in organophosphate poisonings. Favorable response to a test dose of atropine can help
differentiate poisoning by anticholinesterase agents from other conditions.
Test Dosage of Atropine
Adults: 1 mg
Children under 12 years: 0.01 mg/kg
Note, however, that lack of response with no evidence of atropinization (atro-
pine refractoriness), may also indicate a more severe poisoning. The adjunctive use of
nebulized atropine has been reported to improve respiratory distress, decrease bron-
chial secretions and increase oxygenation.43
Dosage of Atropine
In moderately severe poisoning (hypersecretion and other end-organ
manifestations without central nervous system depression), the following
dosage schedules have been used.
Adults and children over 12 years: Initial dose 1-3 mg
IV. Repeat in 3-5 minutes if no change in clinical symptoms.
Dose may be doubled with each administration until the
patient is atropinized. Once adequate atropinization has
been achieved, the patient can be maintained on an atropine
continuous infusion at about 10%-20% of the loading dose
and titrated to effect.4444546
Children under 12 years: There is less agreement
regarding pediatric dosing. Recent studies recommend
beginning with 0.02 mg/kg body weight, and doubling the
dose every 5 minutes until atropinization is achieved.4'44
Patients seen in a pediatric ICU setting were given 0.05 mg/
kg every 15 minutes.31 Since children sometimes present
differently than adults and have more CNS findings,
aggressive atropinization should proceed when there are
muscarinic signs such as bradycardia, salivation, diarrhea
and miosis that can be observed to change with adequate
atropine.31
48
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CHAPTER 5
Organophosphates
Clear breath sounds and absent pulmonary secretions are the primary end-
point. Other signs of atropinization may occur, including flushing, dry mouth,
dilated pupils and tachycardia (pulse of 140 per minute). Early in therapy, monitor
for improving blood pressure and heart rate (above 80 beats/minute), normal pupil
size and drying of the skin and axillae.4'45
WARNING: In cases of ingestion of liquid concentrates of organophosphate
pesticides, hydrocarbon aspiration may complicate these poisonings. Pulmo-
nary edema and poor oxygenation in these cases will not respond to att-opine
and should be treated as a case of acute respiratory distress syndrome.
Maintain atropinization by repeated doses based on recurrence of symptoms
for 2-12 hours or longer depending on severity of poisoning. Crackles in the lung
bases usually indicate inadequate atropinization. Pulmonary improvement may
not parallel other signs of atropinization. Continuation of or return of cholinergic
signs indicates the need for more atropine.
Maintain atropinization with repeated dosing as indicated by clinical status.
When symptoms are stable for as much as 6 hours, the dosing may be decreased.
Severely poisoned individuals may exhibit remarkable tolerance to atro-
pine; two or more times the dosages suggested above may be needed. The dose
of atropine may be increased and the dosing interval decreased as needed to
control symptoms. Continuous intravenous infusion of atropine may be necessary
when atropine requirements are massive. The desired end-point is the reversal
of muscarinic symptoms, most predominantly drying of secretions, and signs of
improvement in pulmonary status and oxygenation, without an arbitrary dose
limit. Preservative-free atropine products should be used whenever possible.
NOTE: Persons not poisoned or only slightly poisoned by Organophosphates
may develop signs of atropine toxicityfrom large doses. Fever, muscle fibrilla-
tions and delirium are the main signs of atropine toxicity. If these appear while
the patient is fully atropinized, atropine administration should be discontinued,
at least temporarily while the severity of poisoning is reevaluated.
3. Consider administering glycopyrrolate. Glycopyrrolate has been studied as an
alternative to atropine and found to have similar outcomes using continuous infu-
sion. Ampules of 7.5 mg of glycopyrrolate were added to 200 mL of saline, and
this infusion was titrated to the desired effects of dry mucous membranes, heart
rate above 60 beats/minute and absent muscle fasciculations. During this study,
atropine was used as a bolus for a heart rate less than 60 beats/minute. The other
apparent advantage to this regimen was a decreased number of respiratory infec-
tions. This may represent an alternative when there is a concern for respiratory
infection due to excessive and difficult-to-control secretions, and in the presence
of altered level of consciousness where distinction between atropine toxicity or
relapse of organophosphate poisoning is unclear.47
4. Draw a blood sample (heparinized) for cholinesterase analysis before administra-
tion of pralidoxime, which tends to reverse the cholinesterase depression.
5. Consider administering pralidoxime (Protopam, 2-PAM), a cholinesterase reacti-
vator, in cases of moderate-to-severe OP poisoning in which respiratory depres-
sion, muscle weakness and/or twitching are severe. Pralidoxime works by reacti-
49
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CHAPTER 5
Organophosphates
vating the cholinesterase and also by slowing the "aging" process, in which there
is a loss of an akyl group. The AChE can no longer be reactivated. It is important
to administer it early in the poisoning, preferably within 48 hours; however, this
varies by the OP that is ingested. Some OPs will age much faster than others, (e.g.,
parathion ages within 20 minutes, while diethyl-OPs tend to require >48 hours).
Pralidoxime given after the aging process will be ineffective. Delayed treatment
appears to be one factor in previous studies with oximes and OP poisoning that
did not show a beneficial effect.48>49
As noted previously, there are limited data supporting the efficacy of oximes
in OP poisoning, particularly from randomized controlled trials (RCTs), although
they have been used for over 50 years.37'50'51 One recent RCT demonstrated that
pralidoxime substantially and moderately reactivated red cell AChE activity in
patients poisoned by diethyl and dimethyl compounds, respectively, when given
as a continuous infusion of 500 mg/hour. Though mortality was higher in the
group receiving pralidoxime, the difference was not statistically significant.9
Another well-designed RCT compared two different dosing regimens after
all patients first received a 2-gram loading dose of pralidoxime. The authors found
that a continuous infusion of 1 gram of pralidoxime per hour was superior to what
had been previously considered a standard bolus dosing of 1 gram pralidoxime
every 4 hours. Mortality and morbidity, as measured by atropine requirements.
need for intubation and duration of ventilator support, were all reduced in the
group receiving continuous infusion. In this study, both groups appear to have
received appropriate intensive care management that would closely match care
provided in a U.S. hospital.10 While further study is needed, particularly as to
optimal dose and delivery time with respect to type of OP ingested, pralidoxime
continues to be recommended in the United States for moderate-to-severe OP
poisoning. Unfortunately, all studies have been performed on adults, so there are
no adequate or updated data regarding proper dosing for children.
NOTE: Pralidoxime is of limited value, and may be hazardous, in poisonings
by the cholinesterase-inhibiting carbamate compounds (see Chapter 6).
Dosage of Pralidoxime
Loading Dose
Adults and children over 12 years: 2.0 gm by intravenous
infusion over a 30-minute period.10
Children under 12 years: 20-50 mg/kg body weight given
intravenously (depending on severity of poisoning), mixed
in 100 mL of normal saline and infused over 30 minutes.
Subsequent Dose
1 gram per hour as a continuous infusion over a 48-hour
period. Subsequent doses, if required, should be given
every 4 hours, infused over an hour. Alternatively, dosage
of pralidoxime may be repeated in 1-2 hours, then at 4-hour
intervals if needed.
50
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CHAPTER 5
Organophosphates
Repeated doses of pralidoxime are usually required. Dosing should continue
while ventilator support is required. In cases that involve continuing absorption
of organophosphate (as after ingestion of large amount) or continuing transfer
of highly lipophilic organophosphate from fat into blood, it may be necessary to
continue administration of pralidoxime for several days beyond the 48-hour post-
exposure interval usually cited as the limit of its effectiveness.
Blood pressure should be monitored during administration because of the
occasional occurrence of hypertensive crisis. Administration should be slowed or
stopped if blood pressure rises to hazardous levels. Be prepared to assist pulmo-
nary ventilation mechanically if respiration is depressed during or after prali-
doxime administration.
If intravenous injection is not possible, the bolus regimen of pralidoxime
may be given by deep intramuscular injection.
6. Decontaminate skin, clothing, hair and/or eyes of patients who have been
poisoned by Organophosphates, concurrently with whatever resuscitative and
antidotal measures are necessary to preserve life. Decontaminate eyes by flushing
with copious amounts of clean water. If no symptoms are evident in a patient who
remains alert and physically stable, a prompt shower and shampoo may be appro-
priate, provided the patient is carefully observed to ensure against sudden appear-
ance of poisoning symptoms. If there are any indications of weakness, ataxia or
other neurologic impairment, clothing should be removed and a complete bath
and shampoo, using copious amounts of soap and water, should be given while the
victim is recumbent. Attendants should wear rubber gloves, as latex or polyvinyl
chloride provides no protection against skin absorption.52'53 Even nitrile buta-
diene rubber gloves exhibited some defects following exposure to chlorpyrifos
and diazinon, although these appeared much later (24-48 hours after exposure)
compared to some almost immediate defects appearing in PVC gloves.52 The
possibility of pesticide sequestered under fingernails or in skin folds should not be
overlooked. Contaminated clothing should be promptly bagged and not returned
until it has been thoroughly laundered. Contaminated leather shoes should be
discarded. Pesticide may have contaminated the inside surfaces of gloves, boots
and/or headgear as well.
7. Consider gastrointestinal decontamination if organophosphate has been ingested
in quantity sufficient to cause poisoning, if the patient receives care within 30
minutes of the exposure and if there is sufficient airway protection. If the patient
has already vomited, which is most likely in serious exposures, further efforts
at GI decontamination may not be indicated. In significant ingestions, diarrhea
and/or vomiting are so constant that charcoal adsorption and catharsis are not
indicated.
A. Take rigorous precautions to protect the airway from aspiration of regurgi-
tated gastric contents. If a victim is unconscious, obtunded, has an altered
mental status or any respiratory compromise, orotracheal intubation should
be performed prior to gastric aspiration.
B. Save a sample of emesis or initial gastric aspirate for chemical analysis.
8. Observe patient closely for at least 72 hours after atropinization has been with-
drawn to ensure that symptoms (sweating, visual disturbances, vomiting, diar-
rhea, chest and abdominal distress, and sometimes pulmonary edema) do not
recur. In very severe poisonings by ingested Organophosphates, particularly the
more lipophilic and slowly hydrolyzed compounds, metabolic disposition of toxi-
51
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CHAPTER 5
Organophosphates
cant may require as many as 5-14 days. In some cases, this slow elimination
may combine with profound cholinesterase inhibition to require atropinization
for several days or even weeks. As dosage is reduced, the lung bases should be
checked frequently for crackles. If crackles are heard, or if there is a return of
miosis, bradycardia, sweating or other cholinergic signs, atropinization must be
reestablished promptly.
9. Monitor pulmonary status carefully even after apparent recovery from muscarinic
symptoms, particularly in poisonings by large ingested doses of organophosphate.
In some cases, respiratory failure has developed several days following organo-
phosphate ingestion, and has persisted for days to weeks.
10. Monitor cardiac status in severely poisoned patients by continuous ECG recording.
Some Organophosphates have significant cardiac toxicity.
11. Do not use the following drugs: morphine, succinylcholine, theophylline, pheno-
thiazines and reserpine. They are contraindicated in nearly all organophosphate
poisoning cases. Adrenergic amines should be given only if there is a specific
indication, such as marked hypotension.
12. If seizures occur despite therapy with atropine and pralidoxime, ensure that causes
unrelated to pesticide toxicity are not responsible: head trauma, cerebral anoxia
or mixed poisoning. Seizures occur rarely in severe organophosphate poisonings.
Drugs useful in controlling seizures are discussed in Chapter 3, General Prin-
ciples. The benzodiazepines - diazepam or lorazepam - are the agents of choice
as initial therapy.
13. Warn persons who have been clinically poisoned by organophosphate pesticides
to avoid re-exposure to cholinesterase-inhibiting chemicals until symptoms and
signs have resolved completely and blood cholinesterase activities have returned
to at least 80% of pre-poisoning levels. If blood cholinesterase was not measured
prior to poisoning, blood enzyme activities should reach at least minimum normal
levels before the patient is returned to a pesticide-contaminated environment.
14. Treat ingestion of liquid concentrates of organophosphate pesticides like a case
of acute respiratory distress syndrome. Hydrocarbon aspiration may complicate
these poisonings. Pulmonary edema and poor oxygenation in these cases will not
respond to atropine.
15. Do not administer atropine or pralidoxime prophylactically to workers exposed
to organophosphate pesticides. Prophylactic dosage with either atropine or prali-
doxime may mask early signs and symptoms of organophosphate poisoning and
thus allow the worker to continue exposure and possibly progress to more severe
poisoning. Atropine itself may enhance the health hazards of the agricultural work
setting, impairing heat loss (due to reduced sweating) and impairing the ability to
operate mechanical equipment (due to blurred vision caused by mydriasis).
52
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CHAPTER 5
Organophosphates
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44. Eddleston M, Buckley NA, Checketts H, et al. Speed of initial atropinisation in significant
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an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors. Crit
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46. Perera PM, Shahmy S, Gawarammana I, Dawson AH. Comparison of two commonly
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48. Cherian AM, Peter JV, Jaydevan R, et al. Effectiveness of P2AM (PAM - pralidoxime) in
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49. Johnson S, Peter JV, Thomas K, Jeyaseelan L, Cherian AM. Evaluation of two treatment
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55
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HIGHLIGHTS
CHAPTER 6
Muscarinic, nicotinic, CMS
effects
Absorbed by inhalation,
ingestion, skin
Lipophilic
Poisonings tend to be of
shorter duration than OPs
SIGNS & SYMPTOMS
Malaise, muscle weakness,
dizziness, sweating
May include blurred vision,
incoordination, muscle
twitching, slurred speech
May include headache,
salivation, nausea, vomiting,
abdominal pain, diarrhea
Blood cholinesterase levels
not reliable indication
Severe symptoms may
include coma, seizures,
hypotonicity, hypertension,
cardio/respiratory
depression
TREATMENT
Ensure clear airway
Administer atropine
Decontaminate concurrently
Consider pralidoxime in
mixed poisonings
Consider Gl
decontamination
CONTRAINDICATED
Adrenergic amines without
specific indication (e.g.,
hypotension)
N-Methyl Carbamate
Insecticides
Toxicology
The N-methyl carbamate esters cause reversible carbamylation of acetylcholines-
terase (AChE) enzyme, allowing accumulation of acetylcholine, the neuromediator
substance, at parasympathetic neuroeffector junctions (muscarinic effects), at skel-
etal muscle myoneural junctions and autonomic ganglia (nicotinic effects) and in the
brain (CNS effects). The carbamyl-acetylcholinesterase combination dissociates more
readily than the phosphoryl-acetylcholinesterase complex produced by organophos-
phate compounds. This lability has several important consequences: (1) it tends to
limit the duration of N-methyl carbamate poisonings, (2) it accounts for the greater
difference between symptom-producing and lethal doses than exists in the case of
most organophosphate compounds and (3) it frequently invalidates the measurement
of blood cholinesterase activity as a diagnostic index of poisoning (see below).
Carbamates are absorbed by inhalation, ingestion and through the skin, although
the last tends to be the less-toxic route. For example, carbofuran has a rat oral LD50
of 5 mg/kg, compared to a rat dermal LD50 of 120 mg/kg, which makes the oral route
approximately 24 times more toxic when ingested.1 The LD50 is only one measure
of pesticide toxicity. The dose must also be considered since a compound with a
high LD50 can produce life-threatening symptoms if a large enough dose is ingested.
N-methyl carbamates are hydrolyzed enzymatically by the liver, and the degradation
products are excreted by the kidneys and the liver.
At cholinergic nerve junctions with smooth muscle and gland cells, high
acetylcholine concentration causes muscle contraction and secretion, respectively.
At skeletal muscle junctions, excess acetylcholine may be excitatory (cause muscle
twitching), but may also weaken or paralyze the cell by depolarizing the end-plate.
In the brain, elevated acetylcholine concentrations may cause sensory and behavioral
disturbances, incoordination, seizures and depressed motor function including leth-
argy and coma.2'3'4 The N-methyl carbamates are lipophilic and penetrate the central
nervous system as evidenced by distribution throughout all tissues including the brain
on post mortum.5'6 Respiratory depression combined with pulmonary edema is the
usual cause of death from poisoning by N-methyl carbamate compounds.
Signs and Symptoms of Poisoning
As with organophosphate poisoning, the signs and symptoms are based on excessive
cholinergic stimulation. Carbamate poisonings tend to be of shorter duration than
organophosphate poisonings because of the reversibility of the AChE binding and the
more rapid metabolism of carbamates.7 However, as mentioned in the next section of
this chapter, blood cholinesterase levels may be misleading because of in vitro reacti-
vation of a carbamylated enzyme.8'9 This falsely normal or near-normal level can make
the diagnosis more difficult in the acute presentation in the absence of an exposure
history.
56
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Malaise, muscle weakness, dizziness and sweating are commonly reported
early symptoms. Miosis with blurred vision, incoordination, muscle twitching and
slurred speech are reported. Headache, salivation, nausea, vomiting, abdominal pain
and diarrhea are often prominent. Transient hyperbilirubinemia may occur.10 Acute
pancreatitis has also been reported in some of the cases of aldicarb and methomyl
poisoning. Some cases of pancreatitis have required surgical drainage of a pancreatitic
pseudocyst.3'11'12'13
The most severe manifestations of carbamate poisoning occur in the respiratory
and central nervous (CNS) systems. CNS findings include coma, seizures and hypoto-
nicity, and nicotinic effects including hypertension and cardiorespiratory depression.
The respiratory depression also results from skeletal muscle impairment in which
the chest wall cannot expand for adequate respiration. Dyspnea, bronchospasm and
bronchorhea with eventual pulmonary edema are other serious signs.3'14 Data indicate
that children and adults differ in their clinical presentation. Children are more likely
than adults to present with the CNS symptoms above. While children can develop
the classic muscarinic signs, the absence of them does not exclude the possibility of
carbamate poisoning in the presence of CNS depression.2'4'15'16
Confirmation of Poisoning
If there are strong clinical indications of acute N-methyl carbamate poisoning, and/or
a history of carbamate exposure, treat the patient immediately. Do not wait for labora-
tory confirmation.
Blood for plasma pseudocholinesterase and RBC AchE should be obtained.
Unless a substantial amount of N-methyl carbamate has been absorbed and a blood
sample is taken within an hour or two, it is unlikely that blood cholinesterase activities
will be found depressed. Even under the above circumstances, a rapid test for enzyme
activity must be used to detect an effect, because enzyme reactivation occurs in vitro
as well as in vivo.
Absorption of some N-methyl carbamates can be confirmed by analysis of
urine for unique metabolites; alpha-naphthol from carbaryl, isopropoxyphenol from
propoxur, carbofuran phenol from carbofuran, and aldicarb sulfone, sulfoxide and
nitrile from aldicarb. These complex analyses, when available, can be useful in iden-
tifying the responsible agent and following the course of carbamate disposition.
Treatment of N-methyl Carbamate Insecticide Toxicosis
CAUTION: Persons attending the victim should avoid direct contact with
heavily contaminated clothing and vomitus. Wear rubber gloves while washing
pesticide from skin and hair. Vinyl gloves provide no protection.
1. Ensure that a clear airway exists. Intubate the patient and aspirate the secretions
with a large bore suction device if necessary. Administer oxygen by mechanically
assisted pulmonary ventilation if respiration is depressed. Improve tissue oxygen-
ation as much as possible before administering atropine, so as to minimize the risk
of ventricular fibrillation. In severe poisonings, it may be necessary to support
pulmonary ventilation mechanically for several days.
2. Administer atropine sulfate intravenously or intramuscularly if intravenous
injection is not possible. Atropine can be administered in small volume doses
through an endotracheal tube if initial IV access is difficult to obtain. Carba-
CHAPTER 6
N-Methyl Carbamates
COMMERCIAL
PRODUCTS
Highly Toxic1
aldicarb (Temik)
aminocarb2 (Matacil)
bendiocarb2 (Ficam, Dycarb,
Multamat, Niomil, Tattoo,
Turcam)
carbofuran (Furadan)
cloethocarb2 (Lance)
formetanate (Carzol)
isolan2 (Primin)
methiocarb (Mesurol)
methomyl (Lannate, Nudrin)
oxamyl (Vydate L, DPX
1410)
Moderately Toxic1
bufencarb2 (Metalkamate,
Bux)
carbaryl (Sevin, Dicarbam)
dimetan2 (Dimethan)
dioxacarb2 (Elecron, Famid)
isoprocarb2 (Etrofolan,
MIPC)
pirimicarb2 (Pirimor, Abol,
Aficida, Aphox, Fernos,
Rapid)
promecarb2 (Carbamult)
propoxur (Aprocarb,
Baygon, various flea/tick
products)
trimethacarb2 (Landrin,
Broot)
' "Highly toxic" N-methyl carbamates
have listed oral LD^ values (rat)
less than or equal to 50 mg/kg body
weight; "moderately toxic" agents
have /.D50 values in excess of 50
mg/kg and less than 500 mg/kg.
2 Products no longer registered in
the United States.
57
-------
CHAPTER 6
N-Methyl Carbamates
mates may reverse with smaller dosages of atropine than those required to reverse
organophosphates, though the required dosage is still considerably larger than
that required to atropinize a non-poisoned patient.17'18 A common dosing pitfall
is giving too little atropine initially to achieve timely atropinization. Severely
poisoned individuals may exhibit remarkable tolerance to atropine and require
large doses.14 (See dosage below.)
The objective of atropine antidotal therapy is to antagonize the effects of
excessive concentrations of acetylcholine at end-organs having muscarinic recep-
tors. Atropine does not reactivate AChE or accelerate excretion or breakdown
of carbamate. Multiple doses of atropine may be necessary, as recrudescence of
poisoning can occur if tissue concentrations of toxicant remain high when the
antidotal effect wears off. Atropine is effective against muscarinic manifestations.
but is ineffective against nicotinic actions, specifically muscle weakness and
twitching, and respiratory depression. Despite these limitations, atropine is often
a lifesaving agent in N-methyl carbamate poisonings.
Reassess the clinical situation after an adequate loading dose has been given.
If symptoms persist, but the history is consistent with carbamate poisoning, then
continue atropine therapy. However, if the clinical picture is unclear, clinicians
should reassess and consider alternative causes of poisoning, such as pyrethroid
insecticide poisoning, which may present a similar clinical picture.
In moderately severe poisoning (hypersecretion and other end-organ mani-
festations without central nervous system depression) the following dosage
schedules have proven effective:
Dosage of Atropine
Adults and Children Over 12 Years
Initial Dose: 1-3 mg IV. Repeat in 3-5 minutes if no
change in clinical symptoms. Dose may be doubled with
each administration until the patient is atropinized. Once
adequate atropinization has been achieved, the patient can
be maintained on an atropine continuous infusion at about
10%-20% of the loading dose and titrated to effect.18192021
Clear breath sounds and absent pulmonary secretions
are the primary end point. Other signs of atropinization
including flushing, dry mouth and dilated pupils;
tachycardia (pulse of 140 per minute) may occur. Early in
therapy, monitor for improving blood pressure and heart
rate (above 80 beats/minute), normal pupil size and drying
of the skin and axillae.20'21 Autoinjectors containing 2.0 mg
atropine for IM injection are also available.
WARNING: Poisonings in which liquid carbamate pesticide
concentrates have been ingested may be complicated by hydrocarbon
aspiration. Pulmonary edema and poor oxygenation in these cases
will not respond to atropine and should be treated as a case of acute
respiratory distress syndrome.
continued next page
58
-------
CHAPTER 6
N-Methyl Carbamates
Dosage ofAtropine, continued
Children Under 12 Years
Initial Dose: 0.02 mg/kg body weight IV. As with
adults, double the dose every 5 minutes until pulmonary
secretions are controlled. Consider continuous infusion at
10%-20% of the required loading dose and titrate. Signs of
atropinization, including: flushing, dry mouth, dilated pupils
and heart rates vary depending on age of child, with young
toddlers having a rate approaching 200. Crackles in the lung
bases nearly always indicate inadequate atropinization,
and pulmonary improvement may not parallel other signs.
Continuation of, or return of, cholinergic signs indicate the
need for more atropine.
Reversal of muscarinic manifestations, rather than a specific dosage, is the
object of atropine therapy.
NOTE: Persons not poisoned or only slightly poisoned by N-methyl carbamates
may develop signs of atropine toxicity from large doses, such as fever, muscle
fibrillations and delirium. If these signs appear and become the predominant
clinical effects, atropine administration should be discontinued, at least
temporarily, while the severity of poisoning is reevahiated.
3. Save a urine sample for metabolite analysis if there is need to identify the agent
responsible for the poisoning.
4. Consider pralidoxime in cases of mixed carbamate/organophosphate poisoning
and cases of an unknown pesticide with muscarinic symptoms on presentation
(see Chapter 5, Organophosphate Insecticides, subsection Treatment, item 5.
page 49.22'23 Pralidoxime has been used in some cases of carbamate poisoning.
although other cases have resolved from supportive care alone.24'25 Pralidoxime is
probably of little value in N-methyl carbamate poisonings and is not indicated in
isolated carbamate poisonings. Atropine alone usually is effective.
5. Decontaminate concurrently with whatever resuscitative and antidotal measures
are needed to preserve life. Contamination of the eyes should be removed by
flushing with copious amounts of clean water. For asymptomatic individuals who
are alert and physically able, skin decontamination should occur as previously
outlined in Chapter 3, General Principles. Specifically, skin and hair should be
washed with soap and water. Attending personnel must take precautions including
rubber gloves to avoid contamination. Contaminated clothing should be promptly
removed, bagged and laundered before returning, and items such as shoes, boots
and headgear should be discarded.
6. Consider gastrointestinal decontamination if N-methyl carbamate has been
ingested in a quantity sufficient to cause probable poisoning. If the patient has
presented with a recent ingestion and still asymptomatic, adsorption of poison
with activated charcoal may be beneficial. If the patient has already vomited or
59
-------
CHAPTER 6
N-Methyl Carbamates
is symptomatic, which is highly likely in significant poisonings, attention should
be placed on oxygen, airway management and atropine. In significant ingestions.
diarrhea and/or vomiting are so constant that charcoal adsorption and catharsis
are not included.
7. Observe patient closely for at least 24-48 hours to ensure that symptoms (sweating.
visual disturbances, vomiting, diarrhea, chest and abdominal distress, and some-
times pulmonary edema) do not recur as atropinization is withdrawn. The obser-
vation period should be longer in the case of mixed pesticide ingestion, because of
the prolonged and delayed symptoms associated with organophosphate poisoning.
As the dosage of atropine is reduced over time, check the lung bases frequently
for crackles. Atropinization must be reestablished promptly if crackles are heard
or if there is a return of miosis, sweating or other signs of poisoning.
8. Monitor pulmonary ventilation carefully, particularly in poisonings by large doses
of N-methyl carbamates, even after recovery from muscarinic symptomatology.
to forestall respiratory failure.
9. Monitor cardiac status in severely poisoned patients by continuous ECG recording.
10. Give adrenergic amines (n-morphine, succinlycholine, theophylline, phenothi-
azines and reserpine) only if there is a specific indication, such as marked hypo-
tension. Otherwise, they are probably contraindicated in N-methyl carbamate
poisoning cases.
11. Treat cases in which liquid concentrates of some carbamates formulated in a
petroleum product base have been ingested as acute respiratory distress syndrome.
Hydrocarbon aspiration may complicate these poisonings. Pulmonary edema and
poor oxygenation in these cases will not respond to atropine.
12. Do not administer atropine prophylactically to workers exposed to N-methyl
carbamate pesticides. Prophylactic dosage may mask early symptoms and
signs of carbamate poisoning and thus allow the worker to continue exposure
and possible progression to more severe poisoning. Atropine itself may enhance
the health hazards of the agricultural work setting, impairing heat loss (due to
reduced sweating) and impairing the ability to operate mechanical equipment due
to blurred vision caused by mydriasis.
60
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CHAPTER 6
N-Methyl Carbamates
References
1. Micromedex I. Registry of Toxic Effects of Chemical Substances: NIOSH; 1991.
2. Lifshitz M, Shahak E, Bolotin A, Sofer S. Carbamate poisoning in early childhood and in
adults. J Toxicol Clin Toxicol. 1997;35(l):25-27.
3. Ragouc-Sengler C, Tracqui A, Chavonnet A, et al. Aldicarb poisoning. Hum Exp Toxicol.
2000;19:657-662.
4. Zwiener RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and chil-
dren. Pediatrics. Jan 1988;81(1):121-126.
5. Tsatsakis AM, Bertsias GK, Mammas IN, Stiakakis I, Georgopoulos DB. Acute fatal
poisoning by methomyl caused by inhalation and transdermal absorption. Bull Environ
Contam Toxicol. Apr2001;66(4):415-420.
6. Yamazaki M, Terada M, Kuroki H, Honda K, Matoba R, Mitsukuni Y. Pesticide poisoning
initially suspected as a natural death. J Forensic Sci. Jan 2001 ;46(1): 165-170.
7. Echobichon DJ. Toxic effect of pesticides. In: Klaassen CD, ed. Casarett & Doull's Toxi-
cology: The Basic Science of Poisons. 5th ed. New York: McGraw-Hill; 1996:659.
8. Jokanovic M, Maksimovic M. Abnormal cholinesterase activity: understanding and inter-
pretation. EurJClin Chem Clin Biochem. Jan 1997;35(1):11-16.
9. Rotenberg M, Almog S. Evaluation of the decarbamylation process of cholinesterase
during assay of enzyme activity. Clin ChimActa. Sep 15 1995;240(2): 107-116.
10. Saadeh AM. Metabolic complications of organophosphate and carbamate poisoning. Trap
Doct. Jul2001;31(3):149-152.
11. Brahmi N, Blel Y, Kouraichi N, Abidi N, Thabet H, Amamou M. Acute pancreatitis subse-
quent to voluntary methomyl and dichlorvos intoxication. Pancreas. Nov 2005;31(4):424-
427.
12. Rizos E, Liberopoulos E, Kosta P, Efremidis S, Elisaf M. Carbofuran-induced acute
pancreatitis. JOP. Jan2004;5(l):44-47.
13. Weizman Z, Sofer S. Acute pancreatitis in children with anticholinesterase insecticide
intoxication. Pediatrics. Aug 1992;90(2 Pt 1):204-206.
14. Nelson LS, Perrone J, DeRoos F, Stork C, Hoffman RS. Aldicarb poisoning by an
illicit rodenticide imported into the United States: Tres Pasitos. J Toxicol Clin Toxicol.
2001;39(5):447-452.
15. Lifshitz M, Shahak E, Sofer S. Carbamate and organophosphate poisoning in young chil-
dren. PediatrEmerg Care. Apr 1999;15(2): 102-103.
16. Verhulst L, Waggie Z, Hatherill M, Reynolds L, Argent A. Presentation and outcome of
severe anticholinesterase insecticide poisoning. Arch Dis Child. May 2002;86(5):352-355.
17. Goswamy R, Chaudhuri A, Mahashur AA. Study of respiratory failure in organophosphate
and carbamate poisoning. Heart Lung. Nov-Dec 1994;23(6):466-472.
18. Perera PM, Shahmy S, Gawarammana I, Dawson AH. Comparison of two commonly
practiced atropinization regimens in acute organophosphorus and carbamate poisoning,
doubling doses vs. ad hoc: a prospective observational study. Hum Exp Toxicol. Jun
2008;27(6):513-518.
19. Eddleston M, Buckley NA, Checketts H, et al. Speed of initial atropinisation in significant
organophosphorus pesticide poisoninga systematic comparison of recommended regi-
mens. J Toxicol Clin Toxicol. 2004;42(6): 865-875.
20. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self-poisoning with
an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors. Crit
Care. Dec 2004;8(6):R391-397.
21. Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning.
BMJ. Mar 24 2007;334(7594):629-634.
61
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CHAPTER 6
N-Methyl Carbamates
22. Kurtz PH. Pralidoxime in the treatment of carbamate intoxication. Am J Emerg Med. Jan
1990;8(1):68-70.
23. Lifshitz M, Sofer S, Shahak E, Rotenberg M, Almog S, Tamiri T. Carbamate poisoning
and oxime treatment in children: a clinical and laboratory study. Pediatrics. Apr
1994;93(4):652-655.
24. Park CH, Kim KI, Park SK, Lee CH. Carbamate poisoning: high resolution CT and patho-
logic findings. JComputAssist Tomogr. Jan-Feb2000;24(l):52-54.
25. CDC. Poisonings Associated with Illegal Use of Aldicarb as a Rodenticide New York
City, 1994-1997. MMWRMorbMortal WklyRep. 1997;46(41):961-963.
62
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CHAPTER 7
HIGHLIGHTS
Organochlorines
The U.S. Environmental Protection Agency has sharply curtailed the availability of
most organochlorines. While use continues in many other regions of the world, in the
United States only dicofol and endosulfan are still registered as pesticides. Lindane is
still marketed as a second-line agent for treatment of lice and scabies under the trade
names Kwell and Thionex, although it is no longer recommended by the American
Academy of Pediatrics and has been banned in California. This is the result of multiple
cases of acute neurological toxicity either from ingestion or in persons treated for
scabies or lice.1'2'3'4'5'6'7 In recent years, the most frequently reported serious or fatal
events were from endosulfan.8'9'10'11'12'13'14
Toxicology
Organochlorines are absorbed from the gut, by the lungs and across the skin in
varying degrees. Hexachlorocyclohexane, lindane, the cyclodienes (aldrin, diel-
drin, endrin, chlordane, heptachlor) and endosulfan are efficiently absorbed across
the skin, while dermal absorption efficiencies of DDT, dicofol, methoxychlor, toxa-
phene and mirex are substantially less.15 Lindane has an estimated 9.3% dermal
absorption rate16 and is absorbed even more efficiently across abraded skin.4'17 This
becomes especially important when taking into account its use on children with severe
dermatitis associated with scabies. Fat and fat solvents enhance gastrointestinal, and
probably dermal, absorption of organochlorines. Many formulations of organochlo-
rines are in hydrocarbon solvents that probably promote absorption. While most of the
solid organochlorines are not highly volatile, pesticide-laden aerosols or dust particles
trapped in respiratory mucous and subsequently swallowed may be vehicles leading to
significant gastrointestinal absorption.
Following exposure to some organochlorines (notably DDT), a significant part
of the absorbed dose is stored in fat tissue as the parent compound. Most organochlo-
rines are in some degree dechlorinated, oxidized and then conjugated. The chief route
of excretion is biliary, although nearly all organochlorines yield measurable urinary
metabolites. Unfortunately, many of the unmetabolized pesticides are efficiently reab-
sorbed by the intestine (enterohepatic circulation), substantially retarding fecal excre-
tion. Metabolic dispositions of DDT and DDE (a DDT degradation product), the beta
isomer of hexachlorocyclohexane, dieldrin, heptachlor epoxide and mirex tend to be
slow, leading to storage in body fat. Storable lipophilic compounds are likely to be
excreted in maternal milk.6'18'19 In contrast, rapid metabolic disposition of lindane.
methoxychlor, dienochlor, endrin, chlorobenzilate, dicofol, toxaphene, perthane and
endosulfan reduce the likelihood that these organochlorines will be detected as resi-
dues in body fat, blood or milk.
The chief acute toxic action of the organochlorine pesticides is on the central
nervous system, where these compounds induce a hyperexcitable state in the brain
leading to convulsions or other less severe signs of neurologic toxicity such as
myoclonic jerking, paresthesias, tremor, ataxia and hyperreflexia.20 Convulsions
caused by cyclodienes may recur over periods of several days and are also character-
istic of acute organochlorine poisoning. Agents such as DDT and methoxychlor tend
Only dicofol, endosulfan,
lindane still registered for
use in U.S.
Absorbed from the gut, by
the lungs and across skin
Fat and fat solvents
enhance absorption
Most are dechlorinated,
oxidized, then conjugated
Chief toxic action is on CMS
SIGNS & SYMPTOMS
Sensory disturbances:
hyperesthesia &
paresthesias of face &
extremities
Possible headache,
dizziness, nausea, vomiting,
tremor, confusion
Cyclodienes & toxaphene
poisoning may result
in seizures (including
delayed ones) without other
symptoms
Severe poisonings:
convulsions, respiratory
depression, coma
TREATMENT
Manage convulsions
Administer oxygen
Decontaminate skin
Consider Gl
decontamination
Monitor cardiac, pulmonary
status
CONTRAINDICATED
Epinephrine, other
adrenergic amines, atropine
in most cases
Animal or vegetable oils by
mouth
63
-------
CHAPTER 7
Organochlorines
COMMERCIAL
PRODUCTS
aldrin*
BHC* (HCH, hexachlor,
hexachloran)
chlordane* (multiple trade
names)
chlorobenzilate*
DDT* (multiple trade names)
dicofol (multiple trade
names)
dieldrin*
dienochlor(Pentac)*
endosulfan (Thionex)
endrin*
heptachlor*
hexacholorobenzene*
lindane (gamma BHC or
HCH)*
methoxychlor (Marlate)*
mi rex*
toxaphene*
to cause the less severe effects, while the cyclodienes, mirex and lindane are associ-
ated with the more severe seizures and fatalities.15 Convulsions may cause death by
interfering with pulmonary gas exchange and by generating severe metabolic acidosis.
High tissue concentrations of organochlorines increase myocardial irritability.
predisposing to cardiac arrhythmia. When tissue organochlorine concentrations drop
below threshold levels, recovery from the poisoning occurs. Organochlorines are not
cholinesterase inhibitors.
High tissue levels of some organochlorines (notably DDT, DDE and cyclodi-
enes) have been shown to induce hepatic microsomal drug-metabolizing enzymes.21
This tends to accelerate excretion of the pesticides themselves but may also stimulate
biotransformation of endogenous steroid hormones and exogenous therapeutic drugs.
occasionally necessitating reevaluation of required dosages of therapeutic drugs in
persons intensively exposed to organochlorines. Human absorption of organochlorine
sufficient to cause enzyme induction is likely to occur only as a result of prolonged.
intensive exposure.
Ingestion of hexachlorobenzene-treated wheat has been associated with human
dermal toxicity diagnosed as porphyria cutanea tarda. The skin forms blisters and
becomes very sensitive to sunlight. Subsequent poor healing results in scarring and
contracture formation.22 Unlike other organochlorine compounds, no cases of convul-
sions caused by the fungicide hexachlorobenzene have been reported in the medical
literature. Lindane and chlordane have been infrequently associated with hematolog-
ical disorders, including aplastic anemia and megaloblastic anemia.23'24'25
Evidence has emerged that the organochlorines interact with endocrine recep-
tors, particularly estrogen and androgen receptors. In vitro studies and animal experi-
mentation suggest that organochlorines may alter the function of the endocrine system
by these interactions.26'27 In addition, the potential for carcinogenicity has resulted in
regulatory action to limit use or remove registration for multiple organochlorines. An
extensive literature has accumulated relevant to neurodevelopmental and neurologic
effects of chronic low-level exposure to organochlorines.28'29'30'31'32'33'34 These chronic
health implications on the endocrine system and nervous system, and carcinogenic
potential are discussed in Chapter 21, Chronic Effects.
*AII U.S. registrations are
suspended.
Signs and Symptoms of Poisoning
Early manifestations of poisoning by some organochlorine pesticides, particularly
DDT, are often sensory disturbances: hyperesthesia and paresthesias of the face and
extremities. Headache, dizziness, nausea, vomiting, incoordination, tremor and mental
confusion are also reported. More severe poisoning results in myoclonic jerking move-
ments, often followed by generalized tonic-clonic convulsions. Coma and respiratory
depression may follow the seizures.
Poisoning by the cyclodienes and toxaphene is more likely to begin with the
sudden onset of convulsions, often not preceded by the premonitory manifestations
mentioned above. Seizures caused by cyclodienes may appear as long as 48 hours
after exposure and then may recur periodically over several days following the initial
episode. Since lindane and toxaphene are more rapidly biotransformed in the body and
excreted, they are less likely than dieldrin, aldrin and chlordane to cause delayed or
recurrent seizures.
There have been reports of mixed poisonings, where anticholinesterase agents
such as organophosphates and anticholinesterase carbamates have been mixed with
organochlorines. In such cases the cholinergic symptoms may be prominent on presen-
tation, but aggressive treatment of the cholinergic findings leave the subject with the
symptoms of the organochlorine poisoning, which need additional treatment.35'36
64
-------
CHAPTER 7
Organochlorines
Medical providers should be alert to the possibility of such mixed poisonings in the
diagnosis and management of pesticide poisonings.
Confirmation of Poisoning
Organochlorine pesticides and/or their metabolites can sometimes be identified in
blood by gas-liquid chromatographic examination of samples taken within a few
days of significant pesticide absorption. Such tests are performed by a limited number
of government, university and private laboratories, which can usually be contacted
through poison control centers or health departments. Some organochlorine pesticides
or their metabolic products (notably DDT, dieldrin, mirex, heptachlor epoxide and
chlordecone) persist in tissues and blood for weeks or months after absorption, but
others are likely to be excreted in a few days, limiting the likelihood of detection.
Blood levels tend to correlate more with acute toxicity, while levels found in adipose
tissue and breast milk usually reflect more long-term and historic exposure.37
Chromatographic methods make possible detection of most organochlorines at
concentrations much lower than those associated with symptoms of toxicity. There-
fore, a positive finding in a blood sample does not, of itself, justify a diagnosis of
acute poisoning. Current general population tissue concentration levels for many of
the organochlorines are available from the Centers for Disease Control and Preven-
tion's Biomonitoring Program and may be helpful in interpreting findings.38
Lindane tissue concentration reports appear in the literature more frequently than
other compounds. The time of the blood sampling in relation to exposure time must
be taken into account when interpreting blood levels. In one study, lindane levels were
measured at 10.3 ng/mL in healthy volunteers 3 days after application to the skin.39 In
a study with childhood dermal absorption in children with scabies and a non-affected
control group, lindane peaked at 28 ng/mL 6 hours after application in the affected
group and at 24 ng/mL in the control group. At 48 hours, levels were 6 ng/mL and
5 ng/mL, respectively. Findings from this study also provide evidence for increased
absorption across abraded skin.17 A child with severely abraded skin was treated for
scabies and developed seizures. Three days after exposure, his lindane level was 54
ng/mL.4 Most reports of acute toxicity from lindane involve blood levels of 130 ng/mL
or greater, with the most severe and fatal cases involving levels exceeding 500 ng/mL.2
DDT, DDE and a few other organochlorines are still found at very low levels in
blood samples from the general U.S. population, presumably due to past and/or current
low-level contamination of food by these environmentally persistent pesticides.
Overall, blood organochlorine levels have the most readily available informa-
tion for understanding the acute clinical implications of exposures. Measurements of
urinary metabolites of some organochlorine pesticides can be useful in monitoring
occupational exposures; however, the analytical methods are complex and are not
likely to detect amounts of metabolites generated by minimal exposures.
Treatment of Organochlorine Toxicosis
1. Observe persons with suspected very high exposure to organochlorine pesticides
by any route for sensory disturbances, incoordination, speech slurring, mental
aberrations and involuntary motor activity that would warn of imminent
convulsions.
65
-------
CHAPTER 7
Organochlorines
2. If convulsions occur, place the victim in the left lateral decubitus position with
the head down. Move away furniture or other solid objects that may be a source
of injury. If jaw movements are violent, place padded tongue blades between the
teeth to protect the tongue. Whenever possible, remove dentures and other remov-
able dental work. Aspirate oral and pharyngeal secretion and, when possible.
insert an oropharyngeal airway to maintain an open passage unobstructed by
the tongue. Minimize noise and any manipulation of the patient that may trigger
seizure activity.
3. Administer oxygen by mask. Maintain pulmonary gas exchange by mechanically
assisted ventilation whenever respiration is depressed.
4. Control convulsions. Seizures in patients caused by organochlorine toxicity are
likely to be prolonged and difficult to control. Status epilepticus is common. For
this reason, patients with seizures that do not respond immediately to anticonvul-
sants should be transferred as soon as possible to a trauma center and will gener-
ally require intensive care admission until seizures are controlled and neurologic
status is improved. Initial therapy with benzodiazepines should be instituted.
Dosage of Diazepam
Adults: 5-10 mg IV and repeat every 5-10 minutes to
maximum of 30 mg.
Children: 0.2 to 0.5 mg/kg every 5 minutes to maximum
of 10 mg in children over 5 years, and a maximum of 5 mg in
children under 5 years.
Although lorazepam is widely accepted as a treatment of choice for status epilep-
ticus, there are no reports of its use for organochlorine intoxication. Some cases have
required aggressive seizure management including the addition of phenobarbital and
the induction of pentobarbital coma.
5. Decontaminate skin thoroughly, as outlined in Chapter 3, General Principles.
6. Consider gastric decontamination procedures as outlined in Chapter 3 if organo-
chlorine has been ingested in a quantity sufficient to cause poisoning and the
patient presents within an hour. If the patient presents more than an hour after
ingestion, activated charcoal may still be beneficial. If the victim is convulsing.
it is almost always necessary first to control seizures before attempting gastric
decontamination. Activated charcoal administration has been advocated in such
poisonings, but there is little human or experimental evidence to support this
modality.
7. Particularly in poisonings by large doses of organochlorine, monitor pulmonary
ventilation carefully to forestall respiratory failure. Assist pulmonary ventila-
tion mechanically with oxygen whenever respiration is depressed. Since these
compounds are often formulated in a hydrocarbon vehicle, hydrocarbon aspira-
tion may occur with ingestion of these agents. The hydrocarbon aspiration should
be managed in accordance with accepted medical practice as a case of acute respi-
ratory distress syndrome and will usually require intensive care management.
66
-------
CHAPTER 7
Organochlorines
8. Monitor cardiac status of severely poisoned patients by continuous ECG recording
to detect arrhythmia.
9. Do not give epinephrine, other adrenergic amines or atropine unless absolutely
necessary. The enhanced myocardial irritability induced by chlorinated hydrocar-
bons predisposes to ventricular fibrillation.
10. Do not give animal or vegetable oils or fats by mouth. They enhance gastrointes-
tinal absorption of the lipophilic organochlorines.
11. Control seizures and myoclonic movements that sometimes persist for several
days following acute poisoning by the more slowly excreted organochlorines.
Phenobarbital orally is likely to be effective. Dosage should be based on manifes-
tations in the individual case and on information contained in the package insert.
12. Use cholestryamine resin to accelerate the biliary-fecal excretion of the more
slowly eliminated organochlorine compounds.40
Dosage of Cholestryamine Resin
Adults: 4-gram doses, 4 times a day, before meals and at
bedtime.
Children: 240 mg/kg/24 hours, divided, every 8 hours.
The dose may be mixed with a pulpy fruit or liquid. It should never be given in
its dry form and must always be administered with water, other liquids or a pulpy fruit.
Prolonged treatment (several weeks or months) may be necessary.
13. During convalescence, enhance carbohydrate, protein and vitamin intake by diet
or parenteral therapy.
67
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CHAPTER 7
Organochlorines
References
1. Unintentional topical lindane ingestionsUnited States, 1998-2003. MMWR Morb Mortal
WklyRep. Jun 3 2005;54(21):533-535.
2. Aks SE, Krantz A, Hryhrczuk DO, Wagner S, Mock J. Acute accidental lindane ingestion
mtoddlers.AnnEmergMed. Nov 1995;26(5):647-651.
3. Fischer TF. Lindane toxicity in a 24-year-old woman. Ann EmergMed. Nov 1994;24(5): 972-
974.
4. Friedman SJ. Lindane neurotoxic reaction in nonbullous congenital ichthyosiform erythro-
derma. Arch Dermatol. Aug 1987;123(8):1056-1058.
5. Solomon BA, Haut SR, Carr EM, Shalita AR. Neurotoxic reaction to lindane in an FflV-
seropositive patient. An old medication's new problem. JFam Pract. Mar 1995;40(3):291-
296.
6. Solomon LM, Fahrner L, West DR Gamma benzene hexachloride toxicity: a review. Arch
Dermatol. Mar 1977;113(3):353-357.
7. Tenenbein M. Seizures after lindane therapy. J Am GeriatrSoc. Apr 1991;39(4):394-395.
8. Brandt VA, Moon S, Ehlers J, Methner MM, Struttmann T. Exposure to endosulfan in
farmers: two case studies. AmJIndMed. Jun2001;39(6):643-649.
9. Eyer F, Felgenhauer N, Jetzinger E, Pfab R, Zilker TR. Acute endosulfan poisoning with
cerebral edema and cardiac failure. J Toxicol Clin Toxicol. 2004;42(6):927-932.
10. Kucuker H, Sahin O, Yavuz Y, Yurumez Y Fatal Acute Endosulfan Toxicity: A Case
Report. Basic Clin Pharmacol Toxicol. 2008;104:49-51.
11. Oktay C, Goksu E, Bozdemir N, Soyuncu S. Unintentional toxicity due to endosulfan: a
case report of two patients and characteristics of endosulfan toxicity. Vet Hum Toxicol. Dec
2003;45(6):318-320.
12. Parbhu B, Rodgers G, Sullivan JE. Death in a toddler following endosulfan ingestion. Clin
Toxicol (Phila). Nov 2009;47(9): 899-901.
13. Roberts DM, Dissanayake W, Rezvi Sheriff MH, Eddleston M. Refractory status epilep-
ticus following self-poisoning with the organochlorine pesticide endosulfan. J Clin
Neumsci. Sep 2004;! 1(7):760-762.
14. Yavuz Y, Yurumez Y, Kucuker H, Ela Y, Yuksel S. Two cases of acute endosulfan toxicity.
Clin Toxicol (Phila). Jun-Aug 2007;45(5):530-532.
15. Echobichon DJ. Toxic effects of pesticides. In: Klaassen CD, ed. Casarett & Doull's Toxi-
cology: The Basic Science ofPoisons. 5th ed. New York: McGraw-Hill; 1996:649-655.
16. Feldmann RJ, Maibach HI. Percutaneous penetration of some pesticides and herbicides in
man. ToxicolApplPharmacol. Apr 1974;28(1): 126-132.
17. Ginsburg CM, Lowry W, Reisch JS. Absorption of lindane (gamma benzene hexachloride)
in infants and children. JPediatr. Dec 1977;91(6):998-1000.
18. Rogan WJ. Pollutants in breast milk. Arch Pediatr Adolesc Med. Sep 1996;150(9):981-
990.
19. Stevens MF, Ebell GF, Psaila-Savona P. Organochlorine pesticides in Western Australian
nursing mothers. MedJAmt. Feb 15 1993;158(4):238-241.
20. Joy RM. The effects of neurotoxicants on kindling and kindled seizures. Fundam Appl
Toxicol. Feb 1985;5(l):41-65.
21. Hunter J, Maxwell JD, Stewart DA, Williams R, Robinson J, Richardson A. Increased
hepatic microsomal enzyme activity from occupational exposure to certain organochlorine
pesticides. Nature. Jun 16 1972;237(5355):399-401.
22. Booth NH, McDowell JR. Toxicity of hexachlorobenzene and associated residues in edible
animal tissues. J Am VetMedAssoc. Mar 15 1975;166(6):591-595.
68
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CHAPTER 7
Organochlorines
23. Furie B, Trubowitz S. Insecticides and blood dyscrasias. Chlordane exposure and self-
limited refractory megaloblastic anemia. JAMA. Apr 19 1976;235(16): 1720-1722.
24. Rauch AE, Kowalsky SF, Lesar TS, Sauerbier GA, Burkart PT, Scharfman WB. Lindane
(Kwell)-induced aplastic anemia. Arch Intern Med. Nov 1990;150(ll):2393-2395.
25. Rugman FP, Cosstick R. Aplastic anaemia associated with organochlorine pesticide: case
reports and review of evidence. JClinPathol. Feb 1990;43(2):98-101.
26. Fry DM. Reproductive effects in birds exposed to pesticides and industrial chemicals.
Environ Health Perspect. Oct 1995;103 Suppl 7:165-171.
27. Vonier PM, Grain DA, McLachlan JA, Guillette LJ, Jr., Arnold SF. Interaction of envi-
ronmental chemicals with the estrogen and progesterone receptors from the oviduct of the
American alligator. Environ Health Perspect. Dec 1996;104(12): 1318-1322.
28. DickFD. Parkinson's disease and pesticide exposures. Br Med Bull. 2006;79-80:219-231.
29. Jurewicz J, Hanke W. Prenatal and childhood exposure to pesticides and neurobehav-
ioral development: Review of epidemiological studies. Int J Occup Med Environ Health.
2008;21(2): 121-132.
30. Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandier DP. Neurologic symp-
toms in licensed pesticide applicators in the Agricultural Health Study. Hum Exp Toxicol.
Mar2007;26(3):243-250.
31. Kanthasamy AG, Kitazawa M, Kanthasamy A, Anantharam V. Dieldrin-induced neurotox-
icity: relevance to Parkinson's disease pamogenesis.MgMroto.rico/ogy. Aug2005;26(4): 701-
719.
32. Ribas-Fito N, Torrent M, Carrizo D, Julvez J, Grimalt JO, Sunyer J. Exposure to hexa-
chlorobenzene during pregnancy and children's social behavior at 4 years of age. Environ
Health Perspect. Mar 2007;! 15(3):447-450.
33. Rosas LG, Eskenazi B. Pesticides and child neurodevelopment. Curr Opin Pediatr. Apr
2008;20(2): 191-197.
34. Sagiv SK, Nugent JK, Brazelton TB, et al. Prenatal organochlorine exposure and measures
of behavior in infancy using the Neonatal Behavioral Assessment Scale (NBAS). Environ
Health Perspect. May 2008;116(5):666-673.
35. Cable GG, Doherty S. Acute carbamate and organochlorine toxicity causing convulsions in
an agricultural pilot: a case report. Aviat Space Environ Med. Jan 1999;70(l):68-72.
36. Thunga G, Sam KG, Khera K, Xavier V, Verma M. Profile of acute mixed organophos-
phorus poisoning. AmJEmergMed. Jun2009;27(5):628 e621-623.
37. Frank R, Braun HE. Organochlorine residues in bird species collected dead in Ontario
1972-1988. Bull Environ Contam Toxicol. Jun 1990;44(6): 932-939.
38. National Report on Human Exposure to Environmental Chemicals. Centers for Disease
Control and Prevention, http://www.cdc.gov/exposurereport/. Accessed on 1/2/11.
39. Hosier J, Tschanz C, Hignite CE, Azarnoff DL. Topical application of lindane cream
(Kwell) and antipyrine metabolism. JInvestDermatol. Jan 1980;74(l):51-53.
40. Cohn WJ, Boy Ian JJ, Blanke RV, Fariss MW, Ho well JR, Guzelian PS. Treatment of chlor-
decone (Kepone) toxicity with cholestyramine. Results of a controlled clinical trial. NEngl
JMed. Feb 2 1978;298(5):243-248.
69
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HIGHLIGHTS
CHAPTER 8
Derived from living systems
Bacillus thuringiensis is the
most important live agent
Generally of low-order
toxicity
Poison control center advice
can help avoid potentially
harmful treatment
SIGNS & SYMPTOMS
Highly variable based on
specific agents
Several cause Gl irritation
Nicotine may have serious
CMS effects
Nicotine and sabadilla may
have cardiovascular effects
Biologicals and Insecticides
of Biological Origin
This chapter concerns several widely used insecticidal products of natural origin, and
also certain agents usually identified as biological control agents. This latter group
includes many living control agents, though only the bacterial agent Bacillus thuringi-
ensis will be discussed in detail, as it is one of the most widely used. Other agents, such
as parasitic wasps and insects, are so host specific they pose little or no risk to man.
Many of the pesticides in this chapter, with the notable exception of nicotine, are
relatively less toxic to mammals than to insects. Consequently, there may be no findings
of toxicity following ingestion of these compounds. While clinicians should always
consider calling their regional poison control center (1-800-222-1222) for advice on
any poisoning, it may be of particular value in the case of some of these biological
pesticides, where no treatment is warranted and poison control center advice can help
avoid potentially harmful treatments.
Agents are presented in alphabetical order.
TREATMENT
Specific to the agent
Skin, eye, Gl
decontamination may be
indicated
Nicotine and sabadilla may
require aggressive support
Avermectin
COMMERCIAL
PRODUCTS
avermectin B1 (Abamectin)
emamectin benzoate
(salt of avermectin)
ivermectin
AVERMECTIN
Source and Products
Avermectin and related products are synthetically derived from the toxin of the soil
bacterium Streptomyces avermitilis. They are used for control of mites, fire ants (ant
bait stations) and other insects. Ivermectin is used as an antihelminth and a miticide.
Toxicology and Signs and Symptoms of Poisoning
Avermectins work by stimulating the gamma amino butyric acid (GABA) receptor.
thereby inhibiting nerve conduction to nerves and muscles. The result is insect paral-
ysis and death within a few days. Mammalian GABA receptors reportedly have a much
lower affinity for avermectins than insect GABA receptors.1 Reports of acute toxicity
are uncommon in the medical literature. Clinical manifestations appear to most promi-
nently involve the nervous, Gl and respiratory systems. Patients may initially present
with nausea, vomiting, salivation, diarrhea and dizziness. More severe manifestations
may include aspiration pneumonia, respiratory failure, hypotension and coma.1'2'3
Rhabdomyolysis has also been reported.2 One case study of 19 patients demonstrated
a dose/response relationship, with the most severe toxicity occurring in patients who
ingested in the range of 67 mg/kg to 227 mg/kg. One exception was a patient who
ingested 15 mg/kg and had severe toxic symptoms. Most patients who ingested less
than 40 mg/kg exhibited either mild or no toxicity.2
Treatment
1. Provide supportive treatment as there is no antidotal therapy.
70
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2. Remove skin contamination with soap and water. Remove eye contamination by
flushing the eyes with clean water or saline.
3. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3,
General Principles.
AZADIRACHTIN
Source and Products
This compound is a biologically obtained insecticide derived from the neem tree
(Azadirachta indica). It is an insect growth regulator that interferes with the molting
hormone ecdysone.
Toxicology and Signs and Symptoms of Poisoning
Azadirachtin causes severe dermal and gastrointestinal irritation. Central nervous
system stimulation and depression have been seen. This agent is primarily used and
manufactured in India, so little use or exposures are expected in the United States.
CHAPTER 8
Biologicals
Bacillus thuringiensis
COMMERCIAL
PRODUCTS
Several varieties
are available:
kurstaki
israelensis
aizawai
morrisoni
tenebrionis
Treatment
1. Wash skin thoroughly with soap and water if skin has been exposed.
2. Do not use gastric emptying or catharsis because of severe gastrointestinal irrita-
tion. Do not use activated charcoal when there is severe GI irritation because of
potential need for gastrointestinal endoscopy.
BACILLUS THURINGIENSIS
Source and Products
Several strains of Bacillus thuringiensis are pathogenic to some insects. The bacterial
organisms are cultured and then harvested in spore form for use as insecticide. Produc-
tion methods vary widely. Proteinaceous and nucleotide-like toxins generated by the
vegetative forms (which infect insects) are responsible for the insecticidal effect. The
spores are formulated as wettable powders, flowable concentrates and granules for
application to field crops and for control of mosquitoes and black flies.
Toxicology and Signs and Symptoms of Poisoning
The varieties of Bacillus thuringiensis used commercially survive when injected into
mice, and at least one of the purified insecticidal toxins is toxic to mice. Infections of
humans have been extremely rare. A single case report of ingestion by volunteers of
Bacillus thuringiensis var. galleriae resulted in fever and gastrointestinal symptoms.
However, this specific agent is not registered as a pesticide. B. thuringiensis prod-
ucts are exempt from tolerances on raw agricultural commodities in the United States.
Neither irritative nor sensitizing effects have been reported in workers preparing and
applying commercial products. A single case of corneal ulcer caused by a splash of B.
thuringiensis suspension into the eye has been reported.4
71
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CHAPTER 8
Biological^
Treatment
1. Remove skin contamination with soap and water. Remove eye contamination by
copious flushing of the eyes with clean water or saline. If irritation persists, or if
there is any indication of infection, refer patient for further treatment.
2. Observe a patient who has ingested a B. thuringiensis product for manifestations
of bacterial gastroenteritis: abdominal cramps, vomiting and diarrhea. The illness
is likely to be serf limited if it occurs at all. The patient should be treated symp-
tomatically and fluid support provided as appropriate.
EUGENOL
Source and Products
This compound is derived from clove oil, which is found in the dried flower bud of
Eugenia caryophyllata. It is used as an insect attractant. It is also used in numerous
dental products, which accounts for some of the reports of toxicity.5
Toxicology
Eugenol is similar in its clinical effects to phenol in terms of its caustic properties.
Although it works as an anesthetic, in large doses, it can cause burns to epithelial
surfaces.6 Sloughing of mucous membranes occurred as an allergic reaction to a small
dose applied topically in the mouth.5 Gastric mucosal lesions have been reported
in animals, but no lesions were seen on endoscopy after clove oil ingestion.7 Large
doses may result in coma, metabolic acidosis, seizures, liver dysfunction and dissemi-
nated intravascular coagulation.8'9'10 Large ingestions can be particularly toxic to chil-
dren. The mechanism of liver toxicity appears to be similar to that of acetaminophen
poisoning, in which eugenol is metabolized by the cytochrome-p450 system to produce
a lexicologically active quinone metabolite and a resultant glutathione depletion.11'12
Treatment
1. Provide supportive treatment as necessary as there is no antidote.
2. Consider gastrointestinal decontamination as outlined in Chapter 3, General
Principles, for ingestions. If mucosal burns are present, consider endoscopy to
look for other ulcerations.
There is one report of the use of n-acetylcysteine, using the same dose prescribed for
acetaminophen ingestion. It is of note that the patient's hepatic transaminase levels
began to decrease sharply after initiating NAC therapy.9 Without further study, it is
difficult to recommend this as routine treatment.
GIBBERELLIC ACID (GIBBERELLIN, GA3)
Source and Products
Gibberellic acid is not a pesticide, but it is commonly used in agricultural produc-
tion as a growth-promoting agent. It is a metabolic product of a cultured fungus.
formulated in tablets, granules and liquid concentrates for application to soil beneath
growing plants and trees.
72
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Toxicology
Experimental animals tolerate large oral doses of gibberellic acid without apparent
adverse effect. No human poisonings have been reported. Sensitization has not been
reported, and irritant effects are not remarkable.
Treatment
1. Provide supportive treatment for any toxic effects in humans, as there is no known
antidote.
2. Wash contamination from skin with soap and water. Flush contamination from
eyes with clean water or saline. If irritation occurs, refer patient for further
medical treatment.
3. For significant ingestion, consider gastrointestinal decontamination as outlined
in Chapter 3, General Principles, although that may not be necessary. Poison
control centers may be helpful to guide whether any therapy is indicated based on
the ingestion.
NICOTINE
Source and Products
Nicotine is an alkaloid contained in the leaves of many species of plants, but is usually
obtained commercially from the tobacco plant (Nicotiana tabacum). A 95% solution of
the free alkaloid in organic solvent has been marketed in the past as a greenhouse fumi-
gant. Another product used for the same purpose is a 40% aqueous solution of nicotine
sulfate. Significant volatilization of nicotine occurs from both products. Commercial
nicotine insecticides have long been known as Black Leaf 40. This formulation was
discontinued in 1992, although old preparations of nicotine insecticides may still be
found on occasion.13 The last remaining registered nicotine product will be discon-
tinued as of 2013 by request of the registrant.14 Today, most nicotine poisonings are
the result of ingestion of tobacco products and ingestion and/or incorrect use of nico-
tine replacement products such as nicotine gum and transdermal patches.15>16 However.
ingestions from old pesticide products may still occur.17
CHAPTER 8
Biological^
Nicotine
HIGHLIGHTS
Efficiently absorbed by gut,
lung, skin
CMS impacts
Respiratory impacts
SIGNS & SYMPTOMS
Salivation, sweating,
dizziness, nausea, vomiting,
diarrhea
Possible burning in mouth/
throat, agitation, confusion,
headache, abdominal pain
Cardiovascular symptoms at
high dosage/exposure
TREATMENT
Decontaminate eyes, skin
Maintain airway
Limit Gl absorption
IV atropine if indicated
Control seizures
Toxicology
Nicotine alkaloid is efficiently absorbed by the gut, lung and skin. Extensive biotrans-
formation occurs in the liver, with 70%-75% occurring as a first-pass effect.1S Both the
liver and kidney participate in the formation and excretion of multiple end-products.
which are excreted within a few hours. Estimates of the half-life of nicotine range
from about 1 hour in smokers to as much as 2 hours in non-smokers.19'20
Toxic action is complex. At low doses, autonomic ganglia are stimulated. At
higher doses, blockade of autonomic ganglia and skeletal muscle neuromuscular junc-
tions and direct effects on the central nervous system occur. Paralysis and vascular
collapse are prominent features of acute poisoning, but death is often due to respira-
tory paralysis, which may ensue promptly after the first symptoms of poisoning.14'17
Nicotine is not an inhibitor of cholinesterase enzyme.
73
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CHAPTER 8
Biological^
Signs and Symptoms of Poisoning
Early and prominent symptoms of poisoning include salivation, sweating, dizziness.
nausea, vomiting and diarrhea. Burning sensations in the mouth and throat, agitation.
confusion, headache and abdominal pain are reported. Cardiovascular symptoms are
prominent with high dosages of exposure. In severe poisoning, cardiovascular collapse
is manifested by bradycardia or other arrhythmias and hypotensive shock.13'17'21'22'23
Patients may have dyspnea, then respiratory failure and unconsciousness.13'21'22'23
In some cases, hypertension and tachycardia may precede hypotension and brady-
cardia.21'22 Seizures may also occur.13'17'22 In one case of ingestion of a large dose of
nicotine alkaloid pesticide, the patient developed asystole within 2 minutes. He later
developed seizures and refractory hypotension.13 A child developed seizures, respi-
ratory depression and hypoxic encephalopathy after ingesting a nicotine-containing
pesticide.17
If symptoms of poisoning appear during exposure to an airborne nicotine insec-
ticide, the person should be removed from the contaminated environment immedi-
ately and any skin areas that may be contaminated should be washed. The victim
should then be transported to the nearest treatment facility. Although mild poisoning
may resolve without treatment, it is often difficult to predict the ultimate severity of
poisoning at the onset.
Confirmation of Poisoning
Urine, plasma and salivary content of the metabolite cotinine can be used to confirm
absorption of nicotine. However, these studies generally need to be sent to a reference
lab and are not clinically useful in acute toxicity. Treatment should be based on clinical
presentation and findings. If necessary, lab confirmation can be done at a later date.
Treatment of Nicotine Toxicosis
1. If liquid or aerosol spray has come in contact with skin, wash the area thoroughly
with soap and water. If eyes have been contaminated, flush them thoroughly with
clean water or saline. If irritation persists, refer patient for specialized medical
treatment.
2. If there is any indication of loss of respiratory drive, maintain pulmonary ventila-
tion by mechanical means. Toxic effects of nicotine other than respiratory depres-
sion are usually survivable. Maintaining adequate gas exchange is therefore of
paramount importance.
3. If a nicotine-containing product has been ingested recently, take immediate steps
to limit gastrointestinal absorption. If the patient is fully alert, immediately admin-
ister activated charcoal orally as outlined in the Chapter 3, General Principles.
This is probably the best initial step in management. Since most patients who
ingest nicotine have significant vomiting, activated charcoal is not always neces-
sary. Do not administer cathartics or syrup of ipecac.
4. Manage patients with severe poisoning in the intensive care environment.
preferably with toxicology consultation if available. Monitor cardiac status by
electrocardiography and measure blood pressure frequently. Cardiopulmonary
resuscitation may be necessary. Vascular collapse may require administration of
vasopressors. Infusions of electrolyte solutions, plasma and/or blood may also be
required to combat shock.
74
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CHAPTER 8
Biological^
5. Treat excessive parasympathetic stimulation, such as severe hypersecretion (espe-
cially salivation and diarrhea) or bradycardia, with intravenous atropine sulfate.
There is no specific antidote for nicotine poisoning.
Dosage of Atropine Sulfate
Adults and children over 12 years: 0.5-1.0 mg slow IV,
repeated every 5 minutes if necessary.
Children under 12 years: 0.02 mg/kg body weight, slow
IV, repeated every 5 minutes if necessary. (Minimum dose of
0.1 mg.)
6. Control seizures as outlined in Chapter 3, General Principles.
ROTENONE
Source and Products
Although this natural substance is present in a number of plants, the source of most
rotenone used in the United States is the dried derris root imported from Central and
South America. It is formulated as dusts, powders and sprays (less than 5% active
ingredient) for use in gardens and on food crops. Many products contain piperonyl
butoxide as a synergist, and other pesticides are included in some commercial prod-
ucts. Rotenone degrades rapidly in the environment. Emulsions of rotenone are applied
to lakes and ponds to kill fish.
Toxicology and Manifestations of Poisoning
Although rotenone is toxic to the nervous systems of insects, fish and birds, commer-
cial rotenone products have presented little hazard to man over many decades. Neither
fatalities nor systemic poisonings in humans have been reported in relation to ordinary
use. However, there is one report of a fatality in a child who ingested a product called
Gallocide, which contains rotenone and etheral oils, including clove oil (eugenol). She
developed a gradual loss of consciousness over 2 hours and died of respiratory arrest.24
There have been some reports of toxic symptoms following occupational
exposure. Eye irritation is the most common. In addition, numbness of oral mucous
membranes has been reported in workers who got dust from the powdered derris
root in their mouths. Dermatitis, respiratory tract irritation, headaches and peripheral
neuropathy have also been reported.25
When rotenone has been injected into animals, tremors, vomiting, incoordina-
tion, seizures and respiratory arrest have been observed. These effects have not been
reported in occupationally exposed humans.
Treatment of Rotenone Toxicosis
1. Provide supportive treatment, as there is no specific antidote.
75
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CHAPTER 8
Biological^
2. Remove skin contamination by washing with soap and water. Remove eye
contamination by flushing the eye thoroughly with clean water or saline. Wash
out any dust in the mouth. If irritation persists, refer for further medical treatment.
3. If a large amount of a rotenone-containing product has been swallowed and
retained, consider gastric decontamination as outlined in Chapter 3, General
Principles.
SABADILLA (VERATRUM ALKALOID)
Source and Products
Sabadilla consists of the powdered ripe seeds of a South American lily. Its only
remaining registered use in the United States is for agricultural application to citrus
fruits, avocados and mangos.26 Insecticidal alkaloids are those of the Veratmm plant.
The concentration of alkaloids in commercial sabadilla is usually less than 0.5%. Little
or no sabadilla is used in the United States today, but it is probably used in other
countries. Although poisoning by medicinal Veratmm preparations may have occurred
in the remote past, systemic poisoning by sabadilla preparations used as insecticides
has been very rare. Much of the toxic encounters with Veratrum alkaloid occur from
the inadvertent ingestion of the Veratmm plant or a related plant from the genus
Zigadenus.27'28
Toxicology
Sabadilla dust is very irritating to the upper respiratory tract, causing sneezing, and is
also irritating to the skin. Veratmm alkaloids are apparently absorbed across the skin
and gut, and probably by the lung as well. Veratmm alkaloids have a digitalis-like
action on the heart muscles (impaired conduction and arrhythmia).27'29'30
Signs and Symptoms of Poisoning
The prominent symptoms of Veratrum alkaloid poisoning are severe nausea and
vomiting, increased salivation and mental status changes. Cardiovascular effects may
be severe, including hypotension and bradycardia. Other arrhythmias or A-V block
may occur in large ingestions. These symptoms often resolve within 24 hours.27'29'30
Treatment of Sabadilla Toxicosis
1. Wash contaminated skin thoroughly with soap and water. Flush eyes, if affected.
with copious amounts of clean water or saline. If skin or eye irritation persists.
refer patient for further medical treatment.
2. Consider gastric decontamination as outlined in Chapter 3, General Principles.
3. If there is a suspicion that significant amounts of sabadilla alkaloids have been
absorbed, monitor cardiac activity for arrhythmia and conduction defects with an
ECG. Place patient with severe toxicity in intensive care. Treat bradycardia with
atropine.29'30
76
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Dosage of Atropine Sulfate
Adults and children over 12 years: 0.5-1.0 mg slow IV,
repeated every 5 minutes, if necessary.
Children under 12 years: 0.02 mg/kg body weight, slow
IV, repeated every 5 minutes, if necessary. (Minimum dose
of 0.1 mg.)
CHAPTER 8
Biological^
Spinosyns
COMMERCIAL
PRODUCTS
Spinosad (a mixture of
Spinosyn A and Spinosyn D)
SPINOSYNS
Source and Products
Spinosad is a biologically based synthetic pesticide that is used to control a variety of
insects including fleas, mites, fire ants, caterpillars, fruit flies and leaf beetle larvae. It
has recently been approved to treat head lice in humans.31 The spinosyns are derived
from the rare soil-dwelling actinomycete bacterium called Saccharopolyspora spinosa.
Toxicology and Manifestations of Poisoning
Spinosad must be ingested by the target pest to control it. It causes rapid excitation
of the insect's nervous system and is relatively fast acting. Spinosyns interfere with
nicotinic function and also disrupt GAB A function in central nervous system neurons;
however, they do not bind to the receptor sites.32 Spinosad has low mammalian oral
toxicity (LD50 rat is >3,000 mg/kg).33 Similar to fipronil, spinosyns have a much higher
affinity for insects than for mammals. There have not been reports of human toxicity
in the medical literature.
Treatment
1. Provide supportive treatment should toxic effects occur in humans, as there is no
known antidote.
2. Wash contamination from skin with soap and water. Flush contamination from
eyes with clean water or saline. If irritation occurs, refer for further medical treat-
ment.
3. For significant ingestion, consider gastrointestinal decontamination as outlined
in Chapter 3, General Principles, although that may not be necessary. Poison
control centers may be helpful to guide whether any therapy is indicated based on
the ingestion.
STREPTOMYCIN
Source and Products
Streptomycin sulfate and nitrate are used as pesticides for the control of a variety
of commercially important bacterial plant pathogens. Streptomycin is an antibiotic
derived from the growth of Streptomyces griseus.
77
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CHAPTER 8
Biological^
Toxicology
Streptomycin shares a toxic profile with the aminoglycoside antibiotics commonly
used to treat human diseases. Its major modes of toxicity are nephrotoxicity and ototox-
icity. Fortunately, it is poorly absorbed from the gastrointestinal tract, so systemic
toxicity is unlikely with ingestion. It may cause some minor nausea and GI upset.
Treatment
If a large amount has been ingested and 1 hour or less has passed, consider gastric
decontamination as outlined in Chapter 3, General Principles.
References
Yen TH, Lin JL. Acute poisoning with emamectin benzoate. J Toxicol Clin Toxicol.
2004;42(5):657-661.
Chung K, Yang CC, Wu ML, Deng JF, Tsai WJ. Agricultural avermectins: an uncommon
but potentially fatal cause of pesticide poisoning. Ann EmergMed. Jul 1999;34(l):51-57.
Soyuncu S, Oktay C, Berk Y, Eken C. Abamectin intoxication with coma and hypotension.
Clin Toxicol (Phila). 2007;45(3):299-300.
2.
3.
4.
Samples JR, Buettner H. Corneal ulcer caused by a biologic insecticide (Bacillus thuringi-
ensis).AmJOphthalmol. Feb 1983;95(2):258-260.
5. Barkin ME, Boyd JP, Cohen S. Acute allergic reaction to eugenol. Oral Surg Oral Med
OmlPathol. Apr 1984;57(4):441-442.
6. Isaacs G. Permanent local anaesthesia and anhidrosis after clove oil spillage. Lancet. Apr
16 1983;1(8329):882.
7. Lane BW, Ellenhorn MJ, Hulbert TV, McCarron M. Clove oil ingestion in an infant. Hum
Exp Toxicol. Jul 1991;10(4):291-294.
8. Brown SA, Biggerstaff J, Savidge GF. Disseminated intravascular coagulation and hepato-
cellular necrosis due to clove oil. Blood CoagulFibrinolysis. Oct 1992;3(5):665-668.
9. Eisen JS, Koren G, Juurlink DN, Ng VL. N-acetylcysteine for the treatment of clove oil-
induced fulminant hepatic failure. J Toxicol Clin Toxicol. 2004;42(l):89-92.
10. Hartnoll G, Moore D, Douek D. Near fatal ingestion of oil of cloves. Arch Dis Child. Sep
1993;69(3):392-393.
11. Mizutani T, Satoh K, Nomura H. Hepatotoxicity of eugenol and related compounds in mice
depleted of glutathione: structural requirements for toxic potency. Res Commun Chem
Pathol Pharmacol. Jul 1991;73(1): 87-95.
12. Thompson D, Constantin-Teodosiu D, Egestad B, Mickos H, Moldeus P. Formation of
glutathione conjugates during oxidation of eugenol by microsomal fractions of rat liver and
\\wg.BiochemPharmacol. May 15 1990;39(10): 1587-1595.
13. Lavoie FW, Harris TM. Fatal nicotine ingestion. J EmergMed. May-Jun 1991;9(3):133-
136.
14. United States Environmental Protection Agency. Reregistration Eligibility Decision (RED)
for nicotine. 2008. http://www.epa.gov/pesticides/reregistration/REDs/nicotine_red.pdf
Accessed December 30, 2012.
15. Pereira CB, Strupp M, Eggert T, Straube A, Brandt T. Nicotine-induced nystagmus:
three-dimensional analysis and dependence on head position. Neurology. Nov 28
2000;55(10):1563-1566.
16. Wain AA, Martin J. Can transdermal nicotine patch cause acute intoxication in a child? A
case report and review of literature. Ulster Med J. May 2004;73(l):65-66.
78
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CHAPTER 8
Biological^
17. Rogers AJ, Denk LD, Wax PM. Catastrophic brain injury after nicotine insecticide inges-
tion. JEmergMed. Feb 2004;26(2): 169-172.
18. Svensson CK. Clinical pharmacokinetics of nicotine. Clin Pharmacokinet. Jan
1987;12(1): 30-40.
19. Feyerabend C, Ings RM, Russel MA. Nicotine pharmacokinetics and its application to
intake from smoking. BrJClin Pharmacol. Feb 1985;19(2):239-247.
20. Kyerematen GA, Damiano MD, Dvorchik BH, Vesell ES. Smoking-induced changes in
nicotine disposition: application of a new HPLC assay for nicotine and its metabolites. Clin
Pharmacol Ther. Dec 1982;32(6):769-780.
21. Malizia E, Andreucci G, Alfani F, Smeriglio M, Nicholai P. Acute intoxication with nico-
tine alkaloids and cannabinoids in children from ingestion of cigarettes. Hum Toxicol. Apr
1983;2(2):315-316.
22. Sanchez P, Ducasse JL, Lapeyre-Mestre M, et al. Nicotine poisoning as a cause of cardiac
arrest? J Toxicol Clin Toxicol. 1996;34(4):475-476.
23. Woolf A, Burkhart K, Caraccio T, Litovitz T. Self-poisoning among adults using multiple
transdermal nicotine patches. J Toxicol Clin Toxicol. 1996;34(6):691-698.
24. De Wilde AR, Heyndrickx A, Carton D. A case of fatal rotenone poisoning in a child. J
Forensic Sci. Oct 1986;31(4):1492-1498.
25. United States Environmental Protection Agency. Reregistration Eligibility Decision (RED)
for Rotenone. 2007; http://www.epa.gov/oppsrrdl/REDs/rotenone_red.pdf.
26. United States Environmental Protection Agency. Reregistration Eligibility Decision (RED)
Exposure and Risk Assessment on Lower Risk Pesticide Chemicals Sabadilla Alkaloids.
2004; http://www.epa.gov/oppsrrdl/REDs/sabadilla_red.pdf
27. Dunnigan D, Adelman RD, Beyda DH. A young child with altered mental status. Clin
Pediatr (Phila). Jan-Feb 2002;41(l):43-45.
28. Heilpern KL. Zigadenus poisoning. Ann EmergMed. Feb 1995;25(2):259-262.
29. Jaffe AM, Gephardt D, Courtemanche L. Poisoning due to ingestion of Veratrum viride
(false hellebore). JEmergMed. Mar-Apr 1990;8(2): 161-167.
30. Quatrehomme G, Bertrand F, Chauvet C, Oilier A. Intoxication from Veratrum album.
HumExp Toxicol. Mar 1993;12(2):111-115.
31. Kirst HA. The spinosyn family of insecticides: realizing the potential of natural products
research. JAntibiot (Tokyo). Mar;63(3):101-lll.
32. Sparks TC, Grouse G.D., Durst, G. Natural products as insecticides: the biology, biochem-
istry and quantitative structure activity relationships of spinosyns and spinodoids. Pest
ManagSci. 2001;57:896-905.
33. Stebbins KE, Bond DM, Novilla MN, Reasor MJ. Spinosad insecticide: subchronic and
chronic toxicity and lack of carcinogenicity in CD-I mice. Toxicol Sci. Feb 2002;65(2):276-
287.
79
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HIGHLIGHTS
CHAPTER 9
Multiple agents with widely
varying toxicity
Agents of concern
include borates, fluorides,
pyrethroids
Neonicotinoids are a newer
class that merits attention
due to widespread use and
toxicity
SIGNS & SYMPTOMS
Variable and highly related
to the specific agent
Boric acid, fluorides,
n-phenylpyrazones and
neonicotinoids should be
suspected in cases with
CMS symptoms
TREATMENT
Specific to agent
Skin/eye decontamination
Consider Gl
decontamination based on
quantity and time interval
factors
Severe CMS symptoms
may require intensive care
management
Other Insecticides and Acaricides
This chapter concerns insecticides and acaricides having toxicologic characteris-
tics distinct from the insecticides discussed in previous chapters. It discusses benzyl
benzoate, borates, chlordimeform, chlorobenzilate, cyhexatin, fluorides, fipronil (an
n-phenylpyrazone insecticide), haloaromatic substituted urea compounds, metho-
prene, neonicotinoids, propargite and sulfur.
BENZYL BENZOATE
Incorporated into lotions and ointments, this agent has been used for many years in
veterinary and human medicine against mites and lice.
Toxicology
Apart from occasional cases of skin irritation, adverse effects have been few. The effi-
ciency of skin absorption is not known. Absorbed benzyl benzoate is rapidly biotrans-
formed to hippuric acid that is excreted in the urine. Oral toxicity in animals is low.
with LD50 values in the 2-3 grams/kg range in rats and cats. When given in large doses
to laboratory animals, benzyl benzoate causes excitement, incoordination, paralysis of
the limbs, convulsions, respiratory paralysis and death.1 Very few human exposures
have been reported to the National Poison Data System.
Treatment
1. If significant irritant effect appears, discontinue use of product and cleanse skin
with soap and water. Treat eye contamination by irrigating exposed eyes with
copious amounts of clean water or saline for at least 15 minutes. Remove contact
lenses, if present, prior to irrigation. If irritation persists after irrigation, obtain
specialized medical treatment in a healthcare facility.
2. If a potentially toxic amount has been swallowed and retained and the patient is
seen soon after exposure, consider gastrointestinal decontamination. If seizures
occur, control may require treatment with benzodiazepines.
BORIC ACID AND BORATES
Boric acid and borate products can be formulated as tablets and powder to kill larvae
in livestock confinement areas and cockroaches in residences. Rarely, solutions are
sprayed as a nonselective herbicide.
Toxicology
When determining toxicity of boric acid from ingestion, it is important to distin-
guish between acute and chronic exposure. Chronic ingestion is more likely to cause
80
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significant toxicity than acute exposure.2'3 Berates are well absorbed by the gut and by
abraded or burned skin, but not by intact skin.4 The kidney efficiently excretes them.
The residence half-life in humans averages 13 hours, in a range of 4-28 hours.2
Signs and Symptoms of Poisoning
Generally, boric acid is of lower toxicity when compared to other insecticides that are
widely used in the United States. A series of 784 patients has been described with no
fatalities and minimal toxicity. Only 12% of these patients had symptoms of toxicity.
mostly to the gastrointestinal tract.2 However, fatal poisonings have been reported.3'5'6
A large number of poisonings in newborns occurred in the 1950s and 1960s and often
resulted in death.7'8 Historically, many poisonings have resulted from injudicious uses
in human medicine aimed at suppressing bacterial growth, such as compresses for
burns, powders for diaper rash, and irrigation solutions.4'9
Boric acid powders and pellets scattered on the floors of homes can present a
hazard to children. Their frequent use for roach control increases access for ingestion.
Consequently, cases of suicidal or accidental ingestion continue to be reported in the
medical literature.5'6'10'11'12 One toddler died following a massive ingestion of boric acid
powder that had been stored in a bathroom cabinet.5 An 82-year-old man accidentally
ingested 30 mL of boric acid instead of the magnesium sulfate he was supposed to take
for a colonoscopy prep.10 Three cases of apparent suicide attempts in adults have been
reported.11>12'13 Borax dust is moderately irritating to skin. Inhaled dust caused irritation
of the respiratory tract among workers in a borax plant. Symptoms included nasal irri-
tation, mucous membrane dryness, cough, shortness of breath and chest tightness.14'15
The gastrointestinal tract, renal system, skin, vascular system and brain are the
principal organs and tissues affected. Nausea, persistent vomiting, abdominal pain and
diarrhea reflect a toxic gastroenteritis.2'3'9 In severe poisonings, a beefy red skin rash.
most often affecting palms, soles, buttocks and scrotum, has been described. It has
been characterized as a "boiled lobster appearance." The intense erythema is followed
by extensive exfoliation.3'8'11'16 This may be difficult to distinguish from staphylococcal
scalded skin syndrome.16 Reversible alopecia has been reported following exposure to
boric acid and related compounds.17'18'19
Headache, agitation, weakness, lethargy, restlessness and tremors may occur, but
are less frequent than gastrointestinal effects.2'10 Seven infants who were exposed to a
mixture of borax and honey on their pacifiers developed seizures.20 Unconsciousness
and respiratory depression signify life-threatening brain injury. Cyanosis, weak pulse.
hypotension and cold clammy skin indicate shock, which is sometimes the cause of
death in borate poisoning.3'6'9 Hypotension and at times hypertension may occur even
in milder cases where victims fully recover.10'11
Acute renal failure (oliguria or anuria) may be a consequence of shock, of
direct toxic action on renal tubule cells, or possibly of both. It occurs in severe borate
poisoning.3'6'8'16 Metabolic acidosis may be a consequence of the acid itself, seizure
activity or metabolic abnormalities.3 Fever is sometimes present in the absence of
infection.
CHAPTER 9
Other Insecticides
and Acaricides
Boric Acid/Borates
COMMERCIAL
PRODUCTS
Boric acid, sodium
tetraborate decahydrate,
sodium polyborates
(discontinued 1992)
HIGHLIGHTS
Chronic ingestion more
likely to cause significant
toxicity than acute
Absorbed by gut and
abraded/burned (not intact)
skin
SIGNS & SYMPTOMS
Nausea, vomiting,
abdominal pain, diarrhea
Severe poisonings:
erythema ("boiled lobster")
and exfoliation
CMS symptoms may be
present
TREATMENT
Skin/eye decontamination
Consider Gl contamination
Large or protracted
ingestion may require
IV fluids and cardiac
monitoring
Confirmation of Poisoning
Borate can be measured in serum by colorimetric methods, as well by high tempera-
ture atomic spectrometric methods. Studies of serum levels of boric acid and boron in
non-poisoned individuals ranged from 0.0 to 0.2 mg/dL in adults and from 0.0 to 0.125
mg/dL in children.9'21'22 Levels reported in toxic incidents have varied widely and it is
felt that serum levels are of little use in guiding therapy.2'9'21
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CHAPTER 9
Other Insecticides
andAcaricides Treatment
1. Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Treat eye contamination by irrigating the exposed eye(s) with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses.
if present, prior to irrigation. If irritation persists after irrigation, send patient for
specialized medical treatment in a healthcare facility.
2. In acute poisonings, if a large amount has been ingested and the patient is seen
within 1 hour of exposure, gastrointestinal decontamination may be considered as
outlined in Chapter 3. It is important to keep in mind that vomiting and diarrhea
are common, and severe poisoning may be associated with seizures.
3. If massive ingestion of borate (several grams) has occurred or if borate inges-
tion has extended over several days, administer IV fluids such as D5NS or
Lactated Ringers to sustain urinary excretion of borate. Monitor fluid balance and
serum electrolytes (including acid base status) regularly. Monitor cardiac status
by ECG. Test the urine for protein and cells to detect renal injury, and monitor
serum concentration of borate if possible. Metabolic acidosis may be treated with
sodium bicarbonate. If shock develops, treat as appropriate. Administer oxygen
continuously. If oliguria (less than 25-30 mL urine formed per hour) occurs, intra-
venous fluids must be slowed or stopped to avoid overloading the circulation.
Such patients should usually be referred to a center capable of providing intensive
care for critically ill patients.
4. Consider hemodialy sis in severe poisonings, if patient fails to respond to conven-
tional therapy. Dialysis has been demonstrated to enhance the clearance of boric
acid eveninthe presence of normal renal function.2'7'10'12 There is no consensus onits
use. Forced diuresis has also been successfully used in early stages of poisoning.13
Peritoneal dialysis was performed historically in borate poisoning and
thought to be as effective as, and safer than, exchange transfusion in removing
borate.8'23 Exchange transfusion has been reported to be effective in chronic expo-
sures. No large study of efficacy has been done. Exchange transfusion and perito-
neal dialysis are rarely used today in acute poison management.2
5. Control seizures as recommended for other agents and as outlined in Chapter 3.
CHLORDIMEFORM
Formulations are emulsifiable concentrates and water-soluble powders. Chlordime-
form demonstrates good dermal absorption and can be inhaled. It is an ovicide and
acaricide. All registrations in the United States are currently canceled.
Toxicology
In a reported episode of occupational exposure to chlordimeform, several workers
developed hematuria. Hemorrhagic cystitis, probably due to chloraniline biodegrada-
tion products, was the source of the blood in the urine. Symptoms reported by the
affected workers included gross hematuria, dysuria, urinary frequency and urgency.
penile discharge, abdominal and back pain, a generalized "hot" sensation, sleepiness.
skin rash and desquamation, a sweet taste and anorexia. Symptoms persisted for 2-8
weeks after exposure was terminated.24 In a single case, methemoglobinemia was
reported.25
82
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CHAPTER 9
Other Insecticides
Chlordimeform is not a cholinesterase inhibitor. and Acaricides
Confirmation of Poisoning
Although methods do exist for measurement of urinary excretion products, these tests
are not generally available in the clinical setting.
Treatment
1. Decontaminate skin thoroughly with soap and water, as outlined in Chapter 3,
General Principles. Decontaminate eyes by irrigating exposed eyes with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses
if present prior to irrigation. If irritation persists after irrigation, send patient for
specialized medical treatment in a healthcare facility.
2. If chlordimeform has been ingested no more than an hour prior to treatment
consider gastrointestinal decontamination as outlined in Chapter 3. Patients are
at risk for fluid loss and subsequent electrolyte disturbances; young children are
especially susceptible. Monitor fluid balance, electrolytes and acid base status
closely.
3. Patients exposed should have serial urinalyses for protein and red cells to detect
injury to the urinary tract. Resolution of hematuria ordinarily can be expected in
2-8 weeks. Relief from other symptoms usually can be expected earlier.
CHLOROBENZILATE
Chlorobenzilate is a chlorinated hydrocarbon acaricide, usually formulated as an
emulsion or wettable powder for application in orchards. All U.S. registrations have
been canceled.
Toxicology
Chlorobenzilate is moderately irritating to the skin and eyes.
Although structurally similar to DDT, Chlorobenzilate is much more rapidly
excreted following absorption, chiefly in the urine as the benzophenone and benzoic
acid derivatives. Based on observation of dosed animals, extreme absorbed doses may
cause diarrhea, tachypnea, tremors, ataxia and muscle weakness.26
Limited human acute poisoning data are available. A case of toxic encephalop-
athy in a male following unprotected pesticide application in a field for 14 days at 10
hours per day has been reported. His symptoms included muscle pain, weakness, fever
and mental status changes, progressing to a tonic-clonic seizure. He recovered without
apparent sequelae within 6 days. Treatment included respiratory support and seizure
management.27
Chlorobenzilate is not a cholinesterase inhibitor.
83
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CHAPTER 9
Other Insecticides
and Acaricides
Fluorides
COMMERCIAL
PRODUCTS
Cryolite
Kryocide
HIGHLIGHTS
Most cases of poisoning
today are sources other than
insecticides
Highly toxic sodium fluoride
and sodium fluosilicate
products no longer
registered for use
SIGNS & SYMPTOMS
Hypocalcemia with possible
tetany
Cardiac arrhythmia, shock
Possible CMS impacts
TREATMENT
Skin, eye, possible Gl
decontamination
May require intensive care
treatment
Treat hypocalcemia with
calcium gluconate or
calcium chloride
Treatment of Chlorobenzilate Poisoning
1. Decontaminate the skin with soap and water as outlined in the Chapter 3, General
Principles. Treat eye contamination by irrigating exposed eyes with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses.
if present, prior to irrigation. If irritation persists after irrigation, send patient for
specialized medical treatment in a healthcare facility.
2. If a large amount of chlorobenzilate was ingested within a few hours prior to treat-
ment, consider gastrointestinal decontamination as outlined in Chapter 3.
3. Treat seizures as outlined in Chapter 3.
CYHEXATIN
All U.S. registrations of this chemical have been canceled.
Toxicology
Tricyclohexyl tin hydroxide is formulated as a 50% wettable powder for control of
mites on ornamentals, hops, nut trees and some fruit trees. It is moderately irritating.
particularly to the eyes. While information on the systemic toxicity of this specific tin
compound is lacking, it should probably be assumed that cyhexatin can be absorbed to
some extent across the skin, and that substantial absorbed doses would cause nervous
system injury (see organotin compounds on page 154 in Chapter 16, Fungicides).
Treatment
1. Promptly decontaminate skin by washing with soap and water and decontaminate
eyes by irrigating with clean water or saline for at least 15 minutes. Remove
contact lenses, if present, prior to irrigation.
2. Manage poisonings by ingestion on the assumption that cyhexatin is toxic, even
though rodent LD50 values are fairly high and no human poisonings have been
reported in the medical literature. Management should be as with other organotin
compounds (see page 154 in Chapter 16, Fungicides).
FLUORIDES
Sodium fluoride is a crystalline mineral once widely used in the United States for
control of larvae and crawling insects in homes, barns, warehouses and other storage
areas. It is highly toxic to all plant and animal life. No commercial products are avail-
able at this time.
Sodium fluosilicate (sodium silico fluoride) has been used to control ectopar-
asites on livestock, as well as crawling insects in homes and work buildings. It is
approximately as toxic as sodium fluoride. Commercial products containing sodium
fluosilicate are no longer registered for use.
Sodium fluoaluminate (sodium aluminofluoride, Cryolite) is a stable mineral
containing fluoride. It is used as an insecticide on some vegetables and fruits. Cryolite
has very low water solubility, does not yield fluoride ion on decomposition and
presents very little toxic hazard to mammals, including man.
84
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CHAPTER 9
Other Insecticides
Most cases of fluoride poisoning now are related to hydrofluoric acid, sulfur and Acaricides
fluoride or excess fluorosis from sources other than insecticides, such as well water
and toothpaste. Hydrofluoric acid is an important industrial toxicant but is not used as
a pesticide. The clinical symptoms from hydrofluoric acid poisoning are essentially
the same as described below for fluoride pesticides and are related to the fluoride
ion's effects on potassium, calcium and magnesium.28 Fluoroacetate is discussed in
Chapter 18, Rodenticides. Sulfuryl fluoride is discussed in Chapter 17, Fumigants.
Toxicology
Sodium fluoride and sodium fluosilicate used as insecticides present a serious hazard
to humans because of high inherent toxicity and the possibility that children crawling
on floors of treated dwellings will ingest the material. They are both used in the water
fluoridation process, which is more likely to be a source of exposure than the insecti-
cide. In a series of 87 pediatric cases of fluoride poisoning reported to a poison center,
only one child had ingested an insecticide. Of note, that child was also the only fatality
in the case series.29
Fluorides are readily and quickly absorbed from the GI tract with near complete
bioavailability.30'31 Plasma fluoride levels peak at around 30 minutes following inges-
tion. Fluoride is also distributed to the bone and saliva.31'32 Excretion is chiefly in the
urine. Within the first 24 hours of intoxication, renal clearance of fluoride from the
blood is rapid. However, patients continue to excrete large amounts of fluoride for
several days. The fluoride ion binds calcium and magnesium, leading to life-threat-
ening cardiac toxicity in severe cases. Children are at relatively greater risk because of
their smaller body mass compared to adults in relation to the amount ingested.33
Signs and Symptoms of Poisoning
The toxic effects of fluoride in mammals are multiple and may be life threatening. The
primary effects from fluoride result from an inhibition of critical intracellular enzymes
and the direct effect on ionized calcium in extra-cellular fluid. The absorbed fluo-
ride ion reduces extracellular fluid concentrations of calcium and magnesium. Hypo-
calcemia commonly occurs, sometimes severe enough to result in tetany or cardiac
toxicity leading death.29'34'35'36-37
While sodium fluoride supplementation is available in the form of liquid drops,
there is a rather narrow therapeutic range; chronic, mild fluorosis is present with an
intake of 0.1 mg/kg/day. Most evidence of minor skeletal fluorosis will disappear
as the fluoride supplementation is stopped, except for the teeth mottling.38 Acutely
toxic dosages usually start at about 3-10 mg/kg, with GI symptoms being the first
to develop.29'39 Ingested fluoride is transformed in the stomach to hydrofluoric acid,
which has a corrosive effect on the epithelial lining of the gastrointestinal tract. Thirst,
abdominal pain, vomiting and diarrhea are usual symptoms. Hemorrhagic gastroen-
teritis, ulceration, erosions and edema are commons signs.40
Cardiac arrhythmia and shock are often prominent features of severe poisoning.
Hypotension and severe arrhythmia including ventricular fibrillation may also
occur.37'41 These probably result from combinations of effects of fluid and electrolyte
disturbances including hypocalcemia,29'34'35'36'37 hyperkalemia41 and direct actions of
fluoride on heart and vascular tissues. Fluoride may directly affect the central nervous
system resulting in headache, muscle weakness, stupor, convulsions and coma.33'34'37
Respiratory failure and ventricular arrhythmias are common causes of death.33'37
85
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CHAPTER 9
Other Insecticides
and Acaricides
Confirmation of Poisoning
A population drinking water with a concentration of 1 mg per liter will have a plasma
inorganic fluoride concentration between 0.01-0.03 mg per liter34 and rarely above
0.10 milligram per liter. In fatal cases of poisoning, plasma levels of 3.5 mg per liter
and higher have been recorded, although survival has been reported in patients with
levels as high as 14 mg per liter.34'37 While not specific for fluoride poisoning, a low
serum calcium level can be helpful in making the diagnosis.29
Treatment
2.
Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Treat eye contamination by irrigating exposed eyes with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses.
if present, prior to irrigation. If irritation persists after irrigation, send patient for
specialized medical treatment in a health carefacility.
If sodium fluoride or sodium fluosilicate has been ingested, consider gastric
decontamination as outlined in Chapter 3. It should be noted that activated char-
coal will not bind the fluoride ion.
3. Severe complications such as hypotension, shock, cardia arrhythymia or cyanosis
should be treated in an intensive care setting. Monitor serum electrolytes (sodium.
potassium, ionized calcium, magnesium, fluoride and bicarbonate) and correct as
needed. Calcium and magnesium replacement are of primary consideration.29'36
If the victim is fully alert and the amount ingested is less than 8 mg/kg of fluo-
ride, consider giving the victim milk.29 Milk provides calcium ions that will bind
to fluoride, thereby reducing absorption. Magnesium-based antacids have also
been used to neutralize the acid and facilitate the production of poorly absorbed
salts.37 There are no data on the optimum amounts to be administered.
4. If hypocalcemia is demonstrated, or if it appears likely that a significant amount
of fluoride has been absorbed, aggressive calcium repletion may be required. Give
10 mL of 10% calcium gluconate intravenously slowly and repeat as necessary to
keep the calcium in the normal or supranormal range:
Dosage of Calcium Gluconate
Supplied as 100 mg/mL(10% solution)
Adults and children over 12 years: 10 mL of 10% solution,
given slowly, intravenously. Repeat as necessary.
Children under 12 years: 200-500 mg/kg/24 hr divided Q6
hr. Repeat dosage as needed.
86
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Severe cases may require use of 10% calcium chloride:
CHAPTER 9
Other Insecticides
and Acaricides
Dosage of Calcium Chloride
Adults and children over 12 years: 5 to 10 mL (500 to
1,000 mg) intravenously over 1 to 5 minutes; may repeat
after 10 minutes.
Children under 12 years: 0.2 to 0.3 mL/kg (20 to 30 mg/
kg) per dose, up to a maximum single dose of 5 mL (500
mg) intravenously over 5 to 10 minutes, repeated up to four
times or until serum calcium increases.
These patients should be managed in the intensive care setting.
5. If hypomagnesaemia is present, administer magnesium sulfate.
6. Consider hemodialysis, as it may be beneficial in patients with significant
toxicity.37
7. Refer patients with evidence of burns in their oral cavity for surgical evaluation
and endoscopy, since these compounds can cause severe burns to the esophagus
and stomach.
8. If a very large amount of sodium fluoaluminate (Cryolite) has been ingested.
although it is much less toxic than other fluorides, measure serum calcium to
ensure that hypocalcemia has not occurred. If it has, intravenous calcium may be
required (see 4 above).
HALOAROMATIC SUBSTITUTED UREA INSECTICIDES
Haloaromatic substituted urea compounds control insects by impairing chitin deposi-
tion in the larval exoskeleton. They are formulated in wettable powders, oil dispersible
concentrate and granules for use in agriculture and forestry and in settings where fly
populations tend to be large, such as feedlots. Diflubenzuron is the most commonly
used product in this class, and most human data are based on this active ingredient.
Toxicology
There is limited absorption of haloaromatic substituted urea compounds across the
skin and intestinal lining of mammals, after which enzymatic hydrolysis and excre-
tion rapidly eliminate the pesticide from tissues. Irritant effects are not reported and
systemic toxicity is low. Based on animal studies, methemoglobinemia is a risk from
the metabolite of diflubenzuron (4-chloroaniline).65'66 There has been a report of occu-
pational exposure to 4-chloroaniline that resulted in methemoglobinemia, although it
is not clear that the source of 4-chloroaniline was diflubenzuron.67
Treatment
1. Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Treat eye contamination by irrigating exposed eyes with copious
Haloaromatic Substituted
Urea Insecticides
COMMERCIAL
PRODUCTS
diflubenzuron
(brand names include, but
are not limited to, Dimilin,
Micromite, Vigilante)
teflubenzuron
(brand names include, but
are not limited to, Nomolt,
Dart, Diaract)
87
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CHAPTER 9
Other Insecticides
and Acaricides
2.
amounts of clean water or saline for at least 15 minutes. Remove contact lenses.
if present, prior to irrigation. If irritation persists after irrigation, obtain special-
ized medical treatment in a healthcare facility. Sensitization reactions may require
steroid therapy.
If large amounts of propargite have been ingested and the patient is seen within
an hour, consider gastrointestinal decontamination as discussed in Chapter 3,
General Principles.
3. If methemoglobinemia is severe (>30%), or the patient is cyanotic, administer
methylene blue.
Dosage of Methylene Blue
Adults and children: 1-2 mg/kg of 1% methylene blue,
slow IV, in symptomatic patients. Additional doses may be
required, given as a slow IV push over a few minutes, every
4 hours as needed. (It is formulated as a 1% solution with 1
mL containing 10 mg of methylene blue.)
METHOPRENE
Methoprene is a long-chain hydrocarbon ester active as an insect growth regulator. It is
effective against several insect species. Formulations include slow-release briquettes.
sprays, foggers, soluble concentrate, suspension concentrate and baits.
Toxicology
Methoprene is neither an irritant nor a sensitizer in humans or laboratory animals.
Systemic toxicity in laboratory animals is very low. No human poisonings or adverse
reactions in exposed workers have been reported.
Treatment
1. Wash contaminated skin with soap and water. Treat eye exposures by irrigating
exposed eyes with copious amounts of clean water or saline for at least 15 minutes.
Remove contact lenses, if present, prior to irrigation. If irritation persists after irri-
gation, send patient to a healthcare facility for further medical attention.
2. If a very large amount of methoprene has been ingested, consider GI decontami-
nation as outlined in Chapter 3, General Principles.
N-PHENYLPYRAZONE INSECTICIDES
Fipronil is a broad-spectrum n-phenylpyrazole insecticide first registered by the U.S.
Environmental Protection Agency in 1996. It is used for pests on agricultural crops and
for lawn treatments. It is also commonly used for ant and cockroach control in the form
of bait stations and as a topical application to domestic animals for flea and tick control.
88
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Toxicology
Fipronil's mechanism of action is by inhibition of GABA-gated chloride channels.
This inhibits passage of chloride ions, thus producing hyperexcitability. This effect is
similar to the mechanism of action for the organochlorine insecticides, the difference
being that fipronil acts only on the GABAA channels, while organochlorines inhibit
both the GAB AA and GAB Ac channels.42'43'44
Fipronil is well absorbed by the GI tract in its parent form. It is rapidly metabo-
lized to a sulfone compound. This metabolite is lexicologically active like the parent
compound. It also binds to the same GABA receptors as fipronil, but at a much higher
affinity.45
Animal studies demonstrate that fipronil has a selectively higher toxicity for
insects than mammals, mostly attributed to a much more selective affinity for insect
GABAA channels than vertebrate GABAA channels.43'45
Signs and Symptoms of Poisoning
Despite the higher selective affinity for insects, there have been some reports of acute
human toxicity. Patients may present with nausea and vomiting within several hours
of ingestion. These appear to be serf limiting, and no long-term gastrointestinal effects
have been reported.46 Consistent with the fact that the central nervous system is the
primary target of fipronil, neurological symptoms have been the most commonly
observed health effects.46'47'48 Neurologic symptoms have been confirmed in cases
of human poisoning following ingestion. Patients may present with altered mental
status.47 In severe cases, unconsciousness and generalized tonic-clonic seizures may
also occur.47'48'49 Most episodes of seizures or altered mental status appeared to be self
limiting and have resolved within hours.46'47
One study analyzed pesticide surveillance data from 2001-2007, where 103
acute illnesses were identified with fipronil exposures in 11 states. The annual number
of reported cases was shown to increase over time. The findings showed that the great
majority of cases demonstrated mild clinical effects or short duration, thus confirming
some of the previous observations. The reported effects in this study included conjunc-
tivitis, headache, dizziness, nausea, vomiting, abdominal pain, oropharyngeal pain.
cough, sweating, sensory impairment, weakness, drowsiness, agitation and seizure.48
Of note, pet-care products were related to more than one-third of cases and accounted
for the majority of childhood cases (64%).
There are no data available for signs and symptoms of chronic or subacute
poisoning or exposure. However, the study of pesticide surveillance data also suggests
that with occupational exposure, there is greater likelihood of repeated exposure to
higher concentrations, thereby resulting in more severe effects.48
Confirmation of Poisoning
The parent compound can be measured in plasma and in urine, although the test is not
widely available in most hospitals. Levels reported with acute symptomatic human
poisoning have been recorded as 1,600 ug/L-3,740 ug/L.46 The levels peaked by
approximately 3-4 hours following ingestion. Reported levels of the sulfone metabo-
lite were not available.
Treatment
1. Provide supportive care, as there is no specific antidote.
CHAPTER 9
Other Insecticides
and Acaricides
N-Phenylpyrazones
COMMERCIAL
PRODUCTS
Fipronil
(brand names include, but
are not limited to Maxforce,
Over'nOut!, Frontline,
Frontline Topspot, Combat,
Chipco Choice)
HIGHLIGHTS
Inhibits GABAAchannels
Well absorbed by GI tract
SIGNS & SYMPTOMS
Nausea, vomiting
CMS impacts
Unconsciousness, seizures
TREATMENT
Supportive care
GI decontamination
Control seizures with
benzodiazepines
Control extreme agitation
with lorazepam or propofol
89
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CHAPTER 9
Other Insecticides
and Acaricides
Neonicotinoids
HIGHLIGHTS
Introduced in U.S. market in
1990s
Large (11-15%) and growing
market share
Developed by modifying
nicotine
Displace ACh from nAChRs
SIGNS & SYMPTOMS
Resembles acute nicotine
poisoning
Usually ingestion or
inhalation
Disorientation, confusion,
agitation, headache,
drowsiness, dizziness,
weakness, tremor,
unconsciousness
Gl symptoms (vomiting, sore
throat, nausea, diarrhea,
abdominal pain) may be
from formulation solvent
Respiratory toxicity can also
occur
TREATMENT
Supportive treatment
Consider Gl
decontamination
Control extreme agitation
with lorazepam or propofol
Consider 1C setting for
patients with mental status
changes or severe poisoning
2. Send patients with significant mental status changes to an intensive care setting.
At least initially, they are better managed there.
3. Use Gl decontamination within the guidelines outlined in Chapter 3, General
Principles. There are insufficient data on the efficacy of activated charcoal.
4. Control seizures as early as possible with benzodiazepines.46
5. Control extreme agitation with lorazepam or propofol.
NEONICOTINOID INSECTICIDES
Neonicotinoids are a relatively new class of insecticides, developed in the mid 1980s
and introduced in the U.S. market in the early 1990s. They are quickly growing in
widespread use and were recently noted to have 11%-15% U.S. market share of insec-
ticide use.50 They are well absorbed into plants and consequently are used in agri-
culture for piercing-sucking insects such as aphids and other crop-damaging insects.
They are also used for flea control on domestic pets. They act fairly selectively on
insects, with comparably less acute toxicity to mammals. As noted below, however.
they are not free from human toxicity. Imidacloprid is the most widely used insecti-
cide in this class, while most others have limited use in the commercial U.S. market.
Reported clinical toxicity in humans is rare. However, increasing use of this insecti-
cide and its potential toxicity among humans warrants a heightened awareness about
these compounds and their toxicity.
In one report of two fatal intoxications with imidacloprid, the diagnosis was
made post mortem by liquid chromatography/mass spectrometric quantification of
insecticide. No clinical descriptions of symptoms were available, as both patients were
found dead.
Toxicology
Similar to synthetic pyrethroids being derived from naturally occurring pyrethrins.
neonicotinoids were developed by modifying nicotine. Modifications include the
nitromethylene, nitroimine or cyanoimine groups, which provide better activity
and stability than nicotine. They are not very effective as contact insecticides but
rather derive their effectiveness by being absorbed into the plant and migrating to the
growing plant tip. They then affect insects that attempt to pierce the plant.
The toxicology of the neonicotinoids and special chemistry of the selective
affinity of these insecticides is discussed in great detail in two recent reviews.50'51 They
act on nicotinic acetylcholine receptors (nAChRs) by displacing acetylcholine (ACh)
from the receptor. Compared to other insecticides, most notably the organophosphate
class, the neonicotinoids exhibit a relatively more selective affinity towards insect
nAChRs than mammalian nAChRs.50
The acute oral LD50 in rats of the neonicotinoids varies from 182 mg/kg (acet-
amiprid) to 2,400 mg/kg (dinotefuran). At an LD50 of >5,000 mg/kg, clothianidin
appears to be an outlier of this group.50 While all neonicotinoids appear to selectively
target insect nAChRs, imidacloprid and others that specifically contain the nitroimine
group - thiamethoxam, clothianidin and dinotefuran - have a significantly higher
affinity for the insect target site.51 Of this subgroup, imidacloprid has the lowest rat
LD50 and by far the highest market share. Thiamethoxam on the other hand, while
having a high LD50, has a much lower NOAEL than imidacloprid and is considered a
likely human carcinogen.50
90
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Mammalian toxicity is thought to be centrally mediated. Toxic effects are similar
to that of nicotine. Vertebrate alpha-4-Beta-2 nAChRs are the primary target. Prolonged
or chronic exposures will up-regulate the receptors without changing receptor affinity.
Perhaps most notably, the neonicotinoids also have some responses outside the target
nAChRs. Following binding to the nAChR, the protein kinase cascade may be acti-
vated, which could decrease neurologic functions. Some also have an analgesic effect
similar to that of nicotine.50
In vitro studies of human intestinal cells find that imidacloprid is well absorbed.
These pesticides are relatively highly soluble in water, and most are excreted unchanged
by the kidney. Most do undergo significant metabolism in insects, and the same occurs
in mammals. However, the process in mammals is slow and likely an insignificant part
of their elimination process in humans. One notable metabolic process of imidacloprid
is reduction by the P450 system in humans to a nitroso derivative. In animal studies
conducted in mice this metabolic byproduct enters the brain.52 It is not known whether
this byproduct or the active ingredient may be responsible for toxic effects.50
Signs and Symptoms of Poisoning
Human data are currently limited to several reports of clinical poisoning, at least
some of which have led to death, as confirmed by autopsy.53'54'55'56 Toxic effects bear
some resemblance to those of acute nicotine poisoning except for GI corrosive inju-
ries, which may be related to solvent effects.52 Human poisoning appears most likely
following ingestion or inhalation. Most clinical effects are based on excessive nico-
tinic stimulation. Patients have presented with disorientation, confusion and agitation
- severe enough to require sedation - headache, drowsiness, dizziness, weakness.
tremor and, in some situations, loss of consciousness.53'54'55 No seizures have been
reported, and chronic residual neuropsychiatric effects have not been studied.
In a series of 68 patients, gastrointestinal effects following oral ingestion of an
imidacloprid formulation were the most commonly reported and included vomiting.
sore throat, nausea, diarrhea and abdominal pain.57 Following ingestion, ulceration
was noted in the posterior pharynx, esophagus and stomach. It was not clear if the
effects were due to the toxicity of the active ingredient or the accompanying solvent.
There is evidence that a solvent found in some formulations, N-methyl pyrrolide
(NMP), has a severe irritant effect.56 This emphasizes the importance of identifying
and understanding the effects of inert ingredients in any pesticide exposure. Unfortu-
nately, identification of such ingredients is usually difficult as they are not disclosed on
the label and it is necessary to contact the formulator directly to determine which inert
ingredients are in the formulation.
Toxicity to the respiratory system can also occur. Signs and symptoms include
labored breathing, chest tightness, dyspnea, hypoxia and aspiration pneumonia. In
severe cases, respiratory failure has ensued, requiring mechanical ventilation.57'58'59
Rhabdomyolysis may occur in severe poisoning; with creatine phosphokinase
levels being reported as high as 1,200 U/L. Renal function and serum electrolytes
were normal in this case. Patients will usually present with tachycardia due to nicotinic
receptor over-stimulation of the autonomic nervous system.53
Cardiovascular effects include tachycardia, bradycardia, hypertension, hypo-
tension and palpitations.55 One case of fatal arrhythmia has been reported in which
the patient presented within hours of ingesting 200 mL of imidacloprid. She initially
had sinus tachycardia that rapidly progressed to ventricular tachycardia and subse-
quently ventricular fibrillation. At the time of presentation, this patient was noted to
have a normal cardiac enzyme panel. Primary coronary artery disease could not be
completely ruled out because of several coronary risk factors.55
CHAPTER 9
Other Insecticides
and Acaricides
Neonicotinoids
COMMERCIAL
PRODUCTS
acetamiprid
clothianidin
dinotefuran
imidacloprid
(brand names include,
but are not limited to
Merit, Admire, Provado,
Gaucho, Imicide, Premise,
Advantage),
thiacloprid
thiamethoxam
91
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CHAPTER 9
Other Insecticides
andAcaricides Confirmation of Poisoning
Imidacloprid can be detected by liquid chromatography/mass spectroscopy, which was
used to identify the cause of death in two patients found dead with no obvious initial
cause.60 However, the test is not widely available, and there are insufficient data on
toxic levels to predict severity of toxicity.
Treatment
1. Provide supportive treatment, as there is no specific antidote for neonicotinoid
poisoning. Patients with significant mental status changes should ideally be
managed in the intensive care setting, at least initially.
2. Use GI decontamination within the guidelines previously outlined in Chapter 3,
General Principles.
3. Control extreme agitation with lorazepam or propofol.
4. Consider cardiac monitoring, especially in patients with risk factors for coronary
artery disease.
5. In a severe poisoning, send patient to an intensive care setting for respiratory
support.
PROPARGITE
Formulations are wettable powders and emulsifiable concentrates. Propargite is an
acaricide with residual action.
Toxicology
Propargite exhibits very little systemic toxicity in animals. No systemic poisonings
have been reported in humans. However, many workers having dermal contact with this
acaricide, especially during the summer months, have experienced skin irritation and
some have had documented positive skin testing.61'62 Eye irritation has also occurred.61
For this reason, stringent measures should be taken to prevent inhalation or any skin or
eye contamination by propargite. Epidemiological studies have related this pesticide to
an increased risk for cancer.63'64 This is discussed in Chapter 21, Chronic Effects.
Confirmation of Poisoning
There is no readily available method for detecting absorption of propargite.
Treatment
1. Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Treat eye contamination by irrigating exposed eyes with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses, if
present, prior to irrigation. If irritation persists after irrigation, specialized medical
treatment in a healthcare facility should be obtained. Sensitization reactions may
require steroid therapy.
2. If large amounts of propargite have been ingested and the patient is seen within an
hour, consider gastrointestinal decontamination as discussed in Chapter 3.
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SULFUR
Elemental sulfur is an acaricide and fungicide widely used on orchard, ornamental.
vineyard, vegetable, grain and other crops. It is prepared as dust in various particle
sizes and applied as such, or formulated with various minerals to improve flowability
or applied as an aqueous emulsion or wettable powder.
Toxicology
Elemental sulfur is moderately irritating to the skin and is associated with occu-
pationally related irritant dermatitis.68 Airborne dust is irritating to the eyes and the
respiratory tract. In hot, sunny environments, there may be some oxidation of foliage-
deposited sulfur to gaseous sulfur oxides, which are very irritating to the eyes and
respiratory tract. Ingested sulfur powder induces catharsis and has been used medici-
nally (usually with molasses) for that purpose. Some hydrogen sulfide is formed in the
large intestine and this may present a degree of toxic hazard; the characteristic smell of
rotten eggs may aid in the diagnosis. An adult has survived ingestion of 200 grams.69
Ingested colloidal sulfur is efficiently absorbed by the gut and is promptly
excreted in the urine as inorganic sulfate.
Treatment
1. Remove skin contamination by washing with soap and water as outlined in
Chapter 3, General Principles. Treat contamination of the eyes by irrigating
exposed eyes with clean saline or water for at least 15 minutes. If present, remove
contact lenses prior to irrigation. If eye irritation persists after irrigation, obtain
specialized treatment in a healthcare facility.
2. Unless an extraordinary amount of sulfur (several grams) has been ingested
shortly prior to treatment, there is probably no need for gastrointestinal decon-
tamination. Absorbability of sulfur on activated charcoal has not been tested.
3. Administer oral or intravenous glucose and/or electrolyte solutions as appropriate
if diarrhea is severe. The most serious consequence of sulfur ingestion is likely to
be that of catharsis, resulting in dehydration and electrolyte depletion, particularly
in children.
CHAPTER 9
Other Insecticides
and Acaricides
Sulfur
COMMERCIAL
PRODUCTS
Many commercial products
are produced by many
manufacturers. It is one of
the agents approved by
USDA for use by organic
growers,
HIGHLIGHTS
Widely used organic
acaricide/fungicide
SIGNS & SYMPTOMS
Skin/eye/respiratory irritant
TREATMENT
Decontaminate skin and
eyes
Oral or IV glucose/
electrolytes if diarrhea is
severe
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Section III
HERBICIDES
Chlorophenoxy Herbicides 98
Pentachlorophenol and Dinitrophenolic Pesticides 103
Paraquat and Diquat 110
Other Herbicides 118
-------
HIGHLIGHTS
CHAPTER 10
Hundreds of products
Names can confuse; check
label for composition
Sometimes mixed with
fertilizers
Irritate skin, eyes,
respiratory & Gl systems
Severe metabolic acidosis
from ingesting large
amounts
SIGNS & SYMPTOMS
Vomiting, diarrhea
Headache, confusion,
bizarre or aggressive
behavior
Peculiar odor on breath
Body temperature may be
elevated
Muscle weakness,
peripheral neuropathy, loss
of reflexes
TREATMENT
Decontaminate skin, hair,
eyes
Consider Gl
decontamination
IV fluids
Consider urine alkalinization
Chlorophenoxy Herbicides
Several hundred commercial products contain chlorophenoxy herbicides in various
forms, concentrations and combinations. In some cases, the same name is used for
products with different ingredients. The exact composition must therefore be deter-
mined from the product label. Chlorophenoxy compounds are sometimes mixed into
commercial fertilizers to control growth of broadleaf weeds. Sodium, potassium and
alkylamine salts are commonly formulated as aqueous solutions, while the less water-
soluble esters are applied as emulsions. Low molecular weight esters are more volatile
than the acids, salts or long-chain esters.
Toxicology
Some of the chlorophenoxy acids, salts and esters are moderately irritating to skin.
eyes and respiratory and gastrointestinal linings. In a few individuals, local cutaneous
depigmentation has apparently resulted from protracted dermal contact with chloro-
phenoxy compounds.1
The chlorophenoxy compounds are well absorbed from the gastrointestinal
tract.2 They are less well absorbed from the lung. Cutaneous absorption appears to
be minimal.3 They are not significantly stored in fat. Excretion occurs almost entirely
by way of urine. Apart from some conjugation of the acids, there is limited biotrans-
formation in the body.2'3 The compounds are highly protein bound.3 Under normal
conditions, the average half-life of 2,4-D in humans is between 13 and 39 hours,2'4'6
that of 2,4,5-T about 24 hours7 and that of MCPP about 17 hours.8 However, half-life
varies markedly with urinary pH, with excretion being greatly enhanced in an alkaline
urine,4'6'9 and with a half-life as prolonged as 70-90 hours with acidic urine.9 Half-life
is also longer with large doses and prolonged exposure.
A unique finding in a recent study is that chlorophenoxy herbicides, particularly
2,4-DP, 2,4-D and MCPP, inhibit the human taste receptor for sweets. Interestingly.
this was not found in animal studies. While not necessarily a toxic effect, this finding
could potentially be of use in diagnosing a poisoning from one of these herbicides.10
Ingestion of large amounts of chlorophenoxy acids has resulted in severe meta-
bolic acidosis in humans. Such cases have been associated with electrocardiographic
changes, myotonia, muscle weakness, myoglobinuria and elevated serum creatine
phosphokinase, all reflecting injury to striated muscle. The medical literature contains
afew reports of peripheral neuropathy, some following dermal exposures to 2,4-D11'12'13
and another following ingestion.14 Chlorophenoxy acids are weak uncouplers of oxida-
tive phosphorylation; therefore, extraordinary doses may produce hyperthermia from
increased production of body heat.6
In the manufacture of some of these herbicides, other more toxic substances canbe
formed at excessive temperatures. These include chlorinated dibenzo dioxin (CDD)
and chlorinated dibenzo furan (CDF). The 2,3,7,8-tetra CDD form is extraordinarily
toxic to multiple mammalian tissues; it is formed only in the synthesis of 2,4,5-T.
However, 2,3,7,8 tetra CDD has been found as a contaminant in samples of 2,4-D.
2,4-DB and MCPA.15 These byproducts are discussed in Chapter 21, Chronic Effects.
Chloracne (a chronic, disfiguring skin condition) has been seen in workers engaged in
98
-------
the manufacture of 2,4,5-T and certain other chlorinated organic compounds, although
it is thought to be related to the resulting 2,3,7,8-tetra CDD exposure as opposed to
acute 2,4-D or 2,4,5-T toxicity. Although chloracne along with other dermal effects
has been reported in an herbicide applicator,16 it has not been reported in other occupa-
tional exposures except the manufacture of these agents.
Signs and Symptoms of Poisoning
Human poisoning from chlorophenoxy compounds was reviewed in detail in 2000.17
In a large case series resulting from intentional serf-poisoning from MCPA, most
patients (85%) had minimal signs of poisoning, with mild gastrointestinal symptoms
being the most commonly reported.18 Other non-specific, mild findings from the Cali-
fornia pesticide illness surveillance system include nausea, abdominal pain, headache.
generalized weakness and dizziness.19
Manifestations of systemic toxicity of chlorophenoxy compounds are known
mainly from clinical experience with cases of deliberate suicidal ingestion of large
quantities. While most clinical reports involve exposure to 2,4-D and mecoprop, it
is reasonable to assume that all chlorophenoxy herbicides will share a similar clin-
ical picture. Most reports of fatal outcomes involve renal failure, acidosis, electrolyte
imbalance and a resultant multiple organ failure.5'9'20 The agents most often involved
in these incidents have been 2,4-D and mecoprop.
Patients will present within a few hours of ingestion with vomiting, diarrhea.
headache, confusion and bizarre or aggressive behavior. In a large case series resulting
from intentional self-poisoning from MCPA, most patients (85%) had minimal signs of
poisoning, with mild gastrointestinal symptoms being the most commonly reported.18
Mental status changes occur, with progression to coma in severe cases.4'6'9'18 Moderate
cerebral edema has also been reported following intentional ingestion.21 A peculiar
odor is often noticed on the breath. Body temperature may be moderately elevated.
but this is rarely a life-threatening feature of the poisoning. The respiratory drive is
not depressed. Conversely, hyperventilation is sometimes evident, probably secondary
to the metabolic acidosis that occurs. Convulsions occur very rarely. With effective
urinary excretion of the toxicant, consciousness usually returns in 48-96 hours.4'6'9
Muscle weakness and peripheral neuropathy have been reported after occupa-
tional exposure.9 The presentations are variable. Myotonia and muscle weakness may
persist for months after acute poisoning.6 Additional findings include loss of reflexes
and fasciculation.4 6'8'20 Electromyography and nerve conduction studies in some recov-
ering patients have demonstrated a mild proximal neuropathy and myopathy.
As mentioned above, there are significant metabolic changes from the chlorophe-
noxy compounds. Metabolic acidosis is manifest as a low arterial pH and bicarbonate
content. The urine is usually acidic. Skeletal muscle injury, if it occurs, is reflected in
elevated creatine phosphokinase and, sometimes, myoglobinuria. Moderate elevations
of blood urea nitrogen and serum creatinine are commonly found as the toxicant is
excreted. Cases of renal failure are reported, often with an accompanying hyperka-
lemia or hypocalcemia, and were thought to result in the cardiovascular instability
that led to death.5'20 Tachycardia is commonly observed and hypotension has also
been reported.4'5'9 T-wave flattening has also been observed.6 Mild leukocytosis and
biochemical changes indicative of liver cell injury have been reported.
CHAPTER 10
Chlorophenoxy Herbicides
COMMERCIAL
PRODUCTS
2,4-D or
2,4-dichlorophenoxyacetic
acid
2,4-DPor
2,4-dichlorophenoxypropionic
acid (Dichlorprop)
2,4-DB, or
2,4-dichlorophenoxybutyric
acid
2,4,5-T, or
2,4,5-trichlorophenoxy acid
4-chloro-2-methyl-
phenoxyacetic acid (MCPA)
MCPB
MCPP (Mecoprop)
2-methyl-3, 6 dichlorobenzoic
acid (Dicamba)
99
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CHAPTER 10
Chlorophenoxy Herbicides
Confirmation of Poisoning
Gas-liquid chromatographic methods are available for detecting chlorophenoxy
compounds in blood and urine. These analyses are useful in confirming and assessing
the magnitude of chlorophenoxy absorption. Poisoning episodes characterized by
unconsciousness have shown initial blood chlorophenoxy concentrations ranging
from 80 to more than 1,000 mg per liter.4 Urine samples should be collected as soon
as possible after exposure because the herbicides may be almost completely excreted
in 24-72 hours in most cases. Urine samples can also confirm overexposure. In a
study of asymptomatic herbicide applicators, their urinary excretion of chlorophenoxy
compounds rarely exceeded 1-2 mg/L.22 The half-life may be much longer in cases
of intoxication depending on the extent of absorption and urine pH. Analyses can be
performed at competent laboratories, usually known to local poison control centers. If
the clinical scenario indicates that excessive exposure to chlorophenoxy compounds
has occurred, initiate appropriate treatment measures immediately, not waiting for
chemical confirmation of toxicant absorption.
Treatment of Chlorophenoxy Toxicosis
1. Decontaminate skin and hair by bathing with soap and water and shampooing.
Individuals with chronic skin disease or known sensitivity to these herbicides
should either avoid using them or take strict precautions to avoid contact (respi-
rator, gloves, etc.).
2. Flush contaminating chemicals from eyes with copious amounts of clean water
for 10-15 minutes. If irritation persists, an ophthalmologic examination should be
performed.
3. If any symptoms of illness occur during or following inhalation of spray, remove
victim from contact with the material for at least 2-3 days. Allow subsequent
contact with chlorophenoxy compounds only if effective respiratory protection
is practiced.
4. Consider gastric decontamination procedures as outlined in Chapter 3, General
Principles. If substantial amounts of chlorophenoxy compounds have been
ingested, spontaneous emesis may occur.
5. Administer intravenous fluids to accelerate excretion of the chlorophenoxy
compound and to limit concentration of the toxicant in the kidney. A urine flow
of 4-6 mL/minute is desirable. Intravenous saline/dextrose has sufficed to rescue
comatose patients who drank 2,4-D and mecoprop several hours before hospital
admission.
CAUTION: Monitor urine protein and cells, BUN, serum creatinine, serum
electrolytes and fluid intake/output carefully to ensure that renal function
remains unimpaired and that fluid overload does not occur.
6. Alkalinize the urine to maintain a pH between 7.6 and 8.8. Urinary alkaliniza-
tion has been used successfully in management of suicidal ingestions of chlo-
rophenoxy compounds, especially when initiated early.4'6'9 Although the term
"forced alkaline diuresis" has been used previously to describe this treatment, the
preferred terminology is now "urinary alkalinization" to emphasize the impor-
100
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CHAPTER 10
Chlorophenoxy Herbicides
tance of urine pH manipulation for clearing the weak acid.23 Alkalinizing the urine
by including sodium bicarbonate (44-88 mEq per liter) in the intravenous solution
accelerates excretion of 2,4-D and mecoprop excretion substantially, because the
weak acid is in an ionized state in the renal tubule and thus cannot diffuse back
across the tubule into the blood. Renal clearance is minimal at an acidic pH of 5.1
(0.14 mL/min) compared to clearance at a pH of 8.3 (63 mL/min).6'23
Controversy and lack of controlled clinical studies exist surrounding the
most effective way to induce clearance of 2,4-D and mecoprop. The AACT and
EAPCCT position paper recommends that urine alkalinization and high urine
flow (forced diuresis) be considered.23 A Cochrane Database of Systemic Reviews
notes the lack of evidence, based on the lack of randomized, controlled trials
for this treatment. The author concluded that it is "not unreasonable to attempt
urinary alkalinization" given the prolonged toxicity and potential for death, and
that, "well conducted randomized, controlled trials are required."24 No patients
in a large case series reported by the same author as the Cochrane Review article
were treated with urinary alkalinization, although it should be noted that 85%
showed signs of minimal toxicity.18
7. Include potassium chloride as needed to offset increased potassium losses, with
20-40 mEq of potassium chloride to each liter of intravenous solution. High urine
flow, approximately 200 mL/h, improves clearance, although an even higher flow
rate may be required for maximal 2,4-D clearance.6'23 Renal failure has occurred
in patients with severe intoxication despite urinary alkalinization. In one case of
renal failure, the urinary alkalinization was begun 26 hours after ingestion,9 and in
another it was initiated on day 2 of the hospitalization.20 Therefore, it is crucial to
carefully monitor renal function, as well as serum electrolytes, especially potas-
sium and calcium.
8. Consider hemodialysis in severe cases, particularly where excess fluid adminis-
tration is not advised."Hemodialysis has been used in four patients who survived
intoxication.25 It is not recommended as first-line therapy.
9. Include electromyography and nerve conduction studies in the follow-up clin-
ical examination to detect any neuropathic changes and neuromuscular junction
defects.
References
1. Garry VF, Tarone RE, Kirsch IR, et al. Biomarker correlations of urinary 2,4-D levels
in foresters: genomic instability and endocrine disruption. Environ Health Perspect. May
2001;109(5):495-500.
2. Kohli JD, Khanna RN, Gupta BN, Dhar MM, Tandon JS, Sircar KP. Absorption and excre-
tion of 2,4-dichlorophenoxyacetic acid in man. Xenobiotica. 1974;4(2):97-100.
3. Arnold EK, Beasley VR. The pharmacokinetics of chlorinated phenoxy acid herbicides: a
literature review. Vet Hum Toxicol. Apr 1989;31(2): 121-125.
4. Friesen EG, Jones GR, Vaughan D. Clinical presentation and management of acute 2,4-D
oral ingestion. Drug Saf. Mar-Apr 1990;5(2): 155-159.
5. Keller T, Skopp G, Wu M, Aderjan R. Fatal overdose of 2,4-dichlorophenoxyacetic acid
(2,4-D). Forensic Sci Int. Mar 1994;65(1):13-18.
6. Prescott LF, Park J, Darrien I. Treatment of severe 2,4-D and mecoprop intoxication with
alkaline diuresis. Br J Clin Pharmacol. Jan 1979;7(1):111-116.
101
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CHAPTER 10
Chlorophenoxy Herbicides
7. Gehring PJ, Kramer CG, Schwetz BA, Rose JQ, Rowe VK. The fate of 2,4,5-trichloro-
phenoxyacetic acid (2,4,5-T) following oral administration to man. Toxicol Appl Phar-
macol. Nov 1973;26(3):352-361.
8. Meulenbelt J, Zwaveling JH, van Zoonen P, Notermans NC. Acute MCPP intoxication:
report of two cases. Hum Toxicol. May 1988;7(3):289-292.
9. Flanagan RJ, Meredith TJ, Ruprah M, Onyon LJ, Liddle A. Alkaline diuresis for acute
poisoning with chlorophenoxy herbicides and ioxynil. Lancet. Feb 24 1990;335(8687):454-
458.
10. Maillet EL, Margolskee RF, Mosinger B. Phenoxy herbicides and fibrates potently inhibit
the human chemosensory receptor subunit T1R3. JMed Chem. Nov 12 2009;52(21):6931-
6935.
11. Berkley MC, Magee KR. Neuropathy following exposure to a dimethylamine salt of 2.
4-D. Arch InternMed. Mar 1963;lll:351-352.
12. Berwick P. 2,4-dichlorophenoxyacetic acid poisoning in man. Some interesting clinical
and laboratory findings. JAMA. Nov 9 1970;214(6):1114-1117.
13. Goldstein NP, Jones PH, Brown JR. Peripheral neuropathy after exposure to an ester of
dichlorophenoxyacetic acid. J Am Med Assoc. Nov 7 1959;171:1306-1309.
14. O'Reilly JF. Prolonged coma and delayed peripheral neuropathy after ingestion of phen-
oxyacetic acid weedkillers. Postgrad Med Journal. 1984;60:76-77.
15. Holt E, Weber R, Stevenson G, Gaus C. Poly chlorinated Dibenzo-p-Dioxins and Diben-
zofurans (PCDD/Fs) Impurities in Pesticides: A Neglected Source of Contemporary Rele-
vance. Environ Sci Technol. Jul 15 2010;44(14):5409-5415.
16. Poskitt LB, Duffill MB, Rademaker M. Chloracne, palmoplantar keratoderma and local-
ized scleroderma in a weed sprayer. Clin Exp Dermatol. May 1994; 19(3):264-267.
17. Bradberry SM, Watt BE, Proudfoot AT, Vale JA. Mechanisms of toxicity, clinical features,
and management of acute chlorophenoxy herbicide poisoning: a review. J Toxicol Clin
Toxicol. 2000;38(2):111-122.
18. Roberts DM, Seneviratne R, Mohammed F, et al. Intentional self-poisoning with the chlo-
rophenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA). Ann EmergMed. Sep
2005;46(3):275-284.
19. Regulation CDoP California Pesticide Illness Query (CalPIQ) August 9, 2010 2009.
20. Kancir CB, Andersen C, Olesen AS. Marked hypocalcemia in a fatal poisoning with chlo-
rinated phenoxy acid derivatives. J Toxicol Clin Toxicol. 1988;26(3-4):257-264.
21. Brahmi N, Mokhtar HE, Thabet H, Bouselmi K, Amamou M. 2,4-D (chlorophenoxy)
herbicide poisoning. Vet Hum Toxicol. Dec 2003;45(6):321-322.
22. Kolmodin-Hedman B, Hoglund S, Akerblom M. Studies on phenoxy acid herbicides.
I. Field study. Occupational exposure to phenoxy acid herbicides (MCPA, dichlorprop,
mecoprop and 2,4-D) in agriculture. Arch Toxicol. Dec 1983;54(4):257-265.
23. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin
Toxicol. 2004;42(l):l-26.
24. Roberts DM, Heilmair R, Buckley NA, et al. Clinical outcomes and kinetics of propanil
following acute self-poisoning: a prospective case series. BMC Clin Pharmacol. 2009;9:3.
25. Durakovic Z, Durakovic A, Durakovic S, Ivanovic D. Poisoning with 2,4-dichlorophen-
oxyacetic acid treated by hemodialysis. Arch Toxicol. 1992;66(7): 518-521.
102
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CHAPTER 11
Pentachlorophenol and
Dinitrophenolic Pesticides
PENTACHLOROPHENOL
Pentachlorophenol (PCP) is presently registered in the United States only as a restricted
use pesticide for use as a "heavy duty" wood preservative. It is registered only for use
in pressure treatment of utility poles. Heavy duty wood preservatives are defined as
those that are applied by pressure treatment rather than by brushing or other surface
applications. PCP is a general biocide that has been used as an herbicide, algaecide.
defoliant, wood preservative, germicide, fungicide and molluscicide.1 As a function
of the manufacturing process, PCP is contaminated with chlorinated dibenzodioxans
(CDDs), chlorinated dibenzofurans (CDFs) and hexachlorobenzene (HCB). These
contaminants are toxic and persistent, but their levels in PCP preparations are usually
low enough to limit the concern to chronic rather than acute effects. Technical PCP
also contains lower chlorinated phenols (4%-12%). Incomplete combustion of PCP -
treated wood may lead to further formation of these contaminant compounds.
Pentachlorophenol volatilizes from treated wood. It has a significant phenolic
odor, which becomes quite strong when the material is heated. Though not registered
for indoor use, heavily treated interior surfaces may be a source of exposure sufficient
to cause irritation of eyes, nose and throat.
Pentachlorophenol
HIGHLIGHTS
Limited use in pressure-
treated utility poles
Volatilizes from treated wood
Skin, lung, Gl absorption
Low urinary clearance
Distributes to kidney, liver,
heart, adrenals
Prenatal implications
SIGNS & SYMPTOMS
Mucosal membrane irritation
Fatigue, headache, lack of
concentration
Contact dermatitis,
chloracne
Wide variety of non-specific
symptoms
Tachycardia, increased
respiratory rate typical in
serious poisonings
Toxicology
Pentachlorophenol (PCP) is readily absorbed across the skin, the lungs and the lining
of the gastrointestinal tract. USEPA data submitted in support of reregistration of PCP
report a dermal LD50 >3,980 mg/kg, suggesting very low dermal toxicity. In animals.
the dermal LD50 has been reported as the same order of magnitude as the oral.2 With
acute exposure it is rapidly excreted, mainly in the urine as unchanged PCP and as PCP
glucuronide. In chronic exposures as well as a volunteer study, the elimination half-life
has been reported to be very prolonged, up to 20 days. The long half-life was attributed
to the low urinary clearance because of high protein binding.3 It is widely distributed
to other tissues in the body, including kidney, liver, heart and adrenal glands.
The primary acute lexicological mechanism appears to be increased cellular
oxidative metabolism resulting from the uncoupling of oxidative phosphorylation.1'4
Heat production is increased and leads to clinical hyperthermia with profuse sweating
and electrolyte disturbances. This clinical state may mimic the signs and symptoms of
hyperthyroidism. Large doses are toxic to the liver, kidneys and nervous system. Due
to depletion of ATP, severe rhabdomyolysis may occur. Numerous additional mecha-
nisms may contribute to chronic toxicity
Based on laboratory experimentation in animals, PCP has been reported to have
fetotoxic and embryotoxic properties and to bind to various hormone receptors.5'6
Epidemiologic evidence suggests exposed women may be at risk for miscarriages, and
maternal or paternal exposure can increase risk for reduced birth weight and infant
malformations.7'8
Pentachlorophenol
& Dinotrophenolic
Pesticides
TREATMENT
Control hyperthermia
Support oxygen, fluids
Stabilize electrolytes
Decontaminate skin, eyes
Consider ICU management
103
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CHAPTER 11
Pentachlorophenol and
Dinitrophenolic Pesticides
Pentachlorophenol
COMMERCIAL
PRODUCTS
chlorophen
PCP
penchlorol
penta
pentacon
penwar
sinituho
The sodium salt is sodium
pentachlorophenate
Albuminuria, glycosuria, aminoaciduria and elevated BUN reflect renal injury.
Liver enlargement, anemia and leucopenia have been reported in some intensively
exposed workers. Elevated serum alkaline phosphatase, AST and LDH enzymes indi-
cate significant insult to the liver, including both cellular damage and some degree of
biliary obstruction.
Signs and Symptoms of Poisoning
The most common effects of airborne PCP include mucosal membrane irritation of
the eyes, nose and throat, producing conjunctivitis, rhinitis and pharyngitis.9'11 Addi-
tional common features include fatigue, lack of concentration and headache.10'11'12 In
adequate concentration, PCP is irritating to skin. Effects include irritation, contact
dermatitis or, more rarely, diffuse urticaria or chloracne.11'13'14 Contact dermatitis is
common among workers having contact with PCP. In a study of employees involved
in the manufacture of PCP, chloracne was found in 7% of the workers, and the risk
was significantly higher among employees with documented skin contact compared
to employees without skin contact.14 Urticaria has also been reported as an uncommon
response in exposed persons. Individual cases of exfoliative dermatitis of the hands
and diffuse urticaria and angioedema of the hands have been reported in intensively
exposed workers. Several infant deaths occurred in a nursery where a PCP-containing
diaper rinse had been used.15 Severe poisoning and death have occurred as a result of
intensive PCP exposure.10'16'17
Acute poisoning occurs with systemic absorption that can occur by any route
of sufficient dosage, although most occupational poisonings occur through dermal
contact.16'17 Most of the signs and symptoms of PCP are non-specific and, therefore.
the diagnosis can be difficult. Symptoms include abdominal pain, anorexia, intense
thirst, dizziness, restlessness and altered mental status. Workers exposed over long
periods may experience weight loss. Serious poisoning may be manifested by hyper-
thermia, muscle spasm, tremor, respiratory distress, chest tightness and altered mental
status, including lethargy and coma.1'10'16'17 Tachycardia and increased respiratory
rate are usually apparent. Most adult fatalities have occurred in persons working in
hot environments where hyperthermia is poorly tolerated. In severe poisonings that
have resulted in death, severe hyperthermia with temperatures up to 108°F has been
reported.16 Multiorgan system failure (seizures and coma, hepatic necrosis, renal
failure, cardiovascular collapse and rhabdomyolysis) are often contributing factors in
fatal outcomes.15'16
PCP has been classified as B2 (probable human carcinogen). Cases of aplastic
anemia and leukemia have been reported that were associated temporally with PCP
exposure. Causal relationships in these cases were not established.18 For more infor-
mation, see the cancer section in Chapter 21, Chronic Effects.
Peripheral neuropathies have also been reported in some cases of long-term
occupational exposure; however, a causal relationship has not been supported by
longitudinal studies.19 Studies of health effects in a community where a wood treat-
ment plant is located have suggested an association with long-term adverse health
effects. Residents in the community had a higher prevalence of cancer, respiratory
disease and neurological disorders than those in the control group. It is unclear from
the study, however, whether PCP or creosote, another wood preservative (see Chapter
19, Miscellaneous Pesticides, Solvents and Adjuvants), was the primary pesticide of
concern.20
104
-------
Confirmation of Poisoning
CAUTION: If poisoning is suspected on the basis of exposure, symptoms
and signs, do not postpone treatment until diagnosis is confirmed.
PCP can be measured in plasma, urine and adipose tissue by gas-liquid chromatog-
raphy. Plasma levels can be much higher than urine levels (ratio of blood to urine
is 1.0 to 2.5), so care must be taken to interpret results.1921 There is no clear-cut
determination of what constitutes an abnormally high level of PCP, and there is great
variability among different references. Most information on the extent of serum
levels in relation to toxicity is based on individual cases or small series of patients.
Reports exist of asymptomatic infants with serum levels as high as 26 parts per million
(ppm);15'21 however, most other reports of non-occupational exposure in the general
public have levels in the parts per billion range.1'22'23'24 Food is probably the main
source of this nanogram-level dosage.1 Serum levels among occupationally exposed
persons often exceed 1 ppm.1 A report of a lethal case describes a plasma level of
16 ppm,17 but most cases generally involve serum levels in the range of 100 ppm or
higher.16 It is reasonable to assume that levels greater than 1 ppm are consistent with
an unusual exposure and that levels approaching 100 ppm are cause for great concern.
DINOTROPHENOLIC PESTICIDES
Dinitrophenolic pesticides have many uses in agriculture worldwide: herbicides (weed
killing and defoliation), acaricides, nematocides, ovicides and fungicides. Relatively
insoluble in water, most technical products are dissolved in organic solvents and
are formulated for spray application as emulsions. There are some wettable powder
formulations. Only dinocap is currently registered in the United States.
Toxicology
Nitroaromatic compounds are highly toxic to humans and animals with LD50s in the
range of 25 to 50 mg/kg.25 Most dinitrophenols are well absorbed from the gastroin-
testinal tract, across the skin and by the lung when fine droplets are inhaled.26
Dinitrophenols undergo some biotransformation in humans, chiefly reduction
(one nitro group to an amino group) and conjugation at the phenolic site. Although
dinitrophenols and metabolites appear consistently in the urine of poisoned indi-
viduals, hepatic excretion is probably the main route of disposition. Elimination is
slow, with a documented half-life in humans between 5-14 days.25 Blood and tissue
concentrations tend to increase progressively if an individual is substantially exposed
on successive days.
The basic mechanism of toxicity is stimulation of oxidative metabolism in cell
mitochondria, by the uncoupling of oxidative phosphorylation. This leads to hyper-
thermia, tachycardia, headache, malaise and dehydration and, in time, depletes carbo-
hydrate and fat stores. The major systems prone to toxicity are the hepatic, renal and
nervous systems. The dinitrophenols are more active as uncouplers than chlorophenols
such as pentachlorophenol. Hyperthermia and direct toxicity to the central nervous
system cause restlessness and headache and, in severe cases, seizures, coma and cere-
bral edema. The higher the ambient temperature, such as in an agriculture environ-
ment, the more difficult it is to dissipate the heat.25'26 Liver parenchyma and renal
tubules show degenerative changes. Albuminuria, pyuria, hematuria and azotemia are
signs of renal injury.
CHAPTER 11
Pentachlorophenol and
Dinitrophenolic Pesticides
Dinotrophenolic
Pesticides
HIGHLIGHTS
Only dinocap currently
registered in U.S.
Absorbed from Gl, skin, lung
Hepatic excretion with 5 to
14-day half-life
SIGNS & SYMPTOMS
Non-specific and may
include
Sweating
Thirst
Fever
Headache
Confusion
Malaise
Restlessness
Serious poisoning
Hyperthermia
Tachycardia
Tachypnea
Renal failure
Bright yellow staining of
skin, hair
TREATMENT
Same as Pentachlorophenol
CONTRAINDICATED
Antipyretic therapy with
salicylates
Atropine
105
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CHAPTER 11
Pentachlorophenol and
Dinitrophenolic Pesticides
Dinotrophenolic
Pesticides
COMMERCIAL
PRODUCTS
While there are many
dinitrophenolic pesticides,
dinocap is the only one that
is still actively registered in
the United States,
Other products (no longer
registered in the United
States) included:
SDinitrophenol (Chemox
PE)
dinitrocresol (DNOC, DNC,
Chemsect DNOC, Elgetol
30, Nitrador, Selinon, Sinox,
Trifocide)
dinobuton (Acrex, Dessin,
Dinofen, Drawinol, Talan)
dinopenton
dinoprop (Crotothane,
Karathane)
dinosam (DNAP, Chemox
General),
dinoseb (DNBP, dinitro,
Basanite, Caldon, Chemox
General, Chemox PE,
Chemsect DNBP, Dinitro,
Dinitro-3, Dinitro General
Dynamyte, Elgetol 318,
Gebutox, Hel-Fire, Kiloseb,
Nitropone C, Premerge,
Snox General, Subitex,
Unicrop DNBP, Vertac,
Dinitro Weed Killer 5, Vertac
General Weed Killer, Vertac
Selective Weed Killer)
dinoseb acetate (Aretit)
continued next page
106
Cataracts occur in laboratory animals given dinitrophenols and have occurred in
humans, both as a result of ill-advised medicinal use and as a consequence of chronic
occupational exposure.27 Cataract formation is sometimes accompanied by glaucoma.
Signs and Symptoms of Poisoning
Most patients present within a few hours of exposure with generalized non-specific
signs and symptoms including profuse sweating, thirst, fever, headache, confusion.
malaise and restlessness. The skin may appear warm and flushed as hyperthermia
develops, along with tachycardia and tachypnea, all of which indicate a serious degree
of poisoning. Apprehension, anxiety, manic behavior, seizures and coma reflect cere-
bral injury, with the latter two signifying an immediately life-threatening intoxication.
Respiratory distress and cyanosis are consequences of the stimulated metabolism and
tissue anoxia. Renal failure may occur early in cases of severe exposure. Liver damage
is first manifested by jaundice, and cell death can occur within 48 hours and is dose
dependent.28 Death may occur within 24 to 48 hours after exposure in cases of severe
poisoning.26 In cases of survival of severe poisoning, complete resolution of symptoms
may be slow due to the toxicant's long half-life.26'29
A characteristic bright yellow staining of skin and hair is often present with
topical exposure and can be an important diagnostic clue to the clinician.25'26'29 Yellow
staining of the sclerae and urine indicate absorption of potentially toxic amounts.
Weight loss occurs in persons continually exposed to relatively low doses of dinitro-
phenols.25'27
Confirmation of Poisoning
If poisoning is probable, do not await confirmation before commencing treatment, but
save urine and blood specimens on ice at a temperature below 20°C in the event confir-
mation is necessary later. Unmetabolized dinitrophenols can be identified spectropho-
tometrically, or by gas-liquid chromatography, in the serum at concentrations well
below those that have been associated with acute poisonings. The data on exposure
and systemic levels of compounds in this group are limited and most reports specify
the compound dinitro-ortho-cresol. In general, blood levels of 10 ug/dL or greater are
usually seen when systemic toxicity is evident.25'30 One fatal case occurred with a level
of 75 ug/dL.30 Blood analysis is useful in confirming the cause of poisoning. Monitor
levels routinely during acute intoxication to better establish a decay curve and deter-
mine when therapy can be safely discontinued.
Treatment of Poisoning
Treatment of pentacholorophenol and dinitrophenol and its derivatives is the same.
though there are some differences in toxicity as noted above.
1. Provide support treatment, including oxygen, fluid replacement and, most impor-
tant, control of hyperthermia. There is no specific antidote for PCP or dinitro-
phenol toxicity.
2. Since these patients require aggressive control of hyperthermia, administer
sponge baths and use fans to increase evaporation.31 Cooling blankets and ice
packs to body surfaces may also be used. In fully conscious patients, administer
cold, sugar-containing liquids by mouth as tolerated. Antipyretic therapy with
salicylates is strongly contraindicated, as salicylates also uncouple oxidative
phosphorylation. Other antipyretics are thought to be of no use because of the
-------
peripherally mediated mechanism of hyperthermia in poisoning of this nature.
Note that profuse sweating is common in this poisoning, indicating that central
acting antipyretics would have no effect. Neither the safety nor the effectiveness
of the other antipyretics has been tested.
3. Administer oxygen continuously by mask to minimize tissue anoxia. Unless
there are manifestations of cerebral or pulmonary edema or of inadequate renal
function, administer intravenous fluids to restore hydration and support physi-
ologic mechanisms for heat loss and toxicant disposition. Monitor serum electro-
lytes, adjusting IV infusions to stabilize electrolyte concentrations. Follow urine
contents of albumin and cells, and keep an accurate hourly record of intake/output
to forestall fluid overload if renal function declines.
CAUTION: In the presence of cerebral edema and/or impaired renal func-
tion, intravenous fluids must be administered very cautiously to avoid increased
intracranial pressure and pulmonary edema. Central monitoring of venous
and pulmonary wedge pressures may be indicated. This is particularly impor-
tant when cardiac dysfunction or heart failure is observed. Such critically ill
patients should be treated in an intensive care unit.
4. Decontaminate the skin with soap and water, as outlined in Chapter 3, General
Principles.
5. Treat eye contamination by irrigating the exposed eyes with copious amounts of
clean water or saline for at least 15 minutes. Remove contact lenses, if present.
prior to irrigation. Send patient for further medical attention if irritation or other
injury persists.
6. Treat severe systemic poisoning in an intensive care unit setting with appropriate
supportive care including respiratory support, intravenous fluids, cardiac moni-
toring and renal function support as necessary. The toxicant itself and severe elec-
trolyte disturbances may predispose the patient to arrhythmias and myocardial
weakness. Atropine is a medication that is absolutely contraindicated, and it is
essential not to confuse the clinical signs for dinitrophenol with manifestations for
cholinesterase inhibition poisoning.26
7. To reduce production of heat in the body, control agitation and involuntary motor
activity with sedation. Lorazepam or other benzodiazepines should be effective.
although use of these drugs in these poisonings has not been studied. Control
seizures as outlined in Chapter 3.
8. Although most occupational poisoning is from inhalation, if ingested, consider
gastrointestinal decontamination as outlined in Chapter 3.
CHAPTER 11
Pentachlorophenol and
Dinitrophenolic Pesticides
Dinotrophenolic
Commercial Products,
cont.
dinoseb methacrylate
(binapacryl, Morocide,
Acricid, Ambox, Dapacryl,
Endosan, FMC 9044, Hoe
002784, Morrocid, NIA
9044)
dinosulfon
dinoterb acetate
dinoterb salts
dinoterbon
107
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CHAPTER 11
Pentachlorophenol and
Dinitrophenolic Pesticides References
1. Jorens PG, Schepens PJ. Human pentachlorophenol poisoning. Hum Exp Toxicol. Nov
1993;12(6):479-495.
2. Pentachlorophenol. National Toxicology Information Program, National Library of Medi-
cine, Bethesda, MD; 2000.
3. Kalman DA, Horstman SW. Persistence of tetrachlorophenol and pentachlorophenol in
exposed woodworkers. J Toxicol Clin Toxicol. Jim 1983;20(4):343-352.
4. Weinbach EC. The effect of pentachlorophenol on oxidative phosphorylation. JBiol Chem.
Octl954;210(2):545-550.
5. Danzo BJ. Environmental xenobiotics may disrupt normal endocrine function by inter-
fering with the binding of physiological ligands to steroid receptors and binding proteins.
Environ Health Perspect. Mar 1997;105(3):294-301.
6. Tran DQ, Klotz DM, Ladlie BL, Ide CF, McLachlan JA, Arnold SF. Inhibition of proges-
terone receptor activity in yeast by synthetic chemicals. Biochem Biophys Res Commun.
Dec 13 1996;229(2): 518-523.
7. DeMaeyer J, Schepens PJ, Jorens PG, Verstaete R. Exposure to pentachlorophenol as a
possible cause of miscarriages. Br J Obstet Gynaecol. 1995;102:1010-1011.
8. Dimich-Ward H, Hertzman C, Teschke K, et al. Reproductive effects of paternal expo-
sure to chlorophenate wood preservatives in the sawmill industry. Scand J Work Environ
Health. Aug 1996;22(4):267-273.
9. Klemmer HW, Wong L, Sato MM, Reichert EL, Korsak RJ, Rashad MN. Clinical findings
in workers exposed to pentachlorophenol. Archives of environmental contamination and
toxicology. 1980;9(6):715-725.
10. Proudfoot AT. Pentachlorophenol poisoning. Toxicol Rev. 2003;22(1):3-11.
11. Walls CB, Glass WI, Pearce NE. Health effects of occupational pentachlorophenol exposure
in timber sawmill employees: a preliminary study. NZMedJ. Sep25 1998;111(1074):362-
364.
12. Daniel V, Huber W, Bauer K, et al. Association of elevated blood levels of pentachlo-
rophenol (PCP) with cellular and humoral immunodeficiencies. Arch Environ Health.
Jan-Feb2001;56(l): 77-83.
13. Kentor PM. Urticaria from contact with pentachlorophenate. JAMA. Dec 26
1986;256(24):3350.
14. O'Malley MA, Carpenter AV, Sweeney MH, et al. Chloracne associated with employment
in the production of pentachlorophenol. Am J IndMed. 1990; 17(4):411-421.
15. Robson AM, Kissane JM, Elvick NH, Pundavela L. Pentachlorophenol poisoning
in a nursery for newborn infants. I. Clinical features and treatment. J Pediatr. Aug
1969;75(2):309-316.
16. Gray RE, Gilliland RD, Smith EE, Lockard VG, Hume AS. Pentachlorophenol intoxica-
tion: report of a fatal case, with comments on the clinical course and pathologic anatomy.
Arch Environ Health. May-Jun 1985;40(3): 161-164.
17. Wood S, Rom WN, White GL, Jr., Logan DC. Pentachlorophenol poisoning. JOccupMed.
Jul 1983;25(7):527-530.
18. Roberts HJ. Aplastic anemia due to pentachlorophenol. N Engl J Med. Dec 31
1981;305(27):1650-1651.
19. Casarett LJ, Bevenue A, Yauger WL, Jr., Whalen SA. Observations on pentachlorophenol
in human blood and urine. Am IndHyg Assoc J. Jul-Aug 1969;30(4):360-366.
20. Dahlgren J, Warshaw R, Thornton J, Anderson-Mahoney CP, Takhar H. Health effects on
nearby residents of a wood treatment plant. Environ Res. Jun 2003;92(2): 92-98.
108
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CHAPTER 11
Pentachlorophenol and
21. Clayton GD, Clayton FE, eds. Patty's Industrial Hygiene and Toxicology. 4th ed. New Dinitrophenolic Pesticides
York: John Wiley & Sons; 1994; No. 2B.
22. Gomez-Catalan J, To-Figueras J, Planas J, Rodamilans M, Corbella J. Pentachlorophenol
and hexachlorobenzene in serum and urine of the population of Barcelona. Hum Toxicol.
Sep 1987;6(5):397-400.
23. Wylie JA, Gabica J, Benson WW, Yoder J. Exposure and contamination of the air and
employees of a pentachlorophenol plant, Idaho-1972. PestMonit. 1975;9:150-153.
24. Wagner SL. Pentachlorophenol. Clinical Toxicology of Agricultural Chemicals. Corvallis:
Oregon State University Press; 1981; 131 -137.
25. Leftwich RB, Floro JF, Neal RA, Wood AJ. Dinitrophenol poisoning: a diagnosis to
consider in undiagnosed fever. SouthMedJ. Feb 1982;75(2):182-184.
26. Finkel AJ, ed Herbicides: Dinitrophenols. 4 ed. Boston: John Wright PSG, Inc; 1983.
Hamilton and Hardy's Industrial Toxicology.
27. Kurt TL, Anderson R, Petty C, Bost R, Reed G, Holland J. Dinitrophenol in weight loss:
the poison center and public health safety. Vet Hum Toxicol. Dec 1986;28(6): 574-575.
28. Palmeira CM, Moreno AJ, Madeira VM. Thiols metabolism is altered by the herbi-
cides paraquat, dinoseb and 2,4-D: a study in isolated hepatocytes. Toxicol Lett. Nov 15
1995;81(2-3):115-123.
29. Smith WD. An investigation of suspected dinoseb poisoning after the agricultural use of a
herbicide. Practitioner. Jun 1981;225(1356):923-926.
30. NIOSH. Criteria for a Recommended Standard: Occupational Exposure to Dinitro-Ortho-
Cresol. 1978.78-131.
31. Graham BS, Lichtenstein MJ, Hinson JM, Theil GB. Nonexertional heatstroke. Physi-
ologic management and cooling in 14 patients. Arch InternMed. Jan 1986;146(1):87-90.
109
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Paraquat & Diquat
HIGHLIGHTS
Toxic doses are life
threatening
Impacts Gl tract, kidney,
lungs, liver, heart, other
organs
Pulmonary fibrosis is the
usual cause of death in
paraquat poisoning
Diquat has greater renal
activity
Can be measured in
blood and urine by
spectrophotometric, gas
chromatographic, liquid
chromatographic and
radioimmunoassay
SIGNS & SYMPTOMS
Ingestion (either): burning
pain in mouth, throat, chest,
upper abdomen; pulmonary
edema, pancreatitis, renal &
CMS effects
Dermal (paraquat): dry and
fissured hands, horizontal
ridging or loss of fingernails,
ulceration, abrasion
Diquat: CMS toxicity as
nervousness, irritability,
combativeness,
disorientation, diminished
reflexes
CHAPTER 12
Paraquat and Diquat
Paraquat and diquat are identified chemically as dipyridyls.
Paraquat is a synthetic, non-selective contact herbicide, marketed as paraquat.
paraquat dichloride salt and bismethylsulfate salt. Liquid technical products range
from 20% to 50% concentration, but the formulations used in the field range from
0.07% to 0.14%. It is a restricted use pesticide.
Diquat is usually prepared as the dibromide monohydrate salt, 15%-25% in
liquid concentrates, but the formulations in the field are usually 0.23%. Diquat dibro-
mide is a non-selective contact herbicide, desiccant and plant growth regulator for use
as a general herbicide for control of broadleaf and grassy weeds in terrestrial non-crop
and aquatic areas; as a desiccant in seed crops and potatoes; and for tassel control and
spot weed control in sugarcane. Unlike paraquat, it is not registered as a restricted use
pesticide.
PARAQUAT
Toxicology
When a toxic dose is ingested (see below), paraquat has life-threatening effects on
the gastrointestinal tract, kidney, liver, heart and other organs. The LD50 in humans
is approximately 3-5 mg/kg, which translates into as little as 10-15 mL of a 20%
solution.1'2 In spite of the fact that the lung is the primary target organ, toxicity from
inhalation is rare.
Although pulmonary toxicity occurs later in paraquat poisoning than other
manifestations, it is the most severe and, therefore, mentioned first. Pulmonary effects
represent the most lethal and least treatable manifestation of toxicity from this agent.
The primary mechanism is through the generation of free radicals with oxidative
damage to lung tissue.1'2 While acute pulmonary edema and early lung damage may
occur within a few hours of severe acute exposures,3'4 the delayed toxic damage of
pulmonary fibrosis, the usual cause of death, most commonly occurs 7-14 days after
the ingestion.5 In those patients who ingest a very large amount of concentrated solu-
tion (20%), some have died more rapidly from circulatory failure (within 48 hours)
prior to the onset of pulmonary fibrosis.5
Both types I and II pneumatocytes appear to selectively accumulate paraquat.
Biotransformation of the paraquat in these cells results in free-radical production with
resulting lipid peroxidation and cell injury.1'2'3 Hemorrhagic proteinaceous edema fluid
and leukocytes infiltrate the alveolar spaces, after which there is rapid proliferation of
fibroblasts. There is a progressive decline in arterial oxygen tension and CO2 diffusion
capacity. Such a severe impairment of gas exchange causes progressive proliferation
of fibrous connective tissue in the alveoli and eventual death from asphyxia and tissue
anoxia.6 One study of survivors suggests that some of the fibrous toxic damage may
be reversible, as evidenced by markedly improved pulmonary function tests 3 months
after survival.7
110
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Local skin damage includes a contact dermatitis. Prolonged contact will produce
erythema, blistering, abrasion, ulceration and fingernail changes.8'9 Although absorp-
tion across intact skin is slow, abraded or eroded skin allows efficient absorption.
The gastrointestinal (GI) tract is the site of initial or Phase 1 toxicity to the
mucosal surfaces following ingestion of the substance. This toxicity is manifested by
swelling, edema and painful ulceration of the mouth, pharynx, esophagus, stomach
and intestine. With higher levels, other GI toxicity includes centrizonal hepatocellular
injury that can cause elevated bilirubin, and hepatocellular enzymes such as AST, ALT.
LDH and alkaline phosphatase.
Damage to the proximal renal tubule occurs and is often more reversible than
the destruction to lung tissue. However, impaired renal function may play a critical
role in determining the outcome of paraquat poisoning. Normal tubule cells actively
secrete paraquat into the urine, efficiently clearing it from the blood; but high blood
concentrations poison the secretory mechanism and may destroy the cells. Diquat
poisoning typically results in greater renal injury than paraquat.10
Focal necrosis of the myocardium and skeletal muscle are the main features of
toxicity to any type of muscle tissue and typically occurs following the Phase 1 gastro-
intestinal toxicity.
Ingestion has been reported to cause cerebral edema and brain damage. At
necropsy, brain damage was found in the form of moderate neuronal depletion, prob-
ably secondary to anoxia, and damage to the central white matter and particularly
the brain around the lateral and third ventricles. Examination of the brain by electron
microscopy showed edema and destruction of myelin, with abundant myelin break-
down products, and astrocytic fibrous gliosis.11
Although much concern has been expressed about effects of smoking paraquat-
contaminated marijuana, toxic effects by this mechanism have been either very rare
or nonexistent. Most paraquat that contaminates marijuana is pyrolyzed to dipyridyl
during smoking, which is a product of leaf (including marijuana) combustion and
presents little toxic hazard.
CHAPTER 12
Paraquat & Diquat
Paraquat & Diquat
TREATMENT
Immediate GI
decontamination with
Bentonite, Fuller's Earth or
activated charcoal
Maintain urinary output by
administering IV, but monitor
fluids in case of renal failure
Decontaminate eyes and
skin
CONTRAINDICATED
Supplemental oxygen
(unless patient develops
hypoxemia)
Signs and Symptoms of Poisoning
Initial clinical signs depend upon the route of exposure. Early symptoms and signs
of poisoning by ingested paraquat are burning pain in the mouth, throat, chest and
upper abdomen, due to the corrosive effect of paraquat on the mucosal lining. Diar-
rhea, which is sometimes bloody, can also occur. Giddiness, headache, fever, leth-
argy and coma are other examples of CNS and systemic findings. Pancreatitis may
cause severe abdominal pain. Proteinuria, hematuria, pyuria and azotemia reflect renal
injury. Oliguria/anuria indicates acute tubular necrosis. Because the kidneys are almost
the exclusive route of paraquat elimination from body tissues, renal failure fosters a
buildup of tissue concentration, including the very important concentration in the lung.
Unfortunately, this pathogenic sequence may occur in the first several hours
following paraquat ingestion, generating lethal concentrations of paraquat in lung
tissue before therapeutic measures to limit absorption and enhance disposition have
taken effect. It is probably for this reason that methods for enhancing paraquat disposi-
tion several hours following ingestion have had little effect on mortality.9
Cough, dyspnea and tachypnea usually appear 2-4 days following paraquat
ingestion but may be delayed as long as 14 days. Progressive cyanosis and dyspnea
reflect deteriorating gas exchange in the damaged lung. In some cases, the coughing
up of frothy sputum (pulmonary edema) is the early and principal manifestation of
paraquat lung injury.9
Dermal signs are common among agriculture workers with acute skin expo-
sure to paraquat. Particularly in concentrated form, paraquat causes localized injury
111
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CHAPTER 12
Paraquat & Diquat
Paraquat
COMMERCIAL
PRODUCTS
Bonfire
Firestorm
Gramoxone
Helmquat
Para-Shot
Parazone
Quik-Quat
Diquat
COMMERCIAL
PRODUCTS
Chemsico
Rapid Kill
Razor Burn
Reglone
Touchdown
Weedtrine-D
to tissues with which it comes into contact. Fatal poisonings are reported to have
occurred as a result of protracted dermal contamination by paraquat, but this is likely
to occur only when the skin's barrier integrity is impaired due to abrasion, erosion
or other pathologic processes. In these cases, more efficient systemic absorption can
occur. With an intact dermal barrier, paraquat leaves the skin of the hands dry and
fissured, and causes horizontal ridging of the fingernails. Chronic exposure may even
result in the loss of fingernails. Prolonged contact with skin will create ulceration and
abrasion sufficient to allow systemic absorption.9
In addition, some agriculture workers can be exposed through prolonged inha-
lation of spray droplets and develop nosebleeds because of local damage. However.
inhalation has not resulted in systemic toxicity because of the low vapor pressure and
lower concentration of paraquat field formulations.
Eye contamination with paraquat concentrate or higher concentration diluted
solutions results in severe conjunctivitis and sometimes protracted corneal opacifica-
tion.12-13
The hepatic injury from paraquat may be severe enough to cause jaundice, which
signifies severe injury. However, hepatotoxicity is rarely a major determinant to clin-
ical outcome. No hepatic signs or symptoms are present other than the abnormal labo-
ratory values mentioned under the toxicology section.
Clinical experience has offered a rough dose-effect scale on which to base prog-
nosis in cases of paraquat ingestion9:
1. Less than 20 mg paraquat ion per kg body weight (less than 7.5 mL of 20% [w/v]
paraquat concentrate). No symptoms or only gastrointestinal symptoms occur.
Recovery is likely.
2. Twenty to 40 mg paraquat ion per kg body weight (7.5-15.0 mL of 20% [w/v]
paraquat concentrate). Pulmonary fibroplasia ensues. Death occurs in most cases.
but may be delayed 2-3 weeks. Multiple organ damage will occur.
3. More than 40 mg paraquat ion per kg body weight (more than 15.0 mL of 20%
[w/v] paraquat concentrate). Multiple organ damage occurs as in Class 2 but is
more rapidly progressive. The gastrointestinal effects are often characterized by
marked ulceration of the oropharynx. Mortality is essentially 100% in 1-7 days.
DIQUAT
Toxicology
Diquat poisoning is less common than paraquat poisoning, thus the human reports
and animal experimental data for diquat poisoning are less extensive than for para-
quat. Systemically absorbed diquat is not selectively concentrated in lung tissue, as is
paraquat, and pulmonary injury by diquat is less prominent. In animal studies, diquat
causes mild, reversible injury to type I pneumatocytes but does not injure the type II
cells. No progressive pulmonary fibrosis has been noted in diquat poisoning.14'15
However, diquat has severe toxic effects on the central nervous system that are
not typical of paraquat poisoning.14'15 While laboratory experimentation has suggested
that diquat is not directly neurotoxic, there have been relatively consistent pathologic
brain changes noted in reported fatal cases of diquat poisoning. These consist of brain
stem infarction, particularly involving the pons.16 It is not clear whether these post-
mortem changes represent direct toxicity or secondary effects related to the systemic
illness and therapy. (See Signs and Symptoms section below for CNS clinical effects.)
112
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CHAPTER 12
Paraquat & Diquat
Signs and Symptoms of Poisoning
In many human diquat poisoning cases, clinical signs of neurologic toxicity tend to be
the most important. These include nervousness, irritability, restlessness, diminished
reflexes, combativeness, disorientation, nonsensical statements and inability to recog-
nize friends or family members. Neurologic effects may progress to coma, accompa-
nied by tonic-clonic seizures, and result in the death of the patient.14'15 Parkinsonism
has also been reported following dermal exposure to diquat.17
Except for the CNS signs listed in the preceding paragraph, early symptoms of
poisoning by ingested diquat are similar to those from paraquat, reflecting diquat's
corrosive effect on tissues. They include burning pain in the mouth, throat, chest and
abdomen; intense nausea and vomiting; and diarrhea. If the dosage was small, these
symptoms may be delayed 1-2 days. Blood may appear in the vomitus and feces. Intes-
tinal ileus, with pooling of fluid in the gut, has characterized several human poisonings
by diquat.10
The kidney is the principal excretory pathway for diquat absorbed into the body.
Renal damage is, therefore, an important feature of poisonings. Proteinuria, hematuria
and pyuria may progress to renal failure and azotemia. Elevations of serum alkaline
phosphatase, AST, ALT and LDH reflect liver injury. Jaundice may develop.
If the patient survives several hours or days, circulatory function may fail
because of dehydration. Hypotension and tachycardia can occur, with shock resulting
in death. Other cardiorespiratory problems may develop such as toxic cardiomyopathy
or a secondary infection such as bronchopneumonia.
Diquat is somewhat less damaging to the skin than paraquat, but irritant effects
may appear following dermal contamination with the concentrate. There is probably
significant absorption of diquat across abraded or ulcerated skin.
The great majority of poisonings by paraquat and diquat (discussed below) have
been caused by ingestion with suicidal intent, particularly in Japan16 and many devel-
oping countries. Since 1987, there has been a decline in most countries in the total
numbers of suicidal deaths attributed to paraquat and diquat. Nearly all of the rela-
tively few occupationally related poisonings have been survived, but the mortality rate
among persons who have swallowed paraquat or diquat remains high.2'5 Avoidance of
this mortality will probably have to rely on preventive strategies or on stopping gastro-
intestinal absorption very soon after the toxicant has been ingested.
Even though intestinal absorption of dipyridyls is relatively slow, lethal uptake
by critical organs and tissues apparently occurs within 18 hours, possibly within 6
hours, following ingestion of toxic quantities of paraquat or diquat. Dipyridyls have
large volumes of distribution. Once distribution to tissues has occurred, measures
to remove dipyridyls from the blood are very inefficient in reducing the total body
burden.
Several strategies are being tested to reduce the frequency of these occurrences.
These include the addition of emetics, stenching agents, gelling substances and
bittering agents such as sodium denatonium.
Confirmation of Poisoning
At some treatment facilities, a simple colorimetric test is used to identify paraquat and
diquat in the urine and give a rough indication of the magnitude of absorbed dose. To
one volume of urine is added 0.5 volume of freshly prepared 1% sodium dithionite
(sodium hydrosulfite) in one normal sodium hydroxide (1.0 N NaOH). The color is
observed after 1 minute. Development of a blue color indicates the presence of para-
quat in excess of 0.5 mg per liter. Both positive and negative controls should be run to
ensure that the dithionite has not undergone oxidation in storage.
113
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CHAPTER 12
Paraquat & Diquat
When urine collected within 24 hours of paraquat ingestion is tested, the dithi-
onite test appears to have some approximate prognostic value: concentrations less than
1 milligram per liter (no color to light blue) generally predict survival, while concen-
trations in excess of 1 milligram per liter (navy blue to dark blue) often foretell a fatal
outcome. Analysis of serum by a sodium dithionite test has been reported to predict
outcome in paraquat exposures. In one center a positive test was associated with 100%
mortality, while negative or equivocal tests resulted in a 68% survival rate.18
Diquat in urine yields a green color with the dithionite test. Although there is less
experience with this test in diquat poisonings, the association of bad prognosis with
intense color is probably similar.
Paraquat and diquat can be measured in blood and urine by spectrophotometric.
gas chromatographic, liquid chromatographic and radioimmunoassay methods. These
tests are available in numerous clinical reference laboratories and sometimes by the
manufacturing company. Paraquat poisonings in which plasma concentrations do not
exceed 2.0, 0.6,0.3, 0.16 and 0.1 mg per liter at 4,6, 10, 16 and 24 hours, respectively.
after ingestion are likely to survive.19 A comparison of several methods of measuring
plasma paraquat levels revealed comparable results. However, while the positive
predictive value for death was quite high, the ability to predict survival was much
lower.20
Lung Imaging
It has been reported that high-resolution computerized tomography of the lungs may
be of predictive value in acute paraquat poisoning. A calculation is made of areas of
ground glass opacities (GGOs) on tomography. In one study no patient survived when
the area was greater than 40% and all survived when the area was less than 20%.21 This
study may be useful in evaluating newer therapeutic approaches.
Treatment of Paraquat and Diquat Toxicosis
1. Flush skin immediately with copious amounts of water to decontaminate. Irrigate
the eyes with clean water for a prolonged period to remove material splashed in
the eyes. Eye contamination should thereafter be treated by an ophthalmologist.
Mild skin reactions usually respond to simple avoidance of further contact, but the
irritation may take several weeks to resolve. Severe dermatitis with inflammation.
cracking, secondary infection or nail injury should be treated by a dermatologist.
2. If paraquat or diquat has been ingested in any amount, immediately administer an
adsorbent. This is the one therapeutic measure most likely to affect the outcome of
paraquat or diquat ingestion favorably. Bentonite (7.5% suspension) and Fuller's
Earth (15% suspension) are highly effective but sometimes not available.
Dosage of Bentonite and Fuller's Earth
Adults and children over 12 years: 100-150 gm
Children under 12 years: 2 gm/kg body weight
CAUTION: Hypercalcemia andfecaliths have sometimes occurred following
administration of Fuller's Earth.
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CHAPTER 12
Paraquat & Diquat
Activated charcoal is nearly as effective, and is widely available. This treatment
is discussed in Chapter 3, General Principles.
3. Secure a blood sample as soon as possible for paraquat analysis and urine samples
for either paraquat and/or diquat. Serial samples of urine for either agent and
plasma for paraquat may be followed for prognostic information.
4. Do not administer supplemental oxygen until the patient develops severe hypox-
emia. High concentrations of oxygen in the lung increase the injury induced by
paraquat and possibly by diquat as well. There may be some advantage in placing
the patient in a moderately hypoxic environment, i.e., 15%-16% oxygen, although
the benefit of this treatment has not been established empirically in human poison-
ings. Inhalation of nitric oxide has been suggested as a method to maintain tissue
oxygenation at low inspired oxygen concentrations but is of unproven efficacy.
When the lung injury is so far advanced that there is no expectation of recovery,
oxygen may be given to relieve air hunger.
5. In serious poisonings, provide care in an intensive care setting to allow proper
monitoring of body functions and skilled performance of necessary invasive
monitoring and procedures.
6. As it is essential to maintain adequate urinary output,3 administer intravenous
fluids: isotonic saline, Ringer's solution or 5% glucose in water. This is highly
advantageous early in poisonings as a means of correcting dehydration, accel-
erating toxicant excretion, reducing tubular fluid concentrations of paraquat and
correcting metabolic acidosis. However, fluid balance must be monitored care-
fully to forestall fluid overload if renal failure develops. Monitor the urine regu-
larly for protein and cells to warn of impending tubular necrosis. Intravenous
infusions must be stopped if renal failure occurs, and extracorporeal hemodialysis
is indicated. Hemodialysis is not effective in clearing paraquat or diquat from the
blood and tissues.
7. Consider hemoperfusion over cellophane-coated activated charcoal. The proce-
dure has been used in many paraquat poisonings because the adsorbent does effi-
ciently remove paraquat from the perfused blood. However, recent reviews of
effectiveness have failed to show any reduction in mortality as a result of hemo-
perfusion.2'3'22 The apparent reason for this is the very small proportion of para-
quat body burden carried in the circulating blood even when only a few hours
have elapsed after ingestion. Theoretically, a patient who can be hemoperfused
within 10 hours of paraquat ingestion may derive some marginal benefit, but this
has not been demonstrated. If hemoperfusion is attempted, blood calcium and
platelet concentrations must be monitored. Calcium and platelets must be replen-
ished if these constituents are depleted by the procedure.
8. Control seizures following procedure in Chapter 3.
CAUTION: Be prepared to assist ventilation mechanically if respiration is
depressed, to intubate the trachea if laryngospasm occurs and to counteract
hypotensive reactions.
9. Consider administering cyclophosphamide and methylprednisolone. Many
drugs have been tested in animals or given in human dipyridyl poisonings
without clear evidence of benefit or harm: corticosteroids, superoxide dismutase,
115
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CHAPTER 12
Paraquat & Diquat
propranolol, cyclophosphamide, vitamin E, riboflavin, niacin, ascorbic acid.
clofibrate, desferrioxamine, acetylcysteine, terpin hydrate and melatonin.23
However, recent evidence regarding the use of cyclophosphamide and methyl-
prednisolone shows that they may be effective in reducing the mortality associ-
ated with moderate-to-severe paraquat poisoning. Two studies found a reduced
mortality associated with the treatment, while one study found no difference.24
The dosages used for cyclophosphamide and methylprednisolone were 1 gram
daily for 2 days and 1 gram daily for 3 days, respectively, given after the hemo-
perfusion. Each drug was administered as a 2-hour infusion; white cell counts.
serum creatinine levels, chest radiography and liver function tests were moni-
tored.24 Two controlled trials seem to have confirmed benefit from cyclophos-
phamide and methylprednisolone therapy with reduction of mortality from 81%
to 33% in one study and 86% to 31% in another.24'25 The protocols for adminis-
tration of the drugs were similar but not identical.
10. Manage pain with morphine sulfate. Morphine sulfate is usually required to
control the pain associated with deep mucosal erosions of the mouth, pharynx and
esophagus, as well as abdominal pain from pancreatitis and enteritis.
Dosage for Morphine Sulfate
Adults and children over 12 years: 10 -15 mg
subcutaneously every 4 hours.
Children under 12 years: 0.1-0.2 mg /kg body weight
every 4 hours.
Mouthwashes, cold fluids, ice cream or anesthetic lozenges may help to relieve
pain in the mouth and throat.
With severe pulmonary toxicity, recovery of the patient may only be accom-
plished by lung transplantation. However, the transplanted lung is susceptible to
subsequent damage due to redistribution of paraquat.26
References
1. Giulivi C, Lavagno CC, Lucesoli F, Bermudez MJ, Boveris A. Lung damage in paraquat
poisoning and hyperbaric oxygen exposure: superoxide-mediated inhibition of phospholi-
paseA2.FreeRadicBiolMed. Feb 1995;18(2):203-213.
2. Pond SM. Manifestations and management of paraquat poisoning. Med J Aust. Mar 5
1990;152(5):256-259.
3. Honore P, Hantson P, Fauville JP, Peelers A, Manieu P. Paraquat poisoning. "State of the
art'.Acta ClinBelg. 1994;49(5):220-228.
4. Nordquist RE, Nguyen H, Poyer JL, Carubelli R. The role of free radicals in paraquat-
induced comeal lesions. Free Radic Res. Jul 1995;23(1):61-71.
5. Bismuth C, Gamier R, Dally S, Foumier PE, Scherrmann JM. Prognosis and treatment of
paraquat poisoning: a review of 28 cases. J Toxicol Clin Toxicol. Jul 1982;19(5):461-474.
6. Harsanyi L, Nemeth A, Lang A. Paraquat (gramoxone) poisoning in south-west Hungary.
1977-1984. lexicological and histopathological aspects of group intoxication cases. Am J
Forensic Med Pathol. Jun 1987;8(2):131-134.
116
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CHAPTER 12
Paraquat & Diquat
7. Lee CC, Lin JL, Liu L. Recovery of respiratory function in survivors with paraquat intoxi-
cation. Annals of Emergency Medicine. 1995;26(2): 721-722.
8. Tungsanga K, Chusilp S, Israsena S, Sitprija V. Paraquat poisoning: evidence of systemic
toxicity after dermal exposure. PostgradMedJ. May 1983;59(691):338-339.
9. Vale JA, Meredith TJ, Buckley BM. Paraquat poisoning: clinical features and immediate
general management. Hum Toxicol. Jan 1987;6(l):41-47.
10. Jones GM, Vale JA. Mechanisms of toxicity, clinical features, and management of diquat
poisoning: a review. J Toxicol Clin Toxicol. 2000;38(2): 123-128.
11. Hughes JT. Brain damage due to paraquat poisoning: a fatal case with neuropathological
examination of the brain. Neumtoxicology. Summer 1988;9(2):243-248.
12. McKeag D, Maini R, Taylor HR. The ocular surface toxicity of paraquat. Br J Ophthalmol.
Mar2002;86(3):350-351.
13. Grant WM, Schuman JS. Toxicology of the Eye. 4th ed. Springfield: Charles C Thomas
Publisher Ltd; 1993.
14. Olson KR. Paraquat and diquat. Poisoning and drug overdose. 2nd ed. Norwalk: Appelton
andLange; 1994:245-246.
15. Vanholder R, Colardyn F, De Reuck J, Praet M, Lameire N, Ringoir S. Diquat intoxication:
report of two cases and review of the literature. AmJMed. Jun 1981 ;70(6): 1267-1271.
16. Lam HF, Takezawa J, Gupta BN, van Stee EW. A comparison of the effects of paraquat and
diquat on lung compliance, lung volumes and single breath diffusing capacity in the rat.
Toxicology. 1980;18(2):111-123.
17. Sechi GP, Agnetti V, Piredda M, et al. Acute and persistent parkinsonism after use of diquat.
Neurology. Jan 1992;42(l):261-263.
18. Koo JR, Yoon JW, Han S J, et al. Rapid analysis of plasma paraquat using sodium dithionite
as a predictor of outcome in acute paraquat poisoning. Am JMedSci. Nov 2009;338(5): 373-
377.
19. Proudfoot AT, Stewart MS, Levitt T, Widdop B. Paraquat poisoning: significance of
plasma-paraquat concentrations. Lancet. Aug 18 1979;2(8138):330-332.
20. Senarathna L, Eddleston M, Wilks MF, et al. Prediction of outcome after paraquat poisoning
by measurement of the plasma paraquat concentration. QJM. Apr 2009;102(4):251-259.
21. Kim YT, Jou SS, Lee HS, et al. The area of ground glass opacities of the lungs as a predic-
tive factor in acute paraquat intoxication. J Korean MedSci. Aug 2009;24(4):636-640.
22. Feinfeld DA, Rosenberg JW, Winchester JF. Three controversial issues in extracorporeal
toxin removal. Semin Dial. Sep-Oct2006;19(5):358-362.
23. Suntres ZE. Role of antioxidants in paraquat toxicity. Toxicology. Oct 30 2002; 180(1): 65-
77.
24. Lin JL, Wei MC, Liu YC. Pulse therapy with cyclophosphamide and methylprednisolone
in patients with moderate to severe paraquat poisoning: a preliminary report. Thorax. Jul
1996;51(7):661-663.
25. Afzali S, Gholyaf M. The effectiveness of combined treatment with methylprednisolone
and cyclophosphamide in oral paraquat poisoning. Arch Iran Med. Jul 2008;11(4):387-
391.
26. Sequential bilateral lung transplantation for paraquat poisoning. A case report. The Toronto
Lung Transplant group. J Thorac Cardiovasc Surg. May 1985;89(5):734-742.
117
-------
Phosphonate Herbicides
COMMERCIAL
PRODUCTS
fosamine ammonium
glyphosate (Brands include
Round-Up and Glyfonox)
CHAPTER 13
Other Herbicides
HIGHLIGHTS
Most commonly used
herbicide in U.S.
Many reported poisonings
Actual toxicity likely from
surfactant
Read label to ascertain
possible additional
ingredients
SIGNS & SYMPTOMS
Gl symptoms predominate
Cardiovascular, respiratory,
renal systems may be
affected
Can be measured in plasma
TREATMENT
Decontaminate skin and
eyes
Consider Gl
decontamination
Control seizures
Consider hemodialysis in
cases of renal failure
No known antidote
Many herbicides are now available for use in agriculture and for lawn and garden weed
control. This chapter discusses herbicides other than the chlorophenoxy compounds.
nitro- and chloro-phenols, arsenicals and dipyridyls, which are subjects of separate
chapters. Many modern herbicides kill weeds selectively by impairing metabolic
processes that are unique to plant life. For this reason, systemic toxicity in mammals
is generally low. Nonetheless, some pose a significant risk of poisoning if not handled
appropriately, and may result in eye, skin and mucous membrane irritation.
Herbicides mentioned in this chapter should be handled and applied only with
proper personal protective equipment and careful attention to hygienic measures that
minimize personal contact. Many formulations contain adjuvants (stabilizers, pene-
trants, surfactants) that may have significant irritating and toxic effects in addition to
the primary herbicide. A number of premixed products may be combination formula-
tions with additional active ingredients that are more toxic than the principal herbicide.
Therefore, it is important to read the label to identify each active ingredient and its
associated toxicities. Good hygienic practice should not be disregarded because only
the primary pesticide is reported to have a high LD50 in laboratory animals.
Healthcare professionals should have a general understanding of the metabo-
lism and health effects of these compounds after human exposures. This knowledge
is necessary to properly assess acute and chronic exposures. Generally, water-soluble
herbicides are not retained in body tissues for long periods of time, as were the previ-
ously used lipophilic organochlorine insecticides such as DDT. Most of the water-
soluble herbicides are primarily excreted, mainly in the urine, within 1-4 days.
This chapter follows a slightly different format than the other chapters in this book.
Glyphosate is discussed separately since it is a widely used herbicide. It has been studied
extensively and is the subject of numerous publications in the medical literature. The
remaining herbicides in the chapter are summarized in a table. A notable inclusion in the
table is propanil, an anilide herbicide. Propanil was previously described as having low
toxicity; however, data from Sri Lanka have documented significant acute toxicity with
the development of methemoglobinemia, including several fatalities.1'2
The rat acute oral LD50 is given as a rough index of potential lethal toxicity (If
several values are reported by various sources, the lowest is recorded here). Adverse
effect information given is drawn from many sources, including reregistration eligi-
bility decisions (REDs), product labels, textbooks and published reports. The listing
cannot be considered inclusive, either of herbicide products or of effects.
PHOSPHONATE HERBICIDES
Glyphosate is the most commonly used herbicide in the United States; it is used as
weed control on numerous agricultural crops and is also registered for home use.3 The
advent of genetically modified seed producing plants resistant to glyphosate allows
the planting of crops such as corn that can tolerate widespread application of glypho-
sate. The National Poison Data System (NPDS) uses 63 generic categories to classify
pesticides. In 2010, among reported human exposures to pesticides, glyphosate ranked
118
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CHAPTER 13
Other Herbicides
eighth.4 Although Round-Up is the most well-known brand of glyphosate, note that
some products with the same brand name may include additional active ingredients.
Always read labels carefully.
Toxicology
Glyphosate is marketed in the United States as isopropylamine salt. Glyphosate and
related compounds have a specific mechanism of action inhibiting the enzyme respon-
sible for synthesizing phenylalanine, tyrosine and tryptophan, which is an enzyme
system that is not present in humans.5'6 Given the plant-specific mechanism of action,
there is theoretically a low risk for acute human toxicity. Indeed, glyphosate has low
acute toxicity in mammals, with a rat LD50 in the range of 4,300 mg/kg. Despite this,
there have been a number of reports in the medical literature of acute glyphosate-
related poisoning. Most, if not all, of the symptoms may actually be related to the
organic surfactant with which glyphosate is combined. Most moderate to severe symp-
tomatic cases have been associated with intentional (suicidal) ingestion.3'7'8
Another formulation of glyphosate is glyphosate-trimesium, which is not
marketed in the United States. Two fatalities have been reported associated with
glyphosate-trimesium exposure.9
Signs and Symptoms of Poisoning
Gastrointestinal symptoms predominate, including mouth and throat pain, nausea,
vomiting, diarrhea and abdominal discomfort, and are usually self limiting. More
severe signs and symptoms may be seen in cases of intentional oral exposures. Cardio-
vascular, respiratory and renal systems may be affected; and signs and symptoms
include tachypnea, dysrhythmias, hypotension, non-cardiogenic pulmonary edema,
hypovolemic shock, oliguria and respiratory failure. Seizures and depressed level of
consciousness may also occur. Death was often caused by severe hypotension and
respiratory failure.3'8 Hyperkalemia may occur as a complication of renal failure.3'7
One study assessed patients prospectively following a report of glyphosate inges-
tion. Of the 601 cases, most were either asymptomatic (27%) or with minor symp-
toms (64%). Approximately 5.5% had moderate to severe poisoning, and 3.2% of the
patients died.8 In another series of acutely poisoned patients, 42% had medical compli-
cations of some type, with metabolic acidosis (37%) and respiratory failure (28%)
being the most common. A late complication in 12% of patients was pancreatitis.3
Confirmation of Poisoning
Glyphosate can be measured in the plasma, with levels above 734 ug/mL being
measured in fatal cases.8
Treatment of Glyphosate Toxicosis
1. Provide supportive treatment, as there is no known antidote.
2. Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Treat eye contamination by irrigating the exposed eye(s) with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses, if
present, prior to irrigation. If irritation persists after irrigation, specialized medical
treatment in a healthcare facility is indicated.
119
-------
CHAPTER 13
Other Herbicides
3. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3.
4. Control seizures using benzodiazepines. See Chapter 3 for specific medications
and dosages.
5. In cases of severe poisoning resulting in acute renal failure, consider hemodialysis
to correct acidosis and hyperkalemia.7
Potential Effects of Other Herbicides
The potential effects of a variety of other herbicides are summarized in the following
multi-page table.
POTENTIAL EFFECTS OF OTHER HERBICIDES
Chemical
Class
in
9)
;o
E
03
8
<
in
9)
;o
<
2,500
8,350
Known or Suspected
Adverse Effects
Irritating to eyes and
skin. Methemoglobinemia
has been reported in a
mixed herbicide ingestion
with the urea derivative
metobromuron; however,
it is likely that the latter
was the cause of the
methemoglobinemia.
Mild irritant, vomiting.
Occasionally hypotension
and CMS depression.10
Dermal irritant and
sensitizer.
Despite the relatively high
LD50 in rats, this compound
has caused significant
methemoglobinemia,
reduced consciousness
and respiratory
depression.1-2
Moderately irritating to
eyes.
continued next page
120
-------
CHAPTER 13
Other Herbicides
POTENTIAL EFFECTS OF OTHER HERBICIDES, continued
Chemical
Class
o to
c -^
< "I
S'
c -a
9) 'o
00 <
J
i:
'c
O
N
C
O
00
o
c
o
c
- s
1 §
£ TJ
N
c
o
00
to
*J
E
ns
£
ns
IE ~o
1- 0
O !Q
c >-
ns 0
to £
o
s
E
ns
.Q
ns
O
>,
c
k.
a.
o
_o
o
Generic
Name
Trichloro-
benzoic acid
Dicamba
Dichlobenil
Bentazone
Asulam
Terbucarb
Butylate
Cycloate
Pebulate
EPIC
Diallate
Triallate
Thiobencarb
Triclopyr
Examples of
Proprietary
Names
TCBA, Tribac,
2,3,6-TBA
Banvel
Casoron,
Dyclomec,
Barrier
Basagran
Asulox
Azac, Azar
Sutan
Ro-Neet
Tillam, PEBC
Eptam,
Eradicane
Di-allate
Far-go
Bolero, Saturn
Garlon,
Turflon
Acute
Oral
50
mg/kg
1,500
2,700
>4,460
>1,000
>5,000
>34,000
3,500
2,000
921
1,630
395
1,675
1,300
630
Known or Suspected
Adverse Effects
Moderately irritating to skin
and respiratory tract.
Minimal toxic, irritant
effects.
Generally described as
irritating to eyes, Gl tract
and respiratory tract. Some
reports of acute renal
failure and respiratory
failure have been reported
with ingestion of large
amounts.11'12
Some are irritating to eyes,
skin, and respiratory tract,
particularly in concentrated
form. Some may be weak
inhibitors of cholinesterase.
Irritating to skin and eyes.
continued next page
121
-------
CHAPTER 13
Other Herbicides
POTENTIAL EFFECTS OF OTHER HERBICIDES, continued
Chemical
Class
o Jo
o ~o
O
litroaminobenzene
derivative
b
5,000
2,250
>10,000
>10,000
>10,000
1,550
>10,000
>5,000
>3,500
8,200
Known or Suspected
Adverse Effects
Irritating to skin and eyes.
May be moderately
irritating, particularly to
the Gl tract following
ingestion.13 These
herbicides do not uncouple
oxidative phosphorylation
or generate
methemoglobin.
May be mildly irritating.
These herbicides do
not uncouple oxidative
phosphorylation or
generate methemoglobin.
Irritating to eyes and skin.
Impaired consciousness,
respiratory distress and
severe vomiting occurs
with large quantity (>100
ml_) ingestion.14 Does not
contain arsenic.
Minimal toxic and irritant
effects.
Irritating to skin, eyes,
and respiratory tract. Low
systemic toxicity.
continued next page
122
-------
CHAPTER 13
Other Herbicides
POTENTIAL EFFECTS OF OTHER HERBICIDES, continued
Chemical
Class
Triazines
7,000
>5,000
2,000
2,500
2,980
>10,000
5,200
>11,000
>5,000
Known or Suspected
Adverse Effects
Systemic toxicity is unlikely
unless large amounts have
been ingested. There is
one report in the literature
of metabolic acidosis
following massive ingestion
of prometryn.15 Some
triazines are moderately
irritating to the eyes, skin
and respiratory tract.
Some formulations of
prometon are strongly
irritating to eyes, skin and
respiratory tract.
Minimal systemic toxicity.
Slight irritant effect.
Irritant to skin, eyes and
respiratory tract.
Moderately irritating.
continued next page
123
-------
CHAPTER 13
Other Herbicides
POTENTIAL EFFECTS OF OTHER HERBICIDES, continued
Chemical
Class
0>
^J
ro
(D
T3
ro
(D
Generic
Name
Chlorimuron
ethyl
Chlorotoluron
Diuron
Ebuthiuron
Flumeturon
Isoproturon
Linuron
Methabenz-
thiazuron
Metobromuron
Metoxuron
Monolinuron
Monuron
Neburon
Siduron
Sulfometuron-
methyl
Examples of
Proprietary
Names
Classic
Dicuran,
Tolurex
Cekiuron,
Crisuron,
Dailon, Direx,
Diurex,
Diuron,
Karmex,
Unidron,
Vonduron
Spike,
Tebusan
Cotoran,
Cottonex
Alon, Arelon,
IP50, Tolkan
Afalon, Linex,
Linorox,
Linurex,
Lorox, Sarclex
Tribunil
Pattonex
Deftor,
Dosaflo,
Purivel,
Sulerex
Aresin
Monuron
Granurex,
Neburex
Tupersan
Oust
Acute
Oral
mg/kg
>4,000
>10,000
>5,000
644
8,900
1,826
1,500
5,000
2,000
3,200
2,100
3,600
>11,000
>7,500
>5,000
Known or Suspected
Adverse Effects
Systemic toxicity is unlikely
unless large amounts have
been ingested.
Chlorimuron ethyl has
been associated with
asthma.16
Many substituted ureas are
irritating to eyes, skin and
mucous membranes.
Metobromuron has
been associated with
methemoglobinemia.17
124
-------
Confirmation of Poisoning
Although there are analytical methods for residues of many of the herbicides mentioned
in this chapter, and for some of the mammalian metabolites generated from them, these
procedures are not generally available to confirm human absorption of the chemicals.
Prior exposure must be determined from a recent history of occupational exposure or
accidental or deliberate ingestion.
Treatment of Toxicosis from Other Herbicides
1. Decontaminate skin promptly by washing with soap and water. Treat contamina-
tion of the eyes immediately by prolonged flushing with copious amounts of clean
water. If dermal or ocular irritation persists, medical attention should be obtained
without delay.
2. Ingestions of these herbicides are likely to be followed by vomiting and diarrhea
because of the irritant properties of most of the toxicants. Management depends
on: (a) the best estimate of quantity originally ingested, (b) the time elapsed since
ingestion and (c) the clinical status of the subject.
If large amounts of herbicide have been ingested and the patient is seen within
an hour of the ingestion, consider gastrointestinal decontamination as outlined in
Chapter 3, General Principles. GI decontamination may be effective in limiting
irritant effects and reducing absorption of most or all of these herbicides.
3. If serious dehydration and electrolyte depletion have occurred as a result of
vomiting and diarrhea, monitor blood electrolytes and fluid balance and admin-
ister intravenous infusions of glucose, normal saline, Ringer's solution or Ring-
er's lactate to restore extracellular fluid volume and electrolytes. Follow this with
oral nutrients as soon as fluids can be retained.
4. Use supportive measures to manage excessive exposures to these herbicides. With
the exception of treating methemoglobinemia associated with some of these herbi-
cides, there are no specific antidotes for poisoning by most of these compounds.
In the case of suicidal ingestions, particularly, the possibility must always be kept
in mind that multiple toxic substances may have been swallowed, especially if the
patient's condition deteriorates in spite of good supportive care.
5. Antidotal therapy for methemoglobinemia is methylene blue.
CHAPTER 13
Other Herbicides
Other Herbicides
TREATMENT
Decontaminate skin and
eyes
GI decontamination if
ingestion within 1 hour
Administer IV fluids and
electrolytes as appropriate
Consider multiple substance
ingestion
Methylene blue for
methemoglobinemia
Dosage of Methylene Blue
1-2 mg/kg of1% methylene blue, slow IV, in symptomatic
patients. Additional doses may be required.
125
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CHAPTER 13
Other Herbicides
References
1. Eddleston M, Rajapakshe M, Roberts D, et al. Severe propanil [N-(3,4-dichlorophenyl)
propanamide] pesticide self-poisoning. J Toxicol Clin Toxicol. 2002;40(7):847-854.
2. Roberts DM, Heilmair R, Buckley NA, et al. Clinical outcomes and kinetics of propanil
following acute self-poisoning: a prospective case series. BMC Clin Pharmacol. 2009;9:3.
3. Moon JM, Chun BJ. Predicting acute complicated glyphosate intoxication in the emer-
gency department. Clin Toxicol (Phila). Aug 2010;48(7):718-724.
4. Bronstein AC, et al. 2010 Annual Report of the American Association of Poison Control
Centers' National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol.
2011;49:910-941.
5. Steinriicken HC, Amrhem N. The herbicide glyphosate is a potent inhibitor of 5-enol-
pyruvylshikimic acid-3-phosphate synthase. Biochem Biophy Res Commun. 30 Jun
1980;94:1207-12.
6. Bradberry SM,ProudfootAJ, Vale JA. Glyphosate poisoning. ToxicolRev. 2004;23(3):159-
167.
7. Moon JM, Min YI, Chun BJ. Can early hemodialysis affect the outcome of the ingestion of
glyphosate herbicide? Clin Toxicol (Phila). 2006;44(3):329-332.
8. Roberts DM, Buckley NA, Mohamed F, et al. A prospective observational study of the
clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning.
Clin Toxicol (Phila). Feb 2010;48(2):129-136.
9. Sorensen FW, Gregersen M. Rapid lethal intoxication caused by the herbicide glyphosate-
trimesium (Touchdown). Hum Exp Toxicol. Dec 1999;18(12):735-737.
10. Lo YC, Yang CC, Deng JF. Acute alachlor and butachlor herbicide poisoning. Clin Toxicol
(Phila). Sep2008;46(8):716-721.
11. Turcant A, Harry P, Cailleux A, et al. Fatal acute poisoning by bentazon. J Anal Toxicol.
Mar2003;27(2):113-117.
12. Wu IW, Wu MS, Lin JL. Acute renal failure induced by bentazone: 2 case reports and a
comprehensive review. JNephrol. Mar-Apr 2008;21(2):256-260.
13. Chuang CC, Wang ST, Yang CC, Deng JF. Clinical experience with pendimethalin
(STOMP) poisoning in Taiwan. Vet Hum Toxicol. Jun 1998;40(3):149-150.
14. Lee HL, Chen KW, Wu MH. Acute poisoning with a herbicide containing imazapyr
(Arsenal): a report of six cases. J Toxicol Clin Toxicol. 1999;37(l):83-89.
15. Brvar M, Okrajsek R, Kosmina P, et al. Metabolic acidosis in prometryn (triazine herbi-
cide) self-poisoning. Clin Toxicol (Phila). Mar 2008;46(3):270-273.
16. Hoppin JA, Umbach DM, London SJ, Lynch CF, Alavanja MC, Sandier DP. Pesticides
associated with wheeze among commercial pesticide applicators in the Agricultural Health
StioAy.AmJEpidemiol. Jun 15 2006;163(12):1129-1137.
17. Turcant A, Cailleux A, Le Bouil A, Allain P, Harry P, Renault A. Acute metobromuron
poisoning with severe associated methemoglobinemia. Identification of four metabolites
in plasma and urine by LC-DAD, LC-ESI-MS, and LC-ESI-MS-MS. J Anal Toxicol. Apr
2000;24(3):157-164.
126
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Section IV
OTHER PESTICIDES
Insect Repellents 128
Arsenical Pesticides 135
Fungicides 143
Fumigants 161
Rodenticides 173
Miscellaneous Pesticides, Synergists, Solvents and Adjuvants 188
Disinfectants 200
-------
N,N-Diethyl-3-
methylbenzamide (DEET)
HIGHLIGHTS
Few cases of toxicity when
used properly
Skin, Gl absorption
CHAPTER 14
Insect Repellents
SIGNS & SYMPTOMS
Skin irritation, contact
dermatitis, urticarial
Rarely: headache,
restlessness, irritability,
ataxia, unconsciousness,
hypotension, seizures
TREATMENT
Decontaminate skin, eyes
Consider topical steroids,
oral antihistamines for
severe skin reactions
Consider Gl
decontamination following
substantial ingestion
Control seizures with
anticonvulsants
CONTRAINDICATED
Induced emesis
Insect repellents are by nature different from all other pesticides because they are the
one class of chemicals applied purposefully to humans. The exceptions to this rule are
several insecticides (permethrin, lindane and malathion) that may be applied purpose-
fully to human skin or hair to treat scabies and lice. Repellents are not insecticidal;
rather they mask the human skin to detection by insects and arthropods (mosquitoes.
gnats, ticks).
Hundreds of insect repellents are marketed in the United States. The primary
synthetic insect repellents used in the U.S. are N,N-diethyl-3-methylbenzamide (also
and formerly known as N,N-diethyl-m-toluamide, DEET) and KBR 3023 (picaridin).
DEET was developed by the military around the time of World War II and has long
been considered the gold standard of insect repellents. Picaridin was developed in the
late 1990s and, prior to being marketed in the United States in the mid 2000s, was
available in Europe and Australia. Several natural products have been used as insect
repellents and are listed by the EPA as minimum risk pesticides, making them exempt
from federal regulation. These include oil of citronella, cedar oil, lemongrass oil and
others that are available in the retail market.1 Oil of lemon eucalyptus, its synthetic
analog PMD, picaridin, and IR3535 are recommended by the Centers for Disease
Control and Prevention (CDC) as alternatives to DEET to control mosquitoes that
carry West Nile virus.2 Picaridin has a duration of action comparable to some formula-
tions with 20%-30% DEET and other repellents.3 It has not been approved for ticks.
N,N-DIETHYL-3-METHYLBENZAMIDE(DEET)
This chemical is a widely used liquid insect repellent, suitable for application to skin or
to fabrics. It comes in a wide range of concentrations from 5% (Off! Skintastic for Kids)
to 100% (Muskol). Despite the widespread use of the product, there are relatively few
cases of toxicity reported in the literature.4 Improper use, ingestion and high-concentra-
tion usage on children are risk factors for the rarely observed severe toxicity.5
Toxicology
The toxicokinetics has been well studied in animal models and humans. Approxi-
mately 19%-48% of DEET penetrates the epidermis in about 6 hours in guinea pigs.
DEET can be detected within the blood and other tissues in mice within 2 hours of
application, and excretion in the form of inactive metabolites is the primary mode of
elimination.6'7 Similar absorption, distribution, metabolism and excretion are found in
humans.8 DEET is efficiently absorbed across the skin and by the gastrointestinal tract.
Blood concentrations of about 3 mg/liter have been reported several hours after dermal
application in the prescribed fashion.9 DEET is rapidly absorbed, peaks at around 6
hours, and within 24 hours its metabolites are completely excreted.8 Skin permea-
bility for DEET is enhanced by an ethanol substrate, which is how most formulations
are prepared.10 Human skin permeability of DEET is decreased using a polyethylene
glycol solvent.11'12
128
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For many years, DEBT has been effective and generally well tolerated as an
insect repellent applied to human skin, although tingling, mild irritation and some-
times desquamation have followed repeated application. It should be pointed out
that the label recommends "to avoid over application" and that the product should
be washed off upon returning indoors. The chemical tends to leave an oily residue on
the skin, and may dissolve plastic or other synthetic materials such as clothing, wrist
watches and other objects.
Signs and Symptoms of Poisoning
Most reports of adverse events following DEBT exposure are skin-related findings.
These include mild skin irritation, contact dermatitis, exacerbation of preexisting skin
disease as well as generalized urticaria.13'14 DEBT is very irritating to the eyes but not
corrosive.
Serious adverse cutaneous effects have occurred in tropical conditions, when
applied to areas of skin that were occluded during sleep (mainly the antecubital and
popliteal fossae). Under these conditions, the skin became red and tender and then exhib-
ited blistering and erosion, leaving painful, weeping, denuded areas that were slow to
heal. Severe scarring occasionally resulted from some of these severe reactions.15
Toxic encephalopathic reactions have been reported in rare instances following
ingestion or dermal application. Manifestations of toxic encephalopathy have been
headache, restlessness, irritability, ataxia, rapid loss of consciousness, hypotension and
seizures. Some cases have shown flaccid paralysis andareflexia. Deaths have occurred
following very large doses.4'5'16 Plasma levels of DEBT found in fatal systemic poison-
ings have ranged for 168 to 240 milligrams per liter.5 One well-documented case of
anaphylactic reaction to DEBT has been reported.17 One fatal case of encephalopathy
in a child heterozygous for ornithine carbamoyl transferase deficiency resembled
Reye's syndrome, but the postmortem appearance of the liver was not characteristic
of the syndrome.18
While most severe toxicity reports relate to multiple dermal applications of
various concentrations including as low as 10%,16'19'20'21 seizures following less frequent
dermal exposure has also been reported.22'23 A summary of the 22 cases reported in
the medical literature was reviewed in Pediatric Annals?-4 The difficulty of such case
reports is that exposure details cannot always be ascertained. The more severe cases of
systemic toxicity have often occurred following ingestion.4 No dose-response patterns
appear to exist among the small number of human toxicity reports.
The National Poison Data System, formerly known as the Toxic Exposure Surveil-
lance System, is used by the American Association of Poison Control Centers (AAPCC)
and allows a retrospective review of reports to poison control centers. Every year in
the annual report of poison control centers (PCCs), reports of adverse events following
insect repellents number in the hundreds, but most are listed as mild-to-moderate effects.
and no details are given as to the nature of the symptoms. Generally, data are based on
reports to PCCs, sometimes with or without follow-up information, so the data are limited
by what is reported and collected. Greater detail can be found in a review published
in 2002, based on 1993-1997 reports to poison control. Of 20,764 exposures reported
to PCCs, information on outcomes was reported for 11,600. Of these, 11,159 (96.2%)
were considered minor, and 437 (3.8%) were classified as moderate (409), major (26) or
fatal (2). The two deaths occurred in adults, both following exposure to a concentration
greater than 50% DEBT Of the 26 cases with major effects, half were adults and half
were 0-19 years of age. Two patients were exposed to less than 11% DEBT, one of whom
had neurological effects and the other was admitted to critical care although symptoms
were not reported. Thirteen of the 26 cases did not have DEBT concentrations available.
CHAPTER 14
Insect Repellents
N,N-Diethyl-3-
methylbenzamide (DEET)
COMMERCIAL
PRODUCTS
Auton
Cutter
Detamide
Metadelphene
MGK
Muskol
OFF!
Sawyer
Skeeter Beater
Skeeter Cheater
129
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CHAPTER 14
Insect Repellents
and 7 did not have symptom data available. Of those with symptom data available (17).
11 reported neurological symptoms.25
Discretion should be exercised in recommending DEBT for persons who have
acne, psoriasis, an atopic predisposition or other chronic skin condition. According to the
label, it should not be applied over cuts, wounds or irritated skin. In addition, it should
not be applied to any skin area that is likely to be opposed to another skin surface for a
significant period of time (antecubital and popliteal fossae, inguinal areas).15
Great caution should be exercised in using DEBT on children. A wide varia-
tion in applied concentrations has been associated with the reported cases of pediatric
seizures or major effects. Care should be taken to balance the risks of prevention of
arthropod-borne diseases, possible adverse effects and the duration of time the child
may be exposed. The adverse event reports suggest that multiple applications can
play a role in toxicity and reinforce the need to follow the product label on reapplica-
tion. Specifically, the label says "Avoid over application. Frequent reapplication and
saturation are unnecessary." The product should also be washed off after returning
indoors. To avoid multiple applications, use the concentration that best fits the dura-
tion of possible exposure. If the child is going to be outside for 1-2 hours, a product
containing 10% DEBT is likely to be effective. If the exposure time is longer, a product
with 5-7 hours of protection time (such as 25%-30% DEBT) may be more appropriate.3
The application should be limited to exposed areas of skin, using as little repellent as
possible. If headache or any emotional or behavioral change occurs, use of DEBT
should be discontinued immediately. The American Academy of Pediatrics does not
recommend using products that contain of DEBT on infants less than 2 months of age.
Confirmation of Poisoning
Methods exist for measurement of DEBT in plasma and tissues and of DEBT metabo-
lites in urine, but these are not widely available. The Centers for Disease Control and
Prevention (CDC) has developed a method for measuring DEBT (not the metabolite)
in the urine. In the nationally representative sample of U.S. residents conducted by
CDC for the years 2001 and 2002, DEBT was detected in approximately 10% of the
U.S. population, with a 90th percentile geometric mean of 0.100 ug/1, and a 95th percen-
tile geometric mean of 0.170 ug/1.26 Because the parent compound is excreted within
24 hours of exposure, this likely reflects individuals with recent exposure.
Treatment of DEET Toxicosis
1. Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Eye contamination should be removed by prolonged flushing of the
eye with copious amounts of clean water or saline. If irritation persists, special-
ized medical treatment should be obtained. Topical steroids and oral antihista-
mines have been used for severe skin reactions that occasionally follow applica-
tion of DEBT15
2. If a substantial amount of DEET has been ingested within an hour of treatment.
consider gastrointestinal decontamination as outlined in Chapter 3. Induced
emesis is usually considered contraindicated in these poisonings because of the
rapid onset of seizures.
3. Provide supportive treatment, controlling seizures with anticonvulsants as
outlined in Chapter 3. Persons surviving poisoning by ingestion of DEET have
usually recovered within 36 hours or less.4'5
130
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PICARIDIN
Picaridin, also known as KBR 3023, is a relatively new synthetic insect repellent.
Marketed in Europe in the 1990s, it was introduced to the U.S. market in 2005. It has
been shown to have relatively similar protection time as DEBT when tested in similar
concentrations. It tends to be less oily, better tolerated and less pungent than DEBT
and, unlike DEBT, does not damage plastics and synthetic fabrics.27
Toxicology
The mechanism of action of picaridin is unknown.28 Animal studies have not demon-
strated dermal, organ-specific or reproductive toxicity.29 Duration of protection from
mosquito bites depends on its concentration. Animal studies did not reveal acute
toxicity in doses as high as 200 mg/kg body weight.30 Likewise, animal studies did
not demonstrate any teratologic, developmental or neoplastic abnormalities.30'31 Most
commercially available products contain 7.5%, 10% and 15% picaridin, with the
lower-concentration product lasting approximately 2 hours and the 15% picaridin
lasting approximately 4-6 hours. Protection appears comparable to DEBT, and this
agent seems better tolerated.27'32'33'34'35
Signs and Symptoms of Poisoning
Allergic contact dermatitis has been reported in a human following routine application
and produced erythema and pruritis. It is not clear whether the solvent methyl glucose-
dioleate had a causative or additive effect.36 Other than the skin irritation, there are no
additional reports of toxic effects in humans.
Treatment of Picaridin Toxicosis
1. Treat skin irritation with oral antihistamines and topical steroids.
2. For eye exposure, irrigate eyes with copious amounts of water or normal saline. If
contact lenses are present, they should be removed.
3. Otherwise, provide supportive treatment.
CHAPTER 14
Insect Repellents
Picaridin
HIGHLIGHTS
Similar protection time
as DEETwith fewer
undesirable impacts
Unknown mechanism of
action
SIGNS & SYMPTOMS
Skin irritation
TREATMENT
Oral antihistamine, topical
steroid
Irrigate eyes if exposed
ESSENTIAL OILS
Numerous natural or essential-oil-based products are in use as insect repellents. The
repellency activity is thought to derive from camphor in some of the products, but
other activity is unknown. There is marked variability of the ingredients of oils in
various repellents and their efficacy, with some results supporting an essential oil as
effective or almost as effective as DEBT,37'38'39 while other results do not support these
efficacy findings.3'40 Of the oils, oil of lemon eucalyptus is the only one that has been
recommended by the CDC as being an effective alternative to DEBT41 Several essen-
tial oils are considered by the EPA to be minimum risk pesticides and are not subject
to federal registration requirements.
Toxicology
Oil of lemon eucalyptus is colorless to pale yellow in color and has an aromatic
odor and pungent taste. It primarily contains 1,8 cinole, along with a small amount of
131
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CHAPTER 14
Insect Repellents
Essential Oils
COMMERCIAL
PRODUCTS
cedar oil
lemongrass oil
oil of citronella
oil of lemon eucalyptus
HIGHLIGHTS
Variability of ingredients and
efficacy
CMS impacts from ingestion
other compounds, including hydrocyanic acid, which is thought to be the source of its
toxicity. Ingestion of eucalyptus oil is known to cause significant neurological toxicity,
and an adult fatality has been reported following ingestion of as little as 3.5 niL.42'43'44'45
Signs and Symptoms of Poisoning
Most reports of toxicity from eucalyptus oil have arisen from ingestion.43'44'45'46 Most
preparations include a combination of camphor, eucalyptus oil and menthol, such as
those used in a vaporizer solution or other medicinal purposes.47'48 The main symptoms
reported include vomiting, lethargy, coma and seizures.43'44
One published case report of systemic toxicity from essential oils related to
dermal application.42 In this case, a 6-year-old girl had numerous applications of
occlusive bandages soaked in a homemade solution including eucalyptus oil. Approx-
imately 24 hours after the applications were initiated, she appeared intoxicated and
progressed to complete loss of consciousness. Removal of the exposure and rinsing
her skin with water resulted in a full recovery within 24 hours.42 Several cases of irri-
tant dermatitis have also been reported, with signs and symptoms including erythema.
pruritis and a burning sensation.45'49
SIGNS & SYMPTOMS
Most toxicities from ingestion
Vomiting, lethargy, coma,
seizures
Dermal irritation possible
Treatment of Essential Oil Toxicosis
1. Provide supportive care, as there is no antidote.
2. If the patient is symptomatic or has ingested a large amount of essential oils.
consider GI decontamination.45 For specific information on GI decontamination.
please see Chapter 3, General Principles.
TREATMENT
Supportive
Consider GI
decontamination
References
1. United States Environmental Protection Agency. Minimum Risk Pesticides. 2010. http://
www.epa.gov/oppbppdl/biopesticides/regtools/25b_list.htm. Accessed December 30.
2012.
2. Center for Disease Control and Prevention. Updated Information regarding Insect Repel-
lents. 2009. http://www.cdc.gov/ncidod/dvbid/westnile/repellentupdates.htm. Accessed
December 30, 2012.
3. Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N
EnglJMed. M4 2002;347(1):13-18.
4. Veltri JC, Osimitz TG, Bradford DC, Page BC. Retrospective analysis of calls to poison
control centers resulting from exposure to the insect repellent N,N-diethyl-m-toluamide
(DEET)from 1985-1989. JToxicolClin Toxicol. 1994;32(1):1-16.
5. Tenenbein M. Severe toxic reactions and death following the ingestion of diethyltolua-
mide-containing insect repellents. JAMA. Sep 18 1987;258(11):1509-1511.
6. Blomquist L, Thorsell W. Distribution and fate of the insect repellent 14C-N, N-diethyl-
m-toluamide in the animal body. II. Distribution and excretion after cutaneous application.
Acta Pharmacol Toxicol (Copenh). Sep 1977;41(3):235-243.
7. Robbins PJ, Chemiack MG. Review of the biodistribution and toxicity of the insect repel-
lent N,N-diethyl-m-toluamide (DEET). J Toxicol Environ Health. 1986; 18(4): 503-525.
8. Selim S, Hartnagel RE, Jr., Osimitz TG, Gabriel KL, Schoenig GP Absorption, metabo-
lism, and excretion of N,N-diethyl-m-toluamide following dermal application to human
volunteers. Fundam Appl Toxicol. Apr 1995;25(1):95-100.
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CHAPTER 14
Insect Repellents
9. Wu A, Pearson ML, Shekoski DL, Soto RJ, Stewart RD. High resolution gas chromatog-
raphy/mass spectrometric characterization of urinary metabolites of N,N-diethyl-m-tolua-
mide (DEET) in man. J High Resolution Chromatogr. 1979;2(9):558-562.
10. Stinecipher J, Shah J. Percutaneous permeation of N,N-diethyl-m-toluamide (DEET) from
commercial mosquito repellents and the effect of solvent. J Toxicol Environ Health. Oct 10
1997;52(2): 119-135.
11. Qiu H, Jun HW, Dzimianski M, McCall J. Reduced transdermal absorption of N,N-diethyl-
m-toluamide from a new topical insect repellent formulation. Pharm Dev Technol. Feb
1997;2(l):33-42.
12. Ross J, Shah J. Reduction in skin permeation of W^V-diethyl-ra-toluamide (DEET) by
altering the skin / vehicle partition coefficient. Journal of Controlled Release. 2000;67:211 -
221.
13. Maibach HI, Johnson HL. Contact urticaria syndrome. Contact urticaria to diethyltolua-
mide (immediate-type hypersensitivity). Arch Dermatol. Jun 1975;111(6):726-730.
14. Wantke F, Focke M, Hemmer W, Gotz M, Jarisch R. Generalized urticaria induced by
a diethyltoluamide-containing insect repellent in a child. Contact Dermatitis. Sep
1996;35(3): 186-187.
15. Reuveni H, Yagupsky P. Diethyltoluamide-containing insect repellent: adverse effects in
worldwide use. Arch Dermatol. Aug 1982;118(8):582-583.
16. Lipscomb JW, Kramer JE, Leikin JB. Seizure following brief exposure to the insect repel-
\entN,N-diethy\-m-to\uamide.AnnEmergMed. Mar 1992;21(3):315-317.
17. Miller JD. Anaphylaxis associated with insect repellent. jV Engl J Med. Nov 18
1982;307(21):1341-1342.
18. Heick HM, Shipman RT, Norman MG, James W. Reye-like syndrome associated with use
of insect repellent in a presumed heterozygote for omithine carbamoyl transferase defi-
ciency. JPediatr. Sep 1980;97(3):471-473.
19. de Garbino P, Laborde A. Toxicity of an insect repellent: N-N-diethyltoluamide. Vet Hum
Toxicol. 1983;25(6):422-423.
20. Hampers LC, Oker E, Leikin JB. Topical use of DEET insect repellent as a cause of severe
encephalopathy inahealthy adult male. AcadEmergMed. Dec 1999;6(12):1295-1297.
21. Zadikoff CM. Toxic encephalopathy associated with use of insect repellent. JPediatr. Jul
1979;95(1): 140-142.
22. Briassoulis G, Narlioglou M, Hatzis T Toxic encephalopathy associated with use of
DEET insect repellents: a case analysis of its toxicity in children. Hum Exp Toxicol. Jan
2001;20(1):8-14.
23. Seizures temporally associated with use of DEET insect repellentNew York and Connect-
icut. MMWRMorbMortal WklyRep. Oct 6 1989;38(39):678-680.
24. Roberts JR, Reigart JR. Does anything beat DEET? PediatrAnn. Jul 2004;33(7):443-453.
25. Bell JW, Veltri JC, Page BC. Human Exposures to N,N-diethyl-m-toluamide insect repel-
lents reported to the American Association of Poison Control Centers 1993-1997. Int J
Toxicol. Sep-Oct2002;21(5):341-352.
26. Department of Health and Human Services Centers for Disease Control and Prevention.
Third National Report on Human Exposure to Environmental Chemicals. 2005.
27. Katz TM, Miller JH, Hebert AA. Insect repellents: historical perspectives and new devel-
opments. JAm AcadDermatol. May 2008;58(5):865-871.
28. Kendrick DB. Mosquito repellents and superwarfarin rodenticidesare they really toxic in
children? Curr Opin Pediatr. Apr 2006; 18(2): 180-183.
29. Picaridin - A New Insect Repellent. The Medical Letter on Drugs and Therapeutics.
2005;47(1210):46-47.
133
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Insect Repellents
30. Astroff AB, Freshwater KJ, Young AD, Stuart BP, Sangha GK, Thy ssen JH. The conduct of
a two-generation reproductive toxicity study via dermal exposure in the Sprague-Dawley
rata case study with KBR 3023 (a prospective insect repellent). Reprod Toxicol. May-Jun
1999;13(3):223-232.
31. Wahle BS, Sangha GK, Lake SG, Sheets LP, Croutch C, Christenson WR. Chronic toxicity
and carcinogenicity testing in the Sprague-Dawley rat of a prospective insect repellent
(KBR 3023) using the dermal route of exposure. Toxicology. Dec 20 1999;142(l):41-56.
32. Costantini C, Badolo A, Ilboudo-Sanogo E. Field evaluation of the efficacy and persistence of
insect repellents DEET, IR3535, and KBR 3023 against Anopheles gambiae complex and other
Afrotropical vector mosquitoes. TmnsRSoc TropMedHyg. Nov2004;98(ll):644-652.
33. Frances SP, Van Dung N, Beebe NW, Debboun M. Field evaluation of repellent formula-
tions against daytime and nighttime biting mosquitoes in a tropical rainforest in northern
Australia. JMedEntomol. May 2002;39(3):541-544.
34. Frances SP, Waterson DG, Beebe NW, Cooper RD. Field evaluation of commercial repel-
lent formulations against mosquitoes (Diptera: Culicidae) in Northern Territory, Australia.
JAmMosq ControlAssoc. Dec 2005;21(4):480-482.
35. ScheinfeldN. Picaridin: a new insect repellent. J Drugs Dermatol. Jan-Feb 2004;3(1):59-
60.
36. Corazza M, Borghi A, Zampino MR, Virgili A. Allergic contact dermatitis due to an insect
repellent: double sensitization to picaridin and methyl glucose dioleate. Acta Derm Vene-
real. 2005;85(3):264-265.
37. Barnard DR, Xue RD. Laboratory evaluation of mosquito repellents against Aedes albop-
ictus, Culex nigripalpus, and Ochierotatus triseriatus (Diptera: Culicidae). J Med Entomol.
Jul2004;41(4): 726-730.
38. Choi WS, Park BS, Ku SK, Lee SE. Repellent activities of essential oils and monoterpenes
against Culex pipiens pollens. JAmMosq Control Assoc. Dec 2002;18(4):348-351.
39. Tawatsin A, Thavara U, Chansang U, et al. Field evaluation of DEET, Repel Care, and
three plant based essential oil repellents against mosquitoes, black flies (Diptera: Simu-
liidae) and land leeches (Arhynchobdellida: Haemadipsidae) in Thailand. J Am Mosq
Control Assoc. Jun 2006;22(2):306-313.
40. Sfara V, Zerba EN, Alzogaray RA. Fumigant insecticidal activity and repellent effect of
five essential oils and seven monoterpenes on first-instar nymphs ofRhodniusprolixus. J
Med Entomol. May 2009;46(3):511-515.
41. KuehnBM. CDC: new repellents for West Nile fight. JAMA. Jun 1 2005;293(21):2583.
42. Darben T, Cominos B, Lee CT. Topical eucalyptus oil poisoning. Australas J Dermatol.
Nov 1998;39(4):265-267.
43. Kindle RC. Eucalyptus oil ingestion. NZMedJ. May 11 1994; 107(977): 185-186.
44. Patel S, Wiggins J. Eucalyptus oil poisoning. Arch Dis Child. May 1980;55(5):405-406.
45. Webb NJ, Pitt WR. Eucalyptus oil poisoning in childhood: 41 cases in south-east
Queensland. J Paediatr Child Health. Oct 1993;29(5):368-371.
46. Orr J. Eucalyptus Poisoning. BrMedJ. May 12 1906; 1(2367): 1085.
47. Day LM, Ozanne-Smith J, Parsons BJ, Dobbin M, Tibballs J. Eucalyptus oil poisoning
among young children: mechanisms of access and the potential for prevention. Aust NZ J
Public Health. Jun 1997;21(3):297-302.
48. Flaman Z, Pellechia-Clarke S, Bailey B, McGuigan M. Unintentional exposure of young
children to camphor and eucalyptus oils. Paediatr Child Health. Feb 2001;6(2): 80-83.
49. Schaller M, Korting HC. Allergic airborne contact dermatitis from essential oils used in
aromatherapy. Clin ExpDermatol. 1995;20(2):143-145.
134
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CHAPTER 15
Arsenical Pesticides
Arsenic Compounds
HIGHLIGHTS
Life-threatening effects on
CMS, blood vessels, kidney,
liver
Many arsenic compounds have been discontinued in the United States as a result
of government regulations. However, they are still widely available in some coun-
tries, and many homes and farms have leftover supplies that continue to present risk.
Arsenic trioxide is still used in some ant bait stations, which have been a source for
childhood exposure via ingestion in recent years.1 Another arsenic compound, arsine
gas, is not a pesticide but is released as a byproduct in pesticide manufacturing and
metal refining operations and is the most toxic of all forms of arsenic. It is discussed
separately in this chapter.
Toxicology
Arsenic is a natural element having both metal and nonmetal physical/chemical prop-
erties. In one respect or another, it resembles nitrogen, phosphorus, antimony and
bismuth in its chemical behavior. In nature it exists in elemental, trivalent (-3 or +3)
and pentavalent (+5) states. It binds covalently with most nonmetals (notably oxygen
and sulfur) and with metals (e.g., calcium and lead). It forms stable trivalent and
pentavalent organic compounds. In biochemical behavior, it resembles phosphorus.
competing with phosphorus analogs for chemical binding sites. Toxicity of the various
arsenic compounds in mammals extends over a wide range, determined, in part, by the
unique biochemical actions of each compound, but also by absorbability and efficiency
of biotransformation and disposition. After arsine gas, arsenites (inorganic trivalent
compounds) represent the next most toxic hazard of arsenic compounds. Doses of
78-180 mg of arsenic trioxide (-1-2.5 mg/kg in a child) are considered high enough to
be lethal.2 Inorganic pentavalent compounds (arsenates) are somewhat less toxic than
arsenites, while the organic (methylated) pentavalent compounds (arsonates) incur the
least hazard of the arsenicals that are used as pesticides.3
The pentavalent arsenicals are relatively water soluble and absorbable across
mucous membranes, while trivalent arsenicals, having greater lipid solubility, are
more readily absorbed across the skin.4 However, acute, systemic poisonings that
arise following dermal absorption of either form have been extremely rare. There are
numerous dermal manifestations of arsenic poisoning, which will be discussed later
in the chapter. Ingestion has been the usual basis of poisoning; gut absorption effi-
ciency depends on the physical form of the compound, its solubility characteristics.
the gastric pH, gastrointestinal motility and gut microbial transformation. Inhalation is
the major route of arsine exposure; toxic effects may also occur with other arsenicals
through inhalation of aerosols.
Once absorbed, many arsenicals cause toxic injury to cells of the nervous system.
bloodvessels, liver, kidney and other tissues. Two biochemical mechanisms of toxicity
are recognized: (1) reversible combination with thiol groups contained in tissue proteins
and enzymes and (2) substitution of arsenic anions for phosphate in many reactions.
including those critical to oxidative phosphorylation.5'6 Arsenic is readily metabolized in
the liver to a methylated form, which is much less toxic and easily excreted. However, it
is prudent to manage cases of arsenical pesticide ingestion as though all are highly toxic.
SIGNS & SYMPTOMS
Acute cases
Garlic odor of the breath and
feces
Metallic taste in mouth
Adverse Gl symptoms
Also CMS, renal &
cardiovascular symptoms
Jaundice
Chronic cases
Muscle weakness
Fatigue
Weight loss
Hyperpigmentation
Hyperkeratosis
Mees lines
TREATMENT
Skin, eye, Gl
decontamination
IV hydration
Chelation therapy with BAL,
DMSA, or d-penicillamine
Consider hemodialysis
135
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CHAPTER 15
Arsenicals
Inorganic Trivalent
Arsenic trioxide
"White arsenic." Arsenous
oxide. Has been
discontinued but still stocks
may still be on hand from
prior registrations.
Sodium arsenite
Sodanit, Prodalumnol
Double. Used as a fungicide
in vineyards.
Calcium arsenite
Mono-calcium arsenite.
Flow/able powder for
insecticidal use on fruit.
Copper arsenite
(Acid copper arsenite)
Wettable powder, for
use as insecticide, wood
preservative
Copper acetoarsenite
Insecticide. Paris Green,
Schweinfurt green, emerald
green, French green, mitis
green. No longer used in
the United States; still used
outside the United States.
Arsine
Not a pesticide.
Occasionally generated
during manufacture of
arsenicals.
See separate discussion in
subsection on p. 140.
Signs and Symptoms of Poisoning
Manifestations of acute poisoning (large amount absorbed over a short time) are distin-
guishable from those of chronic poisoning (lesser doses absorbed over a longer time
interval).
The symptoms and signs of acute arsenic poisoning usually appear within 1 hour
after ingestion, but may be delayed several hours. A garlic odor to the breath and feces
may help to identify the responsible toxicant in a severely poisoned patient. There
is often a metallic taste in the mouth. Gastrointestinal (GI) adverse effects predomi-
nate, with vomiting, abdominal pain and rice-water or bloody diarrhea being the most
common.1'3'7'8 Other GI effects include inflammation, vesicle formation and eventual
sloughing of the mucosa in the mouth, pharynx and esophagus.7 These effects result
from the action of an arsenical metabolite onblood vessels generally, but the splanchnic
vasculature particularly, causing dilation and increased capillary permeability.
The central nervous system is another system commonly affected during acute
poisoning. Symptoms may begin with headache, dizziness, drowsiness and confu-
sion. Symptoms may progress to include muscle weakness and spasms, hypothermia.
lethargy, delirium, coma and convulsions.3 Renal injury is manifest as proteinuria.
hematuria, glycosuria, oliguria, casts in the urine and, in severe poisoning, acute
tubular necrosis. Cardiovascular manifestations include shock, cyanosis and cardiac
arrhythmia,9'10 which are due to direct toxic action and electrolyte disturbances. Liver
damage may manifest as elevated liver enzymes and jaundice. Injury to blood-forming
tissues may cause anemia, leukopenia and thrombocytopenia. In lethal exposures death
usually occurs 1-3 days following symptom onset and is often the result of circulatory
failure, although renal failure may also contribute.3 If the patient survives, painful
paresthesias, tingling and numbness in the hands and feet may be experienced as
delayed sequelae of acute exposure. This sensorimotor peripheral neuropathy, which
may include muscle weakness and spasms, typically begins 1-3 weeks after expo-
sure.11 The muscle weakness may be confused with Guillain-Barre syndrome.12
Other organ systems are affected with arsenic toxicity. Liver injury reflected in
hepatomegaly and jaundice may progress to cirrhosis, portal hypertension and ascites.
Arsenic has direct glomerular and tubular toxicity resulting in oliguria, proteinuria
and hematuria. Electrocardiographic abnormalities (prolongation of the QTc interval
and torsades de pointes) and peripheral vascular disease have been reported. The latter
includes acrocyanosis, Raynaud's phenomenon and frank gangrene.3'13 Hematologic
abnormalities include anemia, leukopenia and thrombocytopenia.3 Late sequelae of
protracted high intakes of arsenic include skin cancer and an increased risk of lung
cancer.3'14
Numerous chronic effects are associated with arsenic. Most uses of arsenic as
a pesticide, as previously noted, have been discontinued, and most arsenic exposure
today is due to naturally occurring arsenic found in shallow well water. Several review
articles summarize the evidence of chronic arsenic toxicity.6'15'16 Repeated absorption
of subacutely toxic amounts of arsenic generally has an insidious onset of clinical
effects and may be difficult to diagnose. Neurologic, dermal and nonspecific manifes-
tations are usually more prominent than the gastrointestinal effects that characterize
acute poisoning. Muscle weakness and fatigue can occur, as can anorexia and weight
loss. Hyperpigmentation is a common sign and tends to be accentuated in areas that
are already more pigmented such as the groin and areola. Hyperkeratosis is another
common sign, especially on the palms and soles.14'17 Subcutaneous edema of the face.
eyelids and ankles; stomatitis; white striations across the nails (Mees lines) and loss
of nails or hair are other signs of chronic, continuous exposure.3'17 Chronic neurologic
effects and carcinogenic risks are discussed in Chapter 21, Chronic Effects.
136
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Confirmation of Poisoning
Measurement of 24-hour urinary excretion of arsenic (micrograms per day) is the most
common way to confirm excessive absorption and is the preferred method to follow
serial levels and evaluate chronic exposure.3'18 Spot urine arsenic analysis expressed
as a ratio with urinary creatinine is the recommended method to evaluate occupa-
tional exposures.19 Methods to determine blood arsenic concentration are available;
however, blood levels tend to poorly correlate with exposure or effect except in the
initial acute phase.18'20 Special metal-free, acid-washed containers should be used
for sample collection. Arsenic excretion above 100 ug per day should be considered
abnormal. Excretions above 200 ug per day reflect a toxic intake, unless seafood was
ingested.18'20'21'22'22 Diets rich in seafood, primarily shellfish eaten in the previous 48
hours, may generate 24-hour urine excretion levels as high as 200 ug/day and some-
times more.1'7'22 In some labs and reports, urinary arsenic levels are expressed as ug/1.
Normal values are 0-50 ug/1 for a 24-hour urine level.1'23
The majority of marine arsenic that is excreted is in the methylated form (arseno-
betaine) and not considered acutely toxic. However, some of the arsenic released from
mussels may contain higher amounts of arsenic trioxide than previously thought.22
Urinary arsenic should be speciated into inorganic and organic fractions to help deter-
mine the source of the exposure and to help guide treatment.
Concentrations of arsenic in blood, urine or other biologic materials can be
measured by either wet or dry ashing, followed by colorimetric or atomic absorption
spectrometric analysis. This latter method is preferred. Arsenic can be measured in
human urine by an inductively coupled plasma mass spectrometry (ICP-MS) method.
Blood concentrations in excess of about 100 ug per liter probably indicate excessive
intake or occupational exposure, provided that seafood was not ingested before the
sample was taken.7'18'20'21 Blood samples tend to correlate with urine samples during
the early stages of acute ingestion,18 but because arsenic is rapidly cleared from the
blood, the 24-hour urine sample remains the preferred method for detection and for
ongoing monitoring.3'18'20
Hair has been used for evaluation for chronic exposure. Levels in unexposed
people are usually less than 1 mg/kg and levels in individuals with chronic poisoning
range between 1 and 5 mg/kg.21 Hair samples should be viewed with caution because
external environmental contamination such as air pollution may artificially elevate
arsenic levels. Additionally, commercial laboratories have not been shown to have
reliably consistent results.24 Therefore, hair arsenic may be a reasonable tool for use in
research but not in the assessment of an acutely poisoned patient.
Special tests for arsine toxicosis are described in the Arsine Gas subsection
beginning on p. 140.
CHAPTER 15
Arsenicals
Inorganic Pentavalent
Arsenic acid
Hi-Yield DesiccantH-10,
Zotox. Water solutions used
as defoliants, herbicides.
Sodium arsenate
Disodium arsenate, Jones
Ant Killer, Terro Ant Killer.
All discontinued, but may
still be encountered from old
registration.
Calcium arsenate
Tricalcium arsenate,
Spra-cal, Turf-Cal. Flow/able
powder formulations used
against weeds, grubs.
Lead arsenate
Gypsine, Soprabel. Limited
use in the United States;
wettable powder used as
insecticide outside the
United States.
Zinc arsenate
Powder once used in the
United States as insecticide
on potatoes and tomatoes.
Treatment of Arsenic Compound Toxicosis
The following discussion applies principally to poisonings by arsenicals in solid
or dissolved form. Treatment of poisoning by arsine gas requires special measures
described in the Arsine Gas subsection beginning on p. 140.
1. Skin decontamination. Wash arsenical pesticide from skin and hair with copious
amounts of soap and water.
2. If a high-concentration solution is in contact with the eyes, wash eyes with a
profuse amount of water and examine the corneas carefully. If burns have
occurred, appropriate ophthalmologic care should be provided. See Chapter 3,
General Principles.
137
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CHAPTER 15
Arsenicals
Organic (Pentavalent)
Cacodylic acid
(sodium cacodylate)
Non-selective herbicide,
defoliant, silvicide.
Bolate, Bolls-Eye, Bophy,
Dilie, Kack, Phytar560,
Rad-E-Cate 25, Salvo.
Methane arsonic acid
MAA. Non-selective
herbicide.
Monosodium methane
arson ate
MSMA. Non-selective
herbicide, defoliant,
silvicide.
Ansar 170, Arsonate Liquid,
Bueno 6, Daconate 6,
Dal-E-Rad, DrexarSSO,
Herbi-AII, Merge 823,
Mesamate, Target MSMA,
Trans-Vert, Weed-E-Rad,
Weed-Hoe.
Disodium methane
arsonate
DSMA. Selective post-
emergence herbicide,
silvicide.
Ansar 8100, Arrhenal,
Arsinyl, Crab-E-Rad, Di-Tac,
DMA, MetharSO, Sodar,
Weed-E-Rad 360.
Monoammonium methane
arsonate
MAMA. Selective post-
emergence herbicide.
Calcium acid methane
arsonate
CAMA. Selective post-
emergence herbicide.
Calar, Super Crab-E-Rad-
Calar, Super Dal-E-Rad.
3. Gastrointestinal decontamination. If an arsenical pesticide has been ingested
within an hour of treatment, consider GI decontamination, as outlined in Chapter
3. Because poisoning by ingested arsenic often results in profuse diarrhea, it is
generally not appropriate to administer a cathartic. Although it is not clear how
well arsenic is absorbed by charcoal, charcoal and whole bowel irrigation were
used in recent case reports.1'8'25 Gastric lavage is also recommended, especially if
there are visible opacities on abdominal X-rays.8'26
4. Intravenous fluids. Administer intravenous fluids to restore adequate hydration.
support urine flow and correct electrolyte imbalances. Aggressive rehydration is
needed to correct the significant amount of fluid lost from the GI tract. Serum
electrolytes including magnesium and calcium should be monitored. Monitor
intake/output continuously to guard against fluid overload. If acute renal failure
occurs, monitor blood electrolytes regularly.
5. Hypovolemic shock. As above, use isotonic fluids (normal saline or lactated
ringers) to treat hypovolemia and hypotension associated with shock. Dopamine
and/or norepinepherine may be needed.
6. Cardiac monitoring. Obtain an electrocardiogram (ECG) to detect ventricular
arrhythmias, including prolonged Q-T interval and ventricular tachycardia and
toxic myocardiopathy (T wave inversion, long S-T interval).
7. Chelation therapy. Use chelation for severe poisoning, including symptomatic
poisoning or someone with a recent significant exposure. While there is not a defin-
itive cut-off value at which an asymptomatic patient should be chelated, a urine
arsenic level of 200 ug/liter has been suggested.1'27 Administration of dimercaprol
(B AL) has long been the chelator of choice in symptomatic arsenic poisonings.8'28
However, it is given as painful and frequent intramuscular injections. Oral agents.
such as dimercaptosuccinic acid (DMSA, also known as succimer) or d-peni-
cillamine, have also been used more frequently in individual cases;1'25'29'30'31'32
however, neither has been approved by the FDA for arsenic toxicity. (DMSA is
FDA-approved for lead toxicity.) DMSA and d-penicillamine are discussed in
greater detail below. The following dosage schedules have proven to be effective
in accelerating arsenic excretion.
Dosage of Dimercaprol (BAL)
Adults: BAL is provided as a 100 mg/mL solution in
peanut oil. The dosage is 3-5 mg/kg q 4-12 hours.
Children: Dosages are similar, but may start with 2.5-3.0
mg/kg.7828
CAUTION: Disagreeable side effects often accompany the use of BAL:
nausea, headache, burning and tingling sensations, sweating, pain in the
back and abdomen, tremor, restlessness, tachycardia and hypertension.
Acute symptoms usually subside in 30-90 minutes. Antihistamine drugs
may provide relief, especially if given prior to BAL. BAL may potentially
have other adverse effects. In rabbits, treatment of arsenite exposure with
BAL increased brain arsenic levels.33 Because of these side effects, consider
an oral chelation agent if tolerated.
138
-------
After the gastrointestinal tract is reasonably free of arsenic or if the patient can
tolerate oral chelation from the outset, consider an oral chelating agent. D-peni-
cillamine has been suggested; however, its effectiveness for arsenic exposure
has been questioned in experimental models, though it has been used with some
success in earlier human case reports.25'30'31'32'34
Dosage of D-penicillamine
Adults and children over 12 years: 0.5 gm every 6 hours,
given 30-60 minutes before meals and at bedtime for about
5 days.
Children under 12 years: 0.1 gm/kg body weight, not
exceeding 1.0 gm per day, every 6 hours, 30-60 minutes
before meals and at bedtime for about 5 days.
CAUTION: Adverse reactions to short-term therapy are rare; however,
persons allergic to penicillin may suffer allergic reactions to d-penicilla-
mine; they should not receive d-penicillamine.
CHAPTER 15
Arsenicals
DMSA (succimer) has also been shown to be an effective chelator of arsenic.
though it is not labeled for this indication.29 In light of the lack of effectiveness
of d-penicillamine, coupled with the low toxicity and high therapeutic index of
DMSA, it appears that the latter agent may be the preferred method for chronic
toxicity or when oral chelation is acceptable.1'25'29'34
Dosage of DMSA (Succimer)
Adults and Children: 10 mg/kg every 8 hours for 5 days,
followed by 10 mg/kg every 12 hours for an additional 14
days. (Maximum 500 mg per dose). It should be given with
food.
8. Extracorporeal hemodialysis. Consider whether to use extracorporeal hemodi-
alysis. When used in combination with BAL therapy, hemodialysis has limited
effectiveness in removing arsenic from the blood. Hemodialysis may be indicated
early in the course of poisoning to enhance arsenic elimination and maintain
extracellular fluid composition if severe acute renal failure occurs.35 A recent case
with acute renal failure resolved without the need for dialysis.8
9. Urinary arsenic excretion. Monitor urinary arsenic excretion while any chelating
agent is being administered. Once arsenic levels fall into the normal reference
range of 0-50 ug/1 or less than 50 ug/day, it is reasonable to discontinue chelation
therapy.1
139
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CHAPTER 15
Arsenicals
Arsine Gas
HIGHLIGHTS
Powerful hemolysin
ARSINE GAS
Arsine is not used as a pesticide. However, some poisonings by arsine have occurred
in pesticide manufacturing plants and metal-refining operations when arsenicals came
into contact with mineral acids or strong reducing agents.36'37 Arsine may also be
released following poisoning by arsenic trioxide.38
SIGNS & SYMPTOMS
Fatigue, headaches,
malaise, dizziness, nausea,
abdominal pain
Hemoglobinuria, jaundice,
very dark plasma
TREATMENT
Fresh air
IV fluids
Consider red blood cell or
plasma exchange transfusion
Toxicology and Signs and Symptoms of Arsine Poisoning
Arsine is a powerful hemolysin, a toxic action not exhibited by other arsenicals.
Arsine exposure occurs through inhalation with very little exposure required to cause
a serious hemolytic reaction. Death is due to hemolysis and secondary renal failure.
Exposure times of 30 minutes at 25-50 parts per million are considered lethal.39
Symptoms of poisoning usually appear 30-60 minutes after exposure but may
be delayed for up to 24 hours. Patients may exhibit a garlic odor to their breath. Signs
and symptoms are the result of sometimes profound hemolysis leading to hemolytic
anemia and include fatigue, headache, malaise, weakness, dizziness, dyspnea, nausea.
abdominal pain and vomiting. Red staining of the conjunctiva may be present. Free
hemoglobin may be present in plasma. Basophilic stippling of red cells, red cell frag-
ments, and ghosts are seen in the peripheral blood smear. Plasma will appear very
dark, almost black, resulting from elevated level of unconjugated bilirubin.36 Hyper-
kalemia secondary to hemolysis is possible.
Elevated concentrations of arsenic are found in the urine, but these are not nearly
as high as are found in poisonings by solid arsenicals. Dark red urine (hemoglobin-
uria) is often passed 4-6 hours after exposure. Usually 1-2 days after hemoglobinuria
appears, jaundice and bronzing of the skin may be evident. Abdominal tenderness.
hepatomegaly, and elevated hepatic enzymes all may occur.36'40
Renal failure due to direct toxic action of arsine and to products of hemolysis
represents the chief threat to life in arsine poisoning.41
Polyneuropathy and a mild psycho-organic syndrome are reported to have
followed arsine intoxication after a latency of 1-6 months.
Treatment of Arsine Toxicosis
1. Remove the victim to fresh air.
2. Administer intravenous fluids to keep the urine as dilute as possible and to support
excretion of arsenic and products of hemolysis. In the past urinary alkalinization
to pH 7.5 has been recommended, but this therapy is not proven.
CA UTION: Monitor fluid balance carefully to avoid fluid overload if renal
failure supervenes. Monitor plasma electrolytes, BUN and creatinine to detect
disturbances (particularly hyperkalemia) as early as possible.
3. Monitor urinary arsenic excretion to assess severity of poisoning. The amount of
arsine that must be absorbed to cause poisoning is small, and therefore high levels
of urinary arsenic excretion may not always occur, even in the face of significant
poisoning.41'42
4. If poisoning is severe, consider red blood cell exchange transfusion. It was
successful in rescuing one adult victim of arsine poisoning.36
140
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CHAPTER 15
Arsenicals
5. Consider plasma exchange, which has also been used to treat acute arsine
poisoning. A retrospective review study in China reported successful treatment
of 12 patients.40 Another case was treated with a combination of plasma exchange
and red blood cell exchange transfusion.36
6. Use extracorporeal hemodialysis to maintain normal extracellular fluid composi-
tion and to enhance arsenic elimination if renal failure occurs, but it is not very
effective in removing arsine carried in the blood.
References
1. Yarns JP, Caravati EM, Horowitz ZB, Stromness JR, Crouch BI, McKeown NJ. Acute
arsenic trioxide ant bait ingestion by toddlers. Clin Toxicol (Phila). Nov 2008;46(9):785-789.
2. Hazardous Substance Data Bank: Arsenic trioxide. 2010. http://toxnet.nlm.nih.gov/cgi-bin/
sis/search/f?./temp/~zoPqmn: 1. Accessed February 23, 2010.
3. Malachowski ME. An update on arsenic. ClinLabMed. Sep 1990;10(3):459-472.
4. Ellenhorn M. Arsenic: Metals and related compounds. In: Schonwald S, Ordog G, Wass-
erberger J, eds. Ellenhorn s Medical Toxicology, Diagnosis and Treatment of Human
Poisoning. 1 ed. Baltimore: Williams & Wilkins; 1997:1540.
5. Hughes MF. Arsenic toxicity and potential mechanisms of action. Toxicol Lett. Jul 7
2002;133(1):1-16.
6. Vahidnia A, van der Voet GB, de Wolff FA. Arsenic neurotoxicitya review. Hum Exp
Toxicol. Oct 2007;26(10):823-832.
7. Campbell JP, Alvarez JA. Acute arsenic intoxication. Am Fam Physician. Dec
1989;40(6): 93-97.
8. Yilmaz Y, Armagan E, Olmez O, Esen M, Alkis N, Dolar E. Acute arsenic self-poisoning
for suicidal purpose in a dentist: a case report. Hum Exp Toxicol. Jan 2009;28(l):63-65.
9. Goldsmith S, From AH. Arsenic-induced atypical ventricular tachycardia. N EnglJ Med.
Nov 6 1980;303(19):1096-1098.
10. St Petery J, Gross C, Victorica BE. Ventricular fibrillation caused by arsenic poisoning. Am
JDis Child. Oct 1970;120(4):367-371.
11. Heyman A, Pfeiffer JB, Jr., Willett RW, Taylor HM. Peripheral neuropathy caused by
arsenical intoxication; a study of 41 cases with observations on the effects of BAL (2, 3,
dimercapto-propanol). N EnglJ Med. Mar 1 1956;254(9):401-409.
12. Donofrio PD, Wilbourn AJ, Albers JW, Rogers L, Salanga V, Greenberg HS. Acute
arsenic intoxication presenting as Guillain-Barre-like syndrome. Muscle Nerve. Feb
1987;10(2): 114-120.
13. Lin TH, Huang YL, Wang MY. Arsenic species in drinking water, hair, fingernails, and
urine of patients with blackfoot disease. J Toxicol Environ Health A. Jan 23 1998;53(2): 85-
93.
14. Maloney ME. Arsenic in Dermatology. Dermatol Surg. Mar 1996;22(3):301-304.
15. Celik I, Gallicchio L, Boyd K, et al. Arsenic in drinking water and lung cancer: a system-
atic review. Environ Res. Sep 2008;108(l):48-55.
16. Rahman MM, Naidu R, Bhattacharya P. Arsenic contamination in groundwater in the
Southeast Asia region. Environ Geochem Health. Apr2009;31 Suppl 1:9-21.
17. Navarro B, Sayas MJ, Atienza A, Leon P. An unhappily married man with thick soles.
Lancet. Jun 8 1996;347(9015):1596.
18. Fesmire FM, Schauben JL, Roberge RJ. Survival following massive arsenic ingestion. Am
JEmergMed. Nov 1988;6(6):602-606.
141
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CHAPTER 15
Arsenicals
19. ACGIH. 1997 TLVs and BEIs. Threshold limit values for chemical substances and phys-
ical agents. Biological exposure indices. Cincinnatil997.
20. Wagner SL, Weswig P. Arsenic in blood and urine of forest workers as indices of exposure
to cacodylic acid. Arch Environ Health. Feb 1974;28(2):77-79.
21. Baselt R, Cravey R. Arsenic. Disposition of Toxic Drugs and Chemicals in Man. 3 ed.
Chicago: Year Book Medical Publishers. 1990:65-69.
22. Buchet JP, Pauwels J, Lauwery s R. Assessment of exposure to inorganic arsenic following
ingestion of marine organisms by volunteers. Environ Res. Jul 1994;66(1):44-51.
23. Agency for Toxic Substance and Disease Registry. Toxicological Profiles. 2010. http://
www.atsdr.cdc.gov/toxprofiles/index.asp.AccessedDecember 14, 2012.
24. BarrettS.Commercialhairanalysis. Scienceorscam? J.4M4. Aug 23-30 1985;254(8): 1041-
1045.
25. Isbister GK, Dawson AH, Whyte IM. Arsenic trioxide poisoning: a description of two
acute overdoses. Hum Exp Toxicol. Jul 2004;23(7):359-364.
26. Michaux I, Haufroid V, Dive A, et al. Repetitive endoscopy and continuous alkaline gastric
irrigation in a case of arsenic poisoning. J Toxicol Clin Toxicol. 2000;38(5):471-476.
27. Kersjes MP, Maurer JR, Trestrail JH, McCoy DJ. An analysis of arsenic exposures referred
to the Blodgett Regional Poison Center. Vet Hum Toxicol. Feb 1987;29(1): 75-78.
28. Roses OE, Garcia Fernandez JC, Villaamil EC, et al. Mass poisoning by sodium arsenite. J
Toxicol Clin Toxicol. 1991;29(2):209-213.
29. Muckter H, Liebl B, Reichl FX, Hunder G, Walther U, Fichtl B. Are we ready to replace
dimercaprol (BAL) as an arsenic antidote? Hum Exp Toxicol. Aug 1997;16(8):460-465.
30. Kuruvilla A, Bergeson PS, Done AK. Arsenic poisoning in childhood. An unusual case
report with special notes on therapy with penicillamine. Clin Toxicol. 1975;8(5):535-540.
31. Peterson RG, Rumack BH. d-penicillamine therapy of acute arsenic poisoning. J Pediatr.
Octl977;91(4):661-666.
32. Watson WA, Veltri JC, Metcalf TJ. Acute arsenic exposure treated with oral d-penicilla-
mine. Vet Hum Toxicol. 1981;23:164-166.
33. Hoover TD, Aposhian HV. BAL increases the arsenic-74 content of rabbit brain. Toxicol
ApplPharmacol. Aug 1983;70(1):160-162.
34. Kreppel H, Reichl FX, Forth W, Fichtl B. Lack of effectiveness of d-penicillamine in
experimental arsenic poisoning. Vet Hum Toxicol. Feb 1989;31(l):l-5.
35. Blythe D, Joyce DA. Clearance of arsenic by haemodialysis after acute poisoning with
arsenic trioxide. Intensive CareMed. Jan2001;27(l):334.
36. Danielson C, Houseworth J, Skipworth E, Smith D, McCarthy L, Nanagas K. Arsine toxicity
treated with red blood cell and plasma exchanges. Transfusion. Sep 2006;46(9): 1576-1579.
37. Pullen-James S, Woods SE. Occupational arsine gas exposure. J Natl Med Assoc. Dec
2006;98(12):1998-2001.
38. Kinoshita H, Hirose Y, Tanaka T, Yamazaki Y Oral arsenic trioxide poisoning and
secondary hazard from gastric content. Ann EmergMed. Dec 2004;44(6): 625-627.
39. Blackwell M, Robbins A. Arsine (arsenic hydride) poisoning in the workplace. Am IndHyg
Assoc J. Oct 1979;40(10):A56-61.
40. Song Y, Wang D, Li H, Hao F, Ma J, Xia Y. Severe acute arsine poisoning treated by plasma
exchange. Clin Toxicol (Phila). Sep 2007;45(6): 721-727.
41. Fowler BA, Weissberg JB. Arsine poisoning. N Engl J Med. Nov 28 1974;291(22):1171-
1174.
42. Rathus E, Stinton RG, Putman JL. Arsine poisoning, country style. Med J Aust. Mar 10
1979;1(5): 163-166.
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CHAPTER 16
HIGHLIGHTS
Fungicides
Fungicides are extensively used in industry, agriculture and the home and garden for:
1. protection of seed grain during storage, shipment and germination;
2. protection of mature crops, berries, seedlings, flowers and grasses in the field, in
storage and during shipment;
3. suppression of mildews that attack painted surfaces;
4. control of slime in paper pulps; and
5. protection of carpet and fabrics in the home.
Approximately 500 million pounds of fungicides are applied worldwide annu-
ally (see Chapter 1, Introduction).
Fungicides vary enormously in their potential for causing adverse effects
in humans. Historically, some of the most tragic epidemics of pesticide poisoning
occurred by mistaken consumption of seed grain treated with organic mercury or
hexachlorobenzene. However, most fungicides currently in use and registered for use
in the United States are unlikely to cause frequent or severe acute systemic poison-
ings for several reasons: (1) many have low inherent toxicity in mammals and are
inefficiently absorbed; (2) many are formulated as suspensions of wettable powders
or granules, from which rapid, efficient absorption is unlikely; and (3) methods of
application are such that relatively few individuals are intensively exposed. Apart
from systemic poisonings, fungicides as a class also cause irritant injuries to skin and
mucous membranes, as well as some dermal sensitization.
The following discussion considers the recognized adverse effects of widely
used fungicides. In the case of those agents that have caused systemic poisoning, some
recommendations for management of poisonings and injuries are provided. For those
fungicides not known to have caused systemic poisonings in the past, only general
guidelines can be offered.
The discussion of fungicide-related adverse effects proceeds in this order:
Numerous fungicides in use
with varying levels of toxicity
Most are unlikely to cause
systemic poisonings,
exceptions being
Organomercury
compounds
Triazoles
Some copper
compounds
Isolated EBDC
exceptions
Substituted Benzenes
Strobilurins
Thiocarbamates
Ethylene Bis
Dithiocarbamates
Thiophthalimides
Triazoles
Copper Compounds
Organomercury Compounds
Organotin Compounds
Cadmium Compounds
Miscellaneous Organic
Fungicides
143
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CHAPTER 16
Fungicides
Substituted Benzine
COMMERCIAL
PRODUCTS
chloroneb (Terraneb SP)
chlorothalonil (Bravo, Clorto
Caffaro, Clortosip, Daconil
2787, Exotherm Termil,
Tuffcide, others)
dicloran (DCNA, Allisan,
Clortran)
hexachlorobenzene (HCB,
Anticarie, Ceku C.B., No
Bunt)
PCNB, also known as
pentachloronitrobenzene
(PCNB, quintozene,
Avicol, Earthcide, Folosan,
Kobu, Kobutol, Pentagen,
Tri-PCNB, terraclor, and
others)
HIGHLIGHTS
No cases of human
systemic poisoning have
been reported in the medical
literature for chloroneb,
chlorothalonil, dicloran or
PCNB
TREATMENT
Decontaminate skin and
eyes
In cases where large
amounts of HCB have
been ingested, consider Gl
decontamination
SUBSTITUTED BENZENES
Toxicology
Chloroneb is supplied as wettable powder for treatment of soil and seed. This agent
exhibits very low oral toxicity in mammals.1 It may be moderately irritating to skin
and mucous membranes. The metabolite dichloromethoxyphenol is excreted in the
urine. No cases of systemic poisoning in humans have been reported.
Chlorothalonil is available as wettable powder, water dispersible granules and
flowable powders. Chlorothalonil has caused irritation of skin and mucous membranes
of the eye and respiratory tract on contact. Cases of allergic contact dermatitis have
been reported.2'3'4'5 There is one report of immediate anaphylactoid reaction to skin
contact.6 Chlorothalonil is poorly absorbed across the skin and the gastrointestinal
lining. In a man known to have atopic dermatitis and allergic rhinitis, occupational
exposure to chlorothalonil was reported to induce asthma symptoms, which resolved
following cessation of exposure.7 No cases of systemic poisoning in humans have
been reported in the published medical literature.
Dicloran, also known as DCNA, is formulated as wettable powder, dust, liquid
and flowable powder. This broad-spectrum fungicide was widely used to protect perish-
able produce. It is absorbed through the skin by occupationally exposed workers, but
promptly eliminated, at least partly, in the urine. Biotransformation products include
dichloroaminophenol, which is an uncoupler of oxidative phosphorylation (enhances
heat production). According to the EPA's Registration Eligibility Decision (RED).
there is low oral toxicity to mammals (rat LD50 is 3,400 mg/kg). There have been no
cases of human systemic poisoning reported in the medical literature.
Hexachlorobenezene (HCB) is principally formulated as dusts and powders. All
registrations in the United States have been canceled. It differs chemically and toxi-
cologically from hexachlorocyclohexane, the gamma isomer of which is also known
as lindane, which is still used in limited amounts as an insecticide and as a pharma-
ceutical agent for the treatment of lice and scabies (see Chapter 7, Organochlorines).
Although this seed-protectant fungicide has only slight irritant effects and rela-
tively low single-dose toxicity, long-term ingestion of HCB-treated grain by Turkish
farm dwellers in the late 1950s caused several thousand cases of toxic porphyria
resembling porphyria cutanea tarda.8 This condition was due to impaired hemoglobin
synthesis, leading to toxic end products (porphyrins) in body tissues. The disease was
characterized by excretion of red-tinged (porphyrin-containing) urine, bullous lesions
of light-exposed skin, scarring and atrophy of skin with overgrowth of hair, liver
enlargement, loss of appetite, arthritic disease and wasting of skeletal muscle mass.
Although most adults ultimately recovered after they stopped consuming the HCB-
treated grain, some infants nursed by affected mothers died.8
Hexachlorobenzene is effectively dechlorinated and oxidized in humans; trichlo-
rophenols are the major urinary excretion products. Disposition is sufficiently prompt
that occupationally exposed workers usually show only slight elevation of blood HCB
concentrations. HCB is sometimes present in blood specimens from "non-occupation-
ally exposed" persons up to concentrations of about 5 ug per liter. Residues in food
are the probable cause. Studies have suggested that adverse neurobehavioral effects in
children may occur following exposure to hexachlorobenzene, and these are discussed
in Chapter 21, Chronic Effects.910
PCNB (also known as Pentachloronitrobenzene) is used to treat seed and soil.
Formulations include emulsifiable concentrates, wettable powders and granules.
Hexachlorobenzene is a minor contaminant to technical PCNB.
Systemic poisonings have not been reported in humans. Clearance in laboratory
animals is chiefly biliary, with some conversion to pentachloroaniline, pentachloro-
phenol and other metabolites in the liver.11'12 Although a methemoglobinemic effect is
144
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suspected (as from nitrobenzene), this has not been reported in man or animals, nor has
toxic porphyria (as from hexachlorobenzene) been reported.
Confirmation of Poisoning
Chloroneb, chlorothalonil, dicloran, HCB and PCNB all have described methods for
analysis by chromatography, but those methods are not widely available. The trichlo-
rophenol metabolites of HCB can be measured in the urine.
Although inherited disease and a number of exogenous agents may cause
porphyrins to appear in the urine, a test for porphyrins may be useful for lexicological
diagnosis if there has been a known exposure to HCB or if a patient exhibits signs
suggestive of porphyria cutanea tarda.
Treatment of Substituted Benzene Toxicosis
1. Wash off dermal contamination with soap and water. Remove contamination of
the eyes by flushing with copious amounts of water. If irritation persists, special-
ized medical care should be obtained. See Chapter 3, General Principles.
2. If a large amount of HCB has been ingested in the last few hours, and if copious
vomiting has not already occurred, consider GI decontamination as outlined in
Chapter 3. If contact with the toxicant has been minimal (for example, oral
contamination only) promptly flushing out the mouth and observation are prob-
ably sufficient.
Persons affected by porphyria should avoid sunlight, which exacerbates the
dermal injury by porphyrins.
STROBILURIN FUNGICIDES
Strobilurin compounds are a relatively newer class of fungicides, discovered in the
1990s and introduced to the market in the late 1990s and early 2000s. They are used
in agriculture to kill numerous types of pathogenic fungi including mildews, molds
and rusts.
Toxicology
Strobilurin fungicidal activity inhibits mitochondria! respiration by disrupting the
cytochrome complex, thus blocking electron transfer.13 Strobilurin compounds work
on a broad range of fungal pests and are now used on a wide range of crops, most
notably corn, since 2004.14
These compounds have a relatively low acute toxicity; most have a reported LD50
oral of over 5,000 mg/kg, except orysastrobin and metominostrobin, with LD50 of 356
mg/kg and 708 mg/kg, respectively.13'15 Few human data are available, though several
separate incidents in July 2007 were reported by the CDC. All reports were based on
pyraclostrobin. Toxic effects were considered minimal and short term, with resolution
after patient was removed from exposure. Symptoms and signs included eye irritation.
upper respiratory tract irritation, weakness, dizziness, purities, skin redness and chest
pain. In one case, workers in an adjacent corn field were exposed and felt the drop-
lets following aerial spraying, and the major symptoms reported in this incident were
upper respiratory tract pain and chest pain.14
CHAPTER 16
Fungicides
Strobilurin
COMMERCIAL
PRODUCTS
azoxystrobin (Abound,
Amistar, Azo-shield, Azotech,
Azoxy, Banner Heritage,
Dynasty, Dyna-shield,
Graduate A+, Heritage,
Protege, Quadris, Quartet,
Quilt, Renown, Soygard,
Sporgard, Trio, Uniform)
kresoxim-methyl (Allegro,
Cygnus, Sovran)
metominostrobin
orysastrobin
picoxystrobin (Benzeneacetic
acid, Cygnus, Juwel, Mentor,
Ogam, Stroby/Sovran)
pyraclostrobin (Bas, Cabrio,
Cornet, Headline, Honor,
Insignia, Opera, Pageant,
Pristine, Stamina)
trifloxystrobin (Absolute,
Armada, Chipco, Compass,
Distinguish, Dyna-shield,
Flint, Four way, Gem,
Prosper, RTU-trifloxystrobin-
metalaxyl, Stratego, Tartan,
Three way, Trilex, USF)
HIGHLIGHTS
Widely used on many crops
Low acute toxicity
SIGNS & SYMPTOMS
Eye & respiratory irritation
Weakness, dizziness
TREATMENT
Supportive
Consider skin/eye
decontamination
145
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CHAPTER 16
Fungicides
Thiocarbamate
COMMERCIAL
PRODUCTS
thiram (Aules, Chipco
Thiram 75, Fermide 850,
Fernasan, Hexathir,
Mercuram, Nomersam,
Polyram-Ultra, Pomarsol
forte, Spotrete-F, Spotrete
WP 75, Tetrapom, Thimer,
Thioknock, Thiotex,
Thiramad, Thirasan,
Thiuramin, Tirampa, TMTD,
Trametan, Tripomol, Tuads)
ziram (Cuman, Hexazir,
Mezene, Tricarbamix,
Triscabol, Vancide MZ-96,
Zincmate, Ziram Technical,
Ziram F4, Zirberk, Zirex 90,
Ziride, Zitox)
ferbam (Carbamate WDG,
Ferbam, Ferberk, Hexaferb,
Knockmate, Trifungol)
Confirmation of Poisoning
Tests to detect these compounds are not readily available.
Treatment of Strobilurin Toxicosis
Remove the patient from the source of exposure.
Provide supportive treatment directed to symptoms. Significant acute toxicity is
not generally expected; therefore, exposure can be asymptomatic and symptoms
usually do not warrant medical attention.
Consider skin decontamination as outlined in Chapter 3, General Principles.
Flush eyes with water or normal saline. If eye irritation, redness or swelling persists
for more than 15 minutes, recommend consultation with an ophthalmologist.
THIOCARBAMATES
Thiocarbamates are commonly formulated as dusts, wettable powders or water
suspensions. They are used to protect seeds, seedlings, ornamentals, turf, vegetables
and fruit including apples. Unlike the N-methyl carbamates (Chapter 6), thiocar-
bamates have very little insecticidal potency. A few exhibit weak anticholinesterase
activity, but most have no significant effect on this enzyme. Overall, they are less of
a threat to human health than the insecticidal carbamates. Fungicidal thiocarbamates
are discussed in this section, while those used as herbicides are considered in Chapter
13, Other Herbicides.
Metam-sodium, thiram and ziram and ferbam are the thiocarbamate pesticides.
They are discussed individually.
Metam-sodium
Metam-sodium is formulated in aqueous solutions for application as a soil biocide to
kill fungi, bacteria, weed seeds, nematodes and insects. All homeowner uses have been
canceled in the United States.
Toxicology
Although animal feeding studies do not indicate high toxicity of metam-sodium
by ingestion, its decomposition in water yields methyl isothiocyanate, a gas that is
extremely irritating to the eyes and to respiratory mucous membranes including the
lower respiratory tract/lungs. Inhalation of methyl isothiocyanate may cause pulmo-
nary edema, manifesting with severe respiratory distress and coughing of bloody,
frothy sputum. For this reason, metam-sodium must be used outdoors only, and strin-
gent precautions must be taken to avoid inhalation of evolved gas. Metam-sodium can
be very irritating to the skin.
Theoretically, exposure to metam-sodium may predispose the individual to
"Antabuse" reactions if alcohol is ingested after exposure. Such occurrences have not
been reported in the medical literature.
Confirmation of Poisoning
There are no tests for metam-sodium or its breakdown products in body fluids.
146
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Treatment of Metam-sodium Toxicosis
Decontaminate skin and GI tract, as outlined in Chapter 3, General Principles.
If pulmonary irritation or edema occurs as a result of inhaling methyl isothiocya-
nate, transport the victim promptly to a medical facility. Treatment for pulmonary
edema should proceed as outlined in Chapter 17, Fumigants in the Treatment of
Fumigant Toxicosis subsection beginning on page 166.
Metam-sodium is not a cholinesterase inhibitor. Atropine is not antidotal.
Thiram
Thiram dust is moderately irritating to human skin, eyes and respiratory mucous
membranes. Contact dermatitis has occurred in occupationally exposed workers. A few
individuals have experienced sensitization to thiram.16 Thiram is a common component
of latex and possibly responsible for some of the allergies attributed to latex.
Toxicology
Systemic human poisonings by thiram itself have been very few, probably due to
limited absorption in most circumstances involving human exposure. Those that have
been reported have been similar clinically to toxic reactions to disulfiram (Anta-
buse), the ethyl analogue of thiram that has been extensively used in alcohol aversion
therapy.16 In laboratory animals, thiram at high dosage has effects similar to those of
disulfiram (hyperactivity, ataxia, loss of muscle tone, dyspnea and convulsions), but
thiram appears to be about 10 times more toxic than disulfiram.
Neither thiram nor disulfiram is a cholinesterase inhibitor. Both, however, inhibit
the enzyme acetaldehyde dehydrogenase, which is critical to the conversion of acetal-
dehyde to acetic acid. This is the basis for the "Antabuse" reaction that occurs when
ethanol is consumed by a person on regular disulfiram dosage. The "reaction" includes
symptoms of nausea, vomiting, pounding headache, dizziness, faintness, mental
confusion, dyspnea, chest and abdominal pain, profuse sweating and skin rash. In rare
instances, Antabuse reactions may have occurred following ingestion of beverages
containing alcohol among workers previously exposed to thiram.
Confirmation of Poisoning
Urinary xanthurenic acid excretion has been used to monitor workers exposed to
thiram, but the test is not generally available.
Treatment of Thiram Toxicosis
Decontaminate skin and GI tract as outlined in Chapter 3, General Principles.
Infuse appropriate intravenous fluids, especially if vomiting and diarrhea are
severe. Monitor serum electrolytes and glucose and replace as needed.
Treatment of Acetaldehyde Toxicosis (Antabuse reaction)
Use oxygen inhalation, trendelenburg positioning and intravenous fluids, which
are usually effective in relieving manifestations of "Antabuse" reactions.
CHAPTER 16
Fungicides
Thiocarbamate
HIGHLIGHTS
Formulated as dusts,
wettable powders, water
suspensions
Less human health threat
than insecticidal carbamates
SIGNS & SYMPTOMS
Skin, eye, respiratory
irritation
For metam-sodium
inhalation, respiratory
distress, bloody sputum
May result in Antabuse-
like reaction if alcohol is
consumed after exposure
TREATMENT
Decontaminate skin and GI
tract
For metam-sodium, treat
pulmonary impacts as for
fumigant toxicosis
For thiram, ziram and
ferbam, IV fluids as needed
For Antabuse reaction,
oxygen, IV fluids and
trendelenburg positioning
147
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CHAPTER 16
Fungicides
EBDC Compound
COMMERCIAL
PRODUCTS
maneb (Kypman 80, Manex
80, Maneba, Manex,
M-Diphar, Sopranebe,
Trimangol)
zineb* (Aspor, Dipher,
Hexathane, Kypzin, Parzate
C, Tritoftorol, Zebtox)
nabam (Chem Bam, DSE,
Parzate, Spring Bak)
mancozeb (Manzeb,
Dithane, Mancozin, Manzin,
Nemispor, Penncozeb,
Ziman-Dithane)
*AII products canceled
HIGHLIGHTS
Most products no longer in
use
Low systemic toxicity
Advise persons who have absorbed any significant amount of thiocarbamates to
avoid alcoholic beverages for at least 3 weeks. Disposition of thiocarbamates is
slow, and their inhibitory effects on enzymes are slowly reversible.
Ziram and Ferbam
Ziram and ferbam are formulated as flowable and wettable powders and are used
widely on fruit and nut trees, apples, vegetables and tobacco.
Toxicology
Since ziram and ferbam are similar to thiram, it is reasonable to assume that similar
toxic effects may occur, including irritation to the skin, respiratory tract and eyes.
However, there are no reports of human poisoning in the medical literature. If absorbed
in sufficient dosage, these metallothiocarbamates may theoretically predispose the
patient to an "Antabuse" reaction following ingestion of alcohol. (See thiram.) No
occurrences of this have been reported.
Confirmation of Poisoning
No tests for these fungicides or their breakdown products in body fluids are available.
Treatment of Ziram and Ferbam Toxicosis
Decontaminate skin and GI tract as needed, as outlined in Chapter 3, General
Principles.
Treat as for thiram.
SIGNS & SYMPTOMS
Skin, eye, respiratory
irritation
Possible behavioral,
neurological symptoms
TREATMENT
Skin, eye decontamination
Consider GI
decontamination
Consider hemodialysis for
renal failure
ETHYLENE BIS DITHIOCARBAMATES (EBDC COMPOUNDS)
Maneb and zineb are formulated as wettable and flowable powders. Nabam is provided
as a soluble powder and in water solution. Mancozeb is a coordination product of zinc
ion and maneb. It is formulated as a dust and as wettable and liquid flowable powders.
Although some products, including maneb and mancozeb, were widely used in the
1990s and 2000s, particularly in agricultural settings and on golf courses, most of
these products are no longer in use.
Toxicology
Maneb, zineb, nabam and mancozeb may cause irritation of the skin, respiratory
tract and eyes. Some cases of chronic skin disease in occupationally exposed workers
have been attributed to both maneb and zineb, possibly by sensitization.17-18
Although marked adverse effects may follow injection of EBDC compounds into
animals, systemic toxicity by oral and dermal routes is generally low. Nabam exhibits
the greatest toxicity, probably due to its greater water solubility and absorbability.
Maneb is moderately soluble in water, but mancozeb and zineb are essentially water
insoluble. Absorption of the latter fungicides across skin and mucous membranes
is probably very limited. Maneb, mancozeb and metriam all are metabolized to the
degradation product ethylene thiourea, which may have toxic properties of its own.19
148
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Reports of acute systemic poisonings in humans have been rare. However, zineb
precipitated an episode of hemolytic anemia in one worker presumably predisposed
because of multiple red cell enzyme deficiencies.20 Maneb toxicity has been reported
in one person who developed acute renal failure and was treated with hemodialysis.21
Behavioral and neurological symptoms may also occur following maneb poisoning.
These include mental status changes, loss of consciousness and tonic-clonic seizures.
These appear to improve with supportive care.22'23 Symptoms similar to Parkinson's
disease have also been reported in settings of chronic, occupational exposure, possibly
due to the manganese component of maneb.24 Animal studies suggest that following
acute exposure at high doses, chronic symptoms similar to Parkinson's may also
occur.19
The EBDC compounds are not inhibitors of cholinesterase or of acetaldehyde
dehydrogenase. They do not induce cholinergic illness or "Antabuse" reactions.
Confirmation of Poisoning
No tests for these fungicides or their breakdown products in body fluids are available.
Treatment of Ethylene Bis Dithiocarbamate Toxicosis
See treatment for substituted benzenes, page 145.
Should severe renal failure occur, consider hemodialysis.
THIOPHTHALIMIDES
Captan, captafol and folpet are widely used to protect seed, field crops and stored
produce. They are formulated as dusts and wettable powders.
Toxicology
Captan, captafol and folpet are moderately irritating to the skin, eyes and respira-
tory tract. Dermal sensitization may occur; captafol has been associated with several
episodes of occupational contact dermatitis.25-26 Very few systemic poisonings by
thiophthalimides have been reported in humans. Captafol has been reported to have
exacerbated asthma after occupational exposure.27 A17-year-old who ingested captafol
in a suicide attempt had symptoms including headache, nausea, weakness, numbness
of upper limbs and substernal chest pain with an accompanying elevation in creatine
kinase and aspartate aminotransferase, and inverted T waves on electrocardiogram. All
abnormalities resolved with supportive care over a 72-hour period.28
Confirmation of Poisoning
Following oral exposure, captan fungicides are rapidly metabolized in the body to
yield two metabolites that can be measured in the urine: tetrahydrophthalimide (THPI)
and thiazolidine-2-thione-4-carboxilic acid (TTCA). Both are considered useful
biomarkers for occupational exposure.29
Treatment of Thiophthalimide Toxicosis
See treatment for substituted benzenes, page 145.
CHAPTER 16
Fungicides
Thiophthalimide
COMMERCIAL
PRODUCTS
captan (Captanex, Captaf,
Merpan, Orthocide,
Vondcaptan)
captafol (Crisfolatan,
Difolatan, Foltaf, Haipen,
Merpafol, Mycodifol,
Sanspor)
folpet (Folpan, Phaltan,
Thiophal, Fungitrol II)
HIGHLIGHTS
Dusts, wettable powders
Used in seed & field crops,
stored produce
Few systemic poisonings
reported in the medical
literature
SIGNS & SYMPTOMS
Skin, eye, respiratory
irritation
TREATMENT
Skin, eye decontamination
Consider Gl
decontamination
149
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CHAPTER 16
Fungicides
Triazole
COMMERCIAL
PRODUCTS
triadimefon (Bayleton,
Amiral)
myclobutanil
propiconazole (Tilt)
flutriafol
HIGHLIGHTS
Moderate acute oral toxicity
Possible chronic effects
Low dermal toxicity
TREATMENT
Skin, eye decontamination
Consider Gl
decontamination
TRIAZOLE FUNGICIDES
Triazoles are supplied as wettable powder, emulsifiable concentrate, suspension
concentrate, paste and dry flowable powder. Most triazoles are used on fruit, cereals,
vegetables, coffee, ornamentals, sugarcane, pineapples and turf. (Another compound
in this class is fluconazole, a pharmaceutical commonly used to treat fungal infections
in humans.) Uses of triadimefon were voluntarily canceled by the registrant in 2008.
Toxicology
Triazole fungicides - triadimefon, myclobutanil, propiconazole and flutriafol -
exhibit moderate acute oral toxicity in laboratory animals, but dermal toxicity is low.
All except for triadimefon will cause hepatocyte hypertrophy in mice.30 Eye exposure
may cause irritation. Triadimefon is absorbed across the skin.
Animal data suggest that the triazole fungicides have some central nervous
system effects. One study in rats demonstrated that flutriafol induces dopamine
release. While this effect is not considered to result in acute toxicity, there is concern
for chronic effects.31 Triadimefon blocks reuptake of dopamine and has demonstrated
hyperactivity in mice and rats.32'33 It is expected that the findings in humans would be
similar, although investigation of this has not been reported in the literature.
Confirmation of Poisoning
No tests for these fungicides or their breakdown products in body fluids are available.
Treatment of Triazole Toxicosis
See treatment for substituted benzenes, page 145.
COPPER COMPOUNDS
Insoluble inorganic and organic copper compounds are formulated as wettable powders
and dusts. Soluble inorganic and organic copper salts are prepared as aqueous solu-
tions. Some organometallic compounds are soluble in mineral oils.
A great many commercial copper-containing fungicides are available. Some are
mixtures of copper compounds. Others include lime, other metals and other fungi-
cides. Compositions of specific products can usually be provided by manufacturers or
by poison control centers.
Copper-arsenic compounds such as Paris Green may still be used in agriculture
in some countries, but their use has been discontinued in the United States. Toxicity of
these is chiefly due to arsenic content (see Chapter IS, Arsenlcals). Another copper-
arsenic compound, copper chromium arsenate, was formerly used as a wood preserva-
tive. That use was discontinued in 2003 on wood being used around the home or on
playgrounds.34
Toxicology
The dust and powder preparations of copper compounds are irritating to the skin,
respiratory tract and particularly the eyes. The soluble copper salts (such as the sulfate
and acetate) are corrosive to mucous membranes and the cornea. Limited solubility and
absorption probably account for generally low systemic toxicity of most compounds.
The more absorbable organic copper compounds exhibit the greatest systemic toxicity
in laboratory animals.
150
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Most of what is known about mammalian toxicity of copper compounds has
come from veterinary toxicology (livestock seem uniquely vulnerable) and poisonings
in man due to deliberate ingestion of copper sulfate or to consumption of water or
food that had been contained in copper vessels. The mechanism of toxicity is not clear,
although copper appears to release an excess of the cupric ion.35 This affects enzymes
including G6PD and glutathione reductase, which can damage the erythrocyte
membrane and produce hemolysis.36'37 Other enzyme systems may also be affected,
including nicotinamide-adenine dinucleotide phosphate (NADPH). Early signs and
symptoms of copper poisoning include a metallic taste, nausea, vomiting and epigas-
tric pain. In more severe poisonings, the gastrointestinal irritation will worsen with
hemetemesis and melanotic stools. Jaundice and hepatomegaly are common.38'39 As
mentioned above, hemolysis can occur, resulting hi circulatory collapse and shock and
may be prolonged, particularly in patients with an existing condition such as G6PD
deficiency. Methemoglobinemia has been reported in these cases, usually related
to copper sulfate.35'38'40'41 Acute renal failure with oliguria can also occur. Shock is
a primary cause of death early in the course, and renal failure and hepatic failure
contribute to deaths occurring more than 24 hours after poisoning.42 A case report
from China describes an adult male developing severe hemolysis and methemoglobin-
emia after ingestion of copper-8-hydroxyquinolate.35
Confirmation of Poisoning
Whole blood and serum copper levels can be measured, with a reported average red
blood cell level in normal adults of 89 ug/dL and average serum level of 114 ug/dL.43
Most reported cases of acute copper poisoning are at levels exceeding 200 ug/dL, and
some as high as 1,650 ng/dL.15-35'41
Treatment of Copper Toxicosis
Management of poisonings by ingestion of copper-containing fungicides depends on
the chemical nature of the compound: the strongly ionized salts present the greatest
hazard; the oxides, hydroxides, oxychloride and oxysulfate are less likely to cause
severe systemic poisoning.
Decontaminate skin with soap and water. The eyes should be flushed free of irri-
tating dust, powder or solution, using clean water or saline. If eye or dermal irrita-
tion persists, medical treatment should be obtained. Eye irritation may be severe.
Give water or milk as soon as possible to dilute the toxicant and mitigate corro-
sive action on the mouth, esophagus and gut. Do not be overly aggressive with
the dilution to avoid accidental inducement of vomiting.44 There is not a specific
amount that should be given, although the Poisondex Editorial Board consensus
is no more than 4 ounces in children and 8 ounces in adults.42'44
Do not induce emesis because the corrosive nature of some copper salts can cause
further damage to the esophagus, although vomiting is usually spontaneous in
acute copper ingestion. Further gastrointestinal decontamination should be deter-
mined on a case-by-case basis as outlined in the Chapter 3, General Principles,
understanding that gastric lavage may cause further damage.42 Charcoal's adsor-
bent effectiveness has not been widely studied in metal poisonings.
CAUTION: If corrosive action has been severe, it may be best to avoid gastric
intubation, as this may pose a serious risk of esophageal perforation. It may
be prudent to consider referral to a gastroenterologistfor endoscopy, given the
caustic nature of the ingestion.
CHAPTER 16
Fungicides
Copper Compound
COMMERCIAL
PRODUCTS
copper acetate
copper ammonium
carbonate
copper carbonate, basic
copper chromium acetate
(CCA)
copper hydroxide
copper lime dust
copper oxychloride
copper potassium sulfide
copper silicate
copper sulfate
copper sulfate, tribasic
(Bordeaux Mixture)
cupric oxide
cuprous oxide
SIGNS & SYMPTOMS
Skin, eye, respiratory
irritation
TREATMENT
Skin, eye decontamination
Water or milk for Gl dilution
IV fluids with glucose,
electrolytes if systemic
Methylene blue for severe
methemoglobinemia
Consider BAL
CONTRAINDICATED
Induced emesis, intubation
151
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CHAPTER 16
Fungicides
Organomercury
COMMERCIAL
PRODUCTS
Methyl mercury
compounds
methyl mercury hydroxide
acetate
propionate
pentachlorophenate
quinolinolate
Methoxyethyl mercury
compounds
methoxyethyl mercury
acetate (MEMA, Panogen,
Panogen M)
methoxyethyl mercury
chloride (MEMC, Emisan 6,
Ceresan)
Phenylmercuric acetate
Agrosan, Shimmer-ex, Tag
HL331, Unisan
Setrete (Gallotox, PMAA) is
phenyl mercury ammonium
acetate
If indications of systemic illness appear, administer intravenous fluids containing
glucose and electrolytes. Monitor fluid balance and correct blood electrolyte
concentrations as needed. If shock develops, give blood transfusions and vaso-
pressor amines as required.
Monitor plasma for evidence of hemolysis (free hemoglobin) and the red cells
for methemoglobin. If methemoglobinemia is severe (>30%), or the patient is
cyanotic, administer methylene blue.
Dosage of Methylene Blue
Adults/children 1-2 mg/kg/dose, given as a slow IVpush
over a few minutes, every 4 hours as needed.42
In patients with severe methemoglobinemia that is unresponsive to methylene
blue, or those with G6PD deficiency, chelation (see below) and plasma
exchange may be required.35
Administer morphine if the patient is in severe pain.
Consider administering BAL. The value of chelating agents in copper poisoning has
not been established.35-45 However, BAL appears to accelerate copper excretion and
may alleviate illness, d-penicillamine is the treatment for Wilson's disease due to
chronic copper toxicity, but in the context of severe vomiting and/or mental status
changes from an acute ingestion, BAL would be a more likely initial choice.40-42 For
a recommended schedule of dosage for initial therapy with BAL and subsequent
d-penicillamine administration, see Chapter IS, Arsenicals.
Although hemodialysis is indicated for patients with renal failure, copper is not
effectively removed in the dialysate.35-38
ORGANOMERCURY COMPOUNDS
Methyl mercury and methoxyethyl mercury compounds and phenyl mercuric acetate
fungicides have been formulated as aqueous solutions and dusts. They have been used
chiefly as seed protectants and had historically been added to household paint. Use
of alkyl mercury fungicides in the United States has been prohibited since the early
1990s. Phenyl mercuric acetate is no longer manufactured or used hi the United States.
Toxicology
The mercurial fungicides methyl mercury and methoxyethyl mercury compounds
and phenyl mercuric acetate are among the most toxic pesticides ever developed,
in terms of both acute and chronic toxicity. Epidemics of severe, often fatal, neurologic
disease have occurred when indigent residents of less developed countries consumed
methyl mercury-treated grain intended for planting of crops.46'47 Poisoning has also
occurred from eating meat from animals fed mercury-treated seed.48 Most of what is
known of poisoning by organic mercurial fungicides has come from these occurrences.
Organic mercury compounds are efficiently absorbed across the gut and possibly
across the skin. Volatile organic mercury is readily taken up across the pulmonary
epithelium. Methyl mercury is selectively concentrated in the tissues of the nervous
system and also in red blood cells. Other alkyl mercury compounds are probably
distributed similarly. Excretion occurs almost entirely through the biliary system. The
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whole body half-life of methyl mercury in humans ranges between 45 and 56 days.49
Significant conversion of organic mercury to inorganic mercury occurs in the red cell.
Early symptoms of poisoning are metallic taste in the mouth, numbness and
tingling of the digits and face, tremor, headache, fatigue, emotional lability and diffi-
culty in thinking. Manifestations of more severe poisoning are incoordination, slurred
speech, loss of position sense, hearing loss, constriction of visual fields, spasticity or
rigidity of muscle movements and deterioration of mental capacity. Many poisonings
caused by ingestion of organic mercurials have been fatal and a large percentage of
survivors have suffered severe, permanent neurologic damage.46'47'48
Phenyl mercuric acetate is not as extremely toxic as the alkyl mercury compounds
and is not as efficiently absorbed from the gut as methyl mercury.50 Phenyl mercuric
acetate is used to prevent fungal growth in latex paint. A case of acrodynia in a child
led to latex paint as a possible source for mercury exposure. Symptoms of acrodynia
include fever, erythema and desquamation of hands and feet, muscular weakness, leg
cramps and personality changes.51 Phenyl mercuric compounds have been banned
from latex paint since 1990.52
Confirmation of Poisoning
Mercury content of blood and tissues can be measured by atomic absorption spectrom-
etry. Blood levels of 5 ug/dL or greater are considered elevated for acute exposure.21
Special procedures are needed for extraction and measurement of specific organic
mercury compounds.
Treatment of Organomercury Toxicosis
Every possible precaution should be taken to avoid potentially life-threatening inges-
tions of organic mercury fungicides. Very little can be done to mitigate neurologic
damage caused by organic mercurials.
The following are the basic steps in the management of organomercury poisoning:
Decontaminate skin and eyes, as discussed in Chapter 3, General Principles.
Remove persons experiencing symptoms (metallic taste in mouth) after inhala-
tion of volatile organic mercury compounds (methyl mercury is the most volatile)
promptly from the contaminated environment and observe closely for indications
of neurologic impairment. Every possible precaution should be taken to avoid
further exposure to organic mercury compounds.
Consider gastrointestinal decontamination as outlined in Chapter 3.
Administer chelation therapy. Chelation is an essential part of the management of
acute mercury poisoning. For dosages of specific agents, see Chapter 15, Arseni-
cals. Succimer (DMSA) appears to be the most effective agent available in the
United States. Dimercaprol (BAL) is contraindicated in these poisonings because
of its potential to increase brain levels of mercury.52 EDTA is apparently of little
value in poisonings by organic mercury. D-penicillamine is probably useful, is
available in the United States and has proven effective in reducing the residence
half-life of methyl mercury in poisoned humans.52 DMPS (2,3-dimercaptopro-
pane-1-sulfonate acid) and NAP (n-acetyl-D,L-penicillamine) are probably also
useful but are not currently approved for use in the United States.
Consider extracorporeal hemodialysis and hemoperfusion, although experience to
date has not been encouraging.
CHAPTER 16
Fungicides
Organomercury
HIGHLIGHTS
Extreme acute and chronic
toxicity
Efficiently absorbed across
gut and possibly skin
SIGNS & SYMPTOMS
Metallic taste in mouth
Numbness, tingling of digits
&face
Tremor, headache, fatigue
Emotional lability, difficulty in
thinking
Incoordination, slurred
speech, hearing loss in
more severe cases
TREATMENT
Skin, eye decontamination
Consider Gl
decontamination
Chelation with DMSA or
other appropriate agent
CONTRAINDICATED
Use of BAL
153
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CHAPTER 16
Fungicides
Organotin Compound
COMMERCIAL
PRODUCTS
triphenyl tin
fentin hydroxide (Suzu-H,
Super Tin, Tubotin)
fentin chloride (Tinmate)
fentin acetate (Batasan,
Brestan, Phenostat-A,
Phentinoacetate, Suzu,
TPTA)
HIGHLIGHTS
Wettable & flow/able powders
Eye, skin, respiratory irritant
Most have been discontinued
in U.S.
SIGNS & SYMPTOMS
Headache, nausea, vomiting,
dizziness
Sometimes convulsions, loss
of consciousness
Photophobia, mental
disturbances
TREATMENT
Skin, eye decontamination
ICU supportive care for CMS
effects
Consider Gl decontamination
for large ingestions
ORGANOTIN COMPOUNDS
Triphenyl tin, fentin hydroxide, fentin chloride and fentin acetate are formulated as
wettable and flowable powders for use mainly as fungicides to control blights on field
crops and orchard trees. Fentin chloride was also prepared as an emulsifiable concen-
trate for use as a molluscicide (Aquatin 20 EC, discontinued in 1995). Tributyltin
salts were at one time used as fungicides and antifouling agents on ships, but this use
has been banned by most countries. They are somewhat more toxic by the oral route
than triphenyltin, but toxic actions are otherwise probably similar. Most organotin
compounds have been discontinued in the United States.
Toxicology
Triphenyl tin, fentin hydroxide, fentin chloride and fentin acetate are irritating to
the eyes, respiratory tract and skin. They are probably absorbed to a limited extent by
the skin and gastrointestinal tract. Manifestations of toxicity are due principally to
effects on the brain: headache, nausea, vomiting, dizziness and sometimes convulsions
and loss of consciousness. Photophobia and mental disturbances occur. Epigastric pain
is reported, even in poisoning caused by inhalation. Elevation of blood sugar, sufficient
to cause glycosuria, has occurred in some cases. The phenyl tin fungicides are less
toxic than ethyl, dimethyl and trimethyl tin compounds that are used in the production
of plastics. Signs and symptoms for poisoning from those compounds have included
disorientation and other mental status changes, cerebral edema, neurologic damage
and death in severely poisoned individuals.34'53'54 No deaths and very few poisonings
have been reported as a result of occupational exposures to phenyltin pesticides.
Treatment of Organotin Toxicosis
Remove skin contamination by washing with soap and water. Flush eyes free of
contaminating material with clean water or saline. If irritation persists, expert
medical treatment should be obtained.
Provide supportive care in an intensive care unit if neurological effects are evident.
If large amounts of phenyltin compound have been ingested in the past hour, take
measures to decontaminate the gastrointestinal tract as outlined in Chapter 3,
General Principles.
B AL, penicillamine, or other chelating agents have not been effective in lowering
tissue stores of organotin compounds in experimental animals.
CADMIUM COMPOUNDS
Cadmium chloride, cadmium sulfate and cadmium succinate have been used to
treat fungal diseases affecting turf and the bark of orchard trees. They were formu-
lated as solutions and emulsions. Miller 531 and Crag Turf Fungicide 531 were
complexes of cadmium, calcium, copper, chromium and zinc oxides. Kromad is a
mixture of cadmium sebacate, potassium chromate and thiram. Cad-Trete is a mixture
of cadmium chloride and thiram. All cadmium fungicides in the United States have
been discontinued. Cadmium exposure may also occur in the occupational setting
from other sources and uses of the toxic metal.
154
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Toxicology
Cadmium salts and oxides are very irritating to the respiratory and gastrointestinal
tracts. Inhaled cadmium dust or fumes can cause respiratory toxicity after a latency
period of several hours, including a mild, self-limited illness of fever, cough, malaise,
headache and abdominal pain, similar to metal fume fever. A more severe form of
toxicity includes chemical pneumonitis and is associated with labored breathing, chest
pain and a sometimes fatal hemorrhagic pulmonary edema.55'56'57'58 Symptoms may
persist for weeks.
Ingested cadmium causes nausea, vomiting, diarrhea, abdominal pain and
tenesmus. Relatively small inhaled and ingested doses produce serious symptoms.
Protracted absorption of cadmium has led to renal damage (proteinuria and azotemia),
anemia, liver injury (jaundice) and defective bone structure (pathologic fractures) in
chronically exposed persons. Prolonged inhalation of cadmium dust has contributed to
chronic obstructive pulmonary disease.59
Confirmation of Poisoning
Cadmium can be measured in body fluids by several methods, including electro-
thermal atomic absorption spectroscopy, graphite furnace atomic spectrophotometry,
and potentiometric stripping analysis.60'61'62 It is reported that blood cadmium concen-
trations tend to correlate with acute exposure and urine levels tend to reflect total body
burden. Blood levels exceeding 5 |ig/dL suggest excessive exposure.55 Urinary excre-
tion in excess of 100 ug per day suggests an unusually high body burden.
Treatment of Cadmium Poisoning
Decontaminate skin and eyes as outlined in Chapter 3, General Principles.
For severe reactions such as pulomonary edema and pneumonitis, use aggressive
measures in an intensive care setting, including positive end-expiratory pressure
mechanical ventilation, monitoring of blood gases and administration of diuretics,
steroid medications and antibiotics.55'63 Codeine sulfate may be needed to control
cough and chest pain. Respiratory irritation resulting from inhalation of small
amounts of cadmium dust may resolve spontaneously, requiring no treatment.
Consider decontaminating the lower GI tract as outlined in Chapter 3 if retention
of some cadmium is suspected. The irritant action of ingested cadmium products
on the gastrointestinal tract is so strong that spontaneous vomiting and diarrhea
often eliminate nearly all unabsorbed cadmium from the gut.
Administer intravenous fluids to overcome dehydration caused by vomiting
and diarrhea. Fluids also limit cadmium toxicity affecting the kidneys and liver.
However, great care must be taken to monitor fluid balance and blood electrolyte
concentrations so that failing renal function does not lead to fluid overload.
Consider chelation therapy with calcium disodium EDTA for acute poisoning,
depending on measured cadmium in blood and urine and the status of renal func-
tion. Chelation therapy has been shown to increase urinary excretion of cadmium.
Its therapeutic value in cadmium poisoning has not been established, and use of
the agent carries the risk that unduly rapid transfer of cadmium to the kidney may
precipitate renal failure. Monitor urine protein and blood urea nitrogen and creati-
nine carefully during therapy.
CHAPTER 16
Fungicides
Cadmium Compound
COMMERCIAL
PRODUCTS
cadmium chloride (Caddy)
cadmium sulfate (generic,
14% solution)
cadmium succinate
(Cadminate)
Miller 531 and Crag Turf
Fungicide 531 (generic)
were complexes of
cadmium, calcium, copper,
chromium, and zinc oxides
Kromad is a mixture
of cadmium sebacate,
potassium chromate, and
thiram
Cad-Trete is a mixture
of cadmium chloride and
thiram
HIGHLIGHTS
Discontinued in U.S.
SIGNS & SYMPTOMS
Inhalation: Fever, cough,
malaise, headache,
abdominal pain
Ingestion: Nausea, vomiting,
diarrhea, abdominal pain,
tenesmus
TREATMENT
Skin, eye decontamination
Consider lower GI
decontamination if retained
Aggressive ICU measures
for severe reactions
IV fluids for dehydration
155
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CHAPTER 16
Fungicides
Miscellaneous Organic
Fungicide
COMMERCIAL
PRODUCTS
anilazine (Dyrene)
benomyl (Benlate, Tersan
1991, Benex)
cycloheximide (naramycin)
dodine (Carpene, Curitan,
Melprex, Venturol)
iprodione (Rovral,
Glycophene)
metalaxyl (Ridomil, Subdue)
etridiazole (Terrazole,
Aaterra, Ethazol, Koban,
Pansoil, Truban)
thiabendazole (Apl-Luster,
Arbotect, Mertect, Tecto,
Thibenzole)
triforine (Funginex, Saprol,
Denarin)
Dosage of Calcium Disodium EDTA
75 mg/kg/day in three to six divided doses for 5 days.
The total dose for the 5-day course should not exceed 500
mg/kg.65
Succimer (DMSA) has also been used in this poisoning but has not been demon-
strated to be efficacious.
6. Because of the risk of renal injury by mobilized cadmium, do not use dimercaprol
(B AL) for treatment of cadmium poisoning.
7. Monitor urinary protein and cells regularly and measure hepatocellular enzymes
and creatinine for indications of injury to these organ systems.
MISCELLANEOUS ORGANIC FUNGICIDES
Some modern organic fungicides are widely used. Reports of adverse effects on
humans are few. Some of the known properties of these agents follow.
Anilazine is supplied as wettable and flowable powders. It was used on vegeta-
bles, cereals, coffee, ornamentals and turf. No products are currently registered in the
United States. This product has caused skin irritation in exposed workers. Acute oral
and dermal toxicity in laboratory animals is low. Human systemic poisonings have not
been reported in the published medical literature.
Benomyl is a synthetic organic fungistat having little or no acute toxic effect
in mammals. There are no active products in the United States. No systemic poison-
ings have been reported in humans in the published literature. Although the molecule
contains a carbamate grouping, benomyl is not a cholinesterase inhibitor. It is poorly
absorbed across skin, and what is absorbed is promptly metabolized and excreted.
Skin injuries to exposed individuals have occurred, and dermal sensitization has
been found among agricultural workers exposed to foliage residues.3'66
Cycloheximide is formulated as wettable powders, sometimes combined with
other fungicides. There are no registered products in the United States. Cycloheximide
is a product of fungal culture, effective against fungal diseases of ornamentals and
grasses. It is selectively toxic to rats and much less toxic to dogs and monkeys. No
human poisonings have been reported. Animals given toxic doses exhibit salivation.
bloody diarrhea, tremors and excitement, leading to coma and death due to cardiovas-
cular collapse. Hydrocortisone increases the rate of survival in deliberately poisoned
rats. Atropine, epinephrine, methoxyphenamine and hexamethonium all relieved the
symptoms of poisoning, but did not improve survival.67
Dodine is formulated as a wettable powder. It is commonly applied to berries.
nuts, peaches, apples, pears and trees afflicted with leaf blight. Dodine is a cationic
surfactant with antifungal activity. It is absorbed across the skin. In animal studies, it
causes severe irritation to the eye, and also is a skin irritant. Acute oral and dermal
toxicity in laboratory animals is moderate. Poisonings in humans have not been
reported in the published medical literature. Based on animal studies, ingestion would
probably cause nausea, vomiting and diarrhea.68
Iprodione is supplied as wettable powder and other formulations. It is used
on berries, grapes, fruit, vegetables, grasses and ornamentals. It is also used as seed
dressing. Iprodione exhibits low acute oral and dermal toxicity in laboratory animals.69
No human poisonings have been reported in the published medical literature.
156
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CHAPTER 16
Fungicides
Metalaxyl is supplied as emulsifiable and flowable concentrates. It is a systemic
fungicide used to control soil-borne fungal diseases on fruit trees, cotton, hops,
soybeans, peanuts, ornamentals and grasses. It is also used as seed dressing. It exhibits
low acute oral and dermal toxicity in laboratory animals.70 No human poisonings have
been reported in the published medical literature.
Etridiazole is supplied as wettable powder and granules for application to soil
as a fungicide and nitrification inhibitor. There are no registered products in the United
States. Human poisonings have not been reported in the published literature.
Thiabendazole is widely used as an agricultural fungicide, but most experi-
ence with its toxicology in humans has come from medicinal use against intestinal
parasites. Oral doses administered for this purpose are far greater than those likely
absorbed in the course of occupational exposure. Thiabendazole is rapidly metabo-
lized and excreted in the urine, mostly as a conjugated hydroxy-metabolite. Symptoms
and signs that sometimes follow ingestion are: dizziness, nausea, vomiting, diarrhea,
epigastric distress, lethargy, headache and tinnitus.71 Blood enzyme tests may indicate
liver injury. Persons with liver and kidney disease may be unusually vulnerable to
toxic effects. Adverse effects in humans from use of thiabendazole as a fungicide have
not been reported in the published literature.
Triforine is supplied as emulsifiable concentrate and wettable powder. It is
used on berries, fruit, vegetables and ornamentals. Mammals rapidly excrete it chiefly
as a urinary metabolite. It exhibits low acute oral and dermal toxicity in laboratory
animals.72 No human poisonings have been reported in the published literature.
Confirmation of Poisoning
Laboratory tests for these organic fungicides or their metabolites in body fluids are not
generally available.
Treatment of Organic Fungicide Toxicosis
See treatment for substituted benzenes, page 145.
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www.epa.gov/oppsrrdl/REDs/dodine-red.pdf Accessed January 3,2011.
69. Reregistration Eligibility Decision (RED) Iprodione. United States EPA. 1998. http://
www.epa.gov/oppsrrdl/REDs/2335.pdf Accessed January 3, 2011.
70. Reregistration Eligibility Decision (RED) Metalaxyl. United States EPA. 1994. http://
www.epa.gov/oppsrrdl/REDs/0081.pdf Accessed January 3, 2011.
71. Tchao P, Templeton T. Thiabendazole-associated grand mal seizures in a patient with Down
syndrome. JPediatr. Feb 1983;102(2):317-318.
72. Reregistration Eligibility Decision (RED) for Triforine. United States EPA. 2008. http://
www.epa.gov/oppsrrdl/REDs/triforine_red.pdf Accessed January 3, 2011.
160
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HIGHLIGHTS
Fumigants
Packaging and formulation of fumigants are complex. Those that are gases at room
temperature (methyl bromide, ethylene oxide, sulfur dioxide, sulfuryl fluoride) are
provided in compressed gas cylinders. Liquids are marketed in cans or drums. Solids
that sublime, such as naphthalene, must be packaged so as to prevent significant
contact with air before they are used. Sodium cyanide is only available in an encap-
sulated form so that when wild canids attack livestock their bite releases the poison.
Mixtures of fumigants are sometimes used. For instance, chloropicrin, which has
a strong odor and irritant effect, is often added as a "warning agent" to other liquid
fumigants. It is important to be aware of the possibility of such mixtures.
Liquid halocarbons and carbon disulfide evaporate into the air while naphtha-
lene sublimes. Paraformaldehyde slowly depolymerizes to formaldehyde. Aluminum
phosphide slowly reacts with water vapor in the air to liberate phosphine, an extremely
toxic gas.
Fumigants have remarkable capacities for diffusion (a property essential to
their function). Some readily penetrate rubber and neoprene personal protective gear.
as well as human skin. They are rapidly absorbed across the pulmonary membranes.
gastrointestinal tract and skin. Special adsorbents are required in respirator canisters
to protect exposed workers from airborne fumigant gases. Even these may not provide
complete protection when air concentrations of fumigants are high.
NAPHTHALENE
Toxicology
Naphthalene is a solid white hydrocarbon long used in ball, flake or cake form as a
moth repellent. It sublimes slowly. The vapor has a sharp, pungent odor that is irri-
tating to the eyes and upper respiratory tract. Inhalation of high concentrations causes
headache, dizziness, nausea and vomiting. Intensive, prolonged inhalation exposure.
ingestion or dermal exposure (from contact with heavily treated fabric) may cause
hemolysis, particularly in persons afflicted with glucose-6-phosphate dehydrogenase
deficiency.1 The metabolites of naphthalene actually are responsible for the hemo-
lysis.2 Secondary renal tubular damage may ensue from the naphthol and from the
products of hemolysis. Convulsions and coma may occur, particularly in children. In
infants, high levels of methemoglobin and bilirubin in the plasma may lead to enceph-
alopathy. Kernicterus has been specifically described as a complication of exposure
to naphthalene with severe hemolysis and resulting hyperbilirubinemia.3 Some indi-
viduals exhibit dermal sensitivity to naphthalene.
Easily absorbed in lung, gut,
skin
SIGNS & SYMPTOMS
Highly variable among
agents
Many are irritants
Carbon disulfide, chloroform,
ethylene dichloride,
hydrogen cyanide, methyl
bromide may have serious
CMS effects
Methyl bromide, ethylene
dibromide, ethylene oxide,
aluminum phosphide
(phosphine gas) can cause
pulmonary edema
Chloroform, carbon
tetrachloride, ethylene
dichloride, ethylene
dibromide, formaldehyde,
carbon disulfide may have
liver and/or kidney impacts
Hydrogen cyanide causes
severe hypoxia without
cyanosis in early stages
TREATMENT
Skin, eye decontamination
Ensure breathing, pulse
Control seizures
Consider Gl
decontamination
Specific measures needed
for various agents
HALOCARBONS
Toxicology
The halocarbons as a group are most commonly encountered as solvent agents. They
have been associated with a wide variety of toxicities, including central nervous
system, liver and renal toxicity, reproductive toxicity and carcinogenicity. However.
not all are equipotent, nor do any of them routinely express this wide variety of effects.4
CONTRAINDICATED
Catecholamine-releasing
agents in carbon disulfide
poisoning
Ipecac in cyanide poisoning
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Fumigants
COMMERCIAL
PRODUCTS
Hydrocarbon: naphthalene
Halocarbons: methylene
chloride,* methyl
bromide, methyl iodide,
chloroform,* carbon
tetrachloride,* chloropicrin,
ethylene dichloride,
ethylene dibromide,*
1,3-dichloropropene,
1,2-dichloropropane,*
dibromochloropropane,
paradichlorobenzene
Oxides and Aldehydes:
ethylene oxide, propylene
oxide,* formaldehyde and
paraformaldehyde, acrolein
Sulfur Compounds: sulfur
dioxide, sulfuryl fluoride,
carbon disulfide*
Phosphorus Compounds:
phosphine
Nitrogen Compounds:
sodium/hydrogen cyanide,
acrylonitrile*
Methyl Isothiocyanate
Generators: Metam sodium,
metam potassium, dazomet
* Discontinued in the U.S.
The individual characteristics of each registered or previously registered as pesticides
will be discussed.
Methylene chloride is one of the less toxic halocarbons. It is absorbed by inhala-
tion and to a limited extent across the skin. Exposure to high concentrations may cause
central nervous system depression, manifesting as fatigue, weakness and drowsiness.
A case has been described of severe optic atrophy after high level exposure to this
agent.5 Some absorbed methylene chloride is degraded to carbon monoxide in humans.
yielding increased blood concentrations of carboxyhemoglobin.6 However, concen-
trations are rarely high enough to cause symptoms of carbon monoxide poisoning.
Ingestion has caused death from gastrointestinal hemorrhage, severe liver damage.
coma, shock, metabolic acidosis and renal injury. In laboratory animals, extraordinary
dosage has caused irritability, tremor and narcosis, leading to death. When heated to
the point of decomposition, one of the products is the highly toxic phosgene gas that
has caused significant, acute pneumonitis.7
The methyl halides (methyl bromide and methyl iodide) are similar in their
toxicity and metabolic fate.8 They are colorless and nearly odorless to moderately
pungent (methyl iodide), but are severely irritating to the lower respiratory tract.
sometimes inducing pulmonary edema, hemorrhage or a confluent pneumonia. The
onset of respiratory distress may be delayed 4-12 hours after exposure. The methyl
halides are central nervous system depressants but may also cause convulsions. Early
symptoms of acute poisoning include headache, dizziness, nausea, vomiting, tremor.
slurred speech and ataxia. The more severe cases of poisoning exhibit myoclonic and
generalized tonic-clonic seizures, which are sometimes refractory to initial therapy.
Residual neurological deficits including myoclonic seizures, ataxia, muscle weakness.
tremors, behavioral disturbances and diminished reflexes may persist in more severely
poisoned patients.8'9'10 If liquid methyl halides contact the skin, severe burning, itching
and blistering occurs. Skin necrosis may be deep and extensive.11
Chloroform has an agreeable, sweet odor and is only slightly irritating to the
respiratory tract. It is well absorbed from the lungs and is also absorbed from the skin
and gastrointestinal tract. It is a powerful central nervous system depressant (in fact.
it has been used as an anesthetic).12 Inhalation of toxic concentrations in air leads to
dizziness, loss of sensation and motor power, and then unconsciousness. Inhalation
of large amounts causes cardiac arrhythmias, sometimes progressing to ventricular
fibrillation.n Large absorbed doses damage the functional cells of the liver and kidney.
Ingestion is more likely to cause serious liver and kidney injury than is inhalation of
the vapor.
Carbon tetrachloride is less toxic than chloroform as a central nervous system
depressant but is much more severely hepatotoxic, particularly following ingestion.
Liver cell damage is apparently due to free radicals generated in the process of initial
dechlorination.14 Sporadic arrhythmias, progressing to fibrillation, may follow inhala-
tion of high concentrations of carbon tetrachloride or ingestion of the liquid. Kidney
injury also occurs sometimes with minimal hepatic toxicity. The kidney injury may be
manifested by acute tubular necrosis or by azotemia and general renal failure. Even
topical exposure has resulted in acute renal toxicity.15
Chloropicrin is severely irritating to the upper respiratory tract, eyes and skin.
Inhalation of an irritant concentration sometimes leads to vomiting. Ingestion could be
expected to cause a corrosive gastroenteritis.16'17
1,2-dichloroethane (ethylene dichloride) is moderately irritating to the eyes
and respiratory tract. Respiratory symptoms may have a delayed onset. It depresses the
central nervous system, induces cardiac arrhythmias and damages the liver. Additional
manifestations of poisoning include headache, nausea, vomiting, dizziness, diarrhea.
hypotension, cyanosis and unconsciousness.18
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Ethylene dibromide is a severe irritant to skin, eyes and respiratory tract. The
liquid causes blistering and erosion of skin and is corrosive to the eyes. Once absorbed,
it may cause pulmonary edema and central nervous system depression. Damage to
testicular tissue has occurred in animals.19 Its chemical similarity to DBCP (dibro-
mochlorpropane) suggests this compound may have some damaging effect on testic-
ular tissue with long-term exposure.20 Persons poisoned by ingestion have suffered
chemical gastroenteritis, liver necrosis and renal tubular damage. Death is usually due
to respiratory or circulatory failure.21 A powerful disagreeable odor is advantageous in
warning occupationally exposed workers of the presence of this gas.
Dichloropropene and dichloropropane are strongly irritating to the skin, eyes
and respiratory tract. Bronchospasm may result from inhalation of high concentra-
tions. Liver, kidney and cardiac toxicity are seen in animals, but there are limited data
for humans.22 It appears that the risk of such toxicity is relatively low for humans
except in large exposures, especially by ingestion.
Paradichlorobenzene is solid at room temperature. It is now widely used as a
moth repellent, air freshener and deodorizer in homes and in public facilities. The vapor
is only mildly irritating to the nose and eyes. Liver injury may occur following inges-
tion of large amounts. Although accidental ingestions, especially by children, have
been fairly common, symptomatic human poisonings have been rare. The last report
in the peer-reviewed literature of acute poisoning was in 1959.23 Chronic intentional
exposure has led to severe encephalopathy and serious withdrawal symptoms.24
OXIDES AND ALDEHYDES
Ethylene oxide and propylene oxide are irritants to all tissues they contact. Aqueous
solutions of ethylene oxide can cause blistering and erosion of the affected skin. The
area of skin may thereafter be sensitized to the fumigant. Inhalation of high concentra-
tions is likely to cause pulmonary edema and cardiac arrhythmias. Headache, nausea,
vomiting, weakness and a persistent cough are common early manifestations of acute
poisoning.25 Coughing of bloody, frothy sputum is characteristic of pulmonary edema.
Airborne formaldehyde is irritating to the eyes and to membranes of the upper
respiratory tract. In some individuals, it is a potent sensitizer, causing allergic derma-
titis. In addition, it has been associated with asthma-like symptoms, though there
remains some controversy as to whether these represent true allergic asthma caused
by formaldehyde.26'27'28 High air concentrations may cause laryngeal edema, asthma or
tracheobronchitis, but apparently not pulmonary edema. Aqueous solutions in contact
with the skin cause hardening and roughness due to superficial coagulation of the
keratin layer. Ingested formaldehyde attacks the lining membrane of the stomach and
intestine, causing necrosis and ulceration. Absorbed formaldehyde is rapidly converted
to formic acid. The latter is partly responsible for the metabolic acidosis that is charac-
teristic of formaldehyde poisoning. Circulatory collapse and renal failure may follow
the devastating effects of ingested formaldehyde on the gut, leading to death.29 Para-
formaldehyde is a polymer that slowly releases formaldehyde into the air. Toxicity is
somewhat less than that of formaldehyde because of the slow evolution of gas.
Acrolein (acrylaldehyde) is an extremely irritating gas used as a fumigant and an
aquatic herbicide. The vapor causes lacrimation and upper respiratory tract irritation,
which may lead to laryngeal edema, bronchospasm and delayed pulmonary edema.
The consequences of ingestion are essentially the same as those that follow ingestion
of formaldehyde. Contact with the skin may cause blistering.30
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SULFUR COMPOUNDS
Sulfur dioxide is a highly irritating gas, so disagreeable that persons inhaling it are
usually prompted to seek uncontaminated air as soon as possible. However, laryngo-
spasm and pulmonary edema have occurred, occasionally leading to severe respiratory
distress and death. It is sometimes a cause of reactive airways disease in occupation-
ally exposed persons.31
Sulfuryl fluoride has been used extensively for structural fumigation. Gener-
ally, use experience has been good, but some fatalities have occurred when fumigated
buildings have been prematurely reentered by unprotected individuals.32 Since this
material is heavier than air, fatal hypoxia may follow early reentry. Manifestations
of poisoning have been nose, eye and throat irritation, weakness, nausea, vomiting.
dyspnea, cough, restlessness, muscle twitching and seizures.33'34
Carbon disulfide vapor is only moderately irritating to upper respiratory
membranes. It has an offensive "rotten cabbage" odor. Acute toxicity is due chiefly
to effects on the central nervous system. Inhalation of high concentrations for short
periods has caused headache, dizziness, nausea, hallucinations, delirium, progres-
sive paralysis and death from respiratory failure.35 More prolonged exposure to lesser
amounts has led to blindness, deafness, paresthesia, painful neuropathy and paralysis.36
Carbon disulfide is a potent skin irritant, often causing severe burns. Long-term occu-
pational exposures have been shown to accelerate atherosclerosis, leading to ischemic
myocardiopathy, polyneuropathy and gastrointestinal dysfunction.37 Toxic damage to
the liver and kidneys may result in severe functional deficits of these organs.38 Repro-
ductive failure has been noted.
PHOSPHORUS COMPOUNDS
Phosphine gas is extremely irritating to the respiratory tract. It also produces severe
systemic toxicity. It is used as a fumigant by placing solid aluminum phosphide (phos-
toxin) near produce or in other storage spaces. By way of hydrolysis, phosphine gas
is slowly released. Most severe acute exposures have involved ingestion of the solid
aluminum phosphide, which is rapidly converted to phosphine by acid hydrolysis in
the stomach. Poisoning due to ingestion carries a high mortality rate (50% to 90%).39'40
The complex chemistry and toxic mechanisms of phosphine were recently reviewed.
Three interdependent mechanisms contribute to phosphine toxicity: disruption of the
sympathetic nervous system, suppressed energy metabolism and oxidative damage to
the cells.41 Extracellular magnesium levels have been found to be slightly elevated.
suggesting a depletion of intracellular magnesium from myocardial damage.42
Poisonings had become quite frequent during the late 1980s and early 1990s in
some parts of India.39'40 The principal manifestations of poisoning are fatigue, nausea.
headache, dizziness, thirst, cough, shortness of breath, tachycardia, chest tightness.
paresthesia and jaundice. Cardiogenic shock is present in more severe cases. Pulmo-
nary edema is a common cause of death. In other fatalities, ventricular arrhythmias.
conduction disturbances and asystole developed.39'43 The odor of phosphine is said to
resemble that of decaying fish.
NITROGEN COMPOUNDS
Sodium cyanide/hydrogen cyanide gas causes poisoning by inactivating cytochrome
oxidase, the final enzyme essential to mammalian cellular respiration. The patient will
have signs of severe hypoxia, but in some cases may not appear cyanotic. This is due
to the failure of hemoglobin reduction in the face of loss of cellular respiration. This
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Fumigants
will result in a pink or red color to the skin and arteriolization of retinal veins. In addi-
tion to the suggestive physical findings, one may also find an unusually high pO2 on a
venous blood gas.44 Cyanosis is a late sign and indicates circulatory collapse.
The cells of the brain appear to be the most vulnerable to cyanide action.
Presenting signs are nonspecific and can be found with many poisonings. Uncon-
sciousness and death may occur immediately following inhalation of a high cyanide
concentration, respiratory failure being the principal mechanism. Metabolic acidosis
is another common presenting sign. Low-dose exposures cause a constriction and
numbness in the throat, stiffness of the jaw, salivation, nausea, vomiting, lighthead-
edness and apprehension. Worsening of the poisoning manifests as violent tonic or
clonic convulsions. Fixed, dilated pupils, bradycardia and irregular gasping respira-
tion (or apnea) are typical of profound poisoning. The heart often continues to beat
after breathing has stopped.44>45 A bitter almond odor to the breath or vomitus may be a
clue to poisoning, but not all individuals are able to detect this odor.44
Acrylonitrile is biotransformed in the body to hydrogen cyanide. Toxicity and
mechanisms of poisoning are essentially the same as have been described for cyanide,
except that acrylonitrile is irritating to the eyes and the upper respiratory tract.
METHYL ISOTHIOCYANATE GENERATORS
Metam sodium, metam potassium and dazomet, when used as fumigants, all rely on
conversion to methyl isothiocyanate.46 There is very limited literature on the effects of
these agents when used as fumigants, but the toxicity appears to be related to exposure
to methyl isothiocyanate. This is discussed in more detail in Chapter 16, Fungicides,
in the subsection, Thiocarbamates.
Confirmation of Poisoning
Naphthalene is converted mainly to alpha naphthol in the body and promptly excreted
in conjugated form in the urine. Alpha naphthol can be measured by gas chromatog-
raphy. Many halocarbons can be measured in blood by gas chromatographic methods.
Some can be measured in the expired air as well.
Methylene chloride is converted to carbon monoxide in the body, generating
carboxyhemoglobin, which can be measured by clinical laboratories.
Paradichlorobenzene is metabolized mainly to 2,5-dichlorophenol, which is
conjugated and excreted in the urine. This product can be measured chromatographically.
Methyl bromide yields inorganic bromide in the body. Methyl bromide itself
has a short half-life and is usually not detectable after 24 hours. The bromide anion
is slowly excreted in the urine (half-life about 10 days) and is the preferred method
of serum measurement.10 The serum from persons having no exceptional exposure
to bromide usually contains less than 1 mg bromide ion per 100 mL. The possible
contributions of medicinal bromides to elevated blood content and urinary excretion
must be considered, but if methyl bromide is the exclusive source, serum bromide
exceeding 6 mg per 100 mL probably means some absorption, and 15 mg per 100 mL
is consistent with symptoms of acute poisoning. Inorganic bromide is considerably
less toxic than methyl bromide; serum concentrations in excess of 150 mg per 100 mL
occur commonly in persons taking inorganic bromide medications. In some European
countries, blood bromide concentrations are monitored routinely in workers exposed
to methyl bromide. Blood levels over 3 mg per 100 mL are considered a warning that
personal protective measures must be improved. A bromide concentration over 5 mg
per 100 mL requires that the worker be removed from the fumigant-contaminated
environment until blood concentrations decline to less than 3 mg per 100 mL.47
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Carbon disuHide can be measured in urine by gas chromatography, but the test
is not generally available.
Cyanide ion from cyanide itself or acrylonitrile can be measured in whole blood
and urine by an ion-specific electrode or by colorimetry. Symptoms of toxicity may
appear at blood levels above 0.10 mg per liter.45 Urine cyanide is usually less than 0.30
mg per liter in nonsmokers, but as much as 0.80 mg per liter in smokers. Thiocyanate.
the metabolite of cyanide, can also be measured in blood and urine. It is considered
elevated at blood levels exceeding 12 mg per liter.45 Urine thiocyanate is usually less
than 4 mg per liter in nonsmokers, but may be as high as 17 mg per liter in smokers.
Serum fluoride concentrations have been measured in fatalities from sulfuryl
fluoride fumigation. Ante-mortem concentrations have ranged from as low as 0.5 mg/
liter in one chronic exposure case to the range of ~20 mg/liter in acute poisoning
deaths.34
There are no practical tests for absorbed alkyl oxides, aldehydes or phosphine
that would be helpful in diagnosis of poisoning.
Large industrial plants sometimes monitor human absorption of halocarbons by
analysis of expired air. Similar technology is available in some departments of anes-
thesiology. These analyses are rarely needed to identify the offending toxicant because
this is known from the exposure history. In managing difficult cases of poisoning.
however, it may be helpful to monitor breath concentrations of toxic gas to evaluate
disposition of the fumigant. Protein and red cells levels in the urine may indicate renal
injury. Free hemoglobin in urine most likely reflects hemolysis, as from naphthalene.
Elevations of alkaline phosphatase, lactate dehydrogenase (LDH), serum GOT, ALT.
AST and certain other enzymes are sensitive indices of insult to liver cells. More
severe damage increases plasma concentrations of bilirubin. A chest X-ray may be
used to confirm the occurrence of pulmonary edema. Electromyography may be useful
in evaluating peripheral nerve injury. Sperm counts may be appropriate for workers
exposed to dibromochloropropane and ethylene dibromide.
Some occupational health agencies now urge periodic neurologic and neuro-
psychological testing of workers heavily exposed to fumigants and solvents to detect
injury to the nervous system as early as possible. This would be particularly desirable
in the case of exposures to such agents as methyl bromide and carbon disulfide that
have well documented chronic neurotoxic effects.
Treatment of Fumigant Toxicosis
1. Flush contaminating fumigants from the skin and eyes with copious amounts of
water or saline for at least 15 minutes. Some fumigants are corrosive to the cornea
and may cause blindness. Specialized medical treatment should be obtained
promptly following flushing. Skin contamination may cause blistering and deep
chemical burns. Absorption of some fumigants across the skin may be sufficient
to cause systemic poisoning in the absence of fumigant inhalation. For all these
reasons, decontamination of eyes and skin must be immediate and thorough.
2. Remove victims of fumigant inhalation to fresh air immediately. Even though
initial symptoms and signs are mild, keep the victim quiet, in a semi-reclining
position. Minimal physical activity limits the likelihood of pulmonary edema.
3. If victim is not breathing, clear the airway of secretions and resuscitate with posi-
tive pressure oxygen apparatus. If this is not available, use chest compression to
sustain respiration. If victim is pulseless, employ cardiac resuscitation.
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4. Manage patients with signs and symptoms of severe poisoning, including pulmo-
nary edema, respiratory failure, shock, renal failure and seizures in an intensive
care unit.
5. Control convulsions. Seizures are most likely to occur in poisonings by methyl
bromide, hydrogen cyanide, acrylonitrile, phosphine and carbon disulfide. See
Chapter 3, General Principles for seizure management. In some cases of methyl
bromide poisoning, seizures have been refractory to benzodiazepines and diphe-
nylhydantoin, so consider resorting to anesthesia using thiopental.10
6. If a fumigant liquid or solid has been ingested less than an hour prior to treat-
ment, consider gastric emptying, followed by activated charcoal, as suggested in
Chapter 3.
7. Monitor fluid balance and check urine sediment regularly for indications of
tubular injury. Measure serum alkaline phosphatase, LDH, ALT, AST and bili-
rubin to assess liver injury.
Specific Treatment Measures for Particular Fumigants
Specific additional measures recommended in poisonings by particular fumigants
follow.
Naphthalene
1. If naphthalene toxicosis is caused by vapor inhalation, this can usually be managed
simply by removing the individual to fresh air.
2. Decontaminate skin promptly by washing with soap and water. Remove eye
contamination by flushing with copious amounts of clean water. Eye irritation
may be severe, and if it persists, should receive ophthalmologic attention. See
Chapter 3, General Principles for more information on decontamination.
3. Examine the plasma for evidence of hemolysis: a reddish-brown tinge. Examine
the blood smear for "ghosts" and Heinz bodies. If present, monitor red blood cell
count and hematocrit for anemia and urine for protein and cells. Measure direct-
and indirect-reacting bilirubin in the plasma. Monitor fluid balance and blood
electrolytes. If possible, monitor urinary excretion of naphthol to assess severity
of poisoning and clinical progress.
4. If hemolysis is clinically significant, administer intravenous fluids to accelerate
urinary excretion of the naphthol metabolite and protect the kidney from products
of hemolysis. Use Ringer's lactate or sodium bicarbonate to keep urine pH above
7.5.
5. Consider the use of mannitol or furosemide to promote diuresis. If urine flow
declines, intravenous infusions must be stopped to prevent fluid overload and
hemodialysis should be considered.2
6. If anemia is severe, blood transfusions may be needed.
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Carbon Tetrachloride
For carbon tetrachloride poisoning, several treatment measures have been suggested to
limit the severity of hepatic necrosis. The limited experience is outlined below.
1. Consider using hyperbaric oxygen, which has been used with some success.14
2. Administer n-acetyl cysteine (Mucomyst) orally as a means of reducing free
radical injury.48
Dosage of Mucomyst
Dilute the proprietary 20% product 1:4 in a carbonated
beverage, and give about 140 mg/kg body weight of the
diluted solution as a loading dose. Then give 70 mg/kg every
4 hours after the loading dose for a total of 17 doses (this
dosage schedule is used for acetaminophen poisonings).
Administration via duodenal tube may be necessary in patients who cannot
tolerate Mucomyst.49 Intravenous administration of n-acetyl cysteine may be
used; more information is available through the poison control centers.
Carbon Disulfide
Mild poisonings by carbon disumde inhalation may be managed best by no more than
careful observation, even though sensory hallucinations, delirium and behavioral aber-
rations can be alarming. Severe poisonings may require specific measures.
1. If manic behavior threatens the safety of the victim, administer diazepam as a
tranquilizer.
Dosage of Diazepam
Adults: 5-10 mg administered slowly, intravenously
Children: 0.2-0.4 mg/kg, administered slowly,
intravenously
Give as much as is necessary to achieve sedation.
2. Do not give catecholamine-releasing agents, such as reserpine or amphetamines.
Phosphine Gas
Experience in India suggests that therapy with magnesium sulfate may decrease the
likelihood of a fatal outcome.39'43'50 The mechanism is unclear, but may possibly be
due to the membrane stabilization properties of magnesium in protecting the heart
from fatal arrhythmias. In one series of 90 patients, magnesium sulfate was found to
decrease the mortality from 90% to 52%.39 Two controlled studies have been done, one
of which showed a reduction in mortality from 52% to 22%.50 The other study found
no effect on mortality.51
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Dosage for Magnesium Sulfate
3 grams during the first 3 hours as a continuous infusion,
followed by 6 grams per 24 hours for the next 3 to 5 days.39
CHAPTER 17
Fumigants
Hydrogen Cyanide and Acrylonitrile
Poisonings by hydrogen cyanide and acrylonitrile gases or liquids are treated essen-
tially the same as poisoning by cyanide salts.
1. Because cyanide is so promptly absorbed following ingestion, commence treat-
ment with prompt administration of oxygen and antidotes. The three antidotes -
amyl nitrite, sodium nitrite and sodium thiosulfate - are available in cyanide anti-
dote kits, available from various sources. Read and follow the package insert.52
The nitrates are intended to produce methemoglobin, which binds cyanide, which
is then released and metabolized by rhodanese with the help of thiosulfate.
2. Hydroxycobalamin has been known from animal studies to be an effective
antidote for cyanide poisoning.53'54 Hydroxycobalamin has a higher affinity for
cyanide than do tissue cytochromes, thereby competitively binding and inacti-
vating both free and cytochrome-bound cyanide. The cyanocobalamin formed is
readily excreted by the kidney. The product became commercially available in
2007 in the United States (Cyanokit, Merck).55
3. Administer oxygen continuously. Hyperbaric oxygen has been evaluated as
effective in this condition.56 If respiration fails, maintain pulmonary ventilation
mechanically.
4. Measure hemoglobin and methemoglobin in blood. If more than 50% of total
hemoglobin has been converted to methemoglobin, consider blood transfusion or
exchange transfusion, because conversion back to normal hemoglobin proceeds
slowly.
Although various cobalt salts, chelators and organic combinations have shown
some promise as antidotes to cyanide, they are not generally available in the United
States. None has been shown to surpass the effectiveness of the nitrite-thiosulfate
regimen.
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References
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2. Gosselin RE, Smith HC, Hodge HC, eds. Napthalene. Clinical toxicology of commercial
products. 5th ed. Baltimore: Williams & Wilkins; 1984.
3. Naiman JL, Kosoy MH. Red Cell Glucose-6-Phosphate Dehydrogenase Deficiency-a
Newly Recognized Cause of Neonatal Jaundice and Kemicterus in Canada. Can Med
AssocJ. Dec 12 1964;91:1243-1249.
4. Ruder AM. Potential health effects of occupational chlorinated solvent exposure. Ann N Y
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7. Snyder RW, Mishel HS, Christensen GC, 3rd. Pulmonary toxicity following exposure to
methylene chloride and its combustion product, phosgene. Chest. Dec 1992; 102(6): 1921.
8. Schwartz MD, Obamwonyi AO, Thomas JD, Moorhead JF, Morgan BW. Acute methyl
iodide exposure with delayed neuropsychiatric sequelae: report of a case. Am J Ind Med.
Jun2005;47(6):550-556.
9. Deschamps FJ, Turpin JC. Methyl bromide intoxication during grain store fumigation.
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10. Hustinx WN, van de Laar RT, van Huffelen AC, Verwey JC, Meulenbelt J, Savelkoul
TJ. Systemic effects of inhalational methyl bromide poisoning: a study of nine cases
occupationally exposed due to inadvertent spread during fumigation. Br J Ind Med. Feb
1993;50(2): 155-159.
11. Hezemans-Boer M, Toonstra J, Meulenbelt J, Zwaveling JH, Sangster B, van Vloten WA.
Skin lesions due to exposure to methyl bromide. Arch Dermatol. Jun 1988; 124(6): 917-921.
12. Dykes MH. Halogenated hydrocarbon ingestion. Int Anesthesiol Clin. Summer
1970;8(2):357-368.
13. Himmel HM. Mechanisms involved in cardiac sensitization by volatile anesthetics: general
applicability to halogenated hydrocarbons? CritRev Toxicol. 2008;38(9):773-803.
14. Truss CD, Killenberg PG. Treatment of carbon tetrachloride poisoning with hyperbaric
oxygen. Gastroenterology. Apr 1982;82(4):767-769.
15. Perez AJ, Courel M, Sobrado J, Gonzalez L. Acute renal failure after topical application of
carbon tetrachloride. Lancet. 1987;1(8531):515-516.
16. Oriel M, Edmiston S, Beauvais S, Barry T, O'Malley M. Illnesses associated with chloro-
picrin use in California agriculture, 1992-2003. Rev Environ Contain Toxicol. 2009;200:1-
31.
17. Barry T, Oriel M, Verder-Carlos M, Mehler L, Edmiston S, O'Malley M. Community
exposure following a drip-application of chloropicrin. J Agromedicine. Jan 2010; 15( 1): 24-
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18. Liu JR, Fang S, Ding MP, et al. Toxic encephalopathy caused by occupational exposure to
1, 2-Dichloroethane. JNeurolSci. May 15 2010;292(1-2):111-113.
19. Amir D. The spermicidal effect of ethylene dibromide in bulls and rams. Mol Reprod Dev.
Janl991;28(l):99-109.
20. Slutsky M, Levin JL, Levy BS. Azoospermia and oligospermia among a large cohort of
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21. Singh N, Jatav OP, Gupta RK, Tailor MK, Jain R. Outcome of sixty four cases of ethylene
dibromide ingestion treated in tertiary care hospital. J Assoc Physicians India. Dec
2007;55:842-845.
22. Stott WT, Gollapudi BB, Rao KS. Mammalian toxicity of 1,3-dichloropropene. Rev
Environ Contam Toxicol. 2001;168:l-42.
23. Hallowell M. Acute haemolytic anaemia following the ingestion of paradichlorobenzene.
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24. Cheong R, Wilson RK, Cortese 1C, Newman-Toker DE. Mothball withdrawal encepha-
lopathy: case report and review of paradichlorobenzene neurotoxicity. Subst Abus. Dec
2006;27(4): 63-67.
25. Lin TJ, Ho CK, Chen CY, Tsai JL, Tsai MS. Two episodes of ethylene oxide poisoninga
case report. Kaohsiung JMed Sci. Jun 2001;17(7):372-376.
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27. Krzyzanowski M, Quackenboss JJ, Lebowitz MD. Chronic respiratory effects of indoor
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ment. Hum Exp Toxicol. Jun 2000; 19(6):360-366.
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31. Rabinovitch S, Greyson ND, Weiser W, Hoffstein V. Clinical and laboratory features of
acute sulfur dioxide inhalation poisoning: two-year follow-up. Am Rev Respir Dis. Feb
1989;139(2):556-558.
32. Scheuerman EH. Suicide by exposure to sulfuryl fluoride. J Forensic Sci. Jul
1986;31(3):1154-1158.
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34. Schneir A, Clark RF, Kene M, Betten D. Systemic fluoride poisoning and death from inha-
lational exposure to sulfuryl fluoride. Clin Toxicol (Phila). Nov 2008;46(9):850-854.
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36. Huang CC, Chu CC, Wu TN, Shih TS, Chu NS. Clinical course in patients with chronic
carbon disulfide polyneuropathy. Clin Neural Neurosurg. May 2002;104(2): 115-120.
37. Wilcosky TC, Tyroler HA. Mortality from heart disease among workers exposed to
solvents. JOccupMed. Dec 1983;25(12):879-885.
38. Klemmer PJ, Harris AA. Carbon disulfide nephropathy. Am J Kidney Dis. Sep
2000;36(3):626-629.
39. Katira R, Elhence GP, Mehrotra ML, et al. A study of aluminum phosphide (A1P) poisoning
with special reference to electrocardiographic changes. J Assoc Physicians India. Jul
1990;38(7):471-473.
40. Singh S, Singh D, Wig N, Jit I, Sharma BK. Aluminum phosphide ingestiona clinico-
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41. Nath NS, Bahattacharya I, Tuck AG, Schlipalius DI, Ebert PR. Mechanisms of phosphine
toxicity. Journal of Toxicology. 201 l;Article ID 494168.
42. Singh RB, Singh RG, Singh U. Hypermagnesemia following aluminum phosphide
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43. Gupta S, Ahlawat SK. Aluminum phosphide poisoning-a review. J Toxicol Clin Toxicol.
1995;33(1): 19-24.
44. Johnson RP, Mellors JW. Arteriolization of venous blood gases: a clue to the diagnosis of
cyanide poisoning. JEmergMed. Sep-Oct 1988;6(5):401-404.
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46. Dourson ML, Kohrman-Vincent MJ, Allen BC. Dose response assessment for effects
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Aug 1981;38(8):529-530.
48. Ruprah M, Mant TG, Flanagan RJ. Acute carbon tetrachloride poisoning in 19 patients:
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51. Siwach SB, Singh P, Ahlawat S, Dua A, Sharma D. Serum & tissue magnesium content in
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sulphate therapy in reducing mortality. J Assoc Physicians India. Feb 1994;42(2): 107-110.
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and methods of their administration in dogs: a comparative study. Anesthesiology. Mar
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1984;76(5):83-86, 89-91, 94-85.
172
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CHAPTER 18
Rodenticides
Rodent poisons are usually added to baits (palatable grain or paste intended to
encourage consumption). Safety for animals and humans depends on the toxicity of
the agents, concentration of the active ingredient in the bait, the likelihood that a toxic
dose will be consumed by non-target species, and bioaccumulation and persistence in
body tissues. The first-generation anticoagulants, for example, are reasonably effec-
tive against pest rodents and are less toxic than second-generation anticoagulants (see
discussion of first- and second-generation anticoagulants in subsection Coumarins and
Indandiones, following). Rodents are more likely than domestic animals or humans
to consume quantities of treated bait that will cause poisoning. However, accidental
ingestionby young children or intentional ingestionby individuals with suicidal intent
is possible with any poison.
Very small amounts of the extremely toxic rodenticides - sodium fluoroace-
tate, fluoracetamide, strychnine, crimidine, yellow phosphorus, zinc phosphide
and thallium sulfate - can cause severe and even fatal poisoning. Cholecalciferol
is also a highly toxic agent. The anticoagulants, indandiones and red squill are
less hazardous to humans and domestic animals. Some of the newer anticoagulant
compounds, termed "second-generation anticoagulants," may cause human toxicity
at a much lower dose than conventional "first-generation anticoagulants"1'2'3 and can
bioaccumulate in the liver.2
Yellow phosphorus is not sold in the United States. Zinc phosphide is still regis-
tered in the United States and can be found in U.S. retail stores. Thallium sulfate is no
longer registered for pesticidal use, but is used by government agencies and in medical
diagnostic testing.
Strychnine and sodium fluoroacetate are still used for control of some mammal
pests such as coyotes, as is cyanide (see Chapter 17, Fumigants for cyanide). Only
specially trained personnel are allowed to use them.
Crimidine and nuoroacetamide are no longer registered in the United States for
use as pesticides. TETS is banned worldwide.
COUMARINS AND INDANDIONES
Toxicology
Anticoagulants (warfarin and related compounds, coumarins and indandiones) are
the most commonly used rodenticides in the United States. While there has been a
modest decline in the number of exposures in 2008 compared to 1996, from 13,345 to
11,487, they still account for the largest number of reported rodenticide exposures.4'5
Gastrointestinal absorption of these toxicants is efficient.
Certain agents in this category are referred to as "first-generation" or "second-
generation" anticoagulants. "First-generation" anticoagulants, as the name implies.
were developed earlier (during World War II), and include hydroxycoumarin deriva-
tives such as warfarin, coumachlor and coumatetralyl. The "second-generation"
anticoagulants, sometimes referred to as "superwarfarins," are generally more toxic.
These include bromodiolone, brodifacoum and difenacoum.
Coumarins and indandiones depress the hepatic synthesis of vitamin K-depen-
dent blood-clotting factors (II [prothrombin] and VII, IX and X). The antiprothrombin
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CHAPTER 18
Rodenticides
Coumarins & Indandiones
HIGHLIGHTS
Most commonly used
rodenticides in U.S.
Efficient Gl absorption
Depress blood clotting and
capillary permeability
SIGNS & SYMPTOMS
Bleeding nose/gums,
hematuria, melena,
eccymoses days after
ingestion
For indandiones, headache,
confusion, loss of
consciousness, seizures
Increase in PT/INR
TREATMENT
Monitor PT/INR
Give Vitamin K, upon PT7
INR evidence
CONTRAINDICATED
Vitamin K3 or K4
effect is best known and is the basis for detection and assessment of clinical poisoning.
The agents also increase permeability of capillaries throughout the body, predisposing
the animal to widespread internal hemorrhage. This generally occurs in the rodent
after several days of warfarin ingestion because of the long half-lives of the vitamin
K-dependent clotting factors,1'2 although lethal hemorrhage may follow smaller doses
of the modern, more toxic compounds.2'3
To identify potential toxic effects from the coumarins or indandiones, a
prothrombin time (PT) is measured. Most laboratories report the PT as being adjusted
to the International Normalized Ratio (INR) for patients on anticoagulant medica-
tion. Therefore, one may see PT or INR reported by a laboratory. The prolonged
prothrombin time (PT/INR) from a toxic dose of coumarins or indandiones may be
evident within 24 hours, but usually reaches a maximum in 36-72 hours.2'6'7 Prolonged
PT/INR occurs in response to doses much lower than that necessary to cause hemor-
rhage. There is concern that the more toxic modern compounds, such as brodifacoum
and difenacoum, may cause serious poisoning of non-target mammals, including
humans, at much lower dosage. Brodifacoum, one of the "second-generation antico-
agulants," is much more toxic, partly due to a longer half-life; a dose as low as 1 mg in
an adult or 0.014 mg/kg in a child is sufficient to produce toxicity.2
Symptomatic poisoning, with prolonged symptoms due to the long half-lives
of second-generation anticoagulants, has been reported even with single exposures;
however, these are usually intentional and are large, single dosages.1 Because of their
toxicity in relation to warfarin, patients may require higher dosages of vitamin K and
will require longer monitoring of their PT. One patient required vitamin K for several
months following discharge.8 Another was released from the hospital with significant
clinical improvement and only slightly elevated coagulation studies after brodifacoum
ingestion. Two-and-a-half weeks later, this patient presented in a comatose state and
was found to have massive intracranial hemorrhage.9 In situations of purposeful inges-
tion, it is difficult to know if the patient is re-exposing himself or herself. Since 1999.
individual case reports continue to appear in the medical literature. Nearly all are
suicidal ingestions, although there are occasional reports of intentional subacute inges-
tion or Munchausen by proxy.10'11'12'13'14'15
In contrast to the intentional ingestions from suicide attempts, accidental single
ingestions are more common, particularly when toddlers ingest a few pellets. The
majority of these incidents did not result in significant bleeding, and most patients did
not have a prolonged PT/INR.7'16'17 It should also be noted that beginning June 2011.
all rodenticide bait products available for sale on the residential consumer market
in the United States must be in the form of blocks (pellets or loose bait no longer
allowed) and be contained a tamper-resistant bait station. Also, since 2011, the second
generation anticoagulants (brodifacoum, bromadiolone, difenacoum, difethialone) are
not allowed in residential consumer products.18
Dermal exposure to the long-acting indandiones has also been reported to cause
symptomatic bleeding. One 18-year-old patient presented with flank pain and gross
hematuria following dermal exposure to 0.106% diphacinone.19 Another patient had
hematuria following exposure to 0.25% chlorophacinone on his torso.20
Clinical effects of these agents usually begin several days after ingestion.
because of the long half-life of the factors. Primary manifestations include nosebleeds.
bleeding gums, hematuria, melena and extensive ecchymoses.1'2'8'9'21 Patients may also
have symptoms of anemia including fatigue and dyspnea on exertion.21 If the poisoning
is severe, the patient may progress to shock and death.
Unlike the coumarin compounds, some indandiones cause symptoms and signs
of neurologic and cardiopulmonary injury in laboratory rats. These lead to death before
hemorrhage occurs, which may account for the greater toxicity of indandiones in
174
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rodents. In several cases of human poisonings, some of the presenting signs included
headache, confusion, loss of consciousness and seizures. These CNS symptoms were
found to be related to intracranial hemorrhage.22'23 One other patient was reported to
present in a comatose state. He had severe intra-abdominal bleeding without any intra-
cranial bleeding and eventually recovered.24
Confirmation of Poisoning
Coumarin or indandione poisoning results in an increase in PT/TNR, the result of
reduced plasma prothrombin concentration. This is a reliable test for absorption of
physiologically significant doses. Detectable reduction in prothrombin occurs within
24-48 hours of ingestion and persists for 1-3 weeks.2'6'7 Blood levels of the second-
generation anticoagulants can be measured, however the test is not immediately avail-
able, nor does it aid in immediate treatment decisions as does the PT or INR.21
Treatment of Anticoagulant Toxicosis
If the amount of agent ingested was assuredly no more than a few mouthfuls of
coumarin- or indandione-treated bait, or a single mouthful of bait treated with the
more toxic brodifacoum or bromadiolone compounds, medical treatment is probably
unnecessary. Otherwise:
1. If there is an unknown amount or deliberate ingestion, assess PT/INR at baseline
and then daily. While the anticoagulant effects of the coumarins might be noted
within 12-24 hours of ingestion, some agents such as brodifacoum may not show
an elevation until 48 hours after ingestion, if it does occur.7 A normal PT/INR
48-72 hours after ingestion makes a significant bleeding event very unlikely.
2. Give phytonadione (vitamin Kj) orally to protect against the anticoagulant effect
of these rodenticides, with essentially no risk to the patient. The indication for
vitamin Kj in these patients is laboratory evidence (elevated PT/INR) of excessive
anticoagulation after ingestion. It is not recommended empirically after ingestion.
On one hand, laboratory evidence may indicate it is not needed. However, most
important, vitamin Kj administration prior to PT/INR elevation may delay the lab
abnormalities and the seriousness of the ingestion can be missed.
CAUTION: Phytonadione, specifically, is required. Neither vitamin K3 (mena-
dione, Hykinone) nor vitamin K4 (menadiol) is an antidote for these anticoagu-
lants. These need to be metabolized by the liver to active vitamin K, and with the
potential of significant bleeding, liver function may be impaired. They were not
effective as antidotes in prior poisonings.22-25
CHAPTER 18
Rodenticides
Coumarins & Indandiones
COMMERCIAL
PRODUCTS
Anticoagulants
brodifacoum (Havoc, Talon)
bromadiolone (Contrac,
Maki)
coumachlor
coumatetralyl
difenacoum
difethialone
warfarin (Cov-R-Tox,
Liqua-Tox)
Indandiones
chlorophacinone (Rozol)
diphacinone (diphacin,
Ditrac, Ramik, Tomcat)
pivalyn (Rival)
radione
3. If possible, administer vitamin Kj by mouth. While vitamin Kj can be given
orally, subcutaneously (SC), intramuscularly (IM) and intravenously (IV), oral
use is preferred because of its good adverse event profile. Anaphy lactoid reactions
resulting in death have been reported via the IV route; therefore, IVs should be
restricted to those patients who are critically ill and cannot take it by any other
route. IM or SC use can result in significant hematoma in anti-coagulated patients
and, again, use of these routes should be reserved for those patients unable to take
Vitamin Kj orally.
175
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CHAPTER 18
Rodenticides
Inorganic Rodenticides
COMMERCIAL
PRODUCTS
Yellow phosphorus
Zinc phosphide
Thallium sulfate
4. Begin dosing with vitamin Kr Dosing can be variable and may depend on the
level of anticoagulation and the agent ingested. The usual starting dose is:
Dosage of Vitamin K,
Adults: 10-50 mg orally, 2-4 times per day
Children: 5-10 mg (or 0.4 mg/kg/dose) orally, 2-4 times
per day
5. Monitor PT/INR for response to vitamin Kj and, once declining, doses can be
decreased accordingly. Patients who ingest large amounts, particularly of the
superwarfarin compounds, will likely have a very prolonged period of decreased
prothrombin activity. Patients may need to be treated for as long as 3 or 4 months.8'9
6. With ingestions of certain agents such as the second-generation anticoagulants.
very large doses of vitamin Kp between 100 mg up to 400 mg, have been needed
initially to reverse the anticoagulation.6'26 These large doses may be required from
weeks to months, depending on the extent of the ingestion and anticoagulation.
Monitor patients closely to assure that they are taking the vitamin Kj and not
deliberately re-exposing themselves.
7. Give patients who present with active bleeding fresh frozen plasma or whole
blood, while also receiving vitamin Kr This will temporize the bleeding until the
vitamin Kj has time to replenish the missing factors.
INORGANIC RODENTICIDES
Toxicology
Yellow phosphorus is a corrosive agent that damages all tissues it contacts, including
skin and the gastrointestinal epithelium. A similar compound, white phosphorus, is
used as an explosive agent in ammunition and fireworks, and some recent reports of
toxicity have been from this source.27'28 The skin is subject to severe burns from white
phosporus, which can be third degree and require grafting.27
Initial symptoms of yellow phosphorus ingestion usually reflect mucosal injury
and occur a few minutes to 24 hours following ingestion. The first symptoms include
severe vomiting and burning pain in the throat, chest and abdomen. The emesis may be
bloody (either red, brown or black)29 and on occasion may have a garlic smell.30'31'32 In
some cases, central nervous system signs such as lethargy, restlessness and irritability
are the earliest symptoms followed by symptoms of gastrointestinal injury. Shock and
cardiopulmonary arrest leading to death may occur within hours in severe ingestions.31
If the patient survives the initial toxic effects, there may be a second stage.
characterized by a period of apparent improvement that can last a few hours or days.
although this is not always the case.29 In severe poisoning, a third stage of toxicity then
ensues with systemic signs indicating severe injury to the liver, myocardium and brain.
Nausea and vomiting recur. There is a severe toxic hepatitis with elevated liver trans-
aminases, and jaundice with elevation in both total and direct bilirubin levels.29'32'33
Neutropenia has also been reported.34 Hypovolemic shock and toxic myocarditis may
develop. Brain injury is manifested by convulsions, delirium and coma. The coma may
result from hyperammonemia due to severe hepatic failure.32'33 Anuric renal failure
176
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commonly develops because of shock and the toxic effects of phosphorus products and
accumulating bilirubin on renal tubules. The mortality rate of phosphorous poisonings
may be as high as 50 percent.29
Zinc phosphide is much less corrosive to skin and mucous membranes than
yellow phosphorus. Both zinc phosphide and aluminum phosphide (often used as a
fumigant) can be very toxic following ingestion, although zinc phosphide ingestion is
relatively less common than its aluminum counterpart.35 In terms of toxicity following
ingestion, phosphine is thought to be released from the metal phosphide following
contact with fluids in the GT tract.35 While the emetic effect of zinc released in the gut
may provide a measure of protection for humans, fatal ingestion of zinc phosphide
has been reported.36'37 Nausea and vomiting, agitation, chills, chest tightness, dyspnea
and cough may progress to pulmonary edema. These symptoms, as well as systemic
toxicity, may be delayed or present after initial benign exam. Patients face many of
the same systemic toxicities encountered with yellow phosphorous, including hepatic
failure with jaundice and hemorrhage, delirium, convulsions and coma (from toxic
encephalopathy); tetany from hypocalcemia and anuria from renal tubular damage.
Ventricular arrhythmias from cardiomyopathy and shock also occur and are another
common cause of death.30'38 Severe hypoglycemia has also been reported, which is
also thought to be of hepatic origin by inhibition of glycogenolysis and gluconeo-
genesis.38'39 (Conversely, hyperglycemia has been reported following ingestion of the
fumigant aluminum phosphide.)40 Inhalation of phosphine gas from improper use
of phosphide rodenticides has resulted in pulmonary edema, myocardial injury and
multisystem involvement.41 For more information about the effects of phosphine gas
poisoning, see the section on aluminum phosphide in Chapter 17, Fumigants.
Thallium sulfate is well absorbed from the gut and across the skin. It exhibits
a very large volume of distribution and is distributed chiefly to the kidney and liver.
both of which participate in thallium excretion. Most blood-borne thallium is in the
red cells. Thallium is thought to exert its toxic effects by competing with intracellular
potassium and interfering with intracellular enzyme reactions.42 Elimination half-life
from blood in the adult human is about 1.9 days. Most authors report the LD50 in
humans to be between 10-15 mg/kg.43
Unlike other inorganic rodenticides such as yellow phosphorous and zinc phos-
phide, thallium poisoning tends to have a more insidious onset with a wide variety of
toxic manifestations. The gastrointestinal, central nervous, cardiovascular, renal and
integumentary systems are prominently affected by toxic intakes of thallium. Early
symptoms include abdominal pain, nausea, vomiting, bloody diarrhea, stomatitis, sali-
vation and ileus. Elevated liver enzymes may occur, indicating tissue damage. Protein-
uria and hematuria may also occur. Other patients experience signs of central nervous
system toxicity including headache, lethargy, muscle weakness or even paralysis, loss
of deep tendon reflexes, paresthesias, tremor, ptosis and ataxia. These signs and symp-
toms usually occur several days to more than a week after exposure.42'43'44 Extremely
painful paresthesias, either in the presence or absence of gastrointestinal signs, may
be the primary presenting complaint.42'45'46'47 Myoclonic movements, convulsions.
delirium and coma reflect more severe neurologic involvement.
Cardiovascular effects include hypotension, due at least in part to a toxic myocar-
diopathy, myocardial ischemia and ventricular arrhythmias.48 Hypertension occurs
later and is probably a result of peripheral arterial vasoconstriction. Patients may also
develop alveolar edema and hyaline membrane formation in the lungs, consistent with
a diagnosis of Acute Respiratory Distress Syndrome.48 Death from thallium poisoning
may be caused by respiratory failure or cardiovascular collapse.47'48 Absorption of
nonlethal doses of thallium has caused protracted, painful neuropathies and paresis.
optic nerve atrophy, persistent ataxia, dementia, seizures and coma.45
CHAPTER 18
Rodenticides
Phosphorus
HIGHLIGHTS
Phosphorus poisonings are
often fatal
SIGNS & SYMPTOMS
Yellow phosphorus usually
causes mucosal injury,
emesis, burning throat
TREATMENT
Decontaminate skin using
PPE
Supportive treatment
Monitor urine albuman,
glucose, sediment
Monitor serum alkaline
phosphatase, LDH, ALT,
AST, prothrombin time,
bilirubin
CONTRAINDICATED
Emesis induction
Potassium permanganate
lavage
177
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CHAPTER 18
Rodenticides
Zinc Phosphide
HIGHLIGHTS
Less corrosive than yellow
phosphorus
Can be very toxic following
ingestion
SIGNS & SYMPTOMS
Nausea, vomiting, agitation,
chills, cough
TREATMENT
Supportive treatment
Control airway
Consider Gl
decontamination
Alopecia is a fairly consistent feature of thallium poisoning that may be helpful in
diagnosing a case of chronic poisoning. Since it occurs 2 weeks or more after the onset
of acute symptoms, it is not diagnostically helpful early in the presentation.42'43'45'49
Confirmation of Poisoning
Phosphorus and phosphides sometimes impart a foul rotten fish odor to vomitus, feces.
and the breath. Luminescence of vomitus or feces is an occasional feature of phos-
phorus ingestion. Hyperphosphatemia and hypocalcemia occur in some cases but are
not consistent findings.
Thallium can be measured in the serum, whole blood, urine and hair. The
most reliable method for diagnosis is considered a 24-hour urine excretion. Values
in non-exposed individuals have been reported to be less than 10 ug/liter per 24
hours.43'46'47'48'49'50 Urinary excretion in the range of 10-20 mg/ liter indicates severe
poisoning.4
Hair analysis is likely to be useful only in establishing protracted
prior absorption. Normal serum concentrations are less than 2 micrograms per liter.47'50
Whole blood thallium levels greater than 100 micrograms/dL indicate poisoning.51
Treatment of Yellow Phosphorus Toxicosis
1. Brush or scrape non-adherent phosphorus from the skin. Wash skin burns with
copious amounts of water. Make sure all particles of phosphorus have been
removed. If burned area is infected, cover with an antimicrobial cream.
2. Take special care to prevent your and other healthcare personnel's exposure when
treating a patient poisoned by yellow phosphorus. While this is true of most
pesticide poisonings, with a yellow phosphorus poisoning, personal protection.
as outlined in Chapter 3, General Principles, must be worn to avoid secondary
contamination and burns from phosphorous particles in the patient's bodily fluids.
3. Provide supportive, symptomatic treatment. Poisonings by ingested yellow phos-
phorus are extremely difficult to manage. Control of airway must be established
prior to considering gastrointestinal decontamination as described in Chapter 3.
4. Do not induce emesis. Lavage with potassium permanganate solution had histori-
cally been recommended in the management of phosphorus ingestion; however.
there is not sufficient evidence for its efficacy. It is not recommend it because of
the corrosive nature of yellow phosphorus.
5. Treat patients with shock in an intensive care unit.
6. Monitor urine albumin, glucose and sediment to detect early renal injury. Extra-
corporeal hemodialysis will be required if acute renal failure occurs, but it does
not enhance excretion of phosphorus. Monitor ECG to detect myocardial impair-
ment.
7. Monitor serum alkaline phosphatase, LDH, ALT, AST, prothrombin time and
bilirubin to evaluate liver damage. Administer AquamephytonR (vitamin Kj) if
prothrombin level declines.
8. Administer parenteral pain medication for pain from burns.
178
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Treatment of Poisoning by Zinc Phosphide
1. Provide supportive, symptomatic treatment in an intensive care setting. There is
no specific antidote for the treatment of phosphine exposure, and poisonings by
ingestion are extremely difficult to manage.
2. Establish control of airway before considering gastrointestinal decontamination
as described in Chapter 3, General Principles.
CAUTION: Highly toxic phosphine gas may evolve from emesis, lavage fluid
andfeces of victims of these poisons. The patient's room should be well venti-
lated. Persons attending the patient must wear gloves to avoid contact with the
phosphorus. Air purifying or supplied-air respiratory equipment should be
worn by healthcare providers if available.
3. See the section on treatment of aluminum phosphide poisoning in Chapter 17,
Fumigants for specific therapy for phosphine gas.
Treatment of Thallium Sulfate Toxicosis
1. If thallium sulfate was swallowed less than an hour prior, consider gastrointestinal
decontamination as outlined in Chapter 3 General Principles. Multiple doses of
activated charcoal may be helpful in increasing thallium elimination.46
2. Give electrolyte and glucose solutions by intravenous infusion to support urinary
excretion of thallium by diuresis. Monitor fluid balance carefully to ensure that fluid
overload does not occur. If shock develops, treat the patient in an intensive care unit.
3. Control seizures and myoclonic jerking as outlined in Chapter 3.
4. Consider hemodialysis. It has been used on victims of severe poisoning.46'50
5. Use potassium ferric ferrocyanide (Prussian blue) orally to enhance fecal excre-
tion of thallium by exchange of potassium for thallium in the gut. It is available
in the United States as an insoluble preparation, primarily for the purposes of
radioactive thallium and radioactive cesium poisoning.53 However, Prussian blue
therapy has often been reported as a therapy in rodenticide poisonings.42'46'50'43
Dosage of Prussian Blue
Adults and adolescents over 13: 3 grams orally, 3 times
a day.53 Unfortunately, there is no established pediatric
dosage by weight. The only available guidance for dosage
by weight is from two adult cases that reported using a
dosage of 250 mg/kg/day.42'5*
CHAPTER 18
Rodenticides
Thallium Sulfate
HIGHLIGHTS
Well absorbed from gut,
across skin
Distributed chiefly to kidney,
liver
SIGNS & SYMPTOMS
Wide variety of symptoms
Alopecia in chronic cases
TREATMENT
Consider Gl
decontamination
IV electrolytes, glucose
Administer Prussian Blue
CONTRAINDICATED
Chelating agents
Potassium chloride
Several methods for chelating and/or accelerating disposition of thallium have
been tested and found either relatively ineffective or hazardous. Chelating agents are
not recommended in thallium poisoning. While potassium chloride has been recom-
mended, it has been reported to increase toxicity to the brain45'48 and has not been
shown to increase elimination in some cases.52
179
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CHAPTER 18
Rodenticides
Severe Multiorgan
Metabolic Toxicant
COMMERCIAL
PRODUCTS
Sodium fluoroacetate, also
known as Compound 1080
Fluoroacetamide
(discontinued)
Strychnine
Crimidine (Castrix,
discontinued)
Tetramethylenedisulfo-
tetramine (TETS)
SEVERE MULTIORGAN METABOLIC TOXICANTS
Toxicology
Sodium fluoroacetate and fluoroacetamide are readily absorbed by the gut but only
to a limited extent across skin. The toxic mechanism is distinct from that of fluoride
salts. Three molecules of fluoroacetate or fluoroacetamide are combined in the liver to
form a molecule of fluorocitrate, which poisons critical enzymes of the tricarboxylic
acid (Krebs) cycle, blocking cellular respiration. The heart, brain and kidneys are the
organs most prominently affected. The effect on the heart is to cause arrhythmias.
progressing to ventricular fibrillation, which is a common cause of death. Metabolic
acidosis, shock, electrolyte imbalance and respiratory distress are all signs of a poor
prognostic. Neurotoxicity is expressed as violent tonic-clonic convulsions, spasms and
rigor, sometimes not occurring until hours after ingestion.55
Strychnine is a natural toxin (nux vomica) that causes violent convulsions by
direct excitatory action on the cells of the central nervous system, chiefly the spinal
cord. Death is caused by convulsive-induced muscle spasms of the diaphragm and
thoracic intercostals, resulting in impaired respiration.56'57 The severe seizures can
cause rhabdomyolysis, and the released myoglobin can result in renal failure. Other
symptoms may include muscle stiffness, pain and hyperreflexia. Patients are generally
conscious and oriented between seizures, which can be helpful in making the diagnosis
in an unknown seizure event.56'57 Since strychnine is rapidly absorbed and distributed.
the onset of symptoms is usually within 15-20 minutes of ingestion. Strychnine is
detoxified in the liver. Residence half-life is about 10 hours in humans. The lethal dose
in adults is reported to be between 50 and 100 mg, although as little as 15 mg can kill
a child.58
Crimidine is a synthetic chlorinated pyrimidine compound that inhibits pyri-
doxine (vitamin B6). In adequate dosage, it causes violent convulsions similar to
those produced by strychnine. Cases of human poisoning are very rare, though one is
presented in the Belgian literature.59
Tetramethylenedisulfotetramine (TETS) is a tasteless and odorless convulsant
rodenticide that is highly toxic, with an estimated human adult lethal dose of about 7-10
mg. It works by antagonizing g-amino butyricacid (GAB A). It has been banned world-
wide since 1984. Unfortunately, it is still available through illegal means and has been
used in mass poisonings in the past. A recent case in the United States reported refrac-
tory seizures in a 15-month-old after playing with a white powder for rodent control that
the parents had purchased in China and brought with them to New York City. Seizures
began within 15 minutes of exposure and became refractory. She required intubation
and mechanical ventilation for 3 days. Following recovery from the acute seizures.
she was noted to have persistent neurological problems including cortical blindness.
absence seizures and severe developmental delays. Eventually, through gas chroma-
tography/mass spectrometry after testing negative for the other well known convulsant
rodenticides and bromethalin, the powder was identified as TETS.60
Confirmation of Poisoning
Strychnine and crimidine can both be detected in the blood using high performance
thin layer chromatography.61 For strychnine detection in small samples (as little as 0.1
mL), another method using liquid chromatography with photodiode-array detection
has been described.57'61 Strychnine levels that exceed 1 mg/L may be lethal, although
one patient survived a blood concentration of 4.73 mg/L.57'62'63'64 Because of the infre-
quency of crimidine poisoning, human blood levels are not well known. These tests
are likely to be only available at specialized laboratories.
180
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Treatment of Sodium Fluoroacetate and Fluoroacetamide
Toxicosis
Poisonings with these compounds have occurred almost entirely as a result of acci-
dental and suicidal ingestions.
1. If the patient is seen within an hour of exposure and is not convulsing, consider
gastrointestinal decontamination as outlined in Chapter 3, General Principles. If
the victim is already convulsing, control the seizures before undertaking gastric
lavage and catharsis.
2. Control seizures as outlined in Chapter 3. Seizure activity from these compounds
may be so severe that doses necessary for seizure control may paralyze respira-
tion. For this reason, as well as severe cardiac toxicity, these patients should be
managed in a critical care environment, with pulmonary ventilation supported
mechanically. This has the added advantage of protecting the airway from aspira-
tion of regurgitated gastric contents.
3. Treat patients in an intensive care unit, with special attention to fluids, electrolytes
and cardiovascular monitoring.
4. Give calcium gluconate (10% solution) slowly, intravenously to relieve hypocal-
cemia. Take care to avoid extravasation.
Dosage of Calcium Gluconate
supplied as 700 mg/mL (10% solution)
Adults and children over 12 years: 10 mL of 10% solution,
given slowly, intravenously. Repeat as necessary.
Children under 12 years: 200-500 mg/kg/24 hr divided
Q6 hour. For cardiac arrest, 100/kg/dose. Repeat dosage as
needed.
Antidotal efficacy of glycerol monacetate and ethanol, observed in animals, has not
been substantiated in humans. These therapies are not recommended in humans.
Treatment of Strychnine, Crimidine or TETS Toxicosis
Strychnine and crimidine cause violent convulsions shortly following ingestion of
toxic doses. Both poisons are probably well adsorbed by charcoal.
1. Control seizures as outlined in Chapter 3, General Principles. Because of the
severity of toxicity from this poison, patients should be treated in an intensive
care unit setting if available. If seen within an hour of ingestion and the patient
is conscious and not convulsing, consider gastrointestinal decontamination with
charcoal. If seizures have already begun, they should be controlled prior to
attempting decontamination.
2. Administer intravenous fluids to support excretion of absorbed toxicants. Inclu-
sion of sodium bicarbonate in the infusion fluid counteracts metabolic acidosis
generated by convulsions caused by strychnine.64'65'66'67'68
3. Avoid hemodialysis and hemoperfusion. Their effectiveness has not been tested.
CHAPTER 18
Rodenticides
Severe Mu Morgan
Metabolic Toxicant
HIGHLIGHTS
Sodium fluoroacetate/
fluoroacetamide readily
absorbed by gut
Strychnine acts on CMS
Crimidine inhibits Vitamin B.
b
TETS antagonizes GABA
TETS banned worldwide
SIGNS & SYMPTOMS
Sodium Fluoroacetate/
Fluoroacetamide
Blocks cellular respiration
Affects heart, brain,
kidneys
Heart arrhythmia
Strychnine/Crimidine
Violent convulsions
TETS
Seizures
TREATMENT
Sodium Fluoroacetate/
Fluoroacetamide
Control seizures
Decontaminate Gl tract
as appropriate
Monitor fluids,
electrolytes,
cardiovascular
IV calcium gluconate
Strychnine/Crimidine
Control seizures
Decontaminate Gl tract
as appropriate
IV fluids with sodium
bicarbonate
Consider pyridoxine
TETS
Supportive treatment
181
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CHAPTER 18
Rodenticides
Miscellaneous
Rodenticides
COMMERCIAL
PRODUCTS
Red squill (Dethdiet, Rodine;
red squill is no longer
registered for rodenticidal
use in the U.S.)
Cholecalciferol (Quintox,
Rampage)
Bromethalin
4. Consider administering pyridoxine. Because of the mechanism of crimidine
toxicity, pyridoxine (vitamin B6) has been suggested for seizures due to this
convulsant, though there are no humans reports of its use.69
5. Provide supportive treatment of TETS poisoning. The patient will likely require
intensive care in order to survive.
MISCELLANEOUS RODENTICIDES
Red squill and cholecalciferol are no longer registered as rodenticides. Bromethalin is
widely used and is available in the form of bait stations and loose pellets.
Toxicology
Red squill is an ancient rodenticide, consisting of the inner portions of a small cabbage
plant grown in eastern Mediterranean countries. The toxic properties are probably
due to cardioactive glycosides. For several reasons, mammals other than rodents are
unlikely to be poisoned: (1) red squill is an intense nauseant, so animals that vomit
(rodents do not) are unlikely to retain the poison; (2) the glycoside is not efficiently
absorbed from the gut; and (3) absorbed glycoside is rapidly excreted. Injection of the
glycosides leads to effects typical of digitalis: alterations in cardiac impulse conduc-
tion and arrhythmias.
Cholecalciferol is the activated form of vitamin D (vitamin D3). Although it is
registered for use as a rodenticide, most toxic exposures from vitamin D result from
over supplementation or ingestion of multivitamins. Cholecalciferol's toxic effect
is probably a combination of actions on the liver, kidneys and possibly the myocar-
dium, the last two toxicities being the result of hypercalcemia. Symptoms and signs
of vitamin D-induced hypercalcemia in humans are fatigue, weakness, headache and
nausea.70 Polyuria, polydipsia, nephrocalcinosis, hypertension and proteinuria may
result from acute renal tubular injury by hypercalcemia.71'72 The rodenticide form of
cholecalciferol has been implicated in numerous poisonings of domestic animals.
however, there are no reports in the published medical literature of toxicity.
Bromethalin is a neurotoxin that works by uncoupling oxidative phosphoryla-
tion, thus depleting adenosine triphosphate (ATP). The resultant loss of ATP results in
disruption of the sodium/potassium channels causing cerebral edema and eventually
increased intracranial pressure.73 Human poisonings are rare, although there is one
reported fatality in the medical literature. Symptoms mirror what may be found in
animal poisonings (dog and cat), which include mental status changes, stupor, coma.
and cerebral edema.74'75'76'77 Although not reported in these case examples, seizures
may also occur. Treatment for bromethalin poisoning is supportive as outlined in the
Chapter 3, General Principles. There are no known antidotes.
Confirmation of Poisoning
Cholecalciferol intoxication is indicated by an elevated concentration of calcium
(chiefly the unbound fraction) in the serum. There are no generally available tests for
the other rodenticides or their biotransformation products.
Treatment of Red Squill Toxicosis
Red squill is unlikely to cause poisoning unless ingested at substantial dosage. The
problem is usually self-correcting because of its intense emetic effect. If, for some
182
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reason, the squill is retained, consider gastrointestinal decontamination as outlined in
Chapter 3, General Principles. Monitor cardiac status electrocardiographically.
Treatment of Cholecalciferol Toxicosis
Cholecalciferol at high dosage may cause severe poisoning and death. Human poison-
ings from its use as a rodenticide have not been reported, but vitamin D overdosage
has occurred under clinical circumstances. Treatment is directed at limiting gastroin-
testinal absorption, accelerating excretion and counteracting the hypercalcemic effect.
1. If Cholecalciferol has been ingested within an hour prior to treatment consider
gastric decontamination as outlined in Chapter 3, General Principles. Repeated
administration of charcoal at half or more the initial dosage every 2-4 hours may
be beneficial.
2. Administer intravenous fluids (normal saline or 5% glucose) at moderate rates
to support excretory mechanisms and excretion. Monitor fluid balance to avoid
overload, and measure serum electrolytes periodically. Measure total and ionized
calcium levels in the blood 24 hours after Cholecalciferol ingestion to determine
severity of toxic effect. Monitor urine for protein, red and white cells to assess
renal injury. Patients should be managed in an intensive care unit setting with
nephrological consultation if possible.
3. Consider using prednisone and similar glucocorticoids to reduce elevated blood
calcium levels. Although prednisone and glucocorticoids have not been tested in
Cholecalciferol overdosage, it is possible that they would be beneficial.
Dosage of Prednisone and Glucocorticoids
Approximately 1 mg per kilogram per day, to a maximum
of 20 mg per day
4. Consider administering calcitonin (salmon calcitonin, Calcimar). It is a logical
antidote for Cholecalciferol actions, but has only very limited use in human
poisoning.78 Calcium gluconate for intravenous injection should be immediately
available if indications of hypocalcemia (carpopedal spasm, cardiac arrhythmias)
appear.
Dosage of Calcitonin
In other conditions, the usual dosage is 4 International
Units per kg body weight every 12 hours, by intramuscular
or subcutaneous injection, continued for 2-5 days. The dose
may be doubled if calcium-lowering effect is not sufficient.
Consult package insert for additional directions and
warnings.
CHAPTER 18
Rodenticides
Miscellaneous
Rodenticides
HIGHLIGHTS
Red squill toxicity probably
due to cardioactive
glycosideds
Cholecalciferol is activated
form of vitamin D3
Bromethalin depletes
ATP, disrupting sodium/
potassium channels
SIGNS & SYMPTOMS
Cholecalciferol
Fatigue, weakness,
headache, nausea
Bromethalin
Mental changes, stupor,
coma, cerebral edema
TREATMENT
Red Squill
Consider Gl
decontamination if no
emesis
ECG monitoring
Cholecalciferol
Consider Gl
decontamination as
appropriate
IV fluids
Consider prednisone
Consider calcitonin
Consider cholestryamine
Bromethalin
Supportive; no known
antidote
5. Consider administering cholestryamine. It appears to be effective in the treatment
of Vitamin D toxicity in animals79 but has seen very limited use in humans.80'81
183
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CHAPTER 18
Rodenticides
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observations on a non-fatal case. J Toxicol Clin Toxicol. 1986;24(3):245-255.
68. Boyd RE, Brennan PT, Deng IF, Rochester DF, Spyker DA. Strychnine poisoning.
Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis. Am J Med.
Marl983;74(3):507-512.
69. Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. EurJEmerg
Med. Apr 2005;12(2):78-85.
70. Vieth R, Pinto TR, Reen BS, Wong MM. Vitamin D poisoning by table sugar. Lancet. Feb
23 2002;359(9307):672.
71. Jehle DR, Keller F, Schwarz A, Jehle PM. Hypercalcemia-induced renal insufficiency
during therapy with dihydrotachysterol. JMed. 1999;30(l-2):39-50.
72. Titan SM, Callas SH, Uip DE, Kalil-Filho R, PC AG. Acute renal failure and hypercal-
cemia in an athletic young man. Clin Nephrol. Apr 2009;71(4):445-447.
73. van Lier RB, Cherry LD. The toxicity and mechanism of action of bromethalin: a new
single-feeding rodenticide. FundamAppl Toxicol. Nov 1988;ll(4):664-672.
74. Pasquale-Styles MA, Sochaski MA, Dorman DC, Krell WS, Shah AK, Schmidt CJ. Fatal
bromethalin poisoning. J Forensic Sci. Sep 2006;51(5): 1154-1157.
75. Dorman DC, Simon J, Harlin KA, Buck WB. Diagnosis of bromethalin toxicosis in the
dog. J VetDiagn Invest. Apr 1990;2(2):123-128.
76. Martin T, Johnson B. A suspected case of bromethalin toxicity in a domestic cat. Vet Hum
Toxicol. Jun 1989;31(3):239-240.
77. Dorman DC, Parker AJ, Dye JA, Buck WB. Bromethalin neurotoxicosis in the cat. Prog
VetNeurol. 1990;!: 189-196.
78. Buckle RM, Gamlen TR, Pullen IM. Vitamin D intoxication treated with porcine calci-
tomn.BrMedJ. Jul22 1972;3(5820):205-207.
79. Queener SF, Bell NH. Treatment of experimental vitamin d3 intoxication in the rat with
cholestyramine. Clin Res. 1976;24:583A.
80. Jibani M, Hodges NH. Prolonged hypercalcaemia after industrial exposure to vitamin D3.
Br Med J (Clin Res Ed). Mar 9 1985;290(6470):748-749.
81. Thomson RB, Johnson JK. Another family with acute vitamin D intoxication: another
cause of familial hypercalcaemia. Postgrad Med J. 1986;62:1025-1028.
187
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4-Aminopyridine
COMMERCIAL
PRODUCTS
Avitrol
HIGHLIGHTS
Toxic to all vertebrates
Used as bird repellent in
grain baits or powdered
sugar formulation
Rapidly absorbed across
gut; less so on skin
Enhances cholinergic
transmission in nervous
system
SIGNS & SYMPTOMS
Severe muscle spasms
Reported abdominal
discomfort, nausea,
vomiting, weakness,
dizziness, diaphoresis
TREATMENT
Decontaminate skin, eyes
Consider Gl
decontamination
Control seizures
Treat severe spasms in ICU
IV fluids if needed
CHAPTER 19
Miscellaneous Pesticides, Synergists,
Solvents and Adjuvants
MISCELLANEOUS PESTICIDES
4-Aminopyridine
Toxicology
4-Aminopyridine is a highly toxic white powder used as a bird repellent. It works by
making one or two birds acutely ill, and they warn off the remaining birds with their
cries of distress.1 It is toxic to all vertebrates.2 It is usually added to grain baits in 0.5%-
3.0% concentration, but 25% and 50% concentrates in powdered sugar are available.
The avian LD50 is between Img/kg and 8 mg/kg.1 Information on human exposure has
come from its use as an investigational drug in the treatment of multiple sclerosis.3'4 It
is rapidly absorbed by the gut and less effectively across skin. The chief mechanism of
toxicity is enhancement of cholinergic transmission in the nervous system through the
release of acetylcholine both centrally and peripherally. Because of enhanced trans-
mission at neuromuscular junctions, severe muscle spasms may be a prominent mani-
festation of toxicity.3 4-aminopyridine is rapidly metabolized and excreted.
No human poisonings have occurred as a result of ordinary use, but toxic effects
following intentional ingestion have been reported. In a report of ingestion of about
60 mg, patients experienced immediate abdominal discomfort, nausea and vomiting.
weakness, dizziness and profuse diaphoresis. One went on to develop a tonic-clonic
seizure and required ventilatory support. Acidosis was also present in those cases.2
Dizziness and gait disturbances are additional reported findings. As seen above.
seizures may also occur and be severe, although recovery with supportive therapy and
ventilatory support has been the usual outcome.2'3'4
Treatment of 4-Aminopyridine Toxicosis
1. Decontaminate the skin with soap and water, as outlined in the Chapter 3,
General Principles. Treat eye contamination by irrigating the exposed eyes with
copious amounts of clean water or saline for at least 15 minutes. Remove contact
lenses, if present, prior to irrigation. If irritation persists after irrigation, special-
ized medical treatment in a healthcare facility should be obtained.
2. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3.
3. Control seizures with benzodiazepines. See Chapter 3 for specific medications
and dosages.
4. Treat severe muscular spasms that may occur with this agent with neuromuscular
blockade in an intensive care unit setting.2
5. Treat dehydration with intravenous fluids if oral fluids cannot be retained.
188
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Calcium Cyanamide
This synthetic compound is marketed as granules containing 44% calcium cyanamide.
yielding 19.5% nitrogen. It is incorporated into soil to serve as fertilizer, fungicide and
herbicide. In contact with water, especially under acidic conditions, hydrogen cyana-
mide is released. Hydrogen cyanamide is a solid with considerable vapor pressure. It
has toxic properties totally different from those of cyanide, and it does not degrade to
cyanide.
Toxicology
While the initial ingredient, calcium cyanamide, is only moderately irritating to skin.
the byproduct hydrogen cyanamide is severely irritating and caustic to skin. Dermal
and mucosal lesions in the mouth, tongue and upper esophagus have occurred after
exposure. Contact dermatitis has been reported manifested by exfoliation. Addi-
tional symptoms include fever, pruritus, anorexia, insomnia and malaise.5 Lichen
planus has also been reported.6 If hydrogen cyanamide is inhaled, it can be strongly
irritating to mucous membranes.7 Systemic poisonings have followed inhalation of
hydrogen cyanamide and ingestion of the salt. Manifestations of systemic poisoning
include flushing, headache, vertigo, dyspnea, tachycardia and hypotension, sometimes
progressing to shock.7
Cyanamide is an inhibitor of acetaldehyde dehydrogenase; therefore, as with
disumram (Antabuse), ingestion of alcohol may significantly worsen the toxic effects.8
A pharmaceutical form of calcium cyanamide has been used in alcohol aversion
therapy, and one patient treated with this experienced peripheral neuropathy.9 Long-
term use of cyanamide has been reported to cause hepatocellular damage.10
Treatment of Cyanamide Toxicosis
1. Decontaminate the skin with soap and water, as outlined in the Chapter 3,
General Principles. Treat eye contamination by irrigating the exposed eyes with
copious amounts of clean water or saline for at least 15 minutes. Remove contact
lenses, if present, prior to irrigation. If irritation persists after irrigation, special-
ized medical treatment in a healthcare facility should be obtained.
2. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3.
3. If hypotension occurs, provide supportive care including intravenous fluids. If
severe, the patient may need vasopressors and intensive care management.11
Creosote
Creosote is a wood preservative that is registered as a restricted use pesticide, which
limits its use to non-residential sites and requires strict worker protection standards.
Creosote was first registered in 1948. It was used in the past as an animal dip and
disinfectant, but is currently only registered for use on heavy-duty, pressure-treated
industrial products, such as railroad ties and utility poles.12
CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Calcium Cyanamide
COMMERCIAL
PRODUCTS
cyanamide
nitrolime (has been
discontinued)
HIGHLIGHTS
Marketed as multi-function
granules
Byproduct hydrogen
cyanamide is severe skin
irritant
Alcohol may worsen toxic
effects
SIGNS & SYMPTOMS
Mouth, tongue, upper
esophageal lesions
Possible contact dermatitis
with exfoliation
Fever, pruritus, anorexia,
insomnia, malaise
Systemic: flushing,
headache, vertigo,
dyspnea, tachycardia,
hypotension
TREATMENT
Decontaminate skin, eyes,
Gl as appropriate
Supportive care, IV fluids
for hypotension
Toxicology
Creosote is obtained by distillation of the tar formed by heating wood or coal in the
absence of oxygen. It is purified by extraction into oils. Creosote from wood consists
of caustic phenol compounds, mainly guaiacol (methoxy phenol) and cresol (methyl
189
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CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Creosote
HIGHLIGHTS
Restricted use pesticide
Used only on heavy-duty,
pressure-treated industrial
wood
Skin, eye, mucous
membrane irritant
Absorbed by gut, lung
SIGNS & SYMPTOMS
Skin irritation, possible
eruptions, pigmentation
Gl lesions, pain
Systemic: salivation,
vomiting, dyspnea,
headache, dizziness, loss
of pupil reflex, cyanosis,
hypothermia, convulsions,
coma
Dark, "smoky" urine
phenol). Coal-derived creosote contains, in addition, some phenol, pyridine and pyrid-
inol. Much of human exposure is in the form of various phenol compounds. Some
phenolic compounds such as cresol are also used as disinfectants; more information
on toxicity from these compounds is found in Chapter 20, Disinfectants. Creosote is
carcinogenic in animals and epidemiological evidence has suggested an association
with some human cancers. This is discussed in the Chapter 21, Chronic Effects.
Creosote is irritating to skin, eyes and mucous membranes. Workers in contact
with technical creosote or with treated timbers sometimes develop skin irritation.
vesicular or papular eruptions, dermal pigmentation and occasionally gangrene and
skin cancer.n Photosensitization has been reported. Eye contamination has resulted in
conjunctivitis and keratitis, sometimes resulting in cornea! scarring.14 The constituents
of creosote are efficiently absorbed across the skin, but acute systemic poisonings
following dermal absorption have occurred very rarely.
Absorption of ingested phenolic compounds from the gut occurs promptly, and
there may be significant absorption of vapor by the lung. Conjugates of absorbed
phenolic constituents are excreted mainly in the urine. Acute toxic effects are similar to
those of Lysol, but the corrosive nature of creosote is somewhat less because of greater
dilution of phenol in the creosote.15 Irritation of the gastrointestinal tract including
mucosal lesions, esophageal ulcers, abdominal pain, toxic encephalopathy and renal
tubular injury are all principal effects following ingestion or inhalation exposure from
phenolic compounds.16'17'18'19'20
Manifestations of acute systemic poisoning are salivation, vomiting, dyspnea.
headache, dizziness, loss of pupillary reflexes, cyanosis, hypothermia, convulsions and
coma. Death is due to multiorgan system failure as patients develop shock, acidosis.
respiratory depression and anuric renal failure. Acute respiratory distress syndrome
(ARDS) has also been reported and is potentially fatal.17'21'22 Some reports of poisoning
have been from related phenolic compounds as opposed to the wood preservative itself.
A chronic toxicosis from continuing gastrointestinal absorption (creosote used medici-
nally) has been described, consisting of gastroenteritis and visual disturbances.19
TREATMENT
Decontaminate skin, eyes
Consider Gl
decontamination with
caution
ICU support may be
indicated
Confirmation of Poisoning
The presence of phenolic oxidation products imparts a dark, smoky color to the
urine.15'20 If creosote poisoning is suspected, addition of a few drops of ferric chloride
solution to the urine yields a violet or blue color indicating the presence of phenolic
compounds. Methods to determine urinary levels of phenolic compounds using capil-
lary gas chromatography have been described.23 Data are limited in determining a
"normal range"; however, in separate fatal cases of phenol poisoning, peak blood and
urine levels were 58-60 ug/mL (blood) and 20-208 ug/mL (urine) using GC/MS.24-25
Treatment of Creosote Toxicosis
2.
Decontaminate the skin with soap and water, as outlined in Chapter 3, General
Principles. Treat eye contamination by irrigating the exposed eyes with copious
amounts of clean water or saline for at least 15 minutes. Remove contact lenses, if
present, prior to irrigation. If irritation persists after irrigation, specialized medical
treatment in a healthcare facility should be obtained.
If ingested, consider gastrointestinal decontamination as outlined in Chapter
3. Given the corrosive nature of phenolic compounds such as creosote, efforts
to use an adsorbent such as charcoal (or repeated use of charcoal) depend on
whether there has been corrosive injury to the esophagus. If pharyngeal redness
190
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3.
and swelling are evident, emesis, whether induced or exacerbated by activated
charcoal, is not advisable because of potential re-exposure of the esophagus to
the creosote. Risk of perforation from a gastric tube precludes the use of gastric
lavage.
Treat severe systemic creosote poisoning in an intensive care unit setting with
appropriate supportive care including respiratory support, intravenous fluids.
cardiac monitoring and renal function support as necessary.
4. Draw a blood sample to test for methemoglobinemia, to measure BUN and blood
electrolytes and to check for signs of liver injury (bilirubin, GOT, LDH, ALT.
AST and alkaline phosphatase). Examine the urine for protein and cells, and for
"smoky" phenolic excretion products.
5. Control seizures with benzodiazepines. See Chapter 3 for specific medications
and dosages. Hemoperfusion over charcoal has been reported to be successful.26
6. Methemoglobinemia is rarely severe, but consicer administration of methylene
blue if 25%-30% of hemoglobin is converted.
Dosage of Methylene Blue
1-2 mg/kg body weight, IV, over 5 minutes, repeated as
needed every 4 hours.
Methylene blue is contraindicated in patients with G6PD deficiency.
7. Refer patients for endoscopic evaluation following a deliberate ingestion. If there
are any signs or symptoms suggestive of mucosal pharyngeal or esophageal injury
(visible burns in the oral mucosa, stridor, drooling, dysphagia, refusal to swallow
or abdominal pain) following inadvertent or unintentional ingestion, those patients
should also have an endoscopy.27'28'29
Endothall
As the free acid or as sodium, potassium or amine salts, endothall is used as a contact
herbicide, defoliant, aquatic herbicide and algaecide. It is formulated in aqueous solu-
tions and granules at various strengths.
Toxicology
Endothall is irritating to skin, eyes and mucous membranes. It is well absorbed across
abraded skin and from the gastrointestinal tract. Recognized systemic toxic mecha-
nisms in mammals include a corrosive effect on the gastrointestinal tract (particu-
larly from high concentrations of the free acid), cardiomyopathy and vascular injury
leading to shock, and central nervous system injury, causing convulsions and respira-
tory depression. A single case has been reported of a lethal poisoning in a previously
healthy 21-year-old man who died after ingestion of 7-8 grams of endothall. In this
patient, hemorrhage and edema were noted in the gastrointestinal tract and lungs.30
CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Endothall
COMMERCIAL
PRODUCTS
Accelerate
Aquathol
Des-i-cate
Endothall Turf Herbicide
Herbicide 273
Hydrothol
HIGHLIGHTS
Well absorbed by gut and
abraded skin
Gl corrosive
Cardiac, respiratory, CMS
impacts
SIGNS & SYMPTOMS
Convulsions
Respiratory depression
"Smoky" urine
TREATMENT
Decontaminate skin, eyes
Consider Gl
decontamination with
caution
ICU support may be
indicated
Control seizures
CONTRAINDICATED
Gastric lavage in most cases
191
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CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Metaldehyde
COMMERCIAL
PRODUCTS
Antimilace
Biodehido Snailkill
Cekumeta
Halizan
META
Metason
Namekil
and others
HIGHLIGHTS
Slug baits and other uses
Inhalation and ingestion
hazard
SIGNS & SYMPTOMS
Nausea, vomiting, dizziness
after ingestion
Severe toxicity: pyrexia,
seizures, metabolic
acidosis, mental changes
Possible headache,
hypersalivation, facial
flushing, tachypnea
TREATMENT
Consider Gl
decontamination
ICU treatment may be
indicated
Confirmation of Poisoning
There are no standards for endothall levels, and they are not considered useful in the
management of acute poisoning.
Treatment of Endothall Toxicosis
1. Decontaminate the skin with soap and water as outlined in the Chapter 3, General
Principles. Irrigate exposed eyes with copious amounts of clean water or saline
for at least 15 minutes. Remove contact lenses, if present, prior to irrigation. If
irritation persists after irrigation, obtain specialized medical treatment in a health-
care facility.
2. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3.
but use treatment procedures appropriate for ingestions of corrosives (strong acids
and alkalis). Due to the corrosive nature of this agent, gastric lavage is usually
contraindicated, because of the risk of esophageal perforation. Refer patient to a
surgeon or gastroenterologist for consideration of endoscopy.
3. Treat severe systemic endothall poisoning in an intensive care unit setting with
appropriate supportive care, including respiratory support, intravenous fluids.
cardiac monitoring and renal function support as necessary.
4. Draw a blood sample to test for methemoglobinemia, measure BUN and blood
electrolytes and check for signs of liver injury (bilirubin, GOT, LDH, ALT.
AST and alkaline phosphatase). Examine the urine for protein and cells and for
"smoky" phenolic excretion products.
5. Control seizures with benzodiazepines. See Chapter 3 for specific medications
and dosages.
Metaldehyde
Toxicology
Metaldehyde is a 4-unit cyclic polymer of acetaldehyde long used to kill slugs and
snails, which are attracted to it without the use of bait. Occasional poisonings of
animals and children have resulted from ingestion of pellets intended as molluscicide.
and tablets designed as a combustible fuel ("meta-fuel") have also been responsible for
human poisonings.31 Another form of exposure is "snow storm tablets," which the user
places at the end of a lighted cigarette to create snow. Toxicity occurs through inhala-
tion of metaldehyde fumes.32 The biochemical mechanism of poisoning is not known.
Both acetaldehyde and metaldehyde produced similar effects in dogs; however, acet-
aldehyde was not detected in the plasma or urine of the metaldehyde-poisoned dogs.33
Poisoned animals show muscle tremors, ataxia, hyperesthesia, salivation, tachycardia
and seizures.33'34
Ingestion of a toxic dose is often followed shortly by nausea, vomiting and
dizziness, if symptoms are even present.35 Primary features of severe toxicity include
pyrexia, generalized seizures, metabolic acidosis and mental status changes such as
irritability, sometimes progressing to coma.31'35'36'37 Other signs and symptoms that
may occur include headache, hypersalivation, facial flushing and tachypnea.31'32 Pneu-
monitis has followed inhalational exposure to metaldehyde.32 Most cases are either
self limiting or with significant but controllable seizures, and fatal events are infre-
192
-------
quent.31'35'36'37 One patient survived what has been considered a lethal dose of 600 mg/
kg.36 Autopsy findings in fatal human poisonings indicate severe damage to liver cells
and renal tubular epithelium.
Confirmation of Poisoning
Metaldehyde can be measured in the serum, although there are very few reports of
levels among poisoned humans. Saito described a method to measure metaldehyde
in serum using headspace solid-phase microextraction and gas chromatography-mass
spectrometry.38 One patient who had severe tonic-clonic seizures and was comatose
had a metaldehyde level in the serum of 125 mg/1, with a half-life of 27 hours. This
patient did not have detectable acetaldehyde in the serum.37
Treatment of Metaldehyde Toxicosis
There is no specific antidote for metaldehyde poisoning.
1. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3,
General Principles.
2. Treat severe systemic metaldehyde poisoning in an intensive care unit setting with
appropriate supportive care, including respiratory support, intravenous fluids.
cardiac monitoring and renal function support as necessary. Early and aggressive
treatment of all of the above may be life saving following a massive ingestion.36
3. Consider sodium bicarbonate in the event of severe metabolic acidosis.36 Monitor
fluid balance and electrolytes carefully to avoid fluid overload if renal failure
supervenes.
4. Order liver function tests and urine sediment examination to assess liver and
kidney injury in poisoned patients.
CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Sodium Chlorate
COMMERCIAL
PRODUCTS
Bladvel
Defol
De-Fol-Ate
Dervan
Drop-Leaf
Fall
KM
Kusatol
Leaf ex
Sodium Chlorate
Sodium chlorate is used in agriculture as a defoliant, nonselective contact herbicide
and semi-permanent soil sterilant. Because of its explosive nature, it must be formu-
lated with a water-soluble, fire-retardant material such as sodium metaborate, soda
ash, magnesium chloride or urea. It is usually applied in water solution.
Toxicology
Sodium chlorate is irritating to skin, eyes and mucous membranes of the upper respi-
ratory tract.39 Dermal absorption is slight. Even though gastrointestinal absorption is
also inefficient, severe poisoning, sometimes fatal, follows ingestion of a toxic dose.
said to be about 20 grams in the adult human. Excretion is chiefly in the urine.
Sodium chlorate poisoning can manifest in many ways. The principal mecha-
nisms of toxicity are hemolysis, coagulation disturbances methemoglobin formation.
cardiac arrhythmia (partly secondary to hyperkalemia) and renal tubular injury.39'40'41
The most common cause of death in early stages of toxicity is anoxia from methemo-
globinemia and hemolysis, resulting in disseminated intravascular coagulation. Renal
failure may occur afterwards and figure prominently as a cause of death.39'40'41
Following ingestion, sodium chlorate may have an irritant action on the gut.
causing nausea, vomiting and abdominal pain. Once absorbed, hemoglobin is rapidly
193
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CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Sodium Chlorate
HIGHLIGHTS
Forms methemoglobin in
unique fashion
Destroys erythrocytes and
enzymatic systems
Irritating to skin, eyes,
mucous membranes
Many poisoning
manifestations
SIGNS & SYMPTOMS
Nausea, vomiting,
abdominal pain
Cyanosis
Dark brown plasma, urine
oxidized to methemoglobin, and hemolysis and intravascular hemolysis subsequently
occur.39'40'41 Cyanosis is prominent if methemoglobinemia is severe and may be the
only presenting sign.41 Acute tubular necrosis and hemoglobinuria may result from the
hemolysis or direct toxic injury. Plasma and urine are dark brown from presence of free
hemoglobin and methemoglobin.39'41'42'43 One fatal case presented with 30% methemo-
globinemia.42 Release of potassium from red cell destruction results in hyperkalemia
that may be severe enough to cause life-threatening arrythmias.43 The liver and spleen
are often enlarged due to uptake of hemolyzed erythrocytes.41 Hypoxemia may lead to
convulsions. Death may be the result of shock, tissue hypoxia, renal failure, hyperka-
lemia or disseminated intravascular coagulation (DIC).39'40'41'43
Although other toxicants will induce methemoglobinemia formation, the mecha-
nism associated with chlorates is unique. Chlorate not only forms methemoglobin.
it also destroys erythrocytes and the enzymatic systems in the process.40 Ordinarily.
methylene blue is used as an antidote to reduce methemoglobin. This process depends
on NADPH formation by the oxidation of glucose-6-phosphate. However, chlorate
will denature the glucose-6-phosphate dehydrogenase, which will in turn render meth-
ylene blue ineffective.40
Confirmation of Poisoning
Sodium chlorate poisoning can be detected by ion chromatography, although this test
may not be widely available.42 Chlorate poisoning should be considered when patients
present with methemoglobinemia. Dark brown-to-black staining of the plasma and
urine indicates the action of a strong oxidizing agent on hemoglobin.41'44
TREATMENT
Decontaminate skin, eyes
Consider Gl
decontamination
ICU may be appropriate
Consider oral or IV sodium
thiosulfate
IV fluids and sodium
bicarbonate
CONTRAINDICATED
Methylene blue unless very
early
Treatment of Chlorate Toxicosis
1. Decontaminate the skin with soap and water as outlined in Chapter 3, General
Principles. Irrigate exposed eyes with copious amounts of clean water or saline
for at least 15 minutes. Remove contact lenses, if present, prior to irrigation. If
irritation persists after irrigation, obtain specialized medical treatment in a health-
care facility.
2. If ingested, consider gastrointestinal decontamination as outlined in Chapter 3.
3. Treat severe systemic sodium chlorate poisoning in an intensive care unit setting.
with appropriate supportive care including respiratory support, intravenous fluids.
cardiac monitoring and renal function support as necessary.44 In addition, monitor
for methemoglobinemia.
4. Sodium thiosulfate has been used as an antidote against absorbed sodium chlo-
rate.39'44 Thiosulfate is thought to inactivate the chlorate ion to form the less toxic
chloride ion.
Dosage of Sodium Thiosulfate
2-5 gm dissolved in 200 mL of 5% sodium bicarbonate,
given orally or as an IV infusion over 60-90 minutes39
5. Administer intravenous fluids and sodium bicarbonate.41'44 Monitor urine produc-
tion closely, so that intravenous fluids can be slowed or discontinued if renal
failure occurs.
194
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6. Transfuse blood if hemolysis and methemoglobinemia are severe. Exchange
transfusion has been recommended to enhance clearance and treat DIG.43
7. Consider hemodialysis, which has been used in several cases of chlorate
poisoning.42'44
8. Consider administration of methylene blue, which has been used to reverse methe-
moglobinemia if as much as 25%-30% of hemoglobin is converted.
Dosage of Methylene Blue
1-2 mg/kg body weight, IV, over 5 minutes, q 4 hours prn
Methylene blue is generally not helpful with sodium chlorate poisoning unless
given very early because of the unique characteristics described above in the
Toxicology subsection.40-44
SYNERGISTS
Piperonyl Butoxide
Synergists are chemical agents included in pesticide products to enhance the killing
power of the active ingredients. The widely used insecticide synergist piperonyl
butoxide acts by inhibiting the enzymatic degradation of pyrethrins, rotenone.
N-methyl carbamates, organophosphates and possibly some other insecticides. There
is limited dermal absorption on contact. Inherent toxicity in mammals is low, with an
oral LD50 in rats of >4,500 mg/kg.45 Large absorbed doses may theoretically enhance
the toxic hazard of the rapidly metabolized insecticides used today, although inhibition
of human drug metabolizing enzymes by these agents has not actually been demon-
strated. Their presence in pesticide products to which humans are exposed does not
change the basic approach to management of poisoning with the focus of treatment
based on the active ingredient involved. The notable exception is that care providers
should be aware of some possibility of enhanced toxicity of the active insecticidal
ingredients.
CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Solvents & Adjuvants
HIGHLIGHTS
Petroleum distillates are
commonly used for lipophilic
pesticides
Hydrocarbon pneumonitis:
rapid respiration, cyanosis,
tachycardia, fever
Some solvents may
enhance dermal absorption
of some pesticides
Some adjuvants, penetrants,
safeners irritate skin, eyes,
mucous membranes
Dust formulations can result
in systemic poisoning via gut
absorption
TREATMENT
Consider Gl
decontamination with
caution, especially with
petroleum distillates
Watch for and treat
hydrocarbon pneumonitis
Monitor urine, heart
SOLVENTS AND ADJUVANTS
Liquid materials in which pesticides are dissolved or the solids on which they are
adsorbed (sometimes called carriers or vehicles) are chosen by producers to achieve
stability of the active ingredient, convenience in handling and application, and
maximum killing power following application. The solvents and adjuvants pesticide
manufacturers choose can give their commercial products a competitive edge. For this
reason, their inclusion in marketed products is usually proprietary information, not
available to the general public except under emergency circumstances. In a poisoning
emergency, pesticide companies will usually cooperate in supplying physicians with
information needed to provide treatment. The physician should seek this information
to assist in evaluating all possible exposures. A direct request to the producer is neces-
sary to secure this information. Some companies put the inert ingredients on the Mate-
rial Safety Data Sheet (MSDS).
195
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CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Petroleum distillates are the most commonly used solvents for lipophilic pesti-
cides. (Most insecticides are lipophilic.) The distillates are mixtures of aliphatic and
aromatic hydrocarbons with low boiling points.
Sometimes specific hydrocarbons, such as toluene or xylene (strongly odif-
erous), are added to stabilize the solution of insecticide or make it more emulsifi-
able. Hydrocarbon-dissolved pesticides are usually diluted for application by adding
measured amounts of water to form emulsions. Some chlorinated hydrocarbons may
be present in particular technical mixtures. A strong odor lingering after application
of a structural pest control spray is often due to the solvent rather than the active
ingredient. Rapid respiration, cyanosis, tachycardia and low-grade fever are the usual
indications of frank hydrocarbon pneumonitis.46
Less lipophilic active ingredients are sometimes dissolved in mixtures of alco-
hols, glycols, ethers or various chlorinated solvents. It is possible that these enhance
the dermal absorbability of some pesticides. A well-described example is increased
dermal absorption of the insect repellent DEBT when dissolved in 70% ethyl alcohol
compared to the solvent polyethylene glycol.47 Also, some solvents (e.g., methanol and
isopropanol) may represent a significant toxic hazard if swallowed in sufficient dosage.
Symptoms may include central nervous system depression ranging from disorienta-
tion to lethargy and coma with severe overdose, as well as respiratory depression and
ketosis.48 The presence of chlorinated solvents in some formulations may add signifi-
cantly to the toxic hazard, particularly if the product is ingested. Certain adjuvants are
irritants to skin, eyes and mucous membranes and may account for the irritant proper-
ties of products with active ingredient(s) lacking this effect. With these exceptions.
however, the presence of adjuvants in most finished pesticide products probably does
not enhance or reduce systemic mammalian toxicity to any great extent.
Granular formulations utilize various clay materials that adsorb pesticide.
retain it in more or less stable form until application and then desorb the material
slowly into treated soil. There is some significant desorption when granules are in
contact with human skin and very substantial desorption into gastrointestinal secre-
tions if granules are swallowed. The clay materials themselves are not a toxic hazard.
Dusts are infrequently used today. Various forms of talc (magnesium silicate
particles) have been used in the past to adsorb pesticides for application to foliage.
Particle sizes are such that these dusts are usually trapped in the upper respiratory
mucous when inhaled. When the mucous is swallowed, the particles desorb pesticide
into gastrointestinal secretions. Dust formulations may, therefore, release enough of
some pesticides to cause systemic poisonings.
Stickers and spreaders (film extenders) are organic substances added to formu-
lations to disperse pesticide over treated foliage surfaces and enhance adhesion.
The availability and persistence of residue on the leaf surfaces is thereby increased.
Substances used include proteinaceous materials (milk products, wheat flour, blood
albumin, gelatin), oils, gums, resins, clays, polyoxyethylene glycols, terpenes and
other viscid organics. Some also include sulfated alcohols, fatty acid esters, alkyl and
petroleum sulfonates. For persons exposed in the course of formulation or application
of pesticides, these adjuvants probably add little or no toxic hazard to that inherent in
the active pesticidal ingredients.
Emulsiflers serve to stabilize water-oil emulsions formed when water is added
to technical hydrocarbon concentrates. Chemically, they are detergent-like (one part
of the molecule lipophilic, the other hydrophilic). Long-chain alkyl sulfonate esters of
polyethylene glycol and polyoxyethylene oleate are exemplary emulsifiers. They have
low inherent mammalian toxicity, and their presence probably has little effect on the
overall toxicity of formulated products that include them.
Penetrants facilitate the transfer of herbicide from foliage surface to the interior
tissues. Some are lipids while others are detergent (surfactant) in nature. Substances
196
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used include heavy petroleum oils and distillates, polyol fatty acid esters, polyethox-
ylated fatty acid esters, aryl alkyl polyoxyethylene glycols, alkyl amine acetate, alkyl
aryl sulfonates, polyhydric alcohols and alkyl phosphates. Some of these are eye and
skin irritants and may account for the irritant effects of particular herbicide formula-
tions whose active ingredients do not have this property.
Safeners are substances added to mixtures of fertilizers with pesticides
(commonly herbicides) to limit the formation of undesirable reaction products. Some
substances used are alcohol sulfates, sodium alkyl butane diamate, polyesters of
sodium thiobutane dioate and benzene acetonitrile derivatives. Some are moderately
irritating to the skin and eyes. Systemic toxicities are generally low.
Anticaking agents are added to granular and dust formulations to facilitate
application by preventing cakes and clumps. Among several products used are the
sodium salt of mono- and di-methyl naphthalene sulfonate, and diatomaceous earth.
Diatomaceous earth has little adverse effect except a drying action on the skin. Methyl
naphthalenes are said to be skin irritants and photosensitizers; whether their derivatives
have this effect is not known.
CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Treatment of Solvent and Adjuvant Toxicosis
Petroleum distillates are mineral hydrocarbons that undergo limited absorption across
the gut. In general, clinical toxicologists do not recommend induced emesis or gastric
lavage in treating ingestions of these materials, because of the serious risk of hydro-
carbon pneumonitis even if tiny amounts of the liquid are aspirated into the lungs.
However, this injunction against emptying the stomach may be set aside when the
petroleum distillate is a vehicle for toxic pesticides in significant concentratioa
1. In such cases, if the patient is seen within 1 hour of exposure, consider gastroin-
testinal decontamination, as outlined in Chapter 3, General Principles.
1. Hospitalize patients with presumed hydrocarbon pneumonitis who are symptom-
atic. If the patient has pulmonary symptoms, order a chest X-ray to detect or
confirm signs of pneumonitis. Mechanically assisted pulmonary ventilation with
pure oxygen may be required. Hydrocarbon pneumonitis is sometimes fatal, and
survivors may require several weeks for full recovery. In milder cases, clinical
improvement usually occurs within several days, although radiographic findings
will remain abnormal for longer periods.49
3. Examine the urine for protein, sugar, acetone, casts and cells; and examine an
ECG for arrhythmias and conduction defects.
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CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
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Bieniek G. Concentrations of phenol, o-cresol, and 2,5-xylenol in the urine of workers
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Helliwell M, Nunn J. Mortality in sodium chlorate poisoning. Br Med J. Apr 28
CHAPTER 19
Miscellaneous Pesticides,
Synergists, Solvents
and Adjuvants
Steffen C, Wetzel E. Chlorate poisoning: mechanism of toxicity. Toxicology. Nov 12
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Steffen C, Seitz R. Severe chlorate poisoning: report of a case. Arch Toxicol. Nov
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Eysseric H, Vincent F, Peoc'h M, Marka C, Aitken Y, Barret L. A fatal case of chlorate
poisoning: confirmation by ion chromatography of body fluids. J Forensic Sci. Mar
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Ranghino A, Costantini L, Deprado A, et al. A case of acute sodium chlorate self-
poisoning successfully treated without conventional therapy. NephrolDial Transplant. Oct
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Anas N, Namasonthi V, Ginsburg CM. Criteria for hospitalizing children who have ingested
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199
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Alcohols
HIGHLIGHTS
Often mixtures, usually
ethanol & isopropanol
Most common household
product 70% isopropyl
alcohol
Well absorbed by Gl, skin,
inhalation
High concentrations can
depress CNS leading to
coma, death
SIGNS & SYMPTOMS
Gl irrigation: gastritis,
vomiting
Can be measured in blood
and urine
TREATMENT
Support for hypotension,
respiratory depression; best
in ICU
Glucose if hypoglycemia
occurs
Consider hemodialysis
CONTRAINDICATED
Induced emesis
CHAPTER 20
Disinfectants
A wide variety of disinfectant agents are used to destroy microorganisms, and they
differ greatly in their toxic effects. However, most can conveniently be grouped into a
few categories, some of which are represented in other classes of pesticides. Many of
these materials are not registered as pesticides but are registered for medical or medic-
inal use. This chapter reviews a few of the more common or more toxic disinfectants.
ALCOHOLS
Alcohols have a long history of use as disinfectants. Often disinfectants are mixtures.
usually of ethanol and isopropyl alcohol (isopropanol). The alcohol most commonly
used in households as a disinfectant is isopropyl alcohol, commonly marketed as a
70% solution. It is a clear, colorless liquid with an odor similar to ethanol.
Toxicology
Isopropyl alcohol is well and rapidly absorbed from the gastrointestinal tract. It is
also well absorbed by skin and by inhalation. It is considered to be more toxic to the
central nervous system than ethanol, with similar effects. Both ingestion and inha-
lation at high concentrations can result in the rapid onset of CNS depression with
subsequent coma and death. Apnea commonly accompanies this CNS depression.1'2
Similar neurological toxicity has been reported with excessive topical exposure to the
umbilicus of a neonate.3 Irritation of the gastrointestinal tract results in gastritis and
severe vomiting. Isopropyl alcohol may also produce mild hepatic injury following
acute exposure. Acute tubular necrosis has been reported with this agent,1 but the
renal toxicity is not as great as with methanol poisonings. Ketosis without metabolic
acidosis can occur, but prominent hypoglycemia is common.2'3 This ketosis is the result
of direct metabolism of this compound to acetone.1'3 Monitoring of isopropyl levels
is useful, when available. In addition, blood levels of acetone and glucose should be
determined to aid in management.
Confirmation of Poisoning
Isopropyl alcohol can be measured in the blood and urine. Serum acetone can also
be measured. Blood isopropyl alcohol levels of 128-200 mg/dL have been associated
with death.
Treatment of Isopropyl Alcohol Toxicosis
1. Do not induce emesis, since the onset of coma is often rapid with this poisoning.
Spontaneous vomiting, however, often occurs.
2. Provide supportive care for hypotension and respiratory depression. This is crit-
ical to survival and should be administered whenever possible in an intensive care
setting.
200
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3. If hypoglycemia occurs, administer glucose.
4. Consider hemodialysis, which has been reported to be beneficial in patients with
severe poisoning who are unresponsive to standard supportive therapy.1'4
ALDEHYDES
The two aldehydes most commonly used as disinfectants are formaldehyde and
glutaraldehyde. Formaldehyde is discussed in Chapter 17, Fumigants. Glutaral-
dehyde is very similar to formaldehyde in its toxicity and treatment, although it is
slightly less toxic. Glutaraldehyde is commonly prepared as an aqueous solution at
a 2% concentration and is slightly alkaline in this solution. It has been reported to
cause respiratory irritation, resulting in rhinitis5'6 and occupational asthma.5'7'8 It has
also resulted rarely in palpitations and tachycardia in human subjects. At high dosage.
given orally, it results in gastrointestinal irritation with diarrhea, which may be hemor-
rhagic.9'10'11 Because of the irritant effects of glutaraldehyde, Occupational Safety and
Health Administration (OSHA) standards may apply for wearing personal protective
equipment to protect the skin (29 CFR 1910.132) and eyes (29 CFR 1910.133). OSHA
standards may also require the use of appropriate respirators by employees who may
be exposed to glutaraldehyde during routine or emergency work procedures (29 CRF
1910.134).12
Treatment of Aldehyde Toxicosis
1. If patient has been in an area with a strong odor of glutaraldehyde due to vaporiza-
tion, move to fresh air and administer oxygen as needed.
2. If skin irritation is noted, decontaminate. Systemic toxicity from skin exposure is
unlikely.
CHAPTER 20
Disinfectants
Aldehydes
HIGHLIGHTS
Formaldehyde also
discussed in Ch. 17
Glutaraldehyde similar but
less toxic
SIGNS & SYMPTOMS
Respiratory irritation
Gl irritation, diarrhea,
possible hemorrhage if oral
TREATMENT
Move to fresh air, administer
oxygen as needed
Decontaminate skin if
irritated
CATIONIC DETERGENTS
Several cationic detergents are used as disinfectants. All share the capacity, in suffi-
cient concentration, to cause rather severe caustic burns. Concentrations greater than
approximately 7.5% appear necessary to produce significant caustic injuries. However.
experience with human exposures to these compounds is very limited. The three agents
most commonly used as detergent disinfectants are benzalkonium chloride, cetrimide
and cetylpyridium chloride.
No cetrimide preparations are available in the United States; several are avail-
able in European Union countries. Concentrated solutions are usually only available
in industrial settings, such as production of consumer products, or for use in hospitals
for disinfectant purposes. Therefore, acute poisonings are uncommon.
Toxicology
In low concentration solutions, cationic detergents have been reported to cause
eye discomfort, as well as skin rashes and irritation. A severe contact dermatitis has
been reported with a bath oil containing benzalkonium chloride and triclosan.13
201
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CHAPTER 20
Disinfectants
Cationic Detergent
HIGHLIGHTS
Caustic agents capable of
causing burns
Most common:
benzalkonium chloride,
cetrimide, cetylpyridium
chloride (no cetrimide in
U.S.)
Acute poisonings are
uncommon
SIGNS & SYMPTOMS
Eye, skin, Gl irritant
Severe exposures: CNS,
liver, pulmonary impacts
TREATMENT
Wash eyes, examine/treat
corneas for burns
Endoscopy within 24 hours if
indicated
Treat CNS, pulmonary, other
systemic effects
CONTRAINDICATED
Gl decontamination
In stronger concentrations, they can cause severe cornea! and skin burns. Likewise.
strong concentrations will result in caustic burns to lips, oral mucosa, esophagus and
stomach.14'15 Vomiting, diarrhea and abdominal pain have been reported.16 Necrosis of
the gut, with peritonitis, has also been reported.17 In severe exposures, there are also
reports of CNS depression, liver injury and pulmonary edema.14'16
Treatment of Cationic Detergent Toxicosis
1. If a high concentration solution is in contact with the eyes, wash the eyes profusely
and then carefully examine the corneas. If burns have occurred, obtain ophthal-
mologic care.
2. Do not use any method of gastrointestinal decontamination, including gastric
emptying. They are contraindicated in these poisonings. Some experts recom-
mend cautious dilution with small amounts of milk or water.14'18 Acidic solutions.
such as juices, should never be offered for dilution.
3. Conduct an endoscopy if a highly concentrated solution was ingested or oral
burns are noted. The patient needs urgent endoscopy for grading of the caustic
injury. The endoscopy should be performed within 24 hours to minimize the risk
of perforation.17 A competent surgeon or gastroenterologist should provide subse-
quent care.
4. Treat CNS, pulmonary and other systemic effects symptomatically, consistent
with sound medical practice.
Although corticosteroids are commonly used to treat these burns, their use remains
controversial. Use of other agents, such as H2 antagonists and sulcralfate, has been
reported, but also remains controversial at this time.
CHLORHEXIDINE
Chlorhexidine is a cationic biguanide, available in concentrations up to 4% as a
topical agent used as a skin cleanser and mouthwash. Skin preparations of 0.5%-4%
are marketed under the trade names Hibiclens and Hibistat. It is also marketed as a
mouthwash in a 0.12% solution under the trade name Peridex. There is very little
human experience with poisonings, as these concentrations do not appear to be signifi-
cantly toxic.
Toxicology
Chlorhexidine is poorly absorbed from skin or the gastrointestinal tract. Therefore, most
effects noted have been primarily local. Low concentration solution ingested or applied
to the skin can cause mild local irritation. Contact dermatitis, urticaria and anaphylaxis
have followed repeated skin exposures to this agent.19'20'21 Cornea! injuries have been
described in several cases after inadvertent exposure of the eyes to the 4% concentration.
These injuries have resulted in permanent cornea! scarring.22 Esophageal burns have
been reported in a single case after ingestion of a large quantity of a 20% solution of this
agent.23 Ulcerative colitis has been described after an enema of the 4% solution mixed
with tap water (10 mL in 2 liters water).24 Liver toxicity can occur with large exposures.23
202
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Treatment of Chlorhexidine Toxicosis
1. If a highly concentrated solution is ingested, manage as a caustic ingestion as
described in the preceding Treatment ofCationic Detergent Toxicosis subsection.
without gastrointestinal decontamination.
2. Perform liver injury panel with large ingestions.
3.
If a high concentration solution is in contact with the eyes, wash eyes profusely
and examine the corneas carefully. If burns have occurred, obtain ophthalmologic
care.
HYPOCHLORITES
Hypochlorites are implicated in a large proportion of the disinfectant exposures
reported to poison control centers in the United States, with more than 30,000 reports
in 2009.25 Most are solutions of sodium or calcium hypochlorite. Chloramine, a
disinfectant used in many municipal water supplies, is an infrequent cause of acute
poisonings. Sodium and calcium hypochlorite solutions are of relatively low toxicity.
They are mildly corrosive to eyes,26 and mucous membrane burns have been reported.27
Despite the large number of reports to poison control, significant poisonings are very
infrequent with these agents in solution.25'28
When hypochlorite solutions are mixed with acids or ammonia solutions, chlo-
rine or chloramine gas is produced, resulting in an irritant with pulmonary toxicity.
Many brief exposures have led to transient symptoms requiring limited emergency
department management.29 Prolonged exposure or exposure to high concentrations
carries the potential of severe toxic pneumonitis.30 Great efforts should be made to
discourage mixing of these materials with acid or ammonia.
Treatment of Hypochlorite Toxicosis
1. After oral exposures, do not use gastric emptying. If a granular material is ingested
and the patient has symptomatic mucosal burns, refer patient to a surgeon or
gastroenterologist for consideration of endoscopy and management.
2. If vomiting has not occurred, give patient water or milk for dilution, not to exceed
approximately 15 mL/kg in a child or 120-240 mL in an adult. Administration of
acids is contraindicated, because of the risk or increasing generation of chlorine
gas.
3. If a high concentration solution is in contact with the eyes, wash eyes profusely
and examine corneas carefully. If burns have occurred, obtain ophthalmologic
care.
4. Manage skin exposure with copious water dilutions.
5. If exposure to vapors or chlorine or chloramine gas has occurred, move patient
immediately to fresh air. If symptoms occur or persist, oxygenation should be
assessed and oxygen administered as needed. If persistent symptoms occur, obtain
a chest film and consider hospitalization. Intensive care may be appropriate in
severe inhalations.
CHAPTER 20
Disinfectants
Chlorhexidine
HIGHLIGHTS
Used as skin cleanser,
mouthwash
Poorly skin, gut absorption
SIGNS & SYMPTOMS
Mild skin irritant, worse if
repeat exposures
Corneal, esophageal injuries
possible
TREATMENT
For highly concentrated/
large doses
Ingested: manage as
caustic ingestion, perform
liver panel
Eye contact: wash,
examine, treat corneas
Hypochlorite
HIGHLIGHTS
Chloramine, sodium/calcium
hypochlorite
Many exposures reported;
significant poisonings few
SIGNS & SYMPTOMS
Pulmonary irritation, toxicity
when mixed with acids or
ammonia solutions
Gl, eye, skin, pulmonary
impacts
TREATMENT
If ingestions result in mucosal
burns, refer to surgeon/
gastroenterologist
Decontaminate eyes, skin
Examine/treat corneas
If vapor exposure, move to
fresh air and consider oxygen
administration, chest film,
hospitalization
CONTRAINDICATED
Administration of acids
Gastric emptying
203
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CHAPTER 20
Disinfectants
Iodine
HIGHLIGHTS
Most common: 7.5%-10%
povidone-iodine solution
Betadine is an example
At standard dilutions, poorly
absorbed from Gl, skin
Symptomatic poisonings
possible on burned skin,
wounds
SIGNS & SYMPTOMS
Initial: headache, dizziness,
delirium, hallucinations,
seizures
Severe: hypotension,
arrhythmias, cyanosis,
metabolic acidosis, shock,
renal failure
TREATMENT
Decontaminate skin
Osmotic agents or diuretics
if indicated
Treat seizures
Monitor thyroid
IODINE
The most common iodine-containing disinfectant is povidone-iodine. A trade name
often associated with this agent is Betadine (7.5%-10% solution). Povidine-iodine is
described as an iodophor, which is a complex of iodine and polyvinylpyrrolidone.
a solubilizing agent. It is intended to liberate free iodine in solution for its effect.
Although reported concentrations of iodine in these solutions is only 80-120 ug/dL.
the total available iodine is approximately 10% of the povidone-iodine. Therefore, a
10% solution will have in the range of 1% total available iodine.
Toxicology
This compound is very poorly absorbed from the gastrointestinal tract, because of the
rapid conversion of free iodine to iodide in the stomach. Though highly concentrated
iodine solutions or iodine salts are corrosive to the gastrointestinal tract,31 solutions
of povidone-iodine have little caustic potential. It is likewise poorly absorbed from
intact skin. All symptomatic poisonings reported have occurred either after repeated
exposure to burned skin or following irrigation of wounds, joints or serosal surfaces.
such as the mediastinum.32'33'34'35 The one exception was an infant who received an
enema of povidone-iodine in a polyethylene glycol solution, followed by whole bowel
irrigation with polyethylene glycol mixed with povidone-iodine. This child died with
severe hyperglycemia and very high iodine levels.31
In povidone-iodine exposures by these routes, the primary symptoms initially
appear to be neurological, with headache, dizziness, delirium, hallucinations and
seizures.35 Hypotension, arrhythmias, cyanosis, metabolic acidosis, shock and acute
renal failure occur in severe cases.32'33'34 Hepatic injury, manifested by elevated serum
transaminase levels, has also been reported with very high level exposures.34 Hyperka-
lemia has occurred, and the serum chloride may be falsely elevated due to the presence
of a second halide.33
Treatment of Iodine Toxicosis
1. Remove skin contamination by vigorous washing with soap and water.
2. Use osmotic agents or diuretics in symptomatic poisonings, since iodine clear-
ance is apparently enhanced by procedures that enhance chloride excretion.
3. Treat seizures with anticonvulsants, as outlined in Chapter 3, General Principles.
4. Monitor thyroid function following recovery to confirm euthyroid state.
MERCURIALS
A wide variety of organic mercurials have been used as disinfectants and as preser-
vatives. These included phenylmercuric acetate, phenylmercuric nitrate, nitro-
mersol, thimerosol, mercurochrome and mercurobutol. None is currently regis-
tered with the U.S. Environmental Protection Agency. The toxicity and treatment of
exposure to these compounds is described in detail in Chapter 16, Fungicides under
the subsection Organomercury Compounds.
204
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PHENOLS
Several phenols are used as disinfectants, including cresol, phenol, thymol, hexachlo-
rophene, o-phenylphenol, 4-tert-amylphenol, 2-benzyl-4-chlorophenol and triclosan.
Cresol and thymol are alkyl derivatives of phenol, while hexachlorophene and triclosan
are chlorinated phenols. Common trade names for commercial products are provided
in the margin. One survey found that triclosan or a similar agent, triclocarban, was
found in 45% of liquid and bar soaps available in consumer outlets.36 However, no
episodes of acute toxicity from triclosan have been reported, so the concerns with
this agent relate to chronic effects, the development of triclosan resistance in micro-
bial organisms, and reports of contact dermatitis caused by exposure to triclosan.13'37'38
Cresols and hexachlorophene will be discussed individually; these compounds are
familiar and some human data are available.
Toxicology of Cresols
Cresols, in common with phenol and other phenolic compounds, are highly corro-
sive. Ingestion of concentrated forms causes severe corrosive injury to the mouth and
upper gastrointestinal tract. Likewise, severe eye and skin caustic injuries can occur
with cresol exposure.39 Symptoms usually include nausea, vomiting and diarrhea.
Hypotension, myocardial failure, pulmonary edema, neurological changes may also
occur.40 Liver and renal toxicity, methemoglobinemia and hemolysis have all been
reported.40'41 After long-term, repeated exposure, contact dermatitis may complicate
these exposures. These compounds are well absorbed from the gastrointestinal tract
and are also significantly absorbed from the skin and by inhalation.
Treatment of Cresol Toxicosis
1. Do not attempt gastrointestinal decontamination because of the corrosive nature
of these compounds. Consider dilution with milk or water if vomiting has not
occurred.
2. If a corrosive injury has occurred with burns to the mouth, or if there is a clear
history of gastrointestinal exposure, consider endoscopy and consult a gastroen-
terologist or surgeon for diagnosis and management.
3. If a high concentration solution is in contact with the eyes, wash eyes with
profuse amounts of water and follow with a careful exam of the corneas. If burns
have occurred, provide ophthalmologic care. Given the corrosive nature of the
substance, referral to an ophthalmologist should be considered.
4. Provide respiratory and circulatory support in accordance with sound medical
management. If severe systemic symptoms persist, the patient should be treated
in an intensive care unit, if possible.
CHAPTER 20
Disinfectants
Phenols
COMMERCIAL
PRODUCTS
Triclosan: many consumer
soap products
Mixed cresols in soap: Lysol
Hexachlorophene: Phisohex,
Bilevon, Dermaadex,
Exofene, Gamophen,
Texosan, Surgi-Cen,
Surofene, various soap bars
and cosmetics
HIGHLIGHTS
Triclosan
Very common, no acute
toxicity reports
Contact dermatitis
Cresols
Highly corrosive
Can cause severe
mouth, Gl, eye, skin
injury
Well absorbed from Gl,
skin, inhalation
Hexachlorophene
Well absorbed via skin,
gut
Not as caustic as other
phenolic compounds
Potent neurotoxicant
Toxicology of Hexachlorophene
Hexachlorophene is well absorbed via the oral and dermal routes. Dermal exposures
have led to severe toxicity and death in neonates, due to application to damaged skin
or repeated or high-concentration skin exposures.42 It should never be used as a disin-
fectant on open wounds or abraded or inflamed skin surfaces. It is not significantly
caustic, however, and exposure does not result in the severe caustic injuries seen with
other phenolic chemicals.
continued next page
205
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CHAPTER 20
Disinfectants
Phenols, cont.
SIGNS & SYMPTOMS
Creso/s
Nausea, vomiting,
diarrhea
Caustic skin, eye injuries
Hexachlorophene
Complex CMS effects
Lethargy, muscle
weakness/fasciculation,
irritability, cerebral
edema, paralysis
Vomiting, diarrhea,
anorexia
Skin rash
TREATMENT
Creso/s
Consider Gl dilution with
water/milk
Consider endoscopy with
gastroenterologist consult
Decontaminate eyes,
examine/treat corneas
Respiratory, circulatory
support
Hexachlorophene
Consider activated
charcoal
Decontaminate skin with
soap and water
Control seizures
Support cardiovascular,
respiratory systems
Hexachlorophene is a potent neurotoxicant. It causes brain edema and spongy
degeneration of white matter.43 This neurotoxicity can be seen after acute or chronic
exposures, either by skin absorption or ingestion. The nervous system symptoms
are complex. Lethargy is an early manifestation, followed by muscular weakness.
muscular fasciculation, irritability, cerebral edema and paralysis, leading to coma and
death. Seizures commonly occur in more severe cases.42'44 Blindness and optic atrophy
have also been seen following exposure to hexachlorophene.45
In addition to the neurological effects, common early symptoms of poisoning are
vomiting, diarrhea and anorexia.44 These findings have been accompanied in animals
by significant hepatotoxicity.46 With skin exposure, an erythematous, desquamative
rash is often noted at the site of exposure.44 With chronic exposure, contact dermatitis
may be noted. In severe poisonings, cardiovascular symptoms, including hypoten-
sion and bradycardia have been noted.47 In a single case, repeated exposure to this
compound led to asthma in a pediatric nurse.48
Treatment of Hexachlorophene Toxicosis
1. Although this compound is quite toxic systemically and enhanced clearance
methods would appear beneficial, there is no evidence to support efficacy of
hemodialysis, peritoneal dialysis, hemoperfusion or exchange transfusion.47
2. Consider using activated charcoal. Since hexachlorophene is thought to have an
enterohepatic recirculation, it is possible that repeated dosing of activated char-
coal, as outlined in the Chapter 3, General Principles, will enhance clearance
of this compound although hexachlorophene does not bind well to charcoal and
there are no clinical trials of this therapy for this agent.
3. If exposure has occurred through the skin, wash skin aggressively with soap or
detergent and water to remove any residues still on the skin. Since hexachloro-
phene is not soluble in water, washing with water alone will not provide signifi-
cant benefit.
4. Perform neurological support and seizure control, as these are critical to survival.
When possible, perform in an intensive care setting. Seizure control should be in
accordance with recommendations in Chapter 3.
5. Provide cardiovascular and respiratory support, which are also very important to
success in treating severe poisonings with this agent. This care should be provided
in an intensive care unit in accordance with accepted medical practice.
CONTRAINDICATED
Creso/s
Gl decontamination
206
-------
PINE OIL
Toxicology
Exposures to pine oil detergent and disinfectant solutions are commonly reported to
poison control centers in the United States.49 Pine oil is an agent commonly contained
in a variety of household and commercial cleaners and disinfectants. It is a mixture of
monoterpenes derived from the distillation of wood from various pine species, with
approximately 57% being alpha-pinene.50 Its most common side effects in smaller
dosage are irritation of mucous membranes, gastrointestinal irritation, mild respira-
tory and CNS depression and renal toxicity. Larger ingestions can result in severe
respiratory distress, cardiovascular collapse, and severe CNS effects. Renal failure and
myoglobinuria have also been reported in severe poisonings.51 Since even small inges-
tions can result in severe aspiration pneumonia, all ingestions should be considered
potentially hazardous.
While many of the reported effects of poisoning with this agent are related to
direct irritant effect on mucous membranes, gastrointestinal tract and lungs (by aspira-
tion), some reports suggest significant absorption from oral and rectal exposures. Other
reports suggest a lesser rate of absorption.50 While alpha terpineol can be measured in
blood, there are no data relating terpineol levels to degree of toxicity; this measure.
therefore, is not considered useful in guiding diagnosis and management.
Treatment of Pine Oil Toxicosis
1. Do not induce emesis. Since there is a high risk of aspiration pneumonia, induced
emesis is usually considered contraindicated in these poisonings. However, spon-
taneous emesis may occur because of direct irritation of the gastric mucosa.
2. If a high concentration solution is in contact with the eyes, flush eyes profusely
and carefully examine corneas. If burns have occurred, obtain ophthalmologic
care.
3. Observe the patient for at least 6 hours with any significant ingestion in order to
observe the onset of any symptoms, particularly pulmonary symptoms.
4. Order chest films and measure oxygenation if any pulmonary symptoms are
observed. If pulmonary symptoms occur, hospitalization is appropriate. With
severe pulmonary symptoms transfer to an intensive care unit is usually appro-
priate. With severe aspiration, manage as with any severe aspiration pneumonia.
in accordance with accepted medical practice.
5. Treat other severe systemic effects in accordance with accepted medical practice.
There is no evidence that activated charcoal is helpful in these poisonings. Likewise.
although a variety of enhanced elimination methods have been proposed and tried.
there is no evidence to support their efficacy.
CHAPTER 20
Disinfectants
Pine Oil
HIGHLIGHTS
Common household/
commercial cleaning
ingredient
Monoterpene wood
derivative
Primarily inhalation and
ingestion route to poisoning
All ingestions have potential
for severe aspiration
pneumonia
Oral, rectal exposure routes
also possible
SIGNS & SYMPTOMS
Mucous membrane, Gl
irritation
Mild respiratory, CNS
depression
Severe respiratory,
cardiovascular, CNS impacts
from larger ingestions
TREATMENT
Flush eyes and examine/
treat corneas
Observe for 6 hours post-
exposure, esp. for pulmonary
symptoms
Pulmonary support
Order chest films and
measure oxygenation
Hospitalize, consider ICU
In severe cases, manage as
aspiration pneumonia
CONTRAINDICATED
Induced emesis
207
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CHAPTER 20
Disinfectants
References
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health care. 2006.
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Australas JDermatol. Feb 2004;45(1):73-75.
14. Mucklow ES. Accidental feeding of a dilute antiseptic solution (chlorhexidine 0.05% with
cetrimide 1%) to five babies. Hum Toxicol. Nov 1988;7(6):567-569.
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1975;129(10):1208-1209.
16. Chan TY. Poisoning due to Savlon (cetrimide) liquid. Hum Exp Toxicol. Oct
1994;13(10):681-682.
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ment of corrosive ingestion and modified endoscopic classification of bums. Gastrointest
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18. Consensus: POISONDEX Editorial Board consensus opinion poll, irritants/caustics
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preservatives in Switzerland. Swiss Contact Dermatitis Research Group. Contact Derma-
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20. Okano M, Nomura M, Hata S, et al. Anaphylactic symptoms due to chlorhexidine gluco-
nate. Arch Dermatol. Jan 1989;125(l):50-52.
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transferase rise after chlorhexidine self-poisoning. Lancet. Jan 30 1982;1(8266):289.
24. Hardin RD, Tedesco FJ. Colitis after Hibiclens enema. J Clin Gastroenterol. Oct
1986;8(5):572-575.
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Annual Report of the American Association of Poison Control Centers' National Poison
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26. Ingram TA, 3rd. Response of the human eye to accidental exposure to sodium hypochlo-
rite.JEndod. May 1990;16(5):235-238.
27. French RJ, Tabb HG, Rutledge LJ. Esophageal stenosis produced by ingestion of bleach:
report of two cases. SouthMedJ. Oct 1970;63(10):1140-1144.
28. Landau GD, Saunders WH. The Effect of Chlorine Bleach on the Esophagus. Arch Otolar-
yngol.Aug 1964;80:174-176.
29. Mrvos R, Dean BS, Krenzelok EP Home exposures to chlorine/chloramine gas: review of
216 cases. SouthMedJ. Jun 1993;86(6):654-657.
30. Reisz GR, Gammon RS. Toxic pneumonitis from mixing household cleaners. Chest. Jan
1986;89(l):49-52.
31. Kurt TL, Morgan ML, Hnilica V, Bost R, Petty CS. Fatal iatrogenic iodine toxicity in a
nine-week old infant. J Toxicol Clin Toxicol. 1996;34(2):231-234.
32. Campistol JM, Abad C, Nogue S, Bertran A. Acute renal failure in a patient treated by
continuous povidone-iodine mediastinal irrigation. J Cardiovasc Surg (Torino). Jul-Aug
1988;29(4):410-412.
33. Means LJ, Rescorla FJ, Grosfeld JL. Iodine toxicity: an unusual cause of cardiovascular
collapse during anesthesia in an infant with Hirschsprung's disease. J Pediatr Surg. Dec
1990;25(12): 1278-1279.
34. Pietsch J, Meakins JL. Complications of povidone-iodine absorption in topically treated
bum patients. Lancet. Feb 7 1976;l(7954):280-282.
35. Ponn RB. Continuous povidone-iodine irrigation. Ann Thorac Surg. Feb 1987;43(2):239.
36. Perencevich EN, Wong MT, Harris AD. National and regional assessment of the antibacte-
rial soap market: a step toward determining the impact of prevalent antibacterial soaps. Am
J Infect Control. Oct 2001;29(5):281-283.
37. Robertshaw H, Leppard B. Contact dermatitis to triclosan in toothpaste. Contact Derma-
titis. Dec 2007;57(6):383-384.
38. Wong CS, Beck MH. Allergic contact dermatitis from triclosan in antibacterial hand-
washes. Contact Dermatitis. Nov2001;45(5):307.
39. Pegg SP, Campbell DC. Children's bums due to cresol. Burns Incl Therm Inj. Apr
1985;ll(4):294-296.
40. Arthurs GJ, Wise CC, Coles GA. Poisoning by cresol. Anaesthesia. Jul-Aug 1977;32(7): 642-
643.
41. Chan TK, Mak LW, Ng RP. Methemoglobinemia, Heinz bodies, and acute massive intra-
vascular hemolysis in lysol poisoning. Blood. Dec 1971;38(6):739-744.
42. Mullick FG. Hexachlorophene toxicity. Human experience at the Armed Forces Institute of
Pathology. Pediatrics. Feb 1973;51(2):395-399.
43. Anderson JM, Cockbum F, Forfar JO, Harkness RA, Kelly RW, Kilshaw B. Neonatal spon-
gioform myelinopathy after restricted application of hexachlorophane skin disinfectant. J
ClinPathol. Jan 1981;34(l):25-29.
44. Martin-Bouyer G, Lebreton R, Toga M, Stolley PD, Lockhart J. Outbreak of accidental
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45. Slamovits TL, Burde RM, Klingele TG. Bilateral optic atrophy caused by chronic oral inges-
tion and topical application of hexachlorophene. Am J Ophthalmol. May 1980;89(5):676-
679.
46. Prasad GV, Rajendra W, Indira K. Brain ammonia metabolism in hexachlorophene-induced
encephalopathy. Bull Environ Contam Toxicol. Apr 1987;38(4):561-564.
47. Boehm RM, Jr., Czajka PA. Hexachlorophene poisoning and the ineffectiveness of perito-
neal dialysis. Clin Toxicol. Mar 1979;14(3):257-262.
48. Nagy L, Orosz M. Occupational asthma due to hexachlorophene. Thorax. Aug
1984;39(8):630-631.
49. Bronstein AC, Spyker DA, Cantilena LR, Jr., Green JL, Rumack BH, Giffin SL. 2008
Annual Report of the American Association of Poison Control Centers' National Poison
Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila). Dec 2009;47(10):911-
1084.
50. Koppel C, Tenczer J, Tonnesmann U, Schirop T, Ibe K. Acute poisoning with pine oil -
metabolism of monoterpenes. Arch Toxicol. Nov 1981;49(l):73-78.
51. Litovitz TL, Schmitz BF, Matyunas N, Martin TG. 1987 annual report of the American
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Sep 1988;6(5):479-515.
210
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Section V
CHRONIC EFFECTS
Chronic Effects* 212
-------
CHAPTER 21
Chronic Effects
In some cases,
persistent effects may
be those lingering
after an acute
poisoning, while in
other situations [they]
may be associated
with chronic,
low-level or subacute
pesticide exposure
over time.
This chapter is a departure from the format and content of the other chapters in
this manual. Rather than discussing signs and symptoms of acute poisoning, this
chapter addresses chronic (also known as persistent) effects that have been asso-
ciated with pesticide exposure. The information in this chapter is designed to
provide the practitioner with evidence for the better-established inferences for
chronic effects of pesticides. This will offer some facility in the basic knowl-
edge of chronic effects, allowing an approach to such effects, aiding the practi-
tioner in answering questions from patients and the public, and providing a basis
for further inquiry into areas of interest. Knowledge of chronic effects of pesticide
exposure is evolving rapidly and providers will need to be alert to new findings as
they become available. The chapter is not intended to be a comprehensive review;
such reviews are referenced when they are available.
The chapter is not intended to be a comprehensive review;
such reviews are referenced when they are available.
In some cases, persistent effects may be those lingering after an acute poisoning.
while in other situations, persistent symptoms or demonstrable physiological altera-
tion may be associated with chronic, low-level or subacute pesticide exposure over
time. Evidence linking pesticide exposure to chronic health conditions relies on obser-
vational epidemiological studies and/or standard chronic toxicity testing using animal
models. For obvious ethical reasons, experimental studies with purposeful dosing
of pesticides are not conducted in humans. Therefore, while cause and effect is not
proven with any one epidemiology study, several well designed studies in different
populations, alone or combined with inferential evidence from animal exposures, can
strongly support the likelihood that a given association is in fact causal in nature.
This chapter covers chronic health conditions that may have an association with
pesticide exposure. Neurological effects, particularly neurodevelopmental abnormali-
ties in children, have been implicated with exposure to insecticides that have toxi-
cological activity on the central nervous system. Numerous studies have examined
the effects of pesticides on the development of cancer in children and adults. Several
classes of pesticides have properties that mimic endocrine hormones and may affect
multiple organ systems and functions including reproductive health and cancer risk.
Recently, data have emerged indicating a potential relationship between certain pesti-
cides and asthma. Chronic, low-level arsenic exposure is associated with multiple
chronic disease endpoints including skin disease, neuropathy and cancer.
212
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CHAPTER 21
Chronic Effects
Evaluating Epidemiological Findings
The conditions that are traditionally used to consider an established statistical asso-
ciation as causal in nature were clearly articulated by Sir Bradford Hill in relation to
epidemiological and other research on smoking and lung cancer. While only rarely
will all conditions be met, the more that are met, the more confident one can be in
the truth of a causal connection. The most important condition that must be met is a
temporal relationship (i.e., exposure precedes outcome). Other supportive conditions
include the strength of effect (described as the size of the effect - e.g., high relative
risk or odds ratio), dose-response relationship (more exposure = more effect), consis-
tency (i.e., multiple studies with similar outcomes), biological plausibility (i.e., the
outcome can be explained biologically), experimental support (usually done on animal
models), and analogy (similar exposures produce similar outcomes).1
One of the most important and major weaknesses
of many epidemiological studies is adequacy
and reliability of exposure assessment.
Disease processes with low incidence represent a particular challenge to evaluate
using epidemiological methods. Although adult cancers are relatively common, cancer
in childhood is rare. Consequently, to adequately study a disease with a low incidence.
case-control studies rather than cohort designs provide adequate power, but they are
subject to greater recall and classification bias. One of the most important and major
weaknesses of many epidemiological studies is adequacy and reliability of exposure
assessment.2'3 Studies that incorporate pesticide-specific exposure assessment, markers
of biological mechanisms, objective assessment of outcomes and consideration of the
influence of timing of exposure across the lifespan are needed to better define the
relationships.
Differences between Children and Adults
When evaluating the effect of chronic, low-level exposures in humans, important
differences in exposure sources and patterns between children and adults stemming
from differences in physiology and behavior must be considered. From a develop-
mental standpoint, children in the first few years of life spend a considerable amount
of time on the floor, where residues following indoor application of pesticides (or
outdoor application that may be tracked inside) accumulate.4'5'6 Children have more
frequent hand-to-mouth activity, which can be an added source of oral exposure.7'8
Children ingest a larger amount of food and water per body weight than adults. For
example, in the first year of life, infants may take in 100-150 cc/kg/day of liquids. For
a 70-kg adult to ingest an equivalent amount of fluid, he/she would need to drink six
2-liter bottles of fluids a day. Dietary composition for children differs from that for
adults. For example, U.S. children are much more likely to routinely ingest a variety
of apple-based products on a daily basis, thus ingesting a greater amount of pesticide
residue from apples than would the typical adult.9
Supportive
Conditions:
temporal
relationship
(most important)
strength of effects
dose-response
relationship
consistency
biological
plausibility
experimental
support
analogy
213
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CHAPTER 21
Chronic Effects
Evidence of
neurodevelopmental
toxidty arising
from chronic,
low-level exposure
in gestational or
early postnatal life is
accumulating.
NEUROLOGICAL AND NEURODEVELOPMENTAL EFFECTS
Many registered pesticides are specifically toxic to the central nervous systems of
target pests including insects and mammals such as rodents. Neurotoxicity to animals
has been a useful attribute for the development of pesticides for use as insecticides and
rodenticides. It is not surprising that these agents also have neurotoxic effects on large
mammals including humans. However, many other pesticides, including herbicides.
fumigants and fungicides, have human neurotoxicant properties. This section summa-
rizes those effects that may persist following acute exposure, as well as describes
subacute and chronic effects following long-term exposure.
Chronic Effects Following Acute Exposure
Acute pesticide intoxications may leave recovered individuals with residual neuro-
logic impairment, particularly if they result in multiorgan failure or nervous system
hypoxia. Such outcomes are noted for individual agents elsewhere in this document.
Several studies document that patients with a history of a single acute organophosphate
or other pesticide poisoning are at risk of neuropsychiatric sequelae when examined
as long as 10 years after the episode. These show significantly impaired performance
on a battery of validated neuro-behavioral tests and, and in some cases, compound-
specific peripheral neuropathy. The findings are subtle and, in some cases, identified
only through formal neuropsychologic testing rather than as frank abnormalities on
clinical neurologic exam.10'11'12
Certain organophosphates have caused damage to the afferent fibers of periph-
eral and central nerves. The mechanism of this type of toxicity is the inhibition of
"neuropathy target esterase" (NTE). This delayed syndrome has been termed organo-
phosphate-induced delayed neuropathy (OPIDN) and is manifested chiefly by weak-
ness or paralysis and paresthesias of the extremities. In addition to acute poisoning
episodes and OPIDN, an intermediate syndrome has been described. This syndrome
occurs after resolution of the acute cholinergic crisis, generally 24-96 hours after the
acute exposure, with signs and symptoms lasting from several days to several weeks.13
It is characterized by acute respiratory paresis and muscular weakness, primarily in the
facial, neck and proximal limb muscles. In addition, it is often accompanied by cranial
nerve palsies and depressed tendon reflexes. Both this syndrome and OPIDN lack
muscarinic symptoms. The intermediate syndrome appears to result from a combined
pre- and post-synaptic dysfunction of neuromuscular transmission. These syndromes
are described in greater detail in Chapter 5, Organophosphates.
Effects Following Low-Level, Chronic Exposure
The effects of chronic, low-level exposures to pesticides on the nervous system are
less well understood, but consistent evidence of neurodevelopmental toxicity arising
from chronic, low-level exposure in gestational or early postnatal life is accumulating.
One well established example of such effects is arsenic exposure. Neurologic symp-
toms are also common with chronic exposure. Peripheral neuropathy, manifested by
paresthesia, pain, anesthesia, paresis and ataxia, may be a prominent feature. These
effects may begin with the sensory symptoms in the lower extremities and progress to
muscular weakness and eventual paralysis and muscle wasting.14'15'16 Central nervous
system effects may also occur, including mood changes such as depression, irritability.
anxiety and difficulty concentrating. Additional symptoms include insomnia, head-
aches and neurobehavioral impairment.16
214
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CHAPTER 21
Chronic Effects
Low-Level Insecticide Exposure
Research on insecticide toxicity to the developing brain and neurodevelopmental
outcomes has been reviewed.17'18 Most studies focus on exposure to organophosphates
and organochlorines. Since these pesticides have historically been and/or currently are
in wide usage for household or agricultural pest control, exposures to the child and
pregnant mother have been common. Since these exposures have been common and
widespread over many years, it is not surprising that they would be studied and that
association of effects from these agents would be among the first documented in epide-
miological research. Little or no research has been done on the neurodevelopmental
effects of other common agents, such as pyrethroids commonly used in households
and agriculture or exposures to herbicides and fungicides used extensively in agricul-
ture. One published longitudinal cohort study assessed prenatal exposure to household
permethrin and piperonyl butoxide by maternal air monitoring and examination of
maternal and cord blood plasma. When assessing neurodevelopment at 36 months,
significant adverse impacts were observed for exposure to piperonyl butoxide (PBO),
the most common synergist used in household pyrethroid products. No adverse asso-
ciations were observed with exposure to the active ingredient permethrin. The authors
note the more challenging task of measuring permethrin in biological and environ-
mental samples compared to assessment of PBO and the need for confirmatory studies
to clarify the roles of pyrethroids and PBO.19
The following sections review some of the data available for neurological and
neurodevelopmental effects by age group of the studied population.
Longitudinal Studies in Preschool Children
Two longitudinal birth cohorts have observed in utero organophosphate exposure
associated with abnormal behavioral effects at birth. Using the Brazelton Neonatal
Behavior Assessment Scale (BNBAS) in young infants born to mothers living and
working in the Salinas Valley of California, a rich agricultural setting, increases in
abnormal reflex functioning among the infants were associated with increases in
maternal organophosphate urinary metabolite concentrations in pregnancy. The effects
were not associated with early postnatal measurement of maternal urinary metabo-
lite concentrations.20 Using a similar design in a cohort of urban women, abnormal
BNBAS responses in newborns were also related to maternal organophosphate
metabolite levels during pregnancy. In this study, polychlorinated biphenyls (PCBs)
and DDE (the primary metabolite of the organochlorine insecticide DDT) were also
measured in maternal blood in the third trimester. There was no observed association
between DDE and BNBAS scores and a very weak beneficial association between
PCBs in one area of the BNBAS: "range of state."21
Assessment tools for preschool children include
the Brazelton Neonatal Behavior Assessment Scale (BNBAS) and
the Bayley Scales of Infant Development (BSID)
Mental Development Index (MDI).
Another birth cohort residing adjacent to a PCB-contaminated harbor in Massa-
chusetts evaluated the relationship between cord blood, PCBs and DDE and perfor-
mance on the BNBAS. This study observed consistent inverse relationships between
BNBAS measures of poor attention and levels of PCBs and DDE in the newborn
215
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CHAPTER 21
Chronic Effects
A body of research
associates pesticide
exposure with ADHD
and autism.
infants.22 In contrast, a similar study in an agricultural community failed to show a
relationship between prenatal DDT/DDE exposure and BNB AS.23 Prospective follow-
up of these birth cohorts suggests that prenatal exposure to pesticides has long-term
effects on children's neurodevelopment.24'25
In a study of children exposed to hexachlorobenzene (HCB) during gestation.
a relationship at 4 years of age between HCB exposure and the California Preschool
Social Competence Scale and an ADHD scoring scale was demonstrated.26 The greater
the exposure, the worse the performance on the Social Competence Scale and the
higher the ADHD scores. In the Salinas Valley agricultural cohort, effects of organo-
phosphate insecticide exposure assessed based on maternal urinary metabolite moni-
toring during pregnancy and postnatal urinary levels assessed in young children has
been investigated. Higher rates of symptoms associated with pervasive developmental
disorder have been observed in association with both prenatal and postnatal exposure.
Prenatal exposure was also associated with lower performance scores on the Bayley
Scales of Infant Development (BSID) Mental Development Index (MDI). In contrast.
the investigators report postnatal exposure associated with improved MDIs in this
cohort. While the reason for this discrepancy is not clear, one hypothesis is that chil-
dren with higher MDIs may have increased exploratory behavior that influences their
postnatal exposure.17
In this cohort, increased prenatal DDT was associated with decreases in psycho-
motor developmental index (PDI) assessed at 6 and 12 months of age but not at 24
months. Prenatal DDE levels were also associated with decreased PDI, but only at
6 months of age. Decreases in MDI at ages 12 and 24 months were related to DDT
levels. No significant relationship to DDE was noted on MDI.27
Similar studies of neurodevelopment in younger children have been performed
in urban birth cohorts. These demonstrate consistent adverse impacts of prenatal
chlorpyrifos exposure on neurodevelopmental function in both the motor and mental
functional domains at 3 years of life.28'29
Chronic Effects in School-Age Children
A rapidly increasing body of research associates pesticide exposure with behavioral
disorders including Attention Deficit and Hyperactivity Disorder (ADHD) and autism
spectrum disorder (ASD), which manifest in preschool and school-age children. A
case-control analysis using State of California data on autism diagnosis and a spatial-
temporal map of pesticide applications found the risk for ASD was consistently asso-
ciated with residential proximity to organochlorine pesticide applications occurring
around the period of CNS embryogenesis.30
Follow-up of the Massachusetts cohort discussed in the prior subsection showed
an association between prenatal organochlorine exposure and higher rates of ADHD
at school age. This association was consistent for both PCBs and DDE.31 A cross-
sectional analysis from the 2000-2004 National Health and Nutrition Examination
Survey (NHANES) linked a representative sample of U.S. children's urinary OP
metabolites with diagnoses of ADHD.32 Increased measures of ADHD behavior using
the child behavior checklist (CBCL) in the Salinas Valley cohort found prenatal OP
exposure associated with a >70 percentile score on the ADHD confidence index, (OR
= 5.1, 95% CI, 1.7-15.7) and the composite ADHD indicator (OR = 3.5, 95% CL
1.1-10.7). Other measures were also positive but did not reach statistical significance.33
The relationship of pesticide exposure on stunting (poor growth) and abnormal
neurodevelopment was investigated in school-age Ecuadorian children.34 Seventy-two
children less than 9 years of age in 2nd and 3rd grades were studied via detailed physical
exam and neurodevelopmental testing. Prenatal exposure to pesticides was determined
by maternal occupational history. Many of these mothers worked in flower production
216
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CHAPTER 21
Chronic Effects
activities leading to extensive pesticide exposure. Concurrent exposure in the chil-
dren was assessed by measuring red blood cell acetylcholinesterase (ACHe) levels
and urinary organophosphate metabolites. Many of the children suffered from stunting
related to poor nutrition in utero and early life. Both stunting and pesticide expo-
sure were associated with decreased performance on the Stanford-Binet copying test,
and some of the best scores on the copying test were from children without stunting
or pesticide exposure. The independent variables of stunting and pesticide exposure
appeared to each contribute independently to the adverse effect. Concurrent exposure
to organophosphates affected only simple reaction time. This study provides evidence
that poor nutrition, common in many pesticide-exposed children in developing coun-
tries or agricultural settings, may increase the adverse effects of pesticide exposure.
Several studies of school-age children with prenatal exposure have been recently
published. Though the results are not identical, these studies suggest adverse neuro-
developmental outcomes persist in both urban and agricultural environments in chil-
dren followed in longitudinal cohorts.24'25'35 One of these studies reported that adverse
neurodevelopmental effects were related to prenatal but not postnatal exposure.25 The
other studies did not differentiate between prenatal and postnatal exposure so it is not
clear whether or not postnatal exposure contributes to the neurodevelopmental effects.
Studies of school-age children with prenatal exposure
suggest adverse neurodevelopmental outcomes in both
urban and agricultural environments.
Chronic Effects in Adults Following Low-Level Exposure
In adults, there has been considerable interest in the effects on the nervous system from
chronic, low-level exposure to pesticides. A recent review of the evidence regarding
the association between pesticide exposure and neurologic dysfunction listed 3 8 publi-
cations reporting various neurologic outcomes of exposure.36 The studies focused on
low-level exposures in adults and can be grouped into two broad categories. The first
category is cross-sectional and longitudinal studies of occupationally exposed indi-
viduals, observing for a wide range of outcomes. The second focuses on similar popu-
lations in relationship to specific disease outcomes, most notably in the neurological
area, Parkinson's disease (PD).
Among the first category of studies, an older cross-sectional study evaluated
neurotoxicity in pesticide applicators exposed to organophosphates. In this study an
increase in vibration sense threshold was thought to represent a loss of peripheral
nerve function.37 A more recent study of termiticide applicators exposed to chlorpy-
rifos suggested some degree of adverse effects on neurologic function in a subset of
tests, specifically pegboard turning and postural sway tests. There was a significant
increase in self-reported symptoms in the exposed group. These differences were
more marked in the individuals with longer exposure, suggesting a long-term cumu-
lative effect.38
A study of farmworkers, as a proxy for pesticide exposure, observed that farm-
workers had poorer performance on several neurobehavioral tests compared to non-
farmworker controls. Most notably, farmworkers performed worse with tapping (coef-
ficient [linear regression] = 4.13, 95% CI, 0.0-8.27) and postural sway (coefficient =
4.74, 95% CI, -2.2-11.7). These effects were strongly related to duration of exposure.
whether observed in current or former workers.39 A 5-year prospective longitudinal
study of licensed pesticide applicators, the Agricultural Health Study (AHS), reported
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CHAPTER 21
Chronic Effects
[in studies of
farmworkers in
the Agricultural
Health Study]
Symptoms such as
headache, fatigue,
insomnia, tension,
irritability, dizziness,
depression and
numbness in the
hands and feet
[in adults] were
related to duration
of exposure to
pesticides.
symptoms at enrollment were strongly correlated with prior pesticide exposure. The
symptoms reported, such as headache, fatigue, insomnia, tension, irritability, dizziness.
depression and numbness in the hands and feet, were related to duration of exposure to
pesticides prior to enrollment. The relationship was still observed after excluding indi-
viduals with histories of acute pesticide poisoning or other isolated events with high
personal exposure. The strongest associations were with fumigants, organophosphates
and organochlorines.40 This same study reported an association between physician-
diagnosed depression and three patterns of exposure to pesticides: acute physician-
diagnosed poisoning (OR 2.57 95% CI 1.74-3.79), a high pesticide exposure event
(OR 1.65 95% CI 1.33-2.05), and high cumulative exposure (OR 1.54 95% CI 1.16-
2.04). It is of interest that the two latter patterns were documented by the study in the
absence of a physician-diagnosed acute poisoning episode.41
Several studies have examined the potential association between pesticide expo-
sures and Parkinson's disease (PD). A cohort of 238 persons in Washington State who
were occupationally exposed to pesticide was compared to 72 non-exposed individ-
uals. In this study, an association between pesticide exposure and PD was reported in
the highest tertile of years of exposure (prevalence ratio 2.0, 95% CI, 1.0-4.2).42 The
AHS evaluated the association between the prevalence of physician-diagnosed PD and
pesticide usage. The cases were compared to a cohort who did not report PD. Asso-
ciations were noted with cumulative days of exposure at initial enrollment, frequent
personal use of pesticides, and with a few specific pesticides (dieldrin, maneb, para-
quat and rotenone).43 Several postmortem studies of persons with PD have reported
a positive association between tissue levels of dieldrin and PD. An evaluation of the
biological plausibility of causation concluded that there was sufficient evidence for
causation to warrant further evaluation and specific mechanistic studies in animal
models.44 Systematic reviews of the evidence for the association between PD and
pesticide exposure have generally concluded that there is evidence for an association.
However, at the present time, there is insufficient evidence to conclude that specific
pesticide exposures are causative of PD.45'46
Following these systematic reviews, several additional studies have evalu-
ated the relationship between PD and pesticides. A multi-country case-control study
of pesticide exposure and PD observed a significant exposure between interviewer-
administered questionnaire results showing high pesticide exposure and PD (OR =
1.41, 95% CI, 1.06-1.88).47 Another multi-site case-control study evaluated the risk
for PD in various occupations where exposure to toxicants, including pesticides, may
occur. Risk of PD was associated with any pesticide use (OR = 1.99, 95% CI, 1.12-
3.21). Higher risk was also noted for any of 8 other pesticides selected a priori that
have a mechanism that may be associated with PD (OR = 2.2, 95% CI, 1.02-4.75)
and for the herbicide 2,4-D (OR = 2.59, 95% CI, 1.03-6.48).48 To address the diffi-
culty of exposure assessment, a case-control study was conducted using a geographic
information system (GIS) that integrated past subject addresses and California pesti-
cide agricultural spray records to characterize exposure. They found that subjects who
lived within 500 meters of a field sprayed with paraquat and maneb during the period
1974-1989 were four times more likely to have Parkinson's disease than the control
group (OR = 4.17, 95% CI, 1.15-15.16).49
Animal studies offer evidence for the basis of a mechanistic association with
some pesticides and the development of PD or Parkinsonian features. Two fungicides.
mancozeb and maneb, have dose-dependent toxicity on dopaminergic cells in rats.
Both the organic component of the fungicide as well as the manganese ion contrib-
uted to the toxicity.50 Additional pesticides of high interest in the relationship with PD
include 2,4-D, paraquat, diquat, permethrin, dieldrin and rotenone.48'51
218
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CANCER
Epidemiological data support associations for both adult and childhood cancer,2'3'52'53
with occupational exposure playing a role in cancer development for both adults and
children. However, the most common types of cancer vary for children and adults.
and as such, associations between pesticides and cancer are treated separately in this
section. As noted at the beginning of this chapter, one common problem in evalu-
ating cancer and pesticide relationships, particularly in children, is the relative rarity
of cancer diagnoses.3'53
Several meta-analyses and systematic reviews have been published on the asso-
ciation between pesticide exposure and cancer. In most instances, these analyses and
reviews serve as the primary source of information for the sections below on child-
hood and adult cancers.
CHAPTER 21
Chronic Effects
Classification Systems for Carcinogenicity in Humans
All active ingredients in pesticides are required to be tested in animals or using in
vitro tests for their likelihood of causing cancer. The Health Effects Division of the
EPA's Pesticide Program performs an independent review of all the available evidence
to classify active ingredients according to their potential to cause cancer. The clas-
sification systems have changed in the past 30 years from using a letter grade system
originally issued in 1986 to a method that uses descriptive phrases based on the weight
of evidence. Under the older letter grade system, a grade of "B" was a "probable
carcinogen," "C" was equivalent to being classified as "possibly carcinogenic," "D"
was "Not classifiable as to human carcinogenicity" and "E" was classified as having
"Evidence for non-carcinogenicity for humans."
The current system was proposed in 1996, revised in 1999, and released as a
final report, Guidelines for Carcinogen Risk Assessment in 2005 by the EPA. The
report uses one of five specific phrases to designate carcinogenicity: "carcinogenic
to humans," "likely to be carcinogenic to humans," "suggestive evidence of carcino-
Data support
associations between
occupational
pesticide exposure
and cancers in both
adults and children.
CARCINOGEN CLASSIFICATION SYSTEMS AT A GLANCE
1986 EPA Classification System
Group B: Probable human carcinogen
Group C: Possible human carcinogen
Group D: Not classifiable as to human carcinogenicity
Group E: Evidence of non-carcinogenicity for humans
2005 EPA Classification System
Carcinogenic: Carcinogenic to humans
Likely: Likely to be carcinogenic to humans
Suggestive: Suggestive evidence of carcinogenic potential
Inadequate: Inadequate information to assess carcinogenic potential
Not Likely: Not likely to be carcinogenic to humans
IARC Classification System
Group 1: Carcinogenic to humans
Group 2A: Probably carcinogenic to humans
Group 2B: Possibly carcinogenic to humans
Group 3: Not classifiable as to its carcinogenicity to humans
Group 4: Probably not carcinogenic to humans
219
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CHAPTER 21
Chronic Effects
The table at the
end of this chapter
lists selected
pesticides and their
classification of
carcinogenicity.
genie potential," "inadequate information to assess carcinogenic potential," and "not
likely to be carcinogenic to humans." This information is available only via an emailed
report from the EPA website http://www.epa.gov/pesticides/carlist. Although the new
guidelines have been in place since 2005, not all pesticides have been evaluated under
the 2005 cancer guidelines. Active ingredients in pesticides classified using the older
letter designation could be reevaluated on a case-by-case basis.
Another classification system for potentially carcinogenic chemicals was estab-
lished by the International Agency for Research on Cancer (IARC). This system clas-
sifies chemicals using a 1 -4 grading system. A classification of 1 indicates the chemical
is carcinogenic to humans. A category of 2 is split between 2A (probably carcinogenic
to humans) and 2B (possibly carcinogenic to humans). A category of 3 indicates the
chemical is not classifiable as to its carcinogenic potential. Generally, this category is
used when there is inadequate evidence in humans or animals to establish a cancer-
causing relationship. Group 4 indicates that the chemical is probably not carcinogenic
to humans.
The table at the end of this chapter lists selected pesticides and their clas-
sification of carcinogenicity. The list is not meant to be all inclusive, but an attempt
to list agents that are more commonly used or have a higher likelihood of being
carcinogenic in humans. It includes a number of chemicals that were classified under
both the newer and older EPA systems. The list includes some pyrethroid insecti-
cides, the residential use of which has increased as many of the organophosphates
have been phased out.
Associations between Childhood Cancer and Pesticides
Relationships between childhood cancers and pesticides were summarized in two
review articles, the first by Zahm and Ward in 1998, and an update published in 2007
by Infante-Rivard. The pediatric cancer types with the most compelling evidence for
an association with pesticides are leukemia and brain tumors. Of note, in most of
the studies reviewed, all forms of leukemia were considered in one group because of
insufficient numbers of certain types of leukemia - e.g., acute lymphocytic leukemia
(ALL) or acute myelocytic leukemia (AML). There were a few studies of sufficient
size that were able to evaluate ALL separately. Brain tumors are also reported as a
group rather than by individual tumor types as they are even rarer than childhood
leukemia.3'53
The pediatric cancer types with the most compelling evidence for
an association with pesticides are leukemia and brain tumors.
Childhood Leukemia
Thirteen of the 18 studies reviewed in the 1998 Zahm and Ward article found an
increased risk of leukemia following pesticide exposure. The most common reported
exposure was not related to agricultural production but rather household insecticide
use during pregnancy or during the preconception period. As mentioned above, mixing
leukemia types and recall bias were among the limitations of these earlier studies.53
Infante-Rivard reviewed 12 more recent studies in 2007.3 Most of these studies
were larger and used higher-quality exposure assessment methodologies. Five found
statistically significant associations between leukemia and pesticide exposure.54'55'56'57'58
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CHAPTER 21
Chronic Effects
Two included a detailed exposure assessment and were able to demonstrate a dose-
response effect.56'58 The largest study included 491 subjects and limited the outcome to
acute lymphocytic leukemia. In this study, maternal residential use during pregnancy
of herbicides (OR = 1.84, 95% CI, 1.32, 2.57), plant insecticides (OR = 1.97, 95%
CI, 1.32-2.94), and "pesticides for trees" (OR = 1.70, 95% CI, 1.12-2.59) were all
associated with ALL. Childhood exposure (from birth to diagnosis of ALL) to plant
insecticides (OR =1.41, 95% CI, 1.06-1.86) and herbicides (OR = 1.82, 95% CI, 1.31-
2.52) were also significantly associated.56 Two studies by the same author did not find
an association between child's residence near agriculture-related pesticide application
and childhood leukemia,59 nor maternal residence near agricultural pesticide applica-
tion at the time of their child's birth and childhood leukemia.60
Two additional meta-analyses have been conducted that further explore asso-
ciations between pesticides and leukemia and support the previously described asso-
ciations. The first meta-analysis examined parental occupational exposure to pesti-
cides and leukemia and the second focused on studies of pesticides in the home and
garden.61'62 In the first study, maternal occupational exposure was found to be associ-
ated with leukemia, the reported ORs were 2.09, 95% CI, 1.51-2.88 for overall pesti-
cide exposure; 2.38, 95% CI, 1.56-3.62 for insecticide exposure; and 3.62, 95% CI,
1.28-10.3 for herbicide exposure. No associations were found for paternal occupa-
tional exposure.62 In the meta-analysis focused on exposure through home and garden
uses of pesticides, 15 studies were included and exposure during pregnancy to unspec-
ified pesticides, insecticides and herbicides were all associated with leukemia (OR
= 1.54, 95% CI,1.13-2.11; OR = 2.05, 95% CI, 1.80-2.32; and OR = 1.61, 95% CI,
1.2-2.16, respectively).61
Childhood Brain Tumors
In the 1998 Zahm and Ward review, 12 of the 16 studies presented evidence of an asso-
ciation between pesticide exposure and childhood brain tumors, and seven of these
reached statistical significance. Similar to the findings with leukemia, household use
by the parent (home and garden and on household pets) were the most commonly asso-
ciated exposures. The number of children with brain tumors is even fewer than that of
leukemia, so all types of brain tumors were used to define "cases."53
As noted with leukemia, the body of evidence estimating an association between
brain tumors and pesticides since 1998 is more robust, with larger studies and improved
exposure assessment. Nine of 10 studies in the 2007 Infante-Rivard review demon-
strated an increased risk of brain tumors following maternal and/or paternal expo-
sure, with three of the studies reaching statistical significance.63'64'65 For all studies, it
appeared that prenatal exposure to insecticides, particularly in the household, as well
as both maternal and paternal occupational exposure before conception though birth
represented the most consistent risk factors.63'64'65'66'67'68'69'70'71 The largest case/control
study (321 cases) limited the case definition to astrocytomas and noted an OR of 1.9.
95% CI, 1.1-3.3, following maternal preconceptual/prenatal exposure to insecticides.65
One cohort study followed 235,635 children and found an association between all
brain tumors and paternal exposure to pesticides immediately before conception (RR
= 2.36, 95% CI, 1.27-4.39.63
In summary, there is relatively consistent evidence for an increased risk of devel-
oping some types of childhood cancers following preconception and/or prenatal expo-
sure to pesticides. The strongest evidence appears to be for ALL, the most common
form of childhood leukemia. Maternal exposure to insecticides and paternal occupa-
tional exposure appear to carry the greatest risk.
There is evidence
for increased risk
of developing some
types of childhood
cancers following
preconception and/or
prenatal exposure to
pesticides.
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CHAPTER 21
Chronic Effects
Tumors of the
prostate, pancreas,
kidney and breast
have been among
the more consistently
reported findings.
Associations between Pesticides and Cancer in Adults
Bassil et al. conducted a systematic review of cancer and pesticides, which included
studies of children and of adults. Each study was evaluated for methodological quality
by two trained reviewers using a standardized assessment tool with a high inter-rater
reliability. Only studies with a global rating of 4 or higher were included in the review.2
Many of the studies evaluating relationships between cancers in adults and pesti-
cides are conducted in the occupational setting. Associations between pesticide expo-
sure and the development of leukemia and non-Hodgkin lymphoma were noted in
most studies. Solid tumors of the prostate, pancreas, kidney and breast were among
the more consistently reported findings in studies of adults. As was noted in numerous
studies of childhood outcomes, ascertainment of whether exposure actually occurred
and the amount of exposure are recurring weaknesses in adult studies.
Non-Hodgkin Lymphoma and Other Hematopoietic Cancers
Of the 27 studies on non-Hodgkin lymphoma (NHL) that met quality criteria in
the Bassil review, 23 found positive associations. Almost half of these studies were
conducted in adult cohorts of various occupational groups including farmers, pesticide
applicators, landscapers and those who worked in pesticide manufacturing. Ten of the
12 cohort studies reported a positive association, with four reaching statistical signifi-
cance. One of the larger cohort studies demonstrated a relative risk RR of 2.1, 95% CI.
1.1-3.9. Eleven of the 13 case-control studies (excludes one positive study in children)
also demonstrated an association between occupational exposure and NHL, with 7
reaching statistical significance. Multiple classes of pesticides were implicated.2
A separate meta-analysis of case-control studies examining the relationship
between pesticide exposure and hematopoietic cancers was published in 2007. The
authors reviewed 36 case-control studies. After excluding studies with methodological
flaws or data concerns, a study that included non-hematopoietic cancers and a study
written in Italian, 13 studies remained for analysis. The cancers assessed in the meta-
analysis were NHL, leukemia and multiple myeloma.72 The overall meta-OR for NHL
was 1.35, 95% CI, 1.2-1.5. An increased risk for leukemia and multiple myeloma
was also demonstrated, though both were just short of reaching statistical significance
(OR = 1.35, 95% CI, 0.9-1.2 and OR = 1.16, 95% CI, 0.99-1.36). The authors also
conducted a meta-regression to account for the heterogeneity among the studies. They
found that exposure for longer than 10 years increased the risk for all hematopoietic
cancers (mOR = 2.18, 95% CI, 1.43-3.35) and for NHL (mOR = 1.65, 95% CI, 1.08-
2.51).72
As with other cancer epidemiologic studies discussed above, the major limitation
was the lack of sufficient exposure information in many of the studies. Additionally.
the cohort studies in the above meta-analysis only listed the class of pesticide and the
corresponding OR (herbicides or insecticides) rather than the individual pesticide.72
Other individual studies have demonstrated risks from certain specific pesticides. One
well-designed cohort study reported risks associated with mecoprop, a chlorophenoxy
herbicide.73 Another study demonstrated risks from another chlorophenoxy herbicide
- methyl phenoxyacetic acid (MCPA) - and from glyphosate.74 Another study demon-
strated a significant increased risk of NHL for subjects exposed to 2,4-D.75 The Agri-
cultural Health Study demonstrated a risk of developing leukemia following exposure
to diazinon.76
Prostate Cancer
It has been suspected that pesticide exposure may be associated with prostate cancer.
This association may be related to hormonally active pesticides, known as endocrine
222
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CHAPTER 21
Chronic Effects
disrupters.77 Of the eight studies included in the Bassil review, all showed positive
associations between pesticide exposure and prostate cancer.77'78'79'80'81'82'83'84 A particu-
larly well-designed study from the Agriculture Health Cohort included 55,000 men in
Iowa and North Carolina. The authors found that farmers who applied pesticides had a
small but significant increase in prostate cancer compared to the general male popula-
tion in Iowa and North Carolina (standardized prostate cancer incidence ratio of 1.14
(1.05-1.24)). The study also evaluated risk to specific pesticides by inquiring about 50
different pesticides to which the farmer was "ever exposed" and found positive associ-
ations with carbofuran, permethrin, aldrin and DDT. Each OR was in the range of 1.25
to 1.38, all with statistically significant 95% CIs. However, among those who were in
the "highest exposure category," a risk estimate of 3.47, 95% CI, 1.37-8.76, was noted
for the fumigant methyl bromide. In addition, six pesticides (chlorpyrifos, fonofos,
coumaphos, phorate, permethrin and butylate) were positively associated with prostate
cancer in men with a family history of prostate cancer.83
Around the same time as Bassil's review was published, Mink et al. conducted a
separate review article on prostate cancer. The two authors reviewed and independently
assessed each study for inclusion or exclusion, and discrepancies were reconciled. The
authors included 13 studies (8 cohort, 5 case-control) in their final review; however,
they did not report the total number of studies reviewed and excluded. Despite some
scattered positive findings in some of the studies they reviewed, the authors concluded
there was no causal link between pesticides and prostate cancer.52
Two case-control studies by Settimi et al. evaluated prostate cancer among agri-
cultural workers and included a comprehensive questionnaire to evaluate exposures
as well as potential confounders. The first study evaluated numerous types of cancers
and demonstrated an excess risk of prostate cancer among farmers and farmworkers
(OR = 1.4, 95% CI, 1.0-2.1). When the analysis was limited to those who applied
pesticides, the OR = 1.7, 95% CI, 1.2-2.6.85 Assessment of pesticide classes and indi-
vidual pesticides within classes demonstrated risk specificity for organochlorine insec-
ticides. Elevated ORs for prostate cancer were found for "ever being exposed" to all
organochlorines, DDT and dicofol and tetradifon. All ORs were statistically signifi-
cant, and were slightly higher for those who reported greater than 15 years of exposure
compared to "ever exposed."78
Another case-control study included data on exposure, diet, lifestyle and occu-
pational factors. A positive association was found for exposure to pesticides, but the
95% CIs were wide. This may have been attributable to the small size of the study - 40
cases - and fewer reporting exposure to pesticides.86 Two other case-control studies
found no association with prostate cancer and pesticide use.87'88
Tumors of the Kidney
A recent review article evaluated renal cancer in adults (primarily renal cell carcinoma)
following occupational exposure to pesticides. This review included four studies, each
of which observed positive associations between pesticides and renal cancer.89'90'91'92
Other Associations between Human Cancer and Pesticides
Several different agents used as wood preservatives are currently classified as probable
carcinogens. Pentachlorophenol (PCP) has been classified as a B2 (probable human
carcinogen). In humans, it has been associated with soft tissue sarcoma and kidney and
GI tract cancers; however, a causal link has not been established.89'93 In animal data
submitted to the U.S. EPA in support of re-registration of PCP liver tumors, pheochro-
mocytomas and hemangiosarcomas were noted, supporting the B2 classification.94
Arsenic is well established as a human carcinogen. Studies show that arsenic
exposure can result in epigenetic dysregulation including DNA methylation, histone
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Chronic Effects
Data relating human
endocrine disruption
has become
progressively stronger
in supporting a
role of pesticides.
Extensive research
continues in this area
of investigation.
modification and microRNA expression. These alterations may play a mechanistic role
in cancer development, but long-term studies have not yet confirmed this.95 Primary
cancers caused by arsenic include tumors of the lung, bladder and skin. On occasion.
the hyperkeratotic papules described above have undergone malignant transforma-
tion. Years after exposure, dermatologic findings include squamous cell and basal cell
carcinoma, often in sun-protected areas.96
A recent review of lung cancer and arsenic evaluated nine cross-sectional studies.
six cohort studies, and two case-control studies. Despite the limitations of some of
the study designs, the risk ratios and standardized mortality ratios were consistently
high on nearly all of the studies. The evidence was most consistent at high exposure
levels. The evidence was weak or lacking for developing cancer from exposure to
lower levels of arsenic via contaminated drinking water (<100 ug/L).97
ENVIRONMENTAL ENDOCRINE DISRUPTOR EFFECTS
Over the last 15 years there has been increasing interest in the ability of environ-
mental chemicals to disrupt endocrine systems. Many pesticides, pesticide vehicles
and contaminants have endocrine-disrupting properties based on in vitro and animal
studies. While data on human effects remain somewhat fragmentary and inconclusive.
the weight of evidence from multiple lines of investigation appears to support the
concern for human effects. These effects are discussed briefly below, along with the
literature that supports these assertions.
The cellular biology of endocrine disruption is very complex and has been exten-
sively reviewed. While the details are beyond the scope of this manual, the reader is
directed to one of several reviews for more specific information.98'99'100 As a group.
exogenous agents including pesticides that affect the endocrine system have been
labeled endocrine disruptive chemicals (EDCs). Several basic mechanisms have been
identified, including direct interaction with nuclear receptors (NR), disturbance of NR
signaling and changes in hormone availability. In vitro evidence of the latter exists for
several pesticides, by alteration of P450 enzyme activity that influences the availability
of steroid hormones either by increasing or decreasing the rates of metabolism. For
instance, methoxychlor has been shown to interfere with 5'deiodinase in the liver.101
Animal Toxicology
Animal studies conducted in the laboratory suggest that some pesticides may disrupt
the endocrine systems of a variety of animals. Vmclozolin, a fungicide with low acute
toxicity, has been shown to be strong antiandrogen in rats when exposure occurs
in utero.102 Exposure of female rats to DDT has been shown to lead to precocious
puberty.103 Lindane has been shown to affect adrenal steroid synthesis.104 There is
considerable evidence that a variety of chemicals, including some pesticides, affect
thyroid function in animals.105'106
Further support for effects comes from observations in wildlife. These studies
represent the most robust evidence base for various endocrine effects from many
different pesticide classes. Only a few examples are mentioned because of space
constraints. A strong antiandrogen effect was shown in alligators in a lake in Florida in
response to heavy contamination with pesticides including dicofol, DDT and DDE.107'108
Likewise, a relatively strong association has been shown between the biocide tribu-
tyltin (TBT) and pseudohermaphroditism in 150 species of snails.109 Marine mammals
have been noted to have high levels of contamination with a variety of chemicals
including pesticides such as DDT, DDE, mirex, dieldrin and chlordane metabolites.110
These contaminants have been potentially linked to reproductive failure and other
effects due to their endocrine action. For example, PCBs in seals and polar bears have
224
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Chronic Effects
been shown to affect thyroid function. Interestingly, levels of PCBs and organochlo-
rine pesticides are negatively correlated with testosterone levels in male polar bears,
but PCBs are positively correlated with testosterone in female polar bears. Each of
these testosterone alterations may contribute to reproductive changes.111
Evidence of Human Effects of Endocrine Disruption
A systematic review by the Endocrine Society has led to a scientific statement on endo-
crine disrupting environmental toxicants and notes potential for a variety of human
effects, including alteration in mammary gland development and possible carcinogen-
esis, alteration in male fertility and testicular cancer, male urogenital malformations,
prostate cancer, thyroid disruption and obesity.112 This is a rapidly evolving field of
investigation.
Human Outcomes Related to Pesticides
Precocious Puberty. DDE has been linked to precocious puberty in one study of
immigrant females in Belgium.113 Though estrogenic pesticides have been proposed as
a contributor to premature thelarche, the evidence to date is not conclusive.
Altered Lactation. A negative correlation has been shown in several cohorts
between DDE and duration of lactation.114
Breast Cancer. There is considerable interest in this outcome because of animal
studies and the estrogenic activities of pesticides such as DDT, DDE, endosulfan
and atrazine. Though atrazine is not a direct mimicker of estrogen, in some models
it induces aromatase formation, which converts testosterone to estradiol.115 This effect
is not consistent in all cell lines or animal models. Despite the evidence that estrogen
is a promoter of breast cancer, the role of these pesticides in breast cancer remains
unclear at this time. AU.S. EPAreview in 1998 concluded that the association between
organochlorines and PCBs was not sufficient to conclude that they were likely causes
of breast cancer.116 A review by The Endocrine Society in 2009 concluded there was
sufficient evidence that endocrine disrupters altered mammary gland morphogenesis
in humans, making them more prone to neoplastic development.112
Female Fertility. There is limited evidence that female fertility may be decreased
in women occupationally exposed to pesticides.117 However, this evidence has not
been linked to specific pesticide exposures.
Semen Quality. Decreased semen quality has been noted in individuals exposed
to dioxins and PCBs, which are persistent organic compounds considered related
to organochlorine pesticides.112 Two agents, chlordecone and DBPC (dibromochlo-
ropropane), have been shown to affect male fertility by direct testicular toxicity at
high levels of exposure.118'119 However, there is not strong evidence for a relation-
ship between organochlorine pesticides and semen quality. On the other hand, there is
significant evidence from epidemiology that non-persistent pesticides may alter semen
quality. This has been documented by the relationship between pesticide metabolites
measured in men and their semen quality. Among the compounds implicated, some
with stronger evidence than others, are alachlor mercapturate, atrazine mercapturate
and some metabolites of diazinon, chlorpyrifos and carbaryl.112'120'121'122'123'124'125'126'127'128
Male Urogenital Tract Malformations. There is limited evidence that exposure
to chemicals, including DDT, is associated with increased rates of cryptorchidism and
hypospadias. In some studies there appears to be a weak association between these
entities and maternal serum concentrations of these chemicals. There is also epidemio-
logical evidence suggesting a relationship between parental or community exposure
to pesticides and these malformations without clear evidence for which pesticides are
responsible.112
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Chronic Effects
Prostate Cancer and Prostatic Hyperplasia. It is well accepted that endocrine
status strongly affects the development of both prostate cancer and prostatic hyperplasia.
Both androgens and estrogen have been shown to promote cancer and hyperplasia of
the prostate. Likewise, antiandrogens and surgical castration can arrest or regress pros-
tate cancer. It seems reasonable then that endocrine-active pesticides would play a role
in recent increases in the rates of these problems. Epidemiologic studies have shown
increased rates of prostate cancer in farmworkers. A direct link has been shown between
methyl bromide exposure and prostate cancer in farmworkers.83'129 In addition, though
arsenical pesticides are in limited use today, arsenic has been associated with prostate
cancer.129 See the Cancer subsection of this chapter for additional information.
Antiandrogens. The active ingredients vinclozolin and DDT, along with DDE
(the primary metabolite of DDT), are known to be antiandrogens. The effect of DDE
and DDT on hypospadias and cryptorchidism is described above, but other antiandro-
genic effects of these agents in humans are unclear at this time.
Reproductive Neuroendocrine Systems. There is a considerable amount of
evidence in laboratory animals that pesticides may disrupt reproductive systems and
affect sexual behavior. As noted above, vinclozolin has been shown to alter sexual
behavior in rats. However, there are limited human data to support such effects in
children or adults.112
Thyroid Function. In the Agricultural Health Study, an association was shown
between pesticide exposure and thyroid disease in female spouses of farmworkers.
Increased odds ratios ranging from 1.2-1.5 for hypothyroidism were seen with
organochlorines including aldrin, DDT, heptachlor, lindane and chlordane, although
only chlordane (OR = 1.3) was statistically significant. Benomyl (3.1) and paraquat
(1.8) also had significantly elevated rates of hypothyroidism. Interestingly, maneb/
mancozeb appeared to be related to both hypothyroidism and hyperthyroidism.130 In a
study of Inuit adults, negative associations were observed between some organochlo-
rine pesticides and thyroid hormone levels.131
The science is rapidly advancing in this field, as most studies in human populations
have been published relatively recently. Endocrine disruption continues to be the subject
of intense research at a pace suggesting significant discovery in the coming decade.
ASTHMA
The role of pesticides in the development of and/or exacerbation of asthma has been
hypothesized and is under investigation. Pyrethrins have some potential as an allergic
sensitizing agent, with reports of contact dermatitis, asthma and anaphy lactic reactions
occurring following exposure.132'133'134 Organophosphates appear to have mechanisms
that could impact the development or exacerbation of asthma. Toxicological studies
demonstrated that subcutaneous injection of the Organophosphates chlorpyrifos.
diazinon and parathion caused airway hyper reactivity in guinea pigs via inhibition of
M2 muscarinic receptors.135'136 Additional studies suggest an organophosphate expo-
sure may induce lipid peroxidation, which will result in oxidative stress.137'138 Organo-
phosphates may also play a role in the immunological sensitization of individuals to
asthma. In a cohort of women farmworkers and their infants, maternal agricultural
work was associated with a 26% increase in proportion of T-helper 2 (TH-2) cells.
the phenotype associated with atopic disease, in their 24-month-old infants' blood
samples. The percentage of TH-2 cells was associated with both physician-diagnosed
asthma and maternal report of wheeze in these infants.139
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CHAPTER 21
Chronic Effects
Pesticides and Asthma in Adults
Some epidemiological evidence supports an association between occupational expo-
sure in adults and asthma. A case-control study conducted in Lebanon evaluated 407
subjects with asthma. Those with any exposure to pesticides exhibited an association
with asthma (OR = 2.11, 95% CI, 1.47-3.02). Occupational use resulted in an even
higher association (OR = 4.98, 95% CI, 1.07, 23.28), although as noted, the intervals
were wide, but significant.140
Several examinations of the Agricultural Health Study (AHS, discussed in
the previous subsection on cancer) evaluated the relationship of asthma to various
exposures occurring in farming occupations.141'142'143'144 In one of these AHS studies.
organophosphate insecticides including chlorpyrifos, malathion and parathion were
all positively associated with wheeze in farmers. Chlorpyrifos, dichlorvos and phorate
were associated with wheeze in the commercial applicators. Chlorpyrifos had the
strongest associations in both groups, with OR = 1.48, 95% CI, 1.00-2.19 for farmers
and OR = 1.96, 95% CI, 1.05-3.66 for commercial applicators.143 The same group of
authors identified in an earlier paper that driving diesel tractors was also associated
with wheezing (OR = 1.31, 95% CI, 1.13-1.52).145 In order to control for such expo-
sures unique to farmers, a second paper from the Agricultural Health Study cohort
limited analysis to 2,255 commercial pesticide applicators. The authors continued
to observe associations with organophosphates including chlorpyrifos (>40 days per
year; OR = 2.4, 95% CI, 1.24-4.65) and dichlorvos (OR = 2.48, 95% CI, 1.08-5.66).
The herbicide chlorimuron ethyl was also associated with asthma (OR = 1.62, 95%
CI, 1.25-2.1).144 A third analysis evaluated risk factors for women who lived and grew
up on a farm. In general, growing up on a farm was found to be protective for having
atopic or non-atopic asthma (defined as "doctor diagnosed, after 19 years of age").
However, any use of pesticides was associated with atopic asthma (OR = 1.46, 95%
CI, 1.14-1.87). Those women who grew up on a farm but did not apply pesticides
had the greatest protection from asthma (OR = 0.41, 95% CI, 0.27-0.62).141 As with
most epidemiological studies, there were some limitations of exposure assessment.
including self-reported behaviors and exposures and misclassification.
Other studies have not found an association between pesticide exposure and
asthma. One case-control study evaluated exposure of aerial pesticide applicators
and community controls. Self-reported asthma rates were similar in the two groups.
There was a slight decrease in lung function among aerial applicators, forced expira-
tory volume in 1 second (FEV1) <80% predicted (8% v. 2%, p = .02), but otherwise
there was no difference between cases and controls of other measures of asthma or
asthma severity.146 Two studies assessed emergency department visits for asthma and
hospital admissions following insecticide application to control for mosquitoes poten-
tially carrying West Nile virus (WNV) in New York City. One study evaluated visits at
a single hospital in the South Bronx after malathion and resmethrin application during
a 4-day period. Using the previous year as a reference point, there was no increase in
the rate of ED visits or in the severity of asthma presentations.147 Another study evalu-
ated the rates of ED visits in all public NYC hospitals during the 14-month period of
October 1999 to November 2000. The authors looked at asthma visits in a 3-day period
before and after spraying events took place, but did not find an increase in daily ED
visit rates that corresponded to pesticide spraying.148 A multicenter prospective study
in Europe did not find any association with asthma and exposure to the fungicide
ethylene bis dithiocarbamate.149
The role of
pesticides including
pyrethrins and
organ oph osph ates
with respect to
asthma is under
investigation.
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CHAPTER 21
Chronic Effects
Pesticide Exposure and Asthma in Children
The few epidemiologic studies on the association between pesticide exposure and
respiratory health in children have reported mixed results. In a cohort of rural lowan
children, multiple farm-related exposures were studied for any associations with
several asthma-related outcomes ranging from doctor-diagnosed asthma to cough with
exercise. Any pesticide use in the previous year was not significantly associated with
asthma symptoms and prevalence.150
A cross-sectional study of Lebanese children was conducted using a randomly
selected sample from public schools. The authors found increased risks of chronic
respiratory symptoms, including wheeze, among children with any pesticide exposure
in the home, exposure related to parent's occupation, and use outside the home. For
any exposure to pesticides, they found an association with asthma (OR = 1.73, 95%
CI, 1.07-2.90). Residential exposure, defined as having regional exposure or living
near a treated field, had a stronger association, OR = 2.47, 95% CI, 1.52-4.01. Finally,
occupational use of pesticides by a family member had the strongest association, OR
= 2.98, 95% CI, 1.58-5.56. In the researchers' multivariable model, parental exposure
persisted as a risk factor (OR = 4.61, 95% CI, 2.06-10.29). However, within the study
population of 3,291, 407 had chronic respiratory disease. Of those, only 84 had medi-
cally confirmed asthma.151 Main shortcomings include the cross-sectional design and
self-reported symptoms versus more objective outcome assessment.
A nested-case control study of the Southern California Children's Health Study
was conducted to evaluate the relationship between multiple environmental exposures.
early life experiences and the occurrence of asthma. Among environmental exposures
in the first year of life, "herbicides" and "pesticides" both had a strong association with
asthma diagnosis before age 5 years (OR = 4.58, 95% CI, 1.36-15.43 and OR = 2.39,
95% CI, 1.17-4.89, respectively). Of note, cockroach exposure in the first year and
later was also associated with having any type of asthma (OR= 2.03, 95% CI, 1.03-
4.02). There were also elevated ORs for cockroach exposure in the first year of life
with early persistent asthma and late onset asthma; however, the findings did not reach
statistical significance.152 This relationship is potentially important, since cockroaches
are known to exacerbate asthma, and pesticides are likely to be used in homes with
cockroach infestation.
Similar studies addressing the respiratory health implications for children for
specific pesticide chemical types or groups are rare. However, some evidence is
emerging for a link between metabolites of DDT and asthma risk.153'154 One study of
343 children in Germany found an association between DDE levels and asthma (OR=
3.71, 95% CI, 1.10-12.56) as well as DDE levels and IgE levels >200 kU/1 (OR = 2.28,
95% CI, 1.2-4.31).153 In a prospective cohort study of children in Spain, wheezing at
4 years of age increased with increasing levels of DDE at birth. The adjusted RR for
the children with exposure in the highest quartile was 2.63, 95% CI, 1.19-4.69. The
use of doctor-diagnosed asthma (occurring in 1.9% of children) instead of wheezing
as the outcome variable also resulted in a positive association, although it was not
statistically significant.154
In summary, the available data regarding chronic exposure to pesticides and
asthma and other respiratory health effects provide some suggestion of effect but are
limited in number with highly variant designs for exposure assessment and outcome
determination.
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Chronic Effects
SELECTED PESTICIDES AND THEIR CARCINOGENIC POTENTIAL
Name of Pesticide
Ace p hate
Alachlor
Arsenic
Benomyl
Bifenthrin
Butachlor
Captafol
Carbaryl
Chlordane
Chlordecone
Chlordimeform
Chloroaniline, p-
Chlorophenoxy
herbicides
Chlorothalonil
Cypermethrin
Dichlorvos
Diclofop-methyl
Diuron
Ethoprop
Fenoxycarb
Ferbam
Fipronil
Furiazole
Heptachlor
Hexachloroethane
Hexythiazox
Iprodione
Iprovalicarb
Mancozeb
Maneb
Metam sodium
Metofluthrin
Metolachlor
Mi rex
Nitrapyrin
Oryzalin
EPA Cancer
Classification*
Group C
Carcinogenic (High
Doses); Not Likely
Group C
Group C
Likely
Group B
Likely
Group B
Group B
2,4-D listed as
Group D
Group B
Group C
Suggestive
Likely
Likely
Likely
Likely
Likely
Group C
Likely
Likely
Likely
Likely
Group B
Group B
Likely
Likely
Group C
Likely
Likely
Notes
Not listed by EPA, all
pesticide uses canceled
Several are Group C (e.g.,
DCPA) or Not Likely (e.g.,
MCPA)
IARC
Classi-
fication**
1
2-A
3
2-B
2-B
3
2-B
2-B
2-B
3
2-B
2-B
3
2-B
229
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CHAPTER 21
Chronic Effects
SELECTED PESTICIDES AND THEIR CARCINOGENIC POTENTIAL, CONT.
Name of Pesticide
Oxyfluorfen
Parathion, ethyl-
Pentachlorophenol
Permethrin
Piperonyl butoxide
Pirimicarb
Propachlor
Propoxur
Resmethrin
Thiacloprid
Thiodicarb
Tolyfluanid
Toxaphene
Trifluralin
Triphenyltin
hydroxide
Vinclozolin
EPA Cancer
Classification*
Likely
Group C
Group B
Likely
Group C
Likely
Likely
Group B
Likely
Likely
Group B
Likely
Group C
Group B
Group C
Notes
Methyl parathion is "Not
Likely"
The most commonly used
neonicotinod, imidacloprid,
is Group E
IARC
Classi-
fication**
3
2-B
3
3
2-B
3
' The most recent EPA classification, whether from the 1986 or the 2005 system
1986 Classification
Group B: Probable human carcinogen
Group C: Possible human carcinogen
Group D: Not classifiable as to human carcinogenicity
Group E: Evidence of non-carcinogenicity for humans
2005 Classification
Carcinogenic: Carcinogenic to humans
Likely: Likely to be carcinogenic to humans
Suggestive: Suggestive evidence of carcinogenic potential
Inadequate: Inadequate information to assess carcinogenic potential
Not Likely: Not likely to be carcinogenic to humans
'*IARC Classification
Group 1: Carcinogenic to humans
Group 2A: Probably carcinogenic to humans
Group 2B: Possibly carcinogenic to humans
Group 3: Not classifiable as to its carcinogenicity to humans
Group 4: Probably not carcinogenic to humans
230
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CHAPTER 21
Chronic Effects
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238
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Section VI
APPENDIXES
Appendix A
Detailed Interview for Occupational and Environmental Exposures 240
Appendix B
Key Competencies for Clinicians 242
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APPENDIX A
Detailed Occupational and Environmental Exposure History Questions
(Items marked in bold type are especially important for a pesticide exposure history)
ADULT PATIENT
OCCUPATIONAL EXPOSURE
What is your occupation? (If unemployed, discuss recent employment as appropriate or go to next section)
How long have you been doing this job?
Describe your work and the hazards to which you are exposed, (e.g., pesticides, solvents or other chemicals, dust,
fumes, metals, fibers, radiation, biologic agents, noise, heat, cold, vibration)
Under what circumstances do you use protective equipment? (e.g., work clothes, safety glasses, respirator,
gloves, and hearing protection)
Do you smoke or eat at the worksite?
List previous jobs in chronological order, include full and part-time, temporary, second jobs, summer jobs and
military experience. (Because this question can take a long time to answer, one option is to ask the patient to fill out a
form with this question on it prior to the formal history taking by the clinician. Another option is to take a shorter history by
asking the patient to list only the prior jobs that involved the agents of interest. For example, one could ask for all current
and past jobs involving pesticide exposure.)
ENVIRONMENTAL EXPOSURE HISTORY
Are pesticides (e.g., bug or weed killers, flea and tick sprays, collars, powders or shampoos) used in your home
or garden or on your pet?
If pesticides are used:
Who applies the pesticides?
Is a licensed pesticide applicator involved?
Where are the pesticides stored?
Do you or any household members have a hobby with exposure to any hazardous materials (e.g., pesticides,
paints, ceramics, solvents, metals, glues)?
Is food handled properly (e.g., washing of raw fruits and vegetables)?
Do you live within 1/4 mile of an agricultural area (e.g., field, orchard, greenhouse) where plants, vegetables or
fruits are grown?
Did you ever live near a facility which could have contaminated the surrounding area (e.g., mine, plant, smelter,
dump site)?
Have you ever changed your residence because of a health problem?
Does your drinking water come from a private well, city water supply and/or grocery store?
Do you work on your car?
Which of the following do you have in your home: air conditioner/purifier, central heating (gas or oil), gas stove, electric
stove, fireplace, wood stove or humidifier?
Have you recently acquired new furniture or carpet, or remodeled your home?
Have you weatherized your home recently?
Approximately what year was your home built?
SYMPTOMS AND MEDICAL CONDITIONS
Does the timing of your symptoms have any relationship to your work hours? (If unemployed, skip to 3rd bullet)
Has anyone else at work suffered the same or similar problems?
Does the timing of your symptoms have any relationship to environmental activities listed above?
Has any other household member or nearby neighbor suffered similar health problems?
NON-OCCUPATIONAL EXPOSURES POTENTIALLY RELATED TO ILLNESS OR INJURY
Do you use tobacco? If yes, in what forms (cigarettes, pipe, cigar, chewing tobacco)? About how many do you smoke or how
much tobacco do you use per day? At what age did you start using tobacco? Are there other tobacco smokers in the home?
240
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APPENDIX A
NON-OCCUPATIONAL ADULT EXPOSURES, CONT.
Do you drink alcohol? How much per day or week? At what age did you start?
What medications or drugs are you taking? (Include prescription and non-prescription uses)
Has anyone in the family worked with hazardous materials that they might have brought home (e.g., pesticides,
asbestos, lead)? (If yes, inquire about household members potentially exposed.)
PEDIATRIC PATIENT
(questions asked of parent or guardian)
ENVIRONMENTAL EXPOSURE HISTORY (PESTICIDE-RELATED QUESTIONS)
Are pesticides (e.g., insect or weed killers, flea and tick sprays, collars, powders, or shampoos) used in your
home or garden or on your pet?
Where (e.g., out of reach of children) are pesticides stored? What types of containers are pesticides stored in?
Do you or any household member have a hobby with exposure to any hazardous materials (e.g., pesticides,
paints, ceramics, solvents, metals, glues)?
If pesticides are used:
Who applies the pesticides?
Do you use a licensed pesticide applicator for treatments?
How long do you wait before letting children play on areas recently treated with pesticides?
Where are the pesticides stored?
Is food handled properly (e.g., washing of raw fruits and vegetables)?
Do you live within 1/4 mile of an agricultural area (e.g., field, orchard, greenhouse) where plants, vegetables or
fruits are grown?
OCCUPATIONAL EXPOSURE
What is your occupation and that of other household members? (If no employed individuals, go to next section)
Describe your work and the hazards to which you are exposed, (e.g., pesticides, solvents or other chemicals, dust,
fumes, metals, fibers, radiation, biologic agents, noise, heat, cold, vibration)
ADDITIONAL ENVIRONMENTAL EXPOSURE QUESTIONS
Has the child ever lived near a facility that could have contaminated the surrounding area (e.g., mine, plant,
smelter, dump site)?
Has the child ever changed residence because of a health problem?
Does the child's drinking water come from a private well, city water supply and/or grocery store?
Which of the following are in the child's home: air conditioner/purifier, central heating (gas or oil), gas stove, electric
stove, fireplace, wood stove or humidifier?
Is there recently acquired new furniture or carpet, or recent home remodeling in the patient's home?
Has the home been weatherized recently?
Approximately what year was the home built?
SYMPTOMS AND MEDICAL CONDITIONS
Does the timing of symptoms have any relationship to environmental activities listed above?
Has any other household member or nearby neighbor suffered similar health problems?
NON-OCCUPATIONAL EXPOSURES POTENTIALLY RELATED TO ILLNESS OR INJURY
Are there any tobacco users in the home? If yes, in what forms (cigarettes, pipe, cigar, chewing tobacco)?
What medications or drugs is the child taking? (Include prescription and non-prescription uses)
Has anyone in the family worked with hazardous materials that they might have brought home (e.g., pesticides,
asbestos, lead)? (If yes, inquire about household members potentially exposed.)
241
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APPENDIX B
Key Competencies for Clinicians
from National Strategies for Healthcare Providers: Pesticides Initiative
EPA, in partnership with several federal agencies and organizations, leads the National Strategies for Health Care
Providers: Pesticides Initiative. Established in 1998, the Initiative goal is to improve the recognition, diagnosis, treatment,
and prevention of pesticide-related illnesses. As a framework to achieve this goal, the Initiative developed a set of practical
skills to guide students, nurses and practicing clinicians in recognizing and managing pesticide-related illnesses. These
skills and competencies can be integrated into existing education and training of healthcare providers to facilitate the
effective management of patients with suspected pesticide-related illnesses.1
NATIONAL PESTICIDE PRACTICE SKILLS GUIDELINES
FOR MEDICAL AND NURSING PRACTICE2
PRACTICE SKILL I: TAKING AN ENVIRONMENTAL HISTORY
Understand the purposes and general principles for taking an occupational and environmental history.
Incorporate general occupational and environmental screening questions into routine patient histories.
Be able to take a complete occupational and environmental exposure/health history for adults and children.
PRACTICE SKILL II: AWARENESS OF COMMUNITY AND INDIVIDUAL PESTICIDE RISK FACTORS
Possess basic awareness of occupational and environmental aspects of communities in which patients live.
Recognize high-risk occupations for pesticide exposure.
Develop community resource list.
PRACTICE SKILL III: KNOWLEDGE OF KEY HEALTH PRINCIPLES
Demonstrate key principles of environmental/occupational health, epidemiology, and population-based health.
Understand the dose-response relationship.
Understand measures of morbidity/mortality and study designs.
PRACTICE SKILL IV: CLINICAL MANAGEMENT OF PESTICIDE EXPOSURE
Know different groups of pesticides, their mechanism of toxicity (pathophysiology) and adverse health effects.
Recognize the signs and symptoms of pesticide exposures (both acute and chronic).
Diagnose pesticide-related illness using appropriate testing procedures and treat pesticide over-exposures.
Treat and manage health conditions associated with pesticide exposure (know anticholinergic agents and dosages,
antidote for organophosphates, treatment of seizures) or refer patients to appropriate specialists and resources, and
follow up appropriately.
PRACTICE SKILL V: REPORTING PESTICIDE EXPOSURE AND SUPPORTING SURVEILLANCE EFFORTS
Understand the importance of surveillance and reporting.
Know the roles of federal and state regulatory agencies with regard to pesticide exposure control.
Report pesticide exposures as required.
PRACTICE SKILL VI: PROVIDING PREVENTION GUIDANCE AND EDUCATION TO PATIENTS
Engage in primary prevention strategies to promote health and prevent disease among patients.
Work proactively with patients and the community to prevent exposure, ensure early detection, and limit effects of
illness.
1Formore information visit EPA's Web page on the National Strategies for Health Care Providers: Pesticide Initiative at:
http://www.epa.gov/oppfead1/safety/healthcare/healthcare.htm
2Derived from http://www.epa.gov/oppfead1/safety/healthcare/practiceskifinal.pdf
242
-------
Section VII
INDEXES
Index of Signs and Symptoms of Acute Poisoning 244
Index of Pesticide Products 257
-------
Index of Signs and Symptoms
of Acute Poisoning
Common symptoms
were not included:
malaise
fatigue
dizziness
nausea
vomiting
This index provides a table of pesticides and their related symptoms and signs and
affected organ systems in poisoned individuals. This may be useful in raising the index
of suspicion for pesticide toxicity where these signs and symptoms occur. Such suspi-
cion can be evaluated further within the differential diagnosis as appropriate.
It is important to keep in mind that the signs and symptoms listed have multiple
causes, pesticidal and nonpesticidal. In addition, no specific symptoms or signs are
invariably present in poisonings by particular pesticides. Toxicological presentation
may vary based on dosage, route(s) of exposure, life stage of the patient, and patient's
genetic vulnerability, co-exposures and/or underlying health status. This complexity
may explain why many poisonings are characterized by unexpected or atypical mani-
festations.
It is important to keep in mind that the signs and symptoms
listed have multiple causes, pesticidal and nonpesticidal.
The table does not differentiate clinical presentation by route of exposure or
dosage. For example, effects of high-dose ingestion are not distinguished from effects
of relatively low-dose dermal absorption, nor are topical effects distinguished from
systemic dermal manifestations. Such details are addressed more fully in the chapters
addressing the specific pesticides, which make up the bulk of this manual. The list of
pesticides in this chapter is intended to serve as a clue for the clinician toward further
inquiry.
The word "poisoning" is used loosely in these headings to include topical as
well as systemic effects that are acute manifestations rather than delayed sequelae
or chronic conditions, although in some cases acute effects may persist. For chronic
health conditions including long-term sequelae after acute poisoning and chronic
conditions associated with lower level, repeat exposures, see Chapter 21, Chronic
Effects.
Pesticides that are relatively consistent in causing particular manifestations are
listed in the column headed "Characteristic of These Poisonings." Agents that are
associated with conditions less consistently or are less prominent features of poisoning
are listed in the right-hand column, headed "May Occur in These Poisonings." Obvi-
ously, the distinction is not always clear cut.
Some symptoms (malaise, fatigue, dizziness, nausea and vomiting) occur so
commonly in poisoned individuals that they have little or no value in differential diag-
nosis, and are therefore not included in these tables.
244
-------
INDEX
Signs and Symptoms
o
0
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Q.
C
O
Z
1: General
SYSTEM
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Rotten egg odor
Hypothermia
Hyperthermia
(fever, pyrexia)
Chills
Hot sensations
Myalgia
Thirst
Anorexia
Alcohol intolerance
Sweet taste in the mouth
Metallic taste in the mouth
Salty, soapy taste
In the mouth
CHARACTERISTIC OF
THESE POISONINGS
Sulfur
Creosote
Nitrophenols
Pentachlorophenol
Phosphine
Arsine
Nitrophenols
Chlordimeform
Paraquat
Chlorophenoxy
compounds
Pentachlorophenol
Nitrophenols
Inorganic arsenicals
Phosphorus
Phosphides
Sodium Fluoride
Cholecalciferol
Aminopyridine
Organophosphates
N-methyl carbamates
Nicotine
Pentachlorophenol
Hexachlorobenzene
Chlordimeform
Cholecalciferol
Thiram
Calcium cyanamide
Chlordimeform
Inorganic arsenicals
Organic mercury
Sodium fluoride
MAY OCCUR IN
THESE POISONINGS
Bo rate
Thallium
Metaldehyde
Inorganic arsenicals
Chlorophenoxy
compounds
Cadmium dusts
Naphthalene
Pentachlorophenol
Bo rate
Endothall
Halocarbon fumigants
Nitrophenols
Inorganic arsenicals
Amino pyridine
General and
Non-Specific
245
-------
INDEX
Signs and Symptoms
Skin
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^
2
lil
1-
(/}
(/}
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Irritation, rash,
blistering, or
erosion (without
sensitization)
Contact dermatitis
Flushing
Beefy red palms, soles
Urticaria
Bullae
Pallor
CHARACTERISTIC OF
THESE POISONINGS
Copper, organotin, and
cadmium compounds
Metam sodium
Paraquat
Diquat
Sodium chlorate
Phosphorus
Sulfur
Thiram
Chlordimeform
Cationic detergents
Hexachlorophene
Ethylene oxide
Formaldehyde
Acrolein
Methyl bromide
Ethylene dibromide
Dibromochlorpropane
Dichloropropane
Endothall
Aliphatic acids
PCP
Paraquat
DEET
Chlorhexidine
Creosote
Hexachlorophene
Pyrethrins/pyrethroids
Chlorothalonil
Thiram
Thiophthalimides
Propachlor
Propargite
Ethylene oxide
Cyanamide
Nitrophenol
Bo rate
Chlorhexidine
PCP
DEET
Liquid fumigants
Organochlorines
Fumigants
Sodium fluoride
Creosote
MAY OCCUR IN
THESE POISONINGS
Pentachlorophenol
Picloram
Chlorophenoxy
Captan
Rotenone
Diethyltoluamide (DEET)
Creosote
Fungicides
Herbicides with irritant
properties
Petroleum distillate
Barban
Captafol
Formaldehyde
Thiram plus alcohol
Fluoride
Pentachlorophenol
Hexachlorobenzene
Coumarins
Indandiones
246
-------
INDEX
Signs and Symptoms
.
c
o
0
d
i*
(/)
lil
(/)
>
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Cyanosis
Yellow stain
Keratoses, brown
discoloration
Ecchymoses
Jaundice
Excessive hair growth
Loss of hair
Loss of fingernails
Brittle nails, white striations
Sweating, diaphoresis
CHARACTERISTIC OF
THESE POISONINGS
Sodium chlorate
Paraquat
Cadmium dusts
Sodium fluoroacetate
Strychnine
Crimidine
Nicotine
Organochlorines
Nitrophenols
Inorganic arsenicals
Coumarins
Indandiones
Carbon tetrachloride
Chloroform
Phosphorus
Phosphides
Phosphine
Paraquat
Sodium chlorate
Thallium
Inorganic arsenicals
Organophosphates
N-methyl carbamates
Nicotine
Pentachlorophenol
Naphthalene
Aminopyridine
MAY OCCUR IN
THESE POISONINGS
Organophosphates
N-methyl carbamates
Phosphorus
Phosphides
Inorganic arsenicals
Diquat
Copper compounds
Hexachlorobenzene
Inorganic arsenicals
Paraquat
Inorganic arsenicals
Thallium
Copper compounds
Skin
247
-------
INDEX
Signs and Symptoms
Eye
0)
UJ
lil
>
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Conjunctivitis
(irritation of mucous
membranes, tearing)
Lacrimation (muscarinic)
Yellow sclerae
Keratitis
Ptosis
Diplopia
Photophobia
Constricted visual fields
Optic atrophy
Miosis
Dilated pupils
Non-reactive pupils
CHARACTERISTIC OF
THESE POISONINGS
Chloropicrin
Acrolein
Copper compounds
Organotin compounds
Cadmium compounds
Metam sodium
Paraquat
Diquat
Acrolein
Chloropicrin
Sulfur dioxide
Naphthalene
Formaldehyde
Ethylene oxide
Methyl bromide
Endothall
Toluene
Xylene
Fipronil
Organophosphates
N-methyl carbamates
Nitrophenols
Paraquat
Thallium
Organophosphates
N-methyl carbamates
Nicotine
Organic mercury
Organophosphates
N-methyl carbamates
Cyanide
Fluoride
Cyanide
MAY OCCUR IN
THESE POISONINGS
Thiophthalimides
Thiram
Thiocarbamates
Pentachlorophenol
Chlorophenoxy
compounds
Chlorothalonil
Picloram
Creosote
Aliphatic acids
Strobilurin fungicides
Pyrethrins
Agents that cause jaundice
(see section on Skin)
Organotin compounds
Thallium
Nicotine (early)
Nicotine (late)
248
-------
INDEX
Signs and Symptoms
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to
(/)
slervous
^^m
HI
1-
>
(O
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Paresthesia
Headache
Behavioral - mood
disturbances
(confusion, excitement,
mania, disorientation,
emotional lability)
CHARACTERISTIC OF
THESE POISONINGS
Pyrethroids
Organochlorines
Inorganic arsenicals
Organic mercury
Carbon disulfide
Pyriminil
Organophosphates
N-methyl carbamates
Nicotine
Inorganic arsenicals
Organic mercury
Cadmium compounds
Organotin compounds
Copper compounds
Thallium
Fluoride
Borates
Naphthalene
Phosphine
Halocarbon fumigants
Creosote
Diquat
Cholecalciferol
Cyanamide
Neonicotinoids
Fipronil
Organic mercury
Inorganic arsenicals
Organotin compounds
Thallium
Nicotine
Sodium fluoroacetate
Diquat
Cyanide
Nitrophenols
Aminopyridine
Carbon disulfide
Methyl bromide
Fipronil
MAY OCCUR IN
THESE POISONINGS
Organophosphates
Thiabendazole Phosphides
Sodium fluoroacetate
Thallium
Organochlorines
Nitrophenols
Thiram
Pentachlorophenol
Paraquat
DEET
Organophosphates
N-methyl carbamates
Pentachlorophenol
Sodium fluoride
DEET
Organochlorines
Neonicotinoids
Nervous
System
249
-------
INDEX
Signs and Symptoms
Nervous
System
c
o
o
0)
t/T
(/)
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Depression, stupor, coma
Seizures/convulsions
(clonic-tonic) sometimes
leading to coma
Muscle twitching/
fasciculation
Myotonia
Tetany, carpopedal spasms
CHARACTERISTIC OF
THESE POISONINGS
Organophosphates
N-methyl carbamates
(particularly in children)
Sodium fluoride
Bo rate
Diquat
Fipronil
Avermectins
Organochlorines
Strychnine
Crimidine
Sodium fluoroacetate
Nicotine
Cyanide
Acrylonitrile
Metaldehyde
Thallium
DEET
Chlorobenzilate
Carbon disulfide
Phosphine
Povidone-iodine
Hexachlorophene
Sodium chlorate
Creosote
Endothall
Fluoride
Organophosphates
N-methyl carbamates
Nicotine
Sulfuryl fluoride
Pyrethroids
Fluoride
Phosphides
Phosphorus
MAY OCCUR IN
THESE POISONINGS
Inorganic arsenicals
Metaldehyde
Sulfuryl fluoride
Halocarbon fumigants
Phosphorus
Phosphine
Paraquat
Chlorophenoxy
compounds
DEET
Alkyl phthalates
Nitrophenols
Pentachlorophenol
Inorganic arsenicals
Organotin compounds
Diquat
Bo rate
Sulfuryl fluoride
Methyl bromide
Chlorophenoxy
compounds
Organophosphates
N-methyl carbamates
Aminopyridine
Fipronil
Organic mercury
Chlorophenoxy
compounds
Chlorophenoxy
compounds
250
-------
INDEX
Signs and Symptoms
.
c
o
o
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"Jo
ervous Sy
z
g
uj
i-
w
>
(/)
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Tremor
Incoordination
(including ataxia)
Paralysis
Paresis, muscle weakness
Hearing loss
CHARACTERISTIC OF
THESE POISONINGS
Organic mercury
Thallium
Organophosphates
N-methyl carbamates
Nicotine
Metaldehyde
Borates
Neonicotinoids
Pyrethroids
Halocarbon fumigants
Organophosphates
N-methyl carbamates
Carbon disulfide
Nicotine
Thallium
Inorganic arsenicals
Organophosphates
N-methyl carbamates
Nicotine
Neonicotinoids
Organic mercury
MAY OCCUR IN
THESE POISONINGS
Pentachlorophenol
Nitrophenols
Thiram
Organic mercury
Organochlorines
Chlorobenzilate
Organic mercury
DEET
,_
3
O
Cardiovas
^
uj
i-
>
w
Hypotension and shock
Hypertension
Cardiac arrhythmias
Phosphorus
Phosphides
Phosphine
Sodium fluoride
Sodium chlorate
Bo rate
Thallium
Copper compounds
Endothall
Cyanamide
Thallium (early)
Nicotine (early)
Sodium fluoroacetate
Halocarbon fumigants
Nicotine
Sodium fluoride
Ethylene oxide
Sodium chlorate
Thallium-ventricular
Povidone-iodine
Veratrum alkaloid
(sabadilla)
Neonicotinoids
Inorganic arsenicals
Nicotine (late)
Creosote
Alkyl phthalate
Cycloheximide
Formaldehyde
Organophosphates
Inorganic arsenicals
Phosphorus
Phosphides
Phosphine
Organochlorines
Cyanide
Acrylonitrile
Fluoride
Nervous
System
Cardiovascular
System
251
-------
INDEX
Signs and Symptoms
Cardiovascular
System
SYSTEM: Cardio, cont.
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Bradycardia (sometimes to
asystole)
Tachycardia
CHARACTERISTIC OF
THESE POISONINGS
Cyanide
Organophosphates
N-methyl carbamates
Nitrophenols
Cyanamide
Nicotine (early)
Neonicotinoids
MAY OCCUR IN
THESE POISONINGS
Nicotine (late)
Metaldehyde
Organophosphates (early,
before bradycardia)
Pentachlorophenol
Respiratory
System
^»
5
2
Q.
0)
QL
HI
1-
>
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Upper respiratory tract
irritation, rhinitis, scratchy
throat, cough
Sneezing
Runny nose
Pulmonary edema
(many chemicals come
packaged in a hydrocarbon
vehicle, well known to
cause pulmonary edema)
CHARACTERISTIC OF
THESE POISONINGS
Naphthalene
Paraquat
Chloropicrin
Acrolein
Dichloropropene
Ethylene dibromide
Sulfur dioxide
Sulfuryl fluoride
Acrylonitrile
Formaldehyde
Cadmium dusts
Pyrethroids
Strobilurin fungicides
Sabadilla
Pyrethrins/ pyrethroids
Inorganic arsenicals
Organophosphates
N-methyl carbamates
Methyl bromide
Phosphine
Phosphorus
Phosphine
Ethylene oxide
Ethylene dibromide
Acrolein
Pyrethroids
Sulfur dioxide
Cationic detergents
Creosote
Methylisothiocyanate
Cadmium
MAY OCCUR IN
THESE POISONINGS
Dry formulation of copper,
tin, zinc compounds
Dusts of thiocarbamate
and other organic
pesticides
Chlorophenoxy
compounds
Aliphatic acids
Rotenone
Dry formulation of copper,
tin, zinc compounds
Dusts of thiocarbamate
and other organic
pesticides
Chlorophenoxy
compounds
Aliphatic acids
Rotenone
Organophosphates
N-methyl carbamates
Paraquat
Phosphides
252
-------
INDEX
Signs and Symptoms
c
o
o
o
'5.
0)
..
uj
i
C/J
C/J
Pulmonary consolidation
Dyspnea
Paraquat
Cadmium dusts
Methyl bromide
Organophosphates
N-methyl carbamates
Nicotine
Paraquat
Cadmium dusts
Cyanamide
Sulfuryl fluoride
Pentachlorophenol
Methyl bromide
Sulfur dioxide
Chloropicrin
Neonicotinoids
Diquat
Nitrophenols
Cyanide
Creosote
Pyrethrins
Pyrethroids
Respiratory
System
0)
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5
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w
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Diarrhea (non-bloody)
Diarrhea (bloody)
Stomatitis
Salivation
CHARACTERISTIC OF
THESE POISONINGS
Organophosphates
N-methyl carbamates
Pyrethroids
Borates
Sulfur
Nicotine
B. thuringiensis
Thiram
Cadmium
Avermectins
Fluoride
Paraquat
Diquat
Thallium
Coumarins
Indandiones
Endothall
Arsenicals
Inorganic arsenicals
Paraquat
Diquat
Copper compounds
Organophosphates
N-methyl carbamates
Pyrethroids
Nicotine
Aminopyridine
Sodium fluoride
Cyanide
Cadmium compounds
MAY OCCUR IN
THESE POISONINGS
Cationic detergents
Cresol
Hexachlorophene
Chlorophenoxy
Phosphorus
Phosphides
Cycloheximide
Thallium
Gastrointestinal
Tract and Liver
253
-------
Signs and Symptoms
Gastrointestinal
Tract and Liver
^J
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re
4->
O
5
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LJJ
1-
>
Abdominal pain
Ileus
Constipation
Organophosphates
N-methyl carbamates
Paraquat
Diquat
Nicotine
Metaldehyde
Fluoride
Bo rate
Phosphorous
Phosphides
Inorganic arsenicals
Cadmium compounds
Copper compounds
Thallium
Organotin compounds
Neonicotinoids
Thallium
Diquat
Pyriminil
Chlorophenoxy
compounds
Aliphatic acids
Sodium chlorate
Creosote
Endothall
Aminopyridine
Coumarins
Indandiones
Fumigants (ingested)
Cycloheximide
Pyriminil
Liver
SYSTEM: Liver
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Enlargement
Jaundice
(see section on Skin)
CHARACTERISTIC OF
THESE POISONINGS
Copper compounds
Sodium chlorate
Phosphine
Carbon tetrachloride
Chloroform
MAY OCCUR IN
THESE POISONINGS
Inorganic arsenicals
Hexachlorobenzene
Kidney
0)
c
;g
LJJ
I-
>
(/)
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Proteinuria/hematuria
and acute renal failure
CHARACTERISTIC OF
THESE POISONINGS
Inorganic arsenicals
Copper compounds
Sodium fluoride
Naphthalene
Bo rate
Nitrophenols
Pentachlorophenol
Sodium chlorate
Sulfuryl fluoride
Paraquat
Diquat
Arsine
Ethylene dibromide
MAY OCCUR IN
THESE POISONINGS
Cadmium compounds
Phosphorus
Phosphides
Phosphine
Chlorophenoxy
compounds
Creosote
Organotin compounds
254
-------
INDEX
Signs and Symptoms
SYSTEM: Kidney
Rhabdomyolysis
Dysuria, hematuria, pyuria
Polyuria
Hemoglobinuria
Wine-red urine
(porphyrinuria)
Smoky urine
Glycosuria
Ketonuria
Neonicotinoids
Avermectins
Chlordimeform
Cholecalciferol
Naphthalene
Sodium chlorate
Arsine
Hexachlorobenzene
Creosote
Endothall
Fluoride
Organotin compounds
Bo rate
Kidney
SYSTEM: Blood
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Hemolysis
Methemoglobinemia
Hypoprothrombinemia
Hyperkalemia
Hypocalcemia
Hypercalcemia
Carboxyhemoglobinemia
Anemia
Leukopenia,
Thrombocytopenia
CHARACTERISTIC OF
THESE POISONINGS
Naphthalene
Sodium chlorate
Arsine
Sodium chlorate
Creosote
Propanil
Metobromuron
Coumarins
Indandiones
Sodium chlorate
Naphthalene
Arsine
Fluoride
Cholecalciferol
Naphthalene
Sodium chlorate
Arsine
Inorganic arsenicals
Inorganic arsenicals
MAY OCCUR IN
THESE POISONINGS
Copper compounds
Cresol
Chlordimeform
Cyanide
Cresol
Copper
Arsine
Diflubenzuron
Nitrophenol
Metolachlor
Phosphorus
Phosphides
Carbon tetrachloride
Sodium fluoride
Thallium
Phosphorus
Phosphides
Organotin compounds
Blood
255
-------
INDEX
Signs and Symptoms
Blood
c
o
o
o
o
CO
§
lil
1-
>
Elevated LDH
GOT, GPT,
alkaline phosphatase,
ALT, AST enzymes
Depressed RBC
acetylcholinesterase
and plasma
pseudocholinesterase
Carbon tetrachloride
Chloroform
Phosphine
Organophosphates
Inorganic arsenicals
Phosphorus
Phosphides
Sodium chlorate
Nitrophenols
Pentachlorophenol
Thallium
Organochlorines
Chlorophenoxy
compounds
N-methyl carbamates
Reproductive
System
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O
3
T3
2
Q.
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01
lil
1-
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(/}
SYMPTOMS/
SIGNS/DISEASE
CATEGORIES
Low sperm count
CHARACTERISTIC OF
THESE POISONINGS
Dibromochloropropane
MAY OCCUR IN
THESE POISONINGS
Kepone
256
-------
Index of Pesticide Products
Symbols
l-2-dichloroethane 162
1,2-dichloropropane 162
1,3-dichloropropene 162
2,3,6-TBA 121
2,3,7,8-tetra CDD 98
2,4-D 98, 99, 101, 218, 222
2,4-DB 98,99
2,4-dichlorophenoxyacetic acid 98, 99
2,4-dichlorophenoxybutyric acid 98, 99
2,4-dichlorophenoxypropionic acid... 98, 99
2,4-DP 98,99
2,4,5-T 98,99
2,4,5-trichlorophenoxy acid 99
2-benzyl-4-chlorophenol 205
2-methyl-3, 6 dichlorobenzoic acid 99
SDinitrophenol 106
4-aminopyridine 188
4-chloro-2-methylphenoxyacetic acid 99
4-chloroaniline 87
4-tert-amylphenol 205
AASTAR 45
Aaterra 156
Aatrex 123
Abamectin 70
Abate 47
Abathion 47
Abol 57
Abound 145
Absolute 145
acephate 45, 229
acetamides 120
acetamiprid 91
acetate 152
Accelerate 191
Accotab 122
Accothion 46
acid copper arsenite 136
Acrex 106
Acricid 107
acrolein 162, 163
acrylaldehyde 163
acrylonitrile 162, 165, 166, 169
Actellic.... ....47
Admire 91
Advantage 91
Afalon 124
Aficida 57
Afugan 47
Agritox 44
Agrosan 152
Agrothion 46
alachlor 120,229
alachlor mercapturate 225
Alanox 120
alcohols 196,200-201
aldicarb 57
aldehydes 201
aldrin 63,64,223,226
Allegro 145
allethrin 41
Allisan 144
Alon 124
aluminum phosphide 161
Amaze 45
Ambox 107
Ambush 42
Amerol 123
Ametrex 123
ametryn 122
Amex 122
aminocarb 57
4-aminopyridine 188
aminotriazole 123
Amiral 150
Amistar 145
amitrole 123
Ammo 41
anisic acid derivatives 121
anilazine 156
anilides 118,120
Ansarl70 138
AnsarSlOO 138
Anthio 46
Anticarie 144
anticoagulants 7,173-176
Antimilace 192
Apachlor 44
Apex 47
Aphox 57
Apl-Luster 156
257
-------
INDEX
Pesticide Products
Aprocarb 57
Aquacide 39
Aquathol 191
Arbotect 156
Arelon 124
Aresin 124
Aretit 106
Armada 145
Arrhenal 138
Arsenal 122
arsenates 135, 137
arsenic 135-139,212,214,
223, 224, 226, 229
arsenic acid 137
arsenic trioxide 135, 136
arsenicals 135-139,226
arsenites 135, 136
arsenobetaine 137
arsenous oxide 136
arsinegas 135, 136, 140-141
Arsinyl 138
Arsonate Liquid 138
arsonates 135, 138
Aspon 47
Aspor 148
asulam 121
Asulox 121
Asuntol 44
Atranex 123
atrazine 123, 225
atrazine mercapturate 225
Aules 146
avermectin 70
Avicol 144
Avitrol 188
Azac 121
Azar 121
azinphos-methyl 44
azadirachtin 71
Azodrin 45
Azolan 123
Azole 123
Azo-shield 145
Azotech 145
Azoxy 145
azoxystrobin 145
B
Bacillus thuringiensis 70, 71-72
Balan 122
Baffin 122
Banner Heritage 145
Banvel 121
barthrin 41
Barricade 41
Barrier 121
Bas 145
Basagran 121
Basalin 122
Basanite 106
Bash 44
Batasan 154
Baygon 57
Bayleton 150
Bayrusil 47
Baytex 46
Baythion 47
Baythion-C 45
Baythroid 41
Belmark 41
bendiocarb 57
Benefin 122
Benex 156
benfluralin 122
Benlate 156
benomyl 156, 226, 229
bensulide 45
benzalkonium chloride 201-202
bentazone 121
benzamide 120
Benzeneacetic acid 145
Benzofuroline 42
benzoic acid derivatives 121
benzonitriles 121
benzothiadiazinone dioxide 121
2-benzyl-4-chlorophenol 205
benzyl benzoate 80
Betadine 204
Betasan 45
Bexton 120
BHC 64
Bidrin 44
Bilevon 205
bifenthrin 229
binapacryl 107
258
-------
INDEX
Pesticide Products
bioallethrin 41
Biodehido Snailkill 192
bioresmethrin 41
biopermethrin 41
Birlane 44
Black Flag 39
Black Leaf 40 73
Bladafum 45
Bladvel 193
Bo-Ana 44
Bolate 138
Bolero 121
Bolls-Eye 138
Bolstar 47
bomyl 44
Bonfire 112
Bophy 138
borates 7,80-82
boric acid 7, 80-82
Bravo 144
Brestan 154
Brodan 45
brodifacoum 173, 174, 175
bromacil 123
bromethalin 182-183
bromodiolone 173, 175
bromophos 45
bromophos-ethyl 45
Broot 57
Bueno6 138
bufencarb 57
butachlor 229
butralin 122
butylate 121,223
Bux... ...57
Cabrio 145
cacodylic acid 138
Caddy 155
Cadminate 155
cadmium chloride 154, 155
cadmium compounds 154-156
cadmium oxide 154, 155
cadmium salts 155
cadmium sebacate 154, 155
cadmium succinate 154, 155
cadmium sulfate 154, 155
Cad-Trete 154, 155
Calar 138
calcium acid methane arsonate 138
calcium arsenate 137
calcium arsenite 136
calcium cyanamide 189
calcium hypochlorite 203
calcium oxide 154, 155
Caldon 106
Caliber 90 123
CAMA 138
Caparol 123
captan 149
Captaf 149
captafol 149,229
Captanex 149
CarbamateWDG 146
carbamates 45, 56-60, 64, 121
Carbamult 57
carbaryl 57, 225, 229
carbophenothion 44
carbofuran 57,223
carbon disulfide 161, 162, 164, 166, 168
carbon tetrachloride 161, 162, 168
Carpene 156
Carzol 57
Casoron 121
Castrix 180
cationic detergents 201-202
CCN52 41
CDD 98,103
CDF 98,103
cedar oil 128
Cekiuron 124
CekuC.B 144
Cekumeta 192
Celathion 44
Ceresan 152
cetrimide 201-202
cetylpyridium chloride 201-202
Chemisco 39, 112
ChemBam 148
Chemox General 106
ChemoxPE 106
ChemRice 120
ChemsectDNOC 106
ChemsectDNBP 106
Chipco 145
259
-------
INDEX
Pesticide Products
Chipco Choice 89
Chipco Thiram75 146
chloramine 203
chlordane 63, 64, 224, 226, 229
chlordecone 225,229
chlordimeform 82-83,229
chlorfenvinphos 44
chlorhexidine 202-203
chlorimuron ethyl 124,227
chlorinated dibenzo dioxin 98, 103
chlorinated dibenzo furan 98, 103
chlorinated solvents 196
chlormephos 44
4-chloro-2-methylphenoxyacetic acid 99
4-chloroaniline 87
chloroaniline, p 229
chlorobenzilate 63,64,83-84
chloroform 161, 162
chloroneb 144, 145
chlorophacinone 175
chlorophen 104
chlorophenoxys 98-101,222,229
chloropicrin 161, 162
chlorothalonil 144, 145,229
chlorphoxim 45
chlorpyrifos 43,45,216,223,
225, 226, 227
chloropyridinyl 121
chlorthiophos 44
chlorotoluron 124
cholecalciferol 182-183
chromium oxide 154, 155
chrysanthemic acids 38
Chrysron 42
cinerins 38
Ciodrin 46
cismethrin 41
citronella oil 128
Classic 124
cloethocarb 57
Clorto Caffaro 144
Clortosip 144
Clortran 144
clothianidin 90, 91
clove oil 72, 75
colloidal sulfur 93
Combat 89
Compass 145
Compound 1080 180
Contrac 175
Contraven 45
copper acetoarsenite 136
copper arsenite 136
copper chromium arsenate 150
copper compounds 150-152
copper oxide 154, 155
Co-Ral 44
Comet 145
Cotoran 124
Cottonex 124
coumachlor 173, 175
coumaphos 44,223
coumarins 173-176
coumatetralyl 173, 175
Counter 45
Cov-R-Tox 175
Crab-E-Rad 138
Crag Turf Fungicide 531 154, 155
creosote 189-190
cresol 189-190,205-206
crimidine 173, 180, 181
Crisazina 123
Crisfolatan 149
Crisuron 124
crotothane 106
crotoxyphos 46
crude pyrethrum 38
crufomate 46
Cryolite 84,86
Cuman 146
Curacron 47
Curamil 47
Curitan 156
Cutter 129
cyanamide 189
cyanofenphos 44
cyanoimine 90
cyanophos 46
Cyanox 46
Cybolt 41
cycloate 121
cyclodienes 63, 64
cyclohexenone derivative 122
cycloheximide 156
Cyflee 46
cyfluthrin 40,41
Cygnus 145
Cygon 47
260
-------
INDEX
Pesticide Products
cyhexatin 84
Cylan 45
Cymbush 41
Cymperator 41
Cynoff 41
Cyolane 45
Cyperkill 41
cypermethrin 40,41,229
Cypona 46
Cyrux 41
cythioate 46
Cythion 47
Cytrolane 45
2,4-D 98, 99, 101, 218, 222
Daconate6 138
Daconil2787 144
Dailon 124
Dal-E-Rad 138
Danitol 41
Dapacryl 107
Dart 87
Dasanit 45
dazomet 162, 165
2,4-DB 98,99
DBPC 225
DCNA 144
De-Green 46
Decis 41
DDE 63, 64, 215, 224, 225, 226, 228
DDT 63,64,118,215,223,224,
225, 226, 228
DEET 128-130,196
DEF 46
DeFend 47
Defol 193
De-Fol-Ate 193
Deftor 124
Delnav 44
DeltaDust 41
DeltaGard 41
deltamethrin 41
Deltex 41
demeton 44
demeton-methyl 44
demeton-S-methyl 46
Demon.... ....41
Denarin 156
Dermaadex 205
Dervan 193
Des-i-cate 191
desmetryn 122
Dessin 106
Distinguish 145
Detamide 129
Dethdiet 182
dialifor 44
diallate 121
Di-allate 121
Diaract 87
diazinon 44, 46, 222, 225, 226
dibrom 47
dibromide monohydrate salt 110
dibromochloropropane 166, 225
Dicamba 99, 121
Dicarbam 57
dichlobenil 121
dichlofenthion 46
dichlorofenthion 44
1-2-dichloroethane 162
2,4-dichlorophenoxyacetic acid 98, 99
2,4-dichlorophenoxybutyric acid 98, 99
2,4-dichlorophenoxypropionic acid... 98, 99
1,2-dichloropropane 162
1,3-dichloropropene 162
Dichlorprop 99
dichlorvos 46,227,229
dicloran 144, 145
diclofop-methyl 229
dicofol 63,64,223
dicrotophos 44
Dicuran 124
dieldrin 63, 64, 218, 224
dienochlor 63, 64
difenacoum 173, 175
difethialone 175
diflubenzuron 87
Difolatan 149
Dilie 138
Dimecron 45
dimefos 44
dimephenthoate 47
dimetan 57
Dimethan 57
dimethoate 44,47
dimethrin.... ....41
261
-------
INDEX
Pesticide Products
Dimilin 87
dibromochloropropane 162
Dinitro 106
Dinitro General Dynamyte 106
Dinitro Weed Killer 5 106
Dinitro-3 106
dinitroaminobenzene derivative 122
dinitrocresol 106
SDinitrophenol 106
dinitrophenols 105-107
dinobuton 106
dinocap 105, 106
Dinofen 106
dinopenton 106
dinoprop 106
dinosam 106
dinoseb 106
dinoseb acetate 106
dinoseb methacrylate 107
dinosulfon 107
dinotefuran 90,91
dinoterb acetate 107
dinoterb salts 107
dinoterbon 107
dioxacarb 57
dioxathion 44
dioxins 225
diphacin 175
diphacinone 175
Dipher 148
Dipterex 47
dipyridyls 110,111
diquat 110, 111, 112-116,218
diquat dibromide 110
Direx 124
Dirimal 122
disodium arsenate 137
disodium methane arsonate 138
disulfoton 44
disulfiram 147, 189
Disyston 44
Di-Tac 138
Dithane 148
Dithione 45
Ditrac 175
Diurex 124
diuron 124,229
DMA 138
DNAP.... ... 106
DNBP..
DNC....
DNOC.
dodine..
106
106
106
156
Dosaflo 124
Dotan 44
2,4-DP 98,99
DPA 120
DPX1410 57
Dragnet 42
Drawinol 106
Drexar530 138
Drop-Leaf. 193
DSE 148
DSMA 138
D-trans 41
Dual 120
Duraphos 45
Duratox 46
Dursban 45
Dycarb 57
Dyclomec 121
Dyfonate 45
Dylox 47
Dyna-shield 145
Dynasty 145
Dyrene 156
E-48..
E601.
E605.
.46
.45
.44
Earthcide 144
EasyOff-D 47
EBDC 148-149
ebuthiuron 124
edifenphos 46
Ekamet 46
Ekatin 47
Eksmin 42
elemental sulfur 93
Elecron 57
ElgetolSO 106
Elgetol318 106
Elimite 42
emerald green 136
Emisan6 152
Endosan.... ... 107
262
-------
INDEX
Pesticide Products
endosulfan 63,64,225
endothall 191-192
Endothall Turf Herbicide 191
endothion 44
endrin 63, 64
Entex 46
EPBP 46
EPN 44
Eptam 121
EPIC 121
Eradicane 121
essential oils 131-132
ethalfluralin 122
ethanol 200
Ethanox 46
Ethazol 156
ethers 196
ethion 46
ethoprop 46,229
ethyl alcohol 196
ethyl parathion 44,229
ethylene bis dithiocarbamates 148-149,
227
ethylene dibromide 161, 162, 163, 166
ethylene dichloride 161, 162
ethylene oxide 161,162,163
etridiazole 156, 157
etrimfos 46
Etrofolan 57
eucalyptus, oil of lemon 131-132
eugenol 72, 75
Evercide 39
Evik 123
Exofene 205
Exotherm Termil 144
E-Z-Off-D..., ....46
Fac 45
Fall 193
Famfos 44
Famid 57
famphur 44
Far-go 121
Femos 57
fenamiphos 44
Fenchlorphos 47
fenitrothion.... .... 46
fenthion 46
Fenkill 41
fenophosphon 44
fenothrin 41
fenoxycarb 229
fenpropathrin 41
fensulfothion 45
fenthion 44
fentin acetate 154
fentin chloride 154
fentin hydroxide 154
fenvalerate 40,41
ferbam 146,148,229
Ferberk 146
FermideSSO 146
Fernasan 146
Ficam 57
fipronil 89,229
Firestorm 112
Flectron 41
Flint 145
fluchloralin 122
flucythrinate 41
flumeturon 124
Fluent 41
fluoracetamide 173, 180, 181
fluorides 80,84-87
fluorodinitrotoluidine compounds 122
flutriafol 150
fluvalinate 41
FMC9044 107
Folcord 41
Folex 47
Folosan 144
Folpan 149
folpet 149
Foltaf 149
fonofos 45,223
formaldehyde 161, 162, 163, 201
formentate 57
formothion 46
fosamine aluminum 118
fosthietan 45
4-aminopyridine 188
4-chloro-2-methylphenoxyacetic acid 99
4-chloroaniline 87
4-tert-amylphenol 205
Four way 145
French green 136
263
-------
INDEX
Pesticide Products
Frontline 89
Frontline Topspot 89
Funginex 156
FungitrolII 149
Furadan 57
furethrin 41
furiazole.... ,...229
G28029 47
GA3 72-73
Gallocide 75
Gallotox 152
gamma BHC 64
gamma HCH 64
Gamophen 205
Gardona 47
Gardoprim 123
Garlon 121
Gaucho 91
Gebutox 106
Gem 145
GesaframSO 123
Gesagard 123
Gesapax 123
Gesatop 123
gibberellin 72-73
gibberellic acid 72-73
glutaraldehyde 201
glycols 196
Glycophene 156
Glyfonox 118
glyphosate 118-120,222
glyphosate-trimesium 119
Go-Go-San 122
Graduate A+ 145
Gramoxone 112
Granurex 124
guaiacol 189
Gusathion 44
Guthion 44
Gypsine 137
H
Haipen 149
Halizan 192
haloaromatic substituted urea
compounds 87-88
halocarbons 161
Hanane 44
Havoc 175
HCB 103,144,145,216
HCH 64
Headline 145
Hel-Fire 106
Helmquat 112
Helothion 47
heptachlor 63, 64, 226, 229
heptenophos 46
Herald 41
Herbodox 122
Herbi-All 138
Herbicide 273 191
Heritage 145
hexaclor 64
hexachoran 64
hexachlorobenzene 64, 103, 144,
215,216
hexachlorocyclohexane 63
hexachloroethane 229
hexachlorophene 205-206
Hexaferb 146
Hexathane 148
Hexathir 146
Hexazir 146
hexythiazox 229
Hibiclens 202
Hibistat 202
Hi-Yield DesiccantH-10 137
Hoe 002784 107
Honor 145
Hostathion 47
Hostaquick 46
Hot Shot Flea Killer 39
hydrofluoric acid 85
hydrogen cyanide.... 161,162,164-165, 169
hydrogen sulfide 93
Hydrothol 191
hypochlorites 203
Hyvar 123
264
-------
INDEX
Pesticide Products
I
IBP 46
inorganic pentavalents 135, 137
inorganic trivalents 135, 136
imazapyr 122
Imicide 91
imidacloprid 90, 91
Imidan 47
indandiones 173-176
Insignia 145
iodine 204
iodofenphos 46
IP50 124
iprodione 156,229
iprovalicarb 229
IR3535 128
isofenphos 45
isolan 57
Isopestox 45
isoprocarb 57
isopropanol 196, 200
isopropyl alcohol 200-201
isopropylamine salt 119
isoproturon 124
isoxathion 46
ivermectin... ,...70
jasmolins 38
Jones Ant Killer 137
Juwel 145
K
Rack 138
Kafil 42
KafilSuper 41
Karathane 106
Karmex 124
Karphos 46
KBR3023 128,131
Kerb 120
Kiloseb 106
Kitazin 46
KM 193
Knockmate 146
Koban 156
Kobu.... ... 144
Kobutol 144
Korlan 47
kresoxim-methyl 145
Kromad 154, 155
Kryocide 84
Kusatol 193
Kwell 63
KypmanSO 148
Kypzin 148
Lance 57
Landrin 57
Lannate 57
Lasso 120
leadarsenate 137
Leafex 193
lemon eucalyptus oil 128, 131, 132
lemongrass oil 128
lenacil 123
leptophos 46
Lexone 123
lindane 63, 64, 128, 224, 226
Linex 124
Linorox 124
Linurex 124
linuron 124
Liqua-Tox 175
Lorox 124
Lorsban 45
Lysol 205
M
MAA 138
Maki 175
malathion 47, 128,227
MAMA 138
mancozeb 148, 226, 229
Mancozin 148
maneb 148-149, 218, 226, 229
Maneba 148
Manex 148
ManexSO 148
Manzeb 148
Manzin 148
marine arsenic 137
Marlate 64
Matacil... ...57
265
-------
INDEX
Pesticide Products
Maxforce 89
MCPA 99,222
MCPB 99
MCPP 98,99
M-Diphar 148
Mecoprop 99,101,222
Melprex 156
MEMA 152
MEMC 152
Mentor 145
Meothrin 41
mephosfolan 45
mercaptophos 46
Mercuram 146
mercurials 204
mercurobutol 204
mercurochrome 204
Merit 91
Merge 823 138
Merpafol 149
Merpan 149
merphos 47
Mertect 156
Mesamate 138
Mesurol 57
META 192
Metadelphene 129
metalaxyl 156, 157
metaldehyde 192-193
Metalkamate 57
metam potassium 162, 165
metam-sodium 146-147, 162, 165,229
Metason 192
Metasystox-R 47
Metasystox-S 46
methabenzthiazuron 124
methamidophos 45
methane arsonic acid 138
methanol 196
MetharSO 138
methidathion 45
methiocarb 57
methomyl 57
methoprene 88
methoxy phenol 189
methoxychlor 63,64,224
methoxy ethyl mercury acetate 152
methoxy ethyl mercury chloride 152
methoxy ethyl mercury compounds 152
methyl bromide 161, 162, 165,223,226
2-methyl-3, 6 dichlorobenzoic acid 99
methyl phenol 190
methyl halides 162
methyl iodides 162
methyl mercury compounds 152
methyl mercury hydroxide 152
methyl parathion 44,45
methyl phenoxyacetic acid 222
methyl trithion 47
methylated pentavalents 135
methylene chloride 162, 165
metobromuron 124
metofluthrin 229
metolachlor 120,229
metominostrobin 145
metoxuron 124
metribuzin 123
mevinphos 45
Mezene 146
MGK 129
Micromite 87
Miller531 154,155
Milo-Pro 123
mipafox 45
MIPC 57
mirex 63,64,224,229
mitis green 136
Mocap 46
Monitor 45
monoammonium methane arsonate 138
mono-calcium arsenite 136
monocrotophos 45
monolinuron 124
monosodium methane arsonate 138
monuron 124
Morocide 107
Morrocid 107
MSMA 138
Multamat 57
Muskol 128,129
myclobutanil 150
Mycodifol 149
266
-------
INDEX
Pesticide Products
N
N-2790 45
naled 47
nabam 148
Namekil 192
naphthalene 161, 165, 167
naramycin 156
neburon 124
Neburex 124
neem 71
Neguvon 47
Nemacur 44
Nem-A-Tak 45
Nemispor 148
neonicotinoids 80,90-92
Neopynamin 42
Nexagan 45
Nexion 45
nicotine 70, 73-75, 90
NIA9044 107
nicotine sulfate 73
nicotinic idisopropylamine
derivative 122
Niomil 57
Nitrador 106
nitrapyrin 229
nitroimine 90
nitrolime 189
nitromersol 204
nitromethylene 90
NitroponeC 106
Nix 42
N-methyl carbamates 56-60
N-methyl pyrrolide 91
NMP 91
N,N-diethyl-3-methylbenzamide.... 128-130
N,N-diethyl-m-toluamide 128-130
No Bunt 144
Nomersam 146
Nomolt 87
n-phenylpyrazones 80, 88-90
NRDC149 41
Nudrin 57
Nuvanol-N.... ....46
0
Off! 129
Off! Skintastic for Kids 128
Oftanol 45
Ofunack 47
Ogam 145
oil, cedar 128
oil of citronella 128
oil of lemon eucalyptus 128, 131, 132
oil of lemongrass 128
OMPA 45
1-2-dichloroethane 162
1,2-dichloropropane 162
1,3-dichloropropene 162
Opera 145
o-phenylphenol 205
organic pentavalents 135, 138
organochlorines 63-67, 89, 215-218,
223, 225, 226
organomercury compounds 143,152-153
organophosphates 30,43-52, 64,
214-218,220,226,227
organotins 154
Orthene 45
orysastrobin 145
oryzalin 122,229
Oust 124
Outflank 42
Over'nOut! 89
oxadiazolinone 122
oxadiazon 122
oxamyl 57
oxydemeton-methyl 47
oxydeprofos 47
oxyfluorfen.... ,...230
Pageant 145
Panogen 152
PanogenC 152
Pansoil 156
paradichlorobenzene 163, 165
paraformaldehyde 161, 163
paraquat 110-116,218,226
Para-Shot 112
parathion 43, 44, 226, 227, 229
Parazone 112
Paris Green.... ...136,150
267
-------
INDEX
Pesticide Products
Parzate 148
ParzateC 148
Pattonex 124
Payoff 41
PCBs 215,224,225
p-chloroaniline 229
PCNB 144,145
PCP 103-105,223
PEBC 121
pebulate 121
penchlorol 104
pendimethalin 122
Pennant 120
Penncap-M 45
Penncozeb 148
penta 104
Pentac 64
pentacon 104
pentachloronitrobenzene 144
pentachlorophenate 152
pentachlorophenol 103-105, 223, 229
Pentagen 144
penwar 104
Peridex 202
Permasect 42
permethrin 40,42,128,215,218,
223,229
perthane 63
Perthrine 42
PestoxXIV 44
PestoxXV 45
petroleum distillates 195, 196, 197
Phaltan 149
phencapton 47
phenols 205-206
Phenostat-A 154
phenthoate 47
Phentinoacetate 154
phenyl mercuric acetate 152,204
phenyl mercuric nitrate 204
phenyl mercury ammonium acetate 152
Phisohex 205
phorate 45,223,227
phosalone 43,47
Phosdrin 45
phosfolan 45
phosphamidon 45
phosphine 161, 162, 164, 168-169
phosphonates 118-120
phosphorus, white 176
phosphorus, yellow 173, 176, 178
Phosvel 46
phoxim 47
phthalthrin 42
Phytar560 138
picaridin 128, 131
picloram 122
picolinic acid compound 122
picoxystrobin 145
pine oil 207
Pinene 122
piperonyl butoxide 75, 195, 215, 229
pirimicarb 57, 229
pirimiphos-ethyl 47
pirimiphos-methyl 47
Pirimor 57
Pival 175
pivalyn 175
PMAA 152
PMD 128
Poast 122
poly chlorinated biphenyls (PCBs) 215,
224, 225
Polyram-Ultra 146
polyethylene glycol 196
Polytrin 41
Pomarsol forte 146
potassium chromate 154, 155
Pounce 42
povidone-iodine 204
Pramitol25E 123
Prebane 123
Prefar 45
Premerge 106
Premise 91
Prentox 39
Primatol 123
PrimatolM 123
Primicid 47
Primin 57
Princep 123
Pristine 145
Proban 46
Prodalumnol Double 136
profenofos 47
Prolate 47
Prolex... ...120
268
-------
INDEX
Pesticide Products
prometon 123
Prometrex 123
prometryn 123
Pronamide 120
propachlor 120,229
Propanex 120
propanil 118, 120
propargite 92
propazine 123
propetamphos 47
propiconazole 150
propionate 152
propoxur 57,229
propyl thiopyrophosphate 47
propylene oxide 162, 163
Prosper 145
Protege 145
prothoate 45
Provado 91
Prowl 122
Proxol 47
Prozinex 123
Purge 39
Purivel 124
Pynamin 41
Pynosect 42
pyraclostrobin 145
pyrazophos 47
pyretholic acids 38
pyrethrins 38-39,226
pyrethroids 38, 39-42,45, 80, 220
pyridaphenthion 47
Pyrocide Fogging Concentrate 39
Quadris 145
Quartet 145
Quik-Quat 112
Quilan 122
Quilt 145
quinalphos 47
quinolinolate 152
Quintox 182
quintozene 144
Rad-E-Cate25 138
radione 175
Raid Ant & Roach Killer 39
RaidFogger 39
Ramik 175
Rampage 182
Rampart 45
Ramrod 120
Rapid 57
Rapid Kill 112
Rapier 120
Razor Bum 112
red squill 173,182-183
Reglone 112
Renown 145
resmethrin 42,229
Ridomil 156
Ripcord 41
Riselect 120
Rodine 182
Rody 41
Ro-Neet 121
ronnel 47
Ronstar 122
rotenone 75-76,218
Round-up 118,119
Rovral 156
Rozol 175
RTU-trifloxystrobinmetalaxyl 145
Ruelene... ....46
sabadilla 70, 76-77
Safrotin 47
SAGA 42
Salvo 138
Sanspor 149
Saprol 156
Sarclex 124
Saturn 121
Sawyer 129
schradan 45
Schweinfurt green 136
Selinon 106
Semeron 123
Sencor 123
Sencoral.... ... 123
269
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INDEX
Pesticide Products
Sencorex 123
sethoxydim 122
Setrete 152
Sevin 57
Shimmer-ex 152
siduron 124
simazine 123
Sinbar 123
sinituho 104
Sinox 106
Siperin 41
Skeeter Beater 129
Skeeter Cheater 129
Snox General 106
Sodanit 136
Sodar 138
sodium aluminofluoride 84
sodium arsenate 137
sodium arsenite 136
sodium cacodylate 138
sodium chlorate 193-195
sodium cyanide 161, 162, 164-165
sodium fluoaluminate 84, 86
sodium fluoride 84,85, 86
sodium fluoroacetate 173, 180, 181
sodium fluosilicate 84, 85, 86
sodium hypochlorite 203
sodium pentachlorophenate 104
sodium polyborates 81
sodium silico fluoride 84
sodium tetraborate decahydrate 81
Sonalan 122
Soprabel 137
Sopranebe 148
Sovran 145
Soygard 145
Spike 124
spinosyns 77
Spinosad 77
Sporgard 145
Spotrete-F 146
SpotreteWP75 146
Spra-cal 137
Spring Bak 148
S-Seven 46
Stam 120
Stamina 145
Stampede 120
Stirofos.... ....47
Stratego 145
streptomycin 77-78
strobilurins 145-146
Stroby/Sovran 145
Stomp 122
strychnine 173, 180, 181
Subitex 106
Subdue 156
substituted benzines 144-145
Sulerex 124
sulfometuronmethyl 124
sulfotep 45
sulfur 93
sulfur dioxide 161, 162, 164
sulfuryl fluoride 161, 162, 164, 166
sulprofos 47
Sumicidin 41
Sumithion 46
Super Crab-E-Rad-Calar 138
Super Dal-E-Rad 138
Super Tin 154
superwarfarins 173
Supracide 45
Supra-Quick Flea & Tick Mist 39
Surecide 44
Surflan 122
Surgi-Cen 205
Surofene 205
Suspend 41
Sutan 121
Suzu 154
Suzu-H 154
Swat 44
Syntax 44
2,4,5-T 98,99
Tag HL 331 152
Talan 106
Talcord 42
Talon 175
Tamex 122
Target MSMA 138
Tartan 145
Tattoo 57
2,3,6-TBA 121
TBT 224
TCBA... ...121
270
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INDEX
Pesticide Products
Tebusan 124
Tecto 156
teflubenzuron 87
Temik 57
temephos 47
TEPP 45
terbacil 123
terbucarb 121
terbufos 45
terbuthylazine 123
Terbutrex 123
Ternit 123
terraclor 144
Terraneb SP 144
Terrazole 156
Terro Ant Killer 137
Tersanl991 156
4-tert-amylphenol 205
Tetrapom 146
tertutryn 123
2,3,7,8-tetra CDD 98
tetrachlorvinphos 47
tetradifon 223
tetraethyl pyrophosphate 45
tetramethrin 42
Tetramethylenedisulfotetramine 180, 181
TETS 180,181
Texosan 205
thallium sulfate 173, 176, 177, 179
thiabendazole 156
thiacloprid 91,229
thiamethoxam 90, 91
Thibenzole 156, 157
Thimer 146
thimerosol 204
Thimet 45
thiobencarb 121
thiocarbamates 121, 146-148
thiodicarb 229
Thioknock 146
thiometon 47
Thionex 63, 64
Thiophal 149
thiophos 44
thiophthalimides 149
Thiotepp 45
Thiotex 146
thiram 146, 147-148, 154, 155
Thiramad.... ... 146
Thirasan 146
Thiuramin 146
SDinitrophenol 106
Three way 145
thymol 205
Tiguvon 46
Tillam 121
Tilt 150
Tinmate 154
Tirampa 146
TMTD 146
Tolkan 124
toluene 196
Tolurex 124
tolyfluanid 229
Tomcat 175
Torak 44
Tordon 122
Touchdown 112
toxaphene 63,64,229
TPTA 154
Tralex 42
tralomethrin 42
Trametan 146
Trans-Vert 138
Treflan 122
triadimefon 150
triallate 121
triazines 123
triazoles 123, 143, 150
triazophos 47
Tribac 121
Tribunil 124
tributyltin 224
Tricarbamix 146
trichlorfon 47
trichlorobenzoic acid 121
trichloronate 44
2,4,5-trichlorophenoxy acid 99
triclocarban 205
triclopyr 121
triclosan 201,205
tricyclohexyl tin hydroxide 84
trifloxystrobin 145
trifluralin 122, 229
trifocide 106
triforine 156, 157
Trifungol 146
Trilex... ...145
271
-------
INDEX
Pesticide Products
Trimangol 148
trimethacarb 57
Trio 145
Tri-PCNB 144
triphenyltin 154
triphenyltin hydroxide 230
Tripomol 146
Triscabol 146
Trithion 44
Tritoftorol 148
Truban 156
Tuads 146
Tubotin 154
Turcam 57
Tuffcide 144
Turf-Cal 137
Tupersan 124
2,3,6-TBA 121
2,3,7,8-tetra CDD 98
2-benzyl-4-chlorophenol 205
2,4-D 98, 99, 101, 218, 222
2,4-DB 98,99
2,4-dichlorophenoxyacetic acid 98, 99
2,4-dichlorophenoxybutyric acid 98, 99
2,4-dichlorophenoxypropionic acid... 98, 99
2,4-DP 98,99
2,4,5-T 98,99
2,4,5-trichlorophenoxy acid 99
2-methyl-3, 6 dichlorobenzoic acid 99
.40
.40
Type I pyrethroids
Type II pyrethroids
u
Ultracide 45
UnicropDNBP 106
Unidron 124
Uniform 145
Unisan 152
uracils 123
urea derivatives 124
USF 145
Ustadd 41
V
VancideMZ-96 146
Venturol 156
Venzar 123
Veratrum alkaloid.... .... 76
Vertac 106
Vertac General Weed Killer 106
Vertac Selective Weed Killer 106
Vigilante 87
vinclozolin 224,226,230
Vondcaptan 149
Vonduron 124
VydateL 57
w
warfarin 173, 175
Wax Up 122
Weedazol 123
Weed-E-Rad 138
Weed-E-Rad 360 138
Weed-Hoe 138
white arsenic 136
white phosphorus 176
X
xylene.
196
yellow phosphorus 173, 176, 178
Zebtox 148
Ziman-Dithane 148
zineb 148
zinc arsenate 137
zinc oxide 154, 155
zinc phosphide 173, 176, 177, 178, 179
Zincmate 146
ziram 146, 148
ZiramF4 146
Ziram Technical 146
Zirberk 146
Zirex90 146
Ziride 146
Zitox 146
Zolone 47
Zotox... ... 137
272
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