early 1980s (132). Usage subsequently dropped and stabilised thereafter, running at 87 tonnes applied in 1984 and 104 tonnes in 1994 (133). Chloramquat use in the UK has increased more dramatically, starting at 239 tonnes per annum in the late 1970s (131), 231 tonnes per annum in the early 1980s (132), then 1112 tonnes per annum in 1984 rising by 110% to 2335 tonnes in 1994 (133) - the highest ranking pesticide in UK usage terms when related to total area treated.
The 'paraquat' class of cations are absorbed into plants (17) after application. They remain persistent in specific environments such as clay soils (134). Paraquat forms stable free radicals (17), crosses the blood/brain/barrier in mammals and has been associated with the aetiology of Parkinsons disease and the induction of auto-oxidation of, dopaminergic/serotonergic neurones (10,13,14). The possible binding of diquat to the copper domain of PrP during CNS Cu deficiency should also be considered alongside the possible involvement of other candidate cations, such as Mn or nickel (as a more reactive oxidative species; eg Mn 4+ or radioactive Mn) in the aetiology of the 'modem' strains of TSE.
Exposures to synthetic estrogen/steroid compounds accelerate the absorption and accumulation of Mn in the CNS: a putative prerequisite in the aetiology of BSE/nv CJD
Individuals who are low in copper or iron demonstrate a markedly increased absorption of Mn (3,4). Any increases in exogenous/endogenous sources of estrogen (54) or glucocorticoid (137,138,139) also mediates a dramatic increase in absorption, concentration and distribution of Mn within the organism. When Panic et al (54) administered estrogen to laying hens, Mn levels were elevated 15-70 times higher than those found in the untreated controls.
Elevated levels of steroids/estrogens are known to increase the permeability of the blood/brain barrier's microvasculature to macromolecules (141,142), and this may partly explain the increased uptake of Mn into the CNS following increased corticosteroid turnover.
The following groups are therefore placed at a higher risk of increased Mn uptake as a result of their exposures to above average levels of estrogens/steroids; Adolescent (143) and pregnant (144) females, those prescribed the contraceptive pill, hormone replacement therapy, body
building steroids/growth hormone, etc, or those directly exposed to high levels of synthetic estrogenic pollutants derived from detergents, pesticides, cosmetics, phallates, etc, or indirectly exposed via residues in recycled water supplies/foodstuffs, or via habitual ingestion of estrogenic foods such as soya which contains the naturally occurring estrogen, genistein (69). Naturally occurring
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estrogens are also at high concentrations in some leguminous crops such as lucerne and clovers (69), and it is interesting that lucerne comprised the staple diet of a greater majority of the captive and wild deer and elk in Colorado (57) and the ostrichs and other zoo animals that have succumbed to TSEs.
The practise of using oestrogenic/progesterone hormones for syncronising the heat period and conception in UK dairy herds during the 1980s/! 990s could have accelerated the absorption of Mn in the herds which adopted this therapy.
Whilst estrogenic growth promoters have been used in many countries worldwide to boost the final fattening stages of beef cattle (banned since the mid 1980s in the UK), all of those animals treated are invariably slaughtered as three year olds before they have had sufficient time to incubate and manifest the clinical stages of TSE.
However, countries that administered these lipophilic hormones intensively to several species of farm livestock (as well as recycling these hormones back into cattle via feeding of the tallow fraction of MBM feed derived from the slaughtered carcases of hormone treated animals) could have contributed to the potential risk of chronic Mn overloading in their herds.
The tallow fraction of MBM carries the lipophilic contaminants present in the feed. Tallow remained in UK MBM feed once the practise of solvent extraction was stopped by the rendering industry in the early 1980s (145). Further estrogenic substances - albeit naturally occurring (69) - permeated the bovine food chain due to the increased feeding of cheaper protein sources such as soya and alfalfa during the 1980s (119).
Cattle and humans drinking in areas where water is drawn from sources polluted by synthetic estrogenic pollutants could potentially absorb Mn at an increased rate.
Overloading with estrogens/steroids can also depress Cu absorption (36) which, in turn, activates the mobilisation of any remaining Cu stores in the liver; thus increasing the turnover of ceruloplasmin (84) in the hepatocytes which could favour an increased oxidation of Mn2+ into its lethal Mn3+ species (7) - particularly at a time when supplies of ceruloplasmin's normal oxidative target, Fe2+, are depleted.
The common thread centres on the role of these hormones in activating the pituitary-adrenal axis, whereby mediating an increased turnover of the adrenocorticotrophic hormone (ACTH) stress response, which increases absorption and hepatic release of Mn as well as increasing permeability of the blood brain barrier (137-139). This permits an increased entry of Mn into the CNS, explaining why higher levels of Mn are found in the serum/whole blood and CNS during times of ‘stress’; eg, during infections, myocardial infarction, rheumatoid arthritis, psychosis, etc. (3) (4), and following surgery.
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