Health
Scientific Committees
Scientific Steering Committee (former MDSC)
Outcome of discussions
Opinion on
possible links between BSE and Organophosphates used as
pesticides against ecto- and endoparasites in cattle -
Report and opinion adopted at the Scientific Steering
Committee meeting of 25-26 June 1998
Remark: the present document contains opinions adopted
by the Scientific Steering Committee of the European
Commission, which is a neutral and independent scientific
body.
Note : Readers should keep in mind that
the present report and opinion only address the scientific
aspects of the risk
assessment of the issue (e.g., identification of
hazards, levels of infectivity in the starting materials
and final products, etc.). The risk
management and policing aspects related to the
implementation of an opinion, are not dealt with.
Executive Summary
In its opinion on Organophosphates and
TSE's of 16 May 1997, the Multidisciplinary Scientific
Committee (MDSC) concluded that no relation existed between
the use of and exposure to organophosphates and the
occurrence of BSE.
In January 1998, the Scientific Steering
Committee (SSC) was requested to evaluate and possibly
amend the MDSC's opinion of 16 May 1997 in the light of
possible additional evidence and scientific literature that
meanwhile may have become available. More precisely, it was
invited to provide its opinion on the
hypothesis that there is a link between the use of some
organopohosphates, especially Phosmet, and the initiation
of BSE by the formation of delayed neuro-excitatoric
proteins as a consequence of the phosphorylation of the PrP
in the foetuses of the treated cows to the toxic PrP
Sc protein.
The Committee carefully analysed the
available evidence. It confirmed the opinion of the MDSC
that there is novidence for such link to exist.
Opinion
I. Framework and mandate
In its opinion on Organophosphates and
TSE's of 16 May 1997, the Multidisciplinary Scientific
Committee (MDSC) concluded that no relation existed between
the use of and exposure to organophosphates and the
occurrence of BSE.
The hypothesis of a link between the use
of and exposure to organophosphates and the occurrence of
BSE was forwarded in two papers by Purdey (1996) (22; 23)
on
"The UK-epidemic of BSE: Slow Virus or
Chronic-Pesticide-Initiated Modification of the
Prion-Protein? Part 1: Mechanism for a Chemically-Induced
Pathogenesis / Transmissibility. Part 2: An Epidemiological
Perspective".
In January 1998, the Scientific Steering
Committee (SSC) was requested to evaluate and possibly
amend the MDSC's opinion of 16 May 1997 in the light of
possible additional evidence and scientific literature that
meanwhile may have become available. More precisely, it was
invited to provide its opinion on the
hypothesis that there is a link between the use of some
organopohosphates, especially Phosmet, and the initiation
of BSE by the formation of delayed neuro-excitatoric
proteins as a consequence of the phosphorylation of the PrP
in the foetuses of the treated cows to the toxic PrP
Sc protein.
The key primary question upon
interpretation of the mandate is whether there are
indications that organophosphates (e.g. Phosmet) bind to
brain prions similarly as they do to the
acetylcholinesterase (AchE), following by aging which
results in a denaturation of the proteins. These
denaturated phosphorylated prions would then possibly and
hypothetically be precursors of BSE.
II. Scientific background information on
organo-phosphorous compounds
II.1. Uses of Organophosphates and
Sources of Consumer Exposure
Commercial compounds usually summarized
under organophosphates comprise esters, amides or thiol
derivatives of phosphoric, phosphonic, thiophophoric and
thiophosphonic acids. About one hundred active ingredients
are or have been used in several hundred products against
arthropode pests. In addition, highly toxic substances out
of the group have been developed as chemical warfare agents
(Tabun, Soman, Sarin, VX). (1).
The major use of organophosphates is as
agricultural insecticides covering the whole range of crop
growing and storage. Most commonly known ingredients are
e.g. Azinphos-methyl, DDVP, Dimethoate, Fenitrothion,
Malathion, Metasystox, Parathion. The insects to be
controlled include the whole range of arthropode pests.
Organophosphates and carbamates represent the second
generation of agricultural insecticides after DDT and
Drin-insecticides. Due to the high mammalian toxicity of
the organophosphates and resistence development in certain
pests to be controlled, they are to some extent followed by
the third generation, the pyrethroids.
A further important area of use is in
animal husbandry against arthopode exo-and endoparasites.
Here only active ingredients at the lower end of the
mammalian toxicity can be used (e.g. Bromphenphos,
Dichlorvos (DDVP), Chlorvinphos, Fenthion, Phosmet (Fosdan,
Imidian, Prolate, is one of the several organophosphates
used on cattle against grub, horn fly or others. Their use
on cattle is world-wide.
Other minor uses of organophosphates,
e.g. additives, are of no relevance.
Most organophosphates are of low
persistence. Nevertheless, there are residues on crops or
stored food as well as in meat and in meat products. These
residues require that acceptable daily intakes for the
active ingredient and maximum residue limits for food
commodities have been set assuring consumer safety.
Although lipophylic (water solubilities typically in the
range of 25-100 mg/l) organophosphates are not considered
to bioaccumulate due to fast range metabolism/low
persistence. The bioaccumulation factor of Phosmet e.g. in
fish is about 50.
Only triesters of phosphoric acid are
considered in the present report.
II.2. Toxicodynamics and
Toxicokinetics
Both the toxicodynamics (mechanism of
action) and toxicokinetics (distribution, metabolism, etc.)
of OP's are largely explained by their biochemical
characteristic of interacting with esterases and proteases
(2). Esterases have been ranked into two main categories:
those inhibited by Op's, B-esterases, representing
potential targets for toxicity, and A-esterases which
hydrolyze OP's, thereby being involved in detoxification.
OP's interact with either esterase as substrates:
B-esterases after the formation of a Michaelis complex are
phophorylated and the reactivation is either very slow or
it does not occur at all. A-esterases, on the contrary,
hydrolyze OP's and their catalytic center is rapidly
restored.
Moreover, a further reaction might occur
on phosphorylated B-esterases, a phenomenon called aging,
involving the loss of a group attached to phosphorus and
leading to the formation of a negatively charged
irreversibely phosphorylated enzyme. On a given enzyme,
rates of reactions depend on the chemistry as well as on
chirality of the inhibitor.
Any given B-esterase is inhibited by
various OP's at different rates. Also rates of reactivation
and aging of phosphorylated enzymes are variable, depending
on the phosphoryl residue which occupies the catalytic
center. Therefore, the degree of inhibition of an esterase
and its duration at the site depend both on the enzyme
itself and on the chemistry of the OP. For instance, while
OP's inhibit acetylcholinesterase (AChE) at variable
concentrations, both spontaneous reactivation and aging
depend on the phosphoryl residue bound to the active site.
As a result of AChE phosphorylation by different OP's, this
residue can be the same.
II.3. Toxic Mechanisms
II.3.a. Cholinergic
Overstimulation
The molecular mechanism of cholinergic
toxicity involves the interaction of OP's with AChE (3), an
elongated molecular structure formed by heterologous
subunits, is localized in the outer basal lamina of the
synapse. A single gen encodes the catalytic subunits of
AChE and the threedimensional structure of AChE has been
determined (4). Both substrate and inhibitor react
covalently with the enzyme in essentially the same manner
because acetylation of the resine residue in the active
center of AChE is analogous to phosphorylation. However, in
contrast with the acetylated enzyme, which rapidly gives
acetic acid and restores the catalytic center, the
phosphorylated enzyme is stable. Calculated turnover rates,
i.e. the number of molecules hydrolyzed per minute by one
molecule are as follows: 300.000 for acetylcholine and
0.008 for OP's. Spontaneous reactivation of enzyme may
require several hours (dimethoxy) or does not occur at all
(secondary, such as DFP, or tertiary alkyl groups). The
loss of one alkyl group, occurring through the
non-enzymatic process of aging, further enhances the
stability of the phosphorylated enzyme.
AChE's crystal structure reveals that
the anionic moiety of AChE's, thought to attract the
quaterny nitrogen of the substrate, is misnamed because it
contains at most one negative charge. It has been proposed
instead that the quaternary moiety of acetylcholine binds
chiefly through interactions with the aromatic residues
which line the walls and floor of the gorge.
When blocked by the phosphoryl residue,
the serine group of the catalytic center is no longer able
to participate in the hydrolysis of acetylcholine. Thus the
neurotransmitter accumulates, its action is enhanced and
given the widespread distribution of cholinergic
neurotransmission, toxic effects of OP's will involve
parasympathetic, sympathetic and somatic motor component of
the PNS and also the CNS (5). Signs and symptoms include
lacrimation, hypersalivation, bronchial hypersecretion and
bronchoconstriction, urination and defecation, skeletal
muscle fasciculation and twitching, ataxia, respiratory
failure, convulsions, hypothermia and death. Death is due
to respiratory failure resulting from the combination of
these effects.
The interaction of acetylcholine with
either muscarinic or nicotinic receptors leads to various
biochemical effects on second messenger systems (6) and
eventually to the toxic response. Single doses of OP's do
not affect brain muscarinic receptors (7) whereas repeated
exposures may reduce both their density and affinity for
specific ligands(8). Reduction in muscarinic receptors
shows regional specificity (9), reflecting either
differences in duration or intensity of cholinergic
stimulation, or a selective access of the inhibitor.
Reductions of high-affinity brain nicotine-binding sites
have also been found after chronic cholinergic stimulation
(10). Symptoms of excessive cholinergic stimulation are
gradually reduced during chronic OP exposure, despite
significant inhibition of AChE, the development of this
tolerance has been in part associated with down-regulation
of muscarinic receptors caused by prolonged AChE inhibition
and acetylcholine stimulation (11).
II.3.b. Delayed Polyneuropathy
Single doses of certain OP's cause a
central-peripheral distal sensory-motor axonopathy known as
organophosphate-induced delayed polyneuropathy (OPIDP)
(12,13,14,15,16).
The molecular target is thought to be a
protein in the nervous system called Neuropathy Target
Esterase (NTE). High inhibition of NTE (> 70%) in the
nervous system, measured within hours after dosing,
correlates with the delayed onset of clinical signs of
OPIDP 10-20 days later. OPIDP is caused by certain, but not
all OP's, providing they inhibit NTE above the threshold.
Doses causing OPIDP depend on the OP, the route of
administration, the species and other factors.
However from the practical point of
view, it is important how the dose causing OPIDP compares
with that causing cholinergic toxicity (17). This concept,
represented numerically by the ratio LD50/neurotoxic dose,
allows comparisons of the potential of OP's to cause OPIDP.
Thus a ratio LD50/neurotoxic > 1 discriminates OP's
causing OPIDP at doses which do not cause cholinergic
toxicity from those which cause OPIDP only if animals are
treated against cholinergic symptoms (ratio < 1). All
commercial OP insecticides have a ration of < 1 and most
have a ratio < 0.1. Therefore among NTE inhibitors,
cholinergic toxicity is the limiting factor for OPIDP
development.
Histopathology of OPIDP has been
described for several species (18, 19). The morphological
hallmark is axonal degeneration of motor and sensory fibers
characterized by focal nerve varicosities and paranodal
demyelination located in the distal but not terminal axons.
There is no evidence of death of corresponding neurons, but
varying degrees of chromatolysis occur in proportion to the
severity of neuropathy. Ultrastructural studies show
aggregation and accumulation of neurofiliments and
neurotubules as well as proliferation of smooth endoplasmic
reticulum, particularly in proximity to nodes of Ranvier.
Lesions are distributed both in the CNS (spinal cord) and
PNS (peripheral nerves of legs mostly. The degree of
pyramidal involvement predicts the pathogenesis of OPIDP.
If only peripheral nerves are involved the neuropathy is
reversible within several months whereas if CNS is
involved, spasticity is permanent.
II.4. Phosmet
II.4.a. Identity and Use
Phosmet is a non-systemic OP insecticide
used on both animals and plants. It can be used in the
treatment of warble-fly in cattle and also as an active
ingredient in some dog collars.
II.4.b. Chemical Structure
The structure of Phosmet is given in the
following Figure. Its IUPAC name is
O-O-dimethyl-S-phthalimidomethyl-
phosphorodithioate.
Figure
II.4.c. Metabolism and Fate (20):
In humans and animals:
- Phosmet shows a very rapid kinetism
with a very quick absorption, distribution and elimination.
Radiolabeled Phosmet was excreted predominantly in the
urine: by the time of sacrifice (120 hours after treatment)
79% had been excreted in the urine and 19% in the faeces,
while very little was expired as 14CO². Tissue levels of
radiolabel were low, especially in fat and the gonads. In
an other labeled study in rats very little label (1-2%) was
detected in the carcass 96 hours after treatment. The
lowest concentrations of label were found in bone and fat
and the highest in the skin. There were no data mentioned
for brain levels.
- It crosses the placenta - a single
dose of 70mg/kg in goats showed no more residues in the
milk after 24 and 48 hours.
- Cattle fed silage with an average
residue level of 19 ppm for 2 months showed no residue
levels in the milk above the detection limit of 0.01 ppm -
dietary levels of 20-100 ppm showed no residues in the
tissues higher than 5 ppb.
- Metabolic breakdown in very quick. A
proposed metabolic pathway is given in the following
figure. Phtalamic acid and phtalic acid and their esters
are the most important metabolites. Phtalamic acid would
have been deaminated to phtalamic anhydride and hydrolysed
to phtalic acid.
(Figure)
Environmental Fate:
- Phosmet is rapidly broken down in
soil. The compound persists longer in dry soil than in
moist soil. Breakdown is also faster under basic
conditions.
- In water it is rapidly broken down by
hydrolysis and by sunlight (photolysis). Under alkaline
conditions (pH 9) the half-life is as short as 16 hours -
in a neutral solution (pH 7) the half-life is 18 hours and
under acidic conditions (pH 5) the half-life is within 9
days.
- Plants break down phosmet quickly,
primarily by oxidation and hydrolysis. Washing and
blanching can reduce residue levels by 50 to 80%.
II.4.d. Effects on Enzymes (20)
Erythrocyte and brain cholinesterases
are more sensitive to Phosmet in rats than is plasma
cholinesterase. Rat aliesterases are more sensitive to
inhibition by Phosmet than is acetylcholinesterase.
A dose of 10 mg/kg orally administered
has no effect on plasma or erythrocyte cholinesterase
activities at either time or on brain cholinesterase
activity at 24h. However 4 hours after treatment with this
dose, brain cholinesterase activity was inhibited by 14% in
males and 21% in females.
II.4.e. Toxicological Effects
(20)
- Acute Toxicity:
Moderately toxic by ingestion -
moderately to highly toxic through the skin - very high
toxic through inhalation.
Oral LD50 in rats is 113 - 369 mg/kg bw
- in mice 23-50 mg/kg bw.
The compound appears to be more toxic to
many domestic animals (cattle, sheep and goats): LD50 from
25-50 mg/kg bw., than for experimental animals.
- Chronic Toxicity:
In rats: NOAEL of 1-2 mg/kg/day
In dogs: NOAEL of 1 mg/kg/day
Cattle: 1-2 mg/kg for 8 weeks provoked a
decrease of blood enzyme activity.
In rabbits: during 3 weeks applied to
their skins showed high mortality at doses of 300-600
mg/kg/day.
- Delayed Neurotoxicity was not observed
in chickens, the most sensitive animal species
known.
- Reproductive Effects:
In rats: 2.0 mg/kg bw for the first
generation -4.0 mg/kg for the second and third generations
did not provoke negative reproductive effects.
In rabbits: 10-60 mg/kg dermally and
orally 3 weeks before mating and on 18 consecutive days of
gestation showed no effects on reproduction
parameters.
Conclusion: Phosmet did not shown
negative effects on reproduction.
- Teratogenic Effects:
In rabbits: 10-60 mg/kg for 3 weeks gave
no birth defects. A NOAEL was estimated to be 35
mg/kg
In monkeys: 8-12/kg for days 22-32 of
gestation gave no birth defects.
In rats: 30 mg/kg between day 9 and 13
of gestation produced an increase in brain damage
(hydrocephaly) in 33 out the 55 embryos examined. With
lower doses (1-5 mg/kg) such effect was not seen.
Conclusion: No convincing evidence for
teratogenic effects has been found in rabbits or monkeys,
whereas in rats only, at high doses of 30 mg, some effect
was seen, probably due to maternal toxicity.
- Mutagenic Effects
In bacteria: no any mutation test was
positive except in two tests with one strain of Salmonella
Typhimurium (reverse mutation).
In animal cells: two mouse lymphoma
tests were performed with a positive result, one (forward
mutation at the tk locus) in the absence of metabolic
activation and one (sister chromatid) in the absence of
metabolic activation (< 0.1 mg/ml) and one in the
presence of metabolic activation (0.008-0.040
mg/ml).
Conclusion: its mutagenic potential is
rather unclear but certainly not proven.
- Carcinogenic Effects:
In rats: 1-20 mg/kg/day for 2 years
showed no differences but there were too few rats at the
end of the test. In another study no tumours were seen that
were attributable to treatment with Phosmet.
In mice: no treatment -related changes
in organ-weights or macroscopic or microscopic appearance
were seen, except in the liver. There was an increase in
the incidence of liver adenomas (25/50) in males at a dose
of 100 ppm. Liver adenomas were found in 13/60 controls,
10/60 at 5 ppm., 14/60 at 25 ppm and 27/60 at 100 ppm. The
prevalence of liver adenomas in the group given the highest
dose was reported to be comparable to that in historical
controls. No increase in the incidence of liver tumours was
seen in females.
III. Comments on the papers of Purdey (1996)
III.1. Paper 1. The mechanism for the
pathogenesis / transmissibility
The author proposes a hypothesis in
which it is said that exposure of the bovine embryo to
specific high-dose lipophylic formulations of
organophosphate insecticides was the primary trigger that
initiated the UK's Bovine Spongiform Encephalopathy
epidemy. The mechanism should be a covalent binding with
phosphorylating and aging serine, tyrosine or histidine
active sites on fetal CNS prion protein. Once this abnormal
prion protein isoform agent is initiated, any stress event
ensuing in adult life induces a
nerve-growth-factor-mediated synthesis of normal cellular
prion protein isoform that aggregates to abnormally
phosphorylated isoform. The abnormally phosphorylated
isoform PrP
Sc is left corrupted by an extra charged
phosphate group. In so far the summary of the
hypothesis.
Comments from the SSC:
Purdey (1996a, 1996b) combines a series
of hypotheses with proven and unproven biochemical and
biophysical features. Some criticisms are formulated
hereafter:
- Phosmet is very quickly metabolized
and eliminated with no significant tissue accumulation
except in fish. Moreover it has been proven that Phosmet
residues have no delayed neurotoxicity in chickens, the
most sensitive animal species. Such a proof is not
demonstrated in the paper.
- No mention is made of any reference or
study which proves the presence of a receptor site on the
surface (membrane) of the prion protein. It is not enough
to speculate on the presence of a serine molecule in order
to propose also a covalent binding of OP's on a prion
protein. The whole hypothesis is speculative.
- According to the paper, the hypothesis
for the trigger effect on brain prion proteins by Phosmet
is supported by its structure-relationship with
Thalidomide, a very well known teratogen.
- Thalidomide:
The chemical structure of Thalidomide is
shown in the following figure.
(Figure)
This product is very intensively
hydrolysed
in vivo
to form secundary, tertiary and quaternary hydrolysis
products. These hydrolysis products however do not appear
to possess significant teratogenic activity.
There is also a very different
sensitivity to Thalidomide between the different animal
species. So the teratogenic effects of Thalidomide are not
still proven in cattle.
An intact Phtalimide or Phtalimidine
group appears to be essential for teratogenic activity.
Thalidomide teratogenicity was dominantly restricted to
skeletal malformations mostly of the limbs.
- Phosmet
It seems indeed that Phosmet contains a
phtalimide moiety. Hence the conclusion that Phosmet may
have identical toxicological properties as Thalidomide and
that this gives an explanation for the so-said CNS protein
toxicity.
However extensive structure-activity
studies have been carried out with over 60 compounds
stereochemically related to Thalidomide (under which
Phosmet (21). Only Thalidomide itself and three other
analogs (See figure) are clearly teratogenic in rabbit, the
most sensitive experimental animal.
(Figure)
- Finally before the whole proposed
hypothesis can scientifically be accepted as real and the
link between the use of OP's and BSE can scientifically be
accepted in the pathogenesis of TSE's, the possible
affinity and convalent binding of OP's for PrP protein
should be shown. Therefore real studies are lacking in his
paper.
Conclusion: DFP (di-iso-propyl
fluorophosphate) is an OP which causes both cholinergic
toxicity and delayed polyneuropathy), approximately at the
same dose. It has been used as a model OP to ascertain if
these chemicals, including phosmet, might bind to prion
proteins. Since no binding was detected it is unlikely that
OP's would be capable of modifying this protein, either
directly or with a mechnism other than
phosphorylation.
III.2. Paper 2: An epidemiological
perspective
This paper tries to elucidate the flaws
in the hypothesis that BSE originated from alterations in
the way that scrapie-contaminated cattlefeeds were
manufactured in the UK. The whole epidemiological evolution
of BSE is explained in the frame of the hypothesis already
described in the first paper.
His conclusion is that both timing,
distribution and dynamics of usage of these specific OP's
(a.o. Phosmet) correlates with the epidemiology of
BSE.
Comments from the SSC:
The first paper provides a scenario in
which the use of Phosmet as treatment for warbles and the
epidemiology of BSE are put in relation with each other.
But data and numbers are lacking and the scenario is rather
speculative and anecdotal. The exact number of farms where
Phosmet was indeed applied in cattle and the exact number
of really diagnozed BSE cases in the same farms are not
provided.
Conclusion: The SSC concludes that the
paper is no a true epidemiological study as it is not
scientifically founded.
IV. Opinion
On the basis of the elements and evaluations presented
in the above report, the Scientific Steering Committee
confirms the opinion of 16 May 1997 of the
Multidisciplinary Scientific Committee and concludes that
there isat present no scientific evidence of possible
links between BSE and organophospahtes used as pesticides
against ecto- and endoparasites in cattle.
V. Acknowledgements
The present report and opinion adopted
by the Scientific Steering Committee is substantially based
on the work of a working group chaired by
Dr.E.Vanopdenbosch. Special thanks are qddressed to
Professor .Dr.M.Debackere for his major role in the
preparation of the present document. The other members of
the working group were Professor Dr. M.Lotti, Professor Dr.
W.Klein and Professor Dr.Med.F.Kemper.
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26. King, J.W., 1996. Bovine Spongiform
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27. Lotti, M.,1997. Letter to the secretariat of the
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28. Poulsen, E., 1997. Comments on the postulated
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29. Poulsen, E., 1997. Letter of 3 March 1998 to the
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