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High Dose

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Scientific papers - High dose - page 3

Spatiotemporal epidemiological correlations between phosmet use and BSE incidence

The UK was unique in its use of systemic phosmet in that it compelled farmers to apply the chemical biannually at a 20 mg/kg dose rate recommending an optional 10 mg/kg follow-up dose 14 days later. By contrast, the few other countries that have licensed phosmet in its systemic pour-on formulation have only licensed it for voluntary treatment of lice in cattle and/or pigs as a 'one off' dose of 10 mg/kg or 2 mg/kg respectively.

Treatment of the UK cattle herd with systemic phosmet became particularly intensive during the early 1980s, when compulsory biannual treatment was instigated in 1982 (2). And then in 1985, dairy farmers had no choice but to apply the phosmet type of warblecide because the use of all the other competing types of OP warblecide became restricted following alterations in licensing criteria.

Whilst the warble fly was largely eradicated from the UK by the end of the 1980s, very small pockets of infestation still occasionally emerge. Cattle residing in these warble-infested zones, as well as all cattle that are importect into tne ut,.-, are stin supjectecl to compulsory treatment with systemic phosmet at the 20 mg/kg warble dose rate.

There is also some usage of systemic phosmet for the voluntary control of lice and mange, etc. in cattle and pigs. Cattle are treated with a 10 mg/kg dose which is followed up by a further 10 mg/kg dose 14 days later, e.g. still 20 mg/kg in total.

Such a substantial drop in phosmet usage since the peak of the warble eradication era in the mid 1980s, coupled to the complete removal of tallow/animal fat from the bovine food chain in 1995, could well account for the substantial down turn in BSE incidence in the UK since 1994.

This theory postulates that various 'optimum' prerequisites surrounding phosmet usage must be fulfilled before BSE can emerge at a significant incidence rate. They are as follows :

1 . Phosmet must be applied onto livestock in a ,systemic' lipophilic pour-on formulation, e.g. enabling the active ingredients to penetrate through all membrane barriers and bind into adipose and phospholipids (5,6) - such as the PI fractions of the CNS nerve membranes to which the prion protein is anchored.

2. Phosmet must be applied twice annually at its high dose rate of 20 mg/kg (with 10 mg/kg 14 day repeat) as was compulsory during the UK's warble eradication programme.

3. Phosmet exposure must take place during early life/in utero stages of the animal - NB, either via direct systemic phosmet treatment and/or indirectly via ingestion of concentrated feeds containing bioconcentrated phosmet in fat derived from rendered-down pigs or cattle.

4. BSE will more likely affect an animal that is genetically or environmentally predisposed to less efficient detoxification of phosmet and to susceptibility to prion disease.

The European/global perspective on phosmet-induced BSE - a comparative study of phosmet used and BSE incidences in various different countries

Apart from the UK, no other country licensed systemic phosmet for veterinary use whilst adhering to the aforementioned 'optimum prerequisites' of intensive exposure. (This information was obtained through communications with the various veterinary pesticide licensing bodies of each country.) However, Eire, the Channel Islands, France and Switzerland appear to be the only other countries that have partially satisfied these prerequisites for BSE onset by exposing their livestock (cattle and/or pigs) to direct applications of systemic phosmet - albeit voluntarily and at relatively lower doses - as well as to feedingstuffs containing the recycled lipids of livestock treated with phosmet.

Apart from Portugal which only exposed its cattle to an in-feed source of bioconcentrated phosmet/ prions in the fat/tallow fraction of MBM imported from the UK, the only other countries affected with endemic BSE outside of the UK are Eire, the Channel Islands, France and Switzerland which are the other countries besides the UK that have exposed their livestock both directly and indirectly to potentially significant doses of phosmet.

Eire first took up the use of systemic phosmet for controlling warble at the end of their warble-fly eradication programme in 1978 (32). But phosmet use was confined to one district of Eire only, where it was applied once annually as an autumn dressing and used at a low dose rate of 6 mg/kg bodyweight (32) - a fivefold lower dose than the 20 mg/kg (plus 10 mg/kg 'follow up') biannual dose employed in the UK.

After warbles were successfully eradicated in Eire, systemic phosmet was still used voluntarily for controlling lice and mange. The dose rate for lice was increased around 1992 in Eire to the same dose rate as applied in the UK, 10 mg/kg, with a repeat treatment recommended for 14 days later. Allowing for the 4-year average incubation period of BSE in cattle, the recent five-fold increase in the annual BSE incidence rate in Eire in 1996 over previous years (Eire Dept of Agriculture) could perhaps be explained by the increase in Eire's phosmet dose in 1992.

Australia and New Zealand are the only countries that have licensed systemic phosmet for veterinary use and have not reported BSE. But their usage on cattle was voluntary and confined to the control of lice at a 10 mg/kg low dose without the 14 day repeat treatment, which constitutes a considerably less intensive application than applied in the UK. There is also little possibility of a source of in-feed phosmet (within MBM) bioconcentrating into calves/cattle in the extensive grass-fed livestock systems practised in these countries. For an almost negligible input of concentrate feeds containing MBM are recycled back into cattle in these countries compared with the intensive reliance upon the recycling of MBM on UK farms prior to 1988 The New Zealand Meat Industry Association reports that 60% of its MBM is exported to Asia, with the remainder being fed to poultry and pigs. The same pattern of MBM distribution is applied in Australia.

Phosmet has also been employed for use on cattle in the USA at a much reduced dose of 2 mg/kg as a non-systemic, back rubber/powder/spray-on 'contact' type of formulation where the chemical is designed to control ectoparasites, and fails to penetrate through the hide of the cow and gain access to the CNS.

US pesticide licensing authorities deem that milk taken from cows that have been treated with this relatively low-dose formulation of phosmet has to be withdrawn from sale for human consumption for a period of 28 days following treatment (in contrast to 6 h in the UK). This measure served to debar the use of phosmet upon milking cows in the USA for economic reasons. It also had the effect of excluding cattle in their first 6 months of pregnancy when they are in milk from exposure to phosmet, thus avoiding any possibility of vulnerable 'in-utero' exposure to this chemical - a developmental stage when PrP could be more susceptible to phosmet modification and the fetus being a target of phosmet concentration.

An interesting comparative study into the different modes of controlling warble fly in various different European countries, by A. Liebisch (33), demonstrates how the UK adopted a far greater degree of 'chernical intensity' in relation to other countries by employing compulsory measures to eradicate warble flies. Such measures enforced biannual treatments of high-dose systemic 'pour-on' 0Ps as opposed to the lower dose or 'spot-on' types of 0Ps (which used considerably less active ingredient per treatment) used by some other countries as a single annual application only.

Apart from the UK, Eire, France and Switzerland, which have adopted compulsory warble control measures, other European countries have adopted voluntary or non-existent measures, which perhaps explains why no other country apart from Eire and the UK has so far succeeded in eradicating the fly.

Liebich's study also demonstrates that phosmet was not recommended for use upon cattle in any other country's compulsory warble control programme operating outside of the UK (apart from some very limited use in Eire and France during the late 1970s). This explains why no correlation exists in the greater majority of BSE endemic countries outside of the UK linking compulsory warble treatment zones with the spatiotemporal distribution of BSE incidence. By contrast, in the UK, where phosinet was employed at high systemic doses, a general correlation does exist (2).

Various countries outside the UK which have attempted to control the warble fly, such as Switzerland, Denmark, France (33), USA, Canada, have all employed non-phosmet types of systemic 0Ps such as trichlorphon, famphur, cournaphos - or the non-OP ivermecti.n. None of these compounds contains the phthalimido moiety that is found exclusively within the phosmet compound. In fact,

Phosmet is the only OP compound and systemically formulated pesticide to contain a phthalimido moiety.

Some of the toxic metabolites that derive from phosmet parent compound, such as oxones and sulphones (34), also derive from the fenthion (35) type of systemic OP warblecide which was widely used in the UK prior to 1985 (2). Such metabolites, common to both fenthion and phosmet degradation, should therefore not be excluded from the list of possible candidate triggers responsible for initiating the misfolded prion. If this were the case, then fenthion, as well as phosmet, would have to be considered as a possible prion initiator.

This theory proposes that, once the offending chemical penetrates the phospholipid membranes of the CNS and attains an optimum critical concentration - as occurs in the UK-specific context of high-dose phosmet treatment - then the transformation of PrPc to PrPbse may be initiated in those cattle carrying TSE-susceptible variants of PrP and inherited deficiencies of liver detoxification enzymes.

Assuming that the OP fenthion (applied at a 5 mg/kg dose) can also play a primary role in the initiation of BSE as well as phosmet, then, because of fenthion's four-fold lesser dose rate in relation to phosmet, it would seem imperative that both direct application of systemic fenthion as well as the indirect bioconcentration route of exposure (via the recycling back of fenthion/phosmet-contaminated animal fat) must coexist before the optimum toxic concentration necessary for PrPbse initiation can be attained.

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Last updated 09-Feb-2007