Submission to the Working Group on Risk Assessment for Mixtures of Pesticides and Veterinary Medicines

2nd May 2001

Dear Sir,

It seems to me that the Working Group has been given an impossible task. From unreliable, incomplete, often inaccurate and poorly understood information frequently based on best guess opinion and flawed assumptions, they are expected to produce a reliable working model to predict exposure risks.
By any standards this is a monumental task but it will all be pointless unless a more determined effort is made to ensure that all products are properly tested before they are released on the market.

I am concerned that the information pack describes synergy as simply a synonym for potentiation.
Whilst potentiation may rightly be regarded as a form of synergy its implications for the task of the Working Group are far more serious than readers of this pack might assume. Synergy, combined or correlated action, is described as when an agent acts with another to produce a result that is greater than adding together the separate effects of the two agents and is utilised in various medical treatments such as in the treatment of Parkinson's disease1. It may also be extremely dangerous to the health of those exposed, as in drug treatments when one medicine may cause another to create dangerous or even fatal side effects. These dangers are well known and widely reported. Potentiation, (from potentiate, to endow with power or potency), is a potentially more serious matter because apparently harmless substances may become toxic in combination. Potentiation is described as "a special form of synergism" in which "one of two agents exerts no effect on exposure; but when exposure to both agents occurs, the effect of the active agent is increased." 2.
Yet another form of potentiation occurs when compounds not apparently toxic in vitro are converted by the metabolism of insects, animals or humans into highly toxic forms. This is a known and admitted problem involving a single active ingredient. An example of this is found with parathion which can be converted to paraoxon in the body. The claim that such exposures would result in summation, or merely additive effects 3.
,must clearly be incorrect since two products which exert no effect at all when added together should also produce no effect and yet such combinations may be harmful. The assumption of summation is dangerous.
There is no mention in the pack of the potential for catalysts to increase the effectiveness of the reactions or for the co-formulants which may protect the active ingredients from breakdown without actually taking part in any resulting action but which may change the target of the active ingredient.
Too many assumptions have been made in this area and there is a desperate need to examine the science in greater detail than is indicated in the information pack.

It is simply not satisfactory to place reliance on the No Observable Adverse Effect Levels or the Lowest Observable Adverse Effect Levels. This may be the preferred approach but it is deeply flawed.

Many of the actions of chemicals take place at levels far lower than those which can create observable effects. Supporting evidence for this view is found in the dreadful histories of thalidomide and DES (diethylstilbestrol) 4.
neither of which showed any observable effects in the mothers upon whom the drugs were administered but both of which induced serious adverse health effects in the unborn children.
It should be noted that these were low dose exposures, within the recommended levels, and yet the effects were both disastrous and in the case of DES with very much delayed effects which resulted in cancers and immune system dysfunction when the children became adults. Recently similar delayed effects in the offspring of exposed humans have been suspected as linked to Agent Orange.
No amount of animal testing or modelling will indicate such dangers since no test animals live that long and few laboratory studies will exceed more than a few years. These reactions illustrate that science is not as well versed in the actions of chemicals in the body as some would suggest but there are concerns over the extent of knowledge in respect to the chemicals themselves.
Recently there came confirmation from scientists in Egypt that glyphosate does indeed behave like other OPs as a cholinesterase inhibitor. This has been denied in correspondence from various Government agencies despite the fact that they were informed of evidence from human exposures. Now it seems that they were entirely wrong in making those denials which allowed the chemical to escape the recent review of anticholinesterase compounds and yet the entire safety policy for that chemical is indicated as grossly unsound by that simple fact. But even this is not the whole story since it is clear that the experiments showed that other vital enzymes were also affected by the presence of the chemical at levels far below those which can induce observable effects. Some of them could have disastrous consequences for human life in the long term and yet the industry continues to promote its greater use despite the warning signs.

Given the unarguable truth of the previous section it is clear that the human race has failed to realise the potential dangers to our future wellbeing from singe active ingredients. However, before we move to the discussion on combined effects of pesticides we should consider the real and not the theoretical world.
In the real world the active ingredient is rarely used alone. Active ingredients are carefully mixed with other, sometimes equally dangerous, ingredients to form a commercially available product for which the formulation is often secret and the purpose of those ingredients largely unknown. In my own correspondence there is evidence that the UK regulators had no idea what the true purpose of ingredients were in a formulation for which the active ingredient had recently undergone "full evaluation".
Although that evaluation document gave an opinion on the toxic potential of the breakdown products formed from the active ingredient the regulatory body concerned had no idea of the toxicity of the products formed by the breakdown of the commercially available formulation. Even though that chemical has been in commercial use for some 25 years, and is used as an undeclared additive in food, little is actually known about the product's lasting effects, not even by the manufacturers themselves.
Again this was proven in correspondence and in law.
So it has to be admitted that even for single ingredients little is known of the toxic effects on the metabolism of humans and the gaps in knowledge are even wider in respect to formulations.

So we turn to the terms of reference and section one which deals with the "Cocktail effect".
It is clear that in many of the published studies any experiments which have been undertaken have employed the active ingredients only. Perhaps this is because the use of the full formulation is known to produce unfavourable results since some of the co-formulants are known carcinogens and sensitisers.
Of interest to me is my early experience when responsible for weed control in growing crops in the 1970s.
I was lucky to know a very good chemical salesman who surprised me by advising me to cut the rate of use of one herbicide by half and add a little of another herbicide to the tank. This he suggested would better control weeds which would otherwise survive the full dose of either product. To my amazement he was absolutely right. Later we discovered that use of the then very expensive glyphosate formulation, Roundup, could be made much cheaper by reducing the rate by half or more and adding a simple wetting agent. The results were often superior to the use of the full rate. These effects have been utilised to great effect by the manufacturers and those who have promoted various low volume application methods.

My studies for the BSE Inquiry indicated the serious potential dangers of the "cocktail effect". I was responsible for a herd of cows exposed to a variety of chemicals, pesticides and their residues, and drugs.
The cows were eating grain treated with OP insecticides. OP warblecides were poured on their backs every winter. In summer came pyrethroid fly control sprays or tags and the cowman would sometimes treat them with lindane to control lice during the winter housing period. In addition they would receive antibiotics for any health problems they might encounter and anthelmintics to control internal parasites.
Other farms may have taken the advice of MAFF and spray companies to spray their grass with Roundup prior to a last grazing, hay or silage cut before the plough. They may also have sprayed the cereal crops with Roundup just before harvest and although claims are made that the residues are unimportant reports suggest that workers handling bales of treated straw suffer from skin rashes.
A herbicide used at that time in the spring on winter cereals, "Cornox 290 plus", carried a warning that the straw from the treated crop should not be used for horticultural purposes. The residues from the spraying operations in the spring presented a risk to horticultural crops grown in the following spring. How much more risk is there from residues resulting from chemicals applied in the autumn? The cows also ate the straw. I would be most surprised if any testing was done in respect to these combinations. Perhaps it is no surprise that the cows succumbed to BSE?

The human food chain is probably even more frightening given the wider range of foodstuffs eaten and the profusion of dangerous chemicals in the environment from industry and its domestic products.
It seems that our cars are now mobile hazardous waste incinerators since the benzenes and other toxins formerly released by industry are now found in the fuel for motor vehicles. Cows rarely cover themselves in the new "everlasting" perfumes or work in chemically loaded environments as chemical applicators.
Perhaps we are lucky that the human system is as robust as it is but the signs are that this is changing.

Asthma is now admitted to be at epidemic levels. There is real cause for concern here since many of the recognised treatments for asthma are contraindicated in poisoning because of the recognised synergistic effects. The theophyllines for example are dangerous to those poisoned by anticholinesterase pesticides and, with increasing numbers of children treated with these drugs, OPs in food only serve to worsen the condition.
Children are therefore at increased risk from residues not only because they are children but also because they are given contraindicated drugs in combination with those residues.
Perhaps more worrying is that if the doctor suspects infection, also mimicked by poisoning, he may use antibiotics in addition to the asthma drugs. Some of these such as Erythromycin actually increase the adverse effects caused by the theophyllines 5.
as I know to my cost and bitter experience.
For the majority of anticholinesterase pesticides this is the base test for safety since it is the most obviously observed adverse effect but it is clear that other enzyme systems of equal or greater importance may be corrupted at much lower levels of exposure.
Indication of the complex effect of OPs is shown by the use of Diazepam to control the tremors induced since this drug acts on the GABA pathway 6.
. Clearly this multiplicity of interdependent actions must be taken into account when making assumptions on the risk of individual pesticides but it is essential to examine them when considering the "Cocktail effect".

Section two of the terms of reference concerns just this matter. I suggest that there are no sound assumptions which can honestly be made when considering the combined effects of two chemicals but the Working Group must consider the effects of hundreds of chemicals taken in every day by humans via the respiratory tract, skin and by ingestion. This I suggest is an impossible task and I respectfully suggest that the Working Group examine more closely the known enzyme targets of such chemicals as organophosphates as a means to demonstrate the dangers of combined effects.
If we examine glyphosate for example we find that in a study reported in the Journal of Environmental Science Health in January 2001, El-Demerdash, Yousef, and Elagamy EI of the Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Egypt glyphosate was shown to be toxic to the vital human enzymes; serum acetylcholinesterase (AChE), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (AlP). Which shows that despite claims made by the manufacturers and their supporters glyphosate is indeed a cholinesterase inhibitor.
In correspondence the Pesticide Safety Directorate denied that the glyphosate had such actions and instead pointed me to a paper produced by the WHO suggesting that the chemical's action is in the mitochondria. "The mechanism of the toxic action of glyphosate has been tested in rats. Olorunsaga et al. (1979) observed dose-related reduced respiratory control ratios and increased phosphatase activity in mitochondria isolated from rat livers 5 hr after single intraperitoneal doses ranging from 15 to 120 mg/kg body weight. This effect was also seen in rat liver mitochondria in vitro (Bababunmi et al., 1979, Olorunsaga, 1982a,b). The authors suggest that acute toxicity at lethal doses may occur as a result of the uncoupling of oxidative phosphorylation."
They later wrote that Mitochondria are the subcellular organelles responsible for energy production. This energy is stored in the form of ATP, Mitochondria contain a small genome that is responsible for producing some of the proteins (enzymes) associated with ATP production. Back in the 1970s B J Walker wrote in his book "Organophosphorus Chemistry" that OPs could indeed interfere with the ATP/ADP energy system but interlinked with that system is cyclic AMP which is essential for the proper utilisation of hormones. Already we have wide ranging potential health effects and we have only considered glyphosate - that "safe" chemical widely promoted as "almost safe to drink" and to eat with GM crops.

So we must now consider another chemical in order to demonstrate the potential toxicity of pesticides in combination. What better than pirimiphos methyl which is another organophosphate and is also widely found as a residue in food crops, not least because it is deliberately added to grain after harvest.
Pirimiphos methyl has a claimed half-life of days in water and just hours in sunlight but the insecticidal ability of the commercially available formulations can be measured in years. This increases the risk of cumulative exposures resulting from the increased half-life because numerous exposures, both by skin contact and inhalation, can follow a single period of use due to the persistence of the compound and its presence in the treated grains. Such grain is protected for up to 12 months according to the manufacturer's own advertising and it is admitted 7.
that up to 50% of the applied chemical can be found in bread made from treated grain. There has also been observed and admitted damage to systems other than the damage caused by its anticholinesterase action including reproduction and the mutation of bacteria. The chemical has also been shown to have adverse effects on the proteolytic enzymes 8.
which form essential proteins in the metabolism.
Pirimiphos methyl is acidic (around pH 5.9) and it seems that when the pH changes the action of the enzymes making the proteins changes too. Also the change in pH changes the polarisation of the protein. Acidic gives a positive charge and the protein moves towards the negative. High pH gives a negative charge and the opposite action. The change in pH "can also alter the ionisation state at the catalytic site on the enzyme or affect the protein molecule so that its conformation and catalytic activity change." Enzymes, mainly globular proteins, are also functionally altered by changes in shape and pH.
"Proteins show an exquisite specificity of biological function - a consequence of the uniqueness of the three-dimensional structural shape or conformation of each protein." The toxicity of poisons depends more on molecular shape than chemical formula. "In humans, disease states are often related to the altered function of a protein. This is due to an anomaly in the structure of the protein, which in turn may be due to a deficiency in its synthesis."
"Primary structure is the covalent "backbone" of the polypeptide formed by the specific amino acid sequence. This sequence is encoded for in DNA and determines the final three dimensional form....."
"secondary structure is the spacial relationships of neighbouring amino acid residues" "If Hydrogen bonds form between peptide bonds in the same chain, helical structures develop.......If the Hydrogen bonds form between peptide bonds in different chains, extended structures form such as .....pleated sheet "
So if the OPs inhibit the enzyme process either by direct bonding or by changing the pH of the enzyme it seems more than likely that proteins will be miss-formed or even missing altogether."In some cases the variance of just one amino acid can be crucial" 9.
to the causation of ill health. If the missing protein is then added - as in the CJD and mouse scrapie experiments the enzymes may well repair the damage and reverse the disease process as was recently reported.

So there we have two of the most common OPs in regular use and which are present at increasing levels in our food but whose combined reactions have the potential to disrupt protein formation and therefore cause long-term disease in man. But our exposures are far more complex than simply two compounds.
The synapses of the nervous system depend on calcium entry which triggers acetylcholine release but apparently the GABA receptors are also involved in the inhibition process. Organochlorines apparently target the GABA system 10.
and there are links here with the effects of OPs by their combined action on both calcium levels and at the synapses - a deadly combination?

Permethrins are not "safe" and were proven to be cumulative and irreversible nerve toxins in the early 1800s according to extracts of a paper by W.J. Rea on pesticides sent to me in 1996. Apparently the pyrethroids act on the sodium channels10.
, and were known to be neurotoxic following investigations on animals even in the early nineteenth century. He wrote that they "are membrane poisons, which are known among other functions, to disturb the nervous conduction not only of insects and other invertebrates, but also of vertebrates and, therefore, humans. Because of their deficient specificity, high effectiveness, irreversibility and accumulation of their effects as well as their persistence in the environment, many investigators predicted that the mass use of pyrethroids in the environment of humans would lead to chronic health impairment. Results of clinical investigations suggest that the predictions have become reality........" In combination with the unavoidable OPs, and with DDT or Lindane to which we have all been exposed it is clear to see that there could be serious and unpredictable effects.

Could I suggest that there is ample evidence here of the risks imposed by exposure to combinations of pesticides, all of which act on different but interdependent systems within the body.
As if the point needed any emphasis the evidence that this risk was long recognised is found in the Government's own papers. One was entitled the "Safe use of Poisonous Chemicals on the Farm" and was published by MAFF in 1975 and there was a similar document called "Poisonous Chemicals on the Farm" which was published by the Health and Safety Executive in 1980.
On page 28 of the former it is clearly stated that:- "67. Although each group of pesticides acts in the body in different ways, it is undesirable on general grounds for an operator who has been removed from contact with a chemical group on medical grounds to be transferred to work with pesticides in a different group, e.g., an operator removed from contact with a dinitro compound should not be transferred to work with an organophosphorus compound or vice versa."
Although the above quote refers to individuals exposed to levels at which some degree of poisoning is apparent it does show that the interactions between the groups was well known even in those days.

Section 3 of the terms of reference refers to the impact of different exposure routes.
It is well recognised that the initial impact of pesticides varies with the route of absorption, with different initial symptom from skin contact, inhaled or ingested chemicals. I suggest that this is likely to be due to the predominance of different enzymes at each absorption site. As the chemical is absorbed into the blood stream then the classical symptoms of poisoning develop. It is of interest to note that an ADAS advice leaflet issued during the warble fly eradication campaign stated quite clearly that pouring the systemic OPs along the skin over the spine had the same effect as injecting the chemical into the bloodstream. The entire animal becomes toxic to the insects within it. The same must be true for humans whose skin has been exposed to these chemicals. If they then ingest food treated with other chemicals, or medication prescribed by their GP, I would suggest that the risks are obvious.
A problem raised in respect to Warble fly treatments, pet flea treatments and human head lice and scabies medications is not only the absorption of the chemicals but the potential formation of greater toxins by the action of sunlight. This too was mentioned by B J Walker who wrote of the transformation of parathion into far more toxic forms simply by the action of the ultraviolet light from the sun.
Pets, farm animals and children often spend long hours in the sun and the potential for harm is obvious.
It is already admitted that some of these chemicals are synergistic for other OPs. e.g. fenitrothion11.

Ingestion is an obvious risk but it seems that much of the data upon which safety levels are set involves the study of human cases of deliberate poisoning in suicide attempts treated in hospital. Many of these will have made full recovery and their cases go forward as supposed demonstrations of the lack of permanent harm caused as the result of ingestion. What is forgotten is that those who are hospitalised following poisoning will all receive the various antidotes designed to prevent the very long-term harm experienced by those poisoned at levels which do not result in hospital treatment. It would seem that the individual is likely to lead a more healthy life should he choose pesticides as a means to commit suicide than if he was to simply work as a pesticide applicator in efforts to help feed the world.
Once those applicators are poisoned they must then attempt to avoid adding to their health problems by avoiding ingesting more pesticides in their food - an almost impossible and very expensive task.

Inhalation of pesticides can occur simply by driving past a field on which spraying has been carried out.
Poisonings have been confirmed as the result of spray drift but reports never seem to tell us if the poisoning occurred as the result of skin contact or through inhalation.
Certainly the risks from inhalation alone were dramatically demonstrated in the Hong Kong, Phillips case where one musician amongst almost a hundred others suffered debilitating and long lasting effects. Why the authorities in this country rarely mention the inhalation risk is a matter requiring further investigation.

It is becoming increasingly difficult in the modern world to escape pesticides, medicines and veterinary products. Residues are supposedly tested but only a small fraction of the food sold are properly sampled and even then the sample is likely to be statistically insignificant. For example some 250 loaves of bread a year were sampled but this would include several different varieties. Of those loaves just a few grams will be sampled and many will have been above the recommended residue levels. Chances are that the highest levels will be discarded as errors but we do not know the full techniques used. However this is done the sampling has not found the reported high incorporation levels that everyone involved in the job knows happens and will admit to on days when their guard is down.
We know that illegally imported pesticides are used and that pre-harvest intervals and maximum dose rates have been ignored because there was a highly publicised successful court case locally but neither the government nor the supermarket sampling schemes detected any problem.
We know that illegally imported drugs have been used but residue testing has not discovered them as yet.
No one knows what damage these actions will have caused to human health and it is clear that the regulatory bodies are trying harder in their efforts not to recognise the problem than they are in their attempts to stop it happening again. Greater monitoring is desperately required, as is a change of attitude on the part of the regulatory bodies whose priorities should always be the protection of human health.

Section 4 of the terms of reference relates to advice on the standard risk assessment procedures in the light of the above considerations.
I would suggest that there is no such thing as "acceptable risk" when it comes to human health. If just 0.1% of human life is susceptible to harm caused by these products it will be some 60,000 people in the UK alone, subject to the new census figures which will doubtless not include illegal immigrants who will be fearful of declaring their presence on these shores.
60,000 people who are suffering from the effects of pesticides, drug reactions or the cancers and other serious illnesses which might result will be 60,000 lives of misery and pain, some for many years.
I suggest that risks are only "acceptable" when we talk of other people's lives. When it becomes a problem in our own lives we suddenly see those risks as entirely unacceptable. Some 3% of the population is known to be genetically deficient in the detoxifying enzymes for OPs and these together with those regularly exposed represent some 2 million souls endangered by the chemicals.
We are told in a very matter of fact way that a third of us will die of cancer. The death is the easy part.
The years of worry, pain, fear, discomfort, and the economic hardships almost always accompanying those deaths are often forgotten by the statisticians who condemn us all to that fate.
Statistics are historical creatures. They cannot predict outcomes. They are at best "guesses" based on probability which is also based on "best guess" levels. Statistically Three Mile Island and Chernobyl could never happen - but they did - and the "probability" of a new event then became more likely.
Statistically BSE was an "acceptable risk" when the OP warblecides, with their known risks12.
, and the rendering process changes were introduced, also ending the use of the OP extracting solvents.

I urge all the members of the Working Group to think very carefully before making assumptions of safety. I hope I have demonstrated above that current thinking is built on very shaky foundations and the results of those false assumptions are beginning to be seen in the health of the entire population.
One third of 60 million people is 20 million cancers. Many will be children born with the problem.
Some of us have done our very best in our attempts to stop this worsening problem. Our consciences are clear.


1. Black's Medical Dictionary 1992, p 566
2. Basic & Clinical Pharmacology 1995, p 880.
3. Penguin Dictionary of Biology 1996, p 600
4. Our Stolen Future, Colborn, Myers & Dumanoski1996, p 47-67
5. New Guide to medicines and drugs, BMA publication by Prof. John Henry, 1999, p 411
6. Basic & Clinical Pharmacology 1995, p 415
7. PSD Evaluation Document on Pirimiphos methyl Oct 1997, p 62
8. Effect of pirimiphos methyl on proteolitic enzyme activities in rat heart, kidney,
brain and liver tissues in vivo. Mantle, Saleem, Williams, Wilkins and Shakoori. Clinica
Chemica Acta 262 1997 p 89-97
9. Human Anatomy & Physiology Solomon & Davis, p 56
10. Pesticide Poisoning DoH publication by Proudfoot 1996.
11. The Pesticide Manual 1991, p 228.
12. Black's Veterinary Dictionary 1979, p 884.


Dated 27/5/2000

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