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Complaint by Canada Report of the Panel (Continued)
VI.121 Dr. Ritter indicated
that he was unaware of any data or other evidence of adverse human
health effects in countries where meat was produced with the aid
of the hormones in question, when compared to countries where
the hormones were not utilized for meat production.
Question 10:
How do the potential adverse
effects on human health from residues in food in general, and
meat in particular, from pesticides administered in accordance
with good agricultural practice compare with potential adverse
effects from residues of the six hormones in question, when the
meat is from animals to which have been administered these hormones
for growth-promotion in accordance with good animal husbandry
practice and/or good veterinary practice?
VI.122 Dr. André
noted that these parameters were not developed with the aim of
comparing the potential health risk of compounds. Each compound
with potential adverse effects on human health was submitted to
individual evaluations, so as to determine specific ADIs and MRLs
(in food of concern). With regards to pesticides, Dr. André
pointed out that some of the pesticides might facilitate adverse
effects of oestrogens on human health.
VI.123 Dr. Arnold responded
that pesticides had biocidal properties and were frequently also
otherwise very potent chemicals. Certain groups of pesticides
were also used as veterinary drugs, e.g. as ectoparasiticides.
These substances might have a significant potential to harm human
health if not used according to good agricultural practices. The
MRLs established in the EU and elsewhere provided sufficient consumer
protection. It appeared that the margin of safety applied when
establishing Codex MRLs for residues of veterinary drugs might
be somewhat higher if the food baskets used and the calculated
Theoretical Maximum Daily Intakes (TMDIs) were compared. JECFA/JMPR
and CRVDF/CCPR had started harmonising MRLs for substances which
were used in both agriculture and animal production.
VI.124 Dr. Lucier replied
that the tools of risk assessment were not sufficiently accurate
to determine if pesticide residues or residues of anti-microbial
agents posed a greater risk than residues of growth promoting
agents. In each case, the risk was somewhere between zero and
a small number.
VI.125 Dr. McLean observed
that there have been very few documented cases of adverse effects
caused by pesticide residues in food, when they were administered
in accordance with "good practice". There did not appear
to be any proven cases linked to hormonal growth promotants.
The use of the word "potential" implied hypothetical
cases. Given that hormones had effects on sexual characteristics
and metabolic processes, then potentially these would change,
if the changes could be perceived or detected.
VI.126 Dr. Ritter indicated
that MRLs need not be established for the natural hormones, when
used in accordance with good veterinary and/or agricultural practice
(see response to question 5). In the case of the synthetic
hormones, the nature of the studies used to establish their safety,
and the methodological approach for the establishment of MRLs,
including determination of a NOEL, calculation of an ADI, establishing
a withdrawal period and proposing MRLs, was virtually identical
for both pesticide residues and hormone residues. As a result,
one would not expect that potential adverse effects on human health
would be lesser or greater for hormone residues than might be
the case for pesticide residues.
Question 11:
How do the potential adverse
effects on human health from residues of carbadox (used in swine
production) differ from the potential adverse effects arising
from residues of the six hormones in question when used for growth-promotion
in accordance with good animal husbandry practice and/or good
veterinary practice? Question 30: Further to question 11 and
26, would you consider that the potential adverse effects on human
health and/ or animal health from residues of carbadox, monensin,
olaquindox, avoparcin, benzylpenicillin, carazolol, ivermectin
and organophosphorous compounds are comparable to the potential
adverse effects arising from residues of the six hormones at issue
when used for growthpromotion in accordance with good animal
husbandry practice and/ or good veterinary practice? Are any of
the above mentioned substances carcinogenic? If any one of these
substances or a combination thereof is administered to the animal,
would there always be a residue of that substance in the meat
of that animal, even if it is so small that it cannot be detected?
VI.127 Dr. André
indicated that carbadox proved to be a genotoxic compound, and
consequently no ADI value had been proposed by JECFA (see also
response to question 10). Olaquindox was known to be carcinogenic.
Dr. André was not familiar with the others.
VI.128 Dr. Arnold noted
that as long as the "good practices" were observed,
there was no relevant difference. If the lengthy withdrawal time
was not observed in the case of carbadox, potentially genotoxic
carcinogenic residues of the parent drug and another carcinogenic
metabolite were likely to be present in meat of treated animals.
In the case of the hormones, only the frequent consumption of
injection sites or implants would potentially cause effects on
human health. VI.129 Olaquindox was genotoxic in a number of tests. However the parent drug was extensively metabolised and was not present as a residue if "good practices" were applied. Ivermectin was extremely potent against parasites, but it was safely used in humans for the treatment of e.g. "river blindness" at much higher than residue levels. Carazolol was a hazardous substance for humans with chronic bronchitis which was a substantial part of the general population. In addition, carazolol was administered to the target animals by injection. Benzylpenicillin was absolutely harmless for the general population but could provoke allergic reactions in some sensitized people even at the level of the MRL. Avoparcin was not registered as feed additive on the American continent; its use in the EU had recently been withdrawn. Strict adherence to the identified "good practices" was an absolute requirement for the use of some of these substances. Nearly all of these substances left detectable residues in meat of treated animals under conditions of "good practice in the use of veterinary drugs". At the oral hearing Dr. Arnold added that there is a commercially available alternative for carbadox mainly oxytetracycline.
VI.130 Dr. Lucier indicated
that it was difficult to accurately compare risks from carbadox
residues to risks from residues of growth-promoting substances
(see also response to question 10). However, he expressed concerns
about carbadox residues and that the risks from these residues
were likely greater than the risks associated with the use of
growth promoters.
VI.131 Dr. McLean replied
that carbadox and its metabolite desoxycarbadox were not permitted
in meat, because the latter compound was carcinogenic. In the
case of carbadox, a withholding period was set to achieve the
situation where there were no detectable residues in food. The
three naturally occurring hormones were normally found in animals
and humans. The data supporting the use of trenbolone and zeranol
was extensive, with toxicological end-points related to their
hormonal effects. Finite residues were permitted for trenbolone
and zeranol. In this way any risk of adverse effects was managed
through the MRL and safety to consumers was assured.
VI.132 Dr. McLean further
noted that olaquindox was considered to be genotoxic and no toxicity
studies were available on its metabolites, therefore JECFA was
unable to determine an ADI or MRL. Benzylpenicillin was widely
used as an antimicrobial agent in animals and humans. Allergenic
potential was the major toxic effect and it was recommended that
the total intake be kept below 30 micrograms per day for
a human. Benzylpenicillin showed no carcinogenic potential.
While carazolol showed no genotoxic or carcinogenic potential,
it was a potent beta-adrenoceptor blocking agent. MRLs had been
established for pig tissues. However, if carazolol was used in
pigs to prevent stress during transport to slaughter, there was
concern that residues at the site of injection could result in
consumers receiving a pharmacologically active dose of the drug.
The toxicity and residue data base for ivermectin and related
compounds was extensive and the drug was also used in humans.
The compound did not show genotoxic or carcinogenic potential
and an ADI and an MRL had been established.
VI.133 The organophosphorus compounds
(OP) were described by Dr. McLean as powerful neurotoxins,
and most of the untoward effects were related to the direct exposure
of operators and others. There was a new syndrome of organophosphate
- induced delayed polyneuropathy - which was of concern when there
was acute exposure.299 The OP had been associated with carcinogenicity
and there were reports of acute poisoning associated with the
consumption of treated food. Very low levels of the parent compound
and/or metabolites might remain, although they could not be detected
by sensitive analytical techniques. Dr. McLean did not comment
on monensin or avoparcin because of the limited amount of registration
data available which was in public domain.
VI.134 Dr. Ritter observed
that carbadox was reviewed by the JECFA in 1990. In its review,
the JECFA considered data from short-term and long-term carcinogenicity,
mutagenicity and reproduction studies with carbadox, and data
from mutagenicity and long term studies of its metabolites. JECFA
noted that results from several long term feeding studies in rats
demonstrated dose-related increases in both benign and malignant
tumours at doses above 1.0 mg/kg BW/day. Positive findings were
also noted in 14 of the 15 mutagenicity studies reported. JECFA
concluded that carbadox appeared to be both genotoxic and carcinogenic.
Results from additional studies carried out with quinoxaline-µ-carboxylic
acid, an important metabolite of carbadox, indicated that there
were no effects on incidence of tumours, even at doses of 100
mg/kg BW/day. In view of the carcinogenic and genotoxic nature
of carbadox and desoxycarbadox, a metabolite of carbadox, JECFA
was not able to establish an ADI. Notwithstanding, the JECFA
recommended MRLs of 0.03 mg/kg in liver and 0.005 mg/kg in muscle
of pigs, based on and expressed as quinoxaline-µ-carboxylic
acid.
VI.135 The establishment of an
ADI and recommendation of an MRL reflected scientific confidence
in the expressed residue levels being essentially devoid of risk
to humans exposed to dietary residues on a lifetime basis. Therefore,
neither carbadox nor the growth promoting hormones should pose
potential adverse human health effects as a result of exposure
to dietary residues at or below the MRLs specified by JECFA.
Notwithstanding, it was noteworthy that carbadox and at least
one of its metabolites was both carcinogenic and mutagenic, while
the hormones were not considered carcinogenic or mutagenic at
biologically relevant doses. In addition, reliable residue monitoring
and risk estimation of carbadox residues was somewhat complicated
by the presence of bound residues, while residues of the hormones
either fell within normal physiological range or could be reliably
and easily measured.
Question 12:
Are residues of the six hormones
in question found in milk or milk products? If yes, how do the
levels of these residues compare to those found in meat from animals
to which hormones have not been administered? How do the residue
levels in milk compare to those found in meat from animals which
have been administered these hormones for growth-promoting purposes?
For therapeutic or zootechnical purposes?
VI.136 Dr. André
replied that residues of hormones in general are found in milk.
However, the comparison with meat levels was not relevant. Moreover,
hormones were not supposed to be used for growth promotion purposes
in lactating cows, only in culled cows. For specific therapeutic
or zootechnical purposes, only individual animals were allowed
to be treated with hormones. In this case, the milk was not to
be delivered for human consumption, as was the case for many other
drugs.
VI.137 Dr. Arnold noted
that after injection of approved products (natureidentical
molecules) permitted for use in the EU to lactating cows, residues
would be found in milk. Depending on the product it could take
several milkings before the residue levels would have returned
to physiological values. Residues found in milk could be higher,
equal or lower, depending on which tissues were compared and depending
on many other factors (dose, route, age, sex, withdrawal time
etc.)
VI.138 Dr. Lucier indicated
that if residues of the hormones in question existed in the human
body, then residues would also be present in human milk.
VI.139 Dr. McLean replied
that hormones are lipid soluble and therefore pass into the fat
portion of milk. More polar metabolites would also pass into
milk, but it must be stressed that the hormones should not be
used for growth promotion in lactating animals. When the various
hormones were used for therapeutic or zootechnical purposes, the
doses were much higher, therefore the levels in the tissues were
higher. It had to be expected that the levels in milk would also
be higher.
VI.140 Dr. Ritter observed
that growth promoting hormones were generally only permitted for
use in beef cattle and veal calves, and not in lactating dairy
cattle. Foxcroft and Hess (1986) reported that, at least in the
case of the natural hormones, the residue levels of the administered
compound or it metabolites in animal products were insignificant
in comparison to the levels of the same steroids to which human
subjects might normally be exposed. This could occur either (i)
as a consequence of the endogenous production rate of sex steroids
in human subjects or (ii) as a consequence of the steroids in
meat and/or milk products derived from untreated animals.
Question 13:
What factors and procedures
should scientists consider in establishing an appropriate assessment
of the potential adverse effects on human health from the use
of the hormones in question?
VI.141 Dr. André
responded that an appropriate assessment of the potential adverse
effects on human health stemming from the use of the hormones
in dispute "should be more rigorous than common veterinary
drugs because of the duration of their use and the very limited,
if any, health benefits to the target species".300 Scientists
should consider all data available at the present time in dealing
with the adverse effects of each compound (see response to question
8), their metabolites and their mechanisms of action, including
their action at the level of exposure. Species-specific metabolite
patterns should be compared, using (as far as possible) a combination
of in vivo and in vitro experiments. Studies should
include long-term feeding trials to address life time exposure.
All studies should be performed with combinations of the hormones
in dispute prior to registration, to obtain valuable data. The
effects of the treatment on the kinetics of other common drugs
had to be assayed. Epidemiological studies in humans concerning
cancer incidence and other hormone related diseases had to be
initiated.
VI.142 Dr. Arnold indicated
the following should be considered: pharmacokinetic data including
metabolism in test animals and target animals, where available
in humans; data (preferably quantitative data) from adequately
designed toxicity studies in suitable animal species, including
information on genotoxicity/carcinogenicity, and no hormonal effect
levels; target animal safety studies; efficacy trials; epidemiological
studies and other relevant observations in humans; kinetic residue
studies; natural occurrence and human exposure from all sources,
including endogenous production of the same or similarly acting
substances; experience from the history of use in human and veterinary
medicine (if applicable); and known or proposed conditions of
use. A marketing authorization should only be given to strictly
formulated products (not to the active substances). Conditions
of use should be fixed in a binding manner in the approval process.
VI.143 Dr. Lucier replied
that there were several factors that should be systematically
studied or evaluated if information was not available for assessment
of risks from the hormones in question. Of special concern were
potential risks for cancer and non-cancer effects (reproduction,
development, cardiovascular disease, etc.). Additionally, information
on effects in sensitive subpopulation should be considered.
Sensitivity could be conferred by genetic predisposition (presence
or absence of cancer susceptibility genes), age (fetus, children
or the aged), gender, existing disease status, nutrition, and
coexposure to other chemicals. These factors needed to
be considered, although it was unlikely that information on them
would ever be complete for any given substance.
VI.144 Dr. McLean noted
that the testing protocols used in countries such as the United States,
Canada, the United Kingdom, Australia and by JECFA were adequate
to assess the effects of the use of hormones on human health.
In addition, there was a need for residue monitoring programmes
to ensure that residues in meat were less than any MRL which had
been established.
VI.145 Dr. Ritter observed
that scientists considered a wide array of toxicological endpoints
and risk assessment procedures in estimating potential adverse
effects on human health from residues of all chemicals, including
anabolic hormones, other veterinary drugs and pesticides. The
issue of factors and procedures which were appropriate to the
assessment of the potential adverse effects on human health included
toxicity studies which established the following: which organs
and/or systems were most vulnerable to the toxic effects and under
what exposure conditions; the nature of any damage and/or disease
produced, and the dose response relationship; the time course
for the onset and any progression of the adverse effect; the
mechanism responsible for the adverse effect; the relevance of
the adverse effect observed in experimental animals to humans;
the potential impact of biological mechanisms which led to the
adverse effect but which, by virtue of the dose utilized, were
not relevant to the assessment of the biological effect in humans
(this was particularly important for the hormones in question
which were only associated with adverse effects at doses which
were not considered to be of relevance to the assessment of human
health effects arising from food residues); whether it was appropriate
to consider the adverse effects observed as a function of a threshold
mechanism, or rather if a genotoxic mechanism was more likely
and hence a threshold mechanism would be an inappropriate risk
model.
VI.146 In addition, Dr. Ritter
noted that it might also be relevant to establish if the nature
of the residue was distinguishable from normal endogenous levels
- this was particularly relevant for the use of the natural gonadal
hormones which resulted in residue levels typically in the range
of untreated animals; whether appropriate and reliable methods
existed for the estimation and monitoring of residues of the hormones
following their use as growth promoting substances; and knowledge
of the uncertainty inherent in the hazard and risk assessment
paradigm.
Question 14:
What are the potential hazards,
if any, to human or animal health of the use of large quantities,
or doses higher than those recommended, of any of the six hormones
in dispute? And from the administration of these hormones contrary
to good animal husbandry practice and/or veterinary practice?
Can you think of any incentives or disincentives for farmers
to use quantities larger than those specified in the label of
the manufacturers or to administer these hormones contrary to
good animal husbandry practice and/or veterinary practice? Are
you aware of any evidence of such use by farmers?
VI.147 Dr. André
indicated that a higher dosage, another route of administration
than those recommended for delivery (other location for implants,
injectable solutions of hormones, etc.), shorter withdrawal periods,
etc., in short, any disrespect of good animal husbandry and/or
good veterinary practices, might induce higher levels of residues
or changes in metabolite patterns. The first consequence would
probably be a modification in animal behaviour and/or health.
It was reasonable to think that a higher residue content in meat
would enhance the risk of hazards to human health.
VI.148 The anabolic effect of
the hormones in question was proportional to the dosage, with
a maximum effect. Farmers tried to obtain larger effects through
administration of more implants than recommended, although it
was not evident that a double dose, even at one time, gave a better
response. In some cases, a parenteral administration (e.g. intramuscular
injection) produced a more rapid effect than implants, and farmers
tried by this mean to obtain faster effects. Disincentives for
farmers to use larger quantities would be a decrease of the benefit/cost
ratio, but implants were usually cheap. In countries where they
were in use for growth promotion purposes, penalties due to higher
residue levels detected in meat products compared to the MRLs
might also have dissuasive effects on farmers. When five out
of the six hormones in dispute were allowed in France, the experience
was that farmers tried to give a second dose later. They did
not respect the withdrawal period and they injected another dose
at half way through the theoretical withdrawal period. Clearly
they saw benefit to do this because the effect was longer at the
time. Dr. André further reported that during the
four to five years when these hormones were allowed as growth
promotants in France, the misuse of other hormones continued and
the black market was also present.
VI.149 Dr. Arnold noted
that there were considerable safety margins built into the established
MRLs for the synthetic residues. As long as "good practices"
were observed, the calculated theoretical maximum daily intakes
of residues would range around 5 per cent of the ADI for
both zeranol and trenbolone acetate. It had been shown that the
implantation of approximately five times the recommended dose
of zeranol would have almost no effect on maximum residue levels
in the muscle and liver of steers slaughtered only five days after
implantation. When a total dose more than 100times higher
than the recommended dose was intravenously administered as 6
split doses over three days to steers and the animals were slaughtered
on the third day after the last dose, consumption of the meat
of these animals would still not have caused an aboveADI
intake of residues of zeranol.301 The studies available to the 32nd
and 34th JECFA showed that residues of trenbolone were highest
if heifers were implanted shortly (15 days) before slaughter.
With respect to the calculated theoretical maximum intakes, there
was no difference whether this implant was the first or the second
which the animal had received. From these data, it seemed unlikely
that even the frequent use of higher doses, or repeat doses or
slaughtering the animals at earlier than recommended times after
implantation, could result in residue intakes in excess of the
ADI by the consumer. For the three natureidentical hormones,
the safety margins (theoretical residue intakes compared with
endogenous production rates of the most sensitive subpopulation)
were much higher than for the synthetic substances.
VI.150 Dr. Arnold had no information
with regard to melengestrol acetate, nor regarding incentives
or disincentives for farmers to use combinations or illegal "cocktails"
of these hormones. Although these pellets and another devices
had been developed to give optimum results when the dose was respected,
this did not necessarily prevent some farmers using more implants.
But this did not necessarily cause higher residue levels in the
carcass. On the other side, it was clear that if twice the amount
was injected directly, all levels increased in plasma and in tissues,
not necessarily in a linear way, but significantly. That was
the difference between a slow release device (like ear implant)
and a direct injection. On the other hand, the long term release
of high doses might influence the pattern of hormone excretion
in the animal's body and this was the intention of using such
compounds.
VI.151 Dr. Lucier indicated
that any increase in the magnitude of exposure would likely increase
any potential risks, but he did not consider himself qualified
to answer the rest of this question.
VI.152 Dr. McLean responded
that the hormones in question, with the exception of MGA, were
not well absorbed when administered orally. Grossly excessive
doses might have an effect on consumers of meat, but these effects
were likely to be mild and transient and could pass without being
noticed. The dose prescribed under "good practice"
was sufficient to exert a commercially satisfactory response,
and there was no advantage in exceeding this dose. The dose suggested
by the sponsor gave the optimum response and therefore, within
limits, there was no need or benefit in administering more than
was suggested. The regulatory authorities also examined the effects
of overdosing during the registration process. Most regulatory
authorities, including JECFA, required that data for residues
setting did take into account dose rates that were in excess of
what was normally used (generally at least twice and sometimes
more) so that the effect of overdosing or variations in uptake
could be seen. In countries where the use of these compounds
was permitted, there were good educational campaigns for farmers
as to the correct use and the reasons why the prescribed dose
should not be exceeded, and the penalties that existed if one
did. The results from residues surveys showed that, by and large,
there was no exceeding of the MRL. In Australia, trenbolone
and zeranol had been targeted in residue surveys very specifically
looking for violations, and to all intents and purposes violations
did not occur. Even if there was misuse, and that was difficult
to prove, there were still no residues that exceeded the MRL.
A similar situation existed with the naturally occurring hormones,
where it was not possible to determine whether or not a violation
had occurred because the levels that were found in the carcass
fall within the normal range.
VI.153 Dr. McLean observed, however,
that in countries where the use was not controlled and there was
no farmer education campaign and where it was difficult to apply
a penalty, then the MRL was significantly exceeded. One of the
important factors of legalizing these compounds was to conduct
an education campaign and to put in place monitoring procedures
to ensure that the MRL is not exceeded. What was important with
the maximum residue limit is to understand that it was a legal
limit and not a health limit. In other words, exceeding of the
MRL did not represent a hazard to health but rather a limit at
which the authorities took action. However, to exceed the MRL
would not be considered to be good practice.
VI.154 Dr. Ritter noted
that it was very difficult, if not impossible, to estimate potential
hazards which might be associated with the administration of the
hormones contrary to good practice, as the magnitude of the potential
hazard would be related to the nature, extent, frequency and magnitude
of the inappropriate administration. It had been reported that
in the case of the anabolic hormones and using commercially available
implants, repetitive implantation had only little influence on
the residue profile.302 Similarly, full and half-dosages led to
similar hormone levels in edible tissues which, in the case of
the endogenous hormones, were within the physiological range.
Further, unlawful and improper use of oestradiol might result
in residue levels some 300-fold in excess of established tolerance
limits, and yet it was virtually impossible to visualize any hazard
to humans ingesting meat from animals treated with zeranol.303 Similarly,
when steer calves were implanted with zeranol in accordance with
recommended procedures, the margin of safety for consumption of
edible products was greater than 25,000 and 150,000 for liver
and muscle, respectively. While this work did not specifically
address the issue of potential abuse, the large margins of safety
postulated by the authors suggested that even under limited circumstances
of abuse, it was unlikely that consumers would be exposed to unacceptable
risks.304 In countries where use of these hormones, the six hormones
in particular, had been permitted for a very extended period of
time, most notably Canada and the United States, monitoring and
compliance programmes which had been conducted for many years
consistently demonstrated that residue levels were entirely within
recommended limits and that instances of violative residues, that
was residues which would indicate abuses taking place, had almost
never been reported. It seemed that at least in those jurisdictions
where use was lawful, the practicality of abuse had never become
a reality. There were few and isolated examples of violative
residues in those countries where use had been permitted.
Question 15:
What are the consequences
in terms of potential hazards to human or animal health from the
use of legally marketed combinations, if they exist, or illegal
"cocktails" of the six hormones in dispute for animal
growth promotion? Have legally marketed combinations been subject
to the same testing regime as each of their individual components?
Is there any evidence of synergistic effects of combinations
of hormones? Can you think of any incentives or disincentives
for farmers to use combinations or illegal "cocktails"
of these hormones?
VI.155 Dr. André
replied that specific consequences stemming from the use of legally
marketed combinations were not known. If they existed potential
hazards could be due to synergistic and/or additive effects of
the residues. This answer was also valid for illegal "cocktails"
of the six hormones in which more than two components could be
present. However there was another important potential hazard
from the systematic use of these combinations: their use could
result in modifications of kinetic parameters of other drugs.
For example, trenbolone and testosterone were shown to dramatically
decrease the elimination rate of sulfamethazine, trimethoprim
and antipyrine in goats, with opposite experimental results in
rats. As a consequence, residue levels could be higher than the
MRLs at slaughter, even when legal withdrawal periods were respected.305
Recently, the increase of the level of beta agonist residues
in liver owing to concomitant oestradiol treatment had been demonstrated
in calves.306
VI.156 Dr. André was aware
of only one combination (TBA + oestradiol) having been assayed
by the JECFA in the context of residue determination in steers.
No other combinations had been tested whereas individual components
had been tested for toxicological effects. Evidence of synergistic
effects of combinations of hormones existed and were well studied
mechanisms. For example, concerning endocrinological therapy in
humans, combinations of oestrogen and progestin hormones were
used; oestrogens induced the synthesis of specific receptors
for progestins, which could then exert their specific action.
Legally marketed combinations had been developed on the basis
of synergistic effects of their components on growth promotion.
VI.157 Incentives for farmers
to use combinations (legally marketed) or illegal "cocktails"
of these hormones were frequently reported by official control
bodies, since farmers tended to think that the more hormones used,
the better the anabolic effect. Moreover, interactions between
these hormones and other endogenous biochemical parameters (e.g.
corticoids, IGF, etc.) were of great importance for human health
and could be documented.
VI.158 Dr. Arnold noted
that fixed combinations were registered in the form of strictly
formulated veterinary medicinal products and were different from
illegal mixtures for which the term "cocktail" had been
coined in Europe. Fixed combinations were not only used for growth
promotion but also for the purposes permitted in the European
Union. These combinations were approved and registered by the
competent authorities under the respective rules governing veterinary
medicinal products. The applicant had to justify the combination
and had to demonstrate the quality, efficacy, target animal safety
and consumer safety of these products before they could be marketed.
For these types of registered products, there was no evidence
of a hazard to human health.
VI.159 Dr. Arnold reported that
the pharmacodynamic and toxic effects of practically all possible
combinations of oestrogens, progestins and androgens had been
studied in whole animals, organs, tissue and cell cultures, and
other in vitro systems under a great variety of conditions.
There was ample evidence of both synergistic and antagonistic
effects. Such effects physiologically played important roles
in endocrinology and metabolism. The current understanding of
these phenomena clearly indicated that concerns over human health
hazards arising from combinations of minute amounts of residues
in meat were not justified.
VI.160 The flourishing grey market
in other veterinary medicines within, for example, Germany showed
that farmers tried bypassing official distribution channels when
purchasing otherwise licensed high quality products, mainly in
order to save costs and prevent having to pay the veterinarian.
To what extent "good practices" in the use were otherwise
followed remained subject to speculation. It seemed, however,
that not all rules were violated at one time. The situation with
prohibited substances (e.g. hormones, chloramphenicol) and with
abused substances (e.g., clenbuterol) was completely different.
There was clearly a blackmarket where the "dirty products"
prevailed. The availability of reasonably priced legal alternative
products could be an incentive for many farmers to legalise their
practices. Whether this would eliminate illegal cocktails now
that the blackmarket has been well established, remained
entirely speculative.
VI.161 Dr. Lucier indicated
that there was a definite research need in area of synergistic
and/or antagonistic responses to combinations of endogenous or
exogenous hormones. Based on current knowledge, it was likely
that interactions existed but it was impossible to say with any
degree of confidence for a given combination whether the interaction
would be synergistic, additive or antagonistic. There was limited
evidence to suggest that synergistic responses were occurring
although the relevance of these findings to human risks had not
been shown. Dr. Lucier noted that the same combinations
of hormones, at certain levels, could have both some adverse health
effects and some positive ones.
VI.162 Dr. McLean replied
that the legally marketed combinations had been examined by regulatory
authorities to ensure that residues did not exceed levels seen
in normal animals or the prescribed MRL. There were synergistic
growth promoting effects seen in treated animals. Illegal "cocktails"
were mostly found in countries where the use of hormones was prohibited,
resulting in the establishment of an illegal market. They were
not normally used where the full range of drugs was available
because there was no advantage in the use of illegal drugs, and
registered products were usually cheaper and of consistent quality.
VI.163 Dr. Ritter noted
that when growth promoting hormones were used as combinations,
this use did not alter existing MRLs which had been either recommended
internationally or established by national regulatory authorities,
and hence the use of hormone combinations was not likely to have
any direct adverse consequences in terms of human health. In
the case of "illegal" cocktails, it was impossible
to speculate on the potential for adverse effects in either humans
or animals, as this potential would be a function of the nature
of the cocktail, the species of use, the dose, frequency and duration
of use, and a range of other factors which could not be assumed.
VI.164 In general, safety (toxicology)
evaluations of drugs, pesticides and other food contaminants were
carried out on single compounds only, rather than as combinations.
There were several reasons for this approach which included prior
pharmacological and biochemical knowledge that toxicity associated
with combinations was not likely to produce effects greater than
the sum of the individual components. On a more practical level,
it was difficult to contemplate the broad range of possible combinations
which would be the subject of testing. Finally, as different
commercial interests might be involved in the production and sale
of various growth promoting hormones, proprietary interests would
make it unlikely that combinations could be evaluated toxicologically.
In some cases, the efficacy of hormone combinations had been
evaluated. In the case of combinations of trenbolone with zeranol
or oestradiol, for example, it was found that (i) the combinations
were equivalent in young bulls and steers, (ii) anabolics containing
oestradiol were more effective in veal calves, and (iii) the composition
and quality of the meat was not modified by the use of combinations
when compared to single use.307 As with any drug or unlawful drug
combination, farmers sometimes were under the incorrect impression
that combinations which had not been evaluated might provide significantly
enhanced efficacy over those which had been approved for use.
Such improper use of illegal cocktails could affect withdrawal
times and residue limits and might, in some jurisdictions, result
in compliance and enforcement as disincentives to the unlawful
use of non-approved cocktails. Dr. Ritter noted that it must
also be recognized that the quest for ever improved yield could
lead some producers to the use of unapproved drug combinations.
VI.165 Dr. Randell indicated
that the monographs which were prepared by JECFA at the 32nd session
clearly indicated that trials were done on mixed implants as well
as on single substance implants. JECFA had considered such mixtures
as oestradiol together with testosterone, oestradiol together
with progesterone, oestradiol benzoate together with testosterone
propionate and also oestradiol with trenbolone acetate under the
oestradiol evaluations. These were known to JECFA at the time,
and the pharma-kcenetics of these substances as they were gradually
metabolized and excreted by the animals were studied by the experts
at that time. Moreover, the information which was available to
JECFA included carcinogenicity studies for all of the substances
concerned.
Question 16:
Which substances in addition
to the hormone compounds at issue are present in the commercially
available products marketed for animal growth promotion? Are
there any potential adverse effects on human or animal health?
Question 33: Further to question 16, are there other substances
in human implants potentially dangerous to human health?
VI.166 Dr. André
noted that if the question referred to the excipient or to potential
sub-products of synthesis, these data, as property of manufacturers,
remained confidential. Concerning the simultaneous use of other
drugs marketed for growth promotion (e.g. antibiotics), their
residue levels could be modified by the use of the hormones (see
response to question 15), so that a potential adverse effect on
human health could appear.
VI.167 Dr. Arnold indicated
that other growth promoters (antibacterials) were used under the
feed additives legislation of the European Communities (e.g.,
flavomycin, virginiamycin, zinc bacitracin, salinomycin, monensin,
lasalocid). The review process was centralised. There were no
known potential adverse effects on human or animal health if these
additives are properly used. The use of glycopeptide avoparcin
was recently withdrawn as a precautionary measure because of some
suspicion that glycopeptidresistance selected by the use
in animal production could be transferred to humanpathogenic
enterococci.
VI.168 Dr. Lucier
responded that there are many known cases of the presence of oestrogenic
substances arising from plant products, pesticides and industrial
contaminants. It was likely that the oestrogenic potency of these
substances, taken together, exceeded that from meat residues of
the six hormones in question.
VI.169 Dr. McLean stated
that there were a number of non-active components used in the
implants to ensure that the drug was delivered over the life of
the implant. These included a carrier for the drug and an inert
matrix which made up the implant. The formulation was approved
by the regulatory authorities in each country. The components
were often used in human and other animal drug formulations and
their safety had been established.
VI.170 Dr. Ritter replied
that the composition of commercially available products was generally
regarded as proprietary information. Consequently, he had no
direct knowledge of the identity of the substances other than
the hormones which might be present in commercially available
hormone preparations.
Question 17:
What are the implications
for human or animal health of residues from misplaced implants
or improper administration, i.e. when administered differently
than indicated in the label of the manufacturer, of any of the
six hormones in dispute ?
VI.171 Dr. André
indicated that the consumption of meat (or of any meat-containing
food preparation) containing a misplaced implant could be a hazard
for human health, in particular for children, fetuses, pregnant
women or immunodeficient people. Misadministration of any of
the six hormones in dispute could change the kinetics of elimination
of these hormones and induce a subsequent higher level of residues.
This could become a real health hazard if there was systematical
misuse.
VI.172 Dr. Arnold observed
that there might be a concern only where misplacement (growth
promotion) or improper administration (therapy, zootechnical treatment)
lead to consumption of a whole implant or injection site. Otherwise,
residues remaining in the carcass of the respective animal would
have no effects, even if they were higher than would be expected
if "good practices" had been applied. The worst case
assumption was that a whole fresh implant containing oestradiol
or an ester of this hormone is consumed, because the implanted
dose was higher than the doses injected for the other purposes
and orally active oestradioldoses were lower than the required
doses of the other hormones. If this entire dose was ingested
at once, only transient effects on hormonal feedback mechanisms
would be expected. Clear hormonal effects would occur if an entire
injection site was processed, e.g., into a meat containing product
and the same person would eat the whole product in divided portions
over a couple of days.
VI.173 Dr. Lucier stated
that improper or misplaced implants could very well increase residues,
thereby increasing the potential risk of the hormones in question.
Preventive strategies for misuse needed to involve veterinary
supervision, educational programmes, monitoring and stiff penalties
for abuse.
VI.174 Dr. McLean replied
that the implants would likely be detected if they were eaten
because the matrix could not be chewed. If swallowed, they would
not be digested but would pass through the human gastrointestinal
tract largely unchanged. The implications of misplaced implants
may not be of great concern because they were often placed under
the skin and removed at slaughter or during processing. In order
to facilitate correct and easy administration, applicators were
generally available from the pharmaceutical companies. One of
the features of injections subcutaneously in the ear was that
there was no massive reaction at the site. It was specifically
designed, and all the residue studies were carried out, with the
implant injected in the ear. The aim of injecting it there was
to get prolonged and slow release at low levels over a period
of time. It was specifically designed to be that way. Moreover,
the injections were usually implanted in the ear because it was
very easy to palpate a pellet or an implant under the skin of
the ear which was a second way of identifying treated animals.
VI.175 Dr. Ritter responded
that the growth promoting hormones were generally administered
as feed additives or as implants. In the event that implants
were implanted at sites other than those recommended, it was possible
that these sites contain unacceptably high residue levels if utilized
as a source of human food. The selection of the ear as a site
of implantation rather than other sites was because it was a tissue
which normally did not enter the food chain and it made identification
of the source of the material very easy. Injection site residues,
which could be much higher than normal tissue residue levels,
were thus extremely unlikely to enter the food supply. The extent
to which acceptable residue levels might be exceeded would depend
on the exact site of implantation and the withdrawal period involved.
The implication for human health would in turn be related to
these two variables.
VI.176 Dr. Ritter indicated
that illegal injection of oestradiol preparation could produce
injection site residues which largely exceeded tolerances. In
the case of feed additives, improper use might imply use of approved
drugs in non-approved species, improper dose, improper combinations,
improper duration of use and improper withdrawal periods. However,
the provision of human safety was assured through the establishment
of maximum residue levels, levels considered to be safe if consumed
by humans in the diet for an entire lifespan. In the event that
any of the improper use conditions noted above occurred, and
to the extent that such improper use would impact on final residue
levels, human safety was assured through appropriate monitoring
of the food supply for compliance with approved MRLs.
Question 18:
What are the effects on growth
promotion of the use of female hormones on male animals and vice-versa?
Are there any potential adverse effects on human or animal health
from such use?
VI.177 Dr. André
said that the effects of hormones on growth promotion was sex-dependent.
The use of male hormones associated with female hormones (ratio
10:1) in heifers had the best anabolic effect without sexual behaviour
problems and vice-versa. Concerning the human health, the level
of residues had to be taken into account, whatever the gender
of the meat producing animals. Concerning animal health, the
use of oestrogenic compounds in male animals was shown to result
in squamous metaplasia, hyperplasia of the collecting ducts and
fibromuscular hypertrophy in the prostate and bulbo-urethral gland,
fibromuscular hypertrophy and hypoplasia of the epithelium in
the seminal vesicles and epididymis and impaired testicular development.
In female animals, oestrogen treatment resulted in squamous metaplasia
and fibromuscular hypertrophy in the Bartholin's gland, hyperplasia
and secretory activity in the vagina and cervix, and impaired
follicular developments in the ovaries. The latter could also
be observed when females were treated with androgens, impaired
follicular developments in the ovaries sometimes resulted in cystic
ovaries.
VI.178 Dr. Arnold indicated
that supplemental oestrogens in castrated males increased growth
rate, presumably through an increase of endogenous levels of growth
hormone, improved feed efficiency and reduced aggressive behaviour.
Testosterone was mainly used to slow down the release rate of
oestradiol because blood levels required for anabolic effects
could not be reached with implants. No adverse effects were known
on humans. The use in animals of hormonally active growth promoters
might have behavioural sideeffects in individual animals.
VI.179 Dr. Lucier observed
that some effects, possibly adverse, could occur in the animals
receiving the growth-promoted substances. These effects could
include feminization of male animals and masculinization of female
animals based on both molecular and biological endpoints. These
effects should not occur in people eating meat containing residues
at the MRL of the hormones in question. TO CONTINUE WITH EC MEASURES CONCERNING MEAT AND MEAT PRODUCTS (HORMONES) COMPLAINT BY CANADA
299 M. Lotti, Toxicology 21, (1992) p.465. 300 Bridges, 1995 EC Scientific Conference Proceedings, p.250. 301 Food and Nutrition Paper 41, pp.44-45, FAO (1988). 302 Hoffman and Evers (1986). 303 Truhaut et al. (1985). 304 Sundlof and Stickland (1986). 305 Van Miert (1988). 306 Kuiper, 1995 EC Scientific Conference Proceedings, p.377. 307 Bouffault and Willemart (1983). |
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