Toxicology of pesticides: organophosphates and carbamates

TOXICOLOGY 2

COURSE 1

CONTENTS

PESTICIDES

• INSECTICIDES
• ORGANOPHOSPHATE INSECTICIDES
• CARBAMATES

Emanuela Badea assistant professor | DVM | PhD | MSc Faculty of Veterinary Medicine of Bucharest UASVMI.

PESTICIDES

Humans and animals have always been subjected to the action of chemical compounds, both natural ones, that occur in the environment and those introduced as a result of the development of the industry. The list of more than two million known chemical compounds is completed annually with approx. 25,000 new products. The residues of many of them enter the environment, polluting the water, the air, the soil.

An important position among the necessary chemical compounds, but still polluting for the environment, is occupied by pesticides.

The first documents relating to the use of pesticides date back to 2500 BC and come from Sumerians who smeared their bodies with sulphur compounds, hoping to act repellent on insects. Many pesticides used in the mid-20th century were produced as a result of technological development sped in the production of chemical weapons during the Second World War.

The permanent increase in agricultural production, as well as the raising of the productive potential of agricultural crops, require the proper protection of cultivated plants against diseases and pests.

The application of pesticides in agriculture, veterinary medicine, in the household, aims to improve the quantity and quality of food, fodder and industrial products, the protection of animals against parasites, etc. But along with the undeniable benefits of using pesticides, they also have a number of drawbacks. Being toxic to a life form (the pest), implicitly, pesticides represent a risk of harm to humans, animals, microflora, etc. A particular place is occupied by pesticides with high persistence, hard to biodegradable, the most dangerous of which are organochlorine and organophosphate insecticides.

"Silent Spring", perhaps the best-known book on pesticide use, was published in 1962, leading to a spread of concern about DDT, an organochlorine insecticide, one of the most popular pesticides. Subsequent research found traces of DDT in mother's milk, and this compound has been banned in many countries since the late 1970s.

Worldwide, agricultural losses caused by pests amount annually to 35-40% of crops (of which approx. 14% due to insects, 12% due to fungi, and 10% due to weeds).

Pesticide classification

Depending on the destination of the pesticides, they can be divided into the following groups:

• insecticides, molluscicides, rodenticides - chemical means for the control of animal pests;
• fungicides and fungistatics - chemical means for the control of fungi;
• herbicides - chemical means for weed control;
• growth regulators - chemical means of stimulating or inhibiting the vital processes of plants;
• attractants - chemical means for luring pests;
• repellents - chemical means for the rejection of pests.

1By their chemical class, pesticides are:

• inorganic (e.g. arsenic compounds, fluorinated derivatives, sulphur, etc.);
• organic (e.g. organochlorine insecticides, organophosphate insecticides, pyrethroids, etc.).

By degree of toxicity, pesticides can be:

• group I - highly toxic substances (LD50 < 50 mg/kg) - e.g. all organochlorine insecticides and some organophosphate insecticides.
• group II - very toxic substances (LD50 = 50-200 mg/kg) - e.g. most organophosphate insecticides.
• group III - moderately toxic substances (LD50 = 201-1000 mg/kg) - comprises most pesticides.
• group IV - substances with low toxicity - contains pesticides not harmful to fish.

By form of use, pesticides can be powders, granules, solutions, suspensions, aerosols, vapours, etc.

I. 1. INSECTICIDES

I. 1. 1. ORGANOPHOSPHATE INSECTICIDES

The toxicity of organochlorine compounds and especially their dangerously long persistence has stimulated interest in the search for other products which, while preserving their pesticide effectiveness, no longer possess harmful properties to animals.

This research has resulted in the discovery of a very long series of organophosphate insecticides, which are esters, amides and simple derivatives of phosphoric acid and thiophosphoric acid.

Since 1930, when they began to be used extensively, organophosphate substances (which arise from the reaction between an alcohol and phosphoric acid) have been used in agriculture and the household mainly as insecticides, fungicides, rodenticides, etc. (e.g. in the USA alone there are over 25,000 organophosphate products with different uses). During World War II, multiple countries, including Germany, the United States, the United Kingdom, and the Soviet Union, were engaged in research and development related to chemical weapons, including organophosphate substances. In addition, in the Tokyo subway attack of 1995 the substance used was also an organophosphate compound, called sarin. There are authors who estimate that only in developed countries of the world around 20,000 people die every year from pesticide poisoning.

Organophosphate insecticides are used as insecticides and contact vermicides, with systemic or topic action, as insecticides for plants, nematicides for soil, fungicides, herbicides, rodenticides, chemosterilizing and repellents for insects.

They are, however, some of the most dangerous chemicals used in agriculture. Organophosphate insecticides are still very numerous and outnumber organochlorine insecticides, and their number is constantly increasing.

2Some of these substances have or have had medical indications in the treatment of dementia, Alzheimer's disease, poliomyelitis sequelae, schistosomiasis or myasthenia gravis, the first organophosphorus synthesized in 1870 being used in the treatment of glaucoma.

The names of organophosphate insecticides present difficulties since a compound can sometimes have 5-6 synonyms. The name of organophosphates contains the full name or part of the name of the chemical class to which the compound belongs. The name of organophosphate insecticides may contain the word "phosphate" or part of it ("phosph", "pirophos", etc.) or other names derived from the word "phosphorus" (e.g., Clorpirifos, Pirimifos, Parathion, Diazinon, etc.).

Causes of intoxication

The causes of intoxication may be represented by:

• consumption of contaminated feed in the process of growing and developing
• contaminated feed during transport, storage or operations carried out on the farm
• accidental spraying of feed with organophosphate insecticides
• drinking water contaminated by spillage or rinsing containers or sprinkler pumps in which organophosphate insecticides have been kept; empty containers in which organophosphate insecticides have been stored cannot be considered to be "empty" (perfectly cleaned)
• storages sprayed with organophosphate insecticides or those in which organophosphate insecticides have been stored
• animals' access to the storage places of organophosphate insecticides waste and packaging
• treatment with overdosed systemic anti-parasitic organophosphates or repeated treatments

Toxicokinetics

Liquid organophosphate insecticides are rapidly absorbed by all routes. The respiratory route is the most severe route, the toxicant reaching the bloodstream immediately. The cutaneous route is easy crossed by the most of organophosphate insecticides, with the exception of Schradan and Malathion, and the digestive route is an important absorption area.

After absorption, some compounds exert their anticholinesterase action directly; others are decomposed into substances that themselves exert anticholinesterase action, giving rise to an insecticide-cholinesterase complex, most of the time very stable.

In general, organophosphate compounds are metabolized in tissues by various mechanisms (hydrolysis, oxidation, reduction, polymerization).

For example, organophosphate insecticides with direct anticholinesterase action are hydrolysed, always resulting in highly toxic products, whereas Parathion is metabolized by oxidation processes, being converted to Paraoxon (in the liver), with strong inhibitory action on cholinesterase.

Instability of organophosphate metabolites in tissues often makes their toxicological detection virtually impossible.

Excretion of organophosphates and their metabolites is mainly through urine, bile and faeces, respectively. In general, they are not eliminated through milk, with the exception of Parathion

3(which can be detected in milk in quantities that may cause inhibition of erythrocyte cholinesterase in infants) and Etrolene (syn. Fenchlorphos, which is eliminated through cow's milk, making it prohibited for consumption). Given that some research has led to the finding that other organophosphate insecticides can be detected in milk within the first 24 hours (sometimes even 8-10 days), it is not recommended to use organophosphate insecticides in dairy cows.

The lethal dose is generally low, regardless of the exposure route.

Toxicity factors

Toxicity depends on:

• target specie (there are differences between insects and non-insects; generally, effects last longer in target insects, than in non-insects/mammals)
• the vehicle used for compound dispersion
• exposure route
• compound characteristics
• other factors o specie o age o sex o preexisting conditions

Toxicity is not identified in all species. Youth is much more sensitive than adults (e.g., Parathion - LD, per os, in calves is 1.5 mg/kg, and in adults it is 60 mg/kg). Sensitivity also differs by sex, with females more susceptible to Diazinon, Parathion, Potasan and EPN, but have resistance to Schradan and Dimefox.

Calves are more sensitive to organophosphate insecticides if the feed is high in protein.

Parathion and its derivatives can cross the placenta, reducing the cholinesterase activity of foetuses by 85%.

A number of physicochemical factors influence the toxicity of organophosphates; thus, the toxicity is decreased if they are degraded by the sun, water, alkalis or metal ions (e.g., Cu, Fe). Increased toxicity can occur through activation during storage, where isomers' higher toxicity causes serious poisoning. Chemical alteration (during storage) can lead to transformation into another much more toxic pesticide (e.g., Trichlorphon at pH 7-8 turns into Dichlorphos). The increased temperature increases the toxicity of Parathion, while the low temperature increases the toxicity of Malathion.

Toxicodynamics

Organophosphate insecticides are cholinesterase inhibitors, i.e. inhibitors of acetylcholinesterase and pseudocholinesterase. Acetylcholinesterase is the enzyme that almost instantly hydrolyses acetylcholine at cholinergic nerve endings and neuromuscular junctions.

Pseudocholinesterases are enzymes capable of hydrolysing acetylcholine, which are found in the brain, liver and blood plasma.

Organophosphate insecticides block cholinesterase, with which they form a stable complex which renders the enzyme unusable. The result is synaptic accumulation of acetylcholine, with exaggerated activation of muscarinic and nicotinic cholinergic receptors, which causes disturbance of nervous excitability and transmission of nervous influx.

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