Pesticides: Economic advantage
or environmental disaster?
MARTIN BRITS, BIOCHEMIST, AMPATH, DRS DU BUISSON & PARTNERS,
614 PRETORIUS STREET, ARCADIA, PRETORIA 0001, TEL: 012 427 1728/012 427 1858,
e-mail: [email protected]
VOLKER R SCHILLACK, ANALYTICAL TOXICOLOGIST, AMPATH, DRS DU BUISSON & PARTNERS,
614 PRETORIUS STREET, ARCADIA, PRETORIA 0001. TEL: 012 427 1728/012 427 1858,
e-mail: [email protected]
INTRODUCTION
pesticides were important early pesticides. Most of them were
Pesticides are defined as substances used to destroy or to repel
pests. Over 16 000 pesticide products are registered for use in
the United States and these contain one or more of the 674 reg-
linked to health or environmental concerns and have since been
banned for use.
istered active ingredients. When used properly, pesticides offer a
variety of benefits to society. Their correct use increases crop
yield, preserves foodstuff, and combats pathogenic and nuisance
ORGANOCHLORIDES
insect infestations. Because pesticides are among the few chemicals that are specifically designed to kill or cause harm, the public continues to express concern about the adverse public health
naturally, the majority of them are synthetic. Synthetic organic
insecticides consist of various groups and include: chlorinated
hydrocarbons, organophosphates, carbamates, pyrethroids, fluori-
and the environmental effects of pesticides.
Pesticides are classified in several ways, each having it own
value for a given purpose. The World Health Organization (WHO)
nated hydrocarbons, etc.
Chlorinated hydrocarbons (organochlorines) vary considerably
in their toxicity to mammalians and are largely prohibited from
recommended that the classification of pesticides be based
primarily on the acute oral and dermal toxicity to the rat since
these determinations are standard procedure in toxicology. This
use in many countries. Examples of this group of pesticides include: DDT, chlordane, dieldrin, endrin, mirex and heptachlor. DDT
is used in managing malaria and chlordane was widely used for
is based on the LD50 obtained for each chemical. The LD50 value
is a statistical estimate of the number of mg of toxicant per kg of
bodyweight required to kill 50% of a large population of test ani-
termites and roach control. DDT includes its DDT isomers and
metabolites, DDE (dichlorodiphenyldichloroethylene) and DDA
(dichlorodiphenylacetic acid). DDT and DDE accumulate in the
mals. Pesticides can also be classified according to their chemical structure and can be divided into three main groups: inorganic,
organic and biological pesticides.
adipose tissue, whereas DDA is excreted in the urine. DDA therefore represents the major urinary metabolite of DDT in occupationally exposed persons. The acceptable daily intake of DDT for
Inorganic pesticides’ chemical structure does not consist of
carbon atoms. They can however contain elements or natural
compounds, such as copper, boron, mercury, sulphur, tin, zinc,
the general population is recommended by the WHO to be
0,25 mg. Mirex was primarily for the control of red fire ants. The
majority of these chemicals are characterized by their persist-
borate, diatomite, silica or other substances. These inorganic
ence in the environment and their ability to accumulate in the
Organic pesticides are classified on the basis that their chemical
structure consists of carbons. Although organic pesticides occur
Figure 1. The graph demonstrates a comparison between the plasma concentrations of 4,4-DDT and its
metabolite, 4,4-DDE in male workers exposed to DDT. Note that the variation in 4,4-DDE levels is due to
accumulation of DDT metabolite over time, or due to the different inter-group catabolic rate of DDT.
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Average concentration of DDT and metabolites in 40 male workers
400,00
350,00
300,00
µg/L
250,00
200,00
150,00
100,00
50,00
0,00
4,4 DDT
2,4 DDT
4,4 DDE
2,4 DDE
4,4 DDD
Figure 2. The indication of the metabolic route of DDT in exposed male workers
Acetylcholinesterase
Acetylcholine
Choline + Acetic acid
Figure 3. The regulatory catabolism of the neurotransmitter, acetylcholine, by acetylcholinesterase to
choline and acetic acid
fatty tissue of birds and mammals. Even persons with only
incidental contact with the pesticides can be found to have tissue
levels of these chemicals. Environmental chemical contamination with organochlorine residues may be an etiologic factor in
the development of breast cancer. Lindane is the gamma isomer
of 1,2,3,4,5,6-hexachlorocyclohexane (?-HCH) and is still used
as a general garden insecticide. It is well absorbed via oral
and inhalation routes. Inhalation and skin absorption are the
predominant routes of uptake in the occupational setting.
Lindane is partially metabolized in the liver and directly excreted
in the urine, faeces and breast milk. It accumulates in fatty
tissue, but to a lesser extent than other organochlorine pesticides, and interferes with the axonal transmission of nerve
impulses by disruption of the normal flow of sodium and potassium across the axon membrane. Lindane also exerts toxic
effects through the release of arachidonic acid in the kidneys.
Overall, organochlorines do not affect serum red blood cell
(RBC) cholinesterase activity.
The blood half-life is about 20 hours. The main metabolites
determined in the urine of workers exposed to γ-HCH are 2,3,
5-, 2,4,5-, and 2,4,6-trichlorophenols. These metabolites account
for almost 58% of the Lindane metabolites identified in the urine
of workers, using Lindanes. The other metabolites identified include other trichlorophenols, monochlorophenols, tetrachlorophenols, dihydroxychlorobenzene and pentachlorophenol. The
WHO recommended that a biological exposure index limit of 2 µg/
100 ml in blood should be set for workers occupationally exposed
(end shift) to Lindane.
ORGANOPHOSPHATES
The organophosphates were the insecticides used on a large scale
OCCUPATIONAL HEALTH SOUTHERN AFRICA
to replace the organochlorines. Because of their unstable chemical structure, they disintegrate into harmless radicals within days
of application and do not persist in body tissues or the environment. The toxicity of organophosphate compounds varies greatly.
The highly toxic group of organophosphates is used primarily for
agriculture and military purposes, the intermediate group is used
as insecticide on animals and those with low toxicity are available
for use by households and on golf courses. Organophosphates
are a heterogeneous group of compounds that are composed of
a phosphoric acid derivative with two organic side chains and an
additional side chain that can be a cyanide, thiocyanate, halide,
phosphate, phenoxy, thiophenoxy, or carboxylate group.
Most of the organophosphate insecticides are rapidly absorbed
by all routes, dermal, respiratory, gastrointestinal, and conjunctival. Organophosphates may be classified as direct or indirect
acetylcholinesterase inhibitors. Acetylcholine is the most important chemical transmitter at synaptic junctions. Acetylcholinesterase is responsible for the catabolism of acetylcholine by hydrolysis
into its two primarily metabolites, acetic acid and choline (Figure
3). This catabolism prevents further neurotransmission at the
synapses. The direct-acting group of organophosphates inhibits
the enzyme acetylcholinesterase, leading to the accumulation of
acetylcholine at synapses and the myoneural junction. Inhibition
of this enzyme is initially by ionic bonding, but the enzyme eventually is progressively phosphorylated by covalent bonding. This
process takes between 24–48 hours and is called ageing, known
as the critical interval. Once the ageing period expires the enzyme cannot be reactivated. Activation of the indirect inhibitors is
primarily metabolized through the cytochrome P-450 system.
Acute effects may be noted almost immediately after exposure to
the direct-acting group, although a delay of 2–3 hours may be
MAY/JUNE 2006
29
noted after dermal absorption. Parathion is an example of the
indirect-acting group, because it first must be converted to
paraoxon by the substitution of oxygen for a sulphur to be physi-
cyanazine, terbumeton, amathrin, desmethrin, simethrin, atrazine,
prometon, promethryn and simazine. The main urinary metabolite
of atrazine in humans is the mercapturic acid conjugate; free
ologically active, for this reason symptoms of parathion intoxication may not begin until 6–24 hours after exposure. The
organophosphates are generally highly lipid soluble. The metabo-
atrazine and the N-dealkylated metabolites are relatively minor
urinary metabolites, and no hydroxylated or other conjugates are
formed. The excreted atrazine metabolites became more polar
lism of organophosphates yields alkylphosphates and
alkyl(di)thiophosphates as terminal products. Exposure to certain organophosphate pesticides may be detected by measure-
with increasing time.
FLUORINATED HYDROCARBONS
ment of these alkylphosphates. Depending on the chemical structure of the pesticide, various alkylphosphates may be detected.
The fluorinated hydrocarbons consist of two classes of insecticides, the amidinohydrazones and fluoroaliphatic sulphones, both
of which contain fluorine in their chemical structure. The
CARBAMATES
Carbamates are mostly represented by mono methyl carbamates
which are esters of carbamic acid where the N atom is substi-
amidinohydrazones include several insecticide products containing the active ingredient hydramethylnon. Hydramethylnon has
relatively low toxicity to mammals and is readily accepted by in-
tuted with a methyl group (Figure 4). Examples of carbamate insecticides are aldicarb (two-step), aldocarb, formetanate, oxamyl,
methomyl, carbofuran, carbosulfan, bendiocarb, carbaryl,
sects. Like the amidohydrazones, the flouroaliphatic sulphones
include one active pesticide ingredient, sulfuramid. Sulfuramid is
also relatively non toxic.
thiodicarb, pirimicarb, propoxur and fenothiocarb. Like the
organophosphates, carbamates are cholinesterase inhibitors,
however their inhibition is reversible. They cause this effect by
CHLOROPHENOXY HERBICIDES
reversible carbamoylation of the enzyme cholinesterase, allowing overabundance of acetylcholine. There is therefore a reduction in acute nerve poisoning, and greatly increased recovery rates.
cause abnormal plant growth that ultimately destroy the plant.
They are all congeners of phenoxyacetic acid and their notoriety
originates from the use of Agent Orange in Vietnam as a defoliant
Serum RBC cholinesterase values are not reliable in confirming
the diagnosis of carbamates poisoning, because the enzyme activity returns to normal within a few hours. Carbamates also do
and its alleged health effects on exposed individuals.
Chlorophenoxy herbicides as a group include various salts of 2,4dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, 4-
not accumulate in the environment and fatty tissue of mammals.
PYRETHROIDS
chloro-2-methylphenoxyacetic acid, 4-methyl, 4-chlorophenoxypropionic acid, Dicamba and Silvex. Their toxicity is similar and
their alleged carcinogenic and neuropathy-inducing potential is
Pyrethroid insecticides are used increasingly. Examples of synthetic pyrethroids are: deltamethrin, fenvalerate, cypermethrin,
permethrin, allethrin, resmethrin, d-phenothrin, tetramethrin,
of concern but not widely accepted as proven. Abnormal renal
and hepatic functions and an elevated creatine phosphokinase
level are commonly noted after a large exposure. Carcinogenicity,
fenpropathrin, tralomethrin, cyhalothrin, tefluthrin, cyfluthrin,
fluvalinate, furamethrin, and tellalethrin. Type I pyrethroids do not
contain a α-cayno-group and type II pyrethroids contain a cayno-
teratogenicity and reproductive abnormalities have been alleged
but not confirmed. Chlorophenoxy herbicides can be measured
in plasma and urine by means of gas-liquid chromatography.
group on the α-carbon position. The most widely used pyrethroids
(cypermethrin, permethrin, deltamethrin, cyfluthrin, fenvalerate)
are absorbed by all routes. The main metabolites are presented
Dermal absorption is the major route of uptake in the occupational setting. They are reversibly bound to proteins, particularly
Chlorophenoxy herbicides are auxins, or growth regulators, which
in Table 1.
The measurement of pyrethroid metabolites in urine is usually
more sensitive than the determination of the parent compounds
for detecting exposure. A great advantage of monitoring pyrethroid
metabolites is the fact that these substances do not occur naturally in urine. Metabolite detection always indicates an exposure
to pyrethroids. It is not always possible to conclude from the
metabolite detected, the pyrethroid used, because some
pyrethroids have metabolites in common.
Several triazines are also used as herbicides and include
O
R1NH
R2 =
R1 =
=
=
OR2
Aromatic or Aliphatic
Methyl group in carbamate insecticides
Aromatic moiety in carbamate herbicides
Benzoimidazole moiety in carbamate fungicides
Figure 4. Constitution of different carbamates
Table 1. Metabolites of pyrethroids
30
Pyrethroid
Cyfluthrin
→
Cypermethrin
→
Permethrin
→
Deltamethrin
→
S-Bioallethrin
→
MAY/JUNE 2006
Metabolites
Fluorophenoxybenzoic acid (FPBA)
Cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA)
Cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA)
3-Phenoxybenzoic acid (3-PBA)
Cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA)
3-Phenoxybenzoic acid (3-PBA)
Cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA)
3-Phenoxybenzoic acid (3-PBA)
Trans-(E)-chrysanthemumdicarboxylic acid
OCCUPATIONAL HEALTH SOUTHERN AFRICA
albumin. They are rapidly eliminated, mainly unchanged, in urine.
Dioxins are a group of compounds that are not deliberately
manufactured for commercial use but are trace contaminants or
products of combustion of other products. The adverse effects of
2,3,7,8-tetrachlorodibenzo-p-dioxin also referred to as TCDD or
dioxin have a very large difference in species susceptibility, with
guinea pigs being the most sensitive. By comparison, hamsters
are more resistant, and humans even more. The only proven
effects of dioxin on humans are chloracne and transient mild hepatotoxicity. Levels of hepatic transaminases, if elevated, should be
monitored over time until normal.
The toxicity of hexachlorobenzene, an aromatic hydrocarbon
fungicide, in humans was demonstrated by the outbreak of cutaneous porphoria when seed wheat treated with hexachlorobenzene
was used for human consumption. Symptoms include
hyperpigmentation, hypertrichosis, weight loss, hepatomegaly and
painless arthritis. The most striking finding was blistering and
epidermolysis of exposed parts of the skin. The infants of affected
axons results in decreased nerve impulse conduction, resulting
in paralysis and eventually death.
Another rodenticide is cholecaliferol (vitamin D3) which causes
hypercalcaemia and subsequently calcification of the organs,
blood vessels and soft tissues in rodents, but are not toxic to
humans. High concentration exposure may produce growth retardation in children.
Pyriminil, one of the discontinued rodenticides, destroys the
β-cells of the islets of Langerhans in the pancreas, resulting in
inadequate production of insulin. Survivors develop classic
diabetes mellitus, and death may result from classic diabetic
ketoacidosis and dysrhythmias. Sensory and motor neuropathies
including other nervous system dysfunctions are also noted.
Sodium monofluoroacetate is a highly toxic rodenticide still in
use. It must first be metabolized to flourocitrate before toxicity
develops. The toxicity may be related to interrupting the Krebs’
cycle, resulting in a decrease in energy production, which is crucial
mothers had a mortality rate of 95%. Hexachlorobenzene can be
absorbed via ingestion, inhalation and skin contact. The low vapour
pressure of hexachlorobenzene probably limits the uptake via the
for normal cell function.
Phosphides (aluminium phosphides, magnesium phosphides
and zinc phosphides) react with moisture or acids to produce
phosphine gas. Toxic exposures to phosphine gas by inhalation
respiratory tract. Resuts of animal studies show that
hexachlorobenzene is excreted in the faeces and urine and is
slowly metabolized to less chlorinated benzene, chlorinated
have been reported. Phosphine inhibits the enzyme cytochrome
C oxidase, resulting in reduced oxidative phosphorilation. This
leads to decreased energy-production in cellular mitochondria and
phenols, other metabolites, and glucuronide and glutathinione conjugates. In humans, the main identifiable metabolite is pentachlorophenol. Hexachlorophenol is very stable and has a biological
subsequently cell death. The majority of deaths occur
approximately 30 hours after ingestion or inhalation.
Biological pesticides consist of the microbial pesticides, in-
half-life of up to 2 years in humans.
Another large group of pesticides is rodenticides. A variety of
inorganic- and organic- or biological compounds have been used
sect growth regulators, pheromones and the botanical pesticides.
Except for the botanicals, this group differs from the other pesticides groups in that they consist of a variety of chemicals of natu-
as rodenticides. Organic rodenticides derived from plant material
such as strychnine and inorganic compounds such as arsenic
trioxide and thallium were of the earliest rodenticides. Newer
ral origin or synthetic versions of natural chemicals which target
specific species and usually have little impact on non-targeted
species.
agents tend to be synthetic organic compounds.
Long-acting anticoagulants (superwarfarins) have the same
mechanism of action as warfarin, however, these second gen-
CONCLUSION
eration substances have two important differences – they are more
potent and their half-life is longer. The longer half-life of these
agents is significant in the case of human exposure. The major
lion pesticide poisonings occur annually worldwide and cause more
than 220 000 deaths. This estimation does not account for exposure to low levels of pesticides and the subsequent health impli-
superwarfarins are brodifacoum, bromadiolone, chlorophacinone,
coumatetral, diphacinone, diphenacoum, isovaleryl, pindone and
valone. These long-acting anticoagulants decrease the activity of
cations induced over prolonged periods. The immense variety of
chemical compounds with pesticide properties means that the
identification of an unknown substance is complicated. To moni-
the vitamin K-dependent blood-clotting factors (II, VII, IX, X) and
result in bleeding.
Warfarin has now been made obsolete by the second genera-
tor the occupational exposure new analytical methods (LC/MS,
GC/MS) must be implemented because not all pesticides exposures can be monitored by red blood cell cholinesterase activity.
tion agents. Warfarin differs from superwarfarins in that it only
decreases the formation of biologically active vitamin K-dependent blood-clotting factors (II, VII, IX, X). Bleeding only occurs if
Although many of the pesticides accumulate in the body it is not
always advisable to detect the original pesticide. An alternative is
to measure the metabolites produced from the parent compound.
these factors are sufficiently reduced.
Bromethalin is one of the newer rodenticides and all animals
including humans are vulnerable to its toxicity. Bromethalin is a
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These pages are sponsored by Drs Du Buisson & Partners
OCCUPATIONAL HEALTH SOUTHERN AFRICA
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