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1 BY Joseph Mwanzia Nguta, PhD (Pharmacol&Toxicol) Lecture notes available at:

2 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.

3 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

4 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

5 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.

6 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.

7 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.

8 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.

9 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.

10 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.

11 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.

12 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.

13 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 (37-40 0 C), 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.

14 Toxic dose/clinical signs The approximate oral LD 50 of DNOC is 25-50 mg/kg, depending on 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.

15 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

16 C). C). Chlorinated compounds Sodium chloroacetate and TCA (sodium trichloro- acetate) are both relatively harmless herbicides. The former is the more toxic, having an LD 50 in rats of 650 mg/kg; the figure for cattle being 150 mg/kg. TCA has an LD 50 in rats of 3000-5000 mg/kg. Free trichloro- acetic acid is an extremely corrosive substance.

17 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.

18 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 LD 50 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.

19 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.

20 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 100- 200 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.

21 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.

22 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.

23 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.

24 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.

25 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.

26 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.

27 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.

28 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.

29 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.

30 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.

31 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

32 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

33 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

34 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!

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