3

Steroid Hormones in Food Producing Animals:

Regulatory Situation in Europe
Annamaria Passantino
Department of Veterinary Public Health,
Faculty of Veterinary Medicine,
University of Messina,
Italy
1. Introduction
Hormones are chemicals produced by animals to co-ordinate their physiological activities.
They act as messengers, produced in and released from one kind of tissue to gradually
stimulate or inhibit some process in a different tissue over a long period.
Steroid hormones fulfill an important role at different stages of mammalian development
comprising prenatal development, growth, reproduction and sexual and social behavior.
The importance of individual hormones varies between sexes and age and a disruption of
the endocrine equilibrium may result in multiple biological effects.
One hormone can have multiple actions, e.g. the male hormone testosterone controls many
processes from the development of the foetus, to libido in the adult. Alternatively, one
function may be controlled by multiple hormones, e.g. the menstrual cycle involves
oestradiol, progesterone, follicle-stimulating hormone and luteinising hormone.
Hormones produced by the bodies of humans and animals are called endogenous or natural
hormones. Compounds chemically synthesised to mimic the effect of natural hormones are
called synthetic or xenobiotic hormones.
Hormones are vital in normal development, maturation and physiological functioning of
many vital organs and processes in the body. However, like any other chemicals of natural
or synthetic origin, hormones may be toxic to living organisms under certain circumstances.
The toxicity may be due to an excess of its normal (physiological) action. This may be the
result of excessive exposure to the substance, for example following absorption of a large
dose, or because the physicochemical nature of the substance gives it greater or more
prolonged activity of the same type, or because the hormonal action occurs at an abnormal
time during development or adult life, or is an action on an organism of the inappropriate
sex. Hormones, like other chemicals, may also exert direct toxic actions not related to their
endocrine (physiological) effects.
Due to the obvious ability to improve weight gain and feed efficiency in meat producing
animals, natural hormones and/or the synthetic surrogates have been used in agricultural
practice for several decades (table 1).

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Substances
Oestrogens alone:
DES
DES
DES
Hexoestrol
Zeranol
Gestagens alone:
Melengestrol acetate
Androgens alone:
TBA
Combined preparations:
DES and Testosterone
DES and Methyl-testosterone
Hexoestrol and TBA
Zeranol and TBA
Oestradiol-17and TBA
Oestradiol-17 benzoate and
testosterone propionate
Oestradiol-17 benzoate and
progesterone

A Bird's-Eye View of Veterinary Medicine

Form

Main use - Animals

Feed additive
Implant
Oil solution
Implant
Implant

Steers, heifers
Steers
Veal calves
Steers, sheep, calves, poultry
Steers, sheep
Heifers

Implant

Heifers, culled cows

Implant
Feed additive
Implant
Implant
Implant
Implant

Calves
Swine
Steers
Steers
Bulls, steers, calves, sheep
Heifers, calves

Implant

Steers

Table 1. Hormonally-active substance used in animal production (by

http://www.fao.org/DOCREP/004/X6533E/X6533E01.htm, modified)
Implanting hormonal growth promoters is currently widespread in the beef cattle industry
of many non-EU countries for the better performance in growth and improvement of feed
efficiency. These hormonal implants may enhance growth during suckling, growing and
finishing stages of production (Mader, 1997; Platter et al., 2003).
Growth hormones are implanted under the skin (usually behind the ear) of the animal in the
form of depot capsules, where they release a specific dose of hormones over a fixed period
of time.
The five hormone types most widely used in meat production include three natural
hormones, oestradiol 17-, testosterone, and progesterone, and two synthetic substances,
trenbolone and zeranol.
Oestradiol 17- has oestrogenic action (i.e. responsible for female characteristics);
testosterone has androgenic action (i.e. responsible for male characteristics); and
progesterone has gestagenic action (i.e. responsible for maintaining pregnancy). The other
two hormones, as aforesaid, mimic the biological activity of the natural hormones:
trenbolone mimics the action of testosterone, and zeranol mimics oestradiol 17-
1.1 Hormonally active substances
1.1.1 Oestradiol 17-
Oestradiol 17- is the most active of the female sex hormones synthesized and secreted
mainly by the ovary, the adrenals and the testis.

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Oestradiol is synthesized and secreted in early stages of embryogenesis and has an active
role in the normal development of the female sex accessories during the lifetime of females.
It has been used to induce parturition (birth) especially in sheep, a species in which an
associated oestradiol-induced increase in mothering ability has also been recorded
(Poindron, 2005).
In non-pregnant animals, oestradiol has been used clinically to increase uterine contractions
and cervical softening for the expulsion of unwanted uterine contents in the absence of a
corpus luteum (i.e. to remove a dead fetus or infected material especially in cattle) (Elmore,
1992; Pepper &, Dobson, 1987; Sheldon & Noakes, 1998).
Oestradiol has been used in the past in turkeys and other poultry to castrate young birds.
Implants would be placed subcutaneously at 5-6 weeks of age, or in slightly older birds, but
certainly 4 weeks before killing. Alternatively, preparations were available as feed-additives.
This approach is not now used in Europe although it was used in slower growing Spanish
breeds. There are very few reproductive problems in rabbits.
Fetal mummifications and macerations occur, as do endometritis and pyometra but
treatment with oestradiol has not been reported (Flecknell, 2000).
In fish, administration of oestradiol at first-fry feeding (approximately 40-70 days of age
depending on species) will induce ovarian development and female characteristics in
salmonids, flat-fish and eels (Shepherd & Bromage, 1988). Sex-control in this way depresses
or inhibits maturation to ensure that metabolism is channelled into body growth (i.e., more
saleable flesh). However, this approach is no longer commercially adopted.
Another use of very low doses of oestradiol is as a growth promoter via appetite stimulating
and increased food-conversion properties. Occasionally in the past, this approach has been
taken to advance the onset of puberty and thus alleviate potential gynaecological problems
in slower maturing species. However, as use of hormonal growth promoters is prohibited
within the European Union1.
1.1.2 Testosterone
Testosterone and its more active metabolite, 5-dihydrotestosterone (DHT), are the main sex
hormones secreted by males. Testosterone is responsible for the early development, and the
appearance and maintenance of male secondary sex accessory organs (prostate, secretory
glands, penis size, etc.) during adulthood. Testosterone secretion is also affected by the
complex interaction among all endocrine glands, especially with those in the brain.
Testosterone is metabolized and as a result, metabolites of different activity are generated.
Some of these metabolites play a more active role in certain organs than in others.
The actions of both testosterone and DHT are mediated through their high affinity and high
specificity binding and activation of an intracellular protein, the androgen receptor (AR).
This AR protein is a member of the steroid hormone superfamily. The ligand-activated
androgen receptor mediates its effects on cell growth and differentiation through the
1

See the following paragraph: Background of the European Union legislation

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A Bird's-Eye View of Veterinary Medicine

activation and/or suppression of specific gene transcription in target organs. Androgen

receptors are detected in tissues of females, as well as males. The presence of this receptor in
organs such as the ovary indicates significant activity of androgens in both sexes.
Furthermore, the androgen receptor is thought to be involved in ovarian tumorigenesis, as it
has been detected in 67 percent of ovarian tumors. Although current information indicates
the presence of only a single androgen receptor, it is known that different subsets of genes
may be activated by either testosterone or DHT (Chang et al., 1995).
In animals, testosterone or testosterone propionate, alone or in combination with other
hormonally active substances, is used primarily to improve the rate of weight gain and feed
efficiency. This effect is most likely a consequence of the anabolic action of androgens.
1.1.3 Progesterone
Progesterone is synthesized and secreted mainly by the corpus luteum in the ovary of
cycling females, and, during pregnancy, by the placenta.
As all hormones, progesterone synthesis and secretion is regulated by a series of positive
and negative feedback mechanisms in which polypeptidic hormones secreted by the brain
(hypothalamus, pituitary) affect circulating progesterone levels.
Progesterone and synthetic progestins are used pharmacologically in women in conjunction
with ovulation stimulation drugs as well as during early pregnancy in cases of luteal phase
dysfunction. Although results have been conflicting, some studies find an association
between pregnancy-related intake of progestins and increased risk of hypospadias
(congenital malformation of the urethral opening on the penis) in the male offspring
(Carmichael et al., 2005). It should however be noted that this was observed in relation to
pharmacological doses of progestins, and as progesterone levels are normally high during
pregnancy, minor additional exogenous progestagenic activity would presumably be
without significant effects in the presence of a high endogenous activity, unless the synthetic
progestins act at different sites and by different mechanisms. In contrast, serum levels of
progestins in children and postmenopausal women are very low. Data on effects of
progesterone in the prepubertal child are scarce and no new data have been identified.
Likewise, no animal studies on the effects of progesterone during the postnatal development
have been published recently.
It is well established that progesterone not only serves as the precursor of all the major
steroid hormones (androgens, oestrogens, corticosteroids) in the gonads and adrenals, but
also is converted into one or more metabolites by most tissues in the body (Wiebe, 2006).
1.1.4 Trenbolone acetate
Trenbolone acetate (TBA) is a synthetic steroid with an anabolic potency that may exceed
that of testosterone. It is a prodrug that converts into its active form 17 -trenbolone, which
isomerises into 17 -trenbolone.
17 -trenbolone is the major form occurring in muscle tissue, whereas the 17 -epimer is the
major metabolite occurring in liver and in the excreta including bile. It is assumed to exert

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Steroid Hormones in Food Producing Animals: Regulatory Situation in Europe

37

its anabolic action via interaction with androgen and glucocorticoid receptors (Danhaive
and Rousseau, 1986, 1988). Experiments with cattle tissues have shown that 17 -trenbolone
binds to the androgen receptor with similar affinity as dihydrotestosterone. It also binds to
the progesterone receptor with an affinity that exceeds that of progesterone. The other
metabolites of TBA, including 17 -trenbolone (17 -hydroxy-estra-4,9,11-trien-3-one) and
TBO (estra-4,9,11-triene-3,17-dione) show a significantly lower binding affinity to both types
of receptors (Bauer et al., 2000).
Reports regarding the (mis)use of TBA as an anabolic agent in sports people describe several
adverse effects, including liver cell injury with an increase in liver-specific enzymes in
serum, cholestatic jaundice, peliosis hepatitis and various neoplastic lesions. Moreover,
decreased endogenous testosterone production and spermatogenesis, oligospermia and
testicular atrophy may be associated with the repeated use of TBA as anabolic (Bahrke and
Yesalis, 2004; Maravelias et al., 2005).
1.1.5 Zeranol
Zeranol is derived from the naturally occurring mycoestrogen zearalenone, and is a potent
oestrogen receptor agonist in vivo and in vitro (Leffers et al., 2001; Le Guevel and Pakdel,
2001; Takemura et al., 2007; Yuri et al., 2006). Its actions resemble those of oestradiol. (Leffers
et al., 2001).
Zeranol stimulates the proliferation of ER-dependent cell proliferation in MCF-7 human
breast cancer cells (which are widely used in the assessment of estrogenic activity) and in
transfected cells (Leffers et al., 2001; Le Guevel and Pakdel, 2001; Liu and Ling, 2004).
It is used alone or in combination with TBA as a hormonal growth promoter in various
products.

2. Background of the European Union legislation

The use of hormonal growth promoters in food-producing animals has been a sensitive
issue of debate in the EU and elsewhere for several decades.
Prior to 1981, the EC had no universal policy on the use of growth promoting hormones in
meat animals.
The use of hormones had been banned in Italy since 1961, in Denmark since 1963, and in
Germany since 1977. Belgium and Greece had never permitted the use of hormones for
fattening purposes. However, Spain, the United Kingdom, France and Netherlands
permitted the use of most hormones for speeding growth in beef cattle2.
The move to impose a Europe wide ban was spurred by the worrying discovery in 1977 of
breast enlargement in girls and boys attending a school in Milan (Italy) (Scaglioni et al.,
1978). Although oestrogen contamination was not detected when samples of school meals
were tested, an uncontrolled supply of poultry and beef was hypothesized as being the
cause of this outbreak (Fara et al., 1979).
2

See http://www.fao.org/DOCREP/004/X6533E/X6533E03.htm#refeecstr Accessed August 19, 2011.

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In 1980 the discovery of 30,000 jars of baby food containing dethylstilboestrol, commonly
known as DES, contaminated French veal was reported. European consumer organizations
called for a boycott of veal, and the market for veal was severely affected. On September 20,
1980, the EC Council of Agriculture Ministers adopted a declaration in favor of a ban on the
use of oestrogen and endorsed the principle of greater harmonization of legislation on
veterinary medicines and of greater control on animal rearing, both at the production and
slaughtering stages.
On October 31, 1980, the EC Commission proposed even more rigorous legislation that would
ban the use of all hormone products in meat production, except for therapeutic purposes3. This
proposal was expanded later by documents COM(80)920 and COM(80)922, presented on 6
January 1981. These allowed for the controlled use for therapeutic and zootechnical purposes
of three natural hormone products, and introduced a number of control measures on the
production and handling of such products, together with proposals on the testing of animals.
Discussions in the European Parliament revealed that three EC member States (Belgium,
Ireland and the United Kingdom) favored the use of some hormones to promote growth in
meat animals, and Ireland and the United Kingdom also argued for the retention of the
synthetic hormones, trenbolone and zeranol. Third countries, including The United States,
Argentina, Australia, Canada, New Zealand and South Africa raised concerns concerning the
potential impact of a ban on their exports to European Communities4.
Subsequently, the European Council adopted its first directive on the hormones issues in
July 1981 (Directive 81/602/EEC)5.
Directive 81/602/EEC prohibits the administering to farm animals of substances having a
thyrostatic action or substances having an oestrogenic, androgenic or gestagenic action; the
placing on the market or slaughtering of farm animals to which these substances have been
administered; the placing on the market of meat from such animals; the processing of meat
from such animals and the placing on the market of meat products prepared from or with
such meat. The Directive provides two exceptions to the prohibition: one exception is
provided for substances with an oestrogenic, androgenic or gestagenic action when they are
used for therapeutic or zootechnical purposes and administered by a veterinarian or under a
veterinarian's responsibility. The other exception was for oestradiol-17, progesterone,
testosterone, TBA and zeranol - when they were used for growth promotion purposes and
their use was governed according to the individual regulatory schemes maintained by EC
member States. This exception was made pending an examination of the effects of these
hormones on the health of consumers and the adoption of an EC rule. EC member States are
obliged to apply their regulatory schemes to imports from third countries in a manner not
more favorable than that applied to intra-EC trade.
3 Commission of the European Communities 1980. Proposal for a Council Regulation (EEC) Concerning
the Uses of Substances with a Hormonal Action and those having a Thyrostatic Action in Domestic
Animals. COM (80) 614, 31 October, Brussels: Commission of the European Communities.
4 WTO, 1997. EC measures concerning meat and meat products (hormones), complaint by the United
States. Report of the WTO Panel, WT/DS26/R/USA, August 18, 1997, 2: 26-28. Available at
http://www.sice.oas.org/dispute/wto/horm-us.asp, Accessed August 20, 2011.
5 Council Directive 81/602/EEC of 31 July 1981 concerning the prohibition of certain substances having
a hormonal action and of any substances having a thyrostatic action. Official Journal of the European
Communities, L Series, No. 222, pp. 32-33.

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The relevant international organizations - FAO, WHO, OIE and Codex - started to seriously
examine the safety of these hormones in meat production only during the 1980s.
The first substantive scientific report had been published by OIE in 1983. The Joint
FAO/WHO Expert Committee on Food Additives (JECFA)6 had discussed and issued a
scientific report on these hormones only in 19887.
There were two other international reports comprising collective scientific work: the 1984
Scientific Report published by the European Commission (based on the Lamming Report8)
and the Proceedings of the 1995 EC Scientific Conference9.
6 It is an independent expert group which deals with specific commodity issues or general health and
safety matters related to food. The JECFA focuses on the scientific evaluation of a veterinary drug and does
not consider government policies and politics.
7 The JECFA Report, on which the Codex standard for zeranol is based, noted that zeranol was a weak
oestrogen which mimicked the action of oestradiol-17. The report concluded that the toxic (in casu
tumorigenic) effect of zeranol is associated with its hormonal (i.e. oestrogenic) properties and that an ADI
could thus be established on the basis of a no-hormonal-effect level. Adopting what it considered to be a
conservative approach by using as a basis studies on ovariectomized female cynomolgus monkeys (highly
sensitive to oestrogenic substances) and using a safety factor of 100, JECFA set an ADI for human beings of
0-0.5 g/kg of body weight. For a 70 kg person consuming 500 g of meat daily over an entire lifetime, the
maximum permissible or safe level of zeranol residues in meat would then, according to JECFA, be 70
g/kg of edible tissue. However, the report noted that when zeranol is administered to cattle according to
good animal husbandry practice, the maximum mean residue levels did not exceed 0.2 g/kg in muscle,
10 g/kg in liver, 2 g/kg in kindney, and 0.3 g/kg in fat at any time after implantation. These residue
levels obtained on the basis of good animal husbandry practice are thus below the maximum permissible
level of 70 g/kg. However, in order to set a level which is detectable by routine residue analysis methods,
the Codex MRL was increased to 2 g/kg in muscle and set at 10 g/kg in liver.
With respect to trenbolone acetate (TBA), the Report concluded that its potential toxic effects only arise as a
consequence of its hormonal activity. The report further concluded that, therefore, an ADI could be
established on the basis of a no-hormonal-effect level. Adopting what it considered to be a conservative
approach by using as a basis studies on castrated male rhesus macaque monkeys (which are highly
sensitive to compounds with antigonadotropic activity) and pigs (which are a sensitive model for assessing
hormonal effects of TBA) and using a safety factor of 100, JECFA later set an ADI for human beings of 00.02 g/kg of body weight (34th JECFA Report of 1989). The maximum ADI for a 60 kg person would thus
be 1.2 g of TBA residues. JECFA then set MRL's for -trenbolone in muscle and -trenbolone in liver of 2
g/kg and 10 g/kg, respectively, based on average residue levels in heifers at 15-30 days after
implantation of 300 mg TBA, noting that concentrations would be even lower at proposed GPVD.
According to JECFA, the MRL's thus obtained on the basis of conservative estimates should not exceed the
Codex ADI or safe level at any time after implantation of the drug, that is, irrespective of the withdrawal
period used.
8 The Lamming Groups interim report, issued in September 1982, found that the three natural hormones
(oestradiol-17, testosterone and progesterone) would not present any harmful effects to the health of the
consumer when used under the appropriate conditions as growth promoters in farm animals.
For the findings of the scientific working group, see Lamming, G.E., Ballarini, G., Baulieu, E.E. et al.,
(1987). Scientific Report on Anabolic Agents in Animal Production. The Veterinary Record, 121, at 389392.
9 The 1995 EC Scientific Conference on Growth Promotion in Meat Production concluded that: "At present,
there is no evidence for possible health risks to the consumer due to the use of natural sex hormones for
growth promotion, since: Residue levels of these substances measured in meat of treated animals fall
within the physiological range observed in meat of comparable untreated animals. The daily production of
sex hormones by humans is much higher than the amounts possibly consumed from meat, even in the
most sensitive humans (prepubertal children and menopausal women).

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The European Communities stressed, however, that these reports did not constitute the
entire body of scientific knowledge on the issue of safe use of these hormones for growth
promotion. There were also important studies made by individual scientists, and other
specialized institutions like the International Agency for Research on Cancer (IARC).
The EC Scientific Veterinary Committee gave its reaction to the Lamming Report
on November 9, 1982, followed by the EC Scientific Committee for Animal Nutrition
on November 17, 1982 and by the EC Scientific Committee for Food on February 4, 1983.
These Committees supported the conclusions and recommendations of the Lamming
Report, but stressed the need to lay down provisions regarding the establishment of proper
programmes to control and monitor the use of anabolic agents with regard, in particular, to
instructions for use, surveillance programmes and analysis methods. In January 1984, the
Commission asked a group of experts within the EC Scientific Committee on Anabolic
Agents to review the information on trenbolone and zeranol. On June 12, 1984, the
Commission published a proposal (COM(84)295 final) for a Council Directive amending
Directive 81/602/EEC, which envisaged the controlled use of the three natural hormones
for growth promotion purposes and proposed re-examining the ban on the two synthetic
hormones after their scientific evaluation had been completed. However, the European
Parliament, the EC Economic and Social Committee and the EC Council of Ministers
rejected the Commission's proposal.
The EC Commission amended its proposal accordingly and on December 31, 1985 the EC
Council adopted Directive 85/649/EEC10. This Directive banned the use of all the
substances concerned for growth promotion purposes and established more detailed
provisions concerning authorized therapeutic uses. Its preamble began by emphasizing that
differing rules on hormone use in different member countries had distorted trade in the
European market and that [] these distortions of competition and barriers to trade must
therefore be removed [].
The Directive was challenged in the European Court of Justice, which annulled it on
procedural grounds. The proposals were re-introduced by the EC Commission and readopted by the EC Council as Council Directive 88/146/EEC on March 7, 198811. This
Directive extends the prohibition imposed by Directive 81/602/EEC to the administration to
farm animals of trenbolone acetate and zeranol for any purpose, and oestradiol-17,
Due to an extensive first-pass metabolism, the bioavailability of ingested hormones is low, thus
providing a further safety margin".
With regard to the synthetic hormones, zeranol and trenbolone, the 1995 EC Scientific Conference
concluded that: "At the doses needed for growth promotion, residue levels [of trenbolone and zeranol]
are well below the levels regarded as safe (the MRLs). There are, at present, no indications of a possible
human health risk from the low levels of covalently-bound residues of trenbolone".
See Assessment of Health Risk - Working Group II", in 1995 EC Scientific Conference Proceedings, pp.
20-21.
10 Council Directive 85/649/EEC of 31 December 1985 prohibiting the use in livestock faring of certain
substances having hormonal action. Official Journal of the European Communities, L Series, No. 382, pp.
228-231.
11 Council Directive 88/146/EEC of 7 March 1988 prohibiting the use in livestock farming of certain
substances having a hormonal action. Official Journal of the European Union, L Series, No. 70, pp. 16-18.

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testosterone and progesterone for fattening purposes. However, the Directive maintains the
permission to administer these three natural hormones to animals for therapeutic and
zootechnical purposes under prescribed conditions; in particular, therapeutic treatment is
defined to mean the administering to an individual animal of any of the substances which
are authorized to treat a fertility problem diagnosed on examination by a veterinarian. The
products which are used for therapeutic treatment may be administered only by a
veterinarian, in the form of an injection (to the exclusion of implantation) to farm animals
which have been clearly identified. Such treatment must be registered by the veterinarian
and these animals may not be slaughtered before expiry of the period fixed. In the case of
animals at the end of their reproductive career, the treatments are prohibited from being
administered during the fattening period following the end of their breeding life. Article 4 of
Directive 88/146/EEC explicitly requires that undertakings in the EC member States
producing the prohibited hormones, those companies authorized to market these hormones
for whatever purposes and undertakings producing pharmaceutical and veterinary
products based on those substances, must keep a detailed register recording (in
chronological order) the quantities produced or acquired and those sold or used for the
production of pharmaceutical and veterinary products. The importation from third
countries of animals and meat from animals to which have been administered substances
with thyrostatic, oestrogenic, androgenic or gestagenic action is prohibited. However, under
certain conditions, Article 7 of Directive 88/146/EEC allows trade in those animals and
meat from those animals treated for therapeutic or zootechnical purposes, including imports
from third countries.
Directive 88/299/EEC12 lays down the conditions for applying the derogations, provided
for in Article 7 of Directive 88/146/EEC, from the prohibition on trade in certain categories
of animals and their meat. The first derogation of the Directive requires EC member States
to authorize trade in animals intended for reproduction and reproductive animals at the end
of their career (and of meat of such animals) which, during their reproductive career, have
undergone one of two categories of treatments. The first category is therapeutic treatment
with one of the following substances: oestradiol-17, testosterone and progesterone; and
those derivatives which readily yield the parent compound on hydrolysis after absorption at
the site of application which appear in a list of approved products. The second category is
the administration of substances having an oestrogenic, androgenic or gestagenic action for
synchronization of oestrus, termination of unwanted gestation, the improvement of fertility
and the preparation of donors and recipients for the implantation of embryos, provided that
the products in which they are contained appear on a list of approved products and with the
respect of strict conditions of use concerning, in particular, the respect of the withdrawal
period, the monitoring of those conditions of use and of the means of identification of the
animals. In addition, Articles 3 and 4 of this Directive provide that trade between the EC
member States of the European Communities in animals intended for reproduction and
reproductive animals and meat from such animals is allowed only if all the conditions laid
down in the Directive are respected, in particular as regards the waiting period and the
requirement that animals have not received any of the above treatments with any of the
Council Directive 88/299/EEC of 17 May 1988 on trade in animals treated with certain substances
having a hormonal action and their meat, as referred to in Article 7 of Directive 88/146/EEC. Official
Journal of the European Union, Series L, No. 87, pp. 36-38.
12

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above substances during the fattening period following the end of their breeding life. The
EC stamp may be affixed to the meat only if the waiting time ended before the animals are
slaughtered. The second derogation in Directive 88/299/EEC allows imports from third
countries of treated animals and meat of such animals under guarantees equivalent to those
for domestic animals and meat.
Following reports of significant use of illegal growth-promoting hormonal substances in a
number of EC member States, on September 26, 1988 the European Parliament established a
Committee of Enquiry into the Problem of Quality in the Meat Sector. The conclusions of
this Committee were published in a document known as the "Pimenta Report", which
recognized the ban on the use of hormones13. On March 29, 1989, the European Parliament
adopted its recommendations to maintain and expand the ban.
The European Parliament adopted another report on the issue of use of hormones for animal
growth promotion, the "Collins Report" of February 7, 198914. This report argued that:
"Current licensing systems for the regulation of veterinary medicines (including at present,
growth promoting products) require that a new product satisfy three criteria: safety, quality
and efficacy. These criteria may well be satisfactory for therapeutic drugs. They are by no
means sufficient for growth promoting products. For the latter it is proposed here that the
Community's veterinary medicine licensing system be adapted to include a "fourth hurdle",
entailing an objective socio-economic and environmental impact assessment". In the
Commission's July 1988 draft proposals for the reform of veterinary medicine licensing in
the Community this idea was accepted in principle. The final version of the proposals
(December 1988) does not include this concept. It is clear, however, that the social,
agricultural and environmental implications of the use of growth and yield promoting
pharmaceuticals require a licensing system somewhat different from that which exists for
these products when used for therapeutic purposes.
Directive 96/22/EC15 replaces Directives 81/602/EEC, 88/146/EEC and 88/299/EEC. It
maintains the prohibition on the use of these hormones for growth promotion purposes;
extends the prohibition on the use of beta-agonists; restricts the use of the hormones at issue
for therapeutic or zootechnical purposes, reinforcing in particular the role of the
The scientific conclusions regarding the use of natural hormones rested upon strict conditions of use
which it believed could not in reality be attained. The Committee was of the opinion that use of the
natural/nature-identical hormones carries the risk of inexperienced application, incorrect dosage and
unsupervised injection which could pose a risk to the animal and the consumer, and also noted doubts
with regard to long-term cumulative and interactive potential carcinogenicity. In addition, the
Committee believed that proven necessity and socio-economic desirability should be criteria of
acceptability for the use of (bio)chemical growth promoters in animal-rearing. In brief, the essential
findings of the Pimenta Report were that the prohibition of hormonal substances for non-therapeutic
(i.e. growth-promoting) purposes must be maintained and expanded.
14 European Parliament, Committee on the Environment, Public Health and Consumer Protection,
Report on "The USA's Refusal to comply with Community legislation on slaughterhouses and
hormones and the consequences of this refusal", EP 128 381/B, 7 February 1989, named after its reporter
Mr. Collins, MEP.
15 Council Directive 96/22/EC of 29 April 1996 concerning the prohibition on the use in stockfarming
of certain substances having a hormonal or thyrostatic action and of beta-agonists, and repealing
Directives 81/609/EEC, 88/146/ECC and 88/299/EEC. Official Journal of the European Union, L
Series, No. 125, pp. 5-9.

13

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veterinarian; and reinforces the provisions on control and testing. Penalties and sanctions in
case of violations are to be increased where checks detect the presence of prohibited
substances or products or residues of substances administered illegally.
In Directive 96/23/EC measures are specified to control the ban16 (Passantino et al., 2001).
The control should be performed by special, dedicated institutes. Analysis of the samples
taken is performed by routine or field laboratories (RFLs). In each member state the RFLs
are coordinated and controlled by at least one national reference laboratory (NRL)
designated by the national government.
Finally, the NRLs are supported, advised and controlled by four community reference
laboratories (CRLs), which were designated in 1991 by the EU and implemented in 1993
(Stephany et al., 1994). Annually a residue monitoring programme must be made in which
the results of the controls of the previous year and the targets for control in the new year are
given. People working on the farms and veterinarians are made co-responsible for the
control of the ban. Samples can be taken at production plants for banned substances and
animal feeds, and at farms, slaughterhouses and butchers. There should be at least one
national reference laboratory for every banned substance. Indications should be available for
sampling and analysis. The main sanction on the use of banned substances is the destruction
of the positive animals. The farmer has to pay for the additional controls that are performed.
When meat is imported from third countries, it must also be controlled. When the products
give a positive result the European Commission should be informed and additional controls
are indicated. Eventually this could lead to a ban on the import from a certain country.
It is important underlines that the Opinion of the Scientific Committee on Veterinary Measures
relating to Public Health (SCVPH)17 of 30 April 1999 on potential adverse effects to human
16 A principal objective of Council Directive 96/23/EC is to detect illegal use of substances in animal
production as well as detecting the misuse of authorized veterinary medicinal products. The Directive
lays down measures requiring European Member States to monitor the substances and their residues in
both live animals and animal products, listed in Annex I to the Directive.
In particular, this directive describes guidelines for residue control and divides all pharmacologically
active substances into two groups:
Group A compounds, which comprise prohibited substances (listed in the Directive 96/22/EC and in
Annex IV of the Regulation 2377/90/EC);
Group B compounds, which comprise substances with final and provisional MRLs (listed in Annexes I
and III of the Regulation 2377/90/EC). See, Council Directive 96/23/EC of 29 April 1996 on measures
to monitor certain substances and residues thereof in live animals and animal products and repealing
Directives 85/358/EEC and 86/469/EEC and Decisions 89/187/EEC and 91/664/EEC. Official Journal
of the European Union, L Series, No. 125, pp. 10-32.
17 The United States and Canada contested the prohibition imposed by the European Communities on
the import from third countries of treated animals with the hormones and, in 1997, a panel of the World
Trade Organisation (WTO) ruled that the measure was not in line with the Agreement on the
Application of Sanitary and Phytosanitary Measures (SPS). The EU appealed against this ruling and, in
1998, the WTO Appellate Body reversed most of the findings of the panel. The WTO Appellate Body
only upheld the finding that prohibition of imports of meat from hormone-treated animals to the EU
did not comply with the requirement that such a measure should be based on a relevant assessment of
the risks to human health. In reaction to these findings, the EU carried out a complementary risk
assessment and mandated the Scientific Committee on Veterinary measures relating to Public Health
(SCVPH) to evaluate the risks to human health from hormone residues in bovine meat and meat
products treated with six hormones for growth promotion.

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health from hormone residues in bovine meat and meat products (which was reviewed on 3
May 2000 and confirmed on 10 April 200218) established that there is a substantial body of
recent evidence suggesting that oestradiol 17 has to be considered as a complete carcinogen,
as it exerts both tumour-initiating and tumour-promoting effects, and that the data currently
available do not make it possible to give a quantitative estimate of the risk to human health19.
In the light of the conclusions of the 1999, 2000, and 2002 Opinions, the European
Communities adopted Directive 2003/74/EC20, which amends Directive 96/22/EC in
relation to the prohibition permanently of the use of hormones in stockfarming.
Directive 2003/74/EC maintains the permanent prohibition of the placing on the market of
meat and meat products from animals treated with oestradiol-17 for growth-promotion
purposes originally contained in Directive 96/22/EC21.
18 The EU Scientific Committee confirmed that the use of hormones as growth promoters for cattle
poses a potential health risk to consumers, following a review of 17 studies and other recent scientific
data.
Subsequent to the adoption of the 1999 Opinion, additional scientific information was made available to
the European Commission in the form of scientific studies conducted by: (i) the United Kingdom's
Veterinary Products Committee sub-group on the 1999 Opinion (October 1999); (ii) the Committee for
Veterinary Medicinal Products ("CVMP") of the European Union (a subcommittee of the European
Medicines Agency (EMEA)) (December 1999); and (iii) the Joint FAO/WHO Expert Committee on Food
Additives ("JECFA") (February 2000). At the request of the European Commission, the SCVPH
examined this scientific information and, on 3 May 2000, issued a review of its 1999 Opinion in which it
declined to alter the conclusions contained therein (the "2000 Opinion").
On 10 April 2002, a second review of the 1999 Opinion was issued by the SCVPH (the "2002
Opinion") on the basis of more recent scientific data collected since the previous review. The
scientific data reviewed by the SCVPH included the final results of all 17 studies that had been
commissioned by the European Commission. Publishing its third opinion on the risks to human
health from hormone residues in beef products, the SCVPH found no reason to change its previous
opinions of 1999 and 2000.
See, Opinion of the Scientific Committee on Veterinary Measures relating to Public Health on
Assessment of potential risks to human health from hormone residues in bovine meat and meat
products, adopted on 30 April 1999. Available at
http://ec.europa.eu/food/fs/sc/scv/out21_en.pdf Accessed August 19, 2011.
See also Opinion of the Scientific Committee on Veterinary Measures relating to Public Health on
Review of specific documents relating to the SCVPH opinion of 30 April 1999 on the potential risks to
human health from hormone residues in bovine meat and meat products, adopted on 3 May 2000, and
on Review of specific documents relating to the SCVPH opinion of 30 April 1999 and 3 May 2000 on
the potential risks to human health from hormone residues in bovine meat and meat products,
adopted on 10 April 2002. Available at http://ec.europa.eu/food/fs/sc/scv/out50_en.pdf Accessed
August 19, 2011.
19 In this context, it is important underlines that Article 168 of the Treaty establishing the European
Union (EU) states that a high level of human health protection shall be ensured in the definition and
implementation of all EU policies and activities. A comprehensive body of EU legislation has been put
in place to achieve this objective. All of this legislation is publicly available at http://eurlex.europa.eu/en/index.htm Accessed August 23, 2011.
20 Directive 2003/74/EC of the European Parliament and of the Council of 22 September 2003 amending
Council Directive 96/22/EC concerning the prohibition on the use in stockfarming of certain substances
having a hormonal or thyrostatic action and of beta-agonists. Official Journal of the European Union, L
Series, No. 262, pp. 17-21.

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In relation to the five other hormones (testosterone, progesterone, TBA, zeranol, and MGA)
Directive 2003/74/EC continues to apply the prohibition contained in Directive 96/22/EC,
but on a provisional basis22.
This Directive specifies that, even though the scientific information available showed the
existence of risks associated with these substances, "the current state of knowledge does not
make it possible to give a quantitative estimate of the risk to consumers"23. Accordingly, the
prohibition of these five hormones should apply "while the Community seeks more
complete scientific information from any source, which could shed light and clarify the gaps
in the present state of knowledge of these substances"24.
On 27 October 2003, the European Communities notified the Dispute Settlement Body (DSB)
of the adoption, publication, and entry into force of Directive 2003/74/EC, as well as the
1999, 2000, and 2002 Opinions, which it considered to be risk assessments that sufficiently
justified the permanent and provisional import prohibitions under the SPS Agreement
(Agreement on the Application of Sanitary and Phytosanitary Measures)25.
The latter use has to be phased out by until 14 October 2006 and for the rest of the uses the
Commission was to present a report in October 2005.
The report was presented on 11 October 2005 to Council and Parliament. It comes to the
conclusion that the use of the alternative substances such as prostaglandins is already
common.
Veterinarians predict an insignificant impact of future unavailability of oestradiol 17 and
its ester like derivates on farmers and on animal welfare. It was moreover observed that the
unavailability of oestradiol and its ester like derivates would have minimal economic effect.
This is because the incidence of fetal mummification and fetal maceration is low, and
although the incidence of pyometra is higher, methods of prevention not involving use of
oestradiol do exist and would be preferable.
Article 11a of Council Directive 96/22/EC as amended by Council Directive 2003/74/EC
requires the presentation of a report on the necessity of the use of the hormone oestradiol
17 in food animal production. A report concerning the availability of alternative veterinary
medicinal products to those containing oestradiol 17 or its ester-like derivatives for the
treatment of fetal maceration or mummification in cattle, and for the treatment of pyometra
prepared (later addressed as the Report) by an independent scientist has been presented by
the Commission in October 200626. The Report concludes that oestradiol 17 is not essential
in food animal production.
21 Directive 2003/74/EC, supra, footnote 20, Recital 10 and Article 1 (amending Articles 2 and 3 of
Directive 96/22/EC).
22 Ibid.
23 Directive 2003/74/EC, supra, footnote 20, Recital 7.
24 Ibid., Recital 10.
25 European Communities Measures concerning meat and meat products (hormones), Communication
from the European Communities, WT/DS26/22, WT/DS48/20, 28 October 2003. Available at
http://trade.ec.europa.eu/doclib/docs/2003/november/tradoc_114641.pdf Accessed August 23, 2011.
26 See, Report concerning the availability of alternative veterinary medicinal products to those
containing oestradiol 17 or its ester-like derivatives for the treatment of fetal maceration or

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3. Situation in other countries

Whereas the EU has banned the use of all hormones, other countries do allow the use of
steroid hormones and hormone-like substances in various combinations with the aim to
improve weight gain and feed efficiency in livestock farming. Recommended application
occurs in the form of small implants or devices, containing the active hormones, into the
subcutaneous tissue of the ears. Both ears are completely discharged at slaughter27 (Galbraith,
2002). Pharmaceutically, these implants represent slow-release devices, containing relatively
large quantities of hormones, which are fractionally released over a period of several months.
In the United States28, Canada, Australia, New Zealand and in some countries in South
America, Asia and Africa the natural hormones - testosterone, 17-oestradiol and
progesterone - and the (semi-) synthetic hormones trenbolone, zeranol and melengestrol
acetate can be used to promote growth.
In particular, in the USA29 five hormones are authorized as the active component of solid ear
implants (17-estradiol - as such or as benzoate, testosterone - as such or as propionate,
mummification in cattle, and for the treatment of pyometra. Commission of the European Communities
SEC(2005) 1303 of 11.10.2005.
27 See European Commission, 1999. Scientific Committee on Veterinary Measures relating to Public
Health (SCVPH). Assessment of potential risks to human health from hormone residues in bovine meat
and meat products. Available at http://europa.eu/comm/food/fs/sc/scv/out21_en.html Accessed
August 23, 2011.
28 The U.S. Food and Drug Administration (FDA) and the U.S. Department of Agriculture (USDA)
cooperate in regulating growth promotants for livestock. Both of these agencies maintain that hormones
in beef from an implanted animal have no physiological significance for humans. All animal drug
products are approved for safety and effectiveness under the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 301 et seq.). Information on approved hormone products are at 21 CFR Parts 522, 556, and 558.
FDA requirements for the review and approval of new animal drug applications is at
http://www.fda.gov/AnimalVeterinary/GuidanceCompliance
Enforcement/GuidanceforIndustry/ucm123821.htm Accessed August 26, 2011.
29 The United States continues to maintain that U.S. beef from cattle treated with certain approved
growth hormones pose no public health risk. Overall, the official U.S. position is that there is a clear
world-wide scientific consensus supporting the safety of these approved and licensed hormones when
used according to good veterinary practice.
The United States claims that this position is supported by scientific reviews of the six hormones,
international standards pertaining to their use, and a longstanding history of administering the six
hormones to cattle for growth promotion purposes. Accordingly, the United States claims that the use
of these hormones as growth promoters in beef production is safe, when applied in accordance with
good veterinary practices.
The United States has criticized the EUs scientific opinions for focusing on only one growth promotant,
estradiol-17 , and on its potential genotoxicity, while directing relatively little attention toward the
other natural and synthetic hormones. The United States also claims that the EU failed to use solid
evaluative methods in their studies and completely disregarded the large body of evidence from
epidemiological studies that indicate that estradiol does not contribute to any increased cancer risk and
that meat from animals tested with estradiol is safe for consumers.
Regarding the EUs more recent reviews, the United States claims they fail to provide any new evidence
that would call into question the findings and conclusions of other authoritative reviews.
More broadly, the United States also disputes whether the EUs scientific reviews serve as a risk
assessment. The United States claims: There has been no new risk assessment based on scientific
information and reasoning presented by the EU, further claiming that the 17 studies funded by the
Commission beginning in 1998 were not intended as a to serve as a risk assessment, but instead were

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progesterone, trenbolone acetate and zeranol) and two hormones as feed additives:
melengestrol acetate (MGA) for feedlot heifers30 (Berende & Ruitenberg, 1983; Meissonnier
& Mitchell-Vigneron, 1983) and ractopamine for swine (Marchant Forde et al., 2003).
As aforementioned, the hormone ban of the EU is currently the cause of a dispute between
the EU and these third countries, led by the United States and Canada. The reason for this
dispute is that those countries want to export meat to EU nations from animals treated with
in their view acceptable hormones. In their opinion the EU blocks international trade on
improper grounds and against international law.
The National Cattlemens Beef Association (NCBA), the largest national group of cattle
producers, has long opposed the EUs ban on imports of U.S. hormone-treated beef,
claiming that the ban is scientifically unjustified and fails to satisfy the EUs WTO
requirements under the SPS. Similar concerns have been expressed by other U.S. farm
groups, including American Farm Bureau Federation (AFBF), the Animal Health Institute
(AHI), and the American Meat Institute (AMI)31. Many trade analysts believe that the
United States has a strong case against the hormone ban under WTO rules that require SPS
restrictions to be based on risk assessment and to have a scientific justification. These
various interest groups have continued to exert pressure on U.S. trade policy officials to
hold to their position regarding the EUs meat hormone ban.
Recently, On May 13, 2009, following a series of negotiations, the United States and the EU
signed a memorandum of understanding (MOU) implementing an agreement that could
resolve this long standing dispute32. On July 13, 2009, the EC adopted regulations opening a
tariff quota for imports of High Quality Beef, effective August 1, 200933

4. Existing community legislation

Currently Council Directive 2008/97/EC34 has been published amending Council Directive
96/22/EC concerning the prohibition on the use in stock farming of certain substances
to fill in the gaps. Accordingly, the United States claims, the EUs 2003 update to its hormone ban is
not in compliance with its WTO obligations and should be discontinued.
For more detailed discussion see USDA, Foreign Agriculture Service, Historic Overview and
Chronology of EUs Hormone Ban, GAIN Report E23206, Nov. 7, 2003, available at
http://www.fas.usda.gov/gainfiles/200311/145986773.pdf Accessed August 26, 2011; USDA, FAS, EU
Presentation on Hormone Ban Directive (2003/74/EC), GAIN Report E23217, Nov. 13, 2003, available at
http://www.fas.usda.gov/gainfiles/200311/145986807.pdf Accessed August 26, 2011.
30
http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055436.htm
Accessed August 23, 2011.
31 See, Coalition Statement on EUs Latest Pronouncement on Hormones, May 14, 2002 by AFBF, AHI,
AMI, and NCBA, Available at http://www.meatami.com/ht/d/sp/i/1482/pid/1482 Accessed
August 23, 2011.
32 For other information, see WTO, European Communities Measures Concerning Meat And Meat
Products (Hormones), Joint Communication from the European Communities and the United States,
WT/DS26/28, September 30, 2009; 74 Federal Register 40864, August 13, 2009; 74 Federal Register
48808, September 24, 2009; and USTR press releases.
33 Council Regulations (EC) No 617/2009 of 13 July 2009 opening an autonomous tariff quota for
imports of high-quality beef. Official Journal of the European Union, L series, No. 182, 1..
34 Directive 2008/97/EC of the European Parliament and of the Council of 19 November 2008 amending
Council Directive 96/22/EC concerning the prohibition on the use in stockfarming of certain substances

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having a hormonal or thyreostatic action and of -agonists, to exclude companion animals

from the prohibition.
In fact, experience gained in particular with national residue plans submitted under
Directive 96/23/EC has shown that the misuse of product presentations intended for pet
animals does not play a role as a source of abuse or misuse. That is partly because it is
economically unattractive to use presentations intended for pet animals for growth
promotion in food-producing animals.
It was considered therefore appropriate to limit the scope of Directive 96/22/EC only to
food-producing animals and withdraw the prohibition for pet animals, as well as to adjust
the definition of therapeutic treatment.

5. Conclusions
The EU continues to maintain that there is a lack of data on the type and amount of
[growthpromoting hormone] residues in meat on which to make a quantitative exposure
assessment that would change the EUs understanding of the possible risks to human
health associated with hormone-treated meat and meat products. It claims that this
position is supported by a series of commissioned research studies and scientific reviews
conducted by the EU, although there has been no conclusive testing on the issue.
The most recent review, conducted in 2007 by the European Food Safety Authority (EFSA),
cites evidence supporting that estradiol-17 be considered as a carcinogen, and states that all
six hormones may pose endocrine, developmental, immunological, neurobiological,
immunotoxic, genotoxic, and carcinogenic effects, particularly for susceptible risk groups
(such as prepubertal children). The toxicological and epidemiological data reviewed by the
Commission panels do not allow a quantitative estimate of the risk, leading to the panels
conclusions that no threshold levels can be defined for any of the six hormones
Based on this series of reviews, the Commission maintains that these reviews reaffirmed
public health concerns about the large scale use of hormones administered to cattle for
growth promoting purposes, and therefore provided the scientific basis for community
legislation not allowing the use of hormones for growth promoting purposes in the EU.35

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A Bird's-Eye View of Veterinary Medicine

Edited by Dr. Carlos C. Perez-Marin

ISBN 978-953-51-0031-7
Hard cover, 626 pages
Publisher InTech

Published online 22, February, 2012

Published in print edition February, 2012

Veterinary medicine is advancing at a very rapid pace, particularly given the breadth of the discipline. This
book examines new developments covering a wide range of issues from health and welfare in livestock, pets,
and wild animals to public health supervision and biomedical research. As well as containing reviews offering
fresh insight into specific issues, this book includes a selection of scientific articles which help to chart the
advance of this science. The book is divided into several sections. The opening chapters cover the veterinary
profession and veterinary science in general, while later chapters look at specific aspects of applied veterinary
medicine in pets and in livestock. Finally, research papers are grouped by specialisms with a view to exploring
progress in areas such as organ transplantation, therapeutic use of natural substances, and the use of new
diagnostic techniques for disease control. This book was produced during World Veterinary Year 2011, which
marked the 250th anniversary of the veterinary profession. It provides a fittingly concise and enjoyable
overview of the whole science of veterinary medicine.

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Annamaria Passantino (2012). Steroid Hormones in Food Producing Animals:, A Bird's-Eye View of Veterinary
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