February 28, 2002
Edited for Typographical Errors, March 1, 2002
Food and Drug Administration/Center for Veterinary Medicine
Report on the risk from pentobarbital in dog food
The
low levels of exposure to sodium pentobarbital (pentobarbital) that dogs might
receive through food is unlikely to cause them any adverse health effects, Food
and Drug Administration scientists concluded after conducting a risk
assessment.
During the 1990s, FDA’s Center for Veterinary Medicine (CVM) received
reports from veterinarians that pentobarbital, an anesthetizing agent used for
dogs and other animals, seemed to be losing its effectiveness in dogs. Based on these reports, CVM officials
decided to investigate a plausible theory that the dogs were exposed to
pentobarbital through dog food, and that this exposure was making them less
responsive to pentobarbital when it was used as a drug.
The investigation consisted of two parts. First, CVM had to determine if dog food could contain residues of
the drug. Second, if residues were
found, the Center had to determine what risk, if any, the residues posed to
dogs.
In conjunction with this investigation, the Center wanted to determine
if pet food contained rendered remains of dogs and cats.
How pentobarbital can
get into dog food
Because in addition to producing anesthesia, pentobarbital is routinely
used to euthanize animals, the most likely way it could get into dog food would
be in rendered animal products.
Rendered
products come from a process that converts animal tissues to feed ingredients.
Pentobarbital seems to be able to survive the rendering process. If animals are euthanized with pentobarbital
and subsequently rendered,
pentobarbital could be present in the rendered feed ingredients.
In order to determine if pentobarbital residues were present in animal
feeds, CVM developed a sophisticated process to detect and quantify minute
levels – down to 2 parts per billion of pentobarbital in dry dog food. To confirm that the methods they developed
worked properly, CVM scientists used the methods to analyze dry commercial dog
foods purchased from retail outlets near to their Laurel, MD,
laboratories. The scientists purchased
dog food as part of two surveys, one in 1998 and the second in 2000. They found some samples contained
pentobarbital (see the attached tables).
Dogs, cats not found in dog food
Because pentobarbital is used to euthanize
dogs and cats at animal shelters, finding pentobarbital in rendered feed
ingredients could suggest that the pets were rendered and used in pet food.
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CVM scientists, as part of their
investigation, developed a test to detect dog and cat DNA in the protein of the
dog food. All samples from the most
recent dog food survey (2000) that tested positive for pentobarbital, as well
as a subset of samples that tested negative, were examined for the presence of
remains derived from dogs or cats. The
results demonstrated a complete absence of material that would have been
derived from euthanized dogs or cats.
The sensitivity of this method is 0.005% on a weight/weight basis; that
is, the method can detect a minimum of 5 pounds of rendered remains in 50 tons
of finished feed. Presently, it is
assumed that the pentobarbital residues are entering pet foods from euthanized,
rendered cattle or even horses.
Finding levels of
pentobarbital residues in dog food
Upon finding pentobarbital residues in dog food, the researchers
undertook an assessment of the risk dogs might face. Dogs were given known quantities of pentobarbital for eight weeks
to determine if consumption of small amounts of pentobarbital resulted in any
physiological changes that could indicate potential effects on health. In short, the scientists wanted to find the
level of pentobarbital dogs could be exposed to that would show no biological
effects. The most sensitive indicator
that pentobarbital had an effect is an increase in the production of certain
enzymes collectively called cytochrome P450.
Virtually
all animals produce enzymes as a normal response to metabolize naturally
occurring and man-made chemicals in their environment. Barbituates, such as pentobarbital, are
especially efficient at causing the liver to produce these enzymes. In dogs, the most sensitive biological
response to pentobarbital is an increase in the production of cytochrome P450
enzymes, which is why the scientists chose that as the best indicator of
biological effect. If a low level of
pentobarbital did not cause a dog to produce additional cytochrome P450 enzymes,
then scientists could assume that the pentobarbital at that low level had no
significant effect on the dog.
In
CVM’s study, experimental animals were each dosed orally with either 50, 150,
or 500 micrograms pentobarbital/day for eight weeks. The results were compared with control animals, which were not
exposed to pentobarbital.
Several
significant pentobarbital-associated effects were identified in this study:
1. Dogs that received 150 and 500 micrograms pentobarbital once daily
for eight weeks had statistically higher liver weights (relative to their
bodyweights) than the animals in the control groups. Increased liver weights are associated with the increased
production by the liver of cytochrome P450 enzymes;
2. An analysis showed that the activity of at least three liver enzymes
was statistically greater than that of the controls at doses of approximately
200 micrograms pentobarbital per day or greater.
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But
researchers found no statistical differences in relative liver weight or liver
enzyme activity between the group receiving 50 micrograms pentobarbital per day
and the controls. Based on the data from this study, CVM scientists were able
to determine that the no-observable-effect level – which is the highest dose at
which no effects of treatment were found – for pentobarbital was 50 micrograms
of pentobarbital per day.
Adverse health
effects unlikely
For
the purposes of CVM’s assessment the scientists assumed that at most, dogs
would be exposed to no more than 4 micrograms/kilogram body weight/day based on
the highest level of pentobarbital found in the survey of dog foods. In reality, dogs are not likely to consume
that much. The high number was based on
the assumption that the smallest dogs would eat dog food containing the
greatest amount of pentobarbital detected in the survey of commercial pet
foods-- 32 parts per billion.
However,
to get to the exposure level of 50 micrograms of pentobarbital per day, which
is the highest level at which no biological response was seen, a dog would have
to consume between 5 to 10 micrograms of pentobarbital per kilogram of body
weight. But the most any dog would
consume, based on the survey results, was 4 micrograms pentobarbital per
kilogram of body weight per day.
It
should be emphasized that induction of cytochrome P450 enzymes is a normal
response to many substances that are naturally found in foods. It is not an
indication of harm, but was selected as the most sensitive indicator to detect
any biological effect due to pentobarbital.
Thus,
the results of the assessment led
CVM to conclude that it is highly unlikely a dog consuming dry dog food will
experience any adverse effects from exposures to the low levels of
pentobarbital found in CVM’s dog food surveys.