Ractopamine

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Ractopamine
Ractopamine2DCSD.svg
Identifiers
CAS number 97825-25-7 N
PubChem 56052
ChemSpider 50604 YesY
MeSH Ractopamine
ChEBI CHEBI:82644 N
ChEMBL CHEMBL509336 YesY
Jmol-3D images Image 1
Properties
Molecular formula C18H23NO3
Molar mass 301.38 g mol−1
Solubility in water 4100 mg/L
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Ractopamine is a feed additive to promote leanness in animals raised for their meat. Pharmacologically, it is a beta-adrenergic agonist. 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 has been banned in the European Union, mainland China and Russia[1][2] 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.[3]

Commercial ractopamine is a mixture of all four possible stereoisomers.[4]

Mode of action[edit]

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 the TAAR1.[5] 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%.[6]

Regulation around the world[edit]

Ractopamine is not allowed in the European Union, based on the EFSA Opinion on safety evaluation of the drug, that concluded that there were insufficient data available to derive a safe residue level for human consumption, particularly in relation to subgroups of people who may be more susceptible than the general population to adverse events from β-adrenergic stimulation, such as people with some cardiovascular diseases or children, and that simply increasing the uncertainty factor would rapidly become arbitrary.[7][8]

Russia and China have also banned ractopamine in beef,[9] and Russia also in pork,[10] deeming it unfit for human consumption. Taiwan banned ractopamine along with other beta-adrenergic agonists in October 2006,[11] but in 2012 its legislature passed amendments to the Act Governing Food Sanitation, authorising government agencies to set safety standards for ractopamine.[12] The Department of Health ultimately established a maximum residual level of 10 ppb for ractopamine in beef on 31 July 2012.[13]

Japan and South Korea allow for the import of meat with ractopamine residues up to a maximum residue level, but it is not licensed for use in their domestic beef production.[14]

Many other countries, including Mexico, Canada, and the United States, have determined that meat from animals fed ractopamine is safe for human consumption.[15] In the USA, 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.

In Canada, ractopamine is only allowed in meal or pellet feed for finishing barrows and gilts, confined finishing cattle, and finishing heavy turkeys.[16]

On 6 July 2012, the Codex Alimentarius Commission narrowly approved the adoption of a maximum residue limit of 10 parts per billion (ppb) for muscle cuts of beef and pork.[17] 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.[17] Consumers International, a world federation of consumer groups that represents 220 consumer organizations in 115 countries, strongly opposed the move.[17]

Human use and route of exposure[edit]

Ractopamine is not for use in humans for any medical purposes. The more probable route of exposure to ractopamine in humans is through the consumption of food animals which have been fed ractopamine and its residue remains.[citation needed]

Pharmacokinetics in humans[edit]

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.[18]

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.[19] The effect of ractopamine on humans is not entirely known, but consumption of products that contain ractopamine residues is not advisable to people with cardiovascular diseases.

Safety concerns[edit]

Target animal safety[edit]

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.[citation needed] 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)[20]

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.[21] She also asserts that meat from ractopamine-treated animals is tougher.[21]

Some show lambs have been illegally given ractopamine, either intentionally or due to accidental contamination of their feed.[22]

Adverse effects[edit]

Acute toxicity[edit]

Oral LD50 levels in mice and rats are 3547–2545 mg/kg body weight (male and female) and 474–365 (male and female), respectively.[23]

Genotoxicity and mutagenicity[edit]

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?][citation needed]

Carcinogenicity[edit]

Ractopamine is not considered to be a direct carcinogen. It is not listed by IARC, NTP, ACGIH, or OSHA. The induction of benign leiomyomas (tumors of smooth muscle) in mice and rats can possibly be due to a general feature of beta-adrenergic activity of ractopamine.

Cardiovascular effects[edit]

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.

Musculoskeletal effects[edit]

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[edit]

Feelings of 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[edit]

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.[24]

International controversies[edit]

Mainland China[edit]

In July 2007, officials of the People's Republic of China seized US-produced pork for containing ractopamine residues.[25] Further shipments of ractopamine-fed pork were seized in September, though this time they were Canadian in origin.[26]

Taiwan[edit]

Ractopamine has been banned in Taiwan since 2006.[27] 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.[28] 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.

Malaysia[edit]

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).[29] 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.[30] 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.[31][32]

Russia[edit]

On 6 June 2011, the Russian Ministry of Agriculture notified key meat exporters in Russia of the coming prohibition on the use of ractopamine in meat exported to Russia, and the requirement of submission of compliance certificates (confirming absence of ractopamine) that accompany such exported meat.

On 7 December 2012, the above prohibition went into force, and the pork and beef export became possible only upon checks that confirm such meat is ractopamine-free.


Comparison to clenbuterol[edit]

Similar to ractopamine, clenbuterol is a growth-promoting compound belonging to the beta-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, including the USA, Canada, Taiwan, and Hong Kong.

See also[edit]

References[edit]

  1. ^ Bottemiller, Helena (January 25, 2012). "Dispute over drug in feed limiting US meat exports". Bottom Line. 
  2. ^ Garina, Anastasia. "Russia throws poisonous meat back to US". Pravda.ru. Retrieved 14 December 2012. 
  3. ^ "The Facts about U.S. Beef and Ractopamine". American Institute in Taiwan. Retrieved 5 March 2012. 
  4. ^ Vivian Vezzoni de AlmeidaI; Amoracyr José Costa NuñezII; Valdomiro Shigueru Miyada (May 2012). "Ractopamine as a metabolic modifier feed additive for finishing pigs: a review" (PDF). Brazilian Archives of Biology and Technology. 25(3). Retrieved 9 December 2014. 
  5. ^ Liu, X; Grandy, DK; Janowsky, A (July 2014). "Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1.". The Journal of Pharmacology and Experimental Therapeutics 350 (1): 124–9. doi:10.1124/jpet.114.213116. PMID 24799633. 
  6. ^ Apple, JK; Rincker, PJ; McKeith, FK; Carr, SN; Armstrong, TA; Matzat, PAS; Matzat, PD (June 2007). "Meta-analysis of the ractopamine response in finishing swine" (PDF). The Professional Animal Science 23: 179–196. 
  7. ^ http://www.globalmeatnews.com/Industry-Markets/EU-opposes-ractopamine-limit
  8. ^ http://www.efsa.europa.eu/en/efsajournal/pub/1041.htm
  9. ^ http://www.usatoday.com/story/money/business/2013/06/14/smithfield-foods-4q-profit-falls-63/2423401/
  10. ^ http://beefmagazine.com/foreign-trade/russian-ban-ractopamine-boosts-brazilian-exports
  11. ^ "行政院農業委員會公告 (Council of Agriculture, Executive Yuan notice)" (in Chinese). 11 October 2006. Retrieved 28 June 2012. 
  12. ^ "Legislature votes to allow ractopamine". Taipei Times. 26 July 2012. Retrieved 3 August 2012. 
  13. ^ "DOH experts choose ractopamine residue cap for beef imports". Taiepei Times. CNA. 2 August 2012. Retrieved 3 August 2012. 
  14. ^ "Description of the Ractopamine Standards in Livestock Products of Different Countries". Food and Drug Administration, Ministry of Health and Welfare. 23 March 2012 accessdate=27 November 2014.  Check date values in: |date= (help)
  15. ^ "The Facts about U.S. Beef and Ractopamine". American Institute in Taiwan. Retrieved 5 March 2012. 
  16. ^ Canadian Food Inspection Agency (September 2014). "Ractopamine Hydrochloride - MIB #82". Retrieved 29 November 2014. 
  17. ^ a b c Bottemiller, Helena (July 6, 2012). "Codex Adopts Ractopamine Limits for Beef and Pork". Food Safety News. Retrieved 29 November 2014. 
  18. ^ RACTOPAMINE (addendum). WHO FOOD ADDITIVES SERIES: 53
  19. ^ "Safety evaluation of ractopamine EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP)". EFSA Journal. 7 April 2009. doi:10.2903/j.efsa.2009.1041. Retrieved 2013-03-21. 
  20. ^ "Dispute Over Drug in Feed Limiting US Meat Exports". The Fern. January 25, 2012. 
  21. ^ a b Rockett, Caitlin (November 20,2014). "Oops, we forgot to study that: U.S. nonprofits file suit against Food and Drug Administration over ractopamine in our meat". Boulder Weekly. Retrieved 29 November 2014.  Check date values in: |date= (help)
  22. ^ BERGIN, NICHOLAS (March 15, 2014). "Family sues feed company over lamb's failed drug test". Lincoln Journal Star. 
  23. ^ Safety evaluation of ractopamine. 2009. p. 10. 
  24. ^ Sakai T et al. (2007). "Determination method for ractopamine in swine and cattle tissues using LC/MS". Shokuhin Eiseigaku Zasshi 48 (5): 144–147. doi:10.3358/shokueishi.48.144. PMID 18027547. 
  25. ^ "China fights back, goes after U.S. meat", USA Today, July 14, 2007.
  26. ^ "China stops imports from Canadian pork plant over banned additive", Canada Press (2007-09-19)[dead link]
  27. ^ Lin, Hermia (August 22, 2007). "Swine farmers get rowdy over ractopamine issue". Taiwan News. Retrieved January 25, 2012. [dead link]
  28. ^ "Taiwanese farmers urge continuation of US pork import ban". Associated Press. August 21, 2007. Archived from the original on January 25, 2012. 
  29. ^ Fifteenth A Schedule, Table 1, Maximum Permitted Proportion of Drug Residues in Food.
  30. ^ "Beta-agonists hog the limelight". The Star. November 5, 2006. Retrieved January 25, 2012. 
  31. ^ "Vet Dept seals 10 pig farms". The Star. December 31, 2008. Retrieved January 25, 2012. 
  32. ^ "10 pig farms under quarantine". The Star. December 30, 2008. Archived from the original on January 25, 2012. 

External links[edit]