Tag Archives: low-dose toxicity

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  It was ultimately withdrawn by the FDA for causing a wide range of serious side-effects.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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