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1. General introduction to PBO. 1.1 Introduction
PBO was originally developed as a synergist for Pyrethrum, the most important insecticide prior to World War II for controlling insect vectors of human diseases such as malaria and dengue fever. The availability of a synergist was important because there were limited supplies of Pyrethrum available.
PBO was first synthesised in 1947 (Wachs, 1947) and was based on the discovery that sesame oil, a known synergist of pyrethrum, was active because of the presence of the methylenedioxyphenyl (MDP) group. In the following two years extensive toxicological testing was undertaken which, together with all the testing over the past 50 years, led to Breathnach (1998) stating that ‘the safety of PBO appears to be extremely high’. In addition, for over 30 years formulations containing over 1.0% PBO have been applied to human skin without reporting of adverse effects; various studies have indicated that human dermal penetration is less than 3%. The safety of PBO is such that the European Economic Community has listed PBO in Annex II of Council Regulation (EEC) No: 2377/90 for bovine, ovine, caprine and equidae topical use only. The significance of the listing in Annex II is seen from their description of its constituent chemicals: ‘where, following an evaluation of a pharmacologically active substance used in veterinary medicinal products, it appears that it is not necessary for the protection of public health to establish a maximum residue limit’
Over the last fifty years a number of other synergists have been synthesised but PBO has remained dominant in worldwide usage. This is because PBO has three advantages: first, it offers minimal environmental impact since it easily degrades in bright sunlight (yet is stable in grain protection formulations for long term bulk storage); secondly, it has excellent solvent properties such that the insoluble material in Pyrethrum which tends to clog spray equipment, is readily dissolved in PBO; and thirdly, it offers a significant advantage in the formulation of modern pyrethroids such as Deltamethrin that have low solubility in hydroxy solvents.
1.2. Mode of Action
The synergistic mode of action of PBO is generally believed to be a function of its ability to act as a substrate, an inhibitor and an indicator of microsomal P450 in mammals and insects. Because of this mode of action, PBO has been widely used in pesticide toxicology studies for determining whether P450-dependent mono-oxygenation is involved in insect resistance (Raffa and Priester, 1985).
Recent studies of two cotton pests in Australia (Helicoverpa armigera and Aphis gossypii) showed, however, that PBO interacts with resistance-related esterases (Gunning et al, 1998). Clearly there is more to discover about this synergist.
PBO also has significant toxic effects when used on its own on mites and some ticks such as the house dust mite and American house dust mite (Eremina and Stepanova, 1995). In addition, PBO has been found to have potential for controlling cotton whitefly (Bemisia tabaci) which has developed resistance to most conventional insecticides (Devine and Denholm, 1998).
PBO has also been found effective in the treatment of benzimidazole-resistant abomasal nematodes in sheep when used in combination with fenbendazole: when used alone PBO had no effect and fenbendazole alone had less than 8% efficacy but together the combination gave over 97% control. This action is thought to be the result of PBO inhibiting the oxidative conversion of fenbendazole into inactive metabolites.
1.3. Manufacture
There are five main manufacturing sites in the world of which the largest is Endura’s, our parent company, with plants in Bologna and Ravenna. Other manufacturers are based in Japan, Brazil and two in the USA; total world production is about 1800 tonnes per year.
A new innovation from Endura is the synthesis of the main starting material, which up till now has been a natural product, so that supply can increase with demand and avoid the inflationary prices that so often occur when there is a shortage. As an indication of the great strides in the manufacturing process and quality, the purity of the technical product has risen from 80% in the early days of manufacture to the present-day 94%.
1.4. Usage
During the last 50 years of use the main application of PBO remains its synergism of pyrethrum extract. However, PBO has also been successfully used with a range of newer, synthetic, pyrethroids such as bioallethrin, permethrin, bioresmethrin and deltamethrin. Nowadays hundreds of formulations containing PBO are used worldwide in homes, on pets, farm animals and extensively in the food industry.
Insect resistance to insecticides has become more common so that usage of PBO is increasing to overcome the resistance. Laboratory studies have shown that PBO has a greater action on resistant strains than non-resistant insect strains. In a very few circumstances PBO does not effect the control of resistant strains and there are examples of antagonism when mixed with two organophosphorus insecticides.
PBO has made a significant contribution to the protection of stored grain in tropical and sub-tropical regions where grain pests are endemic. As far ago as 1947 the use of PBO with Pyrethrum was begun in the USA and became widespread by the early 1950s. This was followed by the use of synergised formulations in Australia and South Africa, first based on Pyrethrum and later using Bioresmethrin and Deltamethrin.
PBO has also been found to synergise many insecticides against garden pests such as aphids and use has been made of PBO with pyrethrum in certain horticultural crops in the USA. Also in the USA, PBO has been used to control Colorado Beetle and in Turkey, to control mosquitoes.
In recent years a major usage of PBO has emerged in Australia as the synergist in a national insecticide management strategy for delaying onset of further resistance in the cotton bollworm (Helicoverpa armigera).
1.5. The PBO Task Force
The cost of providing the data required by regulatory authorities around the world is very large, estimated at about $10million for each pesticide ingredient, so that many small specialist companies cannot afford the regulatory process when acting alone. Because of this, such companies have got together with their competitors and major users to form ‘Task Forces’ to share the costs of regulation and producing new data. This has happened with PBO such that the PBO Task Force has successfully obtained registrations in the USA without breaching anti-trust legislation. The PBO Task Force studies, discussions and conclusions have also been published (Glynne Jones, 1998) to make the information available to all formulators and users of PBO.
1.6. The Future?
PBO is certainly a chemical for the 21st Century with its ability to overcome resistance in insect pests and as a way of reducing the amount of insecticide applied to crops. However, it is unfortunate that the trend in regulation, particularly in the European Union, is moving to greater complexity and greater cost but reduced flexibility so that for companies to reformulate their products to make them more effective but with reduced environmental impact, is becoming prohibitively expensive.
Note: much of this section was taken from Glynne Jones D G, 1999 (June). Piperonyl Butoxide. Pesticide outlook, 117–120.
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