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High Dose

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Scientific papers - High dose - page 8

Organophosphorus-induced susceptibility of gastro and blood-brain barrier towards passage of recycled PrPbse contained in feeds derived from bovine CNS tissues

0Ps are widely, recognized to inhibit serine esterases such as trypsin and chymotrypsin. As sporadic and conventional prion variants are supposedly degraded by trypsin in the healthy and intact gastro tract, oral intake of significant doses of OP residues in feed could theoretically invoke susceptibility to prion intake across the gut wall because of their direct inhibition of trypsin activity (98) as well as disrupting permeability gradients across the wall (99) or affecting neuroendocrine mediation of 'Peyer's patches' in some way. Or perhaps the new variant prion is conformationally modified in a manner that blocks trypsin from accessing its normal cleavage/degradation sites.

Thus an OP such as phosmet, may not only be initiating the endogenous production of the prion agent within the bovine CNS, but also enabling an exogenous source of recycled prions (from rendereddown bovine CNS tissues in meat and bone) to cross the gut wall and blood-brain barrier (100,101), and thus re-enter the CNS - hence, initiating and exacerbating the bioaccumulating 'prion pyramid' effect.

0Ps could also be compromising the bovine's susceptibility to prion disease by altering the metabolism and permeability gradients of CNS neurones and their plasma membranes, thus facilitating transmission of exogenous PrPbse back into the cell where fresh supplies of normal PrPc are available for conversion to PrPbse.

Other factors such as ulceration of the gastro tract due to chronic daily intake of chemical silage additive residues (based on formic acid) for instance, or gastrointestinal infestations of parasitic nematode worms (102) could create sufficient physical damage to the gut membranes to permit leakage of prions into the internal body environment.

Similarly in relation to human new-variant CJD; ulceration, gut worms, gastro surgery or exposure to pesticidal or 'abusive' recreational psychotrophic drugs which agonize serotonergic/peptide turnover in the gut and CNS (103), could all lead to the physical or biochemical impairment of gastro and blood-brain barrier permeability gradients which might normally be protecting the human against intake of prions from contaminated feed.

Initiation of pathogenic PrP in new-variant CJD.

The UK government's Spongiform Encephalopathy Advisory Committee (SEAC) have consistently pointed out that people occupationally involved with pets or farm animals are more at risk of developing 01) (8). As the licensing of phosmet in the UK has been exclusively limited for use upon farm animals and pets, then it would seem relevant to consider phosmet as a possible common cause of nvCJD as well as a common cause of BSE in cattle. Chemical exposures can be hypothetically correlated to the clusters of CJD that have emerged.

Dr Randall Crom of the Epidemic Intelligence service of the Arizona Department of Health Services at Phoenix reports that a cluster of six cases of sporadic/famililial CJD variants has emerged around a missile production plant in Tucson, Arizona from between 1980 and 1986. MAO inhibiting chemicals (e.g., serotonin agonists) such as cuprizone are invariably employed as propellants in the manufacture of missiles. Cuprizone induces a type of spongiform encephalopathy (30). Three of these CJD cases implicated workers occupationally involved at this plant who were diagnosed between 1985 and 1986.

Another cluster of six confirmed/suspected CJD cases to date is currently emerging in people who have worked or resided in villages 10 miles east/south of an OP insecticide manufacturing plant sited at Yalding in Kent. On 17 April 1986, there was a major leak of an OP gas from the plant which had an 'offensive' odour (Kent Messenger 18 April 1986). The 10-year delay prior to manifestation of C.11) symptoms in susceptible residents averaging 10 miles downwind of this plant could be postulated as the incubation period of the CID.

The fact that this CJD cluster to date has largely only implicated individuals who were occupationally and residentially confined to the rural areas of the 'Weald' district of Kent, could also be part explained by the unique presence of hop and fruit farms within this region of the UK which utilize a 100-fold greater intensity of systemic OP applications per acre in 1983 than were applied upon the common types of cereal/ arable crops grown all over the UK (104).

The villages where these CJD victims resided or were temporarily employed - High Halden, Mersham, Bethersden, Sissinghurst, East Peckham- were all home to hop farms that applied a range of the highly toxic 'class 2' types of systemic 0Ps containing sulphur such as TEPP, omethoate, mephosfolan, methidathion and oxydemeton-methyl, which, on the greater part, contain the same 0,0-dimethyl phosphorodithioate moiety as found in phosmet (40).

Those who were occupationally involved or living near to these hop fields in the sheltered valleys of the Weald would invariably be chronically exposed to the atmospheric 'fall-out' of low doses of these 0Ps after their field application.

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Last updated 09-Feb-2007