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Ractopamine is a feed additive to promote leanness in animals raised for their meat. Pharmacologically, it is a TAAR1 agonist and β adrenoreceptor agonist that stimulates β1 and β2 adrenergic receptors. It is the active ingredient in products known as Paylean for swine and Optaflexx for cattle, developed by Elanco Animal Health, a division of Eli Lilly and Company, for use in food animals for growth promotion.
Ractopamine use has been banned in most countries, including the European Union, mainland China and Russia while 27 other countries, such as Japan, the United States, Canada, and South Korea, have deemed meat from livestock fed ractopamine safe for human consumption.
- 1 Mode of action
- 2 Regulation around the world
- 3 Pharmacokinetics in humans
- 4 Safety concerns
- 5 Adverse effects
- 6 Analytical method for residues in meat
- 7 International controversies
- 8 Comparison to clenbuterol
- 9 See also
- 10 References
- 11 External links
Mode of action
When used as a food additive, ractopamine added to feed can be distributed via the blood to the muscle tissues, where it serves as a full agonist at mouse (not necessarily human) TAAR1. It is also an agonist at beta-adrenergic receptors. A cascade of events will then be initiated to increase protein synthesis, which results in increased muscle fiber size. Ractopamine is known to increase the rate of weight gain, improve feed efficiency, and increase carcass leanness in finishing swine. Its use in finishing swine yields about three kilograms of additional lean pork and improves feed efficiency by 10%.
Regulation around the world
As of 2015, ractopamine use as a feed additive is authorized in the United States, Canada, and Mexico. The American Institute in Taiwan, which represents U.S. interests in Taiwan, claims that these "and many other countries have determined that meat from animals fed ractopamine is safe for human consumption"; this is in the context of an ongoing trade dispute between Taiwan and the U.S. on this subject, which threatened to prevent Taiwan's entry to the Trans-Pacific Partnership trade pact. In the U.S., ractopamine is allowed to be used at a feed concentration of 5–20 mg/kg feed for finishing pigs and in dosages of 5–10 mg/kg feed for finishing pigs heavier than 109 kg. The maximum residue limit for ractopamine for meat in the USA is 50 ppb.
The U.S.D.A. approved of a new label, "no ractopamine — a beta-agonist growth promotant" to be used.  Currently, the U.S.D.A. label for organic means no antibiotics or growth hormones, but Ractopamine isn't covered by this label as it is neither a growth hormone or an antibiotic. 
Japan, which had permitted its feed additive use at least until 2009,:1 and South Korea only allow import of meat with ractopamine residues up to the maximum residue limit (MRL), but do not permit its use in beef production.
On 6 July 2012, the international reference standard Codex Alimentarius Commission narrowly approved the adoption of a maximum residue limit (MRL) of 10 parts per billion (ppb) for muscle cuts of beef and pork. Setting any limit was a controversial move. Countries with major meat export markets had been lobbying for the establishment of such a standard for several years in order to use it as leverage to erode individual national-level bans in World Trade Organization disputes. Consumers International, a world federation of consumer groups that represents 220 consumer organizations in 115 countries, strongly opposed the move.
As of 2013[update] Ractopamine use in food animals has been banned in over 160 countries. It has not been allowed in the 27 member countries of the European Union, based on the 2009 European Food Safety Authority's (EFSA) opinion on its safety evaluation, which concluded that available data were insufficient to derive a maximum residue limit (MRL) as a 'safe residue level for human consumption'. The uncertainty was particularly great for people who might be thought to be more susceptible than most to an increase in β adrenergic stimulation from consuming the additive, such as people with cardiovascular disease or children, and that simply increasing the "uncertainty factor" built into the calculation as a safety factor would rapidly become arbitrary.
Russia and China banned ractopamine in pork, and Russia also in beef, deeming it unfit for human consumption. Taiwan banned ractopamine along with other beta-adrenergic agonists in October 2006, but in 2012 its legislature passed amendments to the Act Governing Food Sanitation, authorising government agencies to set safety standards for ractopamine. The Department of Health ultimately established a maximum residual level of 10 ppb for ractopamine in beef on 31 July 2012.
Pharmacokinetics in humans
A study was conducted to define the pharmacological response of humans to ractopamine. A single oral dose of 40 mg of ractopamine hydrochloride was given to human volunteers. The drug was rapidly absorbed; the mean blood plasma half-life was around 4 hrs and it was not detected in plasma 24 hrs after dosing. Less than 5% of total ractopamine excreted represented the parent drug, while the urinary metabolites were monoglucuronide and monosulfate conjugates, with ractopamine monosulfate being the major metabolite present.
The metabolic fate of ractopamine hydrochloride is similar in the target species (pigs and cattle), laboratory animals, and humans. Besides the pharmacology effect, ractopamine may cause intoxication effect; therefore, any consumption by humans of a meat and/or byproducts of animals that consumed ractopamine with feed for growth stimulation, may result in such clinical effects as tachycardia and other heart rate increases, tremor, headache, muscle spasm, or high arterial blood pressure. The effect of ractopamine on humans is not entirely known, but consumption of products that contain ractopamine residues is not advisable for persons with cardiovascular diseases.
Target animal safety
Ractopamine is safe for finishing pigs heavier than 240 lb (110 kg) when administered in the diet at concentrations up to 10 ppm and fed for up to 35 days. However, the number of ractopamine hydrochloride–treated animals exhibiting signs of injury increased during the final drive to slaughter. Since the drug was introduced, more than 160,000 pigs taking ractopamine were reported to have suffered adverse effects, as of March 2011, according to a review of FDA records. The drug has triggered more adverse reports in pigs than any other animal drug on the market. Pigs suffered from hyperactivity, trembling, broken limbs, inability to walk and death, according to FDA reports released under a Freedom of Information Act request.(FDA)
Colorado State University Professor of Animal Science Temple Grandin, an expert on animal welfare, says that she has personally seen harmful effects of ractopamine on feedlot animals, such as cattle with stiff, sore, and lame limbs and symptoms of heat stress, and has stated that some cattle have lost feet due to extreme ractopamine overdoses. She also asserts that meat from ractopamine-treated animals is tougher.
Some show lambs have been illegally given ractopamine, either intentionally or due to accidental contamination of their feed.
Genotoxicity and mutagenicity
Mutation studies in prokaryotes and eukaryotes show that ractopamine is not mutagenic. However, the results of several in vitro studies, including chromosome aberration tests in human lymphocytes, are positive. The positive genotoxic results are explained with limited evidence to be due to a secondary auto-oxidative mechanism from ractopamine-catechol-producing reactive intermediates.[which?]
Ractopamine is not considered to be a carcinogen and not listed by IARC, NTP, ACGIH, or OSHA. The observation benign leiomyomas (tumors of smooth muscle) in mice and rats could be due to a general feature of beta-adrenergic activity of ractopamine.
Dose-dependent changes of heart rate and cardiac output are observed within the first hour after administration of ractopamine and gradually return to baseline values. The systolic blood pressure will also increase in a dose-dependent manner, while the diastolic pressure remains unchanged.
Skeletal muscle tremor is the most common adverse effect of beta-agonists, and is more likely to be seen after oral administration than after inhalation. Tremor results from an imbalance between fast- and slow-twitch muscle groups of the extremities, and its severity varies greatly between individuals. No such effects were recorded at the NOEL determined in the toxicological studies conducted in laboratory animals given ractopamine or in the study in humans on cardiovascular effects of ractopamine.
Behavioral changes in humans
Restlessness, apprehension, and anxiety were reported effects after the use of various beta-agonists, particularly after oral or parenteral treatment. In pilot clinical trials with ractopamine, four patients showed little evidence for central nervous system stimulation. It is unclear whether long-term treatment with these drugs results in the development of tolerance to these adverse effects.
Analytical method for residues in meat
The determinative procedure for the analysis of ractopamine residues in tissue can be performed, using liver or muscle as the target tissues, by high performance liquid chromatography with fluorescence detection. The confirmatory method include reversed-phase HPLC/electrospray ionization triple tandem quadrupole mass spectrometry. The limit of quantification of the drug using this LC/MS instrument was shown to be 1 ng/g.
In July 2007, officials of the People's Republic of China seized US-produced pork for containing ractopamine residues. Further shipments of ractopamine-fed pork were seized in September, though this time they were Canadian in origin.
Ractopamine has been banned in Taiwan since 2006. In the summer of 2007, two US shipments including ractopamine-laced pork were rejected by Taiwan's health authorities, while the Taiwan government had been considering lifting the ban on such imports. This resulted in mass protests in the capital city, Taipei, by swine farmers insisting that the ban remain in place. Health Minister Hou Sheng-mou (侯勝茂) declared there would be no lifting of the ban unless related laws were amended. In August 2012, Taiwan's legislature passed amendments to the food safety act allowing ractopamine in beef.
According to the Malaysian Food Act 1983 and Regulations (as of 5 January 2010), ractopamine is allowed in pig muscle and fat (MRL of 10 ppb), pig liver (MRL of 40 ppb) and pig kidney (MRL of 90 ppb). Ractopamine is allowed as its half-life is lower, leading to reduced residues in the food, and the dose required to affect humans is much higher than other beta agonists. On 30 December 2008, the Malaysian Veterinary Services Department quarantined 10 of the 656 pig farms in Malaysia, as the livestock were found to contain the banned chemical.
The use of ractopamine in Russia is prohibited. On 6 June 2011, the Russian Ministry of Agriculture notified key meat import/exporters in Russia of a future prohibition of ractopamine in meat imported to Russia.
On 7 December 2012, the prohibition went into force, and pork and beef export to Russia required submission of compliance certificates confirming absence of ractopamine in exported meat.
Comparison to clenbuterol
Similar to ractopamine, clenbuterol is a growth-promoting compound belonging to the β agonist family. It is known to have the effect of enhancing weight gain and proportion of muscle to fat. However, clenbuterol is known to have a much longer half-life in blood than ractopamine, thus has a greater potential for bioaccumulation .
Clenbuterol is reported to induce unintended side effects on humans, such as increased heart rate, muscular tremors, headache, nausea, fever, and chills. The US FDA has concluded these side effects to be unacceptable . The use of clenbuterol in food animals has been prohibited in almost all countries  .
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