CANADA – CONTINUED SUSPENSION OF OBLIGATIONS IN THE EC – HORMONES DISPUTE
Document: Report of the Panel Addendum
Date: 31 March 2008
Document codes: WT/DS321/R/Add.6; WT/DS321/R.
Complainant: EU
Respondent: Canada
Third parties: Australia, Brazil, China, Taiwan, India, Mexico, New Zealand, Norway, U.S.
Dispute stage: Appellate Body
Agreements cited: Art. I, II  GATT 1994Art. 3.7, 22, 23.1, 23.2, 21.5  Dispute Settlement Understanding (DSU)

CANADA – 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 Canada 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 Canada 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-152

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 relationshi p ..." 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 untreated 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)

3. The responses provided by the experts and intern ational organizations generally confirm the
explanations of the scientific and technical issues provided by Canada in its previous submissions.
1
With some limited exceptions, these responses indicat e that (1) the EC's regulatory opinions do not
properly evaluate the potential for adverse effects to human health from residues of oestradiol 17 β in
meat from cattle treated when used for growth pr omotion, and (2) that the available scientific
evidence is sufficient to conduct an assessment of the risks from consuming meat that has been treated
with any of the remaining five HGP.
4. The issues are complex, however, and Canada su bmits these comments with a view to further
assisting the Panel in understanding these matters. Ca nada has sought to identify where the experts
and international organizations ag ree with one another and with Canada's explanations of the
scientific and technical issues, to reconcile an y inconsistencies among the responses received, to
elaborate on certain responses that require clarification or amplification, and to address advice by
certain experts that is not supported by the available scientific evidence. In several instances, Canada
suggests follow-up questions that the Panel may consider asking the experts at a later date.
II. COMMENTS ON THE RESPONSES FROM THE EXPERTS
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.

5. Canada has no comment on the responses to this question provided by Drs. Boisseau, Boobis
and Guttenplan other than to note that there doe s not appear to be any material disagreement
concerning these terms.
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.

6. Drs. Boobis and Guttenplan provide definitions of the terms identified by the Panel. While the
responses appear to be consistent, Dr. Boobis' reply is more thorough and supported by references.
7. A few key definitions warrant highlighting. A ccording to Dr. Boobis, carcinogenicity is the
"[p]rocess of induction of malignant neoplasms", or what is commonly referred to as cancer.
Neoplasms, which are new and abnorma l formation of tissue, can be malignant or benign. Malignant
neoplasms (cancer) pose the greatest risk to human health. In contrast, mutagenicity is the "[a]bility of
a physical, chemical or biological agent to induce he ritable changes (mutations) in the genotype in a
cell as a consequence of alterations or loss of genes or chromosomes (or parts thereof)." Mutagenicity
does not necessarily lead to the formation of malignant neoplasms (cancer).
8. Genotoxicity is the "[a]bility to cause gene tic damage." Genotoxicity does not necessarily
lead to mutagenicity, if the damage to the DNA is not inherited into the genotype of the affected cell.
Genotoxic potential means that a compound "possesses characteristics such that it might be capable of
causing genotoxicity (usually in vivo), based on considerations such as the results of tests in vitro."

1 Canada First Written Submission, at paras. 86-131; Ca nada First Oral Statement, at paras. 41-73; and
Canada Rebuttal Submission, at paras. 45-146.

Dr. Boobis emphasizes that "[i]t remains to be de termined whether genotoxicity is indeed expressed
in vivo, i.e. that the potential is realized". Thus, "pot ential" does not refer to the statistical likelihood
that the genotoxic mode of action will occur in vivo, but, rather that the genotoxic mode of action is
theoretically possible.
9. Combining these concepts, if a compound is only identified as having genotoxic potential, the
compound is still several steps removed from carcinoge nicity. The genotoxic potential will have to be
realized in vivo, the genetic damage to the cell would have to be "fixed" into the genome created a
mutated cell, the mutated cell in turn would have to replicate to form neoplasms, and the neoplasm
would have to be malignant (cancer). Any one of th ese steps may be thwarted by the various effective
and redundant defence and repair mechanisms.2
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.

10. This question was also posed to the intern ational bodies (Question 3). Drs. Boisseau and
Boobis, as well as JECFA and Codex, responded.
11. Dr. Boobis, JECFA and Codex identify a signi ficant number of relevant international
guidance documents. A review of this documentation indicates that the development of risk
assessment techniques by international organizations has been ongoing for decades. The International
Program on Chemical Safety (a collaborative vent ure between the World Health Organization, the
United Nations Environment Programme and the In ternational Labour Organisation), as early as
1987, published a comprehensive guidance document entitled Principles for the Safety Assessment of
Food Additives and Contaminants in Food, Environmental Health Criteria 70 (EHC 70).
3 EHC 70
sets out principles and approaches to safety asse ssment for food additives and contaminants,
consolidating of 30 years of JECFA experience. While not specific to veterinary drug residues, much
of the detailed guidance is relevant to the risk assessment generally, including the assessment of
veterinary drugs.
12. Building on EHC 70 and recognizing that the assess ment of veterinary drug residues can pose
specific issues, the WHO and FAO have issued sev eral guidance documents outlining risk assessment
techniques and procedures specific to veterinary drug residues. These include:
• JECFA, Procedures for Recommending Maximum Residue Limits – Residues of
Veterinary Drugs in Food (1987 – 1999) , (Rome: FAO/WHO, 2000) (JECFA
Procedures);4

• WHO, Residues of veterinary drugs in food – WHO procedural guidelines for the
Joint FAO/WHO Expert Committee on Food Additives (Geneva: January 2001);5

2 For a clear explanation of the relationship between genotoxic potential and carcinogenicity, see
Dr. Boobis' answer to Question 19.
3 The International Program on Chemical Safety, Principles for the Safety Assessment of Food
Additives and Contaminants in Food , Environmental Health Criteria 70 (Geneva: WHO,1987); online:
http://www.inchem.org/documents/ehc/ehc/ehc70.htm (Exhibit CDA-43).
4 Exhibit CDA-44 ("JECFA Procedures for Recommending Maximum Residue Limits").
5 Attached to JECFA's answers to the Panel's questions.

• WHO, Residues of veterinary drugs in food – Guidelines for the preparation of
toxicological working papers for the Join t FAO/WHO Expert Committee on Food
Additives (Geneva: August 1996);
6 and

• FAO, Residues of veterinary drugs in food – FAO procedural guidelines for the Joint
FAO/WHO Expert Committee on Food Additives, (Rome: September 2002).7

13. In addition to the above, Codex also identifies several relevant guidance documents, including
the Statements of principles relating to th e role of food safe ty risk assessment 8 and the Working
Principles for Risk Analysis for Application in the Framework of the Codex Alimentarius
Commission.9
14. The JECFA Procedures for Recommending Maximum Residue Limits is a consolidation of
JECFA's collective experience developing risk assessment techniques and methodologies for
veterinary drugs from 1987 to 1999. This document confirms that many of the general risk assessment
techniques and methodologies developed by internationa l organizations are also relevant to the risk
assessment of veterinary drugs.10
15. As JECFA points out in its response to Question 3, there is a continuous effort to update and
harmonize international level risk assessment techniques for chemicals. However, the fact alone that
international risk assessment techniques are continuo usly subject to refinement and elaboration does
not, a priori , suggest that existing international tec hniques and methodologies are inadequate or
problematic.
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 the hormones at issue? [see para. 192 of EC
Rebuttal Submission (US case)].

16. The experts confirm the accuracy of the EC's st atement referred to in the Panel's question.
However, while the statement is technically correct , the experts confirm that the absence of a Codex
standard does not imply an absence of interna tionally developed risk assessment guidelines or
principles. Furthermore, the experts confirm that JECFA based its risk assessment of the hormones at
issue on relevant international risk assessment methodologies and techniques.
17. Specifically, Dr. Boisseau states in his reply that:
In the conduct of its risk assessment with r espect to the hormones at issue, as for all
the other pharmacologically active substances used in veterinary medicine, JECFA
has followed the general rationale used by all the countries which have assessed the
safety of veterinary drug residues. This ra tionale has been internationally harmonised
through scientific conferences and it is possibl e to say that there was an international
non written agreement on this rationale.

6 Exhibit CDA-45.
7 Attached to JECFA's answers to the Panel's questions.
8 Quoted in the answer by Codex to Question 3 addre ssed to the international bodies; reproduced in the
Procedural Manual of the Codex Alimentarius Commission (15th edition), at p. 161.
9 Annex 6 to the answers by Codex.
10 For example, a significant portion of the general toxicological data requirements that have been
established for food additives and contaminants are equa lly applicable to veterinary drug residues. JECFA,
Procedures for Recommending Maxium Residue Limits, at p. 3 (Exhibit CDA-44).

18. Referring to the documents identified in his res ponse to Question 3, Dr. Boobis also confirms
that JECFA relied upon a number of relevant guida nce documents in its risk assessments of the
hormones at issue. Moreover, Dr. Guttenplan acknowledges that the "principles for risk
assessment…were used in determining Acceptable Daily Intakes (ADI) for estradiol, progesterone,
and testosterone."
19. It is apparent from the experts' answers th at international organi zations have expended
considerable effort in developing risk assessment tec hniques relevant to the assessment of veterinary
drugs. Much of that effort has been the result of contributions from the EC's own Member States11 and
much of the resulting guidance used as a basis for decisions taken by European regulatory authorities,
including the Committee for Veterinary Medicina l Products (CVMP). Thus, any suggestion that
relevant risk assessment techniques or guidance de veloped by international organizations for the
conduct of veterinary drug risk assessments do not exist is baseless.
Q5. Please briefly describe the three components of a risk analysis exercise (risk assessment,
risk management and risk communication) and explain how they differ.

20. The responses of all four experts who replied to th is question appear to be consistent with the
response provided by Codex to a similar question posed to the international bodies (Question 5). In all
cases, the experts and Codex identify a functiona l separation between risk assessment and risk
management. In the context of food safety, a risk assessment is a scientific process in which data are
evaluated and on this basis, together with the wei ght of evidence and expert judgment, a conclusion is
reached as to the nature of the hazards, the potentia l risk to exposed individuals and the extent to
which exposure is within those levels cons idered to be without appreciable risk.
12 The descriptions of
risk assessment provided by the experts are consistent with the definition of risk assessment set out in
Annex A(4) of the SPS Agreement, namely an evaluation of the potential for adverse effects on human
health.
21. Risk management, on the other hand, is the process of weighing policy alternatives,
considering the risk assessment and other factors rele vant for the health protection of consumers and
for the promotion of fair trade practices, and, if needed, selecting appropriate prevention and control
options.13 This description of risk management is akin to the process of identifying and selecting SPS
measures appropriate to the circumstances.
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.

22. This question is the same as Question 6 addressed to the international bodies. Drs. Boisseau,
Boobis and Guttenplan, as well as JECFA and Codex, respond to this question. Their answers reflect
principles for the conduct of a risk assessment generally accepted by the international community.
Hazard Identification

23. With slight differences, the experts and inte rnational bodies appear to agree that hazard
identification involves the determination of whet her an agent has the potential to cause adverse
effects.

11 For instance, the UK Department of Health and Social Security was instrumental in providing
support for EHC 70.
12 See e.g. Dr. Boobis, at p. 12.
13 Codex, at p. 6.

Hazard Characterization

24. Again, with slight differences, the experts appear to agree that hazard characterization
involves the quantitative and/or qualitative evaluation of the nature of the identified adverse effects
caused by the agent. The experts agree that, where possible, hazard characterization should involve a
dose-response assessment and a determination of wh ether a threshold can be established below which
no adverse effects can be expected to occur.
14 The outcome of this step is the establishment of a No-
Observed-Adverse-Effects-Level (NOAEL), from which an Acceptable Daily Intake (ADI) is derived.
The experts' answers are consistent with JECFA' s response that "[d]ose-response assessment is an
integral part of each assessment and is an essentia l part of the hazard characterization step." As
Canada has stated previously, central to this disp ute is whether the EC's failure to complete this
"integral part" of the risk assessme nt implies that the assessment conducted by the EC fails to meet
the requirements of the SPS Agreement.15
Exposure Assessment

25. In terms of exposure assessment, the experts conf irm that the objective of this step is to
evaluate quantitatively exposure by relevant population groups to the substance under review. In order
to do so, risk assessors typically use a "food basket" which is based on "available intake data at the
upper limit of the range for individual consump tion of edible tissues and animal products". 16 The
"food basket" used by JECFA is as follows:
Muscle 300 g
Liver 100 g
Kidney 50 g
Tissue Fat 50 g
Milk 1.5 litre
Eggs 100 g

26. The Panel may wish to seek clarification fro m the experts on whether the food basket is
adjusted to reflect estimated consumption by prepubertal populations.
Risk Characterization

27. The experts all appear to agree with the Codex definition of risk characterization: a qualitative
and/or quantitative estimation, including attendant uncertainties, of the probability of occurrence and
severity of known or potential adverse health e ffects in a given population based on the three
preceding three steps of a risk assessment. Dr. Boisseau specifics that:
… the goal of the risk analysis for these compounds is not to assess qualitatively and
quantitatively the likelihood and the gravity of the adverse effects for the health of
consumers associated with the veterinary drug residues they are exposed to through
the animal derived food[,] but to protect consumers' health from any adverse effect
associated with these residues. [emphasis added]

14 Dr. Boisseau, at p. 5; Dr. Boobis, at p. 13.
16 JECFA, Procedures for Recommending Maxium Residue Limits ,, at p. 31 (Exhibit CDA-44). Also
see JECFA, Evaluation of certain veterinary drug residues in food: Fifty-second Report of the Joint FAO/WHO
Expert Committee on Food Additives , WHO Technical Report Series 893 (Geneva: WHO, 2000), at p. 67
(Exhibit CDA-16).

28. The experts confirm that to achieve the goal of no adverse effects on human health,
Maximum Residue Limits (MRL) are established. Th e purpose of the MRL is to ensure that the
exposure to residues of the veterinary drug in ques tion consumed in edible animal products does not
exceed the ADI established for that drug.
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]

29. The same question was put to the internationa l bodies (Question 7). JECFA, Drs. Boobis and
Boisseau respond. The experts confirm that JECFA was aware of "non-linear situations" and took
these into account in conducting its risk assessment for the hormones at issue.
30. The assumption implicit in the EC's statement is that, in non-linear situations, no threshold
can be established below which there is no appreciable risk. As the experts and JECFA point out, this
is simply not true. JECFA explains that "probab ilistic or deterministic approaches can be applied,
independent [of whether] a compound is assumed to act via a threshold mechanism, i.e. non-linear"
and "non-linearity is assumed if the adverse effect of a compound is caused via a mechanism with a
threshold of effect." Thus the important issue is not linearity, as the EC has asserted, but rather
whether a threshold mechanism operates and an ADI can be set. In deciphering the EC's logic,
Dr. Boobis states that the EC's assertion presupposes a specific outcome to the risk assessment, i.e.,
that no threshold can be set below which no adverse effects occur. This is simply not true. JECFA
explains that "[i]n such a case, as for the hormon es, a no-effect-level can be determined from which
an ADI can be established."
31. In support of its "non-linearity" claim, the EC argues that "here, the risks are embedded in
changes in exposure to biologically active molecules which may, within minute differences in their
bioavailability, have dramatic effects, such as tu rning on or off complete developmental programs of
the human genome, or inducing pathological conditions."
17 The EC presents no evidence that the
minute increases in exposure to the hormones resulti ng from residues of growth promoting hormones
in treated meat "turn[] on or off complete deve lopmental programs of the human genone, or induc[e]
pathological conditions." This is not surprising give n that wide variation in background levels of
hormones endogenously produced by humans and c onsiderable exposure to dietary sources of
hormones.
Q8. Please describe the procedure followed by JECFA in the identification of ADIs and the
development of recommendations on MRLs. Please identify and describe any steps that are
taken in the risk assessment process to build a margin of safety into the final recommendation.

32. This question is the same as Question 10 addressed to the international bodies. The
description provided by the experts of the procedur e followed by JECFA in the identification of ADIs
and development of recommendations on MRLs appear s to be consistent with JECFA's answer to
Question 10. In terms of the steps taken in the risk assessment process to build in a margin of safety,
Dr. Boobis describes similar steps in his an swer to Question 12 when addressing scientific
uncertainty. Canada would like to highlight the following:

17 EC Replies to Questions from the Panel, Question 24. at para. 140. The EC refers to no scientific
evidence in support of this assertion.

Establishment of ADI

33. The experts and JECFA have confirmed that the ADI is the highest quantity of residue that
can be ingested on a daily basis over a lifetime that w ill not result in adverse effects to health, or, as
Dr. Boobis states in response to a later question, that will pose zero risk.
18 The establishment of the
ADI is a two-step process involving the determin ation of a NOAEL and the application of safety
factors.19 A NOAEL is established for each advers e effect. The NOAEL from the most sensitive
adverse effect is used as the NOAEL for the substance. 20 "Safety factors" are applied to the NOAEL
to take into account inherent uncertainties in extrapol ating animal toxicity data to potential effects in
human beings and variation in the human species. 21 The experts and JECFA confirm that JECFA
typically uses a default safety factor of 100, representing a safety factor of 10 for extrapolation from
animal to human species and a safety factor of 10 for diversity within the human population. Smaller
safety factors may be justified in certain circum stances, such as where the NOAEL is derived from
data from human studies. Extra factors may be applie d in other circumstances such as where there is
an identifiable sub-group that might reasonably be e xpected to be more sensitive than the group in
which data were obtained (e.g., children relative to adults).22
34. In the case of the six hormones at issue, JECFA has established the following ADIs:
Hormone JECFA Meeting Exhibit # Pg. ADI Safety
Factor
Oestradiol 17β 52 nd Meeting CDA-17 60 0-0.05 µg/kg 100
Progesterone 52 nd Meeting CDA-17 62 0-30 µg/kg 100
Testosterone 52 nd Meeting CDA-17 64 0-2 µg/kg 1000
Trenbolone Acetate 34 th Meeting CDA-30 107 0-0.02 µg/kg 100
Zeranol 32 nd Meeting CDA-29 145 0-0.5 µg/kg 100
Melengestrol Acetate 54 th Meeting CDA-31 179 0-0.03 µg/kg 200

Proposal of an MRL

35. The experts have confirmed that the MRL is a ri sk management tool designed to ensure that
exposure to veterinary drug residues does not exceed the established ADI. In other words, if residues
are within the MRL, then the ADI is unlikely to be exceeded and no adverse effects to human health
are to be expected.
36. The experts and JECFA have set out various ways in which a margin of safety is built into the
establishment of the MRL. In this regard, th e risk assessor makes the following conservative
assumptions:
• the parent substance and all its metabolit es have the same potential toxicity unless
demonstrated otherwise;
23

• the parent substance and all its metabolit es are considered to be bioavailable (or
biologically active) unless demonstrated otherwise;24 and

18 Dr. Boobis, answer to Question 54.
19 JECFA's answer to Question 10, at p. 6.
20 Dr. Boobis, at p. 15.
21 JECFA's answer to Question 10, at p. 6.
22 Dr. Boobis, at pp. 14-15.
23 Dr. Boisseau's answer to Question 13(B), at p. 10.
24 Dr. Boisseau, at p. 23; Dr. Boobis, at pp. 14-15.

• the standard food consumption figures (the "f ood basket"), used to estimate exposure,
overestimate actual consumption.25

37. As can be observed from the foregoing, JECFA has developed risk assessment techniques that
build into its risk assessments a significant margin of safety.
Q9. Please confirm or comment on the followin g 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]

38. The same question was put to the international bodies as Question 11. JECFA states in its
response that "[i]f there are substantial data ga ps and important information missing, JECFA can not

establish an ADI." [emphasis added] This confirms Canada's statement quoted in the question was
correct. Thus, given that JECFA established ADI for all six hormones at issue, it is reasonable to infer
that the record was complete and sufficient for all hormones in question.
39. The experts who responded to this question, Dr. Boisseau and Dr. Boobis, confirm that
Canada's statement is correct as a general rule. Dr. Boobis identified a number of exceptions in which
JECFA might issue an ADI without a complete dataset. As he explains, the "critical issue is whether a
sufficiently cautious default can be adopted in the absence of certain information." He concludes that
"JECFA would require a complete data base unless it could adopt default assumptions that would if
anything lead to a more conservative risk assessment than would be the case otherwise".
Q10. In paras. 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?

40. The same question was put to the interna tional bodies as Question 12. JECFA's answer
clarifies that its role is to conduct risk assessments. It will only consider the health impact of specific
risk management options, if requested to do so by the Codex Committee on Residues of Veterinary
Drugs in Foods (CCRVDF). The response by Codex to Question 12 indicates that it is not necessarily
limited to the three risk management options liste d in the question, and mentions the possibility of
developing "codes of practice" through the CCRVDF.
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]

41. The experts with specific expertise on risk assessments of veterinary drugs explain that a
qualitative risk assessment may be c onducted under certain limited circumstances. Both Dr. Boisseau
and Dr. Boobis agree that a qualitative risk asse ssment should comprise the main steps of a
conventional risk assessment, including hazard iden tification, hazard characterization and exposure
assessment. Both experts also agree that if the mode of action is such that a dose-response relationship
cannot be established and, thus, no safe intake thr eshold can be set, then a quantitative dose-response
assessment is not necessary. However, Dr. Boobis e xplains that even where the need for detailed
dose-response analysis would be questionable, a risk assessment still needs "scientific rigour", a

25 Dr. Boisseau, at p. 7.

statement supported by the Appellate Body's description of the risk assessment process as
characterized by "systematic, disciplined and objective enquiry and analysis."
26
42. Dr. Boisseau provides examples of where JECFA has based its conclusions on a qualitative
risk assessment and declined to recommend an ADI ( e.g., chloramphenicol and nitroimidazole). Both
Dr. Boisseau and Dr. Boobis also confirm in subse quent answers that, in respect of the hormones at
issue in this dispute, a dose-r esponse assessment can be undertaken and a safe threshold (ADI) can be
established for each hormone. 27 Thus, it can be inferred that, acco rding to internationally developed
risk assessment techniques, a risk assessment for these substances that does not include a dose-
response assessment would be incomplete.
43. Dr. Cogliano also responds to this question with references to IARC's practice in developing
its monographs. However, the type of assessment to which Dr. Cogliano refers only satisfies the first
element of a risk assessment contemplated by the SPS Agreement , which includes both the
identification of adverse effects aris ing from the substance at issue and the evaluation of the potential
of occurrence of such effects. In this regard, it is important to recall the Appellate Body's conclusion
regarding previous IARC Monographs relied upon by the EC in the first hormones dispute. After
citing the Panel's conclusion that the IARC Monographs were "in the nature of general studies of…the
carcinogenic potential of the named hormones" and ha ve not "evaluated the carcinogenic potential of
those hormones when used specifically for growth promotion purposes "28, the Appellate Body, in
EC – Hormones, concluded as follows:
We believe that the above findings of the Panel are justified. The 1987 IARC
Monographs and the articles and opinions of individual scientists submitted by the
European Communities constitute general studies which do indeed show the
existence of a general risk of cancer; but they do not focus on and do not address the
particular kind of risk here at stake – the carcinogenic or genotoxic potential of the
residues of those hormones found in meat derived from cattle to which the hormones
had been administered for growth promotion purposes – as is required by paragraph 4
of Annex A of the SPS Agreement. Those general studies, are in other words, relevant
but do not appear to be sufficiently specific to the case at hand.
29
44. It is also worth noting that Codex has estimate d general principles in relation to the use of
quantitative information. For instance, the Codex Statements of principles relating to the role of food
safety risk assessment include requirements that "[f]ood saf ety risk assessment should be soundly
based on science, … ", and that "[r]isk assessment should u se available quantitative information to the
greatest extent possible …" [emphasis added] More over, paragraph 20 of the Working Principles for
Risk Analysis for Application in the Framework of the Codex Alimentarius restates the same
principles while recognizing that a risk assessment may also take into account qualitative information.
Paragraph 23 of the Working Principles also provides:
Constraints, uncertainties and assumptions having an impact on the risk assessment
should be explicitly considered at each step in the risk assessment and documented in
a transparent manner. Expression of uncertain ty or variability in risk estimates may
be qualitative or quantitative, but should be quantified to the extent that is
scientifically achievable. [emphasis added]

26 EC – Measures Concerning Meat and Meat Products (Hormones) , Report of the Appellate Body,
WT/DS26/AB/R, WT/DS48/AB/R, adopted February 13, 1998, at para. 187 (EC – Hormones).
27 See answers to Questions 36 and 37.
28 EC – Hormones, Report of the Appellate Body, at para. 199.
29 Ibid., at para. 200.

Q12. How is scientific uncertainty addressed in risk 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 uncertainty 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?

45. Both Drs. Boisseau and Boobis explain the numero us ways in which scientific uncertainty is
addressed in a risk assessment. Dr. Boobis' response is worth quoting at length:
One way of dealing with uncertainty is [1 ] to default to the worst case in the absence
of evidence to the contrary. Hence, the most sensitive relevant endpoint in the most
sensitive species is used as the basis of th e risk assessment. [2] In extrapolating to
humans a default factor of 10 is used to allow for species differences, which assumes
that humans are more sensitive than the expe rimental species. [3] A further factor of
10 is included for interindividual differe nces. These differences may be due to
gender, genetics, life stage or other factors. [4] However, to some extent such
differences have already been taken into account in the choice of endpoint, as this
will usually represent the most sensitive lifest age, gender and to some extent genetics
by using data from the most sensitive species. [5] Where there are additional
uncertainties, such as no NOEAL or the absen ce of a non-critical study, an additional
safety factor will be included, and this is almost always conservative, as when the
data gaps have been completed, the appropriate safety factor is almost always less
than that used to account for these data gaps. [6] The residue may be assumed to be
all as active as the most active moiety, which is almost always a conservative
assumption. [7] Dietary intake is based on conservative data for food consumption.
[8] It is also assumed that all meat that could contain veterinary drug residue will
contain the residue and that this will be pr esent at the high end of the range (MRL or
other appropriate level). [9] In respect of the ADI, the assumption is that intake will
be at this high level for a lifetime, when in reality there will be occasions when little
or no meat is consumed or that which is consumed contains less or even no residue.
In their risk assessment of the hormones, JECFA applied all of these approaches to
dealing with the uncertainty.
46. Dr. Boisseau indicates that the EC "did not consider any scientific uncertainty", because it had
decided as a matter of "principle" that it was not possible to establish an ADI for genotoxic
substances. Clearly, however, this "principle" is one of selective rather than general application, if one
considers that the EC knowingly allows its population to consume, without so much as a warning, the
very same "genotoxic" substance ( i.e., oestradiol 17β) naturally present in many dietary sources ( e.g.,
milk, eggs, meat) and in oral contraceptives, at levels many times higher than that which would be
present as residues of growth promotants.
B. 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 accordance with good veterinary practice? To
what extent does the EC risk assessment eval uate the potential occurrence of these adverse
effects?

47. Drs. Boisseau, Boobis and Guttenplan chose to an swer this question, and all of them indicate
that the EC's "risk assessment" ( i.e., the three SCVPH opinions) wa s deficient in one manner or

another in its evaluation of the potential occurrence of adverse effects
(whether carcinogenic,
genotoxic or other) from the consumption of residues of oestradiol 17β in meat from treated animals.
48. Dr. Boisseau acknowledges the general intern ational agreement that oestradiol 17 β is
associated with "carcinogenic potential", but also confirms what Canada has explained in its
submissions: that this potential is due to the hormonal effect of estrogens,30 which requires "prolonged
exposure to high concentrations" for adverse effects to occur. Exposure to residues of these hormones
from meat from treated cattle does not generate the "high concentrations" considered by Dr. Boisseau
and others to be required for these effects to occur.
49. Dr. Boisseau further confirms that, despite th e growing acknowledgement that oestradiol 17 β
may have "genotoxic potential", there is no ev idence that this potential is realized in vivo (as opposed
to in vitro). He points out that, as a result of what must be done to observe a genotoxic effect ( i.e., use
far higher than realistic doses of the parent compound w ith an assumption that the toxicity is the same
as that for residues), such tests are more useful for identifying modes of action than for assessing
dose-response relationships. He therefore disagre es with the EC, as do most other experts and
international scientific bodies, that no threshold can be set for substances for which "genotoxic
potential" has been identified.
50. Dr. Boisseau also shares Canada's concern that the EC did not conduct any "quantitative risk
assessment" of other adverse effects, known to be dose-dependent, that would lead to the
establishment of thresholds and ADIs that would differ from those established by JECFA. The
quantitative assessment referred to here is not the sam e as that contemplated by the Appellate Body
when it found that a risk assessm ent need not quantify the risk.
31 Rather, Dr. Boisseau refers to
analyses of the dose-response relationship that is completely absent from the EC's opinions, but which
is a crucial component of internationally accepted risk assessment techniques and is essential if the
EC is to demonstrate that existing international st andards are insufficient to achieve its appropriate
level of protection.
51. Dr. Boobis also cites the flaws in the EC opinions as a risk assessment, in particular that the
analysis "focused primarily on hazard identification" . He confirms what Canada has explained in its
submission,32 that there was "little in the way of hazard characterization and no independent exposure
assessment". Without the data generated in these steps, which have been shown in responses to
previous questions to be necessary components of a risk assessment, Dr. Boobis advises the Panel that
"it was not possible [for the EC] to complete th e risk characterization phase". Most importantly,
Dr. Boobis indicates that the EC "essentially stopped" the assessment of risk after it concluded that no
thresholds of exposure could be est ablished. In light of the later re sponses of all the experts about the
issue of thresholds, 33 this observation by Dr. Boobis is critical: it means that the EC decision not to
conduct a complete risk assessment was based on a conclusion that is not supported by the evidence.
52. For his part, Dr. Guttenplan similarly finds that the EC's evaluation of the potential
occurrence of adverse effects is "weak", even as he accepts that the EC did identify potential adverse
effects. However, identifying potential adverse effects ( i.e., the hazard identification) is only the
starting point of a valid risk assessment. As for the remaining components of such an assessment,
Dr. Guttenplan points to several deficiencies in the EC's opinions ( i.e., limited utility of animal
models, absence of epidemiological studies, etc.) and concludes that "little can be inferred about the
potential occurrence of the adverse effects".

30 Canada First Written Submission, at paras. 95-97; Canada Rebuttal Submission, at paras. 90-96.
31 EC – Hormones, Report of the Appellate Body, at paras. 186-187.
32 Canada Rebuttal Submission, at paras. 76-85.
33 See Canada's comments below on the experts' responses to questions 16-19.

Q14. In your view, does the risk assessment undertaken by the European Communities on
oestradiol 17 β 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?

53. In addition to their responses to the more ge neral question above, Drs. Boisseau, Boobis and
Guttenplan also agree with Canada that the EC failed to follow the Codex guidelines on risk
assessments. The experts share Canada's concerns that the EC (and SCVPH) took significant and
unjustified short-cuts in the conduct of its risk assessment.
34
54. Dr. Boisseau is very critical of the EC's d ecision not to follow the Codex guidelines,
concluding that the EC's own science did not jus tify the abandonment of these guidelines. At most,
Dr. Boisseau concedes that the sci entific studies relied upon by the EC indicate that it should have
refined its approach to assessing exposure to hormone residues, not abandon the entire risk assessment
methodology. But as Canada has indicated in its submissions, 35 the EC has done very little that
resembles an exposure assessment.
55. Dr. Boobis states simply that the EC did not fo llow Codex guidelines (which include the four
steps), adding that even if the EC concluded that oestradiol 17 β was genotoxic – a conclusion with
which Dr. Boobis disagrees in his response to Ques tions 15, 18 and 19 – the EC should still have
followed all four steps.
56. Dr. Guttenplan also finds it difficult to give the EC's risk assessment anything more positive
than a "mixed rating". For many of the same reaso ns advanced by the others, Dr. Guttenplan finds
fault in the EC's hazard characterization and risk characterization, the first because of the questionable
relevance of studying hamster kidneys for the task at hand and the second because it is "qualitative at
best", and not based on any data or confirmed by epidemiological studies. Moreover, Dr. Guttenplan's
limited support for the EC's exposure assessment is left unexplained; he simply declares it to be
"thorough", which is itself an odd declaration in light of the EC's own admission that it did not,
because it could not, conduct an exposure assessment.36
C. 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 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]

57. Drs. Boisseau, Boobis and Guttenplan all agree with Canada that the mere identification of
oestradiol 17 β as a carcinogen is not itself sufficient to conclude that there are potential adverse
effects when consumed as residues in meat from treated animals. Not only is the evidence of the
substance's carcinogenicity in general not indicative
 of carcinogenicity of the substance from a given
source, but most of the experts conclude affirmativ ely that there would be "no appreciable risk" of
adverse effects from exposure from this one minimal source of oestradiol 17β.

35 Ibid., at paras. 83-85.
36 EC Rebuttal Submission, at para. 141; 1999 SCVPH Opinion, at p. 20 (Exhibit CDA-2).

58. The experts arrive at this conclusion follo wing the tried and tested methods of the
international scientific community. Dr. Boobis' explains the relationship between findings of
carcinogenicity in general and adverse effects from this one source in particular by stating that "the
entire basis of risk assessment in [ sic] based on the fact that there is a relationship between dose and
effect"; and second, that a "key consideration in th e risk assessment is whether there is a threshold in
the dose-response". Applying these two principles to oestradiol 17 β, which is naturally produced in
the human body, Dr. Boobis considers that the ma in task is to determine whether the additional
exposure to hormones from meat from treated animals changes the circulating levels of the hormone.
The answer given by JECFA (and not contradicted by the EC) is that it does not; therefore, even
though oestradiol 17β is considered a human carcinogen when exposure is prolonged and significantly
greater than the ADI, exposure to it from this single source does not present such risks.
59. The experts do not agree on whether the answer would be different if good veterinary practice
(GVP) was not followed. On the one hand, Drs. Bo isseau and Guttenplan indicate that there might be
a potential for adverse effects if GVP were not follo wed. As general answers, they are not really
surprising. These experts are simply applying a general scientific principle that changes in
assumptions in the course of predicting an outcome ( e.g., cancer) may change the prediction. While
neither expert would guarantee that the outcomes w ould be the same if GVP had not been followed,
they did not state categorically, nor could th ey have, that the failure to follow GVP will
 create the
potential for adverse effects to occur. In fact, even the studies on this issue submitted by the EC
demonstrate that multiple hormone implants resulted in residues that were still less than the ADIs.37
60. Whereas the answers of Drs. Boisseau and Guttenplan are based on general principles about
the effect of changing assumptions, Dr. Boobis d eals more specifically with the conditions of
exposure from the failure to follow GVP. He states th at failure to follow GVP would only affect the
cancer risk if it resulted in exposure levels above the ADI, and even then it would have to be on a
"regular basis". Since he believes that neither of these conditions will be met, Dr. Boobis advises that
the failure to follow GVP "would not be associated with any increase in risk of cancer".
61. Dr. Boobis' response suggests an obvious point, but one worth emphasizing: that it is not the
conditions under which the hormones are administered that cause adverse effects, but the resulting
hormone exposure levels, which de pend on many factors. This reinforces the Appellate Body's
findings that the EC has to demonstrate through an assessment of the risk arising from the failure to
follow GVP that it increases the risk of adverse effects. 38 As the advice from the experts confirms, the
EC has not done so.
62. For his part, Dr. Cogliano simply asserts, without explanation or support, that the
identification of oestradiol 17 β as a human carcinogen indicates consuming it via meat from treated
cattle has the potential to cause adverse effects. His an swer seems to suggest that he believes there is
no threshold below which adverse effects will not o ccur, a point which he does not support and which
is also contrary to the findings of JECFA, Codex and his colleagues who also answered this question.
His point that adverse effects depend on the "presen ce of hormones in the meat that people consume"
is also inconsistent with the fact that hormones ar e already present in meat regardless of whether it is
derived from treated cattle or non-treated cattle.
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]

37 Canada Rebuttal Submission, at para. 110 and Exhibit EC-52.
38 EC – Hormones, Report of the Appellate Body, at paras. 205-208.

63. Drs. Boisseau and Boobis agree with Canada th at any potential carcinogenic effects of these
hormones are related to their hormonal activity, wh ich is dose-dependent and exhibits a threshold
exposure level below which these effects will not occur. More importantly, they agreed that the
evidence relied upon by the EC does not support the conclusion that adverse effects will arise from
anything other than the hormonal activity of th ese substances, such that existing international
standards will be insufficient to meet the EC's level of protection.
64. Dr. Boobis provides extensive analysis of the EC's controversial theory that carcinogenic
effects of these hormones may be caused by a mechan ism other than hormonal activity, in particular a
genotoxic mechanism. Dr. Boobis acknowledges that some studies demonstrate that the hormones
may be genotoxic in vitro , but categorically rejects, with supporting evidence, that this has been
demonstrated in vivo. He advises that "guidelines for genotoxicity testing require confirmation of an
in vitro positive result using an appropriate in vivo assay" for such in vitro positive result to have any
validity. Dr. Boobis provides a number of explanations of why this in vivo confirmation is so critical,
in particular because the in vitro conditions that allow the genotoxicity to be observed do not contain
the many defence and repair mechanisms that would exist in vivo to prevent cell damage from
occurring. The failure to observe positive genotoxicity test results in vivo confirms that these defence
and repair mechanisms operate to ensure that ther e is a threshold exposure below which genotoxicity
will not occur.
65. Only Dr. Guttenplan attempts to support the EC's conclusion, but he does so with no analysis
of his own, choosing instead simply to cite the EC 's regulatory opinions. In simply referring to the
conclusions of the SCVPH, Dr. Guttenplan has in fact failed to adequately answer the question, which
was not whether the SCVPH had concluded that there were non-hormonal adverse effects, but
whether the scientific evidence relied upon by the SCVPH supported that conclusion.
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]

66. Drs. Boisseau and Boobis confirm the evidence th at catechol metabolites are largely absent in
meat from treated animals, and that even if such metabolites were present in small quantities (which
they acknowledged may be possible), it would not be enough to make the genotoxic potential of
oestradiol 17β an issue with respect to residues in meat from treated animals.
67. Dr. Boobis advises that the absence of catechol metabolites confirms the effectiveness of the
mechanisms for detoxification and elimination of these metabolites in vivo. He further confirms that
the formation of such metabolites in meat would only be relevant to the risk assessment if it were true
that catechol metabolites were responsible for adver se effects and if it were true that there is no
threshold for any effects for which they are respons ible. In his response to this and other questions,
Dr. Boobis advises that neither of these are th e case, so the presence or absence of catechol
metabolites preformed in meat does "not impact on the risk assessment".
68. Dr. Guttenplan's seemingly contrary acknowle dgement that "only very small amounts of
catechol metabolites were detected" overstates the case. As other experts confirm in greater detail, the
study commissioned by the EC that looked at the issue observed that "no metabolites coming from the
catechol oestrogen biosynthesis could be isol ated" and that "metabolic studies performed in vivo …
and in vitro… failed to demonstrate a significant aromatic hydroxylation activity that would lead to
catechol oestrogen derived metabolites".39 In other words, contrary to Dr. Guttenplan's claim, catechol

39 Exhibit EC-51A, at p. 18.

metabolites have not been found in meat from treated animals, at least not in detectable quantities, and
to the extent that they exist in undetectable quan tities, they are not present in sufficient quantities to
create a genotoxic potential. In light of the discrep ancy between the explicit conclusions of even the
EC evidence on this issue and the unsupported clai m of Dr. Guttenplan, the Panel may wish to ask
him to support his claim.
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 ca se), 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]

69. Drs. Boisseau and Boobis both confirm Canada 's explanation that the EC has failed to
demonstrate that oestradiol 17 β is genotoxic in vivo.
40 They acknowledge what other reputable
international scientists and scientific authorities now see as the "genotoxic potential" of oestradiol
17β, but deny that this "potential" is relevant in vivo at doses to which humans are exposed from
consuming meat from treated animals.
70. Dr. Boobis reiterates his detailed analysis in response to Question 15 that sets out the many
reasons for which genotoxic potential identified in in vitro will not be confirmed in vivo. In particular,
he highlights the important point that the genotoxi city that has been "observed in vitro would be
expected to exhibit a threshold." The EC's c onclusion that there is no threshold below which
genotoxicity will not occur runs directly counter to this advice, and is therefore not supported by the
scientific evidence.
71. Dr. Boisseau also highlights an attempt by the EC to misrepresent certain of JECFA's
findings. In particular, he points to the EC's efforts to represent JECFA's findings about the
"genotoxic potential" of oestradiol 17 β, combined with its decision to establish an ADI, as a finding
that oestradiol 17β is
 "genotoxic". Dr. Boisseau correctly points out in his answer to Question 13 that
there is a difference between a substance having "genotoxic poten tial" and it being "genotoxic",
confirming that JECFA has never considered that oestradiol 17 β is "genotoxic". Dr. Boisseau then
explains the rationale behind JECFA's decision to a dopt an ADI in 1999, pointing to the need to place
exposure to oestradiol 17β from this source into context. His explanation was confirmed by JECFA in
its answer to Question 20. Citing exposure valu es identified by JECFA, Dr. Boisseau advises the
Panel that exposure to residues of the three natu ral hormones remains a mere fraction of the ADI
(conservatively estimated between 0.03% and 4.0%, depending upon the substance). In other words,
the EC claims to the contrary notwithstanding, 41 JECFA's establishment of an ADI for the three
natural hormones was not related to its findings a bout "potential genotoxicity". In fact, just the
opposite is true: JECFA would not have established ADI s at all if it considered the hormones to be
genotoxic in vivo.
72. For their part, Drs. Cogliano and Guttenplan both suggest that the EC has demonstrated that
oestradiol 17 β is genotoxic, but neither of them does so with reference to supporting scientific
evidence. Dr. Cogliano simply repeats the EC's ass ertion that it is, and endorses an excerpt from the
EC Rebuttal Submission that was itself from a re port of the UK Veterinary Products Committee

40 See Canada First Written Submission, at paras. 95-98; also see Canada Rebuttal Submission, at
paras. 86-98.
41 EC Rebuttal Submission (Canada case), at paras. 100-101.

(VPC).42 However, the EC neglected to include, wh en quoting from that report, the very next
paragraph, which concluded that:
[a]lthough there is evidence that oestroge n metabolites may be directly genotoxic
in vitro, in vivo their formation is affected by opposing activation and inactivation
metabolic pathways, the presence of anti- oxidants and DNA repair capacity and thus
it is likely this genotoxicity will have a thresholded response.43
73. Even as Dr. Cogliano endorses the EC's selective quote from the VPC Report, he also appears
to understand and accept the broader context of that quote when he admits that "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-ex isting levels occurring in exposed humans". This observation brings
him in line with Drs. Boisseau and Boobis, who e xplain that there is a threshold exposure below
which genotoxicity will not occur.
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 the re exist a safe level below which intakes from
residue should be considered to be safe. Therefo re 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 you r 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]

74. Drs. Boisseau and Boobis (and, to a lesser extent, Dr. Cogliano, but not Dr. Guttenplan)
explicitly confirm the main point that Canada has ma de from the beginning of this dispute: that for
substances that are endogenously produced by the human body, there simply must be a threshold
below which no adverse effects are observed, or el se humanity would have been wiped out by cancer
millennia ago. This simple reality, repeatedly ig nored by the EC, but stressed time and again by
experts from around the world,44 contradicts directly the EC's claim about the genotoxicity of the three
natural hormones, and its corresponding claim that no threshold can be established.
75. Even though JECFA acknowledged that oestradiol 17 β may have genotoxic potential, it
decided to establish an ADI. If there had been no threshold below which exposure to the substance
would be safe, JECFA would not have been able to establish an ADI. More recently even, the
European Food Safety Authority (EFSA) (the succe ssor to the SCVPH) has recognized thresholds for
genotoxic substances when it concluded that, "based on the current understanding of cancer biology
there are levels of exposure to substances wh ich are both genotoxic and carcinogenic below which
cancer incidence is not increased (biological thresholds in dose-response)".45
76. As pointed out by many of the experts in their responses, the consensus among the experts on
the issue of thresholds is based not only on their scientific understanding of the modes of action of the

42 EC Rebuttal Submission (Canada case) at para. 124. See also UK, Veterinary Products Committee,
Risks Associated with the Use of Hormonal Substances in Food-Producing Animals: Draft report of the UK
Veterinary Products Committee, May 2005 (UK VPC Draft Report), at p. 27 (Exhibit CDA-26).
43 Ibid.
44 Not only do the experts relied upon by the Panel confirm this, but this conclusion has been confirmed
by all international bodies that have addressed the issue. See, for example, VPC and JECFA.
45 EFSA, Opinion of the Scientific Committee on a Request from EFSA Related to a Harmonised
Approach for Risk Assessment of Substances which are both Genotoxic and Carcinogenic (Request No. EFSA-
Q-2004-020, adopted October 18, 2005) (The EFSA Journal, 282, 1-31, 2005), at p. 18 (Exhibit CDA-46).

substances but also on the absence of any epidemiological studies that demonstrate a relationship
between exposure to hormones and adverse health effects.
77. Dr. Cogliano's response does not directly address the question. He offers his view that the
difference between the parties to the dispute is simply one of differing assumptions
 about the nature
of genotoxic mechanisms. But the question is not about what Canada or even the EC assume about
genotoxic mechanisms, but rather which assumption is supported by the science, in particular whether
the "genotoxic potential" of these hormones exhibits a threshold below which it will not be realized
in vivo. He also does not cite any evidence that suppor ts the EC's conclusion that no such threshold
exists.
78. Dr. Guttenplan appears to be more explicit in his suggestion that the science relied upon by
the EC supports its conclusion, but his answer is at the same time contradictory. In admitting that
"repair enzymes are unlikely to be saturated" at physio logical levels, he seems to suggest that there is
a level at which repair will always occur. He then goes on to say that "[f]or any toxin the dose
determines the risk". These two statements together suggest that at the dose to which consumers are
exposed to oestradiol 17 β residues from treated meat, the "genotoxic potential" of these hormones is
not relevant. This is consistent with what the ot her experts have indicated: that there is indeed a
threshold below which these hormones are safe.
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 bein gs 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?

79. Drs. Boisseau, Boobis and Guttenplan all consider the EC's conclusions about the absence of
thresholds to be inconsistent w ith the Codex standards, whereas it remains somewhat unclear what
Dr. Cogliano thinks about this issue. However, to th e extent that most of the experts found that the
EC's conclusions on the matter are unsupported by the evidence and are "questionable", they support
the existing Codex standards.
80. Dr. Boobis elaborates on the concept of "increment al risk"; first by clarifying what in his
mind is the more important issue of whether low le vels of exposure affect "circulating levels". He
makes three important points: (1) homeostatic c ontrol mechanism combined with low bioavailability
means there is a "range of exposures for which there are compensatory alterations in endogenous
levels"; (2) depending on endogenous levels, which vary by physiological state, some increments in
exposure may "perturb endocrine effects", but th ese exposures would have to be above the ADI; and
(3) genotoxic effects, to the extent that they w ill occur at all, will respond more to the natural
variations in endogenous levels than the small changes in these levels that might arise from hormones
from meat from treated animals. All of these poi nts support the conclusion that there are clear
thresholds for exposure to exogeno us sources of substances that are also produced endogenously in
variable amounts.
81. The experts' answers also confirm again that even though JECFA acknowledged that
oestradiol 17 β has "genotoxic potential", this acknowledgeme nt did not generate concern about the
safety of the substances and therefore did not aff ect its recommendation. JECFA essentially did not
consider that this "genotoxic potential" was rele vant to the carcinogenic effects of oestradiol 17 β,
which it considered dependent on hormonal activity.
82. For his part, Dr. Guttenplan attempts to justif y the EC's conclusion with reference to new
"areas of concern, such as developmental e ffects". However, Canada has some difficulty
understanding the relationship Dr. Guttenplan seems to be drawing between the purported inability to

set thresholds for genotoxic substa nces and the identification of new concerns that appear to result
from hormonal activity. Dr. Guttenplan seems to be using new concerns abou t one type of adverse
effect (developmental effects) to demonstrate that concerns about th e occurrence of another type of
adverse effect (genotoxicity) are justified. The Pa nel may wish to ask Dr. Guttenplan to elaborate on
the relationship he suggests in this response.
Q21. Does the scientific evidence referred to by the European Communities demonstrate that
the five hormones other than oestradiol 17 β, 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]

83. Drs. Boisseau, Boobis and Guttenplan all refu te the EC's claims about the potential
genotoxicity of the other five hormones. Drs. Boisseau and Boobis survey the various tests by which
these substances failed to show genotoxicity (the former in his answer to Question 16), and
Dr. Guttenplan simply states generally that there is "no conclusive evidence presented by the EC" that
they have genotoxic potential.
84. Whereas Drs. Boisseau and Boobis both indicate without qualification that the failure to
follow GVP would not affect the "genotoxic potential" of the five hormones, Dr. Guttenplan's advice
on this matter contradicts his advice given in r esponse to other questions. In some of his other
responses, he seems to support the EC's contention th at no threshold can be established for substances
that are genotoxic. At the same time, he provides in his response to this question that genotoxic effects
will be "minimized by good veterinary practice". To the extent that the purported risks from failure to
follow GVP are that cattle (and ultimately consumers) will be exposed to higher doses, Dr. Guttenplan
seems to be suggesting a dose-response relationshi p between exposure to hormones and genotoxicity.
The Panel could ask him to clarify his views on whether there is a dose-response relationship.
Q22. How would you define in vivo DNA repair mechanisms? How effective or relevant are
in vivo DNA repair mechanisms with respect to potent ial genotoxic effects from residues of the
growth promoting hormones at issue when consumed 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]

85. Drs. Boobis and Guttenplan both extensively discuss the effectiveness of DNA repair
mechanisms in what the former calls a "flexible and very efficient DNA repair process" and what the
latter considers a mechanism with "considerable re dundancy". They also both agree that the repair
mechanisms that operate to repair the "consider able oxidative DNA damage" (Dr. Boobis) caused by
endogenous processes are as effective for damage caused by exogenous agents.
86. Importantly, Dr. Boobis points out that because of DNA repair mechanisms, the creation of
DNA adducts does not in itself always indicate th at mutations will occur, let alone malignant
neoplasms (i.e., cancer). He further confirms that the ki nd of DNA damage that might be expected
from hormones from meat from treated animals ( i.e., active oxygen) is also the kind of repair
mechanism that is "amongst the most efficient".

87. For his part, Dr. Guttenplan makes some unsuppor ted statements, in particular when he
suggests that repair mechanisms are "not really relevant" to a risk assessment of oestradiol 17 β
because the repair will not be different than for other types of damage. He does not attempt to
describe the "other types of damage" and whether re pair of these other types of damage means that
such damage does not lead to adverse effects. In the absence of a specific assessment of the
effectiveness of the repair mechanisms for comparab le types of damage, the statement that they are
comparable is not helpful.
88. Quite apart from the lack of clarity in Dr. Gu ttenplan's response, it is inconsistent with the
more thorough advice provided by Dr. Boobis. The central issue differentiating JECFA's conclusion
that even though oestradiol 17β has "genotoxic potential" it is possible to establish an ADI, on the one
hand, and the SCVPH's conclusion that oestradiol 17 β is genotoxic and therefore no threshold
exposure can be determined, on the other, is th e degree to which damaged DNA, if indeed it is
damaged, is repaired and adverse ef fects avoided. Far from being "not r eally relevant", therefore, this
issue is one of the most relevant issues to the r esolution of the controversies surrounding the safety of
these hormones. It is therefore also central to the issue of whether the EC has conducted a valid risk
assessment.
89. With respect to whether the EC had failed to take into account these repair mechanisms in its
evaluation, Dr. Guttenplan considers that it failed to do so. Ultimately, to the extent that the SCVPH
takes so many short-cuts in its opinions on the basi s that the hormones are seen to be genotoxic, the
failure to address the role of mechanisms that counter this genotoxic potential is a critical
shortcoming. Ignoring such evidence results in a signi ficant overestimation of the risk, to the point of
concluding there are risks where none exist.
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)]

90. There is both agreement and disagreement betw een the experts who answered this question
(Drs. Boisseau, Boobis, Cogliano and Guttenplan) on the importance of cancer's long latency periods
to the conduct of risk assessments that purport to identify cancer risks from hormones in meat. On the
one hand, the experts tend to agree that the horm ones in question have been in use long enough as
growth promoters (a minimum of 20 years, accordi ng to some) for any long-term health effects to
manifest themselves. On the other hand, they disagree about whether it is possible to positively
identify the use of these hormones for growth-p romotion purposes as the source of any observed
adverse health effects. Dr. Cogliano does not weig h in on either of these points, confining himself
instead to the observation that it is "definitely necess ary" to take long latency periods into account in
general, a point not disputed by any other expert.
91. Dr. Guttenplan advises that it is possible to identify a relationship between hormones
consumed in meat and carcinogenic effects, but he does not explain how this would be accomplished.
He provides no information on how to account for th e fact that the populations he says would be
studied to observe the relationship would also be exposed to many other sources of hormones other
than that consumed through meat from treated animal s, such that it would be very difficult to identify
any causal relationship between the effect and the specific source.
92. Dr. Boobis is sceptical, but does seem to suggest that it might be possible with a well
designed study involving "extremely large populations to detect any increase in cancer incidence".
Dr. Boisseau is even more sceptical that a relationship can be identified with any certainty, finding not

only that it is not possible to study such a relationshi p, but it is not even "useful". Drs. Boisseau and
Boobis explain their scepticism in two separate, but related, ways: the former says it would be
impossible to discriminate between different factors in allocating responsibility (see also the experts'
responses to the next question on confounding factors) ; the latter says that since the risk from such a
small dose is so minimal, "it is questionable whether an increase in risk, even if it existed, could be
detected in exposed populations." In other words, epidemiological studies are of little use in risk
assessments of hormones in meat from treated cattle.
93. The answers from these two experts confirm again the essential point: that exposure to
residues of hormones in meat from treated animals is only a small fraction of the overall exposure to
the substance from a variety of sources, includi ng that produced endogenously within the human
body. Given the wide variety of sources of, and vari ability of exposure to, hor mones, any correlation
observed between exposure to hormon es and adverse effects cannot be attributed to the single source
of hormones that comes from residues of hormones in meat from treated animals. Nothing in the
SCVPH's opinions, in the scientific evidence submitte d by the EC, or in the answers of the experts
supports a conclusion other than this.
Q24. To what extent is it possible to iden tify possible co-founding factors causing cancer and
attribute them to identified sources? What are 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?

94. Drs. Boisseau, Boobis, Cogliano and Guttenplan all agree that it is extremely difficult to
attribute
 causal roles to different confounding factors in the study of the causes of cancer, even as
some of them advise that it is at least possible to identify what some of these factors may be.
According to Dr. Boobis, this would be particular ly the case in the circumstances of these hormones,
where "the risk from the confounder is appreciably greater than the risk of the exposure of interest".
95. To the extent that any of the experts respond to the second part of the question, they seem to
suggest that the difficulty with attributing cau sality to a specific factor reduces the value of
epidemiological studies in risk assessments of the nature under review here ( i.e., where the source of
the agent under review comprises such a small am ount of overall exposure and the adverse effects
have multiple causes). Dr. Boobis offers the view that confounding factors do not affect the risk
assessment, but the "interpretation of the data used in the risk assessment", which Canada understands
to mean that all causal factors should be taken into account, and not just single factors.
96. Contrary to advice from the experts that it is extremely difficult to isolate confounding factors
in circumstances such as these, the EC has claimed that it has done just that. It has taken observed
adverse effects and then has ascribed the cause of these effects to one source of hormones (that from
meat from treated animals). In light of the advice from the experts, the EC has failed on two accounts:
it has not observed adverse effects that can be co-rela ted to hormones; and even to the extent that it
has observed such effects, it has not investigated th e role of hormones writ large, preferring instead to
focus on the single source of hormones.
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 th e 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 anim al 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]

97. Drs. Boisseau, Boobis and Guttenplan expressly de ny that the three studies referred to by the
EC confirm a risk to human health from expos ure to hormone residues from meat from treated
animals. Only Dr. Cogliano endorses the EC's atte mpt to use these studies as evidence of risk from
consuming hormones from meat from treated animals, but he does so without any supporting evidence
or analysis.
98. With respect to the study on zeranol
46, Drs. Boobis and Guttenplan both indicate that the
study was based only on in vitro experiments and therefore cannot be extrapolated to human
exposure. They find it particularly difficult to ex trapolate to exposure from meat consumption since
the dose used in the study was high, a point that even Dr. Cogliano acknowledges. In response to the
observations of positive genotoxicity findings in vitro , Dr. Boobis notes that "genotoxicity by this
mechanism [redox cycling] should exhibit a threshol d and is also militated against in vivo by
antioxidant defence systems and efficient repair of oxidant-damaged DNA."
99. With respect to the study on the relationship be tween intake of red meat and colorectal
cancer,47 Dr. Boisseau simply refers to his general scepti cism of the ability of epidemiological studies
to identify specific causal agents due to confoundi ng factors. Dr. Boobis is even more specific in
dismissing the relevance of this study, noting that its results are not new, that they are consistent
across geographical area, and that even the auth ors point to possible explanations, such as the
formation of mutagens during the cooking of meat and the generation of nitroso compounds. He notes
that the study provides "little support for a contribution from hormones present in meat from their use
as growth promoters … because the association is just as strong in regions where hormones are not
used as where they are used".
100. Dr. Boobis is the only expert to make any de tailed comments on the study of the relationship
between hormone replacement therapy and the incidence of breast cancer. 48 He notes again that this
study did not find any relationship that had not already been observed in the past, and that had not
already been acknowledged by JECFA. The real issu e, therefore, is not whether there is such a
relationship, but whether that relationship has an y relevance for the assessment of risk from the
consumption of hormones in meat from treated animal s. On this point, Dr. Boobis advises that it does
not, because the "weight of evidence is such th at the hormones cause cancer by a mechanism
exhibiting a threshold" and the doses of hormones i nvolved in this study were considerably higher
than that found in meat from treated animals.
101. Ultimately, the experts' reactions to the sp ecific quote from the EC (about the studies having
been conducted after the ban) capture the overa ll response to the EC's use of these studies.
Dr. Boisseau considers that this comment "expresses a concern but does not provide any scientific
evidence supporting this concern", wh ereas Dr. Guttenplan considers that it "negates any relevance to
the possible connection of hormone-treated meat c onsumption and cancer". Dr. Boobis considers that
the only way the timing of the studies would matter w ould be if it were proven that there were risks
from hormones from meat from treated animals, wh ich Dr. Boobis confirms again has not been
demonstrated. Dr. Boobis is more pointed in his cr iticism of the EC's suggestion that "it can not be
excluded" that there is greater risk. He advises th at since the same statement can be made in the
absence of any study whatsoever of the risk from hormones, this st atement is "not scientifically
defensible".

46 Exhibit EC-73.
47 Exhibit EC-71.
48 Exhibit EC-72.

102. These reactions highlight a tactic employed by the EC, namely, the manipulation of a genuine
scientific interest in assessing the possible adverse effects arising from exposure to a substance in
general (i.e., hormones) to create specific and unjustified concern about possible adverse effects from
one single and insignificant source of that substance in particular.
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, the 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 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 pages 17-19 of
1999 Opinion of the SCVPH and related Tables A4-A5 on pages 83-91]

103. As with their responses to the previous questi ons related to the potential of epidemiological
studies, Drs. Boisseau, Boobis, Cogliano and Guttenp lan all agree that the studies relied upon by the
EC, in particular the epidemiological studies, do not identify a relationship between cancer and
residues of hormones from meat from treated animals.
104. Many of the reasons they provide have already been discussed above, such as confounding
factors, etc. The EC places considerable emphasis on statistics comparing breast and prostrate cancer
rates between Europe, where hormones are ba nned for growth-promotion purposes, and North
America, where they are not. Not surprisingly, wh ile there may be some observable differences in
rates between certain regi ons and ethnic groups, on the whole th e rates are relatively similar. The
experts agree that the differences that do exist are so slight as to be not statistically significant. To the
extent that there are differences at all, Dr . Boobis cautions against inferring too much from
geographical differences in cancer rates, because of what he calls an "ecological fallacy" (the belief
that differences observed between groups will al so be observed between individuals). More
importantly, none of these studies relied upon by th e EC included assessments of data on hormone
intake, so even if the differences were signifi cant (and they are not) no link can be made between
these statistics and the consumption of meat from animals treated with the hormones at issue.
(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?

105. The experts who respond to this question (Drs. Boisseau and de Brabander) agree that since
the chemical structures of the three synthetic hormones (zeranol, trenbolone acetate (TBA) and
melengestrol acetate (MGA)) are different from th e structure of the three natural hormones
(oestradiol 17β, testosterone, progesterone), the residues of the synthetic hormones in the meat of
treated cattle will be different from the residues in meat from cattle treated with natural hormones.
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?

106. Dr. Boisseau and Dr. de Brabander address this question. Dr. Boisseau states:
The definition of residues encompasses both the parent substance and all the
metabolites derived from this parent substance. Therefore, in the case of the part of
residues of the natural hormones which consis ts of parent substances, there is no
difference between hormones naturally presen t in food producing animals, meat or

human beings. Metabolites of these natural hor mones existing in cattle and meat are,
obviously, the same. To my knowledge, there is no scientific evidence showing that
the main metabolites of the three natural hormones existing in cattle and humans are
not similar.
107. For the sake of clarity, the Panel may wish to ask that Dr. Boisseau clarify whether the
residues, both parent and metabolite, in meat fro m cattle treated with the three natural growth
promoting hormones are the same as their respectiv e endogenous natural hormones found in animals,
meat or human beings.
108. Dr. de Brabander's opinion is much less clear. Fi rst he states that "there are no differences",
then he qualifies his statement with references to unspecified "ongoing research". He states that "[t]he
residues of the natural hormones in cattle are in the 17 α form (inactive) while the use of ‘natural'
hormones used for growth promotion purposes may lead to residues in the β form (active form)." If
Dr. de Brabander is suggesting that residues of na tural hormones in untreated cattle do not occur in
the β (active) form, he is contradicting his own answer to Question 31. There, he agrees that "residue
levels in meat from hormone-treated cattle are well w ithin the physiological range of residue levels in
untreated cattle". Moreover, his position would be in consistent with the detailed residue evidence
reviewed by JECFA in its 1999 residue monogra ph. The monograph presents detailed data on
hormone concentrations 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.
49
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 ass essment 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 th ey 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]

109. Dr. Boisseau confirms that the level of residues is typically taken into consideration at the
third step of the risk assessment process, name ly the exposure assessment, after the ADI has been
established. The purpose of evaluating the level of r esidues in food is to ensure that dietary exposure
to the substance does not exceed the ADI. Dr. Bois seau confirms that the SCVPH did not "conduct a
quantitative assessment of the exposure of consumers to the residues of [synthetic] hormonal growth
promoters including the determinati on of the levels of residues in food from treated animals, the
impact of the non observance of good veterinary practices on these levels and the comparison between
these levels and the MRLs set up by Codex".
110. Dr. de Brabander fails to directly answer the Pa nel's question. Instead, he appears to offer his
own opinion regarding the inaccuracy of published con centrations of residues. Referring to Table 8 in
the SCVPH 1999 Opinion
50, he indicates that residue levels for trenbolone are "extremely low…and
serious doubts about their accuracy can be made." Tabl e 8 is drawn in part from the extensive review
of residue data contained in the JECFA Monograph to the 34 th Meeting.51 By quoting the JECFA data
without qualification, the SCVPH does not appear to share Dr. de Brabander's concerns about the

49 JECFA, Residues of some veterinary drugs in animals and foods, FAO Food and Nutrition Paper No.
41/12 (Rome: FAO, 2000), at p. 38 (Exhibit CDA-17).
50 1999 SCVPH Opinion, Section 4.4.2, at p. 56 (Exhibit CDA-2).
51 JECFA, Residues of some veterinary drugs in animals and foods: Monographs prepared by the
Thirty-fourth Meeting of the Joint FAO/WHO Expert Committee on Food Additives , FAO Food and Nutrition
Paper, No. 41/2 (Rome: FAO, 1990), at pp. 88-100, in particular p. 96 (Exhibit CDA-38).

inaccuracy of the trenbolone residue data. 52 In any event, in contrast to the JECFA analysis, Dr. de
Brabander fails to provide a single reference for hi s conclusion that "concentrations may seriously be
underestimated."
111. Dr. de Brabander's statement that the MRLs set by Codex are high in relation to "modern
analytical limits" is confusing. MRLs are a f unction of the ADI and are not set on the basis of
detection methods, but toxicological data. As Dr . Boisseau states in response to Question 32, for
control purposes, a validated analytical method need be only as sensitive as is necessary to detect
residues at the established MRL. Thus, it makes littl e sense to assert that the MRLs are high unless
there is evidence to suggest that the ADI is set too high. Moreover, Dr. de Brabander lists the MRL
for MGA, an MRL that was recommended by JECFA as recently as February 2004 (62 nd meeting).
Dr. de Brabander appears to suggest that the analyt ical techniques used by JECFA in 2004 were not
sufficiently "modern". However, his cursory conclusion is in stark contrast to the extensive evaluation
of residue data conducted by JECFA. 53 In particular, recent residue data from studies using "modern"
validated methods (HPLC-MS, GC-MS and LC -MS) were assessed in the JECFA Residue
Monograph for the 58th Meeting.54 All ten studies cited date from 1999 to 2002.
112. Lastly, Dr. de Brabander indicates that "[a]s demonstrated in several documents a major part
of the hormones used are excreted through the f aeces (for MGA ca. 75%)…" It would be helpful if
Dr. de Brabander could provide citations for doc uments to which he re fers. In addition, for
completeness, it would be helpful if Dr. de Br abander could provide corresponding statistics in
relation to excretion for all the hormones at issue, synthetic and natural.
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 recomm ended by JECFA in 1999? Are specific references
provided as to how the evidence on residues re lates 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 52nd JECFA
Report in Exhibit US-5]

113. Both Dr. Boobis and Dr. Boisseau confirm that the SCVPH did not itself evaluate evidence of
actual residue levels of the three natural hormon es in its assessment of risks from such residues. 55 In
addressing the impact of GVP on residue levels in meat, Dr. Boobis explains that, while the SCVPH
considered potential exposure fo llowing inappropriate use scenarios, "these data are limited in the

52 1999 SCVPH Opinion, Section 4.4.2, at p. 56 (Exhibit CDA-2).
53 See JECFA, Residues of some veterinary drugs in animals and foods: Monographs prepared by the
Sixty-second Meeting of the Joint FAO/ WHO Expert Committee on Food Additives , FAO Food And Nutrition
Paper, No. 41/16 (Rome: FAO, 2004) (Exhibit CDA-33); JECFA, Residues of some veterinary drugs in animals
and foods: Monographs prepared by the Fifty-eighth Meeting of the Joint FAO/WHO Expert Committee on
Food Additives, FAO Food And Nutrition Paper, No. 41/14 (Rome: FAO, 2002) (Exhibit CDA-35); and JECFA,
Residues of some veterinary drugs in animals and foods: Monographs prepared by the Fifty-fourth Meeting of
the Joint FAO/WHO Expert Committee on Food Additives , FAO Food And Nutrition Paper, No. 41/13 (Rome:
FAO, 2000) (Exhibit CDA-37).
54 JECFA, Residues of some veterinary drugs in animals and foods: Monographs prepared by the Fifty-
eighth Meeting of the Joint FAO/WHO Expert Committee on Food Additives , FAO Food And Nutrition Paper,
No. 41/14 (Rome: FAO, 2002) (Exhibit CDA-35), pp. 56-59. All of the 10 studies cited by JECFA in this
Monograph are from 1999-2002.
55 Dr. Boobis, at p. 33. Dr. Boisseau refers back to his answer to Question 29, in which he concluded
that the EC failed to "conduct a quantitative assessment of the exposure of consumers to the residues of [natural]
hormonal growth promoters including the determination of th e levels of residues in fo od from treated animals,
the impact of the non observance of good veterinary pr actices on these levels and the comparison between these
levels and the [ADI] set up by Codex."

absence of any information on the frequency of occu rrence of such misuse in the use of the products
in question." Moreover, he confirmed that "[i]t would have been possible to compare the SCVPHs
estimates of exposure [in the misuse scenarios] with the ADIs derived by the JECFA but this was not
done." Lastly, he concludes that the "ADI would ha ve exceeded the exposure estimates for the three
[natural] hormones." This advice supports the c onclusion that the EC has not properly assessed the
potential occurrence of adverse affects from the misuse of the natural hormones in question.
114. Unfortunately, Dr. de Brabander fails to direc tly answer the Panel's question. Instead, he
refers to "old" data for residue c oncentrations and concludes without any analysis that their "accuracy
could be doubted." Rather than responding direct ly to the Panel's question, he discusses, amongst
other things, the potential environmental effects of hormone residue in excrement and the side-effects
of testosterone spray used to enhance a woman's enjoyment of sex.
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 your 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]

115. Dr. de Brabander offers qualified agreement with the US statement.
116. Both Drs. Boisseau and de Brabander indicate that meat consumption from pregnant heifers is
exceptional. However, this conclusion is at odds with the evidence considered by the UK Sub-Group
of the Veterinary Products Committee.
56 The Sub-Group analyzed the effect on exposure to oestradiol
17β in meat from the termination of the Over Thir ty Months Scheme (OTMS) in the UK, a program
that removes culled adult cows from the food chain. The Sub-Group concluded that "the removal of
these pregnant cull cows to the food chain [as a result of the OTMS] has reduced the quantity of
oestradiol in the food chain by 37% … which will be returned as the BSE controls are removed and
the market returns to normal." 57 This is based on the assumption that 25% of slaughtered cows are in
calf, at stages of pregnancy evenly distributed over the three trimesters.
117. In a different vein, Dr. Boisseau's response to th is question also supports Canada's basic point
that the EC is attempting to divorce the use of growth-promoting hormones from their appropriate
context and, as a result, presents a distorted assessmen t of the risks associated with the use of growth-
promoting hormones. He states:
Even if, accepting the substance of the EC comment [meat consumption from
pregnant heifers is exceptional], it is po ssible to limit the physiological range of

56 UK, Sub-Group of the Veterinary Products Committee, Executive summary and critical evaluation of
the scientific reasoning and methods of argument adopted in the opinion of the Scientific Committee on
Veterinary Measures Relating to Public Health which assessed the potential risks to human health from
hormone residues in bovine meat and meat products, October 1999 (Exhibits CDA-6, US-12).
57 Ibid., at para. 56, pp. 19-20.

oestradiol 17β and of progesterone in cattle, it has nevertheless to be recognized that
(1) consumers are exposed to these two na tural hormones through their consumption
of meat and milk from the different non treated food producing animals and, mainly
as least for women, through their endogenous production, (2) this exposure cannot be
avoided. Therefore, the use of the concept of threshold in the risk assessment of the
natural hormone residues is legitimate and the additional intake of residues of these
natural hormones from the meat from treated cattle has to be considered in this
context and not according to a theoretical "no additional intake of residues is
acceptable".[emphasis added]
118. In essence, Dr. Boisseau advises that, in order appropriately to understand the risks associated
with the use of growth-promoting hormones, one mu st view the exposure to these hormones in their
overall context, including the wide exposure to natural hormones from other dietary sources and
endogenous production of natural horm ones. To posit that the risks arising from the use of HGPs are
such that no threshold for acceptable intake can be established is simply irrational and scientifically
unjustified.
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?

119. The SCVPH's statement concerning ultra-sensitiv e detection methods appears to relate its
discussion of analytical techniques set out in Section 4.1.1 of its 2002 Opinion. In that section, the
SCVPH acknowledges that the "low number of samples does not allow a qualified validation of
typical characteristics such as sen sitivity, specificity, accuracy and reproducibility (study 1,
study 8)."
58 The experts who answered this question app ear to agree on the importance of validating
analytical methods.59 Dr. Boisseau states that "validation must be carried out in compliance with well
defined and internationally accepte d criteria". These criteria include accuracy, precision, sensitivity,
specificity, reproducibility, and reliability.60
120. In terms of the second part of the Panel's ques tion, Dr. Boisseau explains that once an MRL
has been established, the sensitivity of the validated analytical method need only be consistent with
the values established by the MRLs. Analytical met hods that are more sensitive, or "ultra sensitive,"
are redundant for control purposes.
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 Drugs in Food? What is the status of these
recommendations? [see paras. 96-97 of EC Rebutta l Submission (US case), paras. 79-80 of EC
Rebuttal Submission (Canada case)]

58 EC, Health & Consumer Prot ection Directorate-General, 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 human health from hormone residues in bovine meat and meat products ,
adopted April 10, 2002, Section 4.1.1, at p. 9 (Exhibit CDA-7). See also p. 21.
59 Drs. Boisseau and de Brabander.
60 JECFA, Procedures for Recommending Maxium Residue Limits, at p. 37 (Exhibit CDA-44).

121. Three experts respond to this question. JECFA also responds to the sa me question asked of
the international bodies (Question 20). JECFA indicates that it can decide to re-evaluate previous
assessments when it is made aware that there are new data which may be pertinent to the risk
assessment of the substances in qu estion. The claim by the EC in EC – Hormones that it had new
evidence showing that oestradiol 17 β was a direct acting genotoxic carcinogen appears to have
promoted, at least in part, JECFA's 1999 re-evaluation. Moreover, JECFA indicates that new studies
had also been published for the other hormones. This is consistent with the advice of Dr. Boisseau.
122. In terms of whether the residue data for the na tural hormones used in 1999 were the same as
those used in 1988, JECFA indicates that while mo st of the residue studies were the same, a few
additional studies were reviewed. JECFA also states that it performed a more detailed review of the
validity of the analytical methods used in the studies and used only data generated using valid
methods.
123. JECFA also confirms that in the 1999 evaluati on new toxicological and epidemiological data
for the three natural hormones were evaluated, a po sition that is supported by Dr. Boobis. JECFA is
quite specific as to the new information that was not available to it in 1988 but was available and
considered by it in 1999.
124. In terms of whether the conclusions from the tw o evaluations differed, Dr. Boisseau confirms
that in substance the conclusions remained the same . The risk assessment indicated a wide margin of
safety for consumption of residues in meat from treat ed cattle. Hence, the establishment of numerical
MRLs was not necessary to protect human health.
61
125. As to the reasons for establishing ADIs for the three natural hormones in 1999, JECFA refers
to "[t]he additional data reviewed and the need to establish and [sic] ADI as quantitative estimate for a
safe oral intake". 62 This is consistent with Dr. Boobis' e xplanation that in the intervening years
between the first and second JECFA evaluations, it b ecame clear that exposure to natural hormones,
albeit at levels much higher than that found in meat from treated cattle, could have adverse effects in
humans. The implicit conclusion was that it was necessary to establish ADIs as benchmarks to ensure
that exposure to these hormones through dietary sources did not cause adverse effects observed in
other areas.
126. JECFA confirms that "the establishment of an ADI implies that there is a threshold of effect
for such a compound, below which now [ sic; read "no"] toxicological effects occur".
63 This
conclusion is supported by both Dr. Boisseau and Dr. Boobis.
127. As to the reasons for CCRVDF's not ha ving considered JECFA's more recent
recommendations in respect of the natural hormo nes, JECFA's answer to Question 20 (to the
international bodies) includes a direct quote from the 12th CCRVDF report, which states:
Recognizing that this Committee had not requested the re-evaluation of these
substances and that the new MRLs recommended by the 52 nd JECFA did not differ
significantly from the current MRLs, the Co mmittee decided not to consider these
new recommendations.
128. As Dr. Boobis explains, the result is that Code x continues to list the three natural hormones
with an indication that MRLs are "unnecessary" for tissues from cattle.

61 JECFA's answer to Question 20 (to the international bodies), at p. 18.
62 Ibid.
63 Ibid.

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 does this compare with the kind of data and studies
used with respect to other ve terinary drugs? [see para. 120 of EC Rebuttal Submission (US
case), para. 102 of EC Rebuttal (Canada case)]

Outdated Residues Data

129. Dr. Boisseau confirms what is generally accep ted within the scientific community: that
scientific data do not deteriorate simply because of the passage of time. He concludes that "the quality
and the number of the available data are more importa nt than the dates at which these data have been
produced." Dr. Boisseau also confirms that it is st andard practice for JECFA to determine the quality
and sufficiency of the data under consideration in its assessment of substances, as well as the validity
of the analytical methods employed.64
130. In the specific case of the hormones at issue, Dr. Boisseau confirms that:
JECFA has considered that the quality and the number of the available residue data
were satisfactory and therefore the fact th at these data were not new had no specific
impact on its evaluation.
131. Thus, the EC's suggestion that old data are ne cessarily unreliable data is simply groundless.
Obviously old data that have been generated using validated analyti cal methods are to be preferred
over more recent data generated by unvalidated and widely ignored analytical techniques. At the end
of the day, the expert advice supports Canada's pos ition that sufficient scientif ic evidence exists to
conduct a risk assessment for all six of the hormones at issue.
Type of Data and Extrapolations from Animal to Human

132. It should first be noted that the EC's statem ent in paragraph 102 of its Rebuttal Submission
makes little sense. Studies with experimental animals are always in vivo and cannot by definition be in
vitro. In vitro studies are studies that are conducted in an artificial environment outside the living
organism.
133. To the extent that the EC's statement suggests that there is something unusual or inappropriate
about making extensive use of studies with experi mental animals and general studies by IARC, the
experts' responses to this question demonstrate that such a suggestion is nonsense. Understandably,
Dr. Boisseau expresses surprise with the EC's statements, stating:
… it is the normal way for assessing the toxicological potential of a substance to take
into consideration in vivo studies with experimental animals, in vitro studies and also
reports already published by internationally recognized scientific organisations such
as IARC.
134. Where human studies are not available, which is typically the case, for ethical reasons, risk
assessors resort to these other studies out of necess ity. Extrapolations from animal studies to humans

64 For a description of JECFA's approach to data quality, see EHC-70, at pp. 22-23. ("JECFA has
always judged studies on their merits, the main criteria be ing that the study was: (a) carried out with scientific
rigour, and (b) reported in sufficient detail to enable comprehensive evaluation of the validity of the results.")

have been standard practice for many years and regularly applied by in ternational and national
agencies in the conduct of risk assessments for food additives and c ontaminants, as well as veterinary
drugs. It should be emphasized however, that in the case of the natural hormones, JECFA made
extensive use of data derived from human studies i nvolving the three natural hormones, in addition to
animal studies. Moreover, this statement is all the more surprising when one considers that the very
type of studies that the EC appears to suggest are inappropriate are precisely the type of studies relied
upon by the SCVPH.
135. As the experts confirm, the data and process used for assessing the safety of the hormones at
issue are the same as those used for other veterinary drugs. JECFA has applied well-recognized
procedures and principles in conducting its various risk assessments for the hormones at issue. Rather,
the EC has strayed from internationally recognized techniques and methodologies.
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]

136. Dr. Boisseau's answer to Question 34 also appli es to this question, namely, that the quality
and quantity of data are more important than the date upon which the data were generated.
137. While the studies referred to in the 2000 JECFA Report on MGA date back to the 1960s and
1970s
65, JECFA assessed these data to determine whethe r the quality and quantity were sufficient to
conduct its risk assessment. As Dr. Boisseau conc ludes, "JECFA considered a wide series of
toxicological studies in its assessment, used as end point a non hormonal effect dose by far more
conservative than a NOAEL based on tumorigenic effect and adopted a 200 safety factor to derive an
ADI from this NOAEL."
(c) Dose-response relationship
Q36. How would you describe a dose-response asse ssment? 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-depe ndent"? 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 geno toxic 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]

138. Two of the three experts who responded to th is question (Drs. Boobis and Boisseau) confirm
that a dose-response assessment is a necessary component of hazard characterization. While these
experts also acknowledge that such an assessment ma y not be feasible or required for substances that
are genotoxic in vivo, they both confirm that this exception is not absolute. Dr. Boisseau confirms that
this exception only applies to xenobiotic substances (i.e., those that are foreign to the human body) or
to substances with "genotoxic potential" where it is thought that this potential can be expressed in
in vivo conditions. At least for the natural hormones i nvolved here, neither of these conditions is met
such that a dose-response assessment should be skipped.

65 Exhibit CDA-37.

139. Dr. Boobis similarly describes at least two ge neral sets of circumstances in which a dose-
response assessment would still be conducted on substances thought to have genotoxic potential. First,
if the mechanism of action of the genotoxic effect was known, and it was of the type of mechanism
that is known to exhibit a threshold (for example, substances with kinetic or dynamic causes, as well
as those caused by reactive oxygen species), then a dose-response asse ssment is necessary. Second, if
the mechanism of action of genotoxicity was know n or assumed to be DNA-reactive, then this
genotoxicity would need to be confirmed in vivo before it would be appropriate to dispense with a
dose-response assessment. As we know from numerous sources, including the EC risk assessment
itself, it has not been demonstrated that an y of these six hormones ha ve genotoxic potential in vivo.
According to the experts, this requires that a dose-response assessment be conducted.
140. Dr. Cogliano's short response suggesting a dose -response may not be required tells only half
the story. His comments seem to be limited to ci rcumstances involving a "hazard-based approach",
without explanation of when such an approach is or is not appropriate. A hazard-based approach
simply identifies whether a substance is capable of causing an adverse effect under certain conditions,
and not whether such adverse effect would actually occur at given doses. This corresponds only to the
"hazard identification" stage of a risk assessment ( i.e., whether a substance can cause an adverse
effect) and disregards the hazard characterizati on stage, which includes an assessment of the dose
required to provoke the identified hazard ( i.e., dose-response assessment). 66 Quite apart from the
explanation from Dr. Boobis that a "hazard-based a pproach" is not appropriate for these hormones, it
would also be inconsistent with obligations under the SPS Agreement that a substance be evaluated for
the potential for occurrence of an adverse effect.
141. Dr. Cogliano's view that a dose-response assessment is optional is incons istent with his later
view that it is "widely accepted that adverse e ffects arising from hormonal activities depend on the
dose".
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]

142. Drs. Boisseau and Boobis confirm Canada's stat ement that international techniques require
that a dose-response assessment always be conducte d as part of an assessment of the risk from
chemical substances such as the six hormones. Dr. Boisseau indicates that it would not be possible to
establish an ADI, and Dr. Boobis indicates that it would not be possible to recommend MRLs, in the
absence of a dose-response assessment. These opinions are confirmed by JECFA in its response to
Question 8 to the international bodies. In light of th e universally held view that the adverse effects of
hormones are dose-dependent, these answers are not at all surprising given the purpose of the dose-
response assessment of determining as closely as possible the level of dose at which there is no
response (i.e., the NOAEL).
(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.

143. In presenting various figures for background levels of sex hormones of different age groups in
response to this question, Dr. Boisseau raises con cerns, as many others have done, about the reliance

66 See Canada's comments on the experts' responses to Question 11.

by the EC on a new "ultrasensitive bioassay" (also re ferred to as the Klein assay). In light of the
SCVPH's decision to revise downward by 100-fold th e estimated physiological level of hormones in
pre-pubertal boys and girls, and the significance of the conclusions it draws as a result, Dr. Boisseau
raises the important point about whether this assay has been validated. More detailed discussion of the
flaws of this methodology follow in Canada's comments on the experts' responses to Question 40.
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]

144. In his reply to this question, Dr. Boisseau confirms that the EC has failed to compare
quantitatively the exposure to oestradiol 17 β from meat from treated animals to that from meat from
non-treated animals and other sources of oestradiol 17 β. Without having conducted such a
comparison, the SCVPH is unable to claim that such exposure is "excess", nor that, even if it is
"excess", the amount of the excess would be sufficient to "present a potential risk to public health".
145. While Dr. Sippell offers the view that the EC's claim is supported, the evidence he refers to
largely involves the controversial, and yet-to-b e validated, methodology for measuring background
levels of oestradiol 17 β (i.e., the Klein assay). Quite apart from the fact that serious concerns have
been expressed about the validity of this methodology,
67 the use of the methodology does not, on its
own, support the conclusion that exposure to oestradiol 17 β residues from treated meat amounts to
"excess exposure", nor that it "presents a potential risk to public health". Almost all the studies cited
by Dr. Sippell apply to oestrogen in general, and not to residues of oestradiol 17 β consumed via meat
from treated animals.
146. Therefore, when Dr. Sippell refers to "eleva ted estrogen levels", he provides no evidence
whatsoever that such levels are achieved from th e consumption of residues of hormones from meat
from treated animals. On the cont rary, to the extent that his gr eatest concern appears to be for
exposure to oestradiol 17 β during "early life" ( i.e., pre- and post-natal periods), Dr. Sippell provides
no evidence for, nor even a plausible explanation of, exposure at this age to residues from meat
products. Certainly a foetus/infant could be exposed via the mother, but since late pregnancy and early
post partum are the periods of a woman's life where the natural oestrogen level is at its most elevated,
the proportion of oestrogen exposure of the foetus/infant that would come from the consumption by
the mother of meat from treated animals would be trivial.
147. Moreover, a review of the full context of the quote cited in the question 68 reveals that it is
based on conclusions that the experts have contes ted elsewhere in their replies. Citing disputed
findings that metabolites of oestradiol 17 β have "genotoxic potential", the SCVPH concludes that
oestradiol 17β is both a tumour initiator as well tumour promoter. It then suggests that this conclusion
is confirmed by epidemiological data and IARC's classification of oestrogen as a human carcinogen.
On the basis of these findings, the SCVPH furthe r concludes that "any excess exposure… presents a
potential risk to public health". 69 However, in establishing the adverse effect threshold as "any excess
exposure", the SCVPH offered no confirmed eviden ce of genotoxicity of the substances, nor any
scientific support for its suggestion of a link between epidemiological data and its conclusions. The
result is that the quote from the SCVPH's opinion is no more than speculation based on tenuous links
drawn between unsupported conclusions.

67 See Canada's comments on Question 40.
68 1999 SCVPH Opinion, at pp. 74-75 (Exhibit CDA-2).
69 Ibid., at p. 74.

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 relatio nship..." 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?

148. Drs. Boisseau and Boobis both share concerns about the methodology (an "ultrasensitive"
recombinant cell bioassay (RCBA) developed by Klein and others
70) that generated the underpinning
the conclusion that endogenous levels of hormones in pre-pubertal child ren are lower than previously
thought. Dr. Boisseau's concerns about the absence of validation of this methodology are reflected in
his answer to Question 38.
149. Dr. Boobis echoes these concerns in a very co mprehensive review of the issues surrounding
this controversial methodology. While he acknowle dges that endogenous levels may be lower than
previously thought, Dr. Boobis expresses grave doubts that this is by the "orders of magnitude"
suggested by the SCVPH, repeating Dr. Boisseau's c oncern when he says that the "reliability of the
Klein et al. assay has yet to be determined". He points to a number of contradictory results in the use
of this assay, including from the original inventors th emselves, that at the very least suggests that it
has not been adequately validated for use in a risk assessment.
150. The concerns highlighted by the experts about the SCVPH's use of this methodology have
been consistently cited by others as one of the flaw s in the analysis of the SCVPH. For example, the
UK Sub-Group Report early on expressed the concer n that the Klein assays have not been
appropriately validated. It expressed:
… concerns about the reliability of this an alytical approach, which has been very
little used in peer-reviewed publications ot her than by the originators of the assay,
despite its initial publication in 1994. Th ese concerns throw doubt upon the values
derived by Klein et al. and therefore also on the conclusions of the [SCVPH]
opinion.
71
151. Not only does the SCVPH fail to point out the obvious problems with the validity of the Klein
data, but it ends up comparing apples with oranges. The 1999 SCVPH Opinion recognizes that
"perhaps the hormone residues in beef, which are al so low and which have also been determined by
Radio Immune Assays (RIA) are equally variable and over representative of the actual hormone
concentrations."
72 Thereafter, without acknowledging that it is using two different analytical
techniques, the SCVPH goes on to compare concentrations of oestradiol in beef using RIA with
concentrations in plasma using the Klein assay. As the UK Sub-Group Report concluded, "[t]his is
inappropriate and may lead to a biased inappropriate perspective."
73
152. Most importantly, even the 1999 SCVPH Opinion calls the data produced by Klein et al.
"experimental evidence", calling the data "insufficien t" to form the basis of a sound risk assessment. 74
A few years later, the SCVPH itself concluded in its 2002 opinion that "[t]he obtained results suggest

70 Ibid., at pp. 30 and 38.
71 UK Sub-Group Report, at pp. 26-28 (Exhibit CDA-6).
72 1999 SCVPH Opinion, at p. 30 (Exhibit CDA-2).
73 UK Sub-Group Report, at para. 96, p. 28 (Exhibit CDA-6).
74 1999 SCVPH Opinion, at pp. 38-9 (Exhibit CDA-2).

that the use of recombinant yeast and rainbow trou t hepatocytes to detect oestrogenic compounds is
not justified in view of their lack of sensitivity."
75).
153. Contrary to the concerns expressed by at least two of his colleagues, Dr. Sippell seems to
believe the recombinant yeast bioassay (RCBA) methodology constitutes a "quantum leap" in assay
methodology. In support of this claim, Dr. Sippell cites a later study (Paris et al., 2002) to suggest that
the Klein RCBA has been validated. Interestingly, the research by Paris et al. was also cited by
Dr. Boobis in support of his opinion that the Klein RCBA had not been validated
 by subsequent
research because the research by Paris et al. , which in Dr. Boobis' mind is more credible,
demonstrated that the Klein RCBA overestimated background oestrogen levels by up to 18 times. The
Paris et al. results in fact were closer to the orig inal data used by JECFA based on the RIA
methodology. In light of these discrepancies, the Pane l may wish to ask Dr. Sippell to clarify why he
believes the Paris et al. results validate the 1994 Klein results.
154. Dr. Sippell makes another ambiguous observation in his advice when he states that "the
complexity of the [Klein] RCBA so far prevents its wider use for routine measurements in small
serum samples from infants and prepubertal childre n". Canada understands th is to be confirmation
that there are very little reliable data related to the use of RCBA.
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?

155. Drs. Boisseau and Boobis agree that alt hough individuals with the lowest endogenous
hormone levels are at the greatest risk from any adverse effects that might result from exposure to
hormones, the exposure to hormones via meat from tr eated animals would not result in any change in
the effect that would be expected from hormones from meat from non-treated animals, or any other
exogenous source for that matter.
156. Dr. Sippell suggests that the risks would be different, but he bases his assessment of "risk" on
what he calls a "new threshold", which appears to be based on the results from the Klein assay.
However, as the experts have advised in respon se to previous questions, this assay has not been
validated sufficiently to support the kinds of conclusions that Dr. Sippell makes.
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 concerning 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 17β?

157. Drs. Boisseau and Boobis both acknowledge the many ways in which JECFA takes into
account the situation of sensitive populations. They point in particular to the use by JECFA in
establishing the ADI for oestradiol 17 β of an additional safety factor of 10 specifically for sensitive
populations, in addition to the initial safety factor of 10 for variation between individuals. The
resulting safety factor of 100 makes for a very conservative assessment of safe exposure. Dr. Boisseau
confirms that the safety factors for some of the other hormones were even greater. Moreover,
Dr. Boisseau highlights two additional safety factors: first, that the estimated exposure to the natural
hormones from meat from treated animals amounts to a very small proportion of the overall exposure
from all sources, and, second, the fact that the bioa vailability of the natural hormones is quite low.

75 2002 SCVPH Opinion, at p. 9 (Exhibit CDA-7).

The approach of JECFA builds in significant safet y margins to take into account the situation of
sensitive populations.
158. Only Dr. Sippell expresses concern about whethe r JECFA's analysis adequately takes into
account the situation of sensitive populations, but his concern is based on estimates of endogenous
levels in these populations that have been gene rated by the Klein RCBA. As discussed above,
however, this methodology has not been adequately validated, and the original results obtained by
Klein have not been reproduced by others. In li ght of more credible measurements of endogenous
levels of hormones, Dr. Boobis indicates in his an swer to Question 40 that exposure up to the ADI
established by JECFA would still be safe for sensitive populations. Nothing in Dr. Sippell's comments
(other than a non-validated methodology) contradicts the analysis conducted by Dr. Boobis.
159. Both Drs. Boisseau and Boobis indicate that the sci entific material referred to by the EC does
not require a revision of the Codex recommendation with respect to oestradiol 17β.
(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 pa rties' differing views on this matter. [see
paras. 123-124 of EC Rebuttal Submission (US ca se), 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]

160. The experts generally agree that bioavailability re fers to the fraction of the substance that is
available for systemic circulation. It is normally estimated by comparing the availability of a
substance after oral administration with the availability of a substance after intravenous administration
(which is assumed to be 100% bioavailable). The experts also agree that only the bioavailable portion
of the substance at issue can produce an adverse ef fect. As a consequence, only that portion of the
substance that is bioavailable will be significant for risk assessment purposes.
161. Dr. Boisseau and Dr. Boobis confirm that the natural hormones are either inactive orally or
have low bioavailability (between 5% to 10%). These conclusions are supported by both JECFA
76 and
CVMP.77 The JECFA analysis is based on a review of the scientific literature on the absorption,
distribution and excretion of oestradiol 17 β set out in the Toxicological Monograph for the natural
hormones prepared for JECFA's 52nd meeting.78
162. Dr. Guttenplan indicates that the "bioavailability of estrogen is low but not insignificant
(probably between 5 and 20%, if estrone is also ta ken into account[)]." He further indicates that the
SCVPH in its 1999 and 2002 opinions questions the sufficiency and accu racy of the data relied upon

76 See JECFA, 52 nd Report, at p. 58. (Exhibit CDA-16). ("In general, oestradiol-17 β is inactive when
given orally because it is inactivated in the gastrointestinal tract and liver".)
77 European Medicines Agency, Committee for Veterinary Medicinal Products, 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, December 1999, at p. 2 (Exhibit CDA-5). ("[T]he bioavailability of 17 β-
oestradiol esters after oral administration is low (3% as unchanged 17 β-oestradiol), but it might be higher if
estron, an estrogenic metabolite, is included".)
78 See JECFA, Toxicological evaluation of certain veterinary drug residues in food : prepared by the
Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series
No. 43, (Geneva: WHO, 2000), Section 1.2.1 Absorption, distribution and excretion, at p. 45 (Exhibit CDA-11).

by JECFA. However, Dr. Boobis places the concept of bioavailability, and by extension the SCVPH
analysis, in its proper context. He states:
However, low bioavailability does not necessar ily increase the margin of safety (the
ratio of ADI to actual exposure). This is because the effects of concern are usually
determined following exposure by the route of interest, in this case oral. Hence, the
ADI represents a "bioavailability adjusted " dose, just as the TMDI does. The
consequence of this is that anything th at increases bioavailability will reduce the
margin of safety whilst anything that re duces bioavailability will increase the margin
of safety. In the case of the natural hormone s, changes in bioavailability are likely to
be a consequence of changes in the enzyme s of metabolism in the liver and/or small
intestine.
163. Thus, as the ADI is a "bioavailability adjusted" dose, for the purposes of establishing the ADI,
it matters not that the estimated bioavailability of th e substance is later revised. The ADI is based on
the dose that represents the NOAEL, together with appropriate safety factors. Thus, even if the
SCVPH is correct that the bioavailability of the hormones at issue is higher than previously estimated,
a conclusion that Canada contests, this has no impact on the ADI. The ADI could be called in
question if, for instance, studies demonstrate that the bioavailability of oestradiol 17 β in residues in
meat from treated cattle was higher than the bioa vailability of the fine-particle oestradiol 17 β used in
the studies that formed the basis of the ADI. Howe ver, the EC has presented no evidence to this
effect. Indeed, the evidence points in the opposite direction.
(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 the relevant Codex standards, guidelines or
recommendations relating to GVP/GPVD? Please co mment 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]

164. Two experts, Dr. Boisseau and Dr. de Brabander, answer this question. Codex also answers a
similar question posed to the international bodies (Q uestion 15). The Codex definition of GPVD, with
which both experts agree, is as follows:
Good Practice in the Use of Veterinary Drugs (GPVD) is the official recommended or
authorized usage including withdrawal peri ods, approved by national authorities, of
veterinary drugs under practical conditions.
165. In terms of Codex standards, guidelines a nd recommendations, Codex and Dr. de Brabander
identify the Codex Recommended International Code of Practice for Control of the Use of Veterinary
Drugs (Codex Recommendations) ,
79 although Dr. de Brabander does so only in passing. Instead of
discussing the Codex Recommendations, Dr. de Brabander extensively quotes from what appears to be
a code of ethics and principles of conduct for the Federation of Veterinarians of Europe (FVE). Two
points need to be made. First, the FVE code is not an international standard, guideline or
recommendation. Second, a code governing ethical conduct is of limited relevance to risk assessments
of veterinary drug residues in meat.
166. In contrast to the FVE, the Codex Recommendations addresses in detail such issues relating to
the use of veterinary drugs as requirements for distribution, transport, and storage ( e.g., temperature,

79 Codex, Recommended International Code of Practice for Control of the Use of Veterinary Drugs
(Codex Recommendations), CAC/RCP 38 (Exhibit CDA-47).

humidity, light, etc.); requirements on handling and administration ( e.g., dose, method of use);
withdrawal periods; disposal; and record keeping. Notably, the Codex Recommendations do not
suggest that all veterinary drugs must be administered by a veterinarian:
[w]hen the administration of a medicine is not under direct veterinary supervision, it
is therefore essential that, after the diagnosis, clear instructions should be provided on
dose and methods of use, taking account of the competence of the user performing the
work and ensuring that the correct calcula tion of, and the importance of adhering to,
withdrawal periods is fully understood.80
167. Regrettably, neither expert discu sses the detailed provisions of the Codex Recommendations
or whether this document sheds light on the EC's claim that GVP is "somewhat circular and hence
problematic." Canada shares Dr. Boisseau's concern that the EC's comment is less than clear. This
concern may flow from the fact that the EC appear s to be questioning a well recognized international
practice, employed by its own agencies.81 He posits that the EC means that the conditions of use of the
veterinary drug may differ in a very significant way from one country to another. Here, Dr. Boisseau's
answer to Question 45 is relevant.
168. Dr. Boisseau states that JECFA and other national authorities conduct risk assessments of
veterinary drugs using studies in which the drug under review has been administered according to
officially approved conditions of use ( i.e., labelled instructions). Thus, he suggests that adherence to
GPVD is intricately linked to compliance with approved conditions of use ( e.g., storage, dose and
method of use, withdrawal periods etc.).
169. The EC suggests that the circularity arises be cause "GVP is … dependent upon what national
authorities consider appropriate". This only becomes problematic if the conditions of use that underlie
the studies relied upon by JECFA are more stringent than approved conditions of use at the national
level. Consequently, it would be helpful if the e xperts could clarify whether the approved conditions
of use in Canada for the hormones in question diffe r from the conditions of use underlying the studies
that JECFA used to assess the safety of these hormones.
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?

170. Both Dr. Boisseau and Dr. de Brabander indicat e that in conducting a risk assessment it is
assumed that GVP is followed.
82 Dr. Boisseau explains in greater detail that JECFA and other national
authorities conduct risk assessments of veterinary dr ugs using studies in which the drug under review
has been administered according to officially appr oved conditions of use. As discussed above, for the
most part, use in accordance with GPVD means us e in accordance with the approved conditions of
use (e.g., storage, transport, dose, method of use, withdrawal period).
171. As regards the second part of the Panel's question, Dr. Boisseau indicates that it is very
difficult for risk assessors to identify all possible pe rmutations of misuse and abuse. In terms of the
risks that might arise from the failure to follow GPVD, Dr. Boisseau states:

81 In this regard, see Dr. Boobis' answer to Question 46, in which he states "appropriate residues studies
are those obtained after the normal use of the hormones, i.e. in accordance w ith GVP. This is the policy of all
agencies and organisations involved in such activities (EEC, 1990; EMEA, 2005; FAO, 2006)."
82 In the light of the answers to Question 44, Canada assumes that, when the Pane l refers to GVP, it is
actually referring to "good practice in the use of veterinary drugs" (GPVD).

It would not be appropriate also because it would not be ethical for the case where
such data, being available, would lead to the conclusion of the risk assessment that,
given a possibly wide margin of safety for a veterinary drug under review, the excess
intake of residues associated with these mi suses/abuses does not raise any problem of
public health.
172. Canada requests that Dr. Boisseau clarify whethe r he is suggesting that, with respect to the
growth-promoting hormones at issue, such a wide marg in of safety has been incorporated into the risk
assessment that any misuse and abuse is unlikely to give rise to adverse effects for human health?
173. Dr. de Brabander fails to respond to the Panel's actual question.
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 sy nthetic hormones at issue, how is GVP relevant
to the establishment of MRLs by JECFA?

174. Drs. Boobis, Boisseau and de Brabander respond to this question. Dr. Boisseau cites his
answer to Question 45, implying he is of the view that the risks of misuse and abuse are not typically
assessed by risk assessors su ch as JECFA. However, Dr. Boobis confirms that in several instances
JECFA did consider the risks of misuse of some of the hormone growth promotants at issue, namely,
zeranol and MGA.
175. Dr. Boobis also states that the point at whic h misuse and abuse is relevant in the risk
assessment is at the risk characterization stage, dur ing which potential exposure is compared with the
ADI. He also states that, where appropriate, one could consider other potential exposure scenarios,
such as the misuse and abuse of the substance in question.
176. Drs. Boobis and Boisseau appear of the view that it is not for JECFA to monitor compliance
with GVP. Dr. Boisseau's answer to Question 45 above, is supported by Dr. Boobis' response to
Question 62 where he states that:
[misuse and abuse] cannot be used as the basis for establishing MRLs. This is
because whilst use according to GVP can be foreseen and regulated, it is not possible
or appropriate to regulate any conceivable misuse or abuse, whether actual or
hypothetical. Normally, the risk management st rategy to deal with this is to ensure
adequate surveillance of residues and to put in place a system of penalties for
violation. This is the situation for veteri nary drugs in all regions where they are
subject to market authorisation, including the EU and the USA.
177. Therefore, to the extent that the EC is sugg esting that JECFA's risk assessment is somehow
flawed because it failed to assess potential misuse and abuse, the EC is fundamentally misconstruing
JECFA's role.
178. Dr. de Brabander's answer is confusing and diffi cult to follow. First, he suggests that JECFA
"denied" that there was misuse and abuse. Canada has carefully reviewed JECFA's reports and can
find no example of JECFA "denying" such a possibility. In the light of the responses of the other
experts, the Panel may wish to ask Dr. de Brabander to support this allegation. Second, he appears to
draw illogical conclusions about the relationship between misuse and abuse and the establishment of
MRLs. He states:
If other substances (like zilpaterol or ZMA etc …) or uncorrect [ sic] use of implants
are used the principle of the establishment of MRLs by JECFA is certainly unvalid
[sic]

179. As Drs. Boobis and Boisseau explain, MRLs ar e established on the basis of the normal use of
hormones, i.e., in accordance with GVP, and are set indepe ndently of potential compliance issues. In
the light of this evidence, Dr. de Brabander's conclusion is questionable, to say the least.
Q47. How significant are any differences in GV P in the European Communities, the United
States, and Canada? Does the EC risk asse ssment 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?

180. Drs. Boisseau and de Brabander respond to this question. Dr. Boisseau, although
acknowledging that he did not think that he was in a position to answer this question, indicates that in
his view the main problem for the EC is that HGPs in North America are sold over the counter
without veterinary supervision. He further states th at "it is not possible to say that the European
Communities took into account relevant control mechan isms with respect to GVPs in place in the
USA and/or Canada" in its risk assessment.
181. On the other hand, in answering this question, Dr. de Brabander appears again to confuse
concepts by suggesting that the very use of growth -promoting hormones is contrary to the principles
of GVP. However, as the Codex Recommendations reveals, GVP establishes principles governing the
use of veterinary drugs, but does not prescribe which substances can be used and for what purpose.
182. As to relevant control mechanisms, Dr. de Brabander again fails to answer the Panel's
question and instead postulates that "any control me chanism, that is only based on audits and paper
work will not prevent farmers to use either uncorrect [ sic] use of legal production aids either the use
of other illegal growth promotors which are read ily available in the US and Canada through the
internet." Aside from the fact that Dr. de Brabande r is straying from his area of expertise, the only
evidence presented to support his assertion is a warni ng issued by Health Canada concerning athletic
performance-enhancing products containing illegal anabolic steroids.
83 Although it is less than clear,
Dr. de Brabander appears to imply that because ana bolic steroids are used illegally in performance
enhancing products in Cana da, control mechanisms short of a complete ban would not prevent the
misuse and abuse of HGPs. This logic is deeply flawed. A warning issued by Health Canada to protect
Canadians from illegal anabolic steroids in bodybu ilding drugs is hardly credible evidence of the
existence or extent of the misuse and abuse of HGPs or an evaluation of relevant control mechanism.
183. Moreover, the illegal use of anabolic steroids by athletes has been a world-wide problem for
decades. Much of the internet trad e in illegal anabolic steroids orig inates in Europe, where controls
over the distribution of these products are more lax. 84 The implication of Dr. de Brabander's logic is
that, because these products are available in Euro pe through the internet, European farmers are
misusing anabolic steroids in the husbandry of cattle.
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

83 Health Canada, Advisory, Health Canada advises consumers not to use unauthorized products
containing anabolic steroids , April 21, 2006; online at: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-
avis/2006/2006_17_e.html.
84 US Drug Enforcement Agency, Anabolic Steroids, A Dangerous and Illegal Way to Seek Athletic
Dominance and a Better Appearance , "For purposes of illegal use there are several sources; the most common
illegal source is from smuggling steroi ds into the United States from ot her countries such as Mexico and
European countries. Smuggling from these areas is easier because a prescription is not required for the purchase
of steroids. Less often steroids found in the illicit market are diverted from legitimate sources (e.g. thefts or
inappropriate prescribing) or produced in clandestine laboratories"; online at:
http://www.deadiversion.usdoj.gov/pubs/brochures/steroids/public/public.pdf.

to GVP, of any of the six hormones? Would you r reply have been different at the time of
adoption of the EC Directive in September 2003? What are the po tential 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?

184. Although Drs. Boisseau, Boobis and de Brabande r all provide answers, only the first two
respond to the question posed by the Panel in a co mprehensive fashion. These experts agree that the
EC failed to assess risks to human health from residues of misplaced implants or improper
administration. Dr. Boobis states directly that:
There 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 "Therefore, these data have to
be considered in any quantitative exposur e assessment exercise", without undertaking
such an exercise.
185. For his part, Dr. Boisseau notes that the EC:
… is right to state that, in case of these different misuses/abuses, the exposure of
consumers may be totally different. Once ag ain, this situation is not specific to
hormones as it applies also to all the vete rinary drugs already assessed by JECFA,
EU, USA or anywhere else in the world.
186. These responses support Canada's explanation that the EC has failed to evaluate the potential
risks to human health from the misuse or abu se of the growth-promoting hormones at issue.
85 The EC
has simply identified the possibility that misuse or abuse could occur without having evaluated its
frequency or the potential risk to human health in the event it occurs. As Dr. Boobis states:
In my view, the potential hazards to the u se of large quantities of the six hormones in
dispute are those dependent on their endocrine activity, including cancer in
hormonally responsive tissues. However, I s hould stress that this is their potential
hazard. The potential risk, i.e. the probabilit y that effects would occur, would depend
on a number of factors. These include the ma gnitude of the exposure, the duration of
the exposure and the life stage of the exposed individual. From the range of exposures
likely from anticipated misuse or abuse the risks are likely to be very low.
187. In his response to Question 62, reviewing the EC's additional research conducted since 1997,
Dr. Boobis further states:
Taking account of all of these factors, 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. Nor do they provide any
indication that even such misuse and abu se as investigated gives rise to undue risk
from the resultant residues, as intake would only very rarely exceed the ADI and then
only on a rare occasion.
 86
188. As Dr. Boisseau notes, the misuse and abuse of a substance could lead to exposure scenarios
different from those contemplated in establishing an MRL. This applies to any veterinary drug, or
indeed any substance for which an MRL is esta blished. If it were sufficient for a WTO Member
simply to raise the possibility, without any evaluatio n, of misuse and abuse as a justification for a ban

85 Canada Rebuttal Submission, at paras. 107-111.
86 Dr. Boobis, at p. 52.

on a substance, the obligation in Article 5.1 of the SPS Agreement to base an SPS measure on a risk
assessment would be rendered illusory, and the work of international scientific risk assessment bodies,
such as JECFA or the Joint Management Pesticid e Committee, could be largely irrelevant. Mere
assertions that misuse and abuse may occur wit hout any evaluation of the factors outlined by
Dr. Boobis on page 52 of his answers do not satisfy the requirements of a risk assessment as defined
by the SPS Agreement.
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 hormon es in dispute for growth promotion purposes in
accordance with good animal husbandry practice and/or good veterinary practice?

189. Only Dr. de Brabander responds to this question. He indicates that:
There are a large number of analytical methods available to control the use of the six
hormones in dispute for growth promotion purposes. New methods are regularly
presented in international conferences and in the open literature. In Europe a system
of community reference (CRL) and national reference laboratories (NRL) is installed
so that the analysis carried out by the field laboratories are kept up to the standards of
the moment. If necessary I can provide the panel with a large number of methods but
I don't think that is the purpose.
190. As it would be helpful to understanding the i ssues in dispute, the Panel may wish to ask
Dr. de Brabander for a complete listing of available analytical methods to detect residues in meat and
meat products for each of the hormones at issue as well as a complete description of the CRL and
NRL networks to which he refers.
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?

191. Both Drs. Boisseau and de Brabander respond to this question. Dr. Boisseau makes a number
of suggestions for addressing human health concerns arising from the failure by the exporting country
to ensure compliance with GVP. He notes that a "[b] an is the last possible measure if all the other
options have failed or have been proved ineffective."
192. In contrast, Dr. de Brabander states that ther e are no measures possible other than a complete
ban that could address the risks arising from misuse a nd abuse. This remark appears inconsistent with
his earlier statement in response to Question 49 that "[t]here are a large number of analytical methods
available to control the use of the six hormones in dispute for growth promotion purposes."
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?

193. Both Drs. Boisseau and de Brabander respond to th is question. Dr. Boisseau refers back to his
answers to Questions 45 and 48, implying that, in his view, the misuse and abuse of hormones used
for growth promotion do not call into question the potential applicability of Codex standards.
Dr. Boisseau earlier commented that the establishment of ADIs and MRLs are based on an

assumption that GVP will be followed. Thus, in th e unlikely event that GVP is not followed, the
applicability of Codex standards is not put into do ubt. Misuse or abuse may cause the residues of the
substance in question to exceed the established MR L and may lead to exposure to the substance in
excess of the established ADI, but it does not imply th at the Codex standard is any less applicable.
Questions of compliance with an MRL differ con ceptually from whether the MRL is valid or
applicable.
194. Unlike Dr. Boisseau, Dr. de Brabander appear s to confuse the applicability of a Codex
standard with the consequences of misuse and abu se. Then, he refers to "older" experiments upon
which the ADIs and MRLs were ba sed and suggests that "scientifi c knowledge on residues, their link
with animal welfare and the impact on the enviro nment has increased consider ably." With respect, it
is somewhat difficult to follow Dr. de Brabander's reasoning in this regard and it is less than clear
how Dr. de Brabander's response addresses the Panel' s question concerning misuse and abuse. To the
extent that Dr. de Brabander suggests that th e experiments on which the Codex ADI and MRL are
based were "old" and no longer valid, he appears to be answering Question 34, on which Canada has
already commented. Moreover, Dr. de Brabander's re ference to his own study of the formation of
boldenone has no bearing on the issue of misuse and abuse.
(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 pote ntial adverse affects? Would your response have
been different at the time of adoption of the Directive in September 2003?

195. Drs. Boisseau and Boobis both agree with Canada that the scientific evidence relied upon by
the EC does not demonstrate that there are adverse effects from the consumption of residues of
hormones through meat from treated animals. Dr. Boisseau states that the EC did not carry out a risk
assessment, but, rather, simply "provided scientific data and hypothesis supporting its worries" about
the safety of the hormones. In particular, he confirms Canada's explanation of some of the flaws of the
EC's risk assessment when he notes that the SCVPH should have:
integrated in its risk assessment the exposure of consumers to these hormones
resulting from the consumption of hormone residues from animals which have not
been treated by hormonal growth promoters and the [sic] from the daily production of
these hormones by humans.
196. Dr. Boobis echoes this evaluation of the EC's risk assessment and its scientific evidence when
he advises that "none of the information provided by the EC demonstrates the potential for adverse
effects for humans" from meat from cattle treated with hormones. More specifically, he adds that:
[t]he studies on genotoxicity provide no convi ncing evidence of potential for harm in
consumers. 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. As
such, there would be no risk of such effects in human from such exposures. The
carcinogenic effects observed are entirely cons istent with a hormonal mode of action
that exhibits a threshold that would be well above the intake arising from
consumption of meat from treated cattle. Other effects of the hormones that have
been observed either in experimental animals or in exposed subjects occur at doses
much higher than those to which consumers would be exposed via meat from treated

cattle. As such, there would be no risk of such effects in humans from such
exposures.
197. For his part, Dr. Guttenplan seems to suggest, but does not explicitly state, that the EC has
identified the potential for adverse effects. Howe ver, his main concern is based on the SCVPH's
conclusion that pre-pubertal children have lower e ndogenous levels of hormones, itself based on data
obtained principally by the Klein assay. As discussed in Canada's comments on Question 40, there are
serious doubts about the validity of this assay. Dr. Gu ttenplan's endorsement of the EC's conclusions
about adverse effects suffers from the same shortcom ings as those conclusions themselves: they both
rely on scientific methodologies that have not been validated.
198. All three experts provide useful advice on the ev idence that would be required to demonstrate
adverse effects, such as toxicological data (Dr. Boisseau), residue data that show that consuming
treated meat leads to any change in circulating levels (Drs. Boisseau, Boobis and Guttenplan), and
specific epidemiological studies (Dr. Boobis). It is important to note that none of them suggests that
the EC has demonstrated such evidence currently exists.
Q53. Please comment on the statement by the European Communities that the natural
hormones progesterone and testosterone are us ed 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 assessments are to be ca rried 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]

199. Both Drs. Boisseau and Guttenplan, the only two experts that addressed this question, 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. They both acknowledge that it is oestradiol
17β that is the most potent, with the addition of the others not significantly changing this potency such
that the risk would increase. Therefore, once oestradiol 17 β has been demonstrated not to have
adverse effects when used as a growth promoter, ther e is little risk that adverse effects would occur if
used in combination with the other hormones.
Q54. What is the acceptable level of risk ref lected in the Codex standards for the five
hormones at issue? How does this compare to th e 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)]

200. Drs. Boisseau, Boobis and Guttenplan all advise th at the acceptable level of risk reflected in
Codex standards is that there is no risk of adver se effects if exposure to hormones is kept below the
established ADI. In that sense, as Dr. Boobis points out, the acceptable level of risk reflected in the
international standards is identical to that purportedly sought by the EC through its ban.
201. While Drs. Boisseau and Guttenplan both appear to suggest that the acceptable level of risk
chosen by the EC is different than that embodied in the Codex standards, a close examination of their
answers reveals that the difference to which they refer is that between theoretical risk and real risk,
and not between acceptable levels of protection. Th at is, whereas the Codex standards indicate that
there is no real risk if exposure is kept below the establishe d ADI, the EC attempts to prevent even
theoretical risk. Dr. Guttenplan confirms that th e EC has not addressed the actual level of risk
presented by consumption of meat from treated an imals, only that there is a potential risk.
Dr. Boisseau also advises that the EC will not accept "any risk, even theoritical [sic]".

202. Dr. Boobis expresses the issue in slightly different terms that lead to the same result. He
advises that there is no difference between the two levels of risk (which are otherwise identical in that
they accept zero risk to consumers of meat from treat ed animals) but there is a difference in how the
evidence has been interpreted. On the one hand, in light of its conclusions that there is
 a threshold
below which no adverse effects will result, Codex has adopted a standard that will not result in risk.
On the other hand, in light of its conclusions that there is not a threshold below which adverse effects
will not result, the EC has adopted a measure that it co nsiders will not result in risk. To the extent that
the experts in their answers to other question advise th at the EC has not demonstrated that there is not
a threshold, the EC has also not demonstrated that the international standards is insufficient to achieve
its acceptable level of risk, which is identical to that embodied in the international standards.
203. The distinction made by the experts between theore tical risk and real risk is an important one
in the context of this dispute also because it confirms that the sole reason for the EC to adopt a ban,
rather than establish maximum accep table exposure levels, was to avoid a theoretical risk, something
that the Appellate Body has confirmed is not permissible under the SPS Agreement.
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 an imals 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]

204. Drs. Boisseau, Boobis and Guttenplan confirm th at the EC did not eval uate additive risks.
Dr. Boisseau's answer suggests that he believes the EC's "position of principle" (that it would not
accept even any theoretical risk) prevented it fro m even trying to assess the "additive risks".
Dr. Boisseau only partly answers the question, in that he only assesses the EC's decision not to
compare hormone levels in treated meat versus untreated meat; he does not comment on the EC's
failure to compare the effects of hormones from treated meat to the effects from all other sources of
hormones, including endogenous production.
205. In the first sentence of his response, Dr. Gu ttenplan agrees that the EC did not evaluate
"additive risks". It is not entirely clear, however , how his reference to the EC's comparison of
exposure to hormones from treated meat and th e background levels in prepubescent children is
relevant to the evaluation of "additive risks". In f act, if anything the EC's selective evaluation of
purported risks to sensitive populations from hormones from treated meat simply confirms that the EC
has not evaluated "additive risks", because it has not conducted a similar evaluation of the risks posed
by exposure from other sources of hormones, many of which are far greater than that from treated
meat.
206. For his part, Dr. Boobis distinguishes between "aggregate risk" (risk resulting from the
aggregate exposure from all sources of a single substance) and "cumulative risk" (risk resulting from
the cumulative exposure from all substances with a common mechanism of toxicity) and then
confirms that the EC evaluated neither kind of ri sk. Dr. Boobis explains that one way to assess the
"aggregate risk" from exposure to exogenous s ources of substances that are also produced
endogenously is to determine th e tolerable upper intake level taking into account endogenous
production, then determine whether exogenous sources ch ange the circulating levels of the substances
in the body. JECFA has essentially done this for the natural hormones when it assessed the exposure
from meat from treated animals relative to the circul ating levels and found that the former fell within
the normal variation of the latter.

207. Dr. Boobis acknowledges that a critical issue in assessing additive risks is whether there is a
threshold below which adverse effects will not occur, something the EC argues is not the case with
these hormones. As discussed previously, the EC's clai m that there is no threshold for adverse effects
from these hormones is simply not supported by th e evidence. Therefore, its claim, from a "position
of principle", that there are "add itive risks" is similarly not credib le in the absence of a quantitative
evaluation of those risks. Indeed, the advice from th e experts confirms Canada's identification of a
critical flaw in the EC's claim that hormones from treated meat present an "a dditive risk": additive to
what? In other words, what is the baseline risk from endogenous sources of hormones, or from other
exogenous sources? Does exposure to hormones from me at from treated animals alter that risk? The
EC does not ask, let alone answer, any of these questions , so it is difficult to see how its answer to the
issue of additive risk can be legitimate.
Q56. Has JECFA/Codex considered in its risk a ssessment of the five hormones such "additive
risks? Are there internationally recognized guid elines for conducting a ssessments of "additive
risks"?

208. Two of the three experts who responded to this question, both of whom are quite familiar with
the work of JECFA, advised that JECFA does take into consideration "additive risk" (covering what
Dr. Boobis refers to as "aggregate risk" but not "cumulative risk"). The manner in which JECFA does
so is similar to the process described above in Canada's comments on the responses to Question 55.
That is, because there is such a wide "margin of safety" (Dr. Boisseau) between the exposure from
hormones from treated meat and the aggregate expos ure from all other sources (both endogenous and
exogenous) and because the increase in aggregate exposure from consuming meat from treated
animals was considered to be "trivial" (Dr. Boobis), there would be no "additional risk" over that from
background levels.
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 17 β 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]

209. Drs. Boisseau, Boobis and Guttenplan indicated that the EC did not take into account in its
risk assessment the risks that arise from the use of these hormones for therapeutic purposes. Both Drs.
Boisseau and Boobis share Canada's difficulty in r econciling the EC's conclusion that there is no
threshold below which there are no adverse effects from hormones from treated meat and its
authorization of the use of these substances fo r certain purposes and not others. Dr. Boisseau
considers it a "problem of principle", whereas Dr. Boobi s suggests that the only way this is justified is
if one assumes that there is a dose-response relati onship, something the EC rejects. Dr. Guttenplan
fails to support his observation that the EC's explan ation for why it allows such use is "reasonable".
On the whole, the experts' advice indicates that th e EC is trying to have it both ways: that hormones
are genotoxic for some purposes and not others.
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.

210. Drs. Boisseau, Guttenplan and Boobis all expressed in their own ways some difficulty with
this statement by the EC. Dr. Boisseau suggests (with reference to his answer to Question 55) that this
constitutes simply a "position of principle", one not supported by evidence that there are additive risks
from higher doses of these hormones. Dr. Guttenplan si mply offers that it is "indeed a very weak
statement". His further suggestion th at it is nonetheless better than an estimate of risk that is "wildly
inaccurate" only reinforces Canada's concern that ther e is simply no basis for the EC to draw such a
conclusion. Dr. Boobis confirms again that this st atement is not supported by the evidence in that
"within quite broad limits, higher e xposure would not result in an increase in risk". Considering that
hormone intake from meat from treated cattle represents only 1.5% of the ADI (the level below which
there is no risk), it simply cannot be "inferred from the available scientific data" that exposure to more
residues from meat from treated animals will lead to greater risk.
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]

211. While the three experts that responded to this question all acknowledge that there can be
adverse effects on the immune system from hormonally active substances, they all confirm that there
is no scientific evidence that such effects will o ccur from exposure to doses of hormones that would
be expected from residues in meat from treated an imals. Dr. Boobis points to the "margin of safety"
inherent in the dose relative to the background le vel; Dr. Boisseau indicates that the EC has not
conducted the "quantitative risk assessment" that would be required to demonstrate risk from what are
known to be dose-dependent adverse effects; an d Dr. Guttenplan simply cites the absence of
"definitive studies" (although he could have just as e asily referred to the absence of "any studies") of
low dose adverse immune system effects. All of the experts therefore confirm that for the EC to
demonstrate that there are risks of adverse effects to the immune system from hormones from treated
meat, it would have to demonstrate that such e xposure would surpass the threshold at which such
adverse effects would occur. It has not.
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?

212. Drs. Boisseau, Boobis and Guttenplan all indicat e that the EC did not demonstrate that the
potential for adverse effects differs depending on the route of administration. Only Dr. Boobis
indicates that there may be a difference in effect as a result of misuse and abuse of implants, which
would not occur in feed additives. However, he only acknowledges that the level of the exposure may
be greater, and not that the level of risk of adverse effect necessarily would be greater. For the level of
risk of adverse effects to be different, the expos ure from one source of administration or the other
would need to exceed the ADI, something that is quite unlikely to happen.
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; an d (e) melengestrol acetate? Would your response

differ in light of the scientific evidence provided which is subsequent to the adoption of the EC
Directive?

213. Both Drs. Boobis and Guttenplan indicate that sufficient scientific evidence was available to
the EC to conduct a risk assessment of the five ot her hormones. Dr. Boisseau indicates that he is
unaware of what the EC had available to it at the time, but goes on to suggest that it is never possible
to eliminate all scientific uncertainty, and that th e EC could have obtained any information it felt it
did not have. Dr. Guttenplan specifically, and Dr. B oobis through reference to his other answers, both
point to work done by JECFA as establishing that the data are complete enough to conduct risk
assessments. It also seems to be the case, especially from Dr. Boobi s' reference to his other answers,
that since there is sufficient evidence to demonstrate the safety of oestradiol 17β , which is considered
to be the more potent substance, the same type of data and principles of analysis that demonstrate the
safety of this substance indicate that the other five hormones will also be safe.
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?

214. While Drs. Boisseau, Boobis and Guttenplan a ll indicate that new scientific evidence has
raised new and interesting issues, they do not agree that this evidence suggests important gaps in the
understanding of the safety of these substances. Dr. Boisseau does not believe that these new data are
contrary to previous conclusions or that they make it impossible to conduct a risk assessment.
Dr. Guttenplan suggests some new areas of potential study, but some of them are already answered
(see, for example, Dr. Boobis' review of the effect of consuming meat from treated animals on blood
levels of oestrogen); some of them are not necessary for the completion of a risk assessment; and at
least one of them (epidemiological studies of c onsumption of treated versus non-treated meat) will
never be able to demonstrate the linkages that Dr. Guttenplan would like to see (see discussion of
confounding factors above). Dr. Boobis provides th e most comprehensive assessment of the new
scientific data, and addresses each and every study that the EC claims raise new scientific issues. As a
result of his review, he concludes that the additi onal information "was often not definitive, sometimes
it was not relevant, in some instances it confirmed or expanded upon previous knowledge".
III. COMMENTS ON INTERNATIONAL ORGANIZATION REPLIES
Q1. Please briefly describe the procedure fo r the elaboration and adoption of an
international standard by Codex. What is the decision-making process for the adoption of an
international standard?

215. Canada has no comments to make at this time.
Q2. Please briefly explain the differences betw een Codex standards, codes of practice,
guidelines, principles and other recommendations.

216. Canada has no comments to make at this time.
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.

217. See Canada's comments on the experts' answers to Question 3.
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 the hormones at issue? [see para. 192 of EC
Rebuttal Submission (US case)]

218. See Canada's comments on the experts' answers to Question 4.
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.

219. See Canada's comments on the experts' answers to Question 5.
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.

220. See Canada's comments on the experts' answers to Question 6.
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]

221. See Canada's comments on the experts' answers to Question 7.
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 co nducted for chemical agents..."? [see Exhibit
CDA-25]

222. See Canada's comments on the answers from the experts to Question 37.
Q9. Please provide definitions for the followin g terms: Acceptable Daily Intake (ADI) and
Maximum Residue Limit (MRL).

223. See Canada's comments on the answers from the experts to Question 8.
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.

224. See Canada's comments on the answers from the experts to Question 8.
Q11. Please confirm or comment on the followin g 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]

225. See Canada's comments on the answers by the experts to Question 9.
Q12. In para. 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?

226. See Canada's comments on the answers from the experts to Question 10.
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 data 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),

227. JECFA confirms in its response that "[u]npub lished confidential studies that are submitted
will be safeguarded and will be used only for ev aluation purposes by JECFA", and that "confidential
data will either be returned to the submitter at the submitter's expense or destroyed after the
evaluations have been completed."
Q14. How are experts involved in JECFA's wo rk selected? What are the selection criteria?

228. Canada has no comments to make at this time.
Q15. Please provide the definition of the term Good Veterinary Practice (GVP). Are there
any relevant Codex standards, guidelines, or recommendations relating to GVP?

229. See Canada's comments on the responses from the experts to Question 44.
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?

230. Canada has no comments to make at this time.
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?

231. JECFA confirms that, with the a ddition of a reference to the 66
th JECFA meeting held
20-28 February 2006 , at which meeting JECFA further deliberated on the MRLs previously proposed
for MGA, Exhibit CDA-32 is complete.
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?

232. See Canada's comments on the answers by the experts to Question 33.
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]

233. JECFA's response states that "[t]he re-evalu ations of compounds follow the same procedure
as an evaluation performed for the first time, with clear identification of the new data that were
assessed." See also Canada's comments on the answers from the experts to Question 33.
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 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 recent recommendations not considered by
CCRVDF? What is the status of these recommendations? [see paras. 96-97 of EC Rebuttal
Submission (US case), paras. 79-80 of EC Rebuttal Submission (Canada case)]

234. See Canada's comments on the answers by the experts to Question 33.
Q21. What is the mandate of the Intern ational Agency for Research on Cancer?

235. Canada has no comments to make at this time.
Q22. Who are the members of the IARC?

236. Canada has no comments to make at this time.
Q23. What are IARC Monographs? How are they prepared?

237. Canada has no comments to make at this time.
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?

238. The Panel may wish to request further explan ation from IARC regarding the considerations
that determine the classification by IARC of a subs tance as belonging to Group 1, 2A or 2B, as well
as the consequences or implications of such a classification.
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 consumpt ion of meat from cattle treated with these
growth promotion hormones been assessed by the IARC?

239. IARC's response states that it has evaluated the three natural hormones but not the three
synthetic hormones. IARC's evaluation and classificati on of the three natural hormones appears not to
have taken into account the differe nt potential sources of these horm ones and the different potential
levels of exposure of individuals. Thus the kind of risk assessment that was conducted by JECFA was
apparently not carried out by IARC. IARC does not respond to the question about the specific risks
from exposure to residues of hormones in meat from treated animals.

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?

240. IARC's response to Question 26 is the same as that to Question 25.
IV. CONCLUDING COMMENTS
241. The experts and international bodies have pr ovided extensive advice on the scientific and
technical matters at issue in this dispute. The e xperts' responses exhibited general agreement that the
scientific evidence and information does not support the conclusions of the EC's evaluation of these
six hormones. While this is the case for most of the issues addressed by the experts, several issues that
are central to the Panel's review of the EC's evaluation warrant specific mention.
242. In particular, the experts indicate that the scientific evidence does not support the following
conclusions:
• that all or some of the hormones (but in particular, oestradiol 17 β) present a risk of
adverse effects (such as genotoxicity) that do not exhibit an exposure dose below
which they will not occur (i.e., a threshold);

• that exposure to the hormones from residues in meat from treated animals will be so
significant in proportion to the endoge nous hormone levels present in certain
sensitive populations such that adverse effects will occur;

• that the exposure from this single source of hormones is sufficiently "additive" to the
exposure from all sources of hormones to in crease the risk of occurrence of adverse
effects;

• that the failure to follow GVP will resu lt in exposure to the hormones at doses
capable of causing adverse effects and that the hormones are administered in Canada
in a manner that fails to follow this GVP; and

• that the scientific evidence is insufficient to conduct an assessment of the safety of
the five hormones other than oestradiol 17β.

243. Canada looks forward to meeting with the expe rts and to the opportunity to discuss these and
other scientific and technical issues in more detail.

by the EC that the burden is on Canada to prove that adverse effects will not arise runs contrary to the
applicable WTO rules on the allocation of burden of proof. Similarly, any suggestion by the EC that
the experts must demonstrate that such adverse ef fects will not arise demonstrates a misunderstanding
of the role of the experts in these proceedings.
3. Therefore, it is the EC – and not Canada or the experts – that must demonstrate that it has
scientific evidence that supports its claim that adverse effects will arise from consuming residues of
hormones in meat from treated animals. Conseque ntly, the focus of the discussion should not be on
the manner of adoption of the international standard s and their scientific underpinnings but rather on
the EC's opinions and whether they meet the requirements of the SPS Agreement.
4. Second, the EC makes a number of assertions in its comments that that are accompanied by
citations of articles that have not been filed as exhi bits. Canada has been able to locate some of the
articles, but not all of them and, accordingly, limits its comments to those it h as been able to locate.
However, to the extent that the EC refers to th is material in relation to claims about scientific
evidence that it is making for the first time, and then fails to provide the supporting material, the
claims remain no more than unsupported assertions that should be given no weight by the Panel.
5. Third, in its comments on certain experts' res ponses, the EC questions the relevance of the
views of Dr. Boisseau and Dr. Boobis because, according to the EC, they did not carry out
"experiments on hormones" and pub lish related scientific papers. 2 The curricula vitae of both these
experts, which demonstrate extensive experience in the risk assessment of many veterinary drugs as
well as other chemicals, and the quality of their rep lies, speak for themselves. While it is the EC's
prerogative to disagree with the an swers provided by any of the experts, there can be no doubt about
the professional competence of Dr. Boisseau and Dr. Boobis that underlies their answers to the Panel's
questions.
6. Fourth, the EC tries to impugn the comments from Codex and JECFA, but not those from
IARC, by questioning the legality of the tran smittal of these comments by the Codex and JECFA
Secretariats respectively to the Panel, without havi ng complied with internal procedures that were not
identified by the EC. It would not be appropriate for the Panel to inquire into the question of
compliance with the internal rules of other intern ational bodies. Also, the information provided by the
Codex and JECFA Secretariats are matters of public record. In any event, it would be open to the EC
to take any steps it deems appropriate within Codex and JECFA to deal with this issue.
7. Canada will address the EC's comments on the responses of the international bodies in Part III
of this submission.
8. And finally, given the short time-frame for th e preparation of these comments, the absence of
comments by Canada on certain assertions by the EC should not, of course, be construed as agreement
with such assertions.
II. COMMENTS ON THE COMMENTS FROM THE EC ON THE RESPONSES FROM
THE EXPERTS
A. GENERAL DEFINITIONS
9. In its comments on the experts' responses to Question 1, the EC quibbles with Dr. Boisseau's
definition of the hormones at issue in this dispute. To the extent that the issues raised by the EC are
relevant, Canada will address them below.

2 Ibid., Questions 2, 17, 21 and 42.

10. The EC's attempt to discredit Dr. Boisseau's response to Question 2 by referring to his earlier
indication of which questions he intended to answer is unjustified. Other experts, such as
Dr. Cogliano and Dr. de Brabander, answered ques tions that they did not originally indicate they
would answer; some of them in the end declined to answer questions they had earlier indicated they
would answer. That is the experts' prerogative a nd nothing more should be read into an expert
responding or not responding to particular questions.
B. R
ISK ASSESSMENT TECHNIQUES
11. In its comments on the experts' responses to the Panel's Questions in this section
(Questions 3-12), the EC raises several issues that warrant comment at this stage. These are:
• the meaning of the phrase "risk assessment techniques developed by the relevant
international organizations", as found in Article 5.1 of the SPS Agreement and its
relevance to this dispute;

• the relevance of the different mandates of the European Me dicines Agency's
Committee for Veterinary Medicinal Products (CVMP) and the Scientific Committee
on Veterinary Measures relating to Public Health (SCVPH);

• the distinction between risk assessment and risk management;

• the meaning of "no appreciable risk";

• the distinction between qualitative and quantitative risk assessments and the
relevance of this distinction to the meaning of "risk assessment" as found in the
SPS Agreement;

• the existence of scientific uncertainty; and

• the relationship between weight of evidence and minority science.

"Risk Assessment Techniques" in Article 5.1 of the SPS Agreement

12. In its comments on the responses to Questions 3, 4 and 6, the EC attempts to dismiss the
various international guidance documents identifie d by the experts and JECFA and Codex as being
relevant to the conduct of veterinary drug risk asse ssments. In doing so, the EC distorts the meaning
of the phrase "risk assessment techniques developed by the relevant international organizations" in
Article 5.1 of the SPS Agreement.
3 The thrust of the EC submission is that unless an international
guidance document is formally adopted by Codex it is not "legally binding" and therefore cannot
constitute a "risk assessment technique" under Article 5.1 and is irrelevant.4 However, the EC's line of
reasoning is misguided. The question is not whether the "risk assessment techniques" are "legally
binding" but whether the "risk assessment techni ques" assist in determining whether the risk
assessment at issue is "appropriate to the circumstances." For a risk assessment to be "appropriate to
the circumstances", the WTO Member must "tak[e] into account the risk assessment techniques…".
Failure to do so suggests that the assessment at issue is not "appropriate to the circumstances".

3 Article 5.1 of the SPS Agreement reads in full "Members shall ensure that their sanitary or
phytosanitary measures are based on an assessment, as a ppropriate to the circumstances , of the risks to human,
animal or plant life or health, taking into account ri sk assessment techniques de veloped by the relevant
international organizations."
4 See EC Comments, Questions 3, 4 and 6.

13. To the extent that the EC is suggesting by th e phrase "legally binding" that "risk assessment
techniques" must be formally established by on e of the international organizations listed in
Annex A(3) as a "standard, guideline and recomme ndation", the EC is incorrect. Had the Members
intended such an effect, then they would have used "standard, guideline and recommendation" in
Article 5.1. The fact that they did not implies th is is not the case. The use of the term "technique"
suggests that the treaty drafters were referring to the technical aspects of risk assessment
methodology. Some "techniques" may be embodied in a formally established "standard, guideline,
and recommendation", while others may not. The "risk assessment technique" must be "developed by
the relevant international organization." Withou t question, Codex is a "relevant international
organization". Given that Codex relies on the wo rk of JECFA to conduct risk assessments and
develop risk assessment techniques for food additives, contaminants and veterinary drugs, it can be
inferred that JECFA is a "relevant international organization" for the purposes of Article 5.1.
14. In this case, "risk assessment techniques" devel oped by Codex include the four steps of the
risk assessment process (h azard identification, hazard characteriz ation, exposure assessment and risk
characterization). Those developed by JECFA are embodied in EHC 70
5 and the JECFA Procedures. 6
More specific to this case are techniques such as the assessment of the qua lity and quantity of
available study data, determination of pivotal studies and the NOAELs (No Observed Adverse Effects
Levels), the conduct of the dose-response assessment, the selection of appropriate safety factors and
the establishment of ADIs (Acceptable Daily Intakes). Therefore, assessments of veterinary drugs that
fail to take into account these techniques are not, prima facie, "appropriate to the circumstances" and,
therefore, do not satisfy the requirements of Ar ticle 5.1 and the definition of risk assessment in
Annex A(4).
Relevance of the different mandates of the CVMP and SCVPH

15. In its comments on responses to Question 3, the EC's attempt to discredit Dr. Boisseau's
advice concerning the CVMP's ability to assess pha rmacologically active substances used in
veterinary medicine "without any written guidelin e about risk assessment" is confused and illogical.
The EC appears to imply that techniques used by the CVMP in conducting risk assessments are not
applicable to the work of the SC VPH on the basis that the SCVPH's mandate differs from that of the
CVMP. This appears to be an indirect attempt to explain the differing conclusions reached by these
committees in relation to adverse effects caused by the use of hormones in animal husbandry.
However, the fact that these two committees assess different uses of the same substances has no
bearing on the nature of the risk assessment t echniques employed. For instance, the techniques
adopted to determine whether oestradiol 17 β is genotoxic apply regardless of the use to which the
substance will be put. If oestradiol 17 β, when used for therapeutic purposes, has a dose threshold, it is
illogical to conclude that it does not have a dose threshold when used for growth-promotion purposes.
The EC cannot escape from the CVMP's conclusion that oestradiol 17 β is not genotoxic by referring
to different committee mandates.
Risk Assessment/Risk Management

16. The EC attempts, in its comments on responses to Question 5, to dismiss all the explanations
provided by the experts of the three components of "risk analysis" by reiterating its previous
arguments concerning the differing scope of, on the one hand, risk assessment as defined by the
SPS Agreement, and, on the other hand, risk assessment as a component of Codex's risk analysis. As

5 International Program on Chemical Safety, Principles for the Safety Assessment of Food Additives
and Contaminants in Food, Environmental Health Criteria 70 (Geneva: WHO, 1987) (EHC 70) (Exhibit
CDA-43).
6 JECFA, Procedures for Recommending Maximum Residue Limits – Residues of Veterinary Drugs in
Food (1987 – 1999) (Rome: FAO/WHO, 2000) (JECFA Procedures) (Exhibit CDA-44).

Canada has explained in deta il in its Rebuttal Submission,
7 the EC is attempting to insulate its SPS
measure, i.e., its ban on all meat and meat products derived from treated animals, from Panel review
by suggesting that the "wider" risk assessment contemplated by the SPS Agreement includes risk
management considerations and that risk management is a priori non-reviewable because it is related
to a WTO Member's autonomous right to set its appropriate level of protection.
17. As Canada explained, the EC cannot escap e the obligation in Article 5.1 of the
SPS Agreement to base its measure on a risk assessment by claiming that a component of the risk
assessment includes non-reviewable risk management considerations. The Appellate Body's statement
that Article 5.1 was "intended as a countervailing factor in respect of the right of Members to set their
appropriate level of protection" 8 implies that risk management and the autonomous right of each
WTO Member to set its level of protection cannot be used to avoid the obligation in Article 5.1.
The concept of "Appreciable Risk"

18. The EC arguments concerning "appreciable ri sk" are a direct challenge to one of the
cornerstones of modern risk assessment techniqu es widely employed by risk assessment bodies at
both the national and international le vel. The EC attempts to discredit this concept by asserting that it
is "subjective", "qualitative" and "unspecific". 9 However, these arguments reflect a profound
misunderstanding of this concept and its role in the risk assessment process.
19. The phrase "without appreciable risk" is found in Codex's definition of ADI: "an estimate by
JECFA of the amount of a veterinary drug, expressed on a body weight basis, that can be ingested
daily over a lifetime without appreciable health risk ".10 To understand what is meant by "appreciable
health risk", or "appreciable risk", one must cons ider the risk assessment process as a whole. On the
basis of detailed scientific experimentation, obser vation and analysis of em pirical data, a NOAEL is
set for each observed adverse effect. The NOAEL represents the dose level at or below which no
adverse effect is empirically observed or measured in the target organism.
20. The NOAEL is then adjusted by safety factors to derive the ADI. If no effect is observed,
then, logically, there is no observable or empirically ascertainable risk. Appreciable, in the sense used
in the ADI, means observable, ascertainable or iden tifiable. Thus, far from being "subjective" or
"qualitative", as the term is used by the EC, the identification of a lifetime daily intake that is "without
appreciable risk" is based on quantitative scientific experiments that lead to objective, measurable
observations. Indeed, the very purpose of the ri sk assessment methodolo gy used by JECFA and
Codex is to identify quantitatively the point at which risks are not observed or ascertained.
21. When "appreciable risk" is properly understood, the EC's comments do not make sense. An
ADI based on "no appreciable risk" implies that ther e is no scientifically identifiable or ascertainable
risk if the daily intake is equal to or below the ADI. Of course, the ADI does not eliminate the
theoretical uncertainty that always exists as "science can never provide absolute certainty that a given
substance will not ever have adverse health effects".
11 However, this theoretical uncertainty, or
hypothetical risk, is not the kind of risk that, under Article 5.1 of the SPS Agreement, is to be
assessed.12 Thus, assuming that good veterinary practice is followed, the difference between the level
of risk inherent in an ADI and the EC's purported "zero risk" level of protection, is not ascertainable

7 Canada Rebuttal Submission, at paras. 55-65.
8 EC – Measures Concerning Meat and Meat Products (Hormones) , Report of the Appellate Body,
WT/DS26/AB/R, WT/DS48/AB/R, adopted February 13, 1998, at para. 177 (EC – Hormones).
9 See EC Comments, Questions 8, 16, 25 and 54.
10 See Codex's reply to Panel IO Question 9 [emphasis added].
11 EC – Hormones, at para. 186 [emphasis in original].
12 EC – Hormones, at para. 186.

or identifiable risk, but theoretical or hypothetical and is not the kind of risk to be assessed under
Article 5.1.
Quantitative and Qualitative Risk Assessments

22. In its comments on the responses to Questions 11, 16 and 36, the EC attempts to neutralize
the evidence of Dr. Boisseau and Dr. Boobis con cerning the distinction between quantitative and
qualitative risk assessments by claiming that the A ppellate Body has confirmed that qualitative risk
assessments are "acceptable" under the SPS Agreement. However, as Canada explained in its Rebuttal
Submission, although the Appellate Body conclu ded that a risk assessment need not establish a
"minimum magnitude of risk" in order to be consis tent with Article 5.1, it did not discuss qualitative
and quantitative risk assessments, writ large. 13 Thus, the EC's attempt to deduce from this conclusion
the more general proposition that a qualita tive risk assessment is acceptable, a priori , under the
SPS Agreement distorts the conclusions of the Appellate Body. The critical question is whether the
risk assessment at issue evaluates the potential for adverse effects in a manner "appropriate to the
circumstances … taking into account risk assess ment techniques developed by the relevant
international organizations". If the nature of the subs tance is such that no threshold for adverse effects
can be established, then a dose-response assessmen t is not necessary. However, when scientific
evidence demonstrates, as it does in this case, th at a dose threshold below which no adverse effects
occur can be established for the s ubstance in question, a risk assessment that fails to include a
quantitative dose-response assessment would not be "appropriate to the circumstances."
The existence of Scientific Uncertainty

23. In its comments on the experts' responses to Question 12, the EC attempts to impugn the use
of safety factors to address certain types of scientific uncertainty. 14 It suggests that where new
scientific evidence casts doubt on previous scientific conclusions, safety factors cannot adequately
compensate for the resulting uncertainty. Whether this assertion is correct as a matter of principle is
debatable; in any event, it does not apply in this case. As the experts have amply demonstrated, the
"new" scientific evidence referred to by the EC do es not call into question the scientific conclusions
concerning the potential for adverse effects from re sidues of hormones in meat from treated cattle,
particularly conclusions relating to their carcinogeni c potential. The EC is simply trying to create
scientific uncertainty where there is none.
The relationship between "weight of evidence" and minority scientific opinion

24. In its comments on the experts' responses to Question 12, the EC highlights Dr. Boobis's use
of the term of "weight of evidence" and seeks to e quate the term with "mainstream scientific views".
The EC further suggests that using a "weight of evidence" approach forces WTO Members to dismiss
or ignore minority scientific views. These arguments reveal a misunderstanding of the term as used in
the context of risk assessments. The term "weight of evidence" is a term of art used to characterize the
interpretation of all scientific evidence relevant to the causal hypothesis under review, in drawing
conclusions about causal relationships. Not all scientific evidence will be of equivalent importance, or
weight, in providing information about presence or absence of a causal relationship. A "weight of
evidence" approach involves assessing the relative strength and conclu siveness of all relevant data,
including the quality of testing methods, size and power of study design, consistency of results across

13 Canada Rebuttal Submission, at paras. 81-82. Also see EC – Hormones , Report of the Appellate
Body, at para. 186.
14 The EC does not appear to sugges t that the use of safety factors is inappropriate to address the
scientific uncertainty arising from inter-species and intra-species variability. Had it done so, it would be
challenging a fundamental ri sk assessment technique widely employed by its own scientific committees and
regulators.

studies, and biological plausibility of exposure-response relationships and statistical associations. It is
not equivalent to "mainstream scientific views", but is a process that should underpin the formation of
scientific opinions generally, be they mainstream or minority, in order to ensure that they are
scientifically sound. Dr. Boobis appears to use "w eight of evidence" to indicate that the EC
conclusions were not based on an evaluation of all
 pertinent scientific evidence, including an
assessment of the relative strength of that evidence.
C. ASSESSMENT OF OESTRADIOL 17Β
25. The EC makes several comments on the experts' responses to Questions 13 and 14 that
warrant further comment. These include the EC's: 1) inaccurate and misleading descriptions of the
adverse effects it purports to have identified; 2) ex aggeration of the role of epidemiological studies in
risk assessments of the kind appropriate to these ci rcumstances; 3) repeated attempt to embellish
scientific results to demonstrate in vivo genotoxicity from oestradiol 17 β; and 4) unjustified reliance
on several new scientific studies and its criticism of the experts for failing to take these into account.
Inaccurate and misleading descriptions of the purported adverse effects

26. In response to the advice from the experts under Question 13 that the SCVPH opinions do
not amount to a risk assessment, the EC makes seve ral confusing assertions about the nature of the
adverse effects that it purports to have identif ied. In particular, on several occasions it uses
interchangeably the terms ‘carcinogenicity' and ‘genotoxic effect', linking them both to the interaction
of these hormones with hormonal receptors.
15 The EC's description of the issues is both wrong and
misleading, so for purposes of restoring clarity to the issues it is useful to restate the basic controversy
related to the potential carcinogenicity of these hormones and to summarize the advice of the experts.
27. The claim made by the EC is that oestradiol 17 β is carcinogenic because it both initiates
tumours and promotes tumour growth, the former through a hypothesized genotoxic effect and the
latter through interaction with hormonal receptors. 16 To the extent that the international scientific
authorities and the experts consulted by the Panel ag ree with the general proposition that oestradiol
17β is carcinogenic, they unanimously attribute this e ffect exclusively to its interaction with hormone
receptors.17 At the same time, the experts have confirmed again that there is no scientific evidence
demonstrating that oestradiol 17β initiates tumours through a genotoxic effect.18
28. The distinction between these two different mechanisms of carcinogenicity is an important
one because the findings of recepto r-mediated carcinogenicity by JECFA, IARC and other scientific
authorities have been exclusively attributed to circumstances involving high dose exposure to
hormones, something that is clearly not a factor in exposure to dietary sources of hormones, including
that from residues in meat from treated cattle. The EC 's careless interchanging of the mechanisms of
action and the role of dose is simply an attemp t to confuse the scientif ic evidence related to
carcinogenicity.

15 See EC Comments, at p. 12 (Question 13).
16 The EC's claim in its comment s that the "genotoxic effect of oestradiol 17 β is associated with its
hormonal activity" [emphasis added] is simply nonsensical. Ibid.
17 Canada's Rebuttal Submission, at paras 90-95.
18 The EC's statement that the "carcinogenicity of estrogens is primarily due to oxidative stress/DNA
adduct formation caused by the catechols [ sic] metabolites of estrogens" is unsupported by any of the evidence
submitted by the EC and is not supported by the experts. Ibid.

Role of epidemiological studies

29. The EC on several occasions in its comment s relies on the results of epidemiological
studies,19 in particular those conducted or sponsored by IARC, as well as those on which the 2002 US
Report on Carcinogens was based, as the central s upport for its claims that it has identified and
evaluated adverse effects from the consumption of meat from treated animals. In doing so, the EC
vastly overestimates the role of epidemiological st udies in risk assessments of the kind required in
these circumstances, that is, of exposure to substances in such small doses.
30. None of the studies cited by the EC purports to identify a relationship between cancer and
residues of hormones from meat derived from treated animals. It is true that in 1987 IARC classified
steroidal oestrogens as a Group I carcinogen on the basis of observed relationships between cancer
and treatments using high doses of oestrogens. 20 However, the Appellate Body has already
specifically rejected the claim that this classifica tion demonstrates anything about the substances at
issue here. In upholding the findings of the panel, it found that the IARC Monographs:
constitute general studies which do indeed s how the existence of a general risk of
cancer [from oestrogen]; but they do not focus on and do not address the particular
kind of risk here at stake - the carcinogeni c or genotoxic potential of the residues of
those hormones found in meat derived from cattle to which the hormones had been
administered for growth promotion purposes -- as is required by paragraph 4 of
Annex A of the SPS Agreement.
21
31. Since that time, IARC further classifi ed postmenopausal oestrogen therapy 22 and combined
oral contraceptives 23 as Group I carcinogens, again on the basis of observed relationships between
cancer and these treatments. However, what all of th ese classifications have in common is that they
involve prolonged, high dose exposure to various fo rms of oestrogen. Therefore, the reasoning used
by the Appellate Body in the above excerpt applies equally to the EC's invocation of more recent
IARC findings, as well as to any use of other findings that are based on the results of epidemiological
studies.
32. As the experts have confirmed,
24 it is simply not possible to draw specific conclusions about
adverse effects from residues of hormones in meat from treated animals on the basis of
epidemiological studies. For that reason, these kinds of studies have limited usefulness in a risk
assessment of the nature required to justify the EC's measure. They may help in identifying possible
adverse effects, but they reveal nothing about th e potential for occurrence of such adverse effects
from a single dietary source of hormones.
33. The EC's claim that epidemiological studies, such as those on which IARC's classification of
oestrogen as a carcinogen are based, support its claim is all the more surprising in light of its
subsequent comment on Dr. Guttenplan's response to Question 13. The EC comments that it:

19 See EC Comments, at pp. 12 (Question 13), 20 (Questions 20), 23 (Question 23) and 24
(Question 24).
20 EC – Hormones, Report of the Appellate Body, at paras. 199-200. Also, the note attached to IARC's
classification indicates that this "evaluation applies to the group of compounds as a whole and not necessarily to
all individual compounds within the group" (online:
http://monographs.iarc.fr/ENG/Classification/crthgr01.php).
21 Ibid., at para. 200.
22 IARC, Vol. 91, Monograph No. 2, Section 5, Combined Estrogen-Progestogen Menopausal Therapy
(Lyon, France: 2005) (Exhibit CDA-48).
23 IARC, Vol. 91, Monograph No. 1, Section 5, Combined Estrogen-Progestogen Contraceptives
(Lyon, France: 2005) (Exhibit CDA-49).
24 See experts' responses to Question 26.

agrees with the statement by Dr. Guttenpl an that there are basically no direct
epidemiological studies comparing matched populations consuming meat from
untreated and hormone-treated cattle. Howeve r, 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.
34. In this statement, the EC acknowledges th e absence of epidemiological studies that
demonstrate that there are risks from consuming residues of hormones from meat from treated
animals. More importantly, the EC acknowledges th e significant limitations of such studies to support
such a conclusion.
Embellishment of scientific evidence related to in vivo genotoxicity

35. In its comments on the experts' responses to Questions 7, 13 and 18, the EC refers to several
scientific studies in support of its claim that oestradiol 17 β can cause genotoxicity in vivo . It is
important to recall that the experts are very clear that evidence of in vivo genotoxicity, as well as
evidence that the mode of action of genotoxicity is of a type that does not exhibit a threshold, are
required to confirm findings of in vitro genotoxicity before it can be concluded that such genotoxicity
is relevant to the development of cancer.
25 The studies cited by the EC do not satisfy these
requirements.
36. In the first study referred to by the EC, by Bhat et al., the authors conclude that their data
"provide evidence that oxidant stress plays a crucial role in estrogen-induced carcinogenesis".
However, as Dr. Boobis has indicated in his respons es, oxidative stress as a genotoxic mode of action
is of a type that is universally considered to de monstrate a threshold response, due to the "efficiency
of endogenous antioxidant systems". 26 Therefore, this study does not demonstrate anything that was
not already known, but simply confirms that genotoxicity can result from overwhelming the
antioxidant systems with high doses of oestradiol 17β.
37. In its comments on the responses to Questions 16, 18 and 62, the EC introduces, also for the
first time, a review by Yager and Davidson that the EC claims confirms that the "evidence is now
sufficient to support a role for the estrogen me tabolites which include the genotoxic, mutagenic
estrogen quinones in estrogen carcinogenicity." The first point is that this article is only a review of
other studies so provides no new evidence on its own. Second, like the studies conducted by Bhat et
al., this review postulates an oxidative stress dama ge pathway for genotoxicity, which, as noted
above, is considered to have a threshold.
New scientific material cited by the EC and the role of the experts' advice

38. In its comments on the experts' replies to Questions 13 and 14, the EC cites a number of
additional studies to support claims made in its co mments and in earlier submissions. Some of these
studies are introduced by the EC for the first time in its comments, very few of them were considered
by the SCVPH in its opinions, and most of them do not support the specific claims made by the EC
about adverse effects arising from residues of hormones in meat from treated animals.
39. The EC introduces several new studies in an a pparent misunderstanding of what the experts
had been asked to do. In it s comments on the responses to Question 13 concerning whether the EC

25 See experts' responses to Questions 16, 18 and 19.
26 Dr. Boobis's response to Question 16. See also EFSA, Opinion of the Scientific Committee on a
Request from EFSA Related to a Harmonised Approach for Risk Assessment of Su bstances which are both
Genotoxic and Carcinogenic (Request No. EFSA-Q-2004-020, adopted October 18, 2005) ( The EFSA Journal,
282, 1-31, 2005), at p. 18 (Exhibit CDA-46).

opinions evaluate the potential occurrence of adver se effects (a question that specifically asks the
experts for advice on the 1999, 2000 and 2002 SCVP H opinions), the EC raises two entirely new
claims about adverse effects that were not even cited in those original opinions.
40. The first new claim is that "there seems now to be agreement" that oestradiol 17 β increases
the risk of "endometrial adenocarcinomas", c iting a single study completed by Takahashi et al. in
1996, well before the completion of the EC's opinions. However, like much of the other scientific
evidence relied upon by the EC, th e Takahashi study examined adve rse effects that result from
exposure to oestradiol at doses above a certain th reshold. The study presents no evidence that the
levels of hormones that would be expected from meat from treated animals cause these effects.
41. The second new claim is that oestrogen plays a ro le in the hypothesized relationship between
stem cells and breast cancer, citing a recent study by Smalley and Ashworth. 27 However, a review of
this study reveals that it did not even investigate the role of "low-dose estrogens" in tissue stem cell
proliferation, but simply hypothesized a relationship between stem cells and breast cancer. Quite apart
from the fact that the study failed to identify adu lt mammary stem cells, which it hypothesized led to
breast cancer, there are many other sources of oestrogen that would affect proliferation of these stem
cells far more than would dietary sources of hormones. In other words, the relevance of this study to a
safety assessment of these hormones for these uses is questionable. The authors themselves indicate
the hypothetical nature of their findings when they conclude that "these issues are going to keep the
field of mammary stem cell biology occupied for many years to come".28
42. The EC then goes on to present two additional studi es, which were also not considered by the
SCVPH, that it claims de monstrate a relationship between pre- pubertal growth and risk of breast
cancer. The first study, by Lampit et al., simply demonstrates that oestrogen replacement therapy for
prepubertal children, already undergoing therapy to delay precocious puberty, resulted in changes to
growth patterns. The EC attempts to combine these results with a second study, by Ahlgren et el., that
postulated a relationship, on the basis of epidemio logical studies, between cancer and a number of
other factors, one of which was prepubertal growth rates. The link that the EC is trying to draw
between these two studies is, however, simply t oo tenuous to support the conclusion that the EC
suggests.
43. Similarly, in its comments on the experts' responses to Question 14 on whether the EC's
opinions on oestradiol 17β follow the four steps in the risk assessment set out in the Codex guidelines,
the EC argues that Dr. Guttenplan failed to take into account two studies concerning the ACI rat and
ERKO/Wnt mouse. That the question was not whet her new scientific evidence supports the EC's
claims, but whether the SCVPH opinions follow the f our steps of a risk assessment seems to have
been lost on the EC. The new studies referred to by the EC do nothing to undermine the "mixed
rating" that Dr. Guttenplan gave the EC's opinions.
44. The EC concludes its presentation of its new claims of adverse effects by lamenting that the
new material was "not at all considered by the experts". However, the new material says nothing
about meat from treated animals and, more importantly, the claims of adverse effects were not
considered by the SCVPH in its opinions. Since the e xperts' role is not to review additional material
and determine whether the hormones at issue pose a ri sk of adverse effects, the EC does not explain
how any of this material – only introduced by the EC with its comments – is relevant to the issue of
whether the SCVPH opinions amount to a risk assessme nt that is appropriate to the circumstances.
The new studies do not change what the SCVPH did or did not do in its 1999, 2000 and 2002
opinions.

27 See Smalley, M. & Ashworth, A., Stem Cells and Breast Cancer: A Field in Transit (2003) Vol. 3
online: www.nature.com 832-844.
28 Ibid., at p. 843.

D. C
ONSUMPTION OF MEAT CONTAINING HORMONES
(a) Carcinogenicity
45. In its comments on the experts' responses to Question 15, the EC only explains half the story
about the Appellate Body's interpretation of the te rm "potential". By suggesting that the Appellate
Body found that a risk assessment need only iden tify whether adverse effects are "possible", the EC
has attempted to reduce the requirements of a risk assessment to only its first step, the hazard
identification.29 To accept the simplistic definition of "pot ential" as "possible" eliminates the most
important element of a risk assessment, that is, the evaluation of the potential for occurrence. In the
entire context of the Appellate Body's ruling, such a narrow reading is not justified. The Panel may
wish to ensure that the experts are aware of the full context of the requirements of a risk assessment
under the SPS Agreement, as set out by the Appellate Body.
46. In its comments on the experts' responses to Question 16, the EC again misrepresents the
Appellate Body's findings related to quantitative ve rsus qualitative risk assessments. Contrary to the
EC's claim, nowhere did the Appellate B ody make a finding as far reaching as a " qualitative
assessment of risk is acceptable for the purposes of the SPS Agreement". As explained above, 30 what
the Appellate Body said was that there is no requirement for a "risk assessment to establish a
minimum magnitude of risk".31 If the EC had identified that there was no threshold dose of hormones
below which adverse effects would not occur, then it would be appropriate not to assess quantitatively
the exposure. However, since the experts confirm th at the EC has not demonstrated there are adverse
effects that do not exhibit a threshold, the EC is required to evaluate exposur e data. This requirement
does not emerge from some general requirement to conduct a quantitative risk assessment, but rather
from the need to evaluate the potential occurrence, even as this evaluation need not lead to the
identification of a "minimum magnitude of risk".
47. In its comments on the experts' responses to Question 17, the EC attempts to compare the
advice provided by Dr. Boisseau and Dr. Boobis to that of Dr. Lucier that was disregarded by the
Appellate Body in EC – Hormones .
32 The comparison is not appropriate. The advice that was
disregarded by the Appellate Body related to Dr. Lu cier's quantification of the risk of developing
breast cancer from consumption of residues of horm ones in meat from treated cattle as one in every
million women in Canada, the United States and Eu rope. The Appellate Body disregarded this
calculation because it was not the result of any study that supported the risk that Dr. Lucier calculated.
In others words, his specific calculation of the qua ntum of risk was merely unsupported speculation.
This is to be contrasted with the expertise and the advice of Dr. Boisseau and Dr. Boobis on the issue
of the formation of catechol oestrogens in meat. These experts are not speculating a quantum of risk,
but rather are providing their expert advice on b asic biological processes well within their area of
expertise developed over long careers of evaluating veterinary drugs and other chemical substances.
48. With respect to the EC's comme nts on the experts' responses to Question 18, Canada has
already commented above33 on the EC's claim it has provided scientific evidence that oestradiol 17β is
genotoxic in vivo. The EC then goes on to make the surpri sing and entirely unjustified claim that in
any event it is Canada that must demonstrate th at residues from hormones from meat from treated
animals will not cause genotoxic effects. Quite apart from the fact that the EC makes no attempt to
justify why Canada would bear such a burden, th is assertion ignores some basic facts about this

29 According to the international techniques for risk assessments, this is the "hazard identification"
stage. According to the Appellate Body, this is the "identification of adverse effects on human health".
30 See Canada's comments above, at para. 22.
31 See EC – Hormones, Report of the Appellate Body, at para. 186.
32 Ibid., at para. 198.
33 See Canada's Comments, Question 13.

dispute: it is the EC that claims to have found ev idence that the hormones cause adverse effects; it is
the EC that has adopted an SPS measure to ban th ese hormones as a result; and it is the EC that now
claims that this measure brings it into complian ce with previous findings of non-compliance. As a
result, there is no question that it is now the EC th at bears the burden of demonstrating that its claims
are justified on the basis of scientific evidence. It has not done so, and no attempt to shift the burden
to Canada alters its failure to do so.
49. In its comments on the experts' responses to Question 19, the EC claims that the mode of
action of cancer is not relevant from a regulatory pers pective. On the contrary, the mode of action is
very relevant to regulators. It is also very re levant for purposes of compliance with obligations under
the SPS Agreement, as the correct identification of the mode of action of cancer will determine
whether a given SPS measure is justified by the sci ence. If the mode of action is through hormonal
activity, which clearly exhibits a threshold response, a risk assessment that ig nores the existence of a
threshold will not be "appropriate to the circum stances", and will not meet the requirements of the
SPS Agreement. On the other hand, if the mode of action is through genotoxicity, regulators would be
justified in eliminating exposure to the substance enti rely if it were a type of genotoxic effect that did
not exhibit a threshold.
50. The experts have indicated in their respon ses that the carcinogenic potential of these
hormones is related to their hormonal activity, and also that there is no evidence of genotoxic effect in
vivo. As a result, SPS measures (i.e., the EC's bans) that are based on an assessment that as a matter of
principle assumes no threshold ( i.e., the SCVPH opinions) can not be considered to be based on an
appropriate risk assessment.
51. Furthermore, the EC's claims that there is al so evidence of a relationship between exposure to
oestradiol 17β during early development and the risk of breast cancer warrant further comment. The
study cited by the EC in support of this claim does not specifically identify hormones from meat from
treated animals as the source of exposure
34 and, more importantly, it only concludes that there "may
be potential" for early hormone-induced changes to the mammary glands to be "prerequisites" for
tumours. The EC therefore significantly oversta tes the case when it concludes that it is "beyond
doubt" that there is such a link. In the absence of any evidence to support this assertion, it is simply
that: an unsupported assertion. In any event, the EC does not explain the relevance of hormone
exposure during early development to the experts' responses to this question, which is about the
relationship between genotoxicity and the ability to establish dose thresholds.
52. In its comments on the experts' responses to Question 20, the EC criticizes Dr. Boobis for
basing his reply on "assumptions" and "hypothesis" that oestradiol 17 β is not genotoxic and that a
threshold can be set. However, Dr. Boobis's advice on the genotoxic potential of oestradiol 17 β is
based on far more than assumptions; it constitutes his reasoned conclusions based on his experience
with the issues, his review of the scientific evidence and his expertise in the area. It is the EC that
bases its SPS measure on an unproven hypothesis about genotoxicity.
53. The EC also argues that it is "no longer seriously disputed" that oestradiol 17 β is genotoxic,
pointing again to the findings of JECFA on the ma tter. Canada has already addressed the significance
of JECFA's findings of "genotoxic potential" in its own comments on the experts' responses to
Question 20. 35 Nothing the EC has indicated in its co mments changes the fact that if JECFA
considered that oestradiol 17β were genotoxic, it would not have established an ADI for it.

34 In fact, as Canada has explained in its own comments on Question 39, there are many sources of
oestrogen during early development, all of which would be far greater than residues of hormones from meat
from treated animals. See Canada's Comments, at para. 146.
35 Ibid., at paras. 79-82.

54. The EC also seems to believe that the issu e is whether the JECFA assessments have now
become outdated simply as a result of the passage of time. On the contrary, the issue is whether the
EC has identified scientific evid ence that the existing assessments, and the international standards
based on them, cannot achieve the EC's level of pr otection, which is, in fact, the same as that
embodied in the international standards. The focus then should be primarily on what the EC's "new"
scientific evidence says about the safety of the hormones. On this point, the experts have not indicated
that this new evidence changes the JECFA assessments.
55. With respect to its comments related to Question 21, the EC again confuses the issues by
responding to a question about the genotoxic potentia l of the other five hormones with reference to
hormone levels in prepubertal children. This respon se seems to suggest that the EC believes that the
genotoxic potential of these hormones is dose depend ent and has a threshold below which it will not
occur. By lumping together its claims that depe nd on doses and thresholds with claims that do not
depend on doses and thresholds, the EC simply dem onstrates that its arguments are internally
inconsistent and contradictory.
56. In its comments on the experts' responses to Question 22, the EC again refers to Dr. Boobis'
"assumptions" about the genotoxic potential of oestradiol 17 β, when in fact his advice is not based on
assumptions, but on extensive evidence and opinion fr om the international scientific community that
oestradiol 17β is not genotoxic in vivo.
57. With respect to its comments on the issue of DNA repair mechanisms, the EC raises concerns
never before raised by it or the SCVPH about an "incr ease in the rate of damage". It suggests that "if
the rate of repair were constant", increases in th e rate of damage caused from residues of hormones
would lead to increases in the rate of unrepaired da mage. Quite apart from the fact that it provides no
scientific evidence to support the ass ertion that the rate of repair is constant, and apart from the fact
that the experts have all said that there is consid erable redundancy in the repair mechanism, even the
EC acknowledges, by presenting the issue as a hypothetical, that its assertion is completely untested.
58. In its comments on the experts'responses to Questions 23 and 24, the EC acknowledges what
it failed to acknowledge in comments on Question 13 above, that "epidemiological studies will not be
able to discriminate (or separate out) the true origin of cancer because of so many co-founding
factors." It is not clear, however, why the EC be lieves that this acknowledgment undermines Canada's
position, since Canada has never argued that epidem iological studies can prove that the hormones are
safe. Rather, Canada has only ever argued that th e results of epidemiological studies provide no
information about causal relationships between ad verse effects and consumption of hormones from
meat from treated animals.
59. The EC's additional comments on the IARC st udies, on which it places so much emphasis in
its response to Question 13, are also notable. Even though it misrepresents what those studies actually
show,
36 it still has to acknowledge that "this is just an indication that there might be a link between
consumption of red meat and breast cancer". In the end, it appears that the EC and Canada agree on
the limited value of epidemiological studies in th e conduct of a risk assessment appropriate to the
circumstances of these substances.

36 The EC's statement that the IA RC studies show that the "frequenc y of breast cancer in countries
where hormones are allowed is higher compared with countries where the hormones have not been used" is
misleading. If it is referring to IARC's classification of oestrogen as a Group I carcinogen, then the data relied
upon in that conclusion did not distinguish between areas where growth-promoting hormones arre used and
where they are not. In other studies, only a very selectiv e reading of the data shows any cancer rate differences
exist between such regions. To the extent these data show any differences at all, Dr. Boobis also cautions against
"ecological fallacies" when interpreting such data.

60. In its comments on the experts' responses to Question 25, the EC again attempts to impugn
the data on which JECFA relied for its assessment th at exposure to the hormones at levels below the
established ADI would not lead to adverse effects. It again tries to claim that simply because the data
are "old", they are no longer valid, without prov iding any scientific evidence that contradicts the
conclusions of JECFA based on those data. Dr. B oobis has not imposed a higher standard on the EC
than was imposed on JECFA; he is simply indi cating that the EC has failed to demonstrate
scientifically, either in the three additional studies or in any other studies, that there is a potential for
adverse effects.
61. The EC also again criticizes JECFA's level of protection of "no appreciable risk" as being
subjective and qualitative. Not only is this criticism ironic in light of the EC's own defence of the
appropriateness of "qualitative" risk assessments, but it is also wrong. As Canada has explained in its
comments above on the EC's comments on risk assessment techniques, 37 "no appreciable risk" can be
equally expressed as "zero observed risk". This is not 1% or 10% risk, as the EC suggests here, but is
zero risk. This does not mean that there is no hypothetical risk; it simply means that no adverse effects
have been observed to support a conclusion that there ar e risks. In other words, any risk that might be
inherent in the expression "no appreciable risk" is simply a theoretical or hypothetical one.
62. In its comments on the experts' responses to Question 26, the EC seems to shift position once
again on the value of epidemiological studies. In earlier comments, it states that epidemiological
studies confirm the existence of adverse effects; in other comments, it states that epidemiological
studies cannot prove one way or another that adverse effects will occur; and now it states that it relies
upon the results of epidemiological studies simply to demonstrate that scientific uncertainty is
growing. The only thing that seems to be uncertain is what the EC actually believes is the value of
such studies in support of its claims. The EC places considerable emphasis on the statements by
several experts that the results are "consistent w ith" an association between hormone residues in meat
and cancer outcomes. However, in light of the cl ear advice from the experts about the inability to
separate confounding factors, finding that they are "consistent with" an association says very little
about demonstrable association.
(b) Residue Analysis
63. In commenting on the responses to Question 27 concerning residues of synthetic hormones,
the EC asserts that the differences in residues are "not only structural/chemical but also qualitative
and quantitative." What the EC means by "qualitative" is left unclear. In terms of "quantitative"
differences, the EC refers to one of the 17 st udies commissioned by the European Commission
conducted by Rainer Stephany and the conclusions cont ained therein relating to the concentration of
oestradiol-17β in meat from treated cattle. 38 However, concentrations of oestradiol 17 β (a natural
hormone) provide no informati on about quantitative differences in residues of synthetic hormones,
which is the focus of this question.
64. The study provides no support for the EC's suggestion that actual residue data for synthetic
hormones differ from data submitted as a part of the authorization of synthetic hormones.
65. In commenting on the experts' replies to Question 28 concerning residues of synthetic
hormones, the EC attempts to discredit Dr. Boisseau 's reply by asserting that "estradiol-alpha", by
which the EC presumably means oestradiol-17 ∀ (alpha), is a main residue found in the liver of cattle
treated with oestradiol 17 β and that this residue gives rise to human health risks. In the next
paragraph, however, the EC cites Dr. de Braba nder's conclusion that residues of endogenously

37 See Canada's comments above, at paras. 18-21.
38 Stephany, R., Hormones in meat: different approaches in the EU and in the USA, (2001) 109 (Suppl.
103) APMIS S357, at p. 361 ("Stephany Study") (Exhibits EC-49, CDA-12).

produced natural hormones in cattle are in the 17 α (alpha) form (inactive), while the use of natural
hormones used for growth promotion "may lead to residues in the [oestradiol 17] β form (active
form)". This latter conclusion suggests that, if indeed the EC is correct that oestradiol-17 ∀ (alpha)
gives rise to human health risks (a bald proposition unsupported by any evidence), the risk comes
from eating meat from untreated
 cattle. Dr. de Brabander does not suggest that meat from treated
cattle contains a higher proportion of oestradiol-17∀ (alpha). Thus the EC's argument disproves itself.
66. In commenting on the experts' replies to Question 29 concerning residues of synthetic
hormones, the EC asserts that the SCVPH considered ADIs and MRLs (Maximum Residue Limits)
recommended by JECFA and "went even further and examined tolerance levels recommended by the
USA." This statement is both inaccurate and misl eading. For trenbolone acetate (TBA), the SCVPH
did not even refer to, let alone consider, MRLs recommended by JECFA, choosing instead to compare
tolerance limits set by the US Food an d Drug Administration (FDA) to JECFA's ADI. 39 Whatever the
merit of this approach, it says nothing about the appropriateness of JECFA's MRLs. Moreover, the
SCVPH failed completely to address JECFA's conclusions, which are in part:
The Committee recommended MRLs for β-TBOH in muscle and α-TBOH in liver of
2 µg/kg and 10 µg/kg respectively….These MR Ls are not likely to be exceeded with
good practice in the use of veterinary drugs.
Conservative estimates using these MRLs a nd the daily intake values for edible
tissues given in Section 2.6 indicate that the ADI for TBA of 0.02 µg per kg of body
weight should not be exceeded at any time after implantation of the drug . The
maximum concentrations of residues occur at 15-30 days after implantation and are
below the recommended MRLs; concentrati ons will be even lower at the usual
withdrawal time of 60 days.40
67. Thus, even if withdrawal periods are not respected, the ADI would not be exceeded.
68. In relation to zeranol, the SCVPH simply refers to the MRLs set by JECFA 41 and again
compares them to the US FDA tolerances. This say s nothing about whether the MRLs set by JECFA
would lead to intake sufficient to exceed the ADI . Nor did the SCVPH evaluate JECFA's conclusion
in its residue monograph for zeranol that "[t]he tota l residues [of zeranol] in liver, kidney, muscle and
fat do not exceed 10, 2, .2 and .3 µg/kg, respectively, at any time post-implantation ".42 Again, even if
the withdrawal periods were not respected, the ADI would not be exceeded.

39 1999 SCVPH Opinion, at p. 57 (Exhibit CDA-2). Surprisingly, the SCVPH used temporary ADIs set
by JECFA in 1987, as opposed to the final ADI set by JECFA in 1989. The final ADIs are found in JECFA,
Evaluation of certain veterinary drug residues in food: Thirty-fourth Report of the Joint FAO/WHO Expert
Committee on Food Additives, WHO Technical Report Series 788 (Geneva: WHO, 1989), at p. 62 (JECFA's 34
th
Report ) (Exhibit CDA-19).
40 JECFA's 34 th Report, at p. 42 [emphasis added] (Exhibit CDA-19). The Residue Monograph for
TBA prepared for the 34th Meeting of JECFA is found at Exhibit CDA-38.
41 JECFA, Evaluation of certain veterinary drug residues in food: Thirty-second Report of the Joint
FAO/WHO Expert Committee on Food Additives, WHO Technical Report Series 7 63 (Geneva: WHO, 1988), at
p. 28 (Exhibit CDA-18).
42 JECFA, Residues of some veterinary drugs in animals and foods: Monographs prepared by the
Thirty-second Meeting of the Joint FAO /WHO Expert Committee on Food Additives , FAO Food and Nutrition
Paper, No. 41/1 (Rome: FAO, 1988), at p. 46 (32 nd JECFA, Residue Monograph for Zeranol) [emphasis added]
(Exhibit CDA-39).

69. Lastly, in relation to MGA, the SCVPH did not consider the MRLs recommended by JECFA
for MGA, let alone the detailed resi due monographs for this substance. 43 It is worth noting that while
the JECFA recommendations were made after the SCVPH opinions, they were made prior to the
establishment of this Panel in January 2005.
70. The foregoing demonstrates that the EC, through the SCVPH, did not consider whether actual
residues of the synthetic hormones in meat from treated cattle would exceed the MRLs recommended
by JECFA. It also failed to consider whethe r compliance with the MRLs recommended by JECFA
would lead to an intake of residues in excess of th e Codex ADI. Thus, in this regard, the EC has not
provided a scientific justification for why establis hed international standards would not meet its
chosen level of protection.
71. In commenting on the experts' replies to Question 30 concerning residues of natural
hormones, the EC again confuses and distorts the JECFA ADI. As will be discussed below, 44 although
JECFA referred to background levels of circula ting hormones, their daily production and metabolic
clearance rates (MCR), 45 the ADI is not based on a calculati on of endogenous pr oduction of natural
hormones, but on the NOAEL. Therefore, even if background levels, daily production rates and
MCRs of the natural hormones in prepubertal children are lower than first thought, the ADI would not
be affected.46
72. In commenting on the experts' replies to Question 31 concerning the variation in
physiological levels of natural hormones in m eat from untreated cattle, the EC again presents
inaccurate information. First, the EC inaccurately st ates that Dr. de Brabander refers to the EC study
indicating that consumption of meat from treated cat tle contains 7.5 times more oestrogens than meat
from untreated cattle. Presumably, the EC is referring to the Stephany Study, cited earlier in relation
to Question 27. However, Dr. de Brabander never on ce refers to this study, nor does he provide any
quantitative estimate of the amount by which natura l hormones in meat from treated cattle vary from
meat from untreated cattle. Second, on a more subs tantive level, the EC inappropriately cites the
average level of oestradiol 17 β as opposed to the more appropriate median value, used by the author
of the study. The author writes:
From ad random studies in 1998 and 1999 with meat imported from the USA to the
EU or obtained from the US domestic market (25-26) it is estimated 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 "b eef" of "Hormone Treated Cattle" is 5
nanogram. This has to be compared with the recently found median dietary intake of
17β -estradiol of 6.5 nanogram via a 50 gr am hens egg….From this comparison the

43 JECFA, Residues of some veterinary drugs in animals and foods: Monographs prepared by the Fifty-
eighth Meeting of the Joint FAO/WHO Expert Committee on Food Additives , FAO Food And Nutrition Paper,
No. 41/14 (Rome: FAO, 2002) (58 th JECFA, Residue Monograph for MGA) (JECFA's 58 th Report ) (Exhibit
CDA-35); and JECFA, Residues of some veterinary drugs in animals and foods: Monographs prepared by the
Sixty-second Meeting of the Joint FAO/ WHO Expert Committee on Food Additives , FAO Food And Nutrition
Paper, No. 41/16 (Rome: FAO, 2004) (62nd JECFA, Residue Monograph for MGA) (Exhibit CDA-33).
44 See Canada's comments below, at paras. 84-87.
45 JECFA, Toxicological evaluation of certain veterinary drug residues in food: prepared by the Fifty-
second meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series No.
43 (Geneva: WHO, 2000) (Toxicological Monographs for Oestradiol-17 β, Progesterone and Testosterone), at
pp. 51, 82 and 90 for each hormone, respectively (Exhibit CDA-11).
46 The EC's comments on misuse and abuse will be addressed later in these comments in the Section on
GVP.

preliminary conclusion is that he ns eggs are a major source of 17 β (and 17α-estradiol
in the daily "normal" diet.
47
73. Thus, residues of natural hormones in meat from treated cattle are only twice the median level
found in meat from untreated cattle. Moreove r, total residues of all oestradiol 17 β in 250 grams of
beef (approximately ½ lb) from treated cattle (5 ng) are less than that found in one egg (6.5 ng)! Not
unexpectedly, the EC ignores this finding and the main recommendation of the Stephany Study that
"[t]he ‘hormones in meat problem' should be evalua ted in relation to all facts about the actual total
dietary intake of ‘hormones', e.g. from meat(pr oducts), poultry, milk, da iry products, eggs, and
fish(products) taking also into account the effect s of various ways of food production and of
‘household' cooking".48
74. The above results and conclusions are consistent with those of the UK Sub-Group of the
Veterinary Products Committee, which reviewed data relating to the natural occurrence of steroid
hormones in a variety of food sources.49 Those data included a study by Sonja Hartmann, et al., which
concluded:
Meat does not play a dominant role in the daily intake of steroid hormones…The
main source of estrogens and progesterone are milk products (60-80%). Eggs and
vegetable food contribute in the same orde r of magnitude to the hormone supply as
meat does.50
75. The Stephany and Hartmann studies support Canada 's basic point that the risks associated
with hormones for growth-promotion purposes cannot be appropriately evaluated without considering
exposure to other sources of dietary hormones. The data also suggest that the EC's stated high level of
protection for its citizenry, particularly prepubertal children, is more rhetoric than reality. One need
only consider that few prepubertal children consum e anything close to 250 grams (½ lb) of beef on a
daily basis, while milk products and eggs are stapl es of a child's diet, to see that such claims ring
hollow. Given the significance of other dietary s ources of hormones in comparison with the trivial
contribution from the use of growth promotants, th e EC's purported concerns about genotoxicity and
endocrine disruption, amongst others, begin to look less and less genuine.
76. In commenting on the replies to Question 32 concerning unvalidated detection methods, the
EC criticizes Dr. Boisseau's advice as being "sci entifically unsound." However, it is clear from
Dr. Boisseau's reply that he is referring to the use of detection methods for determining compliance
with MRLs. In that context, his statement that detection methods need only be sensitive enough to
detect residues in excess of MRLs is scientifically accurate. To the extent that the "ultra-sensitive"
detection methods referred to by the EC are inte nded to evaluate levels of naturally occurring
hormones in a variety of food sources, 51 it should be recalled that data on these levels currently exist
and are before this Panel.52 Unless and until new, more sensitive detection methods are developed and

47 Stephany Study, at p. 361 (Exhibits EC-49, CDA-12).
48 Ibid.
49 UK, Sub-Group of the Veterinary Products Committee, Executive summary and critical evaluation of
the scientific reasoning and methods of argument adopted in the opinion of the Scientific Committee on
Veterinary Measures Relating to Public Health which assessed the potential risks to human health from
hormone residues in bovine meat and meat products, October 1999, at pp. 11-12 (Exhibit CDA-6).
50 Hartmann, S., et al., Natural occurrence of steroid hormones in food, (1998) 62:1 Food Chemistry, at
p. 18 ("Hartmann study") (Exhibit CDA-50).
51 It is unclear to what use the "ultra-sensitive" de tection methods are to be put. However, one could
infer from the introduction to Section 4.1 in the 2002 SCVPH Opinion that the intended use is to determine with
greater precision the levels of naturally occurring endogenous hormones in the entire food basket.
52 See UK Sub-Group Report (Exhibit CDA-6); and Hartmann study (Exhibit CDA-50).

validated that call into question the accuracy of th e current data, the current data should be accepted
as accurate.
77. In commenting on the experts' replies to Question 33, the EC implies that JECFA is keeping
from the Panel and the public the residue data it relied upon during its 1999 review, thereby
preventing an "open and objective" verification. One need only review the 50-odd pages of residue
data summarized in the residue monograph prepared for JECFA's 52 nd Meeting (summarized by
Dr. Arnold from the German Federal Institute of H ealth, no less!) to appreciate the exaggerated and
sensationalist nature of the EC's claim in this regard.53
78. In relation to the EC's comments on the experts' replies to Question 35 concerning MGA and
whether "subsequent reports of JECFA, prior or sub sequent to the adoption of the EC Directive, also
relied on the same studies", it is important to reca ll that the MRLs recommended by JECFA in 2000
were only "temporary" pending the "receipt of info rmation on an analytical method suitable for
quantifying residues of melengestrol acetate in liver and fat tissue. This in formation is required for
evaluation in 2002". 54 Indeed, as explained by Canada in its comments on the experts' answers
(Question 29), a validated detection method w as submitted and accepted by JECFA during its 58 th
meeting in 2002.55 Contrary to the EC's view, these data are hardly "old" and "outdated".
(c) Dose-Response Relationship
79. In its comments on the experts' responses to Question 36, the EC again misrepresents the
Appellate Body findings related to "quantitative" analysis, which Canada has already addressed in its
comments above.56
80. With respect to its further claim in its comments on that question that Dr. Boobis
acknowledged that no dose-response assessment may be required, it is important to note that
Dr. Boobis only accepted that to be the case if two c onditions were present: 1) the particular mode of
action for the genotoxic effect is of a kind that does not exhibit a threshold response; and 2) it is
confirmed in in vivo tests.
57 As Dr. Boobis advised, neither of these conditions has been met in the
case of these hormones when used as growth promoters.
81. The EC then cites the absence of "internationa lly agreed principles" on when to conduct a
dose-response assessment to justify its failure to ha ve conducted one. However, the real issue is not
whether the EC is required to do so under international risk assessment techniques but, rather, whether
it is appropriate in these circumstances to fail to conduct a dose-response assessment in the course of a
risk assessment. As Canada has argued elsewhere, 58 it is not possible appropriately to evaluate the
potential occurrence of adverse e ffects from residues of hormones fro m treated meat without first
knowing the dose at which such adverse effects will not occur.
82. With respect to the EC's comment s on the experts' responses to Question 37 concerning
whether a dose response assessment is necessary, it is sufficient to note that contrary to the EC's claim
Dr. Boobis and Dr. Boisseau do not agree with the EC, but rather they agree with Canada's statement.

53 JECFA, Residues of some veterinary drugs in animals and foods, FAO Food and Nutrition Paper No.
41/12 (Rome: FAO, 2000), at 37-90, and 137-140 (Exhibit CDA-17).
54 JECFA, Evaluation of certain veterinary drug residues in food: Fifty-fourth Report of the Joint
FAO/WHO Expert Committee on Food Additives , WHO Technical Report Series 900 (Geneva: WHO, 2001)
(54th JECFA, Technical Report for MGA), at pp. 79-80 (Exhibit CDA-36).
55 See Canada's Comments, at para. 111. Also see JECFA's 58 th Report, Residue Monograph for MGA,
at pp. 56-59 (Exhibit CDA-35).
56 See Canada's comments above, at para. 22.
57 See Canada's Comments, Question 36.
58 See Canada Rebuttal Submission, at paras. 80-82.

To the extent that they describe any circumstances in which the statement would not be true, such as
when genotoxicity is confirmed in vivo, those circumstances do not apply here. In fact, they clearly
indicate that a dose-response assessment is critical to establishing an ADI and MRL.
(d) Sensitive Populations
83. In commenting on the experts' responses to sev eral questions under this section, the EC
makes a number of claims that reflect a misu nderstanding of the relationship between the
establishment of ADIs and the identification of background levels
59 and that rely too much on a single
unvalidated measurement methodology (i.e., the Klein recombinant cell bioassay (RCBA)60).
84. The EC claims in its comments on the experts' responses to Question 38 that JECFA cannot
set ADIs and MRLs without accurate data on bac kground levels. However, nowhere – at least,
nowhere that Canada can find and the EC has not provided a source – is it indicated that JECFA
considers data on background levels to be "essential for determining the ADI". On the contrary, the
establishment of an ADI, and hence an MRL, does not depend at all on the identification of
background levels. Rather, it depends on actual observations of adverse effects at given dose levels, to
which appropriate safety factors are applied to protect against variation in sensitivity between
different human populations.
85. The general intention behind linking backgroun d levels with the establishment of ADIs for
these hormones – which the EC does in almost all its comments in this section – is to create confusion
between two distinct approaches to measuring e xposure. On the one hand, there is the JECFA
approach of identifying a NOAEL, applying safety factors and establishing an ADI, none of which
depends on the identification of b ackground levels. On the other hand, there is the EC's attempt to
compare the proportion of intake exposure (which , incidentally, it never actually estimates) to
background levels, and assert that if background levels are lower th an once thought, the risk must
therefore be higher simply because the ratio of intake (exogenous) dose to background (endogenous)
levels would be higher.
86. At no point, however, does the EC explain this relationship. Even if the EC demonstrates
background levels are lower (which it has not), since JECFA's ADI approach is based on actual
observed adverse effects regardless of the backgrou nd level, a change in b ackground levels is not
relevant to whether adverse effects have been observed and therefore is not relevant to the ADI.
87. To place this issue in a slightly different contex t, if no evidence exists that consuming an egg
(which has 6ng of oestradiol 17 β, an amount equivalent to that in 250 grams of beef from treated
cattle) has adverse effects on the endocrine system s of prepubertal children, then studies using
genetically modified yeast that suggest that the background levels of endogenous hormones in
prepubertal children are lower than first thought, do not demonstrate that c onsuming an egg now has
greater risk.
88. The experts in their responses to Question 41 have of course confirmed that populations with
lower background levels are at greatest risk of a dverse effects from exposure to hormones, and they
have also confirmed that this is so because the proportion of exogenous hormone levels to endogenous
exposure would be greater. However, this statement of basic physiology does not in itself confirm that
even if it turns out that background levels are lowe r than once thought, the appreciation of the risk

59 Canada understands that for the general purposes of the review of the scientific and technical
material, the term "background levels" can be used interchangeably with "circulating levels" "endogenous
levels" and "physiological levels".
60 Klein K.O., et al ., Estrogen levels in childhood determined by an ultrasensitive recombinant cell
bioassay (1994) 94 J Clin Invest 2475–2480 (Klein RCBA).

would be greater. New test results that suggest b ackground levels are lower than once thought simply
change the understanding of the levels themselves, and not the risks of adverse effects.
89. In other words, for the purposes of establishing the ADI, the ratio that matters is not that
between hormone intake and background hormone le vels, but rather that between the background
hormone levels of the populations used to iden tify the NOAEL and other subpopulations. And as the
experts indicate in their answers to Question 42, JECFA already takes into account the expected
lower background levels in sensitive populations.
90. In its comments on the experts' responses to Questions 38, 39 and 40, the EC makes several
confusing and unfounded assertions about the vali dity and importance of background level data
generated by the Klein RCBA. First, in its comments on Question 38, it discounts the importance of
validation of scientific methodologies in support of scientific conclusions, claiming that the
ultrasensitive Klein RCBA need not be validated at all for the results to have any importance. There is
no basis for such a claim. It requires more than one unvalidated attempt to generate competing data to
cast doubt on the data generated by radioimmune assay s (RIA). The claim that JECFA uses data from
assays that have not been validated is also unfounde d. JECFA goes to great lengths to validate the
quality and precision of the data on which its re commendations are based. The EC did nothing to
validate the data generated by the Klein RCBA.
91. In its own comments on the experts' responses to Question 39, the EC seems to indicate that
it does not even believe the Klein RCBA is va lid, when it contradicts the comments it made on
Questions 38 and 40. In its comments on these latter questions, the EC claims that the Paris assay
results overestimate the levels compared to th e Klein RCBA results. But in its comments on the
question coming between these two, it supports Dr. Sippell's attempt to validate the Klein RCBA
results with reference to a "number of sources confir ming the values" generated by Klein. It seems to
have been lost on the EC that the only "confirming" source offered by Dr. Sippell was that of the Paris
assay. So, whereas the EC does not consider the Paris assay results to be credible enough to be used to
demonstrate that Klein is inaccurate (as suggested by Dr. Boobis), the EC does believe that these
results are credible enough for purposes of confirming that Klein is accurate (as suggested by
Dr. Sippell).
92. In the end, the EC itself dispels any doubt about whether it is convinced of the validity of new
methodologies for measuring background levels, or th e legitimacy of the data these have produced. It
sums up its concerns in its comments on both Questions 38 and 40 when it notes that the "real values
for serum 17 β-oestradiol in prepubertal children still remain to be properly documented". In light of
the uncertainty about the validity of the new measu rements and the continued legitimacy of JECFA's
ADI approach – which does not depend on these m easurements – the EC has not demonstrated that
JECFA's recommendations need to be modified.
(e) Bioavailability
93. In its comments on the experts' respon ses to the only question of this section ( Question 43),
the EC makes the same mistake as it makes under the section on sensitive populations when it
suggests that new information on bioavailability ca lls into question the validity of the JECFA-
established ADIs. As Canada has already explained in its own comments on the experts' responses to
the questions,61 the actual amount of hormones that is bioavailable does not affect the validity of the
ADI. Rather, the ADI is based on observed adverse e ffects from a given oral dose, which means that
the ADI represents, in the words of Dr. Boobis, a "bioavailability adjusted" dose. The EC makes no
comment on this concept. Instead, just as it does wi th the questionable re-e valuation of background
levels, it also exaggerates the importance of wh at it considers "credible evidence" that the

61 See Canada's Comments, at paras. 162-163.

bioavailability of hormones might be higher than once thought. Neither issue, in the end, demonstrates
that the international standards would not meet the EC's chosen level of protection.
(f) Good Veterinary Practice (GVP)
94. In the EC – Hormones dispute, the Appellate Body found that the EC did not submit a risk
assessment "demonstrating and evaluating the existence and level of risk arising…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".
62 Thus, one of the central
issues in this dispute is whether, this time around, the EC has actually evaluated the potential adverse
effects on human health related to the failure to co mply with good practice in the use of veterinary
drugs (GVP). As explained by Canada elsewhere, the EC has not done so.63
95. In its comments on experts' respon ses to questions in this section ( Questions 44-51), the EC
challenges the unequivocal conclusion of the experts that the SCVPH made "no attempt to evaluate
the risks from the resu ltant exposures [from] misuse or abuse". 64 The EC claims that it indeed
conducted a proper assessment of these risks, citing sev eral exhibits to support its claim, the most
important of which is the European Commission's Draft Report on the Assessment of Risks of
hormonal growth promoters in cattle with respect to risks arising from abusive use and difficulties of
control.65 However, a close review of these exhibits reveals that the EC claim is profoundly flawed.
96. It is important to clarify up front a few issu es concerning GVP generally raised by the EC.
First, with respect to Question 46, the EC's attempt to discredit JECFA's assessments of these
hormones on the basis that JECFA did not assess poten tial misuse/ abuse is unsound. As explained by
Dr. Boisseau, in recommending MRLs, JECFA assumes that GVP will be followed; for practical
purposes JECFA does not examine potential compliance or control issues. While the failure to follow
GVP may lead to residues that exceed the recommended MRL, and to a corresponding intake of
residues in excess of the established ADI, such a failure does not undermine the validity of the
MRL.66
97. Second, in relation to Question 48, the EC's attempt to discredit Dr. Boobis's opinion by
suggesting that he does not appreciate the distinctio n between "probability" and "possibility" as laid
down by the Appellate Body is equally flawed. 67 The Appellate Body concluded that it is insufficient
merely to identify the possibility of misuse/abuse, wh ich is in effect all the EC did during the first EC
– Hormones panel. 68 In correctly finding that the EC's assessment of this issue did not meet the
requirements of a risk assessment consistent with Articles 5.1 and 5.2 of the SPS Agreement, the
Appellate Body implies that a if WTO Member alle ges risks to human health from failure to comply
with GVP, that Member must evaluate the existence and level of risk arising from the abusive use of
such a substance, not simply identify the possibility that such abusive use may occur.

62 EC – Hormones, Report of the Appellate Body, at para. 207.
63 Canada Rebuttal Submission, at paras. 107-111.
64 Response by Dr. Boobis to Question 48, at p. 42.
65 European Commission, Assessment of Risks of hormonal growth promoters in cattle with respect to
risks arising from abusive use and difficulties of control , Draft Report by special wo rking group of external
private experts and European Commission officials, Brussels, 29 April 1999 (Commission Draft Report on
Assessment of Risks of Abusive Use) (Exhibit EC-73). This document was exhibited for the first time in the EC
Rebuttal Submission, despite the Panel's specific request to the EC to identify the documents that encompass the
risk assessment for its permanent ban. See Questions from the Panel after the First Substantive Meeting, 3
October 2005, Question 16.
66 See Canada's Comments, Question 46.
67 See EC Comments, Question 48, at p. 40.
68 EC – Hormones, Report of the Appellate Body, at paras. 206-208.

98. Third, compliance with GVP is not an end in itself, but only a means for estimating whether
actual residues in meat from treated cattle exceed re commended MLRs and/or lead to intake in excess
of established ADIs. The EC devotes considerable e ffort to the question of whether Canada and the
United States can demonstrate to the satisfaction of the EC that compliance with GVP has been
assured in their respective territories, while practic ally ignoring the more fundamental question of
whether actual residues in Canadian meat from treated cattle exceed recommended MLRs and/or lead
to intakes in excess of established ADIs.
99. On a more substantive level, the EC's purported assessment of the misuse/abuse of hormones
in Canada and the United States is based on a num ber of assumptions about both the occurrence of
misuse/abuse and the risks to human health in the unlikely event that such misuse/abuse occurs. In
terms of the former, the EC assumes that because there are economic incentives to using hormones for
growth-promotion purposes (increased weight gain, greater feed efficiency, etc.), farmers will
invariably misuse/abuse them in the absence of control measures as st ringent as those applied in the
EC. These assumptions may be based in part on the unfortunate fact that Europe has faced a
"continuous series of residue scandals w ith illegal ‘anabolic hormones' in cattle".
69 However, without
concrete evidence, extrapolating illegal conduct in one's own jurisdic tion to illegal conduct in another
is unjustified.
100. The notion that economic incentives will invariab ly lead to misuse/abuse does not reflect
realistic conditions of use. It presupposes that fa rmers are irresponsible, concerned only about profit,
and insensitive to issues of animal welfare and human health. Moreover, it assumes that weight gain is
proportional to the amount of hormone administered (i.e., increasing the number of implants increases
weight gain and the corresponding economic benefit). This assumption is not valid. It also ignores the
possibility that misuse/abuse can lead to perform ance below optimum levels, negative effects on
future reproductive performance and side effects su ch as vaginal and rectal prolapses. All of this
demonstrates that the simplistic notion that "economic incentives" lead to misuse/abuse does not
reflect realistic conditions of use.
101. Similarly, the absence of control measures as stringent as those found in Europe does not
imply that misuse/abuse is more likely. Control measures are typically proportional to the magnitude
of the problem. There is simply no evidence that misuse/abuse of hormones in Canada is a problem
sufficient to warrant the control measures that the EC appears to deem necessary.
102. With those comments in mind, Canada will now turn to a detailed review of the assessment
report contained in Exhibit EC-73. The EC asser ts that higher risk flows from misuse/abuse of
hormones in several ways: (a) misplaced implants , (b) off-label uses, (c) simultaneous multiple
implants, and (d) black-market drugs.
103. In terms of misplaced implants, the EC postula tes that tissue from the site of application
containing excessive concentrations of hormones may find its way into the human food chain. The EC
then presents in Table 4 of Exhibit EC-73 hypothetical exposure scenarios for various elevated
concentrations of hormones and concludes that th ere is a risk to human health from misplaced
implants.
70 This risk can occur either because the ear in to which the implant has been subcutaneously
inserted may not be discarded or because implants may be incorrectly inserted in edible tissues, such
as the neck muscle, shoulder or hind leg. In suppor t of this concern, the EC cites one example from
Canada that found residues in muscle tissue that could only be explained by improper placement of an
implant or the application of unapproved intramus cular injections of liquid hormone preparations.
71
This anomalous result hardly constitutes compelling evidence of the frequency of misplaced implants.

69 Stephany Study, at p. 358 (Exhibits EC-49, CDA-12).
70 Commission Draft Report on Assessment of Risks of Abusive Use, at p. 15 (Exhibit EC-73).
71 Ibid., at para. 16.

Other than this one example, there is no evidence that in Canada ears with implants are processed into
food or that implants are inserted into other edible parts of the cow. The EC has merely identified a
possibility, unsupported by any analysis of frequenc y of occurrence or assessment of the impact on
human health in the unlikely event that such a possibility materializes.
104. Canada notes that the risk of excessive concen trations of hormones entering the food chain is
far greater when liquid hormone preparations are injected into the muscle of the animal (intramuscular
injection). However, this is far more likely a probl em in countries that ban outright the use of growth
promotants than in North America, where subcutan eous implants in the pinna of the ear of cattle
(middle third of the back-side of the ear) are permitted. In order to avoid detec tion, it is reasonable to
assume that European farmers using illegal anabolic steroids would likely use intramuscular injections
rather than pinna implants, as the latter can remain in situ for up to 120 days and are easier to detect.
72
Thus, the more realistic exposure scenario for the cal culations presented in Table 4 of Exhibit EC-73
is excessive exposure from residues in edible tissu es (muscle and fat) resulting from intramuscular
injections, a practice far more likely in Europe than in Canada.
105. In terms of off-label uses, the EC cites the presence of TBA and zeranol in veal calves (calves
less than 45 days of age). This implies that some growth promotants may have been used earlier than
recommended, but says nothing about the potential misuse of growth-promoting hormones later in the
life of cattle.
106. In terms of simultaneous multiple implants, the EC simply fails to present any evidence
relating to the frequency of inappropr iate multiple dosing in practice in Canada, a fact highlighted by
Dr. Boobis.
73 Moreover, the EC's own studies confirm that, with most applications, even at doses 10
times the recommended level, residu es remain below recommended MRLs, 74 a finding also noted by
Dr. Boobis. Thus, even in the unlikely event of in appropriate multiple dosing, the EC's own evidence
suggests that residues, for the most part, would remain below safe thresholds.
107. Lastly, in terms of black-market drugs, the EC speculates that the economic incentives for
using growth-promoting hormones "cannot exclude the emergence of a black market for less
expensive or more effective substances".75 The EC presents no evidence of illegal use of black-market
drugs for growth-promotion purposes in cattle in Ca nada. Although the EC's own studies reveal that
"[i]n the EU dozens of illegal hormones are used", 76 it is not logical to extrapolate the apparent
problem with illegal hormone use in countries that outright ban all growth promotants to the North
American context where growth promotants are permitted under specific circumstances. Indeed, the
very availability of legal growth promotants in North America suggests that the likelihood of the
misuse of illegal drugs would be much lower in Ca nada than in countries that prohibit outright any
growth promotants.
108. In conclusion, the EC's claim that it has prope rly evaluated the potential for adverse effects
from the misuse/abuse, a claim contradicted by the e xperts, does not withstand scrutiny. In addition to
being based on several flawed assumptions that do not reflect realistic conditions of use, the
assessment simply fails to evaluate the frequenc y of occurrence of misuse/abuse and the potential

72 In the Stephany Study, the author suggests that in the EU the mode of application of growth
promotants is intramuscular injection (Exhibits EC-49, CDA-12).
73 Dr. Boobis's reply to Panel Question 62, at pp. 50-51.
74 Lange, I., et al., Hormone contents in peripheral tissues after correct and off-label use of growth
promoting hormones in cattle: Effect of the implant preparations Finaplix-H®, Ralgro®, Synovex-H® and
Synovex Plus® (2001) 109 APMIS 53-65, at pp. 382-383 (Exhibit EC-17).
75 Commission Draft Report on Assessment of Risks of Abusive Use, at para. 47 (Exhibit EC-73).
76 Stephany, R., Hormones found in Meat Samples from Regular Controls in the European Union and
from US Imports (2000) Chemical Awareness: Issue 9, at p. 1 (Exhibit EC-19). Also see the Stephany Study, at
p. 358 (Exhibits EC-49, CDA-12).

impact on human health in the unlikely event that misuse occurs. It does not satisfy the requirements
for a risk assessment under Article 5.1 and 5.2 as se t down by the Appellate Body in the previous
Hormones dispute.
(g) Other
109. The EC, in its comments on the experts' responses to Question 52, again erroneously
characterizes the advice of Dr. Boobis and Dr. Boisseau as based on "assumptions and conservative
interpretation", and further that th ese experts hold the EC's opinion to a higher standard than that to
which companies were held when they first receiv ed approval for the sale of the hormones as growth
promoters.
110. First, the advice from Dr. Boobis and Dr. Boisseau is based on far more than assumptions; it
is based on their qualified expertise in their own areas of specialization. The EC may disagree with
their advice, but that in itself does not mean it is based on assumptions. If any party in this dispute is
making assertions unsupported by the scientific evid ence, it is the EC itself, such as with its
genotoxicity hypothesis and its reliance on unvalidated measurement methodologies.
111. Second, the EC's accusation that Dr. Boisseau and Dr. Boobis are applying a double standard
ignores the history of the evaluation of the safety of these substances. Quite apart from the standard of
review to which the original applicants for approva l of the hormones were held, the fact remains that
the hormones have been repeatedly reviewed and approved by national author ities and international
standards bodies, such as Codex and JECFA, on seve ral occasions since the original approval. None
of these subsequent reviews, all of which use th e latest methodologies and scientific evidence, found
that there was any evidence of adverse effects. On the other hand, it is the EC that now claims to have
demonstrated that there are adverse effects. It is not only reasonable but legally necessary for the EC
to demonstrate, with more than hypothesis and unvalidated methodologies, the potential for the
purported adverse effects to occur. Far from being a double standard, this is simply holding the EC to
the same standard.
112. The EC also places considerable emphasis on a si ngle statement by Dr. Boobis that the risks
from consuming residues in meat from treated animal s are "minimal". However, the EC conveniently
ignores almost the entirety of the preceding paragraphs in Dr. Boobis's response, in which he states,
inter alia, that: "none
 of [the] information provided by the EC demonstrates the potential for adverse
effects in humans"; "[t]he studies on genotoxicity provide no convincing evidence of potential for
harm in consumers"; "t here would be no risk of … [adverse] effects from … exposures" from meat
from treated cattle; and "there is no evidence that low level exposure is causing harmful effects in
humans" [emphasis added]. Therefore, in light of Dr. Boobis's responses above to the issue of whether
the EC has demonstrated the potential for adverse effects, it is quite clear what Dr. Boobis means
when he uses the word "minimal".
113. The EC further endorses the responses of Dr. Guttenplan in a manner that is not supported by
the advice of the other experts and the comments by the EC itself. The EC cites Dr. Guttenplan's
support of the data generated by the Klein RCBA, despite the obvious concerns expressed about these
data from all the other experts. 77 The EC then endorses Dr. Guttenplan 's favourable reference to the
Paris assay data to validate the Klein RCBA data, even though it stated that the former methodology
was not appropriate to validate the latter methodology. 78 Finally, the EC cites these statements
favourably without acknowledging that Dr. Guttenpl an was simply saying that "more accurate
methods of analysis could now be used " [emphasis added] to corroborate the EC's concerns, not that
in fact they had been used or that the EC's concerns had been corroborated using these methods.

77 See Canada's comments above, at paras. 89-92.
78 See EC Comments, Question 38.

114. In its comments on the experts' responses to Question 53, it is sufficient to note that in
quoting generously the response of Dr. Guttenplan, the EC tellingly failed to address the statement by
him that "by far, estrogen is the major agent of risk and, because the concentrations of all the
hormones in beef are so low, that they would be unlikely to affect the potency of estrogen".
Dr. Boisseau made a very similar statement, which was also tellingly ignored by the EC.
115. The EC's comments on the experts' responses to Question 54 are confusing and misleading.
First, immediately after quoting Dr. Boisseau that the ADI represents the quantity of these residues
that can be ingested daily "without causing any problem
 of health" [emphasis added], the EC
concludes that his reply meant that "there is no doub t … that there is a risk", without explaining how
the former idea supports the latter conclusion.
116. The EC then misrepresents Dr. Boobis's answer in the same manner when it interprets his
statement that the "Codex standard [of no appreciable risk] is equivalent to the EC's stated objective
of ‘no risk from exposure to unnecessary addition al residues…'" to mean that "Codex's standard
recognises that there is an [ sic] scientifically identified risk but recommends its members to follow
it…". The EC again leaves unexplained how it jus tifies going from the former idea to the latter.
Indeed, as Canada has explained above, 79 the concept of "no appreciable risk" does not mean that
JECFA/Codex have identified some risk, even if minimal; rather, it means that any risk that might
exist is purely hypothetical ( i.e., not observable). And as the Appellate Body made clear, a risk
assessment cannot be based on hypothetical risk.80
117. In its comments on the experts' responses to Question 55, the EC disagrees with what the
experts have to say, so it simply tries to change the subject. Instead of addressing the unanimous
advice from the experts that the EC opinions did not evaluate additive risks, the EC chooses to attack
the integrity of the experts and the legitimacy of th eir opinions, and then diverts attention to whether
JECFA conducted an evaluation of such risks. The a ttack on the experts is unjustified: first, because
they were asked whether the EC had conducted such an assessment and not whether JECFA did; and
second, since it is the EC that claims that there are additive risks, it is up to the EC to demonstrate that
such risks exist. In any event, the experts did indicate that JECFA had evaluated additive risks and
there were no concerns about such risks arising from meat from treated animals given the extremely
low doses of exposure from this source.
118. The EC then acknowledges that the SCVPH did not address additive risks "because the state
of scientific knowledge available by then … did not allow such an assessment to be completed".
Given that the EC's justification for its bans rela tes to concerns about proven additive risks, it is
nothing short of a remarkable admission that additive risks were not even assessed.
119. The EC provides contradictory comments on the experts' responses to Question 56.81 First, it
provides that is has "clearly been shown that th e effects from exposure to different estrogens are
additive". Then it indicates that it "has tried to do such an assessment [of the additive risks] when the
information available was sufficient, but could not complete it because of gaps in our scientific
knowledge". Whichever it is, both of th ese statements are remarkable in light of the importance to the
EC's justification of its bans of an assessment of addi tive risks. And to the extent that the studies cited
by the EC say anything about additive risks from oe strogens, they still do not answer the question of
whether hormones from meat from treated animals contribute to such additive risks.

79 See Canada's comments above, at paras. 18-21.
80 EC – Hormones, Report of the Appellate Body, at paras. 199-200.
81 It is also necessary to note the irony in the EC's criticism of the experts for failing to provide precise
references in its answers.

120. In its comments on the experts' responses to Question 57, the EC completely ignores the
advice of two of the three experts that cast serious doubt on the EC's justification of its authorization
of the hormones for therapeutic and zootechnical purposes. In declaring this question unnecessary and
irrelevant by virtue of certain Appellate Body fi ndings, the EC completely misses the nature of the
experts' criticism of the EC use fo r these purposes. The issue is not whether there was a violation for
authorizing these uses, but that the mere authorization itself undermines the EC's dramatic claims that
no threshold for adverse effects from these hormones can be established. This is what leads
Dr. Boisseau to call it a "problem of principle" a nd Dr. Boobis to indicate that this demonstrates the
EC believes there is in fact a threshold response. Moreover, the claim that the use of oestradiol for
"such purposes is now virtually terminated" does nothing to respond to the criticisms.
121. Since the EC's comments on the experts' responses to Question 58 merely demonstrate the
degree to which its arguments rest on hypotheti cal situations and assumptions, nothing in its
statements warrants further comment from Canada.
122. In commenting on the experts' responses to Question 59 concerning the EC's non-existent
evaluation of the potential for adverse effects on the immune system from residues of hormones
consumed in meat from treated animals, the EC em ploys two diversionary tactics. The first is to
indicate that the existing international recommenda tions that these substances are safe are based on
"outdated" data, not on the basis that the data have been superseded, but simply on the basis that they
are "old". This line of argument ignores both the fact that the age of the data does not determine their
currency and, further, that in an y event the hormones have been rep eatedly re-evaluated by JECFA as
new information becomes available, and the reco mmendations have remained largely unchanged. The
second tactic of course is to argue that it is not the EC that must demonstrate that these adverse effects
will occur, but, rather, that it is Canada that must demonstrate that they will not occur. For reasons
already discussed on many occasions, this claim is without merit.
123. In its comments on the experts' responses to Question 60, the EC comments at great length
about the bioavailability of MGA as a feed additive a nd on the potency of cons uming implants of the
other five hormones that have not been removed, but in the end provides very little by way of relevant
commentary on whether one route of administration leads to adverse effects that are any different

from the other route. The EC goes on to challenge Dr. Boobis's comments about the risks from misuse
and abuse of MGA implants. However, the EC seem s to have understood him to be advising on the
implanting of MGA, which is not an approved use, even though it was clear that he was referring to
only those hormones that could be administered with implants. To the extent that the EC
misunderstood Dr. Boobis's comments, its own comments are of little value.
124. In commenting on the experts' responses to Question 61 concerning the sufficiency of the
evidence to conduct a risk assessment of the othe r five hormones, the EC does little more than
continue its direct attack on the objectivity a nd professionalism of Dr. Boobis and Dr. Boisseau. The
participation in this process of experts that have extensive experience with the evaluations of JECFA
of these substances only enhances the Panel's abilit y to understand the considerable scientific
evidence related to the safety of these hormones. Fa r from lacking objectivity, these experts are best
placed to advise the Panel on the sufficiency of the evidence to conduct a risk assessment according to
the internationally agreed techniques employed by JECFA. In this case, they both indicated the
evidence was sufficient to do so.
125. In commenting on the experts' responses to Question 62, the EC continues again its attack,
this time singling out the comprehensive and informed review by Dr. Boobis of all of the new
material provided by the EC. While the EC indicates that a "more careful examination by a real expert
of the same body of evidence" led to the opposite conclusions to those offered by Dr. Boobis, it
neglects to inform the Panel and Canada who this "real expert" is and why his or her anonymous
views should be considered more authoritative that those offered by the expert specifically chosen for

the task. In any event, it is difficult to see how th e EC could consider Dr. Guttenplan's one paragraph
enumeration of gaps a "more considered and objective view" than the 11 pages of analysis offered by
Dr. Boobis.
III. COMMENTS ON THE COMMENTS FROM THE EC ON THE RESPONSES FROM
THE INTERNATIONAL BODIES
126. In relation to the EC's comments on the responses by the international bodies to Questions 1,
5, 16, 17, 18 and 19, Canada will not comment at this time.
127. In relation to the EC's comments on Questions 3 and 4, Canada refers to paragraphs 12-14 of
this document.
128. In relation to Question 7, Canada refers to paragraphs 23, 35-44, and 83-92 of this document.
129. In relation to Question 8, Canada refers to paragraphs 35-44 of this document.
130. In relation to Question 9, Canada refers to paragraphs 18-21 of this document.
131. In relation to Question 10, Canada refers to paragraphs 12-14, 83-92, 116-118 of this
document.
132. In relation to Question 11, Canada refers to paragraph 77 of this document.
133. In relation to Question 12, Canada refers to paragraphs 16 and 17, 18-21 of this document.
134. In relation to Question 13, Canada refers to paragraph 77 of this document.
135. In relation to Question 14, Canada refers to paragraph 5 of this document.
136. In its comments on the responses Question 15, the EC continues to ignore the existence of the
Recommended International Code of Practice for Control of the Use of Veterinary Drugs , of Codex,
which was mentioned by Codex as well as Dr. de Brabander.
137. In relation to Question 20, despite the explanation by JECFA that the three natural hormones
had been placed on the agenda of JECFA in 1999 at the initiative of the JECFA Secretariat to ensure
that all the latest information had been evaluated, th e EC insists that, in its words, "most of the data
were the same old data". The Panel may wish to as k JECFA for further clarification in this regard.
Canada also refers to paragraph 77 of this document.
138. In relation to Questions 23, 24, 25 and 26, Canada refers to para graphs 29-34 of this
document.
IV. CONCLUDING COMMENTS
139. As the above comments demonstrate, rather th an address specifically many of the important
concerns raised by the experts about the EC's ev aluation of the safety of the hormones, the EC has
chosen instead to attempt to create confusion a bout these issues. It has done so by presenting the
responses of experts in a misleading and flawed manner; it has done so by misrepresenting the
meaning of much of the scientific evidence and international guidance documents; and it has done so
by attacking the professionalism and objectivity of the experts and the Secretariats of the international
organisations.

140. Canada is confident, however, that the Pane l will see through these efforts and will keep the
focus on the real issues, and on the legitimate scie ntific and technical material, on which it needs
advice to decide this case. Ultimately, on the basi s of the substance of the responses from the experts
and the lack of substance in the comments by the EC, Canada is confident that the experts have
provided sufficient advice to allow the Panel to conc lude that the EC's bans are not justified by the
scientific evidence.