Organophosphate insecticides

Organophosphate (OP) compounds are the most widely used group of insecticides in the world. Their acute toxicity causes a hazard both to professional and amateur users. In the UK, this has led to concern over OP use in sheep-dips, in agriculture generally and in the home. OPs are the commonest subject of questions asked by members of the public calling the Pesticides Trust [now PAN UK] information line. We have produced this fact sheet on OP insecticides in response to these concerns, and because this group has many similar properties.

What are OPs?
OPs were first recognised in 1854, but their general toxicity was not established until the 1930s. Tetraethyl pyrophosphate (TEPP) was the first OP insecticide, which was developed in Germany during World War Two as a by-product of nerve gas development(1).
   
OPs are all derived from phosphoric acid. They are generally among the most acutely toxic of all pesticides to vertebrate animals. They are also unstable and therefore break down relatively quickly in the environment. Altogether, over 100,000 OP compounds have been screened for their insecticidal properties, of which over 100 have been developed for commercial use. The Pesticides Trust holds details of 111 OPs on its active ingredient database.
   
OPs are nerve poisons which kill the target pest (usually insects). Most OP pesticides are insecticides, although there are also a number of related herbicide and fungicide compounds.

Uses and usage
OPs are marketed by many of the world's major agrochemical companies. Some of the main agricultural products are Hostathion (triazophos), Metasystox-R (oxydemeton-methyl), Dursban and Lorsban (chlorpyrifos), Sumithion (fenitrothion) and Actellic (pirimiphos-methyl)(2). OPs have a wide range of pest control applications as contact, systemic and fumigant insecticides. Whilst widely used in agriculture, they are also used against household and catering establishment pests. They are used against head lice in humans and a number of ectoparasites in domestic animals. The aerial application of OPs (such as dimethoate) is permitted in the UK to control cereal and vegetable pests. Recently OPs have been in the news because of health concerns following their use in sheep dips, and as insecticides in military premises, on equipment and even on personnel during the Gulf War. The latest issue of Current Research Monitor provides a full list of OPs on the market.

World market
In 1992, global OP sales were US$ 2,880 million out of a total insecticide market of US$7,400 million. This makes OPs the most widely used group of insecticides, worth nearly 40% of the market - and they are likely to maintain dominance throughout the 1990s(3).
   
In the cotton growing industry where 22.5% of all insecticide use occurs, synthetic pyrethroid use overtook OP use in the early 1990s. By 1994, the synthetic pyrethroids accounted for 42.5% of the cotton insecticide market, with OP products still approaching 40%(4).

Developing countries
In developing countries OPs are widely used because they are cheaper than the newer alternatives. The Prior Informed Consent (PIC) procedure identifies pesticides banned, severely restricted or which cause 'problems under conditions of use under in developing countries' (PCU) to enable developing countries governments to prohibit imports if required. The PCU category is the hardest to identify as no regulatory decision has been made by a government. But, of the five that have now been identified all are OPs: parathion, methyl parathion, phosphamidon, monocrotophos and methamidophos.

UK usage
UK Farmers and growers regularly use OPs. They treated over a million ha with these products during 1994, representing a third of all insecticide applications. By weight of active ingredient, OPs represent about 60% of the UK arable insecticide market. A total of 395 tonnes were applied on arable farms in Britain during 1994(5). Data on OP usage by value of sales is not readily available.
   
Between 1992 and 1994, usage of dimethoate increased by 89%, and chlorpyrifos by almost eight times - both were used to control aphids and orange wheat blossom midge levels, which had been unusually high(6).

Acute toxicity
OPs are generally acutely toxic. However active ingredients within the group possess varying degrees of toxicity. Minton and Murray have divided OPs into three groups. The first most and toxic group, e.g. chlorfenvinphos, has an LD50 in the range 1-30 mg/kg. The LD50 range for the second group, e.g. dichlorvos, is 30-50 mg/kg, and the least toxic group, e.g. malathion, has a range of 60-1,300 mg/kg(7).
   
OPs work by inhibiting important enzymes of the nervous system which play a vital role in the transmission of nerve impulses. Nerve impulses usually travel along neurons (nerve cells) by way of electrical signals. However, at a junction between two neurons (a synapse) and between a neuron and a muscle (neuromuscular junction) the impulse is transmitted in the form of a chemical substance (neurotransmitter). The neuro-transmitter operating in the autonomic nervous system, neuromuscular junctions and parts of the central nervous system is acetylcholine which is released by cholinergic neurons. It is broken down and inactivated in milliseconds by the enzyme cholinesterase. With exposure to OPs, the enzyme is unable to function and a build-up of acetylcholine occurs, which causes interference with nerve impulse transmission at nerve endings.
   
In humans, poisoning symptoms include: excessive sweating, salivation and lachrimation, nausea, vomiting, diarrhoea, abdominal cramp, general weakness, headache, poor concentration and tremors. In serious cases, respiratory failure and death can occur.
   
Other consequences may follow high acute exposures. From one to several weeks after exposure, organophosphate - induced delayed neuropathy (OPIDN) [nerve damage] may set in. This may begin with burning and tingling sensations and progress to paralysis of the lower limbs.

Chronic toxicity
Neurological effects

Much attention has been focused on the chronic effect associated with occupational exposure of OP sheep dips. This is because exposure levels in this sector have been high. Exposure levels are also high in developing countries, which may mean chronic effects on sheep dippers in the UK are similar to those experienced generally in developing countries.
   
A number of studies have shown behavioural, psychological or electro-physical changes after exposure of humans or experimental animals to a number of OPs. There are also a number of studies which show no association(8).
   
Epidemiological studies have been carried out on the long term effects of OPs. One by Savage(9) showed OPs caused adverse response during psychometric testing and a test of motor reflexes, although it is not clear whether these effects were as a result of severe acute exposure. Another study carried out the by the Institute of Occupational Medicine in Birmingham suggested that subtle changes in the nervous system may be associated with exposure to OPs(10).
   
After assessing the available data, Dr Tim Marrs, Senior Medical Officer at the Department of Health concludes that we have not yet really answered the question: "is there a long-term effect of OPs on the central nervous system at sub-convulsive (low) doses?"(11).
   
A different view is taken by Dr Goran Jamal, a consultant neurophysiologist at the Southern General Hospital, Glasgow . He says there is experimental evidence that OPIDN may be more frequent among the users of OPs than previously thought. Dr Jamal notes: "Exposure to very small doses could result in cumulative poisoning which may produce sub-clinical effects initially but render the individual susceptible to further toxic insults, thus producing progressive effects on the nervous systems(12)."
   
It is clear that more extensive research of low level occupational exposure to OP compounds is required. Little is known about the long-term neurological consequences of mild and repeated exposures which may have important health risks for those using these compounds.

Other effects
Psychiatric effects: Research reports have suggested that exposure to agricultural use of OPs produces depression, a major risk factor in suicides(13). Research from Spain has shown that suicide rates are higher in areas of greater OP use(14).

Cardiac effects: A number of studies have drawn attention to cardiac effects associated with occupational exposure to OPs(15). In a Health and Safety Executive publication (MS 17 December 1980) there is mention of "slowing of the heart with decreased cardiac output."
   
Professor William McKenna of St George's Hospital, London, believes that myocarditis (akin to a heart attack) can be caused after exposure to propetamphos, an OP sheep dip(16).

Teratogenicity (birth defects): There is conflicting evidence concerning the teratogenic effects of OPs in animals. Data on the effects of OP occupational exposure on pregnant women and their foetuses are not available(17).

Cancer: There is little evidence of strong mutagenic or carcinogenic effects in mammals from exposure to OPs. The exception is dichlorvos which the US EPA classifies in its C category as a possible human carcinogen, in which there is limited evidence of carcinogenicity in animals in the absence of human data(18).

Eye defects: Research from Japan and the US has found OP exposure during use in agriculture is related to an increase incidence of myopia (short-sightedness) and a more advanced ocular disease syndrome, Saku disease(19).

Areas of further research: There may be other chronic effects associated with OP exposure which are receiving current research interest. Firstly, there may be important but as yet un-characterised protein targets of OPs. Secondly, OP exposure may be affecting bone cells. The hypothesis is that chronic exposure to OPs carries the risk of developing severe metabolic bone disease(20).

Poisoning statistics
An accurate assessment of the numbers of people affected by OP use and misuse is impossible. The World Health Organisation estimates that there are in total three million acute severe cases of pesticide poisonings and 20,000 unintentional deaths each year, mostly in developing countries21. Of these poisonings a large (but unknown) proportion involves OPs. Poisoning data on OPs is difficult to come by in developing countries. An assessment by the Pesticides Trust revealed azinphos methyl, chlorpyrifos, methamid-ophos, methomyl, monocrotophos, parathion and phosphamidon have caused a number of health concerns in a range of developing countries(22).
   
In 1995, there were 15,300 pesticide poisoning cases in China, 91% of which were caused by OPs (67% were caused by just three OPs, parathion, methamidophos and omethoate)(23).
   
In 1995, Ciba withdrew its product Miral 500 CS product (isazofos) from 16 countries following three serious accidents in Africa and Latin America linked with its use(24).
   
Kyle Steenland at the US National Institute for Occupational Safety and Health maintains that acute poisoning from OPs remains a problem in industrialised countries. An estimated 3,000-5,000 cases of accidental poisoning occur annually in the US, according to the Environmental Protection Agency (EPA)(25).
   
An FAO study in Indonesia found that most symptoms associated with pesticide toxicity were significantly greater in the time of year when spraying occurred. Farmers sprayed often using mixtures of hazardous pesticides, and over 50% were OPs. This study was typical of OP poisoning in developing countries where it is impossible to match specific pesticides with symptoms(26).

Resistance
Resistance to OPs, first reported 14 years after their introduction, numbers 260 insect and mite species. Resistance to carbamate insecticides has appeared after five years, partly due to conditioning by previous OP exposure(27). In November 1996 the first European case of sheep scab mite resistance to an OP (propetamphos) sheep dip occurred(28).

OPs in food
OPs are regularly detected at low levels in a range of food items. Usually residue levels are below the statutory maximum residue levels. OP residues found in UK carrots has proved a recent exception. Ministry of Agriculture, Fisheries and Food figures for 1995 showed that 1-2% of carrots contain OP residues up to 25 times higher than expected. OPs implicated included chlorfenvinphos, quinalophos and triazophos. In the higher residue samples, the acceptable daily intake was exceeded by up to three times(29).

OPs in the environment
OPs tend not to persist or bioaccumulate in the environment. They do however figure in many official cause-for-concern priority lists because of their toxicity, especially to the aquatic environment.
   
All OPs are part of the EU Black List, a priority list of the harmful chemicals set out in EU Directive 76/464/EEC which aims to protect the aquatic environment. The UK Department of the Environment classified dichlorvos, fenitrothion and malathion as Red List substances in 1989. The use of these chemicals should be reduced in order to combat environmental pollution(30).

Conclusion
By the late 1970s, the use of OPs began to over-take the organochlorine insecticides which included DDT. While organochlorines were relatively safe to use, their problem was persistence in the environment and detection in the human food chain. OPs on the other hand are more acutely toxic, but, do not persist in the environment beyond a few months. So with the switch from organochlorines to OPs, it can be assumed that the consumer has benefited at the expense of the pesticide operator.
   
In terms of sheep dips in the UK and OP use in developing countries, safer non-OP methods should be brought forward as a matter of urgency to reduce the risks to operators. There should be a moratorium on OPs until safer alternatives exist, and OP use should be severely restricted in developing countries where protective clothing cannot always be guaranteed.

References
1. Minton, N.A. and Murray, V.S.G., A review of Organophosphate Poisoning, Medical Toxicology, 1988, 3: 350-375.
2. Agrow's Top 25, 1995, Agrow, PJB Publications, 254pp.
3. Agrow No 199, January 7 1994.
4. Cotton: the crop and its agrochemicals market, Allan Woodburn Associates, Edinburgh, 1995.
5. Pesticide Usage Survey Report 127: Arable farm crops in Great Britain 1994, MAFF publications, 97pp.
6. Ibid.
7. Op. cit. 1.
8. Marrs, T.C., Organophosphate poisoning, Pharmaceutical Therapy, 1993, 58:51-66.
9. Savage, E.P., et al, Chronic neurological sequalae of acute organophosphate pesticide poisoning, Archives of Environmental Health, 1988, 43:223-227.
10. Stevens, R and Spurgeon, A., Neuropsychological effects of long-term exposure to OP sheep dips, Lancet, Vol. 345, May 6 1995.
11. Op cit. 7 .
12. Ibid.
13. Davies, D.R., Organophosphates, affective disorders and suicide, Journal of Nutritional & Environmental Medicine, 1995, 5:367-374.
14. Parron, T., et. al., Increased risk of suicide with exposure to pesticides in an intensive agricultural area: A 12-year retrospective study. Forensic Science International, 1996, 79:53-63.
15. Pesticides News No 31, March 1996, p11.
16. Ibid.
17. Op. cit 1.
18. US EPA, 1996.
19. Dementi, B., Ocular effects of organophosphates: a historical perspective of Saku disease, Journal of Applied Toxicology, 1994, 14:119-129.
20. OP briefing, OP Information Network, August 1996.
21. WHO/UNEP, Public Health Impact of Pesticides Used in Agriculture, 1990.
22. Dinham, B, The Pesticides Hazard, The Pesticides Trust [now PAN UK], 1993.
23. Shuyang Chen and Peipei Yap, Heavy OP poisoning toll in China, Pesticides News No 32, June 1996.
24. Op. cit. 2. p54. [Agrow's Top 25]
25. Steenland, K, Chronic neurological effects of organophosphate pesticides: subclinical damage does occur, but longer follow studies are needed, British Medical Journal, 25 May 1995.
26. Hirshhorn, N., Study of the Occupational Health of Indonesian Farmers who spray Pesticides, the Indonesian National IPM Program, FAO, Jakarta, August 1993.
27. Green., M., et. al., Managing Resistance to Agrochemicals, ACS Series 421, US, 1990, 496pp.
28. Farmers Weekly, 8 November 1996.
29. Consumer risk assessment of insecticide residues in carrots, Pesticide Safety Directorate, York, 1995.
30. The List of Lists.

[This article first appeared in Pesticides News No.34, December 1996, p20-21]