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High Dose

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Scientific papers - High dose - page 4

Like phosmet, fenthion also has a high solubility in lipids (9). It has been experimentally demonstrated that fenthion can bioconcentrate up to 62 times following a single step up the trophic layers of the food pyramid (36). When fenthion-treated tadpoles were fed to untreated amphibians, the amphibians bioconcentrated fenthion up to a 62-fold greater concentration than the tadpoles.

Systemic fenthion was generally used as a 'spoton' treatment in BSE-free countries like Germany, Denmark, Canada and Spain (33), where it was licensed for use on cattle. An overall lower total dosage of fenthion is applied per treatment per cow when the compound is formulated as a spot-on' treatment as opposed to when it is applied as a 'pour-on' treatment.

The UK and Eire warble-fly programmes employed pour-on fenthion extensively. The French compulsory warble-fly programme also employs fenthion as one of three systemic pour-on formulations approved as warblecides (33). Interestingly, France appears to be the only country outside of the UK whose spatiotemporal distribution of compulsory warble-fly zones bears some correlation with the spatiotemporal dynamics of their BSE incidence.

Compulsory warble eradication measures were intro-duced into France 8 years ago (33), but compulsory treatment was exclusively confined to the Brittany region at that time. This implies that the MBM derived from cattle slaughtered in the Brittany region would have passed through local slaughter houses and continuous-flow rendering plants for recycling back into cattle via concentrates produced by the local feedmills. This whole operation, coupled to importation of phosmet-contaminated MBM and live cattle from the UK into this region (as well as the recycling back of phosmet-treated pigs from the intensive units of the C6te d'Amour (see following section on bioconcentration)), would have opened up possibilities for a small degree of fenthion/phosmet bioconcentration (relative to the UK) to occur within the bovine food chain of the Brittany region, sufficient to have triggered off the small incidence of BSE (20 cases) in local cattle.

Warble treatment zones have been extended considerably over the last 3 years to cover the more southerly provinces of France.

Interestingly, six fresh cases of BSE have subsequently surfaced in these southerly regions, suggesting that the spatiotemporal distribution of BSE in France may be following warble treatment dynamics likewise, where, much like the UK, an average 4 year delayed lag exists between direct/7 indirect exposure to OP warblecide and the emer, gence of clinical BSE.

Bioconcentration of fat-bound phosmet in the farm animal food chain (see Fig. 1)

Deficiency of published research

There is little research in the literature which focuses on the bioconcentration of 0Ps in the food chain. Conclusions have been drawn from the limited amount of research that has been executed in this area (36-39), which suggests that potentially significant toxicological complications could arise in certain specific environmental contexts of OP application. Surprisingly, the most likely areas where bioconcentration of 0Ps could be presenting a health hazard, such as in the context of systemic OP warblecides, do not appear to have been investigated.

No published research exists on the bioconcentration of systemic phosmet or other warblecides within the farm animal food chain, despite their widespread intensive use in the UK farming system.

However, two studies (40) have investigated the concentration of phosmet in various cattle tissues following 'spray on' application of an aqueous based 'non-systemic' formulation of phosmet containing a low-dose, 25% concentration of active ingredient (a.i.). Although residues of phosmet in the various fat samples analysed a day after treatment did not exceed 1 p.p.m. on any count, this trial failed to screen for the highly toxic oxone and other intermediate metabolites, and also failed to acknowledge and assess existence of 'undetectable' phosmet residues that would have coupled up with phospholipid fractions.

Another study (41) investigated the problems encountered with the accumulation of certain types of OP residues (the substituted aryl derivatives) in the meat of domestic animals after application or intake of OPs, and its findings tend to contradict the findings of the aforementioned studies (40) by suggesting that a problem of OP bioaccumulation could exist in certain contexts.

But all of these studies entirely fail to reflect the specific 'in vivo' potential for bioconcentration of the high-dose systemic pour-on formulations of phosmet in the phospholipids of CNS membranes following direct application along the spinal column.

Other studies provided by the pesticide manufacturers for the World Health Organization's pesticide reviews have looked at the distribution of phosmet following oral administration of the compound (42). But the 'oral' route of phosmet entry as opposed to the systemic 'backline' route provides a much greater opportunity for hydrolytic and other degrading enzymes (abundant in the gastro tract) to metabolize the chemical before it reaches the safe haven of its lipid depots, thus preventing the possibility of any significant amount of phosmet concentrating in lipids and reaching levels of contan-fination that are toxicologically significant.

The criteria surrounding field application of systemic phosmet in the UK satisfies Hassall's four postulates for bioconcentration

Much like the organochlorine DDT, both systemic phosmet and fenthion satisfy all four of 'Hassall's Postulates' necessary for bioconcentration of chemical pollutants in the lipid phase of the food chain. Two of the postulates (43), low solubility in water and high solubility in fat, are strongly fulfilled by phosmet and fenthion (6,34,35), implying that both phosmet and fenthion possess partition coefficients (6) that strongly favour bioaccumulation in lipids.

In fact, one study (6) demonstrates that phosmet has a partition coefficient of 677, whilst other common 0Ps such as trichlorphon, dimethoate and dichlorvos have much lower partition coefficients of 3.7, 0.51 and 29, respectively. NB, trichlorphon is used as an a.i. of some warblecide brands.

Fig. 1 Bioconcentration of systemic phosmet up the farm animal food pyramid due to the practice of recycling phosmetcontarmnated bovine/porcine fat via meat and bone meal which has been manufactured by the 'continuous flow' system of rendering.

One toxicological assessment test (44) looking at various OP compounds found that a precise correlation existed between the partition coefficients and the bioaccumulation abilities of the OPs studied, hence indicating that phosmet's high partition coefficient signals a strong potential for bioaccumulation. Another assessment test (45) correlated partition coefficients with the degree of chronic toxicity that an OP exerts.

Thirdly, (43 [p. 1211), the systemic route of phosmet entry as prescribed to be 'poured along the spine', guarantees a rapid penetration and binding of lipophilic phosmet into the phospholipids of the CNS. For the systemic route of entry largely enables the chemical to bypass the batteries of hydrolytic and oxidative enzymes that are abundant in the gastro tract/liver and normally responsible for catalysing the primary pathways of phosmet degradation.

Several of the solvents (46 [p. 271) that have been more recently employed in compiling systemic formulations of OP not only guarantee rapid penetration of phosmet into lipid depots, but the actual toxicological properties of the solvent itself may also impair hydrolytic enzyme activity, thus enabling phosmet to evade enzymic degradation whilst in passage to the relative safety of its lipid depots.

Once phosmet, like other lipophilic OPs, is bound into the lipids and non-vital sites (46 [p. 41, p. 481) (47), hydrolases are prevented from accessing the P-O bonds of the phosmet molecule for catalytic attack and primary degradation. Hence, phosmet becomes locked into the lipid, which acts like a sort of molecular 'lobster pot' (43) until times of stress cause a sudden surge of demand for fat assimilation, with the subsequent decoupling and release of phosmet into the general circulation. Other lipophilic 0Ps such as leptophos (48) and fenitrothion (47) have been shown to bind and decouple with mammalian fat in the 'in vivo' context in this way.

And fourthly (43), if phosmet bioconcentration is to be fulfilled up through the food pyramid, then the predator at each trophic level (e.g. the cannibalistic cow in this context) needs to ingest a constant supply of phosmet-contaminated fat at a rate that is sufficiently speedy to outmatch the body's rate of degradation and disposal of the chemicals.

Adult UK dairy cattle ingested significant quantities of animal fat on a daily basis. For animal fat became a significant constituent of MBM-containing concentrates once solvent extraction was phased out of the UK rendering process in the early 1980s (49) and was fed up until the MBM ban in 1988, and the feeding of animal tallow to cattle in artificial milk powders, etc. was not prohibited until 199 .

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