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UNIT 5

TOXIC AGENTS
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CHAPTER 22

TOXIC EFFECTS OF PESTICIDES

Donald J. Ecobichon

INTRODUCTION BOTANICAL INSECTICIDES

HISTORICAL DEVELOPMENT Nicotine
REGULATORY MANDATE Rotenoids

Exposure HERBICIDES

INSECTICIDES Chlorophenoxy Compounds

Bipyridyl Derivatives
Organochlorine Compounds
Chloroacetanilides
Signs and Symptoms of Poisoning
Phosphonomethyl Amino Acids
Site and Mechanism of Toxic Actions
Glyphosate
Biotransformation, Distribution, and Storage
Glufosinate
Treatment of Poisoning
Anticholinesterase Agents FUNGICIDES
Signs and Symptoms of Poisoning Hexachlorobenzene
Mechanism of Toxic Action Pentachlorophenol
Biotransformation, Distribution, and Storage Phthalimides
Treatment of Poisoning Dithiocarbamates
Pyrethroid Esters
Signs and Symptoms of Poisoning FUMIGANTS
Site and Mechanism of Toxicity Phosphine
Biotransformation, Distribution, and Storage Ethylene Dibromide/Dibromochloropropane
Treatment of Poisoning
RODENTICIDES
Avermectins
Mechanism of Action Zinc Phosphide
Newer Chemical Insecticides Fluoroacetic Acid and Derivatives
Nitromethylenes A-Naphthyl Thiourea
Chloronicotinyl Anticoagulants
Phenylpyrazoles CONCLUSIONS

INTRODUCTION and microorganisms that constantly threatened the supply of food

The U.S. Environmental Protection Agency (U.S. EPA) defines a
pesticide as any substance or mixture of substances intended for
preventing, destroying, repelling, or mitigating any pest. A pesti-
cide may also be described as any physical, chemical, or biologi-
cal agent that will kill an undesirable plant or animal pest. The
term pest includes harmful, destructive, or troublesome animals,
plants, or microorganisms. Pesticide is a generic name for a vari-
ety of agents that are classified more specifically on the basis of
the pattern of use and organism killed. In addition to the major
agricultural classes that encompass insecticides, herbicides, and
fungicides, one finds pest-control agents grouped as acaricides, lar-
vacides, miticides, molluscides, pediculicides, rodenticides, scabi-
cides, plus attractants (pheromones), defoliants, desiccants, plant
growth regulators, and repellants.
HISTORICAL DEVELOPMENT
Over the centuries, humans have developed many ingenious
methods in their attempts to control the invertebrates, vertebrates,
and fiber as well as posing a threat to health. The historical liter-
ature is replete with descriptions of plant diseases and insect
plagues and the measures taken to control them. Sulfur was used
as a fumigant by the Chinese before 1000 B.C. and as a fungicide
in the 1800s in Europe against powdery mildew on fruit; it is still
the major pesticide used in California today. In sixteenth-century
Japan, poor-quality rendered whale oil was mixed with vinegar and
sprayed on paddies and fields to prevent the development of insect
larvae by weakening the cuticle. The Chinese applied moderate
amounts of arsenic-containing compounds as insecticides in the
sixteenth century. As early as 1690, water extracts of tobacco leaves
(Nicotiana tabacum) were sprayed on plants as insecticides, and
nux vomica, the seed of Strychnos nux-vomica (strychnine), was
introduced to kill rodents. In the mid-1800s, the pulverized root of
Derris eliptica, containing rotenone, was used as an insecticide, as
was pyrethrum extracted from the flowers of the chrysanthemum
(Chrysanthemum cineariaefolum). In the late 1800s, arsenic triox-
ide was used as a weed killer, particularly for dandelions. Bordeaux
mixture—copper sulfate, lime [Ca(OH)2], and water—was intro-
duced in 1882 to combat vine downy mildew (Plasmopara viti-

763
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764 UNIT 5 TOXIC AGENTS
cola), a disease introduced into France from the United States when
phylloxera-resistant vine rootstocks were imported. Sulfuric acid,
at a concentration of 10% v/v, was used in the early 1900s to de-
stroy dicotyledonous weeds that would absorb the acid, whereas
cereal grains and substitute plants, having a smooth and waxy
monocotyledon, were protected. Paris Green (copper arsenite) was
introduced to control the Colorado beetle in the late 1800s; cal-
cium arsenate replaced Paris Green and lead arsenate was a major
cornerstone in the agriculturalist’s armamentarium against insect
pests in the early 1900s. By the 1900s, the widespread use of ar-
senical pesticides caused considerable public concern because
some treated fruits and vegetables were found to have toxic
residues. Although some of these early pesticides caused only min-
imal harm to the humans exposed, other agents were exceedingly
toxic, and the medical literature of the era is sprinkled with anec-
dotal reports of poisonings. Looking back over the early years of
pesticide development, before the 1930s, it is somewhat surprising
to realize just how few pesticides were available (Cremlyn, 1978).
The 1930s ushered in the era of modern synthetic chemistry,
including the development of a variety of agents such as alkyl thio-
cyanate insecticides, dithiiocarbamate fungicides, ethylene dibro-
mide, methyl bromide, and ethylene oxide (Cremlyn, 1978). By
the beginning of World War II, there were a number of pesticides,
including dichlorodiphenyltrichloroethane (DDT), dinitrocresol,
4-chloro-2-methyloxyacetic acid (MCPA), and 2.4-dichlorophe-
noxyacetic acid (2,4-D) under experimental investigation, much of
this activity being kept under wraps during the war (Kirby, 1980).
In the postwar era, there was rapid development in the agrochem-
ical field, with a plethora of insecticides, fungicides, herbicides,
and other chemical agents being introduced. In no other field of
chemistry has there been such a diversity of structures arising from
the application of the principles of chemistry to the mechanism(s)
of action in pests to develop selectivity and specificity in agents
toward certain species while reducing toxicity to other forms of
life.
Despite the modern-day development of second- and third-
generation derivatives of the early chemical pesticides, all pesti-
cides possess an inherent degree of toxicity to some living organ-
ism, otherwise they would be of no practical use. Unfortunately,
the target-species selectivity of pesticides is not as well developed
as might be hoped for, and nontarget species frequently are affected
because they have physiologic and/or biochemical systems similar
to those of the target organisms. There is no such thing as a com-
pletely safe pesticide. There are, however, pesticides that can be
used safely and/or that present a low level of risk to human health
when applied with proper attention to the label’s instructions.
Despite the current controversy over pesticide use and the presence
of low levels of residues in food, groundwater, and air, these agents
are integral components of our crop- and health-protection pro-
grams. As long as pesticides continue to be used, accidental and /or
intentional poisoning of wildlife, domestic stock, and humans can
be anticipated and will require treatment.
On a worldwide basis, intoxications attributed to pesticides
have been estimated to be as high 3 million cases of acute, severe
poisoning annually, with as many or more unreported cases and
some 220,000 deaths (WHO, 1990). These estimates suffer from
inadequate reporting of data for developing countries, but they may
not be too far off the mark. From estimations based on California
data, a total of some 25,000 cases of pesticide-related illness oc-
cur annually among agricultural workers in that state, with national
estimate for the United States as a whole being on the order 80,000
cases per year (Coye et al., 1986). Results from California, a state
that uses a vast amount of chemical pesticides, revealed that 1087
occupationally related exposures occurred in 1978. A breakdown
of these poisonings by job category, as shown in Fig. 22-1, revealed
that ground applicators were at greatest risk, whereas aerial appli-
cators and workers involved in mosquito-abatement programs had
the least pesticide-related illness (Kilgore, 1980, 1988). Of 1211
cases of pesticide-related illness reported to California physicians
in 1986, a total of 1065 were occupational in nature (Edmiston and
Maddy, 1987). However, in other countries, the incidence of poi-
soning is very low; for example, in the United Kingdom, fewer
than 20 agricultural incidents with organophosphates are reported
each year (Weir et al., 1992). Such data are not representative of
the rest of the agricultural world.
The incidence of poisoning is 13-fold higher in developing
countries than in highly industrialized nations, which consume 85
percent of world’s pesticide production (Forget, 1989). A recently
published proceedings gives a good overview of the situation in
developing nations, where there are few regulations controlling the
importation, registration, and sale of pesticides (Forget, 1993).
Many countries in Central and South America, Africa, and South-
east Asia are becoming “breadbaskets” for countries of more tem-
perate climate, being sources of fresh fruits, vegetables, cut flow-
ers, and so on in the off-season, since they are capable of growing
two or three crops of export produce each year. Figure 22-2 shows
the quantities of pesticidal active ingredients used in a number of
countries in 1994 (UN FAO, 1994). A more complete listing can
be found in O’Malley (1997). In developed countries, more herbi-
cides are used than any other class of pesticides, whereas in trop-
ical, developing nations, there is a predominant use of insecticides.
As other developing nations explore the global export produce mar-
ket, pesticide consumption—now around 3000 to 10,000 metric
tons—will increase dramatically. Most developing nations have yet
Ground Applicators
Gardeners and Nurserymen
Warehouse and Indoors
Mixers and Loaders
Structural
Field Workers
Agricultural Workers and Others
Manufacturing and Pest Control
Firemen, Police
Fumigators
Aerial Applicators
Mosquito Abatement
0 50 100 150 200 250
Number of Human Pesticide Exposure Illnesses
Figure 22-1. Frequency of pesticide poisoning related to occupation and
potential for exposure. [From the records of the California Department
of Public Health (Kilgore, 1988)].
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES 765

100,000 individual farmers, cooperative members, and workers for

Costa Rica small companies (Boon-Long et al., 1986). In 1981 in Sri Lanka,
approximately 10,000 to 13,000 persons were admitted to hospi-
Ecuador tals for acute poisoning annually, with almost 1000 deaths
(Jeyaratnam, 1993; Jeyaratnam et al., 1982). In Taiwan, for the
Vietnam
years 1985 to 1993, some 7386 out of a total of 23,436 chemical-
Columbia related poisonings involved pesticides (Yang et al., 1996). In Costa
Rica in 1996, some 920 out of a total of 1274 pesticide-related
Turkey poisonings were due to occupational or accidental exposure
(Leveridge, 1998). Poisonings by organophosphorus and carbamate
Korea insecticides represented 38.5 percent of the total (438 out of 1274),
while only 8 intoxications were associated with organochlorine in-
Canada secticides (Leveridge, 1998). None of the above values included
affected individuals who either did not seek medical attention or
Mexico could not afford the time away from work to do so.
No one can doubt the efficacy of pesticides for the protection
Thailand
of crops in the field, thereby providing us with abundant, inex-
Malaysia pensive, wholesome, and attractive fruits and vegetables. It has
been estimated that in 1830 it took 58 person-hours to tend and
Brazil harvest an acre of grain, whereas today it takes approximately
2 person-hours (Kirby, 1980). Over this time period, the price of
India cereal grain has not risen proportionally to the costs of the labor
to produce it. Along with improved strains of crops, an important
Australia role in crop improvements and yields has been played by insecti-
cides, fungicides, and herbicides. Even with such advances, it is
China
estimated that up to 50 percent of harvested crops can be damaged
USA by postharvest infestation by insects, fungi, rodents, and the like
(Table 22-1).
The medical miracles accomplished by pesticides have been
0 50 100 150 200 250 300 (x1000)
documented: the suppression of a typhus epidemic in Naples, Italy,
Metric Tons of Active Ingredients
by DDT in the winter of 1943–1944 (Brooks, 1974); the control
Figure 22-2. Quantities of pesticides (active ingredients) used in repre- of river blindness (onchocerciasis) in West Africa by killing of the
sentative countries around the world in 1994. (From O’Malley, 1997, with insect vector (black fly) carrying the filariae for this disease (WHO,
permission.)
1977; Calamari et al., 1988); and the control of malaria in Africa,
the Middle East, and Asia by elimination of the plasmodium-
bearing mosquito populations with a variety of insecticides
to develop stringent “philosophies” concerning pesticide control (Matsumura, 1985). There is still a great need for advancement in
and usage (Mbiapo and Youovop, 1993). the control of disease vector with pesticides: 600 million people
Most pesticide-related poisonings in developing nations can are at risk from schistosomiasis in the Middle East and Asia; 200
be attributed to inexperience with such chemicals, negligible train- million suffer from filariasis in tropical Africa, Asia, Indonesia, and
ing in their use, and the absence of appropriate personal protective the Caribbean region; 20 million people in tropical Africa, the
equipment. In 1983 in Thailand, 117 incidents per 100,000 agri- Middle East, Mexico, and Guatemala are infected by the filarium
cultural workers were reported for compensation claims by com- causing onchocerciasis; and 1000 million people worldwide har-
panies having more than 20 employees; by comparison, hospital bor pathologic intestinal worm infestations (Albert, 1987). Al-
admissions/deaths due to pesticide poisonings totaled 8268 per though the benefits of pesticides are recognized by those who re-

Table 22-1
Worldwide Harvest Losses in Five Important Crops

Losses Through
POTENTIAL HARVEST
HARVEST 1978 WEEDS DISEASES INSECTS
CROP (1000 TONS) (1000 TONS) % % %

Rice 715,800 378,645 10.6 9.0 27.5

Maize 563,016 362,582 13.0 9.6 13.0
Wheat 578,400 437,236 9.8 9.5 5.1
Sugarcane 1,603,200 737,483 15.1 19.4 19.5
Cotton 63,172 41,757 5.8 12.1 16.0

SOURCE:
GIFAP: International Group of National Association of Agrochemical Manufacturers. Brussels. GIFAP Bulletin, vol 12,
March/April 1986.
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766 UNIT 5 TOXIC AGENTS
quire them, certain parts of the world are experiencing an envi-
ronmentalist- and media-evoked backlash toward all pesticide use
because of the carelessness, misuse, and/or abuse of some agents
by a relatively few individuals in a limited number of well-publi-
cized incidents. Without bearing any direct responsibility for plan-
ning or involvement in health care or food or fiber production, some
environmental and consumer advocacy groups propose a total ban
on pesticide use. Between the two extremes of overwhelming use
and total ban lies a position advocating the careful and rational use
of the beneficial chemicals.
REGULATORY MANDATE
The widespread use and misuse of the early, toxic pesticides cre-
ated an awareness of the potential health hazards posed by them
and the need to protect the consumer from residues in foods. It was
not until 1906 that the Wiley or Sherman Act was passed, creating
the first Federal Food and Drugs Act. This was replaced by the
Federal Food, Drug and Cosmetic Act (FDCA) in 1938, with spe-
cific pesticide amendments being passed in 1954 and 1958; these
required that pesticide tolerances be established for all agricultural
commodities. The 1958 amendment contained the famous Delaney
clause (Section 409), which states that “no additive shall be deemed
safe if it is found to induce cancer when ingested by man or ani-
mal or, if it is found, after tests which are appropriate for the eval-
uation of the safely of food additives, to induce cancer in man or
animals” (National Academy of Sciences, 1987). It should be noted
that the Delaney clause does not require proof of carcinogenicity
in humans. Pesticides fall under this “additive” legislation.
The Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA) was originally passed by Congress in 1947 as a labeling
statute that would group all pest control products—initially only
insecticides, fungicides, rodenticides, and herbicides—under one
law to be administered by the U.S. Department of Agriculture
(USDA). Amendments in 1959 and 1961 added nematicides, plant
growth regulators, defoliants, and desiccants to FIFRA jurisdiction,
plus the authorizations to deny, suspend, or cancel registrations of
products, although it assured the registrant’s right to appeal. In
1972, FIFRA was reorganized and administrative authority was
turned over to the newly formed Environmental Protection Agency
(EPA). The new law, along with subsequent amendments in 1975,
1978, 1980, and 1984, defines the registration requirements and
appropriate chemical, toxicologic, and environmental impact stud-
ies, label specifications, use restrictions, tolerances for pesticide
residues on raw agricultural products, and the responsibility to
monitor pesticide residue levels in foods. FIFRA is not all-
encompassing because the Food and Drug Administration (FDA)
retains the basic responsibility for both monitoring residue levels
and for seizure of foods not in compliance with the regulations;
what is more, the USDA continues to be the authority responsible
for the monitoring of meat and poultry for pesticides as well as for
other chemicals. The Food Quality Protection Act (FQPA), passed
by the U.S. Congress in 1996, amended federal laws regarding pes-
ticides to give special consideration for children by (1) providing
additional protection when allowable levels of pesticides for foods
are set (data providing children’s food consumption patterns, recog-
nition of all possible routes of exposure in risk assessment); and
(2) considering whether infants and children are disproportionally
susceptible to pesticides. Where data on the pesticides are not ad-
equate, pesticide tolerances for children must incorporate an addi-
tional 10-fold safety factor.
FIFRA regulations set out the requirements essential before
EPA-Office of Programs review of any pesticide and/or formulated
product can occur for registration purposes. This information base
includes product and residue chemistry, environmental fate, toxi-
cology, biotransformation/degradation, occupational exposure and
reentry protection, spray drift, environmental impact on nontarget
species, and product performance and efficacy. Depending on the
proposed use pattern of the pesticide, results from different
“groups” or toxicologic studies are required to support the regis-
tration. The typical spectrum of basic pesticide toxicity data re-
quired under FIFRA regulations is summarized in Table
22-2. Extensive ancillary studies of environmental impact on birds,
mammals, aquatic organisms, plants, soils, environmental persist-
ence, and bioaccumulation are also required. A schematic diagram
showing the “information package” required in support of a regis-
tration and the appropriate time span required to develop this data-
base—from the point of patenting the newly synthesized chemical
until its registration, production, marketing, and user acceptabil-
ity—is shown in Fig. 22-3. Although the ultimate uses of the par-
ticular chemical will govern the extent of the information base re-
quired prior to registration, estimates of average development costs
on the order of $30 to $80 million are not unrealistic.
Other nations including Canada, the United Kingdom, Japan,
and, more recently, the European Economic Community (EEC)
have promulgated harmonizing legislation similar to that of the
United States as safeguards in human exposure to pesticides in food
commodities. Some developing nations, with a shortage of trained
technical, scientific, and legal professionals to develop their own
legislation, have adopted the regulatory framework of one or an-
other of the industrialized nations, permitting the sale and use of
Table 22-2
Basic Requirements Regarding Toxicity Data for New
Pesticide Registrations
Acute
Oral (rat)
Dermal (rabbit)
Inhalation (usually rat)
Irritation studies
Eye (rabbit)
Skin (rabbit, guinea pig)
Dermal sensitization (guinea pig)
Delayed neurotoxicity (hen)
Subchronic
90-Day feeding study
Rodent (rat, mouse)
Nonrodent (dog)
Dermal
 Dependent upon use pattern and po-
Inhalation tential for occupational exposure
Neurotoxicity
Chronic
One- or two-year oral study
Rodent (usually rat)
Nonrodent (dog)
Oncogenicity study (rat or mouse)
Reproductive
In vitro mutagenicity (microorganisms, etc.)
Fertility/reproduction (rat, mouse, rabbit)
Teratogenicity (rat, mouse, rabbit)
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
Figure 22-3. A schematic diagram depicting the generation of an appropriate toxicity database, the time
frame for data acquisition and the significant milestones in the life cycle of a pesticide in the United States.
Stages I to III represent the sales of the pesticide once the commercial product enters the marketplace. (GI-
FAP Bulletin, Sept. 1983, with permission.)
pesticides registered under the legislation of that country but pro-
hibiting the use of agents unable to meet the stringent requirements.
In still other countries, almost any pesticide ever manufactured is
available, no legislation having been introduced to curb adverse ef-
fects to the environment and human health.
Exposure
The evaluation of the hazards of pesticides to human health begins
with the development of a dose-effect relationship based on docu-
mented and anecdotal information on human exposure (Fig. 22-4).
Several populations of individuals may be identified as having ex-
posure to a range of concentrations of a particular agent, includ-
ing: (1) accidental and/or suicidal poisonings that no amount of
legislation or study can prevent; (2) occupational (manufacturing,
mixing/loading, application, harvesting, and handling of crops) ex-
posure (Albertson and Cross, 1993; Edmiston and Maddy, 1987);
(3) bystander exposure to off-target drift from spraying operations
with, in some cases, the development of hypersensitivity (Bartle,
1991); (4) the general public who consume food items containing
pesticide residues as a consequence of the illegal use of an agent
(e.g., aldicarb on melons and cucumbers) or its misuse, in terms
of an incorrect application rate or picking and shipping a crop too
soon after pesticide application, resulting in residue concentrations
above established tolerance levels. The media are replete with doc-
umented incidents of environmental contamination by pesticides:
(1) of surface and/or groundwater essential as sources of potable
drinking water; (2) of commercial fish stock as well as sporting
fish; (3) of wildlife upon which native peoples depend as a major
source of dietary protein; and (4) of long-distance aerial transport
of undeposited and/or revolatilized pesticide.
The shape of the dose-effect curve is dependent on a detailed
knowledge of the amount of exposure received by each of these
groups. Within each group, variability will be considerable. Fre-
quently, exposure evaluations begin at the top of the relationship
where exposure is greatest, more easily estimated, and, in most
767
cases, the acute biological effects are clearly observed and may be
associated with a specific agent or a class of chemicals over a rel-
atively narrow dosage range. If no discernible adverse health ef-
fects are seen at high levels of exposure, it is unlikely that any-
thing will be observed at lower levels of exposure. Although this
hypothesis may be true for acute systemic effects, it is not appli-
cable to chronic effects (changes in organ function, mutagenicity,
teratogenicity, carcinogenicity) that may develop after some latent
period following either a single high-level exposure, repeated mod-
erate or high-level exposure, or annual exposure to low levels of
the agents for decades.
There is sufficiently detailed documentation on many pestici-
dal poisonings to permit an estimation of exposure (Hayes, 1982).
In some 48 suicide attempts by ingestion of the herbicide
glyphosate, the average volume of product (concentrate containing
active ingredient and a surfactant) ingested was 120 mL [range of
104 mL (nonfatal) to 206 mL (fatal)] (Swada et al., 1988). In other
cases, such as one involving the insecticide fenitrothion, where the
individual experienced dermal exposure to a 7.5% solution of the
agent in corn oil wiped up with facial tissues by a bare hand, ex-
posure was more difficult to assess (Ecobichon et al., 1977). It is
imperative that forensic and clinical toxicologists and emergency
service personnel attempt to ascertain how much of the material
was involved in the poisoning.
Worker exposure can be estimated within reason by consid-
ering the various job functions performed (e.g., diluting concen-
trated formulations, loading diluted end-use formulations into
tanks, spray application, harvesting sprayed crops, postharvest han-
dling of sprayed crops, etc.). The potential level(s) of pesticide en-
countered in each job category and the route(s) of exposure can be
estimated. The majority of occupational illnesses arising from pes-
ticides involve dermal exposure enhanced, in certain job categories,
by acquisition of a portion of the dosage by the inhalation of the
aerosolized spray. Many exposures appear to be entirely dermal in
character (Vercruysse et al., 1999). The surface areas of the un-
clothed parts of the body of an unprotected worker are shown in
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768 UNIT 5 TOXIC AGENTS

Figure 22-4. A theoretical dose–effect relationship for acute toxicity, comparing the potential for exposure
in terms of occupation, level of exposure and possible biological effects.

Table 22-3, being derived from the U.S. EPA (1987). Data for the
entire surface area of a “50 percentile man,” as determined by Spear
and coworkers (1977), are shown in Table 22-4. With surface patch
(gauze, fabric) testing on various parts of the body, accurate esti-
mates of dermal exposure can be obtained. The reader is referred
to the following studies for details: Wolfe and colleagues (1967,
1972), Wojeck and coworkers (1981), and Franklin and coworkers
(1981). Where inhalation can be considered to contribute signifi-
cantly to the total exposure, as in greenhouse and other structural
spraying operations in enclosed environments, drivers in tractor
cabs, operators of rotary fan mist sprayers, and other operations,
measurements of aerial concentrations in the working environment
can be made and related to respiratory rates and length of time
spent in that environment. Assessment of the inhalation component
of an exposure can be obtained with personal air sampling moni-
tors worn during the day (Trumbull et al., 1985; Grover et al.,
1986).
In the past, direct exposure was estimated by measuring dep-
osition (on skin, clothing, or surrogate patch) or by ambient air
concentrations of the potentially toxic agent (Durham and Wolfe,
1962). In reality, direct exposure should be attributed only to pes-
ticide residues gaining entry into the body by systemic absorption
following ingestion, inhalation, and/or transdermal penetration. To-
tal exposure can be estimated by measuring excretory products (the
parent chemical, degradation products) in urine and feces over a
suitable postexposure time interval (Durham et al., 1972;
Kolmodin-Hedmann et al., 1983; Frank et al., 1985; Grover et al.,
1986; Takamiya, 1994; Azaroff, 1999). Potential biological effects
of exposure can be monitored, including plasma and erythrocy-
tic cholinesterase measurements, -aminolevulinic dehydratase
(ALAD), superoxide dismutase (SOD) activities, cytogenic analy-
Table 22-4
Percent of Total Body Surface Area Represented by Body
Regions*
SURFACE AREA
BODY REGION (% OF TOTAL)

Head 5.60
Table 22-3
Neck 1.20
Estimated Surface Area of Exposed Portions of a Body
Upper arms 9.70
of a Casually Dressed Individual
Forearms 6.70
SURFACE AREA PERCENT OF Hands 6.90
UNCLOTHED SURFACE (SQ FT) TOTAL Chest, back, shoulders 22.80
Hips 9.10
Face 0.70 22.0 Thighs 18.00
Hands 0.87 27.6 Calves 13.50
Forearms 1.30 41.3 Feet 6.40
Back of neck 0.12 3.8
Front of neck and “v” of chest 0.16 5.1 *Estimated proportions from the “50 percentile man” having a surface area of 1.92 m2,
height of 175 cm, and body weight of 78 kg.
SOURCE: Batchelor and Walker, 1954. SOURCE: Spear et al., 1977.
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
sis of lymphocytic micronuclei, semen quality, fertility, etc.
(Lopez-Carillo and Lopez-Cervantes, 1993; Ciesielski et al., 1994;
Davies et al., 1998; Panemangalore et al., 1998; Venegas et al.,
1998; Larsen et al., 1999). A more complete discussion of the topic
of occupational exposure can be found in Ecobichon (1998a).
Minimal protection of certain parts of the body can markedly
reduce exposure to an agent. Protection of the hands (5.6 percent
of the body surface) by appropriate chemical-resistant gloves may
reduce contamination by 33 percent (in forest spraying with a knap-
sack sprayer having a single-nozzle lance), by 66 percent (in weed
control using tractor-mounted booms equipped with hydraulic noz-
zles), or by 86 percent (involving filling tanks on tractor-powered
sprayers) (Bdonsall, 1985). Studies monitoring the absorption of
pesticides applied to the skin of different areas of the human body
have revealed marked regional variations in per cutaneous absorp-
tion, with the greatest uptake being in the scrotal region, followed
by the axilla, forehead, face, scalp, the dorsal aspect of the hand,
the palm of the hand, and the forearm in decreasing order (Feldman
and Maiback, 1974).
The exposure of a bystander, where an individual is acciden-
tally sprayed directly or exposed to aerial off-target drifting aerosol,
is considerably more difficult to assess. The levels encountered may
be severalfold lower than those in the occupational setting, mak-
ing the analysis of residue and the detection of meaningful bio-
logical changes more difficult. Greater variation in exposure esti-
mates and biological effects can be anticipated. The adverse health
effects may be subtle in appearance and nonspecific, reflecting a
slow deterioration of physiologic function clouded by the individ-
ual’s adjustment or adaptation to the changes, taking many years
to develop to the point of detection. The identification of pesticide-
related adverse health effects in the general population, who inad-
vertently acquire low levels of pesticides daily via food and water,
is extremely difficult. The residue levels in these media are often
orders of magnitude lower than those encountered in occupational
or bystander exposure and are at or near the limits of analytical
detection by sophisticated techniques. Any biological effects re-
sulting from such low-level exposure are unlikely to be distinctive
and any causal association with a particular chemical or class of
agents is likely to be tenuous and confounded by many other fac-
tors of a given lifestyle.
Many of the public concerns about pesticides are related to
“older” chemicals, these having entered the market in the 1950s
and 1960s without the benefit of the extensive toxicity and envi-
ronmental impact studies demanded prior to the registration of
chemicals today. It must also be pointed out that many of these
older pesticides have received little reassessment using the more
definitive techniques and protocols required today. Although gov-
ernment agencies and industry have been slow in their reevalua-
tion of a vast array of pesticides in use, reassessment often comes
in the wake of or concomitant with some recently disclosed ad-
verse environmental or health effect. Given the above-mentioned
costs of conducting a full range of studies (introductory section,
this chapter), the time frame required, and the limited market for
some of these chemicals in North America or even worldwide, the
registration of many of these pesticides will be withdrawn volun-
tarily by industry, and the answers to some of the public’s con-
cerns will never be obtained. Hazardous chemicals will be removed
from use but, unfortunately, it is possible that some very benefi-
cial and essential pesticides will be lost. The problems of today’s
situation, created by the last generation and inherited by the pres-
ent one, still must be dealt with.
769
INSECTICIDES
The literature pertaining to the chemistry and development of the
various classes of insecticides over the past 45 years is extensive
and the reader is referred to the monographs of O’Brien (1960,
1967), Melnikov (1971), Fest and Schmidt (1973), Brooks (1974),
Eto (1974), Hayes (1982), Kuhr and Dorough (1976), Buchel
(1983), Leahey (1985), Chambers and Levi (1992), and Ecobichon
and Joy (1994) for detailed discussions of the chemistry, nomen-
clature (chemical, common, and trade names), biotransformation
and degradation, and environmental effects as well as target and
nontarget species toxicity. Compilations of LD50 values in the lab-
oratory rat may be found in Gaines (1969), Frear (1969), and
Worthing (1987). Acute toxicity data for laboratory animals, fish,
and wildlife are recorded in a number of reports (Pickering et al.,
1962; Tucker and Crabtree, 1970; Worthing, 1987). Several com-
pilations of pesticide monographs exist, giving brief but succinct
profiles of the physical and chemical properties of various
pesticides as well as their environmental persistence and toxicity
to wildlife, domestic animals, and humans (Kamrin, 1997;
Montgomery, 1997; Tomlin, 1997). Only selected examples of the
classes of insecticides are discussed in this chapter, with emphasis
on their toxicity to humans.
All of the chemical insecticides in use today are neurotoxi-
cants and act by poisoning the nervous systems of the target
organisms. The central nervous system (CNS) of insects is highly
developed and not unlike that of the mammal (O’Brien, 1960).
While the peripheral nervous system (PNS) of insects is not as
complex as that of mammals, there are striking similarities
(O’Brien, 1960). The development of insecticides has been based
on specific structure-activity relationships requiring the manipula-
tion of a basic chemical structure to obtain an optimal shape and
configuration for specificity toward a unique biochemical or phys-
iologic feature of the nervous system. Given the fact that insecti-
cides are not selective and affect nontarget species as readily as
target organisms, it is not surprising that a chemical that acts on
the insect’s nervous system will elicit similar effects in higher forms
of life. The target sites and/or mechanism(s) of action may be sim-
ilar in all species; only the dosage (level of exposure and duration)
will dictate the intensity of biological effects. It is sufficient at this
stage to indicate the potential sites of action of the insecticide
classes (Fig. 22-5) and their interference with the membrane trans-
port of sodium, potassium, calcium, or chloride ions; inhibition of
selective enzymatic activities; or contribution to the release and/or
the persistence of chemical transmitters at nerve endings.
Organochlorine Compounds
No longer considered an important class of insecticides in North
America and Europe, the organochlorine insecticides see contin-
ued use in developing, tropical countries because they are effec-
tive, inexpensive, essential chemicals in agriculture, forestry, struc-
tural protection, and public health. The risk-benefit ratio is highly
weighted in favor of their continued use for the control of insects
causing devastation to crops and human health. For example,
technical-grade hexachlorocyclohexane (HCH), banned in Canada,
the United States, China, the Soviet Union, and Australia in 1971,
1976, 1983, 1990 and 1994, respectively, still sees extensive use
in a number of African nations, Brazil, India, and others (Li, 1999).
While banned in the early 1970s, DDT was still being manufac-
tured in the United States and exported at the rate of 1 ton per day
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770 UNIT 5 TOXIC AGENTS

demise because of their persistence in the environment, biocon-

centration and biomagnification in food chains, and the acquisition
of biologically active body burdens at higher trophic levels (Carson,
1962). Definitive studies in wild, domestic, and laboratory species
demonstrated potent enzyme-inducing and/or estrogenic proper-
ties, with interference indirectly or directly with fertility and re-
production (Stickel, 1968; McFarland and Lacy, 1969; Peakall,
1970; Longcore et al., 1971; McBlain et al., 1977; Crum et al.,
1993).
The organochlorine (chlorinated hydrocarbon) insecticides are
a diverse group of agents belonging to three distinct chemical
classes including the dichlorodiphenylethane-, chlorinated cyclo-
diene- and chlorinated benzene- and cyclohexane-related structures
(Table 22-5). The historical development of these chemicals from
the mid-1940s and their impact on agriculture and human health
can be found in O’Brien (1967), Metcalf (1973), and Brooks
(1974).

Signs and Symptoms of Poisoning Given the diversity of chem-

Figure 22-5. Potential sites of action of classes of insecticides on the
axon and terminal portions of the nerve.
in 1994 (Smith, 1995). Global transport of such chemicals from
equatorial regions to Arctic and Antarctic regions, with contami-
nation of wildlife food sources, suggests that these agents are still
toxicologically important. Currently, major concerns are centered
on the indigenous people living in Arctic regions, where the sources
of dietary protein (fish, seals, walruses, whales, etc.) have proven
to be major depositories of organochlorine insecticides and other
chlorinated hydrocarbons (PCBs, PBBs, PCDDs, PSDFs) (Berti et
al., 1998; Chan, 1998).
The properties (low volatility, chemical stability, lipid solu-
bility, slow rate of biotransformation and degradation) that made
these chemicals such effective insecticides also brought about their
ical structures, it is not surprising that the signs and symptoms of
toxicity and the mechanisms of action are somewhat different
(Table 22-6).
Exposure of humans and animals to high oral doses of DDT
results in paresthesia of the tongue, lips, and face; apprehension;
hypersusceptibilty to external (light, touch, sound) stimuli; irri-
tability, dizziness, and vertigo; tremor and tonic and clonic con-
vulsions. Motor unrest and fine tremors associated with voluntary
movements progress to coarse tremors without interruption in mod-
erate to severe poisonings. Symptoms generally appear several
hours (6 to 24 h) after exposure to large doses. Little toxicity is
seen following the dermal exposure to DDT, presumably because
the agent is poorly absorbed through the skin, a physiologic phe-
nomenon that has contributed to the fairly good safety record of
DDT despite careless handling by applicators and formulators
(Hayes, 1971). It has been estimated that a dose of 10 mg/kg will
cause signs of poisoning in humans. Chronic exposure to moder-
ate concentrations of DDT causes somewhat milder signs to toxi-
city, as listed in Table 22-6.

Table 22-5
Structural Classification of Organochlorine Insecticides

Dichlorodiphenylethanes DDT, DDD

Cl CH Cl Dicofol
Perthane
C
Methoxychlor
Methlochlor
Cyclodienes Cl Aldrin, Dieldrin
Cl Heptachlor
C(CCl)2 Chlordane
Endosulfan
Cl
Cl Cl

Chlorinated benzenes Cl HCB, HCH

Cyclohexanes Cl Cl Lindane (-BHC)

Cl Cl
(Cl)6
Cl
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES 771

Table 22-6
Signs and Symptoms of Acute and Chronic Toxicity Following Exposure to Organochlorine Insecticides

INSECTICIDE CLASS ACUTE SIGNS CHRONIC SIGNS

Dichlorodiphenylethanes
DDT Parethesia (oral ingestion) Loss of weight, anorexia
DDD (Rothane) Ataxia, abnormal stepping Mild anemia
DMC (Dimite) Dizziness, confusion, headache Tremors
Dicofol (Kelthane) Nausea, vomiting Muscular weakness
Methoxychlor Fatigue, lethargy EEG pattern changes
Methiochlor Tremor (peripheral) Hyperexcitability, anxiety
Chlorbenzylate Nervous tension

Hexachlorocyclohexanes
Lindane (-isomer)
Benzene hexachloride (mixed isomers)
Cyclodienes
Endrin Dizziness, headache Headache, dizziness,
Telodrin Nausea, vomiting hyperexcitability
Isodrin Motor hyperexcitability Intermittent muscle twitching
Endosulfan Hyperreflexia and myoclonic jerking
Heptachlor Myoclonic jerking Psychological disorders
Aldrin General malaise including insomnia,
Dieldrin Convulsive seizures anxiety, irritability
Chlordane Generalized convulsions EEG pattern changes
Toxaphene Loss of consciousness
Epileptiform convulsions
Chlordecone (Kepone) Chest pains, arthralgia
Mirex Skin rashes
Ataxia, incoordination, slurred
speech, opsoclonus
Visual difficulty, inability to
focus and fixate
Nervousness, irritability, depression
Loss of recent memory
Muscle weakness, tremors of
hands
Severe impairment of spermatogenesis

Although the functional injury of DDT poisoning can be as-
sociated with effects on the CNS in humans, few pathologic
changes can be demonstrated in CNS tissue in animals. However,
following exposure to moderate or high nonfatal doses or subse-
quent to subacute or chronic feeding, major pathologic changes are
observed in the liver and reproductive organs. Morphologic
changes in mammalian liver include hypertrophy of hepatocytes
and subcellular organelles such as mitochondria, proliferation of
smooth endoplasmic reticulum and the formation of inclusion bod-
ies, centrolobular necrosis following exposure to high concentra-
tions, and an increase in the incidence of hepatic tumors (Hayes,
1959; Hansell and Ecobichon, 1974; IARC, 1974). However, there
has yet to be conclusive epidemiologic evidence linking DDT to
carcinogenicity in humans (Hayes, 1982; Baris et al., 1998;
Takayama et al., 1999). When technical-grade DDT (20 percent
o,p-DDT plus 80 percent p,p-DDT) was administered to male
cockerels or rats, reduced testicular size was observed and, in fe-
male rats, the estrogenic effects of the o,p-isomer were observed
in the edematous, blood-engorged uteri (Hayes, 1959; Ecobichon
and MacKenzie, 1974). The o,p-isomer has been shown to com-
pete with estradiol for binding the estrogen receptors in rat uterine
cytosol (Kupfer and Bulger, 1976). The DDT analog methoxychlor
[1,1,1-trichloro-2,2-bis(4-methoxyphenyl) ethane] is estrogenic in
the mouse; problems in initiating and/or maintaining a pregnancy
are seen, due possibly to alterations in preimplantation embryonic
development and estrogenic effects on the oviduct and uterus (Hall
et al., 1997; Swartz and Eroschenko, 1998).
Dicofol (p-p-dichlorodiphenyl-2,2,2-trichloroethanol) — an
analog of DDT still registered as an agricultural miticide for cot-
ton, beans, citrus, and grapes—has been associated with acute tox-
icity (nausea, dizziness, double vision, ataxia, confusion, disorien-
tation) in a 12-year-old male whose clothing because saturated in
an accident (Lessenger and Riley, 1991). These acute effects pro-
gressed to chronic signs (headaches, blurred vision, horizontal nys-
tagmus, numbness/tingling in the legs with shooting pains, clum-
siness, memory loss and decreasing academic performance,
impulsive behavior, restlessness and fatigue), which persisted in
some fashion for up to 4 months. Continuing emotional and aca-
2996R_ch22_761-810 4/16/01 4:37 PM Page 772
772 UNIT 5 TOXIC AGENTS
demic difficulties, impairment of certain cognitive skills, poor self-
esteem and depression, all of which were subtle cognitive and psy-
chological changes, persisted for over 18 months. Dicofol is known
to be contaminated by a small percentage of p-p-DDT, showing
estrogenicity in birds (Peakall, 1970).
Unlike the situation with DDT, in which there have been few
recorded fatalities following poisoning, there have been a number
of fatalities following poisoning by the cyclodiene- and hexa-
chlorocyclohexane-type insecticides. The chlorinated cyclodiene
insecticides are among the most toxic and environmentally per-
sistent pesticides known (Hayes, 1982). One recent study of two
patients, one with a history of chronic exposure to aldrin and the
other with a chronic exposure to lindane/heptachlor, reported death
within 2 years of developing clinical and electromyographic signs
and symptoms of chronic motor disease with aggravation of dys-
phagia and weight loss resulting in the mobilization of adipose tis-
sue and stored insecticide to enhance the neuronal toxicity (Fon-
seca et al., 1993). Even at low doses, these chemicals tend to induce
convulsions before less serious signs of illness occur. Although the
sequence of signs generally follows the appearance of headaches,
nausea, vertigo, and mild clonic jerking, motor hyperexcitability,
and hyperreflexia, some patients have convulsions without warn-
ing symptoms (Hayes, 1982). An important difference between
DDT and the chlorinated cyclodienes is that the latter are efficiently
absorbed through the skin and therefore pose an appreciable haz-
ard to occupationally exposed individuals. Chronic exposure to low
or moderate concentrations of these agents elicits a spectrum of
signs and symptoms, involving both sensory and motor compo-
nents of the CNS (Table 22-6). In addition to the recognized neu-
rotoxicity, aldrin and dieldrin interfere with reproduction, with in-
creased pup losses (vitality, viability) being reported in studies in
rats and dogs (Kitselman, 1953; Treon and Cleveland 1955). Treat-
ment with dieldrin during pregnancy caused a reduction in fertil-
ity and increased pup mortality (Treon and Cleveland, 1955). The
treatment of pregnant mice with dieldrin resulted in teratologic ef-
fects (delayed ossification, increases in supernumerary ribs) (Cher-
noff et al., 1975).
Exposure to lindane (the -isomer of hexachlorocyclohexane,
HCH) produces signs of poisoning that resemble those caused by
DDT (e.g., tremors, ataxia, convulsions, stimulated respiration,
and prostration). In severe cases of acute poisoning, violent tonic and
clinic convulsions occur and degenerative changes in the liver and
renal tubules have been noted. Technical-grade HCH used in in-
secticidal preparations contains a mixture of isomers: the - and
-isomer are convulsant poisons; the - and -isomers are CNS
depressants. The mechanisms of action remain unknown. Lifetime
feeding studies in mice have revealed that technical-grade HCH
and some of the isomers caused an increase in hepatocellular tu-
mors (IARC, 1974). Only the -isomer (lindane) sees any medic-
inal use today, as a component of a pediculicide shampoo for head
lice. One undocumented case of lindane toxicity, known to the au-
thor, resulted in mild tremors in a child on whose head the sham-
poo was used vigorously and repeatedly for more than a week. The
symptoms disappeared rapidly when the treatment was terminated.
Industrial carelessness during the manufacture of an
organochlorine compound chlordecone (Kepone) brought this
agent and mirex, the closely related insecticide, to the attention of
toxicologists in 1975, when 76 of 148 workers in a factory in
Hopewell, Virginia, developed a severe neurologic syndrome
(Cannon et al., 1978; Taylor et al., 1978; Guzelian, 1982). This
condition, known as the “Kepone shakes,” was characterized by
tremors, altered gait, behavioral changes, ocular flutter (opso-
clonus), arthralgia, headache, chest pains, weight loss, he-
patomegaly, splenomegaly, and impotence, the onset of symptoms
generally occurring with a latency of approximately 30 days from
the initiation of exposure and persisting for many months after the
termination of exposure (Joy, 1994a). Laboratory tests showed a
reduced sperm count and reduced sperm motility. Routine neuro-
logic studies showed nothing untoward, but microscopic examina-
tion of biopsies of the sural nerve revealed relative decreases in the
populations of small myelinated and unmyelinated axons. With
electron microscopy, a number of abnormalities were visible; the
significant findings included damage to Schwann cells (membra-
nous inclusions, cytoplasmic folds), prominent endoneural collagen
pockets, vacuolization of unmyelinated fibers, focal degeneration
of axons with condensations of neurofilaments and neurotubules,
focal interlamellar splitting of myelin sheaths, and the formation
of myelin bodies and a complex infolding of inner mesaxonal mem-
branes into axoplasm (Martinez et al., 1977). The involvement of
unmyelinated fibers and small myelinated fibers may partially ex-
plain the clinical picture. It has been suggested that chlordecone
may interfere with metabolic processes in Schwann cells. How-
ever, it should be noted that all of these degenerative changes are
nonspecific in nature and are commonly seen in other toxic
polyneuropathies. Many of the toxic manifestations of chlordecone
poisoning in these workers have been confirmed in animal studies,
the major target organs being the CNS, liver, adrenals, and testes,
as summarized by Joy (1994a). As with other organochlorine in-
secticides, chlordecone is an excellent inducer of hepatic micro-
somal monooxygenase enzymes and, in rats and mice, has been
associated with the formation of hepatomas and malignant tumors
in organs other than the liver, female animals being more suscep-
tible than male (Guzelian, 1982). In many ways, mirex behaves
like chlordecone, and there is evidence for the oxidative biotrans-
formation of mirex to chlordecone in vivo. Mirex causes he-
patomegaly and a dose-dependent increase in neoplastic nodules
and hepatocellular carcinomas, particularly in male animals (Innes
et al., 1969; Waters et al., 1977).
Site and Mechanism of Toxic Actions Essential to the action of
organochlorine insecticides is an intact reflex are consisting of af-
ferent (sensory) peripheral neurons impinging on interneurons in
the spinal cord, with accompanying ramifications and intercon-
nections up and down the CNS and interactions with efferent mo-
tor neurons, as shown schematically in Fig. 22-6. In terms of the
mechanism of action of the DDT-type insecticides, the most strik-
ing observation in a poisoned insect or mammal is the display of
periodic sequences of persistent tremoring and/or convulsive
seizures suggestive of repetitive discharges in neurons. These char-
acteristic episodes of hyperactivity interspersed with normal func-
tion were recognized as early as 1946. The second most striking
observation is that these repetitive tremors, seizures, and electrical
activity can be initiated by tactile and auditory stimuli, suggesting
that the sensory nervous system appears to be much more respon-
sive to stimuli. An examination of the sequence of electrical events
in normal and DDT-poisoned nerves reveals that, in the latter, a
characteristic prolongation of the falling phase of the action po-
tential (the negative afterpotential) occurs (Fig. 22-7). The nerve
membrane remains in a partially depolarized state and is extremely
sensitive to complete depolarization again by very small stimuli
(Joy, 1994a). Thus, following exposure to DDT, the repetitive stim-
ulation of the peripheral sensory nerves by touch or sound is mag-
2996R_ch22_761-810 4/18/01 7:58 AM Page 773
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
Figure 22-6. A simple, intact reflex arc involving a peripheral, afferent
(sensory) neuron, interneurons, and a peripheral, efferent (motor) neu-
ron that innervates a muscle.
nified in the CNS, causing generalized tremoring throughout the
body.
How does DDT elicit this effect? There are at least four mech-
anisms, possibly all functioning simultaneously (Matsumura,
1985), as seen in Fig. 22-8. At the level of the neuronal membrane,
DDT affects the permeability to potassium ions, reducing potas-
sium transport across the membrane. DDT alters the porous chan-
nels through which sodium ions pass. These channels activate
(open) normally, but, once open, are inactivated (closed) slowly,
thereby interfering with the active transport of sodium out of the
nerve axon during repolarization. DDT inhibits neuronal adenosine
triphosphatase (ATPase), particularly the Na,K-ATPase and
Ca2-ATPase, which play vital roles in neuronal repolarization.
DDT also inhibits the ability of calmodulin, a calcium mediator in
nerves, to transport calcium ions essential for the intraneuronal re-
lease of neurotransmitters. All of these inhibited functions reduce
the rate at which depolarization occurs and increase the sensitiv-
ity of the neurons to small stimuli that would not elicit a response
in a fully depolarized neuron.
The chlorinated cyclodiene-, benzene-, and cyclohexane-type
insecticides are different from DDT in many respects, both in the
appearance of the intoxicated individual and possibly also in the
mechanism(s), which appear to be localized more in the CNS than
Figure 22-7. A schematic diagram of an oscilloscope recording of the
depolarization and repolarization of a normal neuron ( ——— ) and one
from a DDT-treated (---) animal, showing the prolonged, negative after-
potential (AP).
773
Figure 22-8. Proposed sites of action of DDT on (1) reducing potassium
transport through pores, (2) inactivating sodium channel closure, (3) in-
hibiting sodium-potassium and calcium-magnesium ATPases, and (4)
calmodulin-calcium binding with the release of neurotransmitter.
in the sensory division of the PNS (Table 22-6). The overall ap-
pearance of the intoxicated individual is one of CNS stimulation.
As shown in Fig. 22-9, the cyclodiene compounds antagonize the
action of the neurotransmitter gamma-aminobutyric acid (GABA)
acting at the GABAA receptors in rat dorsal root ganglia and ef-
fectively blocking the GABA-induced uptake of chloride ions by
desensitizing the current in the receptor-channel complex (Nagata
and Narahashi, 1994). A more recent paper explains the fact that
dieldrin has a dual effect on the GABAA receptor-channel: an ini-
tial enhancement of the GABA-induced chloride ion current (with
an EC50 of 754 nM) followed by a suppression (Narahashi et al.,
1995). Two types of chloride currents exist, one having a high sen-
sitivity to dieldrin (IC50  5 nM) and the other having a lower
sensitivity to dieldrin (IC50  92 nM). The dieldrin-suppressive
action is responsible for the hyperactivity observed in poisoned an-
imals. The nature of the GABAA receptor-channel is still being
explored. The cyclodienes are also potent inhibitors of Na,K-
ATPase and, more importantly, of the enzyme Ca2, Mg2-ATPase
essential for the transport (uptake and release) of calcium across
membranes (Matsumura, 1985; Wafford et al., 1989). Evidence
suggests that gamma-hexachlorocyclohexane (-HCH, lindane)
neurotoxicity is primarily related to the blockade of chloride ion
flux through the inotropic GABAA receptors, resulting in depolar-
ization and hyperexcitation of post-synaptic membranes (Mat-
sumura and Tanaka, 1984). There is also evidence that -HCH can
alter calcium homeostasis, elevating free calcium ion levels intra-
cellularly with the release of neurotransmitters (Joy, 1994a). The
inhibition of Ca2, Mg2-ATPase, located in the terminal ends of
neurons in synaptic membranes, results in an accumulation of in-
tracellular free calcium ions with the promotion of calcium-induced
2996R_ch22_761-810 4/16/01 4:37 PM Page 774
774 UNIT 5 TOXIC AGENTS
Figure 22-9. Proposed sites of action of cyclodiene-type organochlorine
insecticides on chloride ion transport through inhibition of the GABAA
receptor channel as well as inhibition of calcium-magnesium ATPase.
release of neurotransmitters from storage vesicles and the subse-
quent depolarization of adjacent neurons and the propagation of
stimuli throughout the CNS.
Biotransformation, Distribution, and Storage The phenome-
non of bioconcentration and biomagnification of the organochlo-
rine insecticides in food chains has been mentioned. Once acquired,
biotransformation/degradation proceeds at an exceptionally slow
pace, in part due to the complex aromatic ring structures and the
number of the chlorine substituents, the latter being exceedingly
difficult to remove by the enzymatic processes available in tissues.
The biotransformation of the various organochlorines has been ex-
tensively studied—for example, DDT (Ecobichon and Saschen-
brecker, 1968), aldrin and heptachlor conversion to dieldrin and
heptachlor epoxide, respectively (Keane and Zavon, 1969;
Matthews and Matsumura, 1969); chlordane (Menzie, 1969); hexa-
chlorocyclohexane (Egan et al., 1965; O’Brien, 1967; Abbott et al.,
1969); and toxaphene (Saleh et al., 1977; Turner et al., 1977). With
the exception of aldrin, chlordane, and heptachlor, most biotrans-
formation reactions reduce the neurotoxicant activities but mar-
ginally affect the weak estrogenicity of the agents.
Slow biotransformation, in addition to the highly lipophilic
nature of the organochlorine compounds, guarantees that these
agents will be sequestered in body tissue having a high lipid con-
tent, where some biological action may result. In the case of adi-
pose tissue, the agents will remain stored and undisturbed, only
small amounts equilibrating with the blood and being degraded
and/or excreted (Dale and Quinby, 1963; Davies et al., 1972). The
depuration of these chemicals from systems occurs slowly, in a
matter of a few weeks for chlordane, and months to years for
aldrin/dieldrin, DDT, and others (Laben et al., 1965; Ecobichon
and Saschenbrecker, 1969; Craan and Haines, 1998; Delorme et
al., 1999).
It is not surprising that humans acquired body burdens of these
chemicals during the 1950s and 1960s, when they were used on
almost all food crops. Depending on the region of the world, the
intensity of use, the extent of occupational and accidental expo-
sure, and dietary habits, the bioconcentration/bioaccumulation of
DDT in human adipose tissue resulted in levels on the order of
5 ppm DDT and approximately 15 ppm of total DDT-derived
material (Quinby et al., 1965; Fiserova-Bergerova et al., 1967;
Abbott et al., 1968; Morgan and Roan, 1970). The levels of other
organochlorine insecticides sequestered in body fat were never as
high as those of DDT. With declining use and the eventual ban of
this class on insecticides from the North American market, body
burdens of these insecticides declined slowly. By the late 1960s,
adipose levels of 2 ppm DDT(0 ppm of total DDT-derived mate-
rial) were detectable. Whereas the daily intake of DDT in the
United States was approximately 0.2 mg/day in 1958, this had de-
creased to about 0.04 mg/day by 1970 (Hayes, 1971). Today, only
trace levels of DDT, less than 2.0 ppm of total DDT-derived
material, are detectable in human adipose tissue (Mes et al., 1982;
Redetzke and Applegate, 1993; Stevens et al., 1993).
Treatment of Poisoning The life-threatening situation in
organochlorine insecticide poisoning is associated with tremors,
motor seizures, and interference with respiratory function (hypox-
emia and resulting acidosis) arising from repetitve stimulation of
the CNS. In addition to general decontamination and supportive
treatment, diazepam (0.3 mg/kg IV; maximum dose of 10 mg) or
phenobarbital (15 mg/kg IV; maximum dose of 1.0 g) may be ad-
ministered by slow injection to control the convulsions. It may be
necessary to repeat the treatment.
Anticholinesterase Agents
The agents comprising this type of insecticide have a common
mechanism of action but arise from two distinctly different chem-
ical classes, the esters of phosphoric or phosphorothioic acid and
those of carbamic acid (Fig. 22-10). The anticholinesterase insec-
ticides are represented by a vast array of structures that have
demonstrated the ultimate in structure-activity relationships in at-
tempts to produce potent and selective insect toxicity while mini-
mizing the toxicity toward nontarget species. Today, there are some
200 different organophosphorus ester insecticides and approxi-
mately 25 carbamic acid ester insecticides in the marketplace, for-
mulated into literally thousands of products. For detailed discus-
sions on the nomenclature, chemistry, and development of these
insecticides, the reader is referred to the books of O’Brien (1960),
Heath (1961), Melnikov (1971), Fest and Schmidt (1973), Eto
(1974), Kuhr and Dorough (1976), Ecobichon and Joy (1994), and
Matsumura (1985) and a review by Holmstedt (1959).
The organophosphorus ester insecticides were first synthe-
sized in 1937 by a group of German chemists led by Gerhard
Schrader at Farbenfabriken Bayer AG (Schrader and Kukenthal,
1937). Many of their trial compounds proved to be exceedingly
toxic and unfortunately, under the management of the Nazis in
World War II, some were developed as potential chemical warfare
agents. It is unwise to dismiss the chemical warfare nerve gases
completely as the weapons of a past, more barbaric era, because it
is known that at least one country has stocks of a number of these
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
Figure 22-10. The basic backbone structures of the two types of anti-
cholinesterase-class insecticides, the organophosphorus and carbamate
esters.
agents (Fig. 22-11) (Clement, 1994; Gee, 1992). The physico-
chemical and toxicologic properties of these agents have been re-
viewed (Sidell, 1992; Somani et al., 1992). Sarin (O-isopropyl
methylphosphonofluoridate) was used in Iraq against Kurdish vil-
lages in northern Iraq in 1988 and residues of isopropyl
methylphosphonic acid were found in soil samples along with
minute traces of sarin (Webb, 1993). These potent agents should
not be ignored, since they are relatively easy to manufacture in
small amounts and have been the toxicants of choice of terrorists
in at least two documented attacks in Japan, in Matsumoto on June
27, 1994 (Morita et al., 1995), and in the Tokyo subway on March
20, 1995 (Masuda et al., 1995; Nazaki and Aikowa, 1995; Nazaki
et al., 1995; Suzuki et al., 1995). The acute and chronic toxicologic
effects of these incidents are discussed below.
Although it is true that all of the organoposphorus esters were
derived from “nerve gases” (chemicals such as soman, sarin, and
tabun), a fact that the media continually emphasizes, the insecti-
cides used today are at least four generations of development away
from those highly toxic chemicals. The first organophosphorus es-
ter insecticide to be used commercially was tetraethylpyrophos-
phate (TEPP); although effective, it was extremely, toxic to all
forms of life and chemical stability was a major problem in that
TEPP hydrolyzed readily in the presenced of moisture. Further de-
velopment was directed toward the synthesis of more stable chem-
icals having moderate environmental persistence, giving rise to
parathion (O,O-diethyl-O-p-nitrophenyl phosphorothioate, E-605)
in 1944 and the oxygen analog paraoxon (O,O-diethyl-O-p-nitro-
phenyl phosphate) at a later date. Although these two chemicals
had the properties desired in an insecticide (low volatility, chemi-
cal stability in sunlight and in the presence of water, environmen-
tal persistence for efficacy), they both exhibited a marked mam-
malian toxicy and were unselective with respect to target and
nontarget species. The replacement of DDT with parathion in the
1950s resulted in a series of fatal poisonings and bizarre accidents
arising from the fact that workers did not appreciate that this agent
was far different from the relatively innocuous organochlorine in-
secticides with which they were familiar (Ecobichon, 1994a). The
number of severe poisonings attributed to parathion provided the
775
stimulus for a search for analogs more selective in their toxicity to
target species and less toxic to nontarget organisms, including
wildlife, domestic stock, and humans.
The first pesticidal carbamic acid esters were synthesized in
the 1930s and were marketed as fungicides. Since these aliphatic
esters possessed poor insecticidal activity, interest lay dormant un-
til the mid-1950s, when renewed interest in insecticides having an-
ticholinesterase activity but reduced mammalian toxicity led to the
synthesis of several potent aryl esters of methylcarbamic acid. The
insecticidal carbamates were synthesized on purely chemical
grounds as analogs of the drug physostigmine, a toxic anti-
cholinesterase alkaloid extracted from the seeds of the plant
Physostigma venenosum, the Calabar bean.
Signs and Symptoms of Poisoning Although their structures are
diverse in nature, the mechanism by which the organophosphorus
and carbamate ester insecticides elicit their toxicity is idential and
is associated with the inhibition of the nervous tissue acetyl-
cholinesterase (AChE), the enzyme responsible the the destruction
and termination of the biological activity of the neurotransmitter
acetylcholine (ACh). With the accumulation of free, unbound ACh
at the nerve endings of all cholinergic nerves, there is continual
stimulation of electrical activity. The signs of toxicity include those
resulting from stimulation of the muscarinic receptors of the
parasympathetic autonomic nervous system (increased secretions,
bronchoconstriction, miosis, gastrointestinal cramps, diarrhea, uri-
nation, bradycardia); those resulting from the parasympathetic di-
visions of the autonomic nervous system as well as the junctions
between nerves and muscles (causing tachycardia, hypertension,
muscle fasciculation, tremors, muscle weakness, and/or flaccid
paralysis); and those resulting from effects on the CNS (restless-
ness, emotional liability, ataxia, lethargy, mental confusion, loss of
memory, generalized weakness, convulsion, cyanosis, coma)
(Table 22-7).
The classic picture of anticholinesterase insecticide intoxica-
tion, first described by DuBois (DuBois, 1948; DuBois et al., 1949),
has become more complicated in recent years by the recognition
of additional and persistent signs of neurotoxicity not previously
associated with these chemicals. First, and frequently associated
with exposure to high concentrations of the insecticides (resulting
from suicide attempts or drenching with dilute or concentrated
Figure 22-11. Structures of the organophosphorus ester chemical war-
fare nerve gases, the forerunners of the organophosphorus ester insecti-
cides.
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776 UNIT 5 TOXIC AGENTS

Table 22-7
Signs and Symptoms of Anticholinesterase Insecticide Poisoning

NERVOUS TISSUE AND RECEPTORS

AFFECTED SITE AFFECTED MANIFESTATIONS

Parasympatheic autonomic Exocrine glands Increased salivation, lacrimation, perspiration

(muscarinic receptors)
postganglionic nerve fibers
Parasympathetic and sympathetic
autonomic fibers
(nicotinic receptors)
Somatic motor nerve fibers
(nicotine receptors)
Brain (acetylcholine receptors)
Eyes Miosis (pinpoint and nonreactive), ptosis, blurring of
vision, conjunctival injection, “bloody tears”
Gastrointestinal tract Nausea, vomiting, abdominal tightness, swelling and
cramps, diarrhea, tenesmus, fecal incontinence
Respiratory tract Excessive bronchial secretions, rhinorrhea, wheezing,
edema, tightness in chest, bronchospasms, broncho-
constriction, cough, bradypnea, dyspnea
Cardiovascular system Bradycardia, decrease in blood pressure
Bladder Urinary frequency and incontinence
Cardiovascular system Tachycardia, pallor, increase in blood pressure
Skeletal muscles Muscle fasciculations (eyelids, fine facial muscles),
cramps, diminished tendon reflexes, generalized muscle
weakness in peripheral and respiratory muscles,
paralysis, flaccid or rigid tone
Restlessness, generalized motor activity, reaction to
acoustic stimuli, tremulousness, emotional lability,
ataxia
Central nervous system Drowsiness, lethargy, fatigue, mental confusion, inability
to concentrate, headache, pressure in head, generalized
weakness
Coma with absence of reflexes, tremors, Cheyne-Stokes
respiration, dyspnea, convulsions, depression of
respiratory centers, cyanosis

SOURCE: Ecobichon and Joy, 1982.

chemicals), are effects that may persist for several months follow-
ing exposure and may involve neurobehavioral, cognitive, and
neuromuscular functions (Marrs, 1993; Ecobichon, 1994a; Jamal,
1997; Ecobichon, 1998b). One author describes this as a chronic
organophosphate-induced neuropsychiatric disorder (COPIND)
(Jamal, 1997). The first evidence of this type of syndrome, delayed
psychopathologic-neurologic lesions, was reported by Spiegelberg
(1963), who had been studying workers involved in the production
and handling of the highly toxic nerve gases in Germany during
World War II. The characteristic symptomatology subdivided these
patients into two distinct groups. The first and largest group was
characterized by persistently lowered vitality and ambition; defec-
tive autonomic regulation leading to cephalalgia and gastrointesti-
nal and cardiovascular symptoms; premature decline in potency
and libido; intolerance to alcohol, nicotine, and various medicines;
and an impression of premature aging. The second group, in addi-
tion to the above symptoms, showed one or more of the following:
depressive or subdepressive disorders of vital function; cerebral
vegetative (syncopal) attacks; slight or moderate amnestic or de-
mential effects; and slight organoneurologic defects. These symp-
toms developed and persisted for some 5 to 10 years following
exposure to these most toxic organophosphorus esters during the
war years. The controversial paper of Gershon and Shaw (1961),
a study of 16 cases of pesticide applicators exposed primarily to
organophosphorus ester insecticides for 10 to 15 years, reported a
wide range of persistent signs of toxicity, including tinnitus, nys-
tagmus, pyrexia, ataxia, tremor, paresthesia, polyneuritits, paraly-
sis, speech difficulty (slurring), loss of memory, insomnia, som-
nambulism, excessive dreaming, drowsiness, lassitude, generalized
weakness, emotional liability, mental confusion, difficulty in con-
centration, restlessness, anxiety, depression, dissociation, and
schizophrenic reactions. Although the results of other studies have
been equivocal in their support of such an array of long-term signs
and symptoms, there is a persistent recurrence of the symptoma-
tology in a number of anecdotal and documented reports
(Ecobichon, 1994a; Marrs, 1993; Jamal, 1997). The literature on
potential, suspected, and established sequelae of organophospho-
rus ester insecticide intoxications does not confirm the frequently
seen statement that clinical recovery from nonfatal poisoning is al-
ways complete in a few days. Continuous and close observation of
acutely intoxicated patients for some weeks following their recov-
ery from the initial toxicity and treatment thereof would be neces-
sary to identify the subtle changes indicated above. The emergency
service physician rarely sees the patient following stabilization and
initial “recovery.” Definitive examples in which such observation
has been possible are few, but one such fortuitous case illustrates
what can be achieved if there is close follow-up (Ecobichon et al.,
1977).
While most clinical manifestations of acute poisoning are re-
solved within days to weeks, some symptoms, particularly those
of a neuropsychological nature, appear to persist for months or
longer. Complete reviews of this aspect have been published re-
2996R_ch22_761-810 4/16/01 4:37 PM Page 777
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
cently (Ecobichon, 1994a; Jamal, 1997). A 4-month surveillance
of 19 acutely poisoned farm workers revealed many subjective
signs and symptoms (blurred vision, muscle weakness, nausea,
headaches, night sweats) to persist through the study period, ac-
companied by a slow recovery of plasma and erythrocytic
cholinesterases (Whorton and Obrinsky, 1983). Rosenstock and
coworkers (1991) described the neuropsychological testing of 36
poisoned Nicaraguan agricultural workers some 2 years postexpo-
sure, reporting that the poisoned group did much worse than con-
trols on all subtests, with significantly worse performance on five
of six subtests in the World Health Organization (WHO) neu-
ropsychological test battery and on three of six additional tests that
assessed verbal and visual attention, visual memory, visuomotor
speed, sequencing and problem solving, motor steadiness, and dex-
terity (Ecobichon, 1998b). More recent examples of acute intoxi-
cations—e.g. “dippers’ flu” from repeated exposure to organophos-
phorus esters (diazinon, propetamphos, chlorfenvinphos) used in
sheep dip—have revealed persistent adverse neurophysiological
and psychological/behavioral effects that can be evaluated by suit-
able test batteries (Cook, 1992; Murray et al., 1992; Sims, 1992;
Stephens et al., 1995; Beach et al., 1996; Stephens et al., 1996).
As has been seen with signs and symptoms in acute intoxications,
those afflicted did not show adverse responses to all test battery
parameters; only some responses were significantly different from
normal-range values. However, such poisoning incidents have pro-
gressed from an anecdotal stage to a testable basis, with refined
test parameters revealing subtle but distinct changes in memory,
academic and motor skills, abstraction, and flexibility in thinking
(Ecobichon, 1998b).
A second distinct manifestation of exposure to organophos-
phorus ester insecticides has been described by clinicians in Sri
Lanka involved in the treatment of suicide attempts (Senanayake
and Karalliedde, 1987). This paralytic condition, called the inter-
mediate syndrome, consisted of a sequence of neurologic signs that
appeared some 24 to 96 h after the acute cholinergic crisis but be-
fore the expected onset of delayed neuropathy, the major effect be-
ing muscle weakness, primarily affecting muscles innervated by
the cranial nerves (neck flexors, muscles of respiration) as well as
those of the limbs. Cranial nerve palsies were common. There was
a distinct risk of death during this time interval because of respi-
ratory depression and distress that required urgent ventilatory sup-
port and was not responsive to atropine or oximes. The chemicals
involved in these distinctive intoxications included fenthion,
dimethoate, monocrotophos, and methamidophos. There were no
obvious clinical differences during the acute intoxication phase in
those patients who developed the intermediate syndrome and oth-
ers who did not, and all patients were treated in the same manner.
A third syndrome, that of organophosphate-induced delayed
neurotoxicity (OPIDN), is caused by some phosphate, phospho-
nate, and phosphoramidate esters, very few of which have ever
been used as insecticides (Fig. 22-12). Historically, this syndrome
has been known for almost 100 years and has been associated with
the chemical tri-o-tolyl phosphate (TOTP) (Ecobichon, 1994a). The
first major epidemic of OPIDN occurred during the prohibition
years in the United States, resulting from the consumption of a par-
ticular brand of alcoholic extract of Jamaican ginger contaminated
or adulterated with mixed tolyl phosphate esters. The syndrome,
affecting some 20,000 individuals to varying degrees, was known
as ginger jake paralysis or jake leg and was studied in detail by
Maurice Smith of the U.S. Public Health Service. He not only con-
firmed that the condition could be reproduced in animals (e.g., rab-
777
Figure 22-12. The basic structures and nomenclature of organophos-
phorus esters, with examples, capable of causing organophosphate-
induced delayed neurotoxicity (OPIDN).
bits, dogs, monkeys, calves) but also demonstrated that only one
of the three isomers found in commercial tri-tolyl phosphate, the
ortho-isomer, was responsible for the toxicity (Smith and Lillie,
1931). The initial flaccidity, characterized by muscle weakness in
the arms and legs—giving rise to a clumsy shuffling gait—was re-
placed by spasticity, hypertonicity, hyperreflexia, clonus, and ab-
normal reflexes, indicative of damage to the pyramidal tracts and
a permanent upper motor neuron syndrome (Ecobichon, 1994a). In
many patients, recovery was limited to the arms and hands and
damage to the lower extremities (foot drop, spasticity, and hyper-
active reflexes) was permanent, suggesting damage to the spinal
cord (Moregan and Penovich 1978), Recent studies have demon-
strated that other commercial triarylphosphates (flame retardants
in lubricants and plastics) did not elicit significant OPIDN-type
neurotoxicity at the maximum dose of 2000 mg/kg (Weiner and
Jortner, 1999). An OPIDN-type neuropathy occurred with an ex-
perimental organophosphorus ester insecticide, mipafox, following
an accident in a manufacturing pilot plant. Details of the effects
on two of the workers were described by Bidstrup and coworkers
(1953) and Ecobichon (1994a). The poisoning of water buffalo in
the early 1970s in Egypt by a phosphonate insecticide, leptophos,
revealed a neurologic syndrome similar to that observed following
exposure to TOTP (Abou-Donia, 1981). There was also evidence
of leptophos-induced neuropathies among workers in a manufac-
turing plant in the United States, but the controversial observations
were obscured by concomitant exposure of the workers to n-hexane,
another neurotoxic chemical (Xintaris et al., 1978).
A number of organophosphorus insecticides—including
omethoate, trichloronate, trichlorfon, parathion, methamidophos,
fenthion, and chlorpyrifos—have been implicated in causing
OPIDN in humans (Abou-Donia and Lapadula, 1990). However,
it should be emphasized that these incidents all involved accidental
or suicidal exposure to excessively high levels. Concern that many
of the over 200 organophosphorus ester insecticides in use might
cause this unique neuropathy has resulted in an intensive study of
the syndrome, the identification of the most susceptible species (the
hen and the cat), the development of standard protocols to test all
insecticides, and at least a partial elucidation of the mechanisms
by which agents elicit this condition. Histologic examination of the
2996R_ch22_761-810 4/16/01 4:37 PM Page 778
778 UNIT 5 TOXIC AGENTS
nervous systems of hens treated with a suitable agent [e.g., TOTP,
O,O-diisopropyl phosphorofluoridate (DFP), mipafox, leptophos]
has revealed a wallerian “dying-back” degeneration of large-
diameter axons and their myelin sheaths in distal parts of the pe-
ripheral nerves and of long spinal cord tracts—the rostral ends of
ascending tracts and the distal ends of descending tracts (Cavanagh,
1954; Sprague and Bickford, 1981). At autopsy, examination of an
unfortunate victim who died 15 months after the sarin attack in the
Tokyo subway revealed moderate-to-severe fiber loss in the sural
and sciatic nerves with little effect in the CNS, results consistent
with the dying-back degeneration of the PNS described above
(Himuro et al., 1998). Surviving victims also showed a higher fre-
quency of sister chromatid exchanges (SCEs) in peripheral blood
lymphocytes (Li et al., 1998). Biochemical studies have demon-
strated that the above-mentioned agents inhibit a neuronal, non-
specific carboxylesterase, neuropathic target esterase (NTE), which
appears to have some, as yet unknown, role in lipid metabolism in
neurons (Johnson, 1982). If acute exposure to an appropriate
organophosphorus ester results in 70 percent inhibition of NTE,
the characteristic OPIDN usually follows, with ataxia being ob-
served some 7 to 14 days following treatment and progression to
moderate to severe muscular weakness and paralysis with con-
comitant changes in neuronal morphology (Johnson, 1982; Slott
and Ecobichon, 1984). It is the considered opinion of many inves-
tigators that many of the commonly used phosphate and phospho-
rothioate ester insecticides might be capable of causing this
syndrome if only sufficient concentrations of the agents could be
attained in vivo. However, taking paraoxon as an example of such
a phosphate ester, the animal(s) would either die as a consequence
of other acute toxic effects or would rapidly detoxify the agent,
thereby preventing the acquisition of sufficient paraoxon to inhibit
NTE. There also appear to be subtle structure-activity relationships
between organophosphorus esters and the active site on the NTE
protein, because many phosphate esters are not good inhibitors of
NTE (Ohkawa et al., 1980; Abou-Donia, 1981). Conversely, while
the nerve gases cause a marked inhibition of NTE, the exposed an-
imals do not develop OPIDN, suggesting that NTE inhibition may
not be obligatory (Johnson et al., 1985, Lotti, 1992; Marrs, 1993;
Jamal, 1997). It should be emphasized that although NTE inhibi-
tion remains a useful function for monitoring the potential of
organophosphorus esters to induce OPIDN, the role of this enzyme
in the initiation of the syndrome remains unknown and histopatho-
logic evidence is a requirement of the U.S. EPA protocol. How-
ever, a recently reported poisoning by methamidophos proved that
lymphocyte NTE inhibition was predictive of the subsequent
OPIDN, the level of activity increasing from 3.1 to 13.3
nmol/min/mg protein between day 3 after poisoning and day 52
(McConnell et al., 1999). Interestingly, serum autoantibodies (IgM,
IgG) to glial fibrillary acidic protein (GFAP), myelin basic protein
(MBP), and cytoskeletal elements increased immediately after poi-
soning in this case and persisted to day 52, suggesting that these
parameters might be useful markers. Two noninsecticidal
organophosphorus esters, the tri-S-alkyl defoliant S,S,S-tributyl
phosphorotrithioite (Merphos) and its oxidation product, S,S,S-trib-
utyl phosphorotrithioate (DEF), have been implicated in produc-
ing OPIDN in at least one agricultural worker and cause a char-
acteristic delayed neurotoxicity in hens (Abou-Donia and
Lapadula, 1990).
The signs and symptoms of acute intoxication by carbamate
insecticides are similar to those described for organophosphorus
compounds, differing only in the duration and intensity of the tox-
icity. The most apparent reasons are that (1) carbamate insecticides
are reversible inhibitors of nervous tissue AChE, unlike most of
the organophosphorus esters (see below, “Mechanism of Toxic Ac-
tion”) and (2) they are rapidly biotransformed in vivo. Despite the
extensive toxicologic short-term toxicity following acute adminis-
tration, carbamate insecticide toxicity has been reported in humans
and fatalities have occurred (Ecobichon, 1994b; Hayes, 1982, Feld-
man, 1999). Invariably, these serious poisonings have involved car-
baryl and have occurred as a consequence of accidental or pur-
poseful (suicidal) exposure to high concentrations (Hayes, 1982;
Cranmer, 1986). Information on the incidences of human intoxi-
cation by carbaryl can be found in the Carbaryl Decision Docu-
ment (EPA, 1980). For the period 1966–1980, a total of 195 hu-
man intoxication cases were reported (3 fatalities, 16 hos-
pitalizations, and 176 cases receiving medical attention). A single
oral dose of 250 mg of carbaryl (2.8 mg/kg body weight) is suffi-
cient to elicit moderately severe poisoning in an adult man (Cran-
mer, 1986). Moderate but transient toxicity has also been observed
following exposure to a few of the more potent carbamate ester in-
secticides methomyl (Lannate) and propoxur (Baygon) (Fandekar
et al., 1968, 1971; Liddle et al., 1979). More recently the illegal
use of aldicarb (Temik), a very acutely toxic carbamate ester, on
watermelons in California and on English cucumbers in British Co-
lumbia, Canada, resulted in moderate to severe toxicity in con-
sumers of these products, with signs and symptoms including nau-
sea, vomiting, gastrointestinal cramps, and diarrhea (Goldman et
al., 1990a,b).
While there is little evidence of prolonged neurotoxicity after
exposure to carbamate ester insecticides, this statement should be
made cautiously because the signal danger appears to involve acute
single exposures to massive doses or at least repeated exposures
to large doses. Examining a number of carbamate (aldicarb,
methomyl) intoxications in children and adults, Lifshitz et al.
(1997) discovered that the predominant symptoms in adults were
miosis and muscle fasciculations, while the children were more
likely to reveal CNS effects (stupor and/or coma) in addition to di-
arrhea and hypotension. The authors suggested that the blood-brain
barrier was more permeable in the children.
Bizarre anecdotal cases exist that are contrary to everything
that we know about carbamates. One case, that of a farmer who
hand-sprayed a vegetable garden with a water-wettable formula-
tion of carbaryl, drenching himself in the process, developed a
chronic polyneuropathy, persistent photophobia and paresthesia,
recent memory loss, muscular weakness, fatigue, and lassitude
(Ecobichon, 1994b). The case study presented by Branch and Jacqz
(1986) developed into a persistent, stocking-and-glove peripheral
neuropathy accompanied by mental confusion and weakness in ma-
jor skeletal muscle groups, with fasciculations and cerebral atro-
phy. Grendon et al. (1994) presented long-term observations of a
group of men who had been exposed acutely to aldicarb, several
experiencing symptoms 3 years after the initial severe intoxication.
Feldman (1999) conducted extensive neurologic and psychologi-
cal investigations on three individuals exposed accidentally to aeri-
ally applied carbaryl some three to five years before. Their per-
sisting subjective symptoms were confirmed by peripheral nerve
conduction studies, electromyography, and neuropsychological
assessment, both peripheral and central impairment being
documented.
There is evidence in animal studies, albeit at near toxic doses,
of a wallerian-type degeneration of spinal cord tracts in rabbits and
hens following treatment with sodium diethyldithiocarbamate
2996R_ch22_761-810 4/16/01 4:37 PM Page 779
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
(Edingon and Howell, 1969). Carbaryl, when fed to hogs (150
mg/kg per day for 72 or 83 days), caused a rear leg paralysis, min-
imal at rest but, when the animals were forced to move, resulting
in marked incoordination, ataxia, tremors, clonic muscle contrac-
tions, and prostration, with histologic evidence of lesions in the
CNS and in skeletal muscle (Smalley et al., 1969). Carbamate es-
ter insecticides do no inhibit NTE or elicit OPIDN-type neurotox-
icity. Behavioral changes have been noted in a number of animal
studies following the subchronic or chronic administration of dif-
ferent carbamate insecticides (Santalucito and Morrison, 1971;
Desi et al., 1974).
Mechanism of Toxic Action Although the anticholinesterase-
type insecticides have a common mode of action, there are signif-
icant difference between organophosphorus and carbamate esters.
The reaction between and organophosphorus ester and the active
site in the AChE protein (a serine hydroxyl group) results in the
formation of a transient intermediate complex that partially hy-
drolyzes with the loss of the “Z” substituent group, leaving a sta-
ble, phosphorylated, and largely unreactive inhibited enzyme that,
under normal circumstances, can be reactivated only at a very slow
rate (Fig. 22-13). With many organophosphorus ester insecticides,
an irreversibly inhibited enzyme is formed, and the signs and symp-
toms of intoxication are prolonged and persistent, requiring vigor-
ous medical intervention including the reactivation of the enzyme
with specific chemical antidotes (see “Treatment of Poisoning,” be-
low, this section). Without intervention, the toxicity will persist
until sufficient quantities of “new” AChE are synthesized in 20 to
30 days to destroy efficiently the excess neurotransmitter. The na-
ture of the substituent groups at “X,” “Y,” and “Z” plays an im-
portant role in the specificity for the enzyme, the tenacity of bind-
ing to the active site, and the rate at which the phosphorylated
enzyme dissociates to produce free enzyme. More recently intro-
duced organophosphorus esters (acephate, temephos, dichlorvos,
trichlorfon) are less tenacious inhibitors of nervous tissue AChE,
the phosphorylated enzyme being more readily and spontaneously
dissociated.
In contrast, carbamic acid esters, which attach to the reactive
site of the AChE, undergo hydrolysis in two stages: the first stage
is the removal of the “X” substituent (an aryl or alkyl group) with
the formation of a carbamylated enzyme; the second stage is the
Figure 22-13. The interaction between an organophosphorus or carba-
mate ester with the serine hydroxyl groups in the active site of the en-
zyme acetylcholinesterase (E-OH). The intermediate, unstable complexes
formed before the release of the “leaving” groups (ZH and XOH) are not
shown. The dephosphorylation or decarbamoylation of the inhibited en-
zyme is the rate-limiting step to forming free enzymes.
779
decarbamylation of the inhibited enzyme with the generation of
free, active enzyme (Fig. 22-13). Carbamic acid esters are nothing
more than poor substrates for the cholinesterase-type enzymes.
When the concept of the interaction between organophos-
phorus and carbamic esters with AChE is presented in another man-
ner (Table 22-8), one can see that the only distinctive difference
between the two anticholinesterase-type insecticides lies in the rate
at which the dephosphorylation or decarbamylation takes place.
The rate is exceedingly slow for organophosphorus esters, so much
so that the enzyme is frequently considered to be irreversibly in-
hibited. The rate of decarbamylation is sufficiently rapid that these
esters are often considered to be reversible inhibitors with low
turnover rates. The characteristics of the various rate constants for
the natural substrate (ACh), organophosphorus, and carbamylation
esters are shown in Table 22-8. It is important to appreciate that
the rate at which step 3 proceeds is thousands of times slower with
carbamate esters than with ACh, whereas with organophosphorus
esters it is several orders of manitude slower (Ecobichon, 1979).
This subject has been extensively reviewed by Aldridge and Reiner
(1972). A number of organophosphorus (phosphate, phosphonate,
and phosphoramidate) esters (Fig. 22-12)—the chemical warfare
agents sarin, soman, and tabun, and a few other compounds such
as DFP, mipafox, and leptophos—have the ability to bind tena-
ciously to the active site of AChE and NTE to produce an irre-
versibly inhibited enzyme by a mechanism known as aging. The
aging process is dependent on the size and configuration of the
alkyl (R) substituent, with the potency of the ester increasing in
the order of diethyl, dipropyl, and dibutyl for such analogs as DFP
and mipafox (Aldridge and Johnson, 1971). The aging process is
generally accepted as being caused by the dealkylation of the in-
termediate dialkylphosphorylated enzymes by one of two possible
mechanisms (Fig. 22-14). The first involves the hydrolysis of a
P–O bond following a nucleophile (base) attack on the phospho-
rus atom. The second mechanism involves the hydrolysis of an
O–C bond by an acid catalysis, resulting in the formation of a car-
bonium ion as the leaving group (O’Brien, 1960; Eto, 1974;
Johnson, 1982). The aging process is believed to fix an extra charge
to the protein, causing some perturbation to the active site and
thereby preventing dephosphorylation. While the exact nature of
this reaction has not been demonstrated for AChE and NTE, evi-
dence from experiments with saligenin cyclic phosphorus esters
(derivatives of TOTP) and -chymotrypsin points to the possibil-
ity of two stabilized forms of “aged” enzyme (Toia and Casida,
1979). Both of the reactions utilize the imidazole group of a neigh-
boring histidine. In one reaction, the hydroxylated substituent is
released and the phosphorylated enzyme is stabilized by a hydro-
gen on the imidazole group. In the other reaction, the leaving sub-
stituent becomes attached to the imidazole, yielding a N–C-hy-
droxylated derivative of the phospyhorylated enzyme. Johnson
(1982) proposed that, in the case of NTE, if one or two of the P–R
bonds were P–O–C (as in phosphates and phosphonates), aging
would occur rapidly, whereas if the P–R bonds were P–C (as in
phosphinates), aging would not be possible.
A number of acute, high-level exposures and intoxications by
organophosphorus and carbamate esters have resulted in persistent
CNS effects as well as debilitating muscle weakness, particularly
in the legs, that cannot be explained on the basis of nervous tissue
AChE inhibition alone. One hypothesis has been put forward that
the excessive amount of undestroyed acetylcholine (ACh) may be
involved by an action at nicotinic (nAChR) and muscarinic
(mAChR) acetylcholine receptors (Ecobichon, 1994a). As shown
2996R_ch22_761-810 4/16/01 4:37 PM Page 780

780 UNIT 5 TOXIC AGENTS

Table 22-8
Kinectics of Ester Hydrolysis

EH 
 AB  EHAB  BH  EA  EH  AOH
COMPLEX FORMATION ACYLATION DEACYLATION
ESTERS (KA  k
1k1) (k2) (k3)

Substrates Small Extremely Extremely

fast fast
Organophosphorus Small Moderately Slow or
esters fast extremely
slow
Carbamate esters Small Slow Slow

SOURCE: Ecobichon, 1979.

in Fig. 22-15, the ACh accumulating at nAChR would elicit stim-
ulation of the neuromuscular junctions, causing fasciculations
(repetitive stimulation) followed by a depolarizing blockade if the
ACh levels remained elevated, leading subsequently to a desensi-
tization process with a more or less permanent reduction in nAChR
numbers and causing the persistent muscle weakness observed
through a lack of response to stimuli. Support for this hypothesis
has been seen in studies revealing chronic abnormal electromyo-
graphic (EMG) activity in human intoxications by anti-
cholinesterase insecticides, the details of which can be found in
Ecobichon (1994a) and Feldman (1999). An alternative theory
bears examination.
In an acute tabun study in rats, necrotic diaphragmatic mus-
cle was observed, the effect being prevented by sectioning the
phrenic nerve to a portion of the diaphragm (Ariens et al., 1969).
Similar diaphragmatic damage has been observed in human poi-
sonings (DeRueck and Willens, 1975; Wecker et al., 1986). Early
work by Dettbarn and colleagues demonstrated that close intra-
muscular injections of parathion or paraoxon resulted in a skeletal
myopathy accompanied by necrosis of the nerve terminal mem-
brane and of the underlying muscle (summarized in Ecobichon,
1994a). There is evidence that organophosphate-induced AChE in-
hibition causes muscle hyperactivity as an initial step that triggers
free radical–induced lipid peroxidation before muscle injury (Yang
and Dettbarn, 1996; Yang et al., 1996). More recent studies, con-
ducted at the level of brain mAChR and nAChR, have demonstrated
that organophosphorus esters (soman, VX, DFP, parathion,
paraoxon, chlorpyrifos) bind to both receptor types, particularly if
the circulatory concentrations are in the micromolar range as would
be encountered in poisoning cases, resulting in desensitization
(Bakry et al., 1988; Eldefrawi et al., 1988; Huff et al., 1994; Katz
et al., 1997). There is also evidence of differential down-regulation
of nAChR subtypes through reduction of messenger RNA expres-
sion in rat brain following repeated injections of parathion (Jett et
al., 1993, 1994; Ward and Mundy, 1996). Adult mice, exposed to
DFP on postnatal day 3 or 10, showed decreases in brain nAChR
Excessive
ACh

Stimulation Fasciculations

Depolarizing
Blockade Paralysis

Desensitization

Down-regulation
of Receptor Numbers

Persistent Muscle Weakness

Figure 22-14. A schematic diagram illustrating two mechanisms by
which the “aging” of organophosphorus ester–inhibited acetyl-
cholinesterase may occur. See text for details.
Neuromuscular Junction
Damage or Necrosis
Figure 22-15. A schematic diagram illustrating the impact of excessive
concentrations of acetylcholine (ACh) on muscarinic and nicotinic acetyl-
choline receptors in order to explain neuromuscular weakness and dam-
age.
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES 781

density as well as significant alterations in spontaneous motor be-
havior (Ahlbom et al., 1995).
Can the carbamate esters induce muscle damage and receptor
alterations through mechanisms involving ACh, direct binding to
receptors, or through receptor expression? The repeated injection
of such reversible anticholinesterase carbamates as physostigmine
or neostigmine has produced myopathies qualitatively similar to
those produced by paraoxon, possibly supporting the ACh-related
theory (Wecker et al., 1978). Skeletal muscle lesions (myodegen-
eration, vacuolization) were observed in swine fed carbaryl over a
period of 80 days (Smalley et al., 1969). The peripheral neu-
ropathy of a carbaryl-exposed elderly male has been described
(Branch and Jacqz, 1986). Some interesting experiments could be
performed with some of the more potent carbamate insecticides.
Biotransformation, Distribution, and Storage Both the
organophosphorus and carbamate ester insecticides undergo ex-
tensive biotransformation in all forms of life. Both the route(s) and
the rate(s) of metabolism are highly species-specific and depend-
ent on the substituent chemical groups attached to the basic “back-
bone” structure of these esters (Fig. 22-10). Tissue enzymes of both
phase I (oxidative, reductive, hydrolytic) and phase II (transfer or
conjugative reactions with glutathione, glucuronic acid, glycine,
and so forth) types are founds in a widespread pattern in plant, in-
vertebrate, and vertebrate species and, indeed, are responsible for
some aspects of the species sensitivity and/or both natural and
acquired restance to many of these insecticides. The phase I detox-
ification processes usually form reactive metabolites, whereas
phase II processes conjugate the polar phase I metabolites with
some natural body substituent to form a product with enhanced
water solubility and excretability. The biotransformation of anti-
cholinesterase-type insecticides has been extensively reviewed in
the literature and the reader is referred to such sources as O’Brien
(1967), Menzie (1969), Eto (1974), Kulkarni and Hodgson (1984),
and Matsumura (1985) for details on the various mechanisms
involved.
Organophosphorus esters undergo simultaneous oxidative bio-
transformation at a number of points in the molecule (Fig. 22-16),
the enzymes utilizing the ubiquitous cytochrome P450 isoenzyme
system. One reaction, that of oxidative desulfuration of phospho-
rothioate (parathion, methyl parathion, fenitrothion, etc.) and phos-
phorodithioate (azinophos methyl, malathion, etc.) esters, results
in a significant increase in the toxicity of the biotransformation
products, oxygen analogs (mechanism 1). This reaction is a major
obligatory pathway in ester detoxification in mammals equipped
with tissue aryl and aliphatic hydrolases (mechanism 8), whereas
insects are deficient in these enzymes, making them more suscep-
tible. Dealkylation with the formation of an aldehyde occurs read-
ily (mechanism 2), but this pathway does not function efficiently
when the alkyl group becomes longer. Dearylation occurs with the
formation of a phenol and either a dialkylphosphoric or di-
alkylphosphorothioic acid (mechanism 3). The cytochrome system
can also catalyze (1) aromatic ring hydroxylation (mechanism 4);
(2) thioether oxidation (mechanism 5); (3) deamination; (4) alkyl
and N-hydroxylation; (5) N-oxide formation; and (6) N-dealkyla-
tion. A number of transferases use glutathione (gamma-glutamyl-

Figure 22-16. A schematic diagram depicting the various phase I and II biotransformation pathways of an
organophosphorus ester and the nature of the products formed as a consequence of oxidative, hydrolytic,
GSH-mediated transfer and conjugation of intermediates in mammals. See text for details.
2996R_ch22_761-810 4/16/01 4:37 PM Page 782
782 UNIT 5 TOXIC AGENTS
L-cysteinyl glycine, GSH) as a cofactor and acceptor for O-alkyl
(methyl) and O-aryl groups (mechanisms 6 and 7) to yield
monodesmethyl products plus S-methylglutathione or aryl-glu-
tathione derivatives plus the respective phosphoric or phospho-
rothioic acids.
Hydrolysis of phosphoric and phosphorothioic acid ester oc-
curs via a number of different tissue hydrolases (nonspecific car-
boxylesterases, arylesterases, phosphorylphosphatases, phospho-
triesteraes, carboxyamidases) scattered ubiquitously throughout the
plant and animal kingdoms, with activity being highly dependent
on the nature of the substituents (Ecobichon, 1979). Slight struc-
tural modifications to substituents on the insecticide molecule can
dramatically alter the specificity of these enzymes toward an
agent and affect species selectivity. The arylesterases [aromatic or
A-esterases (ArE), EC 3.1.1.2] preferentially hydrolyze aryl
(phenol, naphtol, indole) esters of short-chain aliphatic or phos-
phorus acids, particulary if there is a double bond present in the
alcohol moiety in position  with respect to the ester bond (mech-
anism 8). Carboxylesterases [carboxylic acid ester hydrolases (CE),
EC 3.1.1.] are capable of hydrolyzing a variety of aliphatic and
aryl esters of short-chain fatty acids. The most important example
of this reaction involving organophosphorus ester insecticides is
with malathion [O,O-dimethyl-S-(1,2-dicarbethoxyethyl) phospho-
rodithioate], in which one of the two available ethylated carboxylic
ester groups is hydrolyzed to yield malathion (or malaoxon)
-monoacids that are biologically inactive (Dauterman and Main,
1966). This CE-catalyzed reaction is an important feature of re-
sistance to this insecticide in insects and to tolerance in mammals.
Potentiation of anticholinergic effects can be produced by the com-
bined administration of certain pairs of organophosphate ester in-
secticides, such as EPN (O-ethyl-O-p-nitrophenylbenzenethio-
phosphonate) and malathion (Frawley et al., 1957). The mechanism
for this effect involves the inhibition of carboxyesterases by EPN
(Murphy, 1969, 1972, 1980). Carboxyamidases (acylamide am-
diohydrolase, EC 3.5.1.4), found extensively in plant, insect, and
vertebrate tissues, are of limited current interest in the degradation
of insecticides; dimethoate (O,O-dimethyl-S-(N-methylcarbamoyl-
methyl) phosphorodithioate] is the only organophosphorus ester in-
secticide shown to be hydrolyzed by mammalian tissue amidases
(mechanism 9). Phosphorylphosphatases and phosphotriesterases
have limited involvement in the biotransformation of organophos-
phorus ester insecticides but play a role in the detoxification of
some of the chemical warfare agents.
Phase II conjugative reactions are of limited use in the bio-
transformation of organophosphorus ester insecticides, and they are
usually relegated to the task of glucuronidating or sulfating the aro-
matic phenols, cresols, and other substances hydrolyzed from the
ester (Yang, 1976). However, one must be wary of these enzyme
systems because metabolism studies of chlorfenvinphos (2-chloro-
1-(29,49-dichlorophenyl)vinyl diethylphosphate) revealed the pres-
ence of glucuronide and glycine conjugates of several products,
whereas studies with trichlorfon (O,O-dimethyl-1-hydroxy-2,2,2-
trichloroethyl phosphonate) revealed direct glucuronidation of the
insecticide without prior biotransformation (Hutson et al., 1967;
Bull, 1972).
Carbamate ester insecticides can undergo simultaneous at-
tack at several points in the molecule, depending on the nature of
the substituents attached to the basic structure. In addition to the
hydrolysis of the carbamate ester group by tissue CE and the re-
lease of a substituted phenol, carbon dioxide, and methylamine
(Fig. 22-10), (mechanism 1), several oxidative and reductive reac-
tions involving cytochrome P450 – related monooxygenases can
proceed, the ultimate products being considerably more polar than
the parent insecticide. The extent of hydrolysis of carbamate ester
insecticides varies greatly between species, ranging from 30 to
95 percent hydrolysis. The type of oxidative reactions observed
with carbamate esters can be simplified into two main groups: (1)
direct ring hydroxylation (mechanism 2) and (2) oxidation of
appropriate side chains as is shown for this “mythical” methylcar-
bamate, resulting in the hydroxylation of N-methyl groups or
methyl groups to form hydroxymethyl groups (mechanism 3),
N-demethylation of secondary and tertiary amines (mechanism 4),
O-dealkylation of alkoxy side chains (mechanism 5), thioether
oxidation (mechanism 6), and so forth. Phase II conjugative reac-
tions can occur at any free reactive grouping with glucuronide and
sulfate derivatives (mechanism 7), and GSH conjugates (mercap-
turates) may be formed (mechanism 8). For a comprehensive ex-
position of the various mechanisms involved, the reader is referred
to those reviews mentioned above, this section, as well as to
pertinent articles by Ryan (1971), Fukuto (1972), and Kuhr and
Dorough (1976).
Treatment of Poisoning Despite the qualitative and quantita-
tive differences between organophosphorus and carbamate insec-
ticide intoxications, all cases of anticholinesterase poisoning should
be treated as serious medical emergencies and the patient should
be hospitalized as quickly as possible. The status of the patient
should be monitored by repeated analysis of the plasma (serum)
cholinesterase and the erythrocyte AChE; the inhibition of the ac-
tivities of these two enzymes is a good indicator of the severity of
organophosphorus ester poisoning, because only the erythrocytic
AChE is inhibited by carbamate esters (except at excessively high
levels of exposure). As a consequence of the extensive involvement
of the entire nervous system, the life-threatening signs (respiratory
depression, bronchospasm, bronchial secretions, pulmonary
edema, muscular weakness) resulting in hypoxemia will require
immediate artificial respiration and suctioning via an endotracheal
tube to maintain a patent airway. Arterial blood gases and cardiac
function should be monitored.
The regimen for the treatment of organophosphorus ester in-
secticide intoxication, based on the analysis of serum pseudo-
cholinesterase, is described in Table 22-9 (Namba et al., 1971;
Ecobichon et al., 1977; Marrs, 1993). Atropine is used to counter-
act the initial muscarinic effects of the accumulating neurotrans-
mitter. However, atropine is a highly toxic antidote and great care
must be taken. Frequent small doses of atropine (subcutaneously
or intravenously) are indicated for mild signs and symptoms fol-
lowing a brief, intense exposure. Large cumulative doses of at-
ropine, up to 50 mg daily, may be essential to control severe mus-
carinic symptoms. The status of the patient must be monitored
continuously by examining for the disappearance of secretions (dry
mouth and nose) and sweating, facial flushing, and mydriasis (di-
latation of pupils). Supplementary treatment to offset moderate to
severe nicotinic and CNS signs and symptoms usually takes the
form of one of the specific antidotal chemicals, the oximes (prali-
doxime chloride or 2-PAM, pralidoxime methanesulfonate or P2S),
administered intravenously to reactivate the inhibited nervous tis-
sue AChE. The use of oximes may not be necessary for cases of
mild intoxication and should be reserved for moderate to severe
poisonings. Treatment by slow intravenous infusion of doses of
1.0 g should be initiated as soon as possible, because the longer
the interval between exposure and treatment, the less effective the
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES 783

Table 22-9
Classification and Treatment of Organophosphorus Insecticide Poisoning Based on Plasma Pseudocholinesterase Activity
Measurement

TREATMENT
CLASSIFICATION ENZYME ACTIVITY
OF POISONING (% OF NORMAL) ATROPINE PRALIDOXIME

Mild 20–50 1.0 mg SC 1.0 g IV over 20 to 30 min

Moderate 10–20 1.0 mg IV every 20 to 30 min 1.0 g IV over 20 to 30 min
until sweating and salivation
disappear and slight flush and
mydriasis appear
Severe 10 5.0 mg IV every 20 to 30 min 1.0 g IV as above. If no improvement,
until sweating and salivation administer another 1.0 g IV. If no
disappear and slight flush improvement, start IV infusion at
and mydriasis appear 0.5 g/h
SOURCE: Ecobichon et al., 1977.

oxime will be. In many poisonings, a single treatment with prali-
doxime will be sufficient to elicit a reversal of the signs and symp-
toms and to reduce the amount of atropine needed. In severe poi-
soning cases, a prodigious amount of pralidoxime may be needed.
If absorption, distribution, and/or metabolism of the organophos-
phorus ester is delayed in the body, pralidoxime may be adminis-
tered repeatedly over several days after the initial treatment. Care
should be taken with repeated dosing because pralidoxime effec-
tively binds calcium ions and causes muscle spasms not unlike
those elicited by the organophosphorus esters. Severe muscle
cramping, particularly in the extremities, may be alleviated by oral
or intravenous calcium solutions (Ecobichon et al., 1977).
The therapeutic action of the oxime compounds resides in
their capacity to reactivate AChE without contributing markedly
toxic actions of their own. Those organophosphorus esters that pos-
sess good “leaving groups” (i.e., the “X” moiety) phosphorylate
the nervous tissue AChE by a mechanism similar to that of acety-
lation by the substrate ACh. These esters are frequently called
irreversible inhibitors because the hydrolysis of the phosphorylated
enzyme by water is exceedingly slow (Table 22-8). However, var-
ious nucleophilic agents containing a substituted ammonium group
will dephosphorylate the phosphorylated enzyme at a much more
rapid rate than water. The basic requirements for a reactivating mol-
ecule consist of a rigid structure containing a quaternary ammo-
nium group and an acidic nucleophile, which would be comple-
mentary with the phosphorylated enzyme, in such a way that the
nucleophilic oxygen would be positioned close to the electrophilic
phosphorus atom. These structure-activity requirements led to the
development of the pralidoxime compounds, with the syn-isomer
of 2-PAM (2-formyl-N-methylpyridinium chloride oxime) being
particularly active (Childs et al., 1955; Askew, 1956; Kewitz and
Wilson, 1956; Namba and Hiraki, 1958). The reaction of 2-PAM
with the phosphorylated enzyme proceeds as shown in Fig. 22-17.
The reactivation is an equilibrium reaction, the oxime react-
ing either with the phosphorylated enzyme or with free, unbound
organophosphorus ester, and the product is a phosphorylated oxime
which in itself can be a potent cholinesterase inhibitor if it is sta-
ble in an aqueous medium (Schoene, 1972). In general, the phos-
phorylated oxime degrades quickly in water.
A practical limitation on the usefulness of oxime reactivators
lies in the inability of these agents to reactivate “aged” AChE, that
enzyme in which the phosphorylated enzyme has been further
dealkylated and the phosphoryl group becomes tightly bound to
the reactive site (see Fig. 22-14). Success with the pyridinium
analogs led to an intensive search for more effective oximes and
the discovery of the bispyridinium compounds toxogonin or
obidoxime [bis(4-formyl-N-methylpyridinium oxime) ether dichlo-
ride], TMB-4 [N,N-trimethylene bis(pyridine-4-aldoxime) bro-
mide], and, more recently, the H-series compounds. However, these
agents are not without toxicity and only pralidoxime and toxogo-
nin have seen extensive antidotal use (Engelhard and Erdmann,
1964; Steinberg et al., 1977).

Figure 22-17. The pralidoxime-catalyzed reactivation of an organo-phosphate-inhibited molecule of acetyl-

cholinesterase, showing the release of active enzyme and the formation of an oxime-phosphate complex.
2996R_ch22_761-810 4/16/01 4:37 PM Page 784
784 UNIT 5 TOXIC AGENTS
With the apparent availability of organophosphorus nerve
gases and their known ability to form rapidly aging complexes with
AChE, the relative ineffectiveness of atropine and pralidoxime in
such poisonings must be taken into account when the treatment of
individuals exposed to these agents is confronted (Koplovitz et al.,
1992; Webb, 1993; Clement, 1994). Toxogonin (obidoxime
chloride) appears to be effective in tabun poisoning while, of the
H-series of bis-pyridinium monooximes, HI-6 appears to be effi-
cacious in soman and cyclohexylmethyl phosphorofluoridate
(CMPF, or CF) poisonings. However, despite striking therapeutic
effects, the issue is clouded by the fact that little reactivation of
erythrocytic or brain AChE occurs (Kusic et al., 1991; Shih, 1993).
The clinical treatment of carbamate toxicity is similar to that
for organophosphorus ester insecticide intoxication with the ex-
ception that the use of oximes is contraindicated. Early reports, in
which pralidoxime or toxogonin was used in treating carbaryl in-
toxications, revealed that the oxime enhanced the carbaryl-induced
toxicity (Sterri et al., 1979; Ecobichon and Joy, 1994). However,
the oximes appear to offer some antidotal properties in patients
exposed to aliphatic oxime carbamates (aldicarb, methomyl)
(Feldman, 1999).
Diazepam (10 mg SC or IV) may be included in the treatment
regimen of all but the mildest cases of organophosphorus and/or
carbamate intoxications. In addition to relieving any mental anxi-
ety associated with the exposure, diazepam counteracts some as-
pects of the CNS and neuromuscular signs that are not affected by
atropine. Doses of 10 mg (SC or IV) are appropriate and may be
repeated. Other centrally acting drugs that may depress respiration
are not recommended in the absence of artificial respiration.
It is important to appreciate that vigorous treatment of anti-
cholinesterase-type insecticide intoxications does not offer protec-
tion against the possibility of delayed-onset neurotoxicity or the
persistent sensory, cognitive, and motor defects discussed earlier.
These deficits, albeit reversible over a long time interval, appear
consistently in intoxications and are caused by mechanisms as yet
unknown. Certain evidence points to severe damage to the neuro-
muscular junctions in skeletal muscle, resulting in a persistent pe-
ripheral muscular weakness (Wecker et al., 1978).
Pyrethroid Esters
A major class of insecticides comprises the synthetic pyrethroids,
a group of chemicals that entered the marketplace in 1980 but, by
1982, accounted for more than 30 percent of worldwide insecti-
cide usage (Anon., 1977; Vijverberg and van den Bercken, 1982).
However, these synthetics arise from a much older class of botan-
ical insecticides, pyrethrum, a mixture of six insecticidal esters
(pyrethrins, cinerins, and jasmolins) extracted from dried
pyrethrum or chrysanthemum flowers (Chrysanthemum cinerari-
aefolium, Chrysanthemum coccineum) (Hartley and West, 1969).
Although it is believed that the natural pyrethroids were discov-
ered by the Chinese in the first century A.D., the first written ac-
counts of these agents are found in the seventeenth-century litera-
ture and commercial preparations made their appearance in the
mid-1800s (Neumann and Peter, 1987). Japanese woodblock prints
from the early 1800s exist in which one can see smoldering in-
secticide coils of pressed pyrethrum powder not unlike those man-
ufactured and used today.
In 1965, the world output of pyrethrum was approximately
20,000 tons, with Kenya alone producing some 10,000 tons
(Cremlyn, 1978). The ever-increasing demand for this product has
far exceeded the limited world production, leading chemists to fo-
cus attention on the synthesis of new analogs, hopefully with bet-
ter stability in light and air, better persistence, more selectivity in
target species, and low mammalian toxicity. In addition to exten-
sive agricultural use, the synthetic pyrethroids are components of
household sprays, flea preparations for pets, plant sprays for home
and greenhouse use, and other applications. For an in-depth dis-
cussion of the development of the pyrethroid ester insecticides,
their chemistry, and their biological activity, the reader is referred
to Elliott (1976), Cremlyn (1978), Casida et al. (1983), Leahey
(1985), Matsumura (1985), Narahashi (1985), Narahashi et al.
(1985), and Joy (1994b).
Natural pyrethrum consists of a mixture of six esters derived
from two acids (chrysanthemic, pyrethric) and three alcohols
(pyrethrolol, cinerolol, jasmolol), producing an effective contact
and stomach poison mixture having both knockdown and lethality.
When the complex structure was identified, the synthetic esters
were marketed (Fig. 22-18). Distinctive molecular structures con-
vey selectivity toward certain insect species and in some cases to
toxicity in mammals. Several of the pyrethroid esters exist in iso-
meric forms around the cyclopropane nucleus, resulting in dis-
tinctly different toxicities and potencies (Casida et al., 1983).
Signs and Symptoms of Poisoning Based on the symptoms pro-
duced in animals receiving acute toxic doses, the pyrethroids fall
into two distinct classes of chemicals (Table 22-10). The type I
poisoning syndrome or T syndrome is produced by esters lacking
the -cyano substituent and is characterized by restlessness, inco-
ordination, prostration, and paralysis in the cockroach, as compared
with the rat, which exhibits such signs as sparring and aggressive
behavior, enhanced startle response, whole-body tremor, and pros-
tration. The type II syndrome, also known as the CS syndrome, is
produced by those esters containing the -cyano substituent and
elicits intense hyperactivity, incoordination, and convulsions in
cockroaches, in contrast to rats, which display burrowing behav-
ior, coarse tremors, clonic seizures, sinuous writhing (choreo-
athetosis), and profuse salivation without lacrimation; hence the
A
CH3 CH3
C
R1 CH CH O R4
C CH C CH
R2
O R3
B
N
O C
R5 C CH
CH O R4
CH
CH3 CH3
Figure 22-18. The basic structures of the synthetic pyrethroid ester in-
secticides showing (A) the intact cyclopropane ring in type I esters, with
R1 and R2 (methyl, bromine, chlorine, etc.), R3 (hydrogens or cyano) and
R4 (3-phenoxybenzoate, other) substituents; and (B) the “open” struc-
ture of type II esters with R4 (3-phenoxybenzoate, other) and R5 (substi-
tuted phenyl substituents).
2996R_ch22_761-810 4/16/01 4:37 PM Page 785
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
Table 22-10
Classification of Pyrethroid Ester Insecticides on the Basis of Chemical Structure
and Observed Biological Activity
Signs and Symptoms
SYNDROME COCKROACH
Type I Restlessness
(“T” syndrome) Incoordination
Prostration
Paralysis
Type II Hyperactivity
(“CS” syndrome) Incoordination
Convulsions
term CS (choreoathetosis/salivation) syndrome. A few of these
agents, fenpropanthrin, for example, cause a mixture of type I and
II effects, depending on the species (rat or mouse) treated and pos-
sibly on the route of administration (Verschoyle and Aldridge,
1980; Gammon et al., 1981; Lawrence and Casida, 1982). The bulk
of evidence points to the fact that the type II syndrome involves
primarily an action in the mammalian CNS, whereas with the type I
syndrome, peripheral nerves are also involved. This hypothesis was
based initially on the observed symptomatology, but more recent
evidence has revealed a correlation between the severity of type II
responses and brain concentrations of deltamethrin in mice, re-
gardless of the route of administration (Barnes and Verschoyle,
1974; Ruzo et al., 1979). Agents eliciting the type II syndrome
have greater potency when injected intracerebrally, relative to in-
traperitoneal injection, than those causing type I syndrome effects
(Lawrence and Casida, 1982). There is no indication of a funda-
mental difference between the mode of action of pyrethroids on
neurons of target and nontarget species, and the neurotoxicologic
responses depend on a combination of physicochemical properties
of the particular pyrethroid ester, the dose applied, the time inter-
val after treatment, and the physiologic properties of the particu-
lar model used (Leaks et al., 1985).
Although these insecticides cannot be considered to be highly
toxic to mammals, their use indoors in enclosed and poorly venti-
lated spaces has resulted in some interesting signs and symptoms
of toxicity to humans. Exposure to the natural pyrethrum mixture
is known to cause contact dermatitis; descriptions of the effects
range from localized erythema to a severe vesicular eruption
(McCord et al., 1921). The allergenic nature of this natural prod-
uct is not surprising, with asthma-like attacks and anaphylactic re-
actions and peripheral vascular collapse among the responses ob-
served. Human toxicity associated with the natural pyrethrins stems
from their allergenic properties rather than from direct neurotoxi-
785
RAT CHEMICALS
Hyperexcitation Allethrin
Sparring Cismethrin
Aggressiveness Phenothrin
Enhanced startle Pyrethrin I
response Resmethrin
Whole-body tremor Tetramethrin
Prostration
Burrowing Acrinathrin
Dermal tingling Cycloprothrin
Clonic seizures Cyfluthrin
Writhing Cyhalothrin
Profuse salivation Cyphenothrin
Cypermethrin
Deltamethrin
Esfenvalerate
Fenvalerate
Flucynthrate
Fluvalinate
city. There has been little evidence of the allergic-type reactions in
humans exposed to synthetic pyrethroid esters.
One notable form of toxicity associated with synthetic
pyrethroids has been a cutaneous paresthesia observed in workers
spraying esters containing an -cyano substituent (deltamethrin,
cypermethrin, fenvalerate). The paresthesia developed several hours
following exposure and was described as a stinging or burning
sensation on the skin which, in some cases, progressed to a tin-
gling and numbness, the effects lasting some 12 to 24 h (LeQuesne
et al., 1980; Tucker and Flannigan, 1983; Zhang et al., 1991).
Reports have appeared in the literature from the People’s
Republic of China, where synthetic pyrethroids have been used
on a large scale on cotton crops since 1982 (Stuart-Harte, 1988;
He et al., 1988, 1989). Associated with the sloppy handling of
deltamethrin and fenvalerate, both of which are type II compounds,
some 573 cases of acute poisoning have occurred with some 229
cases of occupational exposure. Some 45 cases of intoxication in-
volved cypermethrin. Occupational exposure resulted in some
dizziness plus a burning, itching, or tingling sensation of the ex-
posed skin, which was exacerbated by sweating and washing with
warm water. The signs and symptoms disappeared by 24 h after
exposure. Spilling these agents on the head, face, and eyes resulted
in pain, lacrimation, photophobia, congestion, and edema of the
conjunctiva and eyelids. Ingestion of pyrethroid esters caused epi-
gastric pain, nausea and vomiting, headache, dizziness, anorexia,
fatigue, tightness in the chest, blurred vision, paresthesia, palpita-
tions, coarse muscular fasciculations in the large muscles of the
extremities, and disturbances of consciousness. In severe poison-
ings, convulsive attacks persisting from 30 to 120 s were accom-
panied by flexion of the upper limbs and extension of the lower
limbs, with opisthotonos and loss of consciousness. The frequency
of these seizures was on the order of 10 to 30 times a day in the
first week after exposure, gradually decreasing in incidence, with
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786 UNIT 5 TOXIC AGENTS

recovery within 2 to 3 weeks (He et al., 1989). The signs and symp-
toms of acute intoxication appear to be reversible and no chronic
toxicity has been reported to date.

Site and Mechanism of Toxicity Several mechanisms of action

of pyrethroid esters exist in the sensory, motor, and central nerv-
ous systems of insects and vertebrates, many of these actions be-
ing studied in vitro using cockroach, crayfish, and squid giant axon
preparations or various cultured cell systems (Narahashi, 1971,
1976, 1985; Casida et al., 1983; Forshaw et al., 1993; Narahashi,
1998; Ray, 2000).
Both type I and type II esters modify the gating kinetics of
sodium channels involved in the inward flow of sodium ions, pro-
ducing the action potential in cells that are normally closed at the
resting potential (Marban et al., 1998). The pyrethroids affect both
the activation (opening) and inactivation (closing) of the channel,
resulting in a hyperexcitable state as a consequence of a prolonged
negative afterpotential that is raised to the threshold membrane po-
tential and producing abnormal repetitive discharges (Ginsburg and
Narahashi, 1993; Narahashi et al., 1998). The observed differences
between type I and type II esters lie in the fact that the former hold
sodium channels open for a relatively short time period (millisec-
onds), whereas type II esters keep the channel open for a prolonged
time period (up to seconds) (Joy, 1994b). Although the repetitive
Figure 22-19. Other proposed cellular mechanisms by which pyrethroid
discharges could occur in any region of the nervous system, those esters interfere with neuronal function.
at presynaptic nerve terminals would have the most dramatic ef-
fect on synaptic transmission (i.e., on the CNS and peripheral sen-
sory and motor ganglia), giving rise to the signs documented in
Table 22-10. The depolarizing action would have a dramatic effect experiments were conducted on cultured neuroblastoma cells,
on the sensory nervous system because such neurons tend to dis- sinoatrial node cells, and so on, with results difficult to reconcile
charge when depolarized even slightly, resulting in an increased with neuronal actions. Several agents (permethrin, cypermethrin,
number of discharges and accounting for the tingling and/or burn- deltamethrin) inhibit Ca2, Mg2-ATPase, the effect of which
ing sensation felt on the skin and observed in particular with type would result in increased intracellular calcium levels accompanied
II esters (van den Bercken and Vijverberg, 1983). The biological by increased neurotransmitter release and postsynaptic depolariza-
actions of different pyrethroid esters at sodium channels is highly tion (Clark and Matsumura, 1982).
variable in that (1) cis and trans stereospecificity exists, the cis iso- Type II esters at relatively high concentrations act on the
mers being as much as 10-fold more toxic than trans isomers GABA-gated chloride channels in mammalian brain, this action
(Soderlund, 1985); (2) an additional chiral center is produced if a perhaps being related to the seizures seen with type II ester intox-
cyano-substituent is added to the alcohol (Fig. 22-18), giving rise ication (Abalis et al., 1986; Bloomquist et al., 1986). However,
to eight possible isomers; (3) the binding of cis and trans isomers other studies have shown pyrethroids to have no GABA-antago-
differs, being competitive at one site and noncompetitive at another nistic activity (Joy and Albertson, 1991; Ray, 2000).
(Narahashi, 1986); (4) tetrodotoxin-resistant sodium channels are Voltage-sensitive calcium-independent chloride channels in
10-fold more sensitive to pyrethroids than are tetrodotoxin- nervous tissue control cell excitability and exist in functionally dif-
sensitive channels (Ginsburg and Narahashi, 1993; Song and ferent kinds, those sensitive to pyrethroid esters belonging to the
Narahashi, 1996); (5) affinity to sodium channels is dependent on maxi-chloride channel type (Franciolini and Petris, 1990; Forshaw
the variable -subunit composition of the 10 or more different and Ray, 1993). The pyrethroid-induced decrease in chloride ion
channels identified to date (Marban et al., 1998); (6) insect sodium current would result in cell excitability, synergizing with the
channels are 100-fold more sensitive than mammalian channels, pyrethroid effect on sodium channels. Only type II esters affect
thereby in part explaining species susceptibility (Warmke et al., maxi-chloride channels and may be responsible for the generation
1997); (7) low temperature (25°C) exerts a greater inhibitory ef- of salivation and myotonia along with those effects elicited on
fect of pyrethroid esters (on sodium channels) than a higher (37°C) sodium channels (Joy, 1994; Ray et al., 1997; Ray, 2000).
temperature due to increased current flow at low temperature
(Narahashi et al., 1998). According to Narahashi et al. (1998), the Biotransformation, Distribution, and Storage Evidence to date
most important factor that causes differential toxicity is the sodium suggests that pyrethroid esters elicit little chronic toxicity in either
channel of the nervous system. in animals or humans. Chronic animal feeding studies yield high
Other sites of action have been noted for pyrethroid esters, as “no effect” levels, suggesting that there is little storage or accu-
shown in Fig. 22-19. Calcium channels have been proposed tar- mulation of a body burden of these agents and, perhaps, an effi-
gets, particularly in insects at levels of 10
7 M (Duce et al., 1999). cient detoxification of the chemicals.
Mammalian calcium channels appear to be less sensitive, with ef- Two ester linkages exist in pyrethroid esters, a terminal methyl
fects being seen only with type I esters. However, many of these ester (pyrethrin II) and one more centrally located ester adjacent
2996R_ch22_761-810 4/16/01 4:37 PM Page 787
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
to the cyclopropane moiety (allethrin, tetramethrin, phenothrin,
deltamethrin) and/or the -cyano substituent (deltamethrin, cyper-
methrin, fenvalerate, cyphenothrin). Pyrethroid esters are suscep-
tible to degradation by hydrolytic enzymes, possibly by nonspe-
cific carboxylesterases found associated with the microsomal
fraction of tissue homogenates in various species (Ecobichon,
1979; Casida et al., 1983). Hydrolysis of the methoxycarbonyl
group in pyrethrin II by an esterase in rat liver has been reported,
but the major site of hydrolytic activity would appear to be at the
central ester linkage (Elliott et al., 1972; Shono et al., 1979; Glick-
man and Casida, 1982). The importance of ester hydrolysis as a
route of detoxification is verified by the fact that many organophos-
phorus esters that are capable of inhibiting tissue esterases poten-
tiate pyrethroid ester toxicity in a variety of species (Casida et al.,
1983). Species susceptibility to pyrethroid ester toxicity would ap-
pear to be highly dependent on the nature of the tissue esterase,
the level of activity detected, the substrate specificity, and rate of
hydrolysis encountered in target and nontarget species. The mi-
crosomal monooxygenase system found in the tissues of almost all
species is extensively involved in the detoxification of every
pyrethroid ester in mammals and of some of these agents in insect
and fish species. Much of the research in this field has been sum-
marized by Shono et al. (1979), Kulkami and Hodgson (1984), and
Casida et al., (1983). The importance of the oxidative mechanisms
in detoxification is demonstrated by the inclusion of the synergist
piperonyl butoxide, a classic monooxygenase inhibitor, in prepa-
rations toxic to houseflies and other insects, in order to enhance
the potency of pyrethroid esters in the 10- to 300-fold range (Casida
et al., 1983; Matsumura, 1985).
Treatment of Poisoning Limited experience with pyrethroid in-
toxications has restricted the development of acceptable protocols
for treatment. Removal from exposure and lavage with vegetable
and/or vitamin E cream will alleviate dermal paresthesia, presum-
ably by binding the lipophilic pyrethroids (Flannigan et al., 1985).
Most other therapies have been symptom-related topical steroids
for contact dermatitis, antihistaminics, decongestants, and steroid
nasal spray for rhinitis and inhaled steroids for asthma (O’Malley,
1997). Systemic poisoning is more difficult to treat, symptomatic
and supportive measures being appropriate (He et al., 1989). Ex-
perimental therapies in animals have included local anesthetics,
phenytoin, phenobarbitone, valproate, diazepam, mephenesin, and
urethane, all at exceptionally high doses with interfering side ef-
fects (Ray, 2000). Only the chloride channel agonists ivermectin
and pentobarbitone appeared to be of any benefit, particularly in
type II ester intoxications (Forshaw, 2000).
Avermectins
The avermectins were discovered in 1975, isolated from a culture
of the actinomycete Streptomyces avermitilis in a soil sample made
available to Merck and Co. by the Kitisato Institute in Japan
(Campbell et al., 1983; Campbell, 1989; Fisher and Mrozik, 1992).
Avermectins are derived from 16-member macrocyclic lactones,
three of which—avermectin B1a, the homolog B1b (abamectin),
and the semisynthetic ivermectin—have come into wide use in vet-
erinary medicine as potent insecticidal, acaricidal, and anthelmintic
agents (Fisher and Mrozik, 1992) (Fig. 22-20). Ivermectin is used
for a wide range of ecto- and endoparasites of domestic and wild
animals. Potent anthelmintic activity against most gastrointestinal
787
and systemic nematodes has been identified at exceptionally low
(0.001 to 0.05 mg/kg body weight) dose levels, but this efficacy
does not extend to tapeworms or flukes (Campbell et al., 1983).
Administered topically or subcutaneously (systemically), iver-
mectin controls grubs, lice, mites, certain ticks, and biting flies on
cattle, horses, sheep, swine, and dogs (except the collie breed,
which appears to be uniquely susceptible) (Fisher and Mrozik,
1992). Ivermectin treatment does not result in the rapid death of
biting insects but appears to disrupt engorgement, molting, and re-
production (Campbell et al., 1983). A mixture of avermectins B1a
and B1b is also used currently as a foliar spray on crops against
various mites, Colorado potato beetle, tomato hornworm, Mexican
bean beetle, pea aphid, cabbage looper, corn earworm, and south-
ern army worm (Fisher and Mrozik, 1992). Emamectin (MK-244),
a derivative of avermectin B1, is more effective against Lepidoptera
larvae.
The discovery that ivermectin was efficacious against the skin-
dwelling microfilaria of Onchocerca species in cattle and horses
suggested that it might be of use in treating onchocerciasis (river
blindness) in humans, a debilitating disease caused by the organ-
ism Onchocerca volvulus (Taylor and Green, 1989). It has become
the drug of choice in treating lightly infected individuals, markedly
reducing the number of microfilaria in the skin though without ef-
fect on the adult worms (Aziz et al., 1982; Taylor and Greene,
1989). It is a safe, long-acting microfilaricide, an applied single
dose (150 ug/kg body weight) killing the immature microfilaria
and keeping the numbers of reappearing microfilaria well below
pretreatment levels for up to 1 year (Fisher and Mrozik, 1992).
Ivermectin treatment can significantly reduce the incidence of on-
chocerciasis by limiting the source of infection.
While the avermectins are highly lipid soluble, dermal ab-
sorption is less than 1.0 percent of the applied dose (Fisher
and Mrozik, 1992). Minimal oxidative biotransformation occurs,
2,4-hydroxymethyl ivermectin and 3-O-desmethyl ivermectin be-
ing formed. Regardless of the route of administration, urinary ex-
cretion accounts for only 0.5 to 2.0 percent of the dose, the re-
mainder being excreted slowly in the feces (Campbell et al., 1983).
While the liver and adipose tissue took up the agent(s), very little
residue was found in muscle, kidney or brain. In the case of the
brain, presumably the agent could not penetrate the blood-brain
barrier. In 28 days, almost complete elimination of ivermectin oc-
curred from the tissues of treated cattle with the exception of the
liver and body fat (Fisher and Mrozik, 1992).
Toxicologically, ivermectin is acutely toxic to rodents and
other species, the oral and intraperitoneal LD50 values being of the
order of 25 to 80 mg/kg body weight (Fisher and Mrozik, 1992).
Dermal toxicity is low, the LD50 for rats and rabbits being 660
and 406 mg/kg body weight, respectively. In subchronic studies,
no treatment-related effects were observed in rats, dogs, and mon-
keys at the usual therapeutic dosage range (0.1 to 1.2 mg/kg body
weight per day). Ivermectin showed no positive genotoxic effects
in microbial assays, in a forward mutation assay (mouse lym-
phoma), or in an unscheduled DNA synthesis assay. In develop-
mental/reproductive studies, offspring abnormalities were observed
only at maternotoxic doses in mice, rats, and rabbits. Oncogenic
effects were not found in studies with abamectin.
Mechanism of Action Early studies, with a variety of inverte-
brate species and model systems, resulted in a number of possible
mechanisms of action on neuronal transmission, chloride channels,
2996R_ch22_761-810 4/16/01 4:38 PM Page 788

788 UNIT 5 TOXIC AGENTS

OCH3
HO 22–23
CH3O
O
CH3 O
H CH3 CH3
H
CH3 O O O
H C2H5
O
H H
CH3 CH3
O O
25
OH H

O
CH3
H
OH

Common Structural Positions

Name
22–23 25

Avermectin Bla As above As above

Avermectin Blb As above CH(CH3)2
Abamectin
Ivermectin CH2 CH2 80% As above
20% CH(CH3)2

Figure 22-20. A structural representation of the macrocyclic lactone avermectin (B1a), abamectin (B1b), and
the semisynthetic insecticide ivermectin showing the structural differences at positions 22 to 23 and 25 of the
ring.

and GABA-like effects, summarized in Fisher and Mrozik (1992).
However, care must be taken in interpreting such results, since in-
terneuronal and neuromuscular junctions are known to differ con-
siderably between species (Gerschenfeld, 1973). The low water sol-
ubility and extensive (nonspecific) binding of avermectins preclude
accurate estimations of target-site concentrations, overestimating
the actual target-site concentrations (Fisher and Mrozik, 1992).
More recent binding affinity studies in rat brain and in insect and
nematode nerve tissue preparations have revealed that, in inverte-
brates, biological activity occurred at nanomolar and picomolar
concentrations (Schaeffer et al., 1989; Fisher and Mrozik, 1992).
Higher concentrations appear to cause secondary events and/or ar-
tifacts. While there may be different species-specific avermectin
“receptors,” this insecticide class has a high binding affinity to
chloride-channel proteins, opening the channels, reducing mem-
brane resistance, and increasing conductance inward. Such bind-
ing sites appear to be distinct from those of other effector mole-
cules and involve GABA-insensitive chloride channels (Arena et
al., 1991; Payne and Soderlund, 1991). Explaining the selective
specificity of avermectins (wide range of nematodes, arthropods,
insects but not tapeworms, flukes, and adult filaria) must await the
molecular study of the receptor proteins in these species. In
mammals, in the nematode Caenorhabditis elegans, and the house
fly, avermectins interact with the GABA-receptor complex, as has
been shown by avermectin-induced changes in GABA receptor–
directed ligands (Deng and Casida, 1992; Arena et al., 1995; Lankas
et al., 1997).
Newer Chemical Insecticides
With the development of insect resistance to various classes of
chemical insecticides, new approaches to insect control are needed.
Utilizing a better understanding of insect neurobiology, some new
and highly specific agents have been developed, capitalizing on the
recognition that various receptors in insect nervous systems are sig-
nificantly different from those in mammals. Shown in Fig. 22-21
are the structures of three types of new agents entering or avail-
able in the marketplace: (1) the nitromethylene heterocycles, de-
veloped from the cyclodienes and cyclohexanes; (2) the nitroimino
derivatives (chloronicotinyl or neonicotinoids), similar to nicotine;
and (3) the phenylpyrazoles. These chemicals are effective at low
application rates (8 to 10 g/ha), are not environmentally persistent,
and show negligible toxicity toward vertebrates. They possess
unique and selective mechanisms of action and perhaps point the
way to future insecticide development. To date, there have been no
reports of toxicity in humans.
Nitromethylenes A search for new classes of insecticides led to
a study of various aromatic heterocycles containing a nitrometh-
ylene substituent, only those containing a pyridine system being
insecticidal (Fig. 22-21A and B) (Soloway et al., 1979). The ni-
tromethylene heterocycle (NMH) insecticides are fast-acting neu-
rotoxicants, effective by both contact or oral ingestion; they are rel-
atively safe to vertebrates and degrade rapidly in the environment
(Schroeder and Flattum, 1984).
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES 789

A of the receptor (Huang et al., 1999). Investigations of a nAChR

Cl CH2 N NH
N
CH NO2 NMI
B properties. The compound fipronil (Fig. 22-21D) is insecticidal and
S has been shown to be highly effective against a broad range of in-
N CH NO2
H NMTHT
C chloride channel (Damgaard et al., 1999).
Cl CH2 N NH
N IMIDACLOPRID
N NO2
(IMI)
Cl D bursts of electrical activity (Gant et al., 1998). Fipronil, a sulfox-
CN
N
CF3 N
O conversion can be blocked by piperonyl butoxide, the cytochrome-
S P450 inhibitor. There is also a photoproduct, desulfinyl fipronil.
Cl NH2
CF3 FIPRONIL
Figure 22-21. Representative structures of the nitromethylene, chlor-
onicotinyl, and phenylpyrazole insecticides.
Using the cockroach ventral nerve cord (the sixth abdominal
ganglion nerve) preparation, various NMHs at micromolar con-
centrations produced a biphasic effect characterized by an initial
increase in the frequency of spontaneous discharges followed by a
blockade of nerve impulse conduction (Schroeder and Flattum,
1984). Elegant, classic neuropharmacologic experiments con-
ducted by these authors demonstrated that the NMHs acted as neu-
rotransmitter mimics and had both excitatory depressant effects,
eventually blocking postsynaptic nicotinic receptors (nAChR).
More recent experiments with 2(nitromethylene)tetrahydro-1,3-
thiazine (NMTHT) (Fig. 22-21B) confirmed the biphasic action at
nAChRs in several insect species and suggested that a binding site
resided on the -subunits of insect nAChRs (Leech et al., 1991).
Chloronicotinyl An outgrowth of studies of the nitromethylene-
type insecticides was the discovery of the nitroimino heterocycles
best known by the compound imidacloprid (Fig. 22-21C), devel-
oped in Japan in the mid-1980s. This agent combines high potency
to insects with exceptionally low mammalian toxicity and a favor-
able persistence (Liu et al., 1993; Bayer Corp., 1994). The potency
of imidacloprid and several analogs can be correlated with the bind-
ing affinity to house fly head membranes and mouse brain mem-
branes, these agents having a low affinity to the latter (Liu et al.,
1993, 1995; Chao and Casida, 1997). Extensive studies have
demonstrated that imidacloprid binds specifically to nAChRs in
various insects’ nervous systems (Liu and Casida, 1993; Nishimura
et al., 1994; Liu et al., 1995). Imidacloprid acts as a partial ago-
nist at the nAChR channel, generating subconductance-state cur-
rents (Nagata et al., 1997). Characterization of cloned nAChRs
from insects (Myzus persicae, peach aphid) revealed that imida-
cloprid affinity was influenced strongly by the -subunit content
structure and function will prove to be a boon to further insecti-
cide development.
Phenylpyrazoles The phenylpyrazole derivatives show extensive
biological activity, including insecticidal, herbicidal, and miticidal
sect pests at low-level foliar or soil application. It was first stud-
ied by Rhone-Poulenc Agro in 1987 and is now available com-
mercially (Gant et al., 1998). It is considered to be a second
generation removed from the earlier organochlorine insecticides
(lindane, -endosulfan) acting at the GABA receptor to block the
Fipronil has a unique mode of action in that it blocks the
passage of chloride ions through the GABA-regulated chloride
channel, disrupting CNS activity, since GABA is an inhibitory neu-
rotransmitter. Fipronil is a noncompetitive inhibitor of GABA-
induced effects, the effects in neurons being an increase in rapid
ide, is biotransformed to the corresponding sulfone in biological
systems, the latter compound still being a potent insecticide. This
Fipronyl and the sulfone selctively bind with high affinity to in-
sect GABA receptors and with much lower affinity to vertebrate
brain receptors (Cole et al., 1993; Hainzl et al., 1998). Comparing
fipronil and its derivatives to earlier chloride-channel blockers, the
IC50 vertebrate/IC50 insect ratios are 158 for fipronil, 140 for
lindane, 31 for the desulfinyl product, 19 for fipronil sulfone, and
4 for -endosulfan (Hainzl et al., 1998). The selectivity ratios rel-
ative to human GABA receptor are 135 for fipronil, 17 for the sul-
fone, and 16 for the desulfinyl photoproduct (Hainzl et al., 1998).
All of the above receptor-specific insecticides have provided
new ligand probes for neurotransmitter receptors as well as a new
approach to insecticide development. The only worrisome concern
is that, with increasing use and reliance on such agents, target in-
sects may develop resistance to these new compounds through
mechanisms similar to those seen for other neurotransmitters. In
the meantime, the high insect selectivity, low mammalian toxicity,
and low rates of application may provide a breathing space in the
ongoing search for efficacious, nontoxic chemical insecticides.
BOTANICAL INSECTICIDES
Naturally occurring agents of plant origin have been used to con-
trol insect pests. These chemicals ranged from highly toxic agents
(to both target and nontarget species), such as nicotine, to relatively
innocuous substances, such as derris root. Interestingly, despite the
overwhelming number of synthetic insecticide formulations on the
market, the two above-mentioned agents can still be purchased and
are still considered effective insecticides.
Nicotine
Nicotine, first used as an insecticide in 1763, has been used as a
contact insecticide, stomach poison, and fumigant in the form of
nicotine alkaloid, the sulfate salt, or in the form of other deriva-
tives. Commercially, nicotine is extracted from the leaves of Nico-
tiana tabacum and Nicotiana rustica by alkali treatment and steam
distillation or by extraction with benzene, trichloroethylene, or di-
2996R_ch22_761-810 4/16/01 4:38 PM Page 790
790 UNIT 5 TOXIC AGENTS
ethyl ether. Nicotine makes up some 97 percent of the alkaloid con-
tent of commercial tobacco. It is marketed under the trade name
of Black Leaf 40, an aqueous solution of the sulfate salt of nico-
tine, containing 40 percent nicotine.
Nicotine is extremely toxic, the acute oral LD50 in rats being
on the order of 50 to 60 mg/kg. It is readily absorbed through the
skin, and any contact with nicotine solutions should be washed off
immediately. Anecdotal accounts of experiences by people who
sprayed this chemical as an agricultural insecticide make an inter-
esting collection of stories, all pointing to the fact that nicotine
mimics the action of acetylcholine at all ganglionic synapses and
at neuromuscular junctions, causing muscular fasciculations, con-
vulsions, and death from paralysis of the respiratory muscles via
blockade of the neuromuscular junctions (see Table 22-7). It func-
tions as an insecticide in much the same manner, causing a block-
ade of synapses associated with motor nerves in insects.
Rotenoids
Six rotenoid esters occur naturally and are isolated from the plant
Derris eliptica found in Southeast Asia or from the plant Lon-
chocarpus utilis or Lonchocarpus urucu, native to South America.
Rotenone, one of the alkaloids, is the most potent and can be pu-
rified by solvent extraction and recrystallization. It can be used ei-
ther as a contact or a stomach poison. However, it is unstable in
light and heat and almost all toxicity can be lost after 2 to 3 days
during the summer. Rotenone is very toxic to fish, and one of its
main uses by native people over the centuries was to paralyze fish
for capture and consumption. The mammalian toxicity varies
greatly with the species exposed, the method of administration, and
the type of formulation. Crystalline rotenone has an acute oral LD50
of 60, 132, and 3000 mg/kg for guinea pigs, rats, and rabbits, re-
spectively (Matsumura, 1985). Because the toxicity of derris pow-
ders exceeds that of the equivalent content of rotenone, it is obvi-
ous that the other esters in crude preparations have significant
biological activity. Acute poisoning in animals is characterized by
an initial respiratory stimulation followed by respiratory depres-
sion, ataxia, convulsions, and death by respiratory arrest (Shimkin
and Anderson, 1936). The anesthetic-like action on nerves appears
to be related to the ability of rotenone to block electron transport
in mitochondria by inhibiting oxidation linked to NADH2, this re-
sulting in nerve conduction blockade (O’Brien, 1967; Corbett,
1974). Although toxicity in laboratory and domestic animals has
been reported with acute LD50 values of 10 to 30 mg/kg, human
intoxications are rare. The estimated fatal oral dose for a 70-kg
man is of the order of 10 to 100 g. Rotenone has been used topically
for treatment of head lice, scabies, and other ectoparasites, but the
dust is highly irritating to the eyes (potentially causing conjunc-
tivitis), the skin (causing contact dermatitis), and the upper respi-
ratory tract (causing rhinitis) and throat (linked with pharyngitis).
HERBICIDES
A herbicide, in the broadest definition, is any compound that is ca-
pable of either killing or severely injuring plants; it may be used
for the elimination of plant growth or the killing off of plant parts
(Jager, 1983). Many of the early chemicals—such as sulfuric acid,
sodium chlorate, arsenic trioxide, sodium arsenite, petroleum oils,
iron and copper sulfate, or sodium borate—were frequently hard
to handle and/or were very toxic, relatively nonspecific, or phyto-
toxic to the crop as well as the unwanted plant life if not applied
at exactly the proper time. In the late 1930s, many studies were
initiated to find agents that would selectively destroy certain plant
species. Many of these early chemicals were more effective but
still possessed considerable mammalian toxicity. However, a few
compounds served as prototype chemicals for further development.
Summaries of the early days of herbicide development are pre-
sented by Cremlyn (l978), McEwen and Stephenson (1979), Kirby
(1980), and Jager (1983).
In the past two decades, the herbicides have represented the
most rapidly growing section of the agrochemical pesticide busi-
ness due in part to (1) movement into monocultural practices, where
the risk of weed infestation has increased because fallowing and
crop rotation, which would change weed species, are no longer in
vogue; and (2) mechanization of agricultural practices (planting,
tending, harvesting) because of increased labor costs. The annual
rate of growth of herbicide production on a worldwide basis be-
tween 1980 and 1985 was 1.9 percent per year, more than double
the rate of growth for insecticides during the same period (Marquis,
1986). The result has been a plethora of chemically diverse struc-
tures rivaling the innovative chemistry of the insecticides, the aim
being to protect desirable crops and obtain high yields by selec-
tively eliminating unwanted plant species, thereby reducing the
competition for nutrients.
Herbicides may be classified by chemical structure, although
this is not very enlightening because of overlapping biological ef-
fects for a variety of chemical structures. The second method of
classification pertains to how and when the agents are applied. Pre-
planting herbicides are applied to the soil before a crop is seeded.
Preemergent herbicides are applied to the soil before the usual time
of appearance of the unwanted vegetation. Postemergent herbicides
are applied to the soil or foliage after the germination of the crop
and/or weeds. Plant biochemists classify herbicides according to
their mechanism of toxicity in plants; their action is referred to as
selective (toxic to some species), contact (act when impinging on
the plant foliage), or translocated (being absorbed via the soil or
through the foliage into the plant xylem and phloem).
ln this chapter, herbicides are classified by their ability to in-
terfere with specific biochemical processes essential for normal
growth and development—interactions that result in severe injury
to the plant and its eventual death. In Table 22-11, the various mech-
anisms by which herbicides exert their biological effects are shown,
along with the generic and chemical names of the classes of her-
bicides and some examples of each class. The claim has been made
that, because the modes of action involve biochemical phyto-
processes having no counterparts in mammalian systems, no risk
of mammalian toxicity is associated with these chemicals. With the
exception of a few chemicals, the herbicides have demonstrated
low toxicity in mammals.
However, the current controversy around these chemicals cen-
ters on demonstrated or suspected mutagenicity, teratogenicity,
and/or carcinogenicity associated either with the agent(s) or with
contaminants and by-products of manufacture found in trace
amounts in technical-grade material. The presence of some of these
contaminants has been largely ignored without any recognition that
the toxicities associated with them are different from those ob-
served with the herbicidal chemical and frequently occur at far
lower dosages.
In terms of general toxicity, because the major route of ex-
posure to herbicides is dermal and these agents tend to be strong
acids, amines, esters, and phenols, they are dermal irritants, caus-
ing skin rashes and contact dermatitis even when exposure involves
2996R_ch22_761-810 4/16/01 4:38 PM Page 791
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
Table 22-11
Mechanisms of Action of Herbicides
MECHANISM(S)
Inhibition of photosynthesis by disruption of light
reactions and blockade of electron transport
Inhibition of respiration by blockade of electron transfer
from NADH or blocking the coupling of electron transfer
to ADP to form ATP
Growth stimulants, “auxins”
Inhibitors of cell and nucleus division
Inhibitors of protein synthesis
Inhibition of carotenoid synthesis, protective pigments in
chloroplasts to prevent chlorophyll from being destroyed
by oxidative reactions
Inhibition of lipid synthesis
Inhibition of acetolase synthase
Inhibition of protoporphyrinogen oxidase
Inhibition of enolpyruvylshikimate-3-phosphate synthetase
Inhibition of glutamine synthetase
Unknown mechanisms, nonselective chemicals
diluted formulations. There appear to be subpopulations of indi-
viduals who are hypersensitive to dermal contact with solutions or
aerosolized mists of certain types of herbicides, and moderate to
severe urticaria has been observed to persist for 5 to 10 days fol-
lowing exposure. Certain individuals, particularly those prone to
allergic reactions, may experience severe contact dermatitis,
asthma-like attacks, and even anaphylactic reactions following der-
mal or inhalation contact with formulated herbicides. Whether
these effects are chemical-specific for the herbicide or for emulsi-
fiers, cosolvents, and so-called inerts found in formulations has not
been established. One such example is discussed below. Although
skin patch testing of herbicidal chemicals has usually proven to be
negative, it is possible that patients’ responses may be associated
with a generalized, nonspecific irritant effect of the formulation.
Many of these dermal and pulmonary reactions respond satisfac-
torily to treatment with antihistaminic agents.
In contrast, there are other herbicides that can elicit a range
of acute and chronic effects following exposure, and it is on these
chemicals that attention is focused here.
Chlorophenoxy Compounds
During World War II, considerable effort was directed toward the
development of effective, broad-spectrum herbicides in both the
United States and the United Kingdom with a view to both
increasing food production and finding potential chemical war-
fare agents (Kirby, 1980). The chlorophenoxy compounds
(Fig. 22-22)—including the acids, salts, amines, and esters—were
the first commercially available products evolving from this re-
search in 1946. This class of herbicides has seen continuous, ex-
791
CHEMICAL CLASSES
Ureas, 1,3,5-triazines, 1,4-triazines, uracils, pyridazones,
4-hydroxybenzonitriles, N-arylcarbamates, acylanilides
Dinitrophenols
Halophenols
Aryloxyalkylcarboxylic acids, benzoic acids
Alkyl N-arylcarbamates
Dinitroanilines
Chloracetamide, hydrazines, o-substituted diphenyl ethers
S-alkyl dialkylcarbamodithioates
Aliphatic chlorocarboxylic acids
Sulfonylureas, imidazolines, triazolopyrimidines,
sulfonamides
Diphenyl ethers, heterocyclic phenyl ethers (benzotriazoles,
indolinones, benzisoxazoles, quinoxalindones,
benzoxazines)
Glyphosate
Glufosinate
Inorganic agents (copper sulfate, sulfuric acid, sodium
chlorate, sodium borate)
Organic agents (dichlobenil, benzoylpropethyl,
chlorthiamid, bentazone)
tensive, and uninterrupted use since 1947 in agriculture for broad-
leafed weeds and in the control of woody plants along roadside,
railway, and utilities’ rights of way and in reforestation programs.
In plants, these chemicals mimic the action of auxins, hormones
chemically related to indoleacetic acid, that stimulate growth. No
hormonal activity is observed in mammals and other species, and
beyond target organ toxicity that can be associated with the phar-
macokinetics, biotransformation, and/or elimination of these chem-
icals, their mechanisms of toxic action are poorly understood. The
chlorophenoxy herbicides are no longer the agents of choice be-
cause of concerns over the formation of chlorinated dibenzofurans
and dibenzodioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD), as a consequence of poorly monitored manufacturing
practices or improper product storage in steel drums sitting beside
Figure 22-22. The molecular structure of the three most common
chlorophenoxyacetic acid herbicides: 2,4-dichlorophenoxyacetic acid
(2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 4-chloro-o-
toloxyacetic acid (MCPA). Ester and amine salt derivatives are also mar-
keted.
2996R_ch22_761-810 4/16/01 4:38 PM Page 792
792 UNIT 5 TOXIC AGENTS
runways under the tropical sun. However, since they are still used
in developing nations around the world, their toxicology cannot be
ignored.
A tremendous volume of mammalian toxicity data has been
collected over the past 42 years from both animal studies and in-
cidents of human exposure (Hayes, 1982; Stevens and Sumner,
1991). It is of interest to note that, in a recent toxicologic reeval-
uation of 2,4-D for the purposes of providing the U.S. EPA with a
new toxicity database for the chemical, an industry task force dis-
covered nothing of toxicologic significance that was not already
known about the chemical, with one exception (Mullison, 1986).
The exceptional finding was the appearance of astrocytomas in the
brains of male Fischer 344 strain rats exposed to the highest
(45 mg/kg per day) dosage. A subsequent review of the findings
suggested that this tumor incidence was not treatment-related
(Koestner, 1986; Solleveld et al., 1984). The acute toxicity elicited
by chlorophenoxy herbicides has been described by Hayes (1982).
The oral LD50 values ranged from 300 to 1000 mg/kg in differ-
ent animal species, and only the dog appeared to be particularly
sensitive, possibly on the basis that it has considerable difficulty
in the renal elimination of such organic acids (Gehring et al., 1976).
Accidental and/or occupational intoxications have been re-
viewed (Hayes, 1982; Stevens and Sumner, 1991; Ecobichon,
1996). An industrial accident in 1949 in a 2,4,5-T manufacturing
plant in Nitro, West Virginia, presented the first large occupational
exposure, with acute symptoms of exposure to the reaction prod-
ucts, including skin, eye, and respiratory tract irritation; headache;
dizziness; nausea; acneiform eruptions; severe muscle pain in the
thorax, shoulders and extremities; fatigue; nervousness; irritabil-
ity; dyspnea; complaints of decreased libido; and intolerance to
cold (Ashe and Suskind, 1953). In an epidemiologic study of these
same workers conducted in 1984, clinical evidence of chloracne
persisted in some 55.7 percent of those exposed (113 out of 204),
and an association was found between the persistence of chloracne
and the presence and severity of actinic elastosis of the skin
(Suskind and Hertzberg, 1984). There was no evidence of increased
risk of cardiovascular, hepatic, or renal disease or of central or pe-
ripheral nervous tissue damage. One study documented neurotox-
icity, decreased peripheral conduction velocities being observed in
workers employed in the manufacture of 2,4-D and 2,4,5-T (Singer
et al., 1982). Earlier literature reported significant peripheral neu-
ropathies in three sprayers using 2,4-D ester, signs and symptoms
progressing from muscle pain and paresthesias to severe paralysis,
all of which was supported by electromyographic analysis
(Goldstein et al., 1959). Chloracne, or “weed bumps,” has been the
most persistent effect observed in almost all incidents of chlorophe-
noxy herbicide exposure, although this is not a specific effect, being
caused by a number of halogenated aromatic compounds includ-
ing polyhalogenated biphenyls, dibenzo-p-dioxins, dibenzofurans,
and naphthalenes (Schultz, 1968; Poland et al., 1971).
A wide range of human lethal dosages of 2,4-D has been re-
ported, the average being in excess of 300 mg/kg, although it may
be as low as 80 mg/kg. The oral dose required to elicit symptoms
is of the order of 50 to 60 mg/kg. Since these chemicals are irri-
tants, oral ingestion has caused focal submucosal hemorrhage,
moderate congestion, and edema as well as necrosis of the intes-
tinal tract, fatty infiltration and necrosis of the liver, degeneration
of the convoluted tubules of the kidney, and pneumonitis and in-
flammation in the terminal bronchioles (Hayes, 1982).
In hindsight, many of the above-mentioned signs and symp-
toms might be attributed to contaminants found in chlorophenoxy
herbicides from early production times, principally from a mixture
of polychlorinated dibenzo-p-dioxins, the main one being TCDD,
found in samples of 2,4,5-T at levels of 30 to 50 ug/g (Hay, 1982;
Gough, 1986). The teratogenicity (cleft palate, renal anomalies)
produced by commercial, TCDD-contaminated (30 ug/g) 2,4,5-T
was not reproduced when highly purified 2,4,5-T was used
(Courtney et al., 1970; Courtney and Moore, 1971). Recent in vitro
and in vivo genotoxicity studies of 2,4-D have proven negative
(Charles et al., 1999a, b; Gollapudi et al., 1999). Recent acciden-
tal/occupational exposures to chlorophenoxy herbicides have not
resulted in peripheral neuropathies, a fact confirmed in animal stud-
ies using purified 2,4-D dimethylamine salt (Mattsson et al., 1986).
While the carcinogenicity of purified 2,4-D and 2,4,5-T has not
been established in rodent studies, that of TCDD has (Van Miller
et al., 1977; Kociba et al., 1978). The toxicology of the polychlo-
rinated dioxins and furans is discussed in other chapters.
Public concerns about the chlorophenoxy herbicides have fo-
cused on birth defects, cancers, and the spurious illnesses reported
among military personnel exposed to the defoliant Agent Orange
(a 50:50 mixture of the n-butyl esters of 2,4-D and 2,4,5-T) sprayed
extensively during the Vietnam conflict and found to be contami-
nated with TCDD to a maximum of 47 ug/g (Hay, 1982; Greenwald
et al., 1984; Gough, 1986; CDC, 1988; Stellman et al., 1988;
Tamburro, 1992). While exposure to this persistent contaminant
can be verified by blood analysis of veterans, the multifaceted na-
ture of the adverse effects has precluded a definitive association
(Ketchum et al., 1999). Epidemiologic studies of cancer in farm-
ers and others occupationally exposed to chlorophenoxy herbicides
for long periods of time have suggested an association with soft
tissue sarcomas, non-Hodgkin’s lymphoma (NHL), and Hodgkin’s
lymphoma (HL) without any definitive conclusions (Hardell and
Sandstrom, 1979; Ott et al., 1980; Eriksson et al., 1981; Hardell et
al., 1981; Cantor, 1982; Theiss et al., 1982; Lynge, 1985;
Schumacher, 1985; Hoar et al., 1986; Pearce et al., 1986; Bond et
al., 1988; Bond and Rossbacher, 1993). A study of wheat farmers
in western Canada, where 2,4-D has been used almost exclusively
from 1947, showed an overall lower mortality and cancer rate than
expected (Wigle et al., 1990). A review of published studies pre-
sented evidence of an association between occupational exposure
to chlorophenoxy herbicides and an increased risk of NHL
(Morrison et al., 1992). The study of an international database set
up by IARC/NIEHS revealed no clearly detectable excess for NHL
and HL but a sixfold excess of soft tissue sarcomas in the cohort
and a ninefold excess among sprayers (Saracci et al., 1991). An in-
crease in prostate cancer mortality among Canadian farmers has
been reported (Morrison et al., 1993). Other studies of databases
have suggested that the carcinogenic impact of chlorophenoxy
compounds was negligible (Munro et al., 1992; Bond and
Rossbacher, 1993). Lacking the ideal “definitive, clean” study, this
controversy will continue in the literature. In the meantime, the
chlorophenoxy herbicides have been phased out of use in devel-
oped nations, being replaced by other agents. However, the con-
cerns persist, particularly in developing countries where use con-
tinues and in Vietnam, where exposure was so heavy.
Animals will tolerate repeated oral exposure to doses of
chlorophenoxy herbicides marginally below the single, toxic oral
dose without showing significant signs of toxicity, an observation
suggesting that there is little cumulative effect on target organs. At
dosages causing toxicity, few specific signs other than muscular
and neuromuscular involvement were observed in animals, al-
though tenseness, stiffness in extremities, muscular weakness,
2996R_ch22_761-810 4/16/01 4:38 PM Page 793
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
ataxia, and paralysis have been reported. Hepatic and renal injury
in addition to irritation of the gastrointestinal mucosa have been
observed in acute lethality studies in animals.
Bipyridyl Derivatives
One chemical class of herbicides deserving of particular attention
is the bipyridyl group, specifically paraquat (1,1-dimethyl-4,4-
bipyridylium dichloride, methyl viologen) and diquat (1,1-ethyl-
ene-2,2-bipyridylium dibromide) (Fig. 22-23). Paraquat was first
synthesized in 1882, but its pesticidal properties were not discov-
ered until 1959 (Haley, 1979). This agent, a nonselective contact
herbicide, is one of the most specific pulmonary toxicants known
and has been the subject of intensive investigation because of the
startling toxicity observed in humans. A high mortality rate is en-
countered in poisoning cases. Many countries have banned or se-
verely restricted the use of paraquat because of the debilitating or
life-threatening hazards from occupational exposure and the large
number of reported accidental and suicidal fatalities (Campbell,
1968; Davies et al., 1977; Haley, 1979; Tinoco et al., 1993). How-
ever, paraquat is still used in some 130 countries and, in third-
world nations, is available to 98 percent of the agricultural work-
ers (WHO, 1984; Ramasamy et al., 1988). In Taiwan, paraquat
accounted for 54 percent of the pesticide-related poisonings in the
years 1985 to 1993 (Yang et al., 1996). The toxicology of this class
. ), which is
of herbicides should not be ignored.
In animals, paraquat shows moderate acute toxicity, the oral
LD50 values for various species ranging from 22 to 262 mg/kg.
Intoxication involves a combination of signs and symptoms that
include lethargy, hypoxia, dyspnea, tachycardia, hyperpnea, adip-
sia, diarrhea, ataxia, hyperexcitability, and convulsions, depending
on the dosage and the species studied (Smith and Heath, 1976;
Haley, 1979). Necropsy reveals hemorrhagic and edematous lungs,
intraalveolar hemorrhage, congestion and pulmonary fibrosis,
centrilobular hepatic necrosis, and renal tubular necrosis. Lung
weights of intoxicated animals increase significantly despite
marked losses in body weight. From a catalog of all the signs and
symptoms, it is obvious that the lung is the most susceptible tar-
get organ, and the same histopathologic picture of pulmonary le-
sions is observed in mice, rats, dogs, and humans (Clark et al.,
1966). In poisonings, immediate effects are usually not seen in
animals; within 10 to 14 days, however, respiration becomes
impaired, rapid, and shallow and the morphologic changes seen in-
clude degeneration and vacuolization of pneumocytes, damage to
Figure 22-23. The chemical structures of paraquat and diquat, marketed
as the dichloride and dibromide salts, respectively.
793
type I and type II alveolar epithelial cells, destruction of the
epithelial membranes, and proliferation of fibrotic cells.
Paraquat, a highly polar compound, is poorly absorbed from
the gastrointestinal tract (5 to 10 percent) (Haley, 1979). Experi-
ments in rats showed that 52 percent of the administered oral dose
was still localized in the intestine some 32 h postadministration,
although 45 percent of the dose had been excreted in the urine and
feces within 48 h, with some detected in urine for up to 21 days
(Murray and Gibson, 1974). Intoxication by the ingestion of for-
mulation concentrates may be enhanced by increased absorption
due to the presence of emulsifiers and cosolvents. Metabolism by
mammalian tissue is not extensive, although intestinal microflora
may account for 30 percent of the excreted metabolites in animal
studies (Daniel and Gage, 1966). Elevated levels of paraquat in re-
nal tissue suggest the kidney as a primary route of excretion (Rose
et al., 1976).
Pulmonary tissue, both in vivo and in vitro, acquires much
higher concentrations of paraquat than other tissues with the ex-
ception of the kidney. Over a 30-h posttreatment period, dispro-
portionately high levels are found in the lung (Sharp et al., 1972;
Rose et al., 1976). Acquisition is due to a unique diamine/
polyamine transport system in the alveolar cells. Upon uptake,
paraquat undergoes a NADPH-dependent one-electron reduction to
a free radical that reacts with molecular oxygen to regenerate the
paraquat cation plus a reactive superoxide anion (O2
converted into hydrogen peroxide (H2O2) by the enzyme superox-
ide dismutase. Both O2 and H2O2 can attack polyunsaturated lipids,
forming lipid hydroperoxides that, in turn, react with unsaturated
lipids to form more lipid-free radicals, perpetuating the destructive
reaction (Smith, 1987). Alveolar cell membrane damage results in
alveolitis, the destruction of alveolar cells, invasion of the space
by fibrotic cells accompanied by a loss of pulmonary elasticity and
respiratory impairment, with an inefficient gas (O2, CO2) exchange.
Cellular events can be modulated by the availability of oxygen, an-
imals kept in air with only 10% oxygen faring better than those
kept in room air (Rhodes, 1974).
Paraquat poisonings in children and adults have been de-
scribed in detail in the literature (Almog and Tal, 1967; Davies et
al., 1977; Haley, 1979; Hayes, 1982; Tinoco et al., 1993). Paraquat
is a favored agent in suicide attempts in many parts of the world
(Wesseling et al., 1993, 1997; Yang et al., 1996). Paraquat-induced
intoxications should be divided into two categories: (1) poisonings
by accidental or intentional ingestion, usually involving formula-
tion concentrates containing up to 20 percent active ingredient, and
(2) functional intoxications, associated with dermal and/or inhala-
tion exposure of diluted spray formulations.
The ingestion of commercial paraquat concentrates is invari-
ably fatal and runs a time course of 3 to 4 weeks. The initial irri-
tation and burning of the mouth and throat, the necrosis and slough-
ing of the oral mucosa, severe gastroenteritis with esophageal and
gastric lesions, abdominal and substernal chest pains, and bloody
stools give way to the characteristic dominant pulmonary symp-
toms, including dyspnea, anoxia, opacity in the lungs seen in chest
x-rays, progressive fibrosis, coma, and death. While the pulmonary
lesions are the most life-threatening, paraquat induces multiorgan
toxicity with necrotic damage to the liver, kidneys, and myocar-
dial muscle plus extensive hemorrhagic incidents throughout the
body.
Survivors of moderate-to-severe paraquat poisonings showed
significant impairment in respiratory function tests, which im-
proved dramatically or partially with time (Lin et al., 1995). How-
2996R_ch22_761-810 4/16/01 4:38 PM Page 794
794 UNIT 5 TOXIC AGENTS
ever, it is as yet unknown whether long-term respiratory health
effects occur with repeated and/or seasonal inhalation and/or
dermal exposure to diluted paraquat aerosols (Wesseling et al.,
1997). Swan (1969) found no detectable changes in workers ex-
posed to sprays 6 days per week for 12 weeks. Senanayake et al.
(1993) found no changes in standard spirometric tests in Sri Lankan
tea plantation workers continually exposed to paraquat aerosols.
More recent studies have confirmed that no correlation exists
between exposure and parameters such as FEV1.0, FVC, etc.
(Castro-Gutierrez et al., 1997; Dalvie et al., 1999). However, in
one study, severity of dyspnea and a threefold increase in episodic
wheezing accompanied by shortness of breath was found among
the most highly exposed workers (Castro-Gutierrez et al., 1997).
Perhaps the standard, spirometric, functional tests are not sensitive
enough since, in the second study, there was a significant rela-
tionship between long-term exposure and arterial oxygen desatu-
ration measured by oximetry during an exercise test (Dalvie et al.,
1999). More sensitive tests may be needed to assess long-term res-
piratory disabilities.
Treatment of paraquat poisoning should be vigorous and ini-
tiated as quickly as possible. Gastric lavage should be followed by
the administration of mineral adsorbents such as Fuller’s earth
(kaolin), bentonite clay, or activated charcoal to bind any unab-
sorbed paraquat remaining in the gastrointestinal tract. Purgatives
may be given. Absorbed paraquat may be removed from the blood-
stream by aggressive, lengthy hemoperfusion through charcoal or
by hemodialysis. To avoid excessive pulmonary damage, supple-
mental oxygen should be reduced to a level just sufficient to main-
tain acceptable arterial oxygen tension ( 40 to 50 mmHg) (Haley,
1979; Hayes, 1982). Even though these patients may suffer from
hypoxia and respiratory insufficiency, hyperbaric oxygen is con-
traindicated because it appears to promote cellular toxicity.
Diquat is a rapid-acting contact herbicide used as a desiccant,
for the control of aquatic weeds, and to destroy potato halums be-
fore harvesting. Diquat is slightly less toxic than paraquat; the oral
LD50 values in various species are on the order of 100 to 400 mg/kg.
Part of the reduced toxicity may be related to the fact that it is
poorly absorbed from the gastrointestinal tract; only 6 percent of
an ingested dose is excreted in the urine, whereas 90 to 98 percent
of the dose is eliminated via the urine following subcutaneous ad-
ministration (Daniel and Gage, 1966). A latency period of 24 h is
seen prior to visible toxic effects.
Following acute, high-dose exposure or chronic exposure of
animals to diquat, the major target organs were the gastrointesti-
nal tract, the liver, and the kidneys (Hayes, 1982; Morgan, 1982).
Chronic feeding studies resulted in an increased incidence of
cataracts in both dogs and rats (Clark and Hurst, 1970). It is con-
sidered that diquat can form free radicals and that the tissue necro-
sis is associated with the same mechanism(s) of superoxide-
induced peroxidation as observed with paraquat. Unlike paraquat,
diquat shows no special affinity for the lung and does not appear
to involve the same mechanism that selectively concentrates
paraquat in the lung (Rose and Smith, 1977).
Few diquat-related human intoxications have been reported to
date (Schonborn et al., 1971; Narita et al., 1978; Hayes, 1982). In
the few cases of suicidal intent described, ulceration of mucosal
membranes, gastrointestinal symptoms, acute renal failure, hepatic
damage, and respiratory difficulties were observed. CNS effects
were more severe. Interestingly, no fibrosis was evident in the
lungs. One individual died of cardiac arrest.
Chloroacetanilides
Alachlor (Lasso) (Fig. 22-24) is an aniline herbicide used to con-
trol annual grasses and broad-leaf weeds in a number of crops
(corn, soybeans, peanuts) as a systemic herbicide absorbed by the
germinating shoots and roots by interfering with protein synthe-
sis and root elongation. It is a slightly toxic (EPA class III) herbi-
cide, the oral LD50 (rat) being 930 to 1350 mg/kg, and is a slight-
to-moderate skin irritant (WSSA, 1994; Kamrin, 1997). Subchronic
studies in rats and dogs, with doses of 1 to 100 mg/kg/day, showed
no adverse effects, but a 6-month dog study showed hepatic toxicity
at all doses above 5 mg/kg/day, while a year-long study revealed
hepatic, renal, and splenic effects above a dosage of 1 mg/kg/day.
In reproductive studies, maternal and fetal toxicity was observed
at the high oral doses used (150 and 400 mg/kg/day), but there was
no effect on reproduction. Neither were teratogenic effects seen in
rats and rabbits, confirming the negative results in microbial mu-
tagenicity studies. Revisiting the toxicity database and providing
replacement studies for carcinogenicity revealed thyroid tumors
and adenocarcinomas of the stomach and nasal turbinates of Long-
Evans rats and in the lungs of CD-1 mice receiving relatively high
doses (126 and 260 mg/kg/day for rats and mice, respectively
(Alachlor Review Board, 1987). Alachlor is considered to be a
category 2B (probable) human carcinogen by the U.S. EPA, a risk
to agricultural workers during mixing and loading, with levels of
exposure ranging from 0.00038 to 2.7 mg/kg/day depending on the
exposure model used. The putative carcinogen metabolite,
2.6-diethylbenzoquinonimine (DEBQ1), is formed by oxidative
and nonoxidative reactions in mice, rats, and monkeys but not in
humans (Coleman et al., 1999). However, the human may form
DEBQ1 via another route. Studies of thyroid tumors in rats sug-
gest that alachlor-induced follicular cell tumors were related to in-
creased metabolism of thyroxine via hepatic enzyme conjugation
(Wilson et al., 1996). To date, there has been no evidence of an
appreciable effect of alachlor exposure on worker mortality or can-
cer rates (Acquavella et al., 1996).
The discovery of alachlor in well water at levels of 0.11 to
2.11 g/L, the highest being 9.1 g/L, led to the cancellation of
its registration in Canada in 1985. Concerns about one analog of
a series has led to the examination of other chloracetanilides and
closely related agents—e.g., acetochlor, amidochlor, butachlor,
Figure 22-24. The chemical structures of alachlor (2-chloro-2, 6-
diethyl-N-(methoxymethyl)acetanilide) and metolachlor (2-chloro-6-
ethyl-ethyl-N-(2-methoxy-1-methylethyl) acet-o-toluidide.
2996R_ch22_761-810 4/16/01 4:38 PM Page 795
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
metalaxyl, metolachlor (Fig. 22-24), propachlor, etc.—all of the
agents showing a consistent pattern of mutagenic activity mediated
via metabolites, possibly even species-specific intermediates
(Dearfield et al., 1999). One example acetochlor is converted into
a rat-specific metabolite that may be related to the nasal tumors,
thus posing no genetic or carcinogenic hazard to humans (Ashby
et al., 1996). However, changes in leopard frog metamorphosis by
acetochlor appears to be related to an interaction with thyroid hor-
mone via a nonthyroid receptor mechanism (Cheek et al., 1999).
No doubt, detailed mechanistic studies will reveal one or more
modes of action.
Phosphonomethyl Amino Acids
Two agents, N-phosphonomethyl glycine (glyphosate, Roundup,
Vision) and N-phosphonomethyl homoalanine (glufosinate, Basta)
must be considered because of their use in attempted suicides in
southeastern Asia (Fig. 22-25). Both agents are broad-spectrum
nonselective systemic herbicides for postemergent control of an-
nual and perennial plants (grasses, sedges, broad-leaf weeds) and
woody plants. While they exist as free acids, these agents are mar-
keted as the isopropylamine or trimethylsulfonium salts of
glyphosate and the ammonium salt of glufosinate in formulation
concentrates of 41 percent and 18.5 percent, respectively. In con-
sidering any toxicity data, one must make the distinction whether
the data pertain to the acid, the salt, or the complete formulation(s)
containing what appear to be biologically active surfactants
(Kamrin, 1997; Watanabe and Sano, 1998).
Glyphosate Glyphosate binds to and inhibits the enzyme
5-enolpyruvyl-shikimate-3-phosphate synthetase (EPSPS), an en-
zyme of the aromatic amino acid biosynthesis pathway essential
for protein synthesis in plants (Haslam, 1993). In mammals, in-
gestion, with oral LD50 values in the rat being 5600 mg/kg, al-
though that of the trimethylsulfonium salt is 750 mg/kg (WSSA,
1994). Formulations of glyphosate show moderate toxicity, LD50
values being between 1000 and 5000 mg/kg (Monsanto, 1985;
WSSA, 1994). Glyphosate is nontoxic by the dermal route, with
dermal LD50 values being in excess of 5000 mg/kg for the acid
and the isopropylamine salt. While glyphosate is not a dermal ir-
ritant in animals and does not induce photosensitization, formu-
lations can cause severe occupational contact dermatitis, although
patch testing in humans resulted in no visible skin changes or sen-
sitization (WSSA, 1994; Maibach, 1986). Glyphosate is an ocu-
O O GLYPHOSATE
HO C CH2 NH CH2 P OH
ROUNDUP™
OH VISION™
GLUPHOSINATE
O O
HO C CH CH2 CH2 P CH3
BASTA™
NH2 OH TOTAL™
Figure 22-25. The chemical structures of glyphosate (N-phospho-
nomethyl glycine) and glufosinate (N-phosphonomethyl homoalanine).
795
lar irritant in the rabbit and human (Acquavella et al., 1999).
Chronic studies with rats, dogs, and rabbits resulted in no
glyphosate-related effects up to the highest doses tested (400 to
500 mg/kg/day) (WSSA, 1994). Reproductive problems were ob-
served in test animals only at very high (150 mg/kg/day) doses
that elicited maternal toxicity. Glyphosate was not teratogenic at
elevated doses in rabbits (350 mg/kg/day) or rats (175 mg/kg/day),
although other signs of toxicity in dams and fetuses were observed.
Glyphosate was not mutagenic in standard tests (Ames and other
bacterial assays, dominant lethal test in mouse) (Li and Long,
1998; WSSA, 1994). However, one study, with glyphosate iso-
propylamine salt and Roundup formulation, showed weak muta-
genic activity in the Ames test and a significant increase in chro-
mosomal aberrations in the Allium root cell when Roundup was
tested (Rank et al., 1993). Carcinogenicity was not observed in
mice, rats or dogs, glyphosate being classified by the U.S. EPA
as a class E agent. Moses (1989) has reported tumors in the pitu-
itary and mammary glands in glyphosate-treated rats. Glyphosate
does not inhibit cholinesterases.
Unfortunately, glyphosate has become the agent of choice to
replace paraquat as a suicidal agent in many countries, the inci-
dence of such poisonings increasing as paraquat is banned or is
more tightly controlled (Talbot et al., 1991; Tominack et al., 1991;
Mendes et al., 1991; Leveridge, 1996; Yang et al., 1996). The for-
mulation concentrate is used. Mild intoxications are characterized
by gastrointestinal symptoms (nausea, vomiting, diarrhea, abdom-
inal pain) due to mucosal irritation and injury, with resolution
within 24 h (Talbot et al., 1991). In moderate intoxications, more
severe and persistent intestinal symptoms (ulceration, esophagitis,
hemorrhage) are seen, along with hypotension, some pulmonary
dysfunction, acid-base disturbance, and evidence of hepatic and re-
nal damage. Severe poisoning is characterized by pulmonary dys-
function requiring intubation, renal failure requiring dialysis, hy-
potension and vascular shock, cardiac arrest, repeated seizures,
coma, and death (Talbot et al., 1991; Tominack et al., 1991). A rea-
sonable dose-effect relationship was established by Talbot et al.
(1991), who estimated the volume(s) of formulation (concentrate)
ingested causing asymptomatic, mild, moderate or severe poison-
ing in humans to be 17, 58, 128 and 184 mL, respectively. This
could be converted to glyphosate concentrations of 87, 298, 658,
and 946 mg/kg based on the formulation containing 360 g/L of
free glyphosate and a 70-kg body weight.
Several reviews of intoxication cases, particularly the Japan-
ese and Taiwanese series, have raised suspicions about the toxic-
ity of the surfactant polyoxyethyleneamine (POEA) in the formu-
lations used currently (Sawada and Nagai, 1987; Sawada et al.,
1988; Talbot et al., 1991; Tominack et al. 1991). The median lethal
dose of POEA is less than one-third that of the formulation or
glyphosate (Sawada et al., 1988). Tai et al. (1990) found that POEA
was responsible for the hypotensive effect in dogs. This class of
surfactants has been associated with hemolysis and with gastroin-
testinal and CNS effects (Grugg et al., 1960; Sawada et al., 1988).
As of 1999, efforts were being made to reformulate the Roundup
product to replace POEA (personal communication).
Glufosinate N-phosphonomethyl homoalanine acts as a suicide
substrate, interfering with glutamate synthesis in plants by irre-
versibly inhibiting the enzyme glutamine synthetase, which plays
an important role in ammonia detoxification and amino acid me-
tabolism (Ebert et al., 1990). The herbicidal effect is caused by cy-
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796 UNIT 5 TOXIC AGENTS

totoxicity from increased ammonia levels and impairment of pho- occupational exposure or with a few atypical but sometimes well-
torespiration and photosynthesis (Hack et al., 1994). publicized incidents (Stevens and Sumner, 1991).
The acute oral toxicity of glufosinate in mice, rats, and rab-
bits was low, the oral LD50 lying between 1500 and 2000 mg/kg FUNGICIDES
(Ebert et al., 1990; Hack et al., 1994). In subchronic feeding stud-
ies in rats, no agent-related deaths occurred, although body weight Fungicidal chemicals are derived from a variety of structures rang-
gains in males were retarded in the 5000-ppm group. Food con- ing from simple inorganic compounds, such as sulfur and copper
sumption was reduced and water consumption increased and, at sulfate, through the aryl- and alkyl-mercurial compounds and chlo-
this high dose, signs of CNS excitation and hypothermia were rinated phenols to metal-containing derivatives of thiocarbamic
noted (Hack et al., 1994). Glufosinate was not considered to be acid (Fig. 22-26). The chemistry of fungicides and their properties
mutaginic, teratogenic, or carcinogenic in animal studies, although have been discussed by Cremlyn (1978), Kramer (1983), and Ed-
in more recent studies using whole-embryo culture, teratogenic wards et al. (1991). Foliar fungicides are applied as liquids or pow-
effects in mice have been observed, the effect being induced apop- ders to the aerial green parts of plants, producing a protective bar-
tosis in the neuroepithelium of developing embryos (Watanabe rier on the cuticular surface and systemic toxicity in the developing
and Iwase, 1996; Watanabe, 1997). While glufosinate did not in-
hibit brain cholinesterase, reductions in erythrocytic and serum
cholinesterases have been seen in 7 of 16 patients affected by this
herbicide (Watanabe and Iwase, 1998). In contrast to plant metab-
olism, glufosinate ammonium inhibited glutamine synthetase in an-
imals, but this did not lead to a problem in ammonia metabolism,
the mammal obviously compensating by using other metabolic
pathways (Hack et al., 1994).
Glufosinate ammonium has been involved in a number of
poisoning cases, particularly in Japan (Koyama et al., 1994;
Watanabe and Sano, 1998; Tanaka et al., 1998). Early clinical
symptoms included nausea, vomiting, and diarrhea associated with
intestinal mucosal irritation but were followed in 24 h by neuro-
logic signs, including impaired respiration, seizures, muscle weak-
ness (post–status epileptic myopathy), convulsions, and death
within 4 days in 6 of 31 patients (Koyama, 1995). Some survivors
showed either a brief loss of memory or amnesia for 7 to 10 days
after intoxication (Koyama, 1995). Any significant role of gluta-
mate in the neurologic events has not been confirmed. Limited in-
formation is available regarding glufosinate persistence in vivo, but
urinary levels higher than concomitant blood levels have been re-
ported and urinary excretion persisted for 3 to 5 days after inges-
tion (Watanabe and Iwase, 1998).
Once again, concerns have been raised about the role of the
surfactant. The direct cause of death seemed to be circulatory dis-
turbance, especially cardiac insufficiency, possibly related to the
surfactant in the formulation involved in the intoxications (Koyama
et al., 1995; Watanabe and Sano, 1998). The absorption of glufos-
inate in animals was 25 to 30 percent higher than the absorption
rate of the agent when given alone (Watanabe and Sano, 1998).
This suggested that the glufosinate-related effects might be en-
hanced by surfactant-induced penetration of the CNS, while the
cardiovascular system effects were surfactant-related.
Many herbicides representative of several chemical classifi-
cations and diverse structures have recently been introduced into
agricultural practice (Table 22-11). In general, these chemicals have
relatively low acute toxicity, the oral LD50 values in rats being of
the order of 100 to 10,000 mg/kg, and they are toxicologically un-
interesting, since—in subchronic and chronic studies—large doses
can be administered without eliciting significant biological effects.
Many of these newer chemicals are applied to crops or soil at
exceedingly low application rates, minimizing nontarget species
toxicity and avoiding environmental contamination. Present con-
cerns focus on groundwater contamination and closer scrutiny of
minor contaminants for mutagenic, teratogenic, and carcinogenic Figure 22-26. Chemical structures of fungicides representative of vari-
effects. Poisonings in humans have usually been associated with ous chemical classifications.
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CHAPTER 22 TOXIC EFFECTS OF PESTICIDES 797

fungus. Soil fungicides are applied as liquids, dry powders, or gran-
ules, acting either through the vapor phase or by systemic proper-
ties. Dressing fungicides are applied to the postharvest crop (ce-
real grains, tubers, corms, etc.) as liquids or dry powders to prevent
fungal infestation of the crop, particularly if it may be stored un-
der less than optimum conditions of temperature and humidity. The
postharvest loss of food crops to disease is a serious worldwide
problem (Table 22-1). Fungicides may be described as protective,
curative, or eradicative, according to their mode of action. Protec-
tive fungicides, applied to the plant before the appearance of any
phytopathic fungi, prevent infection by either sporicidal activity or
by changing the physiologic environment on the leaf surface. Cu-
rative fungicides are used when an infestation has already begun
to invade the plant, and these chemicals function by penetrating
the plant cuticle and destroying the young fungal mycelium (the
hyphae) growing in the epidermis of the plant, preventing further
development. Eradicative fungicides control fungal development
following the appearance of symptoms, usually after sporulation,
by killing both the new spores and the mycelia and by penetrating
the cuticle of the plant to the subdermal level (Kramer, 1983).
An effective fungicide must possess the following properties:
(1) low toxicity to the plant but high toxicity to the particular
fungus; (2) activity per se or ability to convert itself (by plant or
fungal enzymes) into a toxic intermediate; (3) ability to penetrate
fungal spores or the developing mycelium to reach a site of action;
and (4) formation of a protective, tenacious deposit on the plant
surface that will be resistant to weathering by sunlight, rain, and
wind (Cremlyn, 1978). This list of properties is never fulfilled en-
tirely by any single fungicide, and all commercially available com-
pounds show some phytotoxicity, lack of persistence due to envi-
ronmental degradation, and so forth. Thus, the timing of the
application is critical in terms of the development of the plant as
well as the fungus.
The topic of fungicidal toxicity has been extensively reviewed
by Hayes (1982) Edwards et al. (1991), and Kamrin (1997). With
a few exceptions, most of these chemicals have a low order of tox-
icity to mammals (Table 22-12). However, all fungicides are cyto-
toxic and most produce positive results in the usual in vitro mi-
crobial mutagenicity test systems. Such results are not surprising
because the microorganisms (Salmonella, coliforms, yeasts, and

Table 22-12
Acute Toxicity of Fungicides

IRRITATION* ORAL LD50, RAT

COMMON NAME CLASS (EYE/SKIN) (mg/kg)

Anilazine Triazine I 2,710

Benomyl Imidazole I 10,000
Captan Phthalimide I 8,400–15,000
Carboxin Oxathiin NI 3,820
Chinomethionate Quinomethionate NI 2,500–3,000
Chlorothalonil Organochlorine I 10,000
Dichloropropene Chlorinated alkene I 130–713
Dinocap Dinitrophenol NI 980
Dodine Aliphatic nitrogen I 1,000
EPTC Thiocarbamate I 1,632
Etridiazole Thiadiazole NI 1,000
Fenarimol Pyrimidine I 2,500
Hexachloroben- Organochlorine I 3,500
Imazalil Imidazole I 227–334
Iprodione Dicarboximide I 3,500
Maneb Dithiocarbamate I 5,000–8,000
Mancozeb Dithiocarbamate I 5,000– 11,200
Metalaxyl Benzenoid I 669
Metiram Dithiocarbamate I 6,180– 10,000
Nabam Dithiocarbamate I 395
Oxycarboxin Oxathiin NI 2,000
Pyrazophos Phosphorothionate NI 151–632
Quintozene Organochlorine I 1,710
Thiabendazole Imidazole NI 3,100–3,600
Thiophanate–Me Dithiocarbamate I 10,000
Thiram Thiocarbamate I 800– 1,900
Triallate Thiocarbamate I 800–2,165
Vinclozolin Dicarboximide I 10,000
Zineb Dithiocarbamate I 7,600–8,900
Ziram Dithiocarbamate I 1,400

*KEY: I, irritant properties; NI, nonirritation.

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798 UNIT 5 TOXIC AGENTS
fungi) used in these test systems are not dissimilar from those cell
systems that fungicides are designed to kill, either through a direct
lethal effect or via lethal genetic mutations (Lukens, 1971). A safe
fungicide (nonmutagenic in test cell systems) would be useless for
the protection of food and health. Public concern has focused on
the positive mutagenicity tests obtained with many fungicides and
the predictive possibility of both teratogenic and carcinogenic
potential. The fact that nearly 90 percent of all agricultural fungi-
cides are carcinogenic in animal models has not reassured the pub-
lic, especially when this is translated into the fact that some 75
million pounds of the fungicides used annually fall into this cate-
gory (NAS, 1987). An evaluation of 11 fungicides concluded that,
although the areas treated with these chemicals represented only
10 percent of the acreage treated annually with pesticides, they
could account for 60 percent of the total estimated dietary car-
cinogenic risk.
While a number of different chemicals are shown in
Fig. 22-26 to illustrate the diversity of structures, agents such as
pentachlorophenol (PCP), hexachlorobenzene (HCB), captafol, and
folpet have been deregistered or banned in many countries but still
see some use in other, less regulated parts of the world. Other fungi-
cides are undergoing reevaluation because of suspected toxicity,
particularly as teratogens or carcinogens and incomplete or out-
dated toxicity databases.
Hexachlorobenzene
From the 1940s through the 1950s, HCB saw extensive use as a
fungidical dressing applied to seed grain as a dry powder. Between
1955 and 1959, an epidemic of poisoning occurred in Turkey, ul-
timately involving some 4000 individuals who consumed treated
grain during times of crop failure. The syndrome, called black sore,
was characterized by dermal blistering and epidermolysis, pig-
mentation and scarring, alopecia, photosensitivity, hepatomegaly,
porphyria, suppurative arthritis, osteomyelitis, and osteoporosis of
the bones of the hands (Cam and Nigogosyan, 1963). Both adults
and children were afflicted, young children and nursing infants be-
ing at particular risk (Schmid, 1960; Wray et al., 1962; Hayes,
1982). While this agent has largely fallen by the wayside, it is still
being used in developing countries and still presents a health haz-
ard.
The mammalian toxicity of HCB has been reviewed by Hayes
(1982) and Hayes and Laws (1991). Like other organochlorine
compounds, HCB possesses all of the properties of chemical sta-
bility, slow degradation and biotransformation, environmental per-
sistence, bioaccumulation in adipose tissue and organs containing
a high content of lipid membranes, and the ability to induce a range
of tissue cytochrome-P450 as well as conjugative enzymes. Re-
peated exposure of animals results in hepatomegaly and porphyria
as well as focal alopecia with itching and eruptions, followed by
pigmented scars, anorexia, and neurotoxicity expressed as irri-
tability, ataxia, and tremors. Immunosuppression was observed in
both mice and rats and a dose-dependent increase in hepatic and
thyroid tumors was observed in hamsters (Lambrecht et al., 1982).
While not mutagenic in microbial test systems and negative in dom-
inant lethal studies, HCB was teratogenic in mice (renal and palate
malformations) and in rats (increased incidence of 14th rib). Hexa-
chlorobenzene was particularly toxic to developing perinatal ani-
mals, acquisition transplacentally and via the milk causing he-
patomegaly, enlarged kidneys, hydronephrosis, and possible effects
on the immune system.
Pentachlorophenol
Once used in tremendous volumes as a biocide in leather tanning,
wood preservation, the paper and cellulose industry, and in paints,
this chemical has been phased out of use because many commer-
cial products were contaminated by polychlorinated dibenzo-
dioxins and dibenzofurans, predominantly by hexachlorinated,
heptachlorinated, and octachlorinated congeners. While these
congeners are considerably less toxic than TCDD, evidence from
animal studies has pointed to the fact that the contaminants in com-
mercial- or technical-grade PCP were responsible for the toxicity
observed. Technical-grade PCP fed to rats caused altered plasma
enzymes, increased hepatic and renal weights, and caused hepato-
cellular degeneration in addition to changes in blood biochemistry
(decreased erythrocyte count, decreased hemoglobin and serum al-
bumin). The administration of purified PCP resulted only in in-
creased liver and kidney weight. Prolonged treatment of female
rats with technical PCP caused hepatic porphyria, increased mi-
crosomal monooxygenase activity, and increased liver weight,
whereas purified PCP caused no changes over the dosage range
studied (Goldstein et al., 1977). Pentachlorophenol was not ter-
atogenic in rats and is not considered to be carcinogenic in mice
or rats (Innes et al., 1969; Johnson et al., 1973; Schwetz et al.,
1977). A number of environmental problems have been associated
with PCP (Eisler, 1989).
Human poisoning by commercial PCP has occurred, usually
associated with occupational exposure and instances of sloppy han-
dling and neglect of hygienic principles (Jorens and Schepens,
1993). The chemical is absorbed readily through the skin, the most
usual route of acquisition, with several products, including PCP,
detected in the urine.
High-level exposure can result in death, preceded by an ele-
vated body temperature (42°C or 108°F), profuse sweating and de-
hydration, marked loss of appetite, decrease in body weight, tight-
ness in the chest, dyspnea following exercise, rapid pulse, nausea
and vomiting, headache, incoordination, generalized weakness, and
early coma (Hayes, 1982). Pentachlorophenol acts cellularly to
uncouple oxidative phosphorylation, the target enzyme being
Na,K-ATPase (Desaiah, 1977). Survivors frequently display
dermal irritation and exfoliation, irritation of the upper respiratory
tract, and possible impairment of autonomic function and
circulation.
Phthalimides
Of this class of chemicals, folpet and captofol, true phthalimides,
have been deregistered and only captan, being structurally differ-
ent with a cyclohexene ring (Fig. 22-26), sees any use today. All
of the agents were embroiled in a prolonged controversy concern-
ing mutagenic and possible teratogenic and carcinogenic proper-
ties. All three chemicals were recognized as effective, persistent
foliar fungicides for rusts and smut, for Botrytis mold on soft fruit,
apple and pear scab, black spot on roses, and as seed dressings
(Cremlyn,1978). All three chemicals have high oral LD50 values
of approximately 10,000 mg/kg in the rat. Mutagenicity associated
with these agents was confirmed, but—because of the exception-
ally high doses (up to 500 mg/kg) required to elicit biological
effects—teratogenicity was not proven or was masked by mater-
nal toxicity and possible nutritional deficits.
Although the mechanism(s) by which captan and its analogs
exerted their cellular toxicity has never been established, captan is
2996R_ch22_761-810 4/16/01 4:38 PM Page 799
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
known to react with cellular thiols to produce thiophosgene, a po-
tent and unstable chemical capable of reacting with sulfhydryl-,
amino-, or hydroxyl-containing enzymes (Cremlyn, 1978). Thiols
reduce the potency of captan. A volatile breakdown product of cap-
tan was responsible for mutagenic activity, the intermediate being
short-lived and forming more quickly at higher levels at an alka-
line pH. It is possible that there may be several mechanisms by
which these chemicals can induce cellular toxicity.
Dithiocarbamates
Dimethyl- and ethylene-bisdithiocarbamate (EBDC) compounds
have been employed since the early 1950s as fungicides, and the
EBDC chemicals saw widespread use on a large variety of small
fruits and vegetables. The nomenclature of these agents arises from
the metal cations with which they are associated; for instance, di-
methyldithio-carbamic acid bound to iron or zinc are ferbam and
ziram, respectively, whereas EBDC compounds associated with
sodium, manganese, or zinc are nabam, maneb, and zineb, respec-
tively. As is shown in Fig. 22-24, these chemicals are polymeric
structures that possess environmental stability and yield good fo-
liar protection as well as a low order of acute toxicity, with LD50
values in excess of 6000 mg/kg with the exception of nabam (395
mg/kg). Mancozeb is a polymeric mixture of a zinc salt and the
chemical maneb.
Although toxicity is negligible in animal feeding trials even
at high doses, acceptance of these agents has been marred by re-
ported adverse health effects. Maneb, nabam, and zineb have been
reported to be teratogenic (Petrova-Vergieva and Ivanova-
Chemischanka, 1973). Mancozeb has not been demonstrated to be
teratogenic in the rat but has been associated with abnormally
shaped sperm (Hemavathi and Ratiman, 1993). Maneb has been
associated with adverse reproductive outcomes (embryotoxicity:
changes in usual number of offspring per litter, pregnancy rate,
estrous cycle, and fetal development) (Lu and Kennedy, 1986).
Maneb caused pulmonary tumors in mice, but studies in the rat
have been equivocal (IARC, 1976). Environmental and mammalian
degradation of the EBDC compounds into ethylene thiourea (ETU),
a known mutagen, teratogen, and carcinogen, as well as an an-
tithyroid compound, has raised suspicions about these agents and
fostered requests for more in-depth studies (IARC, 1976). Recent
chronic studies of mancozeb administered to rats at high (500 to
1500 mg/kg/day) doses demonstrated increased thyroid weight, re-
duced iodine uptake, reduced protein-bound iodine and thyroxine,
as well as a dose-related decrease in thyroid peroxidase activity
(Kackar et al., 1997). Significant histopathologic changes were ob-
served, including thyroid hyperplasia and hypertrophy of the
follicular mass with a loss of colloid mass. A study of EBDC fun-
gicide–exposed backpack sprayers in Mexico demonstrated that
ETU was formed in vivo and excreted in the urine and that thyroid-
stimulating hormone levels were increased, although there was a
nonsignificant reduction in thyroxine and significant increases in
sister chromatic exchanges and chromosomal translocations in
blood lymphocytes (Steenland et al., 1997).
Neurotoxicity has not been attributed to EBDC fungicides in
either experimental animals or humans except at excessively high
doses (Ecobichon, 1994c). A double (within 2 weeks) acute occu-
pational, dermal exposure to Mandizan (mixture of maneb and
zineb) resulted in initial complaints of muscle weakness, dizziness,
and fatigue, with disorientation, slurred speech, muscle incoordi-
nation, loss of consciousness, and tonic/clonic convulsions ap-
799
pearing rapidly following the second exposure (Israeli et al., 1983).
A recent report from Brazil on two apparent Parkinson patients re-
vealed that, as sprayers, they had experienced significant annual
exposure to maneb over 4 to 5 years (Ferraz et al., 1988). Signs
and symptoms included inability to walk, difficulty in talking,
tremors in hands and feet, a short-stepped gait with cogwheeling,
and bradykinesia. An extended study of 50 rural workers, 84 per-
cent of whom admitted to using maneb improperly or carelessly,
revealed milder but similar signs and symptoms. It was suggested
that the effects might be related to the manganese content, although
blood manganese levels were not elevated. Other evidence might
point to breakdown products of EBDC, such as carbon disulfide,
as the neurotoxicant, although it is hard to accept such a high level
of absorption. It is also known that dithiocarbamates can bind var-
ious divalent metals to form more lipophilic complexes capable of
entering the CNS (Ecobichon, 1994c).
FUMIGANTS
Such agents are used to kill insects, nematodes, weed seeds, and
fungi in soil as well as in silo-stored cereal grains, fruits and veg-
etables, clothes, and other consumables, generally with the treat-
ment carried out in enclosed spaces because of the volatility of
most of the products. Fumigants range from acrylonitrile and car-
bon disulfide to carbon tetrachloride, ethylene dibromide, chloropi-
crin, and ethylene oxide; their toxicologic properties are discussed
under other headings because many have other uses. Attention in
this section is directed only to a very few agents, although all of
the chemicals mentioned have the potential for inhalation exposure
and, for some of them, dermal and ingestion exposure.
Fumigants may be liquids (ethylene dibromide, dibro-
mochloropropane, formaldehyde) that readily vaporize at ambient
temperature, solids that can release a toxic gas on reacting with
water (Zn2P3, AlP) or with acid [NACN, Ca(CN)2], or gases
(methylbromide, hydrogen cyanide, ethylene oxide). These chem-
icals are nonselective, highly reactive, and cytotoxic. The physico-
chemical properties of these agents and hence their pattern(s) of
use vary considerably (Cremlyn, 1978). With proper attention to
use and appropriate safety precautions, there should be little effect
other than occasional occupational exposure, because the volatil-
ity of the agents is such that, when the enclosed space is opened,
the gas or vapor escapes readily. However, reports in the literature
have indicated the presence of low residual levels of ethylene dibro-
mide, methylbromide, and other chemicals in various samples of
treated foods. More extensive descriptions of fumigant toxicity can be
found in Hayes (1982), Morgan (1982), and Hayes and Laws (1991).
Phosphine
Used extensively as a grain fumigant, phosphine (PH3) is released
from aluminum phosphide (AlP) by the natural moisture in the
grain over a long period of time, giving continual protection dur-
ing transhipment of the grain. One serious accident with this chem-
ical has been reported, in which this author played a small role in
identifying the causative agent, as the problem originated in the
port of Montreal, Canada (Wilson et al., 1980). Grain leaving
Canada for European destinations is fumigated by adding a certain
number of sachets of AlP per ton of grain in the hold of the ship
while loading. Phosphine (PH3), being heavier than air, sinks
slowly through the grain. The particular ship in question ran into
a bad storm off Nova Scotia and began to leak, hastening the break-
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800 UNIT 5 TOXIC AGENTS

down of the AlP to form PH3. The toxicant penetrated the quarters selectivity (Fig. 22-27). With some chemicals, advantage has
of the crew and officers, where 29 out of 31 crew members be- been taken of the physiology and biochemistry unique to rod-
came acutely ill and two children, family members of one of the ents. With other rodenticides, the sites of action are common to
officers, were seriously affected, one dying before reaching a hos- most mammals but advantage is taken of the habits of the pest
pital in Boston. Symptoms of PH3 intoxication in the adults in- animal and/or the dosage, thereby minimizing toxicity to nontar-
cluded shortness of breath, cough and pulmonary irritation, nau- get species.
sea, headache, jaundice, and fatigue. The highest concentrations of Although most rodenticides are formulated in baits that are
PH3 (20 to 30 ppm) were measured in a void space on the main unpalatable to humans, thereby minimizing the potential hazard,
deck near the air intake for the ship’s ventilation system. In some there are surprising numbers of rodenticide intoxications each year.
of the living quarters, PH3 levels of 0.5 ppm were detected. Al- With only a few exceptions, the accidental or intentional ingestion
though this could be considered a bizarre situation, it does illus- of most rodenticides poses a serious, acute toxicologic problem be-
trate an apparent problem with the use of this type of agent in an cause the dosage ingested is invariably high and the signs and
atmosphere of excess moisture. symptoms of intoxication are generally well advanced and severe
when the patient is seen by a physician. As with other household
Ethylene Dibromide/ products, rodenticide poisoning is more frequently seen in chil-
dren, whose added hazard is a small body weight in relation to the
Dibromochloropropane
dosage ingested. The toxicology of the various classes of rodenti-
When inhaled at relatively high ( 200 ppm) concentrations, eth- cides has been extensively reviewed and the reader is referred to
ylene dibromide can cause pulmonary edema and inflammation in Hayes and Laws (1991) and to Ellenhorn and Barceloux (1988) for
the exposed animals. As one might expect, repeated exposures to in-depth coverage of the subject.
lower concentrations produced hepatic and renal damage visual-
ized as morphologic changes. Centrolobular hepatic necrosis and
proximal tubular damage in the kidneys were observed in one fa-
tal poisoning in which the individual ingested 4.5 ml of ethylene
dibromide. This chemical, along with 1,2-dibromo-3-chloro-
propane (DBCP), was found to elicit malignant gastric squamous
cell carcinomas in mice and rats (IARC, 1977). DBCP was also
found to cause sterility in male animals, and concentrations as low
as 5 ppm had an adverse effect on testicular morphology and sper-
matogenesis. However, these results in animals came to light only
when a similar situation was detected in workers who manufac-
tured the agent. Equivocal results have been reported for the mu-
tagenicity of DBCP, the agent that causes base-pair substitution but
not a frame-shift mutation in Salmonella strains. In animal studies
of the dominant lethal assay, DBCP was positive (mutagenic) in
rats but not in mice. DBCP was a reproductive toxicant in rabbits
and rats but not in mice (IARC, 1977).

RODENTICIDES
Many vertebrates—including rats, mice, squirrels, bats, rabbits,
skunks, monkeys, and even elephants—on occasion can be con-
sidered to be pests. Rodents, the most important of which are the
black rat (Rattus rattus), the brown or Norway rat (Rattus norvegi-
cus), and the house mouse (Mus musculus), are particularly seri-
ous problems because they act as vectors for several human dis-
eases. They can consume large quantities of postharvest stored food
and/or foul or contaminate even greater amounts of foodstuffs with
urine, feces, hair, and bacteria that cause diseases.
To be effective yet safe, a rodenticide must satisfy the fol-
lowing criteria: (1) it must not be unpalatable to the target species
and therefore must be potent; (2) it must not induce bait shyness,
so that the animal will continue to eat it; (3) death should occur in
a manner that does not raise the suspicions of the survivors; (4) it
should make the intoxicated animal go out into the open to die
(otherwise the rotting corpses create health hazards); and (5) it
should be species-specific, with considerably lower toxicity to
other animals that might inadvertently consume the bait or eat the
poisoned rodent (Cremlyn, 1978). The agents used constitute a di-
verse range of chemical structures having a variety of mechanisms Figure 22-27. Representative structures of inorganic and organic ro-
of action for at least partially successful attempts to attain species denticides from various chemical classifications.
2996R_ch22_761-810 4/16/01 4:38 PM Page 801
CHAPTER 22 TOXIC EFFECTS OF PESTICIDES
A number of inorganic compounds—including thallium sul-
fate, arsenious oxide, other arsenic salts, barium carbonate, yellow
phosphorus, aluminum phosphide, and zinc phosphide—have been
used as rodenticides. A mixture of sodium cyanide with magne-
sium carbonate and anhydrous magnesium sulfate has been used
in rabbit and mole burrows, causing hydrogen cyanide gas to be
liberated slowly on contact with moisture. Natural or synthetic or-
ganic chemicals, including strychnine, red squill (scillaren glyco-
sides), and DDT have been used in the past. All of these agents are
nonselective, highly toxic, and hazardous to other forms of life and,
with the exception of zinc phosphide, have been abandoned in fa-
vor of target-specific, selective chemicals.
Zinc Phosphide
This agent is used in developing nations because it is both cheap
and effective. The toxicity of the chemical can be accounted for
by the phosphine (PH3) formed following a hydrolytic reaction with
water in the stomach on ingestion. Phosphine causes widespread
cellular toxicity with necrosis of the gastrointestinal tract and in-
jury to other organs, such as the liver and kidneys. Although moist
zinc phosphide emits an unpleasant, rotten-fish odor, it is accepted
by rodents at concentrations of 0.5 or 1.0 percent in baits.
Accidental poisonings are rare in adults but a definite problem
in children. Hayes (1982) recounts a poisoning attributed to the in-
halation of zinc phosphide dust from treated grain, with signs of
intoxication that included vomiting, diarrhea, cyanosis, tachycar-
dia, rhales, restlessness, fever, and albuminuria several hours fol-
lowing exposure. It is a favorite chemical in suicides in Egypt (A.
Amr, personal communication). The signs and symptoms include
nausea, vomiting, headache, light-headedness, dyspnea, hyperten-
sion, pulmonary edema, dysrrhythmias, and convulsions. Doses of
the order of 4000 to 5000 mg have been fatal, but other individu-
als have survived doses of 25,000 to 100,000 mg if early vomiting
has occurred. The usual decontamination measures and supportive
therapy are often successful if initiated early.
Fluoroacetic Acid and Derivatives
Sodium fluoroacetate (compound 1080) and fluoroacetamide
(compound 1081) are white in color, odorless, and tasteless. The
extreme toxicity of these two chemicals has restricted their use to
prepared baits. Both agents are well absorbed from the gastroin-
testinal tract. Acute oral toxicity of fluoroacetate in the rat is of the
order of 0.2 mg/kg, whereas that of fluoroacetamide is 4 to 15
mg/kg. The mechanism of action involves the incorporation of the
fluoroacetate into fluoroacetyl–coenzyme A, which condenses with
oxaloacetate to form fluorocitrate, which inhibits the enzyme
aconitase and prevents the conversion of citrate to isocitrate in the
tricarboxylic (Krebs) cycle. Inhibition of this system by fluoroci-
trate results in reduced glucose metabolism and cellular respiration
and affects tissue energy stores. These chemicals are uniquely ef-
fective in mice and rats because of the high metabolic rate in the
tissues susceptible to inhibition.
Estimates of the lethal dose of fluoroacetate in humans lie in
the range of 2 to 10 mg/kg. Gastrointestinal symptoms are seen
initially at some 30 to 100 min following ingestion. Initial nausea,
vomiting, and abdominal pain are replaced by sinus tachycardia,
ventricular tachycardia or fibrillation, hypotension, renal failure,
muscle spasms, and such CNS symptoms as agitation, stupor,
seizures, and coma. Histopathologic examination of postmortem
801
samples has revealed cerebellar degeneration and atrophy. There
are no known antidotes to fluoroacetate intoxication, although glyc-
erol monoacetate has proved beneficial in the treatment of poisoned
monkeys.
A-Naphthyl Thiourea
Following the discovery that phenylthiourea was lethal to rats but
not toxic to humans, -naphthyl thiourea (ANTU) was introduced
as a relatively selective rodenticide (Richter, 1946). A wide range
of acute oral LD50 values has been reported for different species,
the rat being the most sensitive at 3 mg/kg and the monkey the
least susceptible at 4 g/kg. The exact mechanism of action is not
known, but it is suspected that ANTU must be biotransformed in
vivo into a reactive intermediate. Young rats are resistant to the
chemical, whereas older rats become tolerant to it, suggesting that
perhaps microsomal monooxygenases in young rats metabolize the
agent too rapidly into nontoxic products, whereas in older rats ei-
ther the lower levels of monooxygenases or the inhibition of these
enzymes results in less activation and affords protection (Boyd and
Neal, 1976). ANTU causes extensive pulmonary edema and pleu-
ral effusion as a consequence of action on the pulmonary capillar-
ies. Studies with 35S- and 14C-labeled ANTU revealed that cova-
lent binding to macromolecules in the lung and liver occurred
following treatment (Boyd and Neal, 1976). Following exposure to
ANTU, there are a number of biochemical effects, such as alter-
ations in carbohydrate metabolism, adrenal stimulation, and inter-
action of the chemical with sulfhydryl groups, but none of these
appear to bear any relationship to the observed signs of toxicity.
Although it would appear that the human is very resistant to
ANTU intoxication, probably because insufficient quantities are
ingested, poisonings have occurred, with tracheobronchial hyper-
secretion of a white, nonmucous froth containing little protein, pul-
monary edema, and respiratory difficulty (Hayes, 1982).
Anticoagulants
With the discovery that coumadin [3-(-acetonylbenzyl)-4-
hydroxycoumarin, warfarin), isolated from spoiled sweet clover,
acted as an anticoagulant by antagonizing the actions of vitamin
K in the synthesis of clotting factors (factors II, VII, IX, and X),
it was introduced as a rodenticide. The onset of anticoagulation is
delayed 8 to 12 h after the ingestion of warfarin, with this latent
period of onset dependent on the half-lives of the various clotting
factors (Katona and Wason, 1986). The safety of warfarin as a ro-
denticide rests with the fact that multiple doses are required before
toxicity develops and that single doses have little effect. However,
the development of resistance to warfarin in rats in the 1950s
prompted research into newer compounds, and the exploration of
structure-activity relationships led to the development of the su-
perwarfarins (brodifacoum, bromadiolone, coumachlor, diphen-
coumarin) and the indanediones (diphacinone, chlorophacinone,
pindone), a new class of anticoagulant compounds that are more
water-soluble. All of these newer agents differ from one another in
terms of acute toxicity, rapidity of action, and acceptance by the
rodent.
Human poisonings by these agents are rare because they are
dispensed in grain-based baits. However, there are sufficient num-
bers of suicide attempts, attempted murders, and a famous classic
case of the inadvertent consumption of warfarin-laden cornmeal
bait by an unsuspecting Korean family to provide adequate docu-
2996R_ch22_761-810 4/16/01 4:38 PM Page 802

802 UNIT 5 TOXIC AGENTS

Table 22-13
The WHO Recommended Classification of Pesticides by Hazard

LD50 FOR THE RAT (mg/kg BODY WEIGHT)

ORAL DERMAL

CLASS SOLIDS LIQUIDS SOLIDS LIQUIDS

Ia Extremely hazardous 5 20
Ib Highly hazardous 5–50
II Moderately hazardous 50–500
III Slightly hazardous 500
III Unlikely to present 2000
hazard in normal use
mentation of the signs and symptoms of poisoning (Lange and
Terveer, 1954; Hayes, 1982; Jones, 1984; Lipton, 1984; Katona
and Wason, 1986). Following consumption over a period of days,
bleeding of the gingiva and nose occurs, with bruising and
hematomas developing at the knee and elbow joints and on the but-
tocks, gastrointestinal bleeding with dark tarry stools, hematuria
accompanied by abdominal or low back (flank) pain, epistaxis, and
cerebrovascular accidents. The signs and symptoms will persist for
many days after cessation of exposure, particularly so in the case
of the superwarfarins, which have prolonged biological half-lives
(e.g., brodifacoun with 156 h compared to 37 h for warfarin)
(Katona and Wason, 1986). In the Korean episode, consumption of
warfarin was estimated to be on the order of 1 to 2 mg/kg/day for
a period of 15 days, and signs and symptoms appeared 7 to 10 days
after initial exposure; 2 out of the 14 affected individuals died as
a consequence of not receiving any treatment (Lange and Terveer,
1954).
CONCLUSIONS
With the advent of the chemical pesticides with their diverse na-
ture, structures, and biological activity, the problem of ranking the
hazard that each one poses to health has arisen. Should a classifi-
cation system be based on acute toxicity alone or should some nu-
merical scoring system be used to evaluate other endpoints of tox-
icity? Should the classification scheme be based on the oral,
dermal, or inhalation routes of exposure to the active ingredient or
to a formulation concentrate? If one chooses acute toxicity and a
definitive endpoint expressed as the LD50, one must be cognizant
of the fact that the LD50 is an estimate, with the range and confi-
dence limits for any particular chemical possibly overlapping a
class boundary. To establish a classification system on the basis of
other toxicologic endpoints would be impossible given the vari-
ability of biological effects, the dosages required to attain them,
and the significance of such results in terms of human exposure.
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