WORLD TRADE  
ORGANIZATION  WT/DS321/R/Add.6 
31 March 2008 
 
 (08-0913) 
 Original:   English 
  
 
  
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 
WT/DS321/R.  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  WT/DS321/R/Add.6 
 Page F-1 
 
 
  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 po sed 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 
 WT/DS321/R/Add.6 
Page F-2  
 
  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, zer anol, 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 70th and 80th JECFA reports. Since then new data 
concerning residues in tissue and their toxicological im pact 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 ".  
  WT/DS321/R/Add.6 
 Page F-3 
 
 
  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. WT/DS321/R/Add.6 
Page F-4  
 
  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 prot ection 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.  WT/DS321/R/Add.6 
 Page F-5 
 
 
  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 not es first that Dr. Boisseau  admits that "in 1987 and 1999, at the time of 
the assessment of oestradiol-17 β, 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 WT/DS321/R/Add.6 
Page F-6  
 
  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 ma rgin 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 an imals 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  WT/DS321/R/Add.6 
 Page F-7 
 
 
  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 ri sk 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 WT/DS321/R/Add.6 
Page F-8  
 
  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 na tural 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 Endocrinol ogy 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 2nd 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-17 β, 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  WT/DS321/R/Add.6 
 Page F-9 
 
 
  the 1999 risk assessment by the SCVPH shows that the reasons for which that scientific committee 
considered that oestradiol-17 β 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 th e level of endogenous production.   
 
Furthermore, neither Dr. Boobis  nor Dr. Boisseau  mention the fact that the IARC has classified 
oestradiol-17 β 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 co mpounds, 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 represen tative 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 . WT/DS321/R/Add.6 
Page F-10  
 
  especially where the risk involved is life-threatening in character and is perceived to 
constitute a clear and imminent threat to pub lic 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 interpreta tion 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 ar e 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 ad ducts 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 e ndogenous and ex ogenous 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 mode l, 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  WT/DS321/R/Add.6 
 Page F-11 
 
 
  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 eff ects 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 incr ease in tumors regardless of the tissue.  
 
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-17 β?  
 
                                                     
 
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). WT/DS321/R/Add.6 
Page F-12  
 
  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 hamste r 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-17 β 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] 
  WT/DS321/R/Add.6 
 Page F-13 
 
 
  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 e ffects. 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 e fficiently 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 tissu es, 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 a nd only a small part of them as gl ucuronides. 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 WT/DS321/R/Add.6 
Page F-14  
 
  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.   WT/DS321/R/Add.6 
 Page F-15 
 
 
   
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 estro gen-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.  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 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, w ould 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 WT/DS321/R/Add.6 
Page F-16  
 
  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 proo f, 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-17 β 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-17 β 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  WT/DS321/R/Add.6 
 Page F-17 
 
 
  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 produci ng 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-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] 
 
EC Comments
 
 
                                                      
8  Available at http://ntp.niehs.nih.gov/index.cfm?objectid=72016262-BDB7-CEBA-  
FA60E922B18C2540 . WT/DS321/R/Add.6 
Page F-18  
 
  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 asse ssment 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 presen ce 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,  WT/DS321/R/Add.6 
 Page F-19 
 
 
  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?  
 WT/DS321/R/Add.6 
Page F-20  
 
  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 uncerta inty? 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?  WT/DS321/R/Add.6 
 Page F-21 
 
 
   
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 eff ect 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 WT/DS321/R/Add.6 
Page F-22  
 
  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 f ound, 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 ho rmones 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 endoge nously 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 absorb ed 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 eviden ce 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  WT/DS321/R/Add.6 
 Page F-23 
 
 
  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 rebutta l 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 Comm unities 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 conseque nces 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.   WT/DS321/R/Add.6 
Page F-24  
 
  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 JECF A 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 11th 
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 11th 
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 11th 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.  
  WT/DS321/R/Add.6 
 Page F-25 
 
 
  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 WT/DS321/R/Add.6 
Page F-26  
 
  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 u sed 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-depend ent"?  Is dose-response assessment a necessary 
component of hazard characterization?  Or, is  there an alternative approach which can replace  WT/DS321/R/Add.6 
 Page F-27 
 
 
  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 WT/DS321/R/Add.6 
Page F-28  
 
  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 prope rly 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-17 β 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  WT/DS321/R/Add.6 
 Page F-29 
 
 
  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-17 β? 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-estim ation of endogenous le vels 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] WT/DS321/R/Add.6 
Page F-30  
 
   
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-17 β 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-17 β in the form of encapsulated powder. Moreover, in the "benchmark study" 
on oestradiol-17 β performed in rats (Cook et al., 1998) the rats were orally dosed with oestradiol-17 β. 
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 est radiol 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 Articl es 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.  WT/DS321/R/Add.6 
 Page F-31 
 
 
  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 assu mption 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?   
 WT/DS321/R/Add.6 
Page F-32  
 
  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 th e 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 th e "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.   WT/DS321/R/Add.6 
 Page F-33 
 
 
  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.  WT/DS321/R/Add.6 
Page F-34  
 
  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 co ncluded 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 ra te 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 Commun ities has presented suggests that "even with low percentages of 
bioavailability of estrogen, the leve ls 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-me nopausal 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.   WT/DS321/R/Add.6 
 Page F-35 
 
 
  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 th at 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 WT/DS321/R/Add.6 
Page F-36  
 
  nor have they ever published something on these substa nces.  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 w ith 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. Fo r 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 becau se 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-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  WT/DS321/R/Add.6 
 Page F-37 
 
 
  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 pa pers 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 s how 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 wh ich 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  WT/DS321/R/Add.6 
Page F-38  
 
  continues with his line of argument that there is a th reshold effect, which preven ts 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 eviden ce 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  WT/DS321/R/Add.6 
 Page F-39 
 
 
  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 don e 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 potentia l 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 WT/DS321/R/Add.6 
Page F-40  
 
  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.  Anothe r example is that he dismisses the relevance of the 
studies on misuse and abuse on the speculative ground th at "… the probability that this would occur is 
extremely low". However, he has no evidence and provi des 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-17 β 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. 
 
  WT/DS321/R/Add.6 
 Page F-41 
 
 
  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 Code x: "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 pr iority 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. 
 WT/DS321/R/Add.6 
Page F-42  
 
  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 cons ideration 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.  WT/DS321/R/Add.6 
 Page F-43 
 
 
   
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 h ealth 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. 
 WT/DS321/R/Add.6 
Page F-44  
 
  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 fo r 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 whic h 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, a nd most clearly with the evaluation of Carbadox  referred 
to by the EC in its rebuttal submi ssions (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  WT/DS321/R/Add.6 
 Page F-45 
 
 
  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 fi rst 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 quantitativ ely, 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 al so 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 WT/DS321/R/Add.6 
Page F-46  
 
  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 accord ing 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  WT/DS321/R/Add.6 
 Page F-47 
 
 
  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 inst ance, 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), 
para. 123 of Canada Rebuttal Submission] 
 
EC Comments
  
 
The European Communities would note th e following statements by JECFA: 
 
• "the data are mainly provided by companies who produce the compounds; WT/DS321/R/Add.6 
Page F-48  
 
  • 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 ev aluations 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? 
  WT/DS321/R/Add.6 
 Page F-49 
 
 
  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 curren tly 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 66th 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 16th 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 w ould have been the probl em 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 WT/DS321/R/Add.6 
Page F-50  
 
  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 s ubmissions and in particul ar 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 mo st 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  WT/DS321/R/Add.6 
 Page F-51 
 
 
  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-17 β 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 WT/DS321/R/Add.6 
Page F-52  
 
  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. Fu rthermore, 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 sp ecific comment at this time.  
 
Q22. Who are the members of the IARC? 
 
EC Comments  
 
The European Communities has no sp ecific 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."   WT/DS321/R/Add.6 
 Page F-53 
 
 
   
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 thr ee hormones that it has assessed and classified? 
 WT/DS321/R/Add.6 
Page F-54  
 
  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 prel iminary 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, th e 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 iden tified 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, zer anol, 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.  WT/DS321/R/Add.6 
 Page F-55 
 
 
  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 ach ieve 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 wh ich 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 WT/DS321/R/Add.6 
Page F-56  
 
  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 asse ssments 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 ).   WT/DS321/R/Add.6 
 Page F-57 
 
 
  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 ca using 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 effect s 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 asp ects 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 seri ous 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 WT/DS321/R/Add.6 
Page F-58  
 
  "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 carci nogenesis 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.   WT/DS321/R/Add.6 
 Page F-59 
 
 
  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 ha ve 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-17 β, Dr. Boisseau  expressly states that "in its 32nd 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 situati ons 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 ma rgin 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). WT/DS321/R/Add.6 
Page F-60  
 
  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 th e 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.  WT/DS321/R/Add.6 
 Page F-61 
 
 
  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 ri sk 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. WT/DS321/R/Add.6 
Page F-62  
 
  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 fo r 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 thr ee 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 treat ed 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 th at 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.  WT/DS321/R/Add.6 
 Page F-63 
 
 
  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). WT/DS321/R/Add.6 
Page F-64  
 
  • 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 (B ianco 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-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-17 β?  
 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, Boobi s 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.  WT/DS321/R/Add.6 
 Page F-65 
 
 
  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 Cana da 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. WT/DS321/R/Add.6 
Page F-66  
 
  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 conclu sion that the carcinogenic effects of oestradiol-17 β 
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-17 β 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 cel ls with 50 to 200nM 4-OH oestradiol-17 β 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 mutati onal spectrum resulting from 4-OH oestradiol-17 β treatment 
was different than the "background" mutations seen in the control (untreated) cells further supporting 
the conclusion that the mutations were in fact cau sed by the 4-OH catechol estrogen. 2-OH oestradiol-
17β did not induce mutations. These results support th e difference in carcinogenicity difference  WT/DS321/R/Add.6 
 Page F-67 
 
 
  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-17 β 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 WT/DS321/R/Add.6 
Page F-68  
 
  genotoxicity of oestradiol 17ß and its catechol metabolites in animal and human tissue as well as the 
mutagenicity of oestradiol 17ß meta bolites 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. Moreove r, the genotoxic activity of oestradiol 17 β 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  WT/DS321/R/Add.6 
 Page F-69 
 
 
  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 carci nogenesis 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 17 β 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 hormon es 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, wh ich 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.  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 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]   WT/DS321/R/Add.6 
Page F-70  
 
  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. Howeve r, 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 ar e 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 statem ent 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 ther e 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,  WT/DS321/R/Add.6 
 Page F-71 
 
 
  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 17 β 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 Carcinogen esis 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 17 β 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 … WT/DS321/R/Add.6 
Page F-72  
 
  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] 
 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, wh at 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 assessm ent that discussed this issue).   WT/DS321/R/Add.6 
 Page F-73 
 
 
  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 paragra phs 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 "the ir 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 WT/DS321/R/Add.6 
Page F-74  
 
  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 paragra ph 59 of its submission a nd 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 othe r 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.   WT/DS321/R/Add.6 
 Page F-75 
 
 
  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 WT/DS321/R/Add.6 
Page F-76  
 
  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 in evitably 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 ho rmones 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 eviden ce 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]   WT/DS321/R/Add.6 
 Page F-77 
 
 
  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 conclu sions 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 58th 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] 
 WT/DS321/R/Add.6 
Page F-78  
 
  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 fi rst 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 thei r 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 11th 
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  WT/DS321/R/Add.6 
 Page F-79 
 
 
  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 hor mones 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 (a t 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 WT/DS321/R/Add.6 
Page F-80  
 
  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 fu lly 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-evaluati on", whereas in its comment to Question 18 Canada 
denied that JECFA's establishment of an ADI was re lated 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 th ese hormones are safe for consumers – is a fact and not 
a matter of assessment.   WT/DS321/R/Add.6 
 Page F-81 
 
 
  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 ove rdosing 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 pr opionate, 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. Cana da 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] WT/DS321/R/Add.6 
Page F-82  
 
  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 uns ound 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-depend ent"?  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 a ssessment 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 unsubs tantiated 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]   WT/DS321/R/Add.6 
 Page F-83 
 
 
  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-17 β 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 WT/DS321/R/Add.6 
Page F-84  
 
  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 RI A 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.  WT/DS321/R/Add.6 
 Page F-85 
 
 
  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 syst em, 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 WT/DS321/R/Add.6 
Page F-86  
 
  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 Eu ropean Communities has al ready 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  WT/DS321/R/Add.6 
 Page F-87 
 
 
  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-17 β? 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 WT/DS321/R/Add.6 
Page F-88  
 
  on the basis of the most recent scientific data, incl uding in particular the direct genotoxicity and the 
low levels of endogenous productio n 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-co nvertible 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  WT/DS321/R/Add.6 
 Page F-89 
 
 
  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 coul d result in bioavailable estrogen appr oaching 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 WT/DS321/R/Add.6 
Page F-90  
 
  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 a buse 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 conclu sion 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.  WT/DS321/R/Add.6 
 Page F-91 
 
 
  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/s tatements to prevent illegal use in veal calves.  WT/DS321/R/Add.6 
Page F-92  
 
   
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? [F or 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?    WT/DS321/R/Add.6 
 Page F-93 
 
 
  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 c oncentrations 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 WT/DS321/R/Add.6 
Page F-94  
 
  "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 Ca nada than in the Europ ean 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 Ca rbadox 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.   WT/DS321/R/Add.6 
 Page F-95 
 
 
  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 scientif ic 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 th em, 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. WT/DS321/R/Add.6 
Page F-96  
 
  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 conven iently omits the rest of Dr. Guttenplan's  statement who went 
on to say "[h]owever, the alternative would be to sugg est 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.  WT/DS321/R/Add.6 
 Page F-97 
 
 
  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 WT/DS321/R/Add.6 
Page F-98  
 
  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]  
  WT/DS321/R/Add.6 
 Page F-99 
 
 
  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 (paragra ph 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 Communiti es 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 ma ternal 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 WT/DS321/R/Add.6 
Page F-100  
 
  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. St eroid 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 tissu e 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 17 β) 
  WT/DS321/R/Add.6 
 Page F-101 
 
 
  ANNEX F-4 
 
COMMENTS BY CANADA TO THE REPLIES 
OF SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC 
TO QUESTIONS POSED BY THE PANEL 
 
(30 June 2006) 
  
TABLE OF CONTENTS 
 
I.
 INTRODUCTION ................................................................................................................101  
II. COMMENTS ON THE RESPONSES FROM THE EXPERTS......................................102  
A. GENERAL DEFINITIONS ...........................................................................................................102  
B. ASSESSMENT OF OESTRADIOL -17Β.........................................................................................111  
C. CONSUMPTION OF MEAT CONTAINING HORMONES ...............................................................113  
(a) Carcinogenicity................................................................................................................ .......113  
(b) Residue analysis............................................................................................................... .......123  
(c) Dose-response re lationship ..................................................................................................... 130 
(d) Sensitive populations .......................................................................................................... ....131  
(e) Bioavailability................................................................................................................ .........135  
(f) Good veterinary practice (GVP) .............................................................................................136  
(g) Other .......................................................................................................................... .............142  
III. COMMENTS ON INTERNAT IONAL ORGANIZATION REPLIES ...........................147  
IV. CONCLUDING COMMENTS............................................................................................151  
 
 
I. INTRODUCTION 
1. Canada is pleased to have this opportunity  to comment on the responses to the Panel's 
questions of the experts and international organi zations. Canada expresses its appreciation to the 
experts and international organizati ons for having agreed to participat e in this proceeding as scientific 
and technical advisors to the Panel. 
2. The Panel has sought advice on the scientific and te chnical matters that arise in the context of 
the dispute between the parties over whether the European Communities (EC) has complied with the 
recommendations and rulings of the WTO Dispute Settlement Body (DSB) in EC – Measures 
Concerning Meat and Meat Products (Hormones) . In light of the nature of this dispute, the most 
relevant questions (and answers) are those that sh ed light on whether the scientific evidence relied 
upon by the EC supports its conclusions that there is  a potential for the occurr ence of adverse effects 
from the consumption of meat from cattle that  have been treated with oestradiol 17 β, and that there is 
insufficient scientific evidence to conduct an assessm ent of the risks from consuming meat from cattle 
that has been treated by any of the othe r five hormone growth promoters (HGP).  WT/DS321/R/Add.6 
Page F-102  
 
  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 th e 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, zer anol, 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' repl y 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 hea lth. 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 char acteristics 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.  WT/DS321/R/Add.6 
 Page F-103 
 
 
  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 a nd 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 answer s to the Panel's questions. 
 WT/DS321/R/Add.6 
Page F-104  
 
  • 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 assessment8 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 answer s 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).  WT/DS321/R/Add.6 
 Page F-105 
 
 
  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 asse ssments 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 ge nerally 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. WT/DS321/R/Add.6 
Page F-106  
 
  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 populati on groups to the substanc e 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 asse ssment. 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. 
15 Canada Rebuttal Submission, at para. 78. 
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).  WT/DS321/R/Add.6 
 Page F-107 
 
 
  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. WT/DS321/R/Add.6 
Page F-108  
 
  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 17 β 52nd Meeting CDA-17 60 0-0.05 µg/kg 100 
Progesterone 52nd Meeting CDA-17 62 0-30 µg/kg 100 
Testosterone 52nd Meeting CDA-17 64 0-2 µg/kg 1000 
Trenbolone Acetate 34th Meeting CDA-30 107 0-0.02 µg/kg 100 
Zeranol 32nd Meeting CDA-29 145 0-0.5 µg/kg 100 
Melengestrol Acetate 54th 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.  WT/DS321/R/Add.6 
 Page F-109 
 
 
  • 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 ha s 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 ri sk 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. WT/DS321/R/Add.6 
Page F-110  
 
  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 promoti on purposes – as is requi red 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 ma y 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.  WT/DS321/R/Add.6 
 Page F-111 
 
 
   
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 wi th 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 cons ider 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 "pri nciple" 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 17 β) 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 WT/DS321/R/Add.6 
Page F-112  
 
  another in its evaluation of the potential occurrence of adverse effects 
(whether carcinogenic, 
genotoxic or other) from the consumption of residues of oestradiol 17 β 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 c onclusion 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.  WT/DS321/R/Add.6 
 Page F-113 
 
 
  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 17 β? 
 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 ch aracterization, 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 17 β. 
                                                      
34 Canada Rebuttal Submission, at para. 86. 
35 Ibid., at paras. 83-85. 
36 EC Rebuttal Submission, at para. 141; 1999 SCVPH Opinion, at p. 20 (Exhibit CDA-2). WT/DS321/R/Add.6 
Page F-114  
 
  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 17 β is considered a human carcinogen when e xposure 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 resulte d 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 associat ed 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.  WT/DS321/R/Add.6 
 Page F-115 
 
 
  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 17 β an issue with respect to residu es 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. WT/DS321/R/Add.6 
Page F-116  
 
  metabolites have not been found in meat from treated an imals, 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 17 β 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 17 β 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.  WT/DS321/R/Add.6 
 Page F-117 
 
 
  (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 selectiv e 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 clai m 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 (biol ogical 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). WT/DS321/R/Add.6 
Page F-118  
 
  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 unnecessa ry"? 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 depende nt 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  WT/DS321/R/Add.6 
 Page F-119 
 
 
  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 est ablished 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 "amongs t the most efficient".  WT/DS321/R/Add.6 
Page F-120  
 
  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 17 β 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 relationshi p can be identified with any certainty, finding not  WT/DS321/R/Add.6 
 Page F-121 
 
 
  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 gr eater 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 take n 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 WT/DS321/R/Add.6 
Page F-122  
 
  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 generati on 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 th at 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.  WT/DS321/R/Add.6 
 Page F-123 
 
 
  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 17 β, 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 ho rmones 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 WT/DS321/R/Add.6 
Page F-124  
 
  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 rega rd 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 eviden ce 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 pr actices 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 34th 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).  WT/DS321/R/Add.6 
 Page F-125 
 
 
  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 (62nd 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 hormon es 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 a nd 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." WT/DS321/R/Add.6 
Page F-126  
 
  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.  WT/DS321/R/Add.6 
 Page F-127 
 
 
  oestradiol 17 β 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 appr opriately 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). WT/DS321/R/Add.6 
Page F-128  
 
   
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 52nd 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.  WT/DS321/R/Add.6 
 Page F-129 
 
 
  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 hum ans? 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.") WT/DS321/R/Add.6 
Page F-130  
 
  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 ri sk assessments for the horm ones 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.  WT/DS321/R/Add.6 
 Page F-131 
 
 
  139. Dr. Boobis similarly describes at least two ge neral sets of circumstances in which a dose-
response assessment would still be c onducted on substances t hought 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 effe ct 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. WT/DS321/R/Add.6 
Page F-132  
 
  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 co mments on the experts' responses to Question 40. 
Q39. Please comment on the SCVPH opinion stating that "any excess exposure towards 
oestradiol 17 β 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 question68 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 17 β 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.  WT/DS321/R/Add.6 
 Page F-133 
 
 
  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). WT/DS321/R/Add.6 
Page F-134  
 
  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 bac kground 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 17 β? 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 17 β? 
 
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 co nservative 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).  WT/DS321/R/Add.6 
 Page F-135 
 
 
  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 sensitiv e 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 17 β. 
(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 availab ility 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, 52nd 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, Progester one, 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). WT/DS321/R/Add.6 
Page F-136  
 
  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 horm ones 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 Practi ce 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 c onduct 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).  WT/DS321/R/Add.6 
 Page F-137 
 
 
  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 diagnos is, 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 th e 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: 
                                                      
80 Codex Recommendations , at para. 5, p. 1. 
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). WT/DS321/R/Add.6 
Page F-138  
 
  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]  WT/DS321/R/Add.6 
 Page F-139 
 
 
  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 whic h 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 pr oducts 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 flaw ed. 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 . WT/DS321/R/Add.6 
Page F-140  
 
  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 th e 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.  WT/DS321/R/Add.6 
 Page F-141 
 
 
  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 horm ones 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 WT/DS321/R/Add.6 
Page F-142  
 
  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 partic ular, he confirms Canada's explana tion 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 ri sk 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 wi th 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  WT/DS321/R/Add.6 
 Page F-143 
 
 
  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 th e 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 pur portedly 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]". WT/DS321/R/Add.6 
Page F-144  
 
  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 fro m 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 leve ls 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.   WT/DS321/R/Add.6 
 Page F-145 
 
 
  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 qu estion, 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. Boobi s), 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. WT/DS321/R/Add.6 
Page F-146  
 
   
210. Drs. Boisseau, Guttenplan and Boobis all expressed in their own ways some difficulty with 
this statement by the EC. Dr. Boi sseau 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 represen ts only 1.5% of the ADI (the level below which 
there is no risk), it simply cannot be "inferred from th e available scientific data " that exposure to more 
residues from meat from treated anim als 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 asse ssment" 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, somethi ng 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  WT/DS321/R/Add.6 
 Page F-147 
 
 
  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 17 β , 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 confir med or expanded upon pr evious 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.  WT/DS321/R/Add.6 
Page F-148  
 
  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  WT/DS321/R/Add.6 
 Page F-149 
 
 
  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), para. 123 of Canada Rebuttal Submission]  
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?  WT/DS321/R/Add.6 
Page F-150  
 
  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 "age nt" 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.   WT/DS321/R/Add.6 
 Page F-151 
 
 
  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 17 β. 
 
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. WT/DS321/R/Add.6 
Page F-152  
 
  ANNEX F-5 
 
COMMENTS BY CANADA TO THE COMMENTS 
OF THE EUROPEAN COMMUNITIES ON THE REPLIES OF THE 
SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC 
TO QUESTIONS POSED BY THE PANEL 
 
(12 July 2006) 
  
TABLE OF CONTENTS  
 
I.
 INTRODUCTION ................................................................................................................152  
II. COMMENTS ON THE COMMENTS FROM THE EC ON THE RESPONSES 
FROM THE EXPERTS .......................................................................................................153  
A. GENERAL DEFINITIONS ...........................................................................................................153  
B. RISK ASSESSMENT TECHNIQUES .............................................................................................154  
C. ASSESSMENT OF OESTRADIOL 17Β.........................................................................................158  
D. CONSUMPTION OF MEAT CONTAINING HORMONES ...............................................................162  
(a) Carcinogenicity................................................................................................................ .......162  
(b) Residue Analysis............................................................................................................... ......165  
(c) Dose-Response Relationship ..................................................................................................169  
(d) Sensitive Populations.......................................................................................................... ....170  
(e) Bioavailability................................................................................................................ .........171  
(f) Good Veterinary Practice (GVP) ............................................................................................172  
(g) Other .......................................................................................................................... .............175  
III. COMMENTS ON THE COMMENTS FROM THE EC ON THE RESPONSES 
FROM THE INTERNATIONAL BODIES........................................................................178  
IV. CONCLUDING COMMENTS............................................................................................178  
  
I. INTRODUCTION 
1. Canada is pleased to have this opportunity to comment on the comments by the European 
Communities (EC) on the responses by the experts a nd by JECFA, Codex and IARC. Before turning 
to comments on the specific responses , several issues of a general na ture raised by the EC warrant 
mention. 
2. First, the EC suggests in many of its comments that it is either Canada or the experts that need 
to demonstrate that adverse effects will not
 arise from consuming residues of hormones in meat from 
treated animals.1 It is important to recall that it is the EC that has adopted bans on these hormones as 
growth promoters on the basis that they cause adverse effects, and it is the EC that has brought this 
case against Canada, alleging that these bans are justified under the SPS Agreement . Any suggestion 
                                                      
1 For example, see EC Comments on the Replies by the Panel Experts, in relation to Questions 18, 20 
and 59 (EC Comments).  WT/DS321/R/Add.6 
 Page F-153 
 
 
  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 th at 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. B oobis 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 res ponses 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. WT/DS321/R/Add.6 
Page F-154  
 
  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 warra nt 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.  WT/DS321/R/Add.6 
 Page F-155 
 
 
  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 internationa l 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 st udies 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 purpo ses, 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). WT/DS321/R/Add.6 
Page F-156  
 
  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 a nd 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 ri sk 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 identif ication 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 quantitativ ely 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.  WT/DS321/R/Add.6 
 Page F-157 
 
 
  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 ev idence" 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 scientif ic 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. WT/DS321/R/Add.6 
Page F-158  
 
  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 descripti ons 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 ‘genot oxic 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 hormo nes 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 17 β 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.  WT/DS321/R/Add.6 
 Page F-159 
 
 
  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 exposur e 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 therapy22 and combined 
oral contraceptives23 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. WT/DS321/R/Add.6 
Page F-160  
 
  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 re lated 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 17 β. 
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).  WT/DS321/R/Add.6 
 Page F-161 
 
 
  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 fro m 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 relationshi p 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 17 β follow the four steps in the risk asse ssment 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. WT/DS321/R/Add.6 
Page F-162  
 
  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 th at 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 ve terinary 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 17 β 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.  WT/DS321/R/Add.6 
 Page F-163 
 
 
  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 hormona l 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 17 β 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 th e 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 17 β 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 Cana da's Comments, at para. 146. 
35 Ibid., at paras. 79-82. WT/DS321/R/Add.6 
Page F-164  
 
  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 hormon es. On this point, the experts have not indicated 
that this new evidence cha nges 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 17 β 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 hypothe tical, 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.  WT/DS321/R/Add.6 
 Page F-165 
 
 
  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 hypoth etical 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-17 β 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). WT/DS321/R/Add.6 
Page F-166  
 
  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 leve ls 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 JECFA41 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 34th 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 (32nd JECFA, Residue Monograph for Zeranol) [emphasis added] 
(Exhibit CDA-39).  WT/DS321/R/Add.6 
 Page F-167 
 
 
  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 childre n 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) (58th JECFA, Residue Monograph for MGA) (JECFA's 58th 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 fo r 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. WT/DS321/R/Add.6 
Page F-168  
 
  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 evalua ted 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).  WT/DS321/R/Add.6 
 Page F-169 
 
 
  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 52nd 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 58th 
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 internati onal 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 su fficient 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 58th 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. WT/DS321/R/Add.6 
Page F-170  
 
  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 adve rse 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 ob served 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 confirme d 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 horm one levels to endogenous 
exposure would be greater. However, this statement of basic physiolog y 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 Inve st 2475–2480 (Klein RCBA).  WT/DS321/R/Add.6 
 Page F-171 
 
 
  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 a ll 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. WT/DS321/R/Add.6 
Page F-172  
 
  bioavailability of hormones might be higher than once thought. Neither issue, in the end, demonstrates 
that the international standards would not m eet 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 existen ce 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 re veals 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 po ssibility 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.  WT/DS321/R/Add.6 
 Page F-173 
 
 
  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 th at 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 Asse ssment of Risks of Abusive Use, at p. 15 (Exhibit EC-73). 
71 Ibid., at para. 16. WT/DS321/R/Add.6 
Page F-174  
 
  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 th at 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 inj ected 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 pr esence 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 Assessm ent 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).  WT/DS321/R/Add.6 
 Page F-175 
 
 
  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 adver se 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". Howeve r, 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. WT/DS321/R/Add.6 
Page F-176  
 
  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 ad ditive 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 th at 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 ex tent 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 anim als 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.  WT/DS321/R/Add.6 
 Page F-177 
 
 
  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 pur poses. 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 th e 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 WT/DS321/R/Add.6 
Page F-178  
 
  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 paragrap hs 35-44 of this document. 
130. In relation to Question 9,  Canada refers to paragrap hs 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 paragr aph 77 of this document. 
133. In relation to Question 12,  Canada refers to pa ragraphs 16 and 17, 18-21 of this document. 
134. In relation to Question 13 , Canada refers to paragr aph 77 of this document.  
135. In relation to Question 14,  Canada refers to paragr aph 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 para graph 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.   WT/DS321/R/Add.6 
 Page F-179 
 
 
  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. 
 
__________