UNITED STATES – CONTINUED SUSPENSION OF OBLIGATIONS IN THE EC – HORMONES DISPUTE
Document: Report of the Panel Addendum
Date: 31 March 2008
Document codes: WT/DS320/R/Add.6; WT/DS320/R.
Complainant: EU
Respondent: U.S.
Third parties: Australia, Brazil, Canada, China, Taiwan, India, Mexico, New Zealand, Norway
Dispute stage: Appellate Body
Agreements cited: Art. I, II  GATT 1994Art. 3.7, 22, 23.1, 23.2, 21.5  Dispute Settlement Understanding (DSU)

UNITED STATES – CONTINUED SUSPENSION OF
OBLIGATIONS IN THE EC – HORMONES DISPUTE

Report of the Panel

Addendum

 This addendum contains Annex F to the Re port of the Panel to be found in document
 The other annexes can be found in the following addenda:

 – Annex A: Add.1
 – Annex B: Add.2
 – Annex C: Add.3
 – Annex D: Add.4
 – Annex E: Add.5
 – Annex G: Add.7

ANNEX F

COMMENTS BY THE PARTIES ON THE REPLIES
OF THE SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC
TO QUESTIONS POSED BY THE PANEL AND
COMMENTS BY THE PARTIES ON THE OTHER PARTIES' COMMENTS

Contents Page
Annex F-1 Comments by the European Communities on the replies of the
scientific experts to questions posed by the Panel (30 June 2006)
F-2
Annex F-2 Comments by the European Communities on the replies of Codex,
JECFA and IARC to questions posed by the Panel (30 June 2006)
F-41
Annex F-3 Comments by the European Communities to the comments by the
United States and Canada on the replies of the scientific experts to
questions posed by the Panel (12 July 2006)
F-54
Annex F-4 Comments by the United States on the replies of the scientific
experts, Codex, JECFA and IARC to questions posed by the Panel
(30 June 2006)
F-101
Annex F-5 Comments by the United States to the comments by the European
Communities on the replies of the scientific experts, Codex,
JECFA and IARC to questions posed by the Panel (12 July 2006)
F-141

ANNEX F-1

COMMENTS BY THE EUROPEAN COMMUNITIES ON THE REPLIES
OF THE SCIENTIFIC EXPERTS TO QUESTIONS POSED BY THE PANEL

(30 June 2006)

A. G
ENERAL DEFINITIONS
Q1. Please provide brief and basic definitions for the six hormones at issue (oestradiol-17 β,
progesterone, testosterone, trenbolone acetate, zeranol, and melengestrol acetate), indicating the
source of the definition where applicable.

EC Comments

Dr. Boisseau's reply does not consider any progress in toxicological knowledge concerning these
hormones, and in particular estradiol, since the 70 th and 80 th JECFA reports. Since then new data
concerning residues in tissue and their toxicological impact have been published. In his answer, he has
only adopted a narrow regulatory definition. More specifically, as regards oestradiol, aromatization
of androgens in estrogens is also very significant in adipose tissue. In his definitions, the sites of
production in the human body is limited to the pr imary source and does not dwell on variability over
the life span of an individual. Furthermore, his defi nition does not stress that Zeranol is a very potent
estrogen. Zeranol is not a "natural estrogen" that humans are exposed to. In fact, great care should be
taken to avoid the presence of fusarium molds in animal feed and especially in products for human
consumption. As regards the implantation of these hor mones, he uses simple present tense ("the ear is
discarded") when precisely this is not known nor it is sure that it happens in practice in all cases. He
should therefore have said that "the ear should be discarded at slaughter". Moreover, implantation can
be made at the dewlap level, not only at the ear one, especially in case of multiple implantations.
Furthermore, in some new recommendations of tre nbolone use, it is possible to proceed to repeated
implantation of steers or heifers.

Q2. Please provide definitions for the following te rms as they relate to the hormones at issue,
indicating the source of the definition where a pplicable: anabolic agents, steroids, steroidal
oestrogens, parent compounds/metabolites, catech ol metabolites, mitogenicity, mutagenicity,
androgenic/oestrogenic activity, genotoxicity , genotoxic potential, carcinogenicity, and
tumorigenicity. In your replies, please be sure to identify and describe any relevant differences
between the terms.

EC Comments

Dr. Boisseau's reply that "In my e-mail of 26/04/06, I have indicated that I did not think that I am in
the position to reply to this question" calls into que stion the reliability of his answer to question no 1
and indeed to the other questions. As the EC has pointed out during the selection procedure,
Dr. Boisseau does not posses any expertise on these substances, as he does not appear to have carried
out any specific research on these substances during his professional life. Dr. Boisseau has explicitly
admitted it in his e-mail to the Pane l secretariat where he wrote: " I did not join any publications as I
have none on hormones".

B. RISK ASSESSMENT TECHNIQUES
Q3. Please identify any international guidance documents relevant to the conduct of a risk
assessment with respect to veterinary drug residu es. Since when have they been available?
Please also indicate if there is any relevant ongoing work at Codex.

EC Comments

The European Communities agrees wi th the statement by Dr. Boisseau that currently there is no
international guidance document relevant to th e conduct of a risk assessment with respect to
veterinary drug residues and in particular th e six hormones under consideration. Indeed, the
documents to which Dr. Boobis refers to in his reply are not "assessment techniques developed by the
relevant international organizations", in the sense of Article 5.1 of the SPS Agreement . They are
informal ad hoc papers without any legal valu e. Moreover, when the European Communities
evaluated these hormones, it applied its standard le gislation for the evaluation of this type of
substances, which complies fully with the general de finitions of risk analysis as described in the
Codex Alimentarius' latest Manual of Procedures.

Moreover, Dr. Boisseau's
 statement that " the situation is similar in the European Union " and that
"The CVMP has assessed all the pharmacologically active substances used in veterinary medecine
without any written guideline about risk assessment " is wrong. It is not the CVMP (Committee on
veterinary medicinal products) which is responsible for these hormones when administered for animal
growth promotion, but it has been the SCVPH ( scientific committee on veterinary measures relating
to public health). This latter Committee, and the European Communities in general, have been
applying advanced principles and techniques of risk analysis which Codex Alimentarius is only now
considering of formally putting in practice. S ee for instance the European Commission Decision
97/579/EC of 23 July 1997 which set up scientific committees in the field of consumer health and
food safety which has established the SCVPH (OJ L 237, 28.8.1997, p. 18-23) and the Opinion of the
Scientific Steering Committee on harmonisation of risk assessment procedures adopted on 26-27
October 2000, which can be found at http://ec.europa.eu/food/fs/sc/ssc/out82_en.html. These
advanced principles of risk analysis have been routinely applied by the European Communities for
quite some time well before 1997. 1 They were applied when the SCVPH evaluated these six
hormones in 1999, 2000 and 2002, and have since then formally been restated in the relevant EC
legislation, in particular Regulation (EC) No 178/ 2002 of the European Parliament and of the Council
of 28 January 2002 laying down the general princi ples and requirements of food law, establishing the
European Food Safety Authority and laying down procedures in matters of food safety, OJ L 31,
1.2.02, p. 1-24, in particular Article 6.

Q4. The European Communities states that there is "no Codex standard specifically on the
risk assessment of effects of residues of veterina ry drugs" but a general one on microbiological
assessment. Is this correct? Which guidelines or principles have been used by JECFA in the
conduct of its risk assessments with respect to th e hormones at issue? [see para. 192 of EC
Rebuttal Submission (US case)].

EC Comments

As already explained above in its comments to the replies to question No 3, the European
Communities agrees with Dr. Boisseau's reply that "there is no Codex standard specifically on the risk
assessment of effect of residues of veterinary drugs". Neither the work of IPCS nor the

1 See, e.g., Commission Directive 93/67/EEC of 20 July 1993 laying down the principles for
assessment of risks to man and the environment of s ubstances notified in accordan ce with Council Directive
67/548/EEC, OJ L 227, 8.9.1993, p. 9-18.

Environmental health Criteria no 70 nor the monograph published in the WHO series no 43,
mentioned by Dr. Boobis
 and Dr. Guttenplan , respectively, constitute legally binding "assessment
techniques" for risk assessment in the sense of Article 5.1 of the SPS Agreement. The EC has been
much more advanced than JECFA in the appli cation of generally acceptable techniques for risk
analysis, as explained in the references to the releva nt EC legislation in the previous question No 3.
The EC documents mentioned above, although publicly accessible, can be made available to the Panel
and its experts upon request.

Q5. Please briefly describe the three components of a risk analysis exercise (risk assessment,
risk management and risk communication) and explain how they differ.

EC Comments

The European Communities submits th at the Panel's question is of little relevance to the issues under
consideration in the present proceedings. Indeed, th e Panel's question appears to ignore the fact that
the Appellate Body in the Hormones case has clarified that the term "risk assessment" in the SPS
Agreement is wider in scope because it covers also evidence, considerations, objectives and factors
that are also taken into account at the "risk management" phase. 2 Consequently, the answers of all
scientists do not take into account the legal requirements of the SPS Agreement in this area, as
interpreted by the Appellate Body . However, the European Comun ities has in any case followed the
three components of risk analysis, as explained abov e and in its reply of 3 October 2005 to question
No 24 of the Panel.

Moreover, none of the replies
 by the scientists describes what is actually going on in Codex. The
reality is that JECFA performs, most of the time, as it did with regard to these hormones, both risk
assessment and risk management functions (something which Dr. Boisseau admits), thus the
subsequent decisions/recommendations by the Codex Alimentarius Commission become a mere
formality. Indeed, JECFA's reports and monographs ar e drafted in such a way as to leave practically
no room to the members of the Codex Alimentarius Commission to decide on the appropriate level of
health protection and the risk management options that are available to its members. That is another
reason for which the European Communities deci ded that the Codex recommendations on these
hormones could not achieve the level of health protection considered appropriate in its territory.

Q6. Please briefly describe the four steps of a risk assessment (hazard identification, hazard
characterization, exposure assessment and risk characterization) as identified by Codex,
indicating any relevant sources.

EC Comments

The European Communities does not understand the re levance of this question for the purposes of
these disputes and the corresponding replies of Dr. Boisseau and Dr. Boobis . This type of formal
distinction between the various components of risk assessment are not mentioned in the SPS
Agreement and they are clearly not legally binding, sin ce they are not risk "assessment techniques"
in the sense of Article 5.1 of the SPS Agreement. Moreover, as the Appellate Body has held in the
Hormones case (at para. 181), to the extent these distin ctions are used "to achieve or support what
appears to be a restrictive notion of risk assessment" this has no text ual basis in the SPS Agreement.
More importantly, however, if these four steps ar e not formally identified in the risk assessment
document of a member, this does not mean that the risk assessment of that member is faulty or
scientifically unsound. For instance, the statements by the above 2 scientists appear to discard the
relevance of some residues that are not pharmacologically active but may interfere with normal
metabolic functioning of cells given their intrinsi c chemical potential to form covalent adducts to

2 See Appellate Body Report in EC - Hormones, at paras. 181 and 206.

biomolecules (trenbolone for example which gives a high level of protein a dducts). Normally, this
biological impact should be considered separately and in addition to the hormonal effects. But until
now, this has never been done by JECFA and the defending parties when they evaluated these
hormones for animal growth promotion purposes. Hence, it is difficult in this context to know what is
really a marker residue of a compound having some toxic impact that are not at all related to
hormonal effects.

Q7. Please comment on the EC statement made in para. 140 of the EC Replies to Panel
Questions that "which ever approach of a risk a ssessment is followed, they are all based on a
deterministic approach to risk characterization [and that they] have serious limitations in non-
linear situations, such as in the current case re garding hormones". Are these situations, in your
view, addressed by the risk assessment gu idance currently available from the Codex
Alimentarius Commission? Have they been addressed in the 1988 and 1999 JECFA risk
assessments of these hormones? [see Canada 's comments in para. 72 of its Rebuttal
Submission]

EC Comments

The European Communities notes first that Dr. Boisseau admits that "in 1987 and 1999, at the time of
the assessment of oestradiol-17β, there was no risk assessment guidance available on this issue". Even
so, he goes on to argue that neither in 1987 nor in 1999 JECFA considered this kind of non-linear
situation, despite the fact that it had found in its 1999 report that "oestradiol-17 β has a genotoxic
potential." However, this approach of JE CFA is scientifically unsound, as Dr. Boobis now accepts
when he says that today "in practice, it is likely that as veterinary drug residues in food are avoidable
by not using the drug, the Committee would have declined to establish an ADI".

The European Communities notes, however, that there are basic flaws in the replies of both
Dr. Boisseau
 and Dr. Boobis. Indeed, the accumulation of so much new peer-reviewed evidence since
1999 establishes clearly that oestradiol-17 β is a direct carcinogen and does not act only through
hormonal receptors. In addition to the peer-revi ewed studies mentioned in the 1999, 2000 and 2002
EC risk assessments, it would be appropriate to refer also to the work of Hari K. Bhat, Gloria Calaf,
Tom K. Hei, Theresa Loya, and Jaydutt V. Vadgama: Critical role of oxidative stress in estrogen-
induced carcinogenesis, published in the Proceedings of the National Academy of Sciences, Vol. 100
(2003) 3913-3918, demonstrating the necessary role of catechols of estradiol or other catechols
(2/4-hydroxy-estradiol-alpha produced from estrad iol-alpha, menadione) in induction of oxidative
stress to induce tumors in the hamster kidney carcinogenesis model. See also the two papers by J.
Russo and his co-workers: 17β-Estradiol is carcinogenic in human breast epithelial cells , and
Estrogen and its metabolites are carcinogeni c agents in human breast epithelial cells , published in
the Journal of Steroid Biochemistry & Molecular Biology, vol. 80 (2002) 149-162 and vol. 87 (2003)
1-25, respectively.

From a more systematic point of view, the views of Dr. Boobis
 can also be criticized because a
threshold is a theoretical concept that provides the justification for the use of the NOAEL and thus the
ADI. In the work of JECFA, the NOAEL is percei ved as evidence of the practical revelation of a
threshold. But a true threshold can only be establishe d with an infinitely large group of animals: thus,
the dose distance between the true threshold and the NOAEL cannot be established. In a genetically
and phenotypically heterogenous human population, there is a risk from endogenous hormone –
induced adverse outcomes. Additionally, there must be a distribution of both consumption of meat
and hormone response sensitivity in the human population. We know that endogenous hormones in
animals and humans are known to cause a wide va riety of adverse effects from reproductive function
to malignancies. These considerations demonstrate that some fraction of the population will be at
higher risk for hormone-related adverse outcome s, no matter the dose, due to consumption of

hormone-implanted meat. A number of publications , some of which have been submitted by the
European Communities to this Panel, have expl ored the threshold concept and the activity of
hormones at very low doses. These are:

Gaylor, D. W., Sheehan, D. M., Young, J. F. a nd Mattison, D. R.: The threshold dose question in
teratogenesis (Letter). Teratology, 38:389-391, 1988.

Sheehan, D. M., and vom Saal, F. S.: Low dose effect s of endocrine disruptors- a challenge for risk
assessment. Risk Policy Report, 31-39, issue of Sept.19, 1997.

Sheehan, D. M., Willingham, E., Gaylor, D., Bergeron, J. M., and Crews, D.: No threshold dose for
oestradiol-induced sex reversal of turtle embryo s: How little is too much? Environmental Health
Perspectives 107:155-159, 1999.

Sheehan, D. M.: Activity of environmentally low doses of endocrine disruptors and the Bisphenol A
controversy: Initial results confirmed, in Proc. Soc. Exp. Biol. Med. 224:57-60, 2000.

Blair, RM, Fang, H, Gaylor, D, Sheehan, D. M.: Th reshold analysis of selected dose-response data for
endrocrine disruptors, in APMIS 109:198-208, 2001.

Q8. Please describe the procedure followed by JECFA in the identification of ADIs and the
development of recommendations on MRLs. Plea se identify and describe any steps that are
taken in the risk assessment process to build a margin of safety into the final recommendation.

EC Comments

The replies of Dr. Boisseau
 and Dr. Boobis are theoretical statements with little scientific relevance as
regards the safety of these hormones. For instance, the appropriate studies in humans would require a
huge study population, and would be seriously c onfounded by medical treatments with hormones and
environmental exposures to hormones. Also the c onclusion that there is a threshold for hormone
action in the absence of other sources of hormone ca nnot provide a sound scientific basis in order to
conclude that endogenous hormones are below the threshold for all actions of the hormones.
Therefore, added hormone from implanted beef shou ld increase risk for endpoints that are already
occurring from endogenous hormones. Appreciable risk is a subjective decisi on, as are the 10-fold
safety margins. Because of the small numbers of animals on studies, the resolution is generally low.

More specifically, the evidence used by JECFA in the evaluation of these hormones is too old (dating
from the 1970s) and has been obtained with outdate d detection methods to be relevant today.
Dr. Boisseau
 also writes that "... taking into consideration the diversity of humans, resulting from the
sex, age, race, which can lead to different sensitivity.. .", but JECFA did not take the low endogenous
levels and thus the high sensitivity of children into account. Also Dr. Boobis states that " where there
was an identifiable sub-group who might reasonably be expected to be more sensitive than the group
in whom data were obtained, for example children relative to adults, an extra factor was applied ."
Indeed, the JECFA expert committee that examin ed these hormones did not include any physicians
and child endocrinologists! It can be argued that for most chemical compounds, such as pesticides, the
knowledge on their potential toxicity resides with toxi cologists. However, when we are dealing with
the natural hormones and compounds that directly affect the endocrine system, the knowledge on how
they potentially can affect humans is a part of the daily work of paediatricia ns and other physicians.
Thus, it is essential that persons with a medical background are present in the JECFA committee (see
more on this below). Dr. Boisseau also writes something about low oral activity of 17 β-oestradiol,
but that is simply not scientifically correct as de monstrated below (comment in relation to question
43). For instance, oral contraceptives and some hormone replacement therapy are taken by the oral

route and are shown to be very active. This de monstrates that oestradiol and progesterone are
bioavailable through the oral route.

Q9. Please confirm or comment on the following Canadian statement: "it is recognized that
JECFA only allocates an ADI for a food additi ve or veterinary drug under review when JECFA
considers that its scientific data base is comple te and that there are no outstanding scientific
issues". [see para. 68 of Canada Rebuttal Submission]

EC Comments

The Canadian statement cannot be scientifically correct in the unqualified manner in which it is
expressed and certainly is not correct as regards the six hormones under consideration. It would all
depend on when JECFA's scientific data base is considered to be complete and that there are no
outstanding scientific issue. For example, when JECFA evaluated in 1988 these hormones, it
considered unnecessary to establish an ADI, presu mably because it considered that there was no
outstanding scientific issue. However, in its 1999 evaluation of the three natural hormones JECFA
changed its evaluation and this time establishe d an ADI. Both in 1988 and in 1999 JECFA's
evaluation was based on the assumption that these substances act only through the hormonal
receptors. However, this assumption is certainly inco mplete and scientifically incorrect because it is
today generally accepted that some of these hormones are genotoxic and can cause cancer directly.
Furthermore, as already explained above, the ADI and MRLs that JECFA established in 1988 and in
1999 for the three synthetic hormones do not take into account the low endoge nous levels and thus
high sensitivity of prepubertal children. In conclu sion, there are so many examples of cases where
JECFA has set an ADI because it considered its scientific data base to be complete and that there were
no outstanding scientific issues, but it had subsequen tly to change its mind in the light of more
accurate reading of the evidence or more recent scientific data. A good recent example is the case of
Carbadox, cited by the European Comm unities in paras. 150 and 151 of its 2
nd Written Submission in
the US Panel. It follows that the issue of when the scientific data base is complete can be very
subjective and prone to many errors of which JECFA's assessments are certainly not immune.

Q10. In para. 129 and 168 of its Replies to the Panel Questions, the European Communities
states that "JECFA's traditional mandate does no t allow it to examine all risk management
options but restricts it to either propose MRLs or not". Does Codex have risk management
options other than (1) the establishment of an MRL, (2) establishing that an MRL is not
necessary or (3) no recommendation?

EC Comments

The European Communities consider s that the reply of Dr. Boisseau confirms that JECFA has a
narrow mandate, even if it frequently oversteps its role and proposes also risk management measures,
thus leaving practically no option to Codex Alim entarius Commission and its members than to follow
its narrow recommendations to adopt or not an MRL. What is also important to note is that JECFA
has not considered as part of its narrow mandate to examine whether there is any likelihood of misuse
or abuse of these hormones and whether the identifie d risks to human and animal health from the use
of these hormones for growth promotion by far exceed any potential benefits.

Q11. What should, in your view, be the components of a qualitative risk assessment,
compared with a quantitative risk assessment? [see para. 82 of Canada Rebuttal Submission]

EC Comments

The European Communities agrees w ith the statement by Dr. Cogliano . The statements by
Dr. Boisseau and Dr. Boobis are simply contrary to the findings of the Appellate Body in the 1998

Hormones case, where it held that a qualitative risk assessment is equally acceptable under the SPS
Agreement and that it does not require the same t ype of analysis as a quantitative risk assessment.
More generally, the issue of whether a threshold mode l or a non-threshold model is used is critical in
determining risk. The literature on no-threshold c ited above, in addition to the no-threshold models
used for example for PCBs and dioxin, are more a ppropriate than the current procedures applied by
JECFA. For instance, endogenous estrogens are active at inducing some responses in most, if not all,
age and population groups. Additivity of exposur e to endogenous and ex ogenous hormones will
necessarily result in increased risk at any exogenous dose, no matter how low. Interestingly, the US
EPA uses no-threshold models for non-genotoxic ch emicals, such as dioxins and PCBs, due to a
combination of very long half-lives and activit y at very low doses. The European Communities
submits that consumption of hormone-treated beef at regular intervals will provide continual or
intermittent exposure of estradiol and other growth hormones and thus increase risk and undermine its
high level of health protection from these substances.

Q12. How is scientific uncertainty addressed in ri sk assessments in general? With respect to
the assessment of risks from the consumption of meat treated with the growth promotion
hormones at issue, how has scientific uncertain ty been considered by JECFA/Codex ? How
does it differ from the way it has been considered by the European Communities in its
assessment of risks from the consumption of meat treated with the growth promotion hormones
at issue?

EC Comments

The European Communities disagrees w ith the statements by Dr. Boisseau and Dr. Boobis because of
their extremely narrow understanding of the concept of scientific uncertainty. They both consider that
scientific uncertainty is adequately addressed by JECFA when applying the so-called safety factors.
There is however now almost universal agreement that this approach is not scientifically correct. A
state of uncertainty may result from a number of factors, such as lack, incomplete or contradictory
data. It is not the quantity but the quality of the data th at is important. It is possible that an issue that
was thought to be scientifically clear to become uncertain as more data become available. When
scientific uncertainty is understood in this sense, th is cannot be tackled with the application of so-
called safety factors or margins, especially for coun tries that wish to apply a high level of health
protection. For example, the genotoxic and carcinogenic potential of oestradiol-17 β cannot be
adequately addressed by the safety factors app lied by JECFA, because the underlying scientific
uncertainty about the mechanisms causing cancer are not amenable to quantification so as to be
adequately addressed by the safety factors (there is always the risk of under-inclusion). Another
example is that when JECFA evaluated the three natural hormones in 1988 and in 1999 and decide not
to set a ADI and a MRL, it based its evaluati on concerning endogenous production of these hormones
by prepubertal children on very old data from 1974 (citing the paper by Angsusingha K. et al:
Unconjugated estrone, estradiol, and FSH and LH in prepubertal and pubertal males and females ,
Journal of Clinical Endocrinology and Metabolism, 39: 63-68 (1974), as reported in the 32
nd report of
JECFA published in the WHO technical report series no 763, page 32). However, the data reported
by Angsusingha et al. are no longer valid in view of the more recent findings with more accurate
detection and measurement tools available (see the discussion in paras. 121-122 of the EC 2 nd written
submission in the US panel and the references ther eto to the papers by Klein and Klein and by
Anderson and Skakkebaek of 1994, 1999 and 2005, respectively).

It follows from the above that the statement by Dr. Boisseau
 that "for the three natural hormones,
oestradiol-17β, progesterone and testosterone, JECFA has d ecided that the margin of safety deriving
from the values of the established ADIs and from a ma ximum estimated intake of residue was such
that it was not necessary to set up MRLs" is plai nly wrong. His statement that the European
Communities "did not consider any scientific uncertain ty" is also false, because a careful reading of

the 1999 risk assessment by the SCVPH shows that the reasons for which that scientific committee
considered that oestradiol-17β is a proven carcinogen and that the un certainty regarding the other five
hormones (resulting from the lack of data or th e presence of contradictory data) are properly
explained and taken into account.

Dr. Boobis
 also made the equally false statement that: "… the EC assessment of the hormones did not
go as far as including some of the considerations for uncertainty used by JECFA because of the
conclusion that there was insufficient information to determine whether there was a threshold for the
carcinogenic effects. However, for some of the co mpounds this was based on the results of a small
number of non-standard tests of genot oxicity, with equivocal of very weak responses. It is not clear
whether the EC applied a weight of evidence approach to evaluating the genotoxicity of all of the
compounds, taking account the totality of the availabl e data, as was the case by JECFA." Indeed, the
three risk assessments of 1999, 2000 and 2002 by the SCVPH did consider the totality of the available
data. In fact, Dr. Boobis' reply does not discusses at all that since 2002, the US authorities concluded
that "steroidal estrogens are known to be hum an carcinogens based on sufficient evidence of
carcinogenicity in humans , which indicates a causal relations hip between exposure to steroidal
estrogens and human cancer." For this reason, the US 2002 Report on Carcinogens (RoC) lists
steroidal estrogens as known to be human carcinogens with the clarification that this listing now
"supersedes the previous listing of specific estrogens in and applies to all chemicals of this steroid
class." Moreover, in the same 2002 US Report it is stat ed that: "Veterinary use of steroidal estrogens
(to promote growth and treat illnesses) can increase estr ogens in tissues of food producing animals to
above their normal levels." 3 So, the 2002 US Report on Carcinogenesis contradicts the allegations
made by the US and Canada in these proceedings, wh ich appear to be supported by Dr. Boobis, that
the additional burden of residues coming from eating hormone-treated meat is so small that it would
make no difference, compared to the level of endogenous production.

Furthermore, neither Dr. Boobis nor Dr. Boisseau mention the fact that the IARC has classified
oestradiol-17β in Group 1 as carcinogenic to humans be cause there is suffi cient evidence of
carcinogenicity and progesterone and testosterone in Group 2B as possibly carcinogenic to humans. It
is therefore a surprising statement by Dr. Boobis that the EC " did not apply a weight of evidence
approach to evaluating the genotoxicity of all of the compounds, taking into account the totality of the
available data, as was the case by JECFA ", because it is precisely JECFA's evaluation that is based
on old and outdated data and does not examine the totality of the available evidence. Moreover, the
argument of Dr. Boobis that a WTO member has to apply a "w eight of evidence approach" is legally
incorrect. It is not very clear what Dr. Boobis means by this approach, but it must not be taken to
mean that only the mainstream sci entific views should be accepted or that such an approach could
remedy the identified scientific uncertainty. Moreov er, this approach would amount to forcing WTO
members to dismiss or ignore minority scientific vi ews, which has clearly been rejected by the
Appellate Body in the 1998 Hormones case, where it held that:

"Article 5.1 of the SPS Agreement does not require that the risk assessment must
necessarily embody only the view of a majority of the relevant scientific community.
In some cases, the very existence of divergent views presented by qualified scientists
who have investigated the particular issue at hand may indicate a state of scientific
uncertainty. In most cases, responsible and representative governments tend to base
their legislative and administrative measures on "mainstream" scientific opinion. In
other cases, equally responsible and representative governments may act in good faith
on the basis of what, at a given time, may be a divergent opinion coming from
qualified and respected sources. By itself, this does not necessarily signal the absence
of a reasonable relationship between the SPS measure and the risk assessment,

3 Available at http://ntp.niehs.nih.gov/index.cfm?objectid=72016262-BDB7-CEBA-
FA60E922B18C2540.

especially where the risk involved is life-threatening in character and is perceived to
constitute a clear and imminent threat to public health and safety." (at para. 194 of the
AB report)
On a more specific point, Dr. Boisseau
 is apparently committing the same error as the defending
parties because he keeps referring to the "differences in the interpretation of data, as illustrated by the
differing conclusions of the CVMP (1999) and the SCVPH (1999)", without knowing that the CVMP
has evaluated some of the natural hormones in different preparations and for different purposes
(therapeutic or zootechnical use) and its findings are not relevant for the use of the six hormones when
administered for animal growth promotion (for which the competence to assess resided with the
SCVPH).

C. A
SSESSMENT OF OESTRADIOL-17Β
Q13. To what extent, in your view, does the EC risk assessment identify the potential for
adverse effects on human health, including the carcinogenic or genotoxic potential, of the
residues of oestradiol-17 β found in meat derived from cattle to which this hormone had been
administered for growth promotion purposes in a ccordance with good veterinary practice? To
what extent does the EC risk assessment eval uate the potential occurrence of these adverse
effects?

EC Comments

The European Communities is surprised by the affi rmative tone in the statements by Dr. Boisseau and
Dr. Boobis that the genotoxic effect of oestradiol-17 β is associated with its hormonal activity, when
JECFA itself was more cautious when stating that "the carcinogenicity of oestradiol-17 β is most
probably a result of its interaction with hormonal r eceptors" (emphasis added). Their statements
become even more questionable in that they both do not take into account nor do they discuss the
most recent and growing scientific evidence li nking, directly or indirectly, oestradiol-17 β and the
other hormones with increased risk of cancer. Unlike what Dr. Boisseau states, there is growing
evidence from in vivo studies, (e.g. by Bhat et al ., already mentioned above, published in PNAS 100
(2003) 3913-3918) which has shown that estradiol is responsible for both initiation and promotion of
tumors in vivo . Moreover, carcinogenicity of estrogens is primarily due to oxidative stress/DNA
adduct formation caused by the catechols metabolites of estrogens. The role of receptor stimulation is
only invoked in the promotion stage of carcinogenesis. For this reason, it is also necessary to consider
estradiol-alpha as residues susceptible to be metabo lised in consumer in catechol derivative with the
same potency as estradiol to give adducts or to induce oxidative stress.

As already explained, it needs to be recalled agai n that estradiol has been classified as a Group 1
carcinogen by IARC and the results from numerous epidemiological studies support the association of
elevated prolonged exposure to endogenous and exogenous estrogen with breast cancer. These studies
are supported by studies in experimental animal m odels that not only include the Syrian hamster
kidney model and mouse uterus model, referred to by Dr. Guttenplan
 in his response to Q. 14, but also
the ACI rat (J. Endocrinology, 183, 91-99, 2004) and the ERKO/Wnt mouse (J. Steroid Biochem.
Mol. Bio., 86, 477-486, 2003). In both of the la tter models a clear dependence of the tumors on
estradiol was shown and, in the latter model, the r esults show that the mammary tumors arise through
effects of estradiol not
mediated through the estrogen recepto r (ER) since the mice lack ER
expression.

So there seems now to be agreement that exposure to oestradiol-17 β may increase the sensitivity to
other carcinogens and thus increase the cancer risk (s imultaneous or later in life). One more example

is the ENU-mediated induction of endometrial adenocarcinomas (Takahashi et al., 1996), 4 where
simultaneous exposure to oestradiol-17 β significantly increased the yield of adenocarcinomas. More
recently, the concept of tissue stem cells, as the cells where breast cancer originates, has led to a new
concept linking breast cancer risk with the stem ce ll potential as a measurable variable of the ‘fertile
soil' for cellular transformation. It is suggested that low-dose estrogen expos ure leads to increased
proliferation of the tissue stem cells and, sin ce it is hypothesised that the number of potentially
carcinogenic tissue stem cells determines the risk of getting the cancer, thereby to an increased risk of
breast cancer later in life. This aspect is not at all considered by these experts.5

Other adverse effects on human health have also b een established. Thus, there are strong data linking
administration of very low doses of oestradiol-17 β to pre-pubertal girls to changes in growth pattern
despite the fact that serum levels of oestradiol-17 β remained below the detection limit (Lampit et al.,
2002).6 This may affect the risk for breast cancer later in life because it has been convincingly
demonstrated that prepubertal growth rates significa ntly influence the breast cancer risk (Ahlgren et
al., 2004).7

The European Communities also dis putes the statements by Dr. Boobis
 that the EC's risk assessment
used "speculative assumptions" about misuse or abuse of the product, that no adequate assessment of
exposure following use according to GVP was undertaken, or that there was no attempt to estimate the
potential occurrence of adverse effects in humans following exposure to levels of the hormones found
in meat from treated animals. The experiments conducted by the EC and its findings are based on
realistic conditions of use and demonstrate that GVP is frequently not respected in the defending
members. The EC exhibits Nos 12, 16, 17, 52, 67, 68, 69 and 73 provide concrete evidence of abuse
and misuse of these hormones by the both the US and Canada.

The European Communities agrees with the statement by Dr. Guttenplan
 that there are basically no
direct epidemiological studies comparing matched populations consuming meat from untreated and
hormone-treated cattle. However, apart from the ethical concerns, it is difficult to conduct such direct
experiments in the presence of so many other confounding factors because of feasibility limitations
for observational studies. This being said, it is co mmon that in animal mode ls used in carcinogenesis
bioassays (rats and mice) one of the more sensitive tissues for tumorigenesis is liver. At the present
time, however, the classification of chemicals as carcinogens does not require that the tumors
produced in the bioassays are the same as would a ppear in humans; chemicals are classified as
carcinogens when they cause a significant increase in tumors regardless of the tissue.

Q14. In your view, does the risk assessment undertaken by the European Communities on
oestradiol-17β follow the Codex Guidelines on risk a ssessment, including the four steps of
hazard identification, hazard characterization , exposure assessment and risk characterization
with respect to oestradiol-17β?

4 See Takahashi M, Iijima T, Suzuki K, Ando-Lu J, Yoshida M, Kitamura T, Nishiyama K, Miyajima
K, Maekawa A.: Rapid and high yield induction of endo metrial adenocarcinomas in CD-1 mice by a single
intrauterine administration of N-ethyl-N-nitrosourea combined with chronic 17 beta-estradiol treatment, in
Cancer Lett. 104:7-12 (1996).
5 See Smalley M., Ashworth A.: Stem cells and breast cancer: A field in transit . Nat Rev. Cancer.
2003, 3(11) :832-44, and Baik I., Becker P.S., DeVito W.J., Lagiou P., Ballen K., Quesenberry P.J., Hsieh C-C.:
Stem cells and prenatal origin of breast cancer. Cancer Causes and Control 15: 517–530 (2004).
6 See Lampit M., Golander A., Guttmann H., Hochberg Z.: Estrogen Mini-Dose Replacement during
GnRH Agonist Therapy in Central Precocious Puberty: A Pilot Study. The Journal of Clinical Endocrinology &
Metabolism 87:687–690 (2002).
7 See Ahlgren M., Melbye M., Wohlfahrt J., Sorensen T.I.: Growth patterns and the risk of breast
cancer in women. N. Engl. J. Med. 351:1619-26 (2004).

EC Comments

The European Communities disagrees with the st atement by Dr. Boobis because from a careful
reading of the 1999, 2000 and 2002 risk assessment by the SCVPH it is obvious that it has followed
the four steps of risk assessment when it carried out its qualitative risk assessment . That this is so is
also confirmed by the statement by Dr. Boisseau although Dr. Guttenplan gives it a "mixed rating" in
following the Codex guidelines which became available in 2003.

For the sake of completeness, however, it should also be clarified that Dr. Guttenplan has not
considered the studies on the ACI rat and ERKO/Wn t mouse. The studies carried in experimental
animal models do not only include the Syrian hamster kidney model and mouse uterus model, referred
to by Dr. Guttenplan, but also the ACI rat (J. Endocrinology, 183, 91-99, 2004) and the ERKO/Wnt
mouse (J. Steroid Biochem. Mol. Bio., 86, 477- 486, 2003). In both of the latter models a clear
dependence of the tumors on estradiol was shown and, in the latter model, the results show that the
mammary tumors arise through effects of estradiol not mediated through the estrogen receptor (ER)
since the mice lack ER expression. In addition, ther e are several additional models in transgenic mice
where mammary tumor formation has been shown to be estrogen dependent.

D. C
ONSUMPTION OF MEAT CONTAINING HORMONES
(a) Carcinogenicity
Q15. Does the identification of oestradiol-17 β as a human carcinogen indicate that there are
potential adverse effects on human health when it is consumed in meat from cattle treated with
hormones for growth promotion purposes? Does your answer depend on whether good
veterinary practices are follo wed? [see para. 206-207 of EC Rebuttal Submission (US case),
para. 121 of EC Rebuttal Submission (Canada case), paras. 97-98 of EC Replies to Panel
Questions, paras. 76-77, 150 and 155-156 of US First Submission, paras. 35-40 and 46 of
US Rebuttal Submission]

EC Comments

The European Communities notes the different and in some parts contradictory statements by the four
experts that replied to this question. It agrees with the reply of Dr. Cogliano. It also agrees that if GVP
is not followed, the risk is even higher. For the benefit of Dr. Guttenplan , the EC would clarify that
the term "potential" in the SPS Agreement has indeed been interpreted by the Appellate Body in the
1998 Hormones case to mean "possible" (at para. 185 of the report).

The position of Dr. Boobis
 and that of Dr. Boisseau is conditioned by their understanding that
oestradiol-17β is causing cancer only through receptor mediated processes. This hypothesis is
however scientifically no longer tenable in light of more recent evidence cited by the European
Communities. Reading between the lines of their re plies, however, these two experts also do not
seem to deny completely the existence of possible adverse effects from residues in meat from animals
treated with this hormone for growth promotion purposes.

Q16. Does the scientific evidence relied upon in the SCVPH Opinions support the conclusion
that carcinogenic effects of the hormones at issue are related to a mechanism other than
hormonal activity? [see para. 148 of the EC Rep lies to Panel Questions and paras. 35-40 and 46
of US Rebuttal Submission]

EC Comments

The European Communities disagrees w ith the statements of Dr. Boisseau and Dr. Boobis . For
Dr. Boisseau there is only one other authoritative source of comparison, that is the JECFA reports,
irrespective of the outdated nature of its reports and old data on which they are based. In his long
reply, Dr. Boisseau interprets lack of data as lack of adverse effects. Is this really a valid approach that
is followed by JECFA? Dr. Boisseau further criticises the SCVPH assessments on the ground that
they did not include a "quantitative assessment" of th e risk or that it did not establish its genotoxicity
with data from experiments in vivo. Dr. Boisseau does not probably know that the Appellate Body has
held that a qualitative assessment of risk is acceptable for the purposes of the SPS Agreement .
Moreover, he does not consider the other more recent evidence cited by the European Communities
showing the direct genotoxic potential of oestradiol-17 β, progesterone, zeranol and most possible
testosterone. As regards MGA and trenbolone acetate the evidence may be inconclusive but there are
sufficient indications to treat them as such, despite the serious gaps in our scientific knowledge.

Amongst the flaws in Dr. Boobis' reply is that he criticises the EC assessment for not having
evaluated these hormones "on a weight of evidence" basis. However, this type of criticism is
scientifically inaccurate and legally in appropriate for the purposes of the SPS Agreement for the
reasons explained in the EC's comments on the repl y to question no 12 above. Moreover, he states
that "JECFA concluded that whilst oestradiol is a hum an carcinogen, its mode of action is such that
there would be no appreciable risk of cancer at exposures up to the ADI ". JECFA's statement that
there is no appreciable risk is a subjective expression, but it does confirm that there is excess risk due
to added hormone. Again, "appreciable risk" is a qua litative and not a quantitative term, and thus fails
to provide the necessary assura nce that the EC's level of protection of no risk from residues of these
hormones in meat will be achieved.

Dr. Guttenplan
 makes a more informed assessment of the scientific situation and concludes that the
more recent evidence cited by the European Comm unities does support the finding that the genotoxic
action of these hormones is not related only to their hormonal activity. Indeed, Dr. Guttenplan
acknowledges that the evidence is now sufficient to support a role for the estrogen metabolites which
include the genotoxic, mutagenic estrogen quinones in estrogen carcinogenicity (New Eng. J. Med.,
354, 270-282, 2006).

Q17. Could you comment on Canada's statem ent that "the studies commissioned by the
European Communities also failed to find evid ence of "catechol metabolites" – that is the
oestradiol metabolites identified as the source of the genotoxic potential – in meat from treated
animals"? What would be the implication of an absence or presence of catechol metabolites?
[see para. 102 of Canada Rebuttal submission, EC Exhibit 51A]

EC Comments

The European Communities agrees with the statements by Dr. Guttenplan and Dr. Cogliano. Indeed, it
is known that, in contrast to humans, cattle do not efficiently metabolize estradiol to catechols and this
apparently explains the very low levels of catechols in meat. Furthermore, the real problem is not to
prove the presence of catechols as residues in edible tissues, but to determine the real part of estradiol,
estradiol-alpha or estrone that will be metabolised in catechols in target tissues. Due to their structure,
catechols metabolites eventually found as residues in edible tissue of treated cattle would exist more
probably as glutathione conjugates and only a small part of them as glucuronides. Nevertheless, due to
their chemical reactivity, catechols as such are not stable enough because they are already transformed
in a more stable form. Therefore, more worrying from the human health point of view is the part of
estrogens (estradiol, estradiol-alpha or estrone) wh ich will be metabolised in catechol derivatives in
target tissues. This is the reason for which it is nece ssary to perform a complete residue analysis with

more powerful detection methods. Thus, as Dr. Guttenplan
 correctly states, the lack of catechols in
meat does not imply that meat from estrogen-treated cattle is without risk for genotoxicity.

Indeed, it is important to keep in mind that in th e ACI rat, mammary tumors were not induced by the
administration of the catechol metabolites of estradiol, but only by administration of estradiol.
Furthermore, the fact that exposure to the catechol metabolites does not cause mammary
tumorigenesis does not
 necessarily negate the possibility that the catechol metabolites formed in
mammary tissue play a role in mammary tumorigenesis. This is because administered metabolites
may not reach levels in mammary tissue comparable to those achieved by metabolism of estradiol to
the catechols within the mammary tissue itself. An alysis of both human and mouse mammary tissue
has demonstrated the presence of catechol metabo lites and conjugates of estrogen quinones with
glutathione, the latter demonstrating that oxidative metabolism of estradiol to the catechols and their
further oxidative metabolism to reactive estrogen quinones occurs in normal human and mouse
mammary tissue (Carcinogenesis, 22, 1573-1576, 2001; Carcinogenesis, 24, 697-702, 2003).

As regards the statements by Dr. Boisseau
 and Dr. Boobis, they can only be explained by their lack of
specific expertise on these hormones, as they ha ve not carried any specific research on these
substances in their professional life. Their statements therefore should carry no weight. Indeed, it
should be recalled that during the 1997 panel repor t on hormones, one of the experts for the panel
(Dr. G. Lucier) had stated:

"For every million women alive in the Unite d States, Canada, Europe today, about a
110,000 of those women will get breast cancer. This is obviously a tremendous
public health issue. Of those 110,000 women get breast cancer, maybe several
thousand of them are related to the total intake of exogenous oestrogens from every
source, including eggs, meat, phyto-oestroge ns, fungal oestrogens, the whole body
burden of exogenous oestroge ns. And by my estimates one of those 110,000 would
come from eating meat containing oestrogens as a growth promoter, if used as
prescribed."
However, the Appellate Body in 1998 denied evid entiary value to Dr. Lucier's statement for the
reason that his opinion "… does not purport to be the result of scientific studies carried out by him or
under his supervision focusing specifically on residue s of hormones in meat from cattle fattened with
such hormones …". (at para. 198 of the 1998 Appellate Body report)

In this case, Dr. Boisseau has explicitly admitte d that he has never carried any experiments on
hormones and has published no scientific paper, an d the same applies for Dr. Boobis who does not
appear to have any publication on hormones either.

Q18. Please comment on the US argument that the European Communities fails to
demonstrate through scientific evidence that oestradiol-17 β is genotoxic. Would your reply
have been different at the time of adoption of the EC Directive in September 2003? If so, why?
[see paras. 118-119 of EC Rebuttal Submission (US case), paras. 123-124 of EC Rebuttal
Submission (Canada case), paras. 87-91 and 153- 156 of US First Submission, paras. 35-40 and
46 of US Rebuttal Submission, and paras. 90-97 of Canada Rebuttal Submission]

EC Comments

The European Communities agrees with the statements by Dr. Guttenplan and Dr. Cogliano . The
evidence both in vitro and in vivo was already strong at the time of adopting the EC Directive and it is
even stronger now establishing the direct genotoxic action of oestradiol-17 β. In support of
Dr. Guttenplan's statement that the evidence for the genotoxicity of estradiol is now stronger, see New
Eng. J. Med., 354, 270-282, 2006.

The question is not whether the European Communities has established that genotoxicity and cell
proliferation would be induced by levels found in meat residues added to the pre-existing levels
occurring in exposed humans, but whether the US a nd Canada have demonstrated to the requisite
standard of proof that this adverse effect would not occur. They both assume (as does JECFA) that it
will not occur, but they have failed to prove it, as has correctly been pointed out by Dr. Cogliano . As
mentioned above, in the ACI rat model, the cat echol estrogens did not cause mammary tumors;
however, estradiol did cause such tumors in a dose-dependent response. Assuming greater
bioavailability of estradiol and the fact that its oxidative metabolism to catechols and quinones occurs
in various tissues as documented by their detecti on, the conclusion stated by Dr. Guttenplan that their
absence in meat does not imply that meat from estrogen-treated cattle is without risk is correct.

The statement by Dr. Boisseau
 is beside the point, since the argument is hardly convincing that in
1999 JECFA established for the first time an ADI "i n order to present in a more convincing way the
outcome of its assessment". There is no trace of su ch an argument in the 1999 JECFA report which, it
should be recalled, had found for the first time that "oestradiol-17 β has genotoxic potential" (this
admission was not in its 1988 report). Equally, the statement by Dr. Boobis lacks conviction because
it is cast in cautious/conditional terms ("some, if not all, of the genotoxicity observed in vitro would
be expected to exhibit a threshold…"). Again, Dr. Boobis appears to disregard the fact that evidence
in vivo existed at the time that showed the direct genotoxicity of oestradiol-17 β, which is reported in
the 1999 SCVPH assessment and in the EC submissions to this Panel.

Q19. The European Communities states that "...it is generally recognized that for substances
which have genotoxic potential (as is the case with oestradiol-17 β) a threshold can not be
identified. Therefore it cannot be said that th ere exist a safe level below which intakes from
residue should be considered to be safe. Therefore the fact that doses used in growth promotion
are low is not of relevance". Does the scienti fic evidence referred to by the European
Communities support these conclusions? Would your reply have been different at the time of
adoption of the EC Directive in September 2003? If so, why? [see para. 201 of EC Rebuttal
Submission (US case), paras. 120-122 of EC Re buttal Submission (Canada case),paras. 73 and
86-98 of Canada Rebuttal Submission, paras. 87-91 and 153-156 of US First Submission and
paras. 35-40 and 46 of US Rebuttal Submission]

EC Comments

The European Communities agrees with the th rust of the statements by Dr. Cogliano and
Dr. Guttenplan. Indeed, it is true that there is no reason to expect a threshold to exist for a genotoxic
chemical. After all, whether cancer will occur as a result of genotoxicity or hormonal action is from
the regulatory point of view less critical, as the end result is the same: human cancer. As
Dr. Guttenplan
 has stated, although DNA repair can occur, it presumably is occurring at all doses and
the fraction of DNA damage repaired probably does not change at physiological levels, because the
repair enzymes are unlikely to be saturated. However, would it not also be true that if the rate of repair
were constant, an increase in the rate of formati on of DNA damage would result in an increase in the
time a mutagenic lesion remained in DNA? If this we re the case, then there would be an increased
likelihood for mutation if cell proliferation were occurring.

The arguments of Dr. Boisseau
 and Dr. Boobis that there is "no good evidence" that oestradiol is
genotoxic in vivo or that it causes cancer by a genotoxic mechanism are unfounded. There are also a
number of papers showing in vivo genotoxicity, some of which are already mentioned in the 1999
SCVPH report. Moreover, there are a number of scie ntific papers linking clearly elevated levels of
17β-oestradiol and other estrogens, at specific time points during development, to increased cancer
risk (e.g. Hilakivi-Clarke L., Cho E., Raygada M., Kenney N.: Alterations in mammary gland

development following neonatal exposure to estr adiol, transforming growth factor alpha, and
estrogen receptor antagonist ICI 182,780, in J. Cell Physiol. 1997 170:279-89). The levels of
17β-oestradiol in children are so low that Dr. Boisseau's
 statement cannot be accepted scientifically.
In the EC's view, it is beyond doubt that there is a link between 17 β-oestradiol exposure during
development (pre- and post-natal) and the risk of breast cancer later in life and this is not only due to
endogenous production.

Q20. In your view, how do the European Communities' conclusions above relate to the
conclusion by Codex that "establishing an ADI or MRL for a hormone that is produced
endogenously in variable levels in human beings was considered unnecessary"? To what extent,
in your view, has JECFA's conclusion that oestra diol "has genotoxic potential" affected its
recommendations on this hormone?

EC Comments

The European Communities notes that Dr. Boobis , after so many assumptions and hypothesis in his
reasoning of which he offers no proof, arrives at the conclusion that:

"… a modest incremental increase in oestradiol concentration from exogenous
exposure (above the ADI) might conceivably perturb endocrine effects, depending on
the physiological state. However, non-endoc rine effects, such as genotoxicity, will
depend on the circulating concentration of oestradiol and will not vary with
physiological state. Hence, the natural va riations in circulating oestradiol levels
should have a much greater effect on any genotoxic response than the much more
modest change that could arise from the hormone in meat from treated animals, at any
conceivable level arising from its use as a growth promoter …".
This reply of Dr. Boobis is based on his more erroneous underlying assumptions that oestradiol-17β is
not genotoxic, that there is a threshold for residues in meat from animals treated with this hormone for
growth promotion purposes, and that the rate of endogenous production by pre pubertal children is as
stated in the JECFA report. If these assumptions are false, as the available scientific evidence clearly
demonstrates, then Dr. Boobis' statement – which is already a qualified one - would make no sense.

In any case, for the information of Dr. Boisseau
 and Dr. Boobis , the European Communities recalls
that in the 1997 WTO hormones panel report (i.e. the first hormones panel), the US, Canada and
JECFA were arguing that oestradiol-17 β is not genotoxic, and this had influenced the findings of the
1987 panel report on these hormones. Since then, as th e European Communities has been consistently
arguing, the genotoxicity of oestradiol-17 β is no longer seriously dis puted and has now for the first
time been accepted and written in the 1999 JECFA re port re-evaluating the th ree natural hormones.
But JECFA was not at all sure whether the genotoxicity of oestradiol-17 β is due to its receptor-
mediated action or by other direct mechanisms, beca use it uses in its 1999 report the soft terms "the
carcinogenicity of oestradiol-17β is most probably a result of its interaction with hormonal receptors"
(emphasis added). This contrasts sharply with the more affirmative and assertive statements to the
contrary by both Dr. Boisseau and Dr. Boobis, who, by the way, have not done any direct experiments
on these hormones in their professional life and so lack specific expertise.

More importantly, as the Appellate Body has held in the 1998 Hormones report:

"… in most cases, responsible and repr esentative governments tend to base their
legislative and administrative measures on "mainstream" scientific opinion. In other
cases, equally responsible and representa tive governments may act in good faith on
the basis of what, at a given time, may be a divergent opinion coming from qualified

and respected sources. By itself, this does not necessarily signal the absence of a
reasonable relationship between the SPS measure and the risk assessment, especially
where the risk involved is life-threatening in character and is perceived to constitute a
clear and imminent threat to public health and safety…".
Indeed, in this case Dr. Boobis
 is basing his arguments on so many assumptions and hypothesis in
order to arrive at the conclusion that oestradiol-17 β is genotoxic only through its hormonal activity;
but can Dr. Boobis provide the necessary assurance to the responsible risk management authorities of
the EC that the residues of these hormones in meat from animals treated for growth promotion will
not increase the risk of cancer? Furthermore, can Dr. Boobis clarify whether he believes that the
evidence on which the EC based its risk assessment on genotoxicity of oestradiol does not come from
"qualified and respected sources"?

It is also noteworthy that Dr. Boobis
 does not comment on other releva nt evidence, for instance the
fact that the US authorities also concluded for th e first time in 2002 that "steroidal estrogens are
known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, which
indicates a causal relationship between exposure to steroidal estrogens and human cancer." For this
reason, the US 2002 Report on Carcinogens (RoC) lists steroidal estrogens as known to be human
carcinogens with the clarification that this listi ng now "supersedes the previous listing of specific
estrogens in and applies to all chemicals of this steroid class." Moreover, in the same 2002 US Report
it is stated that: "Veterinary use of steroidal est rogens (to promote growth and treat illnesses) can
increase estrogens in tissues of food producing animals to above their normal levels."8

Dr. Boisseau and Dr. Boobis
 consider the assessments of JECFA as the Bible, although they know
that the 1988 and the 1999 JECFA assessments are outdated by today's evidence and scientific
standards. The European Communities has asked JE CFA back in 1998 to withhold for a couple of
years its assessment in order to take into account the new evidence which was then going to become
available soon as a result of the studies that ha ve been commissioned by the European Communities
following the 1998 Appellate Body report in hormon es. But JECFA for unknown reasons decided not
to wait, despite the lack of any kind of urgency to review the three natural hormones in 1999. The
European Communities hopes that JECFA will carry soon another assessment of these hormones on
the basis of the most recent evidence available.

The European Communities agrees with the st atements of Dr. Cogliano and Dr. Guttenplan
. Indeed,
the European Communities is arguing that a thr eshold cannot be established for the incremental
human exposures that would be found in meat resi dues because there can be no assurance – and the
US, Canada and JECFA did not provide one - that these additional exposures may not increase cancer
risk, especially for the mo st sensitive parts of the population (prepubertal children), taking also into
account the other identified areas of concern, such as developmental effects.

Q21. Does the scientific evidence referred to by the European Communities demonstrate that
the five hormones other than oestradiol-17β, when consumed as residues in meat have genotoxic
potential? Does your answer depend on whether good veterinary practices are followed? Would
your reply have been different at the time of adoption of the Directive in September 2003? If so,
why? [see, inter alia , the SCVPH Opinions and paras. 63, 83, 89-91 and 93 of US First
Submission, paras. 131-136 of Canada Rebuttal Submission]

EC Comments

8 Available at http://ntp.niehs.nih.gov/index.cfm?objectid=72016262-BDB7-CEBA-
FA60E922B18C2540.

The European Communities is puzzled by the dismissive statements by Dr. Boisseau and Dr. Boobis

It is noteworthy that the 1999 JECFA report, on which they so much rely, states that "… equivocal
results have been reported for the induction of single-strand DNA breaks and DNA adducts have been
seen in vivo and in vitro in some studies… " (see WHO, technical series report no 893, at page 61).
Because it is said that progesterone is not f ound to be mutagenic, JECFA concluded that " on balance,
progesterone has no genotoxic potential " (emphasis added). It is recalled that no such statement was
available in the 1988 JECFA evaluation report on this hormone. So, unlike Dr. Boisseau and
Dr. Boobis, JECFA was more prudent when rejecting th e genotoxicity of progesterone in 1999. Since
then, more evidence has become available, as e xplained in the submissions of the European
Communities, which increases the likelihood of possible genotoxic effects of progesterone and the
other hormones. The 1999, 2000 and 2002 risk assessment by the SCVPH provide enough evidence to
demonstrate that genotoxicity and other adverse effects from these hormones are possible and that
there are a number of uncertainties surrounding their mechanism of action to warrant further
investigation. As Dr. Guttenplan
 states, their genotoxic potential may be weak but cannot be
excluded. In particular, the evidence available to the US, Canada and JECFA on the basis of which
these hormones were authorised for animal growth promotion purposes, which dates in most of these
hormones since the 1970s, is today not complete nor adequate to respond, with the required degree of
certainty, to the gaps in our scientific knowledge which have been clearly identified in the 1999 and
2002 evaluations by the SCVPH. It should also be recalled that the European Communities did not
permanently prohibit these hormones as proven carcinogens, as it did with regard to oestradiol 17 β,
but on a provisional basis taking into account th e numerous and serious gaps in our scientific
knowledge which have been clearl y identified in the SCVPH assessments. The relevant question
therefore is whether these two scientists, who – it should be recalled have no specific expertise on
hormones - contest that there exists at least some uncertainty regarding the genotoxicity and other
possible risks from the residues of these hormones in meat that have been identified by the SCVPH?

As regards the respect or not of good veterinary prac tice, the increased presence of these hormones in
meat from cattle presumably treated with prepara tions containing these hormones has the potential to
affect the hormone levels, in partic ular in infants and prepubertal ch ildren, whose levels of serum are
much lower than those used by JECFA, as the more sensitive RCBA assays now demonstrate.

Q22. How would you define in vivo DNA repair mechanisms? How effective or relevant are
in vivo DNA repair mechanisms with respect to potential genotoxic effects from residues of the
growth promoting hormones at issue when cons umed in meat? Does your answer depend on
whether good veterinary practices are followed in the administration of these hormones? To
what extent does the scientific material referred to by the European Communities take into
account these mechanisms in its evaluation of potential occurrence of adverse effects from
residues of growth promoting hormones? Would you r reply have been different at the time of
adoption of the Directive in September 2003 and if so, why? [see para. 40 and 46 of US Rebuttal
Submission, footnote 107 of US First Submission, and para. 89 of Canada Rebuttal
Submission].

EC Comments

Dr. Boobis's reply summarises more or less accurately th e difficulties authorities face with genotoxic
substances by stating that: "…A major difficulty in the risk assessment of such compounds however,
is the identification of the threshold for such effects. This is because they occur with low incidence,
and experimental studies do not have the statistical power to determine the location of the threshold
with any confidence. Thus, whilst recognizing the likelihood for a threshold for even genotoxic
effects the risk assessor is faced w ith the impossibility of locating it. The conservative solution is to
assume that the response is linear and that there is no dose below which exposure is safe." (references
omitted) Dr. Boobis then goes on to deny direct genotoxic potential to residues in meat from these
hormones. However, if his underlying assumptions concerning lack of direct genotoxicity are false,

i.e. that oestradiol-17 β is genotoxic and that there is no threshold for residues in meat from animals
treated with this hormone for growth promotion purposes and that the rate of endogenous production
by prepubertal children are much lower than tho se stated in the JECFA report, then Dr. Boobis should
accept that DNA repair mechanisms are not sufficient to eliminate DNA damage.

Moreover, Dr. Boobis and Dr. Guttenplan
 appear to miss another important point. If the rate of repair
were constant, an increase in the rate of formati on of DNA damage would result in an increase in the
time a mutagenic lesion remained in DNA. If this is the case, then there would be an increased
likelihood for mutation if cell proliferation were occurring. Dr. Guttenplan states that "…most DNA
damage by any agent is repaired and there is considerable redundancy in DNA repair, insuring that
repair is effective. However, a small fraction of damage inevitably escapes repair …". The implication
of this should be that the unrepaired fraction w ould be increased with an increase in the rate of
damage formation resulting from increased exposure to estradiol and the resulting estrogen genotoxic
metabolites. In other words, a higher rate of dama ge may be accompanied by an increased fraction of
unrepaired potentially mutagenic lesions.

The European Communities notes also the in teresting statements by Dr. Guttenplan
 that "… there is
no reason to assume that DNA repair processes involved in DNA damage produced by estrogen
metabolites are any more or less effective than t hose involved in repair of other carcinogens …", and
that "… since it is not likely to be different for est rogen derived damage than other types of damage it
is not really relevant [if this is not examined in detail by the SCVPH]. There is some evidence referred
to in the SCVPH Opinions that error-prone DNA repair of certain estrogen derived damage can
occur."

Q23. To what extent is it nece ssary or possible to take into account the "long latency period"
of cancer in the conduct of a risk assessment, wh ich is supposed to assess carcinogenic effects of
these hormones when consumed in meat? Have the hormones in dispute been used as growth
promoters over a sufficient number of years for an assessment of their long-term effects on
human health to be made? [see para. 149 of EC Rebuttal Submission (US Case), para. 143 of EC
Rebuttal Submission (Canada case)].

EC Comments

The European Communities notes the different and par tly contradictory replies of the experts. It
agrees, however, with Dr. Cogliano and Dr. Guttenplan that a sufficiently long latency period (at least
20 years) is extremely important. However, it is also true that such epidemiological studies will not be
able to discriminate (or separate out) the true origin of cancer because of so many co-founding factors.
This is admitted by both Dr. Boisseau and Dr. Boobis , thus undermining the position of the US and
Canada that these hormones have been in use for a long time to be able to rule out their carcinogenic
effects on humans. And Dr. Boobis concludes by stating that "…Hence, a negative result from such
an observational study would not resolve the i ssue." However, the European Communities would
recall the evidence cited in the 1999 SCVPH repor t – coming from the studies published by the IARC
– showing that the frequency of breast cancer in countries where hormones are allowed is higher
compared with countries where the hormones have not b een used. Thus, this is just an indication that
there might be a link between consumption of red meat and breast cancer.

Q24. To what extent is it possible to identi fy possible confounding fa ctors causing cancer and
attribute them to identified sources? What a re the implications of these factors for the conduct
of a risk assessment evaluating the adverse affects caused by residues of growth promoting
hormones in meat? Would your reply have been different at the time of adoption of the EC
Directive in September 2003? If so, why?

EC Comments

The European Communities notes that the replies of all the scientists substantially agree with the EC
position and the reasons for which it was not possible to carry out such an epidemiological study after
the 1998 Appellate Body report in the hormones case. Moreover, their replies also undermine
indirectly the position of the US and Canada that th ese hormones have been in use for a long time to
be able to identify and, hence, rule out their carcinogenic effects on humans. However, the European
Communities would recall the evidence cited in the 1999 SCVPH report – coming from the studies
published by the IARC – showing that the frequency of breast cancer in countries where hormones are
allowed is higher compared with countries where the hormones have not been used. This is of course
no conclusive proof, but just an indication suffici ent to raise concerns about the gaps of our
knowledge in this area.

Q25. To what extent do the three recent st udies referred to by the European Communities
confirm a risk to human health from the consum ption of meat from cattle treated with growth
promoting hormones? Please also comment on the EC statement that one of the studies "was
carried out after the introduction of the ban on the use of hormones for growth promotion in
Europe, which means that the subjects should have been exposed to hormone-free meat in their
diet. This may further imply that it cannot be excluded that the risk of cancer may be further
increased if meat treated with hormones for animal growth promotion were to be consumed".
[see paras. 145-148 of EC Rebuttal Submission (US case) and paras. 139-142 of EC Rebuttal
Submission (Canada case), footnote 97 in para. 147 of EC Rebuttal Submission (US case), and
Exhibits EC-71,72,73]

EC Comments

The European Communities notes the different and partly contradictory views expressed by the
experts. Dr. Boobis
 dismisses the relevance of the studies cited by the Europ ean Communities for
reasons that have to do essentially with what he ca lls the "weight of the evidence" approach. But as
the European Communities explained before, this a pproach is not appropriate nor is it required under
the SPS Agreement. It appears that Dr. Boobis' strongly held views - which it is worth recalling do not
come from specific research he has conducted himself on these hormones - would only change if the
evidence produced by the European Communities "confirms a risk to human health". Dr. Boobis is
apparently not restrained in displaying such stro ngly held views, despite the fact that JECFA's
evaluation is based on data from the 1970s – 1980s, when the experiments con ducted by the industry
then seeking regulatory approval in the US did not comply either with the kind of criticism now
levelled by Dr. Boobis against the more recent ev idence produced by the Eu ropean Communities. In
other words, Dr. Boobis is now demanding evidence of positive proof of harm, which the applicant
pharmaceutical industry did not disprove (i.e. the lack of possible harm) with the data it submitted for
regulatory approval in the 1970s and 1980s in the US.

Dr. Boobis
 apparently feels no restrain as an expert to state that: " as long as exposure does not
consistently exceed the ADI, there should be no appreciable risk to human health ." But this is both
speculative and unspecific. What is an appreciable risk? How do we interpret the qualitative term
"no appreciable risk"? Is it 1% or 10% or some other value? And why would a scientific expert, who
is supposed to do only a risk assessment, decide what is "appreciable" risk, a task reserved normally
for the risk manager? Is it not normally the task of a scientific expert in a risk assessment exercise to
explain the scientific evidence and see if there is scientific uncertainty? How confident can Dr. Boobis
be when stating that: "However, as indicated else where in my responses, the evidence is against an
increased risk from such exposures". Would Dr. Boobis accept that there is some uncertainty
surrounding his statements rejecting an increased ri sk of cancer from the re sidues of these hormones
in meat? And would Dr. Boobis contest that the evidence with which he does not agree comes from
reliable and credible sources?

Another example of the "absolutist" appro ach by Dr. Boobis is his comment on the EC
epidemiological study making a correlation between meat consumption and colorectal cancer,
showing an increased frequency in the US and Aust ralia compared to Europe. But he dismisses these
results because he relates the lower risk observe d in Europe by linking it with a lower meat
consumption in Europe. However, the numbers show ing a lower frequency of colorectal cancer is
only from Northern Europe, whereas the data for meat consumption is for all European countries
combined. If so, would Dr. Boobis
 accept that this data might indicat e that some uncertainty exists
concerning the alleged by the US and Canada safety of hormone residues in meat treated for animal
growth promotion?

The European Communities agrees wi th the comments of Dr. Cogliano , who rightly summarises the
issues at stake. The European Communities also agrees with the careful and scientifically sound
statement by Dr. Guttenplan concerning the study by Liu S and Lin YC (2004) , in that their "...
observation was not previously reported …" and that "… the study does suggest that additional tests
of zeranol should be carried out." Consequently, the relevant legal question is who is to conduct these
additional experiments and what should the regulator y regime be until their results become available?
One of provisionally prohibiting or one of allowing the use of these hormones for growth promotion
purposes?

Q26. Does the scientific evidence referred to by the European Communities, in particular any
epidemiological studies, identify a relationship between cancer and residues of hormonal growth
promoters? In its risk assessment of 1999, th e European Communities makes reference to the
higher rates of breast and prostate cancer observ ed in the United States as compared to the
European Communities. Can a link be established between these statistics and the consumption
of meat from animals treated with the horm ones at issue? Would your reply have been
different at the time of adoption of the EC Directive in September 2003? If so, why? [see
pages 17-19 of 1999 Opinion of the SCVPH and related Tables A4-A5 on pages 83-91]

EC Comments

The European Communities notes the different views expressed by the experts. What is important,
however, is that there appears to be some con sensus for the proposition – nicely summarised by
Dr. Cogliano – that: "… it is possible that differences in ex posure to exogenous hormones can be one
cause, but the data are not sufficiently spec ific to establish a link between these observations ."
Indeed, Dr. Boobis also states that: " There is no scientific evidence demonstrating any association
between consumption of meat from animals treate d with growth promoting hormones and the risk of
cancer in humans. There are some studies that are consistent with such an association , but there are
several other possible explanations for the findings, some of which are more plausible than hormones
in meat as being causal.." (emphasis added). And Dr. Guttenplan states that: "… However, the results
are at least consistent with a possible effect of hormones on breast and prostate cancer ...".

As already explained above, their replies undermine indirectly the position of the US and Canada that
these hormones have been in use for a long time to be able to identify and, hence, rule out their
carcinogenic effects on humans. It should also be pointed out that the European Communities cited
this epidemiological evidence in the 1999 SCVPH not as an affirmative or adequate proof but just as
an indication and possible explanation. In this sen se, the three experts appear to agree, although at
varying degrees. Furthermore, the pl ausibility of the EC argument is s lightly reinforced by the fact
that the differences in the cancer rates observed in the European Communities and US go in the
expected direction in case of an effect, with highe r rates in places where hormone-treated meat is
consumed; and, similarly, the study of time trends is in agreement with the use patterns of these
products in animal production. Again, the Eu ropean Communities advanced this argument to
demonstrate that the scientific uncertainty
 is growing concerning the harmless nature of the residues

of these hormones in meat and to counter the argu ments of the US and Canada that there is no
uncertainty surrounding the safety of residues of these hormones.

(b) Residue analysis
Q27. How do the residues in meat from cattl e treated with the three synthetic growth
promoting hormones differ from residues in meat from cattle treated with the three natural
growth promoting hormones at issue?

EC Comments

The European Communities wishes to stress that the difference in the residues is not only
structural/chemical but also qualitative and quantita tive. For instance, one of the studies by the EC
(Stephany 2001, APMIS 109, 357-364) (see exhibits EC-49 and EC-19) gives some data on residues
in meat samples from the US market. In the so called "HQ clean HFC US beef" study (i.e. hormone-
free meat), an average 0.004 ppb of estradiol was found, whereas in the so called "M/LQ domestic US
beef" study (i.e. hormone-treated beef) an averag e of 0.030 ppb estradiol was present. So this study
indicates that the consumption of meat from the regular US market contains 7.5 times more estrogens
than in meat from untreated cattle. This is important and completely different information from that
provided in the data from the controlled studies wh ich were conducted in th e 1960s, 1970s and 1980s
by the pharmaceutical industry for the purpose of se eking authorisation of these hormones in the US
and Canada (and on which JECFA based its evaluations in 1988 and in 1999).

Q28. How do the hormones naturally present in animals, meat, or human beings differ from
the residues in meat of the three natural hormones used for growth promotion purposes?

EC Comments

The European Communities would note that the statement by Dr. Boisseau is partially incomplete and
partially false. First, no estradiol-alpha is produced endogenously by humans, whereas this is the main
residue in the target tissue (liver) in cattle treated with oestradiol 17 β. This metabolite, when ingested
by humans, is highly susceptible to give catechols in target organs (colon, liver) which may react with
nucleophilic compounds and induce some disruptions. Moreover, the hormonal effect of estradiol-
esters which are found as residues in treated cattle are not examined in the old data submitted by the
pharmaceutical industry for the approval of this hormone , despite the fact that we know that they are
orally active and probably partially absorbed in the intestine lymph circulation.

The European Communities considers the statement by Dr. De Brabander
 very informative, in
particular the statements the three natural hormones used for growth promotion purposes are
synthetised (prepared) from plant materi al and that in plant material the 13C/12C ratio is different from
the 13C/12C ratio of animals. Equally, the finding th at the residues of the endogenously produced
natural hormones in cattle are in the 17 α form (inactive) while the use of the natural hormones for
growth promotion purposes may lead to residues in the ß form (active form). The first of these
remarks may provide a better understanding to the simplistic argument made by the US and Canada
that humans are exposed to much higher burdens of residues from these hormones when eating natural
products (e.g. broccoli) and they should not worry about the little increment they receive from eating
meat treated with these hormones for animal growth promotion purposes.

Q29. To what extent do the SCVPH Opinions eval uate evidence on the actual residue levels of
the synthetic hormones found in meat in their as sessment of the risks from such residues? Are
specific references provided as to how the evidence on residues relates to the observance of good
veterinary practices or lack thereof? How do they compare with the MRLs set by Codex? [see
paras. 165-176 of EC Rebuttal Submission (US ca se); pages 55-68 of the Opinion of the SCVPH

of 30 April 1999 in US Exhibit 4, para. 144 of US First Submission, Exhibits US-6 and 7,
footnote 46 of US Rebuttal Submission]

EC Comments

The European Communities considers that the statement of Dr. Boisseau
 is incorrect because the 1999
opinion of the SCVPH was structured in two levels: one making the analysis stated by Dr. Boisseau ,
but also a second one where an exposure assessme nt was nevertheless made to residues of the
synthetic hormones (trenbolone, zeranol and MGA) in m eat, in particular to underscore the point that
the ADIs fixed by JECFA are most likely to be exceeded as regards sp ecifically prepubertal children,
taking into account their low levels of endogenous production. Specific reference can be made to
paras. 165-176 of the EC's rebuttal submission and to the clearly marked sections of the 1999 SCVPH
opinion. The European Communities not only considered the ADIs and MRLs set by JECFA but went
even further and examined the tolerance levels recommended by the USA. Moreover, it is obvious,
even from a cursory look at the 1999 and 2002 SCVPH opinions, as well as from the Exhibits EC-65,
67, 68, 69, 70 and 73, that the European Communities did examine the consequences from observance
or lack thereof of GVP.

The statement by Dr. De Brabander
 confirms the EC argument that the data used by JECFA are not
only too old but have also been obtained with methods that are no longer reliable today. This may also
explain why the parties and JECFA have so strongly refused to provide those data to the European
Communities and the Panel.

Q30. To what extent do the SCVPH Opinions eval uate evidence on the actual residue levels of
the three natural hormones in meat in their asse ssment of the risks from such residues? Is it
possible to compare these to the ADIs recommended by JECFA in 1999? Are specific
references provided as to how the evidence on residues relates to the observance of good
veterinary practices or lack thereof? [see paras. 120-123 and 155-164 of EC Rebuttal
Submission (US case), pages 33-54 of 1999 Opinion in Exhibit US-4, para. 144 of US First
Submission, and 52
nd JECFA Report in Exhibit US-5]

EC Comments

For the reasons already explained above rega rding the synthetic hormones, the European
Communities considers that the statement of Dr. Boisseau is also incorrect as regards the three natural
hormones. Specific reference can be made to para s. 155-164 of the EC's rebuttal submission and to
the clearly marked sections of the 1999 SCVP H opinion. The European Communities not only
considered the ADIs and MRLs set by JECFA but went even further and examined the acceptable
levels and tolerances recommended by the USA. Moreover, it is obvious, even from a cursory look at
the 1999 and 2002 SCVPH opinions, as well as from the exhibits EC-65, 67, 68, 69, 70 and 73, that
the European Communities did examine the consequences from observance or lack thereof of GVP.

The European Communities considers that the statement by Dr. Boobis
 is clearly wrong. In section
4.1.5 of the 1999 opinion, the SCVPH made a detailed exposure assessment both for the ADI
established by JECFA and the acceptable levels and tolerance recommended by the US authorities. It
is recalled that JECFA did not recommend MRLs for the different types of tissue, while the US has
identified acceptable levels. Therefore, for comparat ive purposes and in order to be exhaustive, the
SCVPH had to apply conversion rates. The resu lt was that the ADI recommended by JECFA (0-50
ng/kg bw/day) is lower than that recommended by the US (102 ng/kg), as calculated by the SCVPH
on the basis of the acceptable levels for individua l tissues. However, both the JECFA and the US
values are based on endogenous production by prepub ertal children that the SCVPH found to be too
high.

As the SCVPH found that the US acceptable leve ls and recommended tolera nce will be exceeded by
about 1,700 fold times, it was obvious that the JECFA ADI, which is lower than the recommended US
tolerance, will also be necessarily exceeded . The SCVPH exposure assessment is made for
prepubertal children, as the most sensitive part of the population. Moreover, the data used in
section 4.1.5 of the 1999 SCVPH report are based on residue values that are assumed to result from
administration of these hormones that respects use as authorised in the US ("GVP"). Indeed, Table A3
attached as Annex to the 1999 opinion uses the TM DI from the 1999 JECFA report. There is another
section in the 1999 SCVPH opinion (section 3.3), which discussed the higher residue values that will
result inevitably from misuse and abuse. It should also be added, that the same methodology and
reasoning was applied for the other 2 natural hormones.

While it is admitted that an exposure assessment on natural hormones is a difficult task that has to
cope with many uncertainties and may therefore not be as straightforward as desired, Dr. Boobis
opinion that the European Communities did not car ry out an appropriate exposure assessment is
clearly not justified.

Q31. Please comment on the US statement that "concentrations of oestradiol-17 β in meat
from treated cattle do not vary significantly from concentrations in untreated cattle, i.e., residue
levels in meat from hormone-treated cattle a re well within the physiological range of residue
levels in untreated cattle. While tissue concentrations of oestradiol-17 β in treated cattle may be
slightly higher than those in untreated cattle, this increase is much smaller than the large
variations observed in (reproductively) cycling a nd pregnant cattle and is thus well within the
range of naturally observed levels." In you r reply please take into account the US 11 th
Carcinogenesis Report where it is stated th at "Meat and milk may contain estrogens.
Veterinary use of steroidal estrogens (to promote growth and treat illness) can increase
estrogens in tissues of food-producing animals to above their normal levels" and the statement
by the European Communities that "meat consumpt ion from pregnant heifers is exceptional as
usually these animals are not slaughtered. [see paras. 51 and 144 of US First Submission and
Exhibits US-6 and 7, para. 98 of EC Replies to Panel Questions, Exhibit EC-101, and
paras. 2.3.2.3 of the 1999 Report of SCVPH]

EC Comments

The European Communities c onsiders that Dr. Boisseau's reply accepts the US statement without
much questioning. However, in the US statement there exist phrases which are imprecise and possibly
misleading, such a "… do not vary significantly …", "… well within the physiological range …", "…
may be slightly higher …". Neither the US nor Dr. Boisseau
 explain what is significant or what is the
physiological range, as we know that the values for these concepts can vary substantially. For
example, as explained by Dr. De Brabander in his reply to question no 27, one of the studies
conducted by the European Communities indicates th at the consumption of meat from the regular
hormone treated meat market in the US contains 7.5 times more estrogens than in meat from untreated
cattle. Moreover, Dr. Boisseau did not comment on the part of the question relating to the US 11 th
Carcinogenesis Report where it is stated that "Meat and milk may contain estrogens. Veterinary use of
steroidal estrogens (to promote growth and treat illness) can increase estrogens in tissues of food-
producing animals to above their norma l levels." Indeed, in this 11 th US report the terms "can
increase estrogens in tissues of food producing anim als to above their normal levels" do not explain
by how much above their normal levels – supposing one could define such normal levels – could such
an increase be. These issues are not unimportant , as the earlier comments of the European
Communities on the absence of a threshold have de monstrated. Given the much lower levels of
endogenous production of these hormones by pre pubertal children, the European Communities
considers that the reply by Dr. De Brabander rightly points out the increased risk which repetitive
exposure to such higher residues can present to the most sensitive parts of the population.

Q32. Please comment on the conclusions of the EC risk assessment (Opinion of the SCVPH of
April 2002) that ultra sensitive methods to detect residues of hormones in animal tissues have
become available but need further validation. What is the significance of this with regard to
identifying whether the natural hormones in meat are endogenously produced or are residues of
hormones used for growth promotion purposes?

EC Comments

The reply by Dr. Boisseau is scientifically unsound. As is very well explained by Dr. De Brabander's
statement, there is an urgent need to apply the la test analytical methods to determine the nature and
level of the residues from these hormones and all their metabolites, in view of the widespread use of
meat and meat products. Moreover, precisely b ecause of the endogenous production of the three
natural hormones, it is imperative that the analytical method used should be able to determine
accurately the true origin of residues in meat and their magnitude (i .e. endogenous or exogenous
source).

Q33. What were the reasons for the re-evaluati on by JECFA of the three natural hormones in
1999? Were the residues data used for the three natural hormones in 1999 the same as those
used in 1988? What additional information was used for the JECFA evaluation in 1999 of the
three natural hormones which was not available in 1988? How did the conclusions differ? What
led JECFA to establish ADIs for the three natura l hormones? What are the implications of
establishing ADIs? Why were JECFA's more re cent recommendations not considered by the
Codex Committee on Residues of Veterinary Drug s in Food? What is the status of these
recommendations? [see paras. 96-97 of EC Rebu ttal Submission (US case), paras. 79-80 of EC
Rebuttal Submission (Canada case)]

EC Comments

The European Communities notes the conflictin g replies of Dr. Boisseau and Dr. Boobis on the
reasons for which JECFA decided to evaluate the three natural hormones in 1999 and on the
significance of the establishment of ADIs for the first time.

The European Communities notes al so the reply of Dr. Boisseau
 that the data on residues used in
1999 where the same as those used in 1988, in other words dated from the 1970s. As Dr. De
Brabander correctly explains, these data should no longer be considered to be credible and reliable. It
is therefore imperative that JECFA discloses to this Panel and the public the residues data it used in
1999 in order to verify in an open and objective ma nner the credibility and validity of its conclusion
on the existence of a threshold, the lack of genotoxicity, etc.

Dr. Boobis
 admits that the 1988 evaluation was made by JECFA even without toxicological
monographs, which means, inter alia, that for the two synthetic hormones – trenbolone acetate and
zeranol – which have not been evaluated since 1988, JECFA's conclusions are no longer reliable.
Moreover, Dr. Boobis accepts that: "…in the intervening time from the first to the second evaluation,
it became clear that exposure to the natural hormones, albeit at levels appreciable higher that found in
meat from treated cattle, could have adverse effects in humans. Hence, the implicit conclusion was
that it was necessary to establish ADIs, to serve as he alth based guidance values. These could then be
used as a benchmark for comparison with exposure via th e diet." It is therefore remarkable that in the
end JECFA did not recommend MRLs.

Q34. Please comment on the EC argument that the 1999 JECFA report based its findings on
(a) outdated residues data and (b) not on evidence from residues in meat but on studies with
experimental animals and on general studies of IARC. If the data were not new, did JECFA
take this into account in its evaluation? What are the implications of using such data for the

purpose of conducting a risk asses sment? How reliable are extrapol ations from animal studies
to possible adverse effects on humans? How do es this compare with the kind of data and
studies used with respect to other veterinary dr ugs? [see para. 120 of EC Rebuttal Submission
(US case), para. 102 of EC Rebuttal (Canada case)]

EC Comments

The European Communities notes that both Dr. Boisseau and Dr. De Brabander agree in that the data
used by JECFA in 1999 are old (since well before 1987). Dr. Boisseau usefully clarifies that some of
them have even not been published in peer-review ed scientific journals, as has been consistently
arguing the European Communities in these pro ceedings. However, the argument advanced by
Dr. Boisseau to minimise the importance of their old nature is not scientifically sound. For example,
Dr. Boisseau does not explain how would it be possible to integrate in the risk assessment procedure
conducted by JECFA in 1999 the residues of estradiol-esters and estradiol-alpha given that their
specific hormonal or metabolic characteristics were not examined at all in the 1988 data? Moreover,
concerning estradiol-alpha, which is the main metabo lite found in target tissue (liver) of treated cattle
and which we know that it will be metabolised in catechol derivatives, no specific evaluation of this
genotoxic mechanism of action has been performed by JECFA. Against this background, is it possible
for Dr. Boisseau that the quality of the data used by JECFA in 1999 was scientifically credible?

As has been explained above, on the critical questions of genotoxicity and the existence of a
threshold, the level of endogenous production of th e natural hormones by pre-pubertal children, etc.,
JECFA's evaluation hinged on a number of instances "on the balance" of the evidence (e.g. on the
genotoxicity of oestradiol, progesterone, zeranol, etc.). Can Dr. Boisseau
 provide an assurance to the
European Communities that JECFA's conclusions woul d have not been different if more recent and
accurate data were available to it?

Q35. Please comment on the European Communiti es claim that nearly all the studies referred
to in the 2000 JECFA report on MGA date from the 1960s and 70s. Is this correct? Have
subsequent reports of JECFA, prior or subsequent to the adoption of the EC Directive, also
relied on the same studies? [see para. 171 of EC Rebuttal Submission (US case), para. 161 of EC
Rebuttal Submission (Canada case), para. 55, including footnote 60 of US First Submission and
Exhibits CDA-20, 33, 34, and 35]

EC Comments

The European Communities notes that both Dr. Boisseau and Dr. De Brabander agree in that the data
used in 2000 by JECFA for MGA date from the 1960s and 1970s. The explanation offered by
Dr. Boisseau is not valid for basic the same reasons as those stated in its comment to the previous
question. For instance, the "low-dose" issue was not recognised in peer-reviewed literature before the
mid 90s. Thus, all the research into possible low- dose effects has not been considered in the 2000
JECFA report. In the light of the new evidence pr ovided by the European Communities in its risk
assessment of 1999, 2000 and 2002, showing so ma ny gaps and uncertainties in our knowledge on
MGA, can Dr. Boisseau assure the Panel that all the relevant and necessary scientific aspects about
the safety of MGA have been completely and properly analysed and assessed or is it rather fair to say
that there is a need for further research because of scientific uncertainties?

(c) Dose-response relationship
Q36. How would you describe a dose-response assess ment? Is it, as suggested by Canada in
para. 78 of its Rebuttal Submission, "widely, if not universally, accepted that adverse effects
arising from hormonal activities are dose-dependent"? Is dose-response assessment a necessary
component of hazard characterization? Or, is there an alternative approach which can replace

the dose-response assessment. Is a dose-response assessment feasible/necessary for substances
that are found to be genotoxic or to have genoto xic potential? [see para. 153 of EC Replies to
Panel Questions, para. 200 of EC Rebuttal Submission (US case); paras. 143, 154, and 156 of US
First Submission, paras. 70-74 of US Replies to Panel Questions, and paras. 34 and 37-40 of US
Rebuttal Submission; paras. 76-82 of Canada Rebuttal Submission]

EC Comments

The European Communities agrees with Dr. Cogliano's statement that "dose-response assessment is
not a necessary component of hazard characterization. " This is also consistent with the Appellate
Body's 1998 decision in the Hormones case that a qualitative assessment of the risk is acceptable
under the SPS Agreement. The European Communities also notes that Dr. Boobis accepts that "in
Europe and generally within JECFA, once a co mpound is identified as an in vivo DNA-reactive
mutagen, or as causing a carcinogenic response via a genotoxic mode of action, no exposure is
considered without risk…". The European Comm unities also notes that the approach for such
compounds that are known or assumed to exhibit no threshold in their dose-response curve, varies
from one region to another, and this possibly explains the sharp difference between the parties to this
dispute. What is also important to note is that there exist no internationally agreed guidelines on this
issue, in the sense of Article 5.1 of the SPS Agreement. In the light of Dr. Boobis
 reply, the fact that
the US and Canada have been arguing, on the basis of experience derived from their domestic
practice, that the European Communities did not pe rform a dose-response assessment in this case is
not really relevant.

Q37. Do JECFA or Codex materials confirm Cana da's statement in para. 80 of its Rebuttal
Submission that "... while international risk a ssessment techniques suggest that a dose-response
assessment is optional for biological or physica l agents when the data cannot be obtained, a
dose-response assessment should always be conducted for chemical agents ..."? [see
Exhibit CDA-25]

EC Comments

The European Communities notes that Canada's ar gument that "…a dose-response assessment should
always be conducted for chemical agents…" is no t a scientifically sound nor a legally binding
proposition. Both Dr. Boisseau and Dr. Boobis appear to agree with the EC argument contesting
Canada's proposition. Furthermore, Dr. Boobis states that JECFA may consider a dose-response
unnecessary for genotoxic substances, although this – in his view- "is a very unlikely occurrence for a
veterinary drug because, in general, producers tend to screen out genotoxic compounds during the
development process." However, Dr. Boobis does not probably take into account the fact that the
hormones at issue have been approved in the US and Canada in the 1970s and since then the
pharmaceutical industry did not carry out any kind of screening and did not generate new set of
genotoxicity data.

(d) Sensitive populations
Q38. Please describe the range of physiological (or background) levels of the sex hormones in
humans and identify the variations in these le vels on the basis of age, sex group, and
physiological stages.

EC Comments

The European Communities notes that Dr. Boisseau does not appear to contest the values stated in the
SCVPH but rather whether the assays have been properly validated. However, it is not very
uncommon in JECFA to use data from assays whic h are not yet properly validated. The European

Communities believes that the values from JECFA for serum 17 β-oestradiol levels in prepubertal
children are not correct. JECFA originally used th e limit-of-detection as the "real" level when they
could not measure the levels (or find it in the old literature as explained earlier). JECFA apparently
questions the very low values determined by Klein et al., 1994, and Dr. Boobis
 suggest using "newer
data from Klein (Klein et al., 1998)". However, Kl ein et al., 1998 only reports values for girls with
precocious puberty, while they in the paper still refers to the original data (Klein et al., 1994) for the
levels in normal prepubertal girls.

Dr. Boobis
 also writes that the values from another ultr a sensitive bioassay (Paris et al., 2002) suggest
that the levels are significantly higher, however, that assay measures estradiol equivalents (includes
other natural estrogens and anything that may interact with the estrogen receptor). Nevertheless, even
if the values from Paris et al., 2002 are used, they ar e still less than 1/3 the values shown in the table.
Dr. Boisseau and Dr. Boobis ask if the bioassays have been properly validated. However, JECFA used
the limit-of-detection when it could not measure the real values, which is clearly not acceptable! The
real values for serum 17 β-oestradiol in prepubertal children s till remain to be properly documented.
Since it is not possible to make the calculation on daily production rates without knowing the serum
levels and the metabolic clearance rate in the mo st sensitive segment (children), and JECFA considers
such data essential for determining an ADI, it must be accepted that JECFA cannot set the ADI and
MRL before the values are known!

Q39. Please comment on the SCVPH opinion stating that "any excess exposure towards
oestradiol-17β and its metabolites resulting from the co nsumption of meat and meat products
presents a potential risk to public health in part icular to those groups of the populations which
have been identified as particularly sensitive su ch as prepubertal children" [see para. 147 of the
EC Replies to Panel Questions]

EC Comments

The European Communities notes that the replies of Dr. Boisseau conflict with those of Dr. Sippel .
The European Communities agrees with Dr. Sippel's assessment, who demonstrates why there are a
number of sources confirming the values mentioned by Klein et al, 1994 and 1999. Dr. Boisseau's
reply is also false, because the SCVPH has perfo rmed – unlike JECFA which based its assessment on
data from 1974 - the quantitative assessment taking a ccount the lower endogen ous production levels
for pre-pubertal children from the most recent a nd reliable data (see also comments on previous
question).

Q40. The European Communities states that "the levels of endogenous production of the
hormones by prepubertal children is much low er than previously thought and this finding,
which is subsequent to the 1999 JECFA report, casts serious doubts about the validity of
JECFA's findings on the dose-response relation ship..." Please comment on the methodology
used by the SCVPH to support the conclusion th at hormone levels are lower than previously
thought, and in particular comment on the validity of these methodologies and their
conclusions. Would your conclusions have been the same at the time of adoption of the
Directive in September 2003?

EC Comments

JECFA originally used the limit-of-detection as th e "real" level when they could not measure the
levels. Dr. Boobis suggest using "newer data from Klei n (Klein et al., 1998)". However, Klein et al.,
1998 only reports values for girls with precocious pube rty, while they in the paper still refers to the
original data (Klein et al., 1994) for the le vels in normal pre-pubertal girls. Dr. Boobis also writes that
the values from another ultra sens itive bioassay (Paris et al., 2002) suggest that the levels are
significantly higher, however, that assay measures estradiol equivalents (includes other natural

estrogens and anything that may interact with the es trogen receptor). Nevertheless, even if the values
from Paris et al., 2002 are used, they are still less th an 1/3 of the JECFA values shown in the table.
The real values for serum 17b-oestradiol in pr epubertal children still remain to be properly
documented, although Dr. Sippel provides convincing explanations and arguments to accept as valid
the results from the RCBA assay.

Q41. Why would individuals with the lowest end ogenous hormone levels be at greatest risk?
How would the risks for these individuals aris ing from hormones naturally present in meat
differ from the risks arising from the residues of hormone growth promoters?

EC Comments

The European Communities considers th at the replies of the experts confirm the basic concerns in the
1999 SCVPH risk assessment about the need to prot ect the pre-pubertal children, and Dr. Sippel has
summarised correctly the reasons. The replies by Dr. Boisseau and Dr. Boobis as to whether the risk
would be the same or different are not entirely convincing. For instance, concerning estradiol-
17-esters and estradiol-alpha found as residues in treated steers (Maume et al, APMIS 109 (2001)
32-38, Maume et al, Anal Chim Acta, 483 (2003) 28 9-297), it would not be true that the risks are the
same. It is preferable to establish a rigorous risk assessment evaluation by considering specific classes
of residues. The European Communities considers that the most important studies available provide a
bioavailability rate which is 10% or higher ( see the 2
nd EC Written Submission).

Q42. To what extent, in your view, has JECFA ta ken into account the particular situation of
sensitive populations, in particular prepubertal children, in its risk assessments with respect to
oestradiol-17β? Please compare the original data concern ing endogenous production of natural
hormones by prepubertal children upon which JE CFA based its assessment and those used by
the European Communities in its risk assessment . In your view, does the scientific material
referred to by the European Communities require a revision of the Codex recommendation with
respect to oestradiol-17 β? [For the questions in this section, see paras. 121-122 of EC Rebuttal
Submission (US case), paras. 103-104 of EC Re buttal Submission (Canada case), Exhibits
EC-88, 99, para. 42-45 of US Rebuttal Submission, paras. 84 and 159 of US First Submission,
and for JECFA's work Exhibits CDA-11, 16, 17, 18, 39]

EC Comments

The European Communities notes the replies of Dr. Boisseau and Dr. Boobis , who incidentally have
not carried out any research themselves on these hormones and so have no specific expertise, are very
monolithic and one-sided. Their views are based agai n on the assumptions that this hormone is not
genotoxic and that the rate of endogenous production by prepubertal children is correctly cited in the
JECFA report. But if an over-estimation of endogenous levels and production rates would exist, as the
more recent evidence demonstrates, then a revision would be immediately necessary. And there are so
many other reasons to believe that the JECFA eval uation is scientifically wrong, as explained above
(old and unreliable data, etc.), no reliance can be placed on the replies by these two experts.

(e) Bioavailability
Q43. Please define bioavailability, comment on the significance of bioavailability to
assessments of risk, and on the degree of bioavaila bility of the residues of the hormones at issue
when consumed in meat, taking into account pa rties' differing views on this matter. [see
paras. 123-124 of EC Rebuttal Submission (US ca se), para. 105-106 of EC Rebuttal Submission
(Canada case), paras. 100, 155-159 of the EC Replies to Panel Questions, paras. 32 and 41-42 of
US Rebuttal Submission, paras. 69, 71, 88-89 and 146 of US First Submission, and para. 134 of
Canada Rebuttal Submission]

EC Comments

The European Communities agrees with the summary on this question as stated by Dr. Guttenplan .
Indeed, Dr. Boisseau writes "oestradiol-17 β is inactive orally". This is simply factually wrong!
Oestradiol-17β is routinely administrated to humans as a powde r or in the form of pills that are taken
orally. For example, in the study reported by Lamp it et al., 2002, the girls were administrated 8 µg
conjugated oestradiol-17β in the form of encapsulated powder. Moreover, in the "benchmark study"
on oestradiol-17β performed in rats (Cook et al., 1998) the rats were orally dosed with oestradiol-17β.
Thus, there are no doubts that oestradiol-17 β is orally active. 9 It is also not disputed that no rigorous
procedure has been used to assess hormonal risk concerning estradiol-ester, in particular on
absorption via the lymphatic route. It is clear that estradiol and estradiol-esters are not devoid of effect
when given orally (Paris et al, APMIS, 2001).

The European Communities has provided credible recen t evidence that the bioavailability of estrogen
is low but not insignificant (probably between 5 a nd 20%, if estrone is also taken into account).
Moreover, the calculations presented in the SCVPH ass essment clearly that suggest that even with
low percentages of bioavailability of estrogen, the le vels in meat could result in bioavailable estrogen
approaching the daily production rate of oestra diol in pre-pubertal children. As Dr. Guttenplan
 states,
this would represent a risk factor. Neither Dr. Boisseau nor Dr. Boobis provide a specific reply to this
other than repeating the general and hypothetical ass umptions of JECFA that their bioavailability "is
rather low". It should also be noted that the bi oavailability of the three synthetic hormones has not
been determined by JECFA.

(f) Good veterinary practice (GVP)
Q44. Please define "good veterinary practice" (GVP) and/or "good practice in the use of
veterinary drugs" (GPVD). What are th e relevant Codex standards, guidelines or
recommendations relating to GVP/GPVD? Please comment on the statement by the European
Communities that the definition of the GPVD is "circular and hence problematic." [see para. 88
of the EC Replies to Panel Questions]

EC Comments

The statement by Dr. Boisseau that "Codex did not adopt any guideline on GVP aimed at minimizing
the occurrence of veterinary drug residues in anim al derived food" confirms what the European
Communities has always been arguing. The European Communities recalls that the Appellate Body in
the 1998 Hormones decision has held that:

"… We consider that the object and purpose of the SPS Agreement justify the
examination and evaluation of all such risk s for human health whatever their precise
and immediate origin may be. We do not mean to suggest that risks arising from
potential abuse in the administration of controlled substances and from control
problems need to be, or should be, evaluated by risk assessors in each and every case.
When and if risks of these types do in f act arise, risk assessors may examine and
evaluate them. Clearly, the necessity or propriety of examination and evaluation of
such risks would have to be addressed on a case-by-case basis. What, in our view, is
a fundamental legal error is to exclude, on an a priori basis, any such risks from the
scope of application of Articles 5.1 and 5.2 …". (at para. 206)

9 See Cook J.C., Johnson L., O'Connor J.C., Biegel L.B., Krams C.H., Frame S.R., Hurtt M.E.: Effects
of dietary 17 beta-estradiol exposure on serum hormone concentrations and testicular parameters in male
Crl:CD BR rats, Toxicol Sci. 1998 44:155-68.

The European Communities also reca lls that the inspections and me asurements of hormone residues
in US meat made by the European Communities revealed that hormones were found in what was
supposed to be a "guaranteed horm one-free beef", and that the leve ls of one of the hormones (MGA)
were too high to be achieved by the legal dosing. The European Communities has also performed two
specific risk assessments for the US and Canada that comply with the requirements laid down in para.
206 of the Appellate Body report me ntioned above (see in particular EC exhibits 67-73). Thus, there
is specific evidence proving that GVP is not followed by at least by some meat producers in the US
and Canada. The debate on this issue demonstrates, as Dr. De Brabander shows, that there is an
important difference between the theoretical assumption of respecting GVP and real life.

Q45. In conducting a risk assessment of specific veterinary drugs, what assumptions are made
concerning GVP, if any? How, if at all, are risk s that might arise from the failure to follow good
veterinary practice in the administration of veterinary drugs addressed?

EC Comments

As Dr. Boisseau states, the Codex recommendations (whether ADIs or MRLs) "are only meaningful
in countries where GVP are effectively implemen ted." There is, however, plenty and undisputed
evidence that frequently GVP is not respected in the US and Canada (although Canada appears to
have a slightly better record). However, as Dr. De Brabander rightly explains, the argument of
Dr. Boisseau is not correct that risk assessors cannot take into account possible misuse or abuse in
their assessment, as the 1999 and 2002 SCVPH opinions have clearly demonstrated and as Dr. Boobis
also admits in his reply to question no 46.

Q46. To what extent were risks from misuse or abuse assessed by JECFA in its evaluation of
the hormones at issue? In terms of the three synthetic hormones at issue, how is GVP relevant
to the establishment of MRLs by JECFA?

EC Comments

Although the theoretical description by Dr. Boobis is more or less accurate, the important point is that
the pharmaceutical industry did not carry out any sy stematic experiments on possible misuse or abuse
of these hormones nor did it submit such data to th e US and Canadian regulatory authorities in the
1970 and 1980s when applied for the authorisation of these substances. The result is that also JECFA,
which based its evaluation on the same old data, did not consider systematically the issue of possible
misuse or abuse. This is a fundamental flaw in JECFA's assessment of these hormones.

As the European Communities has already explained, even the US authorities now accept (see e.g. the
2002 US Carcinogenesis Report) that the admi nistration of these hormones to cattle, which
presumably respects GVP, leads to residue levels th at exceed the levels from endogenous production.
This means that when misuse or abuse occurs th e excess levels are inevitably going to be much
higher. According to the studies cited by the European Communities, e.g. Exhibits EC-12 and 17 and
73, the level of residues in case of misuse or abuse by far exceed the ADIs recommended by JECFA
and the acceptable levels and tolerances recommended in the US and Canada.

Q47. How significant are any differences in GV P in the European Communities, the United
States, and Canada? Does the EC risk assess ment take into account relevant control
mechanisms with respect to GVP in place in the United States and/or Canada? If so, what are
their conclusions?

EC Comments

The statement of Dr. Boisseau is partly false. The European Communities has carried out a specific
assessment of the US and Canadian situation concer ning respect of GVP (see EC Exhibits 67 and 68)
and has taken into account the multiple sources of mi suse and abuse that frequently occur there (see
EC Exhibits 69 -70, and 71-72, 96, and 102-103). As Dr. Boisseau states these hormones are sold
over the counter in the US and Canada, which means that there is in reality no way to control their
possible misuse by the authorities th ere. The evidence available does s how that such misuse or abuse
occurs frequently, because these hormones are admini stered in combinations and the farmers have
incentives to apply multiple doses.

Q48. To what extent does the scientific evid ence referred to by the European Communities
assess risks to human health from residues of misplaced implants or improper administration,
i.e. when administered differently than indicate d on the label of the manufacturer or contrary
to GVP, of any of the six hormones? Would your reply have been different at the time of
adoption of the EC Directive in September 2003? What are the potential hazards, if any, to
human health of the use of large quantities, or doses higher than recommended, of any of the six
hormones in dispute?

EC Comments

The criticism of both Dr. Boisseau and Dr. Boobis
 is based on their understanding that the European
Communities did not perform a quantitative risk assessment, which they think is a necessary
requirement for a proper risk assessment under the SPS. However, as the European Communities has
explained several times in previous qu estions, this in not required under the SPS Agreement as
interpreted by the Appellate Body. But as alre ady explained, the European Communities has
nevertheless performed a quantitative dose-respon se assessment in particular with regard to
prepubertal children. As the exposure from residues in meat treated with these hormones according to
GVP was found to lead to residues that exceeded several times the ADIs and MRLs, it is obvious that
the higher levels of residues that will inevitably result from misuse or abuse of these hormones will
also exceed the ADIs and MRLs recommended by JECFA.

Furthermore, Dr. Boobis
 states that "…the potential risk, i.e. the probability that effects would occur,
would depend on a number of factors...". But as the European Communities has already explained, the
risk and risk assessment under the SPS Agreement, as interpreted by the Appellate Body, is not the
"probability" of the identified risk occurring but the "possibility" of the identified risk occurring under
real conditions of use.

Q49. What analytical methods, or other technical means, for residue detection in tissues exist
to control the use of the six hormones in dis pute for growth promotion purposes in accordance
with good animal husbandry practice and/or good veterinary practice? What tools are
available to control the use by farmers of the six hormones in dispute for growth promotion
purposes in accordance with good animal husbandry practice and/or good veterinary practice?

EC Comments

To the list of tools listed by Dr. De Brabander to control the possible misuse or abuse of these
hormones, the European Communities would add that these hormones should not be sold freely on the
counter but by veterinary prescription only. Of course all these apply only for the countries that would
be prepared to assume that the possible risk w ould not undermine their chosen level of health
protection.

Q50. Are there other measures available to the European Communities (other than a
complete ban) which could address risks aris ing from misuse and failure to follow good
veterinary practice with respect to the use of the hormones at issue for growth promotion
purposes? Would your reply have been different at the time of adoption of the EC Directive in
September 2003? If so, why?

EC Comments

The European Communities notes that the rep lies by Dr. Boisseau and Dr. De Brabander agree on the
point that if GVP is not respected, then the importing country should have the right to restrict imports,
even with a total ban, depending on the importing country's chosen level of health protection.

Q51. Does the material put forth by the Europe an Communities regarding misuse or abuse of
the hormones at issue in the United States and Canada call into question the potential
applicability of Codex standards with regard to imports of meat from cattle treated with
hormones from the United States and Canada?

EC Comments

The European Communities understands that the answer by Dr. Boisseau to this question is that the
Codex standards would not be applicable. The Eur opean Communities also agrees with the statement
by Dr. De Brabander.

(g) Other
Q52. Do the risk assessment of the European Communities or any other scientific materials
referred to by the European Communities demons trate that a potential for adverse effects on
human health arises from the consumption of me at from cattle treated with any of the six
hormones in dispute for growth-promotion purposes? If yes, why? If not, what kind of evidence
would be required to demonstrate such potentia l adverse affects? Would your response have
been different at the time of adoption of the Directive in September 2003?

EC Comments

The European Communities considers that the statements by Dr. Boisseau and Dr. Boobis are
scientifically incorrect because they are based on many assumptions and conservative interpretation of
the available and constantly growing evidence that directly implicates these hormones in causing and
promoting cancer and a number of other adverse effects in humans. If the views of these experts were
to be adopted the prerogative of cautious public au thorities to regulate risk in order to reduce or
eliminate it would completely vanish. Dr. Boisseau and Dr. Boobis apply double standards because
they require for the prohibition of these hormones evidence which the pharmaceutical industry did not
provide nor did it even examine when it applied for the approval of these substances in the US and
Canada in the 1970s and 1980s.

Dr. Boisseau
 states that: "… the kind of evidence required to demonstrate such potential adverse
effects should be (1) toxicological data indicating that the values of the ADIs established by JECFA
are not conservative enough, (2) data on residues in treated/non treated cattle and on daily production
of hormones in sensitive individuals indicating that the hormonal residue intake associated with the
consumption of meat from treated cattle is such that the established ADIs would be exceeded in the
case of use of growth promoters." The European Communities submits that such data have been
provided and taken into account in the 1999, 20 00 and 2002 SCVPH risk assessment, which he has
apparently not properly examined.

Dr. Boobis
 states again that: "… the weight of evidence is that the hormones are not genotoxic in vivo
even at doses well above those that would be present in meat from treated cattle (…) However, all of
the major reviews in this topic have concluded that whilst there are data gaps, there is no evidence that
low level exposure is causing harmful effects in hu mans (…) However, it should be emphasised that
on the basis of the information available, I would rate the risk of adverse effects in humans consuming
meat from treated cattle as minimal ." (emphasis added). So, according to Dr. Boobis conservative
reading of "the weight of available evidence" , which means that scientific views outside the
mainstream or the majority held view do not count for him, it cannot be excluded that there is a risk,
even though this is evaluated by him to be "m inimal". However, he does not explain what is
"minimal" risk, nor does he seem to pay any attenti on to the fact that the "gaps in our knowledge –
which he admits exist – may indicate that there is scientific uncertainty with potentially disastrous
consequences for the consumers.

The European Communities considers that Dr. Guttenplan
 has rightly summarised the issue: the
evidence which the European Communities has presented suggests that "even with low percentages of
bioavailability of estrogen, the levels in meat could result in bioa vailable estrogen exceeding the daily
production rate of oestradiol in prepubertal children" . When the evidence is not to their liking, the US
and Canada contest the accuracy of the assay orig inally employed for estrogens at the low levels
found in children. However, they consistently refu se, as dose JECFA, to provide their old data in
order to examine in an open and transparent ma nner the kind of assays used by the pharmaceutical
industry in the 1970s and 1980s fo r the approval of these hormones in the US and Canada. But as
Dr. Guttenplan rightly points out, recent reports indicate that "more recently reported levels used by
the EC are accurate. In addition, levels in post-menopausal women were also very low." Moreover, he
explains that: "For pre-pubertal children, even w ith the low bioavailability of estrogen along with and
its low levels in meats, it appears possible that intake levels would be within an order of magnitude of
those of the daily production rate. This is greater than FDA's ADI and suggests some risk to this
population."

Q53. Please comment on the statement by the European Communities that the natural
hormones progesterone and testosterone are used only in combination with oestradiol-17 β or
other oestrogenic compounds in commercial prep arations? Would the systematic use of these
and the synthetic hormones in combination h ave any implications on how the scientific
experiments and the risk assessment s are to be carried out? If so, have the scientific materials
referred to by the European Communities or re levant JECFA reports taken into account the
possible synergistic effects of such combinations on human health? [see sections 4.2-4.3 of the
Opinion of the SCVPH of 2002 in US Exhibit 1]

EC Comments

The European Communities notes that both Dr. Boisseau and Dr. Guttenplan recognise that the
statement by the European Commun ities is correct. Dr. Boisseau's reply is, however, partly false
because it ignores the potential stimulatory estrogen receptor mediated effects of estradiol on cell
proliferation which tend to be increased by progestins (see New Eng. J. Med., 354, 270-282, 2006).

Moreover, Dr. Guttenplan
 accepts that "… in principle the u se of mixtures should complicate risk
assessments/scientific experiments, as they would have to evaluate/investigate each component alone
and in combination. This is a major undertaking as effects of individual agents may be additive,
inhibitory, and synergistic or there may no effect ." What is even more important, he acknowledges
that "… it appears that no experiments on effects of combinations were performed, so some
uncertainty exists there." The European Communi ties submits that this is still another kind of
uncertainty that should be taken into account by the Panel in deciding whether the evaluations by
JECFA are credible and reliable.

Q54. What is the acceptable level of risk ref lected in the Codex standards for the five
hormones at issue? How does th is compare to the European Communities' stated objective of
"no risk from exposure to unnecessary additional residues in meat of animals treated with
hormones for growth promotion". [see para. 149 of EC Rebuttal Submission (US case)]

EC Comments

The European Communities notes that Dr. Boisseau and Dr. Boobis differ as to the acceptable level of
risk reflected in the Codex standards for the five hormones at issue: the first argues that Codex's
"... ADI represents the quantity of these residues whic h can be ingested daily by consumers over life
time without causing any problem of health ...", but the reply of the second suggests that the level is
"no appreciable risk with daily exposure ". If one were to follow Dr. Boisseau's reply, then there is no
doubt, and most of the experts have explicitly accepte d it, that there is a risk although for some of
them – like Dr. Boobis - this is viewed as "minimal". On the other hand, if Dr. Boobis' reply is
followed, this would mean that Codex's standard r ecognises that there is an scientifically identified
risk but recommends its members to follow it because it thinks (as a risk manager) that it is "not
appreciable". If that were the case, however, Codex and the SPS Agreement cannot oblige a sovereign
country to accept a risk, whether it is viewed as small, medium or big. This is the autonomous right of
each member to decide and the Appellate Body h as explicitly said that WTO members have the right
to fix a level of protection of "zero risk".

For the benefit of Dr. Guttenplan
, Codex has not set an ADI or an MRL for MGA yet, since no
decision has been taken by the Codex Alimentarius Commission. So, no international standard exists
for MGA yet.

Q55. Do the Opinions of the European Communi ties or other scientific materials referred to
by the European Communities evaluate the extent to which residues of growth promoting
hormones in meat contribute to what the Euro pean Communities calls "additive risks arising
from the cumulative exposures of humans to mult iple hazards, in addition to the endogenous
production of some of these hormones by anim als and human beings"? Would your reply have
been different at the time of adoption of the EC Directive in September 2003? If so, why? [see
para. 151 of EC Replies to Panel Questions, paras. 43-44 of US Rebuttal Submission,
paras. 83-85 of Canada's Rebuttal Submission]

EC Comments

The European Communities disagrees with Dr. Boisseau's reply that its position is "a position of
principle" or that it is based on economic grounds (as he implied with his reply to the previous
question). The time, effort and money spent by th e European Communities to clarify the scientific
issues identified by the Appellate Body in its 1998 report on Hormones clearly establish that the EC's
position and legislation are based on sound and up to date scientific grounds. The precautionary
principle comes after proper consideration of the scientifically identified and analysed risk.

Dr. Boobis accepts that additive risks arising from the cumulative exposures is a scientifically sound
approach and that can and is done in some cases. Fr om his reply, one may infer that he accepts that
this is not done by JECFA nor by the US and Canada . He only thinks this is not appropriate for these
hormones because of his preconceived approach that there is a dose-response relationship (threshold)
in the carcinogenic mode of action of these hormones.

The European Communities disag rees with the statements by Dr. Boisseau and Dr. Boobis for the
reasons that have been developed extensively in its submissions and in some of its comments above. It
urges the Panel to disregard their comments because they are purely theoretical and for the additional
reason that they come from two experts that ha ve never done any specific research on these hormones

nor have they ever published something on these substances. Instead of criticising the risk assessment
produced by the European Communities, these experts should have examined in their replies whether
such an additive risk assessment ought to have b een examined by JECFA in the first place before
issuing the recommendation that the risk is "not significant".

The European Communities notes that Dr. Guttenplan
 would have liked to see much more evidence in
the 1999 SCVPH assessment. To the extent this was not provided in 1999 and in 2002, this is not
because of omission but because the state of scientific knowledge available by then – i.e. the gaps and
scientific uncertainty clearly identified in those opinions – did not allow such an assessment to be
completed.

Q56. Has JECFA/Codex considered in its risk a ssessment of the five hormones such "additive
risks? Are there internationally recognized gu idelines for conducting assessments of "additive
risks"?

EC Comments

The European Communities disagrees with both Dr. Boisseau's and Dr. Boobis' replies. They provide
no precise reference of where in the JECFA 2000 repor t it is stated that such a cumulative risk
assessment was carried out. The European Co mmunities understands that such a cumulative
assessment of the additive risk has not been performed (and this is also what apparently
Dr. Guttenplan believes, as words seem to be missing from his reply).

The European Communities notes that it has clearly been shown that the effects from exposure to
different estrogens are additive; i.e. when several estrogens are given simultaneously at concentrations
where none of them alone results in any detectable effects, the combined exposure leads to a clear
effect. Thus, any additional dose will lead to an in creased effect (Rajapakse N., Silva E., Kortenkamp
A.: Combining Xenoestrogens at Levels below I ndividual No-Observed-Effect Concentrations
Dramatically Enhances Steroid Hormone Action., Envir. Health Perspec. 110, 917-921 (2002); and
Tinwell H., Ashby J.: Sensitivity of the Immature Rat Uterotrophic Assay to Mixtures of Estrogens,
Envir. Health Perspec.112, 575-582 (2004)). More over, there are several hormonal preparations
containing two hormones (estradiol plus trenbolone) and there are several publications in the animal
science literature recommending different preparati ons in consecutive applications. Therefore, the
additive risk needs to be carefully evaluated. For instance, trenbolone as such has a complex hormonal
activity (at the same time progestin, androgen and glucocorticoid). Estradiol and trenbolone residues
therefore may have 4 different hormonal activities.

The European Communities further notes that alt hough there is agreement that "there is no
international agreement on how to undertake a combin ed risk assessment of compounds acting by the
carcinogenic mechanisms suggested by the EC for the hormones, i.e. genotoxicity via direct or
indirect interaction with DNA", yet the performance of such a risk assessment is not impossible. The
European Communities has tried to do such an assessment when the information available was
sufficient, but could not complete it because of gaps in our scientific knowledge.

Q57. Canada comments that "one single mol ecule that the European Communities considers
so dangerous from meat derived from animals treated with hormone growth promoters
 is
suddenly not at all that dangerous when cons umed from meat from animals treated for
therapeutic or zootechnical purposes. The Europe an Communities' concern about the genotoxic
potential of oestradiol-17β suddenly and inexplicably disappears." To what extent are hormone
treatments of cattle for purposes other than grow th promotion, such as for therapeutic or
zootechnical purposes, taken into account by th e European Communities, if at all, in its
assessment of the cumulative effects from the consumption of meat containing residues of the
hormones at issue? Would your reply have been different at the time of adoption of the EC

Directive in September 2003? If so, why? [see para. 97 of Canada Rebuttal Submission;
paras. 17-20 of US Opening Statement]

EC Comments

The European Communities considers that asking th is question in the first place was unnecessary and
irrelevant, because the Appellate Body did not find any violation from the use of some of these
hormones for therapeutical or zootechnical purposes. As Dr. Guttenplan
 points out, the conditions
imposed by the European Communities for such limite d use are such that it would not be possible to
undermine its chosen level of protection.

Therefore, the European Communities is consistent because the use of oestradi ol for such purposes is
now virtually terminated.

Q58. Please comment on the EC statement in para. 94 of the EC Replies to Panel Questions
that "the only rationale that can be inferred from the available scientific data is that the higher
the exposure to residues from these hormones, the g reater the risk is likely to be", taking into
account para. 105 of Canada Rebuttal Submission.

EC Comments

The European Communities n eeds to clarify that the quoted statem ent was made in response to the
US and indeed Canadian argument that there is no risk from cumulative exposure to residue of these
hormones in meat treated with one or several of these hormones for growth promotion purposes.
Moreover, the statement is framed cautiously to say "is likely to be" precisely because such a
complete cumulative risk assessment has not been carried out by JECFA and the other countries.
Moreover, if the assumption of JECFA and of the US and Canada that there is a threshold is false, the
relevance of the EC comment is a realistic even tuality. The European Communities has in fact
provided the Panel with recent evidence (e.g. the papers by Dr. D. Sheehan, see Exhibit EC-87) which
has showed the absence of such a th reshold. It is indicative that n one of the experts discuss it in his
replies. The studies mentioned in these exhibits show that under the circumstance that the endogenous
hormone is active, there can be no threshold unl ess metabolism is 100% effective before the dose
reaches the target tissue. It is also noteworthy that none of the scientists discusses the reference made
by the European Communities to the US 2002 Ca rcinogenesis Report which states as regards
oestradiol that residues in meat from animals treat ed with hormones for growth promotion lead to
levels higher than the endogenously produced ones. The question therefore is by how much and of
what kind of biological and toxicological nature. In the EC's comments to previous questions, it has
been shown that the level of residue formation in meat can be significantly higher and may contain
residues from different metabolites. It seems ther efore that the experts criticise the European
Communities for making an assumption, but they are not apparently able to prove either that their
own assumption is correct.

Q59. Does the scientific evidence referred to by the European Communities identify any
adverse effects on the immune system from the consumption of meat from cattle treated with
the growth promoting hormones at issue? Would your reply have been different at the time of
adoption of the Directive in September 2003? If so, why? [see para. 132 of Canada Rebuttal
Submission]

EC Comments

The European Communities notes the different views which the replies of the scientists display on this
critical question. Dr. Boisseau accepts that such adverse effects ha ve been identified, but faults the
European Communities for not having conducted a "quantitative" risk assessment. Dr. Boobis

continues with his line of argument that there is a threshold effect, which prevents this kind of adverse
effects on the immune system from occurring. The poin t, however, is that neither the US nor Canada
(and a fortiori nor JECFA) have identified such a dverse effects because of the outdated nature of the
data on which they based their assessments. The European Comm unities has offered some serious
evidence, some of which appeared for the first ti me recently, and pointed to a number of gaps and
uncertainty in our knowledge. This is recognised by Dr. Guttenplan
, who states that "…there is
evidence that estrogens can be involved in Lupus, rheumatoid arthritis, thyroiditis. In addition the
development of allergies is thought to be at l east partially related to estrogens. The studies in
experimental animals also did not identify any immu ne-related effects, although it is not certain the
types of possible effects in humans would be detect ed in experimental animals…". The question,
therefore, is the degree of confidence by which th e US and Canada (and JECFA) can ensure the Panel
that such adverse immune effects are not possible to occur from residues in meat treated with these
hormones for animal growth promotion. The European Communities thinks they have failed to do so
to the required standard of proof.

Q60. Does the scientific evidence referred to by the European Communities identify and
evaluate whether there is a difference in term s of potential adverse effects on human health
from the consumption of meat from cattle treated with hormones for growth promotion
purposes when these hormones are administered as feed additives (MGA) or implanted? Are
you aware of any differences?

EC Comments

The EC contests the accuracy of the statements by Dr. Boisseau and Dr. Boobis . It is known that
MGA is the only hormone that is administered as a feed additive, which confirms that the
bioavailability of this hormone is rather high. Moreover, it has been shown that MGA is highly
lipophilic and accumulates in adipose tissue. The 199 9 and 2002 SCVPH and exhi bits EC-14, 16 and
19 have shown that the route of administration of MGA is conducive to misuse or abuse, as the
residues of MGA detected in the US samples of meet were much higher than the levels which should
have been normally expected (exhibit EC-16). The study mentioned in exhibit EC-16 has also shown
that the residues in fat of oestradiol-17 β increased by about 300% following labelled MGA treatment.
The consequence of this is that given the tr emendous "boosting" effect which MGA has on the
residues of oestradiol in meat and the easiness by which its administration can be misused, the
possibility to increase substantially the level of residues, and hence the risk of cancer, is significantly
increased. This is not examined either by Dr. Boisseau or Dr. Boobis
, who apparently have not read
this material.

Hormone MGA has been in use in the US and Canada since the 1970s and it is interesting to note that
JECFA has not been seized of a request to evalua te it until 2000. Yet, until today there is no Codex
standard for MGA. It is also clear that the evidence upon which JE CFA based its evaluation has not
been made available to anyone, has not been publis hed in peer-reviewed jour nals and it is outdated
but today's standards. The most important evidence on MGA is the one generated by the EC following
the Appellate Body 1998 hormones decision. This info rmation is publicly ava ilable and demonstrates
the gaps in our knowledge, the uncertainty surroundi ng this hormone and the multiple risks which the
administration of MGA poses to human health.

As regards the risks from eating meat treated with implanted hormones, the evidence shows that non-
removed implants contain milligrams of residues. These are 10
7 to 109 fold more residues than present
in the peripheral tissue (pikograms per gram). The to tal dosage in an implantation site is therefore
about a thousand fold higher than the residues in the whole carcass of the animal. There is no doubt
that the risk from implanted hormones is in a comp letely different order of magnitude from the risk
posed from untreated animals. Dr. Boobis makes again his unfounded statement that: "However,
whilst this would lead to increased exposures, it is still unlikely this w ould exceed the ADI, and

certainly not for any period of time. It is also an unlikely occurrence in view of the way in which the
hormones are used and controlled." First of all, he has and provides no factual basis to argue that it is
"unlikely" that misuse will exceed the ADI. Neith er Codex nor JECFA have fixed yet an ADI, and
even if they were to do it one day, he has now no data to suggest that it is unlikely to be exceeded.
Moreover, it has already been shown that even th e administration of MGA that does respects GVP
leads to a tremendous "boosting" effect on the residues of oestradiol in fat and the attending risk of
exceeding the ADIs is very high.

Q61. In your view and in the light of information provided by the parties as well as the work
undertaken at JECFA and Codex, did the sci entific evidence available to the European
Communities at the time it adopted its Dire ctive (September 2003) allow it to conduct an
assessment (quantitatively or qualitatively) of th e potential for adverse effects on human health
arising from the consumption of meat from cattle treated with (a) progesterone; (b)
testosterone; (c) trenbolone; (d) zeranol; and (e) melengestrol acetate? Would your response
differ in light of the scientific evidence provided which is subsequent to the adoption of the EC
Directive?

EC Comments

The reply of Dr. Boisseau is surprising as the data available to the EC are mentioned in the 1999,
2000 and 2002 SCVPH assessments and the additional evidence from other sources is explained in the
written submissions of the EC to the Panel and were pr ovided as exhibits thereto. It is recalled that he
has explicitly admitted that he has not done nor published any work on these hormones.

The reply by Dr. Boobis and Dr. Boisseau
 can only be explained by their exclusive reliance on the
JECFA reports, which Dr. Boobis thinks represent the "weight of the evidence" that should be taken
into account. This is probably not surprising, as they have both served in the JECFA panel that
examined some of these hormones, although they both lack any specific expertise on these hormones,
as they have not carried themselves any experiment on them when used for animal growth promotion
purposes.

Their entire reasoning – whose objectivity and impartia lity is therefore in great doubt for the reasons
the EC has explained to the Panel during the expe rt selection procedure - is based on the assumption
that there is a dose-response relationship (thres hold), despite the accumulation of so much recent
evidence showing that this assumption can no longer be valid for a number of these hormones,
certainly for oestradiol 17 β, progesterone, testosterone and zeranol. Their reasoning is also based on
the idea that a risk assessment to be acceptable has to perform a quantitative analysis and assessment
of risk even of aspects for which the available eviden ce is insufficient or there are total areas of gaps
in our knowledge.

The EC considers that the reply by Dr. Guttenplan
, as well as those by Dr. Shippel, Dr. De Brabander
and Dr. Cogliano who have not expressed themselves on this precise question but this can be seen
from their replies to the other qu estions, show that there is suffi cient evidence which "does indicate
that potential adverse effects exist for all of th e hormones. However, the ability to make a risk
assessment (qualitative or qualitative) does vary between compounds." (Dr. Guttenplan). The
available evidence, at the varying degrees mentioned by Dr. Guttenplan , does establish that "…
accurate ADI's cannot be established at this point", and that "… studies in experimental animals and
studies on levels in beef are still needed." Most importantly, the EC agrees that "from the data
available at the time of the Directive, the potential for adverse effects could not be ruled out."

Q62. Does the scientific evidence relied upon by the European Communities support the EC
contention that the new scientific studies that ha ve been initiated since 1997 have identified new
important gaps, insufficiencies and contradictions in the scientific information and knowledge

now available on these hormones such that more sci entific studies are necessary before the risk
to human health from the consumption of me at from cattle treated with these hormones for
growth promotion purposes can be assessed? Would your reply have been different at the time
of adoption of the Directive in September 2003? If so, why?

EC Comments

The EC considers that its comments on the positions of Dr. Boisseau and Dr. Boobis to the previous
question no. 61 are equally and fully applicable here.

It is difficult to grasp the idea of Dr. Boisseau
 for a temporary risk assessment, unless his statement
was to be understood that the gaps and uncertaintie s identified by the EC in its risk assessment are
such as to require further research and investigation.

As regards the long and dismissive reply by Dr. Boobis
, who despite his lack of any specific expertise
on these hormones tried to discredit all the studies mentioned by the EC, it is now clear on the basis of
a more careful examination by a real expert of the same body of evidence that it would necessarily
lead to the opposite conclusion. Dr. Boobis'
 comments on the studies generated by the EC are flawed
in almost all respects.

For instance, he comments on the Leffers et al., 20 01 study on the low-dose effects of Zeranol and
other estrogens on gene expression in MCF7 cells. He writes: "Many of the changes will reflect the
proliferative response to an oestrogenic stimulus". However, in the applied assay changes in gene
expression were assayed after 24h exposure, whereas the first up-regulation of proliferation-sensitive
genes becomes detectable after 36h exposure. T hus, the observed effects are a likely direct
consequence of gene activation by the estrogen re ceptor, reflecting activation of the receptor by
Zeranol and the other compounds. (see Jorgensen M., Hummel R., Bevort M., Andersson A.M.,
Skakkebaek N.E., Leffers H.: Detection of oestrogenic chemicals by assaying the expression level of
oestrogen regulated genes. APMIS. 1998 106:245-51.)

Another example is that he dismisses the bovine metabolism of oestradiol-17 β and oestrogenic
potency of fatty acid residues on the unsubstantiated ground that "the difference in potency from the
parent hormone is not very great or even apparent at low doses, where effects were minimal", where
the opposite is rather true in the study cited. Another example is that he dismisses the relevance of the
studies on misuse and abuse on the speculative ground that "… the probability that this would occur is
extremely low". However, he has no evidence and provides no credible basis for that conclusion. Still
another example is that he dismisses the relevanc e of the recent findings on the mutagenicity and
genotoxicity of oestradiol-17β despite the fact that this has been shown both in vitro and now in vivo.
The findings of the study he criticises for no valid reason have been largely confirmed in other recent
studies supporting a role for the estrogen metabo lites which include the genotoxic, mutagenic
estrogen quinones in estrogen carcinogenicity (New Eng. J. Med., 354, 270-282, 2006). And the list
of examples showing lack of specific knowledge or impartial presentation of the available evidence
by Dr. Boobis
 is much longer.

Conversely, a more considered and objective view is to be found in the reply of Dr. Guttenplan , who
provides some examples of the areas in which ga ps and uncertainties have been identified and
indicates some of the additional research that is re quired before the EC w ould be able to conduct a
more complete risk assessment. The EC agrees with his comments.

ANNEX F-2

COMMENTS BY THE EUROPEAN COMMUNITIES ON THE
REPLIES OF CODEX, JEFCA AND IARC ON
QUESTIONS POSED BY THE PANEL

(30 June 2006)

Introduction

The European Communities appr eciates this opportunity to comment on the replies of the
international bodies to the questions posed to them by the Panel. The European Communities
considers it necessary to recall the position it has alre ady expressed to the Panel at the time it decided
to ask questions from these bodies, namely that Co dex and JECFA lack appropriate and transparent
procedures for submitting this kind of comments and re plies to other international organisations, such
as the WTO dispute settlement bodies. In particular, replies and comments that come simply from the
secretariat of those bodies, without following the legally required procedures for their internal
elaboration and transmission, should be disregarde d because they are likely to influence unlawfully
the Panel’s deliberations.

The European Communities notes that the comment s submitted in these cases by those bodies do not
explain whether the required internal rules and procedures for their adoption have been fully
respected. Therefore, the European Communities requests the Panel to clarify this question with these
bodies; in the absence of an adequate and legally sound reply – with precise references to the rules
that were applied in the elaboration of their re plies - the European Communities would request the
Panel to disregard them.

Q1. Please briefly describe the procedure fo r the elaboration and adoption of an
international standard by Codex. What is th e decision-making process for the adoption of an
international standard?

EC Comments

The European Communities notes that according to Codex: "In the case of MRLs for veterinary drugs,
submission of project documents is not required; instead, the Codex Committee on Residues of
Veterinary Drugs in Foods (CCRVDF) prepares a priority list of veterinary drugs requiring evaluation
or re-evaluation by JECFA, which is submitted to the Commission for approval." However, it is
noteworthy that this procedure was not followed when JECFA decided to re-evaluate the three natural
hormones in 1999, because the CCRVDF did not request such a re-evaluation.

The European Communities also notes the statemen t whereby: "The Commission attaches a great
importance of achieving consensus at all stages of the elaboration of standards and that draft standards
should, as a matter of principle, be submitted to the Commission for adoption only where consensus
has been achieved at the technical level." However, the European Communities draws the attention of
the Panel to the uncontested fact that the 1988 Code x standards for the five hormones (except MGA)
were not adopted by consensus and the 1999 review by JECFA of only the three natural hormones
were not even presented to Codex for adoption because the relevant committee [CCRVDF] decided
not to consider them as it had not requested their re-evaluation.

Q2. Please briefly explain the differences betw een Codex standards, codes of practice,
guidelines, principles and other recommendations.

EC Comments

The EC has no comments at this stage.

Q3. Please identify any international guidance documents relevant to the conduct of a risk
assessment with respect to veterinary drug residu es. Since when have they been available?
Please also indicate if there is any relevant ongoing work at Codex.

EC Comments

As the European Communities explained by its comments to question no 3 of the Panel experts
questions, its legislation complies with the Working Principles for Risk Analysis for Application in the
Framework of the Codex Alimentarius, which where adopted by Codex in 2003, and these working
principles were complied with in the assessment of the six hormones at issue and in the adoption of
the Hormones Directive 2003/74/EC.

The European Communities further notes the statemen t that: "Following the adoption of the Working
Principles, the Commission requested that relevant Codex Committees devel op or complete specific
guidelines on risk analysis in their respective area s for inclusion in the Procedural Manual…The two
documents will be considered by the 30th Sessi on of the Codex Alimentarius Commission in 2007
(after review by the Codex Committee on Genera l Principles) for adoption and inclusion in the
Procedural Manual." This statement confirms the EC position (see also its comments to question no 3
of the Panel experts questions) that until now there exist no guidelines on risk analysis for residues of
veterinary drugs in the sense of Article 5.1 of the SPS Agreement. The consideration in 2007 of the
two working documents does not mean that they will be adopted, if one were to judge from previous
experience in the work of the Codex Committee on General Principles.

The European Communities also draws the attention of the Panel to the statement that the principles
to be adopted one day will "…define the res ponsibilities of the various parties involved: the
responsibility for providing advice on risk manageme nt concerning residues of veterinary drugs lies
with the Codex Alimentarius Commission and its subsidiary body, the Codex Committee on
Residues of Veterinary Drugs in Foods, while the respon sibility for risk a ssessment lies primarily
with the Joint FAO/WHO Expert Committee on Food Additives (JECFA)." This confirms again the
EC position (see also the EC comments to question no 5 of the Panel experts questions) that such a
clear definition of the responsibilities does currently not exist, and that in reality it is JECFA that is
informally doing also the risk management, leaving practically no real risk management choice to the
Codex members to adopt measures aiming to achieve a high level of health protection. This is clearly
the situation in the case of the six hormones in disput e, since the old data used by JECFA and the way
in which it drafted its reports (e.g. "genotoxic potential", "unlikely to be exceeded", "pose an
insignificant risk", "MRLs considered unnecessary", etc.) in effect deprive the Codex members from
applying a very high level of protection, which in the context of the WTO can be "no or zero
(additive) risk" according to the Appellate Body.

The European Communities considers that the repl y of JECFA confirms the EC position that there
exists currently no international guidance documents relevant to the conduct of a risk assessment with
respect to veterinary drug residues in food. What JECFA calls "key intern ational risk assessment
documents" are in reality nothing more than inform al papers prepared for certain specific purposes
and substances which were never presented for consideration and adoption by the competent decision-
making bodies of Codex Alimentarius Commission and JECFA. They do not have, therefore the
status of legally binding risk assessment techniques in the sense of Article 5.1 of the SPS Agreement.
In fact, if such risk assessment techniques already ex isted, quod non, there wo uld have been no need
to start this kind of work in the CCRVDF in 2000. Indeed, the reply of Codex to the next question
(No 4) confirms explicitly the accuracy of the EC position.

It should be further clarified that the above EC co mments do not intent to diminish the work that is
being done in the framework of Codex and JECFA, which is of importance primarily for the countries
which do not have in their internal legislation such rules and procedures on risk assessment. The
informal technical work to wh ich JECFA and Codex refer cannot, However, be invoked to resolve
differences between the parties in a formal WTO dis pute settlement with very serious legal, health
and economic consequences for the parties to the dispute. This could be the case only when Codex
and JECFA formally adopt some time in the future the relevant standards on risk assessment for this
kind of residues of veterinary drugs in food. As the European Communities has explained with its
comments on question no 3 of the Panel experts questi ons, its internal legislation on risk assessment
applied to the six hormones in question is far more advanced than the informal working documents to
which Codex and JECFA referred to in their replies.

Q4. The European Communities states that there is "no Codex standard specifically on the
risk assessment of effects of residues of veterina ry drugs" but a general one on microbiological
assessment. Is this correct? Which guidelines or principles have been used by JECFA in the
conduct of its risk assessments with respect to th e hormones at issue? [see para. 192 of EC
Rebuttal Submission (US case)]

EC Comments

The European Communities notes the reply of Code x that: "There is no adopt ed Codex standard or
related text on the risk assessme nt of residues on veterinary drugs that provides guidance to
governments (…) the CCRVDF in 2000 started develop texts on risk analysis principles (…) The
documents may be adopted by the Commission in 2007". This statement confirms clearly the EC
position that such standards or guidance are absent in the relevant legal framework. The European
Communities also notes the Codex reply "[no] standard or related text
", which clarifies that there is
absence not only of standards but also of guidelines and recommendations , in the sense of Articles 3
and 5 of the SPS Agreement.

Q5. Please briefly describe the three components of a risk analysis exercise (risk assessment,
risk management and risk communication) as defined by Codex and explain how they differ.

EC Comments

The European Communities has no specific comments other than to recall that its legislation, as
applied to the six hormones, complies fully with the three components and actually goes further than
the Codex work in progress. It is, however, true th at there are some differences between the European
Communities’ and the US’ and Canadian conception of these steps, as Drs. Cogliano and Guttenplan
have explained in their replies, and the question is which philosophy will ev entually prevail in the
future work of Codex. The basic differences between the European Communities and the US and
Canada reside, inter alia , in that the European Communities (i ) is more strict with potentially
genotoxic substances, (ii) does not always require a quantitative assessment of the risk (a qualitative
assessment is acceptable wh en the data support it), (iii) pays more attention to scientific uncertainty
and (iv) applies a higher level of health and environmental protection.

Q6. Please briefly describe the four steps of a risk assessment (hazard identification, hazard
characterization, exposure assessment and risk characterization) as identified by Codex,
indicating any relevant sources.

EC Comments

The European Communities has no speci fic comment at this stage other than to refer the Panel to its
comments on question no 3 of the Panel experts questions.

Q7. Please comment on the EC statement made in para. 140 of the EC Replies to Panel
Questions that "which ever approach of a risk a ssessment is followed, they are all based on a
deterministic approach to risk characterization [and that they] have serious limitations in non-
linear situations, such as in the current case regarding hormones". Are these situations
addressed by the risk assessment guidance cur rently available from the Codex Alimentarius
Commission? [see Canada's comments in para. 72 of its Rebuttal Submission]

EC Comments

The European Communities notes the reply of JE CFA whereby "(…) most risk assessments of
chemicals today on a national and in ternational level are deterministic , i.e. they use a point estimate
for the toxicological endpoint and a point estimate for the exposure assessment (…) this is (…) often a
necessity due to the information at hand. Un certainties around these point estimates should be
considered in the risk assessment process. The current risk assessment process, which includes
consideration of sensitive subpopula tions, is considered to be suffi ciently conservative to be public
health protective." The European Communities also notes the reply whereby "(…) increasing efforts
are under way (…) to explore methods to perform probabilistic risk assessment, i.e. include
distributions rather than point estimates in th e risk assessment process (...) however probabilistic
methods in the toxicological assessment are not ye t internationally agreed and are not yet commonly
applied (…) the outcome of a probabilistic risk assess ment is much more difficult to interpret and
apply by risk managers." More important is JECFA’s comment that: "(…) the probabilistic or
deterministic approaches can be a pplied, independent if a compound is assumed to act via a threshold
mechanism, i.e. non-linear, or not. JECFA’s asse ssment process is based on the mechanism of action
of the compound to be evaluated, non-linearity is assumed if the adverse effect of a compound is
caused via a mechanism with a threshold of effect. In such a case, as for the hormones, a no-effect-
level can be determined from which an ADI can be established."

These comments confirm the EC point that JECFA assumes non-linearity, but dos not look for it nor
does it attempt to prove it. If JECFA’s guess abou t the mechanism of action of the hormones is
wrong, as the evidence submitted by the European Communities shows, then its assumption of non-
linearity (on safe threshold) is obviously wrong. It is recalled again that in the 1999 assessment,
JECFA concluded that oestradiol 17 β has " genotoxic potential ", it found that progesterone " on
balance" is not genotoxic, and that the evid ence on testosterone was ambivalent . This shows that a
slight error when JECFA draws its balance of th e evidence can be catastrophi c for human health, as
its was with so many substances in the past, and most clearly with the evaluation of Carbadox referred
to by the EC in its rebuttal submissions (at paras. 150-152 of US panel).

The Panel would have to understand that these comments by the European Communities are not
trivial. Dr. Boobis
 (like JECFA) came to the conclusion that these hormones are not genotoxic on the
basis of the so-called "weight of the evidence" appr oach, meaning that in their view the majority of
the evidence does not yet accept that th ey are genotoxic by a direct mechanism of action, and this is
because on their view there are not yet enough experiments in vivo. This, however, is disputed by the
European Communities on the basis of evidence conducted both in vitro and in vivo.

Finally, JECFA states that in its reports and in the toxicological monographs on the safety assessment
of the hormones it has"(…) used risk assessment prin ciples particularly targeted to the evaluation of
such substances (…) [and has considered] (…) othe r relevant toxicological end-points, such as
reproductive toxicity, genotoxicity and potentia l carcinogenicity." The European Communities

contests the scientific accuracy and truth of this statement, because JECFA did not consider carefully
many important end-points, such as the effects on pre-pubertal children, on the immune system,
endocrinological effects, etc. The European Comm unities refers the Panel to the replies of Drs.
Cogliano, Sippel and Guttenplan to the Panel questions in this regard.

Q8. Do JECFA or Codex materials confirm Cana da's statement in para. 80 of its Rebuttal
Submission that "... while international risk a ssessment techniques suggest that a dose-response
assessment is optional for biological or physica l agents when the data cannot be obtained, a
dose-response assessment should always be conducted for chemical agents ..."? [see
Exhibit CDA-25]

EC Comments

The European Communities first likes to clarify that the question should have not asked whether there
are "JECFA or Codex materials" but "JECFA or Codex materials that have been lawfully approved by
the members of the Codex Alimentarius Commi ssion". Furthermore, the European Communities
considers that there is no reason to evaluate differently chemicals as opposed to biological or physical
agents. The dose-response assessment can be done bot h qualitatively and quantitatively, if the data so
permit. The European Communities has done a qualita tive assessment in the c ase of these hormones.
The difference is that JECFA based its findings on a no-effect-level only, whereas the European
Communities found also that there is no safe threshold.

Q9. Please provide definitions for the followin g terms: Acceptable Daily Intake (ADI) and
Maximum Residue Limit (MRL).

EC Comments

The European Communities notes that the above definition from the 66 JECFA meeting, which covers
also metabolites and associated impurities, was not the one followed when JECFA evaluated these
hormones. Moreover, the definition of an ADI does not mean that there is no risk, as the defending
parties and JECFA imply, but that there would be no "appreciable
 health risk". But whether the risk is
"appreciable" or not is for each WTO Member to deci de. This is precisely the function of its desired
level of health protect which can be no (or zero) additive risk, and which is the level of protection
applied by the European Communities in the case of these hormones when administered for animal
growth promotion purposes.

Q10. Please describe the procedure followed by JECFA in the identification of ADIs and the
development of recommendations on MRLs. Please also identify and describe any steps that are
taken in the risk assessment process to build a margin of safety into to the final
recommendation.

EC Comments

The European Communities notes that according to JECFA, "(…) in setting ADIs, an attempt is made
to take account of special subpopulations that may be exposed." However, as the European
Communities has shown, this is not properly done in the case of these hormones because the data used
by JECFA for the endogenous production by pre-p ubertal children are no longer valid. Moreover,
JECFA states that it "(…) uses the risk assessment process when setting the ADI, i.e. the level of "no
apparent risk" is set on the basis of quantitative
 extrapolation from animal data to human beings."
This statement contrasts with its statement to the previous question, where it claims that it performed
a qualitative assessment. In any case, whether qualitative or quantitative, JECFA did not use in all of

its calculations data from residues in meat from animals treated with these hormones for growth
promotion purposes, as it is erroneously stated by the defending parties and the Codex and JECFA.

The European Communities also notes that JE CFA "may recommend MRLs "not specified" or
"unnecessary" when there is a wide margin of safety of residues when compared with the ADI (...)"
and that "(…) JECFA may determine that MRLs cannot be recommended because of significant
deficiencies in either residue data or available anal ytical methods or when an ADI is not established."
It is crucial to note, however, that in the case of the three natural hormones JECFA did not specify
MRLs because it found them "unnecessary". But this is utterly unscientific because there is no "wide
margin of safety" for residues of these hormones give n that it has been already established clearly that
the endogenous circulating levels alone have been found to cause cancer for some individuals. It was,
therefore, imperative for JECFA to evaluate the ad ditive risk that the residues in meat from treated
animals can pose to human health. This JECFA has fa iled entirely to do so, for the simple reason that
there are currently no sufficiently powerful analytical methods to detect the origin of residues from
the three natural hormones in meat, i.e. whether th ey are of endogenous or exogenous source. This is
the only true reason for which JECFA did not specify MRLs in 1988 and in 1999, after it had found
that an ADI had to be established. This is clearly stated in the 1988 evaluation of the three natural
hormones by JECFA, where it is explicitly stated:

"The Committee concluded that residues arising from the use of oestradiol-17 β [and
progesterone and testosterone] as a growth promoter in accordance with good animal
husbandry practice are unlikel y to pose a hazard to human health. The Committee
recognized that most methods of analysis for orstradiol-17 β [and progesterone and
testosterone] are radioimmunoassays, whic h usually have a large co-efficient of
variation at the concentrations being measured. While these methods may be
satisfactory for measuring oestradiol-17 β [and progesterone and testosterone] levels
in experimental situations, improvements would be needed if routine analytical
methods for the control of residues were required. On the basis of its safety
assessment of residues of oestradiol-17 β [and progesterone and testosterone], and in
view of the difficulty of determining the leve ls of residues attributable to the use of
these hormones as growth promoters in ca ttle, the Committee concluded that it was
unnecessary to establish an Acceptable Residue Level [i.e. an MRL]" (see WHO
Technical Report Series no 763, page 19, 1988).
However, this passage from the 1988 JECFA re port on the three natural hormones has now
mysteriously disappeared from the 1999 JECFA re port on these hormones without any explanation,
other than that there is now "a wide margin of safety". So, JECFA finds itself now in the paradoxical
situation of having for the first time to establish ADIs for the three natural hormones but is not in a
position to fix MRLs for their residues! And the expl anation it has offered was to say that they are
"unnecessary". But are they really "unnecessary", given the endogenous production levels by
prepubertal children and the widespread misuse and abuse of these hormones found in the US and
Canada?

The European Communities would su ggest to the Panel to ask JECFA to clarify its position on these
precise points.

Finally, it is also interesting to note that according to JECFA "[A]s a general principle, the Committee
will not normally recommend an MRL that results in residue levels that lead to dietary intake
exceeding the ADI based on toxicological or micr obiological considerations." The European
Communities has demonstrated that there is such a clear possib ility of the ADIs being exceeded
routinely. As the European Communities has expl ained in its Written Submissions, this has been
explicitly recognised also in the US Carcinogen esis Report since 2002, and it is confirmed by the

replies of the experts to the questions of the Pane l, in particular those of Dr. De Brabander and
Dr. Sippel.

Q11. Please confirm or comment on the following Canadian statement: "it is recognized that
JECFA only allocates an ADI for a food additi ve or veterinary drug under review when JECFA
considers that its scientific data base is comple te and that there are no outstanding scientific
issues". [see para. 68 of Canada Rebuttal Submission]

EC Comments

The European Communities notes that there is a wide discrepancy between the theory and reality, in
particular given the narrow mandate of JECFA, th e potentially subjective interpretation of the data,
and the opaqueness of its procedures and the data it uses in its assessments. JECFA’s reply does not
convince because it does not provide the data upon which it based its assessment for verification and
peer-review by independent scientists.

Q12. In paras. 129 and 168 of its Replies to the Panel's questions, the European Communities
states that "JECFA's traditional mandate does no t allow it to examine all risk management
options but restricts it to either propose MRLs or not." Does Codex have risk management
options other than (1) the establishment of an MRL, (2) the establishment that an MRL is not
necessary, or (3) no recommendation?

EC Comments

The European Communities notes that the replies of both Codex and JECFA confirm that the latter
does not have the mandate to examine risk management options other than to propose or not ADIs and
MRLs, and it has not been asked to consider such options when it examined these hormones.
Moreover, both Codex and JECFA appear to have an extremely narrow understanding of what
constitutes risk management: for instance, they appear to think that the question whether an identified
(and characterised) risk is or is not "appreciable" is a risk assessment issue. This is not correct, as this
issue is by definition a risk management question an d it is a function of the chosen level of protection
by the risk manager. A risk assessor’s role, like that of JECFA, should be to identify only if there is a
risk and to explain any scientific uncertainties that may surround its assessment. Its assessment of the
risk may be qualitative or quantitative, but the decisi on whether a scientifically assessed risk (e.g. of
cancer) is "significant" or "appreciable" is, strictly speaking, a risk management decision. It follows
that JECFA does perform also risk management f unctions in the Codex system, despite its formal
denial of doing so.

Q13. With respect to the data used in the eval uation of chemical substances, such as the
hormones at issue, what are the data requi rements for JECFA's work and how are they
determined? Who provides data for such eval uations? Are any records/archives kept by
JECFA? Do any confidentiality rules apply to da ta submitted to JECFA or should all data be
publicly available? If confidentiality rules apply, in which circumstances? [see paras. 95-96 of
EC Rebuttal Submission (US case), paras. 78-79 of EC Rebuttal Submission (Canada case),

EC Comments

The European Communities would note the following statements by JECFA:

• "the data are mainly provided by companies who produce the compounds;

• the submitted data may be published or unpublished and should contain detailed
reports of laboratory studies, including individual animal data;
• summaries in the form of monographs are he lpful, but they are not in themselves
sufficient for evaluation;
• the unpublished confidential studies that ar e submitted will be safeguarded and will
be used only for evaluation purposes by JECFA;
• neither FAO nor WHO have facilities for st oring printed data for long periods of
time, so confidential data will either be re turned to the submitter at the submitter's
expense or destroyed after the evaluations have been completed;
• key material can be stored up to five years and will then be destroyed."

These statements confirm the EC position that JECF A has had access to the detailed reports provided
by the industry, but failed to provide them to the European Communities. The European Communities
has been asking for these confidential and unpublished data since 1999, so JECFA cannot pretend that
it had destroyed them already at that time!

JECFA claims that "it is important to note that JE CFA evaluations are completely publicly available,
and a detailed description of the data evaluate d is accessible through the monographs." But these
monographs are not the original of the data used but processed and reworked information which does
not enable scientists to verify the accuracy of the design of the st udy, of the experiments carried out,
of the interpretations made and the conclusi ons drawn and for what reasons. The European
Communities has not been asking for informati on regarding "the manufacturing process of
substances, which are considered confidential for commercial purposes", but for the specific scientific
studies (toxicological and residues analysis) in order to verify the scientific validity of these studies
and the accuracy of the conclusions drawn by JECFA (and the defending parties). The European
Communities has rendered public and pr ovided its own studies to all the parties; therefore, it fails to
understand why the US, Canada and JECFA (and Codex) continue to deny access to their own data.

The European Communities reiterates, therefore, its standing request to the Panel to order the
production of their so-called conf idential and unpublished data, if the credibility of their assessments
and of this process is to be maintained. Otherwi se it has to draw the necessary negative inferences
from the failure to provide the requested data.

Q14. How are experts involved in JECFA's work selected? What are the selection criteria?

EC Comments

The European Communities simply notes that in th e evaluation of the six hormones by JECFA have
participated scientists who have no specific e xpertise on these hormones, like Drs. Boisseau and
Boobis, since they have not worked on nor have pub lished anything on these substances when used
for animal growth promotion purposes. From the JECFA reply it is not clear to the European
Communities whether the selection of JECFA’s experts is as strict as that applied in the case of IARC
(see its reply to Panel question no 22). The European Communities would ask the Panel to clarify
further this point.

Q15. Please provide the definition of the term Good Veterinary Practice (GVP). Are there
any relevant Codex standards, guidelines, or recommendations relating to GVP?

EC Comments

The European Communities notes that there is cu rrently no definition nor guidelines on GVP in
Codex and JECFA, as this is confirmed by the replies of Dr. Boisseau and Dr. De Brabander (question
no 44 to experts).

Q16. Please provide an update on the status of international standards with respect to the six
hormones at issue. What are the remaining pro cedures before the adoption of a standard on
melengestrol acetate (MGA)? What is the timeframe for their completion?

EC Comments

The European Communities notes that the Codex sta ndards on the five hormones were adopted by a
very slim majority vote in Codex, despite the Codex’ statement that decisions are taken by consensus.
Indeed, the Codex standards were adopted in 1995 with 33 votes in favour, 29 votes against and 7
abstentions, that is by a minority of the members present and voting (see para. 4.77 of the 1997 Panel
report, WT/DS26/R/USA, at page 39). Their assessment by JECFA dates of 1988. The Codex reply
also confirms the EC position that currently there exists no standard for MGA.

Q17. Is the table in Exhibit CDA-32 outlining th e chronology of JECFA's assessment of the
hormones at issue and the resulting documentation complete?

EC Comments

The European Communities wish es to clarify that the 66 th JECFA meeting (held 20 - 28 February
2006) deliberated on the MRLs previously proposed for melengestrol acetate. It did, however not
consider any new data but limited itself to the corr ection of a calculation error. The EC highlighted
this during the recent 16 th Session of the CCRVDF that no original data were presented in the review
(see ALINORM 06/29/31 paragraph 69).

Q18. What happens if new evidence or studies throw into doubt a Codex standard? What are
the procedures for incorporating more recent developments into Codex work? Has the
European Communities approached Codex for th is purpose with respect to the hormones at
issue in this case?

EC Comments

The European Communities notes the statement that "in the case of estradiol-17 beta, progesterone
and testosterone, they were re-evaluated by th e 52n JECFA (1999) at the initiative of the JECFA
Secretariat", and that "the 12
th CCRVDF (2000), in recognising that it had not requested the re-
evaluation of the three substances and that the new MRLs recommended by the 52n JECFA did not
differ significantly from the current MRLs, decided to not consider the new recommendation of the
52
nd JECFA." There are many comments one can make on this statement. First, it is quite unusual for
substances to be re-evaluated at the request of JE CFA’s Secretariat, despite the written request of one
of its members (who represented at the time 15 countr ies) to postpone the re-evaluation for a couple
of years in view of the expected new evidence that was about to become soon available. Indeed, most
of the new evidence generated by the European Communities became available between 1999 to
2002. The European Communities would like to ask JE CFA if this has ever happened in other cases.
The European Communities has never understood what would have been the problem if its request for
postponement were taken into account.

The European Communities notes that JECFA and Codex do not reply to the second part of the
question. In any case, it is surprising that the same JECFA Secretariat, which used to be common with

that of Codex, is now not propos ing to review again these hormones, despite the wealth of the new
evidence that became available from so many s ources and the standing request by the European
Communities.

It is also noteworthy that the CCRVDF did not adopt the 1999 assessment of the three natural
hormones by JECFA, which may mean that this 1999 assessment is of no relevance for the purposes
of these disputes.

As regards MGA, the European Communities has re quested its re-evaluation on the basis of more
recent scientific evidence.

Q19. What would be the procedures fo r requesting JECFA to re-evaluate its
recommendations in light of new concerns/eviden ce? How would an amendment be adopted?
Has the European Communities approached JECF A for this purpose with respect to the
hormones at issue in this case? [see Exhibit EC-63]

EC Comments

The European Communities notes the statement by JECFA that the "European Union has not asked
the JECFA Secretariat to bring their data referred to in the report of the 11
th session of CCRVDF (see
below point 1 of question 20) before JECFA for re view." This is not correct because there is a
standing EC request to review the hormones on the basi s of the latest information available, including
that generated by the European Communities.

Q20. What were the reasons for the re-evaluati on by JECFA of the three natural hormones in
1999? Were the residues data used for the three natural hormones in 1999 the same as those
used in 1988? What additional information was used for the JECFA evaluation in 1999 of the
three natural hormones, which was not availabl e in 1988? How did the conclusions differ?
What led JECFA to establish ADIs for the three natural hormones? What are the implications
of establishing ADIs? Why were JECFA's mo re recent recommendations not considered by
CCRVDF? What is the status of these recommendations? [see para. 96-97 of EC Rebuttal
Submission (US case), para. 79-80 of EC Rebuttal Submission (Canada case)]

EC Comments

The European Communities refers the Panel to its submissions and in particular Exhibit EC-63, which
provides a more detailed account of the events with precise references to the original letters. It is
unfortunate that JECFA states that it "decide d to re-evaluate previous assessment when the
Committee is made aware that there is new data whic h may be pertinent to th e risk assessment of the
substances in question", but failed to wait for the most important part of these data to become publicly
available.

The European Communities draws the attention of the Panel to the statement that "most of the studies
were the same", which confirms the EC position. The European Communities also notes that "a
complete dossier submitted to the US Food and Drug Administration" was provided and that the
"FDA kindly permitted the FAO expert to the Committ ee to search all their relevant files for data."
This statement confirms again the EC position that the US and JECFA could have provided the same
data also to the European Communities as it has been consistently requesting.

JECFA states that it performed "a more detailed th orough review of the validity of the analytical
methods used in the studies and used only data gene rated using valid methods. It also performed more
detailed statistical and graphical analyses of the data." However, since most of the data were the same
old data, one wonders what kind of thorough processing JECFA now di d, which it had failed to do in

its 1988 assessment of the same data. This is all the more crucial given that the data in question are
unpublished data of the 1970s. The European Co mmunities recalls that th is so-called "thorough
review" seems to have been performed by Dr. Arnol d, who has himself declared to this Panel during
the selection procedures that he believes eating m eet treated with these hormones poses "no increased
health risk for consumers".

JECFA also states that "a few additional investiga tional studies were also reviewed", but it does not
explain which ones and how important they were for its assessment. JECFA further states that "since
the FAO FNP 41/12 monograph provides all raw data used (in graphical form) and all the calculations
performed, the document is also more transparent than the corresponding monograph produced by the
32nd Meeting". The European Communities reitera tes that it precisely has been claiming for
transparency in the JECFA proceedings, and a graphi cal presentation of the same old data is not what
one would normally understand by transparency.

JECFA states that "this conclusion was based on studi es of the patterns of use of estradiol for growth
promotion in cattle, the residues in animals, analytical methods, toxicological data from studies in
laboratory animals, and clinical findings in hu man subjects." The European Communities disputes
that such detailed studies have been performed and re iterates its standing request to be given access to
these data or to be made available to the Panel and its experts for review.

JECFA further states that "at its 52nd meeting in 1999, estradiol-17 β was re-evaluated to take into
consideration any data that had b een generated since the previous review and to make a quantitative
estimate of the amount that could be consumed safely. The Committee established an ADI of 0-50
ng/kg bw on the basis of the NOEL of 0.3 mg/day (equivalent to 5 μg/kg bw per day) in studies of
changes in several hormone-dependent parameters in postmenopausal women. A safety factor of 10
was used to account for normal variation among indi viduals, and an additional factor of 10 was added
to protect sensitive populations." This confirms that (i) JECFA did not consider residues in meat from
animals treated with these hormones for growth pr omotion purposes, (ii) it based its ADI on "changes
in several parameters in postmenopausal women" but not on the much lower rates of prepubertal
children (as did the European Communities), and (iii) it sought to address these problems with the
application of safety factors!

The European Communities notes that statement of JECFA that "the 52nd JECFA performed a
detailed theoretical intake assessment based on a wors t case scenario (all anim als are slaughtered at
the time of the highest hormone levels - this time point differs largely from the time point at which the
benefit due to the anabolic effect is greatest). In this assessment intake estimates for preferential meat
eaters were performed on the basis of the hormone le vels of treated animals in comparison with the
corresponding levels in untreated animals and the additional "burden" or "excess intake" was
calculated. For total estrogens the highest excess intakes from approved uses calculated this way were
in the order of magnitude of 30 – 50 ng/person/day. This range of intake is less than 2% of the ADI
for estradiol-17β established by JECFA at the 52nd meeting. For certain experimental studies carried
out with experimental combinations resulted in an excess intake of around 4% of the ADI." The
European Communities would like to see the original of these underlying data, as the similar or more
detailed studies and experiments in has generated itself provided di fferent and in many cases much
higher values (see e.g. Exhibits EC-16, 17, 18, 19, 34, 47, 52, 53 and 78). The same applies for
testosterone and progesterone.

JECFA states that "hormone concentrations found in individual populations of treated animals,
although they were typically statistically significan t higher than untreated controls, were well within
the physiological range of these substances in bovi ne animals. The data assessed and the worst case
scenario calculations made indicated a wide margin of safety of consumption of residues from
animals treated in accordance with good practice of use of the veterinary drugs containing the
hormones in question. JECFA therefore concluded that there was no need to specify numerical

maximum residue levels for the three hormones and recommended MRLs not specified in bovine
tissues." This is an important statement that need s to be factually substantiated. The European
Communities notes that the hormone concentrations found in treated animals were significantly
higher than in untreated animals.

As for the reasons for which JECFA established in 1999 ADIs, the European Communities notes the
statement that this was due to "the additional da ta reviewed and the need to establish an ADI as
quantitative estimate for a safe oral intake. The e xposure assessment performed would then allow the
comparison of the estimated intake with the ADI." Th us, this confirms the EC position that it was the
new evidence showing risk of cancer that le d JECFA review its 1988 assessment. And if JECFA
postponed its assessment until the new and more recen t data generated by the European Communities
were taken into account, it could have reached still a nother and arguably more accurate conclusion. In
any case, it is clear that in 1999 JECFA did not establi sh ADI in order explain better its evaluation, as
it is claimed erroneously by Dr. Boisseau
 (see his reply to Panel question to the experts no 18).

JECFA states that "sufficient new data from ob servations in humans were available to the 52nd
JECFA which were suitable to derive ADIs." The European Communities does not know and has not
seen these "data from observations in humans" and, if th ey exist, they are certainly different from the
data it has generated itself with its own studies. JECFA should therefore provide them to the parties,
the Panel and its experts for review. Moreover, th e so-called "wide margin of safety" claimed by
JECFA to exist is no longer credible in view of the "significantly higher levels" identified in treated
animals and the need to establish ADIs, not to men tion their direct genotoxicity and the other adverse
effects established by the European Communities. Furthermore, the EC scientists rightly question why
MRLs were not established in 1999, given that JECF A had felt nevertheless the need to establish
ADIs. Was it for the alleged "wide safety margin" or simply because "of the difficulty of determining
the levels of residues attributable to the use of this hormone as a growth promoter in cattle", as
JECFA had admitted in 1988? But if the latter was the real reason, this means that JECFA did not
carry out a quantitative dose-response assessment of residues in meat from treated animals under
realistic conditions of use, as it is argued by the European Communities.

Q21. What is the mandate of the Intern ational Agency for Research on Cancer?

EC Comments

The European Communities has no specific comment at this time.

Q22. Who are the members of the IARC?

EC Comments

The European Communities has no specific comment at this time.

Q23. What are IARC Monographs? How are they prepared?

EC Comments

The European Communities notes the IARC statemen t that "when the epidemiological evidence is
sufficient, the final evaluation is carcinogenic to humans, regardless of the experimental evidence. In
other cases, the mechanistic and other relevant data are considered to determine whether the default
evaluation should be modified, upwards or downwar ds. A subgroup of experts in cancer mechanisms
assesses the strength of the mechanistic data and wh ether the mechanisms of tumour formation in
experimental animals can operate in humans. The overall evaluation is a matter of scientific
judgement, reflecting the combined weight of the evidence."

The European Communities would like further clarif ications on the following points: Does the above
statement mean that a substance can be classified in Group 1 even if there are no or a limited number
of experiments showing genotoxicity in vivo? Moreover, in which of the different groups are
genotoxic substances classified? How does IARC define genotoxic substances?

Q24. Please briefly explain the groupings that a re used to categorize "potentially carcinogenic
agents"? What are the implications when an "agent" is placed in one of the IARC categories?

EC Comments

The European Communities would like to request the following clarifications: 1) Would the IARC
describe its assessments as risk assessments or as assessments that also include risk management? 2)
When a substance is placed in Groups 1, 2A a nd 2B, what is the majority of IARC’s members
normally expected to do? To authorise or prohibit th e substances in question? On what else does their
decision depend? 3) Is the assessment performed by IARC a qualitative or a quantitative assessment
of potential risk? 4) Is the IARC classification of various groups based on dose-response estimations
under realistic conditions of use of the various su bstances? 5) Is the classification based only on
experimental data in animals and extrapolations to humans or do they include also data from residues
which such substances may leave in food?

Q25. Which of the six hormones at issue in this dispute (oestradiol-17 β, progesterone,
testosterone, trenbolone acetate, zeranol, and me lengestrol acetate) have been evaluated by the
IARC? Have any specific risks from the consum ption of meat from cattle treated with these
growth promotion hormones been assessed by the IARC?

EC Comments

The European Communities notes the statement that "Trenbolone acetate, zeranol, and melengestrol
acetate have not been evaluated by IARC, nor have the specific risks from the consumption of meat
from cattle treated with these growth promotion hormones", and would like the following
clarifications: 1) Does it mean that IARC’s evalua tion of the three natural hormones covers also the
specific risks from the consumption of meat from cattle treated with those hormones for growth
promotion? 2) Can the IARC be more specific on the last part of the question? 3) Is it possible a
pharmacologically active substance that is classified in Group 1 to ever lead residues in food of this
substance to be classified into a different categor y? 4) If so, under what conditions can this take
place?

Q26. How does the work of the IARC feed into the work of national regulatory agencies or
international bodies, in particular with respect to assessments of risks from the consumption of
meat from cattle treated with the six growth promoting hormones at issue in this dispute?

EC Comments

The European Communities would like IARC to clar ify what it means by "as scientific support for
their actions"? Does it mean that they can be used as risk assessments? Are they normally
scientifically complete and adequate to be used as risk assessments? Could IARC be more specific
and reply to the last part of the question concerni ng the consumption of meat from cattle treated with
the six hormones or at least for the three hormones that it has assessed and classified?

ANNEX F-3

COMMENTS BY THE EUROPEAN COMMUNITIES TO THE COMMENTS
BY THE UNITED STATES AND CANADA ON THE REPLIES
OF THE SCIENTIFIC EXPERTS TO QUESTIONS POSED BY THE PANEL

(12 July 2006)

Introduction and general comments

1. The European Communities tha nks the Panel for the opportunity to comment on the other
Parties' comments on the Panel's experts' replies. Before setting out its comments the European
Communities would like to make two preliminary remarks of a general nature.
2. First, the European Communities notes that the United States, in its comments, has chosen to
follow its own structure in what may well be cons idered a full-fledged additional submission. Apart
from the fact that reference is made to legal cl aims which the United States has not made anywhere
(e.g. Article 5.6 of the SPS Agreement , see paragraph 5 of the US submission), the European
Communities considers that this approach is conf using and of little assistance to the Panel and its
experts as well as to the other parties. It is not surp rising that the US has resorted to this tactic, as the
replies of the majority of the experts support the scientific evidence and the arguments of the
European Communities.
3. In order to facilitate a structured debate, the European Communities will try to disentangle the
misleading comments made by the United States . Also, for the same purpose, the European
Communities makes but one set of comments, which a ddresses the Canadian and (as best as possible)
the US comments following the order of the questions as asked by the Panel to the experts and the
international bodies.
4. Second, in light of the other Parties' comments on this general issue, it seems appropriate to
briefly come back to the role of experts in th ese panel proceedings. As the European Communities
has pointed out in earlier submissions (in particul ar in its submission of 15 March 2006), the purpose
of the scientific questions and the role of the expe rts is to help the Panel understand the scientific
issues involved. Neither the Panel nor the experts should aim to conduct their own risk assessment or
to conduct a de novo review of the sanitary risks identified by the European Communities.
 The task of
the scientific experts is to assist the Panel in assessing whether the scientific basis of the measure
taken by the European Communities complies with the recommendations and rulings of the DSB in
the EC – Hormones case. But the experts should not make comments on risk management options,
since this is not their expertise or role. Therefore, the focus of the scientific questions should be to
help the Panel understand the risk assessment co nducted by the European Communities since the
adoption of the Panel and the Appellate Body re ports in 1999. Unfortunately, as the European
Communities has demonstrated by its comments of 30 June 2006, the replies of Dr. Boisseau and
Dr. Boobis have not always complied with the above requirements.
A. GENERAL DEFINITIONS
Q1. Please provide brief and basic definitions for the six hormones at issue (oestradiol-17 β,
progesterone, testosterone, trenbolone acetate, zeranol, and melengestrol acetate), indicating the
source of the definition where applicable.

5. The United States and Canada have not referred to or commented in substance on the experts'
(Drs. Boisseau, Boobis and Guttenplan
) replies to this question.

Q2. Please provide definitions for the following te rms as they relate to the hormones at issue,
indicating the source of the definition where a pplicable: anabolic agents, steroids, steroidal
oestrogens, parent compounds/metabolites, catech ol metabolites, mitogenicity, mutagenicity,
androgenic/oestrogenic activity, genotoxicity , genotoxic potential, carcinogenicity, and
tumorigenicity. In your replies, please be sure to identify and describe any relevant differences
between the terms.

US comment

6. The United States has not referred to or comme nted on the experts' (Drs. Boisseau, Boobis
and Guttenplan) replies to this question.
Canada's comment

7. The comments by Canada (at paras. 8-9) are not accurate. The statement that a substance (in
this case oeastradiol-17 β) "has genotoxic potential" does not mean that there is a "statistically
likelihood" that it is carcinogenic (this is not wh at the European Communities has argued) but that on
the basis of the evidence av ailable, in particular in vitro studies, the genotoxicity of the substance is
possible. This is not a theoretical statement but a fr equent conclusion scientists make for this type of
substances. In addition, in this case there is also in vivo evidence supporting that statement.
Dr. Boobis and Canada may not like this evidence or would like to see more in vivo evidence before
they are convinced, but this is irrelevant. The Eur opean Communities is entitled to rely on this recent
and credible evidence if necessary to achieve its level of health protection.
B. RISK ASSESSMENT TECHNIQUES
Q3. Please identify any international guidance documents relevant to the conduct of a risk
assessment with respect to veterinary drug residu es. Since when have they been available?
Please also indicate if there is any relevant ongoing work at Codex.

US comment

8. The US comments on Question 3 are contained in paragraph 13 of its submission. The
European Communities notes that there is genera l agreement among the parties that there is no
internationally agreed risk assessment technique , within the meaning of Article 5.1 of the SPS
Agreement, for the assessment of these hormonal substances. It is equally uncontested by all that there
exists a number of documents which represent at most a practical understanding among some
international experts on certain principles. These documents do not have an y legal value under the
SPS Agreement since they are not "risk assessment techniques developed by the relevant international
organisations." In any event, the European Co mmunities notes that neither the US nor the experts
claim that the European Communities has not followed these.
Canada's comment

9. Canada's comments (in particular at paras. 14-15) do not accurately describe the legal
relevance of the documents to which it and JECFA ha ve referred to. Canada states that many of the
risk assessment techniques and methodologies "are also relevant to the risk assessment of veterinary
drugs". However, these are no risk "assessment t echniques" in the first place, in the sense of
Article 5.1 of the SPS Agreement and, secondly, they cannot be applied by analogy to other kind of
substances than for those for which they have been foreseen.
Q4. The European Communities states that there is "no Codex standard specifically on the
risk assessment of effects of residues of veterina ry drugs" but a general one on microbiological

assessment. Is this correct? Which guidelines or principles have been used by JECFA in the
conduct of its risk assessments with respect to th e hormones at issue? [see para. 192 of EC
Rebuttal Submission (US case)].

US comment

10. The US comments on the experts' replies to this question are contained in paragraph 13 of its
submission. As stated above, these documents reflect the general discussion in the absence of an
internationally agreed risk assessment technique and the presence of certain guidance documents.
However, the United States misquotes Dr. Boisseau
 when pretending that he was referring to the
"assessment of such drugs "[i.e. the hormonal substa nces in question] when stating that "it has been
internationally harmonised through scientific conferences …". Dr. Boisseau was not referring to the
assessment as such, but to a "general rationale " on that assessment. Indeed, if there is some
understanding among certain scientists on a gene ral way of conducting a risk assessment, the
European Communities applies this as much as any other country.
Canada's comment

11. Canada maintains that, despite of the accuracy of the relevant EC statement "any suggestion
that relevant risk assessment techniques or guidan ce developed by international organizations for the
conduct of veterinary drug risk assessments do not exist is baseless".
12. In the European Communities' view, Canada is misinterpreting the replies of Dr. Boisseau
and Dr. Boobis. First, it should be underlined that bo th experts (and in addition Dr. Guttenplan ) have
confirmed the accuracy of the EC statement. Se cond, the existing general JECFA guidelines to which
Drs. Boisseau and Boobis refer can not be taken – as Canada does – as a replacement of an
international detailed Codex st andard which alone would be of legal relevance under the
SPS Agreement.
13. JECFA might have produced certain intern al guidelines on risk assessment for certain
substances. However, it is a totally different matt er to elevate internal JECFA papers, which have
never been approved by Codex Members, into the ra nk of an international standard. Thus, Canada's
insinuation and interpretation of the replies by Dr. Boisseau and Dr. Boobis is inaccurate and
unacceptable.
Q5. Please briefly describe the three components of a risk analysis exercise (risk assessment,
risk management and risk communication) and explain how they differ.

US comment

14. The United States has not provided comments on the experts' (Drs. Boobis, Boisseau,
Cogliano, Guttenplan) replies to this question.
Canada's comment

15. In summarizing the experts' replies, Canada reproduces Dr. Boobis' response and presents this
as the common denominator of the experts. However, there are differences. For instance, in respect of
the "risk assessment" Dr. Boobis introduces a concept of the "weight of evidence", which is not found
in the replies by Dr. Boisseau, Dr. Cogliano or Dr. Guttenplan . These experts rather emphasize the
risk assessment as an evaluation of risk (Dr. Guttenplan ), a description of the "adverse effects of
exposure of hazardous agents (Dr. Cogliano ) or the "likelihood and the gravity of any unexpected
unwanted effect for the consumer" on the basis of " scientific date, relevant with regard to assessing
this risk" (Dr. Boisseau).

16. These differences are important since Dr. Boobis' reply, which obviously suits Canada best,
implies a margin of discretion in (or balancing and weighing of) the scientific risk assessment
procedure, based on the "weight of evidence", which is not the case for the other experts.
17. Furthermore, as regards the risk management step, Canada again uses the language of
Dr. Boobis reply and tries to "present" it as the common vi ew of all experts. This is, in particular,
interesting since Dr. Boobis refers in this context to "ensuring fair trade" which is not mentioned by
any of the other experts. Instead, these experts refe r to the use of other scientific criteria such as
"economical, sociological, cultural" (Dr. Boisseau ) or "legal mandates, technical feasibility, cost,
equity, and social norms" (Dr. Cogliano ). This is an interesting di fference, because the concept of
"fair trade" is not clearly defined and Canada and Dr. Boobis may have a different interpretation of
this concept than for instance the United States, the European Communities or other experts.
18. Moreover, Canada claims that all experts appear to support the so-called "functional
separation" between risk assessment and risk mana gement (at para. 20). Even if this were so, quod
non, this is irrelevant for the SPS Agreement, because the Appellate Body has interpreted correctly its
provisions in the 1998 Hormones case to partially overlap (at para. 181 of its report).
Q6. Please briefly describe the four steps of a risk assessment (hazard identification, hazard
characterization, exposure assessment and risk characterization) as identified by Codex,
indicating any relevant sources.

US comment

19. The United States refers to the experts' rep lies on this question in paragraph 14 of its
submission trying to make again the erroneous point that the European Communities risk assessment
did not engage in a hazard characterization because it did not evaluate a dose-response relationship.
This is discussed in more detail below under Question 11.
Canada's comment

20. Canada's summary of the experts' rep lies (Drs. Boisseau, Boobis and Guttenplan)
 concerning
"hazard identification" is not accurate. According to Canada, "the experts" agree that hazard
identification "involves the determination of whether an agent has the poten tial to cause adverse
effects" (Emphasis added). However, this is not what Dr. Boisseau, Dr. Boobis and Dr. Guttenplan
say. All of them do not define this step as to "w hether" or not there are adverse effects. Rather,
Dr. Boisseau, Dr. Boobis and Dr. Guttenplan define hazard characterization in respect of the
identification of the different elements causing adverse health effects in humans.
21. In respect of the "hazard characterization" it is not true, as Canada summarizes it, that all
experts refer in their definition to a "dose-response assessment" or the determination of thresholds, i.e.
an NOAEL or an ADI. Indeed, Dr. Guttenplan merely refers to the "quantitative and/or qualitative
evaluation of the nature of the adverse health effects associated with the hazard" without referring to a
dose-response relationship or the establishment of whatever threshold. But even Dr. Boobis or
Dr. Boisseau clearly condition the dose-response threshold aspects to "whether or not this is possible".
Consequently, Canada's implied conclusion that these elements form an "integral part" of the risk
assessment which the EC failed to complete are a serious mischaracterization of the experts' replies.
22. As regards the definition of the "exposure assessment" Canada, again, does not provide a
proper summary of the experts' replies even though it pretends that all experts have the same view.
Canada uses the words of Dr. Boobis to define the exposure assess ment as a step to evaluate

"quantitatively" the exposure of consumers to veterinary drugs.
1 However, Dr. Boobis and
Dr. Guttenplan refer explicitly not only to the quantitative aspects, but also to the " qualitative
evaluation of the likely intake".
23. In respect of the "risk characterization" Cana da again generalizes from one expert reply and
presents them as a common reply of all experts. This is obvious when Canada quotes Dr. Boisseau's
statement whereby risk characterization "is not to assess qualitatively and quantitatively the likelihood
and gravity of the adverse effects of consumers (…) but to protect consumer's health from any adverse
effect associated with residues". In this context, Ca nada also pretends that all experts confirm that an
MRL would be established. This presentation is simply wrong. In fact, neither Dr. Boobis nor
Dr. Guttenplan refer to the "protection of consumer h ealth from any adverse effects" and to the
establishment of MRLs. Rather, both experts limit th emselves to the qualitative and, where possible,
quantitative determination, includi ng attendant uncertainties, of the likelihood of occurrence or
severity of potential adverse health effects. It follows, therefore, that Dr. Boisseau's reply contains a
subjective judgement and a procedural step which is not supported by Dr. Boobis and Dr. Guttenplan,
contrary to what Canada pretends. Moreover, Canada persists in its error to consider that it is the
"probability" of occurrence of the adverse effect that counts, when the Appellate Body has clarified in
the Hormones case that it is not the probability but the likelihood (or possibility) that is meant by
Annex A(4) of the SPS Agreement.
Q7. Please comment on the EC statement made in para. 140 of the EC Replies to Panel
Questions that "which ever approach of a risk a ssessment is followed, they are all based on a
deterministic approach to risk characterization [and that they] have serious limitations in non-
linear situations, such as in the current case re garding hormones". Are these situations, in your
view, addressed by the risk assessment gu idance currently available from the Codex
Alimentarius Commission? Have they been addressed in the 1988 and 1999 JECFA risk
assessments of these hormones? [see Canada 's comments in para. 72 of its Rebuttal
Submission]

US comment

24. The United States refers to the experts' replies to this question in paragraphs 15, 16 and 17 of
its submission. Here again the US refers selectivel y to the "experts" views, when only Drs. Boisseau
and Boobis appear to support what the US is arguing. Mo reover, the basic error of these scientists, of
the US (and Canada for this matter) and of JECFA is that they all argue that oestradiol is not
genotoxic but acts only through hormone-mediated re ceptors. On the basis of this erroneous
assumption, based on old and outdated data, they all come to the conclusion that there is a threshold
dose below which there was no appreciable risk over a lifetime of exposure.
25. This kind of statement by the US is surprisi ng given that its own scientists no longer agree
with this assertion. The US Carcinogenesis Repor t since 2002 has classified oestradiol as a proven
human carcinogen (see Exhibit EC-101). Indeed, the above US report states inter alia:
"The evidence is strong that estrogen carcinogenesis is mediated through activation of
the estrogen receptor. In addition, there is evidence that other mechanisms may play a
role in the carcinogenic effects of estrogens in some tissues. Prolonged estrogen
exposure induces cell proliferation in estroge n-dependent target cells, affects cellular
differentiation, and a lters gene expression. Although the molecular mechanisms
responsible for estrogen carcinogenicity are not well understood, the evidence
indicates that estrogen carcinogenesis is complex, involving pr oliferative effects and

1 Canada and Dr. Boisseau, however, differ on th e food basket which according to Canada contains
300g muscle, whereas Dr. Boisseau refers to 500g muscle.

possibly direct and indirect genotoxic effects. The relative importance of each
mechanism is likely a function of the specific estrogen and of the exposed tissue or
cell type and its metabolic state (Yager and Liehr 1996)." (emphasis added)
It is clear from the above excerpt that all the relevant US scientific institutions that have collaborated
in the preparation of this Report have come to the conclusion that oestrogen acts not only through the
estrogen receptors but, in addition,
 also by "other mechanisms". The report states also that "the
evidence indicates that estrogen carcinogenesis is complex, involving proliferative effects and
possibly direct and indirect genotoxic effects". This finding was made for the first time in the 2002
Report and is being repeated ever since. It is ve ry strange that neither Dr. Boisseau nor Dr. Boobis
commented on this, and it is even stranger that neither of the defending parties have ever said
something about this, which clearly supports the EC assessment on this crucial point. Indeed, the
European Communities is not doing other than what Dr. Boobis has described in his reply to Question
no 7, namely that: "In practice, it is likely that as veterinary drug residues in food are avoidable by not
using the drug, the Committee would have declined to establish an ADI".

Canada's comment

26. The European Communities is again opposed to Canada's selective perception of the experts'
replies. Canada merely pretends that "the e xperts confirm that JECFA was aware of "non-linear
situations" and took these into account in conducting its risk assessment for the hormones at issue".
27. However, Dr. Boisseau's reply is more nuanced than Canada would like to see. Dr. Boisseau
replied that JECFA was aware in 1987 of non-linear s ituations but this was a general comment. In its
reply, Dr. Boisseau only exemplifies this general awareness in respect of specific substances which
are unrelated to the hormones in dispute and where at the time, JECFA concluded not to establish an
effect-dose relation or to recommend an ADI.
28. Yet, in respect of oestradiol-17β, Dr. Boisseau expressly states that "in its 32 nd session held in
1987, JECFA did not address this kind of non-linear situation for oestradiol-17 β (…)". Similarly, in
1999, according to Dr. Boisseau , JECFA "did not take into account consideration a non-linear
situation in its risk assessment (…)". Against this background, Canada's presentation of Dr. Boisseau's
reply on non-linear situations is unsustainable.
29. Canada finds support in the statement of Dr. Boobis . But his statement and that of JECFA are
scientifically unsound for the reasons already ex plained by the European Communities. Canada
claims (at para. 31) that the European Communitie s has presented no evidence; however, this is not
true because the evidence is there but Canada ch ooses to ignore it. For instance, Canada did not
comment so far on the 2002 US Carcinogenesis Report quoted above.
Q8. Please describe the procedure followed by JECFA in the identification of ADIs and the
development of recommendations on MRLs. Plea se identify and describe any steps that are
taken in the risk assessment process to build a margin of safety into the final recommendation.

US comment

30. The United States does not refer to or comment on the experts' replies to this question nor to
JECFA's and Codex replies to the same question (q uestion 10 in questions asked to Codex, JECFA
and IARC).

Canada's comment

31. Canada's description of the expert replies demonstrates again a lack of precision and
accuracy. Canada, for instance, refers to Dr. Boobis answer (to Question 54) that an ADI is a
threshold "that will pose zero risk" to human h ealth. However, in this reply, Dr. Boobis only refers to
a WHO definition of an ADI whereby there would be "no appreciable risk with daily exposure over a
lifetime". It goes without saying that the difference of "no risk" and "no appreciable risk" is
considerable since the latter one involves a subj ective judgement. Indeed, what may be "appreciable"
to somebody may not be "appreciable" to others. Ye t, in this sensitive hormones' discussion, these
fine differences make a difference. This is an issue of risk management, not of risk assessment, in the
sense that Dr. Boobis
 cannot decide for the democratically elected governments in the European
Communities what risk is "appreciable". It is, ther efore, necessary to make the Panel aware of such
rather blunt presentations of the experts' replie s by Canada. Indeed, Canada is confusing its own
subjective (policy) judgements with the remarks of the scientific experts.
32. It may not come as a surprise that Canada's description regarding the experts' replies on
MRLs is also misleading. First, it is inaccurate to say that "the experts have confirmed that the MRL
is a management tool (…)" and that "if residues ar e within the MRL, then the ADI is unlikely to be
exceeded and no adverse effects to human health are to be expected". First, only Dr. Boisseau refers
in its answer to MRL but not the other experts. S econd, Dr. Boisseau clearly states that a MRL is "an
operational tool which offers a practical way to be sure that this ADI will not be exceeded".
Conversely, contrary to what Canada describes Dr. Boisseau does not say "no adverse effects to
human health are to be expected". Rather it appears th at at this stage one would have to go back to the
discussion whether an ADI poses "no risk" or "no appreciable risk". Moreover, Canada states (at para.
36) that JECFA has built into its calculations large safety margins. However, none of the points made
by Canada here is correct, at least not in the ca se of these hormones. First, because JECFA did not
consider all the metabolites for instance of oestradiol, like the esters. Indeed, Maume et al. have
confirmed the presence of estradiol esters in meat of treated animals in an order of magnitude not
very different to the free estradiol residues. But th e estradiol esters is a totally new class of residues
that have not been considered before in any risk evaluation. Their potential bioactivity may be much
higher than the bioactivity of estradiol as such. Th e recent data provide clear evidence (1) for their
existence after application of estradiol to cattle and (2) for their elevated oral bioactivity.
Undoubtedly, these are important new data, and an accurate evaluation of the risk originating from
steroid hormone esters will only be possible, if many more data become available. This includes the
additional need to look for trenbolone esters and their bioactivity. (see Maume D, Deceuninck Y,
Pouponneau K, Paris A, Le Bizec B and Andre F (2001): Assessment of estradiol and its metabolites
in meat, APMIS, 109:32-38, Exhibit EC-47 ). Second, because the bioavailability of these hormones
has been seriously underestimated, and thirdly, beca use the so-called food ba sket can easily lead to
residues intakes that by far exceed the endogenous production of these hormones, especially by pre-
pubertal children.
Q9. Please confirm or comment on the following Canadian statement: "it is recognized that
JECFA only allocates an ADI for a food additi ve or veterinary drug under review when JECFA
considers that its scientific data base is comple te and that there are no outstanding scientific
issues". [see para. 68 of Canada Rebuttal Submission]

US comment

33. The United States refers to Drs. Boisseau's and Boobis' and to JECFA's replies to this
question in paragraph 17 of its submission.2 The US approves the statement by Dr. Boisseau about the
quality and the quantity of the data used by JECFA. However, this is not surprising because the data

2 Question 11 in questions asked to Codex, JECFA and IARC.

used by JECFA are too old. Conversely, the data used by the European Co mmunities are more recent
and converge on this point with the statement of the US Carcinogenesis report which states that
"… Although the molecular mechanisms respons ible for estrogen carcinogenicity are not well
understood, the evidence indicates that estrogen car cinogenesis is complex, involving proliferative
effects and possibly direct and indirect genotoxic effects ...". Thus, there is no doubt that there are
several gaps in our knowledge but the new evidence available confirms the direct and indirect
genotoxicity of oestradiol and of the other hormones.
Canada's comment

34. Canada draws conclusions from JECFA's rep lies which are plainly wrong. JECFA was
making a general and abstract statement on this point , but this tells us nothing of whether the ideal
situation described in its reply is applicable in the case of these hormones, because JECFA's
evaluations date from 1988 and are too old by today's scientific evidence.
Q10. In para. 129 and 168 of its Replies to the Panel Questions, the European Communities
states that "JECFA's traditional mandate does no t allow it to examine all risk management
options but restricts it to either propose MRLs or not". Does Codex have risk management
options other than (1) the establishment of an MRL, (2) establishing that an MRL is not
necessary or (3) no recommendation?

US comment

35. The United States does not refer to or comment on Dr. Boisseau's and on Codex' and JECFA's
replies to this question.3
Canada's comment

36. The European Communities observes that, like the question itself, Canada's comments are
confusing again what is a risk management measur e in the terminology of Codex Alimentarius and
JECFA and what this term should be understood to include in the SPS Agreement, as interpreted by
the Appellate Body in the Hormones case.
Q11. What should, in your view, be the components of a qualitative risk assessment,
compared with a quantitative risk assessment? [see para. 82 of Canada Rebuttal Submission]

US comment

37. The United States does not refer to or comment on the experts' (Drs. Boisseau, Boobis,
Cogliano) replies to this question.
Canada's comment

38. Canada draws (at paras. 42-43) from the rep lies of the two scientists (Dr. Boisseau and
Dr. Boobis) to this and to subsequent questions the c onclusion that a risk assessment that does not
include a dose-response assessment would be incomplete. However, as the other scientists who
replied to these questions have explained, the European Comm unities has performed a qualitative
(and where possible a quantitative) dose-response as sessment. Moreover, Canada criticises (at para.
43) the relevance of the monographs produced by the IARC as a basis for conducting a dose-response
assessment and cites in support the 1 998 Appellate Body report in the Hormones case. However, the
statement by the Appellate Body quoted by Canada is pa rtly incorrect and partly irrelevant today. It is

3 Question 12 in questions asked to Codex, JECFA and IARC.

incorrect because the evaluation of substances by IARC, like the three natural hormones, have served
for so many years responsible governments in thei r risk assessments and it is simply inaccurate and
scientifically unsound to suggest that they do not pr ovide a sufficient basis for a risk assessment. This
is because the toxicological and other scientific evidence on which both the JECFA and the IARC
base their findings is the same
: they both decide on the carcinogenicity of a substance on studies
conducted in vitro and in vivo and extrapolate from animal models to humans (if there is no direct
evidence from experiments on humans). There is nothing in the JECFA data base and the
methodology used by it which is different from the data on carcinogenicity and the methodology used
by IARC. This is very important to understand. If there are residue data from meat treated with these
hormones for animal growth promotion, IARC w ill use them in the same way as JECFA normally
does. The difference is that JECFA has come to th e conclusion that the three natural hormones are not
genotoxic, which is not the conclusion reached by IARC on the basis of broadly the same
toxicological evidence. But once JECFA had reached th e conclusion that there is a safe threshold, it
then used the residues data from treated meat in order to see if the presumed safe theoretical threshold
would be exceeded. This, the IARC did not have to do, as the other direct and indirect evidence it
examined supported the characterisation of these hormones as proven human carcinogens. Moreover,
the most recent data cited and used by the Europ ean Communities and also those cited (for the first
time) in the 2002 US Carcinogenesis Report confirm that oestrogen is genotoxic by direct and indirect
mechanisms of action. Therefore, the data from r esidues in treated meat, to which para. 200 of the
1998 Appellate Body report refers, are irrelevant.
39. It should however be stressed that, in a ny case, the 1999, 2000 and 2002 risk assessment
conducted by the European Communities were based also on residues in meat treated with these
hormones for animal growth promotion purposes, wh ich were generated under realistic conditions of
use, that is where GVP is respected but also wh ere abuse or misuse could occur. These studies have
shown that the resulting residues in treated meat are by far higher than the residue levels considered
by the old and outdated studies on which the de fending parties and JECFA based their findings.
Moreover, the intake of residues from treated me at consumed by prepubertal children would exceed
the ADIs and MRLs established by JECFA if the much lower levels of endoge nous production of the
three natural hormones is taken into account. Th at is why the European Communities considers
imperative that these old data and the methods by which they have been measured and assessed
should be provided to this Panel, its experts and the European Communities for a review. It is only
then that a proper conclusion could be drawn on th e accuracy and relevance of these old data for the
risk assessment.
Q12. How is scientific uncertainty addressed in ri sk assessments in general? With respect to
the assessment of risks from the consumption of meat treated with the growth promotion
hormones at issue, how has scientific uncertain ty been considered by JECFA/Codex ? How
does it differ from the way it has been considered by the European Communities in its
assessment of risks from the consumption of meat treated with the growth promotion hormones
at issue?

US comment

40. The United States while referring to Dr. Boobis' reply to this questi on in paragraphs 17 and
20 of its submission4 does not discuss or comment the issue of scientific uncertainty.
Canada's comment

41. Canada makes again (at para. 46) the irreleva nt argument that the European Communities is
not consistent because it prohibits hormone-treated meat but allows the consumption of foods (e.g.

4 There is no reference to Dr. Boisseau's reply to the same question.

milk, eggs, meat) containing some of these hormon es at levels many times higher. But this argument
has been made by both parties before the 1997 pane l and has been rejected clearly by the Appellate
Body in the 1998 Hormones report (at para. 221) as "an absurdity". So the European Communities
wonders why Canada keeps repeating it.
C. ASSESSMENT OF OESTRADIOL-17Β
Q13. To what extent, in your view, does the EC risk assessment identify the potential for
adverse effects on human health, including the carcinogenic or genotoxic potential, of the
residues of oestradiol-17 β found in meat derived from cattle to which this hormone had been
administered for growth promotion purposes in a ccordance with good veterinary practice? To
what extent does the EC risk assessment eval uate the potential occurrence of these adverse
effects?

US comment

42. The United States refers to the experts' (Drs. Boobis, Boisseau, Guttenplan ) replies to this
question in paragraphs 19, 20, 21, 32, 37 and 84 of its submission. However, the underlying theme in
all US comments is the fundamental error that these hormones, and in particular oestradiol 17 β, are
not carcinogenic because a safe threshold exists. This is a fundamental error on which the European
Communities has already commented above (e.g. to Question no 7).
Canada's comment

43. Canada's statement that the replies by Dr. Boisseau, Dr. Boobis and Dr. Guttenplan all
indicate that the EC risk assessment "was deficient in one manner or another in its evaluation of the
potential occurrence of adverse effects" is a very unqualified summary. In particular, Dr. Guttenplan

has expressly stated that the European Commun ities has done a "thorough job in identifying the
potential adverse effects on human health of oestradiol-17 β" and that the European Communities has
"performed thorough studies of residues levels in cattle, and the environment". Most importantly,
Canada states (at paras. 49-51) that "there is no ev idence that this [genotoxic] potential is realized in
vivo (as opposed to in vitro)", that Dr. Boisseau disagrees with the Eur opean Communities "as do
most other experts and internati onal scientific bodies", and that the European Communities decision
not to conduct a complete risk assessment "is not supported by the evidence". None of these
statements is correct. The European Communities h as shown that there is sufficient and constantly
growing evidence from studies in vivo that show the direct genotoxicity of oestradiol 17ß and its
catechol metabolites in animal and human tissue as well as the mutagenicity of oestradiol 17ß
metabolites in experimental animals:
• Li et al. (2004) have demonstrated that the N7-guanine adduct (N7Gua) and the N3-
adenine adduct (N3Ade) of E2-3,4-quinone (the putative carcinogenic E2 metabolite)
were present in the DNA of the mammary gl and of ACI rats after injection of 4-HO-
E2 or E2-3,4-quinone (Exhibit EC – 121).
• Markushin et al. (2003) have detected th e N3Ade (and in part N7Gua) adducts of 4-
HO-E2 and 4-HO-estrone (E1) in the breast tissue of women (Exhibit EC – 118).
• Chakravarti et al. (2001) demonstrated mu tations in the H-ras gene of SENCAR
mouse skin after topical application of E2 -3,4-quinone, and Chakravarti et al. (2003)
found similar mutations in the mammary gland of ACI rats after administration of E2-
3,4-quinone. The type of mutations in both in vivo animal systems can be explained
by depurination of the N3Ade adducts. These experiments are reviewed in Cavalieri
et al. (2006) (Exhibit EC – 48).

• Cavalieri et al. (2006) used the Big Blue
® rat model to assess the mutagenicity of E2
and 4-HO-E2 in vivo and found both compounds to be mutagenic. The mutational
spectrum observed for 4-HO-E2 was consiste nt with the formation and depurination
of N3Ade adducts (Exhibit EC – 125)

44. It should be noted that the magnitude of DNA adduct levels and mutagenic activities reported
in these studies is not very high and seems to be much lower than encountered with most known
genotoxins, which indicates that oestradiol may be a weak genotoxin. This may also be true for the
other hormones and this may explain why standard genotoxicity assays show negative or borderline
effects with these compounds. Moreover, the genotoxic activity of oestradiol 17 β and its metabolites
determined in rodent assays in vivo may be obscured by the diet , which usually contains high
concentrations of phytoestrogens, e.g. from soy. It has been recently reported that several
phytoestrogens induce the enzyme quinone reduct ase, which inactivates the quinones of catechol
estrogens and thereby reduces DNA damage (Bianco et al., 2005, Exhibit EC – 124)).
45. The question, therefore, is not that there is no evidence of genotoxicity in vivo, but rather how
much evidence more is needed by the defending par ties before they would be forced to reconsider
their views, as did JECFA and Canada recently in relation to other substances, e.g. for Carbadox.
Q14. In your view, does the risk assessment undertaken by the European Communities on
oestradiol-17β follow the Codex Guidelines on risk a ssessment, including the four steps of
hazard identification, hazard characterization, exposure assessment, , and risk characterization
with respect to oestradiol-17β?

US comment

46. The United States refers to the experts' (Drs. Boobis, Boisseau and Guttenplan ) replies to this
question in paragraphs 19, 20 and 32 of its submissi on. In paragraph 19 of its submission, the United
States claims that "the experts' responses confir m that, while the EC Opinions engage in hazard
identification, the first step of a risk assessment , the Opinion fail to complete any of the remaining
three components." The European Communities di sagrees with the selective citation and the biased
conclusions drawn by the US. Dr. Guttenplan has certainly supported the EC position on this point.
Canada's comment

47. Canada's presentation that "Drs. Boisseau, Boobis and Guttenplan also agree with Canada that
the EC failed to follow the Codex guidelines on ri sk assessments" and that "[t]he experts share
Canada's concerns that the EC (and SCVPH) took significant and unjustified short-cuts in the conduct
of its risk assessment" is plainly wrong.
48. Neither Dr. Boisseau nor Dr. Boobis or Dr. Guttenplan make any specific comments on
Canada's concerns. Thus, to present the experts' repl ies as if these had said: "Yes, Canada is right" is,
to say the least, wishful thinking.
49. More specifically, Dr. Boisseau's position can hardly be described as being "very critical of
the EC's decision not to follow the Codex guidelines" as Canada presents it. Dr. Boisseau has
explicitly stated that "[T]he Eur opean Communities does not indicate anywhere in its submission that
it does not intend to follow the Codex guidelines on ri sk assessment including the four steps of hazard
identification, hazard characterization, exposure assessment and risk characterization. On the
contrary, the following indicates that the Europ ean Communities considers the same approach for
assessing the risk associated with the residues of grow th promoters." On that basis, how is it possible
for Canada to describe Dr. Boisseau's position as "very critical on the EC's decision not to follow
Codex guidelines"? Just the opposite is true.

50. While it is true that Dr. Boisseau at the end of his reply has put in brackets a comment
whereby "[t]hese two statements call for refining th e exposure assessment of hormones residues" it is
a complete mischaracterization by Canada to interp ret this statement as a criticism that the European
Communities should "not abandon the entire risk assess ment methodology" and, even more, to take
this conclusion as a confirmation of Canada's submission. Again, this is little more than wishful
thinking by Canada.
51. It is no surprise that Canada's comment on Dr. Guttenplan's reply is also more than selective.
Canada refers to Dr. Guttenplan's alleged criticism on the European Communities' hazard
characterization and risk characterization "for the same reasons advanced by others". The European
Communities is wondering who are these others a nd on what basis Canada can make such an
unqualified statement.
52. On substance, Canada also completely ignores that Dr. Guttenplan has expressly stated that
the "EC has been thorough in fo llowing Codex guidelines on h azard characterization and very
thorough in exposure assessment." This indeed invali dates directly Canada's own statement whereby
the "EC has done very little that resembles an exposure assessment". 5 In this context, the European
Communities is also surprised about Canada's description that the European Communities has
admitted "that it did not, because it could not conduc t an exposure assessment". The paragraph 141 of
the EC rebuttal submission quoted by Canada does not support this statement.
D. CONSUMPTION OF MEAT CONTAINING HORMONES
(a) Carcinogenicity
Q15. Does the identification of oestradiol-17 β as a human carcinogen indicate that there are
potential adverse effects on human health when it is consumed in meat from cattle treated with
hormones for growth promotion purposes? Does your answer depend on whether good
veterinary practices are followed? [see paras. 206-207 of EC Rebuttal Submission (US case),
para. 121 of EC Rebuttal Submission (Canada case), paras. 97-98 of EC Replies to Panel
Questions, para. 76-77, 150 and 155-156 of US First Submission, paras. 35-40 and 46 of US
Rebuttal Submission]

US comment

53. The United States refers to the experts' (D r. Boobis, Boisseau and Guttenplan, Cogliano )
replies in paragraphs 34, 38, 42 and 43 of its submission. Conveniently, the United States does not
comment on Dr. Boisseau's categorical statement regarding the dependence of his reply on the
efficient implementation of good veterinary practices.
Canada's comment

54. From the outset, it should be noted that none of the experts "agree with Canada" on the effect
of the carcinogenicity of oestradiol-17 β. Indeed, none of the expert s take any position on any
statement made by Canada.
55. Canada's blunt summary of the experts' rep lies whereby "most of the experts conclude
affirmatively that there would be "no appreciable risk" of adverse effects from exposure from this one
minimal source of oestradiol 17 β" is inaccurate as the experts differ considerably in their replies and
most of them agree with the EC position.

5 See Canada's comments on expert replies, para. 54.

56. Dr. Boisseau
 merely says that "oestradiol-17 β (…) is not likely to produce adverse effects on
human health when it is consumed in meat from cattle treated with hormones for growth promotion
purposes". Yet, what is "likely" or not appears to be quite a subjective judgement. Moreover, even
Dr. Boisseau explicitly subjects this view to the respect of good veterinary practices as otherwise all
the work "to protect human health with regard to veterinary drug residues is meaningless".
57. Dr. Cogliano explicitly states that "the identification of oestradiol-17 β as a human carcinogen
indicates that there are potential adverse e ffects on human health when oestradiol-17 β is consumed in
meat from cattle treated with hormones for grow th promotion purposes." This statement hardly
supports Canada's theory that the consump tion of beef treated with oestradiol-17 β does not entail an
"appreciable risk".
58. Furthermore, Dr. Guttenplan states that "if potential is taken to mean possible, then an
adverse effect cannot be ruled out, but it is unlik ely if good veterinary practices are followed". As
Dr. Boisseau, Dr. Guttenplan thus refers to the likelihood of adve rse human health effect. Yet, as can
be seen from his reply (and it is also interes ting to contrast this reply with Dr. Boisseau's ), such an
assessment contains a subjective judgement which jus tifies that in case of a political decision to take
"zero risks" even the slightest minimal chance should be excluded. This is even more justified in this
specific case where there are considerable doubts ab out whether GVP are always respected and which
even according to Dr. Boisseau would render all the assumptions "meaningless".
59. Finally, Canada argues that the EC evidence demonstrates that "multiple hormone implants
resulted in residues that were still less than the ADI s." However, the data generated by the EC study
in question (by Daxenberger et al. 2000 ) documented that the residues after improper use would
exceed by far the ADIs.
Q16. Does the scientific evidence relied upon in the SCVPH Opinions support the conclusion
that carcinogenic effects of the hormones at issue are related to a mechanism other than
hormonal activity? [see para. 148 of the EC Rep lies to Panel Questions and paras. 35-40 and 46
of US Rebuttal Submission]

US comments

60. The United States refers to the expe rts' (Drs. Boisseau, Boobis, Guttenplan ) replies to this
question in paragraphs 34, 36 and 50 of its submission. While pretending that all experts confirm the
view that no scientific evidence supports the conclusion that the carcinogenic effects of oestradiol-17β
are related to a mechanism other than hormonal activit y, the United States has to admit, in the same
paragraph (34) that Dr. Guttenplan has taken a much more nuanced view on this issue. The United
States' interpretation of other statements made by Dr. Guttenplan , which allegedly suggest, that he
links the carcinogenic effects to the hormonal activity, are simply erroneous. The European
Communities has explained several times (also above in relation to question 13) that in 2002 there
was sufficient evidence from experiments in vivo a nd this evidence is still growing further. In
addition, there is evidence for th e mutagenicity of oestradiol-17 β as determined in cell culture. For
example, Kong et al (Int. J. Oncology, 17: 1141-1149, 2000) reported on the mutagenicity of
oestradiol-17β in V79 hamster ovary cells and recently Zhao et al., in a paper whose authorship
included Dr. Guttenplan
 himself (Chem. Res. Toxicol. 19: 475-479, 2006, Exhibit EC-110), reported
the mutagenicity of the 4-OH catechol metabolite of oestradiol-17 β in BB Rat2 embryonic cells. In
this study, multiple treatment of the cells with 50 to 200nM 4-OH oestradiol-17β induced mutations in
the BB Rat2 cells in a dose response fashion, with a significant increase being observed after 3 and 3
treatments at the 200nM level. The mutational spectrum resulting from 4-OH oestradiol-17β treatment
was different than the "background" mutations seen in the control (untreated) cells further supporting
the conclusion that the mutations were in fact caused by the 4-OH catechol estrogen. 2-OH oestradiol-
17β did not induce mutations. These results support th e difference in carcinogenicity difference

between these 2 catechol metabolites and differences in their ability to cause transformation of normal
human breast epithelial cell line MCF-10F as reported by Russo, et al. (J. Steroid Biochem. Mol. Biol.
87: 1-25, 2003, Exhibit EC-115). Furthermore, these results are particularly significant in that the 4-
OH catechol metabolite of oestradiol-17β has been detected in the mammary tissue of mice in a model
where mammary tumorigenesis is dependent on the presence of estradiol (Devanesan et al.
Carcinogenesis, 22: 1573-1576, 2001 (Exhibit EC – 122) ; Yue et al. J. Steroid Biochem. Mol. Biol.
86: 477-486, 2003, Exhibit EC-90) and in human bre ast tissue (Yue et al. J. Steroid Biochem. Mol.
Biol. 86: 477-486, 2003, Exhibit EC-90).
61. With regard to the study by Chakravarti et al (Oncogene, 20; 7945-7953, 2001, Exhibit
EC-48), which is criticised by Dr. Boobis
, it should be explained that it detected mutations in the
H-ras gene in the skin of SENCAR mice following de rmal treatment with E2-3,4-quinone, with the
specific nature of the mutations detected being cons istent with the expected depurination of adenine
due to the formation of an E2-3,4-quinone-Adeni ne adduct. This is re levant to the potential
mutagenicity of estradiol in humans because: First, we know that oxidative metabolism of oestradiol-
17β to the E2-3-4-quinone metabolite occurs in human breast tissue because E2-quinone adducts to
glutathione have been detected (Yue et al. J. Steroid Biochem. Mol. Biol. 86: 477-486, 2003, Exhibit
EC-90). Second, adducts of the E2-3,4-quinone with ademine and guanine have been detected in the
mammary tissue of ACI rats injected into the mamma ry gland tissue with 4-OH E2 or E2-3,4-quinone
(Carcinogenesis, 25:, 289-297, 2004, Exhibit EC-121). These findings are ignored by Dr. Boobis as
well as by the US.
Canada's comment

62. Unlike the US, Canada criticizes Dr. Guttenplan's
 support for the EC conclusion on the basis
that he has not made an analysis on its own. Howe ver, Canada has obviously no difficulties in relying
on Dr. Boisseau who, in turn is merely invoking (old) JECFA reports and who, therefore, has also not
made an analysis on its own. Canada thereby app lies a double standard just as it sees fit for its own
purposes. In any case, the European Communitie s has explained above that Dr. Guttenplan has
published together with other scientists several pape rs in peer-reviewed journals, the most relevant
one a few months ago (Chem. Res. Toxicol. 19: 475-479, 2006, Exhibit EC-110) which has used the
Big Blue® rat model to assess the mutagenicity of oestradiol-17 β and 4-HO-E2 in vivo and found both
compounds to be mutagenic. The mutational spectru m observed for 4-HO-E2 was consistent with the
formation and depurination of N3Ade adducts.
Q17. Could you comment on Canada's statem ent that "the studies commissioned by the
European Communities also failed to find evid ence of "catechol metabolites" – that is the
oestradiol metabolites identified as the source of the genotoxic potential – in meat from treated
animals"? What would be the implication of an absence or presence of catechol metabolites?
[see para. 102 of Canada Rebuttal submission, EC Exhibit 51A]

US comment

63. The United States refers to Drs. Boisseau's, Boobis' and Cogliano's replies to this question in
paragraph 44 of its submission and very conveni ently omits any reference to Dr. Guttenplan's
straightforward reply.
64. Furthermore, its refere nce to Dr. Cogliano's reply is misleading as Dr. Cogliano does not
conclude "that detectable levels of catechol metabolites were not formed from the parent compound",
but rather concludes that "the absence of catechol metabolites could imply either (1) [the above] or (2)
that some level of catechol metabolites was formed that the test methods were not sufficiently
sensitive to detect it." (emphasis added) Indeed, as the EC has explained above (in relation to question
no 13), there is sufficient and cons tantly growing evidence from studies in vivo that show the direct

genotoxicity of oestradiol 17ß and its catechol metabolites in animal and human tissue as well as the
mutagenicity of oestradiol 17ß metabolites in experimental animals.
65. It should be noted that the magnitude of DNA adduct levels and mutagenic activities reported
in these studies may not be very high. It seems indeed to be much lower than encountered with most
known genotoxins, which indicates that oestradiol may be a weak genotoxin. However, this can also
be true for the other hormones and this may expl ain why standard genotoxicity assays show negative
or borderline effects with these compounds. Moreover, the genotoxic activity of oestradiol 17β and its
metabolites determined in rodent assays in vivo may be obscured by the diet (Bianco et al., 2005,
Exhibit EC-124).
66. Finally, that oestrogen may be genotoxic by direct or indirect mechanisms of action is now
admitted even by the US since its 2002 Carcinogene sis Report, cited above, and any argument now to
the contrary by the US is necessarily not credible.
Canada's comment

67. Canada takes issue with Dr. Guttenplan on the amounts of catechol metabolites by referring to
"other experts'" confirmation. Ho wever, since Canada does not iden tify these other experts this is a
rather unqualified remark. On substance, the Eur opean Communities finds it re markable that Canada
does not criticize Dr. Guttenplan's statement that even "the lack of catechols in meat does not imply
that meat from estrogen-treated cattle is without risk for genotoxicity".
68. Moreover, the European Communities would emph asize that, in the absence to the contrary,
Canada obviously agrees with Dr. Cogliano's statement whereby "the presence of catechol metabolites
would support the potential for adverse effects to occur. The absence of catechol metabolites could
imply either (1) that detectable levels of catechol metabolites were not formed from the parent
compound or (2) that some level of catechol metabo lites was formed that the test methods were not
sufficiently sensitive to detect it." This is the most likely explanation, as stated above.
Q18. Please comment on the US argument that the European Communities fails to
demonstrate through scientific evidence that oestradiol-17 β is genotoxic. Would your reply
have been different at the time of adoption of the EC Directive in September 2003? If so, why?
[see paras. 118-119 of EC Rebuttal Submission (US case), paras. 123-124 of EC Rebuttal
Submission (Canada case), paras. 87-91 and 153- 156 of US First Submission, paras. 35-40 and
46 of US Rebuttal Submission, and paras. 90-97 of Canada Rebuttal Submission]

US comment

69. The United States refers to Drs. Boobis' and Cogliano's replies to this question in
paragraphs 35 and 44 of its submission and very co nveniently omits to refer to Drs. Boisseau's and
Guttenplan's replies. The latter's reply certainly does not "confirm" - as the United States claims (at
paragraph 35) – "that the scientific evidence cited by the EC in its Opinions does not support the
conclusion that estradiol 17 β is genotoxic at levels found in residu es in meat from cattle treated with
growth promoting hormones." Quite to the contrary, Dr. Guttenplan confirms the existence of such
evidence and states that "the evidence now is much stronger" citing a study of 2004.
70. Moreover, the US argues (at para. 36) that th e European Communities has failed to explain
why its evaluation of estradiol 17 β was not subject to a CVMP guideline requiring confirmation of an
in vitro positive using an appropriate in vivo assay. This comment is disingenuous because the
pharmaceutical industry, the defending members and JE CFA, i.e. those arguing that these substances
are safe, should produce the ev idence showing that estradiol 17 β is not genotoxic in vivo. The EC has
fulfilled its obligations by funding a number of st udies and also by collecting the growing evidence

from experiments in vivo showing the direct genotoxicity of these hormones, in particular of estradiol
17β. It is now high time that the US (and Canada ) stops criticising the European Communities for
absence of evidence which itself did not have wh en it approved these hormones more that 30 years
ago and makes an effort to prove what it preaches, that is that these hormones are not genotoxic by
direct action. Instead of criticising the Europ ean Communities on the basis of purely hypothetical
assumptions, the US should have tried to explain the statement from its 2002 Carcinogenesis Report
which states:
"The evidence is strong that estrogen carcinogenesis is mediated through activation of
the estrogen receptor. In addition, there is evidence that other mechanisms may play a
role in the carcinogenic effects of estrogens in some tissues. Prolonged estrogen
exposure induces cell proliferation in estroge n-dependent target cells, affects cellular
differentiation, and a lters gene expression. Although the molecular mechanisms
responsible for estrogen carcinogenicity are not well understood, the evidence
indicates that estrogen carcinogenesis is complex, involving pr oliferative effects and
possibly direct and indirect genotoxic effects. The relative importance of each
mechanism is likely a function of the specific estrogen and of the exposed tissue or
cell type and its metabolic state (Yager and Liehr 1996)." (emphasis added)
Canada's comment

71. Canada's interpretation of Dr. Boisseau reply is quite astonishing. First, Canada tries to
construe from Dr. Boisseau's reply a difference for a substance having "genotoxic potential" and being
"genotoxic". Yet, nowhere in his reply does Dr. Boisseau address this issue so that Canada can hardly
take this response as support for its own th eory. Moreover, Canada describes Dr. Boisseau 's reply on
the establishment of an ADI by JECFA in 1999 as "pointing to the need to place exposure to
oestradiol 17β from this source into context." It will remain Canada's secret what it means by such a
description, since Dr. Boisseau instead submitted that the ADI was established "in order to present in
a more convincing way the outcome of its [JECFA's] assessment".
72. In respect of Dr. Boisseau's reply it is also difficult to see how Canada can claim support for
its assumption that oestradiol 17 β is not genotoxic in vivo . He does not say so in his reply to
Question 18 and even Dr. Boisseau's reply to Question 13 does not contain such a general statement.
73. The comments by Canada (at paras. 72-73) are subject to the same criticism mentioned above
for the statements made by the US. Indeed, the UK VPC constitutes quite a remarkable evolution on
this point from its previous evaluation of these hormones in 1995, and it is certainly less categorical in
its findings (it uses the terms "is likely") than Ca nada. Even so, however, the statement quoted by
Canada (at para. 72) contrasts sharply with the fi ndings in the 2002 US Carcinogenesis Report quoted
above by the European Communities, which Canada has chosen to ignore.
Q19. The European Communities states that "... it is generally recognized that for substances
which have genotoxic potential (as is the case with oestradiol-17 β) a threshold can not be
identified. Therefore it cannot be said that th ere exist a safe level below which intakes from
residue should be considered to be safe. Therefore the fact that doses used in growth promotion
are low is not of relevance". Does the scienti fic evidence referred to by the European
Communities support these conclusions? Would your reply have been different at the time of
adoption of the EC Directive in September 2003? If so, why? [see para. 201 of EC Rebuttal
Submission (US case), paras. 120-122 of EC Rebu ttal Submission (Canada case), paras. 73 and
86-98 of Canada Rebuttal Submission, paras. 87-91 and 153-156 of US First Submission and
paras. 35-40 and 46 of US Rebuttal Submission]

US comment

74. The United States refers to the experts' (Drs. Boobis, Boisseau, Cogliano, Guttenplan ) replies
to this question in paragraphs 37 through 40 of its submission. Its reading of Dr. Guttenplan's and
Dr. Cogliano's replies is erroneous. On Dr. Guttenplan , the United States claims that he does not take
a clear view on whether oestradiol 17 β is genotoxic at level found in residues in meat from cattle
treated with growth promoting hormones. However, this is not what Dr. Guttenplan has said.
75. On Dr. Cogliano, the United States' claims that he "concurs [with Dr. Boobis ] "noting that the
EC's statement regarding the lack of a thres hold has not been demonstrated by the scientific
evidence." Quite to the contrary, however, Dr. Cogliano said: "The EC's statement that a threshold
cannot be identified reflects their view of genotoxic mechanisms, just as the contrary statement that
there is a threshold and that this threshold is above the levels found in meat residues reflects how
Canada and the US view genotoxic mechanisms. Ne ither statement has been demonstrated by the
scientific evidence, rather, they are different assumptions that each party uses in their interpretation of
the available evidence."
Canada's comment

76. Canada's statement that Dr. Boobis' and Dr. Cogliano's replies would support its own
argument that for substances endoge nously produced by human body there must be threshold is, at
least, a challengeable conclusion. Indeed, neither Dr. Boobis nor Dr. Cogliano , who apart from this
question obviously have a different perception about the genotoxicity of these hormones, do at all
address this argument. Canada makes (at para. 74) the rhetoric argument that "humanity would have
been wiped out by cancer millennia ago". This statement is highly unscientific. First, humanity did not
use to eat meat treated with hormones, save for a pproximately the last 30 years and this only in the
US (and a bit later in Canada). Secondly, the rates of cancer in general (including prostate and breast)
are increasing, in particular in the US, where th ey are higher by about 20% compared to those in
Europe. Third, as the European Communities has explained above, it may be that these hormones are
weak carcinogens, which explains why they could not be detected by the old and most of the existing
assays. But the rates of cancer observed today are a serious cause for concern. Furthermore, the
implication of the Canadian claim that a subs tance that is produced endogenously cannot be
carcinogenic when administered exogenously is incomprehensible.
77. The same applies for Canada's claim (at para. 75 and 76) that even EFSA has recognised safe
thresholds for genotoxic substances. This is simp ly not true because the EFSA opinion cited by
Canada, although issued for another purpose, simply states that the incidence of cancer may not be
increased, but it does not state that there is no risk from such substances.
78. Canada states (at para. 74) "that experts from around the world" contradict the EC' claim, but
it manages to cite only the UK VPC and the JECFA reports. These are the "experts around the world".
Canada fails however to cite th e well known reports from the IARC – which as its name indicates is
the best placed international institution on issues of cancer research and prevention – nor does Canada
pay any attention to the US Carcinogenesis Report.
79. It is clear from the replies of the experts that they are divided on this issue (2 against 2), but if
the expected replies of the other 2 experts are a dded, then the majority of the experts agrees in
substance with the EC position.
Q20. In your view, how do the European Communities' conclusions above relate to the
conclusion by Codex that "establishing an ADI or MRL for a hormone that is produced
endogenously in variable levels in human beings was considered unnecessary"? To what extent,

in your view, has JECFA's conclusion that oestra diol "has genotoxic potential" affected its
recommendations on this hormone?

US comment

80. The United States refers to the experts' (D rs. Boobis, Boisseau, Guttenplan and Cogliano) and
JECFA's (to a related question) 6 replies to this question in pa ragraph 41 of its submission. The
European Communities disagrees w ith the summary of the statemen ts made by the US in that
paragraph. That oestradiol 17β is carcinogenic by both direct and receptor mediated mechanisms is no
longer in doubt (see the latest article by Cavalieri et al., 2006, see Exhibit EC-125). This has been
stated also by the US since its 2002 Carcinogenesis Report to which the US fails to refer.
Canada's comment

81. Canada draws an unjustified conclusion from th e experts' replies whereby "Drs. Boisseau,
Boobis and Guttenplan all consider the EC's conc lusion about the absence of thresholds to be
inconsistent with the Codex standards." Yet, the answers of these experts are much more nuanced
than Canada presents. For instance, Dr. Boisseau only states that the "European Communities'
conclusions are questionable". It goes without saying that there exists a difference between
"inconsistent" (as Canada qualif ies it) and "questionable". The same applies to Dr. Boobis who
submits that the "EC conclusion on the absence of safe ty at any level of exposure is somewhat at odds
with the underlying basis of the Codex conclusion regarding the need for an ADI or MRL". Again, if
something is "somewhat at odds" it does not mean that it is "inconsistent". Finally, Dr. Guttenplan
merely states that the European Communities' conclusions above are "at variance" with those of
Codex. It is difficult to see how this can be re conciled with Canada's statement that the EC's
conclusions are "inconsistent" with Codex standard.
82. In this context, it is also an unqualified assumption by Canada that "to the extent that most of
the experts found the EC conclusions on the matter are unsupported by the evidence and are
"questionable", they support the existing Codex st andards." Indeed, the mere comparison between a
Codex standard and a respective EC conclusion do es not lend any support whatsoever about the value
of this standard.
83. Finally, the European Communities would take issue with Canada's unsupported conclusion
that the "experts' answers also confirm that even though JECFA acknowledged that oestradiol 17β has
"genotoxic potential", this acknowledgment did not generate concern about the safety of the
substances and therefore did not affect its recomme ndation". Indeed, none of the experts makes any
qualified statement to this effect and Canada's inference from the experts' replies is therefore
completely baseless. At most, Dr. Boobis stated that "I do not believe that JECFA's conclusion that
oestradiol has "genotoxic potential" affected its recommendations on this hormone (…)". As can
easily be seen this is a mere unsubstantiated gu ess and personal opinion by one expert whereas the
other experts remain mute on this issue. Thus, Cana da's presentation is far from being an objective
description of the facts.
84. What is even more important is that th e statements by Dr. Boisseau and Dr. Boobis are partial
because they do not consider the to tality of the available evidence, such as that mentioned by the
European Communities and in particular the re ports from the IARC and the US Carcinogenesis
Report which have been made available to them. Dr. Boobis concentrates only on the JECFA reports,
which are based on very old data.

6 Question 20 of the questions asked to Codex, JECFA and IARC is about …

Q21. Does the scientific evidence referred to by the European Communities demonstrate that
the five hormones other than oestradiol-17β, when consumed as residues in meat have genotoxic
potential? Does your answer depend on whether good veterinary practices are followed? Would
your reply have been different at the time of adoption of the Directive in September 2003? If so,
why? [see, inter alia , the SCVPH Opinions and paras. 63, 83, 89-91 and 93 of US First
Submission, paras. 131-136 of Canada Rebuttal Submission]

US comment

85. The United States refers to the experts' (Drs. Boobis, Guttenplan and Boisseau ) replies to this
question in paragraph 50 of its submission. Overall, the experts' replies are much more nuanced than
what the United States suggests when claiming that they all "confirm that the scientific materials cited
by the EC in its Opinions do not demonstrate or support the conclusion that any of the five hormones
has genotoxic potential or is carcinogenic by a mech anism other than hormonal activity." As both
Dr. Boobis and Dr. Guttenplan report, there are some data that indicate the possibility of genotoxic
effects. The data are probably not "conclusive" (Dr. Guttenplan ) and perhaps not "convincing"
(Dr. Boobis) to everyone, but it is more than a sufficient and legitimate basis for a legislator acting on
the basis of precaution to adopt provisional measures.
Canada's comment

86. Canada's blunt statement that "Drs. Boisseau , Boobis and Guttenplan all refute the EC's
claims about the potential genotoxicity of the other five hormones" is not supported by the experts'
replies. For instance, Dr. Boobis merely states that "there is no convincing evidence that trenbolone
acetate, MGA and zeranol are genotoxic". However, what is "convincing evidence"? In the same vein,
Dr. Guttenplan refers to "no conclusive evidence" or "some evidence that certain of the hormones
have genotoxic potential". Yet, what is "conclusi ve" or what means "some evidence"? Whatever it
means, it can in any case not justify Canada's unqualified conclu sion that there is no "potential
genotoxicity of the other five hormones". Rather, th eir statements confirm the EC position that there
are considerable gaps and uncertainties in our k nowledge, which justify applying Article 5.7 of the
SPS Agreement in order to achieve ones chosen level of health protection.
Q22. How would you define in vivo DNA repair mechanisms? How effective or relevant are
in vivo DNA repair mechanisms with respect to potential genotoxic effects from residues of the
growth promoting hormones at issue when cons umed in meat? Does your answer depend on
whether good veterinary practices are followed in the administration of these hormones? To
what extent does the scientific material referred to by the European Communities take into
account these mechanisms in its evaluation of potential occurrence of adverse effects from
residues of growth promoting hormones? Would you r reply have been different at the time of
adoption of the Directive in September 2003 an d if so, why? [see paras. 40 and 46 of US
Rebuttal Submission, footnote 107 of US First Submission, and para. 89 of Canada Rebuttal
Submission]

US comment

87. The United States refers to the experts' (Drs. Boobis, Guttenplan ) replies in paragraph 31 of
its submission. The US again misrepresents the vi ews of the scientists, in particular those of
Dr. Guttenplan, who stated inter alia that "a small fraction of da mage inevitably escapes repair" and
that consideration of this issue by the SCVPH is in fact irrelevant to the debate (even though he found
some references in the SCVPH assessment that discussed this issue).

Canada's comment

88. Canada spends again a number of paragraphs (a t paras. 85-89) trying to interpret the experts'
replies as supporting its views on this question. But as Dr. Guttenplan has explained in his reply,
there is no reason to believe that the repair mechanism in the case of these hormones would be
different from what is happening in other instances. It is also inevitable that some DNA damage will
remain unrepaired, as is the case with so many ot her direct genotoxic subs tances. As the 2002 US
Carcinogenesis Report states: "… prolonged estrogen exposure indu ces cell proliferation in estrogen-
dependent target cells, affects cellular differen tiation, and alters gene expression…[and that]…the
relative importance of each mechanism is likely to be a function of the specific estrogen and of the
exposed tissue or cell type and its metabolic state" . This means that to go down the road advocated
by the defending parties and Dr. Boobis , i.e. in trying to estimate how much of the DNA damage is
likely to be repaired in time and what would be the carcinogenic potential of the damage left
unrepaired would not be possible in view of so many specificities involved, supposing one could
undertake this kind of estimation in a re liable way. That is why Dr. Guttenplan states that this issue is
irrelevant for the debate on the genotoxicity of oestradiol and whether an ADI for such substances
could or should be fixed.
Q23. To what extent is it nece ssary or possible to take into account the "long latency period"
of cancer in the conduct of a risk assessment, wh ich is supposed to assess carcinogenic effects of
these hormones when consumed in meat? Have the hormones in dispute been used as growth
promoters over a sufficient number of years for an assessment of their long-term effects on
human health to be made? [see para. 149 of EC Rebuttal Submission (US Case), para. 143 of EC
Rebuttal Submission (Canada case)].

US comment

89. The United States refers to the experts' (D rs. Boobis, Boisseau, Guttenplan and Cogliano )
replies on this question in paragraphs 57 and 58 of its submission.
90. In Footnote 127 the United States is suggesting that there is no eviden ce of adverse effects
after more than 20 years of consumption of beef from cattle treated for growth promotion purposes.
However, as Dr. Boobis rightly concludes "... a negative resu lt from such an observational study
would not resolve the issue."
91. Furthermore, the United States misinterprets Dr. Guttenplan's statement that "hormones in
meat [...] have now been consum ed for a sufficient number of year s to observe strong or moderate
increases in risk." The United St ates pretends that Dr. Guttenplan hereby suggest that there is no such
evidence. However, the European Communities does not interpret in the same way Dr. Guttenplan's
statement, quite the opposite.
Canada's comment

92. Canada summarises the replies of the scientists in a partial way in paragraphs 90-93 to come
to the conclusion that "… exposure to residues of hormones in meat from treated animals is only a
small fraction of the overall exposure to the subs tance from a variety of sources, including that
produced endogenously within the human body ...". A car eful reading of the replies of the scientists
however does not support this conclusion. Indeed , none of the scientists explicitly said that the
exposure is only "a small fraction", because it is not easy to estimate the level of the residues. For
instance, the 2002 US Carcinogenesis Report simply stated that the use of these hormones for growth
promotion increases the level of residues to above "their normal levels". The point therefore is that the
two scientists cited by Canada have not and could not have come to the conclusion that the residues is

a small fraction, not least because they do not know it and could not prove it (because of the
background and other confounding factors).
Q24. To what extent is it possible to iden tify possible co-founding factors causing cancer and
attribute them to identified sources? What a re the implications of these factors for the conduct
of a risk assessment evaluating the adverse affects caused by residues of growth promoting
hormones in meat? Would your reply have been different at the time of adoption of the EC
Directive in September 2003? If so, why?

US and Canada's comments

93. The United States refers to the experts' (D rs. Boobis, Boisseau, Guttenplan and Cogliano )
replies on this question in paragraph 59 of its submission and Canada in paragraphs 94-96. They both
appear to accept (as do all the scientists) that th ere is now an association established between meat
consumption and cancer, but they dispute that the evidence is there to clearly establish a causal link
between the residues in meat from hormone-treated cattle and the high cancer incidence. But the
European Communities has not argued it and does not take issue with the fact that it is difficult to
establish that causal link. What is very important to note, however, is that the defending parties cannot
make the argument that because the establishment of the causal link is difficult, there should be
assumed that such a risk is insignificant or does not exist because the added burden is thought to be
small. Furthermore, the defending parties can no lo nger make their simplistic argument that humans
are exposed to hormonal residues from so many other sources, so a small additional exposure from the
residues in treated meat would not make any differe nce. This simplistic argument has been made over
and over again by the defending parties to the Panel a nd it is now clear that there is no scientific basis
to this claim because they cannot establish the causal link of what th ey argue. However, the evidence
is there, and it is indeed growing, associating high rates of cancer with meat consumption, and these
rates of cancer are higher in the US than in Europe , and one day if the US and Canada would like to
find out more about any possible causal link between the two so as to protect their people the same
way as the European Communities does, it coul d undertake the studies which Drs. Cogliano
 and
Guttenplan have suggested.
Q25. To what extent do the three recent st udies referred to by the European Communities
confirm a risk to human health from the consum ption of meat from cattle treated with growth
promoting hormones? Please also comment on the EC statement that one of the studies "was
carried out after the introduction of the ban on the use of hormones for growth promotion in
Europe, which means that the subjects should have been exposed to hormone-free meat in their
diet. This may further imply that it cannot be excluded that the risk of cancer may be further
increased if meat treated with hormones for animal growth promotion were to be consumed".
[see paras. 145-148 of EC Rebuttal Submission (US case) and paras. 139-142 of EC Rebuttal
Submission (Canada case), footnote 97 in para. 147 of EC Rebuttal Submission (US case), and
Exhibits EC-71, 72, 73]

US and Canada's comments

94. The United States refers to the experts' (D rs. Boobis, Boisseau, Guttenplan and Cogliano )
replies on this question in paragra phs 61 through 63 of its submission. Contrary to what the United
States suggests, the experts are far from "[agreeing] that the three studies demonstrate no such risk."
While Dr. Boobis holds this view, both Dr. Cogliano and Dr. Guttenplan , on the contrary, confirm
that these studies indicate or suggest risks. I ndeed, as the European Co mmunities has explained
above, at least 2 out of the 4 scientists seem to ag ree that this kind of epidemiological evidence could
provide indirect information indicating that there may be a causal link.

95. It is therefore surprising the Canadian comment (in para. 102) that the European Communities
is "manipulating a genuine scientific interest". This kind of manipulating tactic has been deployed by
the defending parties since 1997, in their argument th at the risk from residues in treated meat with
these hormones is miniscule compared to the higher exposure of humans to intake from other natural
foods (meat, broccoli, soya, eggs, etc.), a statem ent which the Appellate Body has dismissed as "an
absurdity" in its 1998 Hormones report (at para. 221). Conversely, the EC argument has been
supported by at least one panel expert in the 1998 Hormones case and appears to be considered
relevant by two of the present experts. Indeed , it is recalled that during the 1997 panel report on
Hormones, one of the experts for the Panel (Dr. G. Lucier) had then stated:
"For every million women alive in the Unite d States, Canada, Europe today, about a
110,000 of those women will get breast c ancer. This is obviously a tremendous
public health issue. Of those 110,000 women get breast c ancer, maybe several
thousand of them are related to the tota l intake of exogenous oestrogens from every
source, including eggs, meat, phyto-oestroge ns, fungal oestrogens, the whole body
burden of exogenous oestrogens. And by my estimates one of those 110,000 would
come from eating meat containing oestroge ns as a growth promoter, if used as
prescribed."
96. However, the Appellate Body in 1998 denied ev identiary value to Dr. Lucier's statement for
the reason that his opinion "… does not purport to be the result of scientific studies carried out by him
or under his supervision focusing specifically on r esidues of hormones in meat from cattle fattened
with such hormones …". (at para. 198 of the 1998 Appellate Body report).
Q26. Does the scientific evidence referred to by the European Communities, in particular any
epidemiological studies, identify a relationship between cancer and residues of hormonal growth
promoters? In its risk assessment of 1999, th e European Communities makes reference to the
higher rates of breast and prostate cancer observ ed in the United States as compared to the
European Communities. Can a link be established between these statistics and the consumption
of meat from animals treated with the horm ones at issue? Would your reply have been
different at the time of adoption of the EC Directive in September 2003? If so, why? [see
pages 17-19 of 1999 Opinion of the SCVPH and related Tables A4-A5 on pages 83-91]

US comment

97. The United States refers to the experts' (Drs. Boobis, Boisseau, Guttenplan, Cogliano ) replies
on this question in paragraphs 59, 60 and 63 of its submission. Th e United States' bold assertion that
"the experts' responses confirm that the epidemiologi cal studies cited by the EC in its Opinion fail to
identify a link between hormone residues in meat and cancer" is once again a misrepresentation of
what these experts actually stated. To take the example of Dr. Boobis , while he does state that "there
is no scientific evidence demonstrating any association between consumption of meat from animals
treated with growth promoting hormones and the risk of cancer in human," he qualifies that statement
in the very next sentence pointing to the existence of "some studies th at are consistent with such an
association …" (studies which admittedly he thinks have other possible explanations, some of which
are more plausible than hormones in meat be ing causal). In the same vain, Dr. Guttenplan also
concedes that "the results are at least consistent with a possible effect of hormones on breast and
prostate cancer."
Canada's comment

98. Canada submits that the breast and prostate ca ncer rates between Europe and North America
are "relatively similar". However, on the basis of the figures mentioned by Dr. Boobis the difference
would still be around 20% higher in the United States, which can hardly be described as "relatively

similar". In this context, it is also amazing how Dr. Boobis
 minimizes the potential hormones treated
beef on these differences by linking any difference rath er to higher meat consumption. Apart from the
fact that Dr. Boobis is just engaging in some "best guessing effort", it is undeniable that the higher
meat consumption is intrinsically linked to highe r hormones consumption. Thus, it defies any logic
and common sense, as Dr. Boobis does, to refer to one single figure on consumption but leaving aside
the very fact that the higher consumption inevitably entails a higher intake of hormones.
(b) Residue analysis
Q27. How do the residues in meat from cattl e treated with the three synthetic growth
promoting hormones differ from residues in meat from cattle treated with the three natural
growth promoting hormones at issue?

US and Canada's comments

99. The United States and Canada do not refer to or comment on the experts' (Drs. Boisseau,
De Brabander) replies to this question.
Q28. How do the hormones naturally present in animals, meat, or human beings differ from
the residues in meat of the three natural hormones used for growth promotion purposes?

US comment

100. The United States does not refer to or comment on the experts' (Drs. Boisseau, De Brabander)
replies to this question.
Canada's comment

101. Contrary to Canada's view, Dr. De Brabander's opinion is not "much less clear". Rather,
Dr. Brabander is very explicit and detailed in his reply suggesting that the residues in meat of the
three natural hormones used for growth promo tion purposes are not identical to the hormones
naturally present in animals. What is even more questionable is that Canada criticises
Dr. De Brabander's statement on the ground that "his position would be inconsis tent with the detailed
residue evidence reviewed by JECFA in its 1999 residue monograph. The monograph presents
detailed data on hormone concentra tions in various tissues, including muscle and fat, in untreated
heifers and steers. Dr. De Brabander's suggestion in this regard simply does not withstand close
scrutiny." Yet, as we know and as JECFA and Codex admitted openly in their replies – including that
by Dr. Boisseau – the residue data used by JECFA in 1999 are essentia lly the same as those used in
1988 and that for the most part they date back to the 1960s and 1970s, whereas those used by
Dr. De Brabander
 are the most recent ones. Therefore, the Canadian claim cannot be taken seriously.
The European Communities reiterates once more its claim to the defending parties to provide their
residues data and the Panel to request those data fro m JECFA and make them available to the experts,
so that close scrutiny could indeed be exercised.
Q29. To what extent do the SCVPH Opinions eval uate evidence on the actual residue levels of
the synthetic hormones found in meat in their as sessment of the risks from such residues? Are
specific references provided as to how the evidence on residues relates to the observance of good
veterinary practices or lack thereof? How do they compare with the MRLs set by Codex? [see
paras. 165-176 of EC Rebuttal Submission (US ca se); pages 55-68 of the Opinion of the SCVPH
of 30 April 1999 in US Exhibit 4, para. 144 of US First Submission, Exhibits US-6 and 7,
footnote 46 of US Rebuttal Submission]

US and Canada's comments

102. The United States refers to the experts' (Drs. Boisseau, De Brabander ) replies to this question
in paragraphs 90, 91 to 93 of its submissi on. The US criticises Dr. De Brabander's reply as not being
based on concrete evidence. Th e US further cites Dr. Boisseau as stating that "…older data is neither
irrelevant or "bad" data simply due to its age. Ra ther, it is the quality and quantity of data that is
important, and for the hormones at issue, a great deal of high quality data exists." As a general
statement, the European Communities surely agr ees with it. However, as regards the data on MGA
used by JECFA date from the 1960s and 1980s, they are industry studies not published in any peer-
reviewed journal, and have not been seen by anyone else except the US and JECFA (see Exhibit
EC-127). Moreover, as long as these parties refuse to make them available for verification, it is
legitimate for an expert and the European Co mmunities to question their scientific quality and
credibility, given that the more recent data produ ced by the EC studies and those available in open
literature do not support the conclusions which the defending parties and JECFA pretend to draw from
those old data.
103. For these reasons, it is very inaccurate and mi sleading the comment made by Canada (at
para. 111) that the methods used by JECFA are "modern" and validated ones. The problem is not only
whether they are modern and validated but whether the residues which they are supposed to measure,
if the MRLs were to be adopted one day by Codex Alimentarius, are taken with these modern
methods or in the 1960s and 1980s when these so-calle d "modern" methods did not even exist. This is
the point. Indeed, Canada (and the US) unjustifiabl y and incorrectly criticise the reply by Dr. De
Brabander because he made his point as follows: " At the time they are [the residues] produced (1987)
there were no analytical methods available to quan tify these residues at that concentration level in a
correct way (methods as GC-MS-MS or LC-MS-MS)" . It is obvious, therefore, that Canada's comment
(at para. 111) that "…his cursory conclusion is in st ark contrast to the extensive evaluation of residue
data conducted by JECFA. In particular, recent residue data from studies using "modern" validated
methods (HPLC-MS, GC-MS and LC-MS) were assess ed in the JECFA Residue Monograph for the
58th Meeting. All ten studies cited date from 1999 to 2002" is inaccura te because: First, JECFA in
2000 did not carry out any extensive evaluation of the data, it simply took for granted the old and
unpublished data of the pharmaceutical indus try; second, the ten studies cited in the 58 th meeting of
JECFA are those that will be used if the MRLs for MGA proposed by JECFA will be accepted one
day in the future by the Codex Commission, but they are clearly not those used to generate the data in
the 1960s and 1970s.
104. Moreover, Canada's summary of Dr. Boisseau's reply is misleading. Dr. Boisseau not merely
stated that the SCVPH did not conduct a quantitative asse ssment but rather states more accurately that
"[a]s, in its 1999 report, SCVPH concluded "that no threshold level and, therefore, no ADI can be
established for any of the six hormones" (including the three synthetic ones), there was no need for
SCVPH to conduct a quantitative assessment (…)." (Emphasis added). Obviously, it makes a
difference if the SCVPH, as Canada insinuates, failed to do a quantitative assessment or, as
Dr. Boisseau states there was a very good reason for SCVPH not to do such an assessment.
Q30. To what extent do the SCVPH Opinions eval uate evidence on the actual residue levels of
the three natural hormones in meat in their asse ssment of the risks from such residues? Is it
possible to compare these to the ADIs recommended by JECFA in 1999? Are specific
references provided as to how the evidence on residues relates to the observance of good
veterinary practices or lack thereof? [see paras. 120-123 and 155-164 of EC Rebuttal
Submission (US case), pages 33-54 of 1999 Opinion in Exhibit US-4, para. 144 of US First
Submission, and 52
nd JECFA Report in Exhibit US-5]

US and Canada's comments

105. The United States refers to Dr. Boobis' reply to this question in paragraph 90 of its
submission. No reference is made to Dr. De Brabander's reply. As the European Communities has
noted in its comments of 30 June 2006 on Dr. Boobis' reply to this question, his position is incorrect
because the SCVPH did perform the comparison of the ADI and MRL values proposed by JECFA
with those generated by the EC studies that were reviewed by the SCVPH. In addition, the reply of
Dr. De Brabander confirms the EC finding that the data used by JECFA are old and their validity can
be questioned, until we are given the means to see and review them. The comment by the US (in
para. 90) on the reply of Dr. Boobis
 is misleading, because it seems that both have not understood that
JECFA reviewed old data that did not take into account realistic conditions of use of these hormones,
unlike the data generated by the EC studies for the first time and examined by the SCVPH. Dr. Boobis
asks the rhetorical question that "the frequency of o ccurrence of such misuse" is not stated. However,
the studies cited at Exhibits EC-65, 67, 68, 69, 70 and 70-73 show that the higher the frequency the
higher the risk will be. But in the case of prepubertal children the EC studies have clarified explicitly
that even a unique occurrence or an occasional one w ould be sufficient to lead to residue levels in
meat that would exceed by many times their endogenous production of these hormones.
106. Since Dr. Boisseau referred back in his answer to this Question to his reply to Question 29,
the same criticism on Canada's summary of Dr. Boisseau's statement applies here.
Q31. Please comment on the US statement that "concentrations of oestradiol-17 β in meat
from treated cattle do not vary significantly from concentrations in untreated cattle, i.e., residue
levels in meat from hormone-treated cattle a re well within the physiological range of residue
levels in untreated cattle. While tissue concentrations of oestradiol-17 β in treated cattle may be
slightly higher than those in untreated cattle, this increase is much smaller than the large
variations observed in (reproductively) cycling a nd pregnant cattle and is thus well within the
range of naturally observed levels." In you r reply please take into account the US 11 th
Carcinogenesis Report where it is stated th at "Meat and milk may contain estrogens.
Veterinary use of steroidal estrogens (to promote growth and treat illness) can increase
estrogens in tissues of food-producing animals to above their normal levels" and the statement
by the European Communities that "meat consumpt ion from pregnant heifers is exceptional as
usually these animals are not slaughtered. [see paras. 51 and 144 of US First Submission and
Exhibits US-6 and 7, para. 98 of EC Replies to Panel Questions, Exhibit EC-101, and
para. 2.3.2.3 of the 1999 Report of SCVPH]

US comment

107. The United States refers to Dr. De Brabander's reply to this question in paragraph 96 of its
submission. No reference is made to Dr. Boisseau's reply. The United States comments on the view
taken by Dr. De Brabander that "there is no need to add more [hormonal substances] by artificial
ways" stating that this is Dr. De Brabander's "personal opinion or policy statement." As a matter of
fact, Dr. Boisseau seems to take the opposite view by refe rring to a "theoretical" of "no additional
intake of residues [being] acceptable." What both expe rts express here, is indeed a policy statement, a
policy statement of the kind the European Communiti es as a risk regulator has every legitimacy to
make.
Canada's comment

108. In its comments to the experts' replies, Canada again demonstrates its very selective
perception of what the experts actually said. While it quotes in extenso Dr. Boisseau (who may be
understood to support Canada's position) it basically ignores Dr. De Brabander's very critical remarks
regarding the significant increase of estradiol-17 β in human food if all animals were treated

accordingly. The Panel would be well advised to take good note of Dr. De Brabander's response and
to draw its own conclusions why Canada is unwilling or unable to comment on the serious questions
in relation to animal welfare, environment and consumer protection as raised by Dr. De Brabander.
109. More importantly, however, Canada resorts (in paras. 116-117) to its dear and old argument
(in the absence of anything else) that "…in order a ppropriately to understand the risks associated with
the use of growth-promoting hormones, one must view the exposure to these hormones in their overall
context, including the wide exposure to natura l hormones from other dietary sources and endogenous
production of natural hormones." However, this ki nd of argument has been clearly rejected by the
Appellate Body in the 1998 Hormones case as "an absurdity". Moreover, the Appellate Body has also
found that the occasional use of meat from pregnant cows or those treated for therapeutical or
zootechnical purposes does not lead to arbitrary or unjustifiable discrimination and do cannot
undermine the EC's level of health protection (at paras. 222-225 of its report).
Q32. Please comment on the conclusions of the EC risk assessment (Opinion of the SCVPH of
April 2002) that ultra sensitive methods to detect residues of hormones in animal tissues have
become available but need further validation. What is the significance of this with regard to
identifying whether the natural hormones in meat are endogenously produced or are residues of
hormones used for growth promotion purposes?

US and Canada's comments

110. The United States refers to Dr. Boisseau's reply to this question in paragraph 93 of its
submission. No reference is made to Dr. De Brabander's reply. However, Dr. De Brabander states
that "there are now new data available demonstrat ing that the pattern change of hormones by the
application of the ‘natural' hormones used for growth promotion purposes." This is in direct
contradiction with Dr. Boisseau's statement that ultrasensitive detection methods would be "less
useful in the case of the three natural hormones, which are endogenously produced by food producing
animals." The United States seems to agree with Dr. Boisseau's comment without, however,
commenting clearly on this contradiction. The basic point Dr. De Brabander was making in his reply
is that the residue examined by JECFA were gene rated with the old methods and that new methods
should be used now to re-evaluate them. This is in agreement with the position of the European
Communities. Dr. Boisseau's reply is besides the point, because the new powerful and ultra sensitive
methods will always be required in order to determine the origin of residues in meat, for example in
order to determine whether is it endogenous or e xogenously administered and whether there was an
abuse or misuse.
Q33. What were the reasons for the re-evaluati on by JECFA of the three natural hormones in
1999? Were the residues data used for the thr ee natural hormones in 1999 the same as those
used in 1988? What additional information was used for the JECFA evaluation in 1999 of the
three natural hormones which was not available in 1988? How did the conclusions differ? What
led JECFA to establish ADIs for the three natura l hormones? What are the implications of
establishing ADIs? Why were JECFA's more re cent recommendations not considered by the
Codex Committee on Residues of Veterinary Drug s in Food? What is the status of these
recommendations? [see paras. 96-97 of EC Rebu ttal Submission (US case), paras. 79-80 of EC
Rebuttal Submission (Canada case)]

US comment

111. The United States refers to the experts' (Drs. Boisseau, Boobis, De Brabander ) replies to this
question in paragraphs 97 through 99 of its submission and also to Codex' and JECFA's replies on

related questions.
7 Contrary to what the United States pretends there is complete dissent among the
experts on the reasons why JECFA re-evaluated the three natural hormones, 8 and the Panel is referred
here to the reply of JECFA which admits that th e ADIs were set because of the new evidence that
became available in the meantime.
Canada's comment

112. It is not clear whether Canada's comment is fully consistent with its comment on Question 18.
In this question Canada assumes that the "genot oxic carcinogen [of oestradiol] appears to have
promoted at least in part JECFA's 1999 re-evaluation", whereas in its comment to Question 18 Canada
denied that JECFA's establishment of an ADI was related to its finding about "potential genotoxicity",
(see para. 71 last sentence).
113. Moreover, what is interesting is that Dr. Boobis
 appears to recognise that "in the intervening
time from the first to the second evaluation, it became clear that exposure to the natural hormones,
albeit at levels appreciable higher than found in meat from treated cattle, could have adverse effects in
humans". This is remarkable, as he admits that ther e is a problem of principle (despite all the talk
about eggs, milk and broccoli etc.), and it appears to be rather a question of "how much" is acceptable
(see also Canada's comment in this respect at para. 125, last sentence).
114. Canada's comment (at paras. 127-128) apparen tly approving the explanations provided by
JECFA and Dr. Boobis is inadequate. Indeed, after the CC RVDF refused to consider the 1999 re-
evaluation of the three natural hormones, where ADIs were considered necessary in order to avoid the
risk of cancer identified, the continued 1988 indica tion that MRLs are not "necessary" do not enable
the countries using these hormones to see if the ADIs are reached or exceeded. It would therefore be
imperative that JECFA and Codex review again all these hormones soon by taking into account all the
latest evidence and data available, in particular , those generated by the studies sponsored by the
European Communities.
Q34. Please comment on the EC argument that the 1999 JECFA report based its findings on
(a) outdated residues data and (b) not on evidence from residues in meat but on studies with
experimental animals and on general studies of IARC. If the data were not new, did JECFA
take this into account in its evaluation? What are the implications of using such data for the
purpose of conducting a risk asses sment? How reliable are extrapol ations from animal studies
to possible adverse effects on humans? How do es this compare with the kind of data and
studies used with respect to other veterinary dr ugs? [see para. 120 of EC Rebuttal Submission
(US case), para. 102 of EC Rebuttal (Canada case)]

US comment

115. The United States refers to Dr. Boisseau's reply to this question in paragraphs 49, 92 and 111
of its submission. No reference is made to Dr. De Brabander's reply. The reference to Dr. Boisseau is
always the same namely his statement that "the qualit y and the number of the available data are more
important than the dates at which these data ha ve been produced." The European Communities has
already commented on this statement, which it c onsiders scientifically unsound (see EC comments on
replies to question 34).

7 Question 20 in questions asked to Codex, JECFA and IARC.
8 Of course, there is agreement on the outcome of that evaluation, but that is not the question that was
put to the experts. The outcome – JECFA finding that these hormones are safe for consumers – is a fact and not
a matter of assessment.

116. The US further claims (at para. 111) that "[ a]s noted by the United States in its Rebuttal
Submission, and confirmed by Dr. Boobis' analysis above, even in the artificial scenarios developed
by EC scientists, in most cases extreme misuse and overdosing of cattle with implants did not result in
violative residue levels, i.e., levels exceeding ADIs and MRLs." This statement is not correct because
the new evidence generated by the European Co mmunities does establish that the ADIs and MRLs
will be exceeded by the residue levels resulting from misuse or abuse. Since the US (and on this point
also Canada) keep arguing that extreme misuse did not result in violative residue levels, it is important
to quote the conclusion from the relevant EC study (Exhibit EC-17) which states:
"Treatement with zeranol and testosterone propionate, even after multiple application,
does not cause any problems, as far as infringement of the threshold levels is
concerned. Off-label application of trenbolone acetate and estradiol benzoate,
however, may lead to illicit values. Exceedi ng of the MRL was found in the liver in
one out of two animals after 3-fold and in two out of two animals after 10-fold dose
of the 200 mg-trenbolone acetate-implant. Estradiol threshold levels were violated in
the liver and in the kidney even after 3-fold dose of Synovex-H. Fattening of calves
with the preparations Synovex-H and Synovex Plus lead to similar residue levels as
after Synovex-H or Finaplix-H treatment of heifers".
117. It is therefore misleading for the US to su mmarise the findings of the study in the way
described above.
Canada's comment

118. Canada completely fails to comment on Dr. De Brabander's reply. Instead, Canada merely
looks for support in Dr. Boisseau's answer. However, contrary to what Canada tries to present as
"what is generally accepted within the scientific co mmunity: that scientific data do not deteriorate
simply because the passage of time", Canada would have been well advised to address Dr. De
Brabander's statement whereby "[t]he implications of not using such (modern) data is that the results
of the risk assessment are biased in favour of th e "allowance" of hormones." Indeed, new data
obviously may lead to different conclusions and it is , therefore, indispensable to update and review
constantly scientific evidence. Canada obviously fails to do so.
119. Furthermore, Canada also misrepresents Dr. Boisseau's answer concerning the assessment of
hormones. Dr. Boisseau merely stated that "[f]or assessing the growth promoters, JECFA has used the
same procedure it has used for all other veterinary drugs". Re-formulated by Canada this statement
reads as follows: "[a]s the experts confirm, the data and process used for assessing the safety of
hormones are the same as those used for other veteri nary drugs" (emphasis added). Thus, Canada just
by convenience adds the word "data" and it presents this as a commonly held view by "the experts"
even though Dr. De Brabander (as the only other experts replying to this question) did not make such
a statement. This is just another example on how Canada tries to manipulate the Panel in its
presentation of the experts' responses.
Q35. Please comment on the European Communities claim that nearly all the studies
referred to in the 2000 JECFA report on MGA date from the 1960s and 70s. Is this correct?
Have subsequent reports of JECFA, prior or subsequent to the adoption of the EC Directive,
also relied on the same studies? [see para. 171 of EC Rebuttal Submission (US case), para. 161
of EC Rebuttal Submission (Canada case), para. 55, including footnote 60 of US First
Submission and Exhibits CDA-20, 33, 34 and 35]

US comment

120. The United States concedes that the experts (Drs. Boisseau, De Brabander ) have confirmed
that the studies relied upon date indeed from the 19 60s and 70s (paragraph 49 f its submission). The
United States relies on Dr. Boisseau's statement cited above (question 34), which the European
Communities considers scientifically unsound for the reasons explained above.
Canada's comment

121. Canada ignores Dr. De Brabander's reply for obvious reasons. But Canada appears also to
accept that the data examined by JECFA in 2000 and again in 2004 for MGA date from the 1960s and
1970s.
(c) Dose-response relationship
Q36. How would you describe a dose-response assess ment? Is it, as suggested by Canada in
para. 78 of its Rebuttal Submission, "widely, if not universally, accepted that adverse effects
arising from hormonal activities are dose-dependent"? Is dose-response assessment a necessary
component of hazard characterization? Or, is there an alternative approach which can replace
the dose-response assessment. Is a dose-response assessment feasible/necessary for substances
that are found to be genotoxic or to have genoto xic potential? [see para. 153 of EC Replies to
Panel Questions, para. 200 of EC Rebuttal Submission (US case); paras. 143, 154, and 156 of US
First Submission, paras. 70-74 of US Replies to Panel Questions, and paras. 34 and 37-40 of US
Rebuttal Submission; paras. 76-82 of Canada Rebuttal Submission]

US comment

122. The United States refers to Drs. Boisseau's and Boobis' reply to this question in paragraph 21
of its submission. No reference is made to Dr. Cogliano's reply. Contrary to what the United States
claims there is no consensus among the experts on whether a dose-response assessment is a necessary
component of hazard characterisation. Indeed, Dr. Cogliano takes the exact opposite view. Also,
Dr. Boobis recognises that there may be differences in approach between Europe and the US and
Canada as regards the assessment of compounds that have been "identified as an in vivo DNA-
reactive mutagen, or as causing a carcinogenic response via a genotoxic mode of action."
Canada's comment

123. Although all the experts, including the Codex an d JECFA, agree that there are no legally
binding risk assessment techniques in the sense of Article 5.1 of the SPS Agreement for this kind of
substances, Canada makes the unsubstantiated statement (at para. 141) that the hazard-based approach
would be inconsistent with the obligations under the SPS Agreement that a substance be evaluated for
the "potential for occurrence" of an adverse effect. The European Communities finds nothing of this
sort in the terms "potential for occurrence", as interpreted by the Appellate Body in the Hormones
case, given also that a qualitative assessment of the ri sk is also permissible. In any case, the European
Communities has carried out such an analysis of the likelihood of occurrence of the scientifically
identified risk in the case of these hormones.
Q37. Do JECFA or Codex materials confirm Cana da's statement in para. 80 of its Rebuttal
Submission that "...while international risk a ssessment techniques suggest that a dose-response
assessment is optional for biological or physica l agents when the data cannot be obtained, a
dose-response assessment should always be co nducted for chemical agents..."? [see Exhibit
CDA-25]

US comment

124. The United States does not refer or comment on the experts' (Drs. Boisseau, Boobis ) replies
to this question.
Canada's comment

125. The European Communities considers that Canada's statement (at para. 142) that "in light of
the universally held view that the adverse eff ects of hormones are dose-dependent", is erroneous
because it is factually not true, as the evid ence presented by the European Communities has
demonstrated. Indeed, except JECFA and the 2 experts Drs. Boisseau and Boobis
 who participated in
the risk assessment of JECFA, the majority view (which is growing steadily since 1999) is that
expressed by the IARC and the 2002 US Carcinogenesi s Report that these hormones act by direct and
indirect mechanisms.
(d) Sensitive populations
Q38. Please describe the range of physiological (or background) levels of the sex hormones in
humans and identify the variations in these le vels on the basis of age, sex group, and
physiological stages.

US comment

126. The United States refers to Dr. Boisseau's reply to this question in paragraph 65 of its
submission, in the context of its comments on the replies given on Question 40 (see below).
Canada's comment

127. Canada pretends that Dr. Boisseau in his reply "raises concerns, as many others have done,
about the reliance by the EC on a new ‘ultrasensitive biosassay'". However, first of all, Dr. Boisseau
has not expressed any "concerns" but he merely said that "[i]t would be important to know whether
these new bioassays have been properly validated (…)". Thus, Dr. Boisseau has merely raised a
question. Second, Canada refers to "many others" while, indeed, all ot her experts have not raised any
concerns. Canada, therefore, is making a misleading general statement, which is not supported by the
facts.
Q39. Please comment on the SCVPH opinion stating that "any excess exposure towards
oestradiol-17β and its metabolites resulting from the co nsumption of meat and meat products
presents a potential risk to public health in part icular to those groups of the populations which
have been identified as particularly sensitive su ch as prepubertal children" [see para. 147 of the
EC Replies to Panel Questions]

US comment

128. The United States refers to the experts' (Drs. Boisseau, Sippel ) in paragraphs 67 and
following of its submission. Contrary to what is claimed by the United States, Dr. Boisseau does not
state that "the EC has failed to assess this risk entirely." Dr. Boisseau merely takes the view that a
quantitative dose-response assessment (as opposed to a qualitative one) would have been needed.
129. The United States discusses Dr. Sippel's reply to this question in great detail (in paras. 64-82).
As regards the validation of the Klein assay, the prin ciple of the yeast assay h as been validated in an
international comparative study of different assay s for estrogens (Andersen et al., Comparison of
short-term estrogenicity tests for identif ication of hormone-disrupting chemicals. Environmental

Health Perspectives ; 107 (Suppl. 1): 89-108, 1999, Exhibit EC-123), so this should not now be in
doubt. Moreover, how can the US (and Canada on this point) claim that an assay cannot be used
because it had not been properly valid ated, since it is clear that JECF A used old "historic" values for
endogenous hormone levels in children that ar e clearly and undisputedly wrong because the old
assays used (RIA) cannot measure such levels? Th erefore JECFA used the LIMIT-OF-DETECTION
as the "real values" in children, which is obviously wrong and scientifically unacceptable.
130. The US criticise the EC statement "any excess e xposure..." but the concept of concentration
additivity has been proven for estrogens, including the demonstration of "0+0 ≈ 0" (i.e. that two doses
which alone do not produce any detectable effects, when added together result in an observable
effect). Thus, any dose matters. On dose additivit y see: Rajapakse N., Silva E., Kortenkamp A.:
Combining Xenoestrogens at Levels below In dividual No-Observed-Effect Concentrations
Dramatically Enhances Steroid Hormone Action , in Envir. Health Perspec. 110, 917-921 (2002)
(Exhibit EC – 116); and also Tinwell H., Ashby J.: Sensitivity of the Immature Rat Uterotrophic Assay
to Mixtures of Estrogens, in Envir. Health Perspec.112, 575-582 (2004) (Exhibit EC – 112).
131. The US criticises (at para. 67) the reply of Dr. Sippell
 for "proposing a different result than
his own research". However, the cited statement from Dr. Sippell is from a 2000 (published in 2001)
study, and a lot has happened since then, including the publication of many of the cited papers. Thus,
Dr. Sippell demonstrates his scientific integrity by ad justing his opinion according to the developing
scientific research. This is contrary to for example Dr. Boobis , who repeatedly claims that his opinion
has not changed since 1999, despite the publication since 1999 of so many papers on direct genotoxic
action.
132. At para. 68 the US cites the study by Schmidt which shows an overall association between
estradiol levels and postnatal breast development fo r the groups as a whole. But the study also shows
large variations in estradiol levels, including a demonstration of breast development without
measurable levels of estradiol. This emphasises the difficulty in measuring the very low estradiol
levels, and the study clearly shows breast developmen t, likely caused by estradiol, also in girls where
the estradiol level cannot be determined by the RIA assay. Whether this is a pathological effect cannot
be answered before the possible outcome of pert urbed breast development (breast cancer) can be
assayed (i.e. in 40-50 years), but recent research in to the origin of breast cancer do suggest that
changes in mammary gland development may play a significant role (see Baik I, Becker PS, DeVito
WJ, Lagiou P, Ballen K, Quesenberry PJ, Hsieh C-C.: Stem cells and prenatal origin of breast cancer,
in Cancer Causes and Control 15: 517–530, 2004).
133. In para. 69 the US discusses the Lampit et al study, which clearly demonstrate an effect of the
administrated estradiol on the growth of th e children. However, the US criticises that Lampit et al. ,
"fails to quantify the amount of estradiol that would be required to accelerate growth in normal
children". However, this is a consequence of the lack of sufficiently sensitive assays, since Lampit et
al. cannot measure the serum levels of estradiol, neither before nor after the administration of
estradiol. Thus, Lampit et al . clearly show an effect of administrated estradiol, despite serum levels
not reaching the current detection limit of the assays. This is very important and an extremely relevant
finding which the US avoids to confront objectively.
134. In paras. 70 and 71 the US advances a numbe r of unscientific arguments. It is textbook
knowledge that estradiol strongly influences the onset of puberty in girls. Is this questioned by the US
and Canada? Given that it is beyond doubt that estra diol is the main determinant for the onset of
puberty in girls, it seems reasonable that Dr. Sippell raises the possibility that exposure to excess
hormones in the US may play a role for trends in puberty disorders.

135. In para. 73 the US discusses the other publications cited. But in line with many other
publications, the Felner & White paper clearly shows that a small amount of estradiol strongly affects
breast development in children.
136. The US statement in para. 74 contains many aspect s that need clarification. First, there are
several publications that show higher estrogen le vels for twins (1.7 to 3 times higher in a twin
pregnancy compared to a singleton pregnancy) (Kappel 1985; TambyRaja 1981; Ikeno 1985).
Second, there are many publications showing lowe r estrogen levels in women with preeclampsia
(Goldkrand 1978; Long 1979; Shibata 2000). Thus, in the absence of other risk factors for breast
cancer that change in exactly the same way as the estrogen levels do in these groups, it is reasonable
to correlate the changes in breast cancer risk to ch anges in the levels of the most likely cause for the
changed risk, and that is the differences in estr ogen levels. The US asks fo r mechanistic evidence.
However, there are so many peer-reviewed papers relating breast cancer to estrogens. Moreover, the
publication by Baik et al. 2004 (cited above) provides a possible m echanistic explanation, especially
when combined with other publicati ons linking the cells described by Baik et al. to cell types that are
the prime candidates for being the cells-of-origin for breast cancer (for example, Petersen et al.,
2003). See on Estrogen levels in twin pregnancies compared to singletons : B. Kappel, K. Hansen, J.
Moller, J. Faaborg-Andersen: Human placental lactogen and dU-estrogen levels in normal twin
pregnancies, Acta Genet Med Gemellol (Roma) 34 (1985) (1–2), pp. 59–65; R.L. TambyRaja, S.S.
Ratnam: Plasma steroid changes in twin pregnancies , Prog Clin Biol Res 69A (1981), pp. 189–195;
N. Ikeno and K. Takahashi: Studies on changes in serum estrone, estradiol, estriol, DHA-S, and
cortisol and urinary estriol excretion , Nippon Sanka Fujinka Gakkai Z asshi 37 (1985) (1), pp. 99–
106. See also on Estrogen levels in women with preeclampsia : W. Goldkrand: Unconjugated estriol
and cortisol in maternal and cord serum and am niotic fluid in normal and abnormal pregnancy ,
Obstet Gynecol 52 (1978) (3), pp. 264–271; P.A. Long, D.A. Abell, N.A. Beischer: Fetal growth and
placental function assessed by urinary estriol excretion before the onset of pre-eclampsia , Am J
Obstet Gynecol 135 (1979) (3), pp. 344–347; A. Shibata, A.Y. Minn. Perinatal sex hormones and
risk of breast and prostate cancers in adulthood, Epidemiol Rev 22 (2000) (2), pp. 239–248; On
breast cancer see: Petersen, O.W., Gudjonsson, T., Villa dsen, R., Bissell, M.J., and Ronnov-Jessen,
L: Epithelial progenitor cell lines as models of normal breast morphogenesis and neoplasia . Cell
Proliferation 36, Suppl. 33-44 (2003).
137. In para. 76 the US discusses the "Testicular dy sgenesis syndrome" (TDS), which describes a
HUMAN syndrome that is observed in the clinic! Th e relationship to animal studies is only made as
an attempt to extrapolate possible reasons for the sy ndrome. In general, animal studies are designed to
show effects in a small number of animals and, ther efore, large doses are used in order to get effects
in essentially all the exposed animals. However, it is a different situation for the human population
where TDS-like symptoms are observed in a relativel y small percentage of me n. Thus, when genetic
variation is taken into consideration, low-dose exposure of hundreds of millions of humans may in a
small percentage of the exposed people lead to e ffects similar to those observed at high doses in all
the animals in a small group of exposed animals. Moreover, humans are exposed to a mixture of
compounds and it has been shown that the effects re present the sum of all the different exposures (i.e.
concentration addition!).
138. In para. 77 the US dismisses the effects of DBP because it "is a well known reproductive
toxicant". However, DBP in an endocrine disrupt er and acts by reducing the testosterone production
in the Leydig cells of the testes and thereby DB P is an example of a compound that induces TDS-like
symptoms via effects on the endocrine system, by lowering the testosterone levels.
139. Unlike the US comments in paras. 79 and 81, it seems clear that Dr. Sippell's conclusion
"exposure during pregnancy might result in severe tran splacental virilisation of a female fetus" is
reasonable, since it has been shown that trenbolone is about 3 times more potent that testosterone and

given that trenbolone is extensively used as an andr ogen by body builders. This strongly suggests that
trenbolone is a potent androgen in humans.
140. Despite the US comments in para. 80, there are now several studies on the estrogenic potency
of Zeranol (e.g. Guevel & Pakdel 2001; Liu & Lin, 2004) and all essentially report the same potency
(which is similar to that of estradiol). The Leffers et al paper analysed the induction of several
estrogen-regulated genes and found that different ge nes responded differently to the tested estrogens.
However, the Leffers et al. paper did not measure cell prolifer ation and none of the analysed genes
were proliferation-sensitive. The observation that DES and estradiol (and Zeranol) were equipotent
depended on which genes were used for the analysis. The key finding in the Leffers et al. paper, which
the US apparently fails or does not wish to accept, is that Zeranol is as potent as estradiol and that has
now been confirmed by other studies. See in particular: Le Guevel R, Pakdel F: Assessment of
oestrogenic potency of chemicals used as growth promoter by in-vitro methods, in Hum Reprod. 2001
16,1030-1036 (Exhibit EC – 108); and Liu S, Lin YC: Transformation of MCF-10A human breast
epithelial cells by zeranol and estradiol-17beta, in Breast J. 2004 10, 514-521 (Exhibit EC – 62).
Canada's comment

141. Contrary to what Canada asserts, Dr. Boisseau
 is not criticizing the "excess exposure" but
merely asks for its assessment and comparison. In other words, by its reply Dr. Boisseau actually
confirms that an "excess exposure" exists.
142. In its comments on Dr. Sippell's reply, Canada is making again an unqualified statement
concerning the "controversial" bioassay met hodology. However, Canada does not offer any
supporting arguments for its blunt statement. Furtherm ore, Canada pretends th at "the experts have
contested" elsewhere the conclusions of the Europe an Communities' quote. This is not true. Canada
would be well advised to respect more accurately th e various experts' replies instead of using an
unqualified and misleading language in order to manipulate the Panel.
Q40. The European Communities states that "the levels of endogenous production of the
hormones by prepubertal children is much low er than previously thought and this finding,
which is subsequent to the 1999 JECFA report, casts serious doubts about the validity of
JECFA's findings on the dose-response relation ship..." Please comment on the methodology
used by the SCVPH to support the conclusion th at hormone levels are lower than previously
thought, and in particular comment on the validity of these methodologies and their
conclusions. Would your conclusions have been the same at the time of adoption of the
Directive in September 2003?

US comment

143. The United States refers to Dr. Boobis' reply to this question in paragraphs 28, 65 through 67
and 83 of its submission. There is a discussion of Dr. Sippell's view on assay validation in
paragraph 66 of the submission, on which the European Communities has already commented above.
Canada's comment

144. Canada refers to the "concerns" by Dr. Boisseau as expressed in its reply to Question 38.
However, as already mentioned above, Canada is not accurately interpreting Dr. Boisseau's reply and
it abuses the expert's response to pursue its own litig ation objective. In the same vein, it is quite
superficial when Canada, in paragr aph 150, refers to "concerns highlighted by the experts about the
SCVPH's use of this methodology". If at all, there is only one expert, Dr. Boobis who makes some
critical remarks, while Dr. Boisseau remains neutral, Dr. Sippell supports the methodology and
Dr. Guttenplan, Dr. Cogliano and Dr. De Brabander do not express themselves at this stage. Even

more, Dr. Guttenplan , in his response to Question 52 states that: "[a]lthough the US and Canada
question the accuracy of the assay originally empl oyed for estrogens at the low levels found in
children, recent reports (…) indicate more recently re ported levels used by the EC are accurate".
145. Concerning the in vitro assay developed independently by Klein et al and F Paris et al to
assay low amounts of receptor-active estrogens, it shoul d be added to what has been explained above
that these biological assays are not absolute in the se nse that they should give precise and absolute
values. Indeed, they are internally validated assay s but not yet inter-laboratory comparison has been
made. But even if one may consider that this is a drawback, the assay is very useful in that it is far
more sensitive than any other spect ro-physical assay based on mass spectrometry. Nevertheless, this
inter-technique comparison will be performed rath er soon thanks to the new generation of mass
spectrometry based on Fourier-Transformed MS. This technological progress should be useful to
perform the complete hormonal expl oration (androgens, estrogens) in plasma of no- and pre-pubertal
girls and boys and the results will be critical to the risk assessment exerci se. Conversely, the JECFA
evaluation was based on old and very questionable data that were not produced at that time by any
spectro-physical method but only by radio-immunologic assays.
Q41. Why would individuals with the lowest end ogenous hormone levels be at greatest risk?
How would the risks for these individuals aris ing from hormones naturally present in meat
differ from the risks arising from the residues of hormone growth promoters?

US comment

146. The United States does not dispute the experts' (Drs. Boisseau, Sippell ) replies to this
question, which confirm the view taken by the European Communities that prepubertal children are
particularly sensitive to hormones exposure.
Canada's comment

147. As in its comments on earlier question, Canada claims support by "the experts" for the
criticism on the Klein assay which, however, is not supported by the facts. Thus, Canada's criticism
on the detailed reply by Dr. Sippell is completely baseless.
Q42. To what extent, in your view, has JECFA ta ken into account the particular situation of
sensitive populations, in particular prepubertal children, in its risk assessments with respect to
oestradiol-17β? Please compare the original data concern ing endogenous production of natural
hormones by prepubertal children upon which JE CFA based its assessment and those used by
the European Communities in its risk assessment . In your view, does the scientific material
referred to by the European Communities require a revision of the Codex recommendation with
respect to oestradiol-17 β? [For the questions in this section, see paras. 121-122 of EC Rebuttal
Submission (US case), para. 103-104 of EC Rebutta l Submission (Canada case), Exhibits EC-88,
99, paras. 42-45 of US Rebuttal Submission, paras. 84 and 159 of US First Submission, and for
JECFA's work Exhibits CDA-11, 16, 17, 18, 39]

US and Canada's comments

148. The United States refers to Dr. Boobis' and Sippell' replies to this question in paragraphs 67,
84 and 85 of its submission (no reference to Dr. Boisseau ). In Footnote 178 of its submission, the
United States dismisses Dr. Sippell's view that JECFA has not adequately taken into account the
particular situation of sensitive po pulations, in particular infants an d prepubertal children. The United
States claims that it is unclear whether Dr. Sippell is familiar with JECFA's safety factors or
whether/why he finds these factors to be inadequa te. However, none of the US comments is valid
because the so-called safety factors cannot substitute for the need of JECFA to review these hormones

on the basis of the most recent scientific data, incl uding in particular the direct genotoxicity and the
low levels of endogenous production by prepubertal children.
149. Similarly, Canada fails to address Dr. Sippell's
 detailed and supported criticism of the JECFA
conclusions. The European Communiti es regrets Canada's selective perception of all experts' replies
and to respond adequately to criticism on the use of hormones as growth promoters.
(e) Bioavailability
Q43. Please define bioavailability, comment on the significance of bioavailability to
assessments of risk, and on the degree of bioavailabilitiy of the residues of the hormones at issue
when consumed in meat, taking into account parti es' differing views on this matter. [see paras.
123-124 of EC Rebuttal Submission (US case) , paras. 105-106 of EC Rebuttal Submission
(Canada case), paras. 100, 155-159 of the EC Replies to Panel Questions, paras. 32 and 41-42 of
US Rebuttal Submission, paras. 69, 71, 88-89 and 146 of US First Submission, and para. 134 of
Canada Rebuttal Submission]

US comment

150. The United States claims that "none of the expe rts' responses appear to indicate otherwise",
when claiming that the European Communities has failed to take in to account the low bioavailability
of estradiol 17 β in its assessment of that hormones (see paragraph 27 of its submission). This is
plainly wrong as Dr. Guttenplan
 comes to the opposite conclusion wh en stating that: "[i]t appears that
the bioavailability of estrogen is low but not insign ificant (probably between 5 and 20%, if estrone is
also taken into account. (Estrone is readily inter-convertible with estrogen). Calculations are presented
in the above reference that suggest that even with low percentages of bioavailability of estrogen, the
levels in meat could result in bioavailable estrogen approaching the daily production rate of oestradiol
in pre-pubertal children (EC Rebut, para. 122). This would represent a risk factor (EC Rebut,
para. 122)."
151. Indeed, the United States tries to refu te the view taken by Dr. Guttenplan by arguing that (1)
he relies on materials cited by the European Comm unities that do not in fact demonstrate a higher
bioavailability for estradiol 17 β than previously thought, and (2) he miscasts as "paradoxical" a US
argument relating to bioavailability (paragraphs 28 and following of the US submission).
152. As for the first argument, it should be recalled that human beings are considered as having a
monogastric physiology and, consequently, the large digestibility of nutrients should be clearly
applicable. Therefore, for risk assessment purposes it is considered that digestibility and hence
bioavailability of steroids ("primary bioavailabilit y" or the amount of xenobiotics absorbed from a
given matrix or formulation) and in particularly est rogens is more or less complete. In the absence of
any specific study on bioavailability of steroids considering the low amounts of residues found in
edible tissues of treated cattle, ther e is a need to consider this bioa vailability parameter at its maximal
value due to a complete intestinal absorption. This point has been formerly anticipated in milk-fed
calves which have kept a seemingly monogastric phys iology and for which the estrogens excretion is
mainly achieved by urinary route, that is stri kingly different from this obtained for ruminant
physiology, which prove the important entero-hepatic cycle and hence the very significant intestinal
absorption of estrogens. This also explains the bioa vailability of hormones present in gut, even if they
are excreted by the biliary route. In addition, there is a need of common understanding of what is the
definition of bioavailability of steroidal hormones, given the greatly varying degrees between gut,
liver and peripheral tissues, due to the progressive me tabolism of those hormones. Again, we need to
consider that there is total intestinal absorption an d a complete hormonal effect at least on intestinal
cells and hepatocytes before their metabolic degrad ation. Therefore, it is very doubtful when JECFA
and Dr. Boobis assume that an oral bioavailability of rate of 5% (Fortherby, 1996) is rightly used in

order to assert there is a low hormonal effect of orally given hormones. This result may be only a
comparative result of hormonal effect of two diffe rent administration routes on classically considered
target tissues and is related to raw bioequivalence measured on a given target tissue, not the
bioavailability. In the context of hormone residues in meat, no specific results have been obtained on
the hormonal response of intestinal cells exposed to those hormonal residues neither on hepatic cells
measurements have been carried.
153. Some specific attention should also be placed on the different bioavailability rates of
estrogens, considering that some are ingested as free or conjugates compounds (thus being easily
hydrolyzed by gut microflora) and some other are lipophilic compounds (estrogen esters) and are
susceptible to take the lymph route after intestinal absorption (see Paris et al, 2000). Therefore, this
class of lipoidal estrogenic residues will partially escape the liver degradation step. This specific
bioavalability of estrogen esters may explain why, ev en by oral route administration, they are about
10 fold more active than estradiol in inducing a significant uterotrophic response in the juvenile
female rat model (Paris et al, APMIS 109 (2001) 365-375) (Exhibit EC-117). This has been taken into
account by the SCVPH, unlike JECFA and Dr. Boobis that seem to disregard it.
Canada's comment

154. Canada fails to address specifically the conclusion by Dr. Guttenplan whereby "calculations
are presented in the above reference that suggest that even with low percentages of bioavailability of
estrogen, the levels in meat could result in bioavailable estrogen approaching the daily production rate
of oestradiol in pre-pubertal children (EC Rebut, para. 122). This would represent a risk factor
(EC Rebut, para. 122)".
(f) Good veterinary practice (GVP)
Q44. Please define "good veterinary practice" (GVP) and/or "good practice in the use of
veterinary drugs" (GPVD). What are th e relevant Codex standards, guidelines or
recommendations relating to GVP/GPVD? Please comment on the statement by the European
Communities that the definition of the GPVD is "circular and hence problematic." [see para. 88
of the EC Replies to Panel Questions]

US comment

155. The United States does not comment on this point and the replies given by Dr. De Brabander
and Dr. Boisseau (on the discussion in paragraph 107 of its submission see below, question 45).
Canada's comment

156. Canada, regrettably, does not address Dr. De Brabander's reply on why the definition of the
GPVD is considered to be "somewhat circular and hence problematic". Instead, Canada just
reproduces a general statement by Dr. Boisseau although even Dr. Boisseau provides an interpretation
which Canada, again, ignores.
Q45. In conducting a risk assessment of specific veterinary drugs, what assumptions are made
concerning GVP, if any? How, if at all, are risk s that might arise from the failure to follow good
veterinary practice in the administration of veterinary drugs addressed?

US comment

157. In the context of this question the United States comments on the reply given by
Dr. De Brabander in paragraph 107 of its submission dismis sing the reference he makes to evidence

of abuse of hormonal substances in the US. Whil e the study referred to by Dr. De Brabander
 is
certainly interesting, the European Communities w ould recall that it has undertaken its own studies to
assess the possibility of misuse and abuse in the US and Canada. It is on these studies that the EC risk
assessment relies on.
Canada's comment

158. Canada does not comment on Dr. De Brabander's
 pertinent response whereby "farmers (and
vets) have indeed economic incentives to misuse grow th promotion substance (implants or others)".
The Panel may draw its own conclusion by this Canadian failure.
Q46. To what extent were risks from misuse or abuse assessed by JECFA in its evaluation of
the hormones at issue? In terms of the three synthetic hormones at issue, how is GVP relevant
to the establishment of MRLs by JECFA?

US and Canada's comments

159. The United States and Canada does not refer to or discuss in detail the experts' (Drs. De
Brabander, Boisseau, Boobis) replies to this question.
Q47. How significant are any differences in GV P in the European Communities, the United
States, and Canada? Does the EC risk assess ment take into account relevant control
mechanisms with respect to GVP in place in the United States and/or Canada? If so, what are
their conclusions?

US and Canada's comments

160. The comments above under Question 45 apply here as well. In addition, Canada argues (at
para. 182) that the comment of Dr. De Brabander that control mechanisms short of total ban is
"deeply flawed". However, Canada - as well as the US – fails to discuss at all the numerous instances
of abuse and misuse documented in the EC inspections in their territories, nor do they comment on the
findings of the evidence reported in exhibits EC-67 to 73.
Q48. To what extent does the scientific evid ence referred to by the European Communities
assess risks to human health from residues of misplaced implants or improper administration,
i.e. when administered differently than indicate d on the label of the manufacturer or contrary
to GVP, of any of the six hormones? Would your reply have been different at the time of
adoption of the EC Directive in September 2003? What are the potential hazards, if any, to
human health of the use of large quantities, or doses higher than recommended, of any of the six
hormones in dispute?

US comment

161. The United States refers to the experts' (Drs. Boobis, De Brabander, Boisseau ) replies to this
question in paragraphs 103, 104 and 109 of its s ubmission. As stated in its own comments, the
conclusions reached by Drs. Boisseau and Boobis rest on the assumption that a quantitative
assessment is required. Indeed, Dr. Boobis concedes that this is not the view taken by the EC risk
assessors, a remark which the United States convenien tly omits to refer to or comment on. The US
criticises the statements by Dr. De Brabander as not based on evidence, but as explained above in
relation to Question 47 the evidence is provided in th e relevant EC exhibits which the US has chosen
to ignore.

Canada's comment

162. The way Canada comments on the three expert replies is again an interesting and typical
example on how Canada attempts to influence th e Panel by a selective reproduction of only those
expert replies which, in Canada's view', supports its position. However, instead of looking for comfort
in replies that merely allegedly confirm its own position (which is a natural and convenient way of
doing but insufficient in this case) Canada s hould have better addressed Dr. De Brabander's very
critical conclusion whereby "more and more scientific data sustain the ban on the use of hormones:
the economical profits resulting from using horm ones does not balance the potential danger [in
respect of, inter alia , animal welfare, environment and transformation of hormones] in all of its
aspects" (emphasis in the original).
Q49. What analytical methods, or other technical means, for residue detection in tissues exist
to control the use of the six hormones in dis pute for growth promotion purposes in accordance
with good animal husbandry practice and/or good veterinary practice? What tools are
available to control the use by farmers of the six hormones in dispute for growth promotion
purposes in accordance with good animal husbandry practice and/or good veterinary practice?

US comment

163. The United States does not refer to or discuss Dr. De Brabander's reply to this question.
Moreover, as the European Communities has expl ained, these hormones ar e dispensed over the
counter (OTC) in the US and Canada. In such a case the concept of GVP is not applicable and can be
even misleading. Veterinarians are not involv ed in the whole process of distribution and
administration of these hormones to animals since any farmer is free to use them at his will.
Therefore, the initial statement by Dr. Boobis that "… it has been used as an anabolic agent in
veterinary practice" is totally misleading as regard s the realistic conditions of use of these hormones
in the US and Canada. Moreover, the pinna of the ear is the only authorized site of application. 9 If
this is not observed, the depot goes directly into th e edible part of the animal. Thus, it is more than
surprising that this issue of utmost importance is not covered by any reply from the defending parties
and the experts. Dr. Boisseau states that the administration of the implant is "… by subcutaneous
implant to the base of the ear …". If this is so, this is already a serious misuse of these implants.
Canada's comment

164. The European Communities agrees that the add itional information asked by Canada may be
asked from Dr. De Brabander. The European Commun ities is confident that this also will support its
position.
Q50. Are there other measures available to the European Communities (other than a
complete ban) which could address risks aris ing from misuse and failure to follow good
veterinary practice with respect to the use of the hormones at issue for growth promotion
purposes? Would your reply have been different at the time of adoption of the EC Directive in
September 2003? If so, why?

9 See in the US the freedom of information summ ary, supplemental new animal drug application,
NADA 140-897; Route of Administration: Subcutaneous implantation on the posterior aspect of the middle
one-third of the ear by means of an implant gun; and freedom of information summary, supplemental new
animal drug application, NADA 140-897, the Center for Veterinary Medicine has concluded that, for these
products, adequate directions for use by layperson ha ve been provided and the products will have over-the-
counter (OTC) status. Label directions are accompanied by pictorial diagrams and detailed instruction in plain
language. The drugs are not controlled substances. The products' status remains OTC. The labelling is adequate
for the intended use and has sufficient warnings/statements to prevent illegal use in veal calves.

US comment

165. The United States does not refer to or comment on Dr. De Brabander's reply to this question,
which is entirely supportive of the position taken by the European Communities.
Canada's comment

166. In its comments on Dr. De Brabander's reply Canada fails to see the difference between, on
the one hand, the theoretical possibilities of cont rol possibilities, as provided by Dr. De Brabander in
his reply to Question 49, and the actual possibility to address risks arising from misuse and the failure
to follow GVP and which, in Dr. De Brabander's view, can only be achieved by the European
Communities through a complete ban. There is no contradiction between these two statements.
Q51. Does the material put forth by the Europe an Communities regarding misuse or abuse of
the hormones at issue in the United States and Canada call into question the potential
applicability of Codex standards with regard to imports of meat from cattle treated with
hormones from the United States and Canada? [For questions on GVP see the SCVPH Opinions
in Exhibits US-1, 4 and 17, paras. 125-127 of EC Rebuttal Submission (US case), paras. 107-109
of EC Rebuttal Submission (Canada case), para. 154 of EC Replies to Panel Questions, Exhibits
EC-12, 67, 68, 69, 70, 73, 96, 102, 103, paras. 32 and 54-65 of US Rebuttal Submission, para. 75
of US First Submission, paras. 107-111 of Ca nada Rebuttal Submission, page 40 of Exhibit
CDA-27]

US comment

167. The United States refers to Dr. Boisseau's reply in paragraph 108 and comments on Dr. De
Brabander's reply in paragraph 111 of its submission. The US relies again on the statements by
Dr. Boobis (in paras. 109-110) to counter the evidence on abuse and misuse produced by the
European Communities. But neither Dr. Boobis nor the US contest as such the accuracy of the
scientific findings reported in those studies. Dr. Boobis' only claim is that (at para. 109) that the
"probability" of these happening is "extremely low". Ho wever, what is "extremely low" is not defined
nor is it true of course.
Canada's comment

168. Canada draws the conclusion from Dr. Boisseau's reply that "in the unlikely event that GVP is
not followed, the applicability of Codex standard s is not put into doubt". However, Dr. Boisseau
never said this. Rather, Dr. Boisseau explicitly agreed that "the Eu ropean Communities is right to
state that, in case of these diffe rent misuses/abuses, the exposure of consumers may be totally
different" (Dr. Boisseau's reply to Question 48).
(g) Other
Q52. Do the risk assessment of the European Communities or any other scientific materials
referred to by the European Communities demons trate that a potential for adverse effects on
human health arises from the consumption of me at from cattle treated with any of the six
hormones in dispute for growth-promotion purpo ses? If yes, why? If not, what kind of
evidence would be required to demonstrate su ch potential adverse affects? Would your
response have been different at the time of adoption of the Directive in September 2003?

US comment

169. Apart from a wholesale reference to Dr. Boobis' reply in footnote 41, the United States does
neither refer to nor discuss the experts' (Drs. Boobis, Boisseau, Guttenplan) replies to this question.
Canada's comment

170. Canada attempts again to mislead the Panel by drawing conclusions that are not warranted, in
particular when it misstates (at paras. 197-198) the reply of Dr. Guttenplan
. If to the reply by
Dr. Guttenplan are added the replies from the other 3 scientists who replied in their areas of expertise,
then 4 out of the 6 scientists, in the view of the European Communities, agree with its scientific basis
and the risk assessment it has conducted on th ese hormones. The European Communities would
suggest that the Panel requests each of the experts to respond to this question for his respective areas
of expertise.
Q53. Please comment on the statement by the European Communities that the natural
hormones progesterone and testosterone are used only in combination with oestradiol-17 β or
other oestrogenic compounds in commercial prep arations? Would the systematic use of these
and the synthetic hormones in combination h ave any implications on how the scientific
experiments and the risk assessment s are to be carried out? If so, have the scientific materials
referred to by the European Communities or re levant JECFA reports taken into account the
possible synergistic effects of such combinations on human health? [see sections 4.2-4.3 of the
Opinion of the SCVPH of 2002 in US Exhibit 1]

US comment

171. The United States does neither refer to nor comment on the experts' (Drs. Boisseau,
Guttenplan) replies to this question.
Canada's comment

172. Canada's statement is, to say the least confusing. First, Canada pretends that Dr. Boisseau and
Dr. Guttenplan "advise that the exposure to these hormones, both alone and in combination is so low
that there is very little risk of any increase in the risk if assessed in combination". Yet, this description
falls short by what Dr. Boisseau or Dr. Guttenplan actually stated. Dr. Boisseau merely states that
"[c]onsidering that it has been established that prog esterone and testosterone are not genotoxic, it is
not likely that the testing of combinations of progesterone and testosterone with oestradiol-17 β would
have led to synergistic effects compared with those obtained from these individual substances".
Dr. Guttenplan, for his part, states that "the use of mixtures should complicate risk
assessment/scientific experiments, as they would ha ve to evaluate/investigate each component alone
and in combination. This is a major undertaking as effects of individual agents may be additive,
inhibitory, and synergistic or there may no effect. It appears from the evidence submitted that, by far,
estrogen is the major agent of risk and because the concentrations of all of the hormones in beef are so
low, that they would be unlikely to affect the potency of estrogen. However, it appears that no
experiments on effects of combinations were performed, so some uncertainty exists here".
173. Against this background, Canada's c onclusion that "once oestradiol 17 β has been
demonstrated not to have effects when used as a gr owth promoter, there is little risk that adverse
effects would occur if used in combination with th e other hormones" has never been stated by any of
the experts.
Q54. What is the acceptable level of risk refle cted in the Codex standards for the five
hormones at issue? How does th is compare to the European Communities' stated objective of

"no risk from exposure to unnecessary additional residues in meat of animals treated with
hormones for growth promotion". [see para. 149 of EC Rebuttal Submission (US case)]

US comment

174. The United States does neither refer to nor co mment on the experts' (Drs. Boisseau, Boobis,
Guttenplan) replies to this question.
Canada's comment

175. The comments by Canada about "theoretical" and "real" risk are again misleading, because
the scientists (Drs. Guttenplan, De Brabander and Sippell ) and the European Communities have
identified a real risk from the consumption of residues in meat from animals treated with these
hormones for growth promotion purposes. The existence of the real risk has been confirmed also by
the US 2002 Carcinogenesis Report and it is simply a question of defining the appropriate level of
protection – which is much lower in the US and Canada than in the European Communities – that has
so far led the defending parties from ignoring the regul atory implications of that finding. This is not
different from what has happened in the case of Carbadox a few years ago, when the defending parties
were arguing this case in 1997 before the WTO. It is useful to recall here how Canada has explained
its 360 turn on Carbadox in 2000, just 3 years after its persistent insistence in the WTO that Carbadox
was a safe substance to use:
"Carbadox is an antibiotic approved in the 1970s for use in swine to prevent and treat
disease as well as to maintain weight gain dur ing periods of stress, such as weaning.
It has been shown that the drug, and the by -products of the drug that occur when the
drug is metabolized in the body, can cau se cancer in rats. However, when an
appropriate withdrawal period (i.e stopping the administration of the drug before
slaughter) is observed, the drug and its br eakdown products are not found in the food
derived from the treated animal. Carba dox was approved on the basis that this
specified 35-day withdrawal period be strictly observed.
However, reports of misuse and accidental contamination, combined with a better
scientific capacity to detect breakdown products of carbadox, resulted in serious
concerns about the safety of the product. The first reported incident occurred in the
fall of 2000 when pigs at a farm in Quebec were accidentally fed carbadox and
slaughtered without respecting the withdr awal period. All affected product was
recalled and removed from store shelves and an investigation into the incident was
launched. The investigation was then br oadened to review the use of carbadox
throughout the Canadian pork industry.
In February 2001, responding to the European Union Fall 2000 audit of the Canadian
Program for the Control of Residues, Canada made a public commitment to reassess
the use of carbadox in pigs.
Based on the reassessment, Health Cana da proposed to amend the Food and Drug
Regulations to ban the sale of any drug containing carbadox for administration to
food-producing animals."
10 (Emphasis added)
Q55. Do the Opinions of the European Communi ties or other scientific materials referred to
by the European Communities evaluate the extent to which residues of growth promoting

10 See at the website of Health Canada at: http://www.hc-sc.gc.ca/ahc-asc/media/nr-
cp/2001/2001_88_e.html, visited on 11 July 2006.

hormones in meat contribute to what the Euro pean Communities calls "additive risks arising
from the cumulative exposures of humans to mult iple hazards, in addition to the endogenous
production of some of these hormones by anim als and human beings"? Would your reply have
been different at the time of adoption of the EC Directive in September 2003? If so, why? [see
para. 151 of EC Replies to Panel Questions, paras. 43-44 of US Rebuttal Submission,
paras. 83-85 of Canada's Rebuttal Submission]

US and Canada's comments

176. The United States refers to Dr. Boisseau's and Dr. Guttenplan's replies in paragraphs 23 and
25 of its submission but fails to put in doubt the accuracy of Dr. Guttenplan's comments. The fact is
that the decision of JECFA to set an ADI for oestradiol 17 β was based on the alleged lack of evidence
for in vivo genotoxicity and the seemingly safe use of oral contraceptives and postmenopausal
estrogen replacements, implying the existence of a threshold for the carcinogenic effect of oestradiol
17β. But both situations are wrong and in any case have changed in the meantime, as there is now
clear evidence for in vivo genotoxicity and evidence for an incr eased risk of cancer in women taking
oral contraceptives and postmenopausal estrogen ther apy. Even if a threshold would exist (which
should not because of genotoxicity), the endogenous production of oestradiol 17 β obviously exceeds
that threshold, because we see oestrogen mediated cancer of the breast, endometrium and ovary in
women. So any additional exposure to estrogens, e.g. from food, will inevitably increase the risk.
177. Moreover, as the EC has explained above, the US criticism that the EC statement "any excess
exposure would increase the risk" is incorrect becau se the concept of concentration additivity has
been proven for estrogens, including the demonstration of "0+0 ≈ 0" (i.e. that two doses which alone
do not produce any detectable effects, when added together result in an observable effect). Thus, it is
clear that any dose matters.
Q56. Has JECFA/Codex considered in its risk a ssessment of the five hormones such "additive
risks? Are there internationally recognized gu idelines for conducting assessments of "additive
risks"?

US comment

178. The European Communities suggests that it be clar ified at the hearing where in its assessment
JECFA is considering the issue of additive risks. United States refers to Drs. Boisseau's and Boobis'
reply to this question in paragraph 26 of its subm ission, but again uses the idea of "trivial increase,
something it is obviously unable to prove with scientific evidence. Indeed, quite the opposite is true. It
has been shown that additivity of an exogenous dose to an endogenous hormone that is already
causing responses will increase risk and have no threshold (see Hoel, D.G., Incorporation of
background in dose-response models, in Fed. Proc . 39, 73-75 (1980)). Nonetheless, non-linearity ( a
threshold) is assumed.
Canada's comment

179. Canada's comments on the expert' replies only tell half of the story. Indeed, Canada fails to
see that Dr. Boisseau stated that for the synthetic hormonal growth promoters, JECFA/CODEX did
not consider such "additive risks" probably b ecause no internationally r ecognized guidelines for
conducting assessment of "additive risks" exists. Ca nada's comment cites with approval Dr. Boobis
reply. But the "additive" risk they both have in mind is quite different from the additive risk the
European Communities has explained. For both of them, JECFA is supposed to take into account such
risks through the mechanism of "safety margins" and default assumptions, which are obviously totally
inadequate and scientifically inappropriate for this type of genotoxic substances.

Q57. Canada comments that "one single mol ecule that the European Communities considers
so dangerous from meat derived from animals treated with hormone growth promoters
 is
suddenly not at all that dangerous when cons umed from meat from animals treated for
therapeutic or zootechnical purposes. The European Communities' concern about the
genotoxic potential of oestradiol-17 β suddenly and inexplicably disappears." To what extent
are hormone treatments of cattle for purposes ot her than growth promotion, such as for
therapeutic or zootechnical purposes, taken into account by the European Communities, if at
all, in its assessment of the cumulative effects from the consumption of meat containing residues
of the hormones at issue? Would your reply have been different at the time of adoption of the
EC Directive in September 2003? If so, why? [see para. 97 of Canada Rebuttal Submission;
paras. 17-20 of US Opening Statement]

US comment

180. The United States refers to the expe rts' (Drs. Boisseau, Boobis, Guttenplan ) replies to this
question in paragraph 24 of its submission. Contrary to what the United States claims, Dr. Guttenplan
does address the Panel's inquiry, i.e. whether the Eu ropean Communities, in its Opinions, took these
treatments into account in an assessment of cumu lative effects. He stat es that the European
Communities "does not really take [these] […] into account in their risk assessment." Dr. Guttenplan
then refers to the reasons why this is so and qualifies these as "a reasonable response."
Canada's comment

181. Canada draws the wrong conclusion from the expert 's reply when it purports that "the experts'
advice indicates that the EC is trying to have it both ways: that hormones are genotoxic for some
purposes and not others". Indeed, while Dr. Boisseau
 is questioning the logic of the EC's limited
exception for the use of hormones for zootec hnical and therapeutic reasons, Dr. Guttenplan expressly
states its support for the EC' approach. This is not a question about the genotoxicity of hormones, as
Canada tries to present it, but it is a pure risk management decision whereby in these limited
circumstances it is assumed that the hormones will not enter into the food chain and, therefore,
logically not present a risk to consumer's health. Fo r this reason, it is by the way also an incorrect
conclusion by Dr. Boisseau
 that this limited exception would raise questions regarding the overall
approach taken by the European Communities. I ndeed, the European Comm unities has always been
pursuing the objective of health protection. This obj ective is not put into danger in case of the use of
these hormones for zootechnical and therapeutic reas ons, which in any case has been rejected by the
Appellate Body back in 1998.
Q58. Please comment on the EC statement in para. 94 of the EC Replies to Panel Questions
that "the only rationale that can be inferred from the available scientific data is that the higher
the exposure to residues from these hormones, the g reater the risk is likely to be", taking into
account para. 105 of Canada Rebuttal Submission.

US comment

182. The United States refers to the experts' (Drs. Boobis, Guttenplan, Boisseau ) replies to this
question in paragraphs 24 and 25 of its submission. Quoting Dr. Guttenplan as referring to an "indeed
very weak statement of the EC", it conveniently omits the rest of Dr. Guttenplan's statement who went
on to say "[h]owever, the alternative would be to suggest a risk that might be wildly inaccurate, due to
the limitations imposed by the lack of solid data on levels of hormones in meat. Perhaps a better
approach would have been to suggest several scen arios. These could be validated or disproved by
subsequent studies." Thus, Dr. Guttenplan suggests that other alternative scenarios. The European
Communities considers that the Panel may request Dr. Guttenplan to explain what other scenarios he
has had in mind.

Canada's comment

183. The comment by Canada (at para. 210) is also incomplete and partly false, because the
European Communities has demonstrat ed that if the appropriate leve ls of endogenous production are
taken into account, the ADIs set by JECFA will be reached and will be even exceeded easily.
Q59. Does the scientific evidence referred to by the European Communities identify any
adverse effects on the immune system from the consumption of meat from cattle treated with
the growth promoting hormones at issue? Would your reply have been different at the time of
adoption of the Directive in September 2003? If so, why? [see para. 132 of Canada Rebuttal
Submission]

US and Canada's comments

184. The United States refers to the experts' (Drs. Boobis, Boisseau and Guttenplan ) replies to this
question in paragraph 86 of its submission. Canada discuss this in para. 211 of its submission. They
both do not comment on the fact that there is a straightforward contradiction in the statements they
quote. While Dr. Boobis denies that there is any evidence of adverse effect on the immune system,
both Dr. Boisseau and Dr. Guttenplan acknowledge that there is such evidence.
Q60. Does the scientific evidence referred to by the European Communities identify and
evaluate whether there is a difference in term s of potential adverse effects on human health
from the consumption of meat from cattle treated with hormones for growth promotion
purposes when these hormones are administered as feed additives (MGA) or implanted? Are
you aware of any differences?

US comment

185. The United States only refers to Dr. Guttenplan's reply to this question. In footnote 114 of its
submission it states that Dr. Guttenplan's statement that MGA can be administered both as feed
additive or implant is incorrect.
Canada's comment

186. Canada's claim (at para. 212) that Dr. Boobis is right in arguing that misuse would "not occur
in feed additives" is without an y basis. The example of Carbadox may be again useful, because this
substance too was administered as a feed additiv e. But as the European Communities has explained
above in relation to Question 54, Canada has adm itted that its misuse has occurred and actually to
such an extent as to lead it to ban this product also on this ground
Q61. In your view and in the light of information provided by the parties as well as the work
undertaken at JECFA and Codex, did the sci entific evidence available to the European
Communities at the time it adopted its Dire ctive (September 2003) allow it to conduct an
assessment (quantitatively or qualitatively) of th e potential for adverse effects on human health
arising from the consumption of meat from cattle treated with (a) progesterone; (b)
testosterone; (c) trenbolone; (d) zeranol; and (e) melengestrol acetate? Would your response
differ in light of the scientific evidence provided which is subsequent to the adoption of the EC
Directive?

US and Canada's comments

187. As so often, the United States' claim that " the experts' responses confirm that the scientific
evidence and information relating to the five hor mones is sufficient to conduct an assessment" does

not reflect the reality of what the experts have said. Indeed, only Dr. Boobis
 has taken this view
(paragraphs 48 and 49 of its submission).
188. Dr. Boisseau declines to comment on the question itsel f noting that "I don't really know what
were the data available to the European Co mmunities at the time it adopted its directive."
Furthermore, Dr. Guttenplan takes a very nuanced and partly opposite view. As regards Trenbolone
and Zeranol, he states that from the data availabl e at the time of the Directive, the potential for
adverse effects could not be ruled out. The United St ates tries to undermine this statement by pointing
out that Dr. Guttenplan mistakenly thinks that trenbolone is an estrogen.
189. However, Dr. Guttenplan may not be wrong completely as Bauer et al. have documented that
trenbolone has three separate hormonal activities combin ed in one substance. It binds to the androgen
receptor, progestin receptor and glucocorticoid recep tor. This was not documented before. Dr. Boobis
and certainly the US (at para. 49) in their stat ements still call trenbolene an androgen. The finding
above is of clear relevance for the risk assessment of trenbolone acetate. If multiple hormonal
activities are exhibited from one and the same comp ound, the potential of the synergistic activity has
to be considered. See Bauer ERS., Daxenberger A., Petri T., Sauerwein H. and Meyer HHD.:
Characterisation of the affinity of different ana bolics and synthetic hormones to the human androgen
receptor, human sex hormone binding globulin and to the bovine progestin receptor , in APMIS 108:
838-846, (2000)(Exhibit EC – 15).
190. The European Communities would disagree howev er with the statement by Dr. Guttenplan

that the evidence for MGA and its assessment "seems sound" and would like that the Panel requests
Dr. Guttenplan to provide a more detailed explanation of his statement on this point, taking into
account in particular the new evidence produced by the European Communities.
191. The European Communities considers that also the other experts who have not expressed an
opinion on this question should be requested by th e Panel to take a position in their own areas of
expertise, since it seems to the European Communi ties – from their replies to the other questions –
that in their view the evidence available did not allow the European Communities to conduct a full
and complete risk assessment.
Q62. Does the scientific evidence relied upon by the European Communities support the EC
contention that the new scientific studies that ha ve been initiated since 1997 have identified new
important gaps, insufficiencies and contradictions in the scientific information and knowledge
now available on these hormones such that more sci entific studies are necessary before the risk
to human health from the consumption of me at from cattle treated with these hormones for
growth promotion purposes can be assessed? Would your reply have been different at the time
of adoption of the Directive in September 2003? If so, why? [Please see the following references
for the two questions above:

– paras. 58-94 and 125-129 of US First Submission, paras. 28-32 of US Rebuttal
Submission
– paras. 116-124 of Canada First Submission, paras. 74, 130-135 of Canada Rebuttal
Submission (Exhibit CDA-23)
– paras. 108, 147, 162-169 of EC Replies to Panel Questions, paras. 143-174 of EC
Rebuttal Submission (US case), and paras. 148-166 of EC Rebuttal Submission (Canada
case)
– Exhibit CDA-32 provides a detailed table outlining the chronology of JECFA's
assessment of these hormones and the resulting documentation]

US and Canada's comments

192. The United States refers to the expert s' (Drs. Boisseau, Boobis and Guttenplan ) replies to this
question in paragraphs 49 through 53, 90, 103, 109 and 110. As so often, it pretends that " the experts'
replies" confirm its view where only one or two have done so and another one has taken the opposite
view (paragraphs 51 and following). Indeed Dr. Guttenplan has listed a number of examples where
the 17 studies have identified important gaps. The Un ited States claims that the majority of those
relate to oestradiol 17 β and therefore are not relevant for the purposes of the provisional an on the
other five hormonal substances (paragraph 52). This allegation is erroneous.
193. In particular, it is again useful to review some of the comments provided by Dr. Boobis for
each of the studies funded by the European Communities in order to determine their relevance and the
gaps and level of uncertainty they have established.
194. Concerning the study "re: experimental studies in rabbits by Rajpert-De Meyts et al.", only a
part of the study concerning metabolism and placental transfer has been published so far (Lange et al.
Xenobiotica 2002). The results on the reproductive e ffects of Zeranol (ZER), Trenbolone Acetate
(TBA) and Melengestrol Acetate (MGA) in rabbits exposed during development were summarized in
a detailed report (by Rajpert-De Meyts et al.) se nt to the European Communities in December 2001
with additional data supplemented in the spring 2002. The study has not yet been submitted for
publication elsewhere for the following reasons:
• similar findings concerning the effects of ZER and Estradiol on spermatogenesis and
epididymal reserves were previously publis hed in another animal model (bull) by
Veeramachaneni et al. Environ & Appl Toxicol 1988; 10: 73-81, thus this part of the
rabbit study was only confirmatory;

• in the course of the rabbit study, hundreds of samples of tissues, sera and semen were
collected and stored, and only a part of i nvestigations have been completed due to
lacking funds. Some ensuing studies are still in progress. The study will be submitted
for publication when these investigations have been finalized.

195. The evaluation of the Lange et al. study and the report (Rajpert-De Meyts et al.) by
Dr. Boobis
 is one-sided. The sentence stating that "there was no net accumulation of the compounds
in fetal tissues" is only partially true. The concentrations of the residues after MGA treatment were in
fact higher in the fetal muscle than in the maternal muscle, the fact not mentioned by him.
196. The unpublished part of the study of the exposure at three different developmental stages
provided a wealth of data, which are dismissed by Dr. Boobis with a following statement: "It is not
clear whether the changes observed were consistent and hence compound-related as only a single
dose was used for each compound ". The report did, in fact, very clearly state that the study was
preceded by a dose-finding pilot study that investig ated three different doses of all three compounds.
Because the higher doses caused extensive adverse ch anges, only the lowest doses were selected for
the definitive study. Contrary to Dr. Boobis' statement - "nor is it apparent whether the magnitude of
all changes discussed reached statistical significance " - a detailed statistical analysis was performed,
with all significant changes at p<0.01 and p<0.05, showing effects of the anabolic steroid used,
clearly highlighted in the report.
197. Concerning the study "re: genotoxic potential of xenobiotic growth promoters and their
metabolites", it is true that this study has not provided clear evidence for the genotoxicity of
trenbolone, melengestrol acetate and zeranol in several in vitro test systems. However, the metabolism
studies have clearly shown that all three compounds give rise to numerous hitherto unknown
metabolites, which may or may not have adverse effects. Therefore, the value of this study is the

demonstration that the fate of all three xenobiotic growth promoters in the organism may be far more
complex than previously thought. Unfortunately, none of the novel metabolites could be structurally
elucidated in the limited time period of the stud y, which prevented publication in peer-reviewed
journals. Nonetheless, the structures of these novel me tabolites and their biological activities need to
be further studied in order to improve the risk assessment. The same applies to the observation of
DNA adduct formation, though at low level, of tr enbolone in rat hepatocytes by the post-labeling
assay. Whether these adducts contain trenbolone or not, they should be further characterized in order
to make sure they do not pose a risk.
198. Concerning the set of studies "re: estr adiol metabolism in cattle", Dr Boobis
 has well noticed
the presence of estradiol-17-esters as tissular residues. Nevertheless, his comment does not integrate a
possible different absorption route by the lympha tic circulation. This specific point has been
demonstrated in the same set of studies in cannulated piglets. Concerning this specific class of
estrogens, currently there is a gap in our knowledge of the extent to which they have some hormonal
effect in peripheral tissue but also in intestin e when ingested. Moreover, when considering the in situ
catechol estrogens formation in target tissues of e xposed consumers (in particular at the intestine
level), there is still a gap about the complete r esidue information on the parent compound but also on
the metabolites, specifically on estradiol-alpha. Th is latter compound gives the same DNA-adducts
pattern from catechols as estradiol (Jouanin et al, Steroids 67 (2002), 1091-1099). This information is
pivotal when considering the risk of genotoxicity of all estrogen residues, not only this of estradiol. It
should be recalled that all residue data on tissular estrogen were obtained by a fully validated spectro-
physical procedure, discarding any doubt on false positive signals. Such reference data were never
obtained at this sensitivity and precision level with any other hormones considered before.
199. As regards the criticism of Dr. Boobis
 of the Chakravarti et al. study concerning in particular
the comment that the two major adducts formed by E2-3,4-quinone are N3Ade and N7Gua, it should
be noted that both adducts are spontaneously rel eased from the DNA (a process called depurination)
but at different rates (Zahid et al., 2006): the N3 Ade is depurinated much faster than the N7Gua.
Therefore, the N7Gua may allow accurate DNA re pair whereas the N3Ade may not be repaired
properly and give rise to mutations of the type observed in the mutagenicity studies. What is
important to stress, however, is that Chakravarti et al (Oncogene, 20; 7945-7953, 2001) has detected
mutations in the H- ras gene in the skin of SENCAR mice fo llowing dermal treatment with E2-3,4-
quinone, with the specific nature of the mutations detected being consistent with the expected
depurination of adenine due to the formation of an E2-3,4-quinone-Adenine adduct. This is relevant to
the potential mutagenicity of estradiol in humans. First, we know that oxidative metabolism of E2 to
the E2-3-4-quinone metabolite occurs in human breast tissue because E2-quinone adducts to
glutathione have been detected (Yue et al. J. Steroid Biochem. Mol. Biol. 86: 477-486, 2003). Second,
adducts of the E2-3,4-quinone with ademine and gua nine have been detected in the mammary tissue
of ACI rats injected into the mammary gland tissue with 4-OH E2 or E2-3,4-quinone (Carcinogenesis,
25:, 289-297, 2004). So, Dr. Boobis
 criticism appears to miss the important point that mutagenicity
in vivo is now established thanks to this and the ot her studies cited by the European Communities in
relation to Question 13 above.
200. It follows that Dr. Boobis provides a partial and selective discussion of certain aspects of
these studies. The importance of these studies is ho wever not questioned. If some of the results
obtained by some of these studies are not clear or unequivocal, this simply strengthens the EC
position that important gaps in our knowledge ha ve become available recently which made the
completion of a risk assessment impossible in 2000-2002 and even today for the five hormones
(except for oestradiol 17β)

ANNEX F-4

COMMENTS BY THE UNITED STATES ON THE REPLIES
OF THE SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC
TO QUESTIONS POSED BY THE PANEL

(30 June 2006)

A. I
NTRODUCTION
1. The United States appreciates this opportunity to provide comments on the responses received
from the six scientific experts and the three interna tional organizations selected by the Panel. The
United States will first provide a context for the expe rts' and organizations' responses in light of the
proper role of scientific experts in this disput e, and then provide comments on the responses and
suggestions for clarifications that may make the re sponses more useful in the context of the present
dispute. Finally, the United States will provide a summary of the conclusions that may be drawn from
the experts' responses.
B. THE ROLE OF SCIENTIFIC EXPERTS
2. As previously noted by the United States in its 3 November 2005 comments on the Panel's
proposed working procedures for consultation with th e experts, the role of scientific experts is a
narrow one. Scientific experts may provide a panel information, advice, and their opinions on certain
aspects of the matter that is the subject of the dispute. 1 Experts can provide a panel with vital
perspectives, information, and advice on technical and scientific issues, affording a panel the ability to
make legal determinations such as whether a measure is indeed based on a risk assessment or satisfies
the conditions for a provisional meas ure within the meaning of the WTO Agreement on the
Application of Sanitary and Phytosanitary Measures ("SPS Agreement").
C. COMMENTS ON THE EXPERTS' RESPONSES
3. The Panel's questions to the experts and interna tional organizations expressed several themes.
While, not surprisingly, the experts have not provided identical responses to each question, they are in
agreement on several key propositions.
4. The United States has observed the following themes in the Panel's questions:
(1) Risk assessment :2 What international guidance materials exist for conducting a risk
assessment for veterinary drug residues? What are the necessar y steps for a risk
assessment? Do the European Communities' ("EC's") Opinions 3 satisfy the necessary
steps comprising a risk assessment?

1 See Agreement on the Application of Sanitary and Phytosanitary Measures , Article 11.2;
Understanding on Rules and Procedures Governing the Settlement of Disputes, Article 13.
2 See, e.g., Panel's Questions to the Experts, Questions 3-14.; 36-37; 55; 57.
3 The EC's Opinions, or "risk asse ssments", are comprised of the "Opinion of the Scientific Committee
on Veterinary Measures Relating to Public Health – Assessment of Potential Risks to Human Health from
Hormone Residues in Bovine Meat and Meat Products", 30 April 1999 ("1999 Opinion") (Exhibit US-4); the
Review of Specific Documents Relating to the SCVPH Opinion of 30 April 99 on the Potential Risks to Human
Health from Hormone Residues in Bovine Meat and Meat Products, dated May 3, 2000 ("2000 Review")
(Exhibit US-17); and the "Opinion of the Scientific Committee on Veterinary Measures Relating to Public
Health on Review of previous SCVPH opinions of 30 April 1999 and 3 May 2000 on the potential risks to

(2) Scientific evidence relating to estradiol 17 β
:4 Does the scientific evidence cited in the
EC's Opinions demonstrate that carcinogenic effects of estradiol 17 β are related to a
mechanism other than hormonal activity? Does the scientific evidence demonstrate
that estradiol 17 β, when consumed as a residue in meat, is genotoxic? Does the
scientific evidence demonstrate that estradiol 17 β will have carcinogenic or
tumorigenic effects at levels found in residues in meat from treated cattle?
(3) Scientific evidence relating to th e five provisionally banned hormones :5 Is the
scientific evidence and information relating to the five hormones sufficient to conduct
an assessment of the risks to human health from consumption of meat from cattle
treated with the five hormones for growth promotion purposes? Does the scientific
evidence cited by the EC in its Opinions demonstrate that any of the five hormones
has genotoxic potential or is carcinogenic by a mechanism other than hormonal
activity? Do the scientific materials produ ced and cited by the EC (including the "17
Studies"
6) identify any gaps or insufficiencies in the scientific evidence such that
more study is necessary before the risk from consumption of meat from cattle treated
with the five hormones for growth promotion purposes can be assessed?
(4) Scientific evidence relating to the hormones generally :7 Has each of the hormones
used for growth promotion purposes in cattle been evaluated for a sufficient period
with no evidence of adverse effects to ade quately address any concern regarding long
latency periods of cancer? Do epidemiol ogical studies cited by the EC identify a link
between cancer and residues of the hormones in meat? Do materials cited by the EC
demonstrate that meat from cattle treated with hormones for growth promotion
purposes poses a risk to sensitive populations? Do materials cited by the EC
demonstrate other human health risks from consumption of residues of the hormones
in meat from cattle treated for growth promotion purposes, such as effects on the
immune system?
(5) Scientific evidence relating to residues
:8 To what extent did the EC evaluate
evidence on the actual residue levels of natu ral and synthetic hormones? Did the EC
take these levels into account in its Opinions? Why, and how did the Joint
FAO/WHO Expert Committee on Food Additives ("JECFA") re-evaluate the three
natural hormones in 1999?
(6) Scientific evidence relating to good veterinary practices
:9 Do materials cited by the
EC demonstrate that there is a risk to human health from the misuse of growth
promoting hormones in the United States? Has the EC assessed this risk? Do
materials cited the EC regarding misuse or abuse of the hormones call into question
Codex Alimentarius Commission ("Codex") st andards regarding the safety of meat
from cattle treated with hormones for growth promotion purposes?

human health from hormone residues in bovine meat and meat products", 10 April 2002 ("2002 Opinion")
(Exhibit US-1).
4 See, e.g., Panel's Questions to the Experts, Questions 13-20.
5 See, e.g., Panel's Questions to the Experts, Questions 21; 25; 38-42; 61-62.
6 The EC commissioned several (17) studies in 1998-1999 (collectively the "17 Studies"), ostensibly to
fill data gaps and develop support for the conclusions set out in the Opinions. See US First Written Submission,
7 See, e.g., Panel's Questions to the Experts, Questions 22-24; 26; 43; 52-54; 59-60.
8 See, e.g., Panel's Questions to the Experts, Questions 27-35.
9 See, e.g., Panel's Questions to the Experts, Questions 44-51.

5. These themes relate to Annex A, paragraph 4 (d efining risk assessment) and to Article 5 of
the SPS Agreement, most notably Article 5.1 (whether the EC's ban on estradiol 17β is based on a risk
assessment, as appropriate to the circumstances); Article 5.2 (whether the EC's purported risk
assessment takes into account av ailable scientific evidence; relevant processes and production
methods; relevant inspection, sampling and testing methods); Article 5.6 (whether the EC's import
ban on meat and meat products is not more trade-restrictive than re quired to achieve its appropriate
level of sanitary protection); and Article 5.7 (most notably, the first two elements of Article 5.7's four-
part cumulative test: whether the EC's provisional bans have been imposed in a case where relevant
scientific evidence is insufficient and whether they have been adopted on the basis of available
pertinent information).
6. In addition, these themes are set against the fo llowing factual backdrop, described in greater
detail in the US first written submission.
10 The EC's hormone ban prohibits the importation and
marketing of meat and meat products from cattle to which any of the six hormones (estradiol 17 β;
testosterone; progesterone; zeranol; trenbolone acetate; and melengestrol acetate) have been
administered for growth promotion purposes. The United States permits the administration of these
hormones to cattle for that very purpose. Five of the six hormones (estradiol 17 β, progesterone,
testosterone, zeranol, and trenbolone acetate) are admi nistered to cattle as subcutaneous implants in
the animals' ears. The ears are then discarded at slaughter and do not enter the human food supply.
The sixth hormone, melengestrol acetate, a synthetic progestogen, is administered as a feed additive.
7. Three of the six hormones at issue in this proceeding (estradiol 17 β; progesterone; and
testosterone) are naturally occurring, "endogenous " hormones produced by both humans and animals
used for human food. Each of these hormones is produced throughout the lifetime of every man,
woman and child, and is required for normal physiological functioning and maturation. With respect
to chemical structure, the natural hormones used for growth promotion purposes in cattle are identical
to the estradiol 17 β, progesterone and testosterone natu rally produced in the human body.
Furthermore, when administered exogenously, each of these hormones enters the same metabolic
pathway as the endogenously produced hormone and its metabolites are indistinguishable from those
that are produced naturally. Endogenous production of estradiol 17β, progesterone and testosterone in
humans is orders of magnitude higher than the re latively small amounts of these hormones ingested
from residues in meat.
8. The other three hormones (zeranol; trenbolone acetate; and melengestrol acetate) are synthetic
hormones that mimic the biological activity of the natural hormones. Trenbolone acetate mimics
testosterone, zeranol mimics estradiol 17β, and MGA mimics progesterone.
9. Codex standards exist for the use of five of th e six hormones for growth promotion purposes.
Upon review of risk assessments conducted by JECFA and recommendations by the Codex
Committee on Residues of Veterinary Drugs in Food ("CCRVDF"), Codex
11 adopted recommended
maximum residue limits ("MRLs"), where appropriate, for estradiol 17 β, progesterone, testosterone,
trenbolone acetate and zeranol. Codex adopted these recommended MRLs to ensure that
consumption of animal tissue containing residues of these hormones do not pose a risk to consumers.
JECFA recommended an acceptable daily intake ("ADI") for melengestrol acetate at its 62
nd Meeting
in 2004.
10. Against this background, the EC has alleged th at it is now justified in permanently banning
the import of meat and meat products from cattle treated with estradiol 17 β for growth promotion
purposes, and provisionally banning the import of meat and meat products from cattle treated with the

10 See US First Written Submission, Sections III.B and III.C (pages 10-25).
11 Codex is recognized as specified as the relevant international standards-setting body in the SPS
Agreement. See SPS Agreement, paragraph 3(a) to Annex A.

five other hormones for growth promotion purposes . The EC alleges to have based its ban on
estradiol 17β on a "risk assessment" within the meaning of Article 5.1 and paragraph 4 of Annex A of
the SPS Agreement, and to have implemented a provisional ban for the five remaining hormones
within the meaning of Article 5.7 of the SPS Ag reement because, unlike JECFA, it was unable to
complete a risk assessment for any of the hormones.
12 While at the same time banning meat from
cattle treated with any of the six hormones for growth promotion purposes, the EC permits the
administration of hormones to farm animals for certain therapeutic and zootechnical purposes, and the
eventual marketing of meat from these animals.
1. Risk assessment
11. The question of what constitutes a risk assessmen t is relevant to the obligation in Article 5.1
of the SPS Agreement in that Members must base their measures on a risk assessment as defined in
Annex A, paragraph 4 of the SPS Agreement. The responses from the experts confirm that there is a
certain internationally-recognized form that risk assessments should take and that there is consensus
among the experts that the EC's purported risk assessment for estradiol 17 β fails to satisfy the
necessary elements comprising such an assessment.
(a) Risk assessment procedures generally
12. The experts' responses confirm several points relating to risk assessment procedures, namely
that: (1) a wealth of international guidance exists for the conduct of a risk assessment of veterinary
drug residues; (2) both quantitative and qualitative risk assessments should satisfy the four steps for a
risk assessment (hazard identification; hazard ch aracterization; exposure assessment; and risk
characterization); (3) risk assessments, including those conducted by JECFA on the six hormones,
have not been limited by a "deterministic approach" 13; and (4) JECFA requires a complete database in
order to recommend an acceptable daily intake (" ADI") unless it can adopt default assumptions that
would lead to a more conservative risk assessment.
13. As noted by Codex, JECFA and Dr. Boobis, th ere are numerous international documents and
guidance materials relevant to the assessment of ve terinary drugs in food, dating back to at least
1987.14 In addition, Dr. Boisseau comments that the assessment of such drugs has been
"internationally harmonised through scientific conf erences and it is possible to say there is an
international non written agre ement on this rationale." 15 As noted by JECFA, "[a]ll of these
documents are the outcome of international expert meetings and represent the agreed views of the

12 See, e.g., EC First Written Submission, para. 17. (No ting that its ban, Directive 2003/74/EC, is
"based on a comprehensive risk asse ssment and, thus, is fully compliant with the DSB recommendations and
rulings. In particular, as stipulated by the Appellate Body, the results of the risk assessment 'sufficiently
warrant' the definite import prohibition regarding one of the hormones (Article 5.1 of the SPS Agreement), and
provide the 'available pertinent information' on the basis of which the provisional prohibition regarding the other
five hormones has been enacted (Article 5.7 of the SPS Agreement).")
13 A "deterministic approach" to risk assessment mean s simple, point (single-value) estimates of risk.
"Deterministic" risk assessment does not account for unce rtainty and variability in the parameters of the risk
assessment including exposures, dose-response and normal variation in the exposed populations, and typically
calls for highly conservative, worst-case assumpti ons in exposure, dose and sensitive populations. See, e.g.,
Hattis and Burmaster, Risk Analysis 14(5): 713-730 (1994).
14 See Codex Responses to Questions from the Panel ("Codex Responses") (Questions 3 and 4), pp. 4-
5; JECFA Responses to Questions from the Panel ("JECFA Responses") (Question 3), pp. 2-3; Responses to
Questions from the Panel of Dr. Alan Boobis ("Dr. Boobis Responses") (Question 3), pp. 10-11.
15 Responses to Questions from the Panel of Dr. Jacques Boisseau ("Dr. Boisseau Responses")
(Question 4), p. 2. Indeed, as noted by the United St ates in its first written submission, the EC acknowledges
that there is a general form which a risk assessment must take. See US First Written Submission, para. 139,
citing EC 1999 Opinion, p. 70 ("Executive Summary") (Exhibit US-4).

participating experts and several of those have also been published in the scientific literature." 16
Although there are no Codex standards per se on the conduct of a risk assessment (such guidance is
currently in draft form 17), as noted by JECFA, "[t]he elaboration and application of risk assessment
principles are within the responsibility of the scientific expert bodies [i.e., JECFA]."18
14. In terms of the components comprising a risk assessment, the experts' responses confirm that
there are four essential elements: (1) hazard identif ication; (2) hazard characterization; (3) exposure
assessment; and (4) risk characterization. 19 The one caveat to this rule is provided by Dr. Vincent
Cogliano, who notes that, for purposes of hazard char acterization, "[a] qualitative risk assessment can
consider the presence or absence of dose-response relationships." 20 JECFA's response takes this
thought a step further, noting that a dose-res ponse assessment is an integral part of hazard
characterization, and can be "done in a quantitativ e or a qualitative way. In the qualitative sense this
is the determination of a no-effect level from an experimental or epidemiological study. For the
hormones JECFA used this approach." 21 The definition of "hazard characterization" provided by
Codex confirms that a dose-response assessment is integral to this step of risk assessment.22 The EC's
Opinions fail to engage in any such evaluation because they rely instead on the conclusion that
estradiol 17 β is genotoxic; however, as discussed in greater detail below, and as confirmed by the
scientific experts, the EC fails to adduce evidence of genotoxic or carcinogenic effects at levels below
those associated with a hormonal response.
15. Finally, the experts' responses clarify two ke y aspects of JECFA's risk assessment procedure,
namely that JECFA's assessments of the six hormones are not limited by a "deterministic approach"
and that JECFA requires a complete database in orde r to complete a risk assessment and set an ADI
(as it has done for the hormones at issue) unless it ca n adopt default assumptions that would lead to a
more conservative risk assessment.
23 As to the former point, Dr. Boisseau notes that, rather than
taking a "deterministic" approach, "JECFA was perfectly aware about this kind of non linear
situation[s]," and that, "[i]f, in 1999, the 52 nd JECFA recognized that oestradiol-17 β 'has a genotoxic
potential', it concluded nevertheless that 'the carcinogenicity of oestradiol-17 β was probably a result
of its interaction with hormone receptors'. Theref ore it did not take into consideration a non linear
situation in its risk assessment."24
16. Dr. Boobis reiterates this point, noting that the results of JECFA's risk assessment are based
on scientific evidence as opposed to a predetermine d result, "JECFA['s] risk assessment concluded
that the dose-response relationship for all of the endpoints was non-linear and that there was a
threshold dose below which there was no appreciable risk over a lifetime of exposure. Hence, a
deterministic approach, via the establishment of ADI s, was appropriate according to the procedures

16 JECFA Responses (Question 3), p. 3.
17 See Codex Responses (Question 4), p. 5; Dr. Boobis Responses (Question 3), p. 11.
18 JECFA Responses (Question 3), p. 2.
19 JECFA Responses (Question 6), p. 3; Codex Resp onses (Question 6), p. 6; Dr. Boobis Responses
(Question 6), p. 13; Dr. Boisseau Responses (Question 6), pp. 4-5; Responses to Questions from the Panel of
Dr. Joseph Guttenplan ("Dr. Guttenplan Responses") (Question 6), p. 2.
20 Responses to Questions from the Panel of Dr. Vincent Cogliano ("Dr. Cogliano Responses")
(Question 11), p. 1.
21 JECFA Responses (Question 8), p. 4.
22 Codex Responses (Question 6), p. 6 ("Hazard characterization. The qualitative and/or quantitative
evaluation of the nature of the advers e health effects associated with biol ogical, chemical and physical agents
which may be present in food. For chemical agents, a dose-response assessment should be performed . For
biological or physical agents, a dose -response assessment should be performed if the data are obtainable.")
(Emphasis added). See JECFA Responses (Question 6), p. 3 (hazard characterization "includes dose-response
assessment, considerations on species sensitivity, relevance of specific effect for humans etc.")
23 See Dr. Boobis Responses (Question 9), p. 15.
24 Dr. Boisseau Responses (Question 7), p. 6.

followed by the Committee."
25 Finally, as noted by JECFA itself, "JECFA's assessment process is
based on the mechanism of action of the compound to be evaluated, non-linearity is assumed if the
adverse effect of a compound is caused via a mechanism with a threshold of effect. In such a case, as
for the hormones, a no-effect level can be determined."26
17. As to the latter point, Drs. Boisseau and Boobis, and JECFA confirm that JECFA only
allocates a final ADI for a veterinary drug if the scientific database is complete and there are no
outstanding scientific issues. As noted by JECFA, "[i]f there are substan tial gaps and important
information missing, JECFA can not establish an ADI." 27 The only alternative to this rule is a
situation where JECFA can "adopt default assumptions that would if anything lead to a more
conservative risk assessment than would be the case otherwise." 28 JECFA has set final ADIs for each
of the hormones in this dispute, indicating that from its point of view, the scientific database on the
hormones was complete and void of substantial gaps . As noted by Dr. Boisseau, "[f]or the hormonal
growth promoters, JECFA has considered that, give n the quality and the quantity of the data, it was
possible to carry out a complete quantitative risk assessment."29
(b) The EC has failed to complete a "risk assessment" for estradiol 17β30
18. The experts' responses confirm that the EC has not completed a risk assessment for estradiol
17β. When prompted to examine the EC's Opinions in light of the four steps of risk assessment
discussed above, the experts expose numerous weakne sses in the EC's purported risk assessments and
elaborate on the EC's failure to complete the nec essary steps as well as assess critical factors such as
the bioavailability of estradiol 17β and human DNA repair mechanisms.
19. The experts' responses confirm that, while the EC Opinions engage in hazard identification, 31
the first step of a risk assessment, the Opinions fail to complete any of the remaining three
components (hazard characterization; exposure assessment; and risk characterization). Dr. Boobis
notes, "[t]he EC has not identified the potential fo r adverse effects on human health of residues of
oestradiol found in meat from treated cattle. This is because the analysis undertaken was focused
primarily on hazard identification. There was little in the way of hazard characterization, and no
independent exposure assessment was undertaken,"
32 indicating that the EC's Opinions "do[ ] not
follow the four steps of the Codex risk assessment paradigm. Even if it were concluded that
oestradiol is a genotoxic carcinogen, the four steps should have been followed." 33 In other words,

25 Dr. Boobis Responses (Question 7), p. 13.
26 JECFA Responses (Question 7), p. 4.
27 JECFA Responses (Question 11), p. 10.
28 Dr. Boobis Responses (Question 9), p. 15; see Dr. Boisseau Responses (Question 9), p. 7 ("The
Canadian statement stipulating that 'it is recognized that JECFA only allocates an ADI for a food additive or a
veterinary drug under review when JECFA considers that its scientific data base is complete and that there is no
outstanding scientific issue' is correct."); JECFA Responses (Question 11), p. 10.
29 Dr. Boisseau Responses (Question 12), p. 8.
30 This Section of the Submission focuses on whether or not the EC has adhered to the relevant steps
for conducting a risk assessment. A discussion of whether or not the scientific conclusions relating to estradiol
17β drawn by the EC are actually supported by the scientif ic evidence is presented in Sections C(2), C(4) and
C(5)-C(6) below.
31 See US First Written Submission, para. 140 ("There is no great challenge to completing this first-step
in a hormone risk assessment – the potential biological effects of hormones, some of which are adverse, are
generally not in dispute in the scientific community.")
32 Dr. Boobis Responses (Question 13), p. 17.
33 Dr. Boobis Responses (Question 14), p. 18. Regarding the notion that residue levels found in meat
from treated cattle cause genotoxic effects, Dr. Boisseau opines "the EC risk assessment did not support that
residues of oestradiol-17β, despite the genotoxic potential of this hormone, can initiate and promote tumours in
humans." Dr. Boisseau Responses (Question 13), p. 11.

"[t]here was no attempt to estimate the potential occurrence of adverse effects in humans following
exposure to levels of hormones found in meat from treated animals."34
20. Dr. Joseph Guttenplan agrees that the EC has satis fied the first element of a risk assessment
(hazard identification) by "identifying the potential for adverse effects on human health of oestradiol-
17β."35 Yet, like Dr. Boobis, Dr. Guttenplan opines that the EC's Opinions "taken together, ha[ve] a
mixed rating in following the Codex guidelines," 36 noting that "[t]he hazard characterization is more
limited since there is only one animal model that is well characterized and this is in the hamster
kidney. As kidney is not a known target of estra diol in humans the extrapolation to humans is
uncertain. The risk characterization is very qualitative at best." 37 Dr. Boobis comments that the EC
appears to have stopped prematurely (at the hazard id entification stage) in its assessment of estradiol
17β "based on the results of a small number of non- standard tests of genotoxicity, with equivocal
weak responses. It is not clear if the EC applie d a weight of evidence approach to evaluating the
genotoxicity of all of the compounds, taking into acc ount the totality of the available data, as was the
case with JECFA."38 As a result, the EC's Opinions make little progress beyond the first step of risk
assessment, hazard identification.
21. The experts' responses confirm that the EC's Opinions fail to engage in a dose-response
assessment, which is part of the hazard characteriza tion stage (the second step of risk assessment).
Such an assessment would have been appropriate in the analysis of a hormone such as estradiol 17 β
for which a wealth of scientific evidence exists indicating that any effects caused by estradiol 17 β are
through the receptor-mediated (endocrine), cell divi sion stimulating activity of the hormone, and not
by genotoxic (non-endocrine) effects. Rather than evaluating this evidence in its Opinions, the EC
relies instead on its assertion that estradiol 17β is genotoxic as an excuse for failing to conduct a dose-
response assessment.39 As noted by Dr. Boobis, it was improper for the EC to stop its assessment of
estradiol 17 β at this stage, "[f]or compounds that are known or assumed to be genotoxic via DNA
reactivity, genotoxic potential would normally have to be confirmed in vivo before this endpoint
would be used as the basis for a risk assessment." 40 As discussed in greater detail below, and as
confirmed by the experts, the scientific studies cite d by the EC fail to demonstrate this potential in
vivo.41
22. The experts' responses also confirm that th e EC has failed to conduct a proper exposure
assessment for estradiol 17β, the third step of risk assessment. The EC describes what it views as the
necessary elements of a proper exposure assessment as follows:
for the purposes of exposure assessment from the residues of these hormones, it is not
so much necessary to compare (if it were onl y possible!) the two situations and then
try to quantify how much one is more risk y than the other and to what measurable
level the risk is likely to occur, but rather to assess a situation of additive risks arising
from the cumulative exposures of human to multiple hazards, in addition to the

34 Dr. Boobis Responses (Question 13), p. 18.
35 Dr. Guttenplan Responses (Question 13), p. 3.
36 Dr. Guttenplan Responses (Question 14), p. 4.
37 Dr. Guttenplan Responses (Question 14), p. 3.
38 Dr. Boobis Responses (Question 12), p. 17.
39 See Dr. Boobis Responses (Question 13), pp. 17-18.
40 Dr. Boobis Responses (Question 36), p. 36, citing CVMP (2004). Studies to Evaluate the Safety of
Residues of Veterinary Drugs in Human Food: Genotoxicity Testing; see Dr. Boisseau Responses (Question
36), p. 20 ("A dose-response assessment is not feasible fo r substances that are found to be genotoxic if ... this
genotoxic potential can be expressed in in vivo conditions.")
41 See Dr. Boobis Responses (Questions 16, 18, 20 and 52), pp. 19-20, 22, 23, and 44 (concluding that
estradiol 17β is not genotoxic in vivo); Dr. Boisseau Responses (Question 13), pp. 9-11; see Section C(2)(b)
below.

endogenous production of some of these hor mones by the animals and the human
beings.42
The Panel accordingly asked the experts whether or not the EC has accomplished this goal by
assessing these "additive risks," thereby completing th e exposure assessment step of its purported risk
assessment. The experts agree that the EC has not.

23. Dr. Boisseau comments, "[t]he European Communities did not assess quantitatively the extent
to which residues of growth promoting hormones in meat contribute [to such a risk]." 43 Dr. Boobis
notes, "[t]he EC Opinions and other materials refe rred to by the EC do not quantify the extent to
which residues of the hormones contribute to aggr egate exposures or cumulative multiple hazards."
Finally, Dr. Guttenplan opines, "[i]n general the EC do not attempt to evaluate 'the additive risks
arising from the cumulative exposures of humans to multiple hazards, in addition to the endogenous
production of some of these hormones by animals and human beings'."44
24. For example, the experts' responses confirm that the EC's Opinions fail to take into account
treatments of cattle with hormones for purposes other than growth promotion, such as therapeutic or
zootechnical administration of the hormones. As noted by Dr. Boisseau:
[a]s soon as the [EC] accepts to cons ider[ ] these residues resulting from these
therapeutic and zootechnical use[s] of oestradiol-17 β as negligible [i.e., by permitting
their ongoing use for these purposes], it enters into a quantitative, or at least in a semi
quantitative, exposure assessment procedure for these [ ] residues and, starting from
that, it has no good reason to object to consider a wider exposure assessment covering
all the residues resulting from the different sources of oestradiol-17β.45
Dr. Boobis comments, "[t]o my knowledge no account is taken of hormone treatments of cattle for
purposes other than growth promotion, such as for therapeutic purposes, by the EC in its assessment
of the aggregate or cumulative effects of the hormones in meat from cattle treated for growth
promotion."46 Dr. Guttenplan indicates that the EC's d ecision to except zootechnical or therapeutic
treatments from its ban is "a reasonable response, " yet he does not appear to address the Panel's
inquiry, i.e., whether the EC, in its Opinions, took these treatments into account in an assessment of
cumulative effects.47

25. In defense of its lack of an exposure assessmen t, the EC has argued that "the only rationale
that can be inferred from the available data is that the higher the exposure to residues from these
hormones, the greater the risk is likely to be."
48 The experts' responses confirm that this is "indeed a
very weak statement by the EC." 49 Dr. Boisseau reiterates his comment that the EC has simply failed
to "assess quantitatively the extent to which r esidues of growth promoting hormones in meat

42 EC Answers to Panel Questions, para. 151.
43 Dr. Boisseau Responses (Question 55), p. 26.
44 Dr. Guttenplan Responses (Question 55), p. 11. Note that Dr. Guttenplan's response appears to
conflict with his earlier opinion that the EC had complete d an exposure assessment. It is unclear how the EC
could have in fact completed an exposure assessment wher e, as confirmed by Dr. Guttenplan in his response to
Question 55, it has failed to engage in the necessary analysis.
45 Dr. Boisseau Responses (Question 57), p. 27. See also Dr. Boisseau Responses (Question 58), p. 26
("The European Communities did not assess quantitatively the extent to which residues of growth promoting
hormones in meat contribute to 'additive risks arising from the cumulative exposures of humans to multiple
hazards, in addition to the endogenous production of some of these hormones by animals and human beings'.")
46 Dr. Boobis Responses (Question 57), p. 47.
47 Dr. Guttenplan Responses (Question 57), p. 12.
48 EC Answers to Panel Questions, para. 94.
49 Dr. Guttenplan Responses (Question 58), p. 12.

contribute to 'additive risks'."50 Dr. Boobis concurs, and notes that "[w]ithin quite broad limits, higher
exposure would not result in any increase in risk."51
26. The EC's failure to conduct an exposure assessment is all the more stark in light of JECFA's
completion of just such an assessment for estradiol 17 β. As noted by Dr. Boisseau, "JECFA/Codex
considered in its risk assessment of the natural hormones such 'additive risks' and concluded that,
given the wide margin of safety ... there was no ri sk for consumers' health associated with the
estimated ingestion of these residues." 52 Dr. Boobis agrees that the additive, or aggregate risk was
assessed by JECFA, and that exposures from residues in meat from cattle treated with the natural
hormones for growth promotion purposes "were consid ered to represent a trivial increase in overall
exposure to hormonally-active material from ot her exogenous sources and in particular from
endogenous sources."53
27. In addition to failing to complete the four step s for a risk assessment, the EC's Opinions also
fail to properly address critical factors su ch as the bioavailability of estradiol 17 β54 and DNA repair
mechanisms.55 The experts' responses note that bioavailability relates to the oral route of exposure to
hormone residues, a route that is "not the most efficient," 56 and that the bioavailability of a substance,
in this case estradiol 17β, "has to be taken into consideration in the risk assessment, in particular at the
third step regarding the expos ure assessment of residues." 57 Indeed, as a general rule "only that
fraction of the dose that is bioavailable is toxicologically relevant." 58 The United States has argued
that the EC has failed to take into account the low bioavailability of estradiol 17 β in its assessment of
that hormone, and none of the experts' responses appear to indicate otherwise.59
28. The experts agree that estradiol 17 β has low oral bioavailability. Indeed, Dr. Boisseau notes
that "oestradiol 17-β is inactive orally,"60 and Dr. Boobis states that "exposure [to estradiol] is via the
oral route, and bioavailability by this route is very low (< 5%)." 61 In contrast, Dr. Guttenplan opines
that the bioavailability of "estrogen" is "low but not insignificant."62 However, Dr. Guttenplan's reply:
(1) relies on materials cited by the EC that do not in fact demonstrate a higher bioavailability for

50 Dr. Boisseau Responses (Question 55), p. 26.
51 Dr. Boobis Responses (Question 58), p. 48. Dr. Boobis notes that "The EC Opinions and other
materials referred to by the EC do not quantify the ex tent to which residues of the hormones contribute to
aggregate exposures or cumulative exposures to multiple hazards." Dr. Boobis Responses (Question 55), p. 45.
52 Dr. Boisseau Responses (Question 56), p. 26.
53 Dr. Boobis Responses (Question 56), p. 46.
54 Note that the EC has also failed to take bioavailability into account for the five provisionally-banned
hormones. A discussion of biovailability is perhaps most pertinent, however, to a discussion of estradiol 17 β,
for which the EC claims to have completed a risk assessment.
55 Bioavailability and DNA repair mechanisms shoul d have been addressed in the EC's exposure
assessment, had it completed one.
56 Dr. Boisseau Responses (Question 43), p. 22.
57 Dr. Boisseau Responses (Question 43), p. 23.
58 Dr. Boobis Responses (Question 43), p. 40. See Dr. Guttenplan Responses (Question 43), p. 10
("only the bioavailable chemical can produce adverse (or any) effects, thus in terms of risk assessment, only the
portion of the dose of chemical that is bioavailable is significant.")
59 See US First Written Submission, paras. 146, 88-89.
60 Dr. Boisseau Responses (Question 43), p. 23. Dr. Boisseau notes that the "[n]atural hormones are
known to be poorly bioavailable in humans," and that the bioavailability of the synthetic hormones "ha[s] not
been determined." Therefore, in a risk assessment of those hormones, as was the case in the JECFA assessment,
"all their residues have been considered as being totally bioavailable." Dr. Boisseau Responses (Question 43),
p. 23. See Dr. Boobis Responses (Question 43), p. 40.
61 Dr. Boobis Responses (Question 40), p. 39.
62 Dr. Guttenplan Responses (Question 43), p. 10. Dr. Guttenplan opines that "[i]t appears that the
bioavailability of estrogen is low but not insignificant (probably between 5 and 20%), if estrone is also taken
into account."

estradiol 17 β than previously thought; and (2) miscast s as "paradoxical" a US argument relating to
bioavailability.
29. The materials cited by the EC in its Opinions and by Dr. Guttenplan in his responses do not
demonstrate a higher bioavailability for estradiol 17 β than previously thought. In support of his
statement that bioavailability is higher than previously thought, Dr. Guttenplan cites directly to the EC
Rebuttal Submission and its statement that "[m] etabolic studies of orally administered 17 β-oestradiol
indicate that as much as 20 percent of a 2 mg do se of micronized E2 is absorbed, with a serum
half-life in the range of 2 to 16 hours (Zimmermann et al., 1998; Vree and Timmer, 1988; Ginsburg et
al., 1998)."
63 However, upon review of these studies, it is clear that none of these references contains
data that allow estimation of bioavailability. Rath er all of the studies were conducted with an entirely
different objective, the demonstration of bioequivalence. As a result, they do not stand for the
conclusion for which they have been cited by the EC and Dr. Guttenplan.
30. Dr. Guttenplan indicates that a conclusion reached by the United States (that bioavailability of
estradiol 17 β is low) 64 based in part on a EC study evaluating the metabolism of estradiol 17 β is
"paradoxical" to the results of the study because, according to Dr. Guttenplan, in the study "estradiol
was converted to estrone, so it must have entered the cell." 65 It is true that estradiol was converted to
estrone in the study; however, the focus of the US argument was the evaluation of whether or not
estradiol 17β, the alleged "bad actor" implicated by the EC as a genotoxic carcinogen was transported
across the single-cell layer (used to mimic the human intestinal wall in the study). Whether or not
estradiol 17β entered the cells is irrelevant to the point made by the United States. Rather than being
transported across the single-cell layer, all of the estradiol 17 β that entered the cells was metabolized
into estrone or other metabolites, which have been shown in studies cited by the EC to be benign in
terms of genotoxic carcinogenicity.66
31. Finally, the experts agree that the EC's Opin ions also fail to take into account available
scientific evidence relating to DNA repair mechanis ms. Dr. Boobis states that "the evidence is
against direct modification of DNA in vivo by hormones in meat from treated animals, or by their
metabolites produced in vivo," in part because "[t] he DNA repair processes for this are amongst the
most efficient (Arai et al, 2006; Russo et al, 2004) and even if such modification did occur, it is
anticipated that no heritable change would result, because of DNA repair." 67 According to
Dr. Boobis, "[t]his would be true even at levels of exposure that could arise should GVP not be
followed."68 Dr. Guttenplan notes, "[t]here is no reason to assume that DNA repair processes
involved in DNA damage produced by estrogen metabo lites are any more or less effective than those
involved in repair of other carcinogens ," and that "the scientific materi als referred to by the [EC] for
the most part doesn't address DNA repair."69

63 See Dr. Guttenplan Responses (Question 43), p. 11.
64 See US Rebuttal Submission, para. 41. Note that the study's author confirms the US argument
regarding bioavailability of estradiol 17 β, concluding that the study's result "indicates that 17 β-estradiol is not
absorbed intact in the human intestinal tract." Hoogenboom, Investigations on the metabolism of 17 β-estradiol
by bovine hepatocytes, human intestinal and breast ce lls, and the genotoxic and estrogenic properties of the
metabolites (unpublished), p. 5. (Exhibit EC-6 (US)).
65 Dr. Guttenplan Responses (Question 43), p. 11.
66 Moreover, any estrone that is absorbed in the in testine will be rapidly transported to liver where it
will undergo extensive first-pass metabolism, thus minimizing any potential effects that might occur from
conversion of estrone back into estradiol.
67 Dr. Boobis Responses (Question 22), p. 25.
68 Dr. Boobis Responses (Question 22), p. 25.
69 Dr. Guttenplan Responses (Question 22), p. 7. Dr. Guttenplan states that "since it [DNA repair] is
not likely to be different for estrogen derived damage than other types of damage it is not really relevant." This
statement requires clarification, as it would appear to the United States that DNA repair of estrogen-derived

(c) Conclusion
32. The experts' responses regarding the necessary co mponents or elements of a risk assessment
and their opinions as to whether or not the EC has sa tisfied each of those elements confirm that the
EC has not conducted a risk assessment for estradiol 17β, the one hormone for which it claims to have
done so.70 Therefore, the EC has failed to base its permanent ban on meat and meat products from
cattle treated with estradiol 17 β on a risk assessment, as required by Article 5.1 and defined in Annex
A, paragraph 4 of the SPS Agreement.
2. Scientific evidence relating to estradiol 17β
33. The question of whether scien tific evidence cited in a ri sk assessment supports the
conclusions reached in the assessment is releva nt to the obligation in Article 5.1 of the SPS
Agreement that Members must base their measures on a risk assessment, as appropriate to the
circumstances,71 as well as Article 5.2's requirement that ri sk assessments take into account available
scientific evidence. The experts' responses conf irm the following points regarding the scientific
evidence relating to estradiol 17 β cited by the EC: (1) the scien tific evidence does not support the
conclusion that any carcinogenic effects of estradiol 17 β are related to a mechanism other than
hormonal (endocrine) activity; (2) the scientific evidence does not support the conclusion that
estradiol 17 β is genotoxic at levels found in residues in meat from cattle treated with growth
promoting hormones; and (3) the scientific evidence does not demonstrate that estradiol 17 β will have
carcinogenic or tumorigenic effects at concentrati ons found in residues in meat from cattle treated
with hormones for growth promotion purposes.
(a) The scientific evidence does not support the conclusion that any carcinogenic effects of
estradiol 17β are related to a mechanism other than hormonal activity
34. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions
does not support the conclusion that the carcinogenic effects of estradiol 17 β are related to a
mechanism other than hormonal activity. Dr. Boi sseau notes, "the scientific evidence relied upon in
the SCVPH Opinions does not support the conclusion that the carcinogenic effects of oestradiol-17 β
are related to a mechanism other than hormonal activity." 72 Dr. Boobis concurs, "[t]he carcinogenic
effects of oestradiol appear to be a consequence of its endocrine activity." 73 One expert,
Dr. Guttenplan, restates the conclusions of both parti es, noting that while the EC has cited materials
that "indicate that a mechanism other than horm onal activity is possible," the "United States and
Canada cite other reports indicating that genotoxic effects of estrogens are unlikely." 74 While this

damage is extremely important to an analysis of whether or not that specific form of damage is occurring, and
the resulting likelihood of said damage.
70 Note that the experts' comments as to whether th e EC completed the fourth step of risk assessment
(risk characterization) are contained in the discussion ab ove. The short answer is that the EC did not complete
this step. Dr. Boobis : "No adequate assessment of exposure following use according to GVP was undertaken.
Hence, it was not possible to complete the risk characterization phase of the assessment." Dr. Guttenplan :
"[t]he risk characterization is very qualitative at best." (Dr. Boobis Responses (Question 13), p. 17;
Dr. Guttenplan Responses (Question 14), p. 4).
71 See Panel Report, Japan – Measures Affecting the Importation of Apples: Recourse to Article 21.5 of
the DSU by the United States , WT/DS245/RW, adopted July 20, 2005, paras. 8.145-8.146 (finding that "[s]ince
the scientific evidence relied upon by Japan does not support the conclusions reached by Japan in its 2004 PRA,
we conclude that the 2004 PRA is not an a ssessment, as appropriate to the circumstances , of the risks to plant
life or health, within the meaning of Article 5.1 of the SPS Agreement.")
72 Dr. Boisseau Responses (Question 16), p. 12.
73 Dr. Boobis Responses (Question 16), p. 19.
74 Dr. Guttenplan Responses (Question 16), p. 4. Rather than elaborating on how the EC's Opinions
support the conclusion ( e.g., with scientific evidence) that the carcino genic effects of the hormones at issue are

statement likely requires further clarification, the United States notes that additional responses from
Dr. Guttenplan appear to indicate that he is of the opinion that any carcinogenic effects of estradiol
17β are indeed linked to hormonal activity or to leve ls greater than those found in residues in meat
from cattle treated with hormones for growth pr omotion purposes. For example, Dr. Guttenplan
concludes that any carcinogenic effect from estradiol 17 β in meat from treated cattle "is unlikely if
good veterinary practices are followed."
75
(b) The scientific evidence does not support the conclusion that estradiol 17 β is genotoxic at
levels found in residues in meat from cattle treated with growth promoting hormones
35. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions
does not support the conclusion that estradiol 17 β is genotoxic at levels found in residues in meat
from cattle treated with growth promoting hormones. As noted by Dr. Cogliano, "it has not been
established by the EC that genotoxicity and cell pr oliferation would be induced by levels found in
meat residues added to the pre-existi ng levels occurring in exposed humans." 76 Dr. Boobis states,
"whilst there are reliable studies demonstrating the genot oxicity of oestradiol in certain in vitro tests,
the evidence is against any genotoxicity in vivo. Some, if not all, of the genotoxicity observed in vitro
would be expected to exhibit a threshold."77
36. Regarding the specific studies relied upon by the EC in reaching its conclusion that estradiol
17β is genotoxic, Dr. Boobis notes that the studies "should have been evaluated on a weight of
evidence basis. Several of the studies suffered fro m significant limitations and there were a number
of well conducted studies on a variety of endpoint s that should have been included in such an
evaluation."78 Dr. Boobis provides numerous citations on th e issue of genotoxicity and estradiol that
were not considered by the EC in its Opini ons, all of which have been published since 2000. 79
According to Dr. Boobis' analysis of the issue, none of the available evidence demonstrates that
estradiol 17β is genotoxic in vivo .80 The importance of this statement is underscored by the fact that
the EC's own Committee for Medicinal Products for Veterinary Use ("CVMP") has a published
guideline for evaluating the safety of residues of veterinary drugs in human food "requiring
confirmation of an in vitro positive using an appropriate in vivo assay." 81 The EC has failed to
explain why their evaluation of estradiol 17β is not subject to this guideline.
37. Dr. Boisseau notes that the EC provides "n o data indicating that oestradiol-17 β is associated
with the increase of tumours in tissues or organs which are not hormone dependent," and that, "[i]n
conclusion, the EC risk assessment did not support that residues of oestradiol-17 β, despite the
genotoxic potential of this hormone, can initiate and promote tumours in humans." 82 This comment
by Dr. Boisseau is further emphasized by Dr. Boobis, who states, "the important point here is that it is
the carcinogenic effect that is of concern, not in vitro genotoxicity."83

related to a mechanism other than hormonal activity, Dr. Guttenplan simply recites the Opinions' conclusion that
this is so.
75 Dr. Guttenplan Responses (Question 15), p. 4.
76 Dr. Cogliano Responses (Question 18), p. 1.
77 Dr. Boobis Responses (Question 18), p. 22.
78 Dr. Boobis Responses, p. 20. See generally Dr. Boobis Responses (Que stion 62), pp. 49-58, in
which Dr. Boobis provides specific critiques of several of the 17 Studies and other scientific materials cited by
the EC.
79 See Dr. Boobis Response (Question 16), pp. 19-20.
80 See Dr. Boobis Response (Question 16), p. 19.
81 Dr. Boobis Response (Question 16), p. 19.
82 Dr. Boisseau Responses (Question 13), p. 11.
83 Dr. Boobis Responses (Question 19), p. 22.

38. It is unclear from Dr. Guttenplan's responses whet her or not he is of the opinion that estradiol
17β is genotoxic at levels found in residues in m eat from cattle treated with growth promoting
hormones. As such, his response appears to neither bolster nor cast any doubt on the responses of the
other experts who examined the issue of genotoxici ty. On the one hand, Dr. Guttenplan recognizes a
genotoxic mechanism, while on the other he notes a hormonal mechanism. 84 At the same time, he
disagrees with the blanket EC conclusion that "it can not be said that there exist[s] a safe level below
which intakes from residue should be considered to be safe." As to this point, Dr. Guttenplan
comments that the EC's conclusion is "not necessar ily true," and that "for any toxin, the dose
determines the risk." 85 Further, as noted above, Dr. Guttenplan has expressed the opinion that any
carcinogenic effect from estradiol 17 β in meat from treated cattle "is unlikely if good veterinary
practices are followed,"86 a conclusion from which one can infer that levels of estradiol 17 β residue in
meat from treated cattle are safe for consumers.
39. The fact that the scientific ev idence cited by the EC in its Opinions fails to support the
conclusion that estradiol 17 β is genotoxic at levels found in residu es in meat from cattle treated with
growth promoting hormones is critical to the EC 's corresponding conclusion that no threshold cannot
be identified for the residues of the hormone and th at there is no "safe level below which intakes from
residue should be cons idered to be safe." 87 The experts' responses confirm that the EC has failed to
adduce the necessary scientific eviden ce to support this conclusion. As noted by Dr. Boisseau, "[t]he
scientific evidence referred to by the European Co mmunities does not demonstrate that this statement
can also apply in the case of oestradiol-17 β, ... as [this] [ ] natural hormone[ ] [is] produced by both
humans and food producing animals. Therefore, even in the absence of any consumption of food
coming from animals treated by growth promoting hormones, humans are naturally and continuously
exposed to these natural hormones."88
40. Dr. Boobis agrees, stating, "[t]here is no good ev idence that oestradiol is genotoxic in vivo or
that it causes cancer by a genotoxic mechanism. I ndeed, the evidence is agai nst this. Hence, the
scientific evidence does not support the EC on this issu e, that the levels of the hormones in meat from
treated cattle are not of relevance." 89 Dr. Cogliano concurs, noting that the EC's statement regarding
the lack of a threshold has not been demonstrated by the scientific evidence. 90 Dr. Cogliano also
opines that the US stance on thresholds has not be en supported by the scientific evidence, but this
opinion does not appear to be relevant to the eval uation at hand, which is whether or not the EC, in
banning the import of meat from cattle treated with estradiol 17 β for growth promotion purposes,
adduces the necessary scientific evidence relating to, inter alia, genotoxic effects of the hormone, to
serve as a basis for its ban.91
41. The experts disagree with the EC's statemen t that JECFA's decision to set an ADI for
estradiol 17 β was affected by its conclusion in its 52 nd Report that estradiol 17 β has "genotoxic
potential". The EC alleges that this finding was critical to JECFA's proposing an ADI for estradiol

84 Dr. Guttenplan Responses (Question 19), p. 5.
85 Dr. Guttenplan Responses (Question 19), p. 5.
86 Dr. Guttenplan Responses (Question 15), p. 4.
87 See Panel's Questions to the Experts, Question 19.
88 Dr. Boisseau Responses (Question 19), p. 16.
89 Dr. Boobis Responses (Question 19), p. 22.
90 Dr. Cogliano Responses (Question 19), p. 2.
91 As noted in paragraph 39 above, Dr. Guttenplan's response appears to neither endorse or deny the
presence of a threshold. His answer does appear to indicate, however, that it would have been possible for the
EC to determine a safe level for estradiol 17 β, or to have examined the effects of low doses, rather than simply
stopping its evaluation once it concluded estradiol 17 β is genotoxic. ("The statemen t that, 'the fact that doses
used in growth promotion are low is not of relevance' is not necessarily true. For any toxin the dose determines
the risk." "When exposure is very low risk will be ve ry low." Carcinogenic effects are "unlikely if good
veterinary practices are followed.") Dr. Guttenplan Responses (Questions 15 and 19), pp. 4-5.

17β for the first time in 1999 at its 52
nd Meeting.92 Dr. Boisseau notes, "JECFA's conclusions that
oestradiol-17β 'has genotoxic potential' did not affect its recommendation on this hormone." 93
Dr. Boobis agrees, highlighting the rationale behind JECFA's conclusion:
I do not believe that JECFA's conclusion that oestradiol has "genotoxic potential"
affected its recommendations on this horm one, which were based on the conclusion
that there was a threshold for its carcinogeni c effects. JECFA's conclusion regarding
genotoxicity was based on positive results in certain in vitro tests, but the evidence
was against a mutagenic response in vivo.94
JECFA, in its responses, makes no mention of the finding that estradiol 17 β has "genotoxic potential"
in its discussion of how its conclusions in 1999 (52 nd Meeting) differed from those in 1987 (32 nd
Meeting).95 Instead, it notes that its decision to set an ADI for estradiol 17 β at its 52 nd Meeting was
based on consideration of:

published data from studies on the oral bi oavailability, metabolism, short-term
toxicity, reproductive toxicity, genotoxicity and long-term toxicity/carcinogenicity of
exogenous estrogens. Numerous reports on st udies of the use of exogenous estrogens
in women were considered, as were studies in experimental animals on the
mechanism of action of estradiol-17 β. The extensive database derived from the
results of epidemiological studies in women taking oral contraceptive preparations
containing estrogens or postmenopausal estr ogen replacement therapy was also used
to evaluate the safety of estradiol-17β.
96
Drs. Cogliano and Guttenplan offer comments on this issue, but neither appears to have addressed the
issue (and Panel's question) of whether JECFA's conclusion regarding genot oxic potential affected
JECFA's conclusion to set an ADI, as alleged by the EC.97

92 The EC avers that JECFA's finding that estradiol 17 β "has genotoxic potential" was essential
"compared to its previous 1988 evaluation - ... to [JECFA ] propos[ing] the definition of an Acceptable Daily
Intake (ADI) for oestradiol 17β, which was not the situation before." EC Answers to Panel Questions, para. 97.
93 Dr. Boisseau Responses (Question 20), p. 16.
94 Dr. Boobis Responses (Question 20), p. 23.
95 JECFA Responses (Question 20), p. 16. JECFA note s that its establishment of an ADI for estradiol
17β (as well as the other two naturally-occurring hormones) was based on "[s]ufficient new data from
observations in humans ... which were suitable to derive AD Is." Rather than the basing its decision to establish
an ADI on the finding of the genotoxic potential of estradiol, as argued by the EC, JECFA notes that "the
establishment of an ADI implies that there is a thre shold of effect for [ ] a compound, below which no[ ]
toxicological effects occur." JECFA Responses (Question 20), p. 18.
96 JECFA Responses (Question 20), p. 16. See Dr. Boisseau Responses (Questions 33 and 34), p. 19;
Dr. Boobis Responses (Question 33), p. 34; see also US First Written Submission, para. 56.
97 Dr. Cogliano notes that "the EC's conclusions seem to reflect a concern that endogenous hormone
levels are variable," yet also concludes that "the variability of endogenously produced hormone levels is
recognized by Codex." Dr. Cogliano Responses (Question 20 ), p. 2. It is unclear how this statement relates to
JECFA's decision making at its 52 nd Meeting, and whether or no t a finding that estradiol 17 β has "genotoxic
potential" affected JECFA's ultimate conclusion to set an ADI for the hormone. Dr. Guttenplan appears to have
misconstrued the Panel's question, opining that JECF A's conclusion "had some effect on the European
Communities' conclusions." Dr. Guttenplan Responses (Question 20), p. 5. This statement is unexceptional, as
the EC has consistently argued and attempted to demonstrate that estradiol 17 β is genotoxic at levels found in
residues in meat from cattle treated with growth promo ting hormones. Indeed, it has raised this limited JECFA
finding several times in an attempt to support its own decision making. See, e.g., EC Answers to Panel
Questions, para. 97.

(c) The scientific evidence does not demonstrate that estradiol 17 β will have carcinogenic or
tumorigenic effects at concentrations found in meat from cattle treated with hormones for
growth promotion purposes
42. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions
does not support the conclusion that estradiol 17 β is carcinogenic or tumorigenic at concentrations
found in meat from cattle treated with hormones for growth promotion purposes. As noted by
Dr. Boisseau, "it is legitimate to conclude that (1) the carcinogenic potential of oestradiol-17 β results
from its hormonal activity, [and] (2) ... derive ... an ADI which represents the highest quantity of
oestradiol-17β causing in humans no hormonal effect and therefore no carcinogenic effect." 98
Therefore, Dr. Boisseau concludes that "oestradiol-17β, even [though] it has been recognized as being
able to generate tumours, is not likely to pr oduce adverse effects on human health when it is
consumed in meat from cattle treated with hormones for growth promotion purposes." 99 Dr. Boobis
comments that "an additional factor in the risk assessment of this compound is whether the levels
from consumption of meat from treated animals impact s on the circulating levels of the hormone. If
not, then there should be no change in risk," 100 and even "occasional exposure above the ADI, such as
might occur if GVP is not followed, would not be associated with any incr ease in risk of cancer." 101
Dr. Guttenplan appears to agree, noting that while "an adverse effect cannot be ruled out, [ ] it is
unlikely if good veterinary practices are followed."102
43. Dr. Cogliano, while noting that the identification of estradiol 17 β as a human carcinogen
"indicates that there are potential adverse effects on human health" 103 when it is consumed in meat
from treated cattle nevertheless also comments that "it has not been establi shed by the EC that
genotoxicity and cell proliferation would be induced by levels found in meat residues added to the
pre-existing levels occurring in exposed humans," 104 a statement which appears to endorse the
conclusion that the EC has failed to demonstrate th at carcinogenic or genotoxic effects will be caused
by estradiol 17β residues in meat from treated cattle.
44. Lastly, since the metabolism of estradiol 17 β to catechol estrogens is a central element of the
EC's claim that estradiol 17 β is carcinogenic via a genotoxic mechanism, the Panel asked the experts
to comment on materials presented by the EC in support of its theory. Although the experts agree that
the presence of these metabolites would be important to consider in assessing the genotoxic potential
of estradiol 17β, they agree that the materials relied on by the EC failed to detect catechol residues in
meat. Dr. Boobis concludes, "[t]he analytical data certainly show that levels of catechol metabolites
in meat from treated animals were below the limits of detection of the method." 105 Dr. Boisseau
states, "it can be said that this study could not find evidence of metabolites coming from the catechol
oestrogen biosynthesis." 106 Finally, Dr. Cogliano concludes "that detectable levels of catechol
metabolites were not formed from the parent compound." 107 In the absence of scientific evidence for
such residues in meat from cattle treated with estradiol 17 β for growth promotion purposes, it is
impossible for the EC to conclude that catechol estrogens derived from edible bovine tissues are
genotoxic and thus have carcinogenic or tumorigenic effects.

98 Dr. Boisseau Responses (Question 15), p. 12.
99 Dr. Boisseau Responses (Question 15), p. 12.
100 The EC has presented no evidence, for any sector of the human population, that consumption of
beef affects circulating (blood) levels of estradiol 17β.
101 Dr. Boobis Responses (Question 15), p. 18.
102 Dr. Guttenplan Responses (Question 15), p. 4.
103 Dr. Cogliano Responses (Question 15), p. 1.
104 Dr. Cogliano Responses (Question 18), p. 1.
105 Dr. Boobis Responses (Question 17), p. 21.
106 Dr. Boisseau Responses (Question 17), p. 14.
107 Dr. Cogliano Responses (Question 17), p. 1.

(d) Conclusion
45. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions
does not support the conclusions on estradiol 17 β reached by the EC in those Opinions. Therefore,
the EC has not based its permanent ban on meat an d meat products from cattle treated with estradiol
17β for growth promotion purposes on a risk assessment, as appropriate to the circumstances, within
the meaning of Article 5.1 of the SPS Agreement.
108 Further, the experts' responses confirm that the
EC's Opinions have failed to take into account ava ilable scientific evidence, as required by Article 5.2
of the SPS Agreement.
3. Scientific evidence relating to the five provisionally banned hormones
46. The question of sufficiency of the scientific ev idence relating to the five provisionally banned
hormones, and the question of what scientific c onclusions may be drawn from that evidence are
essential to determinations of whether the scientif ic evidence relating to the hormones was indeed
insufficient for the EC to conduct a risk assessment, and whether the EC's provisional bans have been
adopted on the basis of available pertinent inform ation within the meaning of Article 5.7 of the SPS
Agreement.
47. The experts' responses confirm the following poi nts regarding the scientific evidence relating
to the five provisionally banned hormones (progest erone; testosterone; trenbolone acetate; zeranol;
and melengestrol acetate): (1) the scientific evidence and information relating to the five hormones is
sufficient to conduct an assessment of the risks to human health from consumption of meat from cattle
treated with the five hormones for growth promotio n purposes; (2) the scientific evidence cited by the
EC in its Opinions does not demonstrate that any of the five hormones has genotoxic potential or is
carcinogenic by a mechanism other than hormonal ac tivity; and (3) scientific materials produced and
cited by the EC (including the "17 Studies") have not identified any gaps or insufficiencies in the
scientific evidence such that more study is necessary before the risk from consumption of meat from
cattle treated with the five hormones for growth promotion purposes can be assessed.
(a) The scientific evidence and information relating to the five hormones is sufficient to conduct
an assessment of the risks to human health fro m consumption of meat from cattle treated with
the five hormones for growth promotion purposes
48. The experts' responses confirm that the scientific evidence and information relating to the five
hormones is sufficient to conduct an assessment of the risks to human health from consumption of
meat from cattle treated with the five hormones fo r growth promotion purposes. Dr. Boobis states,
"[i]n my view there was sufficient information av ailable to the EC to have enabled it to have
conducted an assessment of the risks to human heal th arising from consumption of meat from cattle
treated with any of the six hormones at issue." 109 Dr. Guttenplan affirms that JECFA was able to
conduct risk assessments for the five hormones, noti ng that there has been substantial analysis of
progesterone, testosterone and MGA. He does note th at "[t]here is more limited evidence available"
for trenbolone and zeranol, 110 but does not indicate whether this fact would prevent the EC from
completing a risk assessment for th ese hormones. In addition, as one of his reasons for opining that
there is more limited evidence available for trenbol one, he notes that it "appears to be significantly

108 See Panel Report, Japan – Apples (21.5), paras. 8.145-8.146.
109 Dr. Boobis Responses (Question 61), p. 49.
110 Dr. Guttenplan Responses (Question 61), p. 13.

estrogenic." The United States has not been able to locate any evidence supporting this conclusion, as
trenbolone is an androgen (mimicking testosterone) and not an estrogen.111
49. In relation to the sufficiency of the scientific evidence relating to MGA, the Panel inquired as
to whether "nearly all the studies referred to in the 2000 JECFA report on MGA date from the 1960s
and 70s," and whether subsequent JECFA reports relied on these same studies. The experts' responses
indicate that this is indeed the case,
112 however, as noted by Dr. Boisseau, it is essential to take into
account the fact that the dates of studies utilized in an assessment is not as critical a factor as indicated
by the EC: "the quality and the number of the ava ilable data are more important than the dates at
which these data have been produced."113 As is apparent from Dr. Guttenplan's evaluation of JECFA's
assessment of MGA, the quality and quantity of eviden ce was more than adequate: "[t]he assessment
for melengestrol acetate seems sound. Thorough meta bolic and estrogenic studies have been carried
out."114 In addition, no new or intervening scientific evidence or studies have cast doubt on the earlier
studies relied on by JECFA, further reaffirming that the dates of those studies and data are irrelevant
to an evaluation of the safety of the hormone.115
(b) Scientific materials cited by the EC in its Op inions do not demonstrate that any of the five
hormones has genotoxic potential or is carcinogenic by a mechanism other than hormonal
activity
50. The experts' responses confirm that the scientific materials cited by the EC in its Opinions do
not demonstrate or support the conclusion that any of the five hormones has genotoxic potential or is
carcinogenic by a mechanism other than hormonal activ ity. Dr. Boisseau notes for each of the five
hormones that, "the scientific evidence relied upon in the SCVPH Opinions does not support the
conclusion that the carcinogenic effects of [any of the hormones] are related to a mechanism other
than hormonal activity."116 Dr. Boobis agrees, commenting, "[t]here is no evidence that the hormones
testosterone or progesterone have genotoxic potenti al [and] [t]here is no convincing evidence that
trenbolone acetate, MGA and zeranol are genotoxic. They were negative in a range of tests for
genotoxicity."117 Therefore, "there is no evidence that any of the hormones are genotoxic in vivo at
the levels found in meat from treated animals."118 Dr. Guttenplan's response confirms this conclusion:

111 Dr. Guttenplan Responses (Question 61), p. 13. Dr. Guttenplan has failed to cite to any evidence
supporting his conclusion on the availability of evidence for trenbolone and zeranol. For example, it may be
useful to know what evidence Dr. Guttenplan relies on in concluding that trenbolone is "potentially significantly
estrogenic." Dr. Boisseau notes that he does not have the necessary data to answer the question of sufficiency of
evidence, but comments that the continual request for more and more data must stop at some point lest the
assessment process become "endless." Dr. Boisseau Responses, p. 61.
112 See, e.g., Responses to Questions from the Panel of Dr. Hubert De Brabander ("Dr. De Brabander
Responses") (Question 35), p. 10; Dr. Boisseau Responses (Question 35), p. 20.
113 Dr. Boisseau Responses (Question 34), p. 19.
114 Dr. Guttenplan Responses (Question 61), p. 13. As a point of clarification on MGA, Dr. Guttenplan
indicates in his answer to Question 60 that MGA may be administered as either a feed additive or an implant
("MGA is the only hormone which might be administered by both methods.") This is incorrect – MGA is only
administered as a feed additive.
115 See Dr. Boobis Responses (Question 62), pp. 49-58 ("There is little information in the scientific
studies initiated by the EC since 1997 that support the contention that they have identified important new gaps,
insufficiencies and contradi ctions in the scientific information and knowledge on the hormones, and that
additional studies are necessary before the risks to health of consumption of meat fr om treated animals can be
assessed. Whilst additional information has been obtaine d on a number of aspects of the hormones in question,
this was often not definitive, sometimes it was not rele vant, in some instances it confirmed or expanded on
previous knowledge. The evidence obtained did not indicate any additional concern regarding the risk from
exposure to residues of the hormones in meat from cattle treated for growth promotion.")
116 Dr. Boisseau Responses (Question 16), p. 16.
117 Dr. Boobis Responses (Question 21), p. 24.
118 Dr. Boobis Responses (Question 21), p. 24.

"[t]here is no conclusive evidence presented by the EC that the five hormones ... when consumed as
residues in meat have genotoxic potential."
119
(c) Scientific materials produced and cited by the EC (including the "17 Studies") have not
identified any gaps or insufficiencies in the scientific evidence such that more study is
necessary before the risk from consumption of meat from cattle treated with the five
hormones for growth promotion purposes can be assessed
51. The experts' responses confirm that the scientific materials produced and cited by the EC
(including the "17 Studies") have not identified any s ubstantial gaps or insufficiencies such that more
study is necessary before the risk from consumpti on of meat from cattle treated with the five
hormones for growth promotion purposes can be as sessed. Dr. Boisseau notes, "[t]hese new [EC]
data do not demonstrate any important gaps, insuffi ciencies and contradictions in the scientific
information."120 Dr. Boobis agrees: "[t]here is little info rmation in the scientific studies initiated by
the EC since 1997 that support the contention that they have identifie d important new gaps,
insufficiencies and contradictions in the scientif ic information and knowledge on the hormones, and
that additional studies are necessary before the risks to health of consumption of meat ... can be
assessed."121 Further, "[t]he evidence obtained did not indicate any additional concern regarding the
risk from exposure to residues of the hormones in meat from cattle treated for growth promotion."122
52. Dr. Guttenplan is the lone expert to identify purported "gaps" in th e scientific evidence or
data. However, the majority of these alleged gaps in the data appear to relate to estradiol 17 β, the
hormone for which the EC claims to have comp leted a risk assessment within the meaning of
Article 5.1 of the SPS Agreement as a basis for its permanent ban on meat fr om cattle treated with
estradiol 17 β for growth promotion purposes. 123 Dr. Guttenplan's comments do not appear to
specifically contemplate the hormones for which one would expect such alleged gaps to exist, i.e., the
provisionally banned hormones for which the EC cl aims insufficient scientific information to
complete a risk assessment.124
53. The EC has not alleged gaps in the informati on it has put forward in support of its permanent
ban on meat and meat products from cattle treated with estradiol 17 β. If a lack of evidence were its
reason for banning imports of estradiol-treated meat , due to gaps or insufficiencies, the EC would
presumably have included estradiol 17 β with the other provisionally-banned hormones. Instead, the
EC contends that the evidence and data are clear en ough and sufficient to c onclude that residues in
meat from cattle treated with estradiol 17 β for growth promotion purposes pose a health risk to
consumers.125 Regardless, purported data gaps in evidence relating to estradiol 17β have no relevance
to the sufficiency of evidence for the five other hor mones. Further study can always be done with
respect to any scientific issue, and Dr. Guttenplan 's response reflects the desire of responsible
scientists to have as much information as possible. At the same time, however, Dr. Guttenplan does

119 Dr. Guttenplan Responses (Question 21), p. 6.
120 Dr. Boisseau Responses (Question 62), p. 28.
121 Dr. Boobis Responses (Question 62), p. 58.
122 Dr. Boobis Responses (Question 62), p. 58.
123 See Dr. Guttenplan Responses (Question 62), p. 14 . (Dr. Guttenplan identifies "gaps" in the
following areas: estrogen levels in children; identifi cation and quantification of lipoidal esters; and matched
population studies comparing various populations of children).
124 Further clarification would be necessary to determine whether Dr. Guttenplan was of the opinion
that data "gaps" existed for any of the five provisionally-banned hormones.
125 See, e.g., EC First Written Submission, para. 17 ("[The EC's ban] is based on a comprehensive risk
assessment and, thus, is fully compliant with the DSB recommendations and rulings. In particular, as stipulated
by the Appellate Body, the results of the risk assessment 'sufficiently warrant' the definite import prohibition
regarding one of the hormones (Article 5.1 of the SPS Agreement).")

not say that any of these alleged gaps prev ented conducting a risk assessment for any of the
hormones.
(d) Conclusion
54. The experts' responses confirm that the scientific evidence or information relating to the five
provisionally banned hormones is indeed sufficient (o r rather, not insufficient) for the EC to have
completed a risk assessment for each of the hormones. Further, the experts' responses confirm that
the EC's provisional bans have not been adopted on the basis of available pertinent information within
the meaning of Article 5.7 of the SPS Agreement because the available pertinent information indicates
that consumption of residues of the hormones in meat from cattle treated for growth promotion
purposes is safe for consumers. In short, the EC h as not implemented provisional bans for any of the
five hormones that satisfy the cumulative conditions of Article 5.7 of the SPS Agreement.
4. Scientific evidence relating to the hormones generally
55. An evaluation of the scientific evidence relating to the six hormones generally is essential to a
determination of whether, on the one hand, the EC has completed a risk assessment for estradiol 17 β
within the meaning of Article 5.1 and whether that assessment takes into acc ount available scientific
evidence within the meaning of Article 5.2 of th e SPS Agreement, and on the other hand whether the
EC has implemented a provisional ba n for the other five hormones within the meaning of Article 5.7
of the SPS Agreement. 126 Several of the Panel's questions ask the experts to opine on the state of the
scientific evidence relating to the six hormones generally.
56. The experts' responses confirm the following poi nts regarding the scientific evidence relating
to the hormones generally: (1) each of the hormones has been used for growth promotion purposes in
cattle and evaluated for a sufficient period of time w ith no evidence of adverse effects to adequately
address any concern regarding long latency periods of cancer; (2) epidemiological studies cited by the
EC do not identify a link between cancer and residues of the hormones in meat; (3) the EC has failed
to demonstrate that meat from cattle treated with hormones for growth promotion purposes poses a
risk to sensitive populations; and (4) the EC has faile d to demonstrate "other risks" to human health
from consumption of residues of the hormones in meat from cattle treated for growth promotion
purposes, such as effects on the immune system.
(a) Each of the hormones has been used for grow th promotion purposes in cattle and evaluated
for a sufficient period of time with no evidence of adverse effects to adequately address any
concern regarding long latency periods of cancer
57. The experts' answers confirm that, while it is necessary to take into account the long latency
period of cancer in evaluating the safety of the six hormones, each of the hor mones has been used for
growth promotion purposes in cattle and evaluated for a sufficient period with no evidence of adverse
effects to consumers to adequately address this concern. 127 Dr. Boobis notes, "the latency period is an
important consideration," but confirms that stud ies of animals and humans "cover[ ] a sufficiently
long period to encompass the latency period fo r any carcinogenic effects of the hormones." 128

126 Note that the majority of the essential questions regarding the state of the scientific evidence relating
to the six hormones has already been addressed above in the discussions of estradiol 17 β and the five
provisionally banned hormones.
127 Dr. Cogliano notes the importance of consid ering latency periods, and cites IARC materials
indicating that a period of at least twenty years should be taken into account. Dr. Cogliano Responses (Question
23), p. 2. The three naturally-occurring hormones at issue in this dispute have been consumed as residues in
meat for millenia without evidence of adverse effects on human health. All of the hormones have been
consumed as residues in meat from cattle treated for growth promotion purposes for longer than twenty years.
128 Dr. Boobis Responses (Question 23), p. 26.

Further, "[t]he long term studies of the hormones unde rtaken in experimental animals and in humans,
involved much higher doses than would be encounter ed on consumption of meat from animals treated
with growth promoting hormones."
129
58. Dr. Boobis notes the difficulty in distinguishing results among effects from hormone residues
in food, naturally-occurring hormones and other factors, but agrees that "the hormones in dispute have
already been used as growth promoters over a suffici ent number of years, the epidemiological studies
in humans already carried out in this domain have failed to identify any relation between the
occurrence of hormonally dependent tumours and th e consumption of meat containing hormonally
active residues resulting from the treatmen t of cattle with growth promoters." 130 Dr. Guttenplan
concurs that hormones have been consumed in m eat for a "sufficient number of years to observe
strong or moderate increases in risk." 131 Yet, as described in detail in the discussion of
epidemiological studies and recent materials cited by the EC below, there is no evidence of such
increases.
(b) Epidemiological studies cited by the EC do not identify a link between hormone residues in
meat and cancer
59. The experts' responses confirm that the epidemiological studies cited by the EC in its
Opinions fail to identify a link between hormone residues in meat and cancer. 132 Dr. Guttenplan
concludes, "[t]he epidemiological studies do not identify a relationship between cancer and residues
of hormonal growth promoters." 133 As noted by Dr. Boobis, "[t]here is no scientific evidence
demonstrating any association between consumpti on of meat from animals treated with growth
promoting hormones and the risk of cancer in humans." 134 Indeed, the correlation lies not between
hormone residues and cancer, but instead the asso ciation with cancer "is strongest with meat
consumption and show[s] little rela tionship with whether the meat is from animals treated with
growth promoting hormones or not."135
60. Dr. Boisseau cites back to an earlier response in which he comments, "the epidemiological
studies in humans already carried out in this doma in have failed to identif y any relation between the
occurrence of hormonally dependent tumours and th e consumption of meat containing hormonally
active residues from the treatment of cattle with growth promoters." 136 Dr. Cogliano agrees, stating
that "[t]he difference between the US and the EC in rates of breast cancer and prostate cancer almost
certainly has multiple causes," and that while it is "p ossible that differences in exposure to exogenous

129 Dr. Boobis Responses (Question 23), p. 26.
130 Dr. Boisseau Responses (Question 23), p. 17.
131 Dr. Guttenplan Responses (Question 23), p. 7.
132 Confounding factors play a role in the evaluation of epidemiological data. The experts are split as
to whether these factors can be identified and thei r effects attributed to a particular source. See Dr. Boisseau
Responses (Question 24), p. 17. However, there is agreem ent that such factors exist, and that they should be
taken into account in the interpretation of data used in a risk assessment. See Dr. Boobis Responses (Question
24), p. 27; Dr. Cogliano Responses (Question 24), p. 2; Dr. Guttenplan Responses (Question 24), p. 9 ("These
are important considerations for risk assessment of adverse affects caused by residues of growth promoting
hormones in meat, as the effects of the hormones (if any) are likely to be small and might be obscured by
confounders.") None of the experts express the opinion that the EC's Opinions took confounding factors into
account in the assessment of the safety of the hormones.
133 Dr. Guttenplan Responses (Question 26), p. 9. Dr. Guttenplan also notes that "[t]he references to
the higher rates of breast cancer and prostate cancer observed in the United States as compared to the [EC] are
not very convincing," and that "the differences in rates of breast cancer and prostate cancer ... are relatively
small." Dr. Guttenplan Responses (Question 24), p. 9.
134 Dr. Boobis Responses (Question 26), p. 32.
135 Dr. Boobis Responses (Question 26), p. 32.
136 Dr. Boisseau Responses (Question 26), p. 17, citing earlier responses on pp. 16-17.

hormones can be one cause, [ ] the data are not su fficiently specific to establish a link between these
observations."137
61. The experts' comments on epidemiological st udies are linked to another of the Panel's
questions, namely whether three studies recently cite d by the EC demonstrate a risk to human health
from the consumption of meat from cattle treated with hormones for growth promotion purposes. The
experts agree that the three studies demonstrate no su ch risk. Dr. Boobis concludes that none of the
studies confirm a risk to human health from the consumption of meat from cattle treated with
hormones for growth promotion purposes. 138 Dr. Guttenplan agrees, noting that in the first study "the
results were obtained in cultured cells and the relevance to human exposure to hormone-treated [meat]
cannot be extrapolated from this study because of a myriad of uncertainties in such extrapolation." 139
Regarding the second and third studies, Dr. Guttenpl an simply comments that "the other two studies
do not confirm a risk from hormone-treated meat." 140 He also notes that, "[t]he [EC] statement that
one of the studies was carried out after the introd uction of the ban on the use of hormones for growth
promotion in Europe, negates any relevance to the possible connection of hormone-treated meat
consumption and cancer."141
62. Dr. Boisseau cites back to earlier responses, r estating his conclusion that "the scientific
evidence relied upon in the SCVPH Opinions does not support the conclusion that the carcinogenic
effects of zeranol are related to a mechanism other than hormonal activity," 142 as evidence of his
opinion that the first EC study provided no such evidence. Regarding the second study, Dr. Boisseau
restates his conclusion that epidemiological studi es in humans have failed to identify a relationship
between tumors and the consumption of meat from treated cattle, thereby indicating his opinion that
this new study demonstrates no such link.143 Finally, Dr. Boisseau notes that despite the EC's concern
regarding the alleged risk of cancer from meat from cattle treated with hormones for growth
promotion purposes, the EC has not "provide[d] any scientific evidence supporting this concern."144
63. The final expert, Dr. Cogliano, appears to suppor t the conclusions of the other experts, noting
that "[t]he study by Norat et al (2005) indicates a risk to human health from the consumption of
meat."145 As noted above, this conclusion is unexceptional, as it is not evidence of a risk from
residues in meat from cattle treated with any of the six hormones for growth promotion purposes, but
rather relates to meat consumption generally. 146 For example, as described in paragraph 59 above,
Dr. Boobis agrees that the correlation between cons umption of meat and any cancer risk lies not
between hormone residues and cancer, but instead "i s strongest with meat consumption and show
little relationship with whether the meat is from an imals treated with growth promoting hormones or
not."147 As for the remaining two studies, Dr. Cogliano concludes that the studies merely "suggest a
risk to human health," and clarifies his response by noting that the word "suggest" is used instead of
"indicates" because "the exposure levels in th ese studies are higher than those found in meat
residues."148

137 Dr. Cogliano Responses (Question 26), p. 2.
138 See Dr. Boobis Responses (Question 25), pp. 29-31.
139 Dr. Guttenplan Responses (Question 25), p. 9.
140 Dr. Guttenplan Responses (Question 25), p. 9.
141 Dr. Guttenplan Responses (Question 25), p. 9.
142 Dr. Boisseau Responses (Question 25), p. 17.
143 See Dr. Boisseau Responses (Question 25), p. 17. Dr . Boisseau notes that the third study is out of
his scope of expertise.
144 Dr. Boisseau Responses (Question 25), p. 17.
145 Dr. Cogliano Responses (Question 25), p. 2.
146 See Dr. Boobis Responses (Question 26), p. 32.
147 Dr. Boobis Responses (Question 26), p. 32.
148 Dr. Cogliano Responses (Question 25), p. 2.

(c) The EC has failed to demonstrate that meat from cattle treated with hormones for growth
promotion purposes poses a risk to sensitive populations
64. The experts' responses indicate that the EC h as failed to demonstrate that meat from cattle
treated with hormones for growth promotion purpo ses poses a risk to sensitive populations because:
(1) the assay relied upon by the EC to demonstrate lower circulating estradiol 17 β levels in children
has not been validated; (2) the EC has not demonstrated that exposure to estradiol 17 β residues in
meat from cattle treated with hormones for growth promotion purposes presents a potential risk to
prepubertal children or other sensitive populations; a nd (3) the materials cited by the EC do not place
into doubt Codex conclusions on the safety of the hormones.
(i) The assay relied upon by the EC to dem onstrate lower circulating estradiol 17 β levels in
children has not been validated
65. The experts' responses confirm that it is critical that assays be validated before they are used
as the basis for conclusions in a risk assessment.
149 Yet, no evidence has been presented
demonstrating that the assay for estradiol 17 β relied on by the EC, the Klein assay, 150 has been
properly validated since it was first used in 1994. As noted by Dr. Boobis, the original Klein assay
(1994) "reported very low levels of oestradiol in male children ..., bu t in a later study (Klein et al,
1998), the same group reported mean levels somewhat higher, at 0.27 pg/ml. The reliability of the
Klein et al assay has yet to be determined." 151 Dr. Boobis comments, "[t]he assay is particularly
sensitive to oestradiol, but there is no obvious explan ation for this, as it relies on the affinity for the
oestrogen receptor." 152 When compared to other results fro m yeast-based assays, it is clear that
"results with the yeast reporter assay are not consistent, and use of such data in risk assessment
requires that the assay be adequately validated."153
66. An important step in assay validation is confir mation of the results reported by the original
author(s) by scientists in another, independent labor atory. Dr. Sippell notes that the "validity of the
[Klein assay] has now been confirmed by another [assay] of E2 [estradiol 17 β] which was developed
by Charles Sultan's group at the University of Montpe llier, France (Paris et al 2002). Unfortunately,
the complexity of the [assay] so far prevents its wider use for routine measurements in small serum
samples from infants and prepubertal children." 154 However, the Klein assay and Paris assay cited by
Dr. Sippell differ in significant ways, and it cannot be stated that the latter independently confirms the
results of, or validates the former. For example, the two assays employ different media – the Klein

149 See Dr. Boisseau Responses (Question 38), p. 21 ("It would be important to know wether these new
bioassays have been properly validated as this SCVPH Opinion says nothing about that and whether the data
obtained with these methods for both men and women are also totally different from those obtained with the
RIA methods.")
150 The EC's own CVMP concludes the following regarding the Klein assay: "It was noted that the
report by Klein et al. (1994) indicated much lower plasma levels of oestradiol when measured with a new
method, based on -galactosidase gene expression in genetically modified yeast, compared to the classical RIA
requirements (Klein et al., 1994). However, (i) the m easure was made only in plasma and needs to be carried
out in other tissue(s) to enable to comparison between the intake of residual oestradiol and the endogenous
levels, [and] (ii) the methodology needs validation and is not (yet) generally accepted." CVMP (1999), Report
of the CVMP on the Safety Evaluation of Steroidal Sex Hormones in particular for 17 β-Oestradiol,
Progesterone, Altrenogest, Flugestone acetate and Norgestomet in the Light of New Data/Information made
available by the European Commission (EMEA/CVMP/885/99) ("1999 CVMP Report"). (Exhibit US-5). See
1999 EC Opinion, § 2.2.2.1 ("Physiological levels of steroids in serum during childhood and puberty"), p. 11;
Table 1, p. 28. (Exhibit US-4).
151 Dr. Boobis Responses (Question 40), p. 37.
152 Dr. Boobis Responses (Question 40), p. 37.
153 Dr. Boobis Responses (Question 40), p. 37.
154 Responses of Dr. Wolfgang Sippell ("Sippell Responses") (Question 40), p. 2.

assay utilizes yeast cells and the Paris assay mammalian cells (a human cancer cell line (HeLa cells)).
In addition, the Paris assay reflects circulating levels of estradiol 17 β at least an order of magnitude
greater than those identified in the 1994 Klein assay. 155 In order to conclude that the work of Paris
validated the assay relied on by the EC in its Opinions , there would have to be congruity in the results
of the assays. Therefore, the EC has based conclusi ons in its Opinions on hormone levels in sensitive
populations on an assay that has not been properly validated.
(ii) The experts' responses confirm that the EC has fa iled to demonstrate that meat from cattle
treated with hormones for growth promotion purposes poses a risk to sensitive populations
67. The experts' responses do not support the conclusion that exposure to estradiol 17β residues in
meat from cattle treated with hormones for growth promotion purposes presents a risk to prepubertal
children or sensitive populations. Indeed, one of the experts notes that the EC has failed to assess this
risk entirely. 156 Another notes that the materials put forward by the EC require no changes in the
JECFA and Codex standards relating to the growth promoting hormones. 157 One of the experts,
Dr. Sippell, disagrees; however, in so doing, Dr. Sippell's responses propose several conclusions
regarding sensitive populations that are both unresponsive to the Panel's questions and unsupported by
the scientific material cited in his answer s. Relying on the (unvalidated) Klein assay,
158 Dr. Sippell's
responses postulate that circulating levels of estradiol 17 β in children are "100 times lower" than
previously thought, and that the "resulting potential E2 [estradiol 17 β] exposure risk from
consumption of meat and meat products has grea tly increased by a factor of at least 160 times." 159
Dr. Sippell draws the following additional conclusions regarding sensitive populations:
[i]t has been shown in numerous scientific publications in vitro, in vivo and in the
human that infants and prepubertal child ren are highly sensitive to increased E2-
levels, resulting in premature breast deve lopment (Schmidt et al 2002), growth
acceleration (Lampit et al 2002), earlier sexual maturation in girls, in particular in the
USA (Sun et al 2002, Wu et al, 2002) and less in Europe (Muinck-Keizer & Mul
2001), and the well known significantly highe r incidence of precocious puberty in
girls than in boys (Teilmann et al 2005). Accidental exposure of prepubertal boys to
estrogen has resulted in gynecomastia and advanced bone maturation.
160
The materials cited by Dr. Sippell do not appear to be responsive to the Panel's question, which
sought comment on the EC statement that "any excess exposure" to estradiol 17 β resulting from the
consumption of meat presents a potential risk to public health in particular sensitive populations such
as prepubertal children. None of the citations made by Dr. Sippell address this specific question, nor
do the studies cited by Dr. Sippell present any evidence that the low levels of estradiol 17β residues in
beef (from either treated or untreated cattle) would be sufficient to affect the health or development of
prepubertal children. Further, Dr. Sippell's responses appear to propose a different result than his own
research, in which he has concl uded "[a]lthough there is concern that oestrogen consumption through
food might have adverse effects on pubertal development and human health, there are no published
data to support the notion that an increased overall exposure to environmental oestrogens has led to an
increased incidence in precocious puberty or to an earlier start of pubertal development."161

155 See Dr. Boobis Responses (Question 40), p. 39.
156 See Dr. Boisseau Responses (Question 39), pp. 21-22.
157 See Dr. Boobis Responses (Question 42), p. 39.
158 See Dr. Boobis Responses (Question 40), p. 37 ("use of such data in risk assessment requires that
the assay be adequately validated.")
159 Dr. Sippell Responses (Question 39), p. 1.
160 Dr. Sippell Responses (Question 39), p. 1.
161 Partsch and Sippell, Pathogenesis and epidemiology of precocious puberty. Effects of exogenous
oestrogens. Hum Reprod Update 2001; 7: 292-302. (Emphasis added).

68. The Schmidt
 study cited by Dr. Sippell as evidence of premature breast development
concludes that the stimulation of the mammary gland by estradiol 17 β in infancy may represent a
window that is of biological significance for breast development in adulthood. However, the Schmidt
study is not relevant to the analysis at hand nor germane to the Panel's question, as the authors
characterize their findings as physiologic, i.e., normal. The study does not describe any pathologic
findings (as implied by Dr. Sippell's use of the phrase "premature breast development") and it was
simply not designed to examine the relationship betw een breast tissue in infants and dietary estradiol
17β (i.e., the form of estrogen of relevance to the consumption of meat).
69. Dr. Sippell also cites a study by Lampit et al. to support his theory that estradiol 17 β residues
in meat from cattle treated for growth promo tion purposes will cause "growth acceleration". The
Lampit study examined girls with central precocious puberty, and demonstrated that a "mini-dose" of
estradiol 17β maintained normal pubertal growth in the girls. However, the results of the study cannot
be extrapolated to the conclusion that estradiol 17 β residues in meat will cause growth acceleration in
sensitive populations. For instance, any results obtai ned in patients with endocrine disorders such as
central precocious puberty must be extrapolated with great caution because the function of their
reproductive axis is fundamentally different from normal children, and it is possible that their
sensitivity to estradiol 17 β is altered compared to normal child ren. More importantly, the Lampit
study fails to quantify the amount of estradiol 17 β (either endogenous or e xogenous) that would be
required to accelerate growth in normal children a nd similarly fails to demonstrate a risk of
accelerated growth due to dietary consumption of estradiol 17β.
70. The Sun paper involved a large-scale study of sexual development in white, black and
Mexican-American children in the United States. The study, which presents national reference data,
concluded that non-hispanic black girls and boys ha d earlier ages for sexual matu rity compared to the
other two groups. The paper is limited to statis tics on children in the United States and makes no
effort to compare these data to t hose for European children. It is therefore unclear how Dr. Sippell
reaches his conclusion that this phenomenon occurs "in particular in the USA and less in Europe." 162
In any event, the study does not examine or measure estradiol 17 β at all, and therefore cannot be used
as evidence in support of Dr. Sippell's conclusion that exposure to estradiol 17 β results in "earlier
sexual maturation in girls, in particular in the USA." 163 The Wu paper uses the same data set as the
Sun paper, concluding that black and Mexican-A merican girls reach puberty at younger ages than
white girls. As is the case with the Sun pape r, Wu simply does not support the conclusions
extrapolated from it by Dr. Sippell. Further, there is absolutely no evidence in either the Sun paper or
the Wu paper to suggest that the observed differen ces in age of puberty may be attributable to the
presence of estradiol 17β residues in meat.
71. The de Muinck Keizer-Schrama and Mul review article (2001) concludes that the age of
puberty in Europe decreased over the last century, bu t that in recent decades this decrease has slowed.
No scientific evidence is provided to definitively id entify the basis for these changes, but the authors
cite socioeconomic conditions and better health car e and prevention as the "most important factors."
Possible dietary influences on age of puberty in Europe, including animal protein, saturated fat, dairy
products and phytoestrogens are also discussed. Th e de Muinck Keizer-Schrama review fails to
present any evidence indicating that estradiol 17 β residues in meat have had any influence on the age
of puberty in either Europe or the United States.
72. The Teilmann
 article concludes that the prevalence of precocious puberty 164 in Denmark was
very low (< 1 in 10,000); that it was higher in girl s than in boys; and that the rate was constant

162 Dr. Sippell Responses (Question 39), p. 1.
163 Dr. Sippell Responses (Question 39), p. 1.
164 In this study, precocious puberty was defined as onset of puberty before nine years of age in girls
and ten years of age in boys.

between 1993 and 2001. However, the Teilmann study does not provide any evidence supporting
Dr. Sippell's conclusion that high sensitivity to increased estradiol 17 β levels results in higher
incidences of precocious puberty in girls than in boys. The cause of preco cious puberty is not only
unknown, it was not even examined by the authors of the Teilmann paper.
73. Finally, the Felner and White paper examined three prepubertal boys with gynecomastia, each
of whom was exposed to an estrogen cream used by his mother. All three boys had elevated blood
levels of estradiol 17 β, which returned to normal once their mothers stopped using the cream. The
authors concluded: "[i]ndirect exposure to excessive amounts of topical estrogen may cause
gynecomastia, rapid changes in growth, and advanced bone age in prepubertal children." 165 It is not
possible to extrapolate data involving exposure to "excessive amounts" of estrogen cream to
conclusions regarding estradiol 17 β residues in meat from cattle treated for growth promotion
purposes. Further, exposure to estradiol 17β in the Felner and White paper was transdermal, a method
of administration that bypasses the extensive first pass metabolism of estradiol 17 β and thus results in
much higher levels of exposure than those that follow oral administration of estradiol 17 β (the
applicable route for consumption of estradiol 17β residues in meat).
74. Dr. Sippell also concludes, "[t]here is now in creasing epidemiological evidence that exposure
to elevated estrogen levels during early life (pre- and postnatally) carries an increased risk of breast
cancer in adult life, whereas conditions with low E2 levels, such as preeclampsia seem to have a
protective effect." 166 Dr. Sippell cites to eight papers in supp ort of this statement, yet none of the
papers appears to demonstrate that the conclusion is correct or responsive to the Panel's question. For
instance, four of the papers (Ekbom (1997); Swerdlow (1997); Weiss (1997); and Innes and Byers
(1999)) are all human epidemiological studies that pur port to document a higher risk of breast cancer
in adult twins (who may have been exposed to higher levels of estradiol 17 β in utero compared to
singletons) and a lower risk of breast cancer in women whose mothers had preeclampsia (which may
be associated with lower estradiol 17 β levels compared to normal pregnancies). However, the
findings of each of these studies are based entirely on correlation/assumption, without any
mechanistic evidence. The fifth paper, by Halkavi-Clarke
 et al., is a rat study showing that in utero
exposure to tamoxifen 167 increases susceptibility to breast can cer (induced by treatment with the
carcinogen DMBA). The results of this study are di fficult to interpret, in that tamoxifen has mixed
estrogen agonist/antagonist activ ity; confounded because tamoxifen caused abnormal reproductive
development; and not relevant to a discussi on of the potential effects of estradiol 17 β from the
consumption of meat and meat products (and therefore not responsive to the Panel's question).
75. In addition, Dr. Sippell concludes from the rema ining three papers that "indirect evidence
suggests that male reproductive disorders such as testicular cancer, cryptorchidism, hypospadias and
poor sperm quality may also have their origin in hormonal disturbances induced by E2 and/or
estrogenic substances during fetal life (Skakkebaek et al 2001) and also during childhood (Higuchi et
al 2003, Ramaswamy 2005)."168 Again, Dr. Sippell's conclusion, premised on "indirect evidence" that
"may" demonstrate an effect, is not supported by the cited evidence nor responsive to the Panel's
question.
76. For instance, the Skakkebaek paper speculates that "[testic ular dysgenesis syndrome] is a
result of disruption of embryonal programming and gonadal development during fetal life." However,
support for this claim is limited to animal studies involving in utero exposure to synthetic compounds
such as DES and ethinyl estradiol, but not estradiol 17 β or any of the other hormones used for growth

165 Felner and White, Prepubertal gynecomastia: indirect exposure to estrogen cream . Pediatrics 105
(2000), E55. (Emphasis added).
166 Dr. Sippell Responses (Question 39), pp. 1-2.
167 Tamoxifen is a drug which has been used in humans to treat breast cancer.
168 Dr. Sippell Responses (Question 39), p. 2.

promotion purposes in cattle.
169 There is ample evidence in animal studies that, at levels of exposure
greater than the levels found in meat residues fro m treated cattle, in utero exposure to estrogen can
affect the development of the male fetus. However, it must be emphasized that this is only the case
when exposure levels are orders of magnitude greater than those relevant to an analysis of residues in
meat from cattle treated with hormones for growth promotion purposes. 170 Further, evidence for
latent or delayed effects on adult reproductive f unction caused by exposure to hormones is limited at
best and confounded by numerous other factors. Dr. Sippell appears to acknowledge this by noting
that the evidence is (at best) "indirect."
77. The Higuchi paper reports that the reproductive functi on of adult male rabbits was impaired
following in utero exposure to dibutyl phtalate (DBP), a plasticizer and well known reproductive
toxicant. The authors assume that these effects were due to a direct toxic effect on the testis, not the
alteration of the endocrine milieu as suggested by Dr. Sippell's response. Moreover, and perhaps of
greater significance to the analysis at hand, th e study focuses on the effects of a compound (DBP)
unrelated to the hormones at issue (such as estradiol 17 β or zeranol). DBP's estrogenic potency
appears to be very low relative to estradiol 17 β,171 and it has been shown to have anti-androgenic
effects which may be more adverse than its estrogenicity. 172 Therefore, it seems highly likely that the
mechanism of toxicity of DBP does not involve "hor monal disturbances", contrary to the conclusion
reached by Dr. Sippell.
78. The final paper by Ramaswamy has very limited applicability to possible risks associated
with the consumption of residues in meat from ca ttle treated with hormones for growth promotion
purposes, and therefore limited applicability to the Panel's question. The Ramaswamy study involved
subcutaneous administration of estradiol 17 β (not oral as is the case with consumed residues, thereby
bypassing extensive first pass metabolism in th e intestine and liver); doses of estradiol 17 β that were
much higher than those that could be derived from consumption of beef; and ~40-fold elevations in
blood estradiol 17 β that were sustained for 5-20 weeks, a situation that is not comparable to the
intermittent, low-level exposure to estradiol 17β which might occur due to consumption of meat.
79. Finally, in response to the Panel's inquiry of how risks for individuals arising from "hormones
naturally present in meat differ from risks arising from the residues of hormone growth promoters,"
Dr. Sippell concludes that "[s]ynthetic hormone grow th promoters such as Zeranol and its metabolites
have been shown to be as potent as E2 and [DES ] in increasing the expression of estrogen-related
genes in human breast cancer cells (Leffers et al 2001). On the other hand, the synthetic androgen
Trenbolone and gestagen Melengestrol bind with high affinity to the human androgen and
progesterone receptors, respectively (Bauer et al 2000)."
173 No scientific evidence is cited by
Dr. Sippell to support his conclusion that "[e] xposure during pregnancy might result in sever

169 The fact that synthetic estrogens were used in th ese studies is an important distinction because the
bioavailability of these estrogens is much higher than the bioavailability of estradiol 17β.
170 Here, Dr. Sippell is making an unsubstantiated ex trapolation to suggest that adverse effects caused
by very high levels of estradiol 17β in animal studies may also occur in humans.
171 Milligan SR et al., Relative potency of xenobiotic estrogens in an acute in vivo mammalian assay .
Environ Health Perspect 106: 23-26 (1998).
172 Leffers et al., Hum Reproduction (2001); 16: 1037-1045 (one of the "17 Studies"). Also, a yeast-
based assay has shown that DBP's estrogenic potency is 1,000,000-fold lower than estradiol 17 β, and that there
is no estrogenic ability in DBP in an in vivo assay using ovariectomized mice. See Ohtani H et al .,
Environmental Health Perspectives (2000); 108; 1189-1193.
173 Dr. Sippell Responses (Question 41), p. 3. In addition, Dr. Sippell notes that "[the increased
percentage of estradiol 17β consumed in meat from treated as opposed to untreated cattle], and thus the potential
health risk, will be considerably higher if the food in take from pork, poultry, eggs and dairy products derived
from E2 -treated farm animals are taken into account." However, estradiol 17β is not used for growth promotion
purposes in poultry or pork. See Dr. Sippell Responses (Question 41), p. 3.

transplacental virilisation of a female fetus." 174 Dr. Sippell's response appears to misconstrue the
Panel's question, in that it discusses the hypotheti cal effects of synthetic hormones rather than
discussing the differences in naturally-present hormone levels as compared to residue levels resulting
from the use of hormones as growth promoters.
80. Dr. Sippell appears to be of the opinion that the potential risk from synthetic hormones may
differ from hormones naturally present in meat be cause the synthetics are more potent than their
natural counterparts. For instance, he cites to a paper by Leffers (one of the EC's "17 Studies") in
support of the statement that zeranol, estradiol 17 β and DES are equipotent. However, as is the case
with most of the in vitro studies cited by the EC, th e physiological relevance of the Leffers findings is
questionable because: (1) the assay utilized a breast cancer cell line (MCF-7) which may not
accurately reflect the sensitivity of normal breast tissue to estrogens ( e.g., estrogen receptor
populations may differ between MCF-7 and normal br east cells); and (2) there are numerous reports
in the literature demonstrating that DES is more potent than estradiol 17 β, yet inexplicably, they
register as equipotent in the Leffers paper. Furt hermore, the Leffers paper simply does not provide
evidence pertinent to the question at hand, i.e., whether zeranol residues in beef present a risk to
sensitive populations that is different from the risks arising from hormones naturally present in beef.
81. The Bauer study is also one of the "17 Studies" co mmissioned by the EC. In the Bauer study,
the primary metabolite of trenbolone acetate found in bovine muscle (17 β-TBOH) bound to the
human androgen receptor with high affinity. While this finding raises the specter that residues of
trenbolone acetate in meat may be androgenic in humans, Dr. Sippell does not provide any scientific
evidence demonstrating that this is the case. On the contrary, the evidence presented thus far
indicates that an androgenic effect of such residu es is highly unlikely due to their extremely low
levels in meat and poor bioava ilability. In addition, Bauer et al. measured the binding of MGA and
MGA metabolites to the bovine
 progesterone receptor, not the human receptor . Therefore,
Dr. Sippell's statement that MGA binds with high a ffinity to the human progesterone receptor is
unsupported by the citation to the Bauer study.
82. In summary, none of the papers cited by Dr. Sippell support the conclusion that exposure to
estradiol 17 β in meat from cattle treated with hormones for growth promotion purposes presents a
potential risk to prepubertal children or sensitive populations. In particular, none of the studies
present evidence that the extremely low amounts of estradiol 17 β in meat are sufficient to affect the
health or development of prepubertal children.
(iii) The materials cited by the EC do not place into doubt Codex conclusions on the safety of the
hormones
83. The experts' responses confirm that the materi als cited by the EC do not place into doubt
Codex conclusions on the safety of the six hormones. Dr. Boobis opines that, even if circulating
estradiol 17 β levels in prepubertal children are lower than previously contemplated,
175 the JECFA
ADI for estradiol 17 β would still "appear to be appropriate for all groups of the population," 176
including prepubertal children. Dr. Boobis notes that several intervening steps and factors must be
considered in an assessment of any risk to this population: "this exposure is via the oral route, and
bioavailability by this route is very low (<5%) (F ortherby 1996). In addition, very little of the

174 Dr. Sippell Responses (Question 41), p. 3.
175 The experts appear to agree that re sults obtained using the estradiol 17 β assay reported by Paris et
al. (2002) are worthy of further consideration. However, this assay also requires further validation. The Paris
assay was not used to estimate estradiol 17 β levels in the EC's Opinions; rather the EC used data from the
unvalidated Klein assay, wh ich estimated estradiol 17 β in prepubertal children at levels at least an order of
magnitude less than the levels of the Paris assay. See 1999 EC Opinion, § 2.2.2.1, p. 11; Table 1, p. 28.
176 Dr. Boobis Responses (Question 40), p. 39.

absorbed hormone will be free, over 95% being bo und to plasma proteins such as SHBG. Such
binding reduces the biological activity of th e hormone (Teeguarden and Barton, 2004)."
177 Therefore,
even if an assay indicates that circulating estradiol 17 β levels are lower, reliance on this fact alone
does not suffice to assess any potential risk.
84. Further, as has been discussed in detail in the experts' responses, JECFA has taken into
account additional safety factors in order to adequate ly compensate for the lower circulating levels of
hormones in sensitive populations such as prepubert al children. As noted by Dr. Boobis, JECFA
employs a 10-fold safety factor to protect sensitiv e populations and another 10-fold adjustment for
inter-individual variation.178 In other words, "[i]n keeping with its risk assessment principles, the ADI
established by JECFA would have been designed to protect all segments of the population, including
prepubertal children." 179 Therefore the ADI for estradiol 17 β has a 100-fold safety factor built in.
Dr. Boisseau concurs that JECFA took into account sensitive populations in its risk assessments, and
notes, "[f]rom a qualitative point of view, the risks for these individuals arising from residues
resulting from the use of hormones as growth promoter s in cattle does not differ from the risks arising
from the residues of hormones naturally present in meat. The potential problem which may exist is
only a quantitative one."
180
85. According to Dr. Boisseau, this information was not taken into account by the EC in its
purported risk assessment. He comments, "[t]his excess exposure of these sensitive populations needs
to be assessed and compared with the exposure resu lting from the daily consumption of meat from
cattle which have not been treated by growth pr omoters, from other food and products of animal
origin and from their own production of hormones." 181 Dr. Boobis concludes, "there is no
requirement for any revision in the Codex recommendation with respect to oestradiol-17 β on the basis
of the material referred to by the EC."182
(d) The scientific evidence cited by the EC fails to demonstrate adverse effects on the immune
system or "other risks" to human health fro m the consumption of meat from cattle treated
with the growth promoting hormones at issue
86. The experts' responses confirm that the scien tific evidence cited by the EC fails to
demonstrate adverse effects on the immune system or "other risks" to human health from the
consumption of meat from cattle treated with the growth promoting hormones at issue. Dr. Boobis
states, "[t]he evidence on immune effects of hormones such as oestradiol referred to by the EC does
not identify any adverse effects on the immune system from consumption of meat from treated cattle.
In general, clear evidence for immune effects were observed only at high doses."
183 He n o t es t h a t

177 Dr. Boobis Responses (Question 40), p. 39.
178 Dr. Boobis Responses (Question 42), p. 39. Dr. Boisseau confirms that JECFA "has considered
appropriate to establish a NOAEL on the basis of the changes in several hormone dependent parameters in post
menopausal women and to derive from this NOAEL an ADI using two safety factors of 10
, one to account for
normal variation among individuals and a second one to protect the sensitive human populations." Dr. Boisseau
Responses (Question 13), p. 9. Note that the EC's CVMP, in determining the estradiol 17 β is safe for use for
zootechnical and therapeutic purposes in cattle "based its risk assessment on the relation between any possible
excess of hormones from zootechnically treated animals in the diet and the endogenous daily production of
oestradiol in prepubertal boys." 1999 CVMP Report, p. 12. (Exhibit US-5). Dr. Sippell disagrees that JECFA
has adequately taken into account sensitive populations, but it is unclear from his response if he is familiar with
JECFA's safety factors or whether/why he finds thes e factors to be inadequate. Dr. Sippell Responses
(Question 42), p. 3.
179 Dr. Boobis Responses (Question 42), p. 39.
180 Dr. Boisseau Responses (Question 41), p. 22.
181 Dr. Boisseau Responses (Question 39), pp. 21-22.
182 Dr. Boobis Responses (Question 42), p. 39.
183 Dr. Boobis Responses (Question 59), p. 48.

"[g]iven the large margin of exposure on anticip ated intake from residues in meat from treated
animals, no effect on the immune system is antic ipated, as immune modulation is dependent on dose
and there are thresholds for such effects." 184 Dr. Guttenplan notes that, while there is evidence that
estrogens generally can be related to certain disord ers, "[n]o definitive studies have related intake of
meat from hormone-treated animals to the above disorders." 185 Finally, Dr. Boisseau comments that,
while the evidence cited by the EC would perm it it to identify potential adverse effects ( i.e., hazard
identification), the EC has performed no assessment of potential effects relating to the consumption of
residues in meat from treated cattle, and it is therefore "not possible to conclude that this scientific
evidence allows to identify any adverse effect s on the immune system associated with the
consumption of meat from cattle treated with the growth promoters at issue."186
(e) Conclusion
87. The experts' responses confirm that the scientific evidence relating to the six hormones
generally demonstrates that the hormones have been studied for sufficient time to take into account
latency periods for cancer; that epidemiological st udies do not demonstrate a link between residues of
hormones in meat and cancer; that the EC has failed to demonstrate that meat from cattle treated with
hormones for growth promotion purposes poses a risk to sensitive populations; and that the EC has
failed to demonstrate "other risks" from consumpti on of residues of the hormones in meat from cattle
treated for growth promotion purposes, such as effect s on the immune system. Therefore, the experts'
responses demonstrate that the EC has failed to base its permanent ban on meat treated with estradiol
17β on a risk assessment within the meaning of Arti cle 5.1 of the SPS Agreement and that the EC's
Opinions have failed to take into account ava ilable scientific evidence within the meaning of
Article 5.2 of the SPS Agreement. Further, th e experts' responses demonstrate that the EC's
provisional bans have not been adopted on the basi s of available pertinent information within the
meaning of Article 5.7 of the SPS Agreement.
5. Scientific evidence relating to residues
88. The scientific evidence relating to residues in meat from cattle treated with any of the six
hormones for growth promotion purposes is relevant to the obligation in Article 5.1 of the SPS
Agreement that Members must base their measures on a risk assessment, as appropriate to the
circumstances, as we ll as Article 5.2's requirement that risk assessments take into account available
scientific evidence. The scientific evidence relating to hormone residues is also relevant to Article 5.7
of the SPS Agreement and an analysis of whethe r the EC's provisional ban is based on available
pertinent information.
89. The experts' responses support the following c onclusions regarding the scientific evidence
relating to residues of the six hormones: (1) the EC has failed to put forward evidence demonstrating
that residues of any of the six hormones in meat from cattle are greater than previously thought, or to
assess the risk to consumers from exposure to residues of any of the hormones from cattle treated with
the hormones for growth promotion purposes; and (2 ) JECFA's recent re-evaluation of the three
naturally occurring hormones reached the same substantive conclusions as earlier evaluations.

184 Dr. Boobis Responses (Question 59), p. 48.
185 Dr. Guttenplan Responses (Question 59), p. 13.
186 Dr. Boisseau Responses (Question 59), p. 27.

(a) The EC has failed to put forward evidence dem onstrating that residues of any of the six
hormones in meat from cattle are greater than pr eviously thought, or to assess the risk to
consumers from exposure to r esidues of any of the hormones from cattle treated with the
hormones for growth promotion purposes
90. The experts' responses indicate that the EC h as failed to put forward evidence demonstrating
that residues of any of the six hormones in meat from cattle are greater than previously thought or to
assess the risk to consumers from exposure to residues of any of the hormones from cattle treated with
the hormones for growth promotion purposes. Dr. Boisseau, citing to the EC's 1999 Opinion and its
determination that no threshold exists for any of the hormones, notes that as a consequence of this
conclusion the EC did not "conduct a quantitative asse ssment of the exposure of consumers to the
residues of hormonal growth promoters including the determination of the levels of residues in food
from treated animals."
187 In the absence of this evaluation, th e EC was therefore unable to make any
meaningful "comparison between these le vels and the MRLs set up by Codex." 188 Dr. Boobis agrees
that the EC failed to evaluate or assess actual residue levels in meat:
In their 2002 Opinion, the Committee [ i.e., the EC's SCVPH] did not revisit exposure
following use according to GVP. Rather , the Committee considered potential
exposure following several inappropriate use scenarios. This was based on a series of
experimental studies, to determine the consequences of a number of defined misuses
on hormone levels in meat. However, whilst of potential value in any risk
assessment, these data are limited in the absence of any information on the frequency
of occurrence of such misuse in the u se of the products in question in normal
veterinary practice.
189
Dr. Boobis provides a detailed critique of these "ina ppropriate use" studies, in which he concludes
that, even in most of the extreme misuse scenario s developed by the EC, safe levels of hormone
residues are not exceeded.190
91. Although Dr. De Brabander raises several hypoth etical concerns regarding hormone residues
in meat, his comments do not appear to be responsiv e to the Panel's inquiry as to whether the EC in
fact evaluated evidence of residue levels in meat from cattle treated with any of the six hormones for
growth promotion purposes in its Opinions nor do his responses cite to any such scientific evidence.
Further, the concerns raised by Dr. De Brabander do not appear to be relevant to a discussion of the
subject matter at hand, i.e., residues in meat from cattle treated with any of the six hormones for
growth promotion purposes. For instance, Dr . De Brabander opines that the earlier studies on
residues are "old", they are "too much focused on th e direct effect on human health", and the MRLs
for the hormones "are high in relation to modern analytical limits (normally ≤ 1 µg/kg)" and "not
acceptable."191
92. However, as noted by Dr. Boisseau, older data is neither irrelevant or "bad" data simply due
to its age. Rather, it is the quality a nd quantity of data that is important, 192 and for the hormones at
issue, a great deal of high quality data exists. 193 Further, the MRL for a veterinary drug is the

187 Dr. Boisseau Responses (Question 29), p. 18.
188 Dr. Boisseau Responses (Question 29), p. 18.
189 Dr. Boobis Responses (Question 30), p. 33.
190 Dr. Boobis Responses (Question 62), pp. 50-52. See Section C(6) below for a detailed discussion of
the misuse studies.
191 Dr. De Brabander Responses (Question 29), p. 3.
192 See Dr. Boisseau Responses (Question 34), p. 19 ("th e quality and the number of the available data
are more important than the dates at which these data have been produced.")
193 As explained in JECFA's Responses (at pp. 7-9), JECFA has specific and extensive requirements for
the residue data that are used to derive MRLs. These requirements include information on the analytical method

maximum concentration of residue that is legally permitted or recognized as acceptable, based on the
toxicological hazard for human health (expressed as the ADI). 194 Therefore, the statement by Dr. De
Brabander that the MRLs for the hormones "are hi gh in relation to modern analytical limits" is
unexceptional; in fact, by definition the MRL for a drug residue should be higher than the analytical
limit of detection.
195
93. It appears that Dr. De Brabander is equating th e goals for detection of illegal anabolic drugs
in humans (doping) with detection of residues of veterinary drugs in food animals For the purpose of
detecting illegal drugs (where the allowable concentration of the drug in question is zero), it is critical
for the analytical method to accurately measure conc entrations as close to zero as possible. For most
veterinary drugs in food animals, the purpose of residue methods is not to detect any non-zero
concentrations of the residue, but to determine if the residues exceed the fin ite concentrations that
have been determined to be safe – in general, these levels do not approach zero and do not require
ultra-sensitive methods as Dr. De Brabander suggests. Dr. Boisseau confirms this point:
Nevertheless, it has to be reminded that, when MRLs have been established for a
given substance, there is not any more a need for highly sensitive analytical methods
but for a validated analytical method the sens itivity of which must be consistent with
the values of the established MRLs. In a ddition, if it is true that ultrasensitive
analytical methods remain useful to cont rol the use of forbidden veterinary drugs,
such as for example growth promoters in EU, they are less useful in the case of the
three natural hormones, which are endogenously produced by food producing
animals.
196
As for actual hormone residue levels in meat, Dr . De Brabander does not present any evidence that
hormone residue levels have been shown to be high er than previously thought, but rather speculates
that "[t]he concentrations may seriously be underestimated."197

94. As to the earlier studies' focus on human health , analysis of the potential effect on human
health is the logical endpoint for an evaluation of hormone residues that are to be consumed by
humans. Dr. De Brabander indicates that these studies should instead have examined hormone
excretions in cattle feces and urine.
198 Here, Dr. De Brabander is alluding to the possible
environmental impact of the use of growth promot ing hormones in cattle. This analysis is not
germane to the question of whether meat and me at products from cattle treated with any of the
hormones are safe for import and consumption; any of the hypothetical effects raised by Dr. De
Brabander would presumably occur in the United States (where the cattle are actually located), rather
than in export markets (where the cattle are not located).

used to measure each residue and the performance fact ors of the method. Importantly, when comparing the
1988 and 1999 evaluations of residue studies for the hormones JECFA states, "[m]ost of the studies were the
same. However, a few additional investigative studies were also reviewed. JECF A also performed a more
detailed thorough review of the validity of the analytical methods used in the studies and only used data
generated using valid methods." Therefore, Dr. De Brabander's statement that "from an analytical point of view
these MRLs are unacceptable" is unfounded.
194 Codex Responses (Question 9), p. 7.
195 Note that the residue data used in the derivation of the MRLs in question were generated using valid
analytical methods that were reviewed in detail by JECFA.
196 Dr. Boisseau Responses (Question 32), p. 18.
197 Dr. De Brabander Responses (Question 29), p. 3.
198 Dr. De Brabander Responses (Questions 29 and 30), pp. 3-4. ( E.g., "[a]s demonstrated in several
studies a major part of th e hormones used are excreted through ur ine and faeces and the administration of
natural hormones to a herd increases the concentration of these hormones in the environment." Note that the
"environment" implicated in this statement would be the United States, where the herd resides; not the EC.)

95. Dr. De Brabander also provides anecdotal inform ation relating to a testosterone sex spray as
well as use of a substance called "Z MA" (a substance allegedly used by athletes) in his response.
However, none of this information is responsive to the Panel's question, nor does it provide evidence
relating to hormone residue levels in meat from cattle treated with any of the six hormones for growth
promotion purposes. For instance, the discussion of the androstenone (boar pheromone) spray neither
provides any information regarding dose levels, nor is it relevant to the pathway at issue in the
consumption of hormone residues in meat (i.e., oral). ZMA is not one of the hormones at issue in this
dispute, and the anecdotal discussion of its use by athletes does not appear to be relevant to a
discussion of residues in meat from cattle treated w ith any of the six hormones for growth promotion
purposes.
96. Dr. De Brabander concludes that, because humans already consume foods like meat and milk
that contain estrogens which "don't give problems at a normal food consumption" that "just therefore
there is no need to add more by artificial ways."
199 Yet, Dr. De Brabander provides no scientific
discussion as to how the small additional amounts of any of the hormones found in meat from cattle
treated for growth promotion purposes might pose any increased risk to consumers. Rather, his
comment appears to be a personal opinion or policy st atement rather than a scientific conclusion.
Humans have consumed hormone residues in food for millenia without any evidence of an adverse
health risk from those residues. Similarly, humans have consumed residues in meat from cattle
treated with the six hormones for growth promo tion purposes for decades without any evidence of a
human health risk from these "additional" residues.200
(b) JECFA's recent re-evaluation of the three na turally occurring hormones reached the same
substantive conclusions as earlier evaluations
97. The experts' responses confirm that JECFA's recent re-evaluation of the three naturally-
occurring hormones reached the same conclusion as earlier evaluations, i.e., that residues of the
hormones in meat from cattle treated for growth promotion purposes are safe for consumers. The EC
argues that JECFA's establishment of ADIs for the three natural hormones at its 52
nd Meeting in 1999
marked a shift in its thinking regarding the safety of the hormones when used as growth promoters in
meat.201 The experts indicate that it did not. Dr. Bo isseau notes "[i]f the wording of the conclusions
adopted by JECFA has been formally different , the substance of these conclusions remains
unchanged," and that "[e]stablishing such ADIs had no specific implications as no MRLs have been
established."202 Further, "[t]hese new recommendations have not been considered by CCRVDF

199 Dr. De Brabander Responses (Question 31), p. 5.
200 See, e.g., discussion of the experts on epidemiological studies relating to the use of hormones for
growth promotion purposes in meat and the lack of a link to evidence of cancer at Section C(4)(b) above.
201 The EC stresses in its answers to questions from the Panel after the first substantive meeting that:
"However, as already explained the above-mentioned JECFA reports found that oestradiol 17 β 'has genotoxic
potential' and that the evidence for progesterone was interpreted 'on balance' as not having genotoxic potential.
On the basis of these findings, JECFA did consid er for the first time that ADIs were necessary to be fixed but
not MRLs, because of the endogenous production of thes e natural hormones and the difficulties in applying the
available detection methods in order to determine the origin of any residues in meat." EC Answers to Panel
Questions, para. 129. See also EC Answers to Panel Questions, para. 97 (noting that JECFA's conclusion that
estradiol 17 β has "genotoxic potential" "led now, again for the first time, to propose the definition of an
Acceptable Daily Intake (ADI) for oestradiol 17 β, which was not the situation before.") The United States has
addressed the argument that JECFA' s determination that estradiol 17 β has "genotoxic potential" in any way
affected its decision making on that hormones. The experts have confirmed that it did not. See Section C(2)(b)
above.
202 Dr. Boisseau Responses (Question 33), p. 19.

because CCRVDF did not request JECFA to reasse ss these hormones and because the new proposals
of JECFA did not change the substance of the previous ones."203
98. Dr. Boobis comments that the re-evaluation of the hormones took into account "a number of
additional studies on the toxicology and human (inc luding epidemiological) evaluation of therapeutic
exposures to the hormones (e.g. in the form of oral contraception or for hormone replacement therapy)
that were not available in 1988." 204 These human therapeutic studies indicated that exposure to the
hormones could have adverse effect s on humans "albeit at levels appreciabl[y] higher tha[n] found in
meat from treated cattle." 205 Establishment of an ADI would serve as a "benchmark for comparison
with exposure via the diet." 206 Against that benchmark, a decision was made not to recommend an
MRL due to the large margin of safety, and "CCRVDF endorsed the recommendation that MRLs for
the natural hormones did not need to be specified."207
99. Dr. De Brabander is the lone expert to disagree with these conclusions, noting that JECFA's
conclusion to set an ADI "is a recognition of the danger of hormones to human health and welfare in
all of his [sic] aspects."
208 Dr. De Brabander does not provide any support for this statement, and does
not clarify whether the "danger to human health .. . in all of [its] aspects" includes levels of the
hormones found in residues in meat from cattle treated for growth promotion purposes. The
responses of JECFA, Codex and the other two experts indicate that the decision to set an ADI is not
evidence of such a danger.
209 Rather, the setting of an ADI permitted an evaluation of residue levels
of the three hormones that could be ingested without any danger or risk to consumers.210
(c) Conclusion
100. The experts' responses indicate that the EC has failed to put forward any scientific evidence
demonstrating that residues of any of the six hormon es in meat are greater than previously thought, or

203 Dr. Boisseau Responses (Question 33), p. 19. Codex confirms Dr. Boisseau's opinion. See Codex
Responses (Question 18), p. 9.
204 Dr. Boobis Responses (Question 33), p. 35.
205 Dr. Boobis Responses (Question 33), p. 35.
206 Dr. Boobis Responses (Question 33), p. 35.
207 Dr. Boobis Responses (Question 33), p. 35. Indeed, on the basis of its detailed analysis, JECFA was
able to conclude that MRLs were not necessary for th e three natural hormones because residues in meat from
cattle treated with the hormones for growth promotion purpos es were equal to or less than 3% of the ADI in the
case of estradiol 17β, and much less than 1% of the ADI in th e case of progesterone and testosterone. See 52nd
JECFA Report (2000), § 3.5, pp. 57-74. (Exhibit US-5).
208 Dr. De Brabander Responses (Question 33), p. 8. The lack of agreement between Dr. De
Brabander's response to the question of why JECFA set ADIs in 1999 and JECFA's justification for establishing
these ADIs may indicate that Dr. De Brabander is not familiar with the international procedures used to evaluate
the safety of residues of veterinary drugs in food animals.
209 See Codex Responses (Question 18), p. 9 ("In the case of estradiol-17 beta, progesterone and
testosterone, they were re-evaluated by the 52nd JECFA (1999) at the initiative of the JECFA Secretariat. The
12th CCRVDF (2000), in recognising that it had not requeste d the re-evaluation of the three substances and that
the new MRLs recommended by the 52nd JECFA did not differ significantly from the current MRLs, decided to
not consider the new recommendation of the 52nd JECFA.") (Emphasis added); JECFA Responses (Question
20), p. 18 ("Sufficient new data from observations in humans were available to the 52nd JECFA which were
suitable to derive ADIs. The ADI not only provides an estimate of daily intakes which can be accepted over life
time without appreciable health risks, it also enables a quantitative comparis on of the excess intakes calculated
on the basis of the above mentioned worst case scenar io (see point 4 above). The Committee found that the
excess intake was in the order of only 0.02 to 4% of the ADI depending on the substance and the product used
for the treatment of the animals. Mo reover, the establishment of an ADI implies that there is a threshold of
effect for such a compound, below which now toxicological effects occur.") (Emphasis added).
210 Indeed, Codex does not take action, or base public health standards, on ADIs, but rather only does
so based on recommendations of MRLs.

assessed the risk related to the exposure of consum ers to residues of any of the hormones in meat
from cattle treated with the hormones for growth promotion purposes. These responses also confirm
that JECFA's decision to set an ADI for the natura l hormones did not mark a change in JECFA's or
Codex's opinion as to the safety of the hormones wh en consumed as residues in meat from cattle
treated for growth promotion purposes. Therefore, the EC has failed to base its permanent ban on
estradiol 17β on a risk assessment within the meaning of Article 5.1 of the SPS Agreement and failed
to take into account available sci entific evidence within the mean ing of Article 5.2 of the SPS
Agreement. Further, the EC has failed to base its provisional ban on availa ble pertinent information
within the meaning of Article 5.7 of the SPS Agreement.
6. Scientific evidence relating to good veterinary practices
101. The scientific evidence relating to good veterina ry practices is relevant to the obligation in
Article 5.1 of the SPS Agreement that Members mu st base their measures on a risk assessment, as
appropriate to the circumstances, as well as Article 5.2's requirement that risk assessments take into
account relevant processes and production methods, and relevant inspection, sampling and testing
methods.
211 Further, an analysis of good veterinary pr actices is relevant to Article 5.7 of the SPS
Agreement and an analysis of whether the EC's provisional ban is based on available pertinent
information. The issue of conditions of use is, however, perhaps best understood in the context of
Article 5.6 of the SPS Agreement, which provides that a Member must ensure that its sanitary and
phytosanitary measures are not more trade-restrictive than required to achieve its appropriate level of
sanitary or phytosanitary protection. The fact that the EC has raised the issue of misuse 212 and
devoted considerable resources to demonstrating th e potential consequences of misuse implies that it

211 For purposes of evaluation of SPS measures unde r the SPS Agreement, the Appellate Body stated,
"[w]e must stress ... that Article 5 and Annex A of the SPS Agreement speak of 'risk assessment' only and that
the term 'risk management' is not to be found either in Article 5 or in any other provision of the SPS
Agreement." Further, the Appellate Body concluded that misuse and the analysis of the potential for failure of
controls are topics that are included in a "risk assessment" for purposes of the SPS Agreement:

It should be recalled that Article 5.2 states that in the assessment of risks, Members shall take into
account, in addition to "available scientific evidence", "relevant processes an d production methods;
[and] relevant inspection, sampling and testing methods". We note also that Article 8 requires
Members to "observe the provisions of Annex C in the operation of control, inspection and approval
procedures ...". The footnote in Annex C states that "control, inspection and approval procedures
include, inter alia, procedures for sampling, testing an d certification". We consider that this language
is amply sufficient to auth orize the taking into account of risks aris ing from failure to comply with the
requirements of good veterinary practice in the administration of hormones for growth promotion
purposes, as well as risks arising from difficulties of control, inspection and enforcement of the
requirements of good veterinary practice.

We disagree with the Panel's suggestion that exclusion of risks resulting from the combination of
potential abuse and difficulties of control is justif ied by distinguishing betw een "risk assessment" and
"risk management". As earlier noted, the concept of "risk management" is not mentioned in any
provision of the SPS Agreement and, as such, cannot be used to sustain a more restrictive interpretation
of "risk assessment" than is justified by the actual terms of Article 5.2, Article 8 and Annex C of the
SPS Agreement. The question that arises, therefore, is whether the European Communities did, in fact,
submit a risk assessment demonstrating and evaluating the existence and level of risk arising in the
present case from abusive use of hormones and the difficulties of control of the administration of
hormones for growth promotion purposes, within the United States and Canada as exporting countries,
and at the frontiers of the European Communities as an importing country.

EC – Measures Concerning Meat and Meat Products (Hormones) , Appellate Body Report adopted on
13 February 1998, WT/DS26/AB/R ("Hormones" or "EC - Hormones"), paras. 181; 205-207.
212 See, e.g., EC Answers to Questions from the Panel, para. 91.

already recognizes that there are conditions under which residues of the six hormones used for growth
promotion are safe. The only health question then would be whether there are particular conditions of
use under which there would be a health risk. If so, then the question b ecomes whether the EC's
sanitary measures are more trade-restrictive than required to achieve th e appropriate level of
protection from that risk within the meaning of Article 5.6 of the SPS Agreement.
102. The responses from the experts indicate that: (1) the EC has failed to demonstrate that there
is a risk to human health from the misuse of grow th promoting hormones in the United States; and (2)
the material put forward by the EC regarding misu se or abuse of the hormones at issue fails to call
into question Codex standards regarding the safet y of meat from cattle treated with hormones for
growth promotion purposes.
(a) The EC has failed to demonstrate that there is a risk to human health from the misuse of
growth promoting hormones in the United States
103. While there is some disagreement among the expe rts as to the extent to which the EC has
assessed a risk to human health from the misuse of growth promoting hormones in the United States,
a close examination of the experts' responses indicat es that the EC has not demonstrated that such a
risk exists. Dr. Boisseau notes that "as the [EC] did not conduct any quantitative risk assessment for
growth promoters, it is not possible to say that the scientific evidence referred to by the [EC] assesses
the risk to human health from residu es resulting from these misuses/abuses." 213 Dr. Boobis agrees,
stating: "[t]here was no attempt to evaluate the ri sks from the resultant exposures on misuse or abuse,
either in the papers cited or by the SCVPH (2002) in their evaluation of these studies. Indeed, the
SCVPH (2002) simply noted that '[t]herefore, these data have to be consid ered in any quantitative
exposure assessment exercise', without undertaking such an exercise."214
104. Dr. De Brabander appears to disagree with Drs. Boobis and Boisseau, but his responses fail to
address the actual questions posed by the Panel, a nd in certain instances his opinions are simply based
on anecdotal information and policy considerations ra ther than scientific evidence or citations to the
EC's purported risk assessments. For example, in response to the Panel's inquiry as to whether the EC
assessed the risk from misplaced implants (Question 48), Dr. De Brabander simply notes, "any control
mechanism, that is only based on audits and pape r work will not prevent farmers to use either
uncorrect use of legal production aids either [ sic] illegal growth promoters which are readily available
in the US and Canada through the internet." Dr. De Brabander fails to substa ntiate this statement,
which appears to be purely conjectural; he does not pr ovide any evidence of failure of controls in the
United States, nor does he cite to any portions of the EC's purported risk assessment where the EC
actually evaluated the risk of failure of controls or misuse. In any event, no measure, be it a ban or a
system of controls, can ever be relied upon to "preve nt" an occurrence entirely. This is evidenced by
the fact that, despite imposing a ban on the use of growth promoting hormones, the EC has been
unable to "prevent" their sale and use in the black market.215
105. As explained by the United States in its Rebuttal Submission, the US system of controls is not
a simple matter of audits and paper work. 216 The United States, through cooperation between the
Food Safety and Inspection Service ("FSIS") of the United States Department of Agriculture

213 Dr. Boisseau Responses (Question 48), p. 24.
214 Dr. Boobis Responses (Question 48), p. 42. See Dr. Boobis Responses (Question 62), p. 52 ("the
data generated by the EU research in question do not provide any indication that it is not possible to conduct a
risk assessment of the hormones used as growth promoters.")
215 See US Rebuttal Submission, paras. 64-65, citing, e.g., Stephany, Hormones in meat: different
approaches in the EU and in the USA , APMIS 109, p. S 357 (2001) ("It has to be concluded that in some EU
Member States an exten[d]ed black market exists. For the USA, no experimental evidence is available for such
a black market.") (Exhibit US-29).
216 See US Rebuttal Submission, paras. 54-66.

("USDA") and the FDA, has rigorous programs in pl ace which provide efficient safeguards against
the hypothetical failure of controls in the productio n of meat and meat products. These programs
include setting safe levels for veterinary drugs; m onitoring for violative residues; and inspection of
meat at the ante mortem, post mortem and processing stages. As large commercial operations, US
feedlots have great incentive to comply with the regulations set and enforced by USDA and the FDA.
In addition to regulation at the fe deral level, many states and even individual feedlots have Beef
Quality Assurance Programs which set high standards for beef management practices to maximize the
quality and safety of beef.
217 Key components of these programs include proper training of feedlot
employees and managers to ensure that management practices do not lead to violative residues or
quality defects.
106. All growth promoting implants are clearly labe led for subcutaneous placement in the middle
third of the ear, and the ears of all cattle are removed at slaughter and discarded. Any evidence at the
time of slaughter of improper use of growth prom oting implants, which the EC claims is common
practice in the United States but provides no data to support, will result in condemnation of the
carcass by FSIS inspectors and significant economic loss to the producer. Therefore, speculation by
the EC about the effects of consumers eating whole implants, implant sites, or meat from over-dosed
cattle
218 are paper exercises at best which ignore US inspection practices and evidence of decades of
experience with the safe use of these products. Clear ly, the US beef production system has numerous
controls in place at multiple levels (federal, state and feedlot) which effectively mitigate the risk to
human health from the misuse of growth promoting hormones in cattle.
107. Dr. De Brabander cites to two pieces of evid ence in support of his conclusion that the US
system of controls does not work or is subject to fa ilure, neither of which appears to be convincing or
germane to the debate of whether or not the EC has indeed evaluated the likelihood of this occurrence.
He notes that "[t]wo years ago we had some american students in veterinary medicine in an exchange
program; their knowledge of 'hormones' their use in the USA and the risks involved was almost
zero."219 At best this statement is anecdotal evidence, and it certainly cannot be extrapolated to the
broader conclusion that controls are likely to fail in the United States. Dr. De Brabander also cites to
a controlled study conducted by scientists at the Univ ersity of California-Davis using Zilpaterol (a
beta-agonist not approved by the FDA for commercia l use in the United States) and Revalor (trade
name for an FDA-approved growth prom oting implant containing estradiol 17 β and trenbolone
acetate) in cattle as evidence "illustrat[ing] that farmers (and vets) have indeed economic incentives to
misuse growth promoting substances." 220 The Zilpaterol study does not support this conclusion, nor
does it document or endorse the commercial use of Zilp aterol. Rather, it is simply an example of a
single research study, conducted under controlled conditions on a limited number of animals, in which
scientists investigated the combin ed effects of two treatments on growth performance in cattle.
Nothing in the Zilpaterol study speaks to the potential of failure of controls or misuse of growth
promoting hormones in the United States.
221

217 Examples of Beef Quality Assurance Programs in Ohio, Minnesota and Iowa can be found at
http://www.ag.ohio-state.edu/~obqa/; http://www.mnbeef.org/bqa/BQA_Manual/Introduction.htm; and
http://www.iabeef.org/BQA/Default.aspx.
218 See, e.g., EC 1999 Opinion, §§ 3.3.1, 3.3.2 (pp. 30-31) (Exhibit US-4).
219 Dr. De Brabander Responses (Question 44), p. 13.
220 Dr. De Brabander Responses (Question 45), p. 14.
221 In the United States, unapproved drugs such as Z ilpaterol are regulated as "new animal drugs for
investigational use." As stated in 21 CFR § 511.1, "[e]dible products of investigational animals in clinical trials
are not to be used for food." Similarly, Dr. De Brabander's discussion of hormones used by body builders and
athletes is irrelevant to a discussion of the use of growth promoting hormones in cattle according to good
veterinary practices. See Dr. De Brabander Responses (Question 47), p. 15.

(b) The material put forward by the EC regarding misuse or abuse of the hormones at issue fails
to call into question Codex standards regarding the safety of meat from cattle treated with
hormones for growth promotion purposes
108. The experts' responses confirm that the material put forward by the EC regarding misuse or
abuse of any of the six hormones fails to call into question Codex standards regarding the safety of
meat from cattle treated with hormones for growth promotion purposes. Dr. Boisseau reiterates that
JECFA does not perform an evaluation of the potential for misuse,
222 and notes that "the [EC] did not
conduct a quantitative risk assessment from growth prom oters, [and that] it is not possible to say the
scientific evidence referred to by the [EC] assesses the risk to hu man health from residues resulting
from these misuses/abuses."223
109. Dr. Boobis agrees that the EC has made "no attempt to evaluate the risks" 224 from misuse,
either in its Opinions or in underlying studies. Accordingly, the EC has not presented any materials
that cast doubt on the JECFA or Codex evaluation of the safety of the hormones. In support of this
conclusion, Dr. Boobis engages in an extensive an alysis of the additional studies commissioned and
cited by the EC since 1997.
225 He cites to several studies analyzed earlier by the United States in its
Rebuttal Submission, and reaches similar conclusions regarding their results:
1. Lange et al., Hormone contents in peripheral tissues after correct and
off-label use of growth promoting horm ones in cattle: effect of the implant
preparations Filaplix-H, Raglo, Synovex-H and Synovex Plus.
"In study 5, the impact of misuse and multip le dosing on residual hormone levels in
meat was determined. Dosing at up to 10 times the approved dose , resulted in an
increase in the tissue concentrations of some hormones in some tissues to value above
the MRL for those hormones for which Codex has established an MRL."226
"'Treatment with zeranol and testosterone propionate, even after multiple application,
does not cause any problems , as far as infringement of threshold levels is
concerned.'"227
"For oestradiol, the maximum increase ob served in any tissue was not greater than
proportional to the dose applied. Hence, ev en at 10-fold the approved dose, intake
would be well below the ADI. This would be offset by the fact that not all tissues had
such elevated levels, and the probability of consuming such high residue levels of a

222 Risk assessments performed by JECFA, the EC's European Medicines Agency ("EMEA") and the
FDA evaluate the use of veterinary drugs assuming that the drugs are administered according to good veterinary
practices. Were this not the case, it would be impossible to develop international food safety standards, i.e.,
there would be no benchmark against which safety evaluations could be conducted. Further, it is important to
note that any veterinary drug could be misused. If regulatory authorities based their evaluations against a
misuse standard, then there would be virtually no approvals of veterinary medicines. The evidence is clear that
there are a large number of veterinary drugs on the market in both the United States and the EC which were
approved assuming that they would be administered according to good veterinary practices, indicating that this
is the norm for such evaluations. It is curious that the EC has not used this standard in its evaluation of the six
hormones at issue in this dispute, assuming instead extreme misuse scenarios for each hormone.
223 Dr. Boisseau Responses (Question 51), p. 25.
224 Dr. Boobis Responses (Question 48), p. 42.
225 See Dr. Boobis Responses (Question 62), pp. 50-52 ("Multiple implanting, multiple dosing").
226 Dr. Boobis Responses (Question 62), p. 50. (Emphasis added).
227 Dr. Boobis Responses (Question 62), p. 50. (Emphasis added).

regular basis is minimal. It should also be noted that Codex did not specify an MRL
for oestradiol, as it was considered unnecessary."
228
2. Daxenberger et al., Detection of anabolic residues in misplaced implantation
sites in cattle.
"In the study on misplaced implantation sit es (Daxenberger et al, 2000), substantial
residual hormone was sometimes found at the implantation site when this was not as
recommended. However, for these findings to have significance for the consumer a
number of factors need to be considered. These include the likelihood of off-label
use of the hormones, the failure to det ect the implantation site, the use of the
implantation site for food use, the contributio n of the contaminated meat to the diet
and the frequency of such contamination. No data have been presented on the
prevalence of such significant contaminati on as a consequence of the veterinary use
of the hormones. Indeed, no evidence is presented that such misuse does occur with
the consequences suggested by the authors."229
3. Daxenberger et al., Detection of melengestrol acetate residues in plasma and
edible tissues of heifers.
"In studies on MGA (Daxenberger et al, 1999) tissue levels increased with dose, most
markedly in fat. Whilst in fat, there was a roughly proportional increase with dose, in
other tissues (muscle, kidney, liver) the fo ld-increase was appreciably less than the
fold-increase in dose. Using the values obt ained in the study of Daxenberger et al
(1999) at 10 times the maximum approved dose
, consumption of all four tissues
(liver, kidney, fat and muscle) at the JECF A levels (300 g muscle, 100 g liver, 50 g
kidney and 50 g fat per day) would result in a slight exceedance of the ADI (2.5 μg cf
1.8 μg). However, it should be noted that this would require all of the tissues to be
from animals treated with the high dose, a nd exposure would have to be over a
prolonged period of time. The probability that this would occur is extremely low."230
110. In summary, Dr. Boobis notes the following regarding the EC's research, including the
17 Studies:
There is little information in the scientific studies initiated by the EC since 1997 that
support the contention that they have identified important new gaps, insufficiencies
and contradictions in the scientific info rmation and knowledge on the hormones, and
that additional studies are necessary before the risks to health of consumption of meat
from treated animals can be assessed . Whilst additional information has been
obtained on a number of aspects of the hormones in question, this was often not
definitive, sometimes it was not relevant, in some instances it confirmed or expanded
on previous knowledge. The evidence obt ained did not indicate any additional
concern regarding the risk from exposure to residues of the hormones in meat from
cattle treated for growth promotion.231
111. Dr. De Brabander disagrees, noting that the mate rials put forward by the EC "call[ ] indeed
into question" the applicability of Codex standards. However, Dr. De Brabander presents no
scientific evidence in support of this conclusion. Dr. De Brabander cites to the "older" experiments

228 Dr. Boobis Responses (Question 62), p. 50. (Emphasis added).
229 Dr. Boobis Responses (Question 62), pp. 50-51. (Emphasis added).
230 Dr. Boobis Responses (Question 62), p. 51. (Emphasis added).
231 Dr. Boobis Responses (Question 62), p. 58. (Emphasis added).

on which JECFA relied in setting ADIs for the horm ones, but fails to provide any context for this
concern by noting any "newer" material that woul d support the conclusion that the "old" evidence is
no longer relevant. 232 Perhaps of greatest interest, Dr. De Brabander does not find support for his
conclusion in the numerous studies produced by th e EC in which extreme misuse scenarios were
created and contemplated. As noted by the United States in its Rebuttal Submission, and confirmed
by Dr. Boobis' analysis above, even in the artificial scenarios developed by EC scientists, in most
cases extreme misuse and overdosing of cattle with impl ants did not result in violative residue levels,
i.e., levels exceeding ADIs and MRLs. 233 In addition, Dr. De Brabander cites to concerns of animal
welfare and impact on the environment, neither of which has been argued by the EC in the course of
these proceedings. Finally, Dr. De Brabander claims that "most consumers aren't prepared to take this
risk."
234 Dr. De Brabander cites to no scientific eviden ce in support of this conclusion, which appears
to be little more than a personal opinion or policy statement.
(c) Conclusion
112. The experts' responses, insofar as they are ba sed on the scientific evidence relating to good
veterinary practices and misuse, confirm that the EC has failed to demonstrate that there is a risk to
human health from the misuse of growth promo ting hormones in the United States and that the
material put forward by the EC regarding misuse or abuse of the hormones at issue fails to call into
question Codex standards regarding the safety of me at from cattle treated with hormones for growth
promotion purposes. Therefore, the experts' res ponses demonstrate that the EC has failed to base its
import ban on meat from cattle treated with estradiol 17 β on a risk assessment, as appropriate to the
circumstances, within the meaning of Article 5.1 of the SPS Agreement, and has similarly failed to
satisfy Article 5.2's requirement that a risk ass essment take into account relevant processes and
production methods and relevant insp ection, sampling and testing methods. In addition, the experts'
responses demonstrate that the EC has not satisfi ed its obligation under Article 5.7 of the SPS
Agreement to base a provisional ban on available pe rtinent information. Finally, the experts'
responses confirm that the EC, by imposing an im port ban (whether permanent or temporary) on
imports of meat from cattle treated with hormones for growth promotion purposes has breached its
obligation to ensure that its sanitary and phytosan itary measures are not more trade-restrictive than
required to achieve its appropriate level of sanitary or phytosanitary protection within the meaning of
Article 5.6 of the SPS Agreement.
D. CONCLUSION
113. It is natural that in six sets of separate res ponses from the experts and three sets of responses
from international organizations there would be some differences in the responses provided.
However, upon analysis of their responses and evaluati on of the scientific evidence cited therein, it is
apparent that there are substantial areas of agre ement amongst the experts. As demonstrated above,
their responses are consistent with the following conclusions:
(1) There are certain necessary components or el ements of a risk assessment, and the EC
has failed to satisfy each of those elements in the Opinions upon which it based its
permanent ban on estradiol 17β.
(2) The scientific evidence does not support th e conclusion that any carcinogenic effects
of estradiol 17β are related to a mechanism other than hormonal activity.

232 See Dr. Boisseau Responses (Question 34), p. 19 ("th e quality and the number of the available data
are more important than the dates at which these data have been produced.")
233 See US Rebuttal Submission, paras. 54-66.
234 Dr. De Brabander Responses (Question 51), p. 18.

(3) The scientific evidence does not support the conclusion that estradiol 17 β is
genotoxic at levels found in residues in meat from cattle treated with growth
promoting hormones.
(4) The scientific evidence does not demonstrate that estradiol 17 β will have
carcinogenic or tumorigenic effects at con centrations found in residues in meat from
cattle treated with hormones for growth promotion purposes.
(5) The scientific evidence and informati on relating to the five provisionally-banned
hormones is sufficient to conduct an assessm ent of the risks to human health from
consumption of meat from cattle treated with any of the five hormones for growth
promotion purposes.
(6) The scientific evidence cited by the EC in its Opinions does not demonstrate that any
of the five provisionally-banned hormones has genotoxic potential or is carcinogenic
by a mechanism other than hormonal activity.
(7) The scientific materials produced and cite d by the EC (including the "17 Studies")
have not identified any gaps or insufficien cies in the scientific evidence such that
more study is necessary before the risk from consumption of meat from cattle treated
with the five provisionally-banned hormone s for growth promotion purposes can be
assessed.
(8) Each of the hormones has been used for growth promotion purposes in cattle and
evaluated for a sufficient period of time with no evidence of adverse effects to
adequately address any concern regarding long latency periods of cancer.
(9) Epidemiological studies cited by the EC do not identify a link between cancer and
residues of the six hormones in meat from cattle treated with the hormones for growth
promotion purposes.
(10) The EC has failed to demonstrate that meat from cattle treated with hormones for
growth promotion purposes poses a risk to sensitive populations.
(11) The EC has failed to demonstrate "other risks" to human health from consumption of
residues of the hormones in meat from cattle treated for growth promotion purposes,
such as effects on the immune system.
(12) The EC has failed to put forward evidence regarding or assessed the risk related to the
exposure of consumers to residues of any of the six hormones in meat from cattle
treated with the hormones for growth promotion purposes.
(13) JECFA's decision to set an ADI for the natural hormones did not mark a change in
JECFA's or Codex's conclusions as to the safety of the hormones when consumed as
residues in meat from cattle treated for growth promotion purposes.
(14) The EC has failed to demonstrate that ther e is a risk to human health from the misuse
of growth promoting hormones in the United States.
(15) The material put forward by the EC re garding misuse or abuse of the hormones at
issue fails to call into question Codex standards regarding the safety of meat from
cattle treated with hormones for growth promotion purposes.

ANNEX F-5

COMMENTS BY THE UNITED STATES TO THE COMMENTS
BY THE EUROPEAN COMMUNITIES ON THE REPLIES
OF THE SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC
TO QUESTIONS POSED BY THE PANEL

(12 July 2006)

A.
INTRODUCTION
1. The United States appreciates this opportunity to provide comments on the comments of the
European Communities ("EC") on the responses receiv ed from the six scientific experts and the three
international organizations selected by the Panel. The United States will first provide general
comments on the EC's comments and then provide specific remarks on individual comments offered
by the EC on the experts' and international organizations' responses.
B. GENERAL COMMENTS
1. Qualifications of experts
2. In several of its comments, the EC questions the credibility of two of the scientific experts
selected by the Panel, Drs. Boobis and Boisseau, and seeks to dismiss their responses based on an
alleged lack of qualification rather than a lack of scientific foundation or basis in the experts'
responses themselves. The United States notes that Drs. Boobis and Boisseau are more than qualified
to provide advice to the Panel on the subject matter at issue, the safety of meat and meat products
from cattle treated with hormones for growth prom otion purposes. This is evidenced by the high
quality of their responses to the Pa nel's questions, their extensive curriculum vitae, their nomination
by the Codex Alimentarius Commission ("Code x") and the Joint FAO/WHO Expert Committee on
Food Additives ("JECFA") to serve in the expert gro up, and the Panel's ultimate choice to seek their
advice as members of the expert group. This is also evidenced by the fact that the EC only seeks to
impugn the qualifications of the experts in scenario s where it has concluded their responses are not
favorable to its arguments.
1
3. In addition to seeking to dismiss expert opinions based on an alleged lack of qualification, the
EC also attempts to discard Dr. Boisseau's respons es to certain questions based on the fact that he
initially informed the Panel that he may not be in a position to respond to those questions. The fact
that Dr. Boisseau was unsure as to his ability to respond to certain questions is not a valid reason for
ignoring his ultimate responses to these questions. I ndeed, Dr. Boisseau's responses appear to be very
well-researched, and he has clearly put a great deal of effort into providing the Panel sound advice on
these issues. Further, the United States notes that this is another example of the EC attempting to
impugn the qualifications of an expert only where th at expert has offered answers or points of view
that do not support the EC's arguments. For example, the EC does not raise similar concerns
regarding Dr. De Brabander's respon ses to Panel Questions 44-48 and 50-51
 despite the fact that
Dr. De Brabander, in an April 24 , 2006 e-mail to the Panel noted, "I am an analytical chemist so I
could only provide adequate answer s to questions on residue analysis . That means Db question

1 See, e.g., EC Comments on the Experts' Responses (Questions 37 and 44), where the EC offers the
opinion of Dr. Boisseau, without qualification , in support of its position. Contrast to EC Comments on Panel
Question 2, where the EC notes, "[a]s the EC has pointed out during the selection procedure, Dr. Boisseau does
not possess any expertise on these substances, as he does not appear to have carried out any specific research on
these substances during his professional life." EC Comments on the Experts' Responses (Question 2), p. 2.

[2]7-35 and f question 49
."2 Despite this statement delimiting his experience to residue analysis,
Dr. De Brabander offers several responses on an entirely unrelated category: good veterinary
practices in the United States and Canada.
2. Scope of experts' responses and legal obligations under the SPS Agreement
4. As previously noted by the United States in its comments on the experts' responses, the role
of the scientific experts is a narrow one of provi ding a panel information, advice and opinions on
certain aspects of the matter that is the subject of a dispute. 3 Despite this fact, the EC has, in several
of its comments, complained that the experts shoul d have tempered their responses based on what the
EC believes are Members' legal obligations under the Agreement on the Application of Sanitary and
Phytosanitary Measures ("SPS Agreement"). For instance, in its comments on the experts' responses
to Panel Question 5, the EC argues, "the answers of all scientists do not take into account the legal
requirements of the SPS Agreement in this ar ea, as interpreted by the Appellate Body." 4 There is no
reason that the experts should have taken these require ments into account. Indeed, their mandate is to
provide the Panel with information and advice on scie ntific and technical issues, not to make legal
judgments regarding Members' measure s, such as whether a measure is based on a risk assessment or
satisfies the conditions for a provisional measure w ithin the meaning of the SPS Agreement. Such
judgments are reserved for the Panel.
5. In addition to confusing the role of experts in offering scientific advice to the Panel, the EC
also notes in its comments that several of the Panel' s questions concern aspects of risk assessment that
are "not legally binding" since they are not referenced in the text of the SPS Agreement. 5 The EC
appears to propose a very broad definition of what constitutes a risk assessment within the meaning of
Article 5.1 of the SPS Agreement. Rather than accepting that guidance from international
organizations such as JECFA and Codex provides important benchmarks for conducting a risk
assessment and for objectively evaluating whether a Member's risk assessment has engaged in an
adequate analysis of a risk, the EC instead proposes a notion of risk assessment devoid of any
apparent form. The EC's concept of what is or is not a risk assessment ignores the text of Article 5.1,
which states:
Members shall ensure that their sanitary or phytosanitary measures are based on an
assessment, as appropriate to the circumstances, of the risks to human, animal or
plant life and health, taking into account ri sk assessment techniques developed by the
relevant international organizations.6
6. The experts' responses clarify that there are a bundant examples of risk assessment techniques
developed by international organizations.7 Indeed, the original Hormones panel concluded that "even
though no formal decision has as yet been taken by Codex with respect to [s anitary] risk assessment
techniques, Codex, and more particularly JECFA, has a long-standing practice with respect to the
assessment of risks related to veterinary drug residues (including hormone residues)."
8 Such an
assessment "consists of the following steps: (i) hazard identification, (ii) hazard characterization, (iii)

2 E-mail of Dr. Hubert De Brabander to the Panel, April 24, 2006. (Emphasis added).
3 See US Comments on the Experts' Responses, Section B. See also Agreement on the Applications of
Sanitary and Phytosanitary Measures , Article 11.2; Understanding on Rules and Procedures Governing the
Settlement of Disputes, Article 13.
4 EC Comments on the Experts' Responses (Question 5), p. 4. (Emphasis in original).
5 See, e.g., EC Comments on the Experts' Responses (Questions 4 and 6).
6 SPS Agreement, Article 5.1. (Emphasis added).
7 See, e.g., Responses to Questions from the Panel of Dr. Alan Boobis ("Dr. Boobis Responses")
(Questions 3 and 4), pp. 10-11.
8 Panel Report, EC – Measures Concerning Mea t and Meat Products (Hormones) , adopted on 13
February 1998, WT/DS26/R ("Panel Report"), para. 8.103.

exposure assessment, and (iv) risk characterization." 9 The EC reiterates this conventional four-step
risk assessment procedure in its 1999 Opinion.10
7. The EC further attempts to blur the notion of what constitutes an appropriate risk assessment
for purposes of the SPS Agreement by repeatedly noti ng that the Appellate Body has concluded that
risk assessments may be either quantitative or qua litative. However, the EC's description of the
Appellate Body's conclusions is overly simplistic. Rather than finding, as the EC appears to argue,
that Members may simply conduct a qualitative risk assessment that is devoid of any structure,
necessary form or scientific rigor, 11 the Appellate Body simply determined that there is no
requirement that a risk assessment establish a minimum quantifiable magnitude or threshold level of
degree of risk.
12
8. In conclusion, the EC's interpretation is not supp orted by the text of Article 5.1, cited above
(either form of risk assessment must "tak[e] into account risk assessment techniques developed by the
relevant international organizations"), nor is it bolst ered by the responses of the experts, nor is it
supported by the conclusions reached by the Appellate Body. To the contrary, the experts agree that
qualitative risk assessments include the same core el ements as quantitative ri sk assessments, save for
some disagreement as to whether this incl udes a dose-response assessment in the hazard
characterization (second step) step of risk assessment. 13 Further, regardless of whether a risk
assessment is qualitative or quantita tive, the scientific conclusions set out in the assessment must
actually be supported by the underpinning sci entific evidence cited in the assessment. 14 The EC has
failed to demonstrate that it has accomplished this goal and the experts' responses confirm that it has
not.
3. Responses of the international organizations are not "adequate and legally sound"
9. The United States believes that the responses of the international organizations speak for
themselves, and that there is therefore no need to provide specific comments on these responses at this
point. The United States has provided specific comm ents on the international organization responses,
where appropriate, in its June 30, 2006 submission. The EC has presented no evidence to discount
any of the conclusions reached by the international organizations. The EC has, however, alleged in a
general comment that the responses from the interna tional organizations are not "adequate and legally
sound." The United States notes that the EC has prov ided no evidence in support of this speculation
or purported standard, and that the input of these organizations, and similar international standard
setting bodies has been sought in other SPS disputes, including the original Hormones dispute.
Indeed, where a dispute involves the analysis of a Member's measure that diverges from relevant
international standards (such as here), it is perfec tly comprehensible why a panel would proceed with
its evaluation by seeking input from international organizations.

9 Panel Report, para. 8.103.
10 See "Opinion of the Scientific Committee on Veterinary Measures Relating to Public Health –
Assessment of Potential Risks to Human Health from Hormone Residues in Bovine Meat and Meat Products",
30 April 1999 ("1999 Opinion"), p. 70. (Exhibit US-4).
11 See, e.g., EC Comments on the Experts' Responses (Question 16).
12 Appellate Body Report, EC – Measures Concerning Meat and Meat Products (Hormones) , adopted
on 13 February 1998, WT/DS26/AB/R ("Appellate Body Report"), paras. 186, 253(j).
13 See Responses of the Experts' to Panel Question 11.
14 See Panel Report, Japan – Measures Affecting the Importation of Apples: Recourse to Article 21.5 of
the DSU by the United States , WT/DS245/RW, adopted July 20, 2005, paras. 8.145-8.146 (" Japan – Apples
(21.5)") (finding that "[s]ince the scientific evidence relied upon by Japan does not support the conclusions
reached by Japan in its 2004 PRA, we conclude that the 2004 PRA is not an assessment, as appropriate to the
circumstances, of the risks to plant life or health, within the meaning of Article 5.1 of the SPS Agreement.")

C. S
PECIFIC COMMENTS ON EXPERTS' RESPONSES
10. Question 1 : The EC proposes several changes to Dr. Boisseau's response that are
unsupported by scientific evidence. For example, the EC attempts to insinuate misuse scenarios
(implant into animal's dewlap 15; new recommendations for use of trenbolone acetate 16) into the basic
definitions of the hormones. In addition, the EC notes that "Dr. Boisseau's reply does not consider
any progress in toxicological knowledge concerning these hormones, and in particular estradiol, since
the 70th and 80th JECFA reports." However, the last meeting of JECFA was the 67th. 17 The "70th
and 80th" JECFA reports do not exist, so it is unc lear how Dr. Boisseau could have possibly taken
their findings into account. The EC provides no comments on the response of Dr. Boobis, who has
drafted detailed and well-documented definitions for the six hormones. 18 The United States notes that
none of the experts' responses appear to alter the basic definitions of the six hormones relied on by the
original Hormones panel.19
11. Question 2: The EC attempts to dismiss Dr. Boisseau's comments based on its view of his
qualifications. The EC provides no scientific ev idence or argument that discounts Dr. Boisseau's
advice.20
12. Question 3 : Contrary to the EC's suggestion, th e experts and international organizations
confirm that there are numerous international doc uments and guidance materials relevant to the
assessment of veterinary drugs in food.21
13. The EC tries to dismiss as irrelevant the work on the hormones conducted by the Committee
on Veterinary Medicinal Products ("CVMP") and the conclusions reached by that body to the analysis
at hand. However, as noted by the United States in its Rebuttal Submission and confirmed by the
experts' responses, the CVMP analysis of estradiol 17 β and progesterone indicates that it was
concerned primarily with hazards and risks ar ising from exogenous exposure of consumers to
hormones and the possible need, in light of recent data, to perform new risk assessments for estradiol
and progesterone.22
14. The CVMP concluded that new risk assessments for estradiol 17 β and progesterone were not
necessary and that certain residue levels of the hormones are safe based on some very basic
conclusions on these hormones ( e.g., lack of genotoxicity, carcinogenic action only after prolonged

15 In a production setting, placing an implant into the dewlap (hanging fold of skin under the neck)
would be highly impractical and potentially dangerous to the handler. It would also likely result in slower, less
effective absorption of the hormone due to the fatty tissu e in the dewlap (versus the ear, which contains very
little fat and is highly vascularized resulting in rapid and effective absorption of hormone from the implant).
The suggestion that implants are deliberately misplaced into the dewlap appears to be speculation.
16 The United States is unaware of any new reco mmendations for trenbolone acetate use and would be
interested in the EC's source of this information. It is true that periodic reimplan tation of cattle with growth
promoting implants is common practice. This is done because each implant has a finite "payout period" during
which the implant releases enough hormone to stimulate growth. The timing of reimplantation is carefully
scheduled to maintain an effective concentration of hormone in the animal. It should be emphasized that
reimplantation of cattle, because it is done near the end of the implant payout period, does not result in
concentrations of growth-promoting hormones in meat that exceed the tolerances or MRLs.
17 67th Meeting, June 20-29, 2006 (Rome) (http://www.who.int/ipcs/food/jecfa/data/en/index.html).
18 See Dr. Boobis Responses (Question 1), pp. 1-5.
19 See, e.g., Panel Report, paras. 2.6-2.9.
20 See Section B.1 above.
21 See US Comments on the Experts' Responses, para. 13, citing Codex Responses to Questions from
the Panel ("Codex Responses") (Questions 3 and 4), pp. 4-5; JECFA Responses to Questions from the Panel
("JECFA Responses") (Question 3), pp. 2-3; Dr. Boobis Responses (Question 3), pp. 10-11.
22 See US Rebuttal Submission, fn. 57. See Responses to Questions from the Panel of Dr. Jacques
Boisseau ("Dr. Boisseau Responses") (Question 13), pp. 9-11; Dr. Boobis Responses (Question 12), p. 17.

exposure at high exposure levels) which contradict fundamental – but unsup ported – conclusions set
out in the EC's Opinions. It should be emphasized that the basic scientific information considered by
the CVMP with respect to the ri sks of therapeutic and zootechnical use of hormones was the same
information used by the SCVPH to assess the risks of hormones used for growth promotion, but the
CVMP and SCVPH reached very different conclu sions. Thus the CVMP evaluation is indeed
relevant to this dispute and an analysis of the EC 's Opinions, despite the EC's attempts to distance
itself from the evaluation.23
15. Question 4: The EC dismisses the responses of two of the scientific experts (Drs. Boisseau
and Boobis) and the international organizations by arguing that their responses are not limited to
"legally binding" assessment techniques w ithin the meaning of the SPS Agreement. 24 As noted
above, it is not appropriate for the experts to comment on the legal nature of any aspect of the dispute.
Further, the EC simply avers that the relevant guidelines or principles cited by the experts are not
"legally binding" for purposes of analysis of a measure under the SPS Agreement, without providing
an explanation of why this is so. Contrary to th e EC's suggestion, the responses of Drs. Boisseau and
Boobis, JECFA and Codex indicate that there are in fact "risk assessment techniques developed by the
relevant international organizations" within the meaning of Article 5.1 of the SPS Agreement that are
pertinent to an analysis of the EC's Opinions, in particular to an analysis of whether the EC has
conducted a risk assessment for the pe rmanently-banned hormone, estradiol 17 β.25 Indeed, the EC
itself has recognized this fact. 26 In addition, the EC provides no explanation to support its allegation
that its risk analysis techniques are "much more advanced than JECFA" nor does it explain what
relevance, if any, this conclusion has to these proceedings.
16. Question 5 : The EC claims that the experts' resp onses "do not take into account the legal
requirements of the SPS Agreement." As noted a bove, it is not appropriate for the experts to
comment on the legal nature of any aspect of the dispute. In addition, the EC attempts to contradict

23 See "Report of the CVMP on the Safety Evaluation of Steroidal Sex Hormones in particular for 17 β-
Oestradiol, Progesterone, Alternogest, Flugeston e acetate and Norgestomet in the Light of New
Data/Information made available by the European Commission", Committee for Veterinary Medicinal Products
(EMEA/CVMP/885/99) ("1999 CVMP Report"), p. 11 ("General Considerations") (Exhibit US-13).
24 As noted in Section B.2 above, the experts are not in a position to determine what is or is not "legally
binding" for purposes of the SPS Agr eement. While experts' advice and responses may be discounted because,
e.g., they lack a scientific foundation or are not base d on scientific evidence, they may not be summarily
dismissed because a party believes that they touch on topics that are not "legally binding."
25 See Dr. Boobis Responses (Question 4), p. 11 ("[T]here are guiding principles [for risk assessment]
in place, that have been in existe nce since before 1999." "Specific guidance was [] developed by JECFA and
adopted by Codex."); Responses to Questions from the Panel of Dr. Jacques Boisseau ("Dr. Boisseau
Responses") (Question 4), p. 2 (The rationale for risk assessment "has been internationally harmonised through
scientific conferences and it is possible to say that there was an international non written agreement on this
rationale."); JECFA Responses to Questions from the Panel ("JECFA Responses") (Question 4), p. 2 (citing
back to its answer to Panel Question 3, in response to which it provide numerous citations to guidance on risk
assessment techniques); Codex Responses to Questions from the Panel (Question 4), p. 5. See Panel Report,
para. 8.103.
26 See 1999 Opinion, p. 70. ("Executive Summary") ("Conventionally, risk assessment is structured to
address independently the intrinsic properties of the co mpound under consideration (hazard identification), the
evaluation of the nature of effects in terms of a dose-response relationship (h azard characterization), the
estimate of the dose/concentration of a compound in the daily diet (exposure a ssessment) resulting in the
incidence and severity of potential adverse effects.") This final evaluation would be what is generally referred
to as "risk characterization." (Exhibit US-4). This is further evidenced by the fact that the EC has argued in
these proceedings that it has completed the four steps of a risk assessment. See EC Comments on the Experts'
Responses (Question 14) ("it is obvious that [the SCVPH] has followed the four steps of risk assessment when it
carried out its qualitative risk assessment.")

the experts' responses with its own opinion, which appears to be of little relevance to the Panel's
question, of how Codex and JECFA interact but provides no evidence to support this opinion.
27
17. Question 6 : The EC dismisses the responses of the scientific experts and international
organizations by arguing that these responses are not limited to "legally binding" risk assessment
techniques within the meaning of the SPS Agreement. 28 The EC simply avers that the relevant
guidelines or principles cited by the experts are not "legally binding" for purposes of analysis of a
measure under the SPS Agreement, without providing an explanation of why this is so other than an
inapt citation to the Hormones Appellate Body Report discussing the distinction between "risk
assessment" and "risk management." Contrary to the EC's suggestion, the experts (Drs. Boisseau,
Boobis and Guttenplan) and JECFA confirm that there are four internationally-recognized steps to a
risk assessment (hazard identification; hazard characterization; exposure assessment; risk
characterization) and that these steps are in fact "risk assessment techniques developed by the relevant
international organizations" within the meaning of Article 5.1 of the SPS Agreement that are pertinent
to an analysis of the EC's Opinions, in particular to an analysis of whether the EC has conducted a risk
assessment for the permanently-banned hormone, estradiol 17 β.29 In addition, the EC's comments
appear to ignore the several cond itions imposed on risk assessments by, e.g., Articles 5.2 and 5.3 of
the SPS Agreement.
18. The EC also notes that Drs. Boobis and Boisseau have "discard[ed] the relevance of some
residues that are not pharmacologically active but ma y interfere with normal metabolic functioning of
cells given their intrinsic chemical potential to form covalent adducts to biomolecules." However, it
is unclear which residues the EC is referring to and the EC provides no scientific evidence indicating
that such protein adducts actually: (1) form in vivo following consumption of beef from cattle treated
with growth-promoting hormones, or (2) interfere with metabolic functioning of cells.
19. Question 7: The EC disagrees with the experts' r esponses because, according to the EC, "the
accumulation of so much new peer-reviewed eviden ce since 1999 establishes clearly that oestradiol-
17β is a direct carcinogen and does not act only through hormonal receptors." This appears to be the
EC's opinion alone. Despite havi ng reviewed the materials relied on by the EC in drafting its
Opinions and the several other studies put forward by the EC in defense of its permanent ban on
estradiol 17 β, the experts do not share the EC's conclusion on the "clear" carcinogenic action of
estradiol 17β.30
20. The EC cites to a study by Bhat et al. (not cited in the EC's Opinions) as demonstrating "the
necessary role of catechols of estradiol ... in indu ction of oxidative stress to induce tumors."

27 See EC Comments on the Experts' Responses (Question 5), p. 4 (in which the EC opines, without
evidentiary support, that "[i]ndeed, JECFA's reports and monographs are drafted in such a way as to leave
practically no room to the members of the Codex Alimentarius Commission to decide on the appropriate level of
health protection and the risk management options that are available to its members.")
28 As noted in Section B.2 above, the experts are not in a position to determine what is, or is not
"legally binding" for purposes of the SPS Agreement.
29 Recall that the form of the EC's "risk assessment" (Articles 5.1 and 5.2 and Annex A, paragraph 4 of
the SPS Agreement) is but one element of the analysis of the EC's measur e (permanent ban on meat and meat
products from cattle treated with estradiol 17 β for growth promotion purposes). The United States has also
argued that the EC's ban is not sufficiently warranted or reasonably supported by the EC's "risk assessment", and
is therefore not "based" on a risk assessment, as appropriate to the circumstances, within the meaning of Articles
5.1 and 5.2 of the SPS Agreement. See also Panel Report, para. 8.103.
30 See, e.g., Experts' Responses to Questions 13 and 16-18. The United States notes that the EC cites to
several studies which were not previously submitted to th e Panel in support of its comments in Question 7 ("[a]
number of publications, some of which have been submitted by the [EC] to this Panel, have explored the
threshold concept and the activity of hormones at very low doses.") The United States notes that these
proceedings are well beyond the deadline for submission of "new" scientific evidence.

However, review of the Bhat study reveals that it did not identify catechol estrogens as the cause of
tumor formation; in fact, catechol estrogens are not even measured in the st udy. Instead, the Bhat
study demonstrates that tumor formation in the Syrian hamster kidney following treatment with
estradiol 17 β is associated with oxidative stress. A lthough oxidative stress can be generated by
metabolic recycling between catec hol estrogens and their corresponding quinones, it is not unique to
catechol estrogens and occurs in a variety of cell types in response to numerous natural and xenobiotic
stimuli. Therefore, the Bhat study does not pr ovide direct evidence of the "necessary role of
catechols" in tumorigenesis in the Syrian hamster kidney.
21. Further, the Bhat study involves the treatment of hamsters with high levels of estradiol 17 β
for an extended period of time (7 months). Therefore, the possibility that estradiol 17 β stimulated the
growth of tumors via recept or-mediated, hormonal effects
 cannot be ruled out. In fact, Bhat
recognizes this possibility, concluding, "[t]he hormonal effects of estrogens may promote the
development of tumors." Finally, it is well-documen ted that the Syrian hamster kidney is particularly
susceptible to estrogen-induced kidney tumors due to a species-specific shift in the pattern of estradiol
17β metabolism to favor production of 4-OH catechol estrogen. 31 Therefore, whether this model is
appropriate to study potential effects of estradiol 17 β from dietary sources on human health is very
questionable.32
22. Question 8 : The EC contrasts the experts' advi ce against its own unsupported scientific
conclusions. For instance, the EC complains that "the evidence used by JE CFA in the evaluation of
these hormones is too old (dating from the 1970s) a nd has been obtained with outdated detection
methods [ sic] to be relevant today." This blanket c onclusion is simply incorrect. For instance,
JECFA based its conclusion to set ADIs for estradiol 17 β, progesterone and testosterone on
"[s]ufficient new data from observations in humans ... which were suitable to derive ADIs."33 Further,
the EC's argument presumes that older data is bad or incorrect data. As we have learned from the

31 This point appears to be confirmed by Dr. Guttenplan, who notes that there is only one animal model
"that is well characterized and this is in the hamster kidne y. As kidney is not a known target of estradiol in
humans the extrapolation to humans is uncertain ." Responses to Questions from the Panel of Dr. Joseph
Guttenplan ("Dr. Guttenplan Responses") (Question 14), p. 4. (Emphasis added)
32 The EC also cites to two papers by Russo et al., neither of which stand for the conclusion drawn
from the papers by the EC. The first paper, Russo et al., Estradiol is carcinogenic in human breast epithelial
cells, was: (1) performed with an immortalized cell line that does not reflect the physiology of normal breast
epithelial cells; (2) not designed to measure catechol estrogens; and (3) provides no evidence for the "necessary
role of catechols" in breast cancer nor genotoxic effects elicited by catechol estrogens in vivo. The second
paper, Russo et al., Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells, appears
to have used estrogen doses much higher than those that might occur in vivo. In addition, this paper reports that
MCF-10F cells have estrogen recepto rs, whereas the first Russo paper concludes that MCF-10F cells do not
express estrogen receptors. Without an explanation for this inconsistency, the potential significance and validity
of these two studies – the first study in particular – is highly questionable.
33 JECFA Responses (Question 20), p. 16. See, e.g., 1999 CVMP Report, pp. 8-9, citing the 52 nd
JECFA Report and the 1999 Report of the Interna tional Agency for Research on Cancer: "[a]s already
demonstrated earlier, the recent studies show that hormonal carcinogens in humans and experimental animals
are characterized by (i) tumorigenic ac tion typically in various endocrine responsive organs and/or tissues, and
(ii) the need for a prolonged exposure to high concentrations before tumorigenic effects become apparent. The
studies are also consistent with the notion of hormone-receptor mediated increase in cell division and
proliferation in epithelial cells of the target tissues. This points to a non-genotoxic mode of action
, which is in
concurrence with (i) the negative results of both earlier an d recently performed genotoxicity tests, and (ii) the
absence of structural alerts for genotoxicity in the molecule. As cited in the introduction, the recent extensive
reviews by IARC and JECFA also confirmed that the tumorigenic action of hormones, in particular
17β-oestradiol, in animals and man are the consequence of the receptor-mediated, cell division stimulating
activity of these compounds in somatic target cells, and that the potential genotoxic properties of the compounds
would not be expressed in vivo and/or not play a role in the tumorigenic activity."

experts' responses, this is not the case, but rather it is the quality and quantity of data that is
essential.
34
23. The EC argues that "JECFA did not take th e low endogenous levels and thus the high
sensitivity of children into account." Again, this c onclusion is incorrect. As noted by the experts,
JECFA did in fact take sensitive populations into account in its use of safety factors. 35 The EC also
opines that use of hormones in oral contraceptiv es and hormone replacement therapy "demonstrates
that estradiol and progesterone are bioavailable through the oral route." It is true that estradiol 17 β
and progesterone are administered orally for some indications. However, because their bioavailability
is so low, very high doses are required to elic it the desired therapeutic effect. For example,
therapeutic doses of estradiol 17β for oral administration range from 0.5 - 4.0 milligrams, 36 or 10,000
- 40,000 times higher than the 50 ng. derived from eating beef from cattle treated with estradiol 17 β
for growth promotion purposes. In addition to high doses, orally administered estradiol 17 β a n d
progesterone are also manufactured as micronized fo rmulations (particle size < 10 microns) to further
increase bioavailability. Even after micronization, the bioavailability of a 2 mg dose of estradiol 17 β
is still only about 5%. Lastly, synthetic estrogens used in these treatments have significantly higher
oral bioavailability compared to the residues of the natural hormone estradiol 17β in meat from treated
cattle.37
24. Question 9: The EC disagrees with the experts' r esponses because, according to the EC, "it is
today generally accepted that some of these hormones are genotoxic and can cause cancer directly."
Although the EC contends that this is the case (and h as so concluded in its Opinions), and argues that
low doses of the hormones (particularly estradiol 17 β) would have a genotoxic effect, it has not
supported this conclusion with scientific evidence. The experts' responses, the continuing use of the
hormones in cattle for multiple purposes around the world (including in the EC itself), and the
intensive study of the hormones by JECFA, Codex and the EC's own CVMP are clear evidence that
the genotoxicity of the hormones, particularly at th e low levels found in residues in meat from treated
cattle, is not "generally accepted."
25. Further, the experts have confirmed that the decision by JECFA to set ADIs for the hormones
in 1999 did not mark a change in its conclusion regarding the safety of the natural hormones. In short,
as noted in the US Comments, the experts have c onfirmed that JECFA will only allocate an ADI for a
food additive or veterinary drug if the scientific database is complete, unless it can adopt default
assumptions that would if anything lead to a more conservative risk assessment than would be the
case otherwise.
38 That database was sufficiently complete for the six hormones at issue in this
dispute. The EC's failure to support its conclusi ons with the scientific evidence it relied upon in its

34 See Dr. Boisseau Responses (Question 34), p. 19 ("the quality and the number of the available data
are more important than the dates at which these data have been produced.")
35 See Dr. Boobis Responses (Question 42), p. 39 ("[i]n keeping with its risk assessment principles, the
ADI established by JECFA would have been designed to protect all segments of the population, including
prepubertal children.") See Dr. Boisseau Responses (Question 41), p. 22.
36 See US Department of Health and Human Services Report on Carcinogens, Eleventh Edition,
"Estrogens, Steroidal" ("2002 US Report on Carcinogens"). (Exhibit US-26)
37 For example, the bioavailability of ethinyl estradiol - the synthetic estrogen contained in combination
oral contraceptives - is 55%. Fother by K. Bioavailability of orally administered sex steroids used in oral
contraception and hormone replacement therapy. Contrace ption 1996; 54: 59-69 (cite d by Dr. Boobis in his
responses to Questions 20 an d 40).This is the reason wh y, e.g., oral contraceptives are not made from estradiol
17ß, but instead contain a synthetic estrogen (ethinyl estradiol) which is much more orally-bioavailable than
estradiol 17ß.
38 Dr. Boobis Responses (Question 9), p. 15; see Dr. Boisseau Responses (Question 9), p. 7 ("[t]he
Canadian statement stipulating that 'it is recognized that JECFA only allocates an ADI for a food additive or a
veterinary drug under review when JECFA considers that its scientific data base is complete and that there is no
outstanding scientific issue' is correct."); JECFA Responses (Question 11), p. 10.

Opinions demonstrates that those Opinions are not risk assessments, as appropriate to the
circumstances, within the meaning of Article 5.1 of the SPS Agreement. Nor do the Opinions provide
"available pertinent information" for a provisional me asure within the meaning of Article 5.7 of the
SPS Agreement.
26. Question 10: The EC argues that JECFA has a na rrow mandate because it has not examined
the likelihood of misuse or abuse of the hormones. As noted by the United States in its comments on
the experts' responses, it would be extremely diffi cult for regulatory or standard-setting bodies to
develop international food safety standards based on the assumption of misuse. Any veterinary drug
can be misused, and if regulatory authorities base th eir evaluations against a misuse standard, then
there would be virtually no approva ls of veterinary medicines. A large number of veterinary drugs
marketed around the world have been approved assum ing that they would be administered according
to good veterinary practices, indicating that this is the norm for such evaluations. It is therefore
curious that the EC has not used th is standard in its evaluation of the six hormones at issue in this
dispute, assuming instead extreme misuse scenarios for each hormone.39
27. Further, the United States notes that the experts have confirmed that the EC itself has failed to
properly examine the likelihood of misuse or abu se of the hormones, as, once it decided to make
misuse a mainstay of its analysis, it was obligated to do pursuant to Articles 5.1 and 5.2 of the SPS
Agreement.40 Finally, if misuse of the hormones is the EC's primary concern and not the safety of the
hormones at levels actually found in residues in meat from treated cattle, then the EC, by imposing an
import ban (whether permanent or temporary) on m eat from cattle treated with hormones for growth
promotion purposes has breached its obligation to ensu re that its sanitary and phytosanitary measures
are not more trade-restrictive than required to achieve its appropriate level of sanitary or phytosanitary
protection within the meaning of Article 5.6 of the SPS Agreement.
28. Question 11: The EC disagrees with two of the experts' responses (Drs. Boisseau and Boobis)
relating to the necessary components of a qualitativ e risk assessment because, according to the EC,
the Appellate Body has determined "that a qualitative risk assessment is equa lly acceptable under the
SPS Agreement and that it does not require the sa me type of analysis as a quantitative risk
assessment." The EC's argument is a non sequitur. Nowhere does the Appellate Body determine that,
just because a Member need not identify a "certain magnitude or threshold level of risk", that the
Member's risk assessment may be devoid of form or scientific rigor. Neither did the Appellate Body
grant Members license to assert scientific conclusion s in their risk assessments that are unsupported
by the scientific evidence.41 Nor does the Appellate Body stipul ate what form a risk assessment must
take. Rather, Members must conduct a risk assessm ent within the meaning of Article 5 and Annex A

39 See US Comments on the Experts' Responses, fn. 222.
40 See Dr. Boobis Responses (Question 62), p. 58 ("[t]he evidence obtained did not indicate any
additional concern regarding the risk from exposure to residues of the hormones in meat from cattle treated for
growth promotion.") See Dr. Boobis Responses (Question 48), p. 42 (the EC has made "no attempt to evaluate
the risks" from misuse, either in its Opinions or in un derlying studies); Dr. Boisseau Responses (Question 51),
p. 25 ("the [EC] did not conduct a quantitative risk assessment from growth promoters, [and that] it is not
possible to say the scientific evidence referred to by th e [EC] assesses the risk to human health from residues
resulting from these misuses/abuses.") See Appellate Body Report, paras 205-207.
41 This fact has been subsequently confirmed by the compliance panel in the Japan – Apples dispute,
which found that the scientific conclusions reached by a Member in its risk assessment must actually be
supported by the scientific evidence relied on in the risk assessment. See Panel Report, Japan – Apples (21.5) ,
para. 8.145 (finding that "[s]ince the scientific evidence relied upon by Japan does not support the conclusions
reached by Japan in its 2004 PRA, we conclude that the 2004 PRA is not an assessment, as appropriate to the
circumstances, of the risks to plant life or health, within the meaning of Article 5.1 of the SPS Agreement.")

of the SPS Agreement. The experts responses are ther efore very informative in terms of what does or
does not constitute a qualitative risk assessment.
42
29. The EC also notes that "[i]nterestingly, the US EPA uses no-threshold models for
non-genotoxic chemicals, such as dioxins and PCBs, due to a combination of very long half-lives and
activity at very low doses." However, the EC's re ference to EPA's assessment of dioxin illustrates the
stark contrast between the EC's analysis of estradiol 17 β and the standard paradigm for risk
assessment. EPA's assessment of dioxin did not so lely rely on generic arguments of additivity to
background as the EC proposes here, but instead reviewed in great depth studies which provided
insight into the appropriate approach to extrapol ation from low doses to likely exposure levels. The
EC's analysis lacks a comparable assessment.
30. Question 12
: The EC argues that the responses of Drs. Boisseau and Boobis are incorrect
"because of their extremely narrow understanding of the concept of scientific uncertainty." In support
of this argument, the EC contends that both Dr. Boisseau and Dr. Boobis have inappropriately relied
on the safety factors employed by JECFA in its risk assessments. According to the EC, "there is now
almost universal agreement that this approach [ i.e., JECFA's use of safety factors] is not scientifically
correct." The EC provides no scientific evidence in s upport of this conclusion. Further, it is unclear
how there can be "universal agreement" that JECFA's use of safety factors is "not scientifically
correct" when the very two experts asked by the Pa nel to speak to this issue believe that JECFA's
approach is scientifically correct
.43
31. The EC also cites to the 2002 US Report on Ca rcinogens as "contradict[ing] the allegations
made by the United States ... in these proceedings, which appears [sic] to be supported by Dr. Boobis,
that the additional burden of residues coming from ea ting hormone-treated meat is so small that it
would make no difference, compared to the level of endogenous production." Contrary to the EC's
claim, in this dispute the US has accepted that concentrations of estradiol 17 β may be slightly higher
in edible tissues following treatment of cattle with estradiol 17 β to promote growth. 44 The United
States has simply argued, and demonstrated with evidence, that residue levels of hormones in meat
from treated cattle would be within the physiological range of residue levels in meat from untreated
cattle.45 This position is entirely consistent with the statement quoted by the EC from the 2002 Report
on Carcinogens.
32. The more complicated question posed to the experts was whether these marginally increased
amounts of estradiol 17 β are sufficient to elicit effects in the human consumer. As noted in the US

42 See, e.g., Dr. Boobis Responses (Question 11), p. 16.
43 For a discussion on sensitive populations, see US Comments on the Experts' Responses, Section
C.4(c)
44 See US First Written Submission, para. 51 ("Further, concentrations of estradiol 17 β in meat from
treated cattle do not vary significantly from concentrations in untreated cattle, i.e., residue levels in meat from
hormone-treated cattle are well within the physiological range of residue levels in untreated cattle. While tissue
concentrations of estradiol 17 β in treated cattle may be slightly higher than those in untreated cattle , this
increase is much smaller than the large variations observed in (reproductively) cycling and pregnant cattle and is
thus well within the range of naturally observed levels.") (Emphasis added).
45 Indeed, the experts agree with the US statement generally, but disagree as to the number of pregnant
cattle actually entering the human food chain. But see 2005 Draft Report of the Veterinary Products Committee,
Risks Associated with the Use of Hormonal Substances in Food-Producing Animals, § 1.6 ("2005 U.K. Report")
(Exhibit US-20) ("In addition, a proportion of cows/heifers entering the food chain are pregnant. Meat from
these individuals can also contain higher levels of oestrogen produced by the foeto-placental unit. When the
predicted removal of the ban on the inclusion of meat from cattle over 30 months into the food chain occurs,
approximately 25% of cull cows entering the food chain are likely to be pregnant (Singleton and Dobson, 1995)

Meat from these animals will add signifi cantly to the oestrogen concentrations currently entering the food chain
from this source.")

Rebuttal Submission, the 2002 Report on Carcinogens indicates that they are not, concluding, "[t]he
evidence is strong that estrogen carcinogenesis is mediated through activation of the estrogen
receptor", in other words, by the much higher con centrations of estrogens necessary to elicit a
hormonal effect. Not, as the EC appears to insinua te, by concentrations found in meat products from
cattle treated with hormones for growth promotion purposes.46
33. As noted by the United States in its Rebuttal Submission, the Report on Carcinogens'
conclusion that estrogens are "known to be human carcinogens" 47 is unexceptional when applied to
estrogens generally, as it is in the cited Report. 48 As noted in the US First Written Submission, there
have been a number of epidemiological tests focu sed on women and the use of hormone replacement
therapies and oral contraception, both of which contain estrogens. 49 The Report on Carcinogens takes
these studies into account in its analysis, as well as the conclusions of the 1999 Report of the
International Agency for Research on Cancer ("IARC"). 50 JECFA took these same studies into
account in 1999, noting the "[e]pidemiological studies on women who took estrogens alone or in
combination with progesterone and androgens, showed that the risks for cancers at most sites were
unaffected; however, the risks for cancers of the endometrium and breast were increased."
51
However, it attributed these effects to the "hormonal effects of estrogens", i.e., to levels of estradiol
17β or other estrogens high enough to ha ve a hormonal effect on the consumer. 52 This is one of the
reasons that JECFA determined that levels of estradiol 17 β found in meat from cattle treated with the
hormone for growth promotion purposes according to good veterinary practices (levels exponentially
lower than those causing hormonal effects) are safe.
34. The EC also notes that "neither Dr. Boobis nor Dr. Boisseau mention the fact that the IARC
has classified oestradiol-17 β in Group 1 as carcinogenic to humans because there is sufficient
evidence of carcinogenicity and progesterone and testosterone in Group 2B as possibly carcinogenic
to humans." However, the fact that Drs. Boobis and Boisseau have not cited to IARC is not at all
surprising in light of the fact that IARC's conclu sions do not relate to the levels of any of these
hormones found in meat from cattle treated for growth promotion purposes (the subject of this
dispute). The EC's CVMP, in concluding that neither estradiol 17 β nor progesterone are genotoxic,
studied the 1999 IARC Report referred to by the EC in its comments. The CVMP concluded: "the
recent extensive reviews by IARC and JECFA also confirmed that the tumorigenic action of
hormones, in particular 17 β-oestradiol, in animals and man ar e the consequence of the receptor-
mediated, cell division stimulating activity of these compounds in somatic target cells, and that
the potential genotoxic properties of the compou nds would not be expressed in vivo and/or not
play a role in the tumorigenic activity ."53 Therefore, if anything, Drs. Boisseau and Boobis could

46 See 2002 Report on Carcinogens, p.1. (Emphasis added). Note also that the Report on Carcinogens
applies to estrogens generally. ("This listing of steroida l estrogens ... applies to all chemicals of this steroid
class.") (Exhibit US-26). See US Rebuttal Submission, paras. 38-40.
47 Replies to Questions from the Panel after the First Substantive Meeting by European Communities,
paras. 98-99.
48 See 2002 Report on Carcinogens, p.1 ("This listing of steroidal estrogens ... applies to all chemicals
of this steroid class.") (Exhibit US-26). Indeed, the 1987 Report of the IARC reached a similar conclusion
regarding estrogens generally, but the Hormones panel determined that this conclusion had been taken into
account by the relevant JECFA safety assessments addressing the relevant risk – that from estradiol 17β residues
in meat from cattle treated with the hormone for growth promotion acco rding to good veterinary practices. See
Panel Report, para. 8.129.
49 See US First Written Submission, paras. 56, 69, 127, 146.
50 See 2002 Report on Carcinogens, p.1. (Exhibit US-26).
51 52nd JECFA Report (2000), p. 60. (Exhibit US-5).
52 52nd JECFA Report (2000), p. 60. (Exhibit US-5).
53 1999 CVMP Report, pp. 8-9 (Exhibit US-5), citing the 52 nd JECFA Report and the 1999 Report of
the International Agency for Research on Cancer. (Emphasis added). See also 2005 U.K. Report, § 1.5.1,

have cited to IARC in support of the conclusion that any effects of estradiol 17 β would result from
levels of the hormone causing hormonal effects, ra ther than the exponentially smaller amounts found
in residues in meat from treated cattle.
35. Finally, as noted in paragraphs 13-14 above, desp ite the EC's statements to the contrary, the
conclusions reached by the EC's CVMP on the natura l hormones are indeed relevant to this dispute
because they relate to the fundamental action of th e hormones. At levels lower than those causing a
hormonal effect, hormones such as estradiol 17 β and progesterone, whether used for growth
promotion, or zootechnical and therapeutic purposes ar e either genotoxic or they are not regardless of
whether they are used for growth promotion, zootechnical or therapeutic purposes. The CVMP
concluded that they are not.
36. Question 13
: The EC attempts to discount the advi ce of Drs. Boisseau (who concludes that
"the EC risk assessment did not supp ort that residues of oestradiol-17 β, despite the genotoxic
potential of this hormone, can initiate and promot e tumours in humans") and Boobis (who concludes
that "[t]he EC has not identified the potential fo r adverse effects on human health of residues of
oestradiol found in meat from treated cattle. This is because the analysis undertaken was focused
primarily on hazard identification") by noting that JECFA concluded that "the carcinogenicity of
oestradiol-17β is most probably a result of its interacti on with hormone receptors." The EC's citation
to JECFA is puzzling in light of the fact: (1) that JECFA determined that the natural hormones had
not been shown to be genotoxic in vivo, and (2) the negative implication of JECFA's conclusion
above is that estradiol 17 β is not carcinogenic at the expone ntially lower levels (non-hormone
receptor stimulating levels) found in residues in me at from treated cattle. If the EC is implying that
one can hypothesize a risk that estradiol 17 β is genotoxic at levels found in meat from treated cattle,
such a hypothetical risk alone cannot support its ba n on meat and meat products treated with estradiol
17β. And the United States has shown that the scie ntific evidence does not support this hypothetical
risk.
37. Although the EC opines that "carcinogenicity of estrogens is primarily due to oxidative
stress/DNA adduct formation caused by the catechol metabolites of estrogens," it has put forward no
evidence that catechol metabolites initiate or promote tumors in vivo.
54 In addition, while the EC
notes that "it is also necessary to consider estradiol -alpha as residues susceptible to be metabolized in
consumer [sic] in catechol derivative with the same potency as estradiol to give adducts or to induce
oxidative stress," it produces no evidence in support of this conclusion. In cattle, estradiol 17 α is the
primary metabolite of estradiol 17 β. Here, the EC is suggesting that estradiol 17 α is present in beef
and may be further metabolized in the human consum er to catechol estrogens. This argument is weak
for several reasons: (1) Maume et al.55 demonstrated that estradiol 17 α concentrations are elevated
only in liver and kidney, but not muscle, following administration of a single implant; (2) the EC
attempted but was unable to provide evidence estradiol 17 α can be converted to catechol estrogens by
human intestinal cells
56; and (3) estradiol 17 α does not appear to be carcinogenic 57 and thus does not
fit into the EC's theory that estrogens are genotoxic carcinogens (via catechol metabolites).
38. Finally, the EC's support of Dr. Guttenplan's remarks ignores the fact that Dr. Guttenplan
notes that "[t]he evidence evaluating the occurrence of adverse effects is weak" 58; that the EC's

("Overwhelming evidence suggests that sex steroids exert effects that are dose-dependent and that a threshold
dose exists, below which, no biological effect will occur.") (Exhibit US-20).
54 See US discussion of the Bhat and Russo papers in its comments on Question 7 above.
55 Exhibit EC-78.
56 Exhibit EC-51C.
57 Fritsche S. and Steinhart H. Occurrence of hormonally active compounds in food: a review. Eur
Food Res Technol 1999; 209:153-179.
58 Dr. Guttenplan Responses (Question 13), p. 3.

Opinions receive a "mixed rating in following Codex guidelines" 59; that "an adverse effect cannot be
ruled out, but it is unlikely if good veterinary practices are followed" 60; and that, regarding the Syrian
hamster model, "[a]s kidney is not a known target of estradiol in humans the extrapolation to humans
is uncertain."61 The EC also cites to additional studies on which it allegedly based its permanent ban
on estradiol 17 β. Several of these studies were not yet pub lished at the time the EC completed the
1999 or 2002 Opinions on which it allegedly based its ban. Therefore, these studies are not relevant
to an analysis of the EC's "risk assessment" or whether its permanent ban on estradiol 17 β is based on
a risk assessment within the meaning of Article 5. 1 of the SPS Agreement. Regardless, as discussed
below, none of these studies supports the EC's argument.
39. For example, in Turan et al., rats that were exposed con tinuously to very high doses of
estradiol 17β – levels much higher than those derived fro m beef from cattle treated with estradiol 17 β
to promote growth – developed mammary tumors. However, treatment of rats with catechol estrogens
(the alleged "bad actors" implicated by the EC's genotoxic hypothesis) did not induce tumors. This
study confirms the "association of elevated prolonged exposure to endogenous and exogenous
estrogen with breast cancer" (a conclusion that is not relevant to the much lower levels of hormones
residues found in meat from treated cattle), but it actually provides evidence against the EC's theory
that catechol estrogens are the mechanistic basis for this cancer.
40. In Yue et al., spontaneous development of mammary tumors was characterized in
ERKO/Wnt-1 mice.62 The authors qualify their results as "preliminary" and point out several pitfalls
of interpreting data from ERKO/Wnt-1 mice. In these mice: (1) circulating estradiol 17 β levels are
3-5 times higher than normal; (2) the capacity of mammary tissue to inactivate 4-OH estradiol (the
alleged "bad actor" in the EC's genotoxic hypothesis) is impaired; and (3) it is possible that low levels
of estrogen receptor may be expressed. Therefore, th e preliminary results of this study do not provide
definitive evidence that mammary tu mors can develop in the absence of estrogen receptors. Instead,
the results simply indicate that mammary tumors in ERKO/Wnt-1 mice develop in the presence of
supraphysiological concentrations of estrogen and abnormally high concen trations of catechol
estrogens, and it cannot be ruled out that this tumorigen esis is mediated, at least in part, by estrogen
receptors.
41. In Takahashi et al., adenocarcinomas were induced in mice exposed subcutaneously to low
doses of estradiol 17 β in conjunction with intrauterine admi nistration of the chemical carcinogen
ENU. As explained in paragra phs 73 and 78 of the US Comments on the Experts' Responses, the
subcutaneous (injected into the animal) route of estradiol 17 β administration is not relevant to oral
ingestion of estradiol in beef (how beef is act ually consumed) because it bypasses the extensive first-
pass metabolism in the intestine and liver which accom pany oral ingestion or consumption of beef.
Therefore, the relevance of the Takahashi study to potential effects of estradiol 17 β in beef is
questionable.
42. The EC also notes that "it is hypothesized that the number of potentially carcinogenic tissue
cells determines the risk of getting the cancer," but at the present time this hypothesis is purely
speculative, and has not been supported by experiment al evidence. As noted in a paper provided by
the EC by Smalley and Ashworth, "no definitive id entification has been made of an adult mammary
stem cell."63

59 Dr. Guttenplan Responses (Question 14), p. 4.
60 Dr. Guttenplan Responses (Question 15), p. 4.
61 Dr. Guttenplan Responses (Question 14), p. 3.
62 ERKO/Wnt-1 mice are genetically engineered to lack expression of estrogen receptor α.
63 Exhibit EC-100.

43. Finally, the Ahlgren et al .
 paper is an epidemiological study of Danish women which
concludes that birth weight and growth during chil dhood are associated with risk of breast cancer.
The Ahlgren study did not examine stem ce ll populations or exposure to estradiol 17 β, and is
therefore irrelevant to the analysis at hand.
44. Question 14: The EC appears to cite to Dr. Boissea u's response in support of its contention
that it has conducted a risk assessment for estradiol 17 β. However, the United States has been unable
to locate any support for the EC's position in Dr. Boisseau's response. Instead, the United States notes
that Dr. Boisseau comments that the EC "only claims " to have conducted a risk assessment. Nowhere
does he note his agreement that the EC has actu ally done so. As for the EC's citation to
Dr. Guttenplan, as noted above, Dr. Guttenplan concl udes that the EC's Opinions receive a "mixed
rating in following Codex guidelines"; that hazard ch aracterization is "limited" due to the animal
model involved (Syrian hamster kidney; kidney is not a known target in humans and therefore
extrapolation is uncertain); and that "risk charact erization is very qualitative at best." The EC
attempts to salvage Dr. Guttenplan's view of its "limited" hazard characterization with citations to
studies that were apparently neither included in th e Opinions nor presented by the EC in the course of
these proceedings in support of its measure.
45. The EC notes that it "disagrees" with Dr. Boobis. The EC provides no rationale for why
Dr. Boobis' response is not appropriate or based on th e scientific evidence, other than that it feels he
has not given the EC Opinions a "careful readi ng." Most likely the EC disagrees with Dr. Boobis
because he concludes that "the EC risk assessment of oestradiol does not follow the four steps of the
Codex risk assessment paradigm. Even if it were concluded that oestradiol is a genotoxic carcinogen,
the four steps should have been followed."
46. Question 15 : The EC notes, for Dr. Guttenplan's "benefit" that the Appellate Body has
interpreted "potential" to mean "possible." It is not clear that this clarification is necessary, however,
as Dr. Guttenplan already assumed that "[i]f potential is taken to mean possible" adverse effects are
"unlikely if good veterinary practices are follo wed." As for Drs. Boobis and Boisseau, the EC
attempts to dismiss their responses by noting that their opinions are "conditioned by their
understanding that oestradiol-17 β is causing cancer only through receptor meditated processes," a
position that, according to the EC "is however scientifi cally no longer tenable in light of more recent
evidence cited by the European Communities." The United States notes that the responses of
Dr. Boobis and Dr. Boisseau are premised on a review of the very same evidence referred to by the
EC. Drs. Boisseau and Boobis determined, upon review of that evidence, that their understanding is
that oestradiol-17β causes cancer only through receptor mediated processes and that the EC has failed
to present any evidence that would cause them to conc lude otherwise. The EC comments that if the
Panel "read[s] between the lines" of Dr. Boobis' and Dr. Boisseau's responses, it will note that they
"do not seem to deny completely the existence of possible adverse effects." The EC provides no
evidence in support of this conjecture.
47. Dr. Cogliano, while noting that the identification of estradiol 17 β as a human carcinogen
"indicates that there are potential adverse effects on human health"
64 when it is consumed in meat
from treated cattle nevertheless also comments that "it has not been establi shed by the EC that
genotoxicity and cell proliferation would be induced by levels found in meat residues added to the
pre-existing levels occurring in exposed humans," 65 a statement which appears to endorse the

64 Responses to Questions from the Panel of Dr. Vincent Cogliano ("Dr. Cogliano Responses")
(Question 15), p. 1.
65 Dr. Cogliano Responses (Question 18), p. 1.

conclusion that the EC has failed to demonstrate th at carcinogenic or genotoxic effects will be caused
by estradiol 17β residues in meat from treated cattle.66
48. Question 16 : As noted above, the EC attempts to dismiss the opinion of Dr. Boisseau by
noting that he has relied on the conclusions of JECFA, which the EC views as outdated, and has
ignored the "more recent evidence" cited by th e EC "showing the direct genotoxic potential of
oestradiol 17β, progesterone, zeranol and most probable [ sic] testosterone." As demonstrated by the
United States and confirmed by th e experts' responses, the EC has not shown these effects. 67
Therefore, it is perfectly reasonable for Dr. Boisse au to rely on JECFA's conclusions regarding the
hormones. Regarding MGA and trenbolone acetate, the EC notes that "the evidence may be
inconclusive but there are sufficient indications to treat them as such [genot oxic], despite the serious
gaps in our scientific knowledge." However, th e experts' responses have confirmed that these
hormones are not genotoxic
68 and that there are not "serious gaps" in the scientific knowledge relating
to MGA and trenbolone acetate. 69 Indeed, results of one of the EC's own "17 Studies" indicate that
MGA was devoid of genotoxic activity, and that tr enbolone and zeranol are non-genotoxic except at
very high, cytotoxic (i.e., high enough to kill the cell) concentrations.70
49. The EC refers to Dr. Boobis' re sponse as "legally inappropriate"71 in an attempt to discard the
factual findings made by Dr. Boobis, which appear to be based on a thorough review of the scientific
literature: "[t]he carcinogenic effects of oestradiol appear to be the consequence of its endocrine
activity"; and "the guidelines on genotoxicity testing require confirmation of an in vitro positive using
an appropriate in vivo assay" (citing to guidance drafted by the EC's own CVMP in 2004).
50. The EC attempts to bolster its argument by claiming that Dr. Guttenplan "concludes that the
more recent evidence cited by the European Comm unities does support the finding that the genotoxic
action of these hormones is not related only to thei r hormonal activity." However, the United States
does not understand Dr. Guttenplan's response to be as unequivocal as the EC suggests. Rather,
without citation to specific scientific evidence,
72 Dr. Guttenplan on the one hand notes that the EC's
Opinions "do indicate that a mechanism other than ho rmonal activity is possible" but that on the other
"the United States and Canada cite other reports indicating that ge notoxic effects of estrogens are
unlikely." This is far from a conclusion that the studies cited by the EC support the conclusions
reached by the EC in its Opinions. Further, Dr . Guttenplan notes elsewhere that while "an adverse
effect cannot be ruled out, [] it is unlikely if good veterinary practices are followed,"
73 which would

66 See US Comments on Experts' Responses, para. 43.
67 See, e.g., US Comments on the Experts' Responses, paras. 34-45; 83-85. See also Dr. Cogliano
Responses (Question 18), p. 1 ("it has not been establis hed by the EC that genotoxicity and cell proliferation
would be induced by levels in meat residues added to the pre-existing levels occurring in exposed humans.")
68 See, e.g., Dr. Guttenplan Responses (Question 21), p. 6 ("[t]here is no conclusive evidence presented
by the EC that the five hormones other than oestradiol-17 β, when consumed as residues in meat have genotoxic
potential.").
69 See, e.g., US Comments on the Experts' Responses, pa ras. 49-58. The EC also comments that
Dr. Boisseau did not take into account "qualitative assessmen t of risk" in his response. As noted above, as an
expert, there is no reason that he should have since this is a legal determination. In addition, the simple fact is
that, regardless of whether a Member conducts a qua litative or quantitative assessment, the conclusions reached
in that assessment must actually be supported by the underlying scientific evidence. The experts have
confirmed that the scientific evidence relied on by the EC does not support the conclusions it has reached on the
hormones ( e.g., that they are genotoxic at levels found in residues from meat from cattle treated for growth
promotion purposes). See Panel Report, Japan – Apples (21.5), paras. 8.145-8.146.
70 See Exhibit EC-8.
71 As noted above, Dr. Boobis' response, as would be appropriate for any experts' response, does not
appear to make any legal statements or findings; it is therefore difficult to see how it is "legally inappropriate".
72 The United States was unable to locate the citation to the study referred to in the EC's Comments in
Dr. Guttenplan's actual response to Question 16.
73 Dr. Guttenplan Responses (Question 15), p. 4.

appear to demonstrate that he is not, in fact, of the mind that levels of residues in meat from cattle
treated with hormones for growth promotion purposes would be carcinogenic.
51. Finally, on a general note, the United States obser ves that the EC defines its appropriate level
of protection for risks from the six hormones as "no risk
 from residues of these hormones," as
evidence for why its situation is different than th at contemplated by JECFA. To date, the United
States understood the EC's appropriate level of protecti on to be one of "no additional or additive risk"
from residues of hormones used as grow th promoters, particularly in light of the fact that the EC
defines its level of protection as such in its 1999 Op inion at Section 1.2 ("[t]he prohibition reflects the
fact that the EC chose a level of sanitary pr otection of accepting no or 'zero' additional risk to human
health from the residues in meat and meat pr oducts of these hormones when used for growth
promotion purposes.") As confirmed by the expert s in their responses to Panel Question 51, the EC
did not address this risk. If the EC now defines its level of protection as "no risk", it should
accordingly ban all uses of the hormones (incl uding the currently permitted zootechnical and
therapeutic administrations), as well as the consum ption of meat, eggs and any other food products
naturally containing any of the six hormones.
52. In addition, the EC notes that its appropriate level of protection is a "quantitative term" (as
opposed to the allegedly unacceptable "qualitative" le vel of protection set by JECFA), yet it goes on
in great detail in its comments to argue that it was simply required to conduct a qualitative
assessment, and that references to quantitative analyses are inappropriate. At best, the EC's position
on what sort of assessment it was required to complete is conflicted, particularly if, as it appears to
argue in its comments on Question 16, JECFA's assessment was too "qua litative" for the EC's
purposes.
53. Question 17 : The United States notes that the EC's conclusion that "as Dr. Guttenplan
correctly states, the lack of catechols in meat does not imply that meat from estrogen-treated cattle is
without risk for genotoxicity," is unexceptional. Neither does the lack of catechols imply that meat
from treated cattle is a risk for genotoxicity. 74 Although the experts agree that the presence of these
metabolites would be important to consider in assessing the genotoxic potential of estradiol 17 β, they
also agree that the materials relied on by the EC fa iled to detect catechol residues in meat. In the
absence of scientific evidence for such residu es in meat from cattle treated with estradiol 17 β for
growth promotion purposes, it is impossible for the EC to conclude that catechol estrogens derived
from edible bovine tissues are genotoxic and thus have carcinogenic or tumorigenic effects.75
54. The EC notes that "more worrying from the human health point of view is the part of
estrogens (estradiol, estradiol-alpha or estrone) wh ich will be metabolized in[to] catechol derivatives
in target tissues." However, as noted in the US discussion in Question 13 above, the EC has not
provided any evidence to indicate that either estradiol 17 α or estrone can be converted to catechol
estrogens in humans. The EC comments that this concern "is the reason for which it is necessary to
perform a complete residue analysis with more powerful detection methods." However, upon review
of the exhibits put forward by the EC, it appears as though the EC has already done just this. In
Exhibit EC-51A, it is concluded that "[a]n almost complete reassessment of estrogen residues in
edible tissues of estradiol-17β treated animals has been performed."76
55. The EC also notes that "the fact that e xposure to catechol metabolites does not cause
mammary tumorigenesis does not necessarily negate the possibility that the catechol metabolites
formed in mammary tissue play a role in mammary tumorige nesis ... because administered

75 See generally US Comments on the Experts' Responses, para. 44.
76 The results of this comprehensive study were not discussed by Dr. De Brabander, the Panel's expert
in residue chemistry.

metabolites may not reach levels in mammary tissue comparable to those achieved by metabolism of
estradiol to the catechols within the mammary itself." However, the credibility of this statement relies
on the comparison between concentrations of ca techol estrogens in the mammary tissue of
experimental animals with those actually found in normal human mammary tissue in vivo. To date,
results of this critical comparison have not be reported by the EC.
56. The EC "can only explain[]" the responses of Drs. Boisseau and Boobis by impugning their
qualifications and by citing to a re mark from a scientist at the meeting of the experts in the original
Hormones proceedings. The EC presents no scientific evidence that discounts the statements of either
Dr. Boobis or Dr. Boisseau. Further, its citation to the Appellate Body remarks appears to focus more
on the Appellate Body's concern that the expert in the original proceedings made a claim without any
apparent scientific underpinning whatsoever . In contrast, the responses of Drs. Boisseau and Boobis
are based on an analysis of the scientific materials on the record in these proceedings.77
57. Question 18: The EC notes its agreement with the st atement of Dr. Cogliano, but apparently
only refers to a limited portion of Dr. Cogliano's re sponse. Dr. Cogliano concludes that "the issue,
though is whether [] genotoxicity would occur at levels found in meat residues." As to this issue, "it
has not been established by the EC that genotoxicity and cell proliferation would be induced by levels
found in meat residues added to the pre-existing levels occurring in exposed humans ." Therefore,
Dr. Cogliano's response appears to directly contradict the EC's assertion that levels of hormone
residues found in meat from treated cattle would be genotoxic.
58. As noted by the United States in its Comments on the Experts' Responses, while
Dr. Guttenplan notes that there is evidence that estradiol 17 β is genotoxic, he does not conclude that it
would be genotoxic at levels found in residues in meat from cattle treated for growth promotion
purposes. Indeed, his statement that while "an adver se effect cannot be ruled out, [] it is unlikely if
good veterinary practices are followed,"78 appears to indicate that he is not of this opinion.79
59. The EC claims that the issue is "not whether the [EC] has established that genotoxicity and
cell proliferation would be induced by levels found in meat residues," but rather whether the United
States has demonstrated that "this adverse effect woul d not occur." This is a remarkable claim by the
EC, and a weak attempt to shift the burden of pr oof. When it chose to impose a ban on meat from
cattle treated with hormones for growth promo tion purposes premised on its conclusion that the
residues would be genotoxic, the EC assumed the burden of proving that this is actually the case. It
has failed to do so, and the experts have confirmed this fact in their responses. The United States has
argued in detail why the EC has failed to support this conclusion with scientific evidence in its various
submissions to the Panel. 80 Further, as noted by the Appellate Body, "science can never provide
absolute certainty that a given substance w ill not ever have adverse health effects." 81 Rather the
relevant analysis is whether the EC, in suppor t of its ban, has adduced sufficient evidence to

77 Dr. Boisseau's response cites directly to the EC exhibit relating to catechol metabolites. Further, it is
unclear to the United States what relevant laboratory experience the other two experts have in examining
catechol metabolites in hormone residues in meat and meat products; yet, the EC does not complain about their
qualifications.
78 Dr. Guttenplan Responses (Question 15), p. 4.
79 The EC cites to a 2006 study it alleges supports Dr. Guttenplan's statement, yet that was not cited by
Dr. Guttenplan himself. The United States notes that the date for submission of scientific evidence is well-past,
and that the EC reached its definitive conclusion (such that it imposed a permanent ban) on this issue in 2003. It
is therefore unclear how a 2006 study can justify Opinions drafted and a measure adopted three years prior to its
publication.
80 See, e.g., US First Written Submission, paras. 152-153; US Rebuttal Submission, Section II.B(3), pp.
15-18 (titled "The EC's Opinions fail to take into acco unt available scientific evidence relating to genotoxicity
and carcinogenicity of estradiol 17β")
81 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153.

demonstrate a risk from meat from cattle treated with estradiol 17 β for growth promotion purposes,
including that estradiol 17β is genotoxic at levels found in residues in meat from treated cattle.
60. Finally, the EC dismisses the comments of Dr. Boisseau as "beside the point" and Dr. Boobis
as "lack[ing] conviction," yet apart from this rhetor ic provides no scientific argument to discount their
advice to the Panel. Contrary to the EC's asserti on, Dr. Boobis has apparently engaged in extensive
analysis, including of the alleged EC evidence clai ming in vivo proof of genotoxicity, in reaching his
conclusion that "the evidence is against any genotoxic ity in vivo." Dr. Boisseau concludes, by citing
to his response to Panel Question 13, directly "on point" to the Panel's query: "[i]n conclusion, the EC
risk assessment did not support that residues of oestradiol 17 β, despite the genotoxic potential of this
hormone, can initiate and promote tumors in humans."
61. Question 19
: The EC notes that it agrees with the "t hrust" of Dr. Guttenplan's response, and
then appears to pose a question and offer a response which is not in fact included in Dr. Guttenplan's
response. The United States analyzes Dr. Guttenplan 's response in detail in paragraph 38 of its
Comments on the Experts' Responses. The EC also notes that "although DNA repair can occur, it
presumably is occurring at all doses and the fract ion of DNA damage repaired probably does not
change at physiological levels, because the repair enzymes are unlikely to be saturated." This
statement, which the EC attributes to Dr. Guttenplan, appears to further highlight the fact that the EC
should have (but failed to) taken DNA repair mechanisms into account in its Opinions. Further, since,
as confirmed by the EC, the repair enzymes are not saturated under physiological conditions, then it
stands to reason that these enzymes have the capacity for increased activ ity when exposed to
xenobiotics or elevated concentrations of endogenous genotoxic substances. 82 Therefore, increased
activity of DNA repair enzymes is a protective mechanism against DNA damage. Of course, the
capacity for increased enzyme activity is finite and can be overwhelmed ( i.e., saturated) in the face of
very high exposure to genotoxic compounds, but there is no ev idence that this will occur in response
to the very low amounts of estradiol 17β in meat from treated cattle.
62. The EC notes that "[a]fter all, whether cancer will occur as a result of genotoxicity or
hormonal action is from the regulatory point of view less critical, as the end result is the same: human
cancer." This statement seems contradictory to th e EC's arguments to date. The EC has devoted
considerable time, effort and resources in its attempt to demonstrate that estradiol 17 β is genotoxic in
vitro, but has failed to provide convincing evidence that genotoxicity is the basis for estrogen-induced
carcinogenicity in vivo.
63. The United States has not been ab le to locate the statement ascr ibed to Dr. Boisseau by the
EC in Dr. Boisseau's response, but notes Dr. Boi sseau's conclusion that "[t]he scientific evidence
referred to by the [EC] does not demonstrate that this statement can also apply in the case of
oestradiol-17β, progesterone and testosterone as these three natural hormones are produced by both
humans and food producing animals." As such, Dr . Boisseau's response appears to address the EC's
concern that he somehow was not aware of, or ignored the studies cited in the EC's Opinions. The EC
cites to the Hilakivi-Clarke paper discussed in detail at paragraph 74 of the US Comments on the
Experts' Responses.
64. The EC also notes that Dr. Boisseau's statemen t "cannot be accepted scientifically" because
"[i]n the EC's view , it is beyond doubt that there is a link between 17 β-oestradiol exposure during
development ... and the risk of breast cancer later in life." However, the "EC's view" of the scientific

82 See Brusick D. Principles and Methods of Toxicology, 4th Ed., 2001, p. 825.

evidence and what the scientific ev idence actually demonstrates are two distinct concepts. The EC
has failed to demonstrate that the scientific evidence actually supports its view.83
65. The EC does not provide any evidence or argumen t to discount Dr. Boobis' advice ("[t]here is
no good evidence that oestradiol is genotoxic in vivo or that it causes cancer by a genotoxic
mechanism. Indeed, the evidence is against this
. Hence, the scientific evidence does not support the
EC on this issue, that the levels of the hormones in meat from treated cattle are not of relevance.")
66. Question 20 : The EC notes that Dr. Boobis' response "is based on his more erroneous
underlying assumption that oestradiol-17 β is not genotoxic" and continues by noting that if
Dr. Boobis' "assumptions are false, as the scientific evidence clearly demonstrates, the Dr. Boobis'
statement – which is already a qualified one – woul d make no sense." The United States has noted at
several points above that Dr. Boobis' conclusions ar e indeed based on the scientific evidence, and that
it is the EC who has failed to adduce the nec essary evidence to support the conclusions it has
proposed regarding estradiol 17 β. Further, Dr. Boobis' conclusions ("I do not believe that JECFA's
conclusion that oestradiol has 'genotoxic potential' affected its recommendations on this hormone";
"JECFA's conclusion on genotoxicity was based on pos itive results in certain in vitro tests, but the
evidence was against a mutagenic response in vi vo") are supported by the responses of JECFA
itself.84 The EC also notes that the responses of Dr s. Boisseau and Boobis should be discounted
because "they have not done any direct experime nts on these hormones in their professional life and
so lack specific expertise." The United States has commented on this issue at several points above. In
this particular instance, judging from their curriculum vitae , it would appear that Drs. Boisseau and
Boobis have more relevant experience in terms of JECFA and Codex decision making than any of the
other experts.
67. The EC faults Drs. Boobis and Boisseau for "consider[ing] the assessments of JECFA as the
Bible, although they know that the 1 988 and 1999 JECFA assessments are outdated by today's
evidence and scientific standards." Nowhere in the responses of either expert was the United States
able to locate a statement along these lines. Rather, the responses of the two experts indicate that they
do not believe the JECFA assessments to be "outdated."
68. The EC also notes that, since the original Hormones dispute, the EC "has been consistently
arguing [that] the genotoxicity of oestradiol-17 β is no longer seriously disputed and has now for the
first time been accepted and written in the 1999 JECFA re port." On the one hand, the fact that the EC
has been arguing a point does not mean that the point is actually supported by scientific evidence. In
fact the EC made this argument in the original dispute and is here simply trying to overturn
established WTO findings. Indeed, the experts have confirmed that, insofar as the issue of
genotoxicity relates to hormone residues in meat from cattle treated for growth promotion purposes,
the evidence does not demonstrate a genotoxic effect. 85 On the other hand, the experts have
confirmed that JECFA's statement of "genotoxic pote ntial" did not affect its ultimate conclusion that
the use of the hormones as growth promoters in cattle is safe.86

83 See the Responses of Drs. Boisseau , Boobis, Cogliano and Guttenplan to Panel Question 26 ("Does
the scientific evidence referred to by the European Communities, in particular any epidemiological studies,
identify a relationship between cancer and residues of hormonal growth promoters? In its risk assessment of
1999, the European Communities makes reference to the higher rates of breast and prostate cancer observed in
the United States as compared to the European Communities. Can a link be established between these statistics
and the consumption of meat from anim als treated with the hormones at issue ?") The experts unanimously
confirm that the EC has not demonstrated a link between consumption of hormones residues in meat and breast
cancer.
84 See US Comments on the Experts' Responses, para. 41.
85 See US Comments on the Experts' Responses, Sections C.2 and C.3(b).
86 See US Comments on the Experts' Responses, para. 41.

69. In addition, the EC poses several questions to Dr. Boobis regarding whether he can "provide
the necessary assurance" to EC author ities that residues in meat "will not increase the risk of cancer."
The United States believes that the EC's rhetoric is entirely inappropriate for this exercise, in which
the experts were requested to provide responses on sp ecific scientific issues presented by the Panel.
The insinuation that Dr. Boobis is responsible for providing an assurance
 to the EC on these matters
appears to be nothing more than a thinly-veiled a ttempt to coerce Dr. Boobis into changing his clear
scientific opinions and honest review of the material s put forward by the EC in support of its ban.
Further, as noted by the Appellate Body, "science can never provide absolute certainty that a given
substance will not ever have adverse health effects." 87 Rather the relevant analysis is whether the EC,
in support of its ban, has adduced sufficient evid ence to demonstrate a risk from meat from cattle
treated with estradiol 17 β for growth promotion purposes. The United States could just as easily ask
the EC if it can provide the neces sary assurance to the United States that EC exports of alcoholic
beverages will not increase the risk to human health, or that EC exports of agricultural commodities
will not increase the risk of exotic pests? No one can provide assurance that a risk could never be
identified in the future, nor does the SPS Agreement call for such an assurance. Rather the question is
what does the current scientific evidence and principles support.
70. Further, the EC quotes the Appellate Body's st atement that, while in most cases responsible
governments base measures on "mainstream" evidence, "[i]n other cases, equally responsible and
representative governments may act in good faith on the basis of what, at a given time may be a
divergent opinion coming from qualified and respected sour ces." Be this as it may, it is clear that the
Appellate Body did not exempt Members from providi ng a scientific basis and scientific evidence in
support of that "divergent opinion",
88 and as argued by the United States and confirmed by the experts
in their responses, the EC has failed to adduce the necessary evidence to support its "divergent
opinion."
71. Finally, the EC cites again to the 2002 Report on Carcinogens. As noted in the US comments
on the EC's comments on Question 12 above, this document simply does not stand for the conclusions
drawn from it by the EC.89
72. Question 21: The EC notes that it is "puzzled" by the responses of Drs. Boobis and Boisseau.
Although the EC claims that JECFA "was more prudent" in its decisions than both of these experts,
the United States fails to see any significant in consistency between JECFA's conclusions on the
hormones and those of Drs. Boobis and Boisseau. The EC claims that its Opinions "provide enough
evidence to demonstrate that genotoxicity and other adverse effects from the hormones are possible,"
but the experts (including not just Drs. Boobis a nd Boisseau, but Dr. Cogliano) disagree, particularly
if the EC is referring to levels of the hormones that would be found in residues in meat from cattle
treated for growth promotion purposes.
73. The EC attempts to bolster its argument by not ing that "[a]s Dr. Guttenplan states, their [the
five hormones'] genotoxic potential may be weak but cannot be excluded." However, this statement
fails to take into account the other conclusions reach ed by Dr. Guttenplan: "[t]here is no conclusive
evidence presented by the EC that the five hormones other than oestradiol-17 β, when consumed as
residues in meat have genotoxic potential," and:
[t]estosterone and progesterone are negativ e in genotoxic assays. Zeranol can induce
transformation of breast epithelial cells in culture with efficiency similar to that of
estradiol, but the mechanism is not known, a nd it is negative or marginally active in

87 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153.
88 See Panel Report, Japan – Apples (21.5), paras. 8.145-8.146.
89 See US Comments on the Experts' Responses, para. 41 and fn. 97 for discussion of the responses of
Drs. Cogliano and Guttenplan. See also US Rebuttal Submission, paras. 38-40.

other assays. Trenbolone is either negative or marginally active in in vitro genotoxic
assays. MGA is negative in genotoxicity assays. Any genotoxic effects of the five
hormones are likely to be minimized by good veterinary practice. My reply for the
hormones would not have been different in September 2003 (SCVPH 2002 Opinion).
It is clear from the actual text of Dr. Guttenplan's response that he does not endorse the EC's argument
that the five hormones are genotoxic.
74. The EC notes that it has provisionally banned the five hormones "taking into account the
numerous and serious gaps in our scientific knowle dge, which have been clearly identified in the
SCVPH assessments." However, as noted in Sec tion C.3(c) of the US Comments on the Experts'
Responses, the experts have not identified "numer ous and serious" gaps in the scientific knowledge
relating to the five hormones.
90
75. Question 22: The EC appears to have omitted a significant portion of Dr. Boobis' response, in
which he concludes, "[t]he DNA repair processes [] are amongst the most efficient (Arai et al., 2006;
Russo et al., 2004) and even if such modification did occur, it is anticipated that no heritable change
would result, because of DNA repair (Arai et al., 2006). This would be true even at the levels of
exposure that could arise should GVP not be followed ." The EC then argues that, if everything
Dr. Boobis assumed were in fact false, then he wo uld have come to a different conclusion and he
"should accept that DNA repair mechanisms are not su fficient to eliminate DNA damage." The EC's
argument is nonsensical, as the evidence underlying Dr. Boobis' response is not false, and he does not
in fact endorse this conclusion.
76. The EC attempts to cast doubt on the response of Dr. Guttenplan by noting that both he and
Dr. Boobis "appear to miss an important point" but fails to present any evidence that discounts
Dr. Guttenplan's conclusions on DNA repair mechanisms: "[t]here is no reason to assume that DNA
repair processes involved in DNA damage produced by estrogen metabolites are any more or less
effective than those involved in repair of other carci nogens"; and "[t]he scientif ic material referred to
by the [EC] for the most part doesn't address DNA repair."
91 The United States provides additional
discussion on DNA mechanisms in its comments on Question 19 above.
77. Question 23 : The EC agrees with the statements of Drs. Cogliano and Guttenplan that a
sufficiently long latency period for cancer should be taken into account in the conduct of a risk
assessment. The United States notes that Dr. Boobis also agrees on this point, which is unexceptional
in the context of this dispute since the six hormone s at issue have been used for growth promotion
purposes in meat for a sufficiently long time (d ecades) to address this concern. Dr. Boisseau : "the
hormones in dispute have already been used as gr owth promoters over a sufficient number of years ,
the epidemiological studies in humans already carried out in this domain have failed to identify any
relation between the occurrence of hormonally dependent tumours and the consumption of meat
containing hormonally active residues resulting from th e treatment of cattle with growth promoters."
Dr. Boobis: "[t]he observational studies of humans (e.g . on HRT or oral contraceptives) and the
experimental studies in animals covered a sufficiently long period to encompass the latency period for
any carcinogenic effects of the hormones." Dr. Guttenplan : "[w]ith respect to hormones in meat, it
appears they have now been consumed for a sufficient number of years to observe strong or moderate
increases in risk."

90 See generally Responses of the Experts to Panel Question 61 and 62. See U S C o m m e n t s o n t h e
Experts' Responses, Section C.3(c) for a discussion of Dr. Guttenplan's response to Question 62.
91 See US Comments on the Experts' Responses, para. 31 for further discussion of Dr. Guttenplan's
response on DNA repair mechanisms.

78. Question 24
: The EC avers that the experts' responses on confounding factors "also
undermine indirectly the position of the US" without providing any argument or explanation for why
this is so. The EC cites again to a study rega rding the frequency of breast cancer (cited in its 1999
Opinion) and purports to draw a link between the use of hormones for growth promotion purposes and
the incidence of cancer. The experts have dismissed this link in their responses to Panel Question 26
(Boisseau: (citing to his response to Question 23) "the hormones in dispute have already been used as
growth promoters over a sufficient number of years, the epidemiological studies in humans already
carried out in this domain have failed to identif y any relation between the occurrence of hormonally
dependent tumours and the consumption of meat containing hormonally active residues resulting from
the treatment of cattle with growth promoters; Boobis : "[t]here is no scientific evidence
demonstrating any association between consumption of meat from animals treated with growth
promoting hormones and the risk of cancer in humans; Cogliano : "[t]he data [relating to the
difference in breast cancer rates] are not sufficiently specific to establish a link between these
observations"; Guttenplan : "[t]he epidemiological studies do not identify a relationship between
cancer and residues of hormonal growth promoters. The references to the higher rates of breast and
prostate cancer observed in the United States as co mpared to the European Communities are not very
convincing as there is considerable variation in ra tes in different geographical locations. Also, the
differences in rates of breast and prostate cancer observed in the United States as compared to the
European Communities are relatively small.")
79. Question 25: The EC again attempts to dismiss the response of Dr. Boobis by questioning his
qualifications as an expert. This has been addressed at several points above. The EC also alleges that
JECFA's views are "based on data from the 1970s – 1980s" and that the EC has now provided "more
recent evidence." The statement regarding the dates of materials examined by JECFA is simply false.
For example, at its 52 nd Meeting in 1999, JECFA evaluated sev eral pieces of recent scientific
evidence. Indeed, the EC recogni zes this fact in its Opinions. 92 Further, the "more recent evidence"
put forward by the EC does not support the conclusions for which the EC cites to it in its Opinions.
80. The EC argues that Dr. Boobis has taken an "absolutist" approach, and attacks his response by
alleging that Dr. Boobis requires "positive proof of harm," and that rather evidence should be
provided of a lack of possible harm. The Appella te Body noted the following regarding the alleged
need to provide evidence of a lack of harm: " [i]n one part of its Reports, the Panel opposes a
requirement of an 'identifiable risk' to the uncerta inty that theoretically always remains since science
can never provide absolute certainty that a given substance will not ever have adverse health effects .
We agree with the Panel that this theoretical uncer tainty is not the kind of risk which, under Article
5.1, is to be assessed."93 As is clear from its comments on Dr. Boobis' response, rather than providing
actual scientific evidence of a risk to consumers from the consumption of residues in meat from cattle
treated for growth promotion purposes and basing a measure on the risk assessment drawn from that
evidence, the EC would instead opt to focus on th e very theoretical uncerta inties described by the
Appellate Body in support of its ban on meat and meat products from cattle treated with estradiol 17β.
All of this is a distraction from Dr. Boobis' respon se, which categorically notes that the three recent
studies referred to by the EC "do[] not confirm a risk to human health from the consumption of meat
from cattle treated with growth promoting hormones."
81. The EC agrees with the comments of Dr. Coglia no, which is surprising since Dr. Cogliano's
comment on the Norat
 study is that it indicates a risk to human health from meat generally 94, and his
comment on the other two studies is qualified by the fact that "the exposure levels found in these
studies are higher than those found in meat residues." The EC cites very selectively to

92 See, e.g., 1999 Opinion, p. 77 ("However, in the 1999 report of JECFA, more recent work on
biotransformation mediated genotoxicity was cited.")
93 Appellate Body Report, para. 186.
94 See US Comments on the Experts' Responses, para. 63.

Dr. Guttenplan's response, which is understandable since he concludes the following regarding the
first EC study (Liu and Lin ): "the results were obtained in cu ltured cells and the relevance to human
exposure to hormone-treated [meat] cannot be extra polated from this study because of a myriad of
uncertainties in such extrapolation ." He concludes the following regarding the second and third
studies: "[t]he other two studies do not confirm a risk from hormone-treated meat ." The results of the
Liu and Lin paper are questionable due to lack of a dose response. The authors claim to have data that
meat and serum from zeranol-implanted cattle are mitogenic and estrogenic, but their reports are all in
abstract form (not publicly available). The US FDA has approached the authors for more information,
but they have not responded to repeated requests.
82. Question 26 : The United States has addressed the issue of the experts' responses on
epidemiological studies at several points above. The EC's comments ignore the conclusions reached
by each of the experts. Boisseau : (citing to his response to Question 23) "the hormones in dispute
have already been used as growth promoters over a sufficient number of years, the epidemiological
studies in humans already carried out in this doma in have failed to identif y any relation between the
occurrence of hormonally dependent tumours and th e consumption of meat containing hormonally
active residues resulting from the treatment of cattle with growth promoters." Boobis : "[t]here is no
scientific evidence demonstrating any association be tween consumption of meat from animals treated
with growth promoting hormones and the risk of cancer in humans." Cogliano : "[t]he data [relating
to the difference in breast cancer rates] are not su fficiently specific to establish a link between these
observations." Guttenplan : "[t]he epidemiological studies do not identify a relationship between
cancer and residues of hormonal growth promoters. The references to the higher rates of breast and
prostate cancer observed in the United States as co mpared to the European Communities are not very
convincing as there is considerable variation in ra tes in different geographical locations. Also, the
differences in rates of breast and prostate cancer observed in the United States as compared to the
European Communities are relatively small."
83. The EC notes that it "advanced this [epide miological] argument to demonstrate that the
scientific uncertainty is growing concerning the harmless natu re of the residues of these hormones."
(Emphasis in original). However, as evidenced by the experts' responses, the EC has demonstrated no
such uncertainty. Further, as noted by the Appellate Body, "theoretical uncertainty is not the kind of
risk which, under Article 5.1, is to be assessed," 95 and "the existence of unknown and uncertain
elements does not justify a departure from the requireme nts of Articles 5.1, 5.2 and 5.3, read together
with paragraph 4 of Annex A, for a risk assessment."96
84. Finally, while the EC downplays the role of ep idemiological studies in its decision making in
its 1999 Opinion, noting that it "cited this epidemiological evidence in the 1999 SCVPH [Opinion]
not as an affirmative [sic] or adequate proof but just as an indication and possible explanation
", it was
not so circumspect in the actual 1999 Opinions, and in fact linked several of that document's "Major
Conclusions" directly to the epidemiological da ta: "[e]pidemiological studies have demonstrated
strong relationships between the levels of e ndogenous oestrogen and risk of breast cancer (Toniolo, et
al., 1995; Berrino, et al., 1996; Bernstein, et al., 1990 a and b; Shimizu, et al., 1990; Pike, et al.,
1992)" (1999 Opinion, p. 42); "[a]s concerns excess intake of hormone residues and their metabolites,
and in view of
 the intrinsic properties of hormones and epidemiological findings , a risk to the
consumer has been identified with different leve ls of conclusive evidence for the 6 hormones in
question" (1999 Opinion, "Major Conclusions ", p. 73); "[i]n view of the intrinsic properties of the
hormones and in consideration of epidemiological findings, no threshold levels can be defined for any
of the 6 substances" (1999 Opinion, "Major Conclusions", p. 73). (Emphasis added).

95 Appellate Body Report, para. 186.
96 Appellate Body Report, Australia – Measure Affecting Importation of Salmon , adopted on 6
November 1998, WT/DS18/AB/R ("Australia – Salmon"), para. 130.

85. As demonstrated above, the experts disagree that this epidemiological evidence supports the
conclusions for which it is cited by the EC. Further, as noted by the compliance panel in Japan –
Apples (21.5) , the scientific materials underpinning a ri sk assessment must actually support the
conclusions reached in that assessment.
97 Materials that do not provide "affirmative [ sic] or adequate
proof" cannot be said to support the conclusions reached by the EC in its 1999 Opinion. The EC has
therefore failed to conduct a risk assessment, as appr opriate to the circumstan ces, within the meaning
of Article 5.1 of the SPS Agreement for estradiol 17β.
86. Question 27 : It is unclear why the EC thinks that the results of Stephany are "completely
different" than those used to support approval of estradiol 17 β as reported in the 1999 JECFA Report.
The concentration of estradiol 17 β reported by Stephany in "M/LQ domestic US beef", 0.03 ppb
(equal to 30 nanograms/kilogram), is we ll within the range of estradiol 17 β concentrations in muscle
reported by JECFA which range from 0.5 - 117 nanograms/kilogram. Although the average
concentrations are correctly quoted from Table 5 of Stephany's paper, Stephany uses the median
values to make the statement that "it is estim ated that the median dietary intake of 17 β-estradiol via a
250 gram steak of 'Hormone Free Cattle' is less than 2.5 nanogram and via 250 gram 'beef' of
'Hormone Treated Cattle' is 5 nanogram", i.e., a 2-fold difference. It is assumed that Stephany used
the median values for this comparison because these values, not average values, are most appropriate
to use when assessing lifetime dietary exposur e to a residue or contaminant in food ( see 1999 JECFA
report, p. 83). Thus, the 7.5-fold difference in estradiol-17 β concentrations in beef between treated
and untreated cattle cited by the EC may be considered an exaggeration.
87. Further, the EC provides no support from the e xperts' responses for its conclusion that "the
difference in the residues is not only structural/c hemical but also qualitative and quantitative," and in
fact makes no reference whatsoever to the response of the relevant scientific expert, Dr. Boisseau.
88. Question 28
: The EC comments that Dr. Boisseau's r esponse ("[i]n the case of ... residues of
the natural hormones, which consist of parent s ubstances, there is no difference between hormones
naturally present in food producing animals, meat or human beings") is "partially incomplete and
partially false." The EC refers again to catechol metabolites of estradiol 17 β, noting specifically that
estradiol 17α, alleged by the EC to be the main residue in cattle liver, "may react with nucleophilic
compounds and induce some disruptions." The EC's suggestion that estradiol 17 α is present in beef
and may be further metabolized in the human cons umer to catechol estrogens is weak for several
reasons: (1) Maume et al.98 demonstrated that estradiol 17 α concentrations are elevated only in liver
and kidney, but not muscle, following administration of a single implant (muscle is the tissue most
often consumed); (2) the EC attempted but was unable to provide evidence estradiol 17 α can be
converted to catechol estrogens by human intestinal cells 99; and (3) estradiol 17 α does not appear to
be carcinogenic100 and thus does not fit into the EC's theory that estrogens are genotoxic carcinogens
(via catechol metabolites). In addition, estradiol 17 α is a relatively weak estrogen, with only 10% of
the in vivo potency of estradiol 17 β and concentrations of estradiol 17 α are undetectable in muscle,
which is consumed in much greater quantities than liver.
89. The EC notes that Dr. De Brabander's statemen t is "very informative", but the United States
notes that Dr. De Brabander's response fails to cite any scientific evidence in support of its

97 See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146 (finding that "[s]ince the scientific
evidence relied upon by Japan does not support the conclusions reached by Japan in its 2004 PRA, we conclude
that the 2004 PRA is not an assessmen t, as appropriate to the circumstances , of the risks to plant life or health,
within the meaning of Article 5.1 of the SPS Agreement.")
98 Exhibit EC-78.
99 Exhibit EC-51C.
100 Fritsche S. and Steinhart H. Occurrence of ho rmonally active compounds in food: a review. Eur
Food Res Technol 1999; 209:153-179.

conclusions, which appear to miss the point of th e Panel's query. The Panel's question speaks to
differences in the fundamental composition of the hormones in their basic form ( i.e., is estradiol 17 β
in the human body the same as estradiol 17 β residues in meat). Dr. De Brabander's response provides
speculation as to how the body breaks down or metabolizes the hormone, making a vague reference to
body builders. The process of metabolization of the hormones has been discussed in detail above. 101
Further, the EC's endorsement of Dr. De Braba nder's "finding that the residues of the endogenously
produced natural hormones in cattle are in the 17 α form (inactive) while the use of the natural
hormones for growth promotion purposes may lead to residues in the β form (active form)," suggests
that tissue residues of estradiol 17 β in cattle treated with estradiol 17 β for growth promotion purposes
are qualitatively different from residues in untreated cattle. This is incorrect, as demonstrated by the
results of the EC's own "17 Studies", 102 which showed that edible tissues from untreated cattle and
cattle treated with a growth-promoting implant contain both estradiol 17 β (muscle, liver, kidney) and
estradiol 17α (liver and kidney only (no muscle)).
90. Question 29: The EC disagrees with Dr. Boisseau, who determined upon evaluation of the
SCVPH Opinions that the EC failed to evaluate act ual residue levels of the synthetic, provisionally-
banned hormones. However, Dr. Boisseau's respon se (which cites to the EC's 1999 Opinion) is
indeed supported by the text of that Opinion (in the "Major Conclusions" section): "[i]n view of the
intrinsic properties of the hormones and in consideration of epidemiological findings, no threshold
levels can be defined for any of the 6 substances." As confirmed by the responses of the experts, this
conclusion is without scientific support. Therefore, it is clear that the EC has not based its provisional
ban on these hormones on "available pertinent inform ation" (which indicates that thresholds can
indeed be set) within the meaning of Article 5.7 of the SPS Agreement.
91. Dr. De Brabander does not appear to offer a sp ecific opinion as to whether the EC's Opinions
indeed evaluate these residue levels, though he notes that "the assessment of risk as evaluated by the
SCVPH is in terms of actual residue levels is less complex
 than in the case of the natural hormones"103
which would appear to indicate that the EC's evalua tion was less than robust. Nevertheless, the EC
notes that Dr. De Brabander "confirms the EC argument that the data used by JECFA are not only too
old but have also been obtained with methods that are no longer reliable today."
92. The United States notes that the residue data used to support approval of the growth
promoting hormones are reviewed in the 52 nd JECFA Report. Included in this Report is a very
detailed description of the method (developed in 1979 and revised in 1982 and 1983) used to generate
these residue data and four pages of data which describe the method's performance (percent recovery,
range of assay detection, intra- and inter-assay va riability, assay precision). Therefore, all of the
information required to evaluate the methods used to generate the residue data used by JECFA in its
determinations have been publicly available since 1999. Despite this fact, neither the EC nor the
scientific expert on residues (Dr. De Brabander) has provided a scientific review or analysis of these
data explaining why or how the methods are "no longer reliable today", nor do they provide any
reasons for why the methods were not adequate to derive MRLs. Instead, they opt to dismiss them as
unreliable simply because they are "old." As explained in the US Comments on the Experts'
Responses at footnote 193, JECFA has specific and extensive requirements for residue data.
Therefore, these "old" data were critically reviewed by JECFA experts in 1999 and deemed to be of
sufficient quality to assess the human food safety of hormone residues in beef.
93. Question 30
: The EC attempts to dismiss the response of Dr. Boisseau for the same
unfounded reason cited in its comments on Question 29 above. The EC opines that Dr. Boobis is

101 See, e.g., Questions 13 and 17 above.
102 Exhibit EC-78.
103 Responses to Questions from the Panel of Dr. Hubert De Brabander ("Dr. De Brabander
Responses") (Question 29), p. 3.

"clearly wrong" because, according to the EC, it has completed a "detailed exposure assessment" for
the three natural hormones. Yet, both Drs. Boobis and Boisseau, upon review of the EC's materials,
disagree. Dr. Boobis notes, as has been argued by th e United States, that rather than evaluating actual
residue levels of the natural hormones, the EC instead concocts several misuse scenarios in its attempt
to demonstrate a risk to consumers.
104
94. The EC claims to have "not only considered the ADIs and MRLs set by JECFA but went even
further and examined the acceptable levels and tolerances recommended by the USA." The United
States notes that the Panel's inquiry was whether th e SCVPH considered or examined actual residue
levels (i.e., those reported by Stephany). These are not the same as and are, in general, much lower
than ADIs, acceptable levels and tolerances. Theref ore, the EC's calculations in its Opinions greatly
overestimate the actual consumption of hormone residues.105
95. Question 31: The EC provides no scientific evidence to dispute Dr. Boisseau's comments or
the US statement in its first written submission re garding hormone residue levels in treated and
untreated meat. Rather, it cites again to the 2002 Report on Carcinogens in an attempt to bolster its
arguments. The United States discusses its argument on residue levels as well as the relevance of the
2002 Report on Carcinogens in detail in its comment s on Question 12 above. The EC also notes that
levels of residues in meat "are not unimportant, as the earlier comments of the [EC] on the absence of
a threshold have demonstrated." The EC has not demonstrated the absence of a threshold. The
experts' responses confirm this fact.
106
96. The EC states that Dr. De Brabander discussed one of its studies indicating "that the
consumption of meat from the regular hormone treated meat market in the US contains 7.5 times more
estrogens than in meat from untreated cattle." Ho wever, the United States was unable to locate this
conclusion in Dr. De Brabander's response. The Un ited States discusses the EC's argument regarding
the "7.5 times" higher levels of estradiol 17 β in detail at paragraph 86 above. Similarly, the United
States could not locate the following conclusion ascr ibed to Dr. De Brabander in his response to
Question 31: "the [EC] considers that the reply of Dr. De Brabander rightly points out the increased
risk which repetitive exposure to such higher residu es can present to the most sensitive parts of the
population."107
97. Question 32 : The EC avers that Dr. Boisseau's response is "scientifically unsound", yet
provides no scientific evidence or discussion for why this is so. 108 The EC also notes that "there is an
urgent need to apply the latest analytical methods to determine the nature and level of the residues
from these hormones and all their metabolites, which is perplexing since a review of the exhibits put
forward by the EC indicates that the EC belie ves it has already accomplished this. In the EC-
sponsored study described in Exhibit EC-51A, it is concluded that "[a]n almost complete reassessment
of estrogen residues in edible tissues of estradiol-17β treated animals has been performed."
98. Question 33 : The EC concludes that the responses of Dr. Boisseau and Dr. Boobis are
"conflicting", yet provides no scientific evidence or di scussion for why and where this is so. The EC
cites to Dr. De Brabander of the proposition that residue data examined by JECFA should "no longer
be considered to be credible or reliable", ye t it provides no scientific evidence in support of the
conclusion that the earlier residue data is no longer adequate.

104 See Dr. Boobis Responses (Question 30), p. 33.
105 See US Comments on the Experts' Responses, paras. 92-96 for a discussion of Dr. De Brabander's
response.
106 See, e.g., Experts' Responses to Panel Question 15.
107 See US Comments on the Experts' Responses, paras. 92-96 for a discussion of Dr. De Brabander's
response.
108 See US Comments on the Experts' Responses, para. 93 for a discussion of Dr. De Brabander's
response.

99. The EC appears to take Dr. Boobis' comment relating to the three natural hormones (the
subject of the Panel's question) (Dr. Boobis : "the view was that it was unnecessary to conduct a
detailed evaluation of the toxicology of substances produced endogenously [i.e., naturally]" in 1988)
and attempt to use it to support the following conclusion: "Dr. Boobis admits that the 1988 evaluation
was made by JECFA even without toxicological monographs, which means, inter alia , that for the
two synthetic hormones - trenbolone acetate and zera nol - which have not been evaluated since 1988,
JECFA's conclusions are no longer reliable." Ho wever, Dr. Boobis' comments on the natural
hormones are unrelated to the synthetic hormones (and therefore do not support the EC's conclusion),
which were not even the subject of the Panel's question.
100. The EC quotes Dr. Boobis' comment that, over tim e "it became clear that exposure to the
natural hormones, albeit at levels appreciabl[y] hi gher [than] that found in meat from treated cattle,
could have adverse effects on human health," as s upport for its arguments. However, Dr. Boobis'
conclusion, which notes that recent epidemiologi cal evidence demonstrated that hormones caused
effects "at levels appreciably higher than that found in meat from treated cattle " contradicts the EC's
argument that the exponentially lower levels of hor mone residues in meat from treated cattle pose a
risk, and instead supports arguments put forward by the United States in its submissions to the
Panel.109
101. The EC agrees with Dr. De Brabander that data relating to the three natural hormones should
"no longer be considered to be credible and reliabl e." Yet, as noted in Question 29 above, there is no
scientific analysis provided by either the EC or Dr. De Brabander for why this is so.
102. Question 34: The EC comments that Dr. Boisseau "agr ee[s] that the data used by JECFA are
old," and notes that his argument "to minimize the importance of their old nature" is "not scientifically
sound." As evidence of this fact, the EC states : "concerning estradiol-alpha, which is the main
metabolite found in target tissue (liver) of tr eated cattle and which we know that it will be
metabolized in[to] catechol derivatives, no specifi c evaluation of the genotoxic mechanism has been
performed by JECFA." However, as discussed in deta il in Questions 13 and 17 above, the EC has not
provided any evidence to indicate that estradiol 17α can be converted to catechol estrogens in humans.
The EC has failed to cast doubt on JECFA's determination that estradiol 17 β is not genotoxic at levels
found in residues in meat from cattle treated for growth promotion purposes.
103. As was the case when the EC was faced with a response from Dr. Boobis to which it had no
response (Question 20), the EC asks "[c]an Dr. Bo isseau provide an assurance to the [EC] that
JECFA's conclusions would have not been different if more recent and accurate data were available to
it?" The United States rejects the implicit assumption in the EC's question that the data relied on by
JECFA are inaccurate or that there is more recent or accurate data available. Furthermore, as noted
above in the comments in relation to Question 20, th e United States believes that the EC's rhetoric is
entirely inappropriate for this exercise, nor could the EC provide any such assurance with respect to
its own exports. As the United States has demonstrated time and again, and the experts have
confirmed, the EC has not adduced any scientific evidence which would call into question JECFA's
determinations on the safety of the hormones. Furt her, as noted by the Appellate Body, "science can
never provide absolute certainty that a given subs tance will not ever have adverse health effects." 110
Rather the relevant analysis is whether the EC, in support of its ban, has adduced sufficient evidence
to demonstrate a risk from meat from cattle treated with estradiol 17 β for growth promotion purposes
or that the available pertinent information supports a provisional ban on the other five hormones.
104. Question 35: The EC comments that Dr. Boisseau ag rees that the data evaluated by JECFA
on MGA "date[s] from the 1960s and 1970s". The EC refers to its comments on Question 34 to

109 See, e.g., US Rebuttal Submission, paras. 38-39.
110 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153.

allegedly support its conclusion that Dr. Boisseau is incorrect in asserting that, just because the
evidence is older does not mean that it is bad or in adequate. However, the quality and quantity of the
evidence point to the opposite conclusion. As furthe r evidence of this fact, the EC has failed to put
forward scientific evidence that would cast doubt on JECFA's conclusions on MGA. This is
confirmed by the experts' responses to Questions 61 (is there sufficient scientific evidence to conduct
a risk assessment for MGA)
111 and 62 (are there any gaps in the scientific information relating to
MGA).
105. The EC argues that "the 'low-dose' issue was not recognized in peer-reviewed literature before
the mid 90s. Therefore, all the research into possibl e low-does effects has not been considered in the
2000 JECFA Report." It is unclear, however, exactly what "low-dose effects" the EC is referring to
here.
106. The EC also concludes that Dr. Boisseau's re sponse is incorrect "[i]n the light of the new
evidence provided by the European Communities in its risk assessment of 1999, 2000 and 2002,
showing so many gaps and uncertainties in our k nowledge on MGA." However, none of the experts
have identified the gaps in evidence relating to MGA referred to by the EC. This is confirmed by the
experts' responses to Question 62. Further, as no ted by the Appellate Body, "the existence of
unknown and uncertain elements does not justify a departure from the requirements of Articles 5.1,
5.2 and 5.3, read together with paragraph 4 of Annex A, for a risk assessment."112
107. Finally, the EC questions whether Dr. Boisseau ca n "assure the Panel that all the relevant and
necessary scientific aspects about the safety of MGA have been completely and properly analyzed and
assessed." Once again, the insinuation that Dr. Boi sseau is responsible for providing an "assurance"
to the Panel on melengestrol acetate appears to be nothing more than a thinly-veiled attempt to coerce
Dr. Boisseau into changing his clear scientific opinions and honest review of the materials put
forward by the EC in support of its ban. This is the very task he was char ged with by the Panel.
Further, as noted by the Appellate Body, "science can never provide absolute certainty that a given
substance will not ever have adverse health effects."
113 Rather the relevant analysis is whether the
EC, in support of its provisiona l ban on melengestrol acetate, h as adduced sufficient evidence to
demonstrate that it has based its provisional ban on av ailable pertinent information and that there is
insufficient scientific evidence fo r the EC to conduct a risk assessment for MGA. The experts'
responses demonstrate that the EC has failed to demonstrate either of these elements.
108. Question 36: The EC notes its agreement with Dr. Cogliano's response, but fails to cite to the
previous sentence of Dr. Cogliano's reply: "[i]n my view, it is widely accepted that adverse effects
arising from hormonal activities depend on the dose; that is, the level of effect depends on the level of
exposure." Further, the EC concludes that Dr. Cogliano's response "is also consistent with the
Appellate Body's 1998 decision in the Hormones c ase that a qualitative assessment of the risk is
acceptable under the SPS Agreement." The United St ates addresses this overly-simplistic description
of the Appellate Body findings at Section B.2 abov e. In addition, the United States notes that the
experts have confirmed that the EC has not complete d the four-steps of a risk assessment (including
hazard characterization).114
109. The EC also cites Dr. Boobis' statement that "once a compound is identified as an in vivo
DNA-reactive mutagen, or as causing a carcinogenic response via a genotoxic mode of action, no
exposure is considered without risk." As has been made clear in Questions 19 and 20 above,

111 See, e.g., Dr. Guttenplan Responses (Question 61), p. 13 ("[t]he [JECFA] assessment for
melengestrol acetate seems sound.")
112 Appellate Body Report, Australia – Salmon, para. 130.
113 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153.
114 See Question 14 above.

Dr. Boobis has concluded that the evidence on the hormones, including estradiol 17 β, does not
indicate that they are in vivo DNA-reactive mutagens (Dr. Boobis concludes: "[t]here is no good
evidence that oestradiol is genotoxic in vivo or that it causes cancer by a genotoxic mechanism.
Indeed, the evidence is against this . Hence, the scientific eviden ce does not support the EC on this
issue, that the levels of the hormones in meat from treated cattle are not of relevance.").
110. Question 37: The EC comment that "[b]oth Dr. Boisseau and Dr. Boobis appear to agree with
the EC argument contesting Canada's position" on dose-response assessments is remarkable in light of
the actual responses of the experts to the Panel's question. Dr. Boisseau : "JECFA has always
established ADIs for veterinary drugs on the basis of a dose-response assessment ." Dr. Boobis :
"Codex and JECFA materials certainly require th at a dose-response assessment should always be
conducted as part of the risk assessment of a chemical agent (CAC, 2005; IPCS: EHC 70, 1987 and
EHC 104, 1990; IPCS, 2005; WHO, 1996 and 2001)." (Emphasis added).
111. Question 38 : Please see US Comments on the Expert s' Responses, Section C.4(c) for a
discussion of Question 38 and sensitive populations. The EC comments that "it is not very
uncommon in JECFA to use data from assays which are not yet properly validated." However, the
EC provides no evidence to support this conjecture. For physiological levels of sex hormones in
prepubertal children, JECFA used values from the literature which were validated as a prerequisite for
publication in a peer-reviewed journal.
115 The EC also claims that "J ECFA originally used the limit-
of-detection as the 'real' level when they could not me asure the levels." This statement by the EC is
also false. In the peer-reviewed reference used by JECFA (Ansusingha et al.), the authors reported
that the circulating concentration of estradiol 17 β was detectable using their assay in every
prepubertal child studied, and the limit of detection was not substituted for actual values.
112. The EC has relied on the Klein assay to make the claim that circulating levels of estradiol 17 β
in prepubertal children are 100-fold lower than prev iously estimated. However, the EC's support for
the Klein assay appears to be waning. Th e EC notes, "[t]he real values for 17 β-oestradiol in
prepubertal children still remain to be properly documented ." With this statement, the EC appears to
recognize that the results of the Klein assay it has employed in its analysis are unreliable, not
definitive and unvalidated. Dr. Boobis questions the validity of the Klein assay and suggests that
significantly higher concentrations of estradiol 17 β in prepubertal children measured by another
sensitive bioassay (Paris et al., 2002) are more credible. The EC disagrees with Dr. Boobis'
assessment on the basis that the Pari s assay also detects, albeit with poor sensitivity, natural estrogens
other than estradiol 17β (estrone and estriol). However, Paris et al. point out that relative to estradiol
17β, their assay is 1-2 orders of magnitude less sensitive to estrone and estriol. Therefore,
concentrations of estrone and estriol in prepubertal children are not high enough to contribute to the
estrogenic activity measured in this assay.
113. Finally, the EC comments that "[s]ince it is not possible to make the calculation on daily
production rates without knowing the serum levels and the metabolic clearan ce rate in the most
sensitive segment (children), and JECFA considers such data essential for determining an ADI, it
must be accepted that JECFA cannot set the ADI and MRL before the values are known!" This is
why safety factors are used by JECFA. In the case of estradiol 17 β, the safety factors were very
conservative (10-fold for sensitive populations a nd an additional 10-fold for inter-individual
variation).
116

115 The reference cited in the 32 nd JECFA Report for concentrations of estradiol 17 β in prepubertal
children is: Angsusingha K. et al. Unconjugated estrone, estradiol and FSH and LH in prepubertal and pubertal
males and females. J Clin Endocrinol Metab 1974; 39:63-68.
116 See Dr. Boobis Responses (Question 42), p. 39.

114. Question 39
: The EC asserts that it has performed a "quantitative assessment taking into
account the lower endogenous production levels for pr e-pubertal children from the most recent and
reliable data." As demonstrated in the US Comment s on the Experts' Responses, the data relied on by
the EC was generated via an unvalidated assay. 117 The EC concludes that Dr. Boisseau's response is
"false", but fails to address the point made by Dr. Boisseau in his comment, i.e., that "[t]his excess
exposure of these sensitive populations needs to be assessed and compared with the exposure
resulting from the daily consumption of meat from ca ttle which have not been treated with growth
promoters, from other food and products of an imal origin and from their own production of
hormones." The EC presents no evidence of how it has assessed and compared these risks in its
Opinions and thus fails to demonstrate that it h as in fact conducted an exposure assessment for
sensitive populations.
115. The EC "agrees with Dr. Sippell's assessment," regarding which the United States has already
provided detailed comments, 118 and notes that he "demonstrates why there are a number of sources
confirming the values mentioned by Klein et al, 1994 and 1999." To the contrary, the only "source"
that Dr. Sippell provides to support the results of the Klein assay is the publication by Paris et al.
However, as discussed in the US Comments on the Expe rts' Responses at paragraph 66, the results of
the Paris assay do not confirm the values reported by Klein et al . Instead, Paris et al. reported
circulating levels of estradiol 17 β that are at least an order of magnitude greater than those obtained
using the Klein assay. It is important to note that concentrations of estradiol 17 β in prepubertal
children reported by Paris et al. Are much closer to the values u sed by JECFA than to the values
reported by Klein et al.
119
116. Question 40: As noted in Question 38 above, the EC's statement that "JECFA originally used
the limit-of-detection as the 'real' level when they could not measure the levels" is pure speculation for
which the EC provides no evidence. To the contrary , in the peer-reviewed reference used by JECFA,
the authors reported that the circulating concentration of estradiol 17β was detectable using their assay
in every prepubertal child studied, and the limit of detection was not substituted for actual values.
Also, the EC notes that "[t]he real values for 17 β-oestradiol in prepubertal children still remain to be
properly documented." With this statement, the EC appears to recognize that the results of the Klein
assay it has employed are unreliable, not definitive and unvalidated.
117. As noted in Question 39 above, the Paris assay does not validate the Klein assay despite the
EC's statement that "Dr. Sippell provides convinci ng explanations and arguments to accept as valid
the results from the RCBA assay." The EC fails to note Dr. Boobis' conclusion that "[t]he reliability
of the Klein et al assay has yet to be determined." The EC also fails to mention Dr. Boisseau entirely,
who states that "[i]t would be important to know whether these new bioassays have been properly
validated as this SCVPH Opinion says nothing about that and whether the data obtained with these
methods for both men and women are also totall y different from those obtained with the RIA
methods."
118. Finally, the EC fails to note Dr. Boobis' ultimate conclusion which is that, even assuming the
lower levels of circulating estradiol 17 β proposed by Paris et al., the simple fact is that "exposure is
via the oral route, and bioavailability by this route is very low (<5%) (Fortherby, 1996). In addition,
very little of the absorbed hormone will be free, over 95% being bound to plasma proteins such as
SHBG. Such binding reduces the biological activity of the hormone (Teeguarden and Barton, 2004).
Hence, the JECFA ADI would appear to be appropriate for all groups of the population."

117 See US Comments on the Experts' Responses, Section C.4(c).
118 See US Comments on the Experts' Responses, Section C.4(c).
119 The mean concentration of estradiol 17 β in prepubertal boys in the study used by JECFA
(Ansusingha et al. J Clin Endocrinol Metab 1974; 39:63-68) was 5 pg/ml. Corresponding values reported by
Paris et al. and Klein et al. were 1.44 pg/ml and 0.08 pg/ml, respectively.

119. Question 41: The EC comments that the replies of Drs. Boisseau and Boobis are "not entirely
convincing," and in support of this claim cites to alleged risks concerning "estradiol-17-esters and
estradiol-alpha found in residues in treated steers." As noted by the United States in Questions 13, 17
and 28 above, the EC's suggestion that estradiol 17α is present in beef and may be further metabolized
in the human consumer to catechol estrogens is weak for several reasons: (1) Maume et al.120
demonstrated that estradiol 17 α concentrations are elevated only in liver and kidney, but not muscle,
following administration of a single implant (muscle is the tissue most often consumed); (2) the EC
attempted but was unable to provide evidence estradiol 17 α can be converted to catechol estrogens by
human intestinal cells121; and (3) estradiol 17α does not appear to be carcinogenic122 and thus does not
fit into the EC's theory that estrogens are genotoxic carcinogens (via catechol metabolites).
120. The EC also concludes that "the most importa nt studies available provide a bioavailability
rate which is 10% or higher (see the 2 nd EC Written Submission)." However, review of the section of
the Second EC Written Submission which discusses bioavailability of hormone residues
(paragraphs 123 to 124) reveals no information to support the statement that bioavailability of these
residues is greater than or equal to 10%. In fact , as the US has pointed out in its Comments on the
Experts' Responses,
123 the EC has failed to provide any evid ence to contradict the statement by
Dr. Boobis indicating that the bioavailability of natu ral hormone residues < 5-10%. This statement is
supported by several peer-reviewed publications.124
121. Question 42: The EC again attempts to dismiss the responses of Drs. Boobis and Boisseau
because they have "not carried out any research themselves on these hormones and so have no
specific expertise." The United States has addressed this unfounded objection at several points above.
Drs. Boobis and Boisseau are intimately familiar with the workings of JECFA and are highly
qualified to respond to the Panel's question (indeed, Dr s. Boisseau and Boobis were initially proposed
as experts by Codex and JECFA). The EC notes that the experts' responses are "very monolithic and
one-sided", presumably because the responses di sagree with the EC position on whether JECFA
adequately took into account sensitive populations.
122. The EC comments that the responses of Drs. Boisseau and Boobis "are based again on the
assumptions that this hormone [estradiol 17 β] is not genotoxic and that the rate of endogenous
production by prepubertal children is correctly cited in the JECFA report." These are not
"assumptions", however, but reflect the views of bot h experts on the state of the scientific evidence
relating to estradiol 17β. Indeed, both Dr. Boobis and Boisseau have concluded, based on a review of
the EC's Opinions, the science cited therein, and a re view of relevant recent scientific literature that
estradiol 17β is not genotoxic in vivo, nor would it be ge notoxic at levels found in residues in meat
from cattle treated for growth promotion purposes.
125

120 Exhibit EC-78.
121 Exhibit EC-51C.
122 Fritsche S. and Steinhart H. Occurrence of ho rmonally active compounds in food: a review. Eur
Food Res Technol 1999; 209:153-179.
123 See US Comments on the Experts' Responses, paras. 27-30.
124 See Dr. Boobis Responses (Question 43), p. 40.
125 See, e.g., Dr. Boobis Responses (Question 16), p. 20 ("[t]he carcinogenic effects of oestradiol
appear to be a consequence of its endocrine activity"; [t]he evidence is against any direct interaction of
oestradiol or its metabolites with DNA."); Dr. Boobis Responses (Question 18), p. 22 ("[t]o reiterate, whilst
there are reliable studies demonstrating the genotoxicity of oestradiol in certain in vitro tests, the evidence is
against any genotoxicity in vivo .") (note that the EC's own guidelines on genotoxicity testing "require
confirmation of an in vitro positive using an appropriate in vivo assay ." See CVMP (2004). Studies to Evaluate
the Safety of Residues of Veterinary Drugs in Human Food: Genotoxicity Testing, European Medicines
Agency, London); Dr. Boobis Responses (Question 19), p. 22 ("[t]here is no good evidence that oestradiol is
genotoxic in vivo or that it causes cancer by a ge notoxic mechanism. Indeed, the evidence is against this.

123. The EC claims that "there are so many other reasons to believe that the JECFA evaluation is
scientifically wrong, as explained above (old and unr eliable data, etc.), [that] no reliance can be
placed on the replies by these two experts." The Unit ed States has demonstrated at length above that
the EC has failed to demonstrate that JECFA's evaluation is "scientifically wrong" and that the EC has
failed to support its conclusions which diverge from t hose of JECFA with scientific evidence. Thus,
the EC has failed, for purposes of Article 3.3 of the SPS Agreement, to maintain its measure
(permanent ban on estradiol 17 β), which allegedly results in a higher level of protection than that
expressed in the JECFA standard, with a "scientific justification."
124. Question 43
: The EC disagrees with Dr. Boisseau, who opines the estradiol 17 β is "inactive
orally" because, according to the EC "[t]his is simply factually wrong! Oestradiol 17 β is routinely
administered to humans as a powder or in the form of pills that are taken orally." In support of its
argument, the EC cites to Lampit et al . However, the Lampit study very clearly indicates that, to
overcome the low bioavailability of estradiol 17 β, very large amounts of the hormone must be
administered orally to achieve a therapeutic effect. The EC comments that there are "no doubts that
oestradiol-17β is orally active." As noted in Question 8 above, while it is true that estradiol 17 β is
administered orally for some indications, because its bioavailability is so low, very high doses are
required to elicit the desired therapeutic effect. For example, therapeutic doses of estradiol 17 β for
oral administration range from 0.5 - 4.0 milligrams, 126 or 10,000 - 40,000 times higher than the 30-50
ng/person/day derived from eating beef from cattle treated with estradiol 17 β for growth promotion
purposes. In addition to high doses, orally administered estradiol 17β are manufactured as micronized
formulations (particle size < 10 microns) to further in crease bioavailability. Even after micronization,
the bioavailability of a 2 mg dose of estradiol 17β is still only about 5%.127
125. The EC also notes that it has provided "credible recent evidence" that "the bioavailability of
estrogen is low but not insignificant (probably between 5 and 20%, if estrone is taken into account."
However, as noted in Question 41 above, review of the section of the EC's Second Written
Submission which discusses bioavailability of horm one residues (paragraphs 123 to 124) reveals no
information to support the statement that bioavailab ility of these residues is greater than or equal to
10%. In fact, as the United States has pointed out in its Comments on the Experts' Responses, 128 the
EC has failed to provide any evidence to contradict the statement by Dr. Boobis indicating that the
bioavailability of natural hormone residues < 5-10 %. This statement is supported by several
peer-reviewed publications.129
126. The EC "agrees with the summary of this questi on as stated by Dr. Guttenplan." However, as
addressed by the United States in paragraph 29 of its Comments on the Experts' Responses,
Dr. Guttenplan appears to be simply restating the EC's conclusions, which ha ve been shown to be
erroneously based on three studies that do not even address bioavailability.
127. The EC asserts that "[n]either Dr. Boisseau nor Dr. Boobis provide a specific reply to
[Dr. Guttenplan's reply concerning prepubertal child ren]," a statement that the United States finds
perplexing based on a review of Dr. Boobis' very de tailed reply to the question of whether estradiol

Hence, the scientific evidence does not support the EC on this issue, that the levels of the hormones in meat
from treated cattle are not of relevance.") (Emphasis added); Dr. Boisseau Responses (Question 13), p. 11 ("[i]n
conclusion, the EC risk assessment did not support that residues of oestradiol-17 β, despite the genotoxic
potential of this hormone, can initiate and promote tumours in humans.") See also Dr. Cogliano Responses
(Question 18), p. 1 ("it has not been established by th e EC that genotoxicity and cell proliferation would be
induced by levels found in meat residues added to the pre-existing levels occurring in exposed humans.")
126 See 2002 Report on Carcinogens. (Exhibit US-26).
127 Fotherby K. Bioavailability of orally administer ed sex steroids used in oral contraception and
hormone replacement therapy. Contraception 1996; 54:59-69.
128 See US Comments on the Experts' Responses, paras. 27-30.
129 See Dr. Boobis Responses (Question 43), p. 40.

17β in beef presents a risk factor for prepubertal children. 130 Indeed, Dr. Boobis takes into account
the possibility that circulating levels of estradiol 17 β are lower than previously estimated. Using this
assumption, together with the well-supported c onclusion that bioavailability of estradiol 17 β is very
low (< 5%), Dr. Boobis shows very convincingly that consumption of beef fr om cattle treated with
estradiol 17 β for growth promotion does not approach the ADI and thus does not pose a risk to
prepubertal children.
128. Finally, the EC notes that "the bioavailability of the three synthetic hormones has not been
determined by JECFA." However, the EC fails to note that, because the bioavailability is unknown,
JECFA made no correction for bioavailability in its assessment (i.e., it assumed 100% bioavailability).
This is obviously a very conservative approach to this issue, since it is unlikely that the bioavailability
of any of the synthetic hormones would be 100% (a nd even if it were, this potential was taken into
account). Ethinyl estradiol (a synthetic estrogen), fo r example, is 55% bioavailable. Thus, the EC's
attempt to cast doubt on the JE CFA risk assessments and standard s relating to those hormones by
arguing that the bioavailability of the three synthetics is unknown is unconvincing.
129. Question 44: The EC cites Dr. Boisseau's opinion that "Codex did not adopt any guideline for
GVP aimed at minimizing the occurrence of veterina ry drug residues in animal derived food" as
supporting its argument. 131 However, the EC does not clarify to what argument it is referring. The
United States notes that Dr. Boisseau's statement th at Codex has not adopted a guideline on GVP is
unexceptional, and reiterates that the essential anal ysis is whether the EC , in its purported risk
assessment, has properly examined and evaluated a ri sk from the failure of good veterinary practices
(per Articles 5.1 and 5.2 of the SPS Agreement). Th e EC appears to accept that it must evaluate this
risk, if the assumption of failure of controls is to be a mainstay of its purported assessment, by citing
to guidance from the Appellate Body.
130. As the United States has demonstrated, the EC has failed to assess a risk from failure of
controls.132 The experts have confirmed this fact. 133 The EC notes that "there is an important
difference between the theoretical assumption of re specting [good veterinary pr actices] and real life,"
but has simply not evaluated the risk of failure of good veterinary practices, nor has it even
demonstrated through scientific evidence that, save fo r the most unrealistic misuse scenarios (extreme
overdosing), residues of the hormones would reach violative levels.134
131. Question 45 : The EC cites Dr. Boisseau for th e proposition that Codex recommendations
"are only meaningful in countries where GVP are eff ectively implemented." This is so because, as
noted by the United States in its Comments on the Experts' Responses at footnote 222, approvals of or
standards relating to veterinary drugs (or any substance for that matter) are not premised on the notion
of misuse. Any drug can be misused, and most drugs can be harmful if consumed at extremely high,
unrealistic levels. If misuse were used as a base line for veterinary drug approvals, no drugs would
ever be approved. However, as noted by the Appellate Body, for purposes of an SPS measure, a

130 See Dr. Boobis Responses (Question 40), p. 37-39.
131 Note the failure to complain about Dr. Boisseau's laboratory experience in this instance.
132 See US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, Section C.6.
133 See Dr. Boobis Responses (Question 48), p. 42 ("There was no attempt to evaluate the risks from the
resultant exposures on misuse or abuse, either in the papers cited or by the SCVPH (2002) in their evaluation of
these studies. Indeed, the SCVPH (2002) simply noted that 'Therefore, these data have to be considered in any
quantitative exposure assessment exercise', without undertaking such an exercise .") (Emphasis added);
Dr. Boisseau Responses (Question 48), p. 24 ("the European Communities did not conduct any quantitative risk
assessment for growth promoters, it is not possible to say that the scientific evidence referred to by the European
Communities assesses the risk to human health from residues resulting from these misuses/abuses .") (Emphasis
added).
134 See generally Dr. Boobis Responses (Question 62), pp. 50-52; see US Comments on the Experts'
Responses, Section C.6; US Rebuttal Submission, Section II.B.4.

Member may take misuse or failure of controls into account as part of their basis for that measure, but
they must actually evaluate or assess that risk. Th e United States has demonstrated at several points
in its Rebuttal Submission and Comments on the Experts' Responses that the EC has failed to evaluate
this risk.
135 The experts have confirmed this fact. 136 The experts have further confirmed that the
scientific evidence relied on by the EC for its conclu sion that artificial misuse scenarios will lead to
violative levels of hormone residues does not support that conclusion.137
132. As noted by the United States in its Comment s on the Experts' Responses at paragraph 101,
the issue of conditions of use, and whether the EC has evaluated the risk from misuse, is essential to a
determination of whether it has ba sed its permanent ban on estradiol 17 β on a risk assessment within
the meaning of Articles 5.1 and 5.2 of the SPS Agr eement and whether its provisional ban on the five
other hormones is based on available pertinent inform ation within the meaning of Article 5.7 of the
SPS Agreement. The fact that the EC has raised the issue of misuse 138 and devoted considerable
resources to demonstrating the potential consequen ces of misuse implies that it already recognizes
that there are conditions under which residues of the six hormones used for growth promotion are
safe. In other words, if, as argued by the EC, the six hormones pose a risk at levels found in residues
in meat from cattle treated according to good veteri nary practices, then why has the EC tried to
refocus attention on the specter of misuse? The only germane question then would be whether there
are particular conditions of use under which there would be a health risk.
133. Question 47: The EC comments that Dr. Boisseau's response is "partially false", because he
has concluded that "the [EC] did not conduct any quantitative risk assessment for growth promoters, it
is not possible to say that the [EC] took into acco unt relevant control mechanisms with respect to
GVPs in place in the USA." The simple fact is that the experts have reviewed the EC's Opinions and
the studies cited therein, and have determined that the EC has failed to assess this risk. 139 Insofar as
Dr. De Brabander has spoken to the issue of whether or not the EC's Opinions adequately evaluate the
risk from misuse, the United States addresses hi s comments in its Comments on the Experts'
Responses at Section C.6.
134. The EC claims that the "evidence available does show that such misuse or abuse occurs
frequently, because these hormones are administered in combinations and the farmers have incentives
to apply multiple doses." Each of these conclusions is speculative and uns upported by the evidence
presented. The experts' responses have confirmed this fact (note that none of the experts cites to any
of this purported evidence of "frequent" misuse), and the United States has demonstrated at great
length in its Rebuttal Submission at paragraphs 54-66 and Comments on the Experts' Responses at
paragraphs 105-106 that there is in fact great disincentive for commercial feedlot operators to misuse
growth promoters. Programs administered by the US Government include setting safe levels for
veterinary drugs; monitoring for violative residues; and inspection of meat at the ante-mortem, post-
mortem and processing stages. As large commercial operations, US feedlots have great incentive to
comply with the regulations set and enforced by USDA and the FDA. In support of its claim that
"farmers have incentives to apply multiple doses" th e EC has cited in previous submissions to a
document entitled "Beef Cattle Implant Update" aut hored by Dr. Dee Griffin (Exhibit US-27). The
United States has submitted a letter from Dr. Griffin in which he explains that this document does not

135 See US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, Section C.6.
136 See Dr. Boobis Responses (Question 48), p. 42; Dr. Boisseau Responses (Question 48), p. 24.
137 See generally Dr. Boobis Responses (Question 62), pp. 50-52; see US Comments on the Experts'
Responses, Section C.6; US Rebuttal Submission, Section II.B.4.
138 See, e.g., Replies to Questions from the Panel after the First Substantive Meeting by European
Communities, para. 91.
139 See Questions 44-46 above.

support the conclusions taken from it by the EC, and c onfirms that there is absolutely no incentive
(either economic or legal) to misuse growth promoting implants.140
135. Question 48: The EC argues that the responses of Drs. Boisseau and Boobis are misguided
because "as the [EC] has explained several times in previous questi ons, [a quantitative assessment] is
not required under the SPS Agreement as interpreted by the Appellate Body." The United States has
addressed both: (1) the notion that experts should be taking legal considerations into account, and (2)
the EC's overly simplistic reading of the Appellate Body statement above. 141 In any event, the EC
does not rely on its assertion that it may just pro duce a qualitative assessment, but instead states that
"the [EC] has nevertheless performed a quantitative dose-response assessment in particular with
regard to prepubertal children." Thus, it is patent ly unclear how on the one hand the EC can dismiss
the comments of the two experts for analyzing th e EC assessment as though it should have been a
quantitative assessment while on the other claiming that it has conducted just such a quantitative
assessment.
136. The experts do not agree with the EC that it has conducted a quantitative assessment.
Dr. Boobis: "There was no attempt to evaluate the risks from the resultant exposures on misuse or
abuse, either in the papers cited or by the SCVP H (2002) in their evaluation of these studies. Indeed,
the SCVPH (2002) simply noted that 'Therefore, thes e data have to be cons idered in any quantitative
exposure assessment exercise', without undertaking su ch an exercise." Dr. Boisseau: "the European
Communities did not conduct any quantitative risk assess ment for growth promoters, it is not possible
to say that the scientific evidence referred to by the European Communities assesses the risk to human
health from residues resulting from these misuses/a buses." As described in detail in the US
Comments on the Experts' Responses, Dr. De Braba nder does not appear to offer an opinion as to
whether the EC has indeed assessed risks to huma n health from misplaced implants or improper
administration.142
137. The EC also claims that "it is obvious that the higher levels of residues that will inevitably
result from misuse or abuse of these hormones will also exceed the ADIs and MRLs recommended by
JECFA." However, as demonstrated by the United States in its Rebuttal Submission 143 and confirmed
by Dr. Boobis (the only expert to specifically analyze the misuse studies conducted by the EC), this
conclusion is unsupported by the scientific evidence. Dr. Boobis
 (Question 62): "the data generated
by the EU research in question [ i.e., concerning artificial misuse scenarios] do not provide any
indication that it is not possible to conduct a risk assessment of the hormones used as growth
promoters. Nor do they provide any indication that even such misuse or a buse as investigated gives
rise to undue risk from the resultant residues, as in take would only very rarely exceed the ADI and
then only on a rare occasion."
138. In short, insofar as the EC's "risk assessment" for estradiol 17 β relies on the conclusion that
the scientific evidence demonstrates that misuse is lik ely to occur and that residue levels posing a risk
to human health will result, that assessment is not a "risk assessment, as appropriate to the
circumstances" within the meaning of Article 5.1 a nd 5.2 of the SPS Agreement. Further, insofar as
the EC's provisional bans are allegedly based on "available pertinent information" regarding misuse or
residue levels posing a risk to human health r esulting from misuse, those bans do not satisfy the
conditions of Article 5.7 of the SPS Agreement. Si milarly, insofar as the EC's provisional bans are
premised on alleged insufficient scientific eviden ce to conduct a risk assessment, those bans do not
satisfy the conditions of Article 5.7 of the SPS Agreement.

140 See Letter from Dr. Dee Griffin explaining results of Beef Cattle Implant Update. (Exhibit US-28).
141 See, e.g., Section B.2.
142 See US Comments on the Experts' Responses, Section C.6.
143 See US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, Section C.6.

139. Finally, the EC comments that Dr. Boobis' refere nce to "probability" of a risk is inappropriate
in light of the Appellate Body's interpretation that a Member must identify the "possibility" of a risk.
The United States addresses the EC's interpretation of the Appellate Body's decision at several points
above.
144 However, the distinction between "probable" a nd "possible" is irrelevant to an analysis of
what the EC has or has not accomplished in its "risk assessment" in light of the fact that it has asserted
that "the [EC] has [] performed a quantitative dose-response assessment ," which would by its very
nature account for probability. The experts do no t believe that the EC has completed such an
assessment.
140. Question 49 : The EC comments that less trade r estrictive measures "apply only for the
countries that would be prepared to assume that th e possible risk would not undermine their chosen
level of protection." The EC's statement presumes that the WTO Member in question has conducted a
risk assessment, upon which it has based a measure that achieves its appropriate level of protection.
The EC has not accomplished this task.
141. Question 50: The EC asserts that "if GVP is not r espected, then the importing country should
have the right to restrict imports, even with a tota l ban." The United States demonstrates that the fact
that the EC has not addressed the risk of failure of controls or good veterinary practices in its
comments above. Again, the experts have confirmed this point. The United States also reiterates that
a focus on good veterinary practices and their potential failure by its very nature marks an acceptance
that the hormones do not pose a risk to consumers when used in ca ttle for growth promotion purposes
(or conversely, that the EC has failed to prod uce a "risk assessment" or scientific materials
demonstrating such a risk).
142. The United States also notes with interest the EC's agreement with the comments of
Dr. De Brabander, who is of the opinion that "the re are no other measures possible to the [EC], other
than a complete ban, which could address risks arising from misuse and failure to follow good
veterinary practices." Dr. De Br abander's response appears to indicate that there is no way to control
the use of these substances other than a ban. If th is is so, and a complete ban is the only possible
remedial measure, then the controls currently em ployed by the EC for the administration of the
hormones to cattle are also inadequate. Further, as demonstrated by the United States, a ban is not, as
it appears to have been cast by Dr. De Brabander and the EC, a iron clad assurance that no misuse will
ever occur. This conclusion is supported by eviden ce of an active, illegal black market for the use of
hormones in the EC, which chose to impose a ban on their use.
145
143. Question 51 : The EC fails to mention that Dr. Boisseau notes that "the European
Communities did not conduct any quantitative risk assessment for growth promoters, [and] it is
[therefore] not possible to say that the scientific evidence referred to by the European Communities
assesses the risk to human hea lth from residues resulting from th ese misuses/abuses." The United
States also notes that Dr. Boobis has provided a deta iled analysis of the studies relied on by the EC as
evidence of misuse leading to residue levels higher than Codex MRLs or ADIs – he concludes that the
EC materials do not threaten these le vels even under extreme circumstances. 146 The EC states that it
"agrees" with Dr. De Brabander's opinion. The Un ited States addresses the notion that JECFA's data
is "older" and therefore inadequate at paragra phs 22, 92, and 102-104 above, and paragraphs 92 and
111 of its Comments on the Experts' Responses. Th e United States addresses the inapplicability of
the other conditions raised by Dr. De Brabander to the situation at hand (i.e., ban on imported meat) at
Section C.6 of its Comment on the Expert Responses.

144 See, e.g., Section B.2.
145 See US Rebuttal Submission, Section II.B.4.
146 See Dr. Boobis Responses (Question 62), pp. 50-52; see also US Rebuttal Submission,
Section II.B.4.

144. Question 52: The EC's comments on Question 52 appear to distract from the Panel's question,
which is "[d]o the risk assessment of the [EC] or a ny other scientific materials referred to by the [EC]
demonstrate that a potential for adverse effects on human health arises from the consumption of meat
from cattle treated with any of the six hormones in dispute for growth-promotion purposes." The EC
describes the responses of Drs. Boobis and Boisseau as "scientifically incorrect", yet fails to provide
any scientific evidence to counter the opinions of these two experts (opinions which appear to be
based on a thorough review of the materials put forward by the EC in alleged support of its ban).
145. Dr. Boisseau states: "the European Communities did not carry out, strictly speaking, a risk
assessment but provided scientific data and hypoth esis supporting its worries regarding the safety of
these six hormones for human health." He also co ncludes that: "the European Communities did not
demonstrate that a potential for adverse effects on human health arises from the consumption of meat
from cattle treated with any of the six hormones in dispute for growth promotion purposes." The EC's
only response to these conclusions is to tout the conc lusions of its own materials, averring that it has
actually conducted a risk assessment in the form of its 1999, 2000 and 2002 Opinions. The experts do
not agree with the EC's opinion of these materials. The EC claims that Dr. Boisseau must not have
"properly examined" its Opinions because he has concluded that they do not constitute risk
assessments. To the contrary, Dr. Boisseau's answers are detailed and indicate a very thorough
reading of the EC's Opinions and other materials.
146. The EC attempts to dismiss Dr. Boobis' response due to the fact that he concludes that "all of
the major reviews in this topic (i.e., genotoxicity) have concluded that whilst there are data gaps, there
is no evidence that low level exposure is causing harmful effects in humans," and "[t]he carcinogenic
effects observed are entirely consistent with a hormona l mode of action that exhibits a threshold that
would be well above the intake arising from consumption of meat from treated cattle." The EC
focuses on the reference to data gaps as in some fashion supporting its deci sion to permanently ban
the import of meat from cattle treated with estradiol 17β for growth promotion purposes. The EC fails
to emphasize: (1) Dr. Boobis' conclusion that "the re is no evidence that low level exposure is causing
harmful effects in humans; (2) Dr. Boobis' respon se to the Panel's question concerning any potential
data gaps (Question 62) (data presented by th e EC "do not demonstrate any important gaps,
insufficiencies and contradictions in the scientific information used by JECFA"); (3) Dr. Boobis
conclusions to other Panel ques tions relating to genotoxicity ( e.g., Question 18 ["the evidence is
against any genotoxicity in vivo."]); (4) relevant discussion from the Appellate Body ("science can
never provide absolute certainty that a given substan ce will not ever have adverse health effects. We
agree with the Panel that this theoretical uncertainty is not the kind of risk which, under Article 5.1, is
to be assessed.")
147; and (5) relevant discussion from the compliance panel in Japan – Apples (21.5)
(scientific conclusions reached in a risk assessment must actually be supported by the scientific
materials cited therein).148
147. The EC agrees with Dr. Guttenplan's comments. As noted by the United States in Question
43 above, however, contrary to Dr. Guttenplan's conclusion, use of hormones according to good
veterinary practice to promote grow th in cattle will not result in residue levels that exceed relevant
ADIs or FDA's safe levels.
148. Question 53 : The EC notes, regarding Dr. Guttenplan's response, that "this is still another
kind of uncertainty that should be taken into account by the Panel in deciding whether the evaluations
by JECFA are credible and reliable." The Unite d States reiterates that the EC has adopted a
permanent ban on estradiol 17 β based on what it claims is a risk assessment, as appropriate to the
circumstances, within the meaning of Article 5.1 of the SPS Agreement. Theoretical uncertainty may

147 Appellate Body Report, para. 186. Recall that the EC claims to have imposed its permanent ban on
estradiol 17β based on a risk assessment within the meaning of Article 5.1.
148 See Panel Report, Japan – Apples (21.5), paras. 8.145-8.146.

not serve as the basis for such an assessment.
149 Further, the EC fails to note Dr. Guttenplan's
conclusion that "because the concentrations of all of the hormones in beef are so low, [] they would be
unlikely to affect the potency of estrogen." Finally, Dr. Guttenplan notes that "no experiments on
effects of combinations were performed, so some un certainty exists there." If the scientific evidence
does not, through a lack of study, demonstrate a risk or support the conclusion that combinations with
estradiol 17 β would increase risks, the EC may not rely on this conclusion in its "risk assessment"
within the meaning of Article 5.1 of the SPS Agreement.
150
149. The EC also appears to ignore the following conclusion from Dr. Boisseau: "[c]onsidering
that it has been established that progesterone and te stosterone are not genotoxic, it is not likely that
the testing of combinations of progesterone or testosterone with oestradiol-17 β would have led to
synergistic effects compared with those obtained from these individual substances."
150. Question 54: As noted in Question 16 above, the EC claims that Codex has set a "qualitative"
appropriate level of protection, wh ereas the EC has set a "quantitative" level of protection. Yet the
EC then argues that it achieves this "quantitative" level of protection with a "qualitative" risk
assessment. The logic of the EC's argument does not follow. Further, the EC appears to have recast
its level of protection as one of "no risk" as opposed to "no additional risk." A "no risk" level of
protection (assuming that the EC were actually able to demonstrate a risk to human health from
residues of the hormones in its Opinions) would presumably capture, and require the cessation of,
several existing uses of the hormones in cattle in the EC as well as the consumption of numerous
foods containing any of the six hormones.
151. In the event that the EC's appropriate level of protection is still one of zero additional or
additive risk from the use of growth promoting horm ones in meat, as it alleged in its 1999 Opinion,
the United States would note the following expert consensus expressed in response to Question 55
(recall the following statement by the EC: "the [EC] has [] performed a quantitative dose-response
assessment in particular with regard to prepubertal children." 151): Dr. Boobis: "[t]he EC Opinions and
other materials referred to by the EC do not quan tify the extent to which residues of the hormones
contribute to aggregate exposures or cumulative exposures to multiple hazards"; Dr. Guttenplan: "[i]n
general the EC do not attempt to evaluate 'the a dditive risks arising from the cumulative exposures of
humans to multiple hazards, in addition to the endogenous production of some of these hormones by
animals and human beings'"; Dr. Boisseau : "[t]he European Communities did not assess
quantitatively the extent to which residues of growth promoting hormones in meat contribute to
'additive risks arising from the cumulative exposures of humans to multiple hazards, in addition to the
endogenous production of some of these hormones by animals and human beings'."
152. The EC fails to note the following comment fro m Dr. Guttenplan: "[t]he question of what
level of risk has not been addressed by the EC." The EC also states, "[f]or the benefit of
Dr. Guttenplan" that "Codex has not
 set an ADI or an MRL for MGA ye t." (Emphasis in original).
JECFA, on the basis of its risk assessment on MGA, recommended an ADI for melengestrol acetate at
its 54th Meeting in 2004. JECFA recommended MRLs for melengestrol acetate at its 66th Meeting.
153. Question 55: The EC requests that the Panel "disregard [the comments of Drs. Boisseau and
Boobis] because they are purely theoretical and fo r the additional reason that they come from two
experts who have never done any specific research on these hormones nor have they ever published
something on these substances." The United States has addressed similar objections by the EC in its
comments above. In this instance, the United States would also note that the Panel's question is one
of interpreting or analyzing materials and conclusion s drawn in a "risk assessment." Both experts are

150 See Panel Report, Japan – Apples (21.5), paras. 8.145-8.146.
151 EC Comments on the Experts' Responses (Question 39).

eminently qualified in conducting, interpreting a nd analyzing risk assessments and Dr. Boobis has
published on matters of risk assessment theory. 152 The EC's assertion that these experts are not
qualified to respond to the Panel's que stions is spurious, and is a w eak attempt to distract from the
responses of Drs. Boobis and Boisseau, i.e., that the EC has not evaluated the "additive risks" in its
Opinions or scientific materials.153
154. The EC notes that Dr. Guttenplan "would have liked to see much more evidence in the 1999
SCVPH assessment." The United States is surprise d that the EC has put this comment forward in
support of its arguments. One would think, partic ularly in an instance wh ere a hormone such as
estradiol 17β has been permanently banned on the basis of a purported risk assessment, that the EC
would be more hesitant to trumpet the lack of ev idence contained in the "risk assessment." Finally,
the EC fails to note Dr. Guttenplan's ultimate conc lusion, which marks a consensus with Drs. Boobis
and Boisseau: "[i]n general the EC do not attempt to evaluate 'the additive risks arising from the
cumulative exposures of humans to multiple hazards, in addition to the endogenous production of
some of these hormones by animals and human beings'."
155. Question 56: The EC notes its disagreement with the response of Drs. Boobis and Boisseau
that JECFA did in fact consider "additive risks" fro m the other five (provisionally banned by the EC)
hormones. The EC simply restates its own opinion of the matter and speculates that Dr. Guttenplan
would have agreed with the EC but that "words seem to be missing from his reply." Neither of the
EC's comments amount to evidence, particularly the la tter since this is not meant to be an exercise
where the parties put their own words in the expert s' mouths and claim that the experts would support
their positions. Indeed, the EC's claim to powers of extrasensory perception may be as scientific as
the EC measures at issue in this dispute.
156. The words actually contained in Dr. Guttenplan 's response read as follows: "I could find
assessment of additive risks of the hormones in the documents." This response marks consensus with
the opinions of Drs. Boobis and Boisseau. (Dr. Boobis : "JECFA/Codex did consider aggregate risk
from exposure to the natural hormones where pr esent as residues in meat from treated cattle. Such
exposures were considered to represent a trivial increase in overall exposure to hormonally-active
material from other exogenous sources and in par ticular from endogenous sources (JECFA, 2000)."
Dr. Boisseau: "JECFA/Codex considered in its risk assessment of the natural hormones such 'additive
risks' and concluded that, given the wide margin of safety between the maximum estimated intake of
residues for the these hormones and the corresponding established ADIs, that there was no risk for
consumers' health associated with the estimated ingestion of these residues.")
157. The EC argues that "it has clearly been shown that the effects from exposure to different
estrogens are additive ... [t]hus any additional dose will l ead to an increased effect." In support of this
conclusion, the EC cites a study by Rajapakse et al. However, the Rajapakse paper reports that a
heterogenous mixture of 11 estrogenic chemicals exhibited additive effects with estradiol 17 β in a
yeast-based reporter assay. The relevance of this stud y to the dispute is questionable because a yeast-
based assay was used to measure estrogen activit y, and the capacity of yeast-based assays to
accurately reflect physiological effects of hormones in mammalian cells in vivo (e.g., humans) has not
been demonstrated.
158. The EC also notes that "the additive risk need s to be carefully evaluated. For instance,
trenbolone as such has a complex hormonal activ ity (at the same time progestin, androgen and
glucocorticoid)." This comment appears to presuppose that JECFA did not engage in such a careful
evaluation. The experts have confirmed, to the contrary, that JECFA did in fact evaluate these
additive risks. Further, the EC has not provid ed scientific evidence to support the claim that

152 See Curriculum Vitae of Drs. Boobis and Boisseau.
153 The comments of Drs. Boisseau and Boobis are quoted in Question 54 above.

trenbolone mimics the biological effects of glucocortico id. In fact, there is evidence in the literature
that trenbolone exerts antiglucocorticoid activity (Mey er H. Biochemistry and physiology of anabolic
hormones used for improvement of meat production. APMIS 2001; 109:1-8). With respect to
progestin, one of the EC's "17 Studies"
154 provided evidence that 17 β-TBOH, the primary metabolite
of trenbolone found in bovine muscle tissue, binds to the bovine progestin receptor. However,
binding of trenbolone and its metabolites to the human progestin receptor was not investigated, and it
must be emphasized that hormone binding in vitro is not equivalent to demonstrating that the hormone
actually exerts receptor-mediated effects in vivo.
159. Question 57: Rather than commenting on the respon ses of Drs. Boisseau and Boobis, the EC
questions the validity of the question, and notes that it is irrelevant. The EC apparently bases this
conclusion on the fact that the "Appellate Body did not find any violation from the use of some of
these hormones for therapeutic or zootechnical purpo ses." The EC does not provide any citation or
context for this statement, and it is therefore uncl ear how it makes the Panel's question "irrelevant."
Further, as noted above, the experts do not provide a dvice on legal matters, or evaluation of measures
under the SPS Agreement. Rather, they assist a pa nel by providing advice and opinions on technical
details of the dispute, thereby permitting the pane l to reach these legal conclusions. One of the
technical or scientific details at issue is the EC's argument, or assertion, that estradiol 17 β is
genotoxic. This is a fundamental assertion made by the EC in support of its ban, as is evidenced by
the sheer number of times the EC refers to the genotoxic potential of estradiol 17 β in its responses.
The experts have, time and again, indicated that estradiol 17 β is not genotoxic at levels found in
residues in meat from cattle treated for growth promotion purposes.
160. Dr. Boobis concludes: "[t]o my knowledge no account is taken of hormone treatments of
cattle for purposes other than growth promotion, su ch as for therapeutic purpo ses, by the EC in its
assessment of the aggregate or cumulative effect s of the hormones in meat from cattle treated for
growth promotion." Dr. Boisseau notes:
The European Communities thinks that, given the conditions of theses uses of
oestradiol-17β (limited number of treated animals, limited use in the life of these
animals and very low probability to see these animals slaughtered after treatment), the
exposure of consumers to oestradiol-17 β residues resulting from these uses can be
considered as negligible. If this EC assumption can be accepted, it raises nevertheless
a problem of principle as it represents an exception regarding the very strict position
of EC stating that it is not possible to accept any increase of the exposure of
consumers to oestradiol-17β residues. As soon as the European Communities accepts
to considers these residues resulting from th ese therapeutic and zootechnical use of
oestradiol-17β as negligible, it enters in a quan titative, or at least in a semi
quantitative, exposure assessment pr ocedure for these oestradiol-17 β residues and,
starting from that, it has no good reason to object to consider a wider exposure
assessment covering all the residues r esulting from the different sources of
oestradiol-17β.
161. The EC agrees with the conclusion of Dr . Guttenplan. The United States notes that
Dr. Guttenplan's opinion, that zootechnical or th erapeutic use would "not constitute a hazard for
public health" appears to indicate that he is of the opinion that low levels of the hormones are not
genotoxic. This comports with his opinion that an adverse effect is " unlikely if good veterinary
practices are followed."
155

154 Exhibit EC-15.
155 Dr. Guttenplan Responses (Question 15), p. 4.

162. Question 58 : The EC's comments fail to address the responses of the experts.
Dr. Guttenplan: "[t]his is indeed a very weak statement by the EC." Dr. Boobis: "[w]ithin quite broad
limits, higher exposure would not result in any increase in risk." Dr. Boisseau : "[t]he European
Communities did not assess quantitatively the extent to which residues of growth promoting
hormones in meat contribute to 'additive risks arising from the cumulative exposures of humans to
multiple hazards, in addition to the endogenous production of some of these hormones by animals and
human beings'." The EC cites again to the 2002 Report on Carcinogens, which has been discussed in
detail by the United States in its comments on th e EC's comments on Question 12 above and in its
Rebuttal Submission.156 As demonstrated in the US comment s above, the EC has not in fact "shown
that the level of residue formation in meat can be significantly higher and may contain residues from
different metabolites."
163. Question 59: The EC notes "the different views which the replies of the scientists display on
this critical question." The United States did not observe much of a difference of views amongst the
experts, however. In fact, the United States notes a consensus in the experts' responses that, per the
Panel's question, the EC has failed "to identify an y adverse effects on the immune system from the
consumption of meat from treated cattle with the growth promoting hormones at issue." Dr. Boobis :
"[t]he evidence on immune effects of hormones such as oestradiol referred to by the EC does not
identify any adverse effects on the immune system from consumpti on of meat from treated cattle. In
general, clear evidence for immune effects were observed only at high doses." (Emphasis added).
Dr. Guttenplan: "[n]o definitive studies have related inta ke of meat from hormone-treated animals to
the above disorders." Dr. Boisseau: "as these data have not been used by the European Communities
to conduct any quantitative risk assessment likely to establish, for these effe cts associated with the
hormonal properties of growth promoters, thres holds and ADIs different from those proposed by
JECFA, it is not possible to conclude that this scientific evidence allows to identify any adverse
effects on the immune system associated with the consumption of meat from cattle treated with the
growth promoters at issue." (Emphasis added).
164. The EC also comments that the real question is not the one asked by the Panel, but "the
degree of confidence by which the United Stat es and Canada (and JECFA) can ensure [ sic] the Panel
that such adverse immune effects are not possible to occur in meat treated with these hormones for
animal growth promotion. The [EC] thinks that th ey have failed to do so to the required standard of
proof." This statement is flawed for several reasons. First, the EC, as the Member imposing a ban on
meat and meat products, bears the burden of proof of demonstrating that its ban comports with its
obligations under the SPS Agreement. The United States has presented more than sufficient argument
and evidence on each of the scientific points raised by the EC to demonstrate that its ban is not, in
fact, sufficiently warranted or reasonably supporte d by a risk assessment within the meaning of
Article 5.1 of the SPS Agreement. Further, th e United States has presented more than sufficient
argument and evidence to demonstrate that the EC's provisional ban does not satisfy the EC's
obligations under Article 5.7 of the SPS Agreement because there is sufficient scientific evidence for
the EC to have conducted a risk assessment for each of the five hormones and the EC has failed to
base its provisional ban on available pertinent info rmation, all of which indicates that the five
hormones do not pose a risk to human health when used as growth promoters in cattle. In other
words, the United States has discharged its burden of proof in this dispute.
165. Second, the notion that the United States or JECF A must assure the EC that there is no risk of
adverse effects from the use of the five hormones is simply a flawed attempt to distract from the issue
at hand. As noted by the Appellate Body, "science can never provide absolute certainty that a given
substance will not ever have adverse health effects."
157 In other words, it is impossible to prove the
absolute negative, despite the EC's demand for su ch proof from the United States and several of the

156 See US Rebuttal Submission, paras. 38-40.
157 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153.

experts. This is why Members, in imposing trad e restrictions, must adduce evidence and evaluation
of an actual risk against which their restriction or measure mitigates. The United States and JECFA
have conducted risk assessments a nd concluded that the hormones do not pose a risk to consumers
when used as growth promoters in cattle. That is why the United States does not, like the EC, impose
a ban on the importation and sale of beef from treat ed cattle. The EC chooses to ban importation of
this same beef. Therefore, the relevant analysis is whether the EC, in support of its provisional ban on
meat from cattle treated with these hormones, has a dduced sufficient evidence to demonstrate that it
has based its provisional ban on available pertinent in formation and that there is insufficient scientific
evidence for the EC to conduct a risk assessment for the hormon es. The experts' responses
demonstrate generally that the EC has failed to de monstrate either of these elements. The experts'
responses to Question 59 specifically indicate that th e EC's conclusion that immune or other adverse
effects from use of the five hormones as growth promoters in cattle is scientifically baseless.
166. Question 60
: Citing to one of its "17 Studies",158 the EC states that residues of MGA detected
in US beef were "much higher than the levels whic h should have been normally expected." However,
the study that the EC refers to does not report actual r esidue levels in US beef, but is one in a series of
studies in which the EC deliberately overdosed cattle with MGA. The EC may have intended to cite
to another of its "17 Studies"159 in which the author reports that measurement of MGA in 103 US beef
samples "revealed MGA at trace levels in about 75 pe rcent of the samples." No quantitative data are
provided in this report, and there is no suggestion th at the "trace levels" were violative according to
US tolerance levels. Therefore, the EC has faile d to provide any evidence to support its claim that
MGA is conducive to misuse or is administered in a manner that would result in unsafe residue levels
in US beef.
167. Citing again to one of its "17 Studies" 160 in which a misuse scenario was created for MGA,
the EC notes that MGA has a "boosting effect" on residues of estradiol 17 β in meat. It is true that this
study demonstrated a 2.6-fold increase (not 3 -fold as suggested by the EC) in estradiol 17 β
concentrations in fat following treatment with the FDA-approved dose of MGA. This is not
surprising in light of the fact that MGA, at low concentrations, increases ovarian estradiol 17 β
secretion via effects on hormone negative feedback to the hypothalamus and pituitary gland.
However, it should be noted that: (1) the results of this study are preliminary due to the limited
number of animals used (only 2-4 animals per treat ment group), and (2) the mean concentration of
estradiol 17 β in fat following MGA treatment (26 ppt) is 19 times lower than the US tolerance
(480 ppt).15161 Again, the evidence put forward by the EC simply fails to substantiate its claim that the
use of MGA according to good veterinary practices resu lts in hormone residues above the levels that
have been determined to be safe for human consumption.
168. The EC's comment that it is interesting that the United States has used melengestrol acetate
since the 1970s but that JECFA only evaluated MGA until 2000 is a non sequitur. The approval of
MGA in the US domestic market has no bearing on where and when JECFA was "seized of a request"
to evaluate MGA. As noted above, JECFA has set an ADI (62nd Meeting) and proposed an MRL (66th
Meeting) for MGA.
169. The United States has reviewed the materials put forward by the EC "following the Appellate
Body 1998 hormones decision" and did not find an y evidence of a risk from melengestrol acetate
when used as a growth promoter in cattle. The Un ited States discussed these studies in detail in its
Rebuttal Submission. The experts reviewed these st udies and concur with the opinion of the United
States. Dr. Boobis : even "whilst [misuse] would lead to increased exposures, it is still unlikely this

158 Exhibit EC-16.
159 Exhibit EC-19.
160 Exhibit EC-16.
161 See 21 C.F.R. § 556.240.

would exceed the ADI, and certainly not for any period of time. It is also an unlikely occurrence in
view of the way in which the hormones are used and controlled." Dr. Guttenplan : "[t]he potential for
excessive exposure to MGA exists by both routes (ora l and implantation), but it cannot be stated and I
am not aware of which route is more likely to c ontribute to high levels in meat." Dr. Boisseau : "the
scientific evidence referred to by the European Communities does not identify and evaluate wether
there is a difference in terms of potential adver se effects on human health from the consumption of
meat from cattle treated with hormones for gr owth promotion purposes when these hormones are
administered as feed additives or implanted." The United States notes that, apart from its general
conclusion that its studies support its ban on MGA, the EC fails to provide any specific discussion as
to how or why this is actually so. Rather, the EC simply complains that the experts must not have
read its materials.
170. The EC provides commentary on levels of residues in the event of non-removed implants.
The United States has provided lengthy discussion of how implants are injected into the ears of cattle,
that those ears are then discarded, and that ante- a nd post-mortem inspections ensure that the implants
are not entering the food chain.
162 The EC's commentary speculates that an ear with an intact implant
will enter the food chain. Again, this is nothing mo re than a paper exercise, and there is no evidence
that this event will occur. The EC dismisses Dr. Boobis' response as "unfounded." However, the
United States notes that Dr. Boobis has engaged in a detailed review of the materials underpinning the
EC's ban, and has based his conclusion on the results of these very materials. 163 The United States
reached the same conclusion after review of the scientific materials put forward by the EC.164
171. Question 61 : The EC attempts to dismiss the opinion of Dr. Boisseau because "he has not
done nor published any work on these hormones." As noted at several points above, this is not a
legitimate reason for dismissing of an experts' opini on, nor is it a criteria that the EC has applied
across the board with other experts (or even with the same expert, depending on the answer).
172. The EC questions the "objectivity and impart iality" of the reasoning of Drs. Boobis and
Boisseau. The EC's rhetoric regarding the responses of these experts is inappropriate. Rather than
citing to evidence that actually supports the EC's stance on these hormones in an attempt to discount
the experts' advice, the EC instead seeks to impugn the credibility of the impartial individuals who
have agreed to assist the Panel in its endeavours. Rather than a negative, the United States views the
fact that Drs. Boisseau and Boobis "have both serve d on a JECFA panel that examined some of these
hormones" as testament to their qualifications, as well as evidence against the EC's refrain that they
lack relevant experience in the study of the hormones.
173. The EC notes that the opinions of Drs. Boobis and Boisseau are "based on the assumption that
there is a dose-response relationship (threshold), despite the accumulation of so much recent evidence
showing that this assumption can no longer be valid for a number of these hormones, certainly for
oestradiol 17β, progesterone, testosterone and zeranol." Despite having stated as much throughout its
comments, the EC again ignores that none of the experts agree with the EC's opinion

Estradiol 17 β: Dr. Boisseau : "the scientific evidence relied upon in the SCVPH
Opinions does not support the conclusion that the carcinogenic effects of oestradiol-
17β are related to a mechanism other than hormonal activity."
15165 Dr. Boobis: "[t]he
carcinogenic effects of oestradiol appear to be a consequence of its endocrine

162 See, e.g., US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses,
Section C.6.
163 See Dr. Boobis' review of the Daxenberger studies on MGA and misuse. Dr. Boobis Responses
(Question 62), p. 51.
164 See, e.g., US Rebuttal Submission, Section II.B.4.
165 Dr. Boisseau Responses (Question 16), p. 12.

activity." Dr. Guttenplan
: "an adverse effect cannot be ruled out, but it is unlikely if
good veterinary practices are followed." Dr. Cogliano : "it has not been established
by the EC that genotoxicity and cell proliferation would be induced by levels found in
meat residues added to the pre-existing levels occurring in exposed humans."166
Testosterone and progesterone : Dr. Boisseau (regarding both hormones): "the
scientific evidence relied upon in the SCVPH Opinions does not support the
conclusion that the carcinogenic effects of [either hormone] are related to a
mechanism other than hormonal activity." 167 Dr. Guttenplan : "Progesterone,
testosterone have been extensively inv estigated and the assess ment seems sound and
is based on the no effect level and a safety factor. (JECFA meeting 52, report-WHA
TRS 893)." Dr. Boobis : "[t]here is no evidence that the hormones testosterone or
progesterone have genotoxic potential."168
Zeranol: Dr. Boisseau: "the scientific evidence relied upon in the SCVPH Opinions
does not support the conclusion that the carcinogenic effects of zeranol are related to
a mechanism other than hormonal activity."
169 Dr. Guttenplan : "[t]here is no
conclusive evidence presented by the EC that the five hormones other than
oestradiol-17β [ i.e., including zeranol], when consumed as residues in meat have
genotoxic potential." 170 Dr. Boobis : "[t]here is no convincing evidence that
trenbolone acetate, MGA and zeranol are genotoxic. They were negative in a range
of tests for genotoxicity ... [t]hus, there is no evidence that any of the hormones are
genotoxic in vivo at the levels found in meat from treated animals. Even if GVP were
not followed, the levels of exposure to the hormones would be such that no
genotoxicity would be anticipated in vivo."171
174. The EC complains that Drs. Boobis and Boisseau reached their conclusions despite the fact
that "available evidence is insufficient or there ar e total gaps in our knowledge." Again, the EC
presents no evidence in support of this conclusion, a nd it is a statement with which the experts do not
agree.172
175. The EC invokes Drs. Sippell, De Brabander a nd Cogliano, and notes that although "they have
not expressed themselves on this precise question" th e EC is sure that, had they responded, they
would have supported the EC's argument. This is simply conjecture, and it contradicts the EC's earlier
objection to experts responding to questions whic h they had not previously indicated themselves
capable of answering.173
176. Question 62: The EC refers to its comments on the responses of Drs. Boisseau and Boobis
from the previous question. The United States does the same. The EC insinuates its opinion for that
of Dr. Boisseau, noting that Dr. Boisseau's statement only makes sense if it "was to be understood that
the gaps and uncertainties identified by the EC in its risk assessment are such as to require further
research and investigation." The United States finds Dr. Boisseau's response to be sufficiently clear
without the EC's additional assistance: "these ne w data do not demonstrate any important gaps,

166 Dr. Cogliano Responses (Question 18), p. 1.
167 Dr. Boisseau Responses (Question 21), p. 16.
168 Dr. Boobis Responses (Question 21), p. 24.
169 Dr. Boisseau Responses (Question 21), p. 16.
170 Dr. Guttenplan Responses (Question 21), p. 6.
171 Dr. Boobis Responses (Question 21), p. 24.
172 See US Comments on the Experts' Responses, Section C.3(c).
173 See EC's Comments on the Experts' Resp onses (Question 2) ("Dr. Boisseau's reply that 'In my
e-mail of 26/04/06, I have indicated that I did not think that I am in the position to reply to this question' calls
into question the reliability of his answer to question no 1 and indeed to the other questions.)

insufficiencies and contradictions in the scientific information used by JECFA for conducting its risk
assessments."
177. The EC complains of Dr. Boobis' lack of "any sp ecific expertise" and claims to have clarified
Dr. Boobis' responses on the basis of " a more care ful examination by a real expert." The EC's
rhetoric is inappropriate and misplaced. The purpose of this exercise is not to have the EC rewrite the
responses of the experts whose assistance the Panel h as solicited with the opinions of "real experts"
assisting the EC in arguing this dispute. This would defeat the entire purpose of the Panel's seeking
advice from an impartial group of experts in order to make sense of the technical arguments raised by
the parties. The United States has provided a detaile d argument of why the Leffers study reviewed by
the EC's "expert" does not stand for the proposition the EC contends it does.174 Dr. Boobis concludes
the following regarding alleged gaps in the scientific information:
There is little information in the scientific studies initiated by the EC since 1997 that
support the contention that they have identified important new gaps, insufficiencies
and contradictions in the scientific info rmation and knowledge on the hormones, and
that additional studies are necessary before the risks to health of consumption of meat
from treated animals can be assessed. Whilst additional information has been
obtained on a number of aspects of the hormones in question, this was often not
definitive, sometimes it was not relevant, in some instances it confirmed or expanded
on previous knowledge. The evidence obt ained did not indicate any additional
concern regarding the risk from exposure to residues of the hormones in meat from
cattle treated for growth promotion.
178. The EC agrees with Dr. Guttenplan, who it conte nds "provides some examples of the areas in
which gaps and uncertainties have been identified and indicates some of the additional research that is
required before the EC would be able to conduct a more complete risk assessment." The EC's
endorsement of Dr. Guttenplan's response is ironic si nce the majority of the purported gaps identified
in his response relate to estradiol 17 β, the hormone for which the EC claims to have conducted a risk
assessment within the meaning of Article 5.1 of the SPS Agreement.
175 If, as the EC appears to
contend in its comments, there are s ubstantial gaps in this data, it is unclear how the EC can justify a
permanent ban on its use. The United States notes the following comments from Dr. Guttenplan
regarding the provisionally banned hormones, for which the EC claims substantial gaps in the
scientific data:
Question 21
: "There is no conclusive evidence presented by the EC that the five
hormones other than oestradiol-17 β, when consumed as residues in meat have
genotoxic potential. There is some evidence that certain of the hormones have
genotoxic potential, but generally the potential is weak. Testosterone and
progesterone are negative in genotoxic assays. Zeranol can induce transformation of
breast epithelial cells in culture with effici ency similar to that of estradiol, but the
mechanism is not known, and it is negative or marginally active in other assays.
Trenbolone is either negative or margina lly active in in vitro genotoxic assays. MGA
is negative in genotoxicity assays. Any genotoxic effects of the five hormones are
likely to be minimized by good veterinary practice."
Question 61
: "Progesterone, testosterone have b een extensively investigated and the
assessment seems sound and is based on the no effect level and a safety factor.
(JECFA meeting 52, report-WHA TRS 893)." "Melengestrol acetate. The
assessment for melengestrol acetate see ms sound. Thorough metabolic and

174 See US Comments on the Experts' Responses, paras. 79-80.
175 See EC First Written Submission, para. 17.

estrogenic studies have been carried out. Actu al levels in beef were not provided.
(JECFA 62 FNP 41/16)."
176
D. CONCLUSION
179. The EC's comments on the experts' responses fa il to provide any evidence or argument that
discounts the experts' advice to the Panel. As de monstrated by the United States in its 30 June 2006
filing on the experts' responses and the US comments above, the experts' responses confirm that the
EC has failed to base its permanent ban on meat and meat products from cattle treated with
estradiol 17β for growth promotion purposes on a risk assessment within the meaning of Article 5.1 of
the SPS Agreement because, inter alia, the EC has failed to conduct a "risk assessment, as appropriate
to the circumstances" and has failed to support the sci entific conclusions set out in its Opinions with
the scientific evidence cited therein. In addition, the EC's bans on meat and meat products from cattle
treated with any of the other five hormones are not provisional measures within the meaning of
Article 5.7 of the SPS Agreement because they are not based on "available pertinent information" nor
is there insufficient scientific evidence to conduct a risk assessment for each of the hormones.