Tag Archives: oxyphenbutazone

The Science Is In: Exposure To Bute In Horsemeat Still A Big Problem

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Written by:  Heather Clemenceau

Phenylbutazone or “bute” was at one time marketed for humans use under the trade name of Butazolidin.  It was a Non-Steroidal Anti-Inflammatory (NSAID) used for arthritis and other inflammatory ailments that worked by inhibiting an enzyme that synthesizes chemical mediators called prostaglandins.  It was ultimately withdrawn by the FDA for causing a wide range of serious side-effects.  It remains however, on the market for treatment for horses and is an effective anti-inflammatory.  It is also prohibited in the food chain as residues of bute and its metabolite, oxyphenbutazone are not known to have safe limits.  None of this is new information to experienced horse advocates.  Therefore, it’s always personally surprising to me when I come across another horse advocate who takes the position that we needn’t be concerned about bute adulteration in food. It’s a pretty rare position to take, IMO, and reaffirms  to me that not all champions of the horse are on the same page when it comes to advocacy. This position not only harms our advocacy,  it’s also scientifically illiterate IMO.

Writing in a recent blog post, Founder and President of the Equine Rescue Network Janine Jacques goes all-in and on the record as being in doubt that bute is harmful to people.  Jacques also assumes that the only possible toxic result from consuming bute or metabolites can be aplastic anemia.

How did the consumption of over 16 million pounds of horsemeat impact the health of those who consumed horse meat tainted with bute? ~ If Google search deaths from phenylbutazone you will find no relevant deaths for humans.”  

While investigation and surveillance of overdoses and poisonings by phenylbutazone are available, there is a tendency to believe that, in order to be hazardous to health, only large amounts of a chemical are needed to cause poisoning. This is not necessarily so. A highly toxic chemical can have a low health hazard if it is used with proper precautions and care. On the other hand, it is possible that a chemical of low toxicity may present a high health hazard if it is used inappropriately, such as in the food supply.  The domain of published works in the field of toxicology contain many presuppositions such as this; regulators have always had difficulty establishing acceptable levels of chemicals and they are expected to show evidence that a level of exposure is harmful before they can ban its use.

Virtually all evidence we have about harmful dosages of drugs come from animals where extrapolations are made from high doses (LD50, Draize, and ADME – Absorption, Distribution, Metabolism, and Excretion tests for example) .  It is also said that effects found in animals in relatively short-lived species cannot necessarily be used to estimate the effects in a long-lived species such as human.  Humans live much longer than most of the species used for drug testing, so we have a longer period of time in which to manifest disease.  Compounding this, we know that much of human disease is idiopathic in nature – without known causes.  Forensic toxicology testing can detect drugs in the blood stream or urine and overdoses in the emergency room, but it can’t predict the cause of idiopathic disease.

What makes chemicals poisonous?

There are several factors which can influence the degree of poisoning caused by a chemical.

  • Route of entry into the body – orally, inhalation, etc
  • Amount or dose entering the body
  • Chemicals that are weakly toxic require large doses to cause poisoning, Strongly toxic chemicals only need small doses to cause poisoning
  • Chemicals that are broken down by the body into sub-products before being excreted may be more or less toxic than the original chemical
  • Biological variation in the person consuming the chemical/drug determines response – slow metabolizers may be affected in addition to those who have susceptibility to phenylbutazone due to different metabolic genes (polymorphisms) that encode enzymes that are involved in the metabolism of drugs.People who are poor metabolizers of a drug may overdose while taking less than the recommended dose. Altered or enhanced drug metabolisms in individuals have been known to cause fatal drug reactions.

PBZ Molecule

Another layer of complexity is added when humans are exposed to chemicals at very low doses – the chemicals may reside in certain regions of the body that are more susceptible to organ damage  which is impossible to measure directly.  Studies have shown that many chemicals impact cancer-causing pathways at low doses. Taken directly, phenylbutazone is associated with various hematologic disorders, including aplastic anemia. Bute is also a cause of agranulocytosis, which can also be fatal. Hypersensitivity reactions can include anaphylactic shock, arthralgia, fever, angiitis (polyarteritis), vasculitis, serum sickness, adenitis, hepatotoxicity, allergic alveolitis, lymphadenopathy, Lyell’s syndrome, activation of systemic lupus erythematosus, and aggravation of temporal arteritis in patients with polymyalgia rheumatica. Asthma may be precipitated or aggravated by phenylbutazone, especially in aspirin sensitive patients. We also know that phenylbutazone interacts with many other drugs.  When administered to lactating cows, it was found that phenylbutazone was distributed into their milk.

When the drug was used therapeutically in humans as Butazolidin, the dose rate would have been around 2 to 6 mg/kg, similar to the current dose for the horse of 4.4 mg/kg. The question is whether the presence of bute in horsemeat can present a risk to human health even in small amounts.  Around the time of the 2013 horse meat adulteration scandal in the EU, the highest amount of bute found in a horse carcass was 1.9 mg.  If a human had been taking Butazolidin in the 50s, they might have taken 200-400 mg a day in total, if we compare it to the current-day dosage of Tylenol or Advil.  Obviously, we would have to consume a significant amount of contaminated horsemeat in order to reach the level of a therapeutic drug dosage. What is not clear, despite reassurances, is the level that is necessary for the average person to consume in order to experience a toxic effect.  If a therapeutic dose of Butazolidin was once considered “safe” at 200-400 mg, then how do we know that some individuals are safe at 1.9 mg?  If Butazolidin was withdrawn from the market as being unsafe for some people at that dosage, we don’t know whether sensitive individuals may have experienced toxicity at lower levels as well.

If it still seems as though a negligible trace of bute in meat might not be enough to cause harm,  there is an analogous cautionary tale of another NSAID – diclofenac, which was also used in human medicine for decades,  and was recently introduced for veterinary use in India.  Obviously, the dynamics are not the same, but vultures appear to have been exposed to the drug while scavenging livestock carcasses, their main food source, and this has accounted for death by renal failure of many vultures examined in a three-year study by the scientific journal Nature.  Further investigation showed tissue residues in livestock treated at the labelled dose rate were sufficient to cause death in vultures. These findings confirmed that diclofenac is the primary cause of the Asian vulture decline.

“Diclofenac is toxic to vultures even in small doses, causing kidney failure. That results in uric acid accumulating in the birds’ blood and crystallizing around their internal organs—a condition called visceral gout.”

Food safety laws are clear.  Companies that produce, trade or sell food or food ingredients are legally obligated to implement a quality assurance system called Hazard Analysis and Critical Control Point (HACCP), which maximizes food safety by minimizing chemical, physical and microbiological hazards.  There is something wrong with a food system whereby the food animal must sit on a feedlot for six months in order that veterinary drugs “degrade” before it can be eaten.

For years, regulators relied on the old adage “the dose makes the poison, which still holds true for many drugs and chemicals.  But one key message there is that source or origin of a chemical usually tells you very little if anything about its toxicity or ability to cause harm.   We now live in a time where exposure to chemicals is unavoidable and we can’t evaluate these chemicals in isolation.  Having said that, bute is not a chemical that is ubiquitous in the environment like other toxins we are exposed to – we can avoid it by not eating horsemeat and not killing horses for food.  In the final analysis, no one is really in a position to make broad statements about the safety of horse meat.  Conrad Brunk,  the co-chair of the 2001 Royal Society of Canada Expert Panel on the Future of Food Biotechnology, wrote that:

“When it comes to human and environmental safety there should be clear evidence of the absence of risks;  the mere absence of evidence is not enough.”  This is the essence of the Precautionary Principle, which states that “when an activity raises threats of harm to human health or the environment,  precautionary measures should be taken even if some cause-and-effect relationships are not fully established scientifically.” The toxicity of a chemical cannot be changed, but the hazard it presents can be controlled.

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The Disquieting Truth About Drug Exposures in Horsemeat

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laboratory-011Written by:  Heather Clemenceau

The most recent news surfacing today is that Nestlé, one of the largest food companies in the world, has now been entangled in the EU horsemeat scandal.  Major supermarket chains Tesco and Aldi were found to be selling beef products that contained horse meat. Burger King sourced thousands of burgers from the same Irish beef supplier, Silvercrest, and Findus “beef” lasagna was found to contain 100% horse meat.

Liffey Meats in Ireland and Dalepak in Yorkshire have both been fingered as well.  Silvercrest and Dalepak are both subsidiaries of ABP Food Group, one of the largest beef processors in Europe.   Huge blocks of frozen meat in cold storage in Northern Ireland – Freeza Foods, which had been quarantined by officials suspicious of its labelling and state of packaging, were found to contain 80% horse.

There is now evidence that both Polish and Italian mafia gangs are running multimillion-dollar scams to substitute horsemeat for beef during food production. There are claims that vets and other officials working within slaughterhouses and food production plants are intimidated into signing off meat as beef when it is in fact cheaper alternatives such as pork or horse.

europe-crisisWhat this multi-level fraud has done is remove informed consent from the public – people believed they were paying for and consuming beef products.  The public also had no idea that they were at risk for consuming minute quantities of veterinary drug phenylbutazone(“bute”) as a result of massive quantities of horsemeat of unknown origin entering the food chain.

The Department for Environment, Food and Rural Affairs (Defra) has announced that there are at least eight known cases of horse carcasses that tested positive for phenylbutazone in the EU out of 206 samples.  British Environment Minister David Heath told the House of Commons that of these eight horses, “three may have entered the food chain in France. The remaining five have not gone into the food chain.”

Phenylbutazone or “bute” was at one time marketed for humans use under the trade name of butazolidin.  It was a Non-Steroidal Anti-Inflammatory (NSAID) used for arthritis and other inflammatory ailments that worked by inhibiting an

Butazolidin

Butazolidin – trade name for the human version of the drug phenylbutazone

enzyme that synthesizes chemical mediators called prostaglandins.  It was ultimately withdrawn by the FDA for causing a wide range of serious side-effects including blood dyscrasias which damage the bone marrow.  It remains however, on the market for treatment for horses and is an effective anti-inflammatory.  It is also prohibited in the food chain as residues of bute and its metabolite, oxyphenbutazone are not known to have safe limits.

Horse welfare advocates and the inadvertent consumers of horse meat have been repeatedly reassured by various government agencies and horse slaughter proponents that any residues of bute or its metabolite are harmless.  We know that the pro-slaughters aren’t relying on science when they tell us this, but what about government agencies?   On what do they base this reassurance?

Professor Tim Morris, veterinary surgeon and Vice Chair of the British Horse Industry Confederation, said:

“It is important to note that the levels of Bute in horsemeat, even if it is found, will be very low, and greatly below the doses following medical treatment in people that have been associated with occasional rare adverse reactions; therefore whilst this is unacceptable the actual risk to consumers is very small.”

Professor Peter Lees, Emeritus Professor of Veterinary Pharmacology, Royal Veterinary College, wrote that:

“The main toxicity concern in humans is that some people developed (very rarely – 1 in 30,000 to 1 in 50,000 persons) an anaemia which was life threatening, when the drug was used clinically in humans. This occurred when the drug was used therapeutically in humans at a dose rate of some 2 to 6 mg/kg, similar to the current dose for the horse of 4.4 mg/kg.”

The question is whether the presence of bute in horsemeat can present a risk to human health even in small amounts.  In the above noted tests, the highest amount of bute found in a horse carcass was 1.9 mg.  If a human had been taking butazolidin in the 50s, they might have taken 200-400 mg a day in total, if we compare it to the current-day dosage of Tylenol or Advil.  Obviously, we would have to consume a significant amount of contaminated horsemeat in order to reach the level of a therapeutic drug dosage.

9601_fig1What is not clear, despite reassurances, is the level that is necessary for the average person to consume in order to experience a toxic effect.  The basis for determining toxicity levels to inform public policy decisions has been the dose-response relationship, which is central to defining “safe” and “hazardous” levels and dosages for drugs, potential pollutants, and other substances to which humans are exposed.

If a therapeutic does of butazolidin was once considered “safe” at 200-400 mg, then how do we know that some individuals are safe at 1.9 mg?  If butazolidin was withdrawn from the market as being unsafe for some people at that dosage, we don’t know whether sensitive individuals may have experienced toxicity at lower levels as well.  What about drug interactions?  There is an acknowledged interaction between phenylbutazone and the anticoagulant drug warfarin, and patients taking warfarin can suffer severe gastrointestinal bleeding if they also take phenylbutazone.  This complicates arguments about safety of bute in horsemeat.  Bute also metabolizes to oxyphenbutazone,  which has been shown to have similar toxicity.  Have any of these horse carcasses been tested for oxyphenbutazone?  Both bute and oxyphenbutazone bind to human serum albumin (HSA) as does warfarin and so they “compete” with each other.  For more information on this interaction, please read this study by the Department of Pharmacology at the University of Western Australia.

Indian vultures poisoned by diclofenac after eating scavenging livestock treated with the drug

Indian vultures poisoned by diclofenac after scavenging livestock treated with the drug

If it still seems as though a negligible trace of bute in meat might not be enough to cause harm,  there is an analogous cautionary tale of another NSAID – diclofenac, which was also used in human medicine for decades,  and was recently introduced for veterinary use in India.  Obviously, the dynamics are not the same, but vultures appear to have been exposed to the drug while scavenging livestock carcasses, their main food source, and this has accounted for death by renal failure of many vultures examined in a three-year study by the scientific journal Nature.  Further investigation showed that diclofenac was fatal to vultures at 10 percent of the recommended dose. Tissue residues in livestock treated at the labelled dose rate were sufficient to cause death in vultures. These findings confirmed that diclofenac is the primary cause of the Asian vulture decline.

“As few as one in 760 carcasses containing diclofenac at a dose lethal to vultures would be sufficient to cause the observed decline in vulture numbers (30% per year). Clearly, even small-scale usage of the drug can have catastrophic consequences.”

The traceability issues with this untraceable horse/donkey meat also bears some similarity to the problem of kangaroo meat diverted into the human food chain in Australia.  Kangaroo meat is often obtained from animals that were shot with machine guns via helicopters and therefore not slaughtered humanely and not bled by conventional standards either.  Possibly also introduced into the food chain dubiously as well.

The ability to treat horses with bute is very important for their welfare.  The EU scandal has also revealed that the passporting system there is subject to fraud, despite strict rules regarding the regulation of medicines.  The fault lies not with horse owners but with individuals or organizations who are motivated by greed and willing to manipulate the system, allow their controls to fail, or commit outright fraud.

Food safety laws are clear.  Companies that produce, trade or sell food or food ingredients are legally obligated to implement a quality assurance system called Hazard Analysis and Critical Control Point house-of-cards(HACCP), which maximizes food safety by minimizing chemical, physical and microbiological hazards.  There is something wrong with a food system whereby the food animal must sit on a feedlot for six months in order that veterinary drugs “degrade,” and 100% of the “raw material” must pass a negative test before they can enter the food chain.

In the final analysis, no one is really in a position to make broad statements about the safety of this horse/donkey meat.  Conrad Brunk,  the co-chair of the 2001 Royal Society of Canada Expert Panel on the Future of Food Biotechnology, wrote that:

“When it comes to human and environmental safety there should be clear evidence of the absence of risks;  the mere absence of evidence is not enough.”  This is the essence of the precautionary principle, which states that “when an activity raises threats of harm to human health or the environment,  precautionary measures should be taken even if some cause-and-effect relationships are not fully established scientifically.”bute  - High res