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PHOSPHAMIDON

1. NAME
   1.1 Substance:
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names/ main trade names
   1.6 Main manufactures/main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstances of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion by route of exposure
7. TOXICOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
         7.2.4.1 Maximum Allowable Concentration
         7.2.4.2 Threshold Limit Value has not been established.
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systemic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.9 Eyes, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbance
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life-supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
      10.6.2 Differences between countries
11. ILLUSTRATIVE CASES
   11.1 Case reports from the literature
   11.2 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes and antisera
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR (S), REVIEWER (S), ADDRESS (ES), DATE (INCLUDING EACH UP-DATE)

International Programme on Chemical Safety

Poisons Information Monograph 454

Chemical

1. NAME

1.1 Substance:

Phosphamidon

1.2 Group

Organophosphorus pesticides;

1.3 Synonyms

2-CHLORO-2-DIETHYLCARBAMOYL-1-METHYLVINYL DIMETHYL PHOSPHATE (IUPAC)

2-CHLORO-3-(DIETHYLAMINO)-1-METHYL-3-OXO-1-PROPENYL DIMETHYL PHOSPHATE (CAS)

DIMETHYL PHOSPHATE ESTER 2-CHLORO-N,N-DIETHYL-3-HYDROXYCROTONAMIDE

O,O-DIMETHYL-O-(2-CHLORO-2-DIETHYLCARBAMOYL-1-METHYLVINYL) PHOSPHATE

NCI-c 00588

ENT 25515

PHOSPHAMIDON

DIMECRON

DIXON

HYDROXYCROTONAMIDE

(2-CHLOR-3-DIAETHYLAMINO-1-METHYL-3-OXO-PROP-1-EN-YL)-DIMETHYL-PHOSPHAT (GERMAN)

1-CHLORO-1-N,N-DIETHYLCARBAMOYL-1-PROPEN-2-YL-DIMETHYL PHOSPHATE

2-CHLORO-2-DIETHYLCARBAMOYL-1-METHYLVINYL DIMETHYLPHOSPHATE

1-CHLORO-DIETHYLCARBAMOYL-1-PROPEN-2-YL DIMETHYL PHOSPHATE

(2-CLORO-3-DIETILAMINO-1 METIL-3-OXO-PROP-1-EN-IL)-DIMETIL-FOSFATO (ITALIAN)

CROTONAMIDE, 2-CHLORO-N,N-DIETHYL-3-HYDROXY-, DIMETHYL PHOSPHATE

DIMETHYL 2-CHLORO-2-DIETHYLCARBAMOYL-1-METHYLVINYL PHOSPHATE

O,O-DIMETHYL O-(2-CHLORO-2-(N,N-DIETHYLCARBAMOYL)-1 -METHYLVINYL) PHOSPHATE

DIMETHYL DIETHYLAMIDO-1-CHLOROCROTONYL (2) PHOSPHATE

(O,O-DIMETHYL-O-(1-METHYL-2-CHLORO-2-DIETHYLCARBAMOYL-VINYL) PHOSPHATE

DIMETHYL PHOSPHATE of 2-CHLORO-N,N-DIETHYL-3-HYDROXYCROTONAMIDE

ML 97

OR 1191

PHOSPHATE DE DIMETHYLE ET DE (2-CHLORO-2-DIETHYLCARBAMOYL-1-METHYL-VINYLE) (FRENCH)

C 570

(2-CHLORO-3-DIETHYLAMINO-1-METHYL-3-OXO-PROP-1-EN-YL)-DIMETHYL-FOSFAAT (Dutch)

2-CHLORO-3-(DIETHYLAMINO)-1-METHYL-3-OXO-1-PROPENYL DIMETHYL PHOSPHATE

2-CHLORO-N,N-DIETHYL-3-HYDROXYCROTONAMIDE DIMETHYL PHOSPHATE

CIBA 570

2-(N,N-DIETHYLCARBAMOYL)-1-METHYLVINYL PHOSPHATE

N,N-DIETHYL 2-CHLORO-3-DIMETHYLPHOSPHATE CROTONAMIDE

DIMECRON 100

DIMECRON 50

DIMECRON-20

O,O-DIMETHYL-O-(1-METHYL-2-CHLOR-2-N,N-DIAETHYL-CARBAMOYL)-VINYL-PHOSPHAT (German)

FOSZFAMIDON (Hungarian)

PHOSPHORIC ACID, 2-CHLORO-3-(DIETHYLAMINO)-1-METHYL-3-OXO-1-PROPENYL DIMETHYL ESTER

SUNDARAM 1975

OMS 1325

1.4 Identification numbers

1.4.1 CAS number

13171-21-6 (mixture), 297-99-4 (trans-isomer),

23783-98-4 (cis-isomer).

1.4.2 Other numbers

RTECS #

TC2800000

ICSC #

0189

UN #

3018

EC #

015-022-00-6

The following UN transportation numbers have been established for organophosphorus pesticides (UN, 1985):

2783

Organophosphorus pesticides, solid, toxic, NOS.

2784

Organophosphorus pesticides, liquid, toxic, flammable, NOS, freezing point \< 61-C, closed cup.

3017

Organophosphorus pesticides, liquid, toxic, flammable, freezing point 23- C, closed cup.

3018

Organophosphorus pesticides, liquid, toxic, NOS.

1.5 Main brand names/ main trade names

Apamidon*, Ciba 570, C-570, D-Cron, Dimecron, Dixon*, ENT 25,515, Famfos, Merkon, ML-97, Or-1,911, Phosphamidone, Phosron, Pillarcron, Sundaram 1975 , Swat*, Umecron.

* Commercial names discontinued

1.6 Main manufactures/main importers

Ciba-Geigy Corp. Agricultural Division (Brazil; USA -Discontinued)

Chevron Chemical Co./Ortho Division (USA)

United Phosphorus (India)

Bharat Pulverising Mills (India)

Hindustan Ciba Geigy Ltd. (India)

Hui Kwang (Taiwan)

2. SUMMARY

2.1 Main risks and target organs

Organophophorus pesticides can be absorbed by all routes. Phosphamidon may be readily absorbed from the gastrointestinal tract, through the skin and by inhalation of spray mists and dusts. Phosphamidon affects the nervous system by inhibiting acetylcholinesterase, an enzyme essential for normal nerve impulse transmission. The toxicological effects result in respiratory, myocardial and neuromuscular transmission impairment.

A few organophosphorus pesticides have produced the so-called "Intermediate Syndrome" and delayed and persistent neuropathy, apparently unrelated to cholinesterase inhibition. Phosphamidon appears not to be involved in both syndromes.

The main target organs are the nervous system, respiratory tract and cardiovascular system.

Degradation products in the environment are not toxic to any significant extent. Thermal decomposition products may be harmful by inhalation and skin contamination. Toxicity may also be due to the effects of solvent vehicles or other components of formulated pesticides.

2.2 Summary of clinical effects

The signs and symptoms of acute organophosphate poisoning are an expression of the effects caused by excess acetylcholine (cholinergic syndrome); they may occur in various combinations and can be manifest at different times.

Signs and symptoms can be divided into three groups:

According to the degree of the severity of poisoning, the following signs and symptoms can occur:-

Intermediate and Delayed Neuropathy Syndrome

Phosphamidon has not been able to cause delayed peripheral neuropathy in hens, also showing one of the weakest NTE inhibition potency in vitro amongst the organophosphorus compounds (Jokanovic et al, 1995).

The "Intermediate Syndrome" has not been also described for phosphamidon. This occurs after initial improvement, approximately 1- 8 days after poisoning. Muscle weakness leading to paralysis and sudden respiratory arrest occurs.

2.3 Diagnosis

In the absence of a reliable history, the diagnosis of organophosphorus pesticides poisoning may be initially clinical, as it is based on the clinical features given in section 2.2. Foul smell (much like garlic) may be present in breath, faeces or vomit or in contaminated clothing, if sulphur-containing insecticides have been ingested, which is not the case of phosphamidon.

Favorable response to atropine is a more useful diagnostic aid than any cholinesterase assay since treatment must often be initiated before any laboratory results are available.

Other relevant laboratory analysis:

Complete blood cell count, serum electrolyte levels, arterial pH and blood gases, blood glucose, liver and spleen function tests, and urine analysis. Investigations may also include ECG and chest X-ray.

Cholinesterase levels are helpful in diagnosing organophosphorus pesticides poisoning, but not in managing the illness. The red cell (acethyl) cholinesterase level is a more accurate assessment of poisoning but it declines more slowly than the pseudocholinesterase. An impurity of the technical product, gamma-chlorphosphamidon, inhibits mammalian cholinesterase 10 to 20 times more than pure phosphamidon. The estimation of pseudocholinesterase is required for earlier diagnosis. Blood should be drawn in a heparinised tube before treatment is begun. In cases of unknown organophosphorus poisoning, the first aspirate or the formulation of the pesticide if available may be used to identify the type of organophosphorus pesticide.

2.4 First-aid measures and management principles

It is important that the chemical be removed as quickly as possible, as well as atropine to be administered (see below). Contaminated clothing and contact lenses should be removed as quickly as possible to prevent further absorption. If skin contact occurs, the area should be washed carefully with soap and water. Wash eyes for 15 to 20 minutes with running water. First-aid personnel should wear rubber or plastic gloves to avoid contamination, which should be changed frequently.

In massive overdoses, acute respiratory failure may occur. It is important to keep the airway open and to prevent aspiration if nausea and vomiting occur.

Oxygen should be administered early if necessary. The patient must be watched constantly and respiratory support should be instituted if necessary. In the case of ingestion, gastric aspiration followed by lavage should be preferably performed within 1 hour of ingestion. Activated charcoal may be effective for organophosphorus pesticides.

The patient should be observed carefully during the early stages of treatment, because the principal concern is severe respiratory depression. Certain drugs, such as phenothiazines, methylxanthines, central nervous system depressants, and parasympathomimetic agents are to be avoided. Drugs metabolised by plasmacholinesterase are contraindicated.

When muscarinic signs are present, organophosphate pesticide poisoning must be treated with atropine. The oximes, such as pralidoxime or obidoxime may also be indicated. Diazepam is used to treat seizures.

Atropine: administered intravenously (IV) in doses of 1 to 2 mg (0.05 mg/kg) every five to ten minutes until signs of atropinisation (dilated and fixed pupils, loss of salivation and bronchial hypersecretion) or complete reversal of symptoms occurs. If IV therapy is not possible, atropine may be given intramuscularly (IM). In severe cases, both tachycardia and mydriasis may be unreliable features, since they may result from nicotinic stimulation. In very severe cases bolus injections of > 10 mg may be necessary. As such, adequate atropinisation should be assessed by dry mouth and the effect on bronchial hypersecretion; frequent auscultation is necessary. Atropine must be continued to maintain atropinisation until the patient recovers.

Pralidoxime: in doses of 30 mg/kg every four to six hours or, preferably, by slow intravenous (IV) infusion at a maximum rate of 8 to 10 mg/kg/h until full recovery occurs, or, 500 mg/h continuously maintained until clinical improvement is obtained.

Obidoxime: the adult dose is usually 3 mg/kg given by slow IV; IM dosing is possible when the IV route is inaccessible. The maintenance dose is 0.4 mg/kg/h.

Diazepam: 5 to 10 mg (0.2 to 0.3 mg/kg) by slow intravenous (IV) over three minutes which may be repeated every 10 to 15 min (maximum 30 mg) in order to control convulsions. Some organophosphorus pesticides may cause a delayed peripheral neuropathy. There is no specific therapy for this condition except for symptomatic measures; e.g., physiotherapy.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of substance

Phosphamidon is an ester of phosphoric acid and is synthetically produced.

3.2 Chemical structure

Structural formula for phosphamidon

Molecular formula C10H19ClNO5P

Molecular weight 299.7D.

Chemical Name O,O-DIMETHYL-O-(2-CHLORO-2-(N,N DIETHYLCARBAMOYL)-1-METHYLVINYL) PHOSPHATE

3.3 Physical properties

3.3.1 Colour

Technical phosphamidon is a pale yellow to colourless

3.3.2 State/Form

Oily liquid with a faint odour . It consists of a mixture in the approximate proportion of 70% (cis)-isomer and 30% (trans)-isomer.

3.3.3 Description

Oil-water partition coefficient

0.79

Vapour pressure

2.5 × 10-5 mmHg or 2.2 mPa 25° C

Boiling point:

162°C at 1.5 mmHg;

Density (d)254

1.2132

Refractive index (n)20D

1.4721.

Stability:

Stable in neutral and acid media but is hydrolyzed by alkali;

Half-life

13.8 days at pH 7 and 2.2 days at pH 10 at 23°C.

Decomposition:

Produces highly toxic phosphorus oxides and chlorides fumes above 160°C

Solubility:

Miscible with water and soluble in most organic solvents except paraffins (non-polar aliphatic hydrocarbons).

3.4 Hazardous characteristics

Phosphamidon is corrosive to iron, tinplate and aluminium.

The majority of organophosphorus pesticides are liquid and have different vapour pressures at room temperature. Phosphamidon is used for agricultural purposes and available mainly as 20-100% soluble concentrates (from 200 to 1000 g a.i./l in 2-propanol), but also as 0.5 g/kg granules for soil applications. Also it is available as ultra low volume (ULV) (fogging) formulations. It is no recommended for indoor use, neither for animal nor for human pharmaceutical preparations.

Dispersion of spray droplets by wind is possible, but in general, only small amounts are likely to be dispersed in this way.

All organophosphorus pesticides are subject to degradation by hydrolysis, yielding water-soluble products that are believed to be non-toxic at all practical concentrations. The toxic hazard is therefore essentially short-term in contrast to that of the persistent organochlorine pesticides, although the half-life at neutral pH may vary from a few hours for dichlorvos to several weeks for parathion (at pH 7 phosphamidon has a t1/2 near 14 days). At the pH of slightly acidic soils (pH 4-5), these half-lives will be extended many times. However, constituents of soil and of river waters may themselves catalyze degradation.

Products of combustion:

Powder, granular, and water-based products will not burn. Most liquid formulations will burn and are miscible with water. The products of combustion may be harmful by inhalation and dermal contamination. Fire Service personnel should extinguish fires with alcohol-resistant foam, water spray, or dry powder. Firefighters should wear full protective clothing including self-contained breathing apparatus.

Environmental risks:

Three routes of entry into water sources are possible. One is from industrial waste or effluent discharged directly into water. A second is by seepage from buried toxic wastes into water supplies. Neither of these should be tolerated since prior treatment of the waste with alkali (or acid ), followed by neutralization, can destroy the toxic agents. Thirdly, contamination of running water directly or from run-off during spraying operations can occur. No studies on the degradation of organophosphorus pesticides in running water have been reported. In static water, in a simulated aquatic environment, there is evidence that light, suspended particles, and bacteria contribute to degradation.

Degradation in the environment involves both hydrolysis and oxidation to mono - or di - substitute phosphoric or phosphonic acids or their thio analogues. There is no evidence that these products are toxic to any significant extent (WHO, 1986). Phosphamidon is highly toxic to bees and to some varieties of sorghum and cherry.

For guidance on safe disposal, see Section 12.2.

4. USES

4.1 Uses

4.1.1 Uses

Primary use:

insecticide

Secondary use:

acaricide

4.1.2 Description

Phosphamidon is a non-cumulative systemic organophosphorus pesticide with a broad spectrum of activity: It is a cholinesterase inhibitor with rapid contact and stomach action. The technical product is very highly toxic to mammals and is listed in WHO Hazard Class Ia (extremely toxic).

Phosphamidon is used to control vectors (sap-feeding insects, sugar cane and rice stemborers and rice leaf beetles), which are found in food (citrus, nuts and deciduous fruits) and commercial (cotton) crops.

4.2 High risk circumstances of poisoning

Accidental poisoning of children can occur when pesticides are stored improperly in the home or garage.

Occupational exposure among adult farm workers and secondary accidental exposure to their families can occur.

Suicide attempts probably account for more severe and more frequent poisonings than accidental or occupational poisonings in some countries.

Exposure of the general population through the consumption of foodstuffs treated incorrectly with pesticides or harvested prematurely before residues have declined to acceptable levels from contact with treated areas, or from domestic use has been reported. Accidental poisonings can also occur through failure to observe safe re-entry time after application.

4.3 Occupationally exposed populations

Factory workers involved in synthesizing pesticides.

Workers involved in formulating and dispensing pesticides.

Agricultural spray workers.

Crop harvesters during disease vector control periods.

Public-health workers involved in vector control.

Health workers not following the correct procedures when handling poisoned patients, especially when ventilatory support is needed.

5. ROUTES OF EXPOSURE

5.1 Oral

a)

Accidental ingestion, especially by children.

b)

Ingesting food containing organophosphorus pesticides residues after incorrect treatment of foodstuffs or harvested prematurely before residues have declined to acceptable levels.

c)

Oral ingestion may also occur through placing contaminated objects in the mouth during eating, drinking or smoking, or through violation of proper procedures, e.g., blowing out clogged spray nozzles by mouth.

d)

Intentional ingestion is common in suicide attempts (see section 4.2).

5.2 Inhalation

The majority of organophosphorus pesticides are liquids that have different vapour pressures at room temperature thus, hazards due to inhalation of vapour vary from compound to compound. Respiratory exposure is greater when dusts are applied than when dilute sprays are used. However, aerosols of concentrated pesticide may be an even greater hazard (WHO, 1986).

5.3 Dermal

Many accidental acute poisonings have occurred after spillage of a pesticide on skin and clothing. The extent of uptake will depend on persistence time (related to volatility, clothing, coverage, and thoroughness of washing after exposure), and also on the presence of solvents and emulsifiers that may facilitate uptake.

Powder formulations also have a potential for skin absorption (Wolfe et al., 1978).

Skin absorption is somewhat greater at high temperatures and may be much greater in the presence of dermatitis, thus, leading to serious poisoning after an exposure that would ordinarily cause no effects (Gallo & Lawryk, 1991).

5.4 Eye

Exposure to vapours, dusts, or aerosols can cause local effects on the smooth muscle of the eyes. Systemic poisoning may follow.

5.5 Parenteral

Accidental or intentional (see section 11.2)

5.6 Others

No data available.

6. KINETICS

6.1 Absorption by route of exposure

Phosphamidon is absorbed by the respiratory and gastrointestinal tracts as well as by the skin.

Dermal exposure:

Absorption by the skin tends to be slow, but because the pesticides are difficult to remove, dermal absorption is frequently prolonged. Uptake of active ingredients through the skin from powdered and granulated formulations may be relatively inefficient; the presence of aqueous dispersing agents or organic solvents in a spray concentrate or formulation may greatly enhance uptake. On the basis of radio autographic studies in man and animals, it appears that skin absorption is transepidermal (Frediksson, 1961).

6.2 Distribution by route of exposure

The intrinsically reactive chemical nature of organophosphorus pesticides means that any that enter the body are immediately liable to a number of biotransformations and reactions with tissue constituents, so that the tracing radiolabel led material alone does not give any clue to the unchanged parent compound. In view of the inherent instability of the organophosphorus pesticides, storage in human tissue is not expected to be prolonged.

Experimental animal studies indicate rapid excretion of these compounds. However, some organophosphorus pesticides are very lipophilic and may be taken into, and then released from, fat depots over a period of many days.

6.3 Biological half-life by route of exposure

It is possible to determine the rate of disposal of metabolites and thereby to estimate an approximate half-life of the pesticide in the body. The half-life of most organophosphorus pesticides and their inhibitory metabolites in vivo is comparatively short (WHO, 1986).

6.4 Metabolism

Metabolism occurs principally by oxidation, and hydrolysis by esterase and by reaction with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphorus pesticides may result in more or less toxic products. Numerous conjugation reactions follow the primary metabolic processes, and elimination of the phosphorus-containing residue may be via the urine or faeces.

Metabolism and excretion is rapid in mammals. After ip injection of 32P-labelled phosphamidon to rats, 60% of the dose was recovered in 24 hours. In rats and goats, oxidative metabolism yielded mostly desethyl phosphamidon, phosphamidon amide and deschloro-phosphamidon. However over 90% of radioactivity in the urine was in the form of nontoxic unextractable polar metabolites.(IPCS,1996).

6.5 Elimination and excretion by route of exposure

There is no evidence of prolonged of organophosphorus pesticides compounds in the body, but the process of elimination can be subdivided roughly according to the speed of the reactions involved. Most organophosphorus pesticides are degraded quickly by the metabolism reactions described. The elimination of the products, mostly in the urine with lesser amounts in the faeces and expired air, is not delayed, so that rates of excretion usually reach a peak within two days and decline quite rapidly (WHO, 1986).

There are six primary alkylphosphate metabolites; dimethylphosphate (DMP) has been detected in the urine of a patient exposed to phosphamidon (Lauwerys & Hoet,1993).

In humans occupationally exposed to phosphamidon, urinary excretion of dimethylphosphate is detectable at an exposure level insufficient to depress plasma or erythrocyte cholinesterase. Also, it has been reported that trace amounts of these alkylphosphate metabolites may occur in urine of unexposed subjects (Maroni et al, 2000). Therefore, a comparison with reference groups or individuals pre-exposure values is recommended when exposed workers are tested.

Experimental animal studies have shown that most of a radiolabelled doses of organophosphorus pesticides is rapidly excreted in expired air, urine, and faeces.

7. TOXICOLOGY

7.1 Mode of action

Organophosphorus pesticides exert their acute effects by inhibiting acetylcholinesterase in the nervous system with subsequent accumulation of toxic levels of acetylcholine. They may also inhibit butylcholinesterases as well as other esterase. The function of butylcholinesterases is unknown, but its inhibition can provide an indication of exposure to an organophosphate.

In many cases, the organophosphorylated enzyme is fairly stable, so that recovery from intoxication may be slow. Reactivation of inhibited enzyme may occur spontaneously, the rates of reactivation depending on the tissue as well as on the chemical group attached to the enzyme. Higher doses of oximes failed to alter the reactivation of in vitro human AchE inhibited by organophosphorus compunds (Worek et al, 1996). These authors also found that phosphamidon inhibited the human acetylcholinesterase in a final concentration of 1.6 mmol/L which, at the end of inhibition period, corresponded to 4.65% AChE activity.

Phosphamidon poisoning inhibits the activity of superoxide dismutase and increases the lipid peroxidation in several regions in the central nervous system (Naqvi & Hasan, 1992).

Delayed neuropathy is initiated by an attack on a nervous tissue esterase distinct from acetylcholinesterase. The target has esterase activity and is called neuropathy target esterase (NTE) (formerly neurotoxic esterase). The disorder develops not because of loss of esterase activity, but because of a change brought about in the protein molecule that results from the process of ageing of inhibited NTE: catalytic activity of NTE appears in the nervous tissue, even during the period of development of neuropathy (WHO, 1986). The putative mechanism appears to involve phosphorylation of esterases in peripheral nervous tissue and results in a "dying back" pattern of axonal degeneration (Cavanagh, 1973). Investigations conducted by Jokanovic et al (1995) and Abdelsalam (1999) in adult hens showed that phosphamidon is potentially neurotoxic because of its ability to inhibit brain NTE activity. However, the extent of inhibition required for the development of clinical delayed neurotoxicity (> 80%) is not likely to occur prior to its signs of severe cholinergic intoxication.

Lotti et al (1983) and Maroni et al (2000) found that monitoring levels of neurotoxic esterase (NTE) activity in human circulating lymphocytes and platelets (lower reference values are 11.5 and 8.4 nmol/min/mg per prot., respectively) would be helpful in providing early warning of delayed neurotoxicity. However, the available data are still insufficient to allow the use of NTE measurements for biological monitoring of subjects exposed to axonopathic organophosphates

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

The probable fatal dose of phosphamidon for an adult by ingestion is 5 to 50 mg/kg b.w. (Gosselin et al., 1984). The estimated fatal dose in humans (~70 kg) is 490mg by oral ingestion (WHO, 1990).

When 32 volunteers were exposed to an ultra low volume formulation sprayed of phosphamidon at 550 g/ha in paddy fields for more than one hour, there was an over 50% reduction of plasma cholinesterase activity in two volunteers, recovery occurring in 9 days, whilst the levels of erythrocyte cholinesterase did not change (WHO, 1986 ).

7.2.1.2 Children

A 10 years-old boy survived an oral dose between 60 to 120 mg/Kg of 20% phosphamidon. Recovery was rapid following the use of an emetic (WHO, 1986).

7.2.2 Relevant animal data

For mammals, in case of phosphamidon, the range of oral toxicity varies from 6.5 to 220 mg/Kg b.w. while the inhalation LC50 lies in between 33 and 1300mg/m3/4h, depending on the animal species.

Phosphamidon (1/4th of LD50 i.p.) in rats has abolished conditioned avoidance responses as well as several autonomic, neurological and behavioral effects in mice at the same dose level (Agarwal et al, 1990).

Animal studies have revealed slight microscopic changes in the kidney although renal toxicity has not been shown to be a feature of acute organophosphorus insecticide poisoning (Gallo & Lawryk, 1991).

A study conducted by the Punjab Agricultural University in buffalo calves showed that long-term oral exposure (120 days) to phosphamidon (0.25-0.5 mg/Kg/day) led to a significant inhibition of acetylcholinesterase activity (35-49%). No signs of poisoning were seen in the animals apart from mild intermitent diarrhoea during the period of treatment (between 35 and 84 days). The higher doses also provoked a gradual but significant increase on blood glucose and total serum proteins (day 70th.) although the values returned to normal by the end of the experiment (Awal & Malik, 1992).

7.2.2.1 LD50/LC50

LD50 oral

 

Rats

17 mg/kg b.w.

Mice

10 mg/kg b.w.

 

6.5 mg/kg b.w. (cis-isomer)

 

220 mg/kg b.w. (trans-isomer)

Dogs

50 mg/kg b.w.

Rabbit

32 mg/kg b.w.

LD50 Dermal:

 

Rats

374 mg/kg b.w.

LC50 Inhalation:

 

Rats

102 mg/m3/4h (head only exposure)

Rats

135 mg/m3/4h (whole body exposure)

Rats

160 mg/m3/4h

Mice

33 mg/m3/4h

Guinea pigs

1300 mg/m3/4h

LD50 I.P.:

 

Rats

9.2 mg/kg b.w.

Mice

5.8 mg/kg b.w.

LD50 I.V.:

 

Mice

6 mg/kg b.w.

Hazard Classification by International Organizations

WHO
(WHO, 1986)

Technical product.: la (extremely hazardous), classification based on oral toxicity

 

Classification of formulations

 

 

oral toxicity

dermal toxicity

 

 

LD50: 9 mg/kg b. w

LD50: 367 mg/kg b. w

 

formulation

a. i. (%)

hazard class

a. i. (%)

hazard class

 

liquid

>50

la

>80

Ib

 

 

>3

Ib

>3

II

 

solid

>20

Ib

 

 

 

 

>1

II

>30

II

EPA

Category 1 (highly toxic)

EU

T+ (very toxic), N (dangerous to the environment), mutagen Category 3

IARC

Not evaluated by IARC

FAO, 1997

7.2.3 Relevant in vitro data

No data available.

7.2.4 Workplace standards

7.2.4.1 Maximum Allowable Concentration

- A study based on the description of the standard setting process in China has proposed a maximum allowable concentration (MAC) in the workplace air of 0.02mg/m3 (Zhuang et al , 1993).

7.2.4.2 Threshold Limit Value has not been established.

7.2.5 Acceptable daily intake (ADI) and other guideline levels

ADI=Acceptable Daily Intake 0-0.0005 mg/kg b. w (JMPR meeting 1986)

(IPCS 1996)

Re-entry Level

Pesticides

24 hours

Any pesticides with registered agricultural uses when used on crops requiring workers to perform labour-intensive activities, unless the pesticides has been granted an exemption.

48 hours

azinphos-methyl

 

carbophenothion

 

demeton

 

dicrotophos

 

disulfoton

 

endosulfon

 

endrin

 

ethion

 

methidathion

 

methyl parathion

 

mevinphos

 

monocrotophos

 

oxydemeton-methyl

 

phorate

 

phosphamidon

7 days

ethyl parathion

(Reference: Ellenhorn et al., 1997)

7.3 Carcinogenicity

No data available.

7.4 Teratogenicity

Detailed data on the effects of organophosphate occupational exposure on pregnant women and their fetuses are not available, although such information would be valuable.

In humans only a few cases of acute organophosphorus insecticide poisoning during pregnancy have been described.

Two patients in their second and third trimesters of pregnancy ingested organophosphorus pesticides in suicide attempts (Karalliedde et al., 1988). On management of the acute cholinergic and the intermediate phases of poisoning, recovery was complete and the pregnancies continued to term unaffected.

Weis et al. (1983) also reported a 21-year-old patient, who was about 34 to 35 weeks pregnant, who was admitted to hospital showing signs of severe organophosphorus pesticide poisoning. However, caesarean section was performed 11 hours after admission to allow an optimal atropine dosage for the mother. Acetylcholinesterase levels were less than 2% of normal in the infant and atropine infusion was given for eight days. Both mother and child made uneventful recoveries and were discharged 30 days post-admission. (Weis et al., 1983).

One pregnant woman who was involved in a serious acute exposure to mevinphos and phosphamidon delivered a normal child; another exposed woman who became pregnant shortly after the incident also had a normal child (Midtling et al, 1985).

7.5 Mutagenicity

Many organophosphorus pesticides have been tested for their mutagenic potential. No generalizations can be made since compounds exhibit mutagenic activity, whereas other compounds do not. The mutagenic and genotoxic potential evaluated by the Ames assay showed phosphamidon as a relatively weak mutagen (Saxena et al, 1997). Interactions

7.6 Interactions

Because different classes of enzymes may inhibited, the effects of organophosphorus pesticide poisoning may be complex and potentially at least could involve interactions with drugs as well as with other pesticides or chemicals. Potentiation may also involve solvents or other components of formulated pesticides (Gallo & Lawryk, 1991). Certain drugs such a phenothiazines, antihistamines, CNS depressants, barbiturates, xanthines (theophylline), aminoglycosides and parasympathomimetic agents are to be avoided because of increased toxicity.

8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

The clinical picture of organophosphorus pesticides poisoning results from accumulation of acetylcholine at nerve endings. Signs and symptoms can be divided into three groups: muscarinic, nicotinic, and central nervous system (CNS) effects (see table 9.1.1). Some of these effects may be more prominent than others or may occur first.

Table 9.1.1 Clinical Effects of Organophosphorus Pesticides Poisoning

MUSCARINIC EFFECTS
Increased bronchial secretion, excessive sweating, salivation, and lacrimation
Pinpoint pupils, bronchoconstriction, abdominal cramps (vomiting and diarrhoea)
Bradycardia

NICOTINIC EFFECTS
Fasciculation of muscles. In more severe cases, paralysis of diaphragm and respiratory muscles
Tachycardia and elevation of blood pressure

CENTRAL NERVOUS SYSTEM EFFECTS
Headache, dizziness, restlessness, and anxiety
Mental confusion, convulsions and coma
Depression of the respiratory center and vasomotor center

(WHO, 1986)

Systemic effects are, in general, similar, irrespective of the route of absorption, but the sequence and times may differ. Respiratory and ocular symptoms are expected to appear first after exposure to airborne organophosphates. Gastrointestinal symptoms and localized sweating are likely to appear after oral and dermal exposure, respectively.

Following ingestion, the onset of symptoms is usually rapid, within a few minutes to 1 or 3 h. Clinical effects vary according to the amount ingested (see table 9.1.1). All of the symptoms and signs may occur in various combinations and can be manifest at different times, ranging from a few minutes to many hours, depending on the chemical, dose, and route of exposure. Mild poisoning may include muscarinic and nicotinic signs and symptoms only. Severe cases always show CNS involvement; the clinical picture is dominated by respiratory failure, sometimes leading to pulmonary oedema, due to the combination of the effects of all three groups.

9.1.2 Inhalation

No data available.

9.1.3 Skin exposure

Localised sweating and fasciculation at the site of contact, with systemic effects occurring following absorption. Secondary exposure of children through contact with their parents contaminated clothing can also occur.

9.1.4 Eye contact

Early miosis and blurred vision may be followed by cholinergic effects if the substance is appreciably absorbed. Miosis, caused by direct contact of the eye with organophosphorus pesticides, may be incorrectly interpreted as a sign of systemic poisoning.

9.1.5 Parenteral exposure

No data available.

9.1.6 Other

No data available.

9.2 Chronic poisoning

No data available.

9.2.1 Ingestion

No data available

9.2.2 Inhalation

No data available

9.2.3 Skin exposure

No data available

9.2.4 Eye contact

No data available

9.2.5 Parenteral exposure

No data available

9.2.6 Other

True chronic poisoning following exposure to organosphosphorus pesticides does not occur. Organophosphorus pesticides in common use are rapidly biotransformed and excreted, and sub-acute or chronic poisoning by virtue of accumulation of the compounds in the body does no occur.

However, acute intoxications or chronic exposure may lead to long-term, or delayed, adverse effects. Several of the organophosphorus pesticides produce slowly reversible inhibition of cholinesterase, and accumulation of this effect can occur. Thus an individual may experience progressive ChE inhibition but remain asymptomatic. Sings and symptoms of poisoning that resemble those produced by a single high dose will occur when the accumulated inhibition of cholinesterase produced by smaller, repeated doses reaches a critical level. Cessation of exposure normally results in complete recovery (Ecobichon, 1996).

9.3 Course, prognosis, cause of death

The first four to six hours are the most critical in acute poisoning. If there is improvement in symptoms after initial treatment then the patient is very likely to survive if adequate treatment is continued. Delayed toxicity represents an onset of effects on the central and peripheral nervous systems appearing days to weeks after exposure. This may occur independently of the effects observed in acute poisoning due to cholinesterase inhibition. Death in cases of heavy exposure is usually related to respiratory collapse, reflecting depression of the respiratory center, weakness of the muscle of respiration, bronchoconstriction and excessive pulmonary secretions. Death may also result from cardiac arrest, due to cardiac dysrhythmias and various degrees of heart block.

9.4 Systemic description of clinical effects

9.4.1 Cardiovascular

Cardiac dysrhythmias, various degrees of heart block, and cardiac arrest may occur. Cardiac rhythm disturbances have occurred with a frequency of less than 5%. These are of many types, such as ventricular rhythm disturbances, alterations of ST segments, T waves, prolongation of the QT interval, complete heart block, and asystole. Tachycardia and ST-wave abnormalities may also be induce by hypoxia (Gallo & Lawryk, 1991). Patients may have elevated blood pressure and tachycardia (nicotinic effects), rather than bradycardia or hypotension (muscarinic effects), depending on the balance between muscarinic and nicotinic receptors (Ellenhorn et al., 1997).

Obtain and monitor 12-lead ECG. Patients with QT interval prolongation or premature ventricular beats (PVB) have a higher incidence of respiratory failure and a worse prognosis (Chuang et al, 1996; Jang et al, 1995). The cardiac cycle length, QT interval and its relationship investigated in isolated rat heart showed that increasing doses of phosphamidon were responsible for ventricular arrhythmias such as PVBs, bigeminies and or ventricular tachycardias (Ben-Haim et al,1992).

9.4.2 Respiratory

Exposure to organophosphorus pesticides by all routes can exert effects on the smooth muscles of the respiratory tract resulting in bronchoconstriction, increased activity of the secretory glands and pulmonary oedema. The immediate cause of death in organophosphate poisonings is asphyxia. Contributing factors are the muscarinic actions of bronchoconstriction and increased bronchial secretions, nicotinic action leading to paralysis of the respiratory muscles and depression of the respiratory center.

9.4.3 Neurological

9.4.3.1 Central nervous system

Depression of the respiratory center can occur. Accumulation of acetylcholine in the CNS is believed to be responsible for the tension, anxiety, restlessness, insomnia, headache, emotional instability and neurosis, excessive dreaming and nightmares, aphathy, and confusion that have been describle after organophosphorus pesticide poisoning. Slurred speech, tremor, generalized weakness, ataxia, convulsions, and coma are the other CNS effects (Echobichon, 1996).

Changes have been associated with a demonstrable depression of plasma or red cell cholinesterase, and are manifest as alterations in psychomotor performance, memory, speech and mood, with features of depression, anxiety, and irritability. Acute confusional psychosis of short duration has occurred following prolonged spraying of diazinon by a farm worker (Milton & Murray, 1988).

Additional neurological investigations may be helpful in elucidating cerebral disturbances: electroencephalographic changes have occurred in organophosphate poisoning and have been considered to represent a specific effect on the mid-brain (Metcalf & Holmes, 1969); computerized cerebral tomography may be of use in the diagnosis and follow-up by cholinesterase inhibition as generalized cerebral atrophy has been demonstrated (Pach et al., 1987).

9.4.3.2 Peripheral nervous system

A few organophosphorus pesticides have produced delayed and persistent neuropathy but this is not the case for phosphamidon.

9.4.3.3 Autonomic nervous system

Both muscarinic and nicotinic effects may occur, depending on the severity of poisoning (see table 9.1.1).

9.4.3.4 Skeletal and smooth muscle

Muscle fasciculation occur and may be followed by profound weakness and eventually flaccid paralysis. The cholinergic nerve endings on smooth muscle and glands are less susceptible than those on skeletal muscle to blocking by an excess of acetylcholine. Therefore, in poisoning, bronchospasm, cramping of the intestinal muscles, and excessive secretions often persist after weakness of the voluntary muscles have become severe.

Contraction of the smooth muscle of the bladder and tenesmus may also occur (Gallo & Lawryk, 1991).

Rhabdomyolysis is a well-known complication of severe poisonings and appears to be also relatively frequent in severe organosphosphorus pesticide intoxications. In the acute phase this may cause acute renal failure and in later stages paresis if not treated correctly.

Gastrointestinal

Gastrointestinal manifestations are usually the first to appear after ingestion and some of them may be due to local anticholinesterase action in the gastrointestinal tract. These symptoms include increased gastrointestinal tone and peristalsis. Nausea, vomiting, abdominal cramps, diarrhoea, tenesmus, and involuntary defecation may develop.

9.4.5 Hepatic

No data available.

9.4.6 Urinary

9.4.6.1 Renal

Rhabdomyolysis is a well-known complication of severe poisonings and appears to be also relatively frequent in severe organophosphorus pesticide intoxication. In the acute phase this may cause acute renal failure and in later stages paresis if not treated correctly (Abend et al., 1994).

9.4.6.2 Others

Symptoms may include strangury and also frequent and involuntary urination due to contraction of the smooth muscle of the bladder.

9.4.7 Endocrine and reproductive systems

Transient hyperglycemia and glycosuria are often found in severe organophosphorus insecticide poisoning (Namba et al., 1971).

Pancreatitis after ingestion of organophosphorus pesticides may be painless and terminate fatally, although all children in one study had a complete recovery (Ellenhorn et al., 1997).

Dermatological

Local effects of dermal exposure include localized sweating and contact dermatitis. It may be associated with fasciculation at the site of contact (Reichert et al., 1978). (See also Section 9.4.13 Allergic reactions).

9.4.9 Eyes, ears, nose, throat: local effects

Exposure to organophosphorus pesticides can have local effects on the smooth muscles of the eyes causing early miosis and blurred vision due to spasm of accommodation, and also conjunctivitis and keratitis. The secretory glands of the respiratory tract, as well as the smooth muscles of the eyes may be affected by minimal inhalation exposure to the organophosphates leading to watery nasal discharge and hyperemia. Acute rhinitis and pharyngitis can also occur (Ecobichon, 1996).

9.4.10 Haematological

No data available.

9.4.11 Immunological

Some deficiency in immune responses has been reported in animals dosed with quantities of organophosphorus pesticides that depressed acetylcholinesterase levels, but not at doses that did not affect acetylcholinesterase (WHO, 1986).

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

Metabolic disturbances may occur in more severe cases. Metabolic acidosis may occur in severe organophosphorus poisonings.

9.4.12.2 Fluid and electrolyte disturbance

Electrolyte and fluid imbalance may occur following vomiting and diarrhoea associated with organophosphorus pesticides poisoning. Hypokalaemia is common in organophosphorus poisoning.

9.4.12.3 Others

No data available.

9.4.13 Allergic reactions

Sporadic cases of contact dermatitis with various organophosphates have been described: however, these appear to reflect individual sensitivities and are not representative of the usual clinical picture of organophosphorus pesticide exposure (Gallo & Lawryk, 1991).

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

Animal studies have shown that organophosphorus pesticides can cross the placental barrier, thus posing potential risk to the foetus; weanlings may also be at risk due to their poorly developed microsomal enzyme systems (Gallo & Lawryk, 1991).

One frequently unrecognized mechanism for the fall in plasma cholinesterase activity is pregnancy. Studies in healthy women demonstrated that cholinesterase levels fall in first trimester of pregnancy (range 17-46%), but they return to normal levels by the third trimester. No mechanism has been given for this phenomenon; however, this fact should be considered when there is an unexplained cholinesterase drop (Howard et al., 1978).

9.5 Others

No data available.

9.6 Summary

Phosphamidon exhibits similar clinical effects with respect to muscarinic, nicotinic and central nervous system effects compared to other organophosphorus compounds except the intermediate and the delayed neuropathy syndrome.

10. MANAGEMENT

10.1 General principles

Treatment of organophosphorus pesticides poisoning should begin with decontamination and resuscitation if needed. Decontamination is vital in reducing the dose of the pesticide absorbed, but care must be taken not to contaminate others, such as medical and paramedical workers. In the case of ingestion, lavage can be performed, and administer activated charcoal. Protect the airways. The patient should be observed carefully during the early stages of treatment because respiratory arrest may occur.

Phenothiazines, parasympathomimetics and antihistamines are contraindicated since they have anticholinesterase activity and may potentiate organophosphorus pesticides toxicity. Central nervous system depressants (e.g., opiates) should also be avoided since they may increase the likelihood of respiratory arrest (Ellenhorn et al., 1997).

Solvent vehicles and other components of the formulated organophosphorus pesticide may complicate the clinical picture and should be taken into consideration.

10.2 Life-supportive procedures and symptomatic/specific treatment

Supportive measures should be directed towards the cardiorespiratory system with particular emphasis on maintenance of cardiac rhythm, blood pressure, and ventilation; the removal by suction of respiratory and oral secretions which may cause respiratory distress; and the oxygenation of the patient. Respiratory arrest may be a feature of organophosphate poisoning (Milton & Murray, 1988). When assisted ventilation is required and a neuro-muscular blocker is needed, the ganglion blocker, suxamethonium, is to be avoided because undue sensitivity to this agent may lead to prolonged respiratory paralysis (Seldon & Curry, 1987). Suxamethonium is normally metabolized rapidly by pseudocholinesterase (Gilman et al., 1985); hence, an alternative neuromuscular blocking agent should be used (e.g. pancuronium bromide).

Organophosphorus pesticides poisoning can be treated with atropine and oximes (see section 10.6).

Severely poisoned patients disconnected from the ventilator when the general condition improves, must be carefully watched for rapid deterioration and development of the Intermediate Syndrome (see section 9.5) during the following few days in the Intensive Care Unit.

Seizures should be treated with diazepam as follows:

Adults:

5 to 10 mg IV slowly over three minutes, which may be, repeated every 10 to 15 minutes (maximum 30 mg).

Children:

0.2 to 0.3 mg/Kg IV slowly over three minutes (maximum 5 mg in children between one month and five years old; maximum 10 mg in children five years old and over).

Some organophosphorus pesticides may cause a delayed peripheral neuropathy. There is no specific therapy for this condition except for symptomatic measures; e.g., physiotherapy.

10.3 Decontamination

Ingested organophosphate should be removed by early gastric aspiration and then lavage, with protection of the airway because they are mostly dissolved in aromatic hydrocarbons; this may be the best remedy in unconscious patients.

Gastric lavage is most effective within 30 minutes of ingestion (but might be still effective up to 4 h post ingestion) as organophosphates are rapidly absorbed from the gastrointestinal tract. Hence, the use of syrup of ipecac as emetic is controversial since vomiting is often delayed. Ipecac is also contraindicated in the case of pesticides dissolved in hydrocarbon solvents.

Administration of oral activated charcoal (preferably with a cathartic such as sorbitol), in conventional doses, may also be considered for reducing further absorption of some organophosphorus pesticides (Haddad & Winchester, 1983; WHO, 1986). If poisoning has occurred by inhalation, the patient should be removed from the source of exposure and given oxygen; the rescuer should also take adequate precautions.

Dermal exposure may be managed by removing and discarding contaminated clothing (particularly leather which absorbs pesticides) into sealed bags and repeated vigorous washing of exposed skin with soap and plenty of warm water. Special attention should be given to washing in skin creases, around the ears, and the external auditory canals, around the umbilicus and genitalia and under the nails (AAP, 1983).

Ocular contamination should be managed by continuous irrigation of the affected eye with clean water for 15 to 20 min. Contact lenses should be removed and irrigated with soap and water.

10.4 Enhanced Elimination

Elimination techniques have not been effective in the treatment of organophosphorus pesticide poisoning.

10.5 Antidote treatment

10.5.1 Adults

Depending on the severity, organophosphorus pesticide poisoning can be treated with:

a) atropine, which is the antidote of choice and is useful in reversing the muscarinic features;

b) oximes, which reactivate cholinesterases inhibited by organophosphorus pesticides.

Atropine acts as a physiological antidote by competitively blocking the action of acetylcholine at muscarinic receptors, and will reverse the excessive parasympathetic stimulation, which results from acetylcholinesterase inhibition. A trial dose of atropine should be instituted on clinical grounds when one suspects organophosphate insecticide poisoning. The fact that large doses of atropine can be given without observable adverse effects is diagnostic of organophosphorus pesticide poisoning.

Oxime reactivators (e.g., pralidoxime, obidoxime) specifically restore cholinesterase activity. The treatment should be administered within 24 to 48 h of poisoning since it is ineffective as an antidote once "ageing" of phosphorylated cholinesterase enzymes, with irreversible loss of function, has occurred. The timing of administration, however, is controversial (see section 10.7).

If absorption, distribution, and metabolism are thought to delayed for any reasons, oximes can be administered for several days after poisoning. Effective treatment with oximes reduced the required doses of atropine.

Atropine

For diagnosis, use an IV dose of 1 mg/Kg and watch for signs of atropinisation (dilated pupils, dry or red skin, confusion, tachycardia, fever, ileus) (Ellenhorn et al., 1997).

For a therapeutic IV dose in symptomatic patients, use 2 - 4 mg/Kg every 15 minutes as needed (Ellenhorn et al., 1997).

Mild atropinisation may be needed for up to 48 hours in cases of moderate toxicity. The administration of atropine as an antidote does not require confirmation by acetylcholinesterase levels. Atropine is rapidly metabolized, and large doses often needed in the first 24 hours. Seriously poisoned patients develop marked resistance to the usual doses of atropine. (Ellenhorn et al., 1997).

The doses and the frequency of atropine varies with each patient, but the patient should remain fully atropinised (signs include dilated pupils, dry mouth, skin flushing). Repeated evaluations of dry mouth and the quantity of the secretions through regular auscultation of the lungs are the only adequate measures of atropinisation in the severely poisoned patient.

Precautions: cyanotic patients should be oxygenated and, if necessary, intubated at the same time that atropine is administered to avoid ventricular tachyarrhythmias. Patients should be weaned slowly from atropine, particularly if they have had atropine for several days.

Adverse effects: possible hypersensitivity to cholinergic stimulation (tremors, rigidity) after prolonged atropine therapy.

Oximes

Pralidoxime chloride, methylsuphate or mesylate should be administered in a dose of 500 mg/h, continuously maintained until clinical improvement is obtained, or 30-mg/Kg-bodyweight bolus IV over 4 - 6 h or 8 - 10 mg/Kg/h IV until full recovery occurs (Ellenhorn et al., 1997).

Precautions and contraindications: the iodide salt of pralidoxime should no longer be used because of the risk of cardiac arrest. Pralidoxime iodide also causes iodism.

Obidoxime: the adult dose is usually 250 mg given by slow IV; IM dosings is possible when the IV route is inaccessible. A second injection is necessary within 2 hours.

Concerning the dosage of oxime, it is essential to adjust the appropriate plasma concentration, i.e. for pralidoxine 20 - 40 mg/L and for obidoxime about 4 mg/L. This concentration is usually attained by a daily dose of 10-15 g P2S or PAMC1 and 0.75-1.0g obidoxime, respectively, either given divided in 4 - 6 single bolus doses or, preferably, by continuous intravenous infusion, following the first loading dose (2g pralidoxime and 0.25g obidoxime, respectively). It is essential for the oxime treatment to be continued until full clinical recovery (usually 2 to 4 days). There are no published data concerning the duration and safety of uses. The administering physician is advised to monitor closely the liver function, with a view to better understanding possible hepatoxicity, particularly with obidoxime.

10.5.2 Children

Atropine

For diagnosis, use an IV dose of 0.015 mg/Kg and watch for signs of atropinisation (dilated pupils, dry or red skin, confusion, tachycardia, fever, ileus) (Ellenhorn et al., 1997).

For a therapeutic IV dose in symptomatic patients, use 0.015 - 0.05 mg/Kg every 15 minutes as needed (Ellenhorn et al., 1997).

Oximes

The dose of Obidoxime is 3-6mg/kg slowly administered IV over at least 5 minutes.

Pralidoxime chloride, methylsuphate or mesylate should be administered in dose of 25 mg/Kg IV for 15 to 30 minutes, followed by a continuous infusion of 10 - 20 mg/Kg/h. The therapy can continue for 18 h or longer, depending on the clinical status (Ellenhorn et al., 1997).

10.6 Management discussion

Main alternatives or controversies

The usefulness of gastric lavage after four hours of ingestion and the effectiveness of activated charcoal for gut decontamination remain to be demonstrated conclusively. The use of emetics may be dangerous due to possible aspiration of the solvent. Whole bowel irrigation has not been demonstrated to be of value and may not be practicable for severely poisoned patients in coma or on a ventilator.

Haemoperfusion is not considered to be generally effective in the management of organophosphorus poisonings.

Atropine is the therapeutic agent of choice for controlling the muscarinic features of organophosphorus pesticide poisoning and should be carefully dosed, according to bronchial and other hypersecretions as well as heart rate to maintain mild atropinisation Although there are no controlled clinical trials, oxime therapy is considered beneficial, in combination with atropine and other supportive treatment. Oximes are ineffective if the OP-AchE complex is aged. Therefore, in poisoning with OP where ageing occurs relatively rapidly, e.g. dimethyl compounds (half-life of ageing 3-4 h) oxime treatment has to be started not later then 12 hours after exposure to be effective. High persisting concentrations of the poison in the body prevent net reactivation by reinhibition of the reactivated enzyme. Nonetheless in the poisoning with OP with slow ageing potential as diethyl OP (half-life of ageing about 30 h) rapid initiation of oxime therapy and continous infusion is indicated even at persisting poison in the body and initially lacking reactivation. After the concentration of the poison decreases in these cases, net reactivation can be expected even 1 week after poisoning.

10.6.2 Differences between countries

While in developed countries the majority of organophosphorus pesticides poisoning cases with pesticides are suicidal, usually involving large doses, the exposures in developing countries are also often accidental due to misuse or inadvertent use and involve more moderate doses. Cases in developed countries are usually rapidly hospitalized and intensive care support is readily available. While health care in developing countries may be accessible to organophosphorus pesticide poisoned patients, intensive care medical treatment facilities may not be. In these latter circumstances, especially where the exposure is not massive, antidotal therapy is particularly useful, in addition to decontamination and supportive care and appropriate management of organophosphorus pesticide-induced convulsions, e.g. with benzodiazepines.

Identification of research needs

There appears to be a correlation between enzyme reactivation and the disappearance of the muscarinic and nicotinic features, i.e. improvement in the clinical condition of the patient, provided that there are no complications. A reliable, simple and cheap method should be established for measuring AChE activity in red blood cells, which can be performed widely using nonsophisticated equipament.

Although clinical observations indicate a possible value of bicarbonate in organophosphorus pesticide poisoning treatment, this needs further investigation both in animal experiments and clinical studies.

Further research is required concerning the therapeutic and adverse effects of the oximes in organophosphorus pesticide poisonings.

There is a clear need for systematic collection of harmonized data on organophosphorus pesticide poisoning cases, including long-term follow-up, with a view to comparing cases, situations and treatment regimens, and also being able to pool data on exposure to the same substances. There is also a need for a universally agreed severity grading system for reporting cases. It would be further useful to consider developing criteria for predicting outcome which takes into consideration both the organophosphorus pesticide and the dose, as well as the clinical features of the poisoning, with a view to identifying the optimum treatment procedures for the particular case. The IPCS and its partners in this area of severity grading are undertaking the work, and case data harmonization and collection should be further promoted.

Further research is needed to better understand the Intermediate Syndrome, as well as the longer-term neurological and other sequelae, and to relate these to the biochemical and physiological evolution of organophosphorus pesticide poisoning.

It is recommended that the health sector in each country make appropriate plans for undertaking studies in follow-up to major incidents involving exposure by organophosphorus pesticides to many people. International guidelines for data collection should be developed in order to promote comparability of data.

11. ILLUSTRATIVE CASES

11.1 Case reports from the literature

Adults inhalation exposure (occupational)

Midtling et al.(1985) studied cauliflower workers who experienced acute poisoning by OP insecticides mevinphos (Phosdrin) and phosphamidon (Dimecron). The workers had begun work tying leaves over the heads of the plants only six hours after the field had been sprayed. Sixteen such workers were followed in weekly clinics with interviews and plasma and red blood cell (RBC) cholinesterase levels. Comparatively non-persistent symptoms (i.e., they had typically resolved by 10 weeks) included nausea, dizziness, vomiting, abdominal pain, ataxia, and night sweats or insomnia. Symptoms that persisted in at least three of the 16 subjects at 10 weeks or more included blurred vision/vision disturbance (56 percent), headache (25 percent), anxiety (41 per-cent), weakness, and anorexia. Symptoms persisted for up to 10 weeks, varying by symptom and individual. Six of the subjects initially had RBC AChE values within the normal laboratory range, but follow-up testing showed activity to have been significantly inhibited. (Midtling, 1985)

One case of poisoning has been reported in which the only recognized exposure was through the uprooting and cutting of shrubs that had been sprayed with phosphamidon 2 weeks before. The 50-year-old man had worked without gloves for only 1 day. In the afternoon following exposure, he suffered dizziness, repeated severe vomiting, and eventually collapsed. When brought to the hospital, he was sweating and showed excessive lacrimation. After minimum treatment, the patient regained full consciousness in a few hours, regained full strength after 2 days and recovered completely. (Hayes, 1991; IPCS, 1993)

Adult, dermal exposure

Two workers were accidentally drenched in 50% phosphamidon and six others suffered soaked feet and splashes to the arms, hands and clothing when a pipe burst. The workers immediately washed with soap and water. They suffered short-term gastric pain, headache and eye irritation; none required an antidote and all returned to work (Hayes, 1991).

11.2 Internal cases

(To be added by the Centre).

12. ADDITIONAL INFORMATION

12.1 Availability of antidotes and antisera

(Each Centre to complete).

12.2 Specific preventive measures

It is essential that persons intending to use organophosphorus pesticides be provided with adequate health precautions and other safety instructions prior to usage. This information should be provided by the manufacturer in the form of either an information leaflet or a label attached to the pesticide container.

Protective clothing is important. Organophosphorus pesticides can be dermally absorbed, resulting in poisoning. The risk is greatest in hot weather when the user is sweating. Protective measures may include a long-sleeved shirt, long trousers or overalls, and a hat of some sort. The more toxic organophosphorus pesticides will require gloves, waterproof outerwear (preferably made of heavy PVC), and rubber boots. The label should list these details.

Clothing worn during spraying should be washed daily after use. Contaminated clothing should be washed separately from the general wash to avoid croos-contamination. When working with liquid concentrates, there is often a danger that they will splash the eyes. This not only can damage the eyes, but also can allow a significant amount of the chemical to be absorbed into the bloodstream. Simple goggles or a face shield will protect against this danger. Eye protection is most important if contact lenses are worn, because the chemical may seep in behind the lenses. The lenses must be removed before the eyes are washed, and in the time it takes to remove them, serious damage can occur. With some pesticides, a respirator may be required. The label will specify when this is necessary. The correct canister or cartridge must be used.

Greater precautions are necessary when mixing the concentrated material than when spraying. Measurements should be accurate and spillages should be cleaned up promptly. Mix the chemicals carefully, using a stick or paddle. Ensure that there is minimal skin exposure by wearing gloves. If any concentrate is spilled on the skin, was it off as soon as possible.

The hazards of spraying increase dramatically on windy days because there is an increased risk of inhaling spray drift or contaminating the skin. Also, the risk of drift on to other properties or crops is increased.

Always wash hands before eating, drinking or smoking. After spraying, shower and change clothing.

By preference, all chemicals should be stored in a locked shed, out of the reach of children and animals. Chemicals should also be kept away from work areas and separate from other stored materials such as animal foods. Always leave chemicals in their original containers. If they must be transferred to another container, ensure that it is one not normally used for food or drink. This secondary container should be labeled properly and be of a variety that is not likely to leak.

Following spillage, empty any of product remaining in damage / leaking container(s) into a clean empty container(s), which should the be tightly closed and suitable labeled. If it is a liquid product, prevent it from spreading or contaminating other products, vegetation, or waterways by building a barrier of the most suitable available material, e.g., earth or sand. Sweep up the spillage with sawdust, sand, or earth (moisten the powders), and place it in a suitable container for disposal. Decontamination and clean-up procedures utilise the instability of organophosphorus pesticides products with alkali. The following procedures has been developed for contaminating spills of organophaphorus pesticides (Shell, 1982):

Apply a 10% sodium carbonate (washing soda solution) to the contaminated area, brush well in, and leave for leave for at least 8 h. Absorb into sawdust, sand, or earth and then rinse. Contaminated sawdust, sand, earth and containers shouldbe burnt in a proper incinerator. When no incinerator is available, bury in an approved dump or in an area where there is no risk of contamination of surface water. Before burying, mix liberally in sodium carbonate (washing soda) crystals to hydrolyse the product.

It is essential that any personnel involved in the procedures be adequately protected before beginning] clean-up operations.

Empty containers must be disposed of carefully, so as to ensure that rivers, streams, and other water source are not polluted, and that people or animals are not exposed to residues of concentrate. Crushing or burning, followed by burial, is generally the best method.

Workers involved in harvesting crops must adhere carefully to re-entry standards which have been set in order to prevent the asymptomatic depression of cholinesterase and the possibility of the development of an insidious, but low-level chronic intoxication syndrome.

For workers who are exposed on a regular basis to organophosphorus pesticides, it is advisable for them to have a pre-employment examination to determine their baseline cholinesterase levels. These tests should be undertaken on a regular basis to determine whether exposure is occurring with sub-clinical findings. When the red blood cell or plasma cholinesterase fall below 25% of baseline levels, workers should be taken off the job and should not return to work until their cholinesterase levels return to normal.

12.3 Other

No data available.

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14. AUTHOR (S), REVIEWER (S), ADDRESS (ES), DATE (INCLUDING EACH UP-DATE)

Authors:

Dr. Luiz Querino de A.Caldas
Alessandro Pinheiro Olimpio de Souza -collaborator.
Alexandre Mansão dos Santos –collaborator
Poison Control Centre/ University Hospital
Federal Fluminense University
Rua Marques do Paraná, 303
Niterói - Rio de Janeiro
24.033-900 – Brazil
Tel/Fax: 552127170521/552127170148
Email: ccilqac@vm.uff.br

Date:

31st august 2001

Peer Review:

Awang R, Besbelli N and Caldas LQA

Date

18th September 2001, Edinburgh


See Also:
        Phosphamidon (ICSC)
        Phosphamidon (PDS)