It is proposed that the traditional strains of TSE emerging in the elderly mammal result from low intensity exposure to naturally occurring sources of the specified environmental causal factors. Whilst the new strain TSEs such as BSE, which represent a more aggressive, pronounced  form of TSE emerging in younger mammals, result from a more intensive synthetic induction of the same mineral imbalance along with more intensive exposures to man made shock bursts of high energy infrasound.

Environmental factors that initiate the three stage pathogenesis of BSE

1.   A systemic organo phosphate (OP) insecticide induced Cu depletion at the octapeptide repeats on PrP?

Following the pioneer soil/vegetation analysis of sporadic/familial TSE cluster regions around the world, the prerequisite of Cu/Zn deficiency was first identified and  proposed as a primary aetiological prerequisite for TSEs (4).

It has also been suggested that the geographical distribution of regions of high BSE incidence in the UK correlates with Cu deficient regions (5), whilst a survey on UK farms suffering endemic BSE  observed problems with Cu deficiency on all farms studied (54).

The key pathogenic mechanism of TSE pivots upon the loss of Cu (and Zn) from the octapeptide repeat domains of the normal PrPc, thereby rendering these domains vacant for substitution by specific foreign cations that can affiliate with these ligands. Loss of Cu/Zn from PrP’s domains can be achieved  in several ways and need not necessarily result from a straightforward external environmental Cu/Zn deficiency; although this appears to be the case in the clusters of traditional TSEs analysed (4).

For instance, significant exposure to chemical sensitising agents such as citrus, bergamot, pine, asphodel plants, hops, synthetic dyes, petroleum, dithiophosphate insecticides was observed in the diets or local atmospheres of the ecosystems supporting all the sporadic/familial /nv TSE clusters studied by the author (5). These agents actually exert their photo/audio/tactile sensitising affects by interfering with the histidine ligands (55) where they can form long term bonds (56); effectively capping histidine residues on metal transporter/metallo proteins, such as PrPc, so that available Cu/Zn can no longer access their specific binding ligands – regardless of the levels of excess or deficiency of the free metal within the CNS.

Interestingly, several photosensitising molecules, such as the porphyrins, congo red and anti-malarials, have been shown to bond to PrP in vitro where they have demonstrated therapeutic benefits in preventing the accumulation of PrPsc in TSE affected cells (57)(1).

In respect of BSE, it has been extensively proposed that the exclusive high dose (20 mg/kg bodyweight) , high concentration (20 %) usage of the systemic pour-on organo dithiophosphate warble fly insecticides containing phosmet played a key primary role in the aetiology of the BSE epidemic in the UK cattle herd (6)(3).  It has been suggested that these systemic acting dithiophosphate compounds readily crossed the blood-brain/blood–CSF barriers and interfered with Cu availability at PrP’s octapeptide repeat by chelating Cu with their two free sulphurs or nitrogen to form a mercaptide ring (4). Experiments in the 1970s demonstrated that OP exposure has a significant influence upon copper metabolism in some way (58).

The oil based, lipophilic insecticide is poured along the base of the head and spinal backline of the cow, just  millimetres from the central nerve tissues where PrP is intensively localised. The active ingredient, phosmet, was designed to penetrate the internal environment of the cow at a dose that was toxic to the warble fly larva. The fact that warble larvae were sometimes exterminated within the fatty regions of the spinal cord (59) – producing the well recognised post treatment anaphylactic shock syndrome in the cow (60)– demonstrates the successful ‘in vivo’ penetration of toxic concentrations of phosmet into the spinal cord following routine field treatment .

The acute neurotoxic side effects of  OP warblecides in cattle have been widely reported, where the OP induced conformational change to various nerve proteins, such as acetylcholinesterase, offers a comprehensive biochemical explanation for these abnormal reactions (60)(61). On the other hand, the likely long term delayed neuropsychiatric effects of warblecide treatment on ‘susceptible’ individual cows has not been reported to date; this more subtle syndrome has only been reported in the actual livestock farmers applying the warblecide  (62) .

However, a few cases of chronic OP poisoning have been reported in cattle that have been exposed to other types of OP application; where the clinical profile duplicates many aspects of the clinical profile of BSE (63)(64). Furthermore, some cases of OP intoxication have invoked a neuropathological profile that specifically exhibits a spongiform encephalopathy (65)(66).

In the UK it first became compulsory in 1982 to treat cattle twice annually with these systemic insecticides for warble control (67). Although used voluntarily during the 1970s, the concentration of the active phosmet ingredient on the market was licensed as 5 % formulation (68). This concentration increased to 20% by the end of the 1970s (68); effectively exposing the UK bovine to uniquely high dose rates of warblecide that had never been employed by any other country using systemic OPs for warble control.

Whilst phosmet and other types of OP have been used in a few other countries across the Northern hemisphere where warbles are prevalent, use of these OP warblecides outside the UK has been restricted to a once annual, lower dose applications of ‘non systemic’ powder or water based ‘pour on’ formulations which are applied to warble infested cattle only (6)(69). These applications are used as ‘contact’ insecticides, whereupon an overall reduced dose of chemical is delivered directly onto the warble during its ectoparasitic stage of the lifecycle when larvae are emerging through the hide of the cow. However, some oil based systemic ‘pour on’ or ‘spot on’ formulations of OP warblecide have been used in a few other countries outside of the UK (70), albeit at a maximum dose rate of 10 mg/kg per bodyweight – half the rate used for warble control in the UK (6).

Interestingly, BSE has also emerged in these countries – albeit at lower incidence rates – where the spatio-temporal distribution of their epidemics have followed an identical delayed lag response to the ‘district by district’ spatio-temporal distribution of compulsory warble eradication measures employed. Such a correlation was initially identified in the UK (71)(72)(6) and then later in France (73). But fully blown BSE will only erupt in those warble controlling countries whose cattle are simultaneously exposed to the other environmental prerequisites putatively responsible for initiating BSE; Mn supplements and intensive ‘supersonic aeroplane’ sources of artificial infrasound.

For example, use of systemic phosmet at a 10 mg/kg dose is voluntarily practised for lice control in warble-free Australia and New Zealand (6). But BSE has probably never erupted in Australasia because, unlike Europe, these countries do not incorporate Mn  into their cattle feeds nor do they overfly livestock populated zones with supersonic turbojet military/passenger aircraft.

Likewise in Japan, Mn supplementation of feeds is practised all over, yet the five cases of BSE that have erupted to date have exclusively originated from herds raised along the coastal belt of Northern Hokaiddo; a farming district which has traditionally  imported breeding stock from the warble infested territories of North America. In order to maintain Japan’s warble free status in an area that is climatically well suited for the establishment of warble flies, these herds are prophylactically treated with a 10 mg/kg dose  of systemic trichlorphon warblecide. Furthermore, patrolling of the coastal waters of North Hokaiddo is routinely practised by low flying Japanese military jets; due to its close bordering with Russian held territory (author’s observations).  

The 10 mg/kg low dose systemic pour-on trichlorphon warblecide compound has been used for warble control in all countries afflicted with a low incidence rate of endemic BSE (70)(74). Trichlorphon was also used early on in the voluntary stages of the Uk and Eire’s warble eradication campaigns, but was used later on in the more recent campaigns run by Holland, Portugal, Switzerland, Japan, Italy, Germany, Spain, France (74)(70) – low incidence BSE endemic countries (6).

Trichlorphon does not chelate Cu like its ‘dithiophosphate’ counterpart warblecide, ‘phosmet’, but it could disrupt copper bonding to the octapeptide repeat domains on PrP by interfering with its histidine residues – a delayed toxic mechanism that has been specifically associated with trichlorphon induced protein aging (75).

Other Cu chelators such as Mn dioxide feed additives (76), silver compounds (77) or tributyltin  contaminants (78) should also be considered  as possible candidates for diminishing the availability of Cu within the CNS. Increased levels of molybdenum (Mo) in the foodchain of cattle could also bring about copper depletion by conjugating with Cu (35). This could result from the increased incorporation of Mo-rich sorghum (79) into concentrated cattle feeds or from grazing cattle on soil that has become progressively acidified due to the modern day effects of acid rain (80), excessive irrigation or overuse of certain artificial nitrogen fertilisers which render Mo more freely ‘available’ for uptake into the plant horizon. (81). 

In summing up the putative role of systemic OP treatments in the aetiology of BSE, it is concluded that bovine exposure to systemic OP treatments helped induce the high Mn/low Cu mineral imbalance in the CNS; not only through their chelating action of copper, but by invoking an increased permeability of the blood brain/ blood CSF barriers (82) that disrupted Mn homeostasis in the CNS by enabling an increased uptake of Mn through these regulatory gateways (52). Exposure to oestrogenic substances has also been shown to influence permeability of the B/B Barrier (83), and  likewise raise levels of Mn in the CNS to seventy times normal levels (84). Exposures to agricultural oestrogen products should also be considered in this respect.  

The oxidative stress generated in the CNS following exposure to these systemic insecticides (85)(86) combined with exposure of the bovine to a cocktail of other CNS penetrating eco-oxidants that are increasing in the modern environment (UV, ozone, microwaves, etc) -  could have assisted in the in situ conversion of Mn 2+ prions into  Mn 3+ prions in the ‘prion factory’ areas like the retina, astrocytes, tonsils, etc See diagram 4.  

Diagram 4

The lack of BSE incidence in beef suckler herds (1) and total lack of BSE in home reared cattle on organic farms (87) can be attributed to the preferential use of the ‘non OP’ ivermectin types of warblecide on these farms. Whereas on conventional dairy farms where BSE incidence rates were high (1), licensing restrictions on the use of ivermectin on ‘in milk’ cows necessitated the exclusive use of OP types of warblecide on dairy farms for economic reasons.

The decline in incidence rate of BSE in the UK during the mid and later half of the 1990s (7)(8) is explained by the virtual eradication of the warble fly during this period (6), with the corresponding decline in use of the systemic OPs at their 20 mg/kg ‘warble’ dose rates to the present day levels of usage; where 10 mg/kg doses for lice/mange control are still used (6). Elimination of the BSE susceptible family lines of cattle – whether through BSE itself or the cohort cull (7)(8) – can also account for the significant reduction in the incidence rate of BSE at the present day.