Select Committee on Environment, Food and Rural Affairs Written Evidence


Memorandum submitted by Integrin Advanced Biosystems (M2)

SUMMARY

    —  The "atypical" problem stemmed from CEFAS and DARD's inexperience in running the DSP Mouse Bioassay. This led to solvent-related deaths of mice most probably because of anaesthetic effects and heart failure.

    —  The lack of controls in the assay meant that this was not immediately recognised as an artefact and CEFAS and DARD did not conduct an appropriate investigation of possible matrix effects. Nor apparently did they seek and heed the advice of the more experienced FRS.

    —  The initial response of the FSA in closing cockle beds was correct. There was the threat of a genuine toxin being present and this merited further investigation even if it was a remote possibility.

    —  As the DSP MBA was uninformative as to the cause of the atypical response, the FSA should have suspended its use in cockles and banned both harvesting and imports of cockles into the UK until it was satisfied that there was not a risk to the public.

    —  The FSA did commission research to investigate possible reasons for the atypical response other than toxins but by giving much of this work to CEFAS it meant that methodological artefact was not investigated as a possible cause.

    —  By the autumn of 2002 the FSA were receiving strong representations from both industry and from FRS that solvent carry-over was the most likely cause of the atypical response. FSA rejected this advice and it took almost a year before it commissioned a proper investigation of this possibility.

    —  Solvent carry-over was demonstrated by these investigations. Despite solvent carry-over being a known cause of artefact in the DSP MBA and causes symptoms similar to those seen in the atypical response, the FSA continued to maintain that solvent carry-over was unrelated to the atypical response, going as far to say that they were satisfied that they had done enough work to eliminate it as a cause.

    —  The FSA did respond to the findings of solvent carry-over and an audit of procedures by introducing a new SOP which produced minimal solvent carry-over. Since the introduction of this new SOP there have been no atypical positives. Despite this firm evidence that solvent carry-over was involved in producing the atypical response, the FSA are still looking for a novel toxin.

    —  While the FSA as an organisation has probably acted in good faith throughout this episode, it can be criticised for the lengthy time taken to properly investigate the atypical response and for inconsistent reaction to it. Of particular concern are the public statements made by the FSA to the press and on their web site. These were often misleading and were not justified by the scientific information available, suggesting a lack of objectivity.

    —  The FSA should be subject to an independent scientific review to highlight lessons from this episode and to recommend robust scientific working practises to help avoid this sort of problem in the future.

INTRODUCTION

  1.  I am a marine biologist with over 20 years professional experience and over 50 scientific publications. In September 1999 I founded Integrin as the first marine biotechnology company in the UK. Integrin is focussed on two areas: drug discovery from marine invertebrates and seafood safety. Our seafood safety activities include providing testing services for marine toxins; contract research and consultancy relating to seafood safety and development of improved methods for the detection of marine toxins.

  2.  Our customers in seafood safety include shellfish harvesters, processors and retailers and we undertake work for major players including Sainsburys. We also do contract research for the FSA and are currently engaged in a desk study for FSAS on domoic acid testing in scallops. We pride ourselves on our independence, integrity and impartiality.

  3.  Integrin was by shellfish industry to provide the Committee with our professional opinion on the science commissioned by the FSA. We have had access to the correspondence between Industry and the FSA; have discussed the problem with persons within the FSA and Government laboratories; read the appropriate reports and discussed the matter at length with overseas experts. This letter gives a synopsis of our findings.

  4.  The Committee should be aware that Integrin were commercially commissioned by Kershaws to produce this piece of research. However, we could equally have been commissioned by the FSA to do this and our findings would have been the same. Kershaws have not asked for any input into the content of this letter and the opinions within it are solely those of Integrin.

  5.  Integrin are not intending to give verbal evidence to the Committee but I would be happy to attend to expand on any of the points in this letter if the Committee would find it useful.

THE MOUSE BIOASSAY AND QUALITY SYSTEMS

  6.  The UK government has a statutory responsibility to test bivalve shellfish for the presence of a number of different toxins that come (mostly) from marine algae. These produce the toxins, are eaten by the bivalve molluscs then humans can become ill when they consume the shellfish. The situation is complex because of the number and variety of toxins that can be found in shellfish and research is continually finding new toxins.

  7.  The main method used to detect shellfish toxins in Europe is the Mouse Bioassay (MBA). It is not universally used, even within Europe, and a number of countries (eg Germany, Sweden and Holland) prefer alternative methods for ethical or practical reasons.

  8.  The MBA falls into two main categories.  the PSP (Paralytic Shellfish Poisoning) MBA which looks for hydrophilic (water loving) toxins (mostly saxitoxins) and the DSP (Diarrhetic Shellfish Poisoning) MBA which looks for lipophilic (fat loving) toxins. The atypical response relates solely to the DSP MBA. It should be noted that the MBA is not used for all shellfish toxins. For detecting domoic acid a chemical method (HPLC) is used as the MBA is insufficiently sensitive.

  9.  The DSP MBA is a very crude assay. It involves injecting mice with a large volume of extract produced from shellfish. The extraction method aims to concentrate any toxins present so they can be detected. Extraction of the toxins is a crucial step and is very sensitive to changes in either the shellfish matrix or the extraction conditions.

  10.  The DSP MBA uses too few mice for any sort of meaningful statistical analysis to be done. It is not a quantitative, nor a discriminatory assay; ie the DSP MBA does not tell us how much of a toxin is present, nor what types of toxins. The assay is so extreme in terms of its severity that if one of the three mice used dies then the assay is considered to have passed. If two or three die then the assay fails. The assay thus accepts that 33% of the mice used may die by accident. An important point is that the MBA is an analytical assay designed to detect a specific group of toxins. It is not a general toxicity assay for assessing the safety of a foodstuff.

  11.  Crucially, the DSP MBA as used in the UK did not involve the use of controls. In any scientific experiment there must be adequate controls to guard against artefact. The importance of controls cannot be over-stated. The lack of controls was very important in the genesis of the atypical story.

  12.  For example, at Integrin we use chemical assays to detect DSP toxins. These are quantitative and always involve the use of both a negative and a positive control. The positive control is a material which is known to contain a defined amount of the toxin of interest. This is usually a reference material. If the assay does not detect the positive control or not at a level that is considered within the assays parameters then the test is rejected. A negative control is a material which is known to lack the toxin of interest. If the negative control produces a positive reaction then the assay is rejected.

  13.  Proper validation of the assay is important. Ideally this should be done on all the matrices that the assay is to be used on. In practise this can be difficult because of the time and expense involved. However, if an assay has been validated on a single matrix (eg mussels) any unusual result coming from a different matrix (eg cockles) should be subject to a separate validation to eliminate the possibility of a matrix effect.

  14.  Another important safeguard is the requirement of reproducibility. A sample being tested must always give a positive or a negative result, it must not give both a positive and a negative result. A lack of reproducibility is a clear indication of a methodological problem.

  15.  The last safeguard is external validation. In short, does another laboratory give similar results to your laboratory when they test the same material? If they do not then attention has to be paid to the reasons why.

  16.  The FSA has been making UKAS accreditation a formal requirement for laboratories tendering for work from them. They have also been supporting the development of new toxin standards, reference materials and ring trials. However, another crucial element in the atypical history was the relative inexperience of many of the bodies and individuals involved in shellfish toxins; the MBA and in running QA systems.

A HISTORY OF THE ATYPICAL RESPONSE

  17.  Through the '90's up till 2001, responsibility for monitoring shellfish in England, Scotland and Wales rested with the Fisheries Research Services (FRS) Laboratory in Aberdeen (and its progenitors).

  18.  In 2001 the FSA put out for tender four year contracts for both the Scottish Shellfish monitoring programme and a similar programme for England and Wales. CEFAS were awarded the England and Wales contract and FRS the Scottish contract. DARD maintained the contract to provide testing in Northern Ireland but introduced the MBA to bring them in line with the other laboratories. FRS also host the National Reference Laboratory for marine biotoxins.

  19.  CEFAS commenced the contract in the Spring of 2001 and almost immediately started having a much higher incidence of mouse deaths in the DSP MBA than FRS had previously encountered. The FSA was informed and they instructed local councils to close affected shellfish areas. Most (though not all) of the DSP MBA deaths were associated with cockle samples.

  20.  With time it emerged that cockles from all areas sampled by CEFAS were producing deaths despite their wide geographic separation. No seasonality appeared and the deaths were apparently random. It also emerged that the deaths were unusual—rapid, very severe and quite unlike "typical" DSP MBA deaths.

  21.  No known UK DSP toxins were found in the cockles samples, nor were any of the known contaminants (such as some fatty acids) that cause false positives in the MBA found. Exotic toxins (eg spirolides) were eventually eliminated as possible causes.

  22.  The FSA announced that continued closures of cockle beds was justified on the grounds of public safety and that the most likely explanation of the atypical positives was the presence of a novel neurotoxin (mostly) in cockles.

  23.  Between the Spring and Autumn of 2002 there was growing scepticism in many quarters that a novel toxin was responsible. This suspicion was strengthened by the failure of other European laboratories using the MBA to replicate the atypical results.

  24.  Of particular concern to the FSA was that FRS was not producing atypical responses while CEFAS contaminants (such as some fatty acids) that cause false positives in the MBA found. Exotic toxins (eg between the laboratories, the obvious implication was that the atypical response was an artefact produced by these differences. To head off this criticism, the FSA commissioned a comparative study between the laboratories all using the same cockle samples. This was undertaken in October 2002. FRS found no atypical positives, while a technician from CEFAS undertaking the MBA at FRS managed to kill all bar one of the mice used. At first sight it looked as if DARD and CEFAS obtained the same results but closer inspection reveals that this is because they are using a different scoring system. Depending on who is doing the assay, the same sample could be positive or negative.

  25.  This was a pivotal moment. FRS reacted strongly to a report from CEFAS on the experiment (that I have not seen but presumably said that FRS methods were inadequate). FRS countered that the lack of an overnight "de-gassing" in the DARD/CEFAS methods meant that the atypical results could be due to solvent carry-over; a known reason for the MBA to be compromised. They also provided some anecdotal evidence that this was occurring. They also suggested a number of other differences that could be producing the atypical responses.

  26.  The FSA was thrown into a degree of turmoil as evidenced by the summoning of an emergency meeting of the labs and FSA on the 6 November. Despite FRS having more experience than CEFAS, DARD or the FSA combined, the "official" Government line to emerge from this meeting was that the FRS SOP was failing to extract the toxin and that the methodology used in the DSP MBA was not the root cause of the atypical response. All parties were said to have agreed this. FRS, in private at least, certainly did not agree.

  27.  The main reason that the FSA rejected the possibility of methodological artefact appears to be that they could not square this with the observation that the atypical problem was mostly associated with cockles. Put simply, if it was a method problem why were not all species of bivalves producing the response? And if it was a matrix problem why were CEFAS and DARD obtaining negatives as well as positives? What they had missed was that the same sample of cockles was producing both negatives and positives.  a sure indication of a problem with the methodology.

  28.  Not only would solvent carry-over "in trace amounts" (Quote from Dr Godfrey Howard, FRS) cause mouse deaths, it would also explain the lack of an obvious candidate molecule; the rapid recovery of mice sometimes witnessed and the apparent loss of activity when samples were stored. Despite FRS putting up a number of testable hypotheses, experimental work on solvent carry-over seems to have been put to one side by the FSA.

  29.  In December 2002, FSA released a detailed "updating report" on the atypical response. It gives a good synopsis of why the FSA rejected ether carry-over as a factor (it did not consider acetone). We see here the emergence of a FSA paradigm based on argument rather than experimental science. This resulted in the "artefact hypothesis" having to pass a much higher bar of proof with the FSA than the alternative "novel toxin hypothesis". This is bad science but it is a crucial factor in explaining FSA's actions.

  30.  Another contributory factor was the claim by Prof Yasumoto to have isolated a polar toxin from cockle samples. This work has not been published so it is impossible to judge its relevance but it definitely had a major influence in FSA thinking. However, the DSP MBA is designed to look for non-polar (lipophilic) molecules and eliminate polar (hydrophilic) molecules. Polar toxins are checked for by the PSP MBA and no problems have been found with it. Work by the LGC to isolate and identify a toxin in the cockle extracts has so far failed to produce a candidate toxin molecule.

  31.  The next major development was the attempt by FSA to introduce a common extraction protocol in June 2003. This led to immediate atypical-like responses at FRS from mussel samples. FRS reported solvent carry-over and that the deaths were consistent with solvent toxicity.

  32.  FSA Scotland funded an immediate study by the Macaulay Institute and FRS. This found carry-over of DEE (ether) but the report was not released until a second and more detailed study, this time funded by FSA London and undertaken by CSL (York), to look at solvent carry-over using head space GC-MS was conducted. This also found considerable solvent carry-over at all three laboratories.

  33.  The FSA then claimed that the lack of statistically significant correlation between solvent carry-over and the atypical response proved that solvent carry-over was not responsible for the atypical response. This was a misuse of statistics (the report gave no indication of whether or not a statistically significant result could be expected given the very limited data set) and an inappropriate use of the data as the experiment had not been designed to look for correlations.

  34.  The use of head space GC-MS was appropriate for determining whether solvents were being carried over but, as was made clear in the Macaulay report, it may not provide a quantitative assessment of the amount of solvents actually in the extracts. Also, there must be some sort of cockle "factor" involved. Without knowing what this is and quantifying it, seeking simple correlations is a misleading waste of time.

  35.  Duplication of analyses showed that the same sample could produce very different levels of solvent carry-over and that the same sample could also produce both atypical results and negatives. All of this pointed to the atypical response being an artefact and the presence of solvent (a known problem) meant that the obvious conclusion was that solvent carry-over was at least involved in the atypical response. Despite this, the summary of the report went as far to say that the FSA was satisfied that solvent carry-over was not a factor in the atypical response!

  36.  The FSA also commissioned Prof Makin to do an audit of procedures at the different laboratories. He criticised the lack of controls generally and was severely critical of QA standards at CEFAS.

  37.  The FSA web site acknowledged the problem of solvent carry-over but was emphatic that it was not causing the atypical response. This was not an accurate reflection of the scientific information available to the FSA.

  38.  The Home Office had been unaware of any solvent carry-over until the release of the report and had immediate talks with the FSA insisting that solvents be removed.

  39.  Before a stakeholder meeting due to take place in October, the FSA released an addendum to their original report. This was necessary as it transpired that CEFAS had made mistakes in the experiment so that the data from one week was not comparable with the other two weeks and had been producing very high values for solvent carry-over. CSL had produced a new dataset correcting for this and this had been hurriedly re-analysed.

  40.  After re-analysis, several of the conclusions of the previous report were no longer valid. In addition, analysis of the new dataset by Integrin showed that week three of the CEFAS data was clearly different from weeks one and two, at least for acetone. In the new dataset these data had been produced by a different calculation than for the other two weeks and it was agreed at the meeting that all the data would be recalculated using the same method and re-released for analysis. To date this has not been done.

  41.  At the stakeholder meeting in October, I outlined how solvents could be causing the atypical results either directly or indirectly and predicted that once solvents were removed the atypicals would disappear.

  42.  At the end of October a new unified SOP was introduced at all three laboratories. This was designed to eliminate solvent carry-over and the presence of solvents was to be routinely monitored for the first time. Since its introduction there have been no atypical responses reported from any of the laboratories. For the same period in 2002 (November and December) there were 36 atypicals and in the month before the introduction of the new SOP (October 2003) there were 13.

  43.  The FSA still does not acknowledge that solvent carry-over is the underlying cause of the atypical response.

WHAT IS DIFFERENT ABOUT COCKLES?

  44.  It is easy with hindsight to assert that the atypical problem should never have arisen and certainly should not have taken as long as it has to resolve. However, what is clear from reviewing the history of the atypical response is that virtually all of the normal scientific checks and balances that exist to prevent us being distracted into wild goose chases such as this were absent or ignored.

  45.  These include:

    —  Controls.  there were no controls used in the DSP Mouse Bioassay. This means that there was no way of ensuring the assay was being conducted properly. It is alarming to read that FSA officials did not believe that a negative control was necessary as they were getting negative results. This shows a lack of understanding of what a negative control is and what it is for.

    —  Blind studies.  an important source of artefact is operator bias. This is controlled for by blind studies—the operator does not know which samples are being looked at. This is vital in experiments such as the DSP MBA where subjective endpoints are increasingly used. The only evidence of the use of blind trials was in the Macaulay report.

    —  Internal reproducibility.  samples must always be positive or negative, not both. This was overlooked or ignored.

    —  External reproducibility and validation.  other laboratories must be able to reproduce your results. This was not the case with the atypical response. When other laboratories could not replicate the atypical result the FSA response was that these labs were wrong. The correct response is to critically examine your own procedures with the presumption that these are wrong.

    —  Proper use of hypotheses to guide experimentation.  Basically a hypothesis is an idea that might explain the phenomena under study. A good hypothesis is testable by experiment and a good experiment provides a yes/no answer. Another discipline is that you should design experiments that will reject your hypothesis rather than try to prove it. The FSA studies did not conform to these standards. The FSA were prepared to reject solvent carry-over as a factor without experimentation to test it and did not test their central hypothesis by carrying out an experiment to show that the atypical response could occur in the absence of solvent carry-over.

    —  Proper understanding of fore knowledge and experience.  If we do not learn the lessons of the past we are condemned to repeat them in the future. Solvent carry-over was a well-understood problem and should have been investigated much sooner even if the FSA could not see how this could be squared with the predominance of cockle samples producing atypicals.

  46.  The FSA were able to diligently eliminate a large number of possible interferences and possible toxins. This left them with their major hypothesis.  that the atypical results were being produced by toxin. The null hypothesis that should have been pursued with equal vigour was that the atypicals were the result of some methodological artefact. The Table below shows that evidence for and against both hypotheses. Clearly there is more evidence for a methodological artefact and against the presence of a toxin than the opposites.
Method Problem For Method Problem AgainstLipophilic Toxin For Lipophilic toxin Against
Good evidence of solvent carryover (known problem with MBA) Problem mostly associated with cockles (why not all shellfish?) Problem mostly associated with cockles No known algal toxins in samples
Good evidence of water carryover (known problem with MBA) No simple correlation between individual results and solvent concentrations New algal toxins are frequently encountered No association with known toxic algae
Association of atypical response with solvent and/or water carryover Yasumoto's opinion that atypical response seen by him in cockles not caused by solvents No candidate lipophilic molecule for toxin despite intensive search
Reproducibility of atypical response from replicate samples poor Atypical response seen in cockles from all areas studied but not in every cockle sample
Solvent carryover from same samples very variable No evidence of toxicity in humans or by rat bioassay
Similar problems seen by other labs and cured by improvements to solvent carryover. "toxin" very labile
Symptoms consistent with solvent toxicity; solvent abuse, saxitoxin poisoning or anaesthetic overdose Toxicity profile unlike other lipophilic toxins including known alternatives such as fatty acids (too fast)
Toxicity decreases on storage suggesting toxicity associated with volatile compound Rapid recovery of mice that survive
Atypical responses start when new labs initiate DSP MBA
MBA protocols between labs confused—perhaps not looking at same thing


  47.  If we focus entirely on the evidence supporting the FSA position (Method problem against and lipophilic toxin for columns): Prof Yasumoto has not published his findings so we cannot comment further on his opinion but it may be a red herring; new algal toxins are frequently discovered but usually when humans become sick after eating shellfish; the datasets available do not allow us to explore whether there are simple correlations present or not but in any case the complexity of the problem may mean that simple correlations cannot be found.

  This leaves in both columns the observation that the atypical response is associated primarily with cockles. This is the cockle conundrum.

  48.  To resolve the cockle conundrum we need hypotheses that fit the facts. In particular the suggested mechanisms should fit the atypical profile:

    1.  Acute and fast acting

    2.  Volatile or extremely labile

    3.  Rapid recovery from non-fatal attacks (suggests volatility)

    4.  Always associated with solvents

    5.  Cockle factor heightens probability of atypical response

  49.  At the October 2003 stakeholder meeting I proposed four possible hypotheses of the atypical results. This is not an exhaustive list, nor does it matter which one (if any) is correct.

  50.   Hypothesis I: Carry-over of a hydrophilic interfering factor

  A known problem of the DSP MBA is the carry-over into the mouse of hydrophilic molecules which result in mouse death. The best understood problem is with saxitoxin and related molecules. Tiny amounts of saxitoxin will produce an atypical-like response if injected into mice during the DSP MBA. Poor extraction technique will allow this to happen.

  This hypothesis would fit three of the criteria, including the cockle factor: cockles live in the sediment and will feed on bacteria at the surface of the sediment that would not usually form the diet of mussels. Saxitoxin can be produced by bacteria as well as algae. However, saxitoxin is not particularly labile nor would rapid recovery be expected. There is a wide range of other hydrophilic substances that might also be producing the response if they are injected in the MBA. Tightening up extraction procedures should prevent any of these causing the atypical response.

  51.   Hypothesis II: Toxicity of solvents

  DEE and acetone are both toxic, and especially so by IP injection. There is scant quantitative data on the toxicity of these molecules and none on their co-toxicity. The mouse deaths could be the result of toxic effects of the solvents present in the injection. This explanation would fit all of the criteria except as to why cockles would be different. It is especially good in explaining the rapid recovery of some mice.

  The Macaulay report suggested a possible model that would explain the cockle factor: intra/inter species differences in the water/lipid content could influence the amount of solvent (particularly DEE) trapped in the extract and thus injected into the mice. One of the interesting findings of the solvent carry-over studies was that some solvent could remain in the extracts even after they had been left overnight. This is difficult to understand unless there is a mechanism for trapping the solvent.

  52.   Hypothesis III: Drug effect of solvents

  DEE and acetone both have an anaesthetic action and this will be additive if both are present together. Anaesthetic effects can occur at levels well below toxic levels but can be just as deadly. Side effects of anaesthesia include malignant hypothermia; cardiac arrhythmia and ventricular fibrillation leading to sudden death. Not only are the side effects of anaesthesia consistent with the atypical response, vets witnessing it commented on it resembling the effects of poor induction of anaesthesia. This hypothesis would explain all of the atypical criteria but like solvent toxicity requires the invocation of a cockle factor based around some trapping mechanism.

  53.   Hypothesis IV: Volatile substance abuse response

  Solvents are abused, mostly by young teenagers (glue sniffing) resulting in fatalities. Over 55% of the fatalities in the UK are associated with "sudden sniffing death" (the rest tend to be accidents while intoxicated, choking on vomit etc). This is manifest by the sniffer being startled and then dropping dead from a heart attack. Clinical presentation is severe cardiac arrhythmia then collapse in ventricular fibrillation with death within 1-2 minutes. This thought to be because the solvents sensitise the myocardium (heart muscle) to endogenous epinephrine or other catecholamines leading to arrhythmias.

  This is an interesting hypothesis as it fits all of the atypical criteria including the cockle factor. Shellfish in general tend to have high levels of chemicals that will act as neurotransmitters in humans and cockles may have higher amounts than mussels because of the greater stress on them between harvesting and processing for the MBA. If present in the injection along with solvents, these neurotransmitters could produce a mouse equivalent of the "sudden sniffing death".

  54.  The symptoms witnessed in the atypical response seem to fit a combination of anaesthetic and cardiac arrest. Working out exactly what is going on would not be a trivial task and probably unethical. The importance of these hypotheses is, however, to illustrate that explaining the atypical response does not require the invocation of an elusive novel toxin. These hypotheses depend on either solvent carry-over or carry-over of water-soluble fractions. Eliminating these should eliminate the atypicals. This is what has happened with the introduction of the new SOP in late October.

  55.  This is not scientific proof that the atypical response is produced by solvent carry-over as there is no control in the experiment. The new SOP introduced a number of other changes which may also have influenced the atypical response. Nevertheless, the fact that the atypicals have disappeared after the new SOP was introduced demonstrates that they are the result of a methodological artefact. Of the possibilities, solvent carry-over remains the most probable cause of the atypical responses, either directly or indirectly.

CONCLUSIONS

  56.  The nature of the mouse bioassay was a fundamental reason for the genesis of the atypical episode. The lack of controls was especially important. Without the normal QA mechanisms to guard against artefact, experience was the only defence. FRS had this experience but the other laboratories did not draw on it when setting up their DSP MBA programmes and so were deceived into thinking that an artefact was a real result. It is possible that inter-laboratory rivalry played a part here, with the new labs either consciously or unconsciously not wanting to confront the possibility that they were incompetent in running the assay.

  57.  The nature of the MBA, which involves mice dying, tends to dramatise the result. However, the assay is very subject to a "garbage in—garbage out" scenario. Mice deaths do not necessarily indicate the possibility of human harm and the possibility of artefact must be eliminated before over-reacting to assay deaths.

  58.  The FSA were not the first regulatory authority to have been foxed by an inappropriate response by the MBA but they were still correct to take the possibility of a new toxin seriously. Previous experience (such as the domoic acid poisonings in Canada) showed that we have to be alert to novel toxins. The FSA response was, however, inconsistent. If there was genuine concern that a health problem was indicated, the FSA should have shut all cockle beds and banned imports. This would have caused a lot of fuss and triggered European Commission interest but it would have shown consistency. It would also have speeded up finding a solution.

  59.  The FSA were not guilty of devoting insufficient resources to the problem. There was a lot of good work done to eliminate possible interfering factors and known toxins. Where they did fall down is in not having a structured response that was designed to tackle the question of possible artefact. In particular the decision to fund CEFAS (without tendering) to investigate possible causes of the atypical response when CEFAS was the main originator of these results was a mistake. This meant that the question of artefact was not likely to be properly tackled.

  60.  FSA was also too reliant on presumption and argument in attempting to unravel the cause of the atypical response. This had disturbing resonance with the original MAFF response to finding scrapie-like disease in cattle where presumption and inter-lab rivalry led to a delay of a crucial year in recognising what was going on. Presumption is no substitute for experiments.

  61.  FSA did seek help from international experts but they would have assumed that the MBA was being performed correctly as this should have been the first thing checked. I have sympathy with the FSA in regard to Prof Yasumoto's input. An international expert is telling the FSA that he thinks there is a toxin present and he may have isolated one.

  62.  After October 2002, the FSA's position and conduct of the investigations is much more open to criticism. The comparative study between the laboratories showed a lack of reproducibility in the atypical response. FSA should have paid more attention to the concerns of FRS as they had the most experience in this area. FSA failed to follow up FRS's suggestions to look at methodological artefact for nine months and then only returned to it when more or less forced to by the actions of FRS.

  63.  Had artefact been tackled seriously from the beginning then it would have taken no more than six months (and probably far less) for the FSA to have resolved the situation to their satisfaction that there was no risk to public health.

  64.  When solvent carry-over was established, the MBA should have been withdrawn until a new SOP that eliminated solvent carry-over was established and validated. FSA should have concluded at this point that solvent carry-over was the most likely cause of the atypical response. That they did not is worrying as it suggests a loss of objectivity.

  65.  Also worrying were the public pronouncements of the FSA. Statements were made that a toxin existed when there was no direct evidence for a toxin being present in cockles. The link with solvent carry-over was repeatedly dismissed but the evidence, as opposed to FSA opinion, increasingly pointed to solvent carry-over as the cause. Public presentation of complex scientific issues is always a tricky art but it is crucial that FSA properly represent the science, including areas of doubt.

  66.  The UK needs a strong, independent food safety body. It should be fearless in protecting public safety and should err on the side of caution. Food safety issues tend to be complex and mistakes will occur. What the atypical episode seems to indicate is that there was a lack of a structured response to emerging issues. This leads to inconsistency and a poor rate of progress to actually solving the problem.

  67.  I would recommend that an independent scientific enquiry team be brought together to examine the atypical episode with a remit to identify areas of the FSA approach that are inconsistent with good scientific practise and to recommend codes of practise and procedure that will give the FSA the tools it requires to fulfil its role in protecting the UK population.

Dr J Douglas McKenzie

Managing Director

December 2003





 
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