Page 141 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

108 SECTION | I General

VetBooks.ir β-agonists can be used to induce tocolysis in bovine and agonists is increased heart rate. This effect may be either
According to the Directive 2008/97/EC (EC, 2008a),
One side-effect of animal treatment with β-adrenergic
a direct or indirect effect of treatment. The acute toxic
equidae as well as to treat respiratory problems, navicular
disease, and laminitis. effects observed in animals include muscle tremors,
In contrast to other β 2 -agonists, clenbuterol is well tachycardia, and nervousness. In addition, treated animals
absorbed after ingestion (bioavailability 70% 80%). Peak show a higher incidence and severity of hoof lesions.
serum levels occur within 3 h, and the elimination half- Furthermore, specific histological changes have been
life is 25 39 h. At larger doses, it also shows β 1 -receptor observed in treated animals, in particular the formation of
mediated cardiac effects. vacuoles of epithelial cells in the prostate and Bartholin’s
The anabolic effect of clenbuterol along with other gland of male and female calves, respectively. The levels
long-acting β 2 -agonists appears to be mediated through of clenbuterol in the edible tissues are expected to be at
the β 2 -receptors in skeletal muscle. Through its thermo- the highest.
genic properties, clenbuterol increases energy expenditure
and hence reduces muscle glycogen and body fat deposi-
tion. In farm animals, clenbuterol accumulates in the Teratogenic Effects
lungs, liver, and kidney, and to a lesser extent in the mus- Another acute toxicity effect that may occur as a result of
cle. Residues of β-agonists in animal tissues used for food exposure to violative animal drug residues is a teratogenic
may result in serious human health risks. effect. Teratogens are active at very low doses and even
Clenbuterol has been implicated in several outbreaks brief exposure during a critical period of development can
of food-borne poisoning following the consumption of result in a lifelong deformation. Although the hazard
liver, meat, and lung of bovine and lung and liver of pig. associated with teratogens is severe, the possibility of the
In 1990, a poisoning incident was reported in Spain when event occurring is infrequent. Therefore, the chances of a
135 people became ill after consuming beef liver contain- woman at the critical stage of pregnancy coming in con-
ing clenbuterol residues (Martinez-Navarro, 1990). A tact with a violative residue are very low (Paige et al.,
second episode of clenbuterol food poisoning was 1997). Other effects caused by a single exposure can be a
reported 1 year later in France affecting 22 people who hemotoxicity, neurotoxicity, and endocrine effects.
consumed veal liver. The patients suffered tachycardia
and tremors for 2 3 days. The infective dose is calcu-
lated as 1 2 μg/kg per day (Pulse et al., 1991). In 1992, a Long-Term Chronic Effects (Carcinogenesis)
further episode of clenbuterol poisoning appeared in
Spain after ingestion of veal liver. Analysis of liver indi- Long-term chronic toxicity studies identify whether or not
cated concentrations of clenbuterol in the range of problems such a cancer are associated with a specific
160 500 μg/kg. Consumption of 100 g of liver would drug. These studies will determine a dose that does not
exceed the pharmacological effect level of clenbuterol of create any health concerns. Most residues of veterinary
5 μg/person. Clenbuterol was detected in 47 urine samples drugs or chemicals occur in food at low concentrations,
in amounts ranging from 11 to 486 ppm. Other instances therefore they rarely pose a chronic or long-term health
occurred in Hong Kong (1997 98) after the consumption hazard to consumers. Furthermore those effects as a result
of pig lung or liver people fell ill after eating pork of exposure to drug or chemical residues in food are
products contaminated with clenbuterol. The common particularly difficult to detect and are certainly under-
clinical symptoms in these food-borne clenbuterol poison- ascertained as well as under-reported. Carcinogenic
ings consisted of muscle tremors, heart palpitation/sinus studies are a cornerstone for toxicological assessment;
tachycardia, nervousness, general myalgia, fever, nausea/ however, carcinogenicity studies are rarely used to estab-
vomiting, headache, dizziness/vertigo, and chills. The lish a NOAEL. Special problems emerge where the
latency period varied between 10 min and 6 h, and the substance in a genotoxic, carcinogen or a mutagen, due to
duration of symptoms between 90 min and 6 days (mostly no threshold. A substance may not have ADI and MRL
lasting less than 3 days). Some patients also presented for a variety of reasons, in particular when important piv-
with weakness or confusion. Others developed transient, otal studies are missing or are of insufficient quality and
mild hypokalemia. Electrocardiograms for some patients the elaboration procedure had to be discontinued because
revealed sinus tachycardia of 120 150 beats/min with the sponsor was not prepared to conduct further work. An
ventricular and supraventricular ectopics. Patients with example can be carcinogenicity studies. No allocation of
underlying cardiac disease are generally expected to be a toxicological ADI and no recommendation of MRL
more susceptible to the cardiac effects of clenbuterol. mean safety concerns as a result of the substance were
There were no reported deaths. negatively evaluated by a competent regulatory body.