Download HERBICIDE AND FUNGICIDE TOXICOLOGY

BY
Joseph Mwanzia Nguta, PhD (Pharmacol&Toxicol)
Lecture notes available at: [email protected]
Herbicide toxicology: Introduction
 The commercial use of weed killers has increased
enormously during recent years. Their effectiveness
has been increased by the introduction of new
compounds, which are derivatives of dinitrophenol
and the triazine derivatives.
 Other older preparations, containing sodium chlorate
and trichloro-acetate are still in use.
 The dinitro-compounds are potentially extremely
dangerous chemicals, both to those who handle them
and to animals which may be accidentally exposed to
them.
Intod (Cont.)
 DNOC (dinitro-ortho-cresol) is the most widely used,
although dinoseb (2-sec-butyl-4, 6-dinitrophenol) has
specific purposes in selective weed control. Deaths have
occurred in spray operators and planned measures have
been introduced to prevent risks to agricultural workers
during application of these weed killers: Animals must be
protected by the care and foresight of their owners.
 DNOC (dinitro-ortho-cresol) is very persistent, and death
has been recorded in young pigs housed in a sty built in a
corner of a stockyard where diluted DNOC solution had
contaminated the soil two years previously
A). Phenoxy derivatives of fatty
acids:
 Examples:
 2, 4-D (2, 4-dichlorophenoxyacetic acid)
 2, 4, 5-T (2, 4, 5-Trichlorophenoxyacetic acid)
 MCPA (MCP) (2-methyl-4-chlorophenoxyacetic acid)
 2, 4-DB (4-(2, 4-dichlorophenoxy) butyric acid
 MCPB (4-(4-chloro-o-tolyloxy) butyric acid or 4-(4-
chloro-2-methylphenoxy) butanoic acid
 Fenoprop (2-(2, 4, 5-trichlorophenoxy) propionic acid
Phenoxy derivatives of fatty acids
 Most of these chemicals are comparatively harmless to
the mammalian species. Their main disadvantages are
that they make poisonous plants such as ragwort
appetizing to livestock, and their ability to increase
cyanide and nitrate content in certain weeds, thus
these chemicals may be harmful indirectly by inducing
cyanide or nitrate poisoning.
Absorption and fate:
 In sheep given an oral dose of 25 mg/kg of a 2,4,5-T,
peak plasma concentrations of 10ppm were found
three to four hours later: with 86% of the administered
dose being recovered from the urine in unaltered
form, and 1.4% as the free acid, within 72 hours.
Toxicity:
 These compounds differ but little in toxicity, the LD50
for most species lying in the range 100-500 mg/kg. The
dog is probably the most susceptible species, poultry
the least.
 This group of herbicides also has a low degree of
chronic toxicity; 2,4-D and 2,4,5,-T can be tolerated
without adverse effects in doses only slightly lower
than those which cause toxic effects when given in a
single dose.
Toxicity
 2, 4, 5-T has been used as a defoliant and is linked with
lung cancer and teratogenic effects.
 It is (2, 4, 5-T) considered very dangerous because of the
presence of small quantities of a highly toxic by product,
tetrachlorodibenzodioxin or TCDD.
 Experimental evidence has confirmed that TCDD is one of
the most poisonous substances known; the acute lethal
dose for a guinea pig is about 1µg. Teratogenic effect in rats
has been shown following dosage with TCDD. Smaller
herbivores are more vulnerable to the toxic effects of TCDD
than larger species.
Clinical signs and lesions.
 Animals poisoned present an overall picture of loss of
appetite, loss of weight, depression, unthrifty
appearance, general tenseness and muscular
weakness, particularly in the hind legs.
 Large oral doses elicit vomiting in those species
capable of doing so. Also abortion, irregular oestrus,
anoestrus and ovarian atrophy in cattle may be
attributed to the consumption of herbage
contaminated with 2, 4-D.
Post mortem findings
 Postmortem findings following oral dosage usually
include irritation of the stomach of small animals and
of the abomasum of ruminants, minor evidence of
liver and kidney injury and in some instances,
congestion of the lungs.
 Dogs show a considerably greater susceptibility to the
development of liver damage than other species. There
is also haemorrhagic gastritis with ecchymotic
haemorrhages on the wall of the intestine, stomach
ulcerations and degenerative changes of the liver and
kidneys.
B). Dinitro Compounds
 This group of herbicides includes 2, 4-dinitrophenol
(DNP), Dinitro-orthocresol (DNOC) and dinoseb. The
free compounds are yellow and form deep orange or
reddish salts.
Absorption and fate:
 Well absorbed via the lungs, skin and gut
 When DNOC is absorbed via the mouth of simple
stomached animals, the liver converts it into a mixture
of less toxic metabolites, mainly the isomeric
monoamines and their derivatives that are excreted via
the kidneys.
 In the case of ruminants, the rumen micro-organisms
rapidly reduce DNOC mainly to the diamino
compound that is then absorbed by the host and
conjugated in the liver. Methaemoglobinaemia has
also been reported in ruminants.
MOA
 The action of dinitrophenols is to uncouple oxidative
phoshorylation: they stimulate tissue respiration and at the
same time impair the synthesis of adenosine triphosphate
(ATP). The overall result is that metabolism is accelerated,
but the energy produced is converted into heat instead of
being passed on, through the mediation of ATP, to those
chemical and physical processes which require it.
 One important factor in the DNOC toxicity is the effect of
environmental temperatures: high temperatures (37-400C),
markedly increase the toxicity of DNOC, and experimental
studies on laboratory animals have indicated that the
toxicity may be increased 25-fold. Low environmental
temperature decreases the toxicity.
Toxic dose/clinical signs
 The approximate oral LD50 of DNOC is 25-50 mg/kg, depending on
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species, environmental temperature and route of administration. There
is some cumulative effect.
In sheep, 12.4 mg/kg produces signs of poisoning in seven weeks, 18.6
mg/kg in six days and 24.8 mg/kg in five days, the latter dose being
lethal.
The toxicity of DNP is similar to that of DNOC, and its magnitude is
dependent on similar factors.
Clinical signs:
The signs of intoxication are much the same in all species and include
listlessness, loss of appetite and activity, deepened and more rapid
respiration, sweating (in some animals only), thirst, oliguria, muscular
weakness, prostration, dyspnoea and death, with terminal
hyperpyrexia. Signs may appear within a few minutes if large amounts
have been ingested, otherwise they may be delayed for several hours.
Diagnosis/treatment
 DNOC and other dinitro compounds are persistent
yellow dye-stuffs, staining exposed skin, hair, wool, fur
and feathers a distinct yellow or orange colour which
remains obvious for weeks or even months afterwards,
despite the action of water and weather.
 Such staining provides evidence of at least external
contact with the chemicals. Stomach contents, liver
and specimens of any yellow coloured organs should
be submitted for laboratory examination.
 RX: Non specific
C). Chlorinated compounds
 Sodium chloroacetate and TCA (sodium trichloro-
acetate) are both relatively harmless herbicides. The
former is the more toxic, having an LD50 in rats of 650
mg/kg; the figure for cattle being 150 mg/kg. TCA has
an LD50 in rats of 3000-5000 mg/kg. Free trichloroacetic acid is an extremely corrosive substance.
D). Triazine Herbicides:
 The triazine herbicides (atrazine; simazine; propazine;
prometone and aminotriazole) are of fairly low toxicity. The
lethal dose of simazine (Weedex) in the sheep is 500
mg/kg. Signs of poisoning such as weakness, ataxia and
posterior paralysis may not appear until three weeks after
ingestion. Prometone is considerably more toxic, with
poultry being less susceptible than sheep and cattle.
 Aminotriazole has a lethal dose of 4g/kg in sheep. It gives
rise to the stimulation of smooth muscle of the gut and
bronchi, and causes oedema of the lungs and severe
haemorrhages of the stomach and intestines.
E). Thiocarbamates
 The thiocarbamates, di-allate and tri-allate, are used
for controlling weeds in farm crops. The former is the
more toxic, having an LD50 in rats of 400 mg/kg
against 2000 mg/kg for tri-allate.
 Sheep may be poisoned by 300 mg/kg of tri-allate,
showing signs of depression, anorexia, salivation,
weakness, convulsions and paresis. Daily dose of 50
mg/kg of di-allate will eventually cause poisoning in
sheep.
F). Bipyridyls:
 The bipyridyl herbicides, diquat and paraquat
(Gramoxone, Weedol), are well known in toxicology
owing to the number of fatal cases of human
poisoning which they have caused. They give rise to a
proliferative alveolitis and bronchiolitis, and unless the
amount consumed is small, treatment is of little avail.
 Poisoning in domestic animals has occurred less
frequently than in man. In all cases, it has been due to
carelessness or malice, as these substances are unlikely
to cause any serious harm if properly used.
Bipyridyls
 Pigs poisoned with paraquat show vomiting, dyspnoea,
depression, jaundice and severe pain; post mortem lesions
include pulmonary oedema, congested liver, interlobular
oedema, gastroenteritis, enlarged spleen and petechiae in
the trachea.
 Dogs poisoned with paraquat show signs similar to those in
poisoned pigs, with congested liver and lungs at post
mortem. A dose of 40 ppm paraquat in the drinking water
has shown no effect on hens except slight decrease in egg
fertility.
 Lethal doses of diquat are: in cattle 30 mg/kg, in dogs 100200 mg/kg, and in poultry 200-400 mg/kg. Of paraquat: in
cattle 50 mg/kg, in sheep 100 mg/kg, in pigs 75 mg/kg, and
in poultry 200 mg/kg.
II. Fungicide toxicology:
Introduction
 They include copper compounds, sulphur
preparations, inorganic and organic derivatives of
mercury and miscellaneous organic compounds.
 The main hazard to livestock from fungicides is likely
to arise from their use as seed dressings for the
protection of stored grain, potatoes and a number of
cases are on record of poisoning in horses, cattle, pigs
and poultry caused by the unwitting feeding of treated
grain.
A). Organomercury compounds
 These include phenyl mercury chloride, phenyl
mercury acetate and various aliphatic compounds such
as ethylmercury chloride, iodide and phosphate;
toluene sulphonanilide, methylmercury acetate,
chloride and hydroxide; methylmercury
dicyandiamide and mercury silicate (methoxethyl)
used as seed dressings in agriculture.
 Experimentally, it has been shown that the lethal dose
of methylmercury dicyandiamide in the pig is 20
mg/kg.
Post mortem findings
 These are gastroenteritis and acute parenchymatous
nephritis.
 After inhalation of mercury vapour, there may also be
oedema of the lung, hydrothorax, hydropericardium,
subpial oedema and haemorrhages in the epicardium
and endocardium.
Diagnosis
 Confirmation of a diagnosis of mercury poisoning may
rest upon the detection of mercury in the stomach
contents and of abnormal amounts in kidney and liver.
Treatment
 In the treatment of acute mercury poisoning, speed is
all important.
 As a first aid measure raw white egg may be given
followed by gastric lavage with saturated sodium
bicarbonate solution.
 When poisoning is due to absorption from an
ointment, the skin should be thoroughly cleansed with
soap and water.
 Dimercaprol (BAL) is the treatment of choice in
mercury poisoning. It is essential that treatment
should be initiated as quickly as possible.
Treatment
 Unithiol is said to be of value in treating chronic
poisoning due to organic mercurials.
 Acetylpenicillamine has been used successfully to treat
poisoning by inorganic mercury.
 It is interesting that spironolactone is said to protect
against both death and kidney damage due to
mercuric chloride.
 Dehydration due to mercurial diuretics is best
controlled by giving large amounts of normal saline
solution.
B). Thiram (TMTD,
Tetramethylthiuram Disulphide)
 Thiram is closely related chemically to the acaricide
monosulfiram.
 The production of abnormal eggs is traced to the
feeding of maize treated with thiram. It has been
shown that feeds containing 10-50 ppm causes a slight
increase and 100-200 ppm a heavy increase in the
proportion of soft shelled or otherwise abnormal eggs
 Clinical signs include anorexia, lethargy, dyspnoea,
loss of weight and convulsions, with death from
cardiac failure. Post mortem findings are multiple
haemorrhages and liver and kidney lesions.
C). Chlorophenols:
 Trichlorophenol, Pentachlorophenol and their derivatives
have been used extensively for many years as fungicides,
especially for preserving timber. The pentachlorophenols
are also used as herbicides and for termite control.
 Pentachlorophenol (PCP) can be absorbed through the
intact skin and deaths in people working with this
compound have been reported.
 The toxic effects of PCP are similar to those of DNOC and
the compound is believed to interfere with metabolism in
the same way.
 Wood preservatives containing PCP or creosote may be
extremely toxic to young pigs, the degree of toxicity
decreasing with increasing age.
Chlorophenols:
 Circumstantial evidence of the toxicity of
Pentachlorophenol for cats has been reported.
 The toxicity of PCP in sheep and calves has been
reviewed by Harrison (1959). The minimum acute
lethal dose rate was found to be approximately 120 and
140 mg/kg respectively in the two species.
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Clinical signs
 The most prominent clinical sign was the accelerated
breathing rate which distinguished dosed animals
from controls one to two hours after drenching.
 Badly affected animals stood swaying, with head
lowered, panted noisily and made little attempt to
move when approached.
 Salivation was observed in the calves and the coat felt
damp. Recovery from this stage of poisoning was rapid
and complete.
Post mortem findings
 Post mortem, acutely poisoned sheep showed a
generalized congestion. The lymph nodes appeared
enlarged and oedematous.
 There were haemorrhages in the epicardium and along
the aorta. The lungs showed isolated areas of collapse
and generalized congestion. Blood splashes were
occasionally seen on the diaphragm.
 The stomach, intestines, liver and kidney sometimes
showed mild congestion. The bladder was invariably
empty
Treatment principles (General)
 Elimination of toxicant from its region of absorption
 Reduction in rate of absorption or re-absorption from
entero-hepatic billiary cycle
 Blockade of the action of the toxicant using specific or
non specific antidotes
 Hastening metabolic inactivation and excretion
 Reversal of side effects
 Making the animal as comfortable as possible
Rx principles
 Antibiotic + corticosteroid +tranquilizer = to provide
sedation and eliminate harmful effects of stress
 Multiple vitamin admin.
 Close observation of the animal
 Elimination of the toxicant source
Future of Veterinary Toxicology
 “If students are not excited by the prospect of
studying how chemical agents make sick animals well,
then they will be interested in studying how chemical
agents make well animals sick”. Both of these areas of
endeavor have held my fascination for many years!