WORLD TRADE  
ORGANIZATION  WT/DS320/R/Add.6 
31 March 2008 
 (08-0904) 
 Original:   English 
  
 
 
UNITED STATES – CONTINUED SUSPENSION OF 
OBLIGATIONS IN THE EC  – HORMONES DISPUTE 
 
 
Report of the Panel 
 
 
Addendum  
   This addendum contains Annex F to the Re port of the Panel to be found in document 
WT/DS320/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/DS320/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 the United States on the replies of the scientific 
experts, Codex, JECFA and IARC to questions posed by the Panel 
(30 June 2006)  F-101 
Annex F-5 Comments by the United States to the comments by the European 
Communities on the replies of the scientific experts, Codex, 
JECFA and IARC to questions posed by the Panel (12 July 2006) F-141 
 WT/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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 relation ship..."  Please comment on the methodology 
used by the SCVPH to support the conclusion th at hormone levels are lower than previously 
thought, and in particular comment on the validity of these methodologies and their conclusions.  Would your conclusions have been the same at the time of adoption of the 
Directive in September 2003?  
EC Comments
 
 
JECFA originally used the limit-of-detection as th e "real" level when they could not measure the 
levels. Dr. Boobis suggest using "newer data from Klei n (Klein et al., 1998)". However, Klein et al., 
1998 only reports values for girls with precocious pube rty, while they in the paper still refers to the 
original data (Klein et al., 1994) for the le vels in normal pre-pubertal girls. Dr. Boobis  also writes that 
the values from another ultra sens itive bioassay (Paris et al., 2002) suggest that the levels are 
significantly higher, however, that assay measures estradiol equivalents (includes other natural  WT/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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 treated animals were significantly 
higher than in untreated animals.   
As for the reasons for which JECFA established in 1999 ADIs, the European Communities notes the 
statement that this was due to "the additional da ta reviewed and the need to establish an ADI as 
quantitative estimate for a safe oral intake. The e xposure assessment performed  would then allow the 
comparison of the estimated intake with the ADI." Th us, this confirms the EC position that it was the 
new evidence showing risk of cancer that le d JECFA review its 1988 assessment. And if JECFA 
postponed its assessment until the new and more recen t data generated by the European Communities 
were taken into account, it could have reached still a nother and arguably more accurate conclusion. In 
any case, it is clear that in 1999 JECFA did not establi sh ADI in order explain better its evaluation, as 
it is claimed erroneously by Dr. Boisseau
 (see his reply to Panel question to the experts no 18).   
 
JECFA states that "sufficient new data from ob servations in humans were available to the 52nd 
JECFA which were suitable to derive ADIs." The European Communities does not know and has not 
seen these "data from observations in humans" and, if th ey exist, they are certainly different from the 
data it has generated itself with its  own studies. JECFA should therefore provide them to the parties, 
the Panel and its experts for review. Moreover, th e so-called "wide margin of safety" claimed by 
JECFA to exist is no longer credible in view of the "significantly higher levels" identified in treated 
animals and the need to establish ADIs, not to men tion their direct genotoxicity and the other adverse 
effects established by the European Communities. 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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/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/DS320/R/Add.6 
 Page F-101 
 
 
  ANNEX F-4 
 
COMMENTS BY THE UNITED STATES ON THE REPLIES 
OF THE SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC 
TO QUESTIONS POSED BY THE PANEL 
 
(30 June 2006) 
  A. I
NTRODUCTION  
1. The United States appreciates this opportunity to provide comments on the responses received 
from the six scientific experts and the three interna tional organizations selected by the Panel.  The 
United States will first provide a context for the expe rts' and organizations' responses in light of the 
proper role of scientific experts in this disput e, and then provide comments on the responses and 
suggestions for clarifications that may make the re sponses more useful in the context of the present 
dispute.  Finally, the United States will provide a su mmary of the conclusions that may be drawn from 
the experts' responses. 
B. THE ROLE OF SCIENTIFIC EXPERTS  
2. As previously noted by the United States in its 3 November 2005 comments on the Panel's 
proposed working procedures for consultation with th e experts, the role of scientific experts is a 
narrow one.  Scientific experts may provide a panel information, advice, and their opinions on certain 
aspects of the matter that is the subject of the dispute.1  Experts can provide a panel with vital 
perspectives, information, and advice on technical a nd scientific issues, affording a panel the ability to 
make legal determinations such as whether a measure is indeed based on a risk assessment or satisfies 
the conditions for a provisional meas ure within the meaning of the WTO Agreement on the 
Application of Sanitary and Phytosanitary Measures  ("SPS Agreement"). 
C. COMMENTS ON THE EXPERTS ' RESPONSES  
3. The Panel's questions to the experts and interna tional organizations expressed several themes.  
While, not surprisingly, the experts have not provided identical responses to each question, they are in 
agreement on several key propositions. 
4. The United States has observed the followi ng themes in the Panel's questions: 
(1) Risk assessment :2  What international guidance materials exist for conducting a risk 
assessment for veterinary drug residues?  What are the necessar y steps for a risk 
assessment?  Do the European Communities' ("EC's") Opinions3 satisfy the necessary 
steps comprising a risk assessment? 
                                                      
1 See Agreement on the Application of Sanitary and Phytosanitary Measures , Article 11.2; 
Understanding on Rules and Procedures Governing the Settlement of Disputes , Article 13. 
2 See, e.g., Panel's Questions to the Experts, Questions 3-14.; 36-37; 55; 57. 
3 The EC's Opinions, or "risk asse ssments", are comprised of the "Opinion of the Scientific Committee 
on Veterinary Measures Relating to Public Health – Assessment of Potential Risks to Human Health from 
Hormone Residues in Bovine Meat and Meat Products", 30 April 1999 ("1999 Opinion") (Exhibit US-4); the 
Review of Specific Documents Relating to the SCVPH Op inion of 30 April 99 on the Potential Risks to Human 
Health from Hormone Residues in Bovine Meat and Meat Products, dated May 3, 2000 ("2000 Review") (Exhibit US-17); and the "Opinion of the Scientific Committee on Veterinary Measures Relating to Public 
Health on Review of previous SCVPH opinions of 30 April 1999 and 3 May 2000 on the potential risks to WT/DS320/R/Add.6 
Page F-102  
 
  (2) Scientific evidence relating to estradiol 17 β
:4  Does the scientific evidence cited in the 
EC's Opinions demonstrate that carcinogenic effects of estradiol 17 β are related to a 
mechanism other than hormonal activity?  Does the scientific evidence demonstrate 
that estradiol 17 β, when consumed as a residue in meat, is genotoxic?  Does the 
scientific evidence demonstrate that estradiol 17 β will have carcinogenic or 
tumorigenic effects at levels found in residues in meat from treated cattle?  
(3) Scientific evidence relating to th e five provisionally banned hormones :5  Is the 
scientific evidence and information relating to the five hormones sufficient to conduct 
an assessment of the risks to human health from consumption of meat from cattle treated with the five hormones for growth  promotion purposes?  Does the scientific 
evidence cited by the EC in its Opinions demonstrate that any of the five hormones 
has genotoxic potential or is carcinogenic  by a mechanism other than hormonal 
activity?  Do the scientific materials produ ced and cited by the EC (including the "17 
Studies"
6) identify any gaps or insufficiencies in the scientific evidence such that 
more study is necessary before the risk from consumption of meat from cattle treated 
with the five hormones for growth promotion purposes can be assessed? 
(4) Scientific evidence relating to the hormones generally :7  Has each of the hormones 
used for growth promotion purposes in cattle  been evaluated for a sufficient period 
with no evidence of adverse effects to ade quately address any concern regarding long 
latency periods of cancer?  Do epidemiol ogical studies cited by the EC identify a link 
between cancer and residues of the hormones in meat?  Do materials cited by the EC 
demonstrate that meat from cattle treated with hormones for growth promotion 
purposes poses a risk to sensitive populations?  Do materials cited by the EC demonstrate other human health risks from  consumption of residues of the hormones 
in meat from cattle treated for growth promotion purposes, such as effects on the immune system? 
(5) Scientific evidence relating to residues
:8  To what extent did the EC evaluate 
evidence on the actual residue levels of natu ral and synthetic hormones?  Did the EC 
take these levels into account in its Opinions?  Why, and how did the Joint 
FAO/WHO Expert Committee on Food Additives ("JECFA") re-evaluate the three natural hormones in 1999? 
(6) Scientific evidence relating to good veterinary practices
:9  Do materials cited by the 
EC demonstrate that there is a risk to human health from the misuse of growth 
promoting hormones in the United States?  Has the EC assessed this risk?  Do 
materials cited the EC regarding misuse or abuse of the hormones call into question Codex Alimentarius Commission ("Codex") st andards regarding the safety of meat 
from cattle treated with hormones for growth promotion purposes? 
                                                                                                                                                                    
 
human health from hormone residues in bovine meat and meat products", 10 April 2002 ("2002 Opinion") 
(Exhibit US-1). 
4 See, e.g., Panel's Questions to the Experts, Questions 13-20. 
5 See, e.g., Panel's Questions to the Experts, Questions 21; 25; 38-42; 61-62. 
6 The EC commissioned several (17) studies in 1998-1999 (collectively the "17 Studies"), ostensibly to 
fill data gaps and develop support for the conclusions set out in the Opinions.  See US First Written Submission, 
para. 24; EC First Written Submission, para. 142. 
7 See, e.g., Panel's Questions to the Experts, Questions 22-24; 26; 43; 52-54; 59-60. 
8 See, e.g., Panel's Questions to the Experts, Questions 27-35. 
9 See, e.g., Panel's Questions to the Experts, Questions 44-51.  WT/DS320/R/Add.6 
 Page F-103 
 
 
  5. These themes relate to Annex A, paragraph 4 (d efining risk assessment) and to Article 5 of 
the SPS Agreement, most notably Article 5.1 (whether the EC's ban on estradiol 17 β is based on a risk 
assessment, as appropriate to the circumstances); Article 5.2 (whether the EC's purported risk assessment takes into account av ailable scientific evidence; relevant processes and production 
methods; relevant inspection, sampling and testing methods); Article 5.6 (whether the EC's import 
ban on meat and meat products is not  more trade-restrictive than re quired to achieve its appropriate 
level of sanitary protection); and Article 5.7 (most nota bly, the first two elements of Article 5.7's four-
part cumulative test:  whether the EC's provisional bans have been imposed in a case where relevant 
scientific evidence is insufficient and whether they  have been adopted on the basis of available 
pertinent information). 
6. In addition, these themes are set against the fo llowing factual backdrop, described in greater 
detail in the US first written submission.
10  The EC's hormone ban prohibits the importation and 
marketing of meat and meat products from cattle to which any of the six hormones (estradiol 17 β; 
testosterone; progesterone; zeranol; trenbolone acetate; and melengestrol acetate) have been 
administered for growth promotion purposes.  The United States permits the administration of these 
hormones to cattle for that very purpose.  Five of the six hormones (estradiol 17 β, progesterone, 
testosterone, zeranol, and trenbolone acetate) are admi nistered to cattle as subcutaneous implants in 
the animals' ears.  The ears are then discarded at slaughter and do not enter the human food supply.  The sixth hormone, melengestrol acetate, a synthetic progestogen, is administered as a feed additive. 
7. Three of the six hormones at issue in this proceeding (estradiol 17 β; progesterone; and 
testosterone) are naturally occurring, "endogenous " hormones produced by both humans and animals 
used for human food.  Each of these hormones is produced throughout the lifetime of every man, 
woman and child, and is required for normal physiological functioning and maturation.  With respect to chemical structure, the natural hormones used for growth promotion purposes in cattle are identical 
to the estradiol 17 β, progesterone and testosterone natu rally produced in the human body.  
Furthermore, when administered exogenously, each  of these hormones enters the same metabolic 
pathway as the endogenously produced hormone and its  metabolites are indistinguishable from those 
that are produced naturally.  End ogenous production of estradiol 17 β, progesterone and testosterone in 
humans is orders of magnitude higher than the re latively small amounts of these hormones ingested 
from residues in meat.  
8. The other three hormones (zeranol; trenbolone acetate; and melengestrol acetate) are synthetic 
hormones that mimic the biological activity of the natural hormones.  Trenbolone acetate mimics 
testosterone, zeranol mimics estradiol 17 β, and MGA mimics progesterone. 
9. Codex standards exist for the use of five of th e six hormones for growth promotion purposes.  
Upon review of risk assessments conducted by  JECFA and recommendations by the Codex 
Committee on Residues of Veterinary Drugs in Food ("CCRVDF"), Codex
11 adopted recommended 
maximum residue limits ("MRLs"), where appropriate, for estradiol 17 β, progesterone, testosterone, 
trenbolone acetate and zeranol.  Codex adopted  these recommended MRLs to ensure that 
consumption of animal tissue containing residues of these hormones do not pose a risk to consumers.  JECFA recommended an acceptable daily intake ("ADI") for melengestrol acetate at its 62
nd Meeting 
in 2004. 
10. Against this background, the EC has alleged th at it is now justified in permanently banning 
the import of meat and meat products from cattle treated with estradiol 17 β for growth promotion 
purposes, and provisionally banning the import of meat  and meat products from cattle treated with the 
                                                      
10 See US First Written Submission, Sectio ns III.B and III.C (pages 10-25). 
11 Codex is recognized as specified as the relevant international standards-setting body in the SPS 
Agreement.   See  SPS Agreement, paragraph 3(a) to Annex A. WT/DS320/R/Add.6 
Page F-104  
 
  five other hormones for growth promotion purposes .  The EC alleges to have based its ban on 
estradiol 17 β on a "risk assessment" within the meaning of Article 5.1 and paragraph 4 of Annex A of 
the SPS Agreement, and to have implemented a provisional ban for the five remaining hormones 
within the meaning of Article 5.7 of the SPS Ag reement because, unlike JECFA, it was unable to 
complete a risk assessment for any of the hormones.
12  While at the same time banning meat from 
cattle treated with any of the six hormones for growth promotion purposes, the EC permits the 
administration of hormones to farm animals for ce rtain therapeutic and zootechnical purposes, and the 
eventual marketing of meat from these animals.  
1. Risk assessment 
11. The question of what constitutes a risk assessmen t is relevant to the obligation in Article 5.1 
of the SPS Agreement in that Members must base  their measures on a risk assessment as defined in 
Annex A, paragraph 4 of the SPS Agreement.  The responses from the experts confirm that there is a 
certain internationally-recognized form that risk assessments should take and that there is consensus 
among the experts that the EC's purported risk assessment for estradiol 17 β fails to satisfy the 
necessary elements comprising such an assessment. 
(a) Risk assessment procedures generally 
12. The experts' responses confirm several points relating to risk assessment procedures, namely 
that:  (1) a wealth of international guidance exists  for the conduct of a risk assessment of veterinary 
drug residues; (2) both quantitative and qualitative risk  assessments should satisfy the four steps for a 
risk assessment (hazard identification; hazard ch aracterization; exposure assessment; and risk 
characterization); (3) risk assessments, including  those conducted by JECFA on the six hormones, 
have not been limited by a "deterministic approach"13; and (4) JECFA requires a complete database in 
order to recommend an acceptable daily intake (" ADI") unless it can adopt default assumptions that 
would lead to a more conservative risk assessment. 
13. As noted by Codex, JECFA and Dr. Boobis, th ere are numerous international documents and 
guidance materials relevant to the assessment of ve terinary drugs in food, dating back to at least 
1987.14  In addition, Dr. Boisseau comments that  the assessment of such drugs has been 
"internationally harmonised through scientific conf erences and it is possible to say there is an 
international non written agre ement on this rationale."15  As noted by JECFA, "[a]ll of these 
documents are the outcome of international expert  meetings and represent the agreed views of the 
                                                      
12 See, e.g., EC First Written Submission, para. 17.  (No ting that its ban, Directive 2003/74/EC, is 
"based on a comprehensive risk asse ssment and, thus, is fully compliant with the DSB recommendations and 
rulings. In  particular, as stipulated by the Appellate Body,  the results of the risk assessment 'sufficiently 
warrant' the definite import prohibition regarding one of  the hormones (Article 5.1 of the SPS Agreement),  and 
provide the 'available pertinent information' on the basis of which the provisional prohibition regarding the other 
five hormones has been enacted (Article 5.7 of the SPS Agreement).") 
13 A "deterministic approach" to risk assessment mean s simple, point (single-value) estimates of risk.  
"Deterministic" risk assessment does not account for unce rtainty and variability in the parameters of the risk 
assessment including exposures, dose-response and normal variation in the exposed populations, and typically 
calls for highly conservative, worst-case assumpti ons in exposure, dose and sensitive populations.  See, e.g., 
Hattis and Burmaster, Risk Analysis 14(5): 713-730 (1994). 
14 See Codex Responses to Questions from the Panel ("Codex Responses") (Questions 3 and 4), pp. 4-
5; JECFA Responses to Questions from the Panel ("JECFA Responses") (Question 3), pp. 2-3; Responses to Questions from the Panel of Dr. Alan Boobis ("Dr. Boobis Responses") (Question 3), pp. 10-11. 
15 Responses to Questions from the Panel of Dr. Jacques Boisseau ("Dr. Boisseau Responses") 
(Question 4), p. 2.  Indeed, as noted by the United St ates in its first written submission, the EC acknowledges 
that there is a general form which a risk assessment must take.  See US First Written Submission, para. 139, 
citing  EC 1999 Opinion, p. 70 ("Executive Summary") (Exhibit US-4).   WT/DS320/R/Add.6 
 Page F-105 
 
 
  participating experts and several of those have also been published in the scientific literature."16  
Although there are no Codex standards per se on the conduct of a risk assessment (such guidance is 
currently in draft form17), as noted by JECFA, "[t]he elaboration and application of risk assessment 
principles are within the responsibility of the scientific expert bodies [ i.e., JECFA]."18 
14. In terms of the components comprising a risk assessment, the experts' responses confirm that 
there are four essential elements:  (1) hazard identif ication; (2) hazard characterization; (3) exposure 
assessment; and (4) risk characterization.19  The one caveat to this rule is provided by Dr. Vincent 
Cogliano, who notes that, for purposes of hazard char acterization, "[a] qualitative risk assessment can 
consider the presence or absence of dose-response relationships."20  JECFA's response takes this 
thought a step further, noting that a dose-res ponse assessment is an integral part of hazard 
characterization, and can be "done in a quantitativ e or a qualitative way.  In the qualitative sense this 
is the determination of a no-effect level from an experimental or epidemiological study.  For the 
hormones JECFA used this approach."21  The definition of "hazard characterization" provided by 
Codex confirms that a dose-response assessment is  integral to this step of risk assessment.22  The EC's 
Opinions fail to engage in any such evaluation because they rely instead on the conclusion that 
estradiol 17 β is genotoxic; however, as discussed in greater detail below, and as confirmed by the 
scientific experts, the EC fails to adduce evidence of genotoxic or carcinogenic effects at levels below 
those associated with a hormonal response. 
15. Finally, the experts' responses clarify two ke y aspects of JECFA's risk assessment procedure, 
namely that JECFA's assessments of the six hormones are not limited by a "deterministic approach" and that JECFA requires a complete database in orde r to complete a risk assessment and set an ADI 
(as it has done for the hormones at issue) unless it ca n adopt default assumptions that would lead to a 
more conservative risk assessment.
23  As to the former point, Dr. Boisseau notes that, rather than 
taking a "deterministic" approach, "JECFA was perfectly aware about this kind of non linear 
situation[s]," and that, "[i]f, in 1999, the 52nd JECFA recognized that oestradiol-17 β 'has a genotoxic 
potential', it concluded nevertheless that 'the carcinogenicity of oestradiol-17 β was probably a result 
of its interaction with hormone receptors'.  Theref ore it did not take into consideration a non linear 
situation in its risk assessment."24   
16. Dr. Boobis reiterates this point, noting that the results of JECFA's risk  assessment are based 
on scientific evidence as opposed to a predetermine d result, "JECFA['s] risk assessment concluded 
that the dose-response relationship for all of the endpoints was non-linear and that there was a 
threshold dose below which there was no appreciable  risk over a lifetime of exposure.  Hence, a 
deterministic approach, via the establishment of ADI s, was appropriate according to the procedures 
                                                      
16 JECFA Responses (Question 3), p. 3. 
17 See Codex Responses (Question 4), p. 5; Dr. Boobis Responses (Question 3), p. 11. 
18 JECFA Responses (Question 3), p. 2. 
19 JECFA Responses (Question 6), p. 3; Codex Resp onses (Question 6), p. 6; Dr. Boobis Responses 
(Question 6), p. 13; Dr. Boisseau Responses (Question 6), pp. 4-5; Responses to Questions from the Panel of 
Dr. Joseph Guttenplan ("Dr. Guttenplan Responses") (Question 6), p. 2. 
20 Responses to Questions from the Panel of Dr. Vincent Cogliano ("Dr. Cogliano Responses") 
(Question 11), p. 1. 
21 JECFA Responses (Question 8), p. 4. 
22 Codex Responses (Question 6), p. 6 (" Hazard characterization.   The qualitative and/or quantitative 
evaluation of the nature of the advers e health effects associated with biol ogical, chemical and physical agents 
which may be present in food.  For chemical agents, a dose-response assessment should be performed .  For 
biological or physical agents, a dose -response assessment should be performed if the data are obtainable.") 
(Emphasis added).  See JECFA Responses (Question 6), p. 3 (hazard characterization "includes dose-response 
assessment , considerations on species sensitivity, rele vance of specific effect for humans etc.") 
23 See Dr. Boobis Responses (Question 9), p. 15. 
24 Dr. Boisseau Responses (Question 7), p. 6. WT/DS320/R/Add.6 
Page F-106  
 
  followed by the Committee."
25  Finally, as noted by JECFA itself, "JECFA's assessment process is 
based on the mechanism of action of the compound to  be evaluated, non-linearity is assumed if the 
adverse effect of a compound is caused via a mechanism with a threshold of effect.  In such a case, as 
for the hormones, a no-effect level can be determined."26 
17. As to the latter point, Drs. Boisseau and Boobis, and JECFA confirm that JECFA only 
allocates a final ADI for a veterinary drug if the scientific database is complete and there are no 
outstanding scientific issues.  As noted by JECFA,  "[i]f there are substan tial gaps and important 
information missing, JECFA can not establish an ADI."27  The only alternative to this rule is a 
situation where JECFA can "adopt default assumptions  that would if anything lead to a more 
conservative risk assessment than  would be the case otherwise."28  JECFA has set final ADIs for each 
of the hormones in this dispute, indicating that from its point of view, the scientific database on the 
hormones was complete and void of substantial gaps .  As noted by Dr. Boisseau, "[f]or the hormonal 
growth promoters, JECFA has considered that, give n the quality and the quantity of the data, it was 
possible to carry out a complete quantitative risk assessment."29 
(b) The EC has failed to complete a "risk assessment" for estradiol 17 β30 
18. The experts' responses confirm that the EC has not completed a risk assessment for estradiol 
17β.  When prompted to examine the EC's Opinions in light of the four steps of risk assessment 
discussed above, the experts expose numerous weakne sses in the EC's purported risk assessments and 
elaborate on the EC's failure to complete the nec essary steps as well as assess critical factors such as 
the bioavailability of estradiol 17 β and human DNA repair mechanisms. 
19. The experts' responses confirm that, while the EC Opinions engage in hazard identification,31 
the first step of a risk assessment, the Opinions  fail to complete any of the remaining three 
components (hazard characterization; exposure assessment; and risk characterization).  Dr. Boobis notes, "[t]he EC has not identified the potential fo r adverse effects on human health of residues of 
oestradiol found in meat from treated cattle.  This  is because the analysis undertaken was focused 
primarily on hazard identification.  There was little  in the way of hazard characterization, and no 
independent exposure assessment was undertaken,"
32 indicating that the EC's Opinions "do[ ] not 
follow the four steps of the Codex risk assessment  paradigm.  Even if it were concluded that 
oestradiol is a genotoxic carcinogen, the four steps should have been followed."33  In other words, 
                                                      
25 Dr. Boobis Responses (Question 7), p. 13. 
26 JECFA Responses (Question 7), p. 4. 
27 JECFA Responses (Question 11), p. 10. 
28 Dr. Boobis Responses (Question 9), p. 15; see Dr. Boisseau Responses (Question 9), p. 7 ("The 
Canadian statement stipulating that 'it is recognized that JECFA only allocates an ADI for a food additive or a 
veterinary drug under review when JECFA considers that its  scientific data base is complete and that there is no 
outstanding scientific issue' is correct." ); JECFA Responses (Question 11), p. 10. 
29 Dr. Boisseau Responses (Question 12), p. 8. 
30 This Section of the Submission focuses on whether or not the EC has adhered to the relevant steps 
for conducting a risk assessment.  A discussion of whether or not the scientific conclusions relating to estradiol 
17β drawn by the EC are actually supported by the scientif ic evidence is presented in  Sections C(2), C(4) and 
C(5)-C(6) below. 
31 See US First Written Submission, para . 140 ("There is no great challenge to completing this first-step 
in a hormone risk assessment – the potential biological effects of hormones, some of which are adverse, are 
generally not in dispute in the scientific community.") 
32 Dr. Boobis Responses (Question 13), p. 17. 
33 Dr. Boobis Responses (Question 14), p. 18.  Regarding the notion that residue levels found in meat 
from treated cattle cause genotoxic effects, Dr. Boisseau opines "the EC risk assessment did not support that residues of oestradiol-17 β, despite the genotoxic potential of this hormone, can initiate and promote tumours in 
humans."  Dr. Boisseau Responses (Question 13), p. 11.  WT/DS320/R/Add.6 
 Page F-107 
 
 
  "[t]here was no attempt to estimate the potential occurrence of adverse effects in humans following 
exposure to levels of hormones found in meat from treated animals."34    
20. Dr. Joseph Guttenplan agrees that the EC has satis fied the first element of a risk assessment 
(hazard identification) by "identifying the potential for adverse effects on human health of oestradiol-
17β."35  Yet, like Dr. Boobis, Dr. Guttenplan opines that  the EC's Opinions "taken together, ha[ve] a 
mixed rating in following the Codex guidelines,"36 noting that "[t]he hazard characterization is more 
limited since there is only one animal model that is well characterized and this is in the hamster 
kidney.  As kidney is not a known target of estra diol in humans the extrapolation to humans is 
uncertain.  The risk characterization is very qualitative at best."37  Dr. Boobis comments that the EC 
appears to have stopped prematurely (at the hazard id entification stage) in its  assessment of estradiol 
17β "based on the results of a small number of non- standard tests of genotoxicity, with equivocal 
weak responses.  It is not clear if the EC applie d a weight of evidence approach to evaluating the 
genotoxicity of all of the compounds, taking into acc ount the totality of the available data, as was the 
case with JECFA."38  As a result, the EC's Opinions make little progress beyond the first step of risk 
assessment, hazard identification. 
21. The experts' responses confirm that the EC's Opinions fail to engage in a dose-response 
assessment, which is part of the hazard characteriza tion stage (the second step of risk assessment).  
Such an assessment would have been appropriate in  the analysis of a hormone such as estradiol 17 β 
for which a wealth of scientific evidence exists indicating that any effects caused by estradiol 17 β are 
through the receptor-mediated (endocrine), cell divi sion stimulating activity of the hormone, and not 
by genotoxic (non-endocrine) effects.  Rather than  evaluating this evidence in its Opinions, the EC 
relies instead on its assertion that estradiol 17 β is genotoxic as an excuse for failing to conduct a dose-
response assessment.39  As noted by Dr. Boobis, it was improper for the EC to stop its assessment of 
estradiol 17 β at this stage, "[f]or compounds that are known or assumed to be genotoxic via DNA 
reactivity, genotoxic potential would normally have to  be confirmed in vivo before this endpoint 
would be used as the basis for a risk assessment."40  As discussed in greater detail below, and as 
confirmed by the experts, the scientific studies cite d by the EC fail to demonstrate this potential in 
vivo.41 
22. The experts' responses also confirm that th e EC has failed to conduct a proper exposure 
assessment for estradiol 17 β, the third step of risk assessment.  The EC describes what it views as the 
necessary elements of a proper exposure assessment as follows: 
for the purposes of exposure assessment  from the residues of these hormones, it is not 
so much necessary to compare (if it were onl y possible!) the two situations and then 
try to quantify how much one is more risk y than the other and to what measurable 
level the risk is likely to occur, but rather  to assess a situation of additive risks arising 
from the cumulative exposures of human to  multiple hazards, in addition to the 
                                                      
34 Dr. Boobis Responses (Question 13), p. 18. 
35 Dr. Guttenplan Responses (Question 13), p. 3. 
36 Dr. Guttenplan Responses (Question 14), p. 4. 
37 Dr. Guttenplan Responses (Question 14), p. 3. 
38 Dr. Boobis Responses (Question 12), p. 17. 
39 See Dr. Boobis Responses (Q uestion 13), pp. 17-18. 
40 Dr. Boobis Responses (Question 36), p. 36, citing CVMP (2004).  Studies to Evaluate the Safety of 
Residues of Veterinary Drugs in Human Food: Genotoxicity Testing; see Dr. Boisseau Responses (Question 
36), p. 20 ("A dose-response assessment is not feasible fo r substances that are found to be genotoxic if ... this 
genotoxic potential can be expressed in in vivo conditions.") 
41 See Dr. Boobis Responses (Questions 16, 18, 20 and 52), pp. 19-20, 22, 23, and 44 (concluding that 
estradiol 17 β is not genotoxic in vivo); Dr. Boisseau Responses (Question 13), pp. 9-11; see Section C(2)(b) 
below. WT/DS320/R/Add.6 
Page F-108  
 
  endogenous production of some of these hor mones by the animals and the human 
beings .42 
The Panel accordingly asked the experts whether or not the EC has accomplished this goal by 
assessing these "additive risks," thereby completing th e exposure assessment step of its purported risk 
assessment.  The experts agree that the EC has not.  
 
23. Dr. Boisseau comments, "[t]he European Co mmunities did not assess quantitatively the extent 
to which residues of growth promoting hormones in meat contribute [to such a risk]."43  Dr. Boobis 
notes, "[t]he EC Opinions and other materials refe rred to by the EC do not quantify the extent to 
which residues of the hormones contribute to aggr egate exposures or cumulative multiple hazards."  
Finally, Dr. Guttenplan opines, "[i]n general the EC  do not attempt to evaluate 'the additive risks 
arising from the cumulative exposures of humans to multiple hazards, in addition to the endogenous 
production of some of these hormones by animals and human beings'."44    
24. For example, the experts' responses confirm that  the EC's Opinions fail to take into account 
treatments of cattle with hormones for purposes other than growth promotion, such as therapeutic or 
zootechnical administration of the hormones.  As noted by Dr. Boisseau: 
[a]s soon as the [EC] accepts to cons ider[ ] these residues resulting from these 
therapeutic and zootechnical use[s] of oestradiol-17 β as negligible [ i.e., by permitting 
their ongoing use for these purposes ], it enters into a quantitative, or at least in a semi 
quantitative, exposure assessment procedure for these [ ] residues and, starting from 
that, it has no good reason to object to c onsider a wider exposure assessment covering 
all the residues resulting from the different sources of oestradiol-17 β.45 
Dr. Boobis comments, "[t]o my knowledge no account is taken of hormone treatments of cattle for 
purposes other than growth promotion, such as for therapeutic purposes, by the EC in its assessment 
of the aggregate or cumulative effects of the hormones in meat from cattle treated for growth 
promotion."46  Dr. Guttenplan indicates that the EC's d ecision to except zootechnical or therapeutic 
treatments from its ban is "a reasonable response, " yet he does not appear to address the Panel's 
inquiry, i.e., whether the EC, in its Opinions, took these treatments into account in an assessment of 
cumulative effects.47 
 25. In defense of its lack of an exposure assessmen t, the EC has argued that "the only rationale 
that can be inferred from the available data is that the higher the exposure to residues from these 
hormones, the greater the risk is likely to be."
48  The experts' responses confirm that this is "indeed a 
very weak statement by the EC."49  Dr. Boisseau reiterates his comment that the EC has simply failed 
to "assess quantitatively the extent to which r esidues of growth promoting hormones in meat 
                                                      
42 EC Answers to Panel Questions, para. 151. 
43 Dr. Boisseau Responses (Question 55), p. 26. 
44 Dr. Guttenplan Responses (Question 55), p. 11.  Note that Dr. Guttenplan's response appears to 
conflict with his earlier opinion that the EC had complete d an exposure assessment.  It is unclear how the EC 
could have in fact completed an exposure assessment wher e, as confirmed by Dr. Guttenplan in his response to 
Question 55, it has failed to engage in the necessary analysis. 
45 Dr. Boisseau Responses (Question 57), p. 27.  See also  Dr. Boisseau Responses (Question 58), p. 26 
("The European Communities did not assess quantitatively the extent to which residues of growth promoting 
hormones in meat contribute to 'additive risks arising from the cumulative exposures of humans to multiple hazards, in addition to the endogenous  production of some of these hormone s by animals and human beings'.") 
46 Dr. Boobis Responses (Question 57), p. 47. 
47 Dr. Guttenplan Responses (Question 57), p. 12. 
48 EC Answers to Panel Questions, para. 94. 
49 Dr. Guttenplan Responses (Question 58), p. 12.  WT/DS320/R/Add.6 
 Page F-109 
 
 
  contribute to 'additive risks'."50  Dr. Boobis concurs, and notes that "[w]ithin quite broad limits, higher 
exposure would not result in any increase in risk."51 
26. The EC's failure to conduct an exposure assessment  is all the more stark in light of JECFA's 
completion of just such an assessment for estradiol 17 β.  As noted by Dr. Boisseau, "JECFA/Codex 
considered in its risk assessment of the natural hormones such 'additive risks' and concluded that, 
given the wide margin of safety ... there was no ri sk for consumers' health associated with the 
estimated ingestion of these residues."52  Dr. Boobis agrees that the additive, or aggregate risk was 
assessed by JECFA, and that exposures from residues in meat from cattle treated with the natural 
hormones for growth promotion purposes "were consid ered to represent a trivial increase in overall 
exposure to hormonally-active material from ot her exogenous sources and in particular from 
endogenous sources."53 
27. In addition to failing to complete the four step s for a risk assessment, the EC's Opinions also 
fail to properly address critical factors su ch as the bioavailability of estradiol 17 β54 and DNA repair 
mechanisms.55  The experts' responses note that bioavailability relates to the oral route of exposure to 
hormone residues, a route that is "not the most efficient,"56 and that the bioavailability of a substance, 
in this case estradiol 17 β, "has to be taken into consideration in th e risk assessment, in particular at the 
third step regarding the expos ure assessment of residues."57  Indeed, as a general rule "only that 
fraction of the dose that is bioavailable is toxicologically relevant."58  The United States has argued 
that the EC has failed to take into account the low bioavailability of estradiol 17 β in its assessment of 
that hormone, and none of the experts'  responses appear to indicate otherwise.59 
28. The experts agree that estradiol 17 β has low oral bioavailability.  Indeed, Dr. Boisseau notes 
that "oestradiol 17- β is inactive orally,"60 and Dr. Boobis states that "exposure [to estradiol] is via the 
oral route, and bioavailability by this route is very low (< 5%)."61  In contrast, Dr. Guttenplan opines 
that the bioavailability of "estrogen" is "low but not insignificant."62  However, Dr. Guttenplan's reply:  
(1) relies on materials cited by the EC that do not in fact demonstrate a higher bioavailability for 
                                                      
50 Dr. Boisseau Responses (Question 55), p. 26. 
51 Dr. Boobis Responses (Question 58), p. 48.  Dr. Boobis notes that "The EC Opinions and other 
materials referred to by the EC do not quantify the ex tent to which residues of the hormones contribute to 
aggregate exposures or cumulative exposures to multiple hazards."  Dr . Boobis Responses (Question 55), p. 45. 
52 Dr. Boisseau Responses (Question 56), p. 26. 
53 Dr. Boobis Responses (Question 56), p. 46. 
54 Note that the EC has also failed to take bioavailability into account for the five provisionally-banned  
hormones.  A discussion of biovailability is perhaps most pertinent, however, to a discussion of estradiol 17 β, 
for which the EC claims to have completed a risk assessment. 
55 Bioavailability and DNA repair mechanisms shoul d have been addressed in the EC's exposure 
assessment, had it completed one. 
56 Dr. Boisseau Responses (Question 43), p. 22. 
57 Dr. Boisseau Responses (Question 43), p. 23. 
58 Dr. Boobis Responses (Question 43), p. 40.  See Dr. Guttenplan Responses (Question 43), p. 10 
("only the bioavailable chemical can pr oduce adverse (or any) effects, thus in terms of risk assessment, only the 
portion of the dose of chemical that is bioavailable is significant.") 
59 See US First Written Submission, paras. 146, 88-89. 
60 Dr. Boisseau Responses (Question 43), p. 23.  Dr. Boisseau notes that the "[n]atural hormones are 
known to be poorly bioavailable in humans," and that the bioavailability of the synthetic hormones "ha[s] not 
been determined."  Therefore, in a risk assessment of  those hormones, as was the case in the JECFA assessment, 
"all their residues have been considered as being totally  bioavailable."  Dr. Boisseau Responses (Question 43), 
p. 23.  See Dr. Boobis Responses (Question 43), p. 40. 
61 Dr. Boobis Responses (Question 40), p. 39. 
62 Dr. Guttenplan Responses (Question 43), p. 10.  Dr. Guttenplan opines that "[i]t appears that the 
bioavailability of estrogen is low but not insignificant (probably between 5 and 20%), if estrone is also taken 
into account." WT/DS320/R/Add.6 
Page F-110  
 
  estradiol 17 β than previously thought; and (2) miscast s as "paradoxical" a US argument relating to 
bioavailability. 
29. The materials cited by the EC in its Opinions  and by Dr. Guttenplan in his responses do not 
demonstrate a higher bioavailability for estradiol 17 β than previously thought.  In support of his 
statement that bioavailability is higher than previ ously thought, Dr. Guttenplan cites directly to the EC 
Rebuttal Submission and its statement that "[m] etabolic studies of orally administered 17 β-oestradiol 
indicate that as much as 20 percent of a 2 mg do se of micronized E2 is absorbed, with a serum 
half-life in the range of 2 to 16 hours (Zimmerm ann et al., 1998; Vree and Timmer, 1988; Ginsburg et 
al., 1998)."
63  However, upon review of these studies, it is clear that none of these references contains 
data that allow estimation of bioavailability.  Rath er all of the studies were conducted with an entirely 
different objective, the demonstration of bioequivalence.  As a result, they do not stand for the 
conclusion for which they have been cited by the EC and Dr. Guttenplan. 
30. Dr. Guttenplan indicates that a conclusion reached by the United States (that bioavailability of 
estradiol 17 β is low)64 based in part on a EC study evaluating the metabolism of estradiol 17 β is 
"paradoxical" to the results of the study because, according to Dr. Guttenplan, in the study "estradiol 
was converted to estrone, so it must have entered the cell."65  It is true that estradiol was converted to 
estrone in the study; however, the focus of the US  argument was the evaluation of whether or not 
estradiol 17 β, the alleged "bad actor" implicated by the EC as a genotoxic carcinogen was transported 
across the single-cell layer  (used to mimic the human intestinal wall in the study).  Whether or not 
estradiol 17 β entered the cells is irrelevant to the point made by the United States.  Rather than being 
transported across the single-cell layer, all of the estradiol 17 β that entered the cells was metabolized 
into estrone or other metabolites, which have been shown in studies cited by the EC to be benign in 
terms of genotoxic carcinogenicity.66 
31. Finally, the experts agree that the EC's Opin ions also fail to take into account available 
scientific evidence relating to DNA repair mechanis ms.  Dr. Boobis states that "the evidence is 
against direct modification of DNA in vivo by hormones in meat from treated animals, or by their 
metabolites produced in vivo," in part because "[t] he DNA repair processes for this are amongst the 
most efficient (Arai et al, 2006; Russo et al, 2004)  and even if such modification did occur, it is 
anticipated that no heritable change  would result, because of DNA repair."67  According to 
Dr. Boobis, "[t]his would be true even at levels  of exposure that could arise should GVP not be 
followed."68  Dr. Guttenplan notes, "[t]here is no reason to assume that DNA repair processes 
involved in DNA damage produced by estrogen metabo lites are any more or less effective than those 
involved in repair of other carcinogens ," and that "the scientific materi als referred to by the [EC] for 
the most part doesn't address DNA repair."69 
                                                      
63 See Dr. Guttenplan Responses (Question 43), p. 11. 
64 See US Rebuttal Submission, para. 41.  Note that the study's author confirms the US argument 
regarding bioavailability of estradiol 17 β, concluding that the study's result "indicates that 17 β-estradiol is not 
absorbed intact in the human intestinal tract."  Hoogenboom, Investigations on the metabolism of 17 β-estradiol 
by bovine hepatocytes, human intestinal and breast ce lls, and the genotoxic and estrogenic properties of the 
metabolites (unpublished), p. 5.  (Exhibit EC-6 (US)). 
65 Dr. Guttenplan Responses (Question 43), p. 11. 
66 Moreover, any estrone that is absorbed in the in testine will be rapidly transported to liver where it 
will undergo extensive first-pass metabolism, thus minimizing any potential effects that might occur from 
conversion of estrone back into estradiol. 
67 Dr. Boobis Responses (Question 22), p. 25. 
68 Dr. Boobis Responses (Question 22), p. 25. 
69 Dr. Guttenplan Responses (Question 22), p. 7.  Dr. Guttenplan states that "since it [DNA repair] is 
not likely to be different for estrogen derived damage than other types of damage it is not really relevant."  This 
statement requires clarification, as it would appear to the United States that DNA repair of estrogen-derived  WT/DS320/R/Add.6 
 Page F-111 
 
 
  (c) Conclusion 
32. The experts' responses regarding the necessary co mponents or elements of a risk assessment 
and their opinions as to whether or not the EC has sa tisfied each of those elements confirm that the 
EC has not conducted a risk assessment for estradiol 17 β, the one hormone for which it claims to have 
done so.70  Therefore, the EC has failed to base its  permanent ban on meat and meat products from 
cattle treated with estradiol 17 β on a risk assessment, as required by Article 5.1 and defined in Annex 
A, paragraph 4 of the SPS Agreement.   
2. Scientific evidence relating to estradiol 17 β 
33. The question of whether scien tific evidence cited in a ri sk assessment supports the 
conclusions reached in the assessment is releva nt to the obligation in Article 5.1 of the SPS 
Agreement that Members must base their measures on a risk assessment, as appropriate to the 
circumstances,71 as well as Article 5.2's requirement that ri sk assessments take into account available 
scientific evidence.  The experts' responses conf irm the following points regarding the scientific 
evidence relating to estradiol 17 β cited by the EC:  (1) the scien tific evidence does not support the 
conclusion that any carcinogenic effects of estradiol 17 β are related to a mechanism other than 
hormonal (endocrine) activity; (2) the scientific evidence does not support the conclusion that 
estradiol 17 β is genotoxic at levels found in residues in meat from cattle treated with growth 
promoting hormones; and (3) the scientific evidence does not demonstrate that estradiol 17 β will have 
carcinogenic or tumorigenic effects at concentrati ons found in residues in meat from cattle treated 
with hormones for growth promotion purposes.  
(a) The scientific evidence does not support the conclusion that any carcinogenic effects of 
estradiol 17 β are related to a mechanism other than hormonal activity 
34. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions 
does not support the conclusion that the carcinogenic effects of estradiol 17 β are related to a 
mechanism other than hormonal activity.  Dr. Boi sseau notes, "the scientific evidence relied upon in 
the SCVPH Opinions does not support the conclusion that the carcinogenic effects of oestradiol-17 β 
are related to a mechanism other than hormonal activity."72  Dr. Boobis concurs,  "[t]he carcinogenic 
effects of oestradiol appear to be a consequence of its endocrine activity."73  One expert, 
Dr. Guttenplan, restates the conclusions of both parti es, noting that while the EC has cited materials 
that "indicate that a mechanism other than horm onal activity is possible," the "United States and 
Canada cite other reports indicating that genotoxic effects of estrogens are unlikely."74  While this 
                                                                                                                                                                     
damage is extremely important to an analysis of whether or not that specific form of damage is occurring, and 
the resulting likelihood of said damage. 
70 Note that the experts' comments as to whether th e EC completed the fourth step of risk assessment 
(risk characterization) are contained in the discussion ab ove.  The short answer is that the EC did not complete 
this step.  Dr. Boobis :  "No adequate assessment of exposure following use according to GVP was undertaken.  
Hence, it was not possible to complete the risk characterization phase of the assessment."  Dr. Guttenplan :  
"[t]he risk characterization is very qualitative at best." (Dr. Boobis Responses (Question 13), p. 17; 
Dr. Guttenplan Responses (Question 14), p. 4). 
71 See Panel Report, Japan – Measures Affecting the Importation of Apples: Recourse to Article 21.5 of 
the DSU by the United States , WT/DS245/RW, adopted July 20, 2005, paras. 8.145-8.146 (finding that "[s]ince 
the scientific evidence relied upon  by Japan does not support the conclusions  reached by Japan in its 2004 PRA, 
we conclude that the 2004 PRA is not an a ssessment, as appropriate to the circumstances , of the risks to plant 
life or health, within the meaning of Article 5.1 of the SPS Agreement.") 
72 Dr. Boisseau Responses (Question 16), p. 12. 
73 Dr. Boobis Responses (Question 16), p. 19. 
74 Dr. Guttenplan Responses (Question 16), p. 4.  Rather than elaborating on how the EC's Opinions 
support the conclusion ( e.g., with scientific evidence) that the carcino genic effects of the hormones at issue are WT/DS320/R/Add.6 
Page F-112  
 
  statement likely requires further clarification, the United States notes that additional responses from 
Dr. Guttenplan appear to indicate that he is of the opinion that any carcinogenic effects of estradiol 
17β are indeed linked to hormonal activity or to leve ls greater than those found in residues in meat 
from cattle treated with hormones for growth pr omotion purposes.  For example, Dr. Guttenplan 
concludes that any carcinogenic effect from estradiol 17 β in meat from treated cattle "is unlikely if 
good veterinary practices are followed."
75 
(b) The scientific evidence does not support the conclusion that estradiol 17 β is genotoxic at 
levels found in residues in meat from cattle treated with growth promoting hormones 
35. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions 
does not support the conclusion that estradiol 17 β is genotoxic at levels found in residues in meat 
from cattle treated with growth promoting hormones.   As noted by Dr. Cogliano, "it has not been 
established by the EC that genotoxicity and cell pr oliferation would be induced by levels found in 
meat residues added to the pre-existi ng levels occurring in exposed humans."76  Dr. Boobis states, 
"whilst there are reliable studies demonstrating the genot oxicity of oestradiol in certain in vitro tests, 
the evidence is against any genotoxicity in vivo.  Some , if not all, of the genotoxicity observed in vitro 
would be expected to exhibit a threshold."77   
36. Regarding the specific studies relied upon by the EC in reaching its conclusion that estradiol 
17β is genotoxic, Dr. Boobis notes that the studies  "should have been evaluated on a weight of 
evidence basis.  Several of the studies suffered fro m significant limitations and there were a number 
of well conducted studies on a variety of endpoint s that should have been included in such an 
evaluation."78  Dr. Boobis provides numerous citations on th e issue of genotoxicity and estradiol that 
were not considered by the EC in its Opini ons, all of which have been published since 2000.79  
According to Dr. Boobis' analysis of the issue, none of the available evidence demonstrates that 
estradiol 17 β is genotoxic in vivo .80  The importance of this statement is underscored by the fact that 
the EC's own Committee for Medicinal Products for Veterinary Use ("CVMP") has a published 
guideline for evaluating the safety of residues of  veterinary drugs in human food "requiring 
confirmation of an in vitro positive using an appropriate in vivo assay."81  The EC has failed to 
explain why their evaluation of estradiol 17 β is not subject to this guideline. 
37. Dr. Boisseau notes that the EC provides "n o data indicating that oestradiol-17 β is associated 
with the increase of tumours in tissues or organs which are not hormone dependent," and that, "[i]n 
conclusion, the EC risk assessment did not  support that residues of oestradiol-17 β, despite the 
genotoxic potential of this hormone, can initiate and promote tumours in humans."82  This comment 
by Dr. Boisseau is further emphasized by Dr. Boobis, who states, "the important point here is that it is 
the carcinogenic effect that is of concern, not in vitro genotoxicity."83 
                                                                                                                                                                     
related to a mechanism other than hormonal activity, Dr. Guttenplan simply recites the Opinions' conclusion that 
this is so. 
75 Dr. Guttenplan Responses (Question 15), p. 4. 
76 Dr. Cogliano Responses (Question 18), p. 1. 
77 Dr. Boobis Responses (Question 18), p. 22. 
78 Dr. Boobis Responses, p. 20.  See generally  Dr. Boobis Responses (Que stion 62), pp. 49-58, in 
which Dr. Boobis provides specific critiques of several of the 17 Studies and other scientific materials cited by 
the EC. 
79 See Dr. Boobis Response (Question 16), pp. 19-20. 
80 See Dr. Boobis Response (Question 16), p. 19. 
81 Dr. Boobis Response (Question 16), p. 19. 
82 Dr. Boisseau Responses (Question 13), p. 11. 
83 Dr. Boobis Responses (Question 19), p. 22.  WT/DS320/R/Add.6 
 Page F-113 
 
 
  38. It is unclear from Dr. Guttenplan's responses whet her or not he is of the opinion that estradiol 
17β is genotoxic at levels found in residues in m eat from cattle treated with growth promoting 
hormones.  As such, his response appears to neither  bolster nor cast any doubt on the responses of the 
other experts who examined the issue of genotoxici ty.  On the one hand, Dr. Guttenplan recognizes a 
genotoxic mechanism, while on the other he notes a hormonal mechanism.84  At the same time, he 
disagrees with the blanket EC conclusion that "it can not be said that there exist[s] a safe level below 
which intakes from residue should be considered to  be safe."  As to this point, Dr. Guttenplan 
comments that the EC's conclusion is "not necessar ily true," and that "for any toxin, the dose 
determines the risk."85  Further, as noted above, Dr. Guttenplan has expressed the opinion that any 
carcinogenic effect from estradiol 17 β in meat from treated cattle "is unlikely if good veterinary 
practices are followed,"86 a conclusion from which one can infer that levels of estradiol 17 β residue in 
meat from treated cattle are safe for consumers. 
39. The fact that the scientific ev idence cited by the EC in its Opinions fails to support the 
conclusion that estradiol 17 β is genotoxic at levels found in residu es in meat from cattle treated with 
growth promoting hormones is critical to the EC 's corresponding conclusion that no threshold cannot 
be identified for the residues of the hormone and th at there is no "safe level below which intakes from 
residue should be cons idered to be safe."87  The experts' responses confirm that the EC has failed to 
adduce the necessary scientific eviden ce to support this conclusion.  As noted by Dr. Boisseau, "[t]he 
scientific evidence referred to by the European Co mmunities does not demonstrate that this statement 
can also apply in the case of oestradiol-17 β, ... as [this] [ ] natural hormone[ ] [is] produced by both 
humans and food producing animals.  Therefore, even in the absence of any consumption of food 
coming from animals treated by growth promoting hormones, humans are naturally and continuously 
exposed to these natural hormones."88  
40. Dr. Boobis agrees, stating, "[t]here is no good ev idence that oestradiol is genotoxic in vivo or 
that it causes cancer by a genotoxic mechanism.  I ndeed, the evidence is agai nst this.  Hence, the 
scientific evidence does not support the EC on this issu e, that the levels of the hormones in meat from 
treated cattle are not of relevance."89  Dr. Cogliano concurs, noting that the EC's statement regarding 
the lack of a threshold has not been demonstrated by the scientific evidence.90  Dr. Cogliano also 
opines that the US stance on thresholds has not be en supported by the scientific evidence, but this 
opinion does not appear to be relevant to the eval uation at hand, which is whether or not the EC, in 
banning the import of meat from cattle treated with estradiol 17 β for growth promotion purposes, 
adduces the necessary scientific evidence relating to, inter alia , genotoxic effects of the hormone, to 
serve as a basis for its ban.91 
41. The experts disagree with the EC's statemen t that JECFA's decision to set an ADI for 
estradiol 17 β was affected by its conclusion in its 52nd Report that estradiol 17 β has "genotoxic 
potential".  The EC alleges that this finding was critical to JECFA's proposing an ADI for estradiol 
                                                      
84 Dr. Guttenplan Responses (Question 19), p. 5. 
85 Dr. Guttenplan Responses (Question 19), p. 5. 
86 Dr. Guttenplan Responses (Question 15), p. 4. 
87 See Panel's Questions to the Experts, Question 19. 
88 Dr. Boisseau Responses (Question 19), p. 16. 
89 Dr. Boobis Responses (Question 19), p. 22. 
90 Dr. Cogliano Responses (Question 19), p. 2. 
91 As noted in paragraph 39 above, Dr. Guttenplan's response appears to neither endorse or deny the 
presence of a threshold.  His answer does appear to indicate, however, that it would have been possible for the EC to determine a safe level for estradiol 17 β, or to have examined the effects of low doses, rather than simply 
stopping its evaluation once it concluded estradiol 17 β is genotoxic.  ("The statemen t that, 'the fact that doses 
used in growth promotion are low is not of relevance' is not necessarily true.  For any toxin the dose determines the risk." "When exposure is very low risk will be ve ry low." Carcinogenic effects are "unlikely if good 
veterinary practices are followed.")  Dr. Guttenplan Responses (Questions 15 and 19), pp. 4-5. WT/DS320/R/Add.6 
Page F-114  
 
  17β for the first time in 1999 at its 52
nd Meeting.92  Dr. Boisseau notes, "JECFA's conclusions that 
oestradiol-17 β 'has genotoxic potential' did not affect its recommendation on this hormone."93  
Dr. Boobis agrees, highlighting the ra tionale behind JECFA's conclusion: 
I do not believe that JECFA's conclusion that oestradiol has "genotoxic potential" 
affected its recommendations on this horm one, which were based on the conclusion 
that there was a threshold for its carcinogeni c effects.  JECFA's conclusion regarding 
genotoxicity was based on positive results in certain in vitro tests, but the evidence 
was against a mutagenic response in vivo.94  
JECFA, in its responses, makes no mention of the finding that estradiol 17 β has "genotoxic potential" 
in its discussion of how its conclusions in 1999 (52nd Meeting) differed from those in 1987 (32nd 
Meeting).95  Instead, it notes that its decision to set an ADI for estradiol 17 β at its 52nd Meeting was 
based on consideration of:  
published data from studies on the oral bi oavailability, metabolism, short-term 
toxicity, reproductive toxicity, genotoxicity and long-term toxicity/carcinogenicity of 
exogenous estrogens.  Numerous reports on st udies of the use of exogenous estrogens 
in women were considered, as were studies in experimental animals on the mechanism of action of estradiol-17 β.  The extensive database derived from the 
results of epidemiological studies in women taking oral contraceptive preparations containing estrogens or postmenopausal estr ogen replacement therapy was also used 
to evaluate the safety of estradiol-17 β.
96 
Drs. Cogliano and Guttenplan offer comments on this issue, but neither appears to have addressed the 
issue (and Panel's question) of whether JECFA's conclusion regarding genot oxic potential affected 
JECFA's conclusion to set an ADI , as alleged by the EC.97 
                                                      
92 The EC avers that JECFA's finding that estradiol 17 β "has genotoxic potential" was essential 
"compared to its previous 1988 evaluation - ... to [JECFA ] propos[ing] the definition of an Acceptable Daily 
Intake (ADI) for oestradiol 17 β, which was not the situation before."  EC Answers to Panel Questions, para. 97. 
93 Dr. Boisseau Responses (Question 20), p. 16. 
94 Dr. Boobis Responses (Question 20), p. 23. 
95 JECFA Responses (Question 20), p. 16.  JECFA note s that its establishment of an ADI for estradiol 
17β (as well as the other two naturally-occurring hormones) was based on "[s]ufficient new data from 
observations in humans ... which were suitable to derive AD Is."  Rather than the basing its decision to establish 
an ADI on the finding of the genotoxic potential of estradiol, as argued by the EC, JECFA notes that "the 
establishment of an ADI implies that there is a thre shold of effect for [ ] a compound, below which no[ ] 
toxicological effects occur."  JECFA Responses (Question 20), p. 18. 
96 JECFA Responses (Question 20), p. 16.  See Dr. Boisseau Responses (Questions 33 and 34), p. 19; 
Dr. Boobis Responses (Question 33), p. 34; see also  US First Written Submission, para. 56. 
97 Dr. Cogliano notes that "the EC's conclusions seem to reflect a concern that endogenous hormone 
levels are variable," yet also concludes that "the variability of endogenously produced hormone levels is 
recognized by Codex."  Dr. Cogliano Responses (Question 20 ), p. 2.  It is unclear how this statement relates to 
JECFA's decision making at its 52nd Meeting, and whether or no t a finding that estradiol 17 β has "genotoxic 
potential" affected JECFA's ultimate conclusion to set an ADI for the hormone.  Dr. Guttenplan appears to have 
misconstrued the Panel's question, opining that JECF A's conclusion "had some effect on the European 
Communities' conclusions ."  Dr. Guttenplan Responses (Question 20), p.  5.  This statement is unexceptional, as 
the EC has consistently argued and attempted to demonstrate that estradiol 17 β is genotoxic at levels found in 
residues in meat from cattle treated with growth promo ting hormones.  Indeed, it has raised this limited JECFA 
finding several times in an attempt to support its own decision making.  See, e.g., EC Answers to Panel 
Questions, para. 97.  WT/DS320/R/Add.6 
 Page F-115 
 
 
  (c) The scientific evidence does not demonstrate that estradiol 17 β will have carcinogenic or 
tumorigenic effects at concentrations found in  meat from cattle treated with hormones for 
growth promotion purposes 
42. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions 
does not support the conclusion that estradiol 17 β is carcinogenic or tumorigenic at concentrations 
found in meat from cattle treated with hormones for growth promotion purposes.  As noted by 
Dr. Boisseau, "it is legitimate to conclude that  (1) the carcinogenic potential of oestradiol-17 β results 
from its hormonal activity, [and] (2) ... derive ... an ADI which represents the highest quantity of 
oestradiol-17 β causing in humans no hormonal effect and therefore no carcinogenic effect."98  
Therefore, Dr. Boisseau concludes that "oestradiol-17 β, even [though] it has been recognized as being 
able to generate tumours, is not likely to pr oduce adverse effects on human health when it is 
consumed in meat from cattle treated with  hormones for growth promotion purposes."99  Dr. Boobis 
comments that "an additional factor in the risk assessment of this compound is whether the levels 
from consumption of meat from treated animals impact s on the circulating levels of the hormone.  If 
not, then there should be no change in risk,"100 and even "occasional exposure above the ADI, such as 
might occur if GVP is not followed, would not be  associated with any incr ease in risk of cancer."101  
Dr. Guttenplan appears to agree, noting that while "an adverse effect cannot be ruled out, [ ] it is 
unlikely if good veterinary practices are followed."102 
43. Dr. Cogliano, while noting that the identification of estradiol 17 β as a human carcinogen 
"indicates that there are potential adverse effects on human health"103 when it is consumed in meat 
from treated cattle nevertheless also comments that "it has not been establi shed by the EC that 
genotoxicity and cell proliferation would be induced  by levels found in meat residues added to the 
pre-existing levels occurring in exposed humans,"104 a statement which appears to endorse the 
conclusion that the EC has failed to demonstrate th at carcinogenic or genotoxic effects will be caused 
by estradiol 17 β residues in meat from treated cattle. 
44. Lastly, since the metabolism of estradiol 17 β to catechol estrogens is a central element of the 
EC's claim that estradiol 17 β is carcinogenic via a genotoxic mechanism, the Panel asked the experts 
to comment on materials presented by the EC in suppor t of its theory.  Although the experts agree that 
the presence of these metabolites would be important  to consider in assessing the genotoxic potential 
of estradiol 17 β, they agree that the materials relied on by the EC failed to detect catechol residues in 
meat.  Dr. Boobis concludes, "[t]he analytical data  certainly show that levels of catechol metabolites 
in meat from treated animals were below the limits of detection of the method."105  Dr. Boisseau 
states, "it can be said that this study could not find evidence of metabolites coming from the catechol 
oestrogen biosynthesis."106  Finally, Dr. Cogliano concludes "that detectable levels of catechol 
metabolites were not formed from the parent compound."107  In the absence of scientific evidence for 
such residues in meat from cattle treated with estradiol 17 β for growth promotion purposes, it is 
impossible for the EC to conclude that catechol  estrogens derived from edible bovine tissues are 
genotoxic and thus have carcinogenic or tumorigenic effects. 
                                                      
98 Dr. Boisseau Responses (Question 15), p. 12. 
99 Dr. Boisseau Responses (Question 15), p. 12. 
100 The EC has presented no evidence, for any sector of the human population, that consumption of 
beef affects circulating (blood) levels of estradiol 17 β. 
101 Dr. Boobis Responses (Question 15), p. 18. 
102 Dr. Guttenplan Responses (Question 15), p. 4. 
103 Dr. Cogliano Responses (Question 15), p. 1. 
104 Dr. Cogliano Responses (Question 18), p. 1. 
105 Dr. Boobis Responses (Question 17), p. 21. 
106 Dr. Boisseau Responses (Question 17), p. 14. 
107 Dr. Cogliano Responses (Question 17), p. 1. WT/DS320/R/Add.6 
Page F-116  
 
  (d) Conclusion 
45. The experts' responses confirm that the scientif ic evidence cited by the EC in its Opinions 
does not support the conclusions on estradiol 17 β reached by the EC in those Opinions.  Therefore, 
the EC has not based its permanent ban on meat an d meat products from cattle treated with estradiol 
17β for growth promotion purposes on a risk assessment, as appropriate to the circumstances, within 
the meaning of Article 5.1 of the SPS Agreement.
108  Further, the experts' responses confirm that the 
EC's Opinions have failed to take into account ava ilable scientific evidence, as required by Article 5.2 
of the SPS Agreement.   
3. Scientific evidence relating to the five provisionally banned hormones 
46. The question of sufficiency of the scientific ev idence relating to the five provisionally banned 
hormones, and the question of what scientific c onclusions may be drawn from that evidence are 
essential to determinations of whether the scientif ic evidence relating to the hormones was indeed 
insufficient for the EC to conduct a risk assessment, and whether the EC's provisional bans have been 
adopted on the basis of available pertinent inform ation within the meaning of Article 5.7 of the SPS 
Agreement.   
47. The experts' responses confirm the following poi nts regarding the scientific evidence relating 
to the five provisionally banned hormones (progest erone; testosterone; trenbolone acetate; zeranol; 
and melengestrol acetate):  (1) the scientific evidence  and information relating to the five hormones is 
sufficient to conduct an assessment of  the risks to human health from consumption of meat from cattle 
treated with the five hormones for growth promotio n purposes; (2) the scientific evidence cited by the 
EC in its Opinions does not demonstrate that any of  the five hormones has genotoxic potential or is 
carcinogenic by a mechanism other than hormonal ac tivity; and (3) scientific materials produced and 
cited by the EC (including the "17 Studies") have not identified any gaps or insufficiencies in the 
scientific evidence such that more  study is necessary before the risk from consumption of meat from 
cattle treated with the five hormones for growth promotion purposes can be assessed. 
(a) The scientific evidence and information relating to  the five hormones is sufficient to conduct 
an assessment of the risks to human health fro m consumption of meat from cattle treated with 
the five hormones for growth promotion purposes  
48. The experts' responses confirm that the scientific  evidence and information relating to the five 
hormones is sufficient to conduct an assessment of the risks to human health from consumption of 
meat from cattle treated with the five hormones fo r growth promotion purposes.  Dr. Boobis states, 
"[i]n my view there was sufficient information av ailable to the EC to have enabled it to have 
conducted an assessment of the risks to human heal th arising from consumption of meat from cattle 
treated with any of the six hormones at issue."109  Dr. Guttenplan affirms that JECFA was able to 
conduct risk assessments for the five hormones, noti ng that there has been substantial analysis of 
progesterone, testosterone and MGA.  He does note th at "[t]here is more limited evidence available" 
for trenbolone and zeranol,110 but does not indicate whether this fact would prevent the EC from 
completing a risk assessment for th ese hormones.  In addition, as one of his reasons for opining that 
there is more limited evidence available for trenbol one, he notes that it "appears to be significantly 
                                                      
108 See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146. 
109 Dr. Boobis Responses (Question 61), p. 49. 
110 Dr. Guttenplan Responses (Question 61), p. 13.  WT/DS320/R/Add.6 
 Page F-117 
 
 
  estrogenic."  The United States has not been able to  locate any evidence supporting this conclusion, as 
trenbolone is an androge n (mimicking testosterone) and not an estrogen.111 
49. In relation to the sufficiency of the scientific evidence relating to MGA,  the Panel inquired as 
to whether "nearly all the studies referred to in the 2000 JECFA report on MGA date from the 1960s and 70s," and whether subsequent JECFA reports reli ed on these same studies.  The experts' responses 
indicate that this is indeed the case,
112 however, as noted by Dr. Boisseau, it is essential to take into 
account the fact that the dates of studies utilized in an  assessment is not as criti cal a factor as indicated 
by the EC:  "the quality and the number of the ava ilable data are more important than the dates at 
which these data have been produced."113  As is apparent from Dr. Guttenplan's evaluation of JECFA's 
assessment of MGA, the quality and quantity of eviden ce was more than adequate:  "[t]he assessment 
for melengestrol acetate seems sound.  Thorough meta bolic and estrogenic studies have been carried 
out."114  In addition, no new or intervening scientific evidence or studies have cast doubt on the earlier 
studies relied on by JECFA, further reaffirming that the dates of those studies and data are irrelevant 
to an evaluation of the safety of the hormone.115 
(b) Scientific materials cited by the EC in its Op inions do not demonstrate that any of the five 
hormones has genotoxic potential or is carcinogenic by a mechanism other than hormonal 
activity 
50. The experts' responses confirm that the scientific materials cited by the EC in its Opinions do 
not demonstrate or support the conclusion that any of the five hormones has genotoxic potential or is 
carcinogenic by a mechanism other than hormonal activ ity.  Dr. Boisseau notes for each of the five 
hormones that, "the scientific evidence relied upon in the SCVPH Opinions does not support the 
conclusion that the carcinogenic effects of [any of  the hormones] are related to a mechanism other 
than hormonal activity."116  Dr. Boobis agrees, commenting, "[t]here is no evidence that the hormones 
testosterone or progesterone have genotoxic potenti al [and] [t]here is no convincing evidence that 
trenbolone acetate, MGA and zeranol are genotoxic.  They were negative in a range of tests for 
genotoxicity."117  Therefore, "there is no evidence that any of the hormones are genotoxic in vivo at 
the levels found in meat from treated animals."118  Dr. Guttenplan's response confirms this conclusion:  
                                                      
111 Dr. Guttenplan Responses (Question 61), p. 13.  Dr. Guttenplan has failed to cite to any evidence 
supporting his conclusion on the availability of evidence for trenbolone and zeranol.  For example, it may be useful to know what evidence Dr. Guttenplan relies on in  concluding that trenbolone is "potentially significantly 
estrogenic."  Dr. Boisseau notes that he does not have the necessary data to answer the question of sufficiency of 
evidence, but comments that the continual request for more and more data must stop at some point lest the 
assessment process become "endless."  Dr. Boisseau Responses, p. 61. 
112 See, e.g., Responses to Questions from the Panel of Dr. Hubert De Brabander ("Dr. De Brabander 
Responses") (Question 35), p. 10; Dr. Boisseau Responses (Question 35), p. 20. 
113 Dr. Boisseau Responses (Question 34), p. 19. 
114 Dr. Guttenplan Responses (Question 61), p. 13.  As a point of clarification on MGA, Dr. Guttenplan 
indicates in his answer to Question 60 that MGA may be administered as either a feed additive or an implant 
("MGA is the only hormone which might be administered by both methods.")  This is incorrect – MGA is only 
administered as a feed additive. 
115 See Dr. Boobis Responses (Question 62), pp. 49-58 ("There is little information in the scientific 
studies initiated by the EC since 1997 that support the contention that they have identified important new gaps, 
insufficiencies and contradi ctions in the scientific information and knowledge on the hormones, and that 
additional studies are necessary before the risks to health  of consumption of meat fr om treated animals can be 
assessed.  Whilst additional information has been obtaine d on a number of aspects of the hormones in question, 
this was often not definitive, sometimes it was not rele vant, in some instances it confirmed or expanded on 
previous knowledge.  The evidence obtained did not indicate any additional concern regarding the risk from 
exposure to residues of the hormones in meat from cattle treated for growth promotion.") 
116 Dr. Boisseau Responses (Question 16), p. 16. 
117 Dr. Boobis Responses (Question 21), p. 24. 
118 Dr. Boobis Responses (Question 21), p. 24. WT/DS320/R/Add.6 
Page F-118  
 
  "[t]here is no conclusive evidence presented by the EC that the five hormones ... when consumed as 
residues in meat have genotoxic potential."
119 
(c) Scientific materials produced and cited by the EC (including the "17 Studies") have not 
identified any gaps or insufficiencies in the scientific evidence such that more study is 
necessary before the risk from consumption of  meat from cattle treated with the five 
hormones for growth promotion purposes can be assessed 
51. The experts' responses confirm that the scientific materials produced and cited by the EC 
(including the "17 Studies") have not identified any s ubstantial gaps or insufficiencies such that more 
study is necessary before the risk from consumpti on of meat from cattle treated with the five 
hormones for growth promotion purposes can be as sessed.  Dr. Boisseau notes, "[t]hese new [EC] 
data do not demonstrate any important gaps, insuffi ciencies and contradictions in the scientific 
information."120  Dr. Boobis agrees:  "[t]here is little info rmation in the scientific studies initiated by 
the EC since 1997 that support the contention that  they have identifie d important new gaps, 
insufficiencies and contradictions in the scientif ic information and knowledge on the hormones, and 
that additional studies are necessary before the risks to health of consumption of meat ... can be 
assessed."121  Further, "[t]he evidence obtained did not indicate any additional concern regarding the 
risk from exposure to residues of the hormones in  meat from cattle treated for growth promotion."122 
52. Dr. Guttenplan is the lone expert to identify purported "gaps" in th e scientific evidence or 
data.  However, the majority of these alleged gaps  in the data appear to relate to estradiol 17 β, the 
hormone for which the EC claims to have comp leted a risk assessment within the meaning of 
Article 5.1 of the SPS Agreement as a basis for its permanent ban on meat fr om cattle treated with 
estradiol 17 β for growth promotion purposes.123  Dr. Guttenplan's comments do not appear to 
specifically contemplate the hormones for which one  would expect such alleged gaps to exist, i.e., the 
provisionally banned hormones for which the EC cl aims insufficient scientific information to 
complete a risk assessment.124 
53. The EC has not alleged gaps in the informati on it has put forward in support of its permanent 
ban on meat and meat products from cattle treated with estradiol 17 β.  If a lack of evidence were its 
reason for banning imports of estradiol-treated meat , due to gaps or insufficiencies, the EC would 
presumably have included estradiol 17 β with the other provisionally-banned hormones.  Instead, the 
EC contends that the evidence and data are clear en ough and sufficient to c onclude that residues in 
meat from cattle treated with estradiol 17 β for growth promotion purposes pose a health risk to 
consumers.125  Regardless, purported data gaps in evidence relating to estradiol 17 β have no relevance 
to the sufficiency of evidence for the five other hor mones.  Further study can always be done with 
respect to any scientific issue, and Dr. Guttenplan 's response reflects the desire of responsible 
scientists to have as much information as possible.   At the same time, however, Dr. Guttenplan does 
                                                      
119 Dr. Guttenplan Responses (Question 21), p. 6. 
120 Dr. Boisseau Responses (Question 62), p. 28. 
121 Dr. Boobis Responses (Question 62), p. 58. 
122 Dr. Boobis Responses (Question 62), p. 58. 
123 See Dr. Guttenplan Responses (Question 62), p. 14 .  (Dr. Guttenplan identifies "gaps" in the 
following areas:  estrogen levels in children; identifi cation and quantification of lipoidal esters; and matched 
population studies comparing various populations of children). 
124 Further clarification would be necessary to determine whether Dr. Guttenplan was of the opinion 
that data "gaps" existed for any of the five provisionally-banned hormones. 
125 See, e.g., EC First Written Submission, para. 17 ("[The EC's ban] is based on a comprehensive risk 
assessment and, thus, is fully compliant with the DSB recommendations and rulings.  In particular, as stipulated by the Appellate Body,  the results of the risk assessment  'sufficiently warrant' the definite import prohibition 
regarding one of the hormones (Article 5.1 of the SPS Agreement).")  WT/DS320/R/Add.6 
 Page F-119 
 
 
  not say that any of these alleged gaps prev ented conducting a risk assessment for any of the 
hormones. 
(d) Conclusion 
54. The experts' responses confirm that the scientific  evidence or information relating to the five 
provisionally banned hormones is indeed sufficient (o r rather, not insufficient) for the EC to have 
completed a risk assessment for each of the hormones.   Further, the experts' responses confirm that 
the EC's provisional bans have not been adopted on the basis of available pertinent information within 
the meaning of Article 5.7 of the SPS Agreement beca use the available pertinent information indicates 
that consumption of residues of the hormones in  meat from cattle treated for growth promotion 
purposes is safe for consumers.  In short, the EC h as not implemented provisional bans for any of the 
five hormones that satisfy the cumulative cond itions of Article 5.7 of the SPS Agreement. 
4. Scientific evidence relating to the hormones generally 
55. An evaluation of the scientific evidence relating to the six hormones generally is essential to a 
determination of whether, on the one hand, the EC  has completed a risk assessment for estradiol 17 β 
within the meaning of Article 5.1 and whether that  assessment takes into acc ount available scientific 
evidence within the meaning of Article 5.2 of th e SPS Agreement, and on the other hand whether the 
EC has implemented a provisional ba n for the other five hormones within the meaning of Article 5.7 
of the SPS Agreement.126  Several of the Panel's questions ask the experts to opine on the state of the 
scientific evidence relating to the six hormones generally.   
56. The experts' responses confirm the following poi nts regarding the scientific evidence relating 
to the hormones generally:  (1) each of the hormones has been used for growth promotion purposes in 
cattle and evaluated for a sufficient period of time w ith no evidence of adverse effects to adequately 
address any concern regarding long latency periods of cancer; (2) epidemiological studies cited by the 
EC do not identify a link between cancer and residues of the hormones in meat; (3) the EC has failed 
to demonstrate that meat from cattle treated with hormones for growth promotion purposes poses a 
risk to sensitive populations; and (4) the EC has faile d to demonstrate "other risks" to human health 
from consumption of residues of the hormones in meat from cattle treated for growth promotion 
purposes, such as effects on the immune system. 
(a) Each of the hormones has been used for grow th promotion purposes in cattle and evaluated 
for a sufficient period of time with no evidence of adverse effects to adequately address any 
concern regarding long latency periods of cancer 
57. The experts' answers confirm that, while it is necessary to take into account the long latency 
period of cancer in evaluating the safety of the six hormones, each of the hor mones has been used for 
growth promotion purposes in cattle and evaluated for a sufficient period with no evidence of adverse 
effects to consumers to adequately address this concern.127  Dr. Boobis notes, "the latency period is an 
important consideration," but confirms that stud ies of animals and humans "cover[ ] a sufficiently 
long period to encompass the latency period fo r any carcinogenic effects of the hormones."128  
                                                      
126 Note that the majority of the essential questions regarding the state of the scientific evidence relating 
to the six hormones has already been addressed above in the discussions of estradiol 17 β and the five 
provisionally banned hormones. 
127 Dr. Cogliano notes the importance of consid ering latency periods, and cites IARC materials 
indicating that a period of at least twenty years should be taken into acco unt.  Dr. Cogliano Responses (Question 
23), p. 2.  The three naturally-occurring hormones at issue in this dispute have been consumed as residues in 
meat for millenia without evidence of adverse effects on human health.  All of the hormones have been consumed as residues in meat from cattle treated for growth promotion purposes for longer than twenty years. 
128 Dr. Boobis Responses (Question 23), p. 26. WT/DS320/R/Add.6 
Page F-120  
 
  Further, "[t]he long term studies of the hormones unde rtaken in experimental animals and in humans, 
involved much higher doses than would be encounter ed on consumption of meat from animals treated 
with growth promoting hormones."
129  
58. Dr. Boobis notes the difficulty in distinguishing results among effects from hormone residues 
in food, naturally-occurring hormones and other factor s, but agrees that "the hormones in dispute have 
already been used as growth promoters over a suffici ent number of years, the epidemiological studies 
in humans already carried out in this domain have failed to identify any relation between the 
occurrence of hormonally dependent tumours and th e consumption of meat containing hormonally 
active residues resulting from the treatmen t of cattle with growth promoters."130  Dr. Guttenplan 
concurs that hormones have been consumed in m eat for a "sufficient number of years to observe 
strong or moderate increases in risk."131  Yet, as described in detail in the discussion of 
epidemiological studies and recent materials cited by  the EC below, there is no evidence of such 
increases. 
(b) Epidemiological studies cited by the EC do not  identify a link between hormone residues in 
meat and cancer 
59. The experts' responses confirm that the epidemiological studies cited by the EC in its 
Opinions fail to identify a link between  hormone residues in meat and cancer.132  Dr. Guttenplan 
concludes, "[t]he epidemiological studies do not identify a relationship between cancer and residues 
of hormonal growth promoters."133  As noted by Dr. Boobis, "[t]here is no scientific evidence 
demonstrating any association between consumpti on of meat from animals treated with growth 
promoting hormones and the risk of cancer in humans."134  Indeed, the correlation lies not between 
hormone residues and cancer, but instead the asso ciation with cancer "is strongest with meat 
consumption and show[s] little rela tionship with whether the meat is from animals treated with 
growth promoting hormones or not."135   
60. Dr. Boisseau cites back to an earlier response in which he comments, "the epidemiological 
studies in humans already carried out in this doma in have failed to identif y any relation between the 
occurrence of hormonally dependent tumours and th e consumption of meat containing hormonally 
active residues from the treatment of cattle with growth promoters."136  Dr. Cogliano agrees, stating 
that "[t]he difference between the US and the EC in  rates of breast cancer and prostate cancer almost 
certainly has multiple causes," and that while it is "p ossible that differences in exposure to exogenous 
                                                      
129 Dr. Boobis Responses (Question 23), p. 26. 
130 Dr. Boisseau Responses (Question 23), p. 17. 
131 Dr. Guttenplan Responses (Question 23), p. 7. 
132 Confounding factors play a role in the evaluation of epidemiological data.  The experts are split as 
to whether these factors can be identified and thei r effects attributed to a particular source.  See Dr. Boisseau 
Responses (Question 24), p. 17.  However, there is agreem ent that such factors exist,  and that they should be 
taken into account in the interpretation of  data used in a risk assessment.  See Dr. Boobis Responses (Question 
24), p. 27; Dr. Cogliano Responses (Question 24), p. 2; Dr. Guttenplan Responses (Question 24), p. 9 ("These are important considerations for risk assessment of adverse affects caused by residues of growth promoting 
hormones in meat, as the effects of the hormones (if any) are likely to be small and might be obscured by 
confounders.")  None of the experts express the opinion that the EC's Opinions took confounding factors into 
account in the assessment of th e safety of the hormones. 
133 Dr. Guttenplan Responses (Question 26), p. 9.  Dr. Guttenplan also notes that "[t]he references to 
the higher rates of breast cancer and prostate cancer observed in the United States as compared to the [EC] are 
not very convincing," and that "the differences in rates of breast cancer and prostate cancer ... are relatively 
small."  Dr. Guttenplan Responses (Question 24), p. 9. 
134 Dr. Boobis Responses (Question 26), p. 32. 
135 Dr. Boobis Responses (Question 26), p. 32. 
136 Dr. Boisseau Responses (Question 26), p. 17, citing  earlier responses on pp. 16-17.  WT/DS320/R/Add.6 
 Page F-121 
 
 
  hormones can be one cause, [ ] the data are not su fficiently specific to establish a link between these 
observations."137  
61. The experts' comments on epidemiological st udies are linked to another of the Panel's 
questions, namely whether three studies recently cite d by the EC demonstrate a risk to human health 
from the consumption of meat from cattle treated with hormones for growth promotion purposes.  The 
experts agree that the three studies demonstrate no su ch risk.  Dr. Boobis concludes that none of the 
studies confirm a risk to human health from the consumption of meat from cattle treated with 
hormones for growth promotion purposes.138  Dr. Guttenplan agrees, noting that in the first study "the 
results were obtained in cultured cells and the rele vance to human exposure to hormone-treated [meat] 
cannot be extrapolated from this study because of a myriad of uncertainties in such extrapolation."139  
Regarding the second and third studies, Dr. Guttenpl an simply comments that "the other two studies 
do not confirm a risk from hormone-treated meat."140  He also notes that, "[t]he [EC] statement that 
one of the studies was carried out after the introd uction of the ban on the use of hormones for growth 
promotion in Europe, negates any relevance to the possible connection of hormone-treated meat 
consumption and cancer."141   
62. Dr. Boisseau cites back to earlier responses, r estating his conclusion that "the scientific 
evidence relied upon in the SCVPH Opinions does not support the conclusion that the carcinogenic 
effects of zeranol are related to a mechanism other than hormonal activity,"142 as evidence of his 
opinion that the first EC study provided no such evidence.  Regarding the second study, Dr. Boisseau 
restates his conclusion that epidemiological studi es in humans have failed to identify a relationship 
between tumors and the consumption of meat from treated cattle, thereby indicating his opinion that 
this new study demonstrates no such link.143  Finally, Dr. Boisseau notes that despite the EC's concern 
regarding the alleged risk of cancer from meat  from cattle treated with hormones for growth 
promotion purposes, the EC has not "provide[d] any scientific evidence supporting this concern."144 
63. The final expert, Dr. Cogliano, appears to suppor t the conclusions of the other experts, noting 
that "[t]he study by Norat et al (2005) indicates a risk to human health from the consumption of 
meat."145  As noted above, this conclusion is unexceptional, as it is not evidence of a risk from 
residues in meat from cattle treated with any of the six hormones for growth promotion purposes, but 
rather relates to meat consumption generally.146  For example, as described in paragraph 59 above, 
Dr. Boobis agrees that the correlation between cons umption of meat and any cancer risk lies not 
between hormone residues and cancer, but instead "i s strongest with meat consumption and show 
little relationship with whether the meat is from an imals treated with growth promoting hormones or 
not."147  As for the remaining two studies, Dr. Cogliano  concludes that the studies merely "suggest a 
risk to human health," and clarifies his response by  noting that the word "suggest" is used instead of 
"indicates" because "the exposure levels in th ese studies are higher than those found in meat 
residues."148 
                                                      
137 Dr. Cogliano Responses (Question 26), p. 2. 
138 See Dr. Boobis Responses (Question 25), pp. 29-31. 
139 Dr. Guttenplan Responses (Question 25), p. 9. 
140 Dr. Guttenplan Responses (Question 25), p. 9. 
141 Dr. Guttenplan Responses (Question 25), p. 9. 
142 Dr. Boisseau Responses (Question 25), p. 17. 
143 See Dr. Boisseau Responses (Question 25), p. 17.  Dr . Boisseau notes that the third study is out of 
his scope of expertise. 
144 Dr. Boisseau Responses (Question 25), p. 17. 
145 Dr. Cogliano Responses (Question 25), p. 2. 
146 See Dr. Boobis Responses (Question 26), p. 32. 
147 Dr. Boobis Responses (Question 26), p. 32. 
148 Dr. Cogliano Responses (Question 25), p. 2. WT/DS320/R/Add.6 
Page F-122  
 
  (c) The EC has failed to demonstrate that meat from cattle treated with hormones for growth 
promotion purposes poses a risk to sensitive populations 
64. The experts' responses indicate that the EC h as failed to demonstrate that meat from cattle 
treated with hormones for growth promotion purpo ses poses a risk to sensitive populations because:  
(1) the assay relied upon by the EC to demonstrate lower circulating estradiol 17 β levels in children 
has not been validated; (2) the EC has not demonstrated that exposure to estradiol 17 β residues in 
meat from cattle treated with hormones for growth  promotion purposes presents a potential risk to 
prepubertal children or other sensitive populations; a nd (3) the materials cited by the EC do not place 
into doubt Codex conclusions on the safety of the hormones. 
(i) The assay relied upon by the EC to dem onstrate lower circulating estradiol 17 β levels in 
children has not been validated 
65. The experts' responses confirm that it is critical that assays be validated before they are used 
as the basis for conclusions in a risk assessment.
149  Yet, no evidence has been presented 
demonstrating that the assay for estradiol 17 β relied on by the EC, the Klein assay,150 has been 
properly validated since it was first used in 1994.  As noted by Dr. Boobis, the original Klein assay 
(1994) "reported very low levels of  oestradiol in male children ..., bu t in a later study (Klein et al, 
1998), the same group reported mean levels somewhat higher, at 0.27 pg/ml.  The reliability of the 
Klein et al assay has yet to be determined."151  Dr. Boobis comments, "[t]he assay is particularly 
sensitive to oestradiol, but there is no obvious explan ation for this, as it relies on the affinity for the 
oestrogen receptor."152  When compared to other results fro m yeast-based assays, it is clear that 
"results with the yeast reporter assay are not consistent, and use of such data in risk assessment 
requires that the assay be adequately validated."153 
66. An important step in assay validation is confir mation of the results reported by the original 
author(s) by scientists in another, independent labor atory.  Dr. Sippell notes that the "validity of the 
[Klein assay] has now been confirmed by another [assay] of E2 [estradiol 17 β] which was developed 
by Charles Sultan's group at the University of Montpe llier, France (Paris et al 2002).  Unfortunately, 
the complexity of the [assay] so far prevents its wider use for routine measurements in small serum 
samples from infants and prepubertal children."154  However, the Klein assay and Paris assay cited by 
Dr. Sippell differ in significant ways, and it cannot be stated that the latter independently confirms the 
results of, or validates the former.  For example,  the two assays employ different media – the Klein 
                                                      
149 See Dr. Boisseau Responses (Question 38), p. 21 ("It would be important to know wether these new 
bioassays have been properly validated as this SCVPH Opinion says nothing about that and whether the data obtained with these methods for both men and women are also totally different from those obtained with the 
RIA methods.") 
150 The EC's own CVMP concludes the following regarding the Klein assay:  "It was noted that the 
report by Klein et al. (1994) indicated much lower plasma levels of oestradiol when measured with a new 
method, based on  -galactosidase gene expression in genetically modified yeast, compared to the classical RIA 
requirements (Klein et al., 1994).  However, (i) the m easure was made only in plasma and needs to be carried 
out in other tissue(s) to enable to comparison between the intake of residual oestradiol and the endogenous 
levels, [and] (ii) the methodology needs validation and is not (yet) generally accepted."  CVMP (1999), Report 
of the CVMP on the Safety Evaluation of Steroidal Sex Hormones in particular for 17 β-Oestradiol, 
Progesterone, Altrenogest, Flugestone acetate and Norgestomet in the Light of New Data/Information made 
available by the European Commission (EMEA/CVMP/885/99) ("1999 CVMP Report").  (Exhibit US-5).  See 
1999 EC Opinion, § 2.2.2.1 ("Physiological levels of steroids in serum during childhood and puberty"), p. 11; Table 1, p. 28.  (Exhibit US-4). 
151 Dr. Boobis Responses (Question 40), p. 37. 
152 Dr. Boobis Responses (Question 40), p. 37. 
153 Dr. Boobis Responses (Question 40), p. 37. 
154 Responses of Dr. Wolfgang Sippell ("Sippell Responses") (Question 40), p. 2.  WT/DS320/R/Add.6 
 Page F-123 
 
 
  assay utilizes yeast cells and the Paris assay mammalian  cells (a human cancer cell line (HeLa cells)).  
In addition, the Paris assay reflects circulating levels of estradiol 17 β at least an order of magnitude 
greater than those identified in the 1994 Klein assay.155  In order to conclude that the work of Paris 
validated the assay relied on by the EC in its Opinions , there would have to be congruity in the results 
of the assays.  Therefore, the EC has based conclusi ons in its Opinions on hormone levels in sensitive 
populations on an assay that has not been properly validated. 
(ii) The experts' responses confirm that the EC has fa iled to demonstrate that meat from cattle 
treated with hormones for growth promotion purposes poses a risk to sensitive populations 
67. The experts' responses do not support the c onclusion that exposure to estradiol 17 β residues in 
meat from cattle treated with hormones for growth promotion purposes presents a risk to prepubertal 
children or sensitive populations.  Indeed, one of the experts notes that the EC has failed to assess this 
risk entirely.156  Another notes that the materials put forward by the EC require no changes in the 
JECFA and Codex standards relating to the growth promoting hormones.157  One of the experts, 
Dr. Sippell, disagrees; however, in so doing, Dr. Sippell's responses propose several conclusions regarding sensitive populations that are both unrespon sive to the Panel's questions and unsupported by 
the scientific material cited in his answer s.  Relying on the (unvalidated) Klein assay,
158 Dr. Sippell's 
responses postulate that circulating levels of estradiol 17 β in children are "100 times lower" than 
previously thought, and that the "resulting potential E2 [estradiol 17 β] exposure risk from 
consumption of meat and meat products has grea tly increased by a factor of at least 160 times."159  
Dr. Sippell draws the following additional c onclusions regarding sensitive populations: 
[i]t has been shown in numerous scientific publications in vitro, in vivo and in the 
human that infants and prepubertal child ren are highly sensitive to increased E2-
levels, resulting in premature breast deve lopment (Schmidt et al 2002), growth 
acceleration (Lampit et al 2002), earlier sexual maturation in girls, in particular in the USA (Sun et al 2002, Wu et al, 2002) and less in Europe (Muinck-Keizer & Mul 2001), and the well known significantly highe r incidence of precocious puberty in 
girls than in boys (Teilmann et al 2005).  Accidental exposure of prepubertal boys to 
estrogen has resulted in gynecomastia and advanced bone maturation.
160 
The materials cited by Dr. Sippell do not appear to  be responsive to the Panel's question, which 
sought comment on the EC statement that "any  excess exposure" to estradiol 17 β resulting from the 
consumption of meat  presents a potential risk to public health in particular sensitive populations such 
as prepubertal children.  None of the citations made  by Dr. Sippell address this specific question, nor 
do the studies cited by Dr. Sippell present any ev idence that the low levels of estradiol 17 β residues in 
beef (from either treated or untreated cattle) would be sufficient to affect the health or development of 
prepubertal children.  Further, Dr . Sippell's responses appear to pr opose a different result than his own 
research, in which he has concl uded "[a]lthough there is concern that  oestrogen consumption through 
food might have adverse effects on pubertal development and human health, there are no published 
data to support the notion that an increased overall exposure to environmental oestrogens has led to an 
increased incidence in precocious puberty or to an earlier start of pubertal development ."161 
 
                                                      
155 See Dr. Boobis Responses (Question 40), p. 39. 
156 See Dr. Boisseau Responses (Question 39), pp. 21-22. 
157 See Dr. Boobis Responses (Question 42), p. 39. 
158 See Dr. Boobis Responses (Question 40), p. 37 ("use of such data in risk assessment requires that 
the assay be adequately validated.") 
159 Dr. Sippell Responses (Question 39), p. 1. 
160 Dr. Sippell Responses (Question 39), p. 1. 
161 Partsch and Sippell,  Pathogenesis and epidemiology of precocious puberty. Effects of exogenous 
oestrogens .  Hum Reprod Update 2001; 7: 292-302.  (Emphasis added). WT/DS320/R/Add.6 
Page F-124  
 
  68. The Schmidt
 study cited by Dr. Sippell as evidence of premature breast development 
concludes that the stimulation of the mammary gland by estradiol 17 β in infancy may represent a 
window that is of biological significance for breast development in adulthood.  However, the Schmidt 
study is not relevant to the analysis at hand nor  germane to the Panel's question, as the authors 
characterize their findings as physiologic, i.e., normal.  The study does not describe any pathologic 
findings (as implied by Dr. Sippell's use of the phrase "premature breast development") and it was 
simply not designed to examine the relationship betw een breast tissue in infants and dietary estradiol 
17β (i.e., the form of estrogen of relevance to the consumption of meat). 
69. Dr. Sippell also cites a study by Lampit  et al. to support his theory that estradiol 17 β residues 
in meat from cattle treated for growth promo tion purposes will cause "growth acceleration".  The 
Lampit study examined girls with central precocious puberty, and demonstrated that a "mini-dose" of 
estradiol 17 β maintained normal pubertal growth in the girl s.  However, the results of the study cannot 
be extrapolated to the conclusion that estradiol 17 β residues in meat will cause growth acceleration in 
sensitive populations.  For instance, any results obtai ned in patients with endocrine disorders such as 
central precocious puberty must be extrapolated with great caution because the function of their 
reproductive axis is fundamentally different from normal children, and it is possible that their 
sensitivity to estradiol 17 β is altered compared to normal child ren.  More importantly, the Lampit 
study fails to quantify the amount of estradiol 17 β (either endogenous or e xogenous) that would be 
required to accelerate growth in normal children a nd similarly fails to demonstrate a risk of 
accelerated growth due to dietary consumption of estradiol 17 β. 
70. The Sun  paper involved a large-scale study of sexual development in white, black and 
Mexican-American children in the United States.  The study, which presents national reference data, 
concluded that non-hispanic black girls and boys ha d earlier ages for sexual matu rity compared to the 
other two groups.  The paper is limited to statis tics on children in the United States and makes no 
effort to compare these data to t hose for European children.  It is therefore unclear how Dr. Sippell 
reaches his conclusion that this phenomenon occurs "in particular in the USA and less in Europe."162  
In any event, the study does not examine or measure estradiol 17 β at all, and therefore cannot be used 
as evidence in support of Dr. Sippell's conclusion that exposure to estradiol 17 β results in "earlier 
sexual maturation in girls, in particular in the USA."163  The Wu  paper uses the same data set as the 
Sun paper, concluding that black and Mexican-A merican girls reach puberty at younger ages than 
white girls.  As is the case with the Sun pape r, Wu simply does not support the conclusions 
extrapolated from it by Dr. Sippell.  Further, there is  absolutely no evidence in either the Sun paper or 
the Wu paper to suggest that the observed differen ces in age of puberty may be attributable to the 
presence of estradiol 17 β residues in meat. 
71. The de Muinck Keizer-Schrama and Mul  review article (2001) concludes that the age of 
puberty in Europe decreased over the last century, bu t that in recent decades th is decrease has slowed.  
No scientific evidence is provided to definitively id entify the basis for these changes, but the authors 
cite socioeconomic conditions and better health car e and prevention as the "most important factors."  
Possible dietary influences on age of puberty in Europe, including animal protein, saturated fat, dairy products and phytoestrogens are also discussed.  Th e de Muinck Keizer-Schrama review fails to 
present any evidence indicating that estradiol 17 β residues in meat have had any influence on the age 
of puberty in either Europe or the United States. 
72. The Teilmann
 article concludes that the prevalence of precocious puberty164 in Denmark was 
very low (< 1 in 10,000); that it was higher in girl s than in boys; and that the rate was constant 
                                                      
162 Dr. Sippell Responses (Question 39), p. 1. 
163 Dr. Sippell Responses (Question 39), p. 1. 
164 In this study, precocious puberty was defined as onset of puberty before nine years of age in girls 
and ten years of age in boys.  WT/DS320/R/Add.6 
 Page F-125 
 
 
  between 1993 and 2001.  However, the Teilmann study does not provide any evidence supporting 
Dr. Sippell's conclusion that high sensitivity to increased estradiol 17 β levels results in higher 
incidences of precocious puberty in girls than in boys.  The cause of preco cious puberty is not only 
unknown, it was not even examined by the authors of the Teilmann paper. 
73. Finally, the Felner and White  paper examined three prepubertal  boys with gynecomastia, each 
of whom was exposed to an estrogen cream used by  his mother.  All three boys had elevated blood 
levels of estradiol 17 β, which returned to normal once their mothers stopped using the cream.  The 
authors concluded:  "[i]ndirect exposure to excessive amounts  of topical estrogen may cause 
gynecomastia, rapid changes in growth, and advanced bone age in prepubertal children."165  It is not 
possible to extrapolate data involving exposure to "excessive amounts" of estrogen cream to 
conclusions regarding estradiol 17 β residues in meat from cattle treated for growth promotion 
purposes.  Further, exposure to estradiol 17 β in the Felner and White paper was transdermal, a method 
of administration that bypasses the extensive first pass metabolism of estradiol 17 β and thus results in 
much higher levels of exposure than those that follow oral administration of estradiol 17 β (the 
applicable route for consumption of estradiol 17 β residues in meat).   
74. Dr. Sippell also concludes, "[t]here is now in creasing epidemiological evidence that exposure 
to elevated estrogen levels during early life (pre- and postnatally) carries an increased risk of breast 
cancer in adult life, whereas conditions with low E2  levels, such as preeclampsia seem to have a 
protective effect."166  Dr. Sippell cites to eight papers in supp ort of this statement, yet none of the 
papers appears to demonstrate that the conclusion is correct or responsive to the Panel's question.  For 
instance, four of the papers (Ekbom  (1997); Swerdlow  (1997); Weiss  (1997); and Innes and Byers  
(1999)) are all human epidemiological studies that pur port to document a higher risk of breast cancer 
in adult twins (who may have been exposed to higher levels of estradiol 17 β in utero compared to 
singletons) and a lower risk of breast cancer in women whose mothers had preeclampsia (which may be associated with lower estradiol 17 β levels compared to normal pregnancies).  However, the 
findings of each of these studies are based entirely on correlation/assumption, without any 
mechanistic evidence.  The fifth paper, by Halkavi-Clarke
 et al., is a rat study showing that in utero 
exposure to tamoxifen167 increases susceptibility to breast can cer (induced by treatment with the 
carcinogen DMBA).  The results of this study are di fficult to interpret, in that tamoxifen has mixed 
estrogen agonist/antagonist activ ity; confounded because tamoxifen caused abnormal reproductive 
development; and not relevant to a discussi on of the potential effects of estradiol 17 β from the 
consumption of meat and meat products (and therefore not respon sive to the Panel's question). 
75. In addition, Dr. Sippell concludes from the rema ining three papers that "indirect evidence 
suggests that male reproductive disorders such as testicular cancer, cryptorchidism, hypospadias and 
poor sperm quality may also have their origin in  hormonal disturbances induced by E2 and/or 
estrogenic substances during fetal life (Skakkebaek et  al 2001) and also during childhood (Higuchi et 
al 2003, Ramaswamy 2005)."168  Again, Dr. Sippell's conclusion, pr emised on "indirect evidence" that 
"may" demonstrate an effect, is not supported by the cited evidence nor responsive to the Panel's 
question.   
76. For instance, the Skakkebaek  paper speculates that "[testic ular dysgenesis syndrome] is a 
result of disruption of embryonal programming and g onadal development during fetal life."  However, 
support for this claim is limited to animal studies involving in utero exposure to synthetic compounds 
such as DES and ethinyl estradiol, but not estradiol 17 β or any of the other hormones used for growth 
                                                      
165 Felner and White, Prepubertal gynecomastia: indir ect exposure to estrogen cream .  Pediatrics 105 
(2000), E55.  (Emphasis added). 
166 Dr. Sippell Responses (Question 39), pp. 1-2. 
167 Tamoxifen is a drug which has been used in humans to treat breast cancer. 
168 Dr. Sippell Responses (Question 39), p. 2. WT/DS320/R/Add.6 
Page F-126  
 
  promotion purposes in cattle.
169  There is ample evidence in animal  studies that, at levels of exposure 
greater than the levels found in meat residues fro m treated cattle, in utero exposure to estrogen can 
affect the development of the male fetus.  However,  it must be emphasized that this is only the case 
when exposure levels are orders of magnitude greater than those relevant to an  analysis of residues in 
meat from cattle treated with hormones for growth promotion purposes.170  Further, evidence for 
latent or delayed effects on adult reproductive f unction caused by exposure to hormones is limited at 
best and confounded by numerous other factors.  Dr. Sippell appears to acknowledge this by noting 
that the evidence is (at best) "indirect." 
77. The Higuchi  paper reports that the reproductive functi on of adult male rabbits was impaired 
following in utero exposure to dibutyl phtalate (DBP), a plasticizer and well known reproductive 
toxicant.  The authors assume that these effects were due to a direct toxic effect on the testis, not the 
alteration of the endocrine milieu as suggested by Dr. Sippell's response.  Moreover, and perhaps of 
greater significance to the analysis at hand, th e study focuses on the effects of a compound (DBP) 
unrelated to the hormones at issue (such as estradiol 17 β or zeranol).  DBP's estrogenic potency 
appears to be very low relative to estradiol 17 β,171 and it has been shown to have anti-androgenic 
effects which may be more adverse than its estrogenicity.172  Therefore, it seems highly likely that the 
mechanism of toxicity of DBP does not involve "hor monal disturbances", contrary to the conclusion 
reached by Dr. Sippell. 
78. The final paper by Ramaswamy  has very limited applicability to possible risks associated 
with the consumption of residues in meat from ca ttle treated with hormones for growth promotion 
purposes, and therefore limited applicability to the Panel's question.  The Ramaswamy study involved 
subcutaneous administration of estradiol 17 β (not oral as is the case with consumed residues, thereby 
bypassing extensive first pass metabolism in th e intestine and liver); doses of estradiol 17 β that were 
much higher than those that could be derived from consumption of beef; and ~40-fold elevations in 
blood estradiol 17 β that were sustained for 5-20 weeks, a situation that is not comparable to the 
intermittent, low-level exposure to estradiol 17 β which might occur due to consumption of meat. 
79. Finally, in response to the Panel's inquiry of how risks for individuals arising from "hormones 
naturally present in meat differ from risks arising from the residues of hormone growth promoters," Dr. Sippell concludes that "[s]ynthetic hormone grow th promoters such as Zeranol and its metabolites 
have been shown to be as potent as E2 and [DES ] in increasing the expression of estrogen-related 
genes in human breast cancer cells (Leffers et al 2001).  On the other hand, the synthetic androgen Trenbolone and gestagen Melengestrol bind with high affinity to the human androgen and 
progesterone receptors, respectively (Bauer et al 2000)."
173  No scientific evidence is cited by 
Dr. Sippell to support his conclusion that "[e] xposure during pregnancy might result in sever 
                                                      
169 The fact that synthetic estrogens were used in th ese studies is an important  distinction because the 
bioavailability of these estrogens is much hi gher than the bioavailability of estradiol 17 β. 
170 Here, Dr. Sippell is making an unsubstantiated ex trapolation to suggest that adverse effects caused 
by very high levels of estradiol 17 β in animal studies may also occur in humans. 
171 Milligan SR et al., Relative potency of xenobiotic estrogens in an acute in vivo mammalian assay .  
Environ Health Perspect 106: 23-26 (1998). 
172 Leffers et al., Hum Reproduction (2001); 16: 1037-1045 (one of the "17 Studies").  Also, a yeast-
based assay has shown that DBP's estrogenic potency is 1,000,000-fold lower than estradiol 17 β, and that there 
is no estrogenic ability in DBP in an in vivo assay using ovariectomized mice.  See Ohtani H et al ., 
Environmental Health Perspectives (2000); 108; 1189-1193. 
173 Dr. Sippell Responses (Question 41), p. 3.  In addition, Dr. Sippell notes that "[the increased 
percentage of estradiol 17 β consumed in meat from treated as opposed to untreated cattle], and thus the potential 
health risk, will be considerably higher if the food in take from pork, poultry, eggs and dairy products derived 
from E2 -treated farm animals are take n into account."  However, estradiol 17 β is not used for growth promotion 
purposes in poultry or pork.  See Dr. Sippell Responses (Question 41), p. 3.  WT/DS320/R/Add.6 
 Page F-127 
 
 
  transplacental virilisation of a female fetus."174  Dr. Sippell's response appears to misconstrue the 
Panel's question, in that it discusses the hypotheti cal effects of synthetic hormones rather than 
discussing the differences in naturally-present hormone levels as compared to residue levels resulting 
from the use of hormones as growth promoters. 
80. Dr. Sippell appears to be of the opinion that the potential risk from synthetic hormones may 
differ from hormones naturally present in meat be cause the synthetics are more potent than their 
natural counterparts.  For instance, he cites to a paper by Leffers  (one of the EC's "17 Studies") in 
support of the statement that zeranol, estradiol 17 β and DES are equipotent.  However, as is the case 
with most of the in vitro studies cited by the EC, th e physiological relevance of the Leffers findings is 
questionable because:  (1) the assay utilized a breast cancer cell line (MCF-7) which may not 
accurately reflect the sensitivity of normal breast tissue to estrogens ( e.g., estrogen receptor 
populations may differ between MCF-7 and normal br east cells); and (2) there are numerous reports 
in the literature demonstrating that DES is more potent than estradiol 17 β, yet inexplicably, they 
register as equipotent in the Leffers paper.  Furt hermore, the Leffers paper simply does not provide 
evidence pertinent to the question at hand, i.e., whether zeranol residues in  beef present a risk to 
sensitive populations that is different from the risk s arising from hormones naturally present in beef.  
81. The Bauer  study is also one of the "17 Studies" co mmissioned by the EC.  In the Bauer study, 
the primary metabolite of trenbolone acetate found in bovine muscle (17 β-TBOH) bound to the 
human androgen receptor with high affinity.  While this finding raises the specter that residues of trenbolone acetate in meat may be androgenic in humans, Dr. Sippell does not provide any scientific 
evidence demonstrating that this is the case.  On the contrary, the evidence presented thus far 
indicates that an androgenic effect of such residu es is highly unlikely due to their extremely low 
levels in meat and poor bioava ilability.  In addition, Bauer et al. measured the binding of MGA and 
MGA metabolites to the bovine
 progesterone receptor, not the human receptor .  Therefore, 
Dr. Sippell's statement that MGA binds with high a ffinity to the human progesterone receptor is 
unsupported by the citation to the Bauer study. 
82. In summary, none of the papers cited by Dr. Sippell support the conclusion that exposure to 
estradiol 17 β in meat from cattle treated with hormones for growth promotion purposes presents a 
potential risk to prepubertal children or sensitive populations.  In particular, none of the studies 
present evidence that the extremely low amounts of estradiol 17 β in meat are sufficient to affect the 
health or development of prepubertal children. 
(iii) The materials cited by the EC do not place into doubt Codex conclusions on the safety of the 
hormones 
83. The experts' responses confirm that the materi als cited by the EC do not place into doubt 
Codex conclusions on the safety of the six hormones.  Dr. Boobis opines that, even if circulating estradiol 17 β levels in prepubertal children are lower than previously contemplated,
175 the JECFA 
ADI for estradiol 17 β would still "appear to be appropriate  for all groups of the population,"176 
including prepubertal children.  Dr. Boobis notes that several intervening steps and factors must be 
considered in an assessment of any risk to this population:  "this exposure is via the oral route, and 
bioavailability by this route is very low (<5%) (F ortherby 1996).  In addition, very little of the 
                                                      
174 Dr. Sippell Responses (Question 41), p. 3. 
175 The experts appear to agree that re sults obtained using the estradiol 17 β assay reported by Paris et 
al. (2002) are worthy of further consideration.  However, this assay also requires further validation.  The Paris 
assay was not used to estimate estradiol 17 β levels in the EC's Opinions; rather the EC used data from the 
unvalidated Klein assay, wh ich estimated estradiol 17 β in prepubertal children at levels at least an order of 
magnitude less than the levels of the Paris assay.  See 1999 EC Opinion, § 2.2.2.1, p. 11; Table 1, p. 28. 
176 Dr. Boobis Responses (Question 40), p. 39. WT/DS320/R/Add.6 
Page F-128  
 
  absorbed hormone will be free, over 95% being bo und to plasma proteins such as SHBG.  Such 
binding reduces the biological activity of th e hormone (Teeguarden and Barton, 2004)."
177  Therefore, 
even if an assay indicates that circulating estradiol 17 β levels are lower, reliance on this fact alone 
does not suffice to assess any potential risk.  
84. Further, as has been discussed in detail in the experts' responses, JECFA has taken into 
account additional safety factors in order to adequate ly compensate for the lower circulating levels of 
hormones in sensitive populations such as prepubert al children.  As noted by Dr. Boobis, JECFA 
employs a 10-fold safety factor to protect sensitiv e populations and another 10-fold adjustment for 
inter-individual variation.178  In other words, "[i]n keeping with  its risk assessment principles, the ADI 
established by JECFA would have been designed to protect all segments of the population, including 
prepubertal children."179  Therefore the ADI for estradiol 17 β has a 100-fold safety factor built in.  
Dr. Boisseau concurs that JECFA took into account sensitive populations in its risk assessments, and 
notes, "[f]rom a qualitative point of view, the risks for these individuals arising from residues resulting from the use of hormones as growth promoter s in cattle does not differ from the risks arising 
from the residues of hormones naturally present in meat.  The potential problem which may exist is 
only a quantitative one."
180 
85. According to Dr. Boisseau, this information was not taken into account by the EC in its 
purported risk assessment.  He comments, "[t]his excess exposure of these sensitive populations needs 
to be assessed and compared with the exposure resu lting from the daily consumption of meat from 
cattle which have not been treated by growth pr omoters, from other food and products of animal 
origin and from their own production of hormones."181  Dr. Boobis concludes, "there is no 
requirement for any revision in the Codex recommendation with respect to oestradiol-17 β on the basis 
of the material referred to by the EC."182 
(d) The scientific evidence cited by the EC fails to demonstrate adverse effects on the immune 
system or "other risks" to human health fro m the consumption of meat from cattle treated 
with the growth promoting hormones at issue 
86. The experts' responses confirm that the scien tific evidence cited by the EC fails to 
demonstrate adverse effects on the immune system or "other risks" to human health from the consumption of meat from cattle treated with the growth promoting hormones at issue.  Dr. Boobis 
states, "[t]he evidence on immune effects of hormones such as oestradiol referred to by the EC does 
not identify any adverse effects on the immune system from consumption of meat from treated cattle.  In general, clear evidence for immune effects were observed only at high doses."
183  He notes that  
                                                      
177 Dr. Boobis Responses (Question 40), p. 39. 
178 Dr. Boobis Responses (Question 42), p. 39.  Dr. Boisseau confirms that JECFA "has considered 
appropriate to establish a NOAEL on the basis of the changes in several hormone dependent parameters in post menopausal women and to derive from this NOAEL an ADI using two safety factors of 10
, one to account for 
normal variation among individuals and a second one to protect the sensitive human populations."  Dr. Boisseau 
Responses (Question 13), p. 9.  Note that the EC's CVMP, in determining the estradiol 17 β is safe for use for 
zootechnical and therapeutic purposes in cattle "based its risk assessment on the relation between any possible 
excess of hormones from zootechnically treated animals in the diet and the endogenous daily production of 
oestradiol in prepubertal boys ."  1999 CVMP Report, p. 12.  (Exhibit US-5).  Dr. Sippell disagrees that JECFA 
has adequately taken into account sensitive populations, but it is unclear from his response if he is familiar with 
JECFA's safety factors or whether/why he finds thes e factors to be inadequate.  Dr. Sippell Responses 
(Question 42), p. 3. 
179 Dr. Boobis Responses (Question 42), p. 39. 
180 Dr. Boisseau Responses (Question 41), p. 22. 
181 Dr. Boisseau Responses (Question 39), pp. 21-22. 
182 Dr. Boobis Responses (Question 42), p. 39. 
183 Dr. Boobis Responses (Question 59), p. 48.  WT/DS320/R/Add.6 
 Page F-129 
 
 
  "[g]iven the large margin of exposure on anticip ated intake from residues in meat from treated 
animals, no effect on the immune system is antic ipated, as immune modulation is dependent on dose 
and there are thresholds for such effects."184  Dr. Guttenplan notes that, while there is evidence that 
estrogens generally can be related to certain disord ers, "[n]o definitive studies have related intake of 
meat from hormone-treated animals to the above disorders."185  Finally, Dr. Boisseau comments that, 
while the evidence cited by the EC would perm it it to identify potential adverse effects ( i.e., hazard 
identification), the EC has performed no assessment of  potential effects relating to the consumption of 
residues in meat from treated cattle, and it is therefore "not possible to  conclude that this scientific 
evidence allows to identify any adverse effect s on the immune system associated with the 
consumption of meat from cattle treated with the growth promoters at issue."186 
(e) Conclusion 
87. The experts' responses confirm that the scientific evidence relating to the six hormones 
generally demonstrates that the hormones have been  studied for sufficient time to take into account 
latency periods for cancer; that epidemiological st udies do not demonstrate a link between residues of 
hormones in meat and cancer; that the EC has failed to  demonstrate that meat from cattle treated with 
hormones for growth promotion purposes poses a risk  to sensitive populations; and that the EC has 
failed to demonstrate "other risks" from consumpti on of residues of the hormones in meat from cattle 
treated for growth promotion purposes, such as effect s on the immune system.  Therefore, the experts' 
responses demonstrate that the EC has failed to base its permanent ban on meat treated with estradiol 
17β on a risk assessment within the meaning of Arti cle 5.1 of the SPS Agreement and that the EC's 
Opinions have failed to take into account ava ilable scientific evidence within the meaning of 
Article 5.2 of the SPS Agreement.  Further, th e experts' responses demonstrate that the EC's 
provisional bans have not been adopted on the basi s of available pertinent information within the 
meaning of Article 5.7 of the SPS Agreement. 
5. Scientific evidence relating to residues 
88. The scientific evidence relating to  residues in meat from cattle treated with any of the six 
hormones for growth promotion purposes is relevant to the obligation in Article 5.1 of the SPS 
Agreement that Members must base their measures on a risk assessment, as appropriate to the circumstances, as we ll as Article 5.2's requirement that risk  assessments take into account available 
scientific evidence.  The scientific evidence relating to hormone residues is also relevant to Article 5.7 
of the SPS Agreement and an analysis of whethe r the EC's provisional ban is based on available 
pertinent information. 
89. The experts' responses support the following c onclusions regarding the scientific evidence 
relating to residues of the six hormones:  (1) the EC has failed to put forward evidence demonstrating 
that residues of any of the six hormones in meat from cattle are greater than previously thought, or to 
assess the risk to consumers from exposure to residues of any of the hormones from cattle treated with 
the hormones for growth promotion purposes; and (2 ) JECFA's recent re-evaluation of the three 
naturally occurring hormones reached the same s ubstantive conclusions as earlier evaluations.  
                                                     
 
184 Dr. Boobis Responses (Question 59), p. 48. 
185 Dr. Guttenplan Responses (Question 59), p. 13. 
186 Dr. Boisseau Responses (Question 59), p. 27. WT/DS320/R/Add.6 
Page F-130  
 
  (a) The EC has failed to put forward evidence dem onstrating that residues of any of the six 
hormones in meat from cattle are greater than pr eviously thought, or to assess the risk to 
consumers from exposure to r esidues of any of the hormones from cattle treated with the 
hormones for growth promotion purposes 
90. The experts' responses indicate that the EC h as failed to put forward evidence demonstrating 
that residues of any of the six hormones in meat from cattle are greater than previously thought or to 
assess the risk to consumers from exposure to residues of any of the hormones from cattle treated with 
the hormones for growth promotion purposes.  Dr. Boisseau, citing to the EC's 1999 Opinion and its 
determination that no threshold exists for any of the hormones, notes that as a consequence of this 
conclusion the EC did not "conduct a quantitative asse ssment of the exposure of consumers to the 
residues of hormonal growth promoters including the determination of the levels of residues in food 
from treated animals."
187  In the absence of this evaluation, th e EC was therefore unable to make any 
meaningful "comparison between these le vels and the MRLs set up by Codex."188  Dr. Boobis agrees 
that the EC failed to evaluate or assess actual residue levels in meat: 
In their 2002 Opinion, the Committee [ i.e., the EC's SCVPH] did not revisit exposure 
following use according to GVP.  Rather , the Committee considered potential 
exposure following several inappropriate use scenarios .  This was based on a series of 
experimental studies, to determine the consequences of a number of defined misuses on hormone levels in meat.  However, whilst of potential value in any risk 
assessment, these data are limited in the absence of any information on the frequency of occurrence of such misuse in the u se of the products in question in normal 
veterinary practice.
189  
Dr. Boobis provides a detailed critique of these "ina ppropriate use" studies, in which he concludes 
that, even in most of the extreme misuse scenario s developed by the EC, safe levels of hormone 
residues are not exceeded.190 
91. Although Dr. De Brabander raises several hypoth etical concerns regarding hormone residues 
in meat, his comments do not appear to be responsiv e to the Panel's inquiry as to whether the EC in 
fact evaluated evidence of residue levels in meat from cattle treated with any of the six hormones for 
growth promotion purposes in its Opinions nor do his responses cite to any such scientific evidence.  
Further, the concerns raised by Dr. De Brabander do not appear to be relevant to a discussion of the 
subject matter at hand, i.e., residues in meat from cattle treated with any of the six hormones for 
growth promotion purposes.  For instance, Dr . De Brabander opines that the earlier studies on 
residues are "old", they are "too much focused on th e direct effect on human health", and the MRLs 
for the hormones "are high in relation to modern analytical limits (normally ≤ 1 µg/kg)" and "not 
acceptable."191   
92. However, as noted by Dr. Boisseau, older data is  neither irrelevant or "bad" data simply due 
to its age.  Rather, it is the quality a nd quantity of data that is important,192 and for the hormones at 
issue, a great deal of high quality data exists.193  Further, the MRL for a veterinary drug is the 
                                                      
187 Dr. Boisseau Responses (Question 29), p. 18. 
188 Dr. Boisseau Responses (Question 29), p. 18. 
189 Dr. Boobis Responses (Question 30), p. 33. 
190 Dr. Boobis Responses (Question 62), pp. 50-52.  See Section C(6) below for a detailed discussion of 
the misuse studies. 
191 Dr. De Brabander Responses (Question 29), p. 3. 
192 See Dr. Boisseau Responses (Question 34), p. 19 ("th e quality and the number of the available data 
are more important than the dates at which these data have been produced.") 
193 As explained in JECFA's Responses (at pp. 7-9), JECFA has specific and extensive requirements for 
the residue data that are used to derive MRLs.  These re quirements include informati on on the analytical method  WT/DS320/R/Add.6 
 Page F-131 
 
 
  maximum concentration of residue that is legally  permitted or recognized as acceptable, based on the 
toxicological hazard for human health (expressed as the ADI).194  Therefore, the statement by Dr. De 
Brabander that the MRLs for the hormones "are hi gh in relation to modern analytical limits" is 
unexceptional; in fact, by definition the MRL for a drug residue should be higher than the analytical limit of detection.
195   
93. It appears that Dr. De Brabander is equating th e goals for detection of illegal anabolic drugs 
in humans (doping) with detection of residues of veterinary drugs in food animals  For the purpose of detecting illegal drugs (where the a llowable concentration of the drug in  question is zero), it is critical 
for the analytical method to accurately measure conc entrations as close to zero as possible.  For most 
veterinary drugs in food animals, the purpose of  residue methods is not to detect any non-zero 
concentrations of the residue, but to determine if the residues exceed the fin ite concentrations that 
have been determined to be safe – in general, these levels do not approach  zero and do not require 
ultra-sensitive methods as Dr. De Brabander sugg ests.  Dr. Boisseau confirms this point:  
Nevertheless, it has to be reminded that, when MRLs have been established for a 
given substance, there is not any more a need for highly sensitive analytical methods 
but for a validated analytical method the sens itivity of which must be consistent with 
the values of the established MRLs.  In a ddition, if it is true that ultrasensitive 
analytical methods remain useful to cont rol the use of forbidden veterinary drugs, 
such as for example growth promoters in EU, they are less useful in the case of the 
three natural hormones, which are endogenously produced by food producing animals.
196 
As for actual hormone residue levels in meat, Dr . De Brabander does not present any evidence that 
hormone residue levels have been shown to be high er than previously thought, but rather speculates 
that "[t]he concentrations ma y seriously be underestimated."197 
 94. As to the earlier studies' focus on human health , analysis of the potential effect on human 
health is the logical endpoint for an evaluation of hormone residues that are to be consumed by 
humans.  Dr. De Brabander indicates that these studies should instead have examined hormone 
excretions in cattle feces and urine.
198  Here, Dr. De Brabander is alluding to the possible 
environmental impact of the use of growth promot ing hormones in cattle.  This analysis is not 
germane to the question of whether meat and me at products from cattle treated with any of the 
hormones are safe for import and consumption; any of the hypothetical effects raised by Dr. De 
Brabander would presumably occur in the United States  (where the cattle are actually located), rather 
than in export markets (where  the cattle are not located). 
                                                                                                                                                                     
used to measure each residue and the performance fact ors of the method.  Importantly, when comparing the 
1988 and 1999 evaluations of residue studies for the hormones JECFA states, "[m]ost of the studies were the 
same.  However, a few additional investigative studies were also reviewed.  JECF A also performed a more 
detailed thorough review of the validity of the analytical methods used in the studies and only used data generated using valid methods."  Therefore, Dr. De Braban der's statement that "from an  analytical point of view 
these MRLs are unacceptable" is unfounded. 
194 Codex Responses (Question 9), p. 7. 
195 Note that the residue data used in the derivation of the MRLs in question were generated using valid 
analytical methods that were reviewed in detail by JECFA. 
196 Dr. Boisseau Responses (Question 32), p. 18. 
197 Dr. De Brabander Responses (Question 29), p. 3. 
198 Dr. De Brabander Responses (Questions 29 and 30), pp. 3-4.  ( E.g., "[a]s demonstrated in several 
studies a major part of th e hormones used are excreted through ur ine and faeces and the administration of 
natural hormones to a herd increases the concentration of  these hormones in the environment."  Note that the 
"environment" implicated in this statement would be th e United States, where the he rd resides; not the EC.) WT/DS320/R/Add.6 
Page F-132  
 
  95. Dr. De Brabander also provides anecdotal inform ation relating to a testosterone sex spray as 
well as use of a substance called "Z MA" (a substance allegedly used by athletes) in his response.  
However, none of this information is responsive to  the Panel's question, nor does it provide evidence 
relating to hormone residue levels in meat from cattle  treated with any of the six hormones for growth 
promotion purposes.  For instance, the discussion of  the androstenone (boar pheromone) spray neither 
provides any information regarding dose levels, nor is it relevant to the pathway at issue in the 
consumption of hormone residues in meat ( i.e., oral).  ZMA is not one of the hormones at issue in this 
dispute, and the anecdotal discussion of its use by athletes does not appear to be relevant to a 
discussion of residues in meat from cattle treated w ith any of the six hormones for growth promotion 
purposes.   
96. Dr. De Brabander concludes that, because humans  already consume foods like meat and milk 
that contain estrogens which "don't give problems at a normal food consumption" that "just therefore 
there is no need to add more by artificial ways."
199  Yet, Dr. De Brabander provides no scientific 
discussion as to how the small additional amounts of  any of the hormones found in meat from cattle 
treated for growth promotion purposes might pose any increased risk to consumers.  Rather, his 
comment appears to be a personal opinion or policy st atement rather than a scientific conclusion.  
Humans have consumed hormone residues in food for millenia without any evidence of an adverse 
health risk from those residues.  Similarly, humans have consumed residues in meat from cattle 
treated with the six hormones for growth promo tion purposes for decades without any evidence of a 
human health risk from these "additional" residues.200 
(b) JECFA's recent re-evaluation of the three na turally occurring hormones reached the same 
substantive conclusions as earlier evaluations 
97. The experts' responses confirm that JECFA's recent re-evaluation of the three naturally-
occurring hormones reached the same conclusion as earlier evaluations, i.e., that residues of the 
hormones in meat from cattle treated for growth promotion purposes are safe for consumers.  The EC argues that JECFA's establishment of ADIs for the three natural hormones at its 52
nd Meeting in 1999 
marked a shift in its thinking regarding the safety of  the hormones when used as growth promoters in 
meat.201  The experts indicate that it did not.  Dr. Bo isseau notes "[i]f the wording of the conclusions 
adopted by JECFA has been formally different , the substance of these conclusions remains 
unchanged," and that "[e]stablishing such ADIs had no specific implications as no MRLs have been 
established."202  Further, "[t]hese new recommendations  have not been considered by CCRVDF 
                                                      
199 Dr. De Brabander Responses (Question 31), p. 5. 
200 See, e.g., discussion of the experts on epidemiological studies relating to the use of hormones for 
growth promotion purposes in meat and the lack of a link  to evidence of cancer at  Section C(4)(b) above. 
201 The EC stresses in its answers to questions from the Panel after the first substantive meeting that:  
"However, as already explained the above-mentioned JECFA reports found that oestradiol 17 β 'has genotoxic 
potential' and that the evidence for progesterone was interpreted 'on balance' as not having genotoxic potential.  
On the basis of these findings, JECFA did consid er for the first time that ADIs were necessary  to be fixed but 
not MRLs, because of the endogenous production of thes e natural hormones and the difficulties in applying the 
available detection methods in order to determine the origin of any residues in meat."  EC Answers to Panel 
Questions, para. 129.  See also  EC Answers to Panel Questions, para. 97 (noting that JECFA's conclusion that 
estradiol 17 β has "genotoxic potential" "led now, again for the first time, to propose the definition of an 
Acceptable Daily Intake (ADI) for oestradiol 17 β, which was not the situation before.")  The United States has 
addressed the argument that JECFA' s determination that estradiol 17 β has "genotoxic potential" in any way 
affected its decision making on that hormones.  The experts have confirmed that it did not.  See Section C(2)(b) 
above. 
202 Dr. Boisseau Responses (Question 33), p. 19.  WT/DS320/R/Add.6 
 Page F-133 
 
 
  because CCRVDF did not request JECFA to reasse ss these hormones and because the new proposals 
of JECFA did not change the substance of the previous ones."203  
98. Dr. Boobis comments that the re-evaluation of  the hormones took into account "a number of 
additional studies on the toxicology and human (inc luding epidemiological) evaluation of therapeutic 
exposures to the hormones (e.g. in the form of oral  contraception or for hormone replacement therapy) 
that were not available in 1988."204  These human therapeutic studies indicated that exposure to the 
hormones could have adverse effect s on humans "albeit at levels appreciabl[y] higher tha[n] found in 
meat from treated cattle."205  Establishment of an ADI would serve as a "benchmark for comparison 
with exposure via the diet."206  Against that benchmark, a decision was made not to recommend an 
MRL due to the large margin of safety, and "CCRVDF endorsed the recommendation that MRLs for 
the natural hormones did not need to be specified."207 
99. Dr. De Brabander is the lone expert to disagree with these conclusions, noting that JECFA's 
conclusion to set an ADI "is a recognition of the danger of hormones to human health and welfare in all of his [ sic] aspects."
208  Dr. De Brabander does not provide any support for this statement, and does 
not clarify whether the "danger to human health .. . in all of [its] aspects" includes levels of the 
hormones found in residues in meat from cattle treated for growth promotion purposes.  The 
responses of JECFA, Codex and the other two experts indicate that the decision to set an ADI is not evidence of such a danger.
209  Rather, the setting of an ADI permitted an evaluation of residue levels 
of the three hormones that could be ingested without any danger or risk to consumers.210 
(c) Conclusion 
100. The experts' responses indicate that the EC has failed to put forward any scientific evidence 
demonstrating that residues of any of the six hormon es in meat are greater than previously thought, or 
                                                      
203 Dr. Boisseau Responses (Question 33), p. 19.  Codex confirms Dr. Boisseau's opinion.  See Codex 
Responses (Question 18), p. 9. 
204 Dr. Boobis Responses (Question 33), p. 35. 
205 Dr. Boobis Responses (Question 33), p. 35. 
206 Dr. Boobis Responses (Question 33), p. 35. 
207 Dr. Boobis Responses (Question 33), p. 35.  Indeed, on the basis of its detailed analysis, JECFA was 
able to conclude that MRLs were not necessary for th e three natural hormones because  residues in meat from 
cattle treated with the hormones for growth promotion purpos es were equal to or less than 3% of the ADI in the 
case of estradiol 17 β, and much less than 1% of the ADI in th e case of progesterone and testosterone.  See 52nd 
JECFA Report (2000), § 3.5, pp. 57-74.  (Exhibit US-5). 
208 Dr. De Brabander Responses (Question 33), p.  8.  The lack of agreement between Dr. De 
Brabander's response to the question of why JECFA set ADIs in 1999 and JECFA's ju stification for establishing 
these ADIs may indicate that Dr. De Brabander is not famili ar with the international pr ocedures used to evaluate 
the safety of residues of veterinary drugs in food animals. 
209 See Codex Responses (Question 18), p. 9 ("In the case of estradiol-17 beta, progesterone and 
testosterone, they were re-evaluated by the 52nd JECFA (1999) at the initiative of the JECFA Secretariat.  The 
12th CCRVDF (2000), in recognising that it had not requeste d the re-evaluation of the three substances and that 
the new MRLs recommended by the 52nd JECFA did not differ significantly from the current MRLs , decided to 
not consider the new recommendation of the 52nd JECFA.") (Emphasis added); JECFA Responses (Question 
20), p. 18 ("Sufficient new data from observations in  humans were available to the 52nd JECFA which were 
suitable to derive ADIs.  The ADI not only provides an estimate of daily intakes which can be accepted over life 
time without appreciable health risks,  it also enables a quantitative comparis on of the excess intakes calculated 
on the basis of the above mentioned worst case scenar io (see point 4 above).  The Committee found that the 
excess intake was in the order of only 0.02 to 4% of the ADI depending on the substance and the product used 
for the treatment of the animals.  Mo reover, the establishment of an ADI implies that there is a threshold of 
effect for such a compound, below wh ich now toxicological effects occur .") (Emphasis added). 
210 Indeed, Codex does not take action, or base public health standards, on ADIs, but rather only does 
so based on recommendations of MRLs.   WT/DS320/R/Add.6 
Page F-134  
 
  assessed the risk related to the exposure of consum ers to residues of any of the hormones in meat 
from cattle treated with the hormones for growth promotion purposes.  These responses also confirm 
that JECFA's decision to set an ADI for the natura l hormones did not mark a change in JECFA's or 
Codex's opinion as to the safety of the hormones wh en consumed as residues in meat from cattle 
treated for growth promotion purposes.  Therefore, the EC has failed to base its permanent ban on 
estradiol 17 β on a risk assessment within the meaning of  Article 5.1 of the SPS Agreement and failed 
to take into account available sci entific evidence within the mean ing of Article 5.2 of the SPS 
Agreement.  Further, the EC has failed to base its  provisional ban on availa ble pertinent information 
within the meaning of Article 5.7 of the SPS Agreement. 
6. Scientific evidence relating to good veterinary practices 
101. The scientific evidence relating to good veterina ry practices is relevant to the obligation in 
Article 5.1 of the SPS Agreement that Members mu st base their measures on a risk assessment, as 
appropriate to the circumstances, as well as Article 5.2's requirement that risk assessments take into 
account relevant processes and production methods, and relevant inspection, sampling and testing 
methods.
211  Further, an analysis of good veterinary pr actices is relevant to Article 5.7 of the SPS 
Agreement and an analysis of whether the EC's provisional ban is based on available pertinent 
information.  The issue of conditions of use is, however, perhaps best understood in the context of 
Article 5.6 of the SPS Agreement, which provides that  a Member must ensure that its sanitary and 
phytosanitary measures are not more trade-restrictive than required to achieve its appropriate level of 
sanitary or phytosanitary protection.  The fact that the EC has raised the issue of misuse212 and 
devoted considerable resources to demonstrating th e potential consequences of misuse implies that it 
                                                      
211 For purposes of evaluation of SPS measures unde r the SPS Agreement, the Appellate Body stated, 
"[w]e must stress ... that Article 5 and Annex A of the SPS Agreement speak of 'risk assessment' only and that 
the term 'risk management' is not to be found either  in Article 5 or in any other provision of the SPS 
Agreement ."  Further, the Appellate Body concluded that misuse and the analysis of the potential for failure of 
controls are topics that are included in a "risk assessment" for purposes of the SPS Agreement:  
 It should be recalled that Article 5.2 states that in the assessment of risks, Members shall take into 
account, in addition to "available scientific evidence", "relevant processes an d production methods; 
[and] relevant inspection, sampling and testing methods".  We note also that Article 8 requires Members to "observe the provisions of Annex C in the operation of control, inspection and approval 
procedures ...".  The footnote in Annex C states that "control, inspection and approval procedures 
include, inter alia, procedures for sampling, testing an d certification".  We consider that this language 
is amply sufficient to auth orize the taking into account of risks aris ing from failure to comply with the 
requirements of good veterinary practice in the administration of hormones for growth promotion 
purposes, as well as risks arising from difficulties of control, inspection and enforcement of the 
requirements of good veterinary practice . 
...  We disagree with the Panel's suggestion that exclusion of risks resulting from the combination of 
potential abuse and difficulties of control is justif ied by distinguishing betw een "risk assessment" and 
"risk management".  As earlier noted, the concept of "risk management" is not mentioned in any provision of the SPS Agreement and, as such, cannot be used to sustain a more restrictive interpretation 
of "risk assessment" than is justified by the actual terms of Article 5.2, Article 8 and Annex C of the 
SPS Agreement.  The question that arises, therefore, is whether the European Communities did, in fact, 
submit a risk assessment demonstrating and evaluating the existence and level of risk arising in the 
present case from abusive use of hormones and the difficulties of control of the administration of 
hormones for growth promotion purposes, within the United States and Canada as exporting countries, and at the frontiers of the European Communities as an importing country. 
 
EC – Measures Concerning Meat and Meat Products (Hormones) , Appellate Body Report adopted on 
13 February 1998, WT/DS26/AB/R ("Hormones" or "EC - Hormones"), paras. 181; 205-207. 
212 See, e.g., EC Answers to Questions from the Panel, para. 91.  WT/DS320/R/Add.6 
 Page F-135 
 
 
  already recognizes that there are conditions under whic h residues of the six hormones used for growth 
promotion are safe.  The only health question then would be whether there are particular conditions of 
use under which there would be a health risk.  If so, then the question b ecomes whether the EC's 
sanitary measures are more trade-restrictive than  required to achieve th e appropriate level of 
protection from that risk within the meaning of Article 5.6 of the SPS Agreement.   
102. The responses from the experts indicate that:  (1) the EC has failed to demonstrate that there 
is a risk to human health from the misuse of grow th promoting hormones in the United States; and (2) 
the material put forward by the EC regarding misu se or abuse of the hormones at issue fails to call 
into question Codex standards regarding the safet y of meat from cattle treated with hormones for 
growth promotion purposes. 
(a) The EC has failed to demonstrate that there is  a risk to human health from the misuse of 
growth promoting hormones in the United States 
103. While there is some disagreement among the expe rts as to the extent to which the EC has 
assessed a risk to human health from the misuse of growth promoting hormones in the United States, 
a close examination of the experts' responses indicat es that the EC has not demonstrated that such a 
risk exists.  Dr. Boisseau notes that "as the [EC] did not conduct any quantitative risk assessment for 
growth promoters, it is not possible to say that the scientific evidence referred to by the [EC] assesses 
the risk to human health from residu es resulting from these misuses/abuses."213  Dr. Boobis agrees, 
stating:  "[t]here was no attempt to evaluate the ri sks from the resultant expos ures on misuse or abuse, 
either in the papers cited or by the SCVPH (2002) in their evaluation of these studies.  Indeed, the 
SCVPH (2002) simply noted that '[t]herefore, these data have to be consid ered in any quantitative 
exposure assessment exercise', without  undertaking such an exercise."214 
104. Dr. De Brabander appears to disagree with Drs.  Boobis and Boisseau, but his responses fail to 
address the actual questions posed by the Panel, a nd in certain instances his opinions are simply based 
on anecdotal information and policy considerations ra ther than scientific evidence or citations to the 
EC's purported risk assessments.  Fo r example, in response to the Panel's inquiry as to whether the EC 
assessed the risk from misplaced implants (Question 48), Dr. De Brabander simply notes, "any control 
mechanism, that is only based on audits and pape r work will not prevent farmers to use either 
uncorrect use of legal production aids either [ sic] illegal growth promoters which are readily available 
in the US and Canada through the internet."  Dr. De  Brabander fails to substa ntiate this statement, 
which appears to be purely conjectural; he does not pr ovide any evidence of failure of controls in the 
United States, nor does he cite to any portions of  the EC's purported risk assessment where the EC 
actually evaluated the risk of failure of controls or  misuse.  In any event, no measure, be it a ban or a 
system of controls, can ever be relied upon to "preve nt" an occurrence entirely.  This is evidenced by 
the fact that, despite imposing a ban on the use of  growth promoting hormones, the EC has been 
unable to "prevent" their sale and use in the black market.215 
105. As explained by the United States in its Rebuttal Submission, the US system of controls is not 
a simple matter of audits and paper work.216  The United States, through cooperation between the 
Food Safety and Inspection Service ("FSIS") of the United States Department of Agriculture 
                                                      
213 Dr. Boisseau Responses (Question 48), p. 24. 
214 Dr. Boobis Responses (Question 48), p. 42.  See Dr. Boobis Responses (Question 62), p. 52 ("the 
data generated by the EU research in question do not provide any indication that it is not possible to conduct a 
risk assessment of the hormones used as growth promoters.") 
215 See US Rebuttal Submission, paras. 64-65, citing , e.g., Stephany, Hormones in meat: different 
approaches in the EU and in the USA , APMIS 109, p. S 357 (2001) ("It has to be concluded that in some EU 
Member States an exten[d]ed black market exists.  For the USA, no experimental evidence is available for such 
a black market.") (Exhibit US-29). 
216 See US Rebuttal Submission, paras. 54-66. WT/DS320/R/Add.6 
Page F-136  
 
  ("USDA") and the FDA, has rigorous programs in pl ace which provide efficient safeguards against 
the hypothetical failure of controls in the productio n of meat and meat products.  These programs 
include setting safe levels for veterinary drugs; m onitoring for violative residues; and inspection of 
meat at the ante mortem, post mortem and processing stages.  As large commercial operations, US feedlots have great incentive to comply with the regulations set and enforced by USDA and the FDA.  
In addition to regulation at the fe deral level, many states and even individual feedlots have Beef 
Quality Assurance Programs which set high standards for beef management prac tices to maximize the 
quality and safety of beef.
217  Key components of these programs include proper training of feedlot 
employees and managers to ensure that management practices do not lead to violative residues or quality defects. 
106. All growth promoting implants are clearly labe led for subcutaneous placement in the middle 
third of the ear, and the ears of all cattle are removed at slaughter and discarded.  Any evidence at the time of slaughter of improper use of growth prom oting implants, which the EC claims is common 
practice in the United States but provides no data to support, will result in condemnation of the 
carcass by FSIS inspectors and significant economic loss to the producer.  Therefore, speculation by 
the EC about the effects of consumers eating whole implants, implant sites, or meat from over-dosed 
cattle
218 are paper exercises at best which ignore US inspection practices and evidence of decades of 
experience with the safe use of these products.  Clear ly, the US beef production system has numerous 
controls in place at multiple levels (federal, state and feedlot) which effectively mitigate the risk to 
human health from the misuse of growth promoting hormones in cattle. 
107. Dr. De Brabander cites to two pieces of evid ence in support of his conclusion that the US 
system of controls does not work or is subject to fa ilure, neither of which appears to be convincing or 
germane to the debate of whether or not the EC has indeed evaluated the likelih ood of this occurrence.  
He notes that "[t]wo years ago we had some american  students in veterinary medicine in an exchange 
program; their knowledge of 'hormones' their use in the USA and the risks involved was almost 
zero."219  At best this statement is anecdotal evidence,  and it certainly cannot be extrapolated to the 
broader conclusion that controls are likely to fail in the United States.  Dr. De Brabander also cites to 
a controlled study conducted by scientists at the Univ ersity of California-Davis using Zilpaterol (a 
beta-agonist not approved by the FDA for commercia l use in the United States) and Revalor (trade 
name for an FDA-approved growth prom oting implant containing estradiol 17 β and trenbolone 
acetate) in cattle as evidence "illustrat[ing] that fa rmers (and vets) have indeed economic incentives to 
misuse growth promoting substances."220  The Zilpaterol study does not support this conclusion, nor 
does it document or endorse the commercial use of Zilp aterol.  Rather, it is simply an example of a 
single research study, conducted under controlled co nditions on a limited number of animals, in which 
scientists investigated the combin ed effects of two treatments on growth performance in cattle.  
Nothing in the Zilpaterol study speaks to the potential of failure of controls or misuse of growth promoting hormones in the United States.
221 
                                                      
217 Examples of Beef Quality Assurance Programs in Ohio, Minnesota and Iowa can be found at 
http://www.ag.ohio-state.edu/~obqa/; http://www.mnbeef.org/bqa/BQA_Manual/Introduction.htm; and 
http://www.iabeef.org /BQA/Default.aspx. 
218 See, e.g., EC 1999 Opinion, §§ 3.3.1, 3.3.2 (pp. 30-31) (Exhibit US-4). 
219 Dr. De Brabander Responses (Question 44), p. 13. 
220 Dr. De Brabander Responses (Question 45), p. 14. 
221 In the United States, unapproved drugs such as Z ilpaterol are regulated as "new animal drugs for 
investigational use."  As stated in 21 CFR § 511.1, "[e]dible products of investigational animals in clinical trials 
are not to be used for food."  Similarly, Dr. De Brabander's discussion of hormones used by body builders and athletes is irrelevant to a discussion of the use of  growth promoting hormones in cattle according to good 
veterinary practices.  See Dr. De Brabander Responses (Question 47), p. 15.  WT/DS320/R/Add.6 
 Page F-137 
 
 
  (b) The material put forward by the EC regarding misuse or abuse of the hormones at issue fails 
to call into question Codex standards regarding the safety of meat from cattle treated with hormones for growth promotion purposes 
108. The experts' responses confirm that the material  put forward by the EC regarding misuse or 
abuse of any of the six hormones fails to call into  question Codex standards regarding the safety of 
meat from cattle treated with hormones for growth promotion purposes.  Dr. Boisseau reiterates that 
JECFA does not perform an evaluation of the potential for misuse,
222 and notes that "the [EC] did not 
conduct a quantitative risk assessment from growth prom oters, [and that] it is not possible to say the 
scientific evidence referred to by the [EC] assesses the risk to hu man health from residues resulting 
from these misuses/abuses."223    
109. Dr. Boobis agrees that the EC has made  "no attempt to evaluate the risks"224 from misuse, 
either in its Opinions or in underlying studies.  Accordingly, the EC has not presented any materials 
that cast doubt on the JECFA or Codex evaluation of the safety of the hormones.  In support of this conclusion, Dr. Boobis engages in an extensive an alysis of the additional studies commissioned and 
cited by the EC since 1997.
225  He cites to several studies analyzed earlier by the United States in its 
Rebuttal Submission, and reaches simila r conclusions regarding their results: 
1. Lange et al., Hormone contents in peripheral tissues after correct and 
off-label use of growth promoting horm ones in cattle: effect of the implant 
preparations Filaplix-H, Raglo, Synovex-H and Synovex Plus.  
"In study 5, the impact of misuse and multip le dosing on residual hormone levels in 
meat was determined.  Dosing at up to 10 times the approved dose , resulted in an 
increase in the tissue concentrations of some  hormones in some tissues to value above 
the MRL for those hormones for which Codex has established an MRL."226 
"'Treatment with zeranol and testosterone propionate, even after multiple application, 
does not cause any problems , as far as infringement of threshold levels is 
concerned.'"227 
"For oestradiol, the maximum increase ob served in any tissue was not greater than 
proportional to the dose applied.  Hence, ev en at 10-fold the approved dose, intake 
would be well below the ADI .  This would be offset by the fact that not all tissues had 
such elevated levels, and the probability of consuming such high residue levels of a 
                                                      
222 Risk assessments performed by JECFA, the EC's European Medicines Agency ("EMEA") and the 
FDA evaluate the use of veterinary drugs assuming that the drugs are admi nistered according to good veterinary 
practices.  Were this not the case, it would be impossible to develop international food safety standards, i.e., 
there would be no benchmark against which safety evaluations could be conducted.  Further, it is important to note that any veterinary drug could be misused.  If regulatory authorities based their evaluations against a 
misuse standard, then there would be virtually no approvals of veterinary medicines.  The evidence is clear that 
there are a large number of veterinary  drugs on the market in both the United States and the EC which were 
approved assuming that they would be administered according to good veterinary practices, indicating that this 
is the norm for such evaluations.  It is curious that the EC has not used this standard in its evaluation of the six 
hormones at issue in this dispute, assuming in stead extreme misuse scenarios for each hormone. 
223 Dr. Boisseau Responses (Question 51), p. 25. 
224 Dr. Boobis Responses (Question 48), p. 42. 
225 See Dr. Boobis Responses (Question 62), pp. 50-52 ("Multiple implanting, multiple dosing"). 
226 Dr. Boobis Responses (Question 62), p. 50.  (Emphasis added). 
227 Dr. Boobis Responses (Question 62), p. 50.  (Emphasis added). WT/DS320/R/Add.6 
Page F-138  
 
  regular basis is minimal.  It should also be noted that Codex did not specify an MRL 
for oestradiol, as it was considered unnecessary."
228  
2. Daxenberger et al., Detection of anabolic residues in misplaced implantation 
sites in cattle.  
"In the study on misplaced implantation sit es (Daxenberger et al, 2000), substantial 
residual hormone was sometimes found at the implantation site when this was not as 
recommended.  However, for these findings to have significance for the consumer a number of factors need to be considered.  These include the likelihood of off-label 
use of the hormones, the failure to det ect the implantation site, the use of the 
implantation site for food use, the contributio n of the contaminated meat to the diet 
and the frequency of such contamination.   No data have been presented on the 
prevalence of such significant contaminati on as a consequence of the veterinary use 
of the hormones.  Indeed, no evidence is presented that such misuse does occur with 
the consequences suggested by the authors ."229 
3. Daxenberger et al., Detection of melengestrol acetate residues in plasma and 
edible tissues of heifers.  
"In studies on MGA (Daxenberger et al, 1999) tissue levels increased with dose, most 
markedly in fat.  Whilst in fat, there was a roughly proportional increase with dose, in other tissues (muscle, kidney, liver) the fo ld-increase was appreciably less than the 
fold-increase in dose.  Using the values obt ained in the study of Daxenberger et al 
(1999) at 10 times the maximum approved dose
, consumption of all four tissues 
(liver, kidney, fat and muscle) at the JECF A levels (300 g muscle, 100 g liver, 50 g 
kidney and 50 g fat per day) would result in a slight exceedance of the ADI (2.5 μg cf 
1.8 μg).  However, it should be noted that this  would require all of the tissues to be 
from animals treated with the high dose, a nd exposure would have to be over a 
prolonged period of time.  The probability that this would occur is extremely low ."230 
110. In summary, Dr. Boobis notes the following regarding the EC's research, including the 
17 Studies: 
There is little information in the scientific studies initiated by the EC since 1997 that 
support the contention that they have identified important new gaps, insufficiencies 
and contradictions in the scientific info rmation and knowledge on the hormones, and 
that additional studies are necessary before the risks to health of consumption of meat 
from treated animals can be assessed .  Whilst additional information has been 
obtained on a number of aspects of the hormones in question, this was often not definitive, sometimes it was not relevant, in some instances it confirmed or expanded 
on previous knowledge.  The evidence obt ained did not indicate any additional 
concern regarding the risk from exposure to residues of the hormones in meat from 
cattle treated for growth promotion .231 
111. Dr. De Brabander disagrees, noting that the mate rials put forward by the EC "call[ ] indeed 
into question" the applicability of Codex standards.  However, Dr. De Brabander presents no 
scientific evidence in support of this conclusion.  Dr. De Brabander cites to the "older" experiments 
                                                      
228 Dr. Boobis Responses (Question 62), p. 50.  (Emphasis added). 
229 Dr. Boobis Responses (Question 62), pp. 50-51.  (Emphasis added). 
230 Dr. Boobis Responses (Question 62), p. 51.  (Emphasis added). 
231 Dr. Boobis Responses (Question 62), p. 58.  (Emphasis added).  WT/DS320/R/Add.6 
 Page F-139 
 
 
  on which JECFA relied in setting ADIs for the horm ones, but fails to provide any context for this 
concern by noting any "newer" material that woul d support the conclusion that the "old" evidence is 
no longer relevant.232  Perhaps of greatest interest, Dr. De Brabander does not find support for his 
conclusion in the numerous studies produced by th e EC in which extreme misuse scenarios were 
created and contemplated.  As noted by the United States in its Rebuttal Submission, and confirmed 
by Dr. Boobis' analysis above, even in the artificial scenarios developed by EC scientists, in most 
cases extreme misuse and overdosing of cattle with impl ants did not result in violative residue levels, 
i.e., levels exceeding ADIs and MRLs.233  In addition, Dr. De Brabander cites to concerns of animal 
welfare and impact on the environment, neither of which has been argued by the EC in the course of these proceedings.  Finally, Dr. De Brabander claims that "most consumers aren't prepared to take this 
risk."
234  Dr. De Brabander cites to no scientific eviden ce in support of this conclusion, which appears 
to be little more than a personal opinion or policy statement. 
(c) Conclusion 
112. The experts' responses, insofar as they are ba sed on the scientific evidence relating to good 
veterinary practices and misuse, confirm that the EC has failed to demonstrate that there is a risk to 
human health from the misuse of growth promo ting hormones in the United States and that the 
material put forward by the EC regarding misuse or abuse of the hormones at issue fails to call into 
question Codex standards regarding the safety of me at from cattle treated with hormones for growth 
promotion purposes.  Therefore, the experts' res ponses demonstrate that the EC has failed to base its 
import ban on meat from cattle treated with estradiol 17 β on a risk assessment, as appropriate to the 
circumstances, within the meaning of Article 5.1 of the SPS Agreement, and has similarly failed to 
satisfy Article 5.2's requirement that a risk ass essment take into account relevant processes and 
production methods and relevant insp ection, sampling and testing methods.  In addition, the experts' 
responses demonstrate that the EC has not satisfi ed its obligation under Article 5.7 of the SPS 
Agreement to base a provisional ban on available pe rtinent information.  Finally, the experts' 
responses confirm that the EC, by imposing an im port ban (whether permanent or temporary) on 
imports of meat from cattle treated with hormones for growth promotion purposes has breached its 
obligation to ensure that its sanitary and phytosan itary measures are not more trade-restrictive than 
required to achieve its appropriate level of sanitary or phytosanitary protection within the meaning of 
Article 5.6 of the SPS Agreement. 
D. CONCLUSION  
113. It is natural that in six sets of separate res ponses from the experts and three sets of responses 
from international organizations there would be  some differences in the responses provided.  
However, upon analysis of their responses and evaluati on of the scientific evidence cited therein, it is 
apparent that there are substantial areas of agre ement amongst the experts.  As demonstrated above, 
their responses are consistent with the following conclusions: 
(1) There are certain necessary components or el ements of a risk assessment, and the EC 
has failed to satisfy each of those elements  in the Opinions upon which it based its 
permanent ban on estradiol 17 β. 
(2) The scientific evidence does not support th e conclusion that any carcinogenic effects 
of estradiol 17 β are related to a mechanism other than hormonal activity. 
                                                      
232 See Dr. Boisseau Responses (Question 34), p. 19 ("th e quality and the number of the available data 
are more important than the dates at which these data have been produced.") 
233 See US Rebuttal Submission, paras. 54-66. 
234 Dr. De Brabander Responses (Question 51), p. 18. WT/DS320/R/Add.6 
Page F-140  
 
  (3)  The scientific evidence does not support the conclusion that estradiol 17 β is 
genotoxic at levels found in residues in meat from cattle treated with growth 
promoting hormones. 
(4) The scientific evidence does not demonstrate that estradiol 17 β will have 
carcinogenic or tumorigenic effects at con centrations found in residues in meat from 
cattle treated with hormones for growth promotion purposes. 
(5) The scientific evidence and informati on relating to the five provisionally-banned 
hormones is sufficient to conduct an assessm ent of the risks to human health from 
consumption of meat from cattle treated with any of the five hormones for growth promotion purposes. 
(6) The scientific evidence cited by the EC in its Opinions does not demonstrate that any 
of the five provisionally-banned hormones has genotoxic potential or is carcinogenic 
by a mechanism other than hormonal activity. 
(7) The scientific materials produced and cite d by the EC (including the "17 Studies") 
have not identified any gaps or insufficien cies in the scientific evidence such that 
more study is necessary before the risk from consumption of meat from cattle treated 
with the five provisionally-banned hormone s for growth promotion purposes can be 
assessed.  
(8) Each of the hormones has been used for growth promotion purposes in cattle and 
evaluated for a sufficient period of time with no evidence of adverse effects to 
adequately address any concern regardi ng long latency periods of cancer. 
(9) Epidemiological studies cited by the EC do not identify a link between cancer and 
residues of the six hormones in meat from ca ttle treated with the hormones for growth 
promotion purposes. 
(10) The EC has failed to demonstrate that  meat from cattle treated with hormones for 
growth promotion purposes poses a risk to sensitive populations. 
(11) The EC has failed to demonstrate "other risks" to human health from consumption of 
residues of the hormones in meat from cattle  treated for growth promotion purposes, 
such as effects on the immune system. 
(12) The EC has failed to put forward evidence regarding or assessed the risk related to the 
exposure of consumers to residues of any of the six hormones in meat from cattle treated with the hormones for growth promotion purposes.   
(13) JECFA's decision to set an ADI for the natural hormones did not mark a change in 
JECFA's or Codex's conclusions as to the safety of the hormones when consumed as residues in meat from cattle treated for growth promotion purposes.   
(14) The EC has failed to demonstrate that ther e is a risk to human health from the misuse 
of growth promoting hormones in the United States. 
(15) The material put forward by the EC re garding misuse or abuse of the hormones at 
issue fails to call into question Codex standards regarding the safety of meat from cattle treated with hormones for growth promotion purposes.  WT/DS320/R/Add.6 
 Page F-141 
 
 
  ANNEX F-5 
 
COMMENTS BY THE UNITED STATES TO THE COMMENTS 
BY THE EUROPEAN COMMUNITIES ON THE REPLIES 
OF THE SCIENTIFIC EXPERTS, CODEX, JECFA AND IARC 
TO QUESTIONS POSED BY THE PANEL 
 
(12 July 2006) 
  
A. 
INTRODUCTION  
1. The United States appreciates this opportunity to provide comments on the comments of the 
European Communities ("EC") on the responses receiv ed from the six scientific experts and the three 
international organizations selected by the Panel.   The United States will first provide general 
comments on the EC's comments and then provide specific remarks on individual comments offered 
by the EC on the experts' and international organizations' responses. 
B. GENERAL COMMENTS  
1. Qualifications of experts 
2. In several of its comments, the EC questions the credibility of two of the scientific experts 
selected by the Panel, Drs. Boobis and Boisseau, and seeks to dismiss their responses based on an alleged lack of qualification rather than a lack of scientific foundation or basis in the experts' 
responses themselves.  The United States notes that Drs. Boobis and Boisseau are more than qualified 
to provide advice to the Panel on the subject matter at issue, the safety of meat and meat products from cattle treated with hormones for growth prom otion purposes.  This is evidenced by the high 
quality of their responses to the Pa nel's questions, their extensive curriculum vitae , their nomination 
by the Codex Alimentarius Commission ("Code x") and the Joint FAO/WHO Expert Committee on 
Food Additives ("JECFA") to serve in the expert gro up, and the Panel's ultimate choice to seek their 
advice as members of the expert group.  This is also  evidenced by the fact that the EC only seeks to 
impugn the qualifications of the experts in scenario s where it has concluded their responses are not 
favorable to its arguments.
1 
3. In addition to seeking to dismiss expert opinions based on an alleged lack of qualification, the 
EC also attempts to discard Dr. Boisseau's respons es to certain questions based on the fact that he 
initially informed the Panel that he may not be in  a position to respond to those questions.  The fact 
that Dr. Boisseau was unsure as to  his ability to respond to certain questions is not a valid reason for 
ignoring his ultimate responses to these questions.  I ndeed, Dr. Boisseau's responses appear to be very 
well-researched, and he ha s clearly put a great deal  of effort into providing the Panel sound advice on 
these issues.  Further, the United States notes that this is another example of the EC attempting to 
impugn the qualifications of an expert only where th at expert has offered answers or points of view 
that do not support the EC's arguments.  For example, the EC does not raise similar concerns regarding Dr. De Brabander's respon ses to Panel Questions 44-48 and 50-51
 despite the fact that 
Dr. De Brabander, in an April 24 , 2006 e-mail to the Panel noted, "I am an analytical chemist so I 
could only provide adequate answer s to questions on residue analysis .  That means Db question 
                                                      
1 See, e.g., EC Comments on the Experts' Responses (Questions 37 and 44), where the EC offers the 
opinion of Dr. Boisseau, without qualification , in support of its position.  Contrast to EC Comments on Panel 
Question 2, where the EC notes, "[a]s the EC has pointed out during the selection procedure, Dr. Boisseau does not possess any expertise on these substances, as he does not appear to have carried out any specific research on 
these substances during his professional life."  EC Comments on the Experts' Responses (Question 2), p. 2. WT/DS320/R/Add.6 
Page F-142  
 
  [2]7-35 and f question 49
."2  Despite this statement delimiting his experience to residue analysis, 
Dr. De Brabander offers several responses on an entirely unrelated category:  good veterinary 
practices in the United States and Canada. 
2. Scope of experts' responses and legal obligations under the SPS Agreement 
4. As previously noted by the United States in its  comments on the experts' responses, the role 
of the scientific experts is a narrow one of provi ding a panel information, advice and opinions on 
certain aspects of the matter that is the subject of a dispute.3  Despite this fact, the EC has, in several 
of its comments, complained that the experts shoul d have tempered their responses based on what the 
EC believes are Members' legal obligations under the Agreement on the Application of Sanitary and 
Phytosanitary Measures ("SPS Agreement").  For instance, in its comments on the experts' responses 
to Panel Question 5, the EC argues, "the answers of all scientists  do not  take into account the legal 
requirements of the SPS Agreement in this ar ea, as interpreted by the Appellate Body."4  There is no 
reason that the experts should have taken these require ments into account.  Indeed, their mandate is to 
provide the Panel with information and advice on scie ntific and technical issues, not to make legal 
judgments regarding Members' measure s, such as whether a measure is  based on a risk assessment or 
satisfies the conditions for a provisional measure w ithin the meaning of the SPS Agreement.  Such 
judgments are reserved for the Panel. 
5. In addition to confusing the role of experts in  offering scientific advice to the Panel, the EC 
also notes in its comments that several of the Panel' s questions concern aspects of risk assessment that 
are "not legally binding" since they are not referenced in the text of the SPS Agreement.5  The EC 
appears to propose a very broad de finition of what constitutes a risk  assessment within the meaning of 
Article 5.1 of the SPS Agreement.  Rather than accepting that guidance from international 
organizations such as JECFA and Codex provides important benchmarks for conducting a risk 
assessment and for objectively evaluating whether a Member's risk assessment has engaged in an adequate analysis of a risk, the EC instead proposes a notion of risk assessment devoid of any apparent form.  The EC's concept of what is or is not a risk assessment ignores the text of Article 5.1, 
which states: 
Members shall ensure that their sanitary or phytosanitary measures are based on an 
assessment, as appropriate to the circumstances, of the risks to human, animal or plant life and health, taking into account ri sk assessment techniques developed by the 
relevant international organizations .6 
6. The experts' responses clarify that there are a bundant examples of risk assessment techniques 
developed by interna tional organizations.7  Indeed, the original Hormones  panel conclude d that "even 
though no formal decision has as yet been taken by Codex with respect to [s anitary] risk assessment 
techniques, Codex, and more particularly JECFA, has a long-standing practice with respect to the assessment of risks related to veterinary drug residues (including hormone residues)."
8  Such an 
assessment "consists of the following steps: (i) hazard identification, (ii) hazard characterization, (iii) 
                                                      
2 E-mail of Dr. Hubert De Brabander to the Panel, April 24, 2006.  (Emphasis added). 
3 See US Comments on the Experts' Responses, Section B.  See also Agreement on the Applications of 
Sanitary and Phytosanitary Measures , Article 11.2; Understanding on Rules and Procedures Governing the 
Settlement of Disputes , Article 13. 
4 EC Comments on the Experts' Responses (Question 5), p. 4.  (Emphasis in original). 
5 See, e.g., EC Comments on the Experts' Responses (Questions 4 and 6). 
6 SPS Agreement, Article 5.1.  (Emphasis added). 
7 See, e.g., Responses to Questions from the Panel of Dr. Alan Boobis ("Dr. Boobis Responses") 
(Questions 3 and 4), pp. 10-11. 
8 Panel Report, EC – Measures Concerning Mea t and Meat Products (Hormones) , adopted on 13 
February 1998, WT/DS26/R ("Panel Report"), para. 8.103.  WT/DS320/R/Add.6 
 Page F-143 
 
 
  exposure assessment, and (iv) risk characterization."9  The EC reiterates this conventional four-step 
risk assessment procedure in its 1999 Opinion.10 
7. The EC further attempts to blur the notion of what constitutes an appropriate risk assessment 
for purposes of the SPS Agreement by repeatedly noti ng that the Appellate Body has concluded that 
risk assessments may be either quantitative or qua litative.  However, the EC's description of the 
Appellate Body's conclusions is overly simplistic.  Rather than finding, as the EC appears to argue, 
that Members may simply conduct a qualitative risk  assessment that is devoid of any structure, 
necessary form or scientific rigor,11 the Appellate Body simply determined that there is no 
requirement that a risk assessment establish a minimum quantifiable magnitude or threshold level of degree of risk.
12   
8. In conclusion, the EC's interpretation is not supp orted by the text of Article 5.1, cited above 
(either form of risk assessment must "tak[e] into account risk assessment techniques developed by the 
relevant international organizations"), nor is it bolst ered by the responses of the experts, nor is it 
supported by the conclusions reached by the Appellate Body.  To the contrary, the experts agree that 
qualitative risk assessments include the same core el ements as quantitative ri sk assessments, save for 
some disagreement as to whether this incl udes a dose-response assessment in the hazard 
characterization (second step) step of risk assessment.13  Further, regardless of whether a risk 
assessment is qualitative or quantita tive, the scientific conclusions set out in the assessment must 
actually be supported by the underpinning sci entific evidence cited in the assessment.14  The EC has 
failed to demonstrate that it has accomplished this goal and the experts' responses confirm that it has 
not. 
3. Responses of the international organizati ons are not "adequate and legally sound" 
9. The United States believes that the responses of  the international organizations speak for 
themselves, and that there is therefore no need to  provide specific comments on these responses at this 
point.  The United States has provided specific comm ents on the internationa l organization responses, 
where appropriate, in its June 30,  2006 submission.  The EC has presented no evidence to discount 
any of the conclusions reached by the international organizations.  The EC has, however, alleged in a 
general comment that the responses from the interna tional organizations are not  "adequate and legally 
sound."  The United States notes that the EC has prov ided no evidence in support of this speculation 
or purported standard, and that the input of these organizations, and similar international standard 
setting bodies has been sought in other SPS disputes, including the original Hormones dispute.  
Indeed, where a dispute involves the analysis of a Member's measure that  diverges from relevant 
international standards (such as here), it is perfec tly comprehensible why a panel would proceed with 
its evaluation by seeking input from international organizations. 
                                                      
9 Panel Report, para. 8.103. 
10 See "Opinion of the Scientific Committee on Veterinary Measures Relating to Public Health – 
Assessment of Potential Risks to Human Health from Hormone Residues in Bovine Meat and Meat Products", 
30 April 1999 ("1999 Opinion"), p. 70.  (Exhibit US-4). 
11 See, e.g., EC Comments on the Experts' Responses (Question 16). 
12 Appellate Body Report, EC – Measures Concerning Meat and Meat Products (Hormones) , adopted 
on 13 February 1998, WT/DS26/AB/R ("Appellate Body Report"), paras. 186, 253(j). 
13 See Responses of the Experts' to Panel Question 11. 
14 See Panel Report, Japan – Measures Affecting the Importation of Apples: Recourse to Article 21.5 of 
the DSU by the United States , WT/DS245/RW, adopted July 20, 2005, paras. 8.145-8.146 (" Japan – Apples 
(21.5) ") (finding that "[s]ince the scientific evidence relied upon  by Japan does not support the conclusions  
reached by Japan in its 2004 PRA, we conclude that the 2004 PRA is not an  assessment, as appropriate to the 
circumstances , of the risks to plant life or health, within the meaning of Ar ticle 5.1 of the SPS Agreement.") WT/DS320/R/Add.6 
Page F-144  
 
  C. S
PECIFIC COMMENTS ON EXPERTS ' RESPONSES  
10. Question 1 :  The EC proposes several changes to Dr. Boisseau's response that are 
unsupported by scientific evidence.  For example, the EC attempts to insinuate misuse scenarios 
(implant into animal's dewlap15; new recommendations for use of trenbolone acetate16) into the basic 
definitions of the hormones.  In addition, the EC  notes that "Dr. Boisseau's reply does not consider 
any progress in toxicological knowledge concerning these hormones, and in particular estradiol, since 
the 70th and 80th JECFA reports."  However, the last meeting of JECFA was the 67th.17  The "70th 
and 80th" JECFA reports do not exist, so it is unc lear how Dr. Boisseau could have possibly taken 
their findings into account.  The EC provides no comments on the response of Dr. Boobis, who has 
drafted detailed and well-documented definitions for the six hormones.18  The United States notes that 
none of the experts' responses appear to alter the b asic definitions of the six hormones relied on by the 
original Hormones  panel.19 
11. Question 2 :  The EC attempts to dismiss Dr. Boisseau's comments based on its view of his 
qualifications.  The EC provides no scientific ev idence or argument that discounts Dr. Boisseau's 
advice.20  
12. Question 3 :  Contrary to the EC's suggestion, th e experts and international organizations 
confirm that there are numerous international doc uments and guidance materials relevant to the 
assessment of veterinary drugs in food.21   
13. The EC tries to dismiss as irrelevant the work on the hormones conducted by the Committee 
on Veterinary Medicinal Products ("CVMP") and the c onclusions reached by that body to the analysis 
at hand.  However, as noted by the United States  in its Rebuttal Submission and confirmed by the 
experts' responses, the CVMP analysis of estradiol 17 β and progesterone indicates that it was 
concerned primarily with hazards and risks ar ising from exogenous exposure of consumers to 
hormones and the possible need, in light of recent data, to perform new risk assessments for estradiol 
and progesterone.22   
14. The CVMP concluded that new risk assessments for estradiol 17 β and progesterone were not 
necessary and that certain residue levels of the hormones are safe based on some very basic 
conclusions on these hormones ( e.g., lack of genotoxicity, carcinogenic action only after prolonged 
                                                      
15 In a production setting, placing an implant into the dewlap (hanging fold of skin under the neck) 
would be highly impractical and potentially dangerous to the handler.  It would also likely result in slower, less 
effective absorption of the hormone due to the fatty tissu e in the dewlap (versus the ear, which contains very 
little fat and is highly vascularized resulting in rapid and effective absorption of hormone from the implant).  The suggestion that implants are de liberately misplaced into  the dewlap appears to be speculation. 
16 The United States is unaware of any new reco mmendations for trenbolone acetate use and would be 
interested in the EC's source of this information.  It is true that periodic reimplan tation of cattle with growth 
promoting implants is common practice.  This is done because each implant has a finite "payout period" during 
which the implant releases enough hormone to stimulate growth.  The timing of reimplantation is carefully 
scheduled to maintain an effective concentration of hormone in the animal.  It should be emphasized that reimplantation of cattle, because it is done near the end of the implant payout period, does not result in 
concentrations of growth-promo ting hormones in meat that exceed the tolerances or MRLs. 
17  67th Meeting, June 20-29, 2006 (Rome) (http://w ww.who.int/ipcs/food/jecfa/data/en/index.html ). 
18 See Dr. Boobis Responses (Question 1), pp. 1-5.  
19 See, e.g., Panel Report, paras. 2.6-2.9. 
20 See Section B.1 above. 
21 See US Comments on the Experts' Responses, para. 13, citing Codex Responses to Questions from 
the Panel ("Codex Responses") (Questions 3 and 4), pp. 4-5; JECFA Responses to Questions from the Panel 
("JECFA Responses") (Question 3), pp. 2-3; Dr. Boobis Responses (Question 3), pp. 10-11. 
22 See US Rebuttal Submission, fn. 57.  See Responses to Questions from the Panel of Dr. Jacques 
Boisseau ("Dr. Boisseau Responses") (Question 13), pp. 9-11; Dr. Boobis Responses (Question 12), p. 17.  WT/DS320/R/Add.6 
 Page F-145 
 
 
  exposure at high exposure levels) which contradict  fundamental – but unsup ported – conclusions set 
out in the EC's Opinions.  It should be emphasized that the basic scientific information considered by 
the CVMP with respect to the ri sks of therapeutic and zootechnical use of hormones was the same 
information used by the SCVPH to assess the risks of hormones used for growth promotion, but the 
CVMP and SCVPH reached very different conclu sions.  Thus the CVMP evaluation is indeed 
relevant to this dispute and an analysis of the EC 's Opinions, despite the EC's attempts to distance 
itself from the evaluation.23 
15. Question 4 :  The EC dismisses the responses of two of the scientific experts (Drs. Boisseau 
and Boobis) and the international organizations by  arguing that their responses are not limited to 
"legally binding" assessment techniques w ithin the meaning of the SPS Agreement.24  As noted 
above, it is not appropriate for the experts to comment on the legal nature of any aspect of the dispute.  
Further, the EC simply avers that the relevant guidelines or principles cited by the experts are not 
"legally binding" for purposes of analysis of a measure under the SPS Agreement, without providing 
an explanation of why this is so.  Contrary to th e EC's suggestion, the responses of Drs. Boisseau and 
Boobis, JECFA and Codex indicate that there are in fact "risk assessment techniques developed by the 
relevant international organizations " within the meaning of Article 5.1 of the SPS Agreement that are 
pertinent to an analysis of the EC's Opinions, in particular to an analysis of whether the EC has 
conducted a risk assessment for the pe rmanently-banned hormone, estradiol 17 β.25  Indeed, the EC 
itself has recognized this fact.26  In addition, the EC provides no explanation to support its allegation 
that its risk analysis techniques are "much more  advanced than JECFA" nor does it explain what 
relevance, if any, this conclusion has to these proceedings. 
16. Question 5 :  The EC claims that the experts' resp onses "do not take into account the legal 
requirements of the SPS Agreement."  As noted a bove, it is not appropriate for the experts to 
comment on the legal nature of any aspect of the dispute.  In addition, the EC attempts to contradict 
                                                      
23 See "Report of the CVMP on the Safety Evaluation of Steroidal Sex Hormones in particular for 17 β-
Oestradiol, Progesterone, Alternogest, Flugeston e acetate and Norgestomet in the Light of New 
Data/Information made available by the European Commission", Committee for Veterinary Medicinal Products 
(EMEA/CVMP/885/99) ("1999 CVMP Report"), p. 11 ("General Considerations") (Exhibit US-13). 
24 As noted in Section B.2 above, the experts are not in a position to determine what is or is not "legally 
binding" for purposes of the SPS Agr eement.  While experts' advice and responses may be discounted because, 
e.g., they lack a scientific foundation or are not base d on scientific evidence, they may not be summarily 
dismissed because a party believes that they t ouch on topics that are not "legally binding." 
25 See Dr. Boobis Responses (Question 4), p. 11 ("[T]here are guiding principles [for risk assessment] 
in place, that have been in existe nce since before 1999." "Specific guidance was [] developed by JECFA and 
adopted by Codex."); Responses to Questions from the Panel of Dr. Jacques Boisseau ("Dr. Boisseau 
Responses") (Question 4), p. 2 (The rationale for risk assessment "has been internationally harmonised through scientific conferences and it is possible to say that there was an international non written agreement on this 
rationale."); JECFA Responses to Questions from the Panel ("JECFA Responses") (Question 4), p. 2 (citing 
back to its answer to Panel Question 3, in response to which it provide numerous citations to guidance on risk 
assessment techniques); Codex Responses to Questions from the Panel (Question 4), p. 5.  See Panel Report, 
para. 8.103. 
26 See 1999 Opinion, p. 70.  ("Executive Summary") ("Conventionally, risk assessment is structured to 
address independently the intrinsic properties of the co mpound under consideration (hazard identification), the 
evaluation of the nature of effects in terms of a dose-response relationship (h azard characterization), the 
estimate of the dose/concentration of a compound in the daily diet (exposure a ssessment) resulting in the 
incidence and severity of potential adverse effects.")  This final evaluation would be what is generally referred 
to as "risk characterization."  (Exhibit US-4).  This is further evidenced by the fact that the EC has argued in 
these proceedings that it has completed the four steps of a risk assessment.  See EC Comments on the Experts' Responses (Question 14) ("it is obvious that [the SCVPH] has followed the four steps of  risk assessment when it 
carried out its qualitative risk assessment.") WT/DS320/R/Add.6 
Page F-146  
 
  the experts' responses with its own opinion, which appears to be of little relevance to the Panel's 
question, of how Codex and JECFA interact but provides no evidence to support this opinion.
27 
17. Question 6 :  The EC dismisses the responses of the scientific experts and international 
organizations by arguing that these responses are not  limited to "legally binding" risk assessment 
techniques within the meaning of the SPS Agreement.28  The EC simply avers that the relevant 
guidelines or principles cited by the experts are not "legally binding" for purposes of analysis of a 
measure under the SPS Agreement, without providing an explanation of why this is so other than an 
inapt citation to the Hormones Appellate Body Report discussing the distinction between "risk 
assessment" and "risk management."  Contrary to the EC's suggestion, the experts (Drs. Boisseau, 
Boobis and Guttenplan) and JECFA confirm that there are four internationally-recognized steps to a 
risk assessment (hazard identification; hazard characterization; exposure assessment; risk 
characterization) and that these step s are in fact "risk assessment techniques developed by the relevant 
international organizations" within the meaning of Article 5.1 of the SPS Agreement that are pertinent 
to an analysis of the EC's Opinions, in particular to an analysis of whether the EC has conducted a risk 
assessment for the permanently-banned hormone, estradiol 17 β.29  In addition, the EC's comments 
appear to ignore the several cond itions imposed on risk assessments by, e.g., Articles 5.2 and 5.3 of 
the SPS Agreement. 
18. The EC also notes that Drs. Boobis and Boisseau  have "discard[ed] the relevance of some 
residues that are not pharmacologically active but ma y interfere with normal metabolic functioning of 
cells given their intrinsic chemical potential to form  covalent adducts to biomolecules."  However, it 
is unclear which residues the EC is referring to and the EC provides no scientific evidence indicating 
that such protein adducts actually:  (1) form in vivo following consumption of beef from cattle treated 
with growth-promoting hormones, or (2) inte rfere with metabolic functioning of cells.  
19. Question 7 :  The EC disagrees with the experts' r esponses because, according to the EC, "the 
accumulation of so much new peer-reviewed eviden ce since 1999 establishes clearly that oestradiol-
17β is a direct carcinogen and does not act only through hormonal receptors."  This appears to be the 
EC's opinion alone.  Despite havi ng reviewed the materials relied  on by the EC in drafting its 
Opinions and the several other studies put forward by the EC in defense of its permanent ban on 
estradiol 17 β, the experts do not share the EC's conclusion on the "clear" carcinogenic action of 
estradiol 17 β.30 
20. The EC cites to a study by Bhat et al. (not cited in the EC's Opinions) as demonstrating "the 
necessary role of catechols of estradiol ... in indu ction of oxidative stress to induce tumors."  
                                                      
27 See EC Comments on the Experts' Responses (Question 5), p. 4 (in which the EC opines, without 
evidentiary support, that "[i]ndeed, JECFA's reports and monographs are drafted in such a way as to leave 
practically no room to the members of the Codex Alimentarius Commission to decide on the appropriate level of health protection and the risk management options that are available to its members.") 
28 As noted in Section B.2 above, the experts are not in a position to determine what is, or is not 
"legally binding" for purpos es of the SPS Agreement. 
29 Recall that the form of the EC's "risk assessment" (Articles 5.1 and 5.2 and Annex A, paragraph 4 of 
the SPS Agreement) is but one element of the analysis of the EC's measur e (permanent ban on meat and meat 
products from cattle treated with estradiol 17 β for growth promotion purposes).  The United States has also 
argued that the EC's ban is not sufficiently warranted or  reasonably supported by the EC's "risk assessment", and 
is therefore not "based" on a risk assessment, as appropriate to the ci rcumstances, within the meaning of Articles 
5.1 and 5.2 of the SPS Agreement.  See also Panel Report, para. 8.103. 
30 See, e.g., Experts' Responses to Questions 13 and 16-1 8.  The United States notes that the EC cites to 
several studies which were not previously submitted to th e Panel in support of its comments in Question 7 ("[a] 
number of publications, some of which  have been submitted by the [EC] to this Panel, have explored the 
threshold concept and the activity of hormones at very low doses.")  The United States notes that these 
proceedings are well beyond the deadline for submission of "new" scientific evidence.  WT/DS320/R/Add.6 
 Page F-147 
 
 
  However, review of the Bhat study reveals that it did not identify catechol estrogens as the cause of 
tumor formation; in fact, catechol estrogens are not  even measured in the st udy.  Instead, the Bhat 
study demonstrates that tumor formation in the Syrian hamster kidney following treatment with estradiol 17 β is associated with oxidative stress.  A lthough oxidative stress can be generated by 
metabolic recycling between catec hol estrogens and their corresponding quinones, it is not unique to 
catechol estrogens and occurs in a variety of cell types in response to numerous natural and xenobiotic 
stimuli.  Therefore, the Bhat study does not pr ovide direct evidence of the "necessary role of 
catechols" in tumorigenesis in the Syrian hamster kidney.  
21. Further, the Bhat study involves the treatment of hamsters with high levels of estradiol 17 β 
for an extended period of time (7 months).  Therefore, the possibility that estradiol 17 β stimulated the 
growth of tumors via recept or-mediated, hormonal effects
 cannot be ruled out.  In fact, Bhat 
recognizes this possibility, concluding, "[t]he hormonal effects of estrogens may promote the 
development of tumors."  Finally, it is well-documen ted that the Syrian hamster kidney is particularly 
susceptible to estrogen-induced kidney tumors due to a species-specific shift in the pattern of estradiol 
17β metabolism to favor production of 4-OH catechol estrogen.31  Therefore, whether this model is 
appropriate to study potential effects of estradiol 17 β from dietary sources on human health is very 
questionable.32   
22. Question 8 :  The EC contrasts the experts' advi ce against its own unsupported scientific 
conclusions.  For instance, the EC complains that "the evidence used by JE CFA in the evaluation of 
these hormones is too old (dating from the 1970s) a nd has been obtained with outdated detection 
methods [ sic] to be relevant today."  This blanket c onclusion is simply incorrect.  For instance, 
JECFA based its conclusion to set ADIs for estradiol 17 β, progesterone and testosterone on 
"[s]ufficient new data  from observations in humans ... which were suitable to derive ADIs."33  Further, 
the EC's argument presumes that older data is bad or incorrect data.  As we have learned from the 
                                                      
31 This point appears to be confirmed by Dr. Guttenplan, who notes that there is only one animal model 
"that is well characterized and this is in the hamster kidne y.  As kidney is not a known target of estradiol in 
humans the extrapolation to humans is uncertain ."  Responses to Questions from the Panel of Dr. Joseph 
Guttenplan ("Dr. Guttenplan Responses") (Question 14), p. 4.  (Emphasis added) 
32 The EC also cites to two papers by Russo et al., neither of which stand for the conclusion drawn 
from the papers by the EC.  The first paper, Russo et al., Estradiol is carcinogenic in human breast epithelial 
cells, was:  (1) performed with an immortalized cell line that does not reflect the physiology of normal breast 
epithelial cells; (2) not designed to measure catechol estrogens; and (3) provides no evidence for the "necessary 
role of catechols" in breast cancer nor genotoxic effects elicited by catechol estrogens in vivo.  The second 
paper, Russo et al., Estrogen and its metabolites are carcinogenic ag ents in human breast epithelial cells, appears 
to have used estrogen doses much higher than those that might occur in vivo.  In addition, this paper reports that 
MCF-10F cells have estrogen recepto rs, whereas the first Russo paper concludes that MCF-10F cells do not 
express estrogen receptors.  Without an  explanation for this inconsistency,  the potential significance and validity 
of these two studies – the first study in particular – is highly questionable. 
33 JECFA Responses (Question 20), p. 16.  See, e.g., 1999 CVMP Report, pp. 8-9, citing the 52nd 
JECFA Report and the 1999 Report of the Interna tional Agency for Research  on Cancer: "[a]s already 
demonstrated earlier, the recent studies  show that hormonal carcinogens in humans and experimental animals 
are characterized by (i) tumorigenic ac tion typically in various endocrine responsive organs and/or tissues, and 
(ii) the need for a prolonged exposure to high concentrations before tumorigenic effects become apparent.  The studies are also consistent with the notion of hormone-receptor mediated increase in cell division and 
proliferation in epithelial cells of the target tissues.  This points to a non-genotoxic mode of action
, which is in 
concurrence with (i) the negative results of both earlier an d recently performed genotoxicity tests, and (ii) the 
absence of structural alerts for genotoxicity in the molecule.  As cited in the introduction, the recent extensive 
reviews by IARC and JECFA also confirmed that the tumorigenic action of hormones, in particular 
17β-oestradiol, in animals and man are the consequence of the receptor-mediated, cell division stimulating 
activity of these compounds  in somatic target cells, and that the potential genotoxic properties of the compounds 
would not be expressed in vivo and/or not play a role in the tumorigenic activity." WT/DS320/R/Add.6 
Page F-148  
 
  experts' responses, this is not the case, but rather  it is the quality and quantity of data that is 
essential.
34   
23. The EC argues that "JECFA did not take th e low endogenous levels and thus the high 
sensitivity of children into account."  Again, this c onclusion is incorrect.  As noted by the experts, 
JECFA did in fact take sensitive populations into account in its use of safety factors.35  The EC also 
opines that use of hormones in oral contraceptiv es and hormone replacement therapy "demonstrates 
that estradiol and progesterone are bioavailable through the oral route."  It is true that estradiol 17 β 
and progesterone are administered orally for some indications.  However, because their bioavailability 
is so low, very high doses are required to elic it the desired therapeutic effect.  For example, 
therapeutic doses of estradiol 17 β  for oral administration range from 0.5 - 4.0 milligrams,36 or 10,000 
- 40,000 times higher than the 50 ng. derived from eating beef from cattle treated with estradiol 17 β 
for growth promotion purposes.  In addition to high doses, orally administered estradiol 17 β  a n d  
progesterone are also manufactured as micronized fo rmulations (particle size < 10 microns) to further 
increase bioavailability.  Even after micronization, the bioavailability of a 2 mg dose of estradiol 17 β 
is still only about 5%.  Lastly, synthetic estrogens  used in these treatments have significantly higher 
oral bioavailability compared to the residues of the natural hormone estradiol 17 β in meat from treated 
cattle.37 
24. Question 9 :  The EC disagrees with the experts' r esponses because, according to the EC, "it is 
today generally accepted that some of these hormones are genotoxic and can cause cancer directly."  Although the EC contends that this is the case (and h as so concluded in its Opinions), and argues that 
low doses of the hormones (particularly estradiol 17 β) would have a genotoxic effect, it has not 
supported this conclusion with scientific evidence.  The experts' responses, the continuing use of the 
hormones in cattle for multiple purposes around the world (including in the EC itself), and the intensive study of the hormones by JECFA, Codex and the EC's own CVMP are clear evidence that 
the genotoxicity of the hormones, particularly at th e low levels found in residues in meat from treated 
cattle, is not "generally accepted."   
25. Further, the experts have confirmed that the decision by JECFA to set ADIs for the hormones 
in 1999 did not mark a change in its conclusion regard ing the safety of the natural hormones.  In short, 
as noted in the US Comments, the experts have c onfirmed that JECFA will only allocate an ADI for a 
food additive or veterinary drug if the scientific  database is complete, unless it can adopt default 
assumptions that would if anything lead to a more  conservative risk assessment than would be the 
case otherwise.
38  That database was sufficiently complete  for the six hormones at issue in this 
dispute.  The EC's failure to support its conclusi ons with the scientific evidence it relied upon in its 
                                                      
34 See Dr. Boisseau Responses (Question 34), p. 19 ("the quality and the number of the available data 
are more important than the dates at which these data have been produced.") 
35 See Dr. Boobis Responses (Question 42), p. 39 ("[i]n keeping with its risk assessment principles, the 
ADI established by JECFA would have been designed to protect all segments of the population, including 
prepubertal children.")  See Dr. Boisseau Responses (Q uestion 41), p. 22.   
36 See US Department of Health and Human Services Report on Carcinogens, Eleventh Edition, 
"Estrogens, Steroidal" ("2002 US Report on Carcinogens").  (Exhibit US-26) 
37 For example, the bioavailability of ethinyl estradiol - the synthetic estrogen contained in combination 
oral contraceptives - is 55%. Fother by K. Bioavailability of orally administered sex steroids used in oral 
contraception and hormone replacement therapy. Contrace ption 1996; 54: 59-69 (cite d by Dr. Boobis in his 
responses to Questions 20 an d 40).This is the reason wh y, e.g., oral contraceptives are not made from estradiol 
17ß, but instead contain a synthetic estrogen (ethinyl estradiol) which is much more orally-bioavailable than estradiol 17ß. 
38 Dr. Boobis Responses (Question 9), p. 15; see Dr. Boisseau Responses (Question 9), p. 7 ("[t]he 
Canadian statement stipulating that 'it is recognized that JECFA only allocates an ADI for a food additive or a veterinary drug under review when JECFA considers that its  scientific data base is complete and that there is no 
outstanding scientific issue' is correct." ); JECFA Responses (Question 11), p. 10.  WT/DS320/R/Add.6 
 Page F-149 
 
 
  Opinions demonstrates that those Opinions are not risk assessments, as appropriate to the 
circumstances, within the meaning of Article 5.1 of the SPS Agreement.  Nor do the Opinions provide 
"available pertinent information" for a provisional me asure within the meaning of Article 5.7 of the 
SPS Agreement. 
26. Question 10 :  The EC argues that JECFA has a na rrow mandate because it has not examined 
the likelihood of misuse or abuse of the hormones.  As noted by the United States in its comments on 
the experts' responses, it would be extremely diffi cult for regulatory or standard-setting bodies to 
develop international food safety standards based on the assumption of misuse.  Any veterinary drug 
can be misused, and if regulatory authorities base th eir evaluations against a misuse standard, then 
there would be virtually no approva ls of veterinary medicines.  A large number of veterinary drugs 
marketed around the world have been approved assum ing that they would be administered according 
to good veterinary practices, indicating that this is  the norm for such evaluations.  It is therefore 
curious that the EC has not used th is standard in its evaluation of the six hormones at issue in this 
dispute, assuming instead extreme misuse scenarios for each hormone.39   
27. Further, the United States notes that the experts have confirmed that the EC itself has failed to 
properly examine the likelihood of misuse or abu se of the hormones, as, once it decided to make 
misuse a mainstay of its analysis, it was obligated  to do pursuant to Articles 5.1 and 5.2 of the SPS 
Agreement.40  Finally, if misuse of the hormones is the EC's primary concern and not the safety of the 
hormones at levels actually found in residues in meat  from treated cattle, then the EC, by imposing an 
import ban (whether permanent or temporary) on m eat from cattle treated with hormones for growth 
promotion purposes has breached its obligation to ensu re that its sanitary and phytosanitary measures 
are not more trade-restrictive than required to achieve  its appropriate level of sanitary or phytosanitary 
protection within the meaning of Article 5.6 of the SPS Agreement. 
28. Question 11 :  The EC disagrees with two of the expe rts' responses (Drs. Boisseau and Boobis) 
relating to the necessary components of a qualitativ e risk assessment because, according to the EC, 
the Appellate Body has determined "that a qualitative risk assessment is equa lly acceptable under the 
SPS Agreement and that it does not require the sa me type of analysis as a quantitative risk 
assessment."  The EC's argument is a non sequitur .  Nowhere does the Appellate Body determine that, 
just because a Member need not identify a "certain  magnitude or threshold level of risk", that the 
Member's risk assessment may be devoid of form or scientific rigor.  Neither did the Appellate Body 
grant Members license to assert scientific conclusion s in their risk assessments that are unsupported 
by the scientific evidence.41  Nor does the Appellate Body stipul ate what form a risk assessment must 
take.  Rather, Members must conduct a risk assessm ent within the meaning of Article 5 and Annex A 
                                                      
39 See US Comments on the Experts' Responses, fn. 222. 
40 See Dr. Boobis Responses (Question 62), p. 58 ("[t]he evidence obtained did not indicate any 
additional concern regarding the risk from exposure to residues of the hormones in meat from cattle treated for 
growth promotion.")  See Dr. Boobis Responses (Question 48), p. 42 (the EC has made "no attempt to evaluate 
the risks" from misuse, either in its Opinions or in un derlying studies); Dr. Boiss eau Responses (Question 51), 
p. 25 ("the [EC] did not conduct a quantitative risk assessment from growth promoters, [and that] it is not possible to say the scientific evidence referred to by th e [EC] assesses the risk to human health from residues 
resulting from these misuses/abuses.")  See Appellate Body Report, paras 205-207. 
41 This fact has been subsequently confirmed by the compliance panel in the Japan – Apples  dispute, 
which found that the scientific conclusions reached by  a Member in its risk assessment must actually be 
supported by the scientific evidence relied on in the risk assessment.  See Panel Report,  Japan – Apples (21.5) , 
para. 8.145 (finding that "[s]ince the scientific evidence relied upon  by Japan does not support the conclusions  
reached by Japan in its 2004 PRA, we conclude that the 2004 PRA is not an  assessment, as appropriate to the 
circumstances , of the risks to plant life or health, within the meaning of Ar ticle 5.1 of the SPS Agreement.") WT/DS320/R/Add.6 
Page F-150  
 
  of the SPS Agreement.  The experts responses are ther efore very informative in terms of what does or 
does not constitute a qualitative risk assessment.
42 
29. The EC also notes that "[i]nterestingly, the US EPA uses no-threshold models for 
non-genotoxic chemicals, such as dioxins and PCBs, due to a combination of very long half-lives and activity at very low doses."  However, the EC's re ference to EPA's assessment of dioxin illustrates the 
stark contrast between the EC's analysis of estradiol 17 β and the standard paradigm for risk 
assessment.  EPA's assessment of dioxin did not so lely rely on generic arguments of additivity to 
background as the EC proposes here, but instead reviewed in great depth studies which provided insight into the appropriate approach to extrapol ation from low doses to likely exposure levels.  The 
EC's analysis lacks a comparable assessment. 
30. Question 12
:  The EC argues that the responses of Drs. Boisseau and Boobis are incorrect 
"because of their extremely narrow understanding of th e concept of scientific uncertainty."  In support 
of this argument, the EC contends that both Dr. Boisseau and Dr. Boobis have inappropriately relied 
on the safety factors employed by JECFA in its risk  assessments. According to the EC, "there is now 
almost universal agreement that this approach [ i.e., JECFA's use of safety factors] is not scientifically 
correct."  The EC provides no scientific evidence in s upport of this conclusion.  Further, it is unclear 
how there can be "universal agreement" that JECFA's use of safety factors is "not scientifically correct" when the very two experts asked by the Pa nel to speak to this issue believe that JECFA's 
approach is scientifically correct
.43 
31. The EC also cites to the 2002 US Report on Ca rcinogens as "contradict[ing] the allegations 
made by the United States ... in these proceedings, which appears [ sic] to be supported by Dr. Boobis, 
that the additional burden of residues coming from ea ting hormone-treated meat is so small that it 
would make no difference, compared to the level of endogenous production."  Contrary to the EC's 
claim, in this dispute the US has accepted that concentrations of estradiol 17 β may be slightly higher 
in edible tissues following treatment of  cattle with estradiol 17 β to promote growth.44  The United 
States has simply argued, and demonstrated with evidence, that residue levels of hormones in meat 
from treated cattle would be within the physiological range  of residue levels in meat from untreated 
cattle.45  This position is entirely co nsistent with the statement quoted by the EC from the 2002 Report 
on Carcinogens.   
32. The more complicated question posed to the experts was whether these marginally increased 
amounts of estradiol 17 β are sufficient to elicit effects in the human consumer.  As noted in the US 
                                                      
42 See, e.g., Dr. Boobis Responses (Question 11), p. 16. 
43 For a discussion on sensitive populations, see US Comments on the Experts' Responses, Section 
C.4(c) 
44 See US First Written Submission, para. 51 ("Further, concentrations of estradiol 17 β in meat from 
treated cattle do not vary significantly from concentrations in untreated cattle, i.e., residue levels in meat from 
hormone-treated cattle are well within the physiological ra nge of residue levels in untreated cattle.  While tissue 
concentrations of estradiol 17 β in treated cattle may be slightly higher than those in untreated cattle , this 
increase is much smaller than the large variations observed in (reproductively) cycling and pregnant cattle and is 
thus well within the range of naturally observed levels.")  (Emphasis added). 
45 Indeed, the experts agree with the US statement generally, but disagree as to the number of pregnant 
cattle actually entering the human food chain.  But see 2005 Draft Report of the Veterinary Products Committee, 
Risks Associated with the Use of Hormonal Substances in Food-Producing Animals, § 1.6 ("2005 U.K. Report") 
(Exhibit US-20) ("In addition, a proportion of cows/heifers entering the food chain are pregnant.  Meat from these individuals can also contain higher levels of oestrogen produced by the foeto-placental unit.  When the 
predicted removal of the ban on the inclusion of meat from cattle over 30 months into the food chain occurs, 
approximately 25% of cull cows entering the food chain are likely to be pregnant (Singleton and Dobson, 1995)
.  
Meat from these animals will add signifi cantly to the oestrogen concentrations currently entering the food chain 
from this source.")  WT/DS320/R/Add.6 
 Page F-151 
 
 
  Rebuttal Submission, the 2002 Report on Carcinogens indicates that they are not, concluding, "[t]he 
evidence is strong that estrogen carcinogenesis is  mediated through activation of the estrogen 
receptor ", in other words, by the much higher con centrations of estrogens necessary to elicit a 
hormonal effect.  Not, as the EC appears to insinua te, by concentrations found in meat products from 
cattle treated with hormones for growth promotion purposes.46 
33. As noted by the United States in its Rebuttal Submission, the Report on Carcinogens' 
conclusion that estrogens are "known to be human carcinogens"47 is unexceptional when applied to 
estrogens generally, as it is in the cited Report.48  As noted in the US First Written Submission, there 
have been a number of epidemiological tests focu sed on women and the use of hormone replacement 
therapies and oral contraception, both of which contain estrogens.49  The Report on Carcinogens takes 
these studies into account in its analysis, as well  as the conclusions of the 1999 Report of the 
International Agency for Research on Cancer ("IARC").50  JECFA took these same studies into 
account in 1999, noting the "[e]pidemiological studies on women who took estrogens alone or in combination with progesterone and androgens, showed that the risks for cancers at most sites were 
unaffected; however, the risks for cancers of the endometrium and breast were increased."
51  
However, it attributed these effects to the "hormonal effects of estrogens", i.e., to levels of estradiol 
17β or other estrogens high enough to ha ve a hormonal effect on the consumer.52  This is one of the 
reasons that JECFA determined that levels of estradiol 17 β found in meat from cattle treated with the 
hormone for growth promotion purposes according to good veterinary practices (levels exponentially 
lower than those causing hormonal effects) are safe.   
34. The EC also notes that "neither Dr. Boobis nor  Dr. Boisseau mention the fact that the IARC 
has classified oestradiol-17 β in Group 1 as carcinogenic to humans because there is sufficient 
evidence of carcinogenicity and progesterone and testosterone in Group 2B as possibly carcinogenic 
to humans."  However, the fact that Drs. Boobis and Boisseau have not cited to IARC is not at all 
surprising in light of the fact that IARC's conclu sions do not relate to the levels of any of these 
hormones found in meat from cattle treated for growth promotion purposes (the subject of this 
dispute).  The EC's CVMP, in concluding that neither estradiol 17 β nor progesterone are genotoxic, 
studied the 1999 IARC Report referred to by the EC in its comments.  The CVMP concluded:  "the 
recent extensive reviews by IARC and JECFA also confirmed that the tumorigenic action of 
hormones, in particular 17 β-oestradiol, in animals and man ar e the consequence of the receptor-
mediated, cell division stimulating activity of these compounds  in somatic target cells, and that 
the potential genotoxic properties of the compou nds would not be expressed in vivo and/or not 
play a role in the tumorigenic activity ."53  Therefore, if anything, Drs. Boisseau and Boobis could 
                                                      
46 See 2002 Report on Carcinogens, p.1.  (Emphasis added).  Note also that the Report on Carcinogens 
applies to estrogens generally.  ("This listing of steroida l estrogens ... applies to all chemicals of this steroid 
class.") (Exhibit US-26).  See US Rebuttal Submission, paras. 38-40. 
47 Replies to Questions from the Panel after the First Substantive Meeting by European Communities, 
paras. 98-99. 
48 See 2002 Report on Carcinogens, p.1 ("This listing of  steroidal estrogens ... applies to all chemicals 
of this steroid class.") (Exhibit US-26).  Indeed, the 1987 Report of the IARC reached a similar conclusion 
regarding estrogens generally, but the Hormones panel determined that this conclusion had been taken into 
account by the relevant JECFA safety assessments addr essing the relevant risk – that from estradiol 17 β residues 
in meat from cattle treated with the hormone for growth promotion acco rding to good veterinary practices.  See 
Panel Report, para. 8.129. 
49 See US First Written Submission, paras. 56, 69, 127, 146.  
50 See 2002 Report on Carcinogens, p.1.  (Exhibit US-26). 
51  52nd JECFA Report (2000), p. 60.  (Exhibit US-5). 
52  52nd JECFA Report (2000), p. 60.  (Exhibit US-5). 
53  1999 CVMP Report, pp. 8-9 (Exhibit US-5), citing the 52nd JECFA Report and the 1999 Report of 
the International Agency for Research on Cancer.  (Emphasis added).  See also  2005 U.K. Report, § 1.5.1, WT/DS320/R/Add.6 
Page F-152  
 
  have cited to IARC in support of the conclusion that any effects of estradiol 17 β would result from 
levels of the hormone causing hormonal effects, ra ther than the exponentially smaller amounts found 
in residues in meat from treated cattle. 
35. Finally, as noted in paragraphs 13-14 above, desp ite the EC's statements to the contrary, the 
conclusions reached by the EC's CVMP on the natura l hormones are indeed relevant to this dispute 
because they relate to the fundamental action of th e hormones.  At levels lower than those causing a 
hormonal effect, hormones such as estradiol 17 β and progesterone, whether used for growth 
promotion, or zootechnical and therapeutic purposes ar e either genotoxic or they are not regardless of 
whether they are used for growth promotion, zootechnical or therapeutic purposes.  The CVMP 
concluded that they are not. 
36. Question 13
:  The EC attempts to discount the advi ce of Drs. Boisseau (who concludes that 
"the EC risk assessment did not supp ort that residues of oestradiol-17 β, despite the genotoxic 
potential of this hormone, can initiate and promot e tumours in humans") and Boobis (who concludes 
that "[t]he EC has not identified the potential fo r adverse effects on human health of residues of 
oestradiol found in meat from treated cattle.  This  is because the analysis undertaken was focused 
primarily on hazard identification") by noting that JECFA concluded that "the carcinogenicity of 
oestradiol-17 β is most probably a result of its interacti on with hormone receptors."  The EC's citation 
to JECFA is puzzling in light of the fact:  (1) that JECFA determined that the natural hormones had not been shown to be genotoxic in vivo, and (2) the negative implication of JECFA's conclusion 
above is that estradiol 17 β is not carcinogenic at the expone ntially lower levels (non-hormone 
receptor stimulating levels) found in residues in me at from treated cattle.  If the EC is implying that 
one can hypothesize a risk that estradiol 17 β is genotoxic at levels found in meat from treated cattle, 
such a hypothetical risk alone cannot support its ba n on meat and meat products treated with estradiol 
17β.  And the United States has shown that the scie ntific evidence does not support this hypothetical 
risk. 
37. Although the EC opines that "carcinogenicity of estrogens is primarily due to oxidative 
stress/DNA adduct formation caused by the catechol metabolites of estrogens," it has put forward no 
evidence that catechol metabolites initiate or promote tumors in vivo.
54  In addition, while the EC 
notes that "it is also necessary to consider estradiol -alpha as residues susceptible to be metabolized in 
consumer [ sic] in catechol derivative with the same potency as estradiol to  give adducts or to induce 
oxidative stress," it produces no evidence in support of this conclusion.  In cattle, estradiol 17 α is the 
primary metabolite of estradiol 17 β.  Here, the EC is suggesting that estradiol 17 α is present in beef 
and may be further metabolized in the human consum er to catechol estrogens.  This argument is weak 
for several reasons: (1) Maume  et al.55 demonstrated that estradiol 17 α concentrations are elevated 
only in liver and kidney, but not muscle, following administration of a single implant; (2) the EC attempted but was unable to provide evidence estradiol 17 α can be converted to catechol estrogens by 
human intestinal cells
56; and (3) estradiol 17 α does not appear to be carcinogenic57 and thus does not 
fit into the EC's theory that estrogens are genotoxic carcinogens (via catechol metabolites). 
38. Finally, the EC's support of Dr. Guttenplan's remarks ignores the fact that Dr. Guttenplan 
notes that "[t]he evidence evaluating the occurrence of adverse effects is weak"58; that the EC's 
                                                                                                                                                                     
("Overwhelming evidence suggests that sex steroids exert effects that are dose-dependent and that a threshold 
dose exists, below which, no biological effect will occur.")  (Exhibit US-20). 
54 See US discussion of the Bhat  and Russo  papers in its comments on Question 7 above. 
55 Exhibit EC-78. 
56 Exhibit EC-51C. 
57 Fritsche S. and Steinhart H.  Occurrence of hormonally active compounds in food: a review.  Eur 
Food Res Technol 1999; 209:153-179. 
58 Dr. Guttenplan Responses (Question 13), p. 3.  WT/DS320/R/Add.6 
 Page F-153 
 
 
  Opinions receive a "mixed rating in following Codex guidelines"59; that "an adverse effect cannot be 
ruled out, but it is unlikely if good veterinary practices are followed"60; and that, regarding the Syrian 
hamster model, "[a]s kidney is not a known target of estradiol in humans the extrapolation to humans 
is uncertain."61  The EC also cites to additional studies on which it allegedly based its permanent ban 
on estradiol 17 β.  Several of these studies were not yet pub lished at the time the EC completed the 
1999 or 2002 Opinions on which it allegedly based its  ban.  Therefore, these studies are not relevant 
to an analysis of the EC's "risk assessment" or whether its permanent ban on estradiol 17 β is based on 
a risk assessment within the meaning of Article 5. 1 of the SPS Agreement.  Regardless, as discussed 
below, none of these studies supports the EC's argument.   
39. For example, in Turan et al., rats that were exposed con tinuously to very high doses of 
estradiol 17 β – levels much higher than those derived fro m beef from cattle treated with estradiol 17 β 
to promote growth – developed mammary tumors.  Ho wever, treatment of rats with catechol estrogens 
(the alleged "bad actors" implicated by the EC's genotoxic hypothesis) did not induce tumors.  This 
study confirms the "association of elevated  prolonged exposure to endogenous and exogenous 
estrogen with breast cancer" (a conclusion that is not  relevant to the much lower levels of hormones 
residues found in meat from treated cattle),  but it actually provides evidence against  the EC's theory 
that catechol estrogens are the mech anistic basis for this cancer.   
40. In Yue et al., spontaneous development of mammary tumors was characterized in 
ERKO/Wnt-1 mice.62  The authors qualify their results as "preliminary" and point out several pitfalls 
of interpreting data from ERKO/Wnt-1 mice.  In these mice:  (1) circulating estradiol 17 β  levels are 
3-5 times higher than normal; (2) the capacity of mammary tissue to inactivate 4-OH estradiol (the 
alleged "bad actor" in the EC's genotoxic hypothesis) is impaired; and (3) it is possible that low levels 
of estrogen receptor may be expressed.  Therefore, th e preliminary results of this study do not provide 
definitive evidence that mammary tu mors can develop in the absence of estrogen receptors.  Instead, 
the results simply indicate that mammary tumors  in ERKO/Wnt-1 mice develop in the presence of 
supraphysiological concentrations of estrogen and abnormally high concen trations of catechol 
estrogens , and it cannot be ruled out that this tumorigen esis is mediated, at least in part, by estrogen 
receptors.   
41. In Takahashi et al., adenocarcinomas were induced in mice exposed subcutaneously to low 
doses of estradiol 17 β in conjunction with intrauterine admi nistration of the chemical carcinogen 
ENU.  As explained in paragra phs 73 and 78 of the US Comments  on the Experts' Responses, the 
subcutaneous (injected into the animal) route of estradiol 17 β administration is not relevant to oral 
ingestion of estradiol in beef (how beef is act ually consumed) because it bypasses the extensive first-
pass metabolism in the intestine and liver which accom pany oral ingestion or consumption of beef.  
Therefore, the relevance of the Takahashi study to potential effects of estradiol 17 β in beef is 
questionable.  
42. The EC also notes that "it is hypothesized that the number of potentially carcinogenic tissue 
cells determines the risk of getting the cancer," but at the present time this hypothesis is purely 
speculative, and has not been supported by experiment al evidence.  As noted in a paper provided by 
the EC by Smalley and Ashworth, "no definitive id entification has been made of an adult mammary 
stem cell."63 
                                                      
59 Dr. Guttenplan Responses (Question 14), p. 4. 
60 Dr. Guttenplan Responses (Question 15), p. 4. 
61 Dr. Guttenplan Responses (Question 14), p. 3. 
62 ERKO/Wnt-1 mice are genetically engineered  to lack expression of estrogen receptor α. 
63 Exhibit EC-100. WT/DS320/R/Add.6 
Page F-154  
 
  43. Finally, the Ahlgren et al .
 paper is an epidemiological study of Danish women which 
concludes that birth weight and growth during chil dhood are associated with risk of breast cancer.  
The Ahlgren study did not examine stem ce ll populations or exposure to estradiol 17 β, and is 
therefore irrelevant to the analysis at hand. 
44. Question 14 :  The EC appears to cite to Dr. Boissea u's response in support of its contention 
that it has conducted a risk assessment for estradiol 17 β.  However, the United States has been unable 
to locate any support for the EC's position in Dr. Bo isseau's response.  Instead , the United States notes 
that Dr. Boisseau comments that the EC "only claims " to have conducted a risk assessment.  Nowhere 
does he note his agreement that the EC has actu ally done so.  As for the EC's citation to 
Dr. Guttenplan, as noted above, Dr. Guttenplan concl udes that the EC's Opinions receive a "mixed 
rating in following Codex guidelines"; that hazard ch aracterization is "limited" due to the animal 
model involved (Syrian hamster kidney; kidney is  not a known target in humans and therefore 
extrapolation is uncertain); and that "risk charact erization is very qualitative at best."  The EC 
attempts to salvage Dr. Guttenplan's view of its "limited" hazard characterization with citations to 
studies that were apparently neither included in th e Opinions nor presented by the EC in the course of 
these proceedings in support of its measure.   
45. The EC notes that it "disagrees" with Dr. Boobis.  The EC provides no rationale for why 
Dr. Boobis' response is not appropriate or based on th e scientific evidence, other than that it feels he 
has not given the EC Opinions a "careful readi ng."  Most likely the EC disagrees with Dr. Boobis 
because he concludes that "the EC risk assessment of  oestradiol does not follow the four steps of the 
Codex risk assessment paradigm.  Even if it were concluded that oestradiol is a genotoxic carcinogen, 
the four steps should have been followed." 
46. Question 15 :  The EC notes, for Dr. Guttenplan's "benefit" that the Appellate Body has 
interpreted "potential" to mean "possible."  It is not  clear that this clarification is necessary, however, 
as Dr. Guttenplan already assumed that "[i]f potential is taken to mean possible" adverse effects are 
"unlikely if good veterinary practices are follo wed."  As for Drs. Boobis and Boisseau, the EC 
attempts to dismiss their responses by noting that their opinions are "conditioned by their 
understanding that oestradiol-17 β is causing cancer only through receptor meditated processes," a 
position that, according to the EC "is however scientifi cally no longer tenable in light of more recent 
evidence cited by the European Communities."  The United States notes that the responses of 
Dr. Boobis and Dr. Boisseau are premised on a review of the very same evidence referred to by the 
EC.  Drs. Boisseau and Boobis determined, upon review  of that evidence, that their understanding is 
that oestradiol-17 β causes cancer only through receptor mediated  processes and that the EC has failed 
to present any evidence that would cause them to conc lude otherwise.  The EC comments that if the 
Panel "read[s] between the lines" of Dr. Boobis' and Dr. Boisseau's responses, it will note that they "do not seem to deny completely the existence of  possible adverse effects."  The EC provides no 
evidence in support of this conjecture. 
47. Dr. Cogliano, while noting that the identification of estradiol 17 β as a human carcinogen 
"indicates that there are potential adverse effects on human health"
64 when it is consumed in meat 
from treated cattle nevertheless also comments that "it has not been establi shed by the EC that 
genotoxicity and cell proliferation would be induced  by levels found in meat residues added to the 
pre-existing levels occurring in exposed humans,"65 a statement which appears to endorse the 
                                                      
64 Responses to Questions from the Panel of Dr. Vincent Cogliano ("Dr. Cogliano Responses") 
(Question 15), p. 1. 
65 Dr. Cogliano Responses (Question 18), p. 1.  WT/DS320/R/Add.6 
 Page F-155 
 
 
  conclusion that the EC has failed to demonstrate th at carcinogenic or genotoxic effects will be caused 
by estradiol 17 β residues in meat from treated cattle.66 
48. Question 16 :  As noted above, the EC attempts to dismiss the opinion of Dr. Boisseau by 
noting that he has relied on the conclusions of JECFA, which the EC views as outdated, and has 
ignored the "more recent evidence" cited by th e EC "showing the direct genotoxic potential of 
oestradiol 17 β, progesterone, zeranol and most probable [ sic] testosterone."  As demonstrated by the 
United States and confirmed by th e experts' responses, the EC has not shown these effects.67  
Therefore, it is perfectly reasonable for Dr. Boisse au to rely on JECFA's conclusions regarding the 
hormones.  Regarding MGA and trenbolone acetate, the EC notes that "the evidence may be inconclusive but there are sufficient indications to treat them as such [genot oxic], despite the serious 
gaps in our scientific knowledge."  However, th e experts' responses have confirmed that these 
hormones are not genotoxic
68 and that there are not "serious gaps" in the scientific knowledge relating 
to MGA and trenbolone acetate.69  Indeed, results of one of the EC's own "17 Studies" indicate that 
MGA was devoid of genotoxic activity, and that tr enbolone and zeranol are non-genotoxic except at 
very high, cytotoxic ( i.e., high enough to kill the cell) concentrations.70 
49. The EC refers to Dr. Boobis' re sponse as "legally inappropriate"71 in an attempt to discard the 
factual findings made by Dr. Boobis, which appear to be based on a thorough review of the scientific literature:  "[t]he carcinogenic effects of oestradiol  appear to be the consequence of its endocrine 
activity"; and "the guidelines on genotoxicity testing require confirmation of an in vitro positive using 
an appropriate in vivo assay" (citing to guidan ce drafted by the EC's own CVMP in 2004).   
50. The EC attempts to bolster its argument by claiming that Dr. Guttenplan "concludes that the 
more recent evidence cited by the European Comm unities does support the finding that the genotoxic 
action of these hormones is not related only to thei r hormonal activity."  However, the United States 
does not understand Dr. Guttenplan's response to be as unequivocal as the EC suggests.  Rather, 
without citation to specific scientific evidence,
72 Dr. Guttenplan on the one hand notes that the EC's 
Opinions "do indicate that a mechanism other than ho rmonal activity is possible" but that on the other 
"the United States and Canada cite  other reports indicating that ge notoxic effects of estrogens are 
unlikely."  This is far from a conclusion that the studies cited by the EC support the conclusions reached by the EC in its Opinions.  Further, Dr . Guttenplan notes elsewhere that while "an adverse 
effect cannot be ruled out, [] it is unlikely if good veterinary practices are followed,"
73 which would 
                                                      
66 See US Comments on Experts' Responses, para. 43. 
67 See, e.g., US Comments on the Experts' Responses, paras. 34-45; 83-85.  See also  Dr. Cogliano 
Responses (Question 18), p. 1 ("it has not been establis hed by the EC that genotoxicity and cell proliferation 
would be induced by levels in meat residues added to the pre-existing levels occurring in exposed humans.") 
68 See, e.g., Dr. Guttenplan Responses (Question 21), p. 6 ("[t]here is no conclusive evidence presented 
by the EC that the five hormones other than oestradiol-17 β, when consumed as residues in meat have genotoxic 
potential."). 
69 See, e.g., US Comments on the Experts' Responses, pa ras. 49-58.  The EC  also comments that 
Dr. Boisseau did not take into account "qualitative assessmen t of risk" in his response.  As noted above, as an 
expert, there is no reason that he should have since this is  a legal determination.  In addition, the simple fact is 
that, regardless of whether a Member conducts a qua litative or quantitative assessment, the conclusions reached 
in that assessment must actually be supported by the underlying scientific evidence.  The experts have 
confirmed that the scientific  evidence relied on by the EC does not supp ort the conclusions it has reached on the 
hormones ( e.g., that they are genotoxic at levels found in residues from meat from cattle treated for growth 
promotion purposes).  See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146. 
70 See Exhibit EC-8. 
71 As noted above, Dr. Boobis' response, as would be  appropriate for any experts' response, does not 
appear to make any legal statements or findings; it is ther efore difficult to see how it is "legally inappropriate".   
72 The United States was unable to locate the citation to the study referred to in the EC's Comments in 
Dr. Guttenplan's actual response to Question 16. 
73 Dr. Guttenplan Responses (Question 15), p. 4. WT/DS320/R/Add.6 
Page F-156  
 
  appear to demonstrate that he is not, in fact, of the mind that levels of residues in meat from cattle 
treated with hormones for growth promotion purposes would be carcinogenic. 
51. Finally, on a general note, the United States obser ves that the EC defines its appropriate level 
of protection for risks from the six hormones as "no risk
 from residues of these hormones," as 
evidence for why its situation is different than th at contemplated by JECFA.  To date, the United 
States understood the EC's appropriate level of protecti on to be one of "no additional or additive risk" 
from residues of hormones used as grow th promoters, particularly in light of the fact that the EC 
defines its level of protection as such in its 1999 Op inion at Section 1.2 ("[t]he prohibition reflects the 
fact that the EC chose a level of sanitary pr otection of accepting no or 'zero' additional risk  to human 
health from the residues in meat and meat pr oducts of these hormones when used for growth 
promotion purposes.")  As confirmed by the expert s in their responses to Panel Question 51, the EC 
did not address this risk.  If the EC now defines its level of protection as "no risk", it should 
accordingly ban all uses of the hormones (incl uding the currently permitted zootechnical and 
therapeutic administrations), as well as the consum ption of meat, eggs and any other food products 
naturally containing any of the six hormones.   
52. In addition, the EC notes that its appropriate level of protection is a "quantitative term" (as 
opposed to the allegedly unacceptable "qualitative" le vel of protection set by JECFA), yet it goes on 
in great detail in its comments to argue that  it was simply required to conduct a qualitative 
assessment, and that references to quantitative analyses are inappropriate.  At best, the EC's position 
on what sort of assessment it was required to complete  is conflicted, particularly if, as it appears to 
argue in its comments on Question 16, JECFA's assessment was too "qua litative" for the EC's 
purposes. 
53. Question 17 :  The United States notes that the EC's  conclusion that "as Dr. Guttenplan 
correctly states, the lack of catechols in meat does not imply that meat from estrogen-treated cattle is 
without risk for genotoxicity," is unexceptional.  Neither does the lack of catechols imply that meat 
from treated cattle is  a risk for genotoxicity.74  Although the experts agree that the presence of these 
metabolites would be important to consider in  assessing the genotoxic potential of estradiol 17 β, they 
also agree that the materials relied on by the EC fa iled to detect catechol residues in meat.  In the 
absence of scientific evidence for such residu es in meat from cattle treated with estradiol 17 β for 
growth promotion purposes, it is impossible for the EC to conclude that catechol estrogens derived 
from edible bovine tissues are genotoxic and thus have carcinogenic or tumorigenic effects.75 
54. The EC notes that "more worrying from the human health point of view is the part of 
estrogens (estradiol, estradiol-alpha or estrone) wh ich will be metabolized in[to] catechol derivatives 
in target tissues."  However, as noted in the US discussion in Question 13 above, the EC has not 
provided any evidence to indicate that either estradiol 17 α or estrone can be converted to catechol 
estrogens in humans.  The EC comments that this  concern "is the reason for which it is necessary to 
perform a complete residue analysis with more powerful detection methods."  However, upon review 
of the exhibits put forward by the EC, it appears as though the EC has already done just this.  In 
Exhibit EC-51A, it is concluded that "[a]n almost  complete reassessment of estrogen residues in 
edible tissues of estradiol-17 β treated animals has been performed."76  
55. The EC also notes that "the fact that e xposure to catechol metabolites does not cause 
mammary tumorigenesis does not necessarily negate  the possibility that the catechol metabolites 
formed in mammary tissue play  a role in mammary tumorige nesis ... because administered 
                                                      
74 See Appellate Body Report, para. 186. 
75 See generally  US Comments on the Experts' Responses, para. 44. 
76 The results of this comprehensive study were not discussed by Dr. De Brabander, the Panel's expert 
in residue chemistry.  WT/DS320/R/Add.6 
 Page F-157 
 
 
  metabolites may not reach levels in mammary tissue comparable to those achieved by metabolism of 
estradiol to the catechols within the mammary itself."  However, the credibility of this statement relies 
on the comparison between concentrations of ca techol estrogens in the mammary tissue of 
experimental animals with those actually found in normal human mammary tissue in vivo.  To date, results of this critical comparison have not be reported by the EC.   
56. The EC "can only explain[]" the responses of Drs. Boisseau and Boobis by impugning their 
qualifications and by citing to a re mark from a scientist at the meeting of the experts in the original 
Hormones  proceedings.  The EC presents no scientific evid ence that discounts the statements of either 
Dr. Boobis or Dr. Boisseau.  Further, its citation to the Appellate Body remarks appears to focus more 
on the Appellate Body's concern that the expert in the original proceedings made a claim without any 
apparent scientific underpinning whatsoever .  In contrast, the responses of Drs. Boisseau and Boobis 
are based on an analysis of the scientific materials on the record in these proceedings.77 
57. Question 18 :  The EC notes its agreement with the st atement of Dr. Cogliano, but apparently 
only refers to a limited portion of Dr. Cogliano's re sponse.  Dr. Cogliano concludes that "the issue, 
though is whether [] genotoxicity would occur at levels  found in meat residues."  As to this issue, "it 
has not been established by the EC that genotoxicity and cell proliferation would be induced by levels 
found in meat residues added to the pre-existing levels occurring in exposed humans ."  Therefore, 
Dr. Cogliano's response appears to directly contradict  the EC's assertion that levels of hormone 
residues found in meat from treated cattle would be genotoxic. 
58. As noted by the United States in its Comments on the Experts' Responses, while 
Dr. Guttenplan notes that there is evidence that estradiol 17 β is genotoxic, he does not conclude that it 
would be genotoxic at levels found in residues in  meat from cattle treated for growth promotion 
purposes.  Indeed, his statement that while "an adver se effect cannot be ruled out, [] it is unlikely if 
good veterinary practices are followed,"78 appears to indicate that he is not of this opinion.79 
59. The EC claims that the issue is "not whether the [EC] has established  that genotoxicity and 
cell proliferation would be induced by levels found in meat residues," but rather whether the United 
States has demonstrated that "this adverse effect woul d not occur."  This is a remarkable claim by the 
EC, and a weak attempt to shift the burden of pr oof.  When it chose to impose a ban on meat from 
cattle treated with hormones for growth promo tion purposes premised on its conclusion that the 
residues would be genotoxic, the EC assumed the burden  of proving that this is actually the case.  It 
has failed to do so, and the experts have confirmed this fact in their responses.  The United States has 
argued in detail why the EC has failed to support this  conclusion with scientific evidence in its various 
submissions to the Panel.80  Further, as noted by the Appellate Body, "science can never provide 
absolute certainty that a given substance w ill not ever have adverse health effects."81  Rather the 
relevant analysis is whether the EC, in suppor t of its ban, has adduced sufficient evidence to 
                                                      
77 Dr. Boisseau's response cites directly to the EC exhibit relating to catechol metabolites.  Further, it is 
unclear to the United States what relevant laboratory experience the other two experts have in examining 
catechol metabolites in hormone residues in meat and meat products; yet, the EC does not complain about their qualifications. 
78 Dr. Guttenplan Responses (Question 15), p. 4. 
79 The EC cites to a 2006 study it alleges supports Dr. Guttenplan's statement, yet that was not cited by 
Dr. Guttenplan himself.  The United Stat es notes that the date for submission of scientific evidence is well-past, 
and that the EC reached its de finitive conclusion (such that it imposed a permanent ban ) on this issue in 2003.  It 
is therefore unclear how a 2006 study can justify Opinions  drafted and a measure adopted three years prior to its 
publication. 
80 See, e.g., US First Written Submission, paras. 152-153;  US Rebuttal Submission, Section II.B(3), pp. 
15-18 (titled "The EC's Opinions fail to take into acco unt available scientific evidence relating to genotoxicity 
and carcinogenicity of estradiol 17 β") 
81 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153. WT/DS320/R/Add.6 
Page F-158  
 
  demonstrate a risk from meat from cattle treated with estradiol 17 β for growth promotion purposes, 
including that estradiol 17 β is genotoxic at levels found in residues in meat from treated cattle. 
60. Finally, the EC dismisses the comments of Dr. Boisseau as "beside the point" and Dr. Boobis 
as "lack[ing] conviction," yet apart from this rhetor ic provides no scientific argument to discount their 
advice to the Panel.  Contrary to the EC's asserti on, Dr. Boobis has apparently engaged in extensive 
analysis, including of the alleged EC evidence clai ming in vivo proof of genotoxicity, in reaching his 
conclusion that "the evidence is against any genotoxic ity in vivo."  Dr. Boisseau concludes, by citing 
to his response to Panel Question 13, directly "on poi nt" to the Panel's query:  "[i]n conclusion, the EC 
risk assessment did not support that residues of oestradiol 17 β, despite the genotoxic potential of this 
hormone, can initiate and promote tumors in humans."  
61. Question 19
:  The EC notes that it agrees with the "t hrust" of Dr. Guttenplan's response, and 
then appears to pose a question and offer a response which is not in fact included in Dr. Guttenplan's 
response.  The United States analyzes Dr. Guttenplan 's response in detail in  paragraph 38 of its 
Comments on the Experts' Responses.  The EC also  notes that "although DNA repair can occur, it 
presumably is occurring at all doses and the fract ion of DNA damage repaired probably does not 
change at physiological levels, because the repair  enzymes are unlikely to be saturated."  This 
statement, which the EC attributes to Dr. Guttenplan, appears to further highlight the fact that the EC 
should have (but failed to) taken DNA repair mechanisms  into account in its Opinions.  Further, since, 
as confirmed by the EC, the repair enzymes are not  saturated under physiological conditions, then it 
stands to reason that these enzymes have the capacity for increased activ ity when exposed to 
xenobiotics or elevated concentrations  of endogenous genotoxic substances.82  Therefore, increased 
activity of DNA repair enzymes is a protective mechanism against DNA damage. Of course, the 
capacity for increased enzyme activity is finite and can be overwhelmed ( i.e., saturated) in the face of 
very high exposure  to genotoxic compounds, but there is no ev idence that this will occur in response 
to the very low amounts of estradiol 17 β in meat from treated cattle. 
62. The EC notes that "[a]fter all, whether cancer will occur as a result of genotoxicity or 
hormonal action is from the regulatory point of view  less critical, as the end result is the same: human 
cancer."  This statement seems contradictory to th e EC's arguments to date.  The EC has devoted 
considerable time, effort and resources in its attempt to demonstrate that estradiol 17 β is genotoxic in 
vitro, but has failed to provide convincing evidence that genotoxicity is the basis for estrogen-induced 
carcinogenicity in vivo.   
63. The United States has not been ab le to locate the statement ascr ibed to Dr. Boisseau by the 
EC in Dr. Boisseau's response, but notes Dr. Boi sseau's conclusion that "[t]he scientific evidence 
referred to by the [EC] does not demonstrate that this statement can also apply in the case of 
oestradiol-17 β, progesterone and testosterone  as these three natural hormones are produced by both 
humans and food producing animals."  As such, Dr . Boisseau's response appears to address the EC's 
concern that he somehow was not aware of, or ignored  the studies cited in the EC's Opinions.  The EC 
cites to the Hilakivi-Clarke  paper discussed in detail at paragraph 74 of the US Comments on the 
Experts' Responses. 
64. The EC also notes that Dr. Boisseau's statemen t "cannot be accepted scientifically" because 
"[i]n the EC's view , it is beyond doubt that there is a link between 17 β-oestradiol exposure during 
development ... and the risk of breast cancer later in life."  However, the "EC's view" of the scientific 
                                                      
82 See Brusick D.  Principles and Methods of Toxicology, 4th Ed., 2001, p. 825.  WT/DS320/R/Add.6 
 Page F-159 
 
 
  evidence and what the scientific ev idence actually demonstrates are two distinct concepts.  The EC 
has failed to demonstrate that the scientif ic evidence actually supports its view.83 
65. The EC does not provide any evidence or argumen t to discount Dr. Boobis' advice ("[t]here is 
no good evidence that oestradiol is genotoxic in vivo or that it causes cancer by a genotoxic mechanism.  Indeed, the evidence is against this
.  Hence, the scientific evidence does not support the 
EC on this issue , that the levels of the hormones in meat from treated cattle are not of relevance.") 
66. Question 20 :  The EC notes that Dr. Boobis' response "is based on his more erroneous 
underlying assumption that oestradiol-17 β is not genotoxic" and continues by noting that if 
Dr. Boobis' "assumptions are false, as the scientific  evidence clearly demonstrates, the Dr. Boobis' 
statement – which is already a qualified one – woul d make no sense."  The United States has noted at 
several points above that Dr. Boobis' conclusions ar e indeed based on the scientific evidence, and that 
it is the EC who has failed to adduce the nec essary evidence to support the conclusions it has 
proposed regarding estradiol 17 β.  Further, Dr. Boobis' conclusions  ("I do not believe that JECFA's 
conclusion that oestradiol has 'genotoxic potential'  affected its recommendations on this hormone"; 
"JECFA's conclusion on genotoxicity was based on pos itive results in certain in vitro tests, but the 
evidence was against a mutagenic response in vi vo") are supported by the responses of JECFA 
itself .84  The EC also notes that the responses of Dr s. Boisseau and Boobis should be discounted 
because "they have not done any direct experime nts on these hormones in their professional life and 
so lack specific expertise."  The United States has co mmented on this issue at several points above.  In 
this particular instance, judging from their  curriculum vitae , it would appear that Drs. Boisseau and 
Boobis have more relevant experi ence in terms of JECFA and Codex decision making than any of the 
other experts. 
67. The EC faults Drs. Boobis and Boisseau for "consider[ing] the assessments of JECFA as the 
Bible, although they know that the 1 988 and 1999 JECFA assessments are outdated  by today's 
evidence and scientific standards."  Nowhere in the responses of either expert was the United States 
able to locate a statement along these lines.  Rather, the responses of the two experts indicate that they 
do not believe the JECFA assessments to be "outdated." 
68. The EC also notes that, since the original  Hormones  dispute, the EC "has been consistently 
arguing [that] the genotoxicity of oestradiol-17 β is no longer seriously disputed and has now for the 
first time been accepted and written in the 1999 JECFA re port."  On the one hand, the fact that the EC 
has been arguing a point does not mean that the point  is actually supported by scientific evidence.  In 
fact the EC made this argument in the original  dispute and is here simply trying to overturn 
established WTO findings.  Indeed, the experts have confirmed that, insofar as the issue of 
genotoxicity relates to hormone residues in meat from cattle treated for growth promotion purposes, 
the evidence does not demonstrate a genotoxic effect.85  On the other hand, the experts have 
confirmed that JECFA's statement of "genotoxic pote ntial" did not affect its ultimate conclusion that 
the use of the hormones as growth promoters in cattle is safe.86 
                                                      
83 See the Responses of Drs. Boisseau , Boobis , Cogliano  and Guttenplan  to Panel Question 26 ("Does 
the scientific evidence referred to by the European Communities, in particular any epidemiological studies, 
identify a relationship between cancer and residues of hormonal growth promoters?  In its risk assessment of 
1999, the European Communities makes reference to the higher rates of breast and prostate cancer  observed in 
the United States as compared to the European Communities.  Can a link be established between these statistics 
and the consumption of meat from anim als treated with the hormones at issue ?") The experts unanimously 
confirm that the EC has not demonstrated a link between consumption of hormones residues in meat and breast 
cancer. 
84 See US Comments on the Experts' Responses, para. 41. 
85 See US Comments on the Experts' Responses, Sections C.2 and C.3(b). 
86 See US Comments on the Experts' Responses, para. 41. WT/DS320/R/Add.6 
Page F-160  
 
  69. In addition, the EC poses several questions to Dr. Boobis regarding whether he can "provide 
the necessary assurance" to EC author ities that residues in meat "will not increase the risk of cancer."  
The United States believes that the EC's rhetoric is entirely inappropriate for this exercise, in which 
the experts were requested to provide responses on sp ecific scientific issues presented by the Panel.  
The insinuation that Dr. Boobis is responsible for providing an assurance
 to the EC on these matters 
appears to be nothing more than a thinly-veiled a ttempt to coerce Dr. Boobis into changing his clear 
scientific opinions and honest review of the material s put forward by the EC in support of its ban.  
Further, as noted by the Appellate Body, "science can  never provide absolute certainty that a given 
substance will not ever have adverse health effects."87  Rather the relevant analysis is whether the EC, 
in support of its ban, has adduced sufficient evid ence to demonstrate a risk from meat from cattle 
treated with estradiol 17 β for growth promotion purposes.  The United States could just as easily ask 
the EC if it can provide the neces sary assurance to the United States that EC exports of alcoholic 
beverages will not increase the risk  to human health, or that EC exports of agricultural commodities 
will not increase the risk of exotic pests?  No one  can provide assurance that a risk could never be 
identified in the future, nor does th e SPS Agreement call for such an assu rance.  Rather the question is 
what does the current scientific evidence and principles support. 
70. Further, the EC quotes the Appellate Body's st atement that, while in most cases responsible 
governments base measures on "mainstream" evidence,  "[i]n other cases, equally responsible and 
representative governments may act in good faith on the basis of what, at a given time may be a divergent opinion coming from qualified and respected sour ces."  Be this as it may, it is clear that the 
Appellate Body did not exempt Members from providi ng a scientific basis and scientific evidence in 
support of that "divergent opinion",
88 and as argued by the United States and confirmed by the experts 
in their responses, the EC has failed to adduce the necessary evidence to support its "divergent 
opinion." 
71. Finally, the EC cites again to the 2002 Report on Carcinogens.  As noted in the US comments 
on the EC's comments on Question 12 above, this document simply does not stand for the conclusions 
drawn from it by the EC.89    
72. Question 21 :  The EC notes that it is "puzzled" by the responses of Drs. Boobis and Boisseau.  
Although the EC claims that JECFA "was more prudent" in its decisions than both of these experts, the United States fails to see any significant in consistency between JECFA's conclusions on the 
hormones and those of Drs. Boobis and Boisseau.  The EC claims that its Opinions "provide enough evidence to demonstrate that genotoxicity and other adverse effects from the hormones are possible," 
but the experts (including not just Drs. Boobis a nd Boisseau, but Dr. Cogliano) disagree, particularly 
if the EC is referring to levels of the hormones that would be found in residues in meat from cattle 
treated for growth promotion purposes.  
73. The EC attempts to bolster its argument by not ing that "[a]s Dr. Guttenplan states, their [the 
five hormones'] genotoxic potential may be weak but cannot be excluded."  However, this statement 
fails to take into account the other conclusions reach ed by Dr. Guttenplan:  "[t]here is no conclusive 
evidence presented by the EC that the five hormones other than oestradiol-17 β, when consumed as 
residues in meat have genotoxic potential," and: 
[t]estosterone and progesterone are negativ e in genotoxic assays. Zeranol can induce 
transformation of breast epithelial cells in culture with efficiency similar to that of estradiol, but the mechanism is not known, a nd it is negative or marginally active in 
                                                     
 
87 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153. 
88 See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146. 
89 See US Comments on the Experts' Responses, para. 41 and fn. 97  for discussion of the responses of 
Drs. Cogliano and Guttenplan.  See also  US Rebuttal Submission, paras. 38-40.  WT/DS320/R/Add.6 
 Page F-161 
 
 
  other assays.  Trenbolone is either negative or marginally active in in vitro genotoxic 
assays. MGA is negative in genotoxicity assays.  Any genotoxic effects of the five hormones are likely to be minimized by good veterinary practice.  My reply for the hormones would not have been different in September 2003 (SCVPH 2002 Opinion). 
It is clear from the actual text of Dr. Guttenplan's  response that he does not endorse the EC's argument 
that the five hormones are genotoxic. 
74. The EC notes that it has provisionally banned the five hormones "taking into account the 
numerous and serious gaps in our scientific knowle dge, which have been clearly identified in the 
SCVPH assessments."  However, as noted in Sec tion C.3(c) of the US Comments on the Experts' 
Responses, the experts have not identified "numer ous and serious" gaps in  the scientific knowledge 
relating to the five hormones.
90 
75. Question 22 :  The EC appears to have omitted a signi ficant portion of Dr. Boobis' response, in 
which he concludes, "[t]he DNA repair processes [] are amongst the most efficient  (Arai et al., 2006; 
Russo et al., 2004) and even if such modification did occur, it is anticipated that no heritable change 
would result, because of DNA repair (Arai et al., 2006).  This would be true even at the levels of 
exposure that could arise should GVP not be followed ."  The EC then argues that, if everything 
Dr. Boobis assumed were in fact false, then he wo uld have come to a different conclusion and he 
"should accept that DNA repair mechanisms are not su fficient to eliminate DNA damage."  The EC's 
argument is nonsensical, as the evidence underlying Dr. Boobis' response is not false, and he does not 
in fact endorse this conclusion. 
76. The EC attempts to cast doubt on the response of Dr. Guttenplan by noting that both he and 
Dr. Boobis "appear to miss an important point" but fails to present any evidence that discounts 
Dr. Guttenplan's conclusions on DNA repair mechanisms:  "[t]here is no reason to assume that DNA repair processes involved in DNA damage produced by estrogen metabolites are any more or less 
effective than those involved in repair of other carci nogens"; and "[t]he scientif ic material referred to 
by the [EC] for the most part doesn't address DNA repair."
91  The United States provides additional 
discussion on DNA mechanisms in its comments on Question 19 above. 
77. Question 23 :  The EC agrees with the statements of Drs. Cogliano and Guttenplan that a 
sufficiently long latency period for cancer should be  taken into account in the conduct of a risk 
assessment.  The United States notes that Dr. Boobis also agrees on this point, which is unexceptional 
in the context of this dispute since the six hormone s at issue have been used for growth promotion 
purposes in meat for a sufficiently long time (d ecades) to address this concern.  Dr. Boisseau :  "the 
hormones in dispute have already been used as gr owth promoters over a sufficient number of years , 
the epidemiological studies in humans already carried  out in this domain have failed to identify any 
relation between the occurrence of  hormonally dependent tumours and the consumption of meat 
containing hormonally active residues resulting from th e treatment of cattle with growth promoters."  
Dr. Boobis : "[t]he observational studies of humans (e.g . on HRT or oral contraceptives) and the 
experimental studies in animals covered a sufficiently long period  to encompass the latency period for 
any carcinogenic effects of the hormones."  Dr. Guttenplan : "[w]ith respect to hormones in meat, it 
appears they have now been consumed for a sufficient number of years  to observe strong or moderate 
increases in risk."  
                                                      
90 See generally  Responses of the Experts to Panel Question 61 and 62.  See U S  C o m m e n t s  o n  t h e  
Experts' Responses, Section C.3(c) for a discussi on of Dr. Guttenplan's response to Question 62. 
91 See US Comments on the Experts' Responses, para. 31 for further discussion of Dr. Guttenplan's 
response on DNA repair mechanisms. WT/DS320/R/Add.6 
Page F-162  
 
  78. Question 24
:  The EC avers that the experts' responses on confounding factors "also 
undermine indirectly the position of the US" without  providing any argument or explanation for why 
this is so.  The EC cites again to a study rega rding the frequency of breast cancer (cited in its 1999 
Opinion) and purports to draw a link between the use of hormones for growth promotion purposes and 
the incidence of cancer.  The experts have dismissed  this link in their responses to Panel Question 26 
(Boisseau :  (citing to his response to Question 23) "the hormones in dispute have already been used as 
growth promoters over a sufficient number of years, the epidemiological studies in humans already carried out in this domain have failed to identif y any relation between the occurrence of hormonally 
dependent tumours and th e consumption of meat  containing hormonally active residues resulting from 
the treatment of cattle with growth promoters; Boobis :  "[t]here is no scientific evidence 
demonstrating any association  between consumption of meat from animals treated with growth 
promoting hormones and the risk of cancer in humans; Cogliano :  "[t]he data  [relating to the 
difference in breast cancer rates] are not  sufficiently specific to establish a link  between these 
observations"; Guttenplan :  "[t]he epidemiological studies do not identify a relationship  between 
cancer and residues of hormonal growth promoters.  The references to the higher rates of breast and 
prostate cancer observed in the United States as co mpared to the European Communities are not very 
convincing as there is considerable variation in ra tes in different geographical locations.  Also, the 
differences in rates of breast and prostate cancer observed in the United States as compared to the 
European Communities are relatively small.") 
79. Question 25 :  The EC again attempts to dismiss the response of Dr. Boobis by questioning his 
qualifications as an expert.  This has been addressed at several points above.  The EC also alleges that 
JECFA's views are "based on data from the 1970s – 1980s" and that the EC has now provided "more 
recent evidence."  The statement regarding the dates of  materials examined by JECFA is simply false.  
For example, at its 52nd Meeting in 1999, JECFA evaluated sev eral pieces of recent scientific 
evidence.  Indeed, the EC recogni zes this fact in its Opinions.92  Further, the "more recent evidence" 
put forward by the EC does not support the conclusi ons for which the EC cites to it in its Opinions. 
80. The EC argues that Dr. Boobis has taken an "absolutist" approach, and attacks his response by 
alleging that Dr. Boobis requires "positive proof of  harm," and that rather evidence should be 
provided of a lack of possible harm.  The Appella te Body noted the following regarding the alleged 
need to provide evidence of a lack of harm: " [i]n one part of its Reports, the Panel opposes a 
requirement of an 'identifiable risk' to the uncerta inty that theoretically always remains since science 
can never provide absolute certainty  that a given substance will not ever have adverse health effects .  
We agree with the Panel that this theoretical uncer tainty is not the kind of risk which, under Article 
5.1, is to be assessed ."93  As is clear from its comments on Dr. Boobis' response, rather than providing 
actual scientific evidence of a risk to consumers from the consumption of residues in meat from cattle 
treated for growth promotion purposes and basing a measure on the risk assessment drawn from that 
evidence, the EC would instead opt to focus on th e very theoretical uncerta inties described by the 
Appellate Body in support of its ban on meat and meat products from cattle treated with estradiol 17 β.  
All of this is a distraction from Dr. Boobis' respon se, which categorically notes that the three recent 
studies referred to by the EC "do[] not confirm a risk to human health from the consumption of meat from cattle treated with growth promoting hormones." 
81. The EC agrees with the comments of Dr. Coglia no, which is surprising since Dr. Cogliano's 
comment on the Norat
 study is that it indicates a risk to human health from meat generally94, and his 
comment on the other two studies is qualified by the fact that "the exposure levels found in these 
studies are higher than those found in meat residues."  The EC cites very selectively  to 
                                                      
92 See, e.g., 1999 Opinion, p. 77 ("However, in the 1999 report of JECFA, more recent work on 
biotransformation mediated genotoxicity was cited.") 
93 Appellate Body Report, para. 186. 
94 See US Comments on the Experts' Responses, para. 63.  WT/DS320/R/Add.6 
 Page F-163 
 
 
  Dr. Guttenplan's response, which is understandable since he concludes the following regarding the 
first EC study (Liu and Lin ):  "the results were obtained in cu ltured cells and the relevance to human 
exposure to hormone-treated [meat] cannot be extra polated from this study because of a myriad of 
uncertainties in such extrapolation ."  He concludes the following regarding the second and third 
studies: "[t]he other two studies do not confirm a risk from hormone-treated meat ."  The results of the 
Liu and Lin  paper are questionable due to lack of a dose r esponse.  The authors claim to have data that 
meat and serum from zeranol-implanted cattle are mit ogenic and estrogenic, but their reports are all in 
abstract form (not publicly available).  The US F DA has approached the authors for more information, 
but they have not responded to repeated requests. 
82. Question 26 :  The United States has addressed the issue of the experts' responses on 
epidemiological studies at several points above.  The EC's comments ignore the conclusions reached 
by each of the experts.  Boisseau :  (citing to his response to Question 23) "the hormones in dispute 
have already been used as growth promoters over a sufficient number of years, the epidemiological 
studies in humans already carried out in this doma in have failed to identif y any relation between the 
occurrence of hormonally dependent tumours and th e consumption of meat containing hormonally 
active residues resulting from the treatment of  cattle with growth promoters."  Boobis :  "[t]here is no 
scientific evidence demonstrating any association be tween consumption of meat from animals treated 
with growth promoting hormones and the risk of cancer in humans."  Cogliano :  "[t]he data [relating 
to the difference in breast cancer rates] are not su fficiently specific to establish a link between these 
observations."  Guttenplan :  "[t]he epidemiological studies do not identify a relationship between 
cancer and residues of hormonal growth promoters.  The references to the higher rates of breast and 
prostate cancer observed in the United States as co mpared to the European Communities are not very 
convincing as there is considerable variation in ra tes in different geographical locations.  Also, the 
differences in rates of breast and prostate cancer observed in the United States as compared to the 
European Communities are relatively small." 
83. The EC notes that it "advanced this [epide miological] argument to demonstrate that the 
scientific uncertainty  is growing concerning the harmless natu re of the residues of these hormones."  
(Emphasis in original).  However, as evidenced by the experts' responses, the EC has demonstrated no 
such uncertainty.  Further, as noted  by the Appellate Body, "theoretical uncertainty is not the kind of 
risk which, under Article 5.1, is to be assessed,"95 and "the existence of unknown and uncertain 
elements does not justify a departure from the requireme nts of Articles 5.1, 5.2 and 5.3, read together 
with paragraph 4 of Annex A, for a risk assessment."96 
84. Finally, while the EC downplays the role of ep idemiological studies in its decision making in 
its 1999 Opinion, noting that it "cited this epidemiological evidence in the 1999 SCVPH [Opinion] not as an affirmative [ sic] or adequate proof but just as an indication and possible explanation
", it was 
not so circumspect in the actual 1999 Opinions, and in fact linked several of that document's "Major 
Conclusions" directly to the epidemiological da ta: "[e]pidemiological studies have demonstrated  
strong relationships between the levels of e ndogenous oestrogen and risk of breast cancer  (Toniolo, et 
al., 1995; Berrino, et al., 1996; Bernstein, et al., 1990 a and b; Shimizu, et al., 1990; Pike, et al., 1992)" (1999 Opinion, p. 42); "[a]s concerns excess intake of hormone residues and their metabolites, 
and in view of
 the intrinsic properties of hormones and epidemiological findings , a risk to the 
consumer has been identified with different leve ls of conclusive evidence for the 6 hormones in 
question " (1999 Opinion, "Major Conclusions ", p. 73); "[i]n view of the intrinsic properties of the 
hormones and in consideration of epidemiological findings , no threshold levels can be defined for any 
of the  6 substances " (1999 Opinion, "Major Conclusions", p. 73).  (Emphasis added).   
                                                      
95 Appellate Body Report, para. 186. 
96 Appellate Body Report, Australia – Measure Affecting Importation of Salmon , adopted on 6 
November 1998, WT/DS18/AB/R (" Australia – Salmon "), para. 130. WT/DS320/R/Add.6 
Page F-164  
 
  85. As demonstrated above, the experts disagree that  this epidemiological evidence supports the 
conclusions for which it is cited by the EC.  Further, as noted by the compliance panel in Japan – 
Apples (21.5) , the scientific materials underpinning a ri sk assessment must actually support the 
conclusions reached in that assessment.
97  Materials that do not provide "affirmative [ sic] or adequate 
proof" cannot be said to support the conclusions reached by the EC in its 1999 Opinion.  The EC has 
therefore failed to conduct a risk assessment, as appr opriate to the circumstan ces, within the meaning 
of Article 5.1 of the SPS Agreement for estradiol 17 β. 
86. Question 27 :  It is unclear why the EC thinks that  the results of Stephany are "completely 
different" than those used to support approval of estradiol 17 β as reported in the 1999 JECFA Report.  
The concentration of estradiol 17 β reported by Stephany in "M/LQ domestic US beef", 0.03 ppb 
(equal to 30 nanograms/kilogram), is we ll within the range of estradiol 17 β concentrations in muscle 
reported by JECFA which range from 0.5 - 117 nanograms/kilogram.  Although the average concentrations are correctly quoted from Table 5 of Stephany's paper, Stephany uses the median 
values to make the statement that "it is estim ated that the median dietary intake of 17 β-estradiol via a 
250 gram steak of 'Hormone Free Cattle' is less  than 2.5 nanogram and via 250 gram 'beef' of 
'Hormone Treated Cattle' is 5 nanogram", i.e., a 2-fold difference.  It is assumed that Stephany used 
the median values for this comparison because these values, not average values, are most appropriate 
to use when assessing lifetime dietary exposur e to a residue or contaminant in food ( see 1999 JECFA 
report, p. 83).  Thus, the 7.5-fold difference in estradiol-17 β concentrations in beef between treated 
and untreated cattle cited by the EC may be considered an exaggeration.   
87. Further, the EC provides no support from the e xperts' responses for its conclusion that "the 
difference in the residues is not only structural/c hemical but also qualitative and quantitative," and in 
fact makes no reference whatsoever  to the response of the relevant scientific expert, Dr. Boisseau. 
88. Question 28
:  The EC comments that Dr. Boisseau's r esponse ("[i]n the case of ... residues of 
the natural hormones, which consist of parent s ubstances, there is no difference between hormones 
naturally present in food producing animals, meat or human beings") is "partially incomplete and 
partially false."  The EC refers again to catechol metabolites of estradiol 17 β, noting specifically that 
estradiol 17 α, alleged by the EC to be the main residue in cattle liver, "may react with nucleophilic 
compounds and induce some disruptions."  The EC's suggestion that estradiol 17 α is present in beef 
and may be further metabolized in the human cons umer to catechol estrogens is weak for several 
reasons: (1) Maume  et al.98 demonstrated that estradiol 17 α concentrations are elevated only in liver 
and kidney, but not muscle, following administration of a single implant (muscle is the tissue most 
often consumed); (2) the EC attempted but was unable to provide evidence estradiol 17 α can be 
converted to catechol estrogens  by human intestinal cells99; and (3) estradiol 17 α does not appear to 
be carcinogenic100 and thus does not fit into the EC's theory that estrogens are genotoxic carcinogens 
(via catechol metabolites).  In addition, estradiol 17 α is a relatively weak estrogen, with only 10% of 
the in vivo potency of estradiol 17 β and concentrations of estradiol 17 α are undetectable in muscle, 
which is consumed in much greater quantities than liver. 
89. The EC notes that Dr. De Brabander's statemen t is "very informative", but the United States 
notes that Dr. De Brabander's response fails to cite any scientific evidence in support of its 
                                                      
97 See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146 (finding that "[s]ince the scientific 
evidence relied upon  by Japan does not support the conclusions  reached by Japan in its 2004 PRA, we conclude 
that the 2004 PRA is not an assessmen t, as appropriate to the circumstances , of the risks to plant life or health, 
within the meaning of Article 5.1 of the SPS Agreement.") 
98 Exhibit EC-78. 
99 Exhibit EC-51C. 
100 Fritsche S. and Steinhart H.  Occurrence of ho rmonally active compounds in food: a review.  Eur 
Food Res Technol 1999; 209:153-179.  WT/DS320/R/Add.6 
 Page F-165 
 
 
  conclusions, which appear to miss the point of th e Panel's query.  The Panel's question speaks to 
differences in the fundamental composition of the hormones in their basic form ( i.e., is estradiol 17 β 
in the human body the same as estradiol 17 β residues in meat).  Dr. De Brabander's response provides 
speculation as to how the body breaks down or meta bolizes the hormone, making a vague reference to 
body builders.  The process of metabolization of the hormones has been discussed in detail above.101  
Further, the EC's endorsement of Dr. De Braba nder's "finding that the residues of the endogenously 
produced natural hormones in cattle are in the 17 α form (inactive) while the use of the natural 
hormones for growth promotion purposes may lead to residues in the β form (active form)," suggests 
that tissue residues of estradiol 17 β in cattle treated with estradiol 17 β for growth promotion purposes 
are qualitatively  different from residues in untreated cattle.  This is incorrect, as demonstrated by the 
results of the EC's own "17 Studies",102 which showed that edible tissues from untreated cattle and 
cattle treated with a growth-promoting implant contain both estradiol 17 β (muscle, liver, kidney) and 
estradiol 17 α (liver and kidney only (no muscle)). 
90. Question 29 :  The EC disagrees with Dr. Boisseau, who determined upon evaluation of the 
SCVPH Opinions that the EC failed to evaluate act ual residue levels of the synthetic, provisionally-
banned hormones.  However, Dr. Boisseau's respon se (which cites to the EC's 1999 Opinion) is 
indeed supported by the text of that Opinion (in the "Major Conclusions" section):  "[i]n view of the 
intrinsic properties of the hormones and in consideration of epidemiological findings, no threshold levels can be defined for any of the 6 substances."  As confirmed by the responses of the experts, this 
conclusion is without scientific support.  Therefore, it is clear that the EC has not based its provisional ban on these hormones on "available pertinent inform ation" (which indicates that thresholds can 
indeed be set) within the meaning of Article 5.7 of the SPS Agreement. 
91. Dr. De Brabander does not appear to offer a sp ecific opinion as to whether the EC's Opinions 
indeed evaluate these residue levels, though he notes that "the assessment of risk as evaluated by the 
SCVPH is in terms of actual r esidue levels is less complex
 than in the case of the natural hormones"103 
which would appear to indicate that the EC's evalua tion was less than robust.  Nevertheless, the EC 
notes that Dr. De Brabander "confirms the EC argument that the data used by JECFA are not only too 
old but have also been obtained with methods that are no longer reliable today."   
92. The United States notes that the residue data used to support approval of the growth 
promoting hormones are reviewed in the 52nd JECFA Report.  Included in this Report is a very 
detailed description of the method (developed in 1979 and revised in 1982 and 1983) used to generate 
these residue data and four pages of data which describe the method's performance (percent recovery, 
range of assay detection, intra- and inter-assay va riability, assay precision).  Therefore, all of the 
information required to evaluate the methods used to  generate the residue data used by JECFA in its 
determinations have been publicly available since 1999.  Despite this fact, neither the EC nor the 
scientific expert on residues (Dr. De Brabander) has provided a scientific review or analysis of these data explaining why or how the methods are "no longer reliable today", nor do they provide any 
reasons for why the methods were not  adequate to derive MRLs.  Instead, they opt to dismiss them as 
unreliable simply because they are "old."  As explained in the US Comments on the Experts' 
Responses at footnote 193, JECFA has specific and extensive requirements for residue data.  Therefore, these "old" data were critically reviewed  by JECFA experts in 1999 and deemed to be of 
sufficient quality to assess the human food safety of hormone residues in beef. 
93. Question 30
:  The EC attempts to dismiss the response of Dr. Boisseau for the same 
unfounded reason cited in its comments on Question 29 above.  The EC opines that Dr. Boobis is 
                                                      
101 See, e.g., Questions 13 and 17 above. 
102 Exhibit EC-78. 
103 Responses to Questions from the Panel of Dr. Hubert De Brabander ("Dr. De Brabander 
Responses") (Question 29), p. 3. WT/DS320/R/Add.6 
Page F-166  
 
  "clearly wrong" because, according to the EC, it has completed a "detailed exposure assessment" for 
the three natural hormones.  Yet, both Drs. Boobis and Boisseau, upon review of the EC's materials, 
disagree.  Dr. Boobis notes, as has been argued by th e United States, that rather than evaluating actual 
residue levels of the natural hormones, the EC instead  concocts several misuse scenarios in its attempt 
to demonstrate a risk to consumers.
104 
94. The EC claims to have "not only considered th e ADIs and MRLs set by JECFA but went even 
further and examined the acceptable levels and tolerances recommended by the USA."  The United 
States notes that the Panel's inquiry was whether th e SCVPH considered or examined actual residue 
levels  (i.e., those reported by Stephany).  These are not the same as and are, in general, much  lower 
than ADIs, acceptable levels and tolerances.  Theref ore, the EC's calculations in its Opinions greatly 
overestimate the actual consumption of hormone residues.105 
95. Question 31 :  The EC provides no scientific evidence to dispute Dr. Boisseau's comments or 
the US statement in its first written submission re garding hormone residue levels in treated and 
untreated meat.  Rather, it cites again to the 2002 Report on Carcinogens in an attempt to bolster its 
arguments.  The United States discusses its argument on residue levels as well as the relevance of the 
2002 Report on Carcinogens in detail in its comment s on Question 12 above.  The EC also notes that 
levels of residues in meat "are not unimportant, as the earlier comments of the [EC] on the absence of a threshold have demonstrated."  The EC has not demonstrated the absence of a threshold.  The experts' responses confirm this fact.
106 
96. The EC states that Dr. De Brabander discussed one of its studies indicating "that the 
consumption of meat from the regular hormone treated meat market in the US contains 7.5 times more 
estrogens than in meat from untreated cattle."  Ho wever, the United States was unable to locate this 
conclusion in Dr. De Brabander's response.  The Un ited States discusses the EC's argument regarding 
the "7.5 times" higher levels of estradiol 17 β in detail at paragraph 86 above.  Similarly, the United 
States could not locate the following conclusion ascr ibed to Dr. De Brabander in his response to 
Question 31:  "the [EC] considers that the reply of  Dr. De Brabander rightly points out the increased 
risk which repetitive exposure to such higher residu es can present to the most  sensitive parts of the 
population."107 
97. Question 32 :  The EC avers that Dr. Boisseau's response is "scientifically unsound", yet 
provides no scientific evidence or discussion for why this is so.108  The EC also notes that "there is an 
urgent need to apply the latest analytical methods  to determine the nature and level of the residues 
from these hormones and all their metabolites, which is  perplexing since a review of the exhibits put 
forward by the EC indicates that the EC belie ves it has already accomplished this.  In the EC-
sponsored study described in Exhibit EC-51A, it is c oncluded that "[a]n almost complete reassessment 
of estrogen residues in edible tissues of estradiol-17 β treated animals has been performed."  
98. Question 33 :  The EC concludes that the responses of Dr. Boisseau and Dr. Boobis are 
"conflicting", yet provides no scientific evidence or di scussion for why and where this is so.  The EC 
cites to Dr. De Brabander of the proposition that residue data examined by JECFA should "no longer 
be considered to be credible or reliable", ye t it provides no scientific evidence in support of the 
conclusion that the earlier residue  data is no longer adequate. 
                                                      
104 See Dr. Boobis Responses (Question 30), p. 33. 
105 See US Comments on the Experts' Responses, paras. 92-96 for a discussion of Dr. De Brabander's 
response. 
106 See, e.g., Experts' Responses to Panel Question 15. 
107 See US Comments on the Experts' Responses, paras. 92-96 for a discussion of Dr. De Brabander's 
response. 
108 See US Comments on the Experts' Responses, para. 93 for a discussion of Dr. De Brabander's 
response.  WT/DS320/R/Add.6 
 Page F-167 
 
 
  99. The EC appears to take Dr. Boobis' comment relating to the three natural hormones (the 
subject of the Panel's question) (Dr. Boobis :  "the view was that it was unnecessary to conduct a 
detailed evaluation of the toxicology of substances produced endogenously  [i.e., naturally]" in 1988) 
and attempt to use it to support th e following conclusion:  "Dr. Boobis  admits that the 1988 evaluation 
was made by JECFA even without toxicological monographs, which means, inter alia , that for the 
two synthetic hormones - trenbolone acetate and zera nol - which have not been evaluated since 1988, 
JECFA's conclusions are no longer reliable."  Ho wever, Dr. Boobis' comments on the natural 
hormones are unrelated to the synthetic hormones (and  therefore do not support the EC's conclusion), 
which were not even the subject of the Panel's question. 
100. The EC quotes Dr. Boobis' comment that, over tim e "it became clear that exposure to the 
natural hormones, albeit at levels appreciabl[y] hi gher [than] that found in meat from treated cattle, 
could have adverse effects on human health," as s upport for its arguments.  However, Dr. Boobis' 
conclusion, which notes that recent epidemiologi cal evidence demonstrated that hormones caused 
effects "at levels appreciably higher than  that found in meat from treated cattle " contradicts the EC's 
argument that the exponentially lower levels of hor mone residues in meat from treated cattle pose a 
risk, and instead supports arguments put forward by the United States in its submissions to the 
Panel.109 
101. The EC agrees with Dr. De Brabander that data  relating to the three natural hormones should 
"no longer be considered to be credible and reliabl e."  Yet, as noted in Question 29 above, there is no 
scientific analysis provided by either the EC  or Dr. De Brabander for why this is so. 
102. Question 34 :  The EC comments that Dr. Boisseau "agr ee[s] that the data used by JECFA are 
old," and notes that his argument "to minimize the im portance of their old nature" is "not scientifically 
sound."  As evidence of this fact, the EC states :  "concerning estradiol-alpha, which is the main 
metabolite found in target tissue (liver) of tr eated cattle and which we know that it will be 
metabolized in[to] catechol derivatives, no specifi c evaluation of the genotoxic mechanism has been 
performed by JECFA."  However, as discussed in deta il in Questions 13 and 17 above, the EC has not 
provided any evidence to indicate that estradiol 17 α can be converted to catechol estrogens in humans.  
The EC has failed to cast doubt on JECFA's determination that estradiol 17 β is not genotoxic at levels 
found in residues in meat from cattle treated for growth promotion purposes.   
103. As was the case when the EC was faced with a response from Dr. Boobis to which it had no 
response (Question 20), the EC asks "[c]an Dr. Bo isseau provide an assurance to the [EC] that 
JECFA's conclusions would have not been different if more recent and accurate data were available to 
it?"  The United States rejects the implicit assumption in the EC's question that the data relied on by 
JECFA are inaccurate or that there is more recent or  accurate data available.  Furthermore, as noted 
above in the comments in relation to Question 20, th e United States believes that  the EC's rhetoric is 
entirely inappropriate for this exercise, nor could the EC provide any such assurance with respect to 
its own exports.  As the United States has demonstrated time and again, and the experts have 
confirmed, the EC has not adduced any scientific  evidence which would call into question JECFA's 
determinations on the safety of the hormones.  Furt her, as noted by the Appellate Body, "science can 
never provide absolute certainty that a given subs tance will not ever have adverse health effects."110  
Rather the relevant analysis is whether the EC, in  support of its ban, has adduced sufficient evidence 
to demonstrate a risk from meat from cattle treated with estradiol 17 β for growth promotion purposes 
or that the available pertinent information suppor ts a provisional ban on the other five hormones. 
104. Question 35 :  The EC comments that Dr. Boisseau ag rees that the data evaluated by JECFA 
on MGA "date[s] from the 1960s and 1970s".  The EC refers to its comments on Question 34 to 
                                                      
109 See, e.g., US Rebuttal Submission, paras. 38-39. 
110 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153. WT/DS320/R/Add.6 
Page F-168  
 
  allegedly support its conclusion that Dr. Boisseau  is incorrect in asserting that, just because the 
evidence is older does not mean that it is bad or in adequate.  However, the quality and quantity of the 
evidence point to the opposite conclusion.  As furthe r evidence of this fact, the EC has failed to put 
forward scientific evidence that would cast doubt  on JECFA's conclusions on MGA.  This is 
confirmed by the experts' responses to Questions 61 (is there sufficient scientific evidence to conduct 
a risk assessment for MGA)
111 and 62 (are there any gaps in the scientific information relating to 
MGA). 
105. The EC argues that "the 'low-dose' issue was not  recognized in peer-reviewed literature before 
the mid 90s.  Therefore, all the research into possibl e low-does effects has not been considered in the 
2000 JECFA Report."  It is unclear, however, exactly what "low-dose effects" the EC is referring to 
here. 
106. The EC also concludes that Dr. Boisseau's re sponse is incorrect "[i]n the light of the new 
evidence provided by the European Communities in  its risk assessment of 1999, 2000 and 2002, 
showing so many gaps and uncertainties in our k nowledge on MGA."  However, none of the experts 
have identified the gaps in evidence relating to MGA referred to by the EC.  This is confirmed by the 
experts' responses to Question 62.  Further, as no ted by the Appellate Body, "the existence of 
unknown and uncertain elements does not justify a departure from the requirements of Articles 5.1, 
5.2 and 5.3, read together  with paragraph 4 of Annex A, for a risk assessment."112 
107. Finally, the EC questions whether Dr. Boisseau ca n "assure the Panel that all the relevant and 
necessary scientific aspects about the safety of MGA have been completely and properly analyzed and 
assessed."  Once again, the insinuation that Dr. Boi sseau is responsible for providing an "assurance" 
to the Panel on melengestrol acetate appears to be nothing more than a thinly-veiled attempt to coerce 
Dr. Boisseau into changing his clear scientific opinions and honest review of the materials put forward by the EC in support of its ban.  This is the very task he was char ged with by the Panel.  
Further, as noted by the Appellate Body, "science can  never provide absolute certainty that a given 
substance will not ever have adverse health effects."
113  Rather the relevant analysis is whether the 
EC, in support of its provisiona l ban on melengestrol acetate, h as adduced sufficient evidence to 
demonstrate that it has based its provisional ban on av ailable pertinent information and that there is 
insufficient scientific evidence fo r the EC to conduct a risk assessment for MGA.  The experts' 
responses demonstrate that the EC has failed to demonstrate either of these elements. 
108. Question 36 :  The EC notes its agreement with Dr. Cogliano's response, but fails to cite to the 
previous sentence of Dr. Cogliano's reply:  "[i]n my view, it is widely accepted that adverse effects 
arising from hormonal activities depend on the dose; that is, the level of effect depends on the level of 
exposure."  Further, the EC concludes that Dr. Cogliano's response "is also consistent with the 
Appellate Body's 1998 decision in the Hormones c ase that a qualitative assessment of the risk is 
acceptable under the SPS Agreement."  The United St ates addresses this overly-simplistic description 
of the Appellate Body findings at Section B.2 abov e.  In addition, the United States notes that the 
experts have confirmed that the EC has not complete d the four-steps of a risk assessment (including 
hazard characterization).114 
109. The EC also cites Dr. Boobis' statement that  "once a compound is identified as an in vivo 
DNA-reactive mutagen, or as causing a carcinogenic response via a genotoxic mode of action, no exposure is considered without risk."  As has been made clear in Questions 19 and 20 above, 
                                                     
 
111 See, e.g., Dr. Guttenplan Responses (Question 61),  p. 13 ("[t]he [JECFA] assessment for 
melengestrol acetate seems sound.") 
112 Appellate Body Report, Australia – Salmon , para. 130. 
113 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153. 
114 See Question 14 above.  WT/DS320/R/Add.6 
 Page F-169 
 
 
  Dr. Boobis has concluded that the evidence on the hormones, including estradiol 17 β, does not 
indicate that they are in vivo DNA-reactive mutagens  (Dr. Boobis concludes:   "[t]here is no good 
evidence that oestradiol is genotoxic in vivo or that it causes cancer by a genotoxic mechanism.  
Indeed, the evidence is against this .  Hence, the scientific eviden ce does not support the EC on this 
issue , that the levels of the hormones in meat from treated cattle are not of relevance."). 
110. Question 37 :  The EC comment that "[b]oth Dr. Boisseau and Dr. Boobis appear to agree with 
the EC argument contesting Canada's position" on dos e-response assessments is remarkable in light of 
the actual responses of the experts to  the Panel's question.  Dr. Boisseau :  "JECFA has always 
established ADIs for veterinary drugs on the basis of a dose-response assessment ."  Dr. Boobis : 
"Codex and JECFA materials certainly require th at a dose-response assessment should always be 
conducted  as part of the risk assessment of a chemical agent (CAC, 2005; IPCS: EHC 70, 1987 and 
EHC 104, 1990; IPCS, 2005; WHO, 1996 and 2001)."  (Emphasis added). 
111. Question 38 :  Please see US Comments on the Expert s' Responses, Section C.4(c) for a 
discussion of Question 38 and sensitive populations.  The EC comments that "it is not very uncommon in JECFA to use data from assays which are not yet properly validated."  However, the 
EC provides no evidence to support this conjecture.  For physiological levels of sex hormones in 
prepubertal children, JECFA used values from the liter ature which were validated  as a prerequisite for 
publication in a peer-reviewed journal.
115  The EC also claims that "J ECFA originally used the limit-
of-detection as the 'real' level when they could not me asure the levels."  This statement by the EC is 
also false.  In the peer-reviewed reference used by JECFA (Ansusingha et al.), the authors reported 
that the circulating concentration of estradiol 17 β was detectable using their assay in every 
prepubertal child studied, and the limit of de tection was not substituted for actual values. 
112. The EC has relied on the Klein assay to make the claim that circulating levels of estradiol 17 β 
in prepubertal children are 100-fold lower than prev iously estimated.  However, the EC's support for 
the Klein assay appears to be waning.  Th e EC notes, "[t]he real values for 17 β-oestradiol in 
prepubertal children still remain to be properly documented ."  With this statement, the EC appears to 
recognize that the results of the Klein assay it has employed in its analysis are unreliable, not 
definitive and unvalidated.  Dr. Boobis questions the validity of the Klein assay and suggests that 
significantly higher concentrations of estradiol 17 β in prepubertal children measured by another 
sensitive bioassay (Paris et al., 2002) are more credible.  The EC disagrees with Dr. Boobis' 
assessment on the basis that the Pari s assay also detects, albeit with poor sensitivity, natural estrogens 
other than estradiol 17 β (estrone and estriol).  However, Paris et al. point out that relative to estradiol 
17β, their assay is 1-2 orders of magnitude less sensitive to estrone and estriol.  Therefore, 
concentrations of estrone and estriol in prepubertal  children are not high enough to contribute to the 
estrogenic activity measured in this assay. 
113. Finally, the EC comments that "[s]ince it is not possible to make the calculation on daily 
production rates without knowing the serum levels and the metabolic clearan ce rate in the most 
sensitive segment (children), and JECFA considers such data essential for determining an ADI, it 
must be accepted that JECFA cannot set the ADI and MRL before the values are known!"  This is why safety factors are used by JECFA.  In the case of estradiol 17 β, the safety factors were very 
conservative (10-fold for sensitive populations a nd an additional 10-fold for inter-individual 
variation).
116 
                                                      
115 The reference cited in the 32nd JECFA Report for concentrations of estradiol 17 β in prepubertal 
children is:  Angsusingha K. et al.  Unconjugated estrone, estr adiol and FSH and LH in prepubertal and pubertal 
males and females.  J Clin Endocrinol Metab 1974; 39:63-68. 
116 See Dr. Boobis Responses (Question 42), p. 39. WT/DS320/R/Add.6 
Page F-170  
 
  114. Question 39
:  The EC asserts that it has performed  a "quantitative assessment taking into 
account the lower endogenous production levels for pr e-pubertal children from the most recent and 
reliable data."  As demonstrated in the US Comment s on the Experts' Responses, the data relied on by 
the EC was generated via an unvalidated assay.117  The EC concludes that Dr. Boisseau's response is 
"false", but fails to address the point made by Dr. Boisseau in his comment, i.e., that "[t]his excess 
exposure of these sensitive populations needs to be assessed and compared with the exposure 
resulting from the daily consumption of meat from ca ttle which have not been treated with growth 
promoters, from other food and products of an imal origin and from their own production of 
hormones."  The EC presents no evidence of how it has assessed and compared these risks in its 
Opinions and thus fails to demonstrate that it h as in fact conducted an exposure assessment for 
sensitive populations.   
115. The EC "agrees with Dr. Sippell's assessment," regarding which the United States has already 
provided detailed comments,118 and notes that he "demonstrates why there are a number of sources 
confirming the values mentioned by Klein et al, 1994 and 1999."  To the contrary, the only "source" that Dr. Sippell provides to support the results of the Klein assay is the publication by Paris et al.  
However, as discussed in the US Comments on the Expe rts' Responses at paragraph 66, the results of 
the Paris assay do not confirm the values reported by Klein et al .  Instead, Paris et al. reported 
circulating levels of estradiol 17 β that are at least an order of magnitude greater than those obtained 
using the Klein assay.  It is important to note that concentrations of estradiol 17 β in prepubertal 
children reported by Paris et al. Are much closer to the values u sed by JECFA than to the values 
reported by Klein et al.
119 
116. Question 40 :  As noted in Question 38 above, the EC's statement that "JECFA originally used 
the limit-of-detection as the 'real' level when they  could not measure the levels" is pure speculation for 
which the EC provides no evidence.  To the contrary , in the peer-reviewed reference used by JECFA, 
the authors reported that the circulating concentration of estradiol 17 β was detectable using their assay 
in every prepubertal child studied, and the limit of  detection was not substituted for actual values.  
Also, the EC notes that "[t]he real values for 17 β-oestradiol in prepubertal children still remain to be 
properly documented."  With this statement, the EC appears to recognize that the results of the Klein 
assay it has employed are unreliable, not definitive and unvalidated.   
117. As noted in Question 39 above, the Paris assay does not validate the Klein assay despite the 
EC's statement that "Dr. Sippell provides convinci ng explanations and arguments to accept as valid 
the results from the RCBA assay."  The EC fails to note Dr. Boobis' conclusion that "[t]he reliability 
of the Klein et al assay has yet to be determined."  The EC also fails to mention Dr. Boisseau entirely, 
who states that "[i]t would be important to know  whether these new bioassays have been properly 
validated as this SCVPH Opinion says nothing about that and whether the data obtained with these 
methods for both men and women are also totall y different from those obtained with the RIA 
methods."  
118. Finally, the EC fails to note Dr. Boobis' ultimate conclusion which is that, even assuming the 
lower levels of circulating estradiol 17 β proposed by Paris et al., the simple fact is that "exposure is 
via the oral route, and bioavailability by this route is very low (<5%) (Fortherby, 1996).  In addition, 
very little of the absorbed hormone will be free,  over 95% being bound to plasma proteins such as 
SHBG. Such binding reduces the biological activity of the hormone (Teeguarden and Barton, 2004).  
Hence, the JECFA ADI would appear to be a ppropriate for all groups of the population." 
                                                      
117 See US Comments on the Experts' Responses, Section C.4(c). 
118 See US Comments on the Experts' Responses, Section C.4(c). 
119 The mean concentration of estradiol 17 β in prepubertal boys in the study used by JECFA 
(Ansusingha et al.  J Clin Endocrinol Metab 1974; 39:63-68) was 5 pg/ml.  Corresponding values reported by 
Paris et al. and Klein et al. were 1.44 pg/ml and 0.08 pg/ml, respectively.  WT/DS320/R/Add.6 
 Page F-171 
 
 
  119. Question 41 :  The EC comments that the replies of Dr s. Boisseau and Boobis are "not entirely 
convincing," and in support of this claim cites to  alleged risks concerning "estradiol-17-esters and 
estradiol-alpha found in residues in treated steers."  As noted by the United States in Questions 13, 17 
and 28 above, the EC's suggestion that estradiol 17 α is present in beef and may be further metabolized 
in the human consumer to catechol estrogens  is weak for several reasons: (1) Maume  et al.120 
demonstrated that estradiol 17 α concentrations are elevated only in  liver and kidney, but not muscle, 
following administration of a single implant (muscle is the tissue most often consumed); (2) the EC 
attempted but was unable to provide evidence estradiol 17 α can be converted to catechol estrogens by 
human intestinal cells121; and (3) estradiol 17 α does not appear to be carcinogenic122 and thus does not 
fit into the EC's theory that estrogens are genotoxic carcinogens (via catechol metabolites). 
120. The EC also concludes that "the most importa nt studies available provide a bioavailability 
rate which is 10% or higher (see the 2nd EC Written Submission)."  However, review of the section of 
the Second EC Written Submission which discusses bioavailability of hormone residues (paragraphs 123 to 124) reveals no information to support the statement that bioavailability of these 
residues is greater than or equal to 10%.  In fact , as the US has pointed out in its Comments on the 
Experts' Responses,
123 the EC has failed to provide any evid ence to contradict the statement by 
Dr. Boobis indicating that the bioavailability of natu ral hormone residues < 5-10%.  This statement is 
supported by several peer-reviewed publications.124 
121. Question 42 :  The EC again attempts to dismiss the responses of Drs. Boobis and Boisseau 
because they have "not carried out any research  themselves on these hormones and so have no 
specific expertise."  The United States has addressed this unfounded objection at several points above.  
Drs. Boobis and Boisseau are intimately familiar with the workings of JECFA and are highly 
qualified to respond to the Panel's question (indeed, Dr s. Boisseau and Boobis were initially proposed 
as experts by Codex and JECFA).  The EC notes that the experts' responses are "very monolithic and one-sided", presumably because the responses di sagree with the EC position on whether JECFA 
adequately took into acc ount sensitive populations. 
122. The EC comments that the responses of Drs. Boisseau and Boobis "are based again on the 
assumptions that this hormone [estradiol 17 β] is not genotoxic and that the rate of endogenous 
production by prepubertal children is correctly cited in the JECFA report."  These are not "assumptions", however, but reflect the views of bot h experts on the state of the scientific evidence 
relating to estradiol 17 β.  Indeed, both Dr. Boobis and Boisseau have concluded, based on a review of 
the EC's Opinions, the science cited therein, and a re view of relevant recent scientific literature that 
estradiol 17 β is not genotoxic in vivo, nor would it be ge notoxic at levels found in residues in meat 
from cattle treated for growth promotion purposes.
125 
                                                      
120 Exhibit EC-78. 
121 Exhibit EC-51C. 
122 Fritsche S. and Steinhart H.  Occurrence of ho rmonally active compounds in food: a review.  Eur 
Food Res Technol 1999; 209:153-179. 
123 See US Comments on the Experts' Responses, paras. 27-30. 
124 See Dr. Boobis Responses (Question 43), p. 40.    
125 See, e.g., Dr. Boobis Responses (Question 16), p. 20 ("[t]he carcinogenic effects of oestradiol 
appear to be a consequence of its endocrine activity"; [t]he evidence is against any direct interaction of 
oestradiol or its metabolites with DNA."); Dr. Boobis Responses (Question 18), p. 22 ("[t]o reiterate, whilst 
there are reliable studies demonstrating the genotoxicity of  oestradiol in certain in vitro tests, the evidence is 
against any genotoxicity in vivo .") (note that the EC's own guidelines on genotoxicity testing "require 
confirmation  of an in vitro positive using an appropriate in vivo assay ."  See CVMP (2004). Studies to Evaluate 
the Safety of Residues of Veterinary Drugs in Human Food: Genotoxicity Testing, European Medicines Agency, London);  Dr. Boobis Responses (Question 19), p. 22 ("[t]here is no good evidence that oestradiol is 
genotoxic in vivo or that it causes cancer by a ge notoxic mechanism.  Indeed, the evidence is against this.  WT/DS320/R/Add.6 
Page F-172  
 
  123. The EC claims that "there are so many other reasons to believe that the JECFA evaluation is 
scientifically wrong, as explained above (old and unr eliable data, etc.), [that] no reliance can be 
placed on the replies by these two experts."  The Unit ed States has demonstrated at length above that 
the EC has failed to demonstrate that JECFA's evalua tion is "scientifically wrong" and that the EC has 
failed to support its conclusions which diverge from t hose of JECFA with scientific evidence.  Thus, 
the EC has failed, for purposes of Article 3.3 of  the SPS Agreement, to maintain its measure 
(permanent ban on estradiol 17 β), which allegedly results in a higher level of protection than that 
expressed in the JECFA standard, with a "scientific justification." 
124. Question 43
:  The EC disagrees with Dr. Boisseau, who opines the estradiol 17 β is "inactive 
orally" because, according to the EC "[t]his is simply factually wrong!  Oestradiol 17 β is routinely 
administered to humans as a powder or in the form of  pills that are taken orally."  In support of its 
argument, the EC cites to Lampit et al .  However, the Lampit study very clearly indicates that, to 
overcome the low bioavailability of estradiol 17 β, very large amounts of the hormone must be 
administered orally  to achieve a therapeutic effect.  The EC  comments that there are "no doubts that 
oestradiol-17 β is orally active."  As noted in Question 8 above, while it is true that estradiol 17 β is 
administered orally for some indications, because its bioavailability is so low, very high doses are 
required to elicit the desired therapeutic effect.  For example, therapeutic doses of estradiol 17 β  for 
oral administration range from 0.5 - 4.0 milligrams,126 or 10,000 - 40,000 times higher than the 30-50 
ng/person/day derived from eating beef from cattle treated with estradiol 17 β for growth promotion 
purposes.  In addition to high doses, orally administered estradiol 17 β are manufactured as micronized 
formulations (particle size < 10 microns) to further in crease bioavailability.  Even after micronization, 
the bioavailability of a 2 mg dose of estradiol 17 β is still only about 5%.127 
125. The EC also notes that it has provided "credible recent evidence" that "the bioavailability of 
estrogen is low but not insignificant (probably between  5 and 20%, if estrone is taken into account."  
However, as noted in Question 41 above, review  of the section of the EC's Second Written 
Submission which discusses bioavailability of horm one residues (paragraphs 123 to 124) reveals no 
information to support the statement that bioavailab ility of these residues is greater than or equal to 
10%.  In fact, as the United States has pointed out in its Comments on the Experts' Responses,128 the 
EC has failed to provide any evidence to contradict  the statement by Dr. Boobis indicating that the 
bioavailability of natural hormone residues < 5-10 %.  This statement is supported by several 
peer-reviewed publications.129 
126. The EC "agrees with the summary of this questi on as stated by Dr. Guttenplan."  However, as 
addressed by the United States in paragraph 29 of its Comments on the Experts' Responses, 
Dr. Guttenplan appears to be simply restating the EC's conclusions, which ha ve been shown to be 
erroneously based on three studies that do not even address bioavailability. 
127. The EC asserts that "[n]either Dr. Boisseau nor Dr. Boobis provide a specific reply to 
[Dr. Guttenplan's reply concerning prepubertal child ren]," a statement that  the United States finds 
perplexing based on a review of Dr. Boobis' very de tailed reply to the question of whether estradiol 
                                                                                                                                                                     
Hence, the scientific evidence does not  support the EC on this issue, that the levels of the hormones in meat 
from treated cattle are not of relevance. ") (Emphasis added); Dr. Boisseau Responses (Question 13), p. 11 ("[i]n 
conclusion, the EC risk assessment did not support that residues of oestradiol-17 β, despite the genotoxic 
potential of this hormone, can initiate and promote tumours in humans.")  See also  Dr. Cogliano Responses 
(Question 18), p. 1 ("it has not been established by th e EC that genotoxicity and cell proliferation would be 
induced by levels found in meat residues added to the pre-existing levels occurring in exposed humans.") 
126 See 2002 Report on Carcinogens.  (Exhibit US-26). 
127 Fotherby K. Bioavailability of orally administer ed sex steroids used in  oral contraception and 
hormone replacement therapy. Contraception 1996; 54:59-69. 
128 See US Comments on the Experts' Responses, paras. 27-30. 
129 See Dr. Boobis Responses (Question 43), p. 40.     WT/DS320/R/Add.6 
 Page F-173 
 
 
  17β in beef presents a risk factor for prepubertal children.130  Indeed, Dr. Boobis takes into account 
the possibility that circulating levels of estradiol 17 β are lower than previously estimated.  Using this 
assumption, together with the well-supported c onclusion that bioavailability of estradiol 17 β is very 
low (< 5%), Dr. Boobis shows very convincingly that  consumption of beef fr om cattle treated with 
estradiol 17 β for growth promotion does not approach the ADI and thus does not pose a risk to 
prepubertal children. 
128. Finally, the EC notes that "the bioavailability of the three synthetic hormones has not been 
determined by JECFA."  However, the EC fails to note that, because the bioavailability is unknown, 
JECFA made no correction for bi oavailability in its assessment ( i.e., it assumed 100% bioavailability ).  
This is obviously a very conservative approach to this  issue, since it is unlikely that the bioavailability 
of any of the synthetic hormones would be 100% (a nd even if it were, this potential was taken into 
account).  Ethinyl estradiol (a synthetic estrogen), fo r example, is 55% bioavailable.  Thus, the EC's 
attempt to cast doubt on the JE CFA risk assessments and standard s relating to those hormones by 
arguing that the bioavailability of the th ree synthetics is unknown is unconvincing. 
129. Question 44 :  The EC cites Dr. Boisseau's opinion that "Codex did not adopt any guideline for 
GVP aimed at minimizing the occurrence of veterina ry drug residues in animal derived food" as 
supporting its argument.131  However, the EC does not clarify to what argument it is referring.  The 
United States notes that Dr. Boisseau's statement th at Codex has not adopted a guideline on GVP is 
unexceptional, and reiterates that the essential anal ysis is whether the EC , in its purported risk 
assessment, has properly examined and evaluated a ri sk from the failure of good veterinary practices 
(per Articles 5.1 and 5.2 of the SPS Agreement).  Th e EC appears to accept that it must evaluate this 
risk, if the assumption of failure of controls is to  be a mainstay of its purported assessment, by citing 
to guidance from the Appellate Body. 
130. As the United States has demonstrated, the EC  has failed to assess a risk from failure of 
controls.132  The experts have confirmed this fact.133  The EC notes that "there is an important 
difference between the theoretical assumption of re specting [good veterinary pr actices] and real life," 
but has simply not evaluated the risk of failure  of good veterinary practices, nor has it even 
demonstrated through scientific evidence that, save fo r the most unrealistic misuse scenarios (extreme 
overdosing), residues of the hormones would reach violative levels.134 
131. Question 45 :  The EC cites Dr. Boisseau for th e proposition that Codex recommendations 
"are only meaningful in countries where GVP are eff ectively implemented."  This is so because, as 
noted by the United States in its Comments on the E xperts' Responses at footnote 222, approvals of or 
standards relating to veterinary drugs (or any subs tance for that matter) are not premised on the notion 
of misuse.  Any drug  can be misused, and most drugs can be harmful if consumed at extremely high, 
unrealistic levels.  If misuse were used as a base line for veterinary drug approvals, no drugs would 
ever be approved.  However, as noted by the Appellate Body, for purposes of an SPS measure, a 
                                                      
130 See Dr. Boobis Responses (Que stion 40), p. 37-39. 
131 Note the failure to complain about Dr. Boisseau's laboratory experience in this instance. 
132 See US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, Section C.6. 
133 See Dr. Boobis Responses (Question 48), p. 42 ("There was no attempt to evaluate the risks from the 
resultant exposures on misuse or abuse , either in the papers cited or by the SCVPH (2002) in their evaluation of 
these studies .  Indeed, the SCVPH (2002) simply noted that 'Therefore, these data have to be considered in any 
quantitative exposure assessment exercise',  without undertaking such an exercise .")  (Emphasis added); 
Dr. Boisseau Responses (Question 48), p. 24 ("the European Communities did not conduct any quantitative risk assessment for growth promoters, it is not possible to say that the scientific evidence referred to by the European 
Communities assesses the risk to human health from residues resulting from these misuses/abuses .")  (Emphasis 
added). 
134 See generally  Dr. Boobis Responses (Question 62), pp. 50-52; see US Comments on the Experts' 
Responses, Section C.6; US Rebuttal Submission, Section II.B.4. WT/DS320/R/Add.6 
Page F-174  
 
  Member may take misuse or failure of controls into account as part of their basis for that measure, but 
they must actually evaluate or assess that risk.  Th e United States has demonstrated at several points 
in its Rebuttal Submission and Comments on the Expert s' Responses that the EC has failed to evaluate 
this risk.
135  The experts have confirmed this fact.136  The experts have further confirmed that the 
scientific evidence relied on by the EC for its conclu sion that artificial misuse scenarios will lead to 
violative levels of hormone residues does not support that conclusion.137 
132. As noted by the United States in its Comment s on the Experts' Responses at paragraph 101, 
the issue of conditions of use, a nd whether the EC has evaluated the risk from misuse, is essential to a 
determination of whether it has ba sed its permanent ban on estradiol 17 β on a risk assessment within 
the meaning of Articles 5.1 and 5.2 of the SPS Agr eement and whether its provisional ban on the five 
other hormones is based on available pertinent inform ation within the meaning of Article 5.7 of the 
SPS Agreement.  The fact that the EC has raised the issue of misuse138 and devoted considerable 
resources to demonstrating the potential consequen ces of misuse implies that it already recognizes 
that there are conditions under which residues of the six hormones used for growth promotion are 
safe.  In other words, if, as argued by the EC, the six hormones pose a risk at levels found in residues 
in meat from cattle treated according to good veteri nary practices, then why has the EC tried to 
refocus attention on the specter of misuse?  The only germane question then would be whether there 
are particular conditions of use under which there would be a health risk. 
133. Question 47 :  The EC comments that Dr. Boisseau's response is "partially false", because he 
has concluded that "the [EC] di d not conduct any quantitative risk asse ssment for growth promoters, it 
is not possible to say that the [EC] took into acco unt relevant control mechanisms with respect to 
GVPs in place in the USA."  The simple fact is that  the experts have reviewed the EC's Opinions and 
the studies cited therein, and have determined  that the EC has failed to assess this risk.139  Insofar as 
Dr. De Brabander has spoken to the issue of whether or not the EC's Opinions adequately evaluate the 
risk from misuse, the United States addresses hi s comments in its Comments on the Experts' 
Responses at Section C.6. 
134. The EC claims that the "evidence available does show that such misuse or abuse occurs 
frequently, because these hormones are administered in combinations and the farmers have incentives 
to apply multiple doses."  Each of these conclusions  is speculative and uns upported by the evidence 
presented.  The experts' responses have confirmed this  fact (note that none of the experts cites to any 
of this purported evidence of "frequent" misuse), and the United States has demonstrated at great 
length in its Rebuttal Submission at paragraphs  54-66 and Comments on the Experts' Responses at 
paragraphs 105-106 that there is in fact great disincentive  for commercial feedlot operators to misuse 
growth promoters.  Programs administered by the US Government include setting safe levels for veterinary drugs; monitoring for violative residues; and inspection of meat at the ante-mortem, post-
mortem and processing stages.  As large commercial operations, US feedlots have great incentive to 
comply  with the regulations set and enforced by USDA and the FDA.  In support of its claim that 
"farmers have incentives to apply multiple doses" th e EC has cited in previous submissions to a 
document entitled "Beef Cattle Implant Update" aut hored by Dr. Dee Griffin (Exhibit US-27).  The 
United States has submitted a letter from Dr. Griffin in  which he explains that this document does not 
                                                      
135 See US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, Section C.6. 
136 See Dr. Boobis Responses (Question 48), p. 42; Dr. Boisseau Responses (Question 48), p. 24. 
137 See generally  Dr. Boobis Responses (Question 62), pp. 50-52; see US Comments on the Experts' 
Responses, Section C.6; US Rebuttal Submission, Section II.B.4. 
138 See, e.g., Replies to Questions from the Panel after the First Substantive Meeting by European 
Communities, para. 91. 
139 See Questions 44-46 above.  WT/DS320/R/Add.6 
 Page F-175 
 
 
  support the conclusions taken from it by the EC, and c onfirms that there is absolutely no incentive 
(either economic or legal) to mi suse growth promoting implants.140 
135. Question 48 :  The EC argues that the responses of Drs. Boisseau and Boobis are misguided 
because "as the [EC] has explained several times in previous questi ons, [a quantitative assessment] is 
not required under the SPS Agreement as interpreted by the Appellate Body."  The United States has 
addressed both:  (1) the notion that experts should be  taking legal considerations into account, and (2) 
the EC's overly simplistic reading of the Appellate Body statement above.141  In any event, the EC 
does not rely on its assertion that it may just pro duce a qualitative assessment, but instead states that 
"the [EC] has nevertheless performed  a quantitative dose-response assessment  in particular with 
regard to prepubertal children."  Thus, it is patent ly unclear how on the one hand the EC can dismiss 
the comments of the two experts for analyzing th e EC assessment as though it should have been a 
quantitative assessment while on the other claiming that it has conducted just such a quantitative 
assessment.   
136. The experts do not agree with the EC that  it has conducted a quantitative assessment.  
Dr. Boobis:  "There was no attempt to evaluate  the risks from the resultant exposures on misuse or 
abuse, either in the papers cited or by the SCVP H (2002) in their evaluation of these studies.  Indeed, 
the SCVPH (2002) simply noted that 'Therefore, thes e data have to be cons idered in any quantitative 
exposure assessment exercise', without undertaking su ch an exercise."  Dr. Boisseau:  "the European 
Communities did not conduct any quantitative risk assess ment for growth promoters, it is not possible 
to say that the scientific evidence referred to by the European Co mmunities assesses the risk to human 
health from residues resulting from these misuses/a buses."  As described in detail in the US 
Comments on the Experts' Responses, Dr. De Braba nder does not appear to offer an opinion as to 
whether the EC has indeed assessed risks to huma n health from misplaced implants or improper 
administration.142 
137. The EC also claims that "it is obvious that the higher levels of residues that will inevitably 
result from misuse or abuse of these hormones will also exceed the ADIs and MRLs recommended by 
JECFA."  However, as demonstrated by the United States in its Rebuttal Submission143 and confirmed 
by Dr. Boobis (the only expert to specifically analyze the misuse studies conducted by the EC), this conclusion is unsupported by the scientific evidence.  Dr. Boobis
 (Question 62): "the data generated 
by the EU research in question [ i.e., concerning artificial misuse scenarios] do not provide any 
indication that it is not possible to conduct a risk assessment of the hormones used as growth promoters.  Nor do they provide any indication that  even such misuse or a buse as investigated gives 
rise to undue risk from the resultant residues, as in take would only very rarely exceed the ADI and 
then only on a rare occasion."   
138. In short, insofar as the EC's "risk assessment" for estradiol 17 β relies on the conclusion that 
the scientific evidence demonstrates that misuse is lik ely to occur and that residue levels posing a risk 
to human health will result, that assessment is  not a "risk assessment, as appropriate to the 
circumstances" within the meaning of Article 5.1 a nd 5.2 of the SPS Agreement.  Further, insofar as 
the EC's provisional bans are allegedly based on "ava ilable pertinent information" regarding misuse or 
residue levels posing a risk to human health r esulting from misuse, those bans do not satisfy the 
conditions of Article 5.7 of the SPS Agreement.  Si milarly, insofar as the EC's provisional bans are 
premised on alleged insufficient scientific eviden ce to conduct a risk assessment, those bans do not 
satisfy the conditions of Article 5.7 of the SPS Agreement. 
                                                     
 
140 See Letter from Dr. Dee Griffin explaining results of Beef Cattle Implant Update.  (Exhibit US-28). 
141 See, e.g., Section B.2. 
142 See US Comments on the Experts' Responses, Section C.6. 
143 See US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, Section C.6. WT/DS320/R/Add.6 
Page F-176  
 
  139. Finally, the EC comments that Dr. Boobis' refere nce to "probability" of a risk is inappropriate 
in light of the Appellate Body's interpretation that a Member must identify the "possibility" of a risk.  
The United States addresses the EC's interpretation of  the Appellate Body's decision at several points 
above.
144  However, the distinction between "probable" a nd "possible" is irrelevant to an analysis of 
what the EC has or has not accomplished in its "risk assessment" in light of the fact that it has asserted 
that "the [EC] has [] performed a quantitative dose-response assessment ," which would by its very 
nature account for probability.  The experts do no t believe that the EC has completed such an 
assessment.  
140. Question 49 :  The EC comments that less trade r estrictive measures "apply only for the 
countries that would be prepared to assume that th e possible risk would not undermine their chosen 
level of protection."  The EC's statement presum es that the WTO Member in question has conducted a 
risk assessment, upon which it has based a measure that  achieves its appropriate level of protection.   
The EC has not accomplished this task. 
141. Question 50 :  The EC asserts that "if GVP is not r espected, then the importing country should 
have the right to restrict imports, even with a tota l ban."  The United States demonstrates that the fact 
that the EC has not addressed the risk of failure  of controls or good veterinary practices in its 
comments above.  Again, the experts have confirmed this point.  The United States also reiterates that 
a focus on good veterinary practices and their potential  failure by its very nature marks an acceptance 
that the hormones do not pose a risk  to consumers when used in ca ttle for growth promotion purposes 
(or conversely, that the EC has failed to prod uce a "risk assessment" or scientific materials 
demonstrating such a risk).   
142. The United States also notes with interest the EC's agreement with the comments of 
Dr. De Brabander, who is of the opinion that "the re are no other measures possible to the [EC], other 
than a complete ban, which could address risks arising from misuse and failure to follow good veterinary practices."  Dr. De Br abander's response appears to indicate that there is no way to control 
the use of these substances other than a ban.  If th is is so, and a complete ban is the only possible 
remedial measure, then the controls currently em ployed by the EC for the administration of the 
hormones to cattle are also inadequate.  Further, as demonstrated by the United States, a ban is not, as 
it appears to have been cast by Dr. De Brabander and the EC, a iron clad assurance that no misuse will 
ever occur.  This conclusion is supported by eviden ce of an active, illegal black  market for the use of 
hormones in the EC, which chose to impose a ban on their use.
145 
143. Question 51 :  The EC fails to mention that Dr. Boisseau notes that "the European 
Communities did not conduct any quantitative risk assessment for growth promoters, [and] it is 
[therefore] not possible to say that the scientific  evidence referred to by the European Communities 
assesses the risk to human hea lth from residues resulting from th ese misuses/abuses."  The United 
States also notes that Dr. Boobis has provided a deta iled analysis of the studies relied on by the EC as 
evidence of misuse leading to residue levels higher than Codex MRLs or ADIs – he concludes that the 
EC materials do not threaten these le vels even under extreme circumstances.146  The EC states that it 
"agrees" with Dr. De Brabander's opinion.  The Un ited States addresses the notion that JECFA's data 
is "older" and therefore inadequate at paragra phs 22, 92, and 102-104 above, and paragraphs 92 and 
111 of its Comments on the Experts' Responses.  Th e United States addresses the inapplicability of 
the other conditions raised by Dr. De Brabander to the situation at hand ( i.e., ban on imported meat) at 
Section C.6 of its Comment on the Expert Responses. 
                                                      
144 See, e.g., Section B.2. 
145 See US Rebuttal Submission, Section II.B.4. 
146 See Dr. Boobis Responses (Question 62), pp. 50-52; see also  US Rebuttal Submission, 
Section II.B.4.  WT/DS320/R/Add.6 
 Page F-177 
 
 
  144. Question 52 :  The EC's comments on Question 52 appear to distract from the Panel's question, 
which is "[d]o the risk assessment of the [EC] or a ny other scientific materials referred to by the [EC] 
demonstrate that a potential for adverse effects on human health arises from the consumption of meat 
from cattle treated with any of the six hormones in  dispute for growth-promotion purposes."  The EC 
describes the responses of Drs. Boobis and Boisseau as  "scientifically incorrect", yet fails to provide 
any scientific evidence to counter the opinions of  these two experts (opinions which appear to be 
based on a thorough review of the materials put forw ard by the EC in alleged support of its ban).   
145. Dr. Boisseau states:  "the European Communities did not carry out, strictly speaking, a risk 
assessment but provided scientific data and hypoth esis supporting its worries regarding the safety of 
these six hormones for human health."  He also co ncludes that:  "the European Communities did not 
demonstrate that a potential for adverse effects on human health arises from the consumption of meat 
from cattle treated with any of the six hormones in dispute for growth promotion purposes."  The EC's 
only response to these conclusions is to tout the conc lusions of its own materials, averring that it has 
actually conducted a risk assessment in  the form of its 1999, 2000 a nd 2002 Opinions.  The experts do 
not agree with the EC's opinion of these materials.  The EC claims that Dr. Boisseau must not have 
"properly examined" its Opinions because he has concluded that they do not constitute risk 
assessments.  To the contrary, Dr. Boisseau's answers are detailed and indicate a very thorough reading of the EC's Opinions and other materials. 
146. The EC attempts to dismiss Dr. Boobis' response due  to the fact that he concludes that "all of 
the major reviews in this topic ( i.e., genotoxicity) have concluded that  whilst there are data gaps, there 
is no evidence that low level exposure is causing harmful effects in humans," and "[t]he carcinogenic 
effects observed are entirely consistent with a hormona l mode of action that exhibits a threshold that 
would be well above the intake arising from consumption of meat from treated cattle."  The EC 
focuses on the reference to data gaps as in some fashion supporting its deci sion to permanently ban 
the import of meat from cattle treated with estradiol 17 β for growth promotion purposes.  The EC fails 
to emphasize:  (1) Dr. Boobis' conclusion that "the re is no evidence that low level exposure is causing 
harmful effects in humans; (2) Dr. Boobis' respon se to the Panel's question concerning any potential 
data gaps (Question 62) (data presented by th e EC "do not demonstrate any important gaps, 
insufficiencies and contradictions  in the scientific information used by JECFA"); (3) Dr. Boobis 
conclusions to other Panel ques tions relating to genotoxicity ( e.g., Question 18 ["the evidence is 
against any genotoxicity in vivo."]); (4) relevant discussion from the Appellate Body ("science can never provide absolute certainty that a given substan ce will not ever have adverse health effects.  We 
agree with the Panel that this theore tical uncertainty is not the kind of risk which, under Article 5.1, is 
to be assessed.")
147; and (5) relevant discussion from the compliance panel in Japan – Apples (21.5)  
(scientific conclusions reached in a risk assessment  must actually be supported by the scientific 
materials cited therein).148  
147. The EC agrees with Dr. Guttenplan's comments.  As noted by the United States in Question 
43 above, however, contrary to Dr. Guttenplan's  conclusion, use of hormones according to good 
veterinary practice to promote grow th in cattle will not result in residue levels that exceed relevant 
ADIs or FDA's safe levels. 
148. Question 53 :  The EC notes, regarding Dr. Guttenplan's response, that "this is still another 
kind of uncertainty that should be taken into account  by the Panel in deciding whether the evaluations 
by JECFA are credible and reliable."  The Unite d States reiterates that the EC has adopted a 
permanent ban on estradiol 17 β based on what it claims is a risk assessment, as appropriate to the 
circumstances, within the meaning of Article 5.1 of the SPS Agreement.  Theoretical uncertainty may 
                                                      
147 Appellate Body Report, para. 186.  Recall that the EC claims to have imposed its permanent ban on 
estradiol 17 β based on a risk assessment within the meaning of Article 5.1. 
148 See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146. WT/DS320/R/Add.6 
Page F-178  
 
  not serve as the basis for such an assessment.
149  Further, the EC fails to note Dr. Guttenplan's 
conclusion that "because the concentrations of all of the hormones in beef are so low, [] they would be 
unlikely to affect the potency of estrogen."  Finally, Dr. Guttenplan notes that "no experiments on effects of combinations were performed, so some un certainty exists there."  If the scientific evidence 
does not, through a lack of study, demonstrate a risk  or support the conclusion that combinations with 
estradiol 17 β would increase risks, the EC may not rely on this conclusion in its "risk assessment" 
within the meaning of Article 5.1 of the SPS Agreement.
150 
149. The EC also appears to ignore the following conclusion from Dr. Boisseau: "[c]onsidering 
that it has been established that progesterone and te stosterone are not genotoxic, it is not likely that 
the testing of combinations of progesterone or testosterone with oestradiol-17 β would have led to 
synergistic effects compared with those obtained from these individual substances." 
150. Question 54 :  As noted in Question 16 above, the EC claims that Codex has set a "qualitative" 
appropriate level of protection, wh ereas the EC has set a "quantitative"  level of protection.  Yet the 
EC then argues that it achieves this "quantitative"  level of protection with a "qualitative" risk 
assessment.  The logic of the EC's argument does not follow.  Further, the EC appears to have recast 
its level of protection as one of "no risk" as opposed to "no additional risk."  A "no risk" level of 
protection (assuming that the EC were actually able  to demonstrate a risk to human health from 
residues of the hormones in its Opinions) would presumably capture, and require the cessation of, 
several existing uses of the hormones in cattle in the EC as well as the consumption of numerous 
foods containing any of the six hormones.   
151. In the event that the EC's appropriate level of  protection is still one of zero additional or 
additive risk from the use of growth promoting horm ones in meat, as it alleged in its 1999 Opinion, 
the United States would note the following expert  consensus expressed in response to Question 55 
(recall the following statement by the EC:  "the [EC] has [] performed a quantitative dose-response 
assessment  in particular with regard to prepubertal children."151):  Dr. Boobis : "[t]he EC Opinions and 
other materials referred to by the EC do not quan tify the extent to which residues of the hormones 
contribute to aggregate exposures or cumulative exposures to multiple hazards"; Dr. Guttenplan :  "[i]n 
general the EC do not attempt to evaluate 'the a dditive risks arising from the cumulative exposures of 
humans to multiple hazards, in addition to the endogenous production of some of these hormones by 
animals and human beings'"; Dr. Boisseau :  "[t]he European Communities did not assess 
quantitatively the extent to which residues of growth promoting hormones in meat contribute to 'additive risks arising from the cumulative exposures of  humans to multiple hazards, in addition to the 
endogenous production of some of these horm ones by animals and human beings'."  
152. The EC fails to note the following comment fro m Dr. Guttenplan: "[t]he question of what 
level of risk has not been addressed by the EC."   The EC also states, "[f]or the benefit of 
Dr. Guttenplan" that "Codex has not
 set an ADI or an MRL for MGA ye t."  (Emphasis in original).  
JECFA, on the basis of its risk assessment on M GA, recommended an ADI for melengestrol acetate at 
its 54th Meeting in 2004.  JECFA recommended MRLs for melengestrol acetate at its 66th Meeting. 
153. Question 55 :  The EC requests that the Panel "disregard [the comments of Drs. Boisseau and 
Boobis] because they are purely theoretical and fo r the additional reason that they come from two 
experts who have never done any specific research  on these hormones nor have they ever published 
something on these substances."  The United States has addressed similar objections by the EC in its comments above.  In this instance, the United States  would also note that the Panel's question is one 
of interpreting or analyzing materials and conclusion s drawn in a "risk assessment."  Both experts are 
                                                     
 
149 See Appellate Body Report, para. 186. 
150 See Panel Report, Japan – Apples (21.5) , paras. 8.145-8.146. 
151 EC Comments on the Experts' Responses (Question 39).  WT/DS320/R/Add.6 
 Page F-179 
 
 
  eminently qualified in conducting, interpreting a nd analyzing risk assessments and Dr. Boobis has 
published on matters of risk assessment theory.152  The EC's assertion that these experts are not 
qualified to respond to the Panel's que stions is spurious, and is a w eak attempt to distract from the 
responses of Drs. Boobis and Boisseau, i.e., that the EC has not evaluated the "additive risks" in its 
Opinions or scientific materials.153 
154. The EC notes that Dr. Guttenplan "would have liked to see much more evidence in the 1999 
SCVPH assessment."  The United States is surprise d that the EC has put this comment forward in 
support of its arguments.  One would think, partic ularly in an instance wh ere a hormone such as 
estradiol 17 β has been permanently banned on the basis of a purported risk assessment, that the EC 
would be more hesitant to trumpet the lack of ev idence contained in the "risk assessment."  Finally, 
the EC fails to note Dr. Guttenplan's ultimate conc lusion, which marks a consensus with Drs. Boobis 
and Boisseau:  "[i]n general the EC do not attempt to  evaluate 'the additive risks arising from the 
cumulative exposures of humans to multiple hazards, in addition to the endogenous production of 
some of these hormones by animals and human beings'." 
155. Question 56 :  The EC notes its disagreement with the response of Drs. Boobis and Boisseau 
that JECFA did in fact consider "additive risks" fro m the other five (provisionally banned by the EC) 
hormones.  The EC simply restates its own opinion of the matter and speculates that Dr. Guttenplan would have agreed with the EC but that "words seem to be missing from his reply."  Neither of the EC's comments amount to evidence, particularly the la tter since this is not meant to be an exercise 
where the parties put their own words in the expert s' mouths and claim that the experts would support 
their positions.  Indeed, the EC's claim to powers of extrasensory perception may be as scientific as 
the EC measures at issue in this dispute.   
156. The words actually contained in Dr. Guttenplan 's response read as follows:  "I could find 
assessment of additive risks  of the hormones in the documents."  This response marks consensus with 
the opinions of Drs. Boobis and Boisseau.  (Dr. Boobis :  "JECFA/Codex did consider aggregate risk 
from exposure to the natural hormones where pr esent as residues in meat from treated cattle.   Such 
exposures were considered to represent a trivial increase in overall exposure  to hormonally-active 
material from other exogenous sources and in par ticular from endogenous sources (JECFA, 2000)."  
Dr. Boisseau :  "JECFA/Codex considered in its risk assess ment of the natural hormones such 'additive 
risks'  and concluded that, given the wide margin of safety between the maximum estimated intake of 
residues for the these hormones and the corresponding established ADIs, that there was no risk for 
consumers' health associated with th e estimated ingestion of these residues. ") 
157. The EC argues that "it has clearly been shown that the effects from exposure to different 
estrogens are additive ... [t]hus any additional dose will l ead to an increased effect ."  In support of this 
conclusion, the EC cites a study by Rajapakse et al.  However, the Rajapakse paper reports that a 
heterogenous mixture of 11 estrogenic chemicals exhibited additive effects with estradiol 17 β in a 
yeast-based reporter assay.  The relevance of this stud y to the dispute is questionable because a yeast-
based assay was used to measure estrogen activit y, and the capacity of yeast-based assays to 
accurately reflect physiological effects of  hormones in mammalian cells in vivo ( e.g., humans) has not 
been demonstrated. 
158. The EC also notes that "the additive risk need s to be carefully evaluated.  For instance, 
trenbolone as such has a complex hormonal activ ity (at the same time progestin, androgen and 
glucocorticoid)."  This comment appears to presuppose that JECFA did not engage in such a careful 
evaluation.  The experts have confirmed, to the contrary, that JECFA did in fact evaluate these 
additive risks.  Further, the EC has not provid ed scientific evidence to  support the claim that 
                                                      
152 See Curriculum Vitae  of Drs. Boobis and Boisseau. 
153 The comments of Drs. Bo isseau and Boobis are quoted in Question 54 above. WT/DS320/R/Add.6 
Page F-180  
 
  trenbolone mimics the biological effects of glucocortico id.  In fact, there is evidence in the literature 
that trenbolone exerts antiglucocorticoid activity (Mey er H. Biochemistry and physiology of anabolic 
hormones used for improvement of meat production.  APMIS 2001; 109:1-8).  With respect to progestin, one of the EC's "17 Studies"
154 provided evidence that 17 β-TBOH, the primary metabolite 
of trenbolone found in bovine muscle tissue, binds  to the bovine progestin receptor.  However, 
binding of trenbolone and its metabolites to the human  progestin receptor was not investigated, and it 
must be emphasized that hormone binding in vitro is not equivalent to demonstrating that the hormone 
actually exerts receptor-mediated effects in vivo.   
159. Question 57 :  Rather than commenting on the respon ses of Drs. Boisseau and Boobis, the EC 
questions the validity of the question, and notes that it is irrelevant.  The EC apparently bases this 
conclusion on the fact that the "Appellate Body did not find any violation from the use of some of 
these hormones for therapeutic or zootechnical purpo ses."  The EC does not provide any citation or 
context for this statement, and it is therefore uncl ear how it makes the Panel's question "irrelevant."  
Further, as noted above, the experts do not provide a dvice on legal matters, or evaluation of measures 
under the SPS Agreement.  Rather, they assist a pa nel by providing advice and opinions on technical 
details of the dispute, thereby permitting the pane l to reach these legal conclusions.  One of the 
technical or scientific details at issue is the EC's argument, or assertion, that estradiol 17 β is 
genotoxic.  This is a fundamental assertion made by  the EC in support of its ban, as is evidenced by 
the sheer number of times the EC refers to the genotoxic potential of estradiol 17 β in its responses.  
The experts have, time and again, indicated that estradiol 17 β is not genotoxic at levels found in 
residues in meat from cattle treated for growth promotion purposes. 
160. Dr. Boobis concludes:  "[t]o my knowledge no account is taken of hormone treatments of 
cattle for purposes other than growth promotion, su ch as for therapeutic purpo ses, by the EC in its 
assessment of the aggregate or cumulative effect s of the hormones in meat from cattle treated for 
growth promotion."  Dr. Boisseau notes:   
The European Communities thinks that, given the conditions of theses uses of 
oestradiol-17 β (limited number of treated animals, limited use in the life of these 
animals and very low probability to see these animals slaughtered after treatment), the 
exposure of consumers to oestradiol-17 β residues resulting from these uses can be 
considered as negligible.  If this EC assu mption can be accepted, it raises nevertheless 
a problem of principle as it represents an exception regarding the very strict position 
of EC stating that it is not possible to accept any increase of the exposure of 
consumers to oestradiol-17 β residues .  As soon as the European Communities accepts 
to considers these residues resulting from th ese therapeutic and zootechnical use of 
oestradiol-17 β as negligible, it enters in a quan titative, or at least in a semi 
quantitative, exposure assessment pr ocedure for these oestradiol-17 β residues and, 
starting from that, it has no good reason to object to consider a wider exposure 
assessment covering all the residues r esulting from the different sources of 
oestradiol-17 β. 
161. The EC agrees with the conclusion of Dr . Guttenplan.  The United States notes that 
Dr. Guttenplan's opinion, that zootechnical or th erapeutic use would "not constitute a hazard for 
public health" appears to indicate that he is of the opinion that low levels of the hormones are not genotoxic.  This comports with his opinion that an  adverse effect is " unlikely if good veterinary 
practices are followed."
155 
                                                      
154 Exhibit EC-15. 
155 Dr. Guttenplan Responses (Question 15), p. 4.  WT/DS320/R/Add.6 
 Page F-181 
 
 
  162. Question 58 :  The EC's comments fail to address the responses of the experts.  
Dr. Guttenplan:   "[t]his is indeed a very weak statement by the EC."  Dr. Boobis : "[w]ithin quite broad 
limits, higher exposure would not result in any increase in risk."  Dr. Boisseau : "[t]he European 
Communities did not assess quantitatively the extent  to which residues of growth promoting 
hormones in meat contribute to 'additive risks arising from the cumulative exposures of humans to 
multiple hazards, in addition to the endogenous production of some of these hormones by animals and 
human beings'."  The EC cites again to the 2002 Report on Carcinogens, which has been discussed in 
detail by the United States in its comments on th e EC's comments on Question 12 above and in its 
Rebuttal Submission.156  As demonstrated in the US comment s above, the EC has not in fact "shown 
that the level of residue formation in meat can be  significantly higher and may contain residues from 
different metabolites." 
163. Question 59 :  The EC notes "the different views which the replies of the scientists display on 
this critical question."  The United States did not observe much of a difference of views amongst the 
experts, however.  In fact, the United States notes a consensus in the experts' responses that, per the 
Panel's question, the EC has failed "to identify an y adverse effects on the immune system from the 
consumption of meat from treated cattle with the growth promoting hormones at issue."  Dr. Boobis :  
"[t]he evidence on immune effects of hormones such  as oestradiol referred to by the EC does not 
identify any adverse effects  on the immune system from consumpti on of meat from treated cattle.  In 
general, clear evidence for immune effects were observed only at high doses."  (Emphasis added).  
Dr. Guttenplan :  "[n]o definitive studies have related inta ke of meat from hormone-treated animals to 
the above disorders."  Dr. Boisseau :  "as these data have not been used by the European Communities 
to conduct any quantitative risk assessment likely to  establish, for these effe cts associated with the 
hormonal properties of growth promoters, thres holds and ADIs different from those proposed by 
JECFA, it is not possible to conclude that this scientific evidence allows to identify any adverse 
effects on the immune system associated with the consumption of meat from cattle treated with the 
growth promoters at issue ."  (Emphasis added). 
164. The EC also comments that the real question is  not the one asked by the Panel, but "the 
degree of confidence by which the United Stat es and Canada (and JECFA) can ensure [ sic] the Panel 
that such adverse immune effects are not possible to occur in meat treated with these hormones for 
animal growth promotion.  The [EC] thinks that th ey have failed to do so to the required standard of 
proof."  This statement is flawed for several reasons.  First, the EC, as the Member imposing a ban on meat and meat products, bears the burden of proof of  demonstrating that its ban comports with its 
obligations under the SPS Agreement.  The United St ates has presented more than sufficient argument 
and evidence on each of the scientific points raised by  the EC to demonstrate that its ban is not, in 
fact, sufficiently warranted or reasonably supporte d by a risk assessment within the meaning of 
Article 5.1 of the SPS Agreement.  Further, th e United States has presented more than sufficient 
argument and evidence to demonstrate that the EC's provisional ban does not satisfy the EC's 
obligations under Article 5.7 of the SPS Agreement because there is sufficient scientific evidence for 
the EC to have conducted a risk assessment for each of the five hormones and the EC has failed to 
base its provisional ban on available pertinent info rmation, all of which indicates that the five 
hormones do not pose a risk to human health when  used as growth promoters in cattle.  In other 
words, the United States has discharged its burden of proof in this dispute. 
165. Second, the notion that the United States or JECF A must assure the EC that there is no risk of 
adverse effects from the use of the five hormones is simply a flawed attempt to distract from the issue 
at hand.  As noted by the Appellate Body, "science can never provide absolute certainty that a given 
substance will not ever have adverse health effects."
157  In other words, it is impossible to prove the 
absolute negative, despite the EC's demand for su ch proof from the United States and several of the 
                                                      
156 See US Rebuttal Submission, paras. 38-40. 
157 Appellate Body Report, para. 186, citing Panel Report at paras. 8.152-8.153. WT/DS320/R/Add.6 
Page F-182  
 
  experts.  This is why Members, in imposing trad e restrictions, must adduce evidence and evaluation 
of an actual risk against which their restriction or measure mitigates.  The United States and JECFA 
have conducted risk assessments a nd concluded that the hormones do not pose a risk to consumers 
when used as growth promoters in cattle.  That is why the United States does not, like the EC, impose 
a ban on the importation and sale of beef from treat ed cattle.  The EC chooses to ban importation of 
this same beef.  Therefore, the relevant analysis is  whether the EC, in support of its provisional ban on 
meat from cattle treated with these hormones, has a dduced sufficient evidence to demonstrate that it 
has based its provisional ban on available pertinent in formation and that there is insufficient scientific 
evidence for the EC to conduct a risk assessment for the hormon es.  The experts' responses 
demonstrate generally that the EC has failed to de monstrate either of these elements.  The experts' 
responses to Question 59 specifically indicate that th e EC's conclusion that immune or other adverse 
effects from use of the five hormones as growth  promoters in cattle is scientifically baseless. 
166. Question 60
:  Citing to one of its "17 Studies",158 the EC states that residues of MGA detected 
in US beef were "much higher than the levels whic h should have been normally expected."  However, 
the study that the EC refers to does not report actual r esidue levels in US beef, but is one in a series of 
studies in which the EC deliberately overdosed cattle with MGA.  The EC may have intended to cite 
to another of its "17 Studies"159 in which the author reports that measurement of MGA in 103 US beef 
samples "revealed MGA at trace levels in about 75 pe rcent of the samples."  No quantitative data are 
provided in this report, and there is no suggestion th at the "trace levels" were violative according to 
US tolerance levels.  Therefore, the EC has faile d to provide any evidence to support its claim that 
MGA is conducive to misuse or is administered in a manner that would result in unsafe residue levels 
in US beef. 
167. Citing again to one of its "17 Studies"160 in which a misuse scenario was created for MGA, 
the EC notes that MGA has a "boosting effect" on residues of estradiol 17 β in meat.  It is true that this 
study demonstrated a 2.6-fold increase (not 3 -fold as suggested by the EC) in estradiol 17 β 
concentrations in fat following treatment with the FDA-approved dose of MGA.  This is not 
surprising in light of the fact that MGA, at low concentrations, increases ovarian estradiol 17 β 
secretion via effects on hormone negative feedback  to the hypothalamus and pituitary gland.  
However, it should be noted that:  (1) the results of this study are preliminary due to the limited 
number of animals used (only 2-4 animals per treat ment group), and (2) the mean concentration of 
estradiol 17 β in fat following MGA treatment (26 ppt) is 19 times lower  than the US tolerance 
(480 ppt).15161  Again, the evidence put forward by the EC simp ly fails to substantiate its claim that the 
use of MGA according to good veterinary practices resu lts in hormone residues above the levels that 
have been determined to be  safe for human consumption. 
168. The EC's comment that it is interesting that  the United States has used melengestrol acetate 
since the 1970s but that JECFA only evaluated MGA until 2000 is a non sequitur .  The approval of 
MGA in the US domestic market has no bearing on where and when JECFA was "seized of a request" 
to evaluate MGA.  As noted above, JECFA has set an ADI (62nd Meeting) and proposed an MRL (66th 
Meeting) for MGA.   
169. The United States has reviewed the materials put forward by the EC "following the Appellate 
Body 1998 hormones decision" and did not find an y evidence of a risk from melengestrol acetate 
when used as a growth promoter in cattle.  The Un ited States discussed these studies in detail in its 
Rebuttal Submission.  The experts reviewed these st udies and concur with the opinion of the United 
States.  Dr. Boobis :  even "whilst [misuse] would lead to increased exposures, it is still unlikely this 
                                                      
158 Exhibit EC-16. 
159 Exhibit EC-19. 
160 Exhibit EC-16. 
161 See 21 C.F.R. § 556.240.  WT/DS320/R/Add.6 
 Page F-183 
 
 
  would exceed the ADI, and certainly not for any period of time.  It is also an unlikely occurrence in 
view of the way in which the hormones are used and controlled."  Dr. Guttenplan :  "[t]he potential for 
excessive exposure to MGA exists by both routes (ora l and implantation), but it cannot be stated and I 
am not aware of which route is more likely to c ontribute to high levels in meat."  Dr. Boisseau :  "the 
scientific evidence referred to by  the European Communities does not  identify and evaluate wether 
there is a difference in terms of potential adver se effects on human health from the consumption of 
meat from cattle treated with hormones for gr owth promotion purposes when these hormones are 
administered as feed additives or implanted."  The United States notes that, apart from its general 
conclusion that its studies support its ban on MGA, the EC fails to provide any specific discussion as to how or why this is actually so.  Rather, the EC  simply complains that the experts must not have 
read its materials. 
170. The EC provides commentary on levels of residues in the event of non-removed implants.  
The United States has provided lengthy discussion of how  implants are injected into the ears of cattle, 
that those ears are then discarded, and that ante- a nd post-mortem inspections ensure that the implants 
are not entering the food chain.
162  The EC's commentary speculates that  an ear with an intact implant 
will enter the food chain.  Again, this is nothing mo re than a paper exercise, and there is no evidence 
that this event will occur.  The EC dismisses Dr. Boobis' response as "unfounded."  However, the 
United States notes that Dr. Boobis has engaged in a detailed review of the materials underpinning the 
EC's ban, and has based his conclusion on the results of these very materials.163  The United States 
reached the same conclusion after review of the scientific materials put forward by the EC.164 
171. Question 61 :  The EC attempts to dismiss the opinion of Dr. Boisseau because "he has not 
done nor published any work on these hormones."  As  noted at several points above, this is not a 
legitimate reason for dismissing of an experts' opini on, nor is it a criteria that the EC has applied 
across the board with other experts (or even w ith the same expert, depending on the answer). 
172. The EC questions the "objectivity and impart iality" of the reasoning of Drs. Boobis and 
Boisseau.  The EC's rhetoric regarding the responses of these experts is inappropriate.  Rather than 
citing to evidence that actually supports the EC's  stance on these hormones in an attempt to discount 
the experts' advice, the EC instead seeks to impugn  the credibility of the impartial individuals who 
have agreed to assist the Panel in its endeavours.  Rather than a negative, the United States views the 
fact that Drs. Boisseau and Boobis "have both serve d on a JECFA panel that examined some of these 
hormones" as testament to their qualifications, as well  as evidence against the EC's refrain that they 
lack relevant experience in the study of the hormones. 
173. The EC notes that the opinions of Drs. Boobi s and Boisseau are "based on the assumption that 
there is a dose-response relationship (threshold), despite the accumulation of so much recent evidence showing that this assumption can no longer be valid  for a number of these hormones, certainly for 
oestradiol 17 β, progesterone, testosterone and zeranol."  Despite having stated as much throughout its 
comments, the EC again ignores that none of the experts agree with the EC's opinion
: 
Estradiol 17 β:   Dr. Boisseau :  "the scientific evidence relied upon in the SCVPH 
Opinions does not support the conclusion that the carcinogenic effects of oestradiol-17β are related to a mechanism other than hormonal activity."
15165  Dr. Boobis :  "[t]he 
carcinogenic effects of oestradiol appear to be a consequence of its endocrine 
                                                      
162 See, e.g., US Rebuttal Submission, Section II.B.4; US Comments on the Experts' Responses, 
Section C.6. 
163 See Dr. Boobis' review of the Daxenberger studies on MGA and misuse.  Dr. Boobis Responses 
(Question 62), p. 51. 
164 See, e.g., US Rebuttal Submission, Section II.B.4. 
165 Dr. Boisseau Responses (Question 16), p. 12. WT/DS320/R/Add.6 
Page F-184  
 
  activity."  Dr. Guttenplan
:  "an adverse effect cannot be ruled out, but it is unlikely if 
good veterinary practices are followed."  Dr. Cogliano :  "it has not been established 
by the EC that genotoxicity and cell prolifer ation would be induced by levels found in 
meat residues added to the pre-existi ng levels occurring in exposed humans."166   
Testosterone and progesterone :  Dr. Boisseau  (regarding both hormones):  "the 
scientific evidence relied upon in the SCVPH Opinions does not support the 
conclusion that the carcinogenic effects of [either hormone] are related to a 
mechanism other than hormonal activity."167  Dr. Guttenplan :  "Progesterone, 
testosterone have been extensively inv estigated and the assess ment seems sound and 
is based on the no effect level and a safety factor. (JECFA meeting 52, report-WHA 
TRS 893)."  Dr. Boobis :  "[t]here is no evidence that the hormones testosterone or 
progesterone have genotoxic potential."168  
Zeranol :  Dr. Boisseau :  "the scientific evidence relied upon in the SCVPH Opinions 
does not support the conclusion that the carcinogenic effects of zeranol are related to a mechanism other than hormonal activity."
169  Dr. Guttenplan :  "[t]here is no 
conclusive evidence presented by the EC that the five hormones other than 
oestradiol-17 β [i.e., including zeranol], when consumed as residues in meat have 
genotoxic potential."170  Dr. Boobis :  "[t]here is no convincing evidence that 
trenbolone acetate, MGA and zeranol  are genotoxic.  They were negative in a range 
of tests for genotoxicity ... [t]hus, there is no evidence that any of the hormones are 
genotoxic in vivo at the levels found in meat from treated animals.  Even if GVP were 
not followed, the levels of exposure to  the hormones would be such that no 
genotoxicity would be anticipated in vivo."171 
174. The EC complains that Drs. Boobis and Boisseau  reached their conclusions despite the fact 
that "available evidence is insufficient or there ar e total gaps in our knowledge."  Again, the EC 
presents no evidence in support of this conclusion, a nd it is a statement with which the experts do not 
agree.172 
175. The EC invokes Drs. Sippell, De Brabander a nd Cogliano, and notes that although "they have 
not expressed themselves on this precise question" th e EC is sure that, had they responded, they 
would have supported the EC's argume nt.  This is simply conjecture, and it contradicts the EC's earlier 
objection to experts responding to questions whic h they had not previously indicated themselves 
capable of answering.173  
176. Question 62 :  The EC refers to its comments on the responses of Drs. Boisseau and Boobis 
from the previous question.  The United States does the same.  The EC  insinuates its opinion for that 
of Dr. Boisseau, noting that Dr. Boisseau's statemen t only makes sense if it "w as to be understood that 
the gaps and uncertainties identified by the EC in its risk assessment are such as to require further 
research and investigation."  The United States finds  Dr. Boisseau's response to be sufficiently clear 
without the EC's additional assistance:  "these ne w data do not demonstrate any important gaps, 
                                                      
166 Dr. Cogliano Responses (Question 18), p. 1. 
167 Dr. Boisseau Responses (Question 21), p. 16. 
168 Dr. Boobis Responses (Question 21), p. 24. 
169 Dr. Boisseau Responses (Question 21), p. 16. 
170 Dr. Guttenplan Responses (Question 21), p. 6. 
171 Dr. Boobis Responses (Question 21), p. 24. 
172 See US Comments on the Experts' Responses, Section C.3(c). 
173 See EC's Comments on the Experts' Resp onses (Question 2) ("Dr. Boisseau's  reply that 'In my 
e-mail of 26/04/06, I have indicated that I did not think that I am in the position to reply to this question' calls 
into question the reliability of his answer to que stion no 1 and indeed to the other questions.)  WT/DS320/R/Add.6 
 Page F-185 
 
 
  insufficiencies and contradictions in the scientific  information used by JECFA for conducting its risk 
assessments." 
177. The EC complains of Dr. Boobis' lack of "any sp ecific expertise" and claims to have clarified 
Dr. Boobis' responses on the basis of " a more care ful examination by a real expert."  The EC's 
rhetoric is inappropriate and misplaced.  The purpose of  this exercise is not to have the EC rewrite the 
responses of the experts whose assistance the Panel h as solicited with the opinions of "real experts" 
assisting the EC in arguing this dispute.  This would defeat the entire purpose of the Panel's seeking 
advice from an impartial group of experts in order to  make sense of the technical arguments raised by 
the parties.  The United States has provided a detaile d argument of why the Leffers study reviewed by 
the EC's "expert" does not stand for the proposition the EC contends it does.174  Dr.  Boobis concludes 
the following regarding alleged gaps in the scientific information:  
There is little information in the scientific studies initiated by the EC since 1997 that 
support the contention that they have identified important new gaps, insufficiencies and contradictions in the scientific info rmation and knowledge on the hormones, and 
that additional studies are necessary before the risks to health of consumption of meat 
from treated animals can be assessed.  Whilst additional information has been 
obtained on a number of aspects of the hormones in question, this was often not definitive, sometimes it was not relevant, in some instances it confirmed or expanded 
on previous knowledge.  The evidence obt ained did not indicate any additional 
concern regarding the risk from exposure to residues of the hormones in meat from cattle treated for growth promotion.  
178. The EC agrees with Dr. Guttenplan, who it conte nds "provides some examples of the areas in 
which gaps and uncertainties have been identified an d indicates some of the additional research that is 
required before the EC would be able to conduct a more complete risk assessment."  The EC's 
endorsement of Dr. Guttenplan's response is ironic si nce the majority of the purported gaps identified 
in his response relate to estradiol 17 β, the hormone for which the EC claims to have conducted a risk 
assessment within the meaning of Article 5.1 of the SPS Agreement.
175  If, as the EC appears to 
contend in its comments, there are s ubstantial gaps in this data, it is  unclear how the EC can justify a 
permanent ban on its use.  The United States notes the following comments from Dr. Guttenplan regarding the provisionally banned hormones, for which the EC claims substantial gaps in the 
scientific data: 
Question 21
:  "There is no conclusive evidence presented by the EC that the five 
hormones other than oestradiol-17 β, when consumed as residues in meat have 
genotoxic potential. There is some evidence that certain of the hormones have genotoxic potential, but generally the potential is weak. Testosterone and 
progesterone are negative in genotoxic assays. Zeranol can induce transformation of breast epithelial cells in culture with effici ency similar to that of estradiol, but the 
mechanism is not known, and it is negative or marginally active in other assays. 
Trenbolone is either negative or margina lly active in in vitro genotoxic assays. MGA 
is negative in genotoxicity assays. Any genotoxic effects of the five hormones are likely to be minimized by good veterinary practice." 
Question 61
:  "Progesterone, testosterone have b een extensively investigated and the 
assessment seems sound and is based on the no effect level and a safety factor.  
(JECFA meeting 52, report-WHA TRS 893)."  "Melengestrol acetate.  The 
assessment for melengestrol acetate see ms sound.  Thorough metabolic and 
                                                      
174 See US Comments on the Experts' Responses, paras. 79-80. 
175 See EC First Written Submission, para. 17. WT/DS320/R/Add.6 
Page F-186  
 
  estrogenic studies have been carried out. Actu al levels in beef were not provided.  
(JECFA 62 FNP 41/16)."
176  
D. CONCLUSION  
179. The EC's comments on the experts' responses fa il to provide any evidence or argument that 
discounts the experts' advice to the Panel.  As de monstrated by the United States in its 30 June 2006 
filing on the experts' responses and the US comments above, the experts' responses confirm that the 
EC has failed to base its permanent ban on meat  and meat products from cattle treated with 
estradiol 17 β for growth promotion purposes on a risk assessment within the meaning of Article 5.1 of 
the SPS Agreement because, inter alia , the EC has failed to conduct a "risk assessment, as appropriate 
to the circumstances" and has failed to support the sci entific conclusions set out in its Opinions with 
the scientific evidence cited therein.   In addition, the EC's bans on meat and meat products from cattle 
treated with any of the other five hormones are not provisional measures within the meaning of Article 5.7 of the SPS Agreement because they  are not based on "available pertinent information" nor 
is there insufficient scientific evidence to conduct a risk assessment for each of the hormones. 
 
__________ 
 
  
                                                     
 
176 See US Comments on the Experts' Responses, para. 48 for a discussion of Dr. Guttenplan's 
comments on trenbolone.