Variability and Uncertainty in Toxicology
Comments on the draft report of 7th April 2006

To the Food Standards Agency
Room 502c, Aviation House
125 Kingsway, London. WC2B 6NH

6th July 2006

Dear Mr Renshaw,

Grateful thanks for the printed copy of the report and for the opportunity to comment. I apologise for the length of time in responding but I am sure that you will understand the difficulties. I am afraid that I am not a scientist and although I have been forced to study these issues in some detail I am only able to comment on those aspects that my direct experience has taught me when using and having been seriously harmed by chemicals that are supposedly safe enough for us all to eat.
The report covers a wide range of toxicological issues and effects but there are other factors determining variability besides those “ inherent biological differences between species, strains, sub-strains and individuals” referred to in the document. Such influences include the levels of exposure and individual susceptibility due to specific weaknesses, previous exposures, or even the use of prescription drugs, all of which can induce variable responses within similar biological groups.
Presumably this factor would be placed under the term “uncertainty” but these reactions are not unexpected in the true sense of the word because such vulnerabilities are in many cases well understood.
True uncertainty is found in the toxicological effects of novel proteins as found in the recent “TGN 1412” drug trial in which volunteers became dangerously ill following the administration of drug at a fraction of the quantity tested successfully in laboratory animals. Unfortunately some pesticides in common use have the capability of disrupting protein formation and they can therefore also induce unexpected effects.
Perhaps this form of pesticides should be restricted in order to reduce the risks posed by such actions.

Evaluation of risk depends on the accuracy of the data before the various decision makers and there are many ways in which decisions can be influenced by false or misleading data.
For example the toxicity of formulations is often assumed to be the same or similar to that of the active ingredient, which itself may have been tested in an almost pure form that is not present in commercially available formulations. When tested the active ingredient may also have been mixed in laboratory conditions with pure distilled water and any data achieved from such experiments may be completely irrelevant to what happens with the same chemical in the commercial world.
Co-formulants, toxic impurities and other factors undermine the usefulness of laboratory data but the data is further undermined by the failure of the post marketing surveillance systems, plagued as they are by the inability of medical examiners to report accurately when they encounter chemically induced illness, for fear, it seems, of the consequences of admitting that chemicals licensed for use can induce illness in man.

Many people suffering the effects of toxic chemicals are told that the effects induced are “surprising” or “unexpected” only to discover years later that there is ample medical knowledge of just such effects.
It would seem therefore that there is a need for greater education in the known effects of toxins before we can say which effects are or are not “unexpected”.

The document refers to “the levels of exposure that are regarded as safe” but here again there is a need to quantify exactly what that term means for what is regarded as “safe” to some may be considered unsafe by others. Perhaps there is too much reliance on the “No Observed Adverse Effect” levels because many toxins can do great harm at sub-clinical levels at which no effects are observable at all.
If we are to accept a level of exposure that is expected to induce no adverse effects in the “majority of the population” then we should ensure that those who are in the minority are properly protected or that there is a suitable scheme to compensate them for any induced injury and illness.
This was the case for vaccines but it seems that it is now deemed expedient to deny that vaccines cause any harm at all rather than to admit to individual vulnerability and compensate for the damage caused by the decision to move toward a “herd immunity” situation. If individuals are to be sacrificed “for the greater good” then the majority should be grateful for the sacrifice and compensate accordingly.
The same must be true for other toxins permitted for use, especially when they are added to our food and cannot easily be detected or avoided by vulnerable groups. Nut allergy is a good example of how vulnerable groups have been protected and it is not easy to see why the simple labelling of presence so that they can be avoided where possible does not equally protect those vulnerable to chemicals added deliberately to food. There seems to be a determination to avoid this simple measure and yet one of the greatest weaknesses in epidemiological studies for chemically induced illness is the difficulty in identifying exposed individuals or groups. In truth the majority are exposed to levels considered as low enough to cause no serious effects but there are individuals and large sub-groups who will have far greater exposures, often on a daily basis, for which epidemiological tools cannot discover or account.

“As- low- as-reasonably- practical” levels for certain toxins is also a measure open to abuse since with most man-made toxins the option not to use them at all is always available. This effectively means that some person, or group of people, has determined that it is more important to maintain the industry producing the toxins than it is to protect humans from the defects induced by those chemicals. In the short term this may be possible but it is likely that the damage will be cumulative and future generations will ask why our generation permitted the damage caused to their lives. Already there are reports of children being born with cancers including brain cancers and leukaemia. No longer can it be said that cancer is a disease of old age or that chemically induced cancers can take 20 years to develop.
As the draft document suggests “it is known that some medical drugs, some recreational drugs and some environmental pollutants can have a developmental neurotoxicological effect” but there can be very serious interactions when humans are exposed to two or more of these chemicals at the same time or during the recovery period after exposure. This is an area where little research appears to have been done.

I cannot see how it can be said that “the current methods used by COT to identify safe levels of exposure to particular food chemicals and to set health-based guidance values/reference doses are pragmatic and appropriate” when there is so much uncertainty with regard to formulations, impurities, application rates, accidental or deliberate overdosing, and the grossly understated half-lives of some of the chemicals added to our food. It seems that we have a situation in which those who make the decisions are also responsible for determining if those decisions are correct and that can result in self-delusion and dangerous mistakes.

There is no doubt that “The degrees of variability and uncertainty attached to a particular risk assessment should be communicated to those involved in risk management, stakeholders and the general public” as stated in the document but at the current time it seems that every effort is made to undermine those who would inform the public and those who work with chemicals of the dangers. At any suggestion of health risk a variety of spokespeople come forward in attempts to undermine those who warn of the known dangers, often making statements that cannot be supported by facts or science. It almost seems as if past scientific knowledge is being ignored in order to protect dangerous chemicals.

Even though the document explains that “Hazard characterisation includes investigation of the ways in which a chemical is dealt with in the body (absorption, distribution, metabolism and elimination, collectively referred to as toxicokinetics) and the toxic effects of the chemical on the body (referred to as toxicodynamics” there are so many combinations of exposures and effects at cellular or molecular level, that such work is unlikely to create reliable information for comparison in normal human exposures.
An example of the above is found in the testing for organophosphorus exposures and although the draft states “for organophosphorus (OP) and carbamate anticholinesterase pesticides, acetylcholinesterase activity in erythrocytes and/or brain and butyrylcholinesterase activity in plasma or serum are measured.“ and “for the potential of OPs to cause OP-induced delayed polyneuropathy (OPIDP)” it is clear that the former misses vital effects on the metabolism, unrelated to cholinesterase, and the latter has been shown to be unreliable in predicting the potential to induce OPIDP in man.

The international harmonisation of the regulatory processes and data requirements owe more to the controlling influences of the manufacturers than to the requirement to protect human health. Evidence for that view is found in the number of chemicals formerly in common use which have had to be withdrawn because of the adverse effects on human health or the environment.
Had those chemicals been correctly assessed before release for commercial use there would have been no adverse effects but it is clear that many currently available formulations are causing harm both to the environment, as seen in the effects of the pyrethroid group of pesticides and oral contraceptives on aquatic life, and, despite determined denial of the evidence, the effects in humans of the organophosphorus compounds in pesticides, oils and other common uses, including veterinary medicines.

The document states that “the reason for not approving marketing of OPs that cause OPIDP is the irreversible and untreatable nature of the neuropathy” but despite evidence to the contrary the COT has suggested that there are no long-term effects from OPs, even though other countries have recognised the dangers and there have been successful court actions even in the UK in which evidence of the inadequacy of the hen test and the potential of OPs in common use to cause diagnosed OPIDN was produced.
There is also evidence that government employs doctors who are prepared to produce false reports on medical examinations during which they have admitted finding peripheral neuropathy in those exposed to OPs, and some of those chemicals are deliberately added to food. At least one of those doctors who have hidden the truth is now employed in a key position in pesticide regulation.

The comment “Post-marketing surveillance and pharmacovigilance systems are used in order to detect any adverse effects that were not foreseen by the pre-marketing safety testing of regulated substances. Regulatory authorities respond by taking measures (eg. withdrawal from sale) to limit the amount of harm that might be caused by unexpected adverse effects on the rare occasions that they occur” is overstating the efficiency of post-marketing surveillance.
There are many instances where chemicals that have caused unexpected health effects in man have remained on the market despite widespread protests by those who have been harmed. Rather than admit the problems it often seems as if the regulators are determined to avoid admitting that they missed a potential problem by denying the obvious effects in those affected, effects that are often looked for in test animals during the development phase.
Similarly even when groups of scientists warn of the cumulative effects of residues in food and recommend that an entire group of pesticides should be removed from commercial use because of the dangers presented in the food of children no steps are taken to enact those recommendations.
I refer to the US publication “Overexposed – Organophosphate Insecticides in Children’s Food” which was published as long ago as 1997 but the chemicals are still deliberately added to food and some of them are also present as true residues of crop spraying. What is clear from that publication is that even if children were exposed to residue levels below the MRLs for the various chemicals the overall exposure attained dangerous levels due to the number of chemicals to which they were exposed.
This is another example of how a grossly underestimated exposure level can be determined as “safe” simply because all exposures are not accounted for in the studies used to set “safe” levels.

Again when the document states “,i>the elderly are not a homogeneous group and those most likely to succumb are the frail elderly” once again misses the combined effects both of multiple exposures and of those in otherwise fit elderly people who none-the-less take prescription drugs which in turn have known contraindicated effects in the chemically exposed.

It is stated that “redistribution of chemicals stored in adipose tissue can result in a small increase in the concentrations present in non-adipose tissues and an increase in risk of acute effects. This may be of greatest importance for chemicals with very long half-lives due to a large apparent volume of distribution“ and yet evidence that the half-life of OPs added to food are grossly understated, and the Parliamentary admission that co-formulants are used protect the active ingredient and therefore prolong activity, was claimed to make no difference at all to safety considerations.
Many such chemicals are considered to be highly lipophilic and therefore present additional risk of harm to the brain and to developing and suckling children.

As admitted “exercise can greatly increase inhalational exposure” and yet the inhalatory exposure to OPs, with all the obvious risks involved have often been dismissed as unimportant or not even considered at all in many studies concerning exposure levels in the strenuous process of dipping sheep.

The paper refers to susceptibility of individuals whose genetic make-up results in the altered amino acid sequence of a protein and yet many OPs are known to adversely affect DNA and to interfere with protein synthesis. They must therefore present specific risks and because of the variability and uncertainty of the action of OPs at cellular and protein level plus the combination of multiple enzyme inhibition it must be extremely difficult to predict any true safe level of exposure. This has recently been admitted in Australia in regard to the sheep dip chemical diazinon but chemicals added to food create a situation in which it is almost impossible even for susceptible groups to avoid these compounds.
It is acknowledged that the organophosphorus group of chemicals, for example, inhibit enzymes other than, or in addition to, cholinesterase including amylase, carbonic anhydrase, carboxylase, choline oxidase, chymotrypsin, cytochrome oxidase, dehydrogenase, liver esterase, milk lipase, and trypsin.
It is reported that enzymes can make upwards of 300 molecular changes each millisecond and the resulting biochemical effects could be entirely unexpected and extremely damaging.
Since the effects of these compounds are well understood there should be no need for human volunteers to risk their health in order to prove what is already known – chemical users experiences appear to have been ignored, even though they offer evidence that would be sought for in any volunteer studies.
Given that OP compounds are known to damage DNA a means should be devised to ensure that DNA differences observed in susceptible individuals are of genetic origin and not the result of changes caused as the result of the exposure to the toxic compounds.
Ways must also be found to determine if such toxin induced changes in the DNA profile are then passed down through the generations in the same way as normal genetic variants.

Increasingly there are suggestions that schizophrenia, autism, and Parkinson’s Disease are the result of environmental exposures. I am personally aware of at least two diagnosed cases of schizophrenia in teenagers poisoned by organophosphorus compounds in pesticides. The effects on the families have been devastating and in neither case did the patients nor their families find the correct support in the medical profession. Richard Lathe, in his book “Autism, Brain and Environment” writes “The rising prevalence of ASD (new phase autism) may be ascribed to environmental toxicity, notably including heavy metals in combination with organic endocrine disruptors and other chemical toxins” and that “Toxic environmental influences are likely to be increasing”.
Attention Deficit Hyperactivity Disorder has also been linked to environmental toxins such as pesticides. I know farmers who have been exposed to OP pesticides and veterinary medicines who have been diagnosed with Parkinson’s Disease and when Professor Holgate of the Royal Commission on Environmental Pollution interviewed us and our GPs he commented on my own Parkinson-like tremor which has developed since exposure to grain store OPs added to food.
None of these effects appear to be recognized as causes for concern by the pesticide regulators.

The potential to disrupt the endocrine system by disruption of the ATP to cyclic AMP conversion is apparently often overlooked and yet many pesticides, including the more dangerous OPs are known to disrupt this energy dependent process. Many hormones and chemical signals depend on adenylate cyclase and this enzyme itself is dependent on the ATP molecule that is a target of such toxins. This may well explain the observed “Low dose effects” of chemicals that do not appear to act directly at receptor sites.
My wife and the wife of a workmate were diagnosed with breast cancers, which were described as being of environmental origin. Highly malignant cancers were oestrogen receptive and although evidence is very difficult to find it is thought that these and other breast cancers involving women and men in rural areas were caused by exposure to pesticides such as the organochlorine lindane, which was linked to breast cancer decades ago in Israel. Interestingly several cases of testicular cancer have also been diagnosed in this area, not least in a workmate’s son shortly after his father died from lymph cancer (which was also thought to be toxin induced) and they were also said to be hormone receptive.
The “Textbook of Modern Toxicology” edited by Ernest Hodgson, states “Epidemiological studies have provided sufficient evidence that exposure to a variety of chemicals, agents, or processes are associated with human cancer”. Many studies into the potential for pesticides to trigger cancer and other illnesses employ only the active ingredient and yet many of the co-formulants are themselves known to be carcinogenic. The chemical glyphosate is known to interfere with the mitochondria, likely because it is an organophosphorus compound, but studies have also suggested that it is a causal factor in lymph cancer and, although hotly denied in some circles, that it is also a nerve toxin. These may, or may not, be effects induced by co-formulants but it matters little in the real world because in commercial use the pure active ingredient is not available and humans are exposed in the environment and the diet to the formulations.
However that is only part of the problem because all of us are exposed to mixtures of formulations and it is known that the co-formulants in one product can enhance the toxicity of the active ingredient in another and with multiple exposures, most of which remain untested, it is difficult to predict or to discount any of the adverse effects on health that could result following exposure in either the short or long-term.

Current approaches to toxicological testing must be inadequate or there would not be the need for this review and there would be no need to withdraw any of the chemicals previously licensed.
For example Rachel Carson wrote in her book “Silent Spring” of the known carcinogenicity of benzene, of the extreme dangers presented by organophosphorus chemicals, and of the environmental persistence of the organochlorines, some 50 years ago and Lord Zuckerman advised serious measures to protect the public from the OPs even earlier in 1951, but no action was taken to protect the public or those who had to work with the chemicals.
History will certainly record this as a serious error of judgement and it is certain that future generations who will have to live with the harm caused to the environment will wish to know why the system designed to protect us all has failed.

It is my considered view that it is the failure, perhaps on instruction, of medical professionals to report accurately on the findings in their exposed patients that is undermining the post-marketing monitoring process by failing to ensure that the regulators and the manufacturers are aware of the problems being caused by exposure to toxins. That failure influences others and induces a belief in “unexpected” toxic effects when in reality those effects should be very much expected.
As an example in my own case, having been diagnosed as a poisoned patient, a highly influential toxicologist then wrote that the symptoms were not consistent with poisoning and yet they are the very symptoms looked for in poisoned workers as reported in the evaluation document for one of the very chemicals to which I was exposed. The proven cardio-respiratory, neurological, digestive, and vision problems, all consistent with poisoning, were then denied with the inference of mental illness.
Blood serum tests then provided evidence of the brain and neurological damage caused by the chemicals. Despite that and confirmation of the diagnosis from numerous experts in the field, and although it is officially recognised that the exposure caused serious disability for life, there is a determination based on false information and false statements to refuse to accept that I have ever been poisoned by the illegal mixture of OP compounds and their solvents following a life-time of high occupational exposures.
I have written records showing daily exposure to OPs and admissions that those exposures lasted for decades, written evidence that illness has followed exposure, scientific analysis proving that half-life figures are grossly understated, written diagnosis, evidence that medical reports have been falsified, and evidence that other people have suffered similarly as the result of exposure to the toxins involved, but still those who have the power to prevent others suffering from similar effects refuse to recognise the reality or the seriousness of the problem.
So many cases of toxin-induced illness are being “overlooked” in this way that any statistical analysis based on official figures is certain to be grossly inaccurate and misleading.
In my opinion it should be a criminal offence worthy of serious punishment to provide false information in regard to the effects on human health of commonly used poisons.
If the reporting system was more accurate the manufacturers and the regulators would have an early warning of the potential for any chemical to cause harm and they could take steps to reduce the damage before too much actual harm was done. As things are those warnings are not being received from the people whose duty it is to inform and as a result manufacturers can potentially create more powerful chemicals without realising what damage is being caused. A dangerous cycle is then established.
This situation must change or the human race will never learn from its mistakes.

“Predicted intakes” are another factor where unreliability is overlooked.
Assumptions are made on application rates, levels of residues, the half-life of chemicals, dietary intakes, environmental and food contamination, and lifestyles and yet considerable variation is found in all those factors.
As an example the official view for the half-life of insecticides permitted for admixture in grain intended for human consumption is that the chemical breaks down in days in water and hours in sunlight. Oddly even though the evaluation document for that chemical reports insecticidal action after weeks exposed to sunlight and rain and increasing levels during storage periods of grain the short half-life claims are relied upon for dietary intake. Scientific analysis of diluted product however indicates a worrying increase in active ingredient content after more than 5 years in water and experiments indicate insecticidal activity after years in sunlight. If it is assumed that the chemical is no longer active after days and yet it is found in baked bread then intake predictions must be called into question, especially given that humans could be exposed to a mixture of product residues daily from pre-conception to death.
As the document suggests these highly lipophilic chemicals pose especial risk to humans.
Similarly environmental exposures will also be greater if the products do not break down as rapidly as is suggested by the accepted data and this could explain why so many people are affected by vapour lift from treated crops for weeks after application. I have reported on these anomalies for over a decade but still the official view is that the chemicals break down rapidly, despite the evidence to the contrary, the admissions in Parliamentary answers that the active ingredients are protected by the co-formulants, and the ease with which this data could be checked by independent scientists.
It matters little which analytical method is employed to determine toxic effects if the data being analysed is fatally flawed by its inaccuracy or by the under-reporting of actual adverse effects in the population. Several reports including that of the British Medical Association in “Pesticides Chemicals and Health” in 1991 and the Royal Commission on Environmental Pollution report last year have criticised the lack of substance in the data from the ineffective monitoring systems in place that supposedly check for post-marketing adverse health effects. Acute poisonings are confirmed although chronic effects are questioned even though there is ample evidence to support the reality of those effects.
Epidemiology, even in specific groups such as agricultural workers, is an inexact determinant because few will admit to mistakes or unlawful mixtures and the group is not static and is open to an extremely high variability, in chemical use, exposure levels, lifestyles, residential circumstances, and so on. It is also possible to save considerable funds for research simply by recognising the scientific knowledge already available instead of finding ever more complex reasons for dismissing past research, as seems to be the frequently used exercise in scientific reviews when a desired result is preordained.

In all cases “expert opinion” is only as good as the data upon which that opinion is based and it is dangerous to assume that an expert in one field of medicine has necessarily taken into account vital factors in areas of medicine in which they have no expertise. Many women and a few men have been wrongly imprisoned because of “expert opinion” that has later proved to be completely incorrect.
Chemicals once deemed to be “safe” have permanently harmed, or killed, many thousands of people.
In toxicology the very future of mankind and the environment as we inherited it is dependent on correct decisions being made in regards to the toxicity of chemicals that contaminate our world.

The importance of total honesty and accuracy in science and medicine cannot be overemphasised.

Yours sincerely,

Dated 07/04/06 - Uploaded to website 05/03/2015

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