Ractopamine

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Ractopamine
Ractopamine.svg
Names
IUPAC name
4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino]butyl]phenol
Identifiers
  • 97825-25-7 No
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:82644 No
ChEMBL
  • ChEMBL509336 YesY
ChemSpider
  • 50604 YesY
MeSH Ractopamine
PubChem CID
  • 56052
UNII
  • 57370OZ3P1 YesY
Properties
C18H23NO3
Molar mass 301.39 g·mol−1
4100 mg/L
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
No verify (what is YesYNo ?)
Infobox references

Ractopamine is a feed additive, banned in most countries, 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.[1][2] 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 is banned in the European Union, mainland China and Russia[3][4] while 27 other countries, such as Japan, the United States,and South Korea, have deemed meat from livestock fed ractopamine safe for human consumption.[5][dead link][6]

Commercial ractopamine is a mixture of all four possible stereoisomers.[7]

Mode of action

When used as a food additive, ractopamine added to feed can be distributed by the blood to the muscle tissues, where it serves as a full agonist at mouse (not necessarily human) TAAR1.[1] It is also an agonist at beta-adrenergic receptors.[2] 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 3 kg (6.6 lb) of additional lean pork and improves feed efficiency by 10%.[8]

Regulation around the world

As of 2015, ractopamine use as a feed additive is authorized in the United States, Canada, and Mexico.[9] 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";[5] 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.[10] 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 parts per billion (ppb).

The USDA approved of a new label, "no ractopamine — a beta-agonist growth promotant" to be used.[11] Currently, the USDA label for organic means no synthetic compounds can be used other than those on the list of allowed synthetics, therefore, ractopamine would not be allowed in certified organic production.[12]

In Canada, ractopamine is only allowed in meal or pellet feed for finishing barrows and gilts, confined finishing cattle, and finishing heavy turkeys.[13]

Japan, which had permitted its feed additive use at least until 2009,[9]: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.[14]

On 6 July 2012, the international reference standard Codex Alimentarius Commission narrowly approved the adoption of a MRL of 10 parts per billion (ppb) for muscle cuts of beef and pork.[15] 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 to use it as leverage to erode individual national-level bans in World Trade Organization disputes.[15] Consumers International, a world federation of consumer groups that represents 220 consumer organizations in 115 countries, strongly opposed the move.[15]

As of 2013, ractopamine use in food animals has been banned in over 160 countries.[16] It has not been allowed in the 27 member countries of the European Union, based on the 2009 European Food Safety Authority's opinion on its safety evaluation, which concluded that available data were insufficient to derive a maximum residue limit 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.[9][17]

Russia and China banned ractopamine in pork,[18] and Russia also in beef,[16] deeming it unfit for human consumption. Taiwan banned ractopamine along with other beta-adrenergic agonists in October 2006,[19] but in 2012, its legislature passed amendments to the Act Governing Food Sanitation, authorising government agencies to set safety standards for ractopamine.[20] The Department of Health ultimately established an MRL of 10 ppb for ractopamine in beef on 31 July 2012.[21]

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.[22]

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.[23] 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.

Safety concerns

Target animal safety

In swine ractopamine is correlated with adverse effects, especially hyperactivity, trembling, and broken limbs, leading to censure by animal rights groups.(FDA)[24]

In a conversation with Boulder Weekly newspaper Colorado State University Professor of Animal Science Temple Grandin, an expert on animal welfare, described harmful effects of ractopamine on feedlot animals, such as cattle with stiff, sore, and lame limbs, and increased heat stress.[25] In the same column she also opines that meat from ractopamine-treated animals may be tougher.[25]

When a winning show lamb tested positive for ractopamine in 2014, the owner claimed it was due to negligent feed contamination by the manufacturer, rather than intentional and illegal doping.[26]

Adverse effects

Acute toxicity

Oral LD50 levels in mice and rats are 3547–2545 mg/kg body weight (male and female) and 474–365 (male and female), respectively.[27]

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?][citation needed]

Carcinogenicity

Ractopamine is not considered to be a carcinogen and not listed by IARC, NTP, ACGIH, or OSHA.

Cardiovascular effects

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

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.

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. Whether long-term treatment with these drugs results in the development of tolerance to these adverse effects is unclear.[citation needed]

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.[28]

International controls

US-EU WTO dispute

In the late 1990s, the World Trade Organization authorized the United States and Canada to impose retaliatory tariffs of US$116.8 million per year on the European Union after it found the EU beef hormone ban to be in violation of the WTO Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement).[29][30] In September 2009, the United States and the European Commission signed a memorandum of understanding, which established a new EU duty-free import quota for grain-fed, high-quality beef as part of a compromise solution.[30]

China

In July 2007, officials of the People's Republic of China seized US-produced pork for containing ractopamine residues.[31] Further shipments of ractopamine-fed pork were seized in September, though this time they were Canadian in origin.[32]

Taiwan

Ractopamine has been banned in Taiwan since 2006.[33] 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.[34] 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 no lifting of the ban would occur unless related laws were amended. Although the use of ractopamine in lifestock is still banned and enforced on the domestic industry, and the government has maintained a “zero tolerance” policy on pork imports that contain it, Taiwan's legislature amended the food safety act in August 2012 to allow the import of beef products containing up to a maximum residue level of 10 parts per billion of the additive.[35] The remaining restrictions have been an obstacle to the two nations signing a free-trade agreement, and the Office of the United States Trade Representative (USTR)’s 2018 Trade Policy Agenda and 2017 Annual Report assert that these remaining restrictions as “are not based upon science” and highlights their removal as among the main priorities for the US in its trade with Taiwan.[35]

Malaysia

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).[36] 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.[37] 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.[38][39]

Russia

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.[citation needed]

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.[citation needed]

In popular culture

Stuntman and comedian Steven Glover has publicly spoken of his involvement as a test subject in an early ractopamine study whose aim was to determine the stress limits of ractopamine saturation in humans. Glover claims, "Based on how dangerous the study was, the more money you get."[40]

References

  1. ^ a b 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. PMC 4170122Freely accessible. PMID 24799633. 
  2. ^ a b Colbert, WE; Williams, PD; Williams, GD (December 1991). "Beta-adrenoceptor Profile of Ractopamine HCl in Isolated Smooth and Cardiac Muscle Tissues of Rat and Guinea-pig". The Journal of Pharmacy and Pharmacology. 43 (12): 844–7. doi:10.1111/j.2042-7158.1991.tb03192.x. PMID 1687583. 
  3. ^ Bottemiller, Helena (January 25, 2012). "Dispute over drug in feed limiting US meat exports". Bottom Line. Archived from the original on January 26, 2012. 
  4. ^ Garina, Anastasia. "Russia throws poisonous meat back to US". Pravda.ru. Retrieved 14 December 2012. 
  5. ^ a b "The Facts about U.S. Beef and Ractopamine". American Institute in Taiwan. Retrieved 5 March 2012. 
  6. ^ AIT- American Institute in Taiwan: 'The Facts about U.S. Beef and Ractopamine' (archived) Accessed January 21, 2018
  7. ^ 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. 
  8. ^ 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. 
  9. ^ a b c http://www.globalmeatnews.com/Industry-Markets/EU-opposes-ractopamine-limit
  10. ^ Lin, Enru (December 30, 2015). "Taiwan's pig farmers threaten large-scale protest over US pork". China Post. Asia News Network. Retrieved 15 January 2016. 
  11. ^ "A Muscle Drug For Pigs Comes Out Of The Shadows". The Salt, what's on your plate. NPR. Retrieved 16 February 2017. 
  12. ^ "7 CFR 205.603 - Synthetic substances allowed for use in organic livestock production". US Code of Federal Regulations CFR › Title 7 › Subtitle B › Chapter I › Subchapter M › Part 205 › Subpart G › Section 205.603. 
  13. ^ Canadian Food Inspection Agency (September 2014). "Ractopamine Hydrochloride - MIB #82". Retrieved 29 November 2014. 
  14. ^ "Description of the Ractopamine Standards in Livestock Products of Different Countries". US Food and Drug Administration, Ministry of Health and Welfare. 23 March 2012. Retrieved 27 November 2014. 
  15. ^ a b c Bottemiller, Helena (July 6, 2012). "Codex Adopts Ractopamine Limits for Beef and Pork". Food Safety News. Retrieved 29 November 2014. 
  16. ^ a b Russian Ban On Ractopamine Boosts Brazilian Exports Simon Quilty, Beefmagazine (Penton), March 27, 2013
  17. ^ Scientific Opinion of the Panel on Additives and Products or Substances used in Animal Feed(FEEDAP) on a request from the European Commission on the safety evaluation of ractopamine The EFSA Journal (2009) 1041, 1-52
  18. ^ Smithfield Foods' profit falls 63% Michael Felberbaum, USA Today (AP) June 14, 2013, s.a. Smithfield Foods
  19. ^ "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. 
  20. ^ "Legislature votes to allow ractopamine". Taipei Times. 26 July 2012. Retrieved 3 August 2012. 
  21. ^ "DOH experts choose ractopamine residue cap for beef imports". Taiepei Times. CNA. 2 August 2012. Retrieved 3 August 2012. 
  22. ^ RACTOPAMINE (addendum). WHO FOOD ADDITIVES SERIES: 53
  23. ^ "Safety evaluation of ractopamine EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP)". EFSA Journal. 7: 1041. 7 April 2009. doi:10.2903/j.efsa.2009.1041. Retrieved 2013-03-21. 
  24. ^ "Dispute Over Drug in Feed Limiting US Meat Exports". The Fern. January 25, 2012. 
  25. ^ 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. 
  26. ^ BERGIN, NICHOLAS (March 15, 2014). "Family sues feed company over lamb's failed drug test". Lincoln Journal Star. 
  27. ^ Safety evaluation of ractopamine. 2009. p. 10. 
  28. ^ 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. 
  29. ^ "DS26: European Communities — Measures Concerning Meat and Meat Products (Hormones)". World Trade Organization. 
  30. ^ a b Office of the United States Trade Representative (March 2017), 2017 National Trade Estimate Report on Foreign Trade Barriers (PDF), pp. 148–149 
  31. ^ "China fights back, goes after U.S. meat", USA Today, July 14, 2007.
  32. ^ "China stops imports from Canadian pork plant over banned additive", Canada Press (2007-09-19)[dead link]
  33. ^ Lin, Hermia (August 22, 2007). "Swine farmers get rowdy over ractopamine issue". Taiwan News. Archived from the original on September 29, 2011. Retrieved January 25, 2012. 
  34. ^ "Taiwanese farmers urge continuation of US pork import ban". Associated Press. August 21, 2007. Archived from the original on January 26, 2012. 
  35. ^ a b "US report identifies pork ban as 'barrier' to trade". The Taipei Times. Central News Agency. 2 March 2018. Retrieved 7 July 2018. 
  36. ^ Fifteenth A Schedule, Table 1, Maximum Permitted Proportion of Drug Residues in Food.
  37. ^ "Beta-agonists hog the limelight". The Star. November 5, 2006. Archived from the original on June 29, 2011. Retrieved January 25, 2012. 
  38. ^ "Vet Dept seals 10 pig farms". The Star. December 31, 2008. Archived from the original on June 8, 2011. Retrieved January 25, 2012. 
  39. ^ "10 pig farms under quarantine". The Star. December 30, 2008. Archived from the original on January 26, 2012. 
  40. ^ YouTube title: Joe Rogan Experience #717 - Steve-O. November 3, 2015. Retrieved November 16, 2017. 

External links

  • Ractopamine page
  • Ractopamine study
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