WORLD TRADE  
ORGANIZATION  WT/DS320/R/Add.7 
31 March 2008 
 (08-0906) 
 Original:   English 
  
 
 
UNITED STATES – CONTINUED SUSPENSION OF 
OBLIGATIONS IN THE EC  – HORMONES DISPUTE 
 
 
Report of the Panel 
 
 
Addendum  
   This addendum contains Annex G 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 F: Add.6   WT/DS320/R/Add.7 
 Page G-1 
 
 
  ANNEX G 
 
TRANSCRIPT OF THE PANEL'S JOINT MEETING  
WITH SCIENTIFIC EXPERT S ON 27-28 SEPTEMBER 2006 
  
27 September 2006, morning
 
 
Chairman  
 
1. Good morning.  I would like to welcome the parties, the Panel's experts and representatives of 
international organizations to this join t meeting of the two Panels; the Panel on United States – 
Continued Suspension of Obligations in the EC Hormones Dispute , referred to as WT/DS320, and the 
Panel on Canada – Continued Suspension of Obligations in the EC Hormones Dispute , referred to as 
WT/DS321.  The experts with us today are Dr. Boisseau, Professor Boobis, Dr. Cogliano, 
Professor De Brabander, Professor Guttenplan and Professor Sippell.  We have representatives from 
the secretariats of the three inte rnational institutions: the Codex Alimentarius Commission, the Joint 
FAO/WHO Expert Committee on Food Additives, known as JECFA, and the International Agency for 
Research on Cancer, known as IARC.  The represe ntatives are Dr. Angelika Tritscher, WHO JECFA 
Secretary, and Dr. Annika Wennberg, FAO JECFA Secretary, Dr. Kazuaki Miyagishima, Codex Secretary, and Dr. Cogliano, one of the Panel six e xperts, who is also head of the IARC's Carcinogen 
Identification and Evaluation Group. 
2. May I now invite the heads of delegations of each party to introduce themselves and the other 
members of their delegations.  I would appreciate if  you could submit the list of your delegations' 
members to the Panel secretary if you have not done  this already.  The European Communities first 
please. 
European Communities
 
 3. Good morning.  My name is Theofanis Christof orou.  I am Principal Legal Advisor of the 
European Commission in Brussels and I will be f unctioning as the head of delegation for these two 
days.  If you agree each member of the de legation will introduce himself or herself. 
4. Good morning.  My name is Thomas Jürgen sen – I work for the European Commission. 
5. Good morning.  My name is Sybilla Fries.  I am from the Legal Service of the European 
Commission, now based in Geneva. 
6. Good morning Chair.  My name is Gudrun Gall hoff.  I work for the European Commission 
Directorate General Health and Consumer Protection. 
7. Good morning.  Brian Marchant of the Commission, working for DG Trade. 
8. Good morning.  Lothar Ehring, European Commission, DG Trade. 
9. Good morning.  My name is Lars Berner and I am with the EC delegation here in Geneva. 
10. Gentlemen, this was the delegation as such, the o fficials, lawyers and other advisors.  Now we 
have a long list of experts with us and will also allo w each one of them to present themselves, starting 
from Mr. Dan Sheehan. 
11. Daniel Sheehan from Daniel M. Sheehan & Associates. WT/DS320/R/Add.7 
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  12. Annie Sasco from the University of  Bordeaux, cancer epidemiologist. 
13. Manfred Metzler, Professor of Food Chemis try, University of Karlsruhe, Germany. 
14. Niels Skakkebaek, Medical Professor, Growth  and Reproduction, C openhagen University. 
15. Henrik Leffers, Microbiologist, Gr owth and Reproduction, Copenhagen. 
16. Professor François Andre from the National Vete rinary School of Nantes, National Reference 
Laboratory for Hormones, Ministry of  Agriculture. 
17. Alain Paris from National Institute for Agronom ic Research.  I specia lize in metabolism of 
steroids. 
18. Professor Heinrich Meyer, Technical University of Munich.  I am the Chair of biochemistry 
and physiology at the Technical University.  Thank you. 
19. I am Professor Frederik Vom Saal of the University of Columbia, Missouri in the 
United States. 
20. With the delegation are also representativ es of the member States of the European 
Community, and if you agree they will present themselves.  Thank you. 
21. Jukka Pesola, Counsellor, Permanent Commission of Finland. 
22. I am Christian Forwick from the German Mission in Geneva. 
23. I am Sebastian Keyserlingk from the German Ministry of Agriculture. 
24. I am Anders Christiansen from the Danish Mission, Geneva. 
25. Luca Burmeister, Danish Mission to Geneva. 
26. Lukas Paul from the German Mission here in Geneva. 
27. Cédric Pène from the Fren ch delegation in Geneva. 
28. Blas Vicente, Spanish Mission in Geneva 
Chairman
 
 29. Thank you.  The United States please. 
United States
 
 
30. Good morning Mr. Chairman, members of the Pa nel.  My name is Jay Taylor with the 
US Trade Representative's Office.  To my left is  Dan Hunter with the US Trade Representative's 
Office here in Geneva.  To my right is Dr. Adele Turzillo with the Food and Drug Administration.  To 
Adele's right is Steve Wolfson with the Envir onmental Protection Agency.  To his right is 
Kelly Stange with the Foreign Agricultural Service.  To her right is George York with the US Trade 
Representative's Office here in Geneva.  Across th e table from George is Dr. Ralph Cooper with the 
Environmental Protection Agency.  Next to Dr. Coop er is Rita Kishore with the US Department of 
Agriculture Food Safety and Inspection Service.  Next to Rita is Dr. Richard Ellis, Consultant,  WT/DS320/R/Add.7 
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  formerly of the Food and Drug Administration.  And next to Richard is Dr. Gregg Claycamp with the 
Food and Drug Administration.  Thank you. 
Chairman  
 31. Then I give the floor to Canada. 
Canada
 
 32. Thank you Mr. Chairman.  I am Rambod Behboodi , First Secretary here at the Canadian 
Commission to the WTO.  Counsel with me today who will argue this case are to my left Mr. Rob McDougall at the Trade Law Bureau, and to  my right Mr. Kevin Thompson, also of the 
Trade Law Bureau of the Department of Foreign A ffairs and International Trade.  The rest of the 
members of the delegation, from the far left, ther e is Angela Webb who is the Paralegal, Dr. Don 
Grant who is adviser to the Government of Canada .  Next to Mr. Thompson we have Dr. Jim MacNeil 
who is head of the Centre for Veterinary Drug Residues of the Canadian Food Inspection Agency.  
We also have Ms. Michele Cooper, First Secretary at the Canadian Mission and Mr. Vasken 
Khabayan, who is Second Secretary at the Canadi an Mission, and across from me Mr. Evan Lewis of 
the Technical Barriers and Regulations Divisions  of the Department of Foreign Affairs and 
International Trade, and Mr. Bill Bryson of th e Department of Agriculture.  Thank you. 
Chairman
 
 33. Thank you.  I would like to continue by introd ucing the members of the Panels.  On my right 
is Ambassador William Ehlers, who is Ambassador of Uruguay to India.  On my left is Madam 
Claudia Orozco, who is a former senior official  of the Colombian Government and who is now 
working in Brussels as an independent consultant .  And myself, Tae-yul Cho, serving as Chair of 
these Panels.  I am Ambassador and Deputy Represen tative in the Korean Mission here in Geneva.  
The two Panels are composed of the same individu als and in agreement with the parties, we are 
holding a joint meeting with the experts consulted by the Panels. 
34. I would also like to introduce the Secretaria t officials who will be assisting the Panel: 
Mr. Yves Renouf, Legal Officer to the Panel;  Ms  Xuewei Feng, Secretary to the Panel, and 
Ms Gretchen Stanton, Ms Serra Ayral and Ms  Christiane Wolff from the Agriculture and 
Commodities Division of the WTO Secretariat.  Finally I would like to inform the parties of the presence of Mr. Walters Nsoh, Intern in the Agricu lture Division and Ms Esther Katende, an intern 
with the WTO Legal Affairs Division. 
35. As you all know, further to the parties' comm on request, the Panel has decided to hold this 
meeting with the experts open for observation by the public through a closed circuit TV broadcast.  I 
would also welcome those who are observing this meeting from another room at this moment.  I 
would like to remind the viewers who are observing th is Panel meeting that tape-recording or filming 
during the Panel meetings by anyone other than the WTO Secretariat is not permitted.  In order to 
ensure an orderly proceeding and as a courtesy to everyone, I also request everybody, including those 
participating in the Panel meeting and those observi ng the meeting of the Panel, to turn off their 
mobile phones during the whole meeting. 
36. In addition I would like to underline that the parties may request that the public microphones 
be switched off when any confidential material or information is being discussed.  Finally, if the 
meeting is adjourned or suspended, I will specify the time at which it will resume for the benefit of 
those in this room, but also for those viewing this hearing from CR II. WT/DS320/R/Add.7 
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  37. May I also remind you that the meetings of panels in the WTO are tape-recorded and that at 
today's meeting as well as the meeting of to morrow, English/Spanis h/French simultaneous 
interpretation will be provide d in relation to the public broadcast of  this hearing through closed circuit 
television into Room CR II at the request of the pa rties.  So please be su re to use the microphones 
when addressing the Panel and above all, speak sl owly.   I would like to express my sympathy with 
the interpreters for this meeting considering its extremely technical nature.  I would also like to 
remind the experts and the parties that there are constraints and difficulties of interpretation and 
therefore technical language will be properly interprete d only if it is delivered at the reasonable pace.  
To the extent possible, any prepared notes or statemen ts should be shared with the interpreters so as to 
facilitate their task and ensu re accurate interpretation. 
38. Turning to a brief history of the Panels' proceed ings, I wish to recall that at its meeting of 
17 February last year the Dispute Settlement B ody decided in accordance with Article 6 of the 
Dispute Settlement Understanding to establish two Panels pursuant to requests of the European 
Communities.  I further recall that the Panels held a joint first substantive meeting with the parties and 
third parties on 12-15 September 2005.   
39. After its first substantive meeting, the Panel deci ded on 20 October last year to consult with 
experts who have specialized scientific expertise on th e issue arising in this dispute.  In consultation 
with the parties, the Panel adopted working pro cedures for its consultations with scientific and 
technical experts.  These working procedures were  communicated to the parties on 25 November 
2005.   
40. The Panel received suggestions from experts from three international organizations, namely,  
the Codex Alimentarius Commission, the Joint FA O/WHO Expert Committee on Food Additives, the 
IARC, and from the parties.  Following consultatio ns with the parties on the candidate experts, the 
Panel appointed, as I mentioned, Dr. Boissea u, Professor Boobis, Dr. Cogliano, Professor 
De Brabander, Professor Guttenplan and Professor Sippell to serve as scientific experts in this dispute. 
41. In accordance with working procedures and afte r having considered the parties' comments, 
the Panel sent questions to the experts and internat ional organizations on 13 April this year.  The 
experts were requested to reply in writing by 12 June 2006, and these replies were communicated to 
the parties.  Comments and counter-comments receiv ed from the parties and the expert replies were 
also provided to the experts in July.   
42. The purpose of today's meeting is for the Panel to  obtain further clarification of the scientific 
issues and to discuss the experts' written responses to the questions.  The parties will also be given an 
opportunity to discuss the responses of the experts to the questions.   
43. This two-day meeting will proceed in the fo llowing manner.  Before proceeding with an 
examination of the specific scien tific issues under consideration,  the Panel will first give an 
opportunity to each expert and international orga nization representative to introduce themselves and 
make some brief introductory remarks, in particul ar in light of parties' written comments on their 
specific responses to these questions .  But please bear in mind that these remarks should be kept as 
general as possible since we will subsequently discuss each issue in more detail.   
44. Afterwards, the Panel intends to hold its di scussions under five areas which are linked closely 
with the specific sections included in the written ques tions of the Panel to the experts.  I will clarify 
the specific areas in a moment.  For each of the five  specific areas, I will open the floor to the parties 
to ask questions to the experts based on the wr itten information and comments received thus far, 
addressed either to a specific expert or to the expe rts in general.  The Panel would also pose some 
questions either at the beginning or following pa rties questions, depending on the issue.  Once the 
question and answer process has been completed for one area, I will invite the experts and  WT/DS320/R/Add.7 
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  international organization representatives to make some  concluding remarks, if they so wish, before 
moving on to next area.  In addition to the four pred etermined areas, we have also foreseen a fifth area 
to address any other issues not covered by any of the four areas. 
45. Concerning the questions by the parties to the experts, the Panel will proceed as follows.   
Under each section, the Panel will first give the European Communities the floor to ask questions to 
the experts.  Thereafter, the United States and Ca nada will be given an opportunity to ask their 
questions to the experts, including any follow-up  questions to those posed by the European 
Communities.  After that, the European Commun ities will be given the opportunity to pose any 
follow-up questions to those posed by the US a nd Canada.  The Panel is mindful that these are 
officially two proceedings and it will make sure that parties are given ample opportunities to ask 
questions necessary for a clear understanding of the fact s.  However, the Panel notes that the scientific 
issues are similar in both cases and would strong ly encourage the parties to avoid duplicating 
questions.  Please all keep in mind that this meeting has been convened primarily to hear the views of 
the experts and that parties will have ample opportu nities to express their views at our meeting next 
week. 
46. Finally, once we have covered all the five speci fic sections, I would like to give each expert 
and international organization representatives an op portunity to make concluding remarks based on 
the discussions held by that time.  I am not intending  to invite parties to make any concluding remarks 
during this meeting since they will have the chan ce to discuss any relevant points further during the 
Panel's second substantive mee ting with parties scheduled for next Monday and Tuesday. 
47. I would like to underline that the Panel may ask follow-up questions at any time during the 
proceedings.  Moreover, although the Panel or th e parties may address a question to one or more 
specific experts, all experts should feel free to re spond to specific questions if they so wish.  In 
making any remarks, both parties and experts are re quested to minimize redundancy with what they 
have already submitted to the Panel in writing.   I would also like to remind you all that experts and 
international organization representatives are expected  to answer scientific and technical questions;  
they must refrain from addressing any legal issues, such as questions of interpretation of the SPS 
Agreement. 
48. I would also like to recall that the purpose of today's meeting is to take advantage of the 
experts' presence to allow the Panel to gain a bette r understanding of the scientific issues before us.  
The Panel's experts have been selected after ex tensive consultations.  I would like to express the 
Panel's appreciation for their contri butions and their presence today.  I am confident that the parties 
will also make the best of their expertise during these two days. 
49. Let me also clarify that the Secretariat staff will prepare a summary of all the information 
provided by the experts and international organizati ons in their written responses to the questions as 
well as a transcript of the information provided  by the experts and international organization 
representatives in the meeting today and tomorrow.  E ach expert will be asked to review this summary 
and the transcript and to confirm its accuracy.  These will be part of the Panel's reports on these 
disputes. 
50. Last but not least, I would like to recall that we the Panel members do not have scientific 
expertise.  Therefore I would like to ask the experts to bear this in mind in replying to questions and 
explain issues in layman's terms, providing informat ion on underlying concepts as necessary.  In order 
to get a clearer picture with respect to the six hormon es at issue, I would also like to invite all those 
taking the floor to clarify which of the six hormones their question or reply applies to. 
51. Now I would like to introduce the fi ve areas that I referred to earlier.  In order to facilitate a 
focussed discussion, the Panel would like to struct ure the meeting under four specific areas which WT/DS320/R/Add.7 
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  relate to the Panel's original written questions:  Area 1 relates to terms and definitions, which 
corresponds mainly to Section A of the Panel's written qu estions to experts;  Area  2 is risk assessment 
techniques, which corresponds roughly to Section B of the Panel's questions and to some of the 
Panel's questions to international organizations;  Area 3 is related to relevant scientific evidence, 
which corresponds roughly to Section D of the Panel' s questions to experts;  Area 4 relates to EC 
assessment of  risks, corresponding roughly to Sec tion C and some elements of Section D of the 
Panel's questions; and Area 5 is, as I mentioned, othe r – any follow-up questions that do not fit in the 
above categories. 
52. In their replies, the experts may want to refe r to various documents, including the parties' 
submissions and exhibits.  These documents are either  filed in the binders placed in the cupboard over 
there, or in the CD-Roms.  The CD-Roms can be  opened and viewed in the laptop computers near 
your seats.  The Secretariat staff are ready to help you locate these documents if necessary.   
53. Unless there are any comments or questions we can now proceed to hear the experts' brief 
introductory remarks.  I will first give experts the floor in an alphabetic order, starting with 
Dr. Boisseau, which will be followed by the repr esentatives of the international organizations.  
Dr. Boisseau, you have the floor. 
Dr. Boisseau
 
 54. Thank you, Mr. Chairman.  Let me begin by apologizing for my voice – I caught a cold some 
time ago and I am afraid that my voice is not ve ry clear, but I shall do my best to make myself 
understood.  So, my name is Jacques Boisseau, and I withdrew from professional life four years ago.  
Before that, I directed the Nati onal Agency for Veterinary Medicinal Products (ANMAV) in France 
for 20 years.  I was a member of the European Union's Committee for Veterinary Medicinal Products 
for 14 years and headed it for six years when it was still in Brussels.  For 13 years I participated in all 
of the meetings of the JECFA, and had the honour to chair four of them and to be Vice-Chairman five 
times.  Finally, for about 15 years I headed the French delegation to the Codex Committee on 
Residues of Veterinary Drugs in Food (CCRVDF).  So , I specified in my curri culum vitae that in the 
above capacities, I had not done any scientific work  on hormones, and that consequently, I had not 
published anything on the subject.  I suppose that I have the honour to be part of  this panel of experts 
thanks to my experience in assessing the safety of resi dues of veterinary drugs in food.  I would like at 
this point to make three remarks that could be of  help to the discussions that will be taking place over 
these two days. 
55. The first comment is as follows:  the experts have been given 64 precise questions, to which 
they were asked to provide precise answers.  Cons equently, I think that any comments on the replies 
of the experts, or criticism thereof, should focus on the replies in relation to the questions asked and 
not in relation to the questions that were not asked.  Secondly, I think it is im portant that we should all 
have a common understanding of the risk analysis pr ocedure.  In other words, we should clarify 
together, and in agreement with each other, what pertains to the risk assessment procedure as opposed 
to the risk management procedure.  We should be  able, as well, to reach a common understanding of 
what a hazard is, and what a risk is.  Finally, we s hould be able to adopt a common approach to what a 
qualitative risk assessment, is as opposed to what we might call a quantitative risk assessment.  
Finally – since I had meant to be brief – I think th at we must clarify together the specificities of 
conducting a risk analysis for an endogenous substa nce as opposed to a risk analysis for xenobiotic 
substances.  There we are, Mr. Chairman, thank you very much. 
Chairman
 
 56. Thank you.  Professor Boobis, please.  WT/DS320/R/Add.7 
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  Dr. Boobis  
 57. Thank you Mr. Chairman.  My name is Alan Boobis.  I am currently a professor of 
biochemical pharmacology at Imperial College London where I am also a director of the Department 
of Health Toxicology Unit.  I originally trained in pharmacology at the University of Glasgow, but 
since 1976 have been involved in studies of xe nobiotic metabolism of foreign compounds and in 
toxicology, particularly mechanisms of carcinogenesis of dietary contaminants.  For the last 15 years I 
have played a role in national, regional and inte rnational advisory committees, as an independent 
member of a number of committees advising on the safety of chemicals, both pesticides, veterinary 
drugs and consumer products .  I have published over 200 papers in peer reviewed journals, including 
a small number on issues of hormone research.  I currently have two PhD students and a post-
doctorate research fellow working on aspects of oestrogen toxicity.   
58. I have very few comments to make specifically about the issue at hand today because I hold 
myself ready to expand upon my responses to the ques tions.  I would just make one general comment 
at this time which is that in ri sk assessment it is important to recognize that it is not possible to 
establish safety with absolute certainty.  Safety is  a concept which is related to the probability of 
harm, and this is the reason that we use terms like "no appreciable risk".  In risk assessment we don't 
have a concept of zero risk, because in strict scientific terms of risk assessment, risk is considered as a probability – the probability of harm based on the hazard of the compound and the specific conditions 
of exposure to the agent under consideration.  Thank you. 
Chairman
 
 
59. Thank you.  Dr. Cogliano, please. 
Dr. Cogliano  
 60. Thank you, Mr. Chairman, members of the Panel.   My name is Vincent Cogliano.  I am the 
Head of the IARC Monographs Programme at the In ternational Agency for Research on Cancer in 
Lyon, France.  The IARC monographs are a system of expert scientific reviews where we convene 
international working groups of scientific experts to  evaluate the potential carcinogenicity of a variety 
of agents.  They started out looking at chemical agents but since then have evolved to look at 
occupational exposures, chemical mixtures, lifestyle factors, physical and biological agents.  Over the 35 year history of the Monographs Programme we  have looked at over 900 agents and identified 
approximately 400 as potentially carcinogenic to hum ans, including 100 agents which are considered 
to be known to cause cancer in humans. 
61. I am here perhaps in a double role; partially in  my role at the International Agency for 
Research on Cancer but also as a member of the e xpert committee.  Before coming to IARC I worked 
for nearly 20 years at the United States Environmen tal Protection Agency in Washington, DC where I 
was part of the Office of Research and Developm ent assessing the health ha zards of chemicals found 
in the environment.  I am not going to make at  this time any particular statements about risk 
assessment or risk but I do stand ready to assist th e Panel in any way I can in answering any questions 
that come up today.  Thank you. 
Chairman
 
 
62. Thank you.  Then I will give the floor to Professor De Brabander.  Please. WT/DS320/R/Add.7 
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  Dr. De Brabander
 
 63. Thank you, Mr. Chairman.  My name is Hubert  De Brabander.  I know that my name is 
difficult to pronounce for non-Dutch speaking people, but we'll do our best.  Maybe you can give me a nickname or something if you want to address me.  I am from Belgium, from Ghent University, 
from the Faculty of Veterinary Medicine.  I am trai ned as a chemist and during my PhD in chemistry I 
also obtained a degree in environmental chemistry, and concern for the environment will stay with me 
for the rest of my life.  Then I was offered a positio n at the Faculty of Veterinary Medicine and I am 
still there as Head of Department of the Department of Veterinary Public H ealth and Food Safety.  
Over the years I worked mostly on analytical chem istry, residue analysis.  I did a second PhD in 
analytical chemistry of food (aggregaat hoger onderwijs ) and also a PhD in veterinary sciences.  As 
you see my background is in analytical chemistry, but over the years I have become a little bit "veterinized", I should say.  What I can offer to the Panel is my background, my experiences with 
residue analysis and practical experience in c ontrol of legal and illegal compounds.  Thank you. 
Chairman
 
 
64. Thank you.  Professor Guttenplan. 
Dr. Guttenplan  
 65. My name is Dr. Guttenplan.  I have a PhD in chemistry but I have been working in 
biochemistry and carcinogenesis for over 30 years.  I also have a Masters in public health and 
environmental sciences.  I have been teaching biochemistry for a number of years and have been 
involved in carcinogenesis for 30 years.  In r esponding to the questions I found one of the most 
difficult points to evaluate was the word "potentia l".  Many times it arose – this is a potential 
carcinogen, this is a potential hazard – and this comes back to the notion of risk; almost any chemical 
can be toxic if the dose is high enough.  I think this  has been a very difficult area for the Panel to 
determine; what a dangerous dose is, and whether th e doses of hormones that are in the cattle produce 
levels in humans that are danger ous.  I am prepared to answer any questions during my responses 
throughout the day.  Thank you. 
Chairman
 
 66. Thank you.  Professor Sippell, please. 
Dr. Sippell
 
 67. Thank you, Mr. Chairman.  I have prepar ed for introduction a few PowerPoint slides.
1  (May I 
have the first one.)  Yes, there you see my affilia tion; I am the only one of the experts who is a 
medical doctor, more specifically a Professor of Pa ediatrics, and I have been running the Division of 
Paediatric Endocrinology and Diabetology for now mo re than 25 years and also running a relatively 
highly-developed paediatric endocrinology lab.  Our sp eciality is to do refined steroid analysis in very 
small samples from children, from prem ature babies to adult individuals. 
68. (Next – just the first line of the second slide please.)  I am a relative newcomer in the field 
and it is very interesting that this dispute has alr eady been going on for more than a decade, and to my 
knowledge no paediatrician, let alone a paediatric endocrinologist, has been involved as a member of 
one of your expert committees.  To my knowledge, neither has one of the very active scientific 
organizations been involved in these disputes, for example the Lawson Wilkins Paediatric Endocrine 
Society which serves North America, so not only Un ited States but also Canada, or the European 
                                                      
1 Dr. Sippell's slides are contained in  Attachment 1 to this transcript.  WT/DS320/R/Add.7 
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  Society for Paediatric Endocrinology.  This fact is  incomprehensible and paradoxical in view of the 
fact that prepubertal children are indisputably the most sensitive and vulnerable members of the 
population. 
69. (Next point, yes, you can leave it there.)  Childre n have the smallest body size but the longest 
life expectancy and I see (next please) my mission here as an advocate of and spokesperson for 
children and their specific needs.  Just remember that children are not  just small adults but something 
very special and they are our future, no doubt.  Through my reading (can you go on) I got the impression that the validity of the supersensitive re combinant cell bioassay for oestradiol is a key 
issue in all the debate at stake.  I would like to remind you that this supersensitive assay has been 
developed at the National Institutes of Health, the foremost and most refined research institution of 
the United States.  And with our American collea gues – who in general really don't question the 
validity of this assay (can you go on please) the nove l finding of significantly higher oestradiol levels 
– E2 stands for oestradiol, the female sexual steroid – in prepubertal girls than in boys readily explains fundamental features of human biology for th e first time.  Many questions that had not been 
answered before, basic biological questions, can be answered now by this quantum leap supersensitive 
assay of oestradiol in small biological samples.  So for instance, the onset of puberty is on average 
one year earlier in girls than in boys.  This is readily explained by a higher oestrogen input in girls endogenously, from the ovaries, which are not sleeping during pre-puberty but are active on a low level.  The second aspect is the much faster bone ma turation in girls than in boys, with a result that 
bone maturation is ready in girls on average at ag e 15, whereas it is mature at age 17 in boys.  
70. (Next point.)  Lower adult height in women than  in men by a mean of 13 centimetres – in all 
populations men are taller than women.  This ca n only be explained by this higher prepubertal 
oestrogen secretion in girls than in boys.  (Next.)  The higher weight for height or body mass index in 
girls than in boys at start of normal puberty is also  readily explained by this.  We have evidence that 
oestrogen exposure increases weight, and you can see in the next slide a piece of our own research.  
You can see on the left-hand side in the yellow box plot were 50 girls with central precocious puberty, 
in some of them puberty started at age two already,  and at diagnosis they were already two standard 
deviations in weight above the mean for age a nd sex.  So oestrogen exposure – in these cases 
endogenous oestrogen supersecretion – leads to increased weight.  And we have shown that treatment 
of this disorder does not increase weight – you can  see that the BMI standard deviation score stays 
stable or goes down.  
71. (Next please, and I am coming to the end.)  The incidence of central precocious puberty, as I 
told you, is about 10 times higher in girls than in boy s.  This is only explained by the fact that girls 
have prepubertally higher levels of oestrogen than boys.  (Next.)  I contrast, the incidence of 
constitutional delay of puberty is much more common in boys than in girls. 
72. (And then the last slide.)  Ethical considerations – they should always be kept in mind.  To 
investigate whether eating hormone-treated beef el evates oestrogen levels in prepubertal children, 
tests cannot be performed in healthy children, becau se this would involve physical and psychological 
injury to them.  (And the next.)  Epidemiol ogical studies comparing adverse effects in mass 
populations – and I have read in some of the comme nts that this is advocated – in healthy children 
eating beef from hormone-treated and untreated animals to compare them would also be unethical.  We have to protect children from unnecessary clinical trials.  This is not only (can you go on) written 
in the Declaration of Helsinki, but also in all good clinical practice guidelin es and in the recent EU 
Parliament ruling on better medicines for ch ildren.  I thank you for your attention. 
Chairman
 
 73. Thank you.  I now request Dr. Miyagishima, the Codex representative, to take the floor. WT/DS320/R/Add.7 
Page G-10  
 
  Dr. Miyagishima
 
 74. Thank you, Mr. Chairman, and I thank all th e members of the Panel for having given the 
opportunity to the Secretariat of the Codex Alimen tarius Commission to be invited to this Panel 
hearing.  The Codex Alimentarius Commission is one of the three international standards-setting 
bodies explicitly enumerated in Annex A of th e SPS Agreement.  The Codex Alimentarius 
Commission was established in the early 1960s by FAO and WHO as an intergovernmental body 
operating under the auspices of these two parent orga nizations.  The core business of Codex is to set 
international food standards and ot her related texts with the objective of protecting the health of 
consumers and ensuring fair practices in food trade.  Codex, by setting international standards, acts as 
an international risk-management body, if I put it in the overall framework of risk  analysis.  Codex, as 
such, does not undertake any risk assessments but dr aws on the work done by FAO/WHO scientific 
bodies in that respect.  The membership of the Codex Alimentarius Commission is open to all member states of FAO or WHO.  Currently th e Codex membership counts 174 countries, thus 
covering more or less 99 per cent of the world's popul ation.  Codex has one member organization, the 
European Community, which made a formal accession to Codex in November 2003.  Codex' highest 
decision-making body is the Codex Alimentarius Commi ssion, which used to meet every year after 
the creation of Codex, then the Commission turned to a biennial meeting rhythm, and since 2003 the Commission is again meeting every year. 
75. The Commission adopts the final draft standards prepared by its subsidiary bodies, and Codex 
has 20-plus subsidiary bodies covering distinct sp eciality fields.  In the 1980s, Codex decided to 
extend its activity area to cover the residues of veteri nary drugs in food.  Codex thus established the 
Codex Committee on Residues of Veterinary Drug s in Foods, known as CCRVDF.  This Committee 
met for the first time in 1986 and c ontinued to meet yearly until 1992; since then it is meeting more or 
less at the interval of 18 months.  CCRVDF acts as a subsidiary body of the Codex Alimentarius 
Commission on matters related to the residues of ve terinary drugs in food, and as mentioned earlier it 
does not conduct any risk assessments.   It bases all recommendations that this Committee forwards to 
the Commission on the scientific advice given by JECFA.  Of course JECFA covers a broader field than just the question of residues of veterinary drugs; it also covers food additives and contaminants 
and as such advises other subsidiary bodies of the Codex Alimentarius Commission. 
76. Mr. Chairman, this is a brief outline of the history and the mission of the Codex Alimentarius 
Commission, and I am willing to provide further cl arification or supplementary information with 
regard to the written information we  have provided.  I would like to stress the fact that we represent – 
together with the joint secretaries of JECFA – our  respective organs and we do not, in my case, 
represent directly the member states.  I would be most happy to reply on questions regarding procedures and facts, but I am rather reluctant to make any comments on those questions requiring 
value judgements or any analysis or assessment of scientific data.  Thank you, Mr. Chairman. 
Chairman
 
 77. Thank you.  May I now invite the JECFA represen tatives, Dr. Tritscher and Dr. Wennberg, to 
take the floor in turn and to make their introductory remarks. 
Dr. Tritscher
 
 
78. Thank you, Mr. Chair.  My name is Angelika Tritscher;  I am from the World Health 
Organization here in Geneva.  And within the WHO I work in the International Programme on 
Chemical Safety.  Within the Programme I am r esponsible for the Chemicals in Food Programme.  
The main part of this Chemicals in Food Programme is to be the scientific se cretariat to international 
expert bodies that perform risk assessment on chemi cal residues in food. We have two expert bodies,  
JECFA and JMPR.  JMPR is the Joint Meeting on Pestic ides Residues, but it is not of relevance here.   WT/DS320/R/Add.7 
 Page G-11 
 
 
  The other expert body, as already mentioned, is the Joint Expert Committee on Food Additives, which 
despite the name, as was already alluded to, deal s not only with food additives but also with 
contaminants, natural toxins and ve terinary drug residues in food. 
79. Very brief to my training:  I myself trained in food science – I have a Masters degree in food 
science and a PhD in biochemical toxicology.  Howeve r, as was already mentioned, I am not here in a 
role as a scientific expert.  My role here in th is Panel is to explain JECFA procedures and risk 
assessment methodologies and definitions as scientific secretary to the committee. 
80. Let me say a few words about JECFA, to explai n what JECFA is.  JECFA is an international 
independent scientific expert body.  It is jointly ad ministered by FAO and WHO.  It is not a standing 
committee, so JECFA experts are invited for each  meeting, depending on the compounds on the 
agenda and the tasks at hand.  As was already expl ained, in the international arena of food safety,  
JECFA is the risk assessment body and does not deal by any means with risk management activities, 
which in the international arena are the respons ibilities of Codex and its subsidiary bodies.  As 
mentioned, JECFA is jointly administered by FAO and WHO, and FAO and WHO have complementary roles in administering this Committee and inviting respective experts.  The role of the 
WHO secretariat, according to the role of the WHO, is to invite experts that perform toxicological 
evaluation of the available data and then toge ther with FAO – and my colleagues from the FAO 
secretariat will explain in more detail the role of FAO and FAO experts overall – the risk assessment is performed.  The WHO experts perform the toxicological evaluation. 
81. JECFA first met 50 years ago – the first meeting was in 1956 – which means JECFA predates 
not only me but also the Codex Alimentarius Commission.  Over the years, JECFA has really laid the 
ground work by developing the principles for how risk assessment of chemicals in food is done 
nowadays, both on the international and on national le vels.  Besides laying the groundwork, there is 
continuous improvement over the years, as publishe d in the reports of each JECFA meeting.  All 
publications of JECFA are publicly available, which nowadays luckily means on the internet, but also 
in print.  We publish reports of each meeting that give the precise description of the data that allow 
the conclusion.  Then we have toxicological  monographs, published in the WHO Food Additives 
Series, that give a detailed description of the full toxicological database, including the full reference 
list.  So far to the transparency of the outcome of the JECFA procedures.  I will be glad to answer any 
questions there may be regarding JECFA procedures , in particular risk assessment methodologies and 
so forth.  And with this I would like to give  over to my colleague from the FAO.  Thank you. 
Dr. Wennberg
 
 
82. Thank you, Mr. Chairman.  My name is Anni ka Wennberg, and as was said by my colleague 
Dr. Tritscher, I am the FAO JECFA Secretary.  We work together; we have complementary roles to 
serve JECFA as the independent scientific committee in international settings.  As was also mentioned, JECFA has been in place for some time , since 1956, and it actually started to evaluate 
veterinary drugs in 1987.  The first meeting dedicat ed to veterinary drugs residues was held in 1987, 
and JECFA also started developing the general prin ciples for the assessment of residues in veterinary 
drugs in food.  Under the FAO constitution, JECFA is convened according to article 6, which lays 
down that the Conference of the Council of F AO may establish committees and working parties to 
study and report on matters pertaining to the purpose of the organization.  These consist of individuals 
appointed in their personal capacity, because of their special competence in technical matters.  Joint 
committees may also be established according to that article.  This is the basis for the support of FAO 
to the work of JECFA. 
83. I myself have a PhD in nutrition and metabolis m from the medical faculty of Gothenburg in 
Sweden.  I have also been involved in evaluations of veterinary drugs in my previous position as 
employee of the Medical Products Agency in Sweden.  But I am here in my role as the JECFA WT/DS320/R/Add.7 
Page G-12  
 
  Secretary to respond to questions and clarifications  that may be asked about the procedures and the 
principles of JECFA, not to respond to any questions on the substance matters.  Thank you for inviting me and I will stop here. 
Chairman
 
 
84. Thank you all for your introductory remarks and particularly for their brevity.  I think that 
concludes our introductory part of this morning' s session, and I now turn to the main business of 
today, the consideration of specific issues in the five  areas I mentioned.  On the first area I would like 
to let you know that the Panel would first like to pose some questions related to certain terms and 
concepts and definitions.  I will pose our questions one by one, and after listening to the replies from 
the experts and from the parties, I will move on to the next question. 
85. The Panel's first question is:  Please explain the terms genotoxic, mutagenic and carcinogenic.  
How are they related?  How do they differ?  What are the consequences if a substance is genotoxic, 
mutagenic and/or carcinogenic?  I would welcome an y replies from any of the experts present, please. 
Dr. Guttenplan  
 
86. A genotoxic substance is one which damages DNA.  Many genotoxic substances are 
mutagenic and many genotoxic substances are carcinoge nic.  Whether they pose a risk depends on the 
dose. 
Chairman  
 
87. Dr. Boobis. 
Dr. Boobis  
 88. Just a further clarification of some of these terms.  A carcinogenic compound is one that 
causes some abnormality of growth control and results in a tumour.  It can arise from many different 
mechanisms.  One of them is through direct damage  to DNA, which is genotoxicity, and mutagenicity 
is a change in the sequence of the DNA caused by  a genotoxin.  So there are several different 
mechanisms of genotoxicity, some of them  due to direct interaction with DNA. 
Chairman
 
 89. My colleagues asked if you could speak a bit more slowly. 
Dr. Boobis
 
 90. So there are many different mechanisms of ge notoxicity, for example one can interfere with 
the mitotic spindle, which is the apparatus that de termines how cells divide, or there could be direct 
modification of the DNA, which could lead to a mutation, a heritable change in the DNA.  These 
mechanisms can give rise to cancer, but there are other possibilities, such as a mitogenic stimulus, 
something that stimulates the cells to divide.  Pe rhaps random errors during normal replication can 
lead to the selection of cells which have a tumorige nic potential and could grow into a tumour.  It is 
critical therefore in the risk assessment of someth ing which produces cancer in an animal – which is 
simply a descriptive term, that is that we observe a tumour in an animal – that if possible we would 
determine the mode of action or mechanism leading to those tumours; and if the compound is shown 
to cause genotoxicity, if possible to determine how that compound caused genotoxicity.  Not all 
genotoxicity is the same, because some of it is direct and some of it is indirect.  WT/DS320/R/Add.7 
 Page G-13 
 
 
  Chairman  
 91. Thank you.  I am wondering whether any of  our colleagues in the Panel have … 
European Communities
 
 
92. Thank you, Chairman.  Would you allow me to ask a clarifying question?  The question is to 
the two scientists that have already expressed themsel ves, I think in particularly to Dr. Boobis.  
Dr. Boobis, in reply to question number two you ha ve stated regarding genotoxic potential that the 
compound might be capable of causing genotoxicity, and then you say usually in vivo .  You continue 
then to say it remains to be determined whether genotoxicity is indeed expressed in vivo .  So there are 
a few words and each word of cour se changes specific meanings and si gnificance.  The question is, do 
we always need to find genotoxicity in vivo ?  Is it sometimes sufficient that we observe in large 
numbers of experiments genotoxicity in vitro , and are there examples of substances for which we 
have accepted that they are genotoxic on the basis of the large number of experiments in vitro ?  I don't 
quite understand what you mean, it remains to be  determined whether genotoxicity is indeed 
expressed in vivo .  Could you please elaborate and eventually …  
Chairman  
 93. Before I give the floor to Dr. Boobis, may I re mind the delegations that we will have further 
opportunities to exchange our discussions on the specif ic issues relating to risk assessment techniques 
and so on.  So why don't you confine your questions to the terms and definitions at this moment, and 
then I will move on to the discussions in detail on the specific issues later. 
European Communities
 
 94. Chairman, my question then is simple.  Do  we always have to observe genotoxicity in vivo  
before we conclude that the s ubstance is genotoxic?  Thank you. 
Chairman
 
 95. Actually, I do have a question.  I have  a question on what is the meaning of in vivo  studies 
and in vitro  studies.  May I ask the experts to respond to this question first before they respond to the 
question put forward by the EC.  Dr. Boobis. 
Dr. Boobis
 
 
96. Well, in vitro  means outside of the body, usually in a cell-based system in a test tube or 
culture dish.  In vivo  means in the whole organism, the intact organism.  And because of the many 
protective mechanisms, both metabolic and repair me chanisms, there is an accepted wisdom that the 
observation of a response in vitro  in an isolated cell does not necessar ily translate into a response in 
the whole animal.  This is one of the reasons, as far as I am aware, that almost all test strategies for 
genotoxicity have in them a component that if one  is performing a risk-based approach, one would 
seek to confirm a positive in vitro  result with an OECD-accepted method in vivo , of which there are 
several. 
Chairman  
 
97. Could you respond to the question by the EC? WT/DS320/R/Add.7 
Page G-14  
 
  Dr. Boobis
 
 98. It is pretty well embedded in that response, Mr . Chairman, that the potential is that there are 
indications of a positive in vitro , but that it is not actually described as an in vivo  genotoxicant or a 
true genotoxicant with relevance to the risk of th at compound until an appropriate study is conducted 
on mechanisms and an in vivo  test to confirm that in vitro  observation.  There are examples of 
compounds which are clearly genotoxic in vitro  where they are negative in vivo , and the risk 
assessment has proceeded on the basis that the genotoxicity is not expressed in the in vivo  situation for 
one of a number of reasons. 
Chairman
 
 
99. Thank you.  You wish to ask a question? 
United States  
 100. Thank you Mr. Chairman.  Dr. Boobis, to follow up on your response, if I may.  Could you 
please explain the relationship, if any, between ge notoxicity and carcinogenicity?  For example, if a 
compound is genotoxic, is it also carcinogenic? 
Dr. Boobis
 
 101. This is the reason I tried to distinguish between, in a narrow sense, genotoxicity and 
mutagenicity.  The answer to the question, is  a compound that's genotoxic always carcinogenic is 
clearly no.  There are a number of compounds that cause genotoxicity in in vitro  tests by mechanisms 
which are not expressed in vivo  because of repair mechanisms and detoxification by enzymes of 
xenobiotic metabolism.  What is clearer is that a compound that is a mutagen, a direct-acting, DNA-
reactive mutagen, is frequently a carcinogen. But to say that a genotoxin equate s to carcinogenicity is 
not correct and is the reason we place such wei ght on understanding the mechanisms of genotoxicity 
and the relevance of observations in vitro  to the outcome in vivo . 
Chairman
 
 102. I also would like to remind the other experts that  they are free to respond to any questions put 
forward by the Panel or by the parties.  Rega rding the parties' questions, I understand that each 
delegation has its own set of questions to be put fo rward to the experts on the terms and definitions.  
So I would appreciate it if you limit your questions at this moment to only those related to answers 
given by the experts, and then I will give the oppor tunity for each delegation to put forward its own 
set of questions to the experts under this particular item.  Is this clear?  OK.  Then as a related 
question, we understand that experts' responses referred frequently to genotoxic and hormonal 
mechanisms.  What does the term mechanism refer to in this context?  And also, as a follow-up 
question, how a hormonal receptor operates and what hormonal receptor really means.  These are two 
related questions from the Panel.  I would give the floor to any of the experts.  Dr. Boobis. 
Dr. Boobis
 
 103. I propose, if you will, to answer the first half and perhaps one of the other experts can answer 
the second half.  In terms of mechanis m, there is this concept that h as evolved during the last ten years 
or more, led by the International Programme on Ch emical Safety and others , to try to understand 
carcinogenicity in a deeper way than simply the obs ervation of abnormalities of growth, which is after 
all what a tumour is.  And this has led to this idea of  a mode of action, and a mo de of action is a series 
of key events which are necessary to lead to th e formation of the tumour, and these key events 
comprise the biological changes induced by the chem ical and subsequent events which then lead to  WT/DS320/R/Add.7 
 Page G-15 
 
 
  the development of cancer.  In the case of a mechan ism, it is the actual molecular events that are 
responsible for those changes.  So a hormonal me chanism in that sense would mean that it is the 
endocrine or hormonal effect of the compound that l eads subsequently to changes that result in the 
development of a tumour, whereas a genotoxic mechanism would be where there is a mechanism independent of the hormonal action that results in  damage to the DNA directly that leads to the 
tumour.  That is not to say that there aren't situ ations where both could apply, that there could be 
elements of more than one mechanism. 
Chairman
 
 104. Thank you.  Dr. Cogliano, please. 
Dr. Cogliano
 
 105. Thank you very much.  At the International Agency for Research on Cancer, the expert 
working groups have been using mechanisms to affect their evaluations of carcinogenicity for 
approximately 15 years.  And the reason it is impor tant to try to understand the mechanism if you can 
is that sometimes it lets you know that the even ts, the processes occurring in experimental animals, 
are relevant to humans, and in other cases it lets  you know that the processes that are happening in 
experimental animals do not operate in humans.  IARC has had experience in many cases elevating the concern because what is happening in experimental  animals is relevant to humans, and in other 
cases it downgrades or discounts the evidence in experi mental animals because it is not relevant to 
humans.  These principles are spelled out in IARC' s guidelines, called the preamble to the IARC 
monographs.  I would also like to say that it is not  always necessary to understand the mechanism.  
For example, many carcinogens, like asbestos,  vi nyl chloride, benzene were determined from 
epidemiological studies to cause cancer before a nybody had any understanding of the mechanism by 
which they cause cancer.  But when we do have an  understanding of the mechanism, it helps us put 
the experimental evidence in better context about wh ether it could be predictive of humans or not.   
Chairman
 
 106. Thank you.  Dr. Boobis. 
Dr. Boobis
 
 107. I would just like to add that one of the reasons  that such weight is placed on understanding the 
mechanism and mode of action is that it can inform  interpretation of a dose response, and that of 
course is one of the issues at hand in this disput e.  If we understand how the tumour arises, we can 
also understand what the likely nature of a dose response is. 
Chairman
 
 
108. Thank you.  Dr. Guttenplan, please. 
Dr. Guttenplan  
 109. A part of the question was the effects of di fferent mechanisms on carcinogenesis, and we 
have already talked about the genotoxic effects.  That is the direct damage to the DNA.  A hormonal 
mechanism results in enhanced grow th or proliferation of certain cells that are responsive to the 
hormones.  You could have an incipient or a single cancer cell that might not grow during the lifetime 
of the organism, but in the presence of a stimulus such as a hormone, that cell might grow and then become a tumour.  So these are basic differences in terminology and that is another reason why mechanism is important, to understand how these different compounds act. WT/DS320/R/Add.7 
Page G-16  
 
  Chairman
 
 110. Thank you.  Is any of the experts ready to respond to the second part of my question on what 
a hormonal receptor is and how it operates in terms of the hormonal mechanism.  Dr. Guttenplan, please. 
Dr. Guttenplan
 
 111. Yes there are certain cells – my nametag fe ll down on my controller and I am listening in 
French and talking in English – alright that sounds better.  There are certain cells that have on their 
surface, if you will, acceptor proteins that can accep t oestrogen, and when they accept the oestrogen, 
they then start to grow, and that's an oestrogen receptor cell, what we call an oestrogen receptor-
positive cell.  So they would normally grow at a very  slow rate or not at all, but in the presence of 
oestrogen they are stimulated to grow. 
Chairman
 
 
112. Thank you.  Any other follow-up questions?  Yes, Dr. Boobis. 
Dr. Boobis  
 113. It is also, I think, relevant that the endocrine system, the system that the hormones act within, 
is a network of hormones and a network of receptors , and is part of the normal physiological control 
mechanisms of the body.  These hormones evolved as one of the processes whereby we can function 
as organisms.  They are signalling molecules which are transported in the blood from remote sites of 
production to their sites of action, so they di ffer from some other signalling molecules which are 
produced locally.  The important thing about a hormone  is that it is actually distributed by the blood 
and is an essential part of normal physiology.  So  we are looking in terms of hormones as residues 
against an existing background of hormonal activity,  certainly for the endogenous hormones, sorry, 
the natural hormones. 
Chairman
 
 114. Thank you.  Dr. Sippell. 
Dr. Sippell
 
 
115. Yes, I would like to add that this network Dr. Boobis was alluding to is particularly sensitive 
in children, more sensitive than in adults.  And this is  very important also in the receptor levels.  Some 
receptor function is really much different from a dult individuals in order to allow growth and 
development at puberty. 
Chairman  
 
116. Thank you.  Dr. Guttenplan. 
Dr. Guttenplan  
 117. Yes, it is probably obvious to most people, but I just mention a few of the well-known 
oestrogen receptive organs, which are the breasts, the prostate, the ovaries and the uterus.  And a 
somewhat different comment on genotoxic effects which Dr. Sippell brought to my mind is that 
genotoxic effects can be a lot more effective if th e cell is rapidly dividing, so children represent an  WT/DS320/R/Add.7 
 Page G-17 
 
 
  exceptionally sensitive population to genotoxic eff ects, too, not just hormonal effects on cell 
replication.   
Chairman  
 118. Thank you.  But why is it causing only pros tate and breast cancer, other than ... 
Dr. Guttenplan
 
 119. Well, nobody is saying it only causes those, oestrogen is probably involved in ovarian cancer 
and uteran cancer. 
Chairman
 
 
120. The next question is:  what is marker residue ?  How is it established?  And what is a bound 
residue?  Why is it significant?  Dr. De Brabander please 
Dr. De Brabander  
 
121. Would you repeat again the question, Mr. Chairman. 
Chairman  
 122. What is a marker residue, how is established, what is a bound residue and why is it significant 
in this? 
Dr. De Brabander
 
 
123. When a drug is given, or if a compound is given to a human being or to an animal, it is 
metabolized, and that metabolization is different  according to the compound, also according to the 
species.  When it is metabolized, it can be different for humans, it can be different for animals, it can 
be different in different animals, and if you want, and I go from the point of control, if you want to 
control that a given compound is administered, you have to look at the metabolite which you will find 
in a given matrix.  What I call a matrix is urine, faeces, meat, whatever is available and you can measure.  The marker residue is the residue which yo u will find.  That is a general definition for me as 
control, it will be different if you look from a veteri nary direction.  And what is a bound residue?  It 
can be a residue which is bound for example to tis sues or to other compounds, so that you must use 
special techniques to extract it.  Thank you. 
Chairman
 
 124. Before I give the floor to my colleagues,  I will give the floor to Dr. Wennberg and 
Dr. Boisseau. 
Dr. Wennberg
 
 
125. Thank you, Mr. Chairman.  JECFA has also provi ded a definition for marker residue, which is 
in line with what Professor De Brabander has stated.  It is a way to actually define what you want to 
analyse.  It is the parent drug, or  any of its metabolites, or a combin ation of these with a relation to the 
concentration of the total residues of the veterinary drugs in each of the tissues,  i.e. the target tissues. 
What you want to measure is the level of the drug at any time between administration of the drug and 
the depletion of the residues to the safe level.  So it means that to be able to recommend maximum 
residue limits which will be useful in the control of the safe use of the veterinary drug, you have to WT/DS320/R/Add.7 
Page G-18  
 
  have a method, an analytical method, which measu res a chemical substanc e which relates to the 
veterinary drug that has been administered, either the drug itself, or a combination of the drug and 
metabolite, or a metabolite of the drug which is form ed in the body of the animal.  The definitions of 
bound residues are the residues which cannot be extr acted by the method used to measure the residues 
of the drug in the tissue in question.  There can be different ways of binding of chemical substances to 
various components of tissue, protein, fats, car bohydrates, etc., and the way to determine whether 
these residues should or should not be included in the residue definition is a matter to be determined 
on a case-by-case basis, depending on the behaviour of these bound residues, whether they can be released by enzymatic or other mechanisms, or whether they are actually completely bound and 
inactivated as such by their bondage to  molecules in the tissue.  Thank you. 
Chairman
 
 126. Thank you.  Dr. Boisseau. 
Dr. Boisseau
 
 
127. Thank you, Mr. Chairman.  To begin with, a few words about marker residues.  It is a 
challenge for those who perform evaluations to  reconcile the frequent complexity of the 
metabolization of a substance, which can give rise to a multitude of derivatives of varying 
concentrations, and with the need for a simple contro l method.  In other words, you have to be able to 
combine the two. 
128. The purpose of toxicological evaluation is to identif y, in terms of a toxicological effect that is 
deemed relevant for the evaluation of the products, all of the residues including the parent substance 
and the metabolites associated with this toxic aspect.  Most of the time, metabolism does not yield one 
single residue associated with the toxic effect.  T hus, to keep the control simple, it is necessary to 
identify among the residues the one that can be cons idered a marker residue – in other words the 
residue that reflects, according to the time in a given matrix, the evolution of all of the residues of 
concern.  Thus, there must be a constant quan titative relationship over time between the marker 
residue content in a given tissue and total residues of c oncern – i.e. that are of interest in terms of the 
toxic effect in question – taken as a whole.  As it is not usually possible, however the modern methods 
used, to analyse different substances at the same ti me, it is much easier to follow a single residue, the 
marker residue, which must reflect, over time, the con centration in a given tissue of all of the residues 
of concern in terms of toxic effect. 
129. Now, as regards bound residues, th ese are what we call – and I do not wish to repeat what 
Doctor Wennberg has just said – residues that are c ovalently bound with macromolecules, and in that 
sense, are not bioavailable – i.e. they are not s pontaneously available – as opposed to the so-called 
free residues, which are not bound to macromolecules.   Since for the most part, these residues cannot 
be extracted, they are identifiable and quantifia ble by so-called radioactive methods.  Once the 
content of bound residues in a given tissue has been identified, we have to know what they signify, 
since the normal metabolism of a substance could lead  to the complete degradation of that substance 
and the reincorporation of very simple monocarbon ic elements, for example in the normal protein 
anabolism in particular.  And where you have CO2, for example, which is radioactive if it is the 
carbon of the CO2 that is marked – it is not because this CO2 is reincorporated in a protein synthesis 
that it will necessarily pose a safety pr oblem for the consumer.  In othe r words, the mere identification 
of a certain bound residue content does not necessarily mean that these bound residues pose a 
problem.  Thus, it is up to those conducting the toxicol ogical evaluations – and this is not easy – to go 
further in the identification of theses bound resi dues, of their possible release according to the 
methods that Doctor Wennberg has just mentioned,  to see if these covalent bindings could have an 
impact on the biology of the cell in which they  have taken place.  Thank you Mr. Chairman.  WT/DS320/R/Add.7 
 Page G-19 
 
 
   
Chairman  
 130. Thank you.  I now give the floor to Madam Orozco – it is OK?  Dr. Wennberg, would you 
like to take the floor?  If that is not the case, Dr. Guttenplan. 
Dr. Guttenplan
 
 131. I would suggest for bound, at least the way it is  being discussed now, that there should really 
be a descriptive term there, covalently bound,  because bound can be somewhat ambiguous.  It just 
means that it is contained very strongly in a tissue,  whereas covalently bound basically means that it is 
unavailable. 
Chairman
 
 132. We have already heard some comments on bioa vailability, but I would like you to further 
elaborate on what bioavailability is, an d why is it relevant.  Dr. Boobis. 
Dr. Boobis
 
 133. Bioavailability is the availability to the interi or; the systemic circulation of a compound, in 
this case via the oral route of exposure, and it can be  less than complete because the material is not 
physically available, for exampl e it is bound covalently to the food matrix, because it does not cross 
the intestinal wall easily, so absorption is incomplete, or it is metabolized either in the small intestine, 
the site of absorption, or the liver ; because the peculiarity of the an atomy of the digestive system is 
that almost everything that is absorbed across the sm all intestine into the circulation first goes through 
the liver before it gets into the body, and th e liver has a tremendous capacity to metabolize 
compounds.  And so for some compounds, drugs and dietary chemicals, it is possible for the small intestine and/or the liver to metabolize to less active or inactive products some or even all of what is 
being absorbed.  So this means bioavailability is le ss than 100 per cent, what is available to have a 
biological effect on the body is less than what wa s anticipated based on the administered dose or the 
ingested dose.  And so in this assessment one w ould like to know how similar are humans to the 
experimental animals for example in terms of bioavailability. 
Chairman
 
 
134. Thank you.  Dr. Sippell, please. 
Dr. Sippell  
 135. Again the special case in children regarding bi oavailability, as an example for instance we 
paediatricians or paediatric endoc rinologists know very well that a twentieth of the daily dose of the 
natural oestradiols being used in adult women is al ready effective in prepubertal girls in stimulating 
growth, weight development and induc ing puberty.  So bioavailability is certainly in children much 
higher in many instances than in adult individuals, and the problem is that pure bioavailability studies 
which tell us which compound is being absorbed to wh ich extent in a two-year-old or three-year-old 
or four-year-old child are simply not available be cause they are unethical to perform in healthy 
children. 
Chairman
 
 136. Thank you.  Dr. Guttenplan. WT/DS320/R/Add.7 
Page G-20  
 
  Dr. Guttenplan
 
 137. Another way of expressing bioavailability is to  compare the blood dose that one would obtain 
by injecting the compound intravenously compared to what one actually obtains when one ingests the 
compound orally.  So if you get a much lower effe ct orally than you would intravenously, you have 
much less bioavailable compounds. 
Chairman
 
 138. You wish to ask a question? 
United States
 
 
139. Just a clarification, Mr. Chairman.  Dr. Sippell, you mentioned, referenced a daily dose in 
women, can you clarify what dose you are talking about or what sort of treatment of women you were referring to? 
Dr. Sippell
 
 
140. Daily replacement dose in women who for instance lack ovarian function. 
United States  
 141. And what would the quantification of that dose be?  Is there an estimate of the level of that 
dose in terms of quantity? 
Dr. Sippell
 
 142. I mean that's the amount necessary to replace endogenous oestradiol production which is not 
functioning or absent. 
Chairman
 
 
143. Thank you. 
European Communities  
 144. Chairman, clarification, what has been said previously by Dr. Boobis on this?  Is it always 
necessary that – either through injection or oral abso rption, in order to determine bioavailability – that 
the drug goes first through the clearing system, th e liver, or is there another route which does not 
necessarily go through the liver?  Is this also po ssible?  And do you know if  any of these substances 
enter the human body in that way? 
Chairman
 
 
145. Dr. Boobis. 
Dr. Boobis  
 146. There are other routes of course for absorption; a small amount will bypass the portal blood 
supply, which is the one that goes to the liver.  It is possible that something could be absorbed into 
lymphatics.  It very much depends upon the phys icochemical properties of the agent that is being 
absorbed.  Of course early on oestrogens were triall ed in adult patients for therapeutic purposes and it  WT/DS320/R/Add.7 
 Page G-21 
 
 
  was apparent then, in those early studies, that there is a very substantial metabolism in the liver which 
made them unusable for nonhepatic targets in adult ma les, and this is the reason that they are given by 
other routes;  to bypass that very extensive first- pass metabolism, pre-systemic, pre-absorption phase 
of metabolism.  So there are data in adults.  I mean  I certainly take the point that has just been made 
by Dr. Sippell, that these data are not available in ch ildren, but in adults there are actually data in 
human subjects.  But I would like to add an additiona l point about the ethical nature of the question of 
data gaps.  There are studies that one could envisag e to answer the question as to whether a child has 
similar or lower first-pass metabolism without giving  a hormone.  There could be oestradiol present in 
normal food; and we have done such studies on othe r compounds where it would be unethical to give 
the compound itself.  But because it also occurs in lo w dosage as part of the natural diet it is possible 
with sophisticated analytical chemistry to design a natural experiment, which is that you just look at 
what is in the diet, measure what is in the blood a nd then determine whether there is any change.  So 
one can think of experiments, if there is considered to be a data gap, to seek to address that data gap. 
Chairman  
 
147. Thank you.  Now the floor is for Madam Orozco. 
Ms Orozco  
 148. Yes, thank you.  I had a question for Dr. Sippell, because I assume that something similar 
happens when you want to test or give drugs, medici nes to children.  You have to know what is the 
bioavailability, so how do you find out th e bioavailability of other substances? 
Dr. Sippell
 
 149. That is indeed a very difficult question and there are special regulations to protect the 
integrity of children.  You know, if they are not h ealthy, then you can do – with the informed consent 
of parents and guardians – you can do such studies, but you cannot take blood, for instance, just to 
study bioavailability.  This is unethical. 
Ms Orozco
 
 150. Just one question.  How do you find out what is the bioavailability of medicines that are being 
developed for children? 
Dr. Sippell
 
 
151. Yes, that is a very very difficult question, and I am not a paediatric pharmacologist, but this is 
very much debated, how this can really be done.  It cannot be properly studied as in experimental 
animals or in adult people. 
Ms Orozco  
 
152. Do you know how it has been done until now?  Because if one goes to any pharmacy one will 
find a cough syrup for children, and someone has studi ed how much is its bioavailability in the child, 
because we know that one spoon or two spoons would be enough or too much. 
Dr. Sippell  
 
153. Most medications we prescribe or give to sick  children are not licensed for, let's say, infants 
or young children, because there have never been done  proper studies, as in adults.  It is just by 
experience, by empiric, and that's a big big gap in our knowledge, that we for instance cannot do WT/DS320/R/Add.7 
Page G-22  
 
  metabolic studies in infants or in small children.   You know the access to their circulation is so 
difficult, and if some of you have ever done a blood puncture in a premature infant or so, its really 
very very difficult, and I am not aware of any big trials which can, or have been applied, to study 
these bioavailability factors. 
Ms Orozco
 
 
154. Just one last question.  Nowadays a child, maybe two years old, might fall ill, might have an 
infection, might have a virus, and antibiotics are being suggested.  So somehow until now someone has been able to find alternatives to find out more or less what bioavailability is, or at least to be able 
to estimate it drawn from something else.  Do you know how? 
Dr. Sippell
 
 155. Exactly.  We deduce from adults or from young adults, and of course observe any risks that 
are being observed, you know the reactions and so on, a nd in general this is of course explained to the 
parents and it's compassionate use, it's, as we call it, individual trial in a sick child.  That's easy.   
Ms Orozco
 
 156. I am not asking about extreme cases, because th ere are situations where there is need to 
consent, but for example something which is daily occurrence, you go and you buy a syrup for coughing, or – it should not be, maybe, but it happe ns all the time – that antibiotics have been 
prescribed as a medicine, they are prescribed to a lo t of children since a very early age, so it is 
common occurrence what I am talking about.   
Dr. Sippell
 
 157. This you can study of course with their metabo lism, their absorbance and their bioavailability 
in sick children.  You know that when a new antibio tic comes up, then of course we are doing studies 
in our patients.  That is different from the health y population in children.  Do you understand what I 
mean? 
Ms Orozco
 
 158. Not really, because when a person, an adult, tak es a child to a paediatrician because it's ill, the 
paediatrician will examine the child and conclude you need this or that.  You go out from there, you 
go to a pharmacy, no one asks you anything; if it's known th at that medicine at that dose is ok, there is 
no further clearance, so somehow the system has been  able to identify ways to make sure to every 
consumer that it does not pose a problem.  What I am trying to find out is: in the normal cases until 
now, how has society been able to estimate the absorption in a child? 
Dr. Sippell
 
 
159. Just by guessing.  Even the dosing is in many many instances pure empiric.  In modern drugs 
its somewhat better, but in the past these old stan dard drugs have never been tested properly in 
clinical trials and therefore many of these drugs in  Europe have lost their licence and have to be 
retested and this creates tremendous ethical prob lems.  And that is a problem of paediatric 
pharmacology worldwide.   
Chairman  
 160. I give the floor to Dr. Boobis first and then to the United States.  WT/DS320/R/Add.7 
 Page G-23 
 
 
  Dr. Boobis  
 161. Just in the interest of clarification, Chairman, I would like to make a couple of points.  One is 
that it is important, when we are talking about chil dren, we don't lump them all together, it is critical 
to recognize that an infant is not the same as a pr epubertal child.  There is a tremendous range of 
biology and physiology that changes from early child hood onwards to adulthood, and we have to treat 
them as distinct groups, and the effects of the hor mones will vary as well depending upon the age.  
We don't use this term child to encompass everything under puberty.   
162. And the second point is, it is actually possibl e for some compounds to design experiments 
that do not require you to take invasive measures.  It  is not necessary to take blood always to get some 
measure of what is in the circulation.  Two examples would be a saliva sample, which could be 
acquired just by passive and non-invasive collectio n, and similarly the collection of excretions, 
particularly urine, where, if the compound is largel y excreted as a parent or metabolite in the urine, 
one can get comparative information on bioavailability.  So it is not always necessary to use invasive 
blood sampling techniques to get some indication of whether the compound is absorbed and the nature 
that the compound is absorbed in.  It is just for clar ification, if one is thinking about data gaps that 
might be filled in the future, for example.  Th ere are possible strategies that exist to do that. 
Chairman
 
 163. Thank you.  The US. 
United States
 
 
164. Thank you, Mr. Chairman.  I think that Dr. Boobis just spoke to the point I wanted to raise.  
Thanks. 
Chairman  
 
165. Thank you.  EC. 
European Communities  
 166. Could we ask the representatives of the intern ational organizations, in particular JECFA, 
whether this type of experiments for the residues of these substances which we are talking about here 
in children or in adults have been performed so  that we know what one member of the Panel, 
Madam Orozco, was looking for, whether this has been  done in this case, and why not.  For example, 
when the United States has licensed  these substances, why did it no t look and why did it not perform 
these kind of experiments here for example.  Thank you. 
Chairman
 
 
167. Is the representative of JECFA ready to respond?  You have the floor. 
Dr. Tritscher  
 168. I don't think we are in a position here to give th e detailed response as to exactly what type of 
data were submitted and looked at by JECFA in indi vidual compounds, that is not our role here.  And 
I would like to point out that JECFA is not a regulatory authority, so we are not talking about drug 
registration; it is not a registration authority, which is very different.  Studies as were just referred to 
would have to be partially done and submitted to a regulatory authority that registers drugs for 
specific drug uses.  JECFA looks at scientific data, toxicological data and human data, epidemiologic WT/DS320/R/Add.7 
Page G-24  
 
  or experimental studies of any kind that are submitted to the experts or that are publicly available in 
the published literature.  And I am in no position now – I would have to go back to all the individual 
evaluations that have been done and that have b een published in order to find out if any specific 
studies in children or young infants would have been performed.  I am not aware of this.   
Chairman
 
 
169. EC. 
European Communities  
 170. Well, Madam, we are aware of what happene d and we can tell you now; because, as you 
know, when JECFA evaluated these substances in 1988, all of the five substances, and in 1999 the 
three natural hormones and in 2000 for melengestro l acetate, we know from what we have seen that 
none of these experiments involved the kinds of experiments Madam Orozco was asking about.  So we would appreciate if the member of JECFA goes b ack next week or the week after and has a look 
and can inform the Panel where this indeed has happ ened.  We will give you the time to do that if 
necessary.  Thank you. 
Chairman
 
 171. Thank you.  Dr. Tritscher please. 
Dr. Tritscher
 
 
172. With all due respect I am not sure what this r eally would contribute to go back on all these 
individual things if you already say that you also ha ve an answer to that.  The question is a different 
one to me: what is the relevance of this kind of st udy in light of the overall weight of evidence, in the 
light of the overall data that has been submitted and that has been looked at? 
Chairman  
 
173. May I remind delegations again we are now on the first area, on terms and definitions, so I 
would like you not to go into discussions on the other specific issues.  EC. 
European Communities  
 174. Chairman, this is all fine and we can let you go on asking questions, no problem, but please 
bear in mind that we will have other questions late r on, and it is only for that purpose we intervene.  
We restrain ourselves from intervening really in order to give you the time which you think you need 
to clarify these questions, but we will have questions  to ask on practically the same issues which are 
being discussed now.  So with this understanding th ere is no problem from us of not asking questions 
now. 
Chairman
 
 175. Thank you.  It is quite clear to the Panel.  Dr. Boobis you would like to – thank you.  And the 
next question from the Panel is very technical and I don't even know whether I can pronounce the 
terminology correctly but I will try.  Please explain the units used in measuring hormone levels, for 
example in Dr. Boisseau's response to question 38 of the Panel, in particular please explain ng per ml 
is or pg per ml, ng per person per day, microgram pe r day, and how they are converted.  Dr. Boobis.  WT/DS320/R/Add.7 
 Page G-25 
 
 
  Dr. Boobis  
 176. There are two main ways of expressing units – actually, I was going to introduce another unit 
which is micromoles, but I will stick to two at th e moment.  These are masses per unit volume, so the 
base would be grams per litre, where we have so mu ch mass in grams per one litre of liquid.  They are 
scaled to units of 10 according to the Système internati onal, the SI units, so they go: micro is 10 to the 
minus 6 of a gram, nano is 10 to th e minus 9, pico is 10 to the mi nus 12.  In expressing dosages in an 
animal study or with respect to human exposure we often divide by the body weight, so we get so 
many nanograms per kilogram of bod y weight per day.  So that is where the kilogram comes from, 
that is to normalize it to the weight, and that  is because many effects scale from one species to 
another – although how much is open to discussion, but  that is a scientific debate – on the basis of 
body weight.  So, in other words, if we give a micr ogram to a mouse it is not equivalent to giving a 
microgram to a human, because a mouse is so small, so we divide by the body weight to get a body 
weight-normalized dose, which allows a better – no t ideal, but better – comparison of dosage.  I was 
going to introduce the micromole if you wish me to clarify that, which is based on molecular weight, 
so it essentially allows compounds to be compared on the basis of how many molecules of one to how 
many molecules of another.  Because when you take  a small molecule, one gram is going to represent 
more molecules than when you take a large molecule ; and if it is interacting with a receptor it is the 
number of individual molecules that counts, not the ab solute weight, so sometimes we express them in 
terms of moles.  I agree it is a technical issue, discussion. 
Ms Orozco
 
 
177. Just one clarification.  This, for example,  nanograms per millilitre – is it already normalized 
by body weight or is that a second stage? 
Dr. Boobis  
 
178. A separate stage.  This is a concentration, nanograms per ml. 
Chairman  
 179. Thank you.  Dr. De Brabander please.   
Dr. De Brabander
 
 
180. Thank you, Mr. Chairman.  I used to teach an alytical chemistry and residue analysis to 
veterinarians, so I developed something to help  them understand these units and maybe it will help 
also the Panel, so it is just not technical.  If y ou start from a lump of sugar which is approximately 
6 grams and you put that lump of sugar in a can of  coffee, which is approximately 0.6 litres, you have 
approximately 1 per cent.  When you put it in a bucket  of water, then you have 1 per cent, and we are 
familiar with that because in alcohol control we are in  that unit, 0.5 per cent is the limit in Belgium.  
When you go down and you place the same lump of suga r in a truck which is bringing the gasoline to 
your home, you are in a range of what we say 1 ppm, one part per million, or 1 milligram per kilogram, or 1 microgram per gram.  If you go down a nd you have it in an oil tanker then you are at a 
level of 1 ppb, or one nanogram pe r gram, that is to say one nanogram per millilitre.  So if you go still 
down (you can go down and down further) then you go rea lly to very very low concentrations, like if 
you can imagine that you have a soccer field a nd you have submerged it with water from 1 metre 
high, and you take 1,000 soccer fields and you put one lump of sugar in it then you are again a 
concentration factor of 1,000 times lower.  Maybe th at can help the Panel understand.  It is not very 
technical, I know, but I try to make it comfortable for you. WT/DS320/R/Add.7 
Page G-26  
 
  Chairman
 
 181. I agree with your point of view on layman's terms explanations, because it was much helpful 
for us to understand.  Dr. Cogliano. 
Dr. Cogliano
 
 
182. Thank you very much.  I would like to address a little bit of the point about the difference 
between nanograms per millilitre and nanograms per pe rson per day, because at IARC many times we 
look at all of the studies that are published in the scientific literature, and di fferent investigators will 
report the doses in different ways, and we need to try to get some kind of common conversion.  It 
helps us to understand, for example, why one st udy might be positive and another study might be 
negative.  The positive study might have been condu cted at 10 times higher dose, but the units are 
expressed differently.  The third one there, the na nogram per person per day, gives a good example of 
why you do want to perhaps normalize the dose, b ecause a nanogram in an adult woman is very 
different than a nanogram in an infant per day.  You could perhaps normalize it by body weight, but 
there might be other ways of doing it.  The fi rst unit that you have on the board, nanograms per 
millilitre, is a different way of normalizing it.  It is the concentration in the blood, so it is one 
nanogram per millilitre of blood, and maybe that is an  equivalent concentration, maybe it's not.   
183. This actually suggests also why mechanism is  important.  I think you heard earlier this 
morning from one of the experts that the rates at which cells are dividing is very important, if you have one nanogram per millilitre while cells are divi ding very rapidly, that might have different 
effects than one nanogram per millilitre in an organ wh ere the cells are not dividing very rapidly.  So 
it is important to try to understand the mechanism, and which of these different units of concentration 
or dose or exposure is most relevant.  Now freque ntly we don't know which is exactly the right one, 
and we make our best professional judgement on that.  But I think – just to help everybody understand 
– the units that you have up there are really measure ments of very different kinds, and it might take a 
mathematical model or a conversion formula to go fro m one to the other.  But if we do know how to 
make those conversions, it can he lp us understand how a dose in different studies or in different 
populations might relate to each other.  
Chairman
 
 184. Thank you.  Dr. Guttenplan. 
Dr. Guttenplan
 
 185. Just another way of maybe expressing what has been expressed before, a microgram per ml is 
one part per million, a nanogram pe r ml is one part per billion, a nd then if somebody consumes a ml 
of a compound that was one microgram per ml that  person would consume one microgram of that 
compound for every ml.  It may sound simplistic, but it might help people to understand some of these 
units.   
Chairman
 
 186. Thank you.  Dr. Boobis. 
Dr. Boobis
 
 
187. So just two additional points of clarificati on.  Dr. Cogliano has already referred to the 
concentrations in blood, and the question was rai sed from the Panel earlier about normalization, they 
would not be normalized for body weight because – de pending on the sensitivity of the receptor – it is  WT/DS320/R/Add.7 
 Page G-27 
 
 
  the circulating concentration that determines respon se, and so one microgram per ml in a human and 
one microgram per ml in a rat are essentially equi valent.  They may not give the same response, 
depending on the receptor, but they are equivalent  because they are distributed throughout the body.  
And the other point is that, on the nanogram versus picogram, just a simple point of explanation is 
that the reason we use these different terms, and it does cause a lot of confusion I recognize, is to 
avoid the situation of getting into a lot of zeros, so  if one expressed something that in picograms was 
0.00001, we would just convert it back down to the ne xt appropriate unit, to make it a slightly more 
manageable number, and that happens in both direc tions, so it is a practical consideration there. 
Chairman  
 
188. Thank you.  Dr. De Brabander. 
Dr. De Brabander  
 189. Yes, for the benefit of the Panel I should also say that if you work with students, you learn 
that they have difficulties to work with those concentrations, they really need a training on that.  You 
can put very difficult questions, and what may be interesting also for you is that you should not 
underestimate the psychological factor, which is co ming with how you will say how the concentration 
is.  For example, if you say it is "0.1 milligram per kilogram" it sounds less than if you said "100 
micrograms per kilogram" – but both are the same.  The psychological factor of expressing the concentration is very important and veterinary  students should learn to see through that.   
Chairman
 
 
190. If there are no other follow-up questions, then th e Panel's last question on this item is: what 
are xenobiotics?  Dr. Boobis. 
Dr. Boobis  
 
191. They are from the Greek root xeno, foreign; biotic, to the life, so they are compounds that are 
not produced naturally in the body, so they are a whole range of so-called foreign compounds.  Usually we exclude from xenobiotics nutrients in the diet, so the essential nutrients in the diet like 
protein, carbohydrates etc. will not be classified as xenobiotics, but everything else, all the chemicals we are exposed to would be regarded as xenobiotics.   It is simply a convenient way of lumping 
together an awful lot of different molecules.   
Chairman
 
 192. Dr. De Brabander. 
Dr. De Brabander
 
 
193. I agree totally, but I would add to that, if you go through all animals and all human beings the 
definition of xenobiotic is a little bit different, b ecause some components may occur naturally in some 
animals and not in other animals and not in human be ings.  We don't have to go into detail, but it can 
be confusing if you speak about xe nobiotic, it can be xenobiotic in one  species and not in another one, 
and also in certain conditions. WT/DS320/R/Add.7 
Page G-28  
 
  Chairman
 
 194. Thank you for your clarification.  This concl udes the list of the Panel's questions on area 1, 
and I now give the floor to the parties to ask thei r own questions to the experts under this particular 
item.  The floor is open.  I will give the floor to the EC delegation first. 
European Communities
 
 195. Thank you, Chairman.  So in this broad area of  terms and definitions we have one question 
first addressed to experts, in particular Dr. B oobis and probably Dr. Guttenplan.  Dr. Boobis says in 
his reply to question number 2, where the definition of  steroidal oestrogens is provided, at the end of 
his reply, that these substances – steroidal oestrogens – act through oestrogen receptors, and my 
question is: is it really the only way they act, is it only through oestrogen receptors, or do they act 
through another mechanism, one or more? 
Chairman
 
 
196. Thank you.  Is Dr. Boobis or Dr. Guttenplan ready to respond?  Dr. Guttenplan. 
Dr. Guttenplan  
 197. The evidence that oestrogens act through a non-r eceptor mechanism is not strong.  There have 
been a lot of studies of what we call in vitro,  in test tube studies, but there is some recent evidence that 
has not been published yet which pretty much co nfirms that oestrogens can act by a genotoxic 
mechanism in humans.  However, the level is very very low and you need supersensitive instruments 
to detect it. 
Chairman
 
 198. Dr. Boobis. 
Dr. Boobis
 
 199. I think it is important that we recognize that  there is a difference between what a given 
oestrogenic compound can do and what we mean by oestrogenicity.  So we can argue or discuss 
whether oestradiol has various properties, but some of those properties may be additional to its oestrogenic activities.  Oestrogenicity is a define d biological term and it functions through specific 
biological pathways, which is not to say that some compounds which are oestrogenic cannot have 
other properties.  So I think we need to make a distinction, we cannot lump everything that is oestrogenic into one chemical class and say that it al ways has other properties.  It is absolutely clear 
that not all oestrogens have any ge notoxicity, not all of them, some of them do, some of them don't.  It 
is probably not a function of oestrogenicity that cau ses that effect, it is some other property that they 
have, in the case of oestradiol, it produces quinones;  not all oestrogens can produce those structures. 
European Communities
 
 200. Gentlemen, I recall, if I may say so, in a st atement by Dr. Guttenplan, that these steroidal 
products, oestrogens, do not act only through the recept or, may they act through another means?  And 
this is my question.  Because in his reply Dr. Bo obis only says they act through receptors, oestrogen 
receptors, which is in fact not true.  There may be another way in which they act.  WT/DS320/R/Add.7 
 Page G-29 
 
 
  Chairman   
 201. Dr. Boobis. 
Dr. Boobis
 
 
202. There are examples of oestrogenic antagonists, th at were designed to interact with oestrogen 
receptors for therapeutic purposes, and these compo unds have been studied using the most sensitive 
methods known to man for interaction with DNA, accelerator mass spectrometry, and have been 
shown to be negative.  Now what that show s to me is that the oestrogenic structure per se  itself does 
not necessarily lead to the capacity for genotoxicity.  I am not saying that some of these compounds 
might not do that, but I think it would be inappropriate to regard that as a property of their 
oestrogenicity.  That is the point I am making.   
Chairman  
 203. Thank you.  Dr. Cogliano. 
Dr. Cogliano
 
 204. I would like to say that last year the IARC monographs evaluated combined oral 
contraceptives and hormone therapy that combined oestrogen and a progestogen at the same time.  And the expert working group c oncluded that both of these kinds of exposures clearly did have 
receptor activities, but that there was also some ev idence of genotoxicity and that it was possible that 
they acted both through a hormone receptor mech anism and a genotoxic mechanism.  The evidence 
was that it is obvious that they do have a hormonal effect, but the expert working group at IARC last year did conclude that these oestrogens and progestoge ns that are used in bi rth-control pills and in 
hormone therapy could have some evidence of genotoxicity as well. 
Chairman
 
 
205. Dr. Guttenplan. 
Dr. Guttenplan  
 206. Just to elaborate on what Dr. Boobis said.  The oestrogenicity has no direct relevance to the 
genotoxicity of the compound – different effects.  And I think of all the compounds and hormones 
that are possibly present in beef, the only one that might have ge notoxic effects is oestradiol, and 
these would be very weak but they might still be there. 
Chairman
 
 207. Thank you.  Does the EC have more questions?  EC. 
European Communities
 
 208. I would like to ask the experts if they could restate or provide again their views on the 
mutagenicity in this case and how that relates to  genotoxicity, in particular the DNA damage?  And 
what is the role in that respect, and the conclusions  we can draw, if a product is or is not mutagenic 
for the purposes of genotoxicity?  Thank you. WT/DS320/R/Add.7 
Page G-30  
 
  Chairman
 
 209. Thank you.  Dr. Guttenplan.   
Dr. Guttenplan
 
 
210. A mutagenic substance alters the structure of the DNA permanently and heritably.  So DNA 
has if you would, an alphabet.  If even one letter of that alphabet is cha nged, you have a permanent 
heritable change in that DNA, which will be tran smitted to future cellular generations.  Very few 
mutations actually are deleterious, most mutations  are innocuous.  And then of those that have 
deleterious effects, very few of them are in growth  control genes.  So the probability of a substance 
that causes mutations also causing, say, a cancer-causing effect would be very small.  An agent that 
damages DNA is a potential mutagen.  That damage is mainly going to be repaired, but if a little bit 
does not get repaired or is misrepaired  – there are DNA damage responses that make errors when 
they repair – then you can get a mutation.  So  a substance that damages DNA may give rise to 
mutations and it may be carcinogenic.  As was el aborated before by Dr. Boobis, there are many 
mechanisms by which chemicals can cause cancer, genotoxicity is only one of them. 
Chairman  
 211. Does that conclude the list of questions from the EC?  I give the floor to the US.  You have 
the floor. 
United States
 
 
212. Thank you, Mr. Chairman.  The United States has on ly one question, so I will keep this brief.  
I would ask Doctors Boobis, Boisseau and Guttenplan, who I think spoke on the terms and definitions section on similar issues, if you could please explain the difference between oestrogen and oestradiol 
17-beta (17 β). 
Chairman
 
 213. Dr. Boobis 
Dr. Boobis
 
 214. Oestradiol-17 β is a specific compound.  Amongst its properties it can bind to oestrogen 
receptors.  Oestrogen is any compound with a steroidal structure that can bind to those receptors, so it 
is a class of compounds.   
Chairman
 
 215. Thank you.  If that is all from the US, then I give the floor to ...  Are there any experts to add 
to the comments made by Dr. Boobis on this questio n before I give the floor to Canada?  If there are 
none then I will give the floor to the delegation of Canada. 
Canada
 
 216. Mr. Chairman, we have no questions at this time on the definitions.  The discussions on the 
definitions has been very fruitful and cl arified some of our questions.  Thank you.  WT/DS320/R/Add.7 
 Page G-31 
 
 
  Chairman  
 217. Thank you.  We have 30 minutes to go before lunch break, but given the time constraints I 
would like to move on to the next item, that is ri sk assessment techniques.  As was the case for the 
first item on terms and definitions, the Panel will pose some questions first and then invite the parties 
to pose their own question to the experts.  The Panel' s first question is composed of three parts;  one 
is: how are ADIs and MRLs determ ined? and how do JECFA and Codex interact?  The floor is open 
to answers by the experts. 
Dr. Tritscher
 
 
218. Thank you.  I would like to start with the firs t part, on how ADIs are set , and the latter part I 
give over to my colleague.  In this context I would like to refer to the basic document that explains 
how ADIs are set.  I will make it very brief in my  explanation, but it is explained in detail in 
Environmental Health Criteria 70, Principles fo r the Safety Assessment of Food Additives and 
Contaminants in Food, published by the World Hea lth Organization in Geneva 1987.  Again in the 
interest of time I will make it very brief and basic and then if there are additional questions I think I 
can explain later.  ADI is an acceptable daily intake  and is a chronic health-based guidance value.  It 
denominates the amount that can be consumed over lifetime without appreciable health risk.  As 
Dr. Boobis alluded to in the beginning, appreciable is  not a legal term or anything like that in this 
sense, it just denominates the basic concept in toxico logy that there is no zero risk, there is always 
some level of risk.   
219. Now the accepted daily intake is established from the overall toxicological database.  Experts 
review all available data, and since it's a chr onic long-term guidance value the emphasis is on long-
term studies.  Mostly we talk about experimental  studies from experimental animals that are treated 
under very defined circumstances and conditions w ith the specific compounds of interest.  And from 
these studies no effect levels are determined;  levels of exposure that do not lead to any adverse health 
effects in the test species.  I have to add that so metimes of course there are also human data available 
that are also taken into consideration.  From this  no observed adverse effects level in the experimental 
studies it is then  – with a number of uncertainty factors, or also called safety factors – extrapolated from experimental species, if we talk about animals, to the human situation.  With another uncertainty 
or safety factor it is then taken into account that th ere is possibly broader variability in the response of 
the human population as compared to a more defined experimental setting, so that no observed effect 
level is divided by these combined safety or uncerta inty factors in order to arrive at an acceptable 
daily intake level for the human population.  Mr. Chai rman, is this sufficient as a brief explanation for 
the Panel? 
Chairman
 
 
220. Yes, I suppose so.  May I ask Dr. Wennberg? 
Dr. Wennberg  
 221. The acceptable daily intake is established by JECFA.  To then go through the procedure 
which is used by JECFA since JECFA started to ev aluate veterinary drugs, is to derive the MRLs 
from the data on the pharmacokinetics, the metabolis m and depletion of the residues from the tissues 
after the last administration of the veterinary drugs in the animal in which the product is to be used.  
JECFA has developed a decision tree procedure to  arrive at the maximum recommended maximum 
residue limit, which consists more or less of the following.  As we were talking about the marker 
residue before, JECFA determines what is the most  appropriate marker residue in the circumstances 
for the various tissues which have been chosen by JECFA to be included in a standard food basket to 
be consumed every day.  This food basket consis ts of 300 grams muscle, which is meat, 100 grams WT/DS320/R/Add.7 
Page G-32  
 
  liver, 50 grams kidney, 50 grams fat, 1½ litres of mi lk, 100 grams of eggs a nd 20 grams of honey – in 
the case of milk and eggs and honey, if the product is to be used in lactating animals, laying hens and 
honeybees, respectively.   
222. Then JECFA requires a study using a radio labelled compound, which means that the 
substance, the veterinary drug, is marked so that all the molecules of the substance can be found in an 
animal and compared to the amount of the marker  residue which can be found by the analytical 
methods that I will come to later, which is u sed to analyse the marker residue.  Then the 
recommendation of the MRL is an iterative process which has been described in our answer to question number 9, in that JECFA tries to find the ba lance of the values where, given the depletion of 
the residue from the various tissues, which can be different, as a marker residue can remain longer in 
the liver or longer in the fat or longer in the kidneys .  So for the practical purposes of using veterinary 
drugs, to establish a time where all the residues, if  they were targeted for the specific food basket, 
would be below the ADI.  So to try to balance the di fferent levels of the total residues to the marker 
residue with the different concentrations at differe nt time points in the tissues of concern, JECFA is 
making these calculations to make the best fit.  And if , for example, the first calculation results in that 
the sum of all the total residues are significantly a bove the acceptable daily intake, then of course one 
has to adjust the calculations to arrive at final recommendations of the maximum residue limits for the 
marker residue, which if the drug is used according to good practice or use of the veterinary drugs, as 
defined by Codex, would result in the total residues being below the ADI.  And then I could remind maybe the Panel and the rest of the experts and the parties that the food basket that has been chosen 
by JECFA is quite a substantial amount of food from an imal original to be consumed every day.  So 
in a sense it is also an over-estimation of the consumption of residues.   
Chairman
 
 223. Thank you.  So who is going to respond to the second part?  Dr. Miyagishima please. 
Dr. Miyagishima
 
 
224. Thank you, Mr. Chairman.  Let me briefly expl ain how Codex interacts with JECFA.  As I 
mentioned in my introductory remarks, Codex is  a risk-management body and, contrary to the 
perception which some people have according to wh ich everything starts with risk assessment and 
then is followed by risk management, in the Co dex/JECFA system the story starts with risk 
management, and the first component of risk ma nagement, called preliminary risk management 
activities.  First of all, in the specialised Comm ittee of Codex dealing with residues of veterinary 
drugs in foods, CCRVDF, the discussion takes place as to what compounds in what foods may pose public-health risks or may lead to barriers in inte rnational trade.  And the Codex members in this 
Committee discuss, among themselves, on what com pounds new work should be started within the 
Codex system.  Of course they take into account va rious factors, such as whether the product itself is 
available as a commercial product, whether good agri cultural practice has been established that goes 
with the use of the compound, whether there are sufficient amounts of scientific work that would 
warrant sound assessments by JECFA.  When these c onditions are considered to be met, then the 
CCRVDF puts the compound on what we call the priori ty list for evaluation by JECFA, and this is 
sent to JECFA for evaluation.  You can put in this list compounds that were already evaluated by JECFA in the past, or you can put a new compound that has never been evaluated by JECFA;  you can 
nominate a compound for which the Codex has already established an MRL, or you can also include a 
compound for which no Codex MRL has been established.   It is up to the CCRVDF to take various 
conditions into account and set priority for compound assessment. 
225. After JECFA has conducted risk assessment on these compounds, and when the result, 
including the recommended MRL, is sent to CCRVDF, CCRVDF usually sends or circulates the 
recommended MRL at step 3 of the Codex step pro cedure; that is the step at which government  WT/DS320/R/Add.7 
 Page G-33 
 
 
  comments are invited.  The comments made are consid ered and are looked at at a physical meeting of 
CCRVDF at step 4, and then MRLs usually follow th e way through the final adoption at step 8; and of 
course at each step the Codex will have due regard to the scientific output of JECFA, but also take 
into account other factors that are deemed necessary to be looked at.  And in this process there is 
interaction between Codex and the JECFA system.  If Codex, namely CCRVDF, wants to have more 
information on certain issues, CCRVDF has the abilit y to ask those questions, either general or 
specific, to JECFA, and also Codex may request a particular type of risk assessment or scenario analysis and other kinds of supplementary informat ion to JECFA, and it is up to JECFA to answer 
those questions.  Thank you. 
Chairman
 
 
226. Thank you.  I understand that Dr. Boisseau would like to add.  Before I give the floor to 
Dr. Boisseau, may I give the floor first to Dr. Tritscher please. 
Dr. Tritscher  
 
227. Thank you very much.  Just to emphasize again the ADI and MRL and the interaction 
between JECFA and Codex.  The ADI is establishe d by JECFA; it is the outcome of the risk 
assessment, if you want, and it is not for discussion at th e Codex, so that is a value that is established 
by the risk assessment body.  The MRL as it is propo sed by JECFA, is based on scientific studies and 
data that are made available to the expert body an d that are evaluated by the risk assessment body, by 
JECFA, and then the MRLs are proposed to the respective Codex Committee,  CCRVDF in that case.  
And then the risk management body, so the Codex,  the CCRVDF is the risk management body, takes 
this proposal into account and can cons ider other factors in setting the fina l MRL.  That is all it is, just 
to emphasize it again.  Thank you. 
Chairman  
 
228. Thank you for your clarification.  Dr. Boisseau has the floor. 
Dr. Boisseau  
 229. Thank you, Mr. Chairman.  I agree, of course, with what was just said by the three preceding 
speakers.  I would simply like to add a few details .  We are accustomed to saying that in order to 
determine an admissible daily intake, we perform an evaluation of the toxicological profile of the 
substance studied.  In fact, toxicology is a some what narrow term, since the experts will focus not 
only on the toxicological effects, but will be looki ng for all of the undesirable effects which, in 
addition to the toxicology, could include physiolo gical and microbiological effects.  And for each 
study concerning one of these aspects – toxicological, physiological or  other – the experts establish an 
intake that has no effect, and depe nding on the nature of the undesi rable effect observed, they will 
allocate to that intake which has no effect an appr opriate safety factor whic h may range from ten to 
1,000, enabling them to obtain a series of accepta ble daily intakes.  Finally, the committee – the 
CVMP or the JECFA – will select the most restrictiv e of these daily intakes, in other words the one 
that is most protective of public health.  So it is important to take account of the great variety of tests involved and the fact that at the end of the day, the daily intake selected is  the one which is most 
protective of public health.  You will probably ask later on about the safety factors considered 
throughout the process of determining the ADI and the MRL, so I will not address that issue now. 
230. Let me add that usually, these toxicological studies are experimental studies that are 
conducted with the parent substance for practical reasons.  But where feasible and justified in view of 
the toxicological profile of a given metabolite, th is kind of study can also be conducted with a WT/DS320/R/Add.7 
Page G-34  
 
  metabolite whose toxicological or pharmacological pr ofile could make it the li miting factor in terms 
of the evaluation of the safety of the residues. 
231. Finally, I just wanted to add a word or two, if  I may, on the distribution of the risk assessment 
and risk management tasks between the JECFA and the Codex.  It is customary, in conducting a risk 
assessment of an environmental product, for the sci entific committee to conclude its risk assessment 
with an indication of the probability of risk for a given population or sub-population.  The residues of 
veterinary drugs are a somewhat special case, since we control the administration of veterinary drugs 
to animals, and the JECFA therefore goes beyond the mere appreciation of the risks, since that 
appreciation more or less stops with the determinat ion of the ADI.  With the determination of the 
MRLs, the JECFA is deliberately entering into the realm of risk management, since an MRL is a tool, 
a proposal to ensure that the ADI is not exceeded  with regard to the standard food basket as 
mentioned a short while ago by Dr. Wennberg.  Th is is a somewhat speci al case, since one can 
effectively manage the situation and the objective.  The objective is not only to assess the risks, but 
also to minimise the risks to which consumers of  foodstuffs of animal origin could be exposed. 
232. However, this does not detract from the JECFA's responsibility for risk assessment and the 
responsibility of the Codex Committee (CCRVDF) fo r risk management, since when it comes to 
MRLs, the JECFA, which is a competent scientif ic committee qualified to make proposals, makes 
proposals only, while the risk manager – in this specific case the CCRVDF – is the one that takes a 
decision.  In other words, the fact that th e JECFA makes MRL proposals on the basis of the 
competence of its WHO or FAO experts does not mean  that it can be accused of interfering in risk 
management.  It is the decision maker that ma nages the risk, i.e. the CCRVDF with the Codex 
member states.  Thank you. 
Chairman
 
 233. Thank you.  Dr. Wennberg. 
Dr. Wennberg
 
 
234. Thank you, Mr. Chairman.  Yes, could I just add a few comments, also regarding the 
possibility of temporary MRLs, or is that anothe r question that you have?  So JECFA will make full 
recommendations for quantitative values for MRLs if there is adequate data to do so and if this is in 
accordance with the ADI.  There ma y be instances where there is enough information to recommend 
MRLs, but the analytical method to determine these MRLs has not been sufficiently validated to the 
use in control laboratories worldwide.  In such  instances, as the process in Codex is quite long, 
JECFA may recommend temporary MRLs, and providing an opportunity for submission of additional 
information to a next meeting or a future meeting of JECFA for evaluation of the validation of the analytical method.  This has happened on occasion.   Also the Committee of JECFA may recommend 
MRLs not specified, or unnecessary as it was termed in  very old reports, where there is a wide margin 
of safety of residues when compar ed to the ADIs, and which would mean that it is not necessary to 
control this substance when it is  used in accordance with good veteri nary practice, because the values 
will never come anywhere close to the ADI.  And fina lly, of course, if there is not enough information 
for JECFA, and there are deficiencies in the data available to the Committee, they will of course not 
recommend MRLs and they never have recomme nded MRLs if there is no ADI established. 
Chairman
 
 
235. What do you mean by temporary?  When and under what conditions will temporary MRLs be 
terminated?  WT/DS320/R/Add.7 
 Page G-35 
 
 
  Dr. Wennberg  
 236. Temporary MRLs are recommended with a qualification that if the specified information, 
which is also specified in the report, is not subm itted within a certain timeframe, then the MRL will 
not exist anymore.  So if the JECFA Secretaria t does not receive the required information, the 
appropriate following meeting of JECFA will take  the decision that a temporary MRL will be 
revoked.  And this information is tr ansmitted to the CCRVDF and Codex.   
Chairman
 
 237. Thank you.  As it is already ... 
Ms Orozco
 
 238. Just one qualification please.  What kind of criteria are brought into consideration when an 
MRL is being considered; information that is differe nt than the one that has been taken into account 
by JECFA?  What kind of other criteria or othe r information is it taken into account by Codex? 
Chairman
 
 239. Dr. Miyagishima. 
Dr. Miyagishima
 
 240. Thank you very much.  Indeed, within the C odex system there has been a lot of discussion 
that took place to better delineate those factors th at can legitimately be taken into account when 
Codex elaborates texts.  In fact the Codex Alimen tarius Commission adopted in 1995 a statement of 
principle concerning the role of science in the C odex decision-making process and the extent to which 
other factors are taken into account.  There are four paragraphs and these statements are reproduced in the Codex procedural manual.  Later, in the year  2001 there were additional criteria adopted by the 
Commission that assist in the consideration of tho se other factors referred to in these statements, and 
this text is also included in the Codex procedur al manual.  Basically, the factors that may be 
considered as relevant for the protection of the cons umers' health and/or for ensuring fair practices in 
the food trade can be taken into account and they can  be moved by any members of the Codex bodies.  
It is up to the CCRVDF and ultimately to the Comm ission to weigh those factors and incorporate and 
take account of them in making a final decision.  One could give some specific examples but I would 
rather not mention them at this stage.  Thank you. 
Chairman
 
 241. US. 
United States
 
 
242. Thank you Mr. Chairman.  Just a quick follo w-up on the response of the representative from 
JECFA, just a point of clarification.  Did JECFA make full recommendations for MRLs for each of the six hormones involved in this dispute?   
Chairman
 
 
243. Dr. Wennberg. WT/DS320/R/Add.7 
Page G-36  
 
  Dr. Wennberg
 
 244. Thank you, Mr. Chairman.  Well, the six hormones which are the matter of this dispute, as far 
as I understood, are oestradiol-17 β, progesterone, testosterone, trenbolone acetate, zeranol and 
melengestrol acetate, is that correct?  OK.  So JECFA evaluated the three endogenous hormones, the 
first three ones, and on three occasions; in 1981 only for general considerati ons; in 1987, concluding 
that an ADI was unnecessary; and in 1999, estab lishing ADIs for all these three hormones.  At the 
same time, a complete residue evaluation of these hormones was performed and is available in FAO 
Food and Nutrition Paper 41/12, and co ncluding that it was not necessary, on the basis of the residue 
data, to recommend full MRLs for these three hormones.  As regards trenbolone acetate, JECFA 
evaluated this substance four times; in 1982, ge neral considerations; in  1983, limited by good 
husbandry practice; and in 1987 and 1989, established first a temporary and then a full ADI.  In the 
same way the residue data were eval uated and no MRLs were considered .  No that is not correct.  Can 
I have the lunch break to go back to the data a nd see about these three other substances, whether there 
were MRLs established for those? 
Chairman
 
 245. Sure.  If you don't have the information now then you can do so.  I would appreciate if you 
can respond to all the questions as briefly as possible.  It is already 1 o'clock, so now I would like to 
have a lunch break and resume the discussions at 3 p.m. sharp in this room.  I will see you all this 
afternoon at 3 p.m.  Have a good lunch. 
27 September 2006, afternoon
 
 
Chairman  
 246. [Beginning of tape] ... when our discussions were suspended, we were on the issues related to 
ADIs and MRLs and I believe that issues on this item,  the risk assessment techniques, are at the heart 
of the discussions this afternoon.  The Panel has a ra ther long list of questions, but as we understand it 
the parties are also very eager to put their own questi ons to the experts.  I would like to be as brief as 
possible, not only in our answers and questions, but al so I would appreciate if the experts will be very 
brief and succinct in their replies to the questions so  that the parties can have more time to ask their 
own questions later. 
247. The two follow-up questions regarding the first one I posed this morning also relate to ADI 
and MRLs, so I would combine these two questions t ogether.  My question is:  does the ADI take into 
account the fact that some of the same hormones ex ist in other food and medi cinal products and that 
therefore there are other sources of intake of th e same compounds?  The second one is:  does the ADI 
take into account all uses of the hormones as veteri nary drugs, including for example for zootechnical 
purposes?  The floor is open for comments and rep lies, from JECFA first, and then I will give the 
floor to Dr. Boobis. 
Dr. Tritscher
 
 248. Thank you Mr. Chair.  If I may ask, I happen to have slides on my computer that explain this 
and answer actually the two questions.
2  Just very quick, to the first question about the interactions of 
JECFA and Codex.  This is illustrated here, but  we have discussed, so JECFA as a risk assessment 
body interacts with the Codex as the risk management body.  (Can I have the next slide please.)  Now 
this illustrates what we actually do with the ADI and the exposure asse ssment, and this is to answer 
questions (b) and (c) that was just raised, if JECF A, in setting the ADI takes account of all possible 
                                                      
2 Dr. Tritscher's slides are contained in Attachment 2 to this transcript.  WT/DS320/R/Add.7 
 Page G-37 
 
 
  exposures, to simplify the two questions.  As I me ntioned briefly earlier, the ADI, the acceptable daily 
intake, is the outcome of the toxicological evaluation, and as was mentioned earlier by one of the experts, in the case of veterinary drug residues, its  toxicological effects, physiological effects, 
pharmacological effects, as well as microbiological  effects are considered, and from that an ADI is 
derived.   
249. Now the exposure assessment is then done sep arately from that, so in setting the ADI 
exposures are not considered.  Exposure assessment is done separately in that the amount of the 
chemicals in the food times the amount of food consumed  is considered, this is the exposure.  And in 
the actual safety assurance you compare this estim ated human exposure with the ADI, so if the 
estimated exposure is below the ADI, then the situa tion is OK, if the estimated exposure is above the 
ADI, then a risk management decision has to be ta ken.  That can also be, from the risk assessment 
point of view, in the first step the refinement of  the exposure assessment and so forth, so in an 
iterative process refining the exposure assessment and th en comparing it with the ADI.  Basically, and 
sure to answer the question, the exposure assessment is done separate of  the ADI, so in a subsequent 
step the exposure has to be compared to the ADI in  order to ensure safety of the overall food supply.   
250. Very quickly a few comments on the internationa l field, so from the perspective of JECFA. 
The exposure assessment in the case of veterinary  drug residues, as my colleague from the FAO 
explained earlier, is based on a food basket diet, so on a model diet.  In a national setting, exposure 
assessments can be done in a more refined way, becau se more specific data for that country would be 
available, for example with food consumption patterns a nd so forth.  So in the international field, in 
the case of veterinary drugs we work with mode l diets in order to assess the estimated human 
exposure and to compare it with the ADI.  And also, then the estimated exposure is compared with the 
MRLs that JECFA proposes in order to ensure that they are compatible with the ADI and hence they 
are compatible with public health.  I would leave it at that and would ask you if you have any additional questions. 
Chairman
 
 
251. Thank you.  Dr. Boobis – ...yes, EC. 
European Communities  
 252. To change the subject a bit right now, because all of  the things that you have not been told is 
that there is a lot of data that you can't get becau se you don't have enough animals to do the testing, in 
many cases, and so there are assumptions made, wh at the dose-response curves looks like when there 
is no data, so it's a guess.  These assumptions are a weak scientific statement and there are dozens of 
these assumptions, and one of them is that there is a threshold, a dose below which there are no 
adverse effects.  A threshold is a theoretical c oncept and it is difficult or impossible to actually 
measure, because there really are not enough animals to  be able to determine that there is a threshold 
or not.  It would take thousands of animals and yo u could still find arguments that there are other data 
that suggest that these assumptions are not right.  Wh en there is a hormone that the body is making 
and is in circulation, and when you add more of th e same kind of hormone, such as an oestrogen, you 
are just increasing the response that is already taking place, and in that case there cannot be a 
threshold.  The threshold has already been ex ceeded by the concentration of hormones in the 
circulation.  So this specific set of conditions results in dose-response curves that will have no 
threshold, and if there is no threshold, there is no safe dose, unlike the suggestion that there is an 
acceptable daily intake, and in a lot of cases an acceptable daily intake is legitimate, as long as there is 
not a counterpart to the chemical that you are givi ng and it does not exist naturally in the body, then 
you have the opportunity to at least justify an acceptable daily intake.  But when those hormones are circulating and are already active and you add more hormones, particularly at lower doses, what you 
expect to get is an increase in  the adverse effects, and under th ese conditions an ADI has no meaning WT/DS320/R/Add.7 
Page G-38  
 
  whatsoever.  There will be risk at any dose no matte r how low, and both Fred and I have demonstrated 
that at experimental studies and we have nobody that  has been able to tell us or to show us where 
what we have done experimentally, and what we ha ve done in terms of our conclusion, no one has 
shown us that it is wrong.   
Chairman
 
 
253. US. 
United States  
 254. Thank you, Mr. Chairman.  Two quick points, one a point of clarification.  The United States 
was under the impression that this was the opportunity of the parties to ask questions of the experts 
selected by the Panel rather than presenting evidence  of perceived situations ourselves in response to 
Panel questions.  On the second hand I would refer back to the Panel' s e-mail or letter of last week 
noting that the evidentiary record in  the proceedings had in fact been closed but for a showing of good 
cause to present new evidence, and we would note th at a presentation of evidence as we just heard 
could fall within the ambit of that letter.  Thank you. 
Chairman
 
 255. As I mentioned this morning, the purpose of this meeting is to request the experts to assist the 
Panel in discharging our duties as panellists, so it is quite clear to us.  I also mentioned that parties 
will be given more opportunities to put their own questi ons at a later time in due course.  So I would 
ask the delegation to limit their questions and comme nts or replies to those particularly related to 
questions put forward by the Panel.  I gi ve the floor to the delegation of Canada. 
Canada
 
 256. Thank you very much, Mr. Chairman.  First of all,  of course we want the Panel to get as much 
information they can out of this process and out of the experts as possible, and we certainly are not in 
any position, we don't want to limit the flow of in formation to you.  But in the same vein as the 
questions raised by my US colleague, and we suppor t the point, I guess as a matter of clarification, 
you mentioned questions may be put, I would like to know whether questions also includes arguments 
and expert testimony by members of the delegation of one of the disputing parties?  I think, to the extent that we are talking about questions, that pr esumes that we are not talking about arguments or 
running monologues, or we don't want to get into a de bate or discussion with the experts at this point, 
it would seem to me. 
Chairman
 
 257. Yes.  As I made it clear in the opening stat ement this morning, the questions and comments 
have to be focussed on the information and replies gi ven by the experts in written form.  So I make it 
clear once again that the discussions that we are goi ng to have this afternoon will also be focused on 
the information and comments and replies by the experts, without going further into the arguments on 
legal issues and those factual issues which have to  be discussed next week on Monday and Tuesday.  
Is that clear to every delegation.  OK.  With that understanding … 
Ms Orozco
 
 
258. Thank you, Mr. Chairman.  I have a follow-up question to the information that has been 
presented by JECFA.  In the case of hormones, for ex ample, it is clear, as we have been told, that 
there are hormones in different types of food, so wh en you take establish the ADI, are you taking into  WT/DS320/R/Add.7 
 Page G-39 
 
 
  account the level of hormones that there is from the consumption of every product that contains 
hormones in an endogenous way? 
Chairman  
 259. Dr. Boobis?  JECFA, Dr. Tritscher 
Dr. Tritscher
 
 260. Just very quick.  In the MRL derivation, the experimental studies are done in the actual food-
producing animal, as it's called, so by default you ha ve the levels that are measured in these studies 
contain endogenous levels of hormone s as well, so if you want, by default they are included in this 
consideration. 
Ms Orozco
 
 261. Yes, but what I would like to understand is, it is the addition of all the hormones that you 
would intake in your diet, because I don't know if it is set by the product, by meat for example in this 
case, or if it takes into account all the intake of hor mones, because you eat different things.  That was 
the first part of the question, and I'll just explain to  you the second part of the question, so I don't have 
to repeat so many times.  In the same vein, do you take into account the intake of a veterinary residue 
that would exist of the same compound because of othe r reasons, so we have also seen that there are 
veterinary drugs that use hormones that are used for zootechnical treatments.  Is that reflected in any 
way in the ADI? 
Chairman
 
 262. I would appreciate it if the replies would be right to the point, as succinct and as brief as 
possible, given the time constraint.  OK? 
Dr. Wennberg
 
 
263. OK.  Thank you, Mr. Chairman.  Well, the questions that are asked to JECFA from the 
CCRVDF are particular questions on the assessment of a particular residue or a veterinary drug, and it 
is used according to good veterinary practice.  It's  also said that for JECFA to assess a veterinary drug, 
it has to be authorized at least somewhere in the world, so there has to be a national authorization 
somewhere.  I think we have to make it clear once again that JECFA is not a regulatory authority that 
authorizes the use of drugs.  So the questions that are asked to JECFA are related, in this case of the 
natural endogenous hormones, to their use as producti on aids in cattle.  So what JECFA has evaluated 
is first of all the toxicological evidence which enab les JECFA to set ADIs, which is irrespective of the 
exposure, as we have just heard.  And following on  from that JECFA evaluated the concentrations of 
the hormones, as evidenced by the residue depletions studies and taking into account the endogenous 
concentrations of hormones in the meat.   
264. Now, the endogenous concentrations of hormone s in the meat are variable, and so its not 
possible to say that is X, Y or Z, because depe nding on the reproductive cycle of the animal, these 
levels vary.  They can be high at certain times and low at certain times for the different hormones.  So 
JECFA evaluated how much of the additional residu es relating to the use of the hormones in question 
would represent in terms of the ADI, and we come to a very low figure, it's less than 2 per cent of the 
ADI for oestradiol, it's less than 0.03 per cent for progesterone and it's less than 0.2 per cent of the 
ADI for testosterone.  That made the Committee conclude that it was not necessary to specify 
numerical MRLs and recommend MRLs not specified for these three natural hormones.  Now, if you are using hormones, you can either use one hormone  or you can use a combination, depending on WT/DS320/R/Add.7 
Page G-40  
 
  what kind of effect you would like to have.  These uses are to be authorized by national authorities.  
JECFA does not enter to efficacy of the use of these hormones.   
265. When you are using xenobiotic hormones which are not natural, these are also governed by 
national authorizations, how much you use and unde r which circumstances.  And in these cases, as I 
was asked before the lunch break, I was going to come back with MRLs that JECFA had proposed, 
recommended for these substances.  So for these subs tances, ADIs were set specifically for these 
substances, so they are not put together with othe r hormones, because the effects that were evaluated 
in the toxicological assessment enab led the Committee to set an ADI fo r these specific substances.  So 
you don't consider all different hormones with different  kinds of effects and different types of profiles 
in the same evaluation.  So if you use one hormone, th at's the hormone that you are using at this time.  
There may be combinations but if they are authori zed on a national level that's it.  So for the three 
xenobiotic hormones, JECFA set full MRLs, recommended full MRLs for all three of them.  This is 
available publicly and unless the United States want me to actually give you the levels, I will make 
my intervention shorter by not mentioning them.  If you have any further questio ns I will be happy to 
answer. 
Chairman
 
 266. Thank you.  So are any other experts intending to add any more comments?  EC. 
European Communities
 
 267. Gentlemen, I think there are other more simple  and I hope more clear ways to reply to the 
question.  Now this is given in the reply of JECFA to question No. 10; it is already in your files.  So 
you will see that JECFA says that they do not take into account data on the intended or actual use and consumption – the way the substances are going to be  used or consumed, they don't take data into 
account.  It is in the file.  This is the reply to the question, the second of the questions.  How they are 
going to be used and how they are going to be cons umed; they don't take this into account.  This is a 
purely generic toxicological study, without considerati on of where they will be used for.  A body with 
good veterinary practice or not, whether they would be misused or not, there would be more implants, 
in one implant there will be more hormones, one, two,  three or not, this is not considered.  As the 
doctor has said, it's only a single s ubstance that is analysed.   
268. Now for the first question, again on the repl y of JECFA to question number 10, you will see 
they speak about the so-called basket and whethe r there are intakes of the substances from other 
sources, and there you will see the basket consists mainly of steak, meat and muscle, meat and liver, 
meat and kidney and they have milk , eggs and honey, but of course  it does not exhaust all the other 
possible sources which humans eat every day and fr om which intake of these hormones can come.  
This is the reply to the first question and it is explained also in the text.  Thank you. 
Ms Orozco
 
 
269. Excuse me, an interruption just for completeness.  What other sources are you thinking about?  
You say that there other ways in the diet of humans, other than the food basket of JECFA, what other sources do you have? 
European Communities
 
 
270. For example, speaking about butter, I can think of a list of substances a human eats every day.  
Some of them may contain more hormones, less hormones.  Or other kind of meat.  So these are things which – I understand it is difficult to devise a basket that is really representative, and the 
representative of JECFA has said they leave it to th e national authorities to see, in each EC member  WT/DS320/R/Add.7 
 Page G-41 
 
 
  State, in each country, according to the nutrition habi ts probably.  If one country eats some substances 
a little more than what is in the basket, they woul d have to be reviewed, these calculations.  But 
certainly humans one day eat not only 300 grams mu scle, 100 grams of liver or 100 grams of kidney 
and so on.  So there are certainly other sources from which we take in these substances.  This is not 
disputed in the science.  And if you allow me to clarify, in reply to what has been said by the 
representative of JECFA – this is very important – the toxicological analysis takes into account a 
substance individually.  We will come back later to  this.  None of the implants as far as we know 
consist of one substance only, there is more than one substance.  It means the majority of the implants 
contain more than one of these hormones together, a nd the data which they have examined, they don't 
take this into account.  The toxicological data they  take into account, they don't examine the possible 
additive or synergistic effects of these implants , and these possible effects they have not been 
examined because it is not done.  It has not been done before by the countries that have authorized these substances, for example.  Thank you. 
Chairman
 
 
271. Dr. Tritscher would like to add some more comments. 
Dr. Tritscher  
 272. Yes, I have to respond to that and clarify a couple of points that were not exactly correct in 
the intervention by the EC.  (May I kindly ask you to put up a second slide, what I have on JECFA MRL, that is what it is called.)  This is just  a little graph, an illustration how JECFA does residue 
evaluations.  Just to illustrate that it is based on specific detailed studies in the food producing animal.  
(Thank you, that's it.)  As I said earlier, so you have detailed studies in respective animal species for what the veterinary drug is intended to be used for.   So by default, and that is what I tried to say 
earlier, you consider endogenously occurring hormon es as well as the additional treatment, that is by 
default, because that is what you measure in the en d if you measure a synthetic hormone for example.  
So based on these studies, the residues, the MRL, is  derived.  And then from the studies, from the 
median residue level in these defined studies accordi ng to good veterinary practice – this is very 
important because it is incorrect what was said before , that this is not considered, it is considered.  
Only studies that are field trials and studies that are performed under good veterinary practice.  And 
we have a small definition, but the problem here is that there is no internationally agreed definition.  
But from these studies the median residue level is taken for the intake assessment according to the 
model food basket, as was correctly said.   
273. Now this model food basket was constructed in  a way to reflect exactly these commodities as 
animal-derived foods that may contain veterinary drug residues, and butter, for example, it is self-
understanding that butter is covered by  milk, because butter is milk fat.  So there are all these different 
types of commodities that are covered in the model basket, in a way, to give you conservative – and 
conservative in our language means a high level – est imate, rather than going too low.  And as I 
mentioned earlier, or what I tried to explain, is that JECFA has to consider a worldwide model, and I 
did by no means say that JECFA leaves it up to na tional authorities to do an exposure assessment.  
JECFA does do an exposure assessment based on this  model diet, taking conservative assumptions to 
give them an idea of what the estimated exposure on the higher level could be.  National authorities 
have the possibilities, based on refined data, to  refine these intake assessments – to use data, 
additional data, that are adapted to, for example, na tional food consumption habits, or that are adapted 
to national registration for a specific purpose of this use of a veterinary drug, that is maybe only allowed in this country.  So there may be additio nal exposure sources in a specific country that only 
that country can take into account, that cannot be taken into account if we have to give a 
recommendation on the international basis.  Moreover , what this model basket reflects and the ADI 
reflects is a chronic exposure.  We are not talki ng about somebody who eats half a beef on one day 
because there is a big wedding party somewhere, excuse me to talk like this, but just to say what we WT/DS320/R/Add.7 
Page G-42  
 
  are trying to do here is to get a conservative – in  a public health protective way – a model that is 
sufficiently protective over a lifetime exposure.  And I think that are most of the comments I wanted to make now.  Thank you. 
Chairman
 
 
274. Dr. Wennberg. 
Dr. Wennberg  
 275. Yes.  I have two more comments to make on th is.  The first one is on this model standard 
food basket.  It is internationally accepted; it is also  used in the EU.  And the second comment is that 
the studies performed in the field trials which we re evaluated by JECFA reflect the use of these 
products also in combination, if it was the case that  these were the authorised uses in the particular 
country.  So for the endogenous hormones, the comb ination in terms of the exposure was evaluated, 
and the additional exposure, based on the use of these hormones compared to the endogenous one in 
relation to the ADI for each of the substances was calculated.  So I do not consider that JECFA only 
looked at one single hormone in one single inst ance.  The ADI is of course specific for each 
substance, because there are speci fic endpoints which have been u sed for the establishment of the 
ADI with the no effect level.  So you cannot combine different hormones which have different 
endpoints in terms of toxicology and say that you can lump them together and say that if I use this and 
this and this I get an increased toxicity.  Y ou have to look at each of the hormones and their 
endpoints, which is what the ADI is based on, to see wh ether there is a risk to public health or not.   
Chairman
 
 276. Thank you.  OK.  EC please. 
European Communities
 
 
277. Mr. Chairman, I don't want to become polemic, but I think in the documentation of JECFA 
and Codex which we have seen, toxicological data, a nd the evaluations of combinations of implants 
have not been performed, as far as we know, not fo r all the substances which we are talking about 
here.  So if the representative of Codex and JECFA th ink otherwise, we would like to see this paper.  
We have asked the United States and Canada to provide th is paper; they didn't give them to us.  So if 
they are claiming something, we need to see these studies, toxicological and residue studies, where 
they claim that the combinations of implants, where more than one hor mone is contained and 
administered, has been performed.  As far as we know th ey have not been done, not for all of them.  If 
you allow me to come back on the first question re plied by Dr. Tritscher, the basket, of course we 
have a basket similar to what Codex and JECFA have  in their evaluation, but the point, I think, that 
the member of the Panel was trying to clarify is  that we eat daily so many food products and 
otherwise which contain the same substances, or  substances which have the same or similar 
toxicological effects and activities, and these of cour se are not taken into account.  This is what we 
would like to clarify.  There are so many other s ubstances which have oestrogenic activity when they 
are consumed in food and this has not  been examined.  I don't know if it is feasible to be examined.  I 
think it is difficult but it is not impossible and probably the countries which have authorized these 
hormones must have performed this before they auth orized it.  And later on we will give you precise 
reference to our assessment where we do mention this potential risk, possibly from these other 
sources.  Thank you. 
Chairman  
 278. Dr. Boobis.  WT/DS320/R/Add.7 
 Page G-43 
 
 
  Dr. Boobis  
 279. I don't propose to get into a long discussion at the moment on this issue, but I would just 
make the comment, since it has been raised, about the totality of exposure to oestrogenic compounds 
in our diet.  There have been estimates of the tota l exposure to oestrogenic compounds, and by far the 
dominant source of those compounds is natural oestroge ns which are produced by plants in our diet.  
These far outweigh the traces of oestrogens from ot her sources, either natural oestrogen coming from 
non-treated animals or the presence of growth-promoting hormones used to treat animals.  That is not 
to say I have addressed the question of incremental ri sk, I assume that will come up later, but just to 
point out, in terms of the total burden of oestrogen e xposure, this is a much broader question than just 
the hormones coming from beef, it would open up the whole question of nutritional exposure as well. 
Chairman
 
 280. If the JECFA representative is not in a position to clarify on the question posed by EC then 
can I ask the representatives to move on to the second pa rt of the question.  Am I right to understand 
that the second part of the question has not been fully responded?   
Dr. Tritscher
 
 281. Could you please repeat the second part of the question? 
Chairman
 
 
282. Does the ADI take into account all uses of th e hormones as veterinary drugs, including for 
example for zootechnical purposes?  Dr. Boobis. 
Dr. Boobis  
 283. I tried to emphasize this, and I think the joint secretariat has made this point, but it bears 
repeating.  There are two different questions here, a nd we have tried to answer the specific question.  
The ADI is derived from toxicological informati on.  We can argue about the security of the 
conclusions, but it does not consider, nor should it cons ider, exposure or the use patterns.  It is based 
simply on the toxicological properties and the biological properties of the compound itself.  You then come up with a health-based guidance value, the allo wable daily intake, that is then compared with 
exposure.  And the second question which one might pur sue, and I think we have been, is to what 
extent are all different exposures taken into account, but that is a separate question from the ones on 
the board, Mr. Chairman, which is that the ADI does not take account of other uses nor should it. 
Ms Orozco
 
 284. Total exposure from food then should be taken into account during the exposure assessment? 
Dr. Boobis
 
 285. Yes, indeed.  That is where it would come in if it was going to be taken into account.  It does 
not come down the left-hand side of Dr. Tritscher's  diagram, which is the ADI derivation based on the 
toxicology, it comes down on the right-hand side, wh ich is exposure evaluation.  And then it becomes 
a risk management question as to how broadly are you going to include exposures other than those 
that arise from GVP, good veterinary practice, beca use of course JECFA bases its evaluations on the 
use of the compound according to good veterinary practice. WT/DS320/R/Add.7 
Page G-44  
 
  Chairman
 
 286. OK.  I hope we can conclude the discussion on this question as early as possible.  I will give 
the last chance to EC. 
European Communities
 
 
287. Chairman, I am afraid we cannot conclude th ese discussions because we have a number of 
other questions, but I would agree with the first reply of Dr. Boobis, that the way the ADI is 
performed by JECFA does not take into account ot her use of these hormones, like zootechnical or 
therapeutic use.  The claim is that they cannot do it,  or they don't want to know that they may be used 
in that way, fine, but for the purposes of your consider ation this is true, they do not take any, and this 
actually has been said in the reply of JECFA, wh ich if you wish I can read today.  The second 
question is the reply of Dr. Boobis about where e xposure from other sources has come in.  If the reply 
of Dr. Boobis were to be true, then what JECFA does is not correct, and I think that the reply is somewhere in between.  It is not as clear-cut as JECFA present it or Dr. Boobis would like to present 
it, because it all depends what these other sources are a nd what they contain.  And if it is biological 
activity, in this case we speak about carcinogenesis, it h as to be taken into account in the first step, in 
hazard identification, it is not only the in exposure assess ment that we need to consider it.  So I think 
we will have the opportunity, if we go down the ques tions later on, to clarify this instead of dwelling 
now on this issue in a generic manner.  But if you allow me – because my questions relate to the two 
questions which you have asked, the first before  the lunch break and the second now – if you allow 
me to have three follow-up questions on this. 
Chairman
 
 288. Please do that at a later stage, as I mentioned ear lier, because I think that the situation may be 
the same for other delegations too on the other specific questions. 
European Communities
 
 289. Well, I think, if you allow, I will ask at  least one question of the three I have.  
Chairman
 
 290. OK. With the understanding of delegations, please go ahead. 
European Communities
 
 291. Chairman, in the reply of Codex to question num ber 4, for your consideration I only read the 
first sentence:  There is no adopted Codex standard  or related text on the risk assessment of residues 
....  So what is being talked about here – there is  no standard about how to do this risk assessment, 
techniques and how you set the ADI and MRL.  These are the methods used and developed by 
JECFA, but they are not presented in an assembly of an organ for adoption so that they become 
standards in the sense of the SPS Agreement.  They  are considered by some committees and JECFA 
and a few scientists, as they say, they are developed by individual persons who happen to sit on those 
committees and they thought that is the relevant model.   But the truth is, and this is relevant for our 
case, there are no agreed international standards on how to do a risk assessment in that sense.  The 
other questions I will keep for later on.  Thank you. 
Chairman
 
 292. Thank you for your cooperation.  Is it on a procedural matter, Canada?  WT/DS320/R/Add.7 
 Page G-45 
 
 
  Canada  
 293. I would simply – I did not hear a question there  – but I would propose a question too.  I think 
Drs. Boisseau and Boobis both spoke to the last point raised by the EC, on how safety assessments are 
conducted and the process by which that's done, a nd I wonder if they had any comments on the EC's 
last statement.   
Chairman
 
 294. Can I give the floor to Dr. Boobis. 
Dr. Boobis
 
 
295. I think it is not entirely accurate to say that  it was a few scientists at JECFA who developed 
risk-assessment methodology; this evolved out of the National Academy in the US.  It has been 
developed by the International Programme on Chem ical Safety and is the cornerstone of risk 
assessments by almost everybody.  The four-step risk assessment paradigm, as we call it, – hazard 
identification, hazard characterization, exposure assess ment and risk characterization – is very very 
widely use.  It has been endorsed by essentially  everybody conducting risk assessment on expert 
bodies.  There has been lots of discussion about whet her or not this is applicable to veterinary 
residues.  The view widely held is that there is  nothing fundamentally different about the philosophy 
of evaluating risk of a veterinary residue, as opposed to any other specifics about the exposure 
assessment; one has to work out th e residues in meat from treated animals, but that is a technical 
detail, as opposed to the overall philosophy that underlies the strategy.  So I think that it is not 
accurate to say that this is something that has be en cooked up or produced by JECFA in an informal 
manner, it has been widely validated by many organi zations.  And in fact I believe it is in the Codex 
Manual as well, at least allusion to the general principles. 
Chairman  
 
296. If Canada's point is not related to the procedural  one, can I give the floor to the experts first, 
because I saw their flags were raised before you did.  Dr. Boisseau and then Dr. Miyagishima. 
Dr. Boisseau  
 297. Thank you, Mr. Chairman.  I am sorry, but there were many questions in rapid succession, 
and I wanted to take the floor following the stat ement by the European Union to the effect that 
ultimately, there were various utilizations that the ADI  could not take into account .  I think we have to 
be fairly precise on terminology, because otherwise we will be going round in circles like this for 
hours, without getting anywhere.  The ADI has not hing to do with exposures, as Dr. Boobis quite 
rightly said.  The ADI does not need to take acc ount of exposures, it is the logical conclusion of a 
toxicological evaluation.  By "toxicology", we may also mean "pharmacology" or any adverse effect.  
In any case, it is important that we bear this in mind.  Now, we must not confuse the Theoretical 
Maximum Daily Intake (TMDI) with the daily am ount ingested which is the sum of the amounts 
actually ingested from different sources, and we comp are, as the joint secretaria t said this morning, I 
think, the amount ingested with the ADI.  So we must stop linking the ADI with the amounts ingested, 
otherwise I can see no way out. 
298. Secondly, regarding the standards and the protoc ol that we have just spoken of, there is 
currently a cascade protocol, so to speak.  We have, today, a general structure for risk analysis and 
risk assessment.  However, it is true that the JE CFA applied this risk assessment to the consumer 
safety assessment of veterinary drug residues, with the exception of antimicrobials, for several years 
without a detailed assessment protoc ol – that work has been going on for a number of years within the WT/DS320/R/Add.7 
Page G-46  
 
  JECFA.  However, before the work was done, this  protocol was perfectly well established in the 
minds of all those throughout the world who, at the JECFA or EU level (I am thinking of the CVMPs), use the same methods.  Moreover, it was th e same people working in the different bodies, 
so we can hardly say today that this work w as done more or less according to the mood of the 
moment.  There was a consensus on the way that  this methodology for assessing the safety of 
veterinary drug residues should be applied.  It was neither written, nor formally adopted, but the 
methodology was perfectly operational a nd universally accepted.  Thank you. 
Chairman
 
 299. Thank you.  Dr. Miyagishima. 
Dr. Miyagishima
 
 300. Thank you, Mr. Chairman.  I would like to add some clarification as to what is meant by the 
Codex reply to question number 4.  We did confirm th at there is no adopted Codex standard or related 
text on the risk assessment of residues of veterina ry drugs.  When we call something a standard or 
related text, that means any text that is part of the Codex Alimentarius.  Th e Codex Alimentarius is a 
collection of adopted standards and related texts that  are there for guidance or for use by governments.  
In this particular case the Codex relies on JECFA, a nd Codex uses primarily MRLs as a tool for risk 
management.  Codex in this sense has not attempte d to provide guidelines for governments to conduct 
risk assessment, because JECFA does the business.   
301. This is the reason why the document on risk assessment policy and the whole risk analysis 
framework related to the work of CCRVDF, which is now  in elaboration, is not meant for inclusion in 
the Codex Alimentarius even if after it has been a dopted by the Commission in the future.  It will be 
eventually included in the Codex Procedural Manual, because the document describes the way the 
Codex interacts with JECFA.  So the scope of the document has no links with the guidance Codex 
intends to provide to governments.  This is the reason why the Codex replied that there is no risk 
assessment guidance within the Codex Alimentarius.  In other areas such as microbiological risks in 
foods, the Codex has taken a different appro ach, and the Commission adopted risk assessment 
guidelines which have been included in the Codex Al imentarius.  But with the approach the CCRVDF 
has taken, and the Codex Commission has taken so fa r, there has been no need for providing guidance 
to governments directly in terms of risk assessment techniques.  Thank you. 
Chairman
 
 
302. Thank you.  EC – sorry, I forgot that the Ca nadian delegation has raised its flag. Canada. 
Canada  
 303. Thank you, Mr. Chairman.  It is always illumin ating and interesting to listen to my friend 
Mr. Christoforou, so I didn't want to deprive him of the podium.  But I think, as this exchange 
demonstrated, in fact it was immediately after the intervention of my American friend who put the statement into the form of a question, we can actually have a very fruitful contribution from the 
experts when instead of making statements and argum ents we put simple questions to them.  And I 
hope that my EC colleague will respect your guidan ce and in fact your initial statements about the 
way this process is to be made, which is that at th is point instead of making arguments it's better to 
simply put clarification questions.  And if later on, on Monday and Tuesday, we have arguments to 
make, we will make them.  Thank you.  WT/DS320/R/Add.7 
 Page G-47 
 
 
  European Communities  
 304. Chairman, there are two clarifications, and I will not  continue this now.  It  is another thing to 
speak about the four stages of risk assessment to  which Dr. Boobis has referred, risk identification, 
risk characterization, dose exposure, risk characterization, that is true .  But here we were not talking 
about these four steps of what is a risk assessment and how to do it, we were talking about the ADI, 
and the maximum limits.  For this concept Dr. Boisseau says there were a few scientists, it was 
probably already before consider ed and was taken into account in JECFA, but there are no 
internationally agreed standards about this concept.  This is what I want to clarify.  The question was 
relating to ADI and MRL not only four steps.  With this we agree, of course, and we claim we can 
follow these four steps of the risk assessment, but that  was not the point, if you allow me to clarify.  
The second question is: Dr. Boisseau himself has said there are no agreements to the national 
standards, in JECFA or otherwise, how to define this concept of ADI and MRL.  There are questions 
one may ask about the details or some other important aspect of this, so that is what I wanted also to clarify.  Dr. Boobis said that it all started from the United States National Academy publications, this 
is all fine.  But for you to understand, there is  the Codex Alimentarius Commission, which is the 
members of the committee adopting texts, where th e four steps of risk assessment have been 
presented and have been adopted and have been accep ted.  That's fine.  But in JECFA there is no 
plenary of members of the WTO, for example, where they meet, and they take the papers of JECFA, 
and they say yes, they are well done, and we accept and adopt them.  This does not exist in JECFA.  And all these papers, as I said, they are publicati ons without legal status in terms of the SPS 
Agreement.  I think that it is as  simple as that, I don't want to conf use the scientists about this, and I 
certainly would agree with my colleague from Canada that we would have the time to clarify this on 
Monday and Tuesday; simply then, on Monday and Tuesd ay, the experts will not be here, so we need 
to take advantage of their presence here as well.  Thank you. 
Chairman
 
 
305. I would ask the representative of JECFA to respond to that question, not in the context of the 
legal analysis of the SPS Agreement, but in the context of the work you are doing in JECFA and 
Codex.  I give the floor to Dr. Tritscher. 
Dr. Tritscher  
 
306. Thank you.  Again, it's not correct the way it wa s just presented by the representative of the 
EC, because specifically the ADI concept, how it is defined, and how this arrives, and how to go 
about to get to an ADI, is exactly described, as I said earlier, in the Environmental Health Criteria 
document No. 70, Principles for the Safety Assessment  of Food Additives and Contaminants in Food.  
This is the document that was elaborated by a la rge group of international scientists convened through 
the International Programme on Chemical Safety.  It is a consensus document of an international 
independent expert scientific panel p ublished in 1987, and this is the basis on how to derive an ADI.  
An ADI cannot be derived if you don't follow the risk  assessment steps as they were defined, so you 
cannot disconnect an ADI from the risk assessme nt procedure, the defined steps of hazard 
identification and hazard characterization.  So agai n, this was not a correct statement.  You cannot 
devise an ADI without following risk assessment steps.   Generally this is the basis, and any of the 
national expert bodies, regional expert bodies, use exactly the same principles and the same 
methodology, let it be the European Food Safety Au thority, former SCF committee, let it be the US 
FDA or whoever.  This is the basis for this IP CS document published at WHO in 1987 and every 
follow-up from this.  Going to JECFA – JECFA is not just a handful of people sitting there and having fun.  JECFA is a scientific peer review pa nel, independent scientific experts that are an 
international peer review panel.  Everybody talks about peer review now.  So what JECFA does, they 
use all the evidence that is availa ble, scrutinize and discuss it to come  to a conclusion, based on all the 
available evidence.  Again JECFA works on a consensus basis to the extent possible; if it is not WT/DS320/R/Add.7 
Page G-48  
 
  possible there will be a minority opinion presented.  That has not been the case to my knowledge in 
the veterinary drug field; in the 50 year history of JECFA it only happened twice.  So it is the highest level expert body in this field that performs a peer  review of all available information.  And just 
saying it is a handful of people sitti ng together doing something, sorry if I am reacting like this, but I 
find this rather offensive towards the experts th at dedicate their time to do this work in the 
international context for public hea lth protection purposes.  Thank you. 
Chairman
 
 307. Dr. Miyagishima. 
Dr. Miyagishima
 
 
308. Thank you, Mr. Chairman.  I will be very brief.  I just wanted to clarify that there is an 
internationally agreed document that governs the w hole framework of risk analysis within Codex, 
which is the Working Principles for Risk Analysis  for Application in the Framework of the Codex 
Alimentarius.  This text was adopted in 2003 and is  now part of the Codex Procedural Manual that 
applies not only to the work of the Commission bu t all subsidiary bodies.  And as Dr. Boisseau 
mentioned, CCRVDF has now finalized the document called Risk Analysis Principles Applied by the 
Codex Committee on Residues of Veterinary Drugs in Food, and this document is awaiting the final 
endorsement by the Commission.  But it does not mean  that CCRVDF is now trying to reinvent the 
wheel; basically this document describes the standing practice applied by CCRVDF from its inception.  Of course, risk analysis is a continui ng process and Codex is trying  to evolve with more 
fine-tuning about risk analysis, but basically th is document describes the ongoing and established 
practice followed by CCRVDF.  In essence, the basi c framework of how JECFA does its work and 
how its work is treated by Codex has not change d substantively since the beginning of the Codex 
work in this area.  Thank you. 
Chairman
 
 
309. Thank you.  I think the replies are good enough for the Panel to clarify all the issues at hand.  
So now I would like to move on to the next question, that is purely procedural in nature again.  The 
question is: How does the work of IARC feed into the work of JE CFA and Codex?  How was this 
done in the case of hormones at issue?  May I ask this question to Dr. Tritscher or Dr. Cogliano?  
Dr. Cogliano. 
Dr. Cogliano  
 310. IARC convenes its own working groups to evalua te the carcinogenicity of various agents.  
They have evaluations of steroidal oestrogens as carcinogenic to humans, non-steroidal oestrogens as 
well, and also oestrogen as used in hormone therapy, and oestrogens and progestogens in 
combination, as they are used in hormone therapy or in oral contraceptives.  There is also an 
evaluation of oestradiol-17 β as carcinogenic in experimental animal s, and there is an evaluation of 
testosterone as carcinogenic in experimental an imals.  IARC publishes those in the form of 
monographs, and they are available to be used by JECFA or any other body that is interested in 
making a decision about those agents. 
Chairman
 
 
311. Has the representative of IARC ever been i nvited by JECFA to the Committee meetings?  WT/DS320/R/Add.7 
 Page G-49 
 
 
  Dr. Cogliano  
 312. I have not personally been, but Jerry Rice, my predecessor, might have been.  I was there for 
something about expert advice, but I have not been there to evaluate any chemicals.  
Dr. Tritscher
 
 
313. IARC is also a WHO organization. We invite  the IARC representative to JECFA meetings 
every time when there are contaminants and relevant  substances evaluated.  We are not talking about 
food additives in the context of IARC.  What IA RC does; IARC does cancer classification, so in the 
IARC assessments the focus is on the carcinogenicity  or potential carcinogenicity of the compounds.  
How the work feeds in was alr eady basically answered.  IARC pub lishes their work in monographs, 
so does JECFA, and we base – depending on which one comes timely first is the starting point of the work of the other, so we take each othe r's work into consideration.  Thank you. 
Chairman
 
 
314. Thank you.  Dr. Boobis. 
Dr. Boobis  
 315. To expand on that a little bit, when JECFA discu ssed the hormones, the natural hormones, for 
the fifty-second meeting there was a staff member of IARC present who was an adviser, a temporary adviser, and we were fortunate that we had access not  only to the published reports, but some of the 
information about to be published, and in fact, if you read the technical documents from JECFA, it 
was made clear that the IARC evaluation and some of  the information they had put together formed 
an important part of the deliberations of the Joint Committee.   
Chairman
 
 
316. Thank you.  EC. 
European Communities  
 317. Chairman, I have one question to both represen tatives of JECFA, actually Codex as well, and 
the International Agency for Resear ch on Cancer.  The Internationa l Agency for Research on Cancer 
has classified, as you know, oestrogen and oestradiol in the first group, which is the proven 
carcinogens of humans, and they have classified th e other two in the second category, group 2A and 
2B.  So I would like to ask JECFA, how it is possible, since they are interacting, these two 
international organizations, that JECFA comes to th e conclusion they are not proven carcinogens – I 
am speaking about oestradiol – whereas the Internati onal Agency for Research of Cancer has come to 
a different conclusion.  I would like to know: is it because they use different data, do they use 
different toxicological studies, do they take other considerations into account which make for this 
different outcome?  Because I guess you would like to  know as we do, since we take the advice of 
these two groups into account, which one of the two to follow.  One says oestradiol is a probable carcinogen, the other says no, there is a threshold, th ere is no risk.  I simplify, but this is the end 
result.  Thank you. 
Chairman
 
 
318. I see many flags raised, so I will give the floor  the JECFA first, and then Codex, and then 
Dr. Boobis. WT/DS320/R/Add.7 
Page G-50  
 
  Dr. Tritscher
 
 319. Thank you.  There are many things mixed up now  in this statement.  So JECFA and IARC are 
doing two different things.  First of all I have to clarify that JECFA never said oestradiol is not a 
carcinogen, you will not find this anywhere in any JECFA publication.  IARC does, as I said, cancer 
classification; it is a totally different thing than what JECFA does in doing risk assessment, and my 
colleague from IARC will explain what it means,  what their work really means to cancer 
classification.  A compound being a carcinogen does not preclude it from a safety assessment being performed and an acceptable daily intake or tolerabl e daily intake being set.  Again, those are not 
mutually exclusive things.  Sorry, let me say it like this:  JECFA has evaluated several compounds 
that have carcinogenic properties and have s till been able to set an ADI or a TDI. 
Ms Orozco
 
 320. Sorry, can I interrupt you there for asking you for an example of other compounds in a similar 
situation.   
Dr. Tritscher
 
 321. Contaminants in food like the chloropropanol s for example, monochlorpropandiol and DCP.  
I think I will leave it at that in the interest of time, because I know that ... 
Chairman
 
 
322. Thank you.  Dr. Miyagishima. 
Dr. Miyagishima  
 323. Simply to say that there is no standing or in stitutional linkage between the Codex system and 
the IARC.  Of course, to the extent that the work of IARC is beneficial to the work conducted by the 
Joint FAO/WHO bodies, such as JECFA, it is up to  JECFA to draw any useful elements from the 
work of IARC.  But there is no direct link between Codex and IARC.  Thank you. 
Chairman
 
 324. Dr. Boobis and Dr. Cogliano. 
Dr. Boobis
 
 
325. Well, it is just to emphasize the point that in the view of JECFA it is necessary to consider the 
mechanism and mode of action for the carcinogenic ity, because, as we alluded to earlier, there are 
many different ways in which one can generate a tumorigenic response.  I am sure tomorrow we will 
discuss exactly how oestrogens cause cancer, but as a philosophical point at the moment, just to 
clarify the point that Dr. Tritscher made, simp ly because a compound causes experimental cancer in 
an animal, or even at high doses in humans, does not  necessarily and automatically mean that it is not 
possible to establish a safe level of exposure.  JECFA sought to do that fo r the hormones.  One can 
argue whether it came to the right conclusions, but it was on the basis of consideration of the mode of 
action and the mechanism of the carcinogenicity.  As  already stated, at no point did we ever exclude 
evidence which was readily av ailable at that time, in 2000 and 1999, that in humans at certain levels 
of exposure oestrogens could cause can cer in endocrine sensitive tissues.  WT/DS320/R/Add.7 
 Page G-51 
 
 
  Chairman  
 326. Thank you.  Dr. Cogliano. 
Dr. Cogliano
 
 
327. I put my flag up just to make one corr ection.  IARC has classified oestradiol 17 β as possibly 
carcinogenic based on sufficient evidence in experiment al animals.  The agents that are known to be 
carcinogenic in humans are the steroidal oestrogens , non-steroidal oestrogens and various oestrogen-
progestin combinations as used either as birt h-control pills or menopausal therapy.   
Chairman  
 
328. Thank you.  EC. 
European Communities  
 329. Chairman, I think it would be useful if we take a little bit of time on this issue, because it is 
interesting to know the scientific basis upon which th e International Agency for Research on Cancer 
re-examine partly the same documentation that is av ailable, the toxicological studies and the profile in 
the mode of action in these substances.  And I un derstand by reading the International Agency for 
Research on Cancer monographs that they consider  that oestradiol, oestrogen and oestradiol-17 β not 
only act through receptor mediation but also they cons ider them to be genotoxic.  This problem, this 
toxicological assessment of this substance and the other natural hormones – I need to clarify, the 
International Agency for Research on Cancer, it ha s not examined the synthetic hormones, but they 
have examined the three natural.  Partly the same  studies have been evaluated by JECFA as well, and 
as you see, they dispute, they go through – if yo u take and read the opinion of JECFA and Codex 
subsequently, which is taken out and published – they go through th e data, but the ultimate conclusion 
is that oestradiol has a genotoxic potential, but they do not define it as genotoxic in the sense that the 
evidence is sufficient.  As Dr. Cogliano has said, th ey thought the evidence w as sufficient to define as 
carcinogenic in humans.  So I am still wondering an d I would like, as a lawyer, and I hope you as 
well, to know why on this crucial aspect the Inte rnational Agency for Resear ch on Cancer comes to a 
different conclusion for oestradiol, and they also come to different conclusions for progesterone in 
particular and testosterone as well, than the conclusions obtained by JECFA.  I am not trying to fudge the issues, no.  But the truth is that part of the scientific documentation is examined by the two bodies, 
and the conclusions and toxicologi cal conclusions they reach are very important, and I have the 
feeling, and we have the feeling here, that they are not getting to the same conclusion on that aspect.  
Dr. Boobis said that he does not, JECFA does not dispute that oestradiol is carcinogenic, fine, but the method by which we define oestradiol as a possible human carcinogen is also important, and I hope it 
is clear what I am asking the two or the three delegates to clarify.  Thank you. 
Chairman
 
 330. The Panel's intention in putting forward these questions was purely procedural, as I 
mentioned, and I think the comment you made is rath er stretching out to the substantive issues to be 
discussed later on, in due course, through exchanges of questions and answers on different issues.  I 
hope we can conclude discussion on th is question here and then come back, if necessary, in due 
course.  OK.  Then the next question of the Panel is  rather broad in concept, or which may capture the 
broader picture of the issues at hand.  The questi on is: how much scientific evidence is needed for a 
valid risk assessment?  What is normally done if data in a specific area are incomplete?  How is 
scientific uncertainty addressed?  The floor is open to any expert to respond.  Dr. Boisseau. WT/DS320/R/Add.7 
Page G-52  
 
  Dr. Boisseau
  
 331. Thank you, Mr. Chairman.  There are two hypothe tical possibilities here:  either the necessary 
scientific data is lacking to the point where the risk assessment cannot be completed – in which case 
the required data is requested so that the risk assessment can be continued;  or a committee, the 
JECFA – but it could just as well be the CVMP – cons iders that the necessary data has been gathered 
and is available, but since there is an element of  uncertainty in any piece of scientific data owing 
either to the experimental protocol used or th e obsolescence of the method used, or with the number 
of animals involved, it uses safety factors to ensure  that the evaluation results in proper protection of 
public health.  Thank you. 
Chairman
 
 332. Thank you.  Any other additio nal comments from the experts.  If there are no follow-up 
questions from parties, then can I move on to the next, please.  Madam Orozco. 
Ms Orozco
 
 
333. I would like to ask a follow-up question, because I am not quite sure.  The question has two 
elements that we would like to clarify:  What wo uld be the procedure when the data is incomplete?  
And what would be the procedure when there is uncertainty about the science? 
Chairman  
 
334. Dr. Tritscher. 
Dr. Tritscher  
 335. Again, very quick, to the completeness of the da tabase;  if you want to look at chronic intakes 
or setting an ADI of course you need sufficient long-term studies that allow an extrapolation or an 
assessment of the compound.  If it is a compound lik e the hormones, with hormonal effect, you would 
definitely require reproductive and developmental studies to check sp ecific effects.  Again, what 
Professor Boobis mentioned a couple of times already is that JECFA puts great emphasis on the mode of action of the compound.  That's part of the first question, sorry that I am going back, but then the rest is better understood.  To the question how much  scientific evidence is needed, it is not a check 
box, it is not a list that then is then just checked o ff.  There are certain basic studies that need to be 
available; over and above that, it is on a case-by-case basis.  Depending on the toxicological profile or 
the suspected profile of the compound, you would re quire certain studies.  If these studies are not 
available, if there are significant – now I am going to  the follow-up question – if significant data gaps 
are identified by the Committee, then these have to be clearly identified.  For example, there is 
concern for reproductive effects, however there is no reproductive study performed, that would 
preclude a safety assessment on that compound, and it would be clearly identified what the significant 
data gaps are, and the conclusion would be that there cannot be a safety assessment performed on this 
compound if there is a significant data gap.  If the da ta gaps are considered to be minor, in the sense 
that a safety assessment could be performed to s till be public health protective, however additional 
data would be required, then there is the option to set a temporary ADI, and then there would be a 
specific definition of what additional data would be required in order to fill these minor data gaps.  A 
temporary ADI usually has a limited lifespan, mean ing the data requirements would have a date 
attached to them.  If a temporary ADI is set, so minor  data gaps that are clearly identified are there, 
then what usually happens is that there are additio nal safety factors, uncertainty factors, added on to 
have an extra level of safety adde d and to take this additional uncertainty into account.  Thank you.  WT/DS320/R/Add.7 
 Page G-53 
 
 
  Chairman  
 336. Dr. Wennberg and then the EC. 
Dr. Wennberg
 
 
337. Thank you, Mr. Chairman.  Just short on the residue part.  I already alluded to the 
requirements related to the data needed to perform  an evaluation of the residue in the animals in 
question.  When I was talking about how to set MRLs  – I am not going to go into that any further – 
and similarly applying, which I also mentioned before, is that if there are minor gaps in the validation 
of the analytical method to be used in residue c ontrol, for example, JECFA could consider to set 
temporary MRLs, but we already talked about that.   
Chairman  
 338. EC. 
European Communities
 
 
339. Chairman, two brief statements and I think we can  be more concrete.  If you look at the 1987, 
1988 evaluation by JECFA of the three natural hormone s, they thought at the time that they had a 
complete set of data, they made the evaluation, but they did not fix an ADI because they thought the data was complete and there was no risk, because of th e wide margin of safety, as they call it.  JECFA 
has re-evaluated the three natural hormones again in  1999, and they came to a different conclusion, 
that this time it was necessary to fix an ADI, becaus e data apparently changed,  were more complete.  
Now, the United States, in its reply to the co mments made by the experts and by the European 
Community, interprets why JECFA fixed in 1999 an  ADI is because the data were now complete.  
This is the terminology, I can find the correct  quotation if necessary.  Whereas the reply of 
Dr. Boisseau, why they fixed an ADI for the first time in 1999, is in order to be more convincing.  I 
can find the correct quotation as well.  So there is quite an uncertainty in the way JECFA proceeds.  
The point is, and this comes to the second question asked by Madam Orozco – practically there is no 
room to take into account uncertainty in JECFA, be cause they think that they can address uncertainty 
through the so-called safety factor.  By applying th e so-called safety factor, sometimes it's 100, 200 or 
1,000 times, they think they can take into account uncertainty in the data, but at least the way we 
understand scientific uncertainty is different.  And I would like to know instances where – if there are, 
there are really very few, very very few in the hi story of JECFA – where they came to the conclusion 
that for a substance we do not have sufficient data to propose an ADI or an MRL.  And I should give 
you another example which is also pertinent in th is case, the case of carbadox, and I will only mention 
it and not go on into the details.  We were arguing th e data were not sufficient in 1996, nevertheless 
JECFA proposed a provisional, as they call it, a pr ovisional ADI and MRL, and ten years later on 
Canada, for example, has agreed that the data we re not enough and were wrongly interpreted.  So I 
think these questions are very important.  Is there any room in the JECFA procedure and the risk assessment to take into account scientific uncertain ties what the real scientists understand what is 
scientific uncertainty?  And our feeling is that there is very limited room for that and I don't thing they 
actually do it.  Thank you. 
Chairman
 
 
340. Thank you.  US. WT/DS320/R/Add.7 
Page G-54  
 
  United States
 
 341. Thank you, Mr. Chairman.  I again had a very difficult time discerning a question in the last 
statement by the EC, but there were quite a lot of  factual assertions made in the course of that 
"question".  I was wondering if, maybe we could ope n up the EC's comments to the experts who have 
spoken on the issue of ADIs and the JECFA/Code x/IARC work.  So I would propose that Doctors 
Boobis, Boisseau, Cogliano and Dr. Tritscher respond to  several of the factual statements made by the 
EC in its last comments. 
Chairman
 
 
342. Well, before I give the floor to the experts, may I remind you again this is the session for the 
Panel to put the questions, and we are allowing the parties to ask additional questions in relation to 
those questions posed by the Panel.  So we are not  going to make any statements from the Panel or 
from the parties at this particular moment, and I would urge the delegations to refrain from making 
any statement and rather focus on the questions put  forward by the Panel and replies given by the 
experts.  With that I will give the floor to Drs. Boisseau and Boobis. 
Dr. Boisseau   
 343. Thank you, Mr. Chairman.  I will try to keep my reply to the EC intervention brief.  Science is 
a discipline which is constantly evolving.  When we manage to resolve a problem, we generally find 
that there is another problem hidden behind it, and so  on ad infinitum.  The assessment of the safety of 
veterinary drug residues is a pragmatic system, beca use the proper use of veterinary drugs depends on 
its conclusions.  We need to be able to decide , at any given moment, whether we should think of 
reconsidering an assessment in the light of scientif ic developments.  But we cannot constantly delay 
that decision, or otherwise it can turn into a Sisy phean challenge.  When the EU speaks of these 
scientific uncertainties, it is the general protocol  that is being called into question.  We must 
understand that the committees, the JECFA and the CVMP , work on the basis of the data available.  
Where do these data come from?  Generally from the industrialists that provide them.  In the end, 
there is very little, relatively speaking, in the way of  data, from independent bodies.  So ultimately, it 
is going to be necessary, in the light of the info rmation available – if it is sufficient – to make 
proposals that it will be up to the Codex to accept or reject.  If not, none of what we call old molecules will ever be evaluated and they will have to be withdrawn from the market, since no one will support 
them.  The same applies to the developing countries.   There are substances which are very important 
for the developing countries, but which represent a minor market.  Most of the time, although their 
files are not complete the JECFA tries to conduct th ese evaluations on the basis of the data available 
and using appropriate safety factors to recomme nd ADI and MRL standards to the CCRVDF, that 
guarantee public health.  Thus, I think it is important  to remember that the approach is a pragmatic 
one. 
344. As regards what happened in th e re-evaluation of natural hormones in 1999, I maintain what I 
wrote, namely that during the preceding re-evaluation, the margin of safety between what might have been envisaged as an ADI and the daily amount ingest ed seemed to the JECFA to be such that it did 
not appear necessary to determine ADIs, and its conclusion at the time was:  ADIs not necessary;  MRLs not necessary.  It emerged that there was a problem of communication, because as a result this 
margin of safety did not appear;  and the JECFA, of its own accord – this was not requested by the 
CCRVDF – reverted to this evaluation, for which, in fact, it had access to a whole data package.  
Please excuse me, I made a mistake in my previous re ply:  there were indeed new data in connection 
with the data package which the FDA placed at the disposal of the JECFA, and which helped, as it 
were, to determine more precisely this margin of saf ety between an ADI that was established at that 
time and the theoretical daily intake of residues.  The JECFA once again determined that it was not 
necessary to establish the MRLs sinc e the margin of safety was still sufficient.  In other words, the  WT/DS320/R/Add.7 
 Page G-55 
 
 
  evaluation remained unchanged, and it is not really th e availability of new data that led the JECFA to 
reconsider its previous evaluation – it was only that the JECFA wanted to be more transparent, more explicit.  The CCRVDF did not want to take account of this new re-evaluation which yielded the same 
results and which it had not itself requested.  Thank you. 
Chairman
 
 
345. Thank you.  Dr. Boobis. 
Dr. Boobis  
 346. Just from my own personal perspective, a nd I am not necessarily speaking for JECFA or 
anybody else here, I think it is probably fair to say that when conducting a risk assessment, we are not 
really looking to see if a data package is comple te as to as much as whether it is adequate for the 
purpose, because I agree entirely with everything th at Dr. Boisseau has just said, that science moves 
on, and it would be complacent for a risk assessme nt body to assume that it knew everything about a 
substance at a particular point in time.  We have to work within the available information, and the 
question we ask is: do we have sufficient information at this point to conduct a risk assessment? – not: 
is the data complete and are there no scientific ques tions remaining to be answered.  And I would add 
that there are numerous examples in the JECFA monographs of substances where it was not possible to establish an ADI on the basis of incomplete data; that has been done on several occasions. 
Chairman
 
 
347. Thank you.  Dr. Tritscher. 
Dr. Tritscher  
 348. I would like to comment on the aspect of uncertainty and if or if not uncertainty is taken into 
account by JECFA assessments.  It is correct that sc ientific uncertainty is difficult to quantify very 
often, and the scientific community is still debating.  There is a lot of debate currently going on to 
better quantify uncertainty in the database, to give a better information to the risk manager as to the 
confidence on the conclusions that are reached.  As the delegate of the EC said, real scientists even 
have problems to define scientific uncertainty.  The experts working in JECFA are also real scientists 
and they also have problems with that.  However, it  is always taken into account and, very briefly, 
there are two aspects that need to be  separated out, that is uncertainty and variability.  Uncertainty is 
what we don't know, and variability is variation in a response between individuals, between species.  
Those are two different concepts and both need to be considered.  Uncertainties as to extrapolations 
from model systems to the real-life situation and so forth, they are taken into account by safety factors 
that are also called uncertainty factors.  Now th ere are default factors that have been used by 
everybody, by all the expert bodies since the inception of the invention of the ADI, and now 
increasingly efforts are undertaken to go away from  default uncertainty factors to data-derived 
uncertainty factors,  meaning to put more science into the derivation of these factors to take account 
of true uncertainties, if possible, if the data are ava ilable.  That is the concep t of the chemical specific 
adjustment factors.  Again, a concept that was de veloped by Andy Renwick, I think, originally, but 
the International Programme on Chemical Safety has published on that and the Expert Committees 
like JECFA and JMPR are trying to apply this c oncept where possible, meaning where data are 
available to extrapolate, for example from the animal to the human situation.  So it is factually entirely 
incorrect to say that JECFA does not take  uncertainty into account.  Thank you. WT/DS320/R/Add.7 
Page G-56  
 
  Chairman
 
 349. Thank you.  I think the comments just made by Dr. Boobis and Dr. Tritscher have already 
answered the Panel's next follow-up question, but I would appreciate it if any other experts would 
further elaborate on this particular question, that is:  how would you distinguish between insufficiency 
of science evidence and scientific uncertainty?  Could you rephrase your comments in more clear 
terms to distinguish between these two concepts.  Dr. Cogliano. 
Dr. Cogliano
 
 350. Yes.  I want to start by agreeing with Dr. Boobi s's comment that it is not so much a matter of 
being incomplete.  But I would also point out that there are several kinds of uncertainty.  There are 
uncertainties as to, for example, what is a null-effect  level in animals, or a safe dose; or how would 
you extrapolate between animals and humans.  There are also wider uncertainties about – are the animals predictive at all of humans, or is a single chemical fed to an animal predictive of the human 
situation?  There are very different levels of uncertainty and I think that the way some types of 
uncertainty are addressed is by trying to quantify them, by trying to get data derived from chemical-
specific uncertainty factors.  Some forms of uncertainty are addressed by general assumptions, like we will assume animal results are relevant to humans unless we had the data to show otherwise.  So that 
is another approach to dealing with  uncertainty, to take a conservative approach and say that we will 
assume that these study results are useful.  And I th ink that as risk assessment evolves there are more 
and more questions that are asked.  We are now asking more questions ; once we understand the 
mechanisms we start to as k: what is the range of variability in  human populations and who is likely to 
be more susceptible?  These are concepts that IARC monographs are trying to address more in the 
future, but they had not really been questions that  were routinely asked 20 or 30 years ago.  I think 
that what we do with uncertainty does evolve over time and there are different forms of uncertainty 
that do get different approaches.  Some are very quantitative and some are much more qualitative.  I 
think I will leave it at that since more specific questio ns – it's a very broad-ranging field, I think, to try 
to really answer in a few words.  I think ther e can be whole books written on uncertainty and how to 
deal with it. 
Ms Orozco
 
 351. Simply, if you have similar explanation as to wh at is or what's not sufficiency of scientific 
evidence? 
Dr. Cogliano
 
 352. Let me try to answer that in the context of the monographs.  If we don't have epidemiological 
studies, good epidemiological studies, we will say we  have inadequate information, and then the 
evaluation will proceed looking at the animal studi es.  If we have good bioassays, we will make our 
conclusion that something is probably carcinogeni c or possibly carcinogenic or not based on the 
animal studies.  If we don't have good animal studi es or good human studies, we have inadequate 
information, and we would end with saying we cannot classify this substance.  So we do want to have 
either epidemiological studies or animal bioassays.  Now let's shift to the mechanism field.  If we 
don't have a good mechanistic understanding, that will not stop us from classifying the substance; we 
will classify the substance based on the human and th e animal studies, even if we do not understand 
the mechanism.  So having epidemiology or animal  bioassays, that's a requirement to come up with a 
classification.  Not having mechanistic studies – its nice to have that, it contributes to our 
understanding, but it does not stop us from a classifi cation.  So I guess you could say what we need, 
and IARC usually has, are some animal bioassays or some epidemiological studies and then we will 
proceed with a classification.  If the rest of the da tabase is somewhat lacking, that does not affect the 
classification.  Now I should mention that IARC does not come up with safe levels of exposure and  WT/DS320/R/Add.7 
 Page G-57 
 
 
  uncertainty factors.  So our uncertainty analysis is really different from what JECFA would do or 
someone else trying to come up with a safe level for consumption in foods.   
Chairman  
 353. Let me put this question to all of the experts.  If there is scientific uncertainty, would you all 
agree that there is always insufficiency of scien tific evidence, or, even if there is scientific 
uncertainty, may there be a situ ation where scientific evidence is  sufficient in terms of risk 
assessment?  Dr. Boobis. 
Dr. Boobis
 
 
354. I will try and answer that question in a slightly different way, if I may, which is just following 
on from the comments of Dr. Cogliano.  Where there is scientific uncertainty, we would tend to adopt 
a worst case default in extrapolating the data to take  account of that, so we will use the most sensitive 
endpoint in the most sensitive species for the extr apolation purposes of a risk assessment, assuming 
that it is relevant to humans and assuming that hum ans are going to be more sensitive than animals.  
Now that is a fairly conservative assumption, based on the totality of scientific information available 
to us at this time.  The insuffi ciency of scientific evidence, I w ould say, as has been indicated, could 
be trivial, it could be that just one test is not ther e and we can fill in, but it could be substantial.  For 
example, there might not be a reproductive toxicity study for a compound that women of child-bearing age would be exposed to, in which case we w ould consider that a major insufficiency of data, 
not a scientific uncertainty, just an absence of data, and we would not proceed without filling that data 
gap.  So I think they are rather different issues; one we can handle with taki ng conservative defaults, 
for the other we really need info rmation to allow us to proceed. 
Chairman
 
 355. Thank you.  Dr. Boisseau, Dr. Cogliano and then Dr. De Brabander. 
Dr. Boisseau
 
 356. Thank you, Mr. Chairman.  I am afraid it will be difficult to reply to the question you have 
just asked.  I can repeat what I said, namely that if  there is a major insufficiency of scientific data, as 
Dr. Boobis just mentioned, we cannot go any further in the evaluation of the safety of residues of veterinary drugs.  There are other cases where scientif ic uncertainty with regard to less important data 
would not prevent a conclusion from being reached with a safety factor that would provide for 
adequate protection of public health.  Beyond th at, it is impossible to draw up a table with two 
columns showing what constitutes insufficiency and uncertainty.  All we have is specific cases, we 
can provide the odd example.  We could speak of in sufficiency in the case of suspicious results of 
short-term mutigenicity tests without a supplementary carcinogenicity test or without any studies 
involving radio-labelled elements for a tissue de pletion or a metabolism study.  That is an 
insufficiency.  We can give you a few examples, but there will always be cases that do not fit the 
examples.  The reply that I am tempted to give you is that a distinction must be drawn between an 
individual evaluation, whatever the competence of the expert involved, and a collective evaluation 
conducted by a committee of competent experts, be it the JECFA, the CVMP, or another committee.  
We must not underestimate the notion of collective evaluation.  When 30 or so experts reach a 
consensus that there is an  insufficiency of data or that a scien tific uncertainty can be managed through 
safety factors, I think that we can be fairly  confident – this is a collective approach. 
Chairman
 
 357. Thank you.  Dr. Cogliano. WT/DS320/R/Add.7 
Page G-58  
 
  Dr. Cogliano
 
 358. I was going to respond. I think similarly – it really depends on what the question is, for 
example: does tobacco cause cancer?  I think the answ er is unequivocally yes.  Are there uncertainties 
or are there things we don't know, for example I was asked the question earlier, am I going to get 
cancer if I smoke for only five years, or only one y ear, or only two cigarettes a day?  We don't really 
know exactly the shape of the do se-response curve.  But we do know enough to know that from a 
public health point of view tobacco is definitely harmful and we should take steps to curb smoking.  
There are always going to be uncertainties or things we don't know at the fringes.  What happens if we 
smoke and we also work in a dusty environment, what happens if we smoke  and we have vitamin 
deficiencies, these are the niceties that scientists will say are uncertainties, and there are things that we 
would like to know more about.  So I think when yo u are asking about insufficiency of evidence it is 
really: insufficient for what purpose, and what is th e question you are trying to ask?  In some cases the 
data set can be absolutely conclusive that tobacco  is harmful, but without necessarily answering every 
single question: what about in combination with this  or in combination with that or two cigarettes a 
day?  So yes, keep in mind the purpose, and data sets are always sufficient to answer some questions 
and there is always more that you could know if you wanted to answer everything. 
Chairman
 
 359. Thank you.  Dr. De Brabander. 
Dr. De Brabander
 
 
360. Thank you, Mr. Chairman.  As you know, I am layman in that area of risk assessment, but in 
answering this question I really want to make so me remark on a question which is important to me 
and perhaps for the whole system.  I agree that science grows continually, we always have new 
evidence.  I also agree th at there are internationally recognized items to make the risk assessment for 
veterinary drugs, but when you as a human being take  medicine, or you give a veterinary drug to an 
animal, it is in order to cure it from a disease, and when you take a medicine, you always balance the profit of taking a medicine against the risks, because  every medicine has its side effects, against the 
profit of being healed.  So the question I ask: by scientific uncertainty, if you are using hormones, 
what is the counterbalance of using hormones except of profit, money?   
Chairman
 
 
361. Thank you.  Any other – EC. 
European Communities  
 362. Thank you, Chair.  A simple question.  In the view of all experts, pe rhaps, and whoever wants 
to reply on this: is direct genotoxicity of oest rogens an issue on which there exists scientific 
uncertainty? 
Chairman
 
 363. The floor is open.  Dr. Cogliano. 
Dr. Cogliano
 
 
364. Yes, I think there is scientific uncertainty.  On e of the exhibits you have was the summary of 
the most recent monograph meeting on the oestr ogen/progestogen combinations, either as birth-
control pills or as menopausal therapies.  And as I mentioned earlier this morning, a hormonal  WT/DS320/R/Add.7 
 Page G-59 
 
 
  mechanism is clearly operating, but there was so me evidence that there could be genotoxicity 
operating; it's not as strong.  It was not the entire wo rking group that put a lo t of credence in it, but 
enough members of the working group thought that  there was some possibility of genotoxic action 
that our summary does have a paragraph for each of those two types of exposures that mentions that 
there could be some genotoxic activity as part of th e cancer mechanism.  I think that is an area of 
continuing research and obviously  more will be known later. 
Chairman  
 365. Thank you.  Dr. Guttenplan. 
Dr. Guttenplan
 
 
366. I think qualitatively one can say that there is very  little uncertainty in the fact that oestrogen is 
genotoxic, however quantitatively I th ink there is a lot of scientific uncertainty.  I don't think we can 
really estimate the risk at this point from such low levels of genotoxic effects.   
Chairman  
 
367. EC. 
European Communities  
 368. Mr. Chairman, I think that this is a very important question and we may replicate the 
examples where we would like to ask the scientists, a ll of them, where there is scientific uncertainty 
and where it comes from.  Does it come from the l ack of sufficient evidence, as you say in your 
question, or does it come from, as I would put it, from evidence which is there on the table but it is 
conflicting?  One does not agree with the other eviden ce?  And I think there is a very important causal 
relationship between these two concepts.  Our sugge stion is – and I would like to see if the experts 
agree or disagree – we would say, and we have said in  our submissions to the Panel, if the evidence is 
insufficient, then I think practica lly always there will be scientific uncertainty, because  the evidence is 
not sufficient.  Dr. Boobis has said: if it is a majo r insufficiency; but it is a value judgement, whether 
the insufficiency is small, higher or major.  Our sugg estion to go about this issue is, if the data are not 
sufficient, there is scientific uncertain ty.  But this is not all, and it is not the most important in this 
case as well, because as Dr. Cogliano and Dr. Gu ttenplan have said, qualitatively there is no doubt 
that oestrogens are genotoxic or carcinogenic, but th e evidence is not sufficient in terms of quantity.  
And there we will also propose to the Panel – and if  the experts agree or disagree they can say so – 
but when there are conflicting interpretations of the evidence that is available, still we will argue that 
there is scientific uncertainty.  Thank you. 
Chairman
 
 
369. Thank you.  I think the EC's comments are somewhat related to the questions that the Panel 
are going to put forward later, so I would appreciate it if the experts would respond to the EC's comments when they respond to the Panel's questi ons, and then I will give the floor to the US. 
United States
 
 370. Thank you, Mr. Chairman,  I want to interject.  I feel with the last question from the EC we 
have strayed into the scientific evidentiary discussions  of tomorrow, and I just wanted to raise that 
point clearly.  The EC's assertion that these hormones function by a genotoxic mechanism at relevant exposure levels is critical to their arguments, a nd I would propose either the United States can go WT/DS320/R/Add.7 
Page G-60  
 
  forward with its questions on genotoxicity and the scientific evidence, or that we hold back until 
tomorrow at the time the Chair had set aside to discuss the scientific elements of the case.   
Chairman
 
 371. OK.  In connection with that comment, may I propose to the delegations: why don't we go 
through all the Panel's questions as quickly as possi ble, and then based upon the answers and replies 
and comments from the experts on all these questions put forward by the Panel we can have more 
structured discussions by the parties, more elabor ate questions on these basic discussions.  So that we 
do not duplicate or repeat discussions we had already.  I think that would be a more structured way of 
debate for today and tomorrow.  So I would request  the understanding of the delegations by way of 
refraining from putting many additional follow-up questions on the issues at hand.  Are there any 
comments or replies from the experts?  Dr. Boobis. 
Dr. Boobis
 
 372. I appreciate your comments, Chairman, and will not  enter into discussion about the evidence.  
I just wanted to make a general point, which is that it would be a mistake to think that risk assessment 
results in the complete and absolute agreement of everybody in the risk assessme nt.  The nature of the 
evidence available on science in genera l is such that we will never get a uniform interpretation.  What 
happens generally is that there is a consensus a nd if necessary the adoption of defaults which are 
conservative to allow us to move forward.  Seeki ng unanimity on the interpretation of all the data is 
futile because it will not happen.   
Chairman
 
 373. Thank you.  Let me put the Panel's next follow- up questions, two questions at the same time.  
The first is: at what step in a risk analysis is a determination made whether the available evidence is 
sufficient to undertake a risk assessment?  The second is: at what step of risk analysis does one factor 
in the level of protection to be achieved by an SPS measure?  Any expert?  Dr. Boobis. 
Dr. Boobis
 
 374. Could I just ask you, Chairman, to repe at the second half of that question?  
Chairman
 
 
375. The second one is: at what step of a risk analysis does one sector in the level of protection to 
be achieved by an SPS measure?  I would rephrase the l ast part of the second question as: by a health 
protection measures, instead of SPS measure.  Dr. Cogliano. 
Dr. Cogliano  
 
376. I would actually still like to clarify that.  It seems to me the level of protection is something 
that was discussed earlier as part of risk management , and I am not sure that it is part of the risk 
assessment.  Well, risk analysis, then, is a new term  we have not talked about.  We have talked in 
terms of risk assessment; is risk analysis  being used to mean risk assessment? 
Chairman  
 
377. I don't want to go into the detailed legal issu es which will be the focus of our discussion next 
week, but there is a difference in the terminology of risk assessment and management, and there is a  WT/DS320/R/Add.7 
 Page G-61 
 
 
  broader concept of risk assessment, risk analysis, so  I think it would be better to avoid that discussion 
at this time, and I give the floor to Dr. Tritscher. 
Dr. Tritscher  
 378. So at what step in the risk analysis is a dete rmination made about the sufficiency of the data 
to undertake a risk assessment?  In the ideal case you would have a step that's called problem 
formulation, when you really formulate the question, wh at is the concern, what is the question that the 
risk assessor should answer, which is followed.  Now,  there are different terms used – a preliminary 
risk profile – this is a step where you really lo ok what kind of data are available.  Now in the 
international field, in the context of JECFA and C odex, these steps have not been formalized as such, 
not in that level of detail, the way I have just described it.  What happens is, the Codex Committee, 
CCRVDF, poses fairly simple, if you allow me to say it that way, a simple questions to JECFA, asks 
JECFA to perform a safety assessment or a risk ass essment on a specific veterinary drug when used 
according to good veterinary practice.  And at that  point it goes over to the risk-assessment body, and 
the risk-assessment body, JECFA in that case, puts out a call for data and performs literature searches, 
the experts perform literature searches on all publicly  available date.  Now in the concrete case of 
JECFA, in the preparation of the meeting, a d esignated expert reviews the available database and 
prepares what we call a draft working paper as a basis of the discussion of the Committee at the 
meeting.  If at that point the expert determines th at the data are insufficient to allow an assessment, 
that would be recorded as such, and why the insufficien cy is there, or what other significant data there 
is.  So the working paper would lay that out, an d then, when the actual JECFA meeting takes place, 
the Committee would discuss that as such.  So to an swer the first question, in the context of the 
JECFA/Codex system – in what step of the risk anal ysis paradigm – in this case it is at the risk 
assessment step.  So JECFA makes that decision if  the database is sufficient, as it concerns us, as 
opinion of an international expert panel.   
379. At what step of the risk analys is does one factor in the level of protection?  Now the level of 
protection is a term that comes from the microbiological  area and is not as such used that much in the 
chemical area and in the context of chemicals in f ood, also veterinary drugs we are now talking about, 
where the risk assessment is performed to set an AD I.  What that actually means, what an ADI is, 
what is done is to set a level of no apparent risk on the basis of the available data.  So it is a little bit 
like an acceptable level of protection, like some othe r agencies or authorities or expert bodies do, in a 
sense, that one additional cancer case in a million popul ation would be an acceptable level of risk.  
This is clearly a risk-management decision.  The risk  manager would have to define this for the risk-
assessment body, to go to a certain level of protectio n.  If we are talking ab out an ADI, setting of an 
ADI, this is not the concept.  What the concept behind there is, to set – again, I repeat – a level of no 
apparent risk.  This is a chronic acceptable intake  level without – this famous term – appreciable 
health risk. 
Chairman
 
 380. Thank you.  Dr. Miyagishima. 
Dr. Miyagishima
 
 381. Thank you, Mr. Chairman.  I will speak only to  the first question because I still have some 
difficulty in understanding the meaning of the second question.  The determination, or any judgement 
as to the sufficiency or insufficien cy of data to undertake risk assessment, may well take place within 
the risk-assessment programme.  For instance, JECF A may come to a conclusion that the scientific 
data is insufficient to undertake a complete risk  assessment, and they may abort their undertaking at 
that stage.  There are also cas es where the risk managers, in this case the Codex Alimentarius 
Commission, may already foresee the insufficiency of scientific data and yet the Commission may WT/DS320/R/Add.7 
Page G-62  
 
  still ask the JECFA to attempt to undertake a risk assessment, or the Commission may decide not to 
waste the resources of JECFA and opt for another ri sk management options that would not require 
stringent risk assessment, for instance the developmen t of a code of practice, rather than numerical 
standards, could be an option.  There may be other options.  I must say that there are cases where risk 
managers make some judgements on this point.  Thank you.  
Chairman
 
 382. Thank you.  Then could you also explain what a deterministic approach to risk assessment is, 
and what other approaches are there?  And in re lation to that: what is a so-called hazard-based 
approach, and under which circumstances is that ap proach used?  I would welcome the replies from 
the experts to these comments in combination.   If there are no specific – Dr. Tritscher. 
Dr. Tritscher
 
 383. I can try to give you the very very brief descrip tion, but there are also written comments to the 
deterministic versus probabilis tic, if this is what is meant in this sense.  I am sorry, but sometimes it's 
not that clear what is really behind the question.   Deterministic approach to risk assessment means 
that we are using point estimates – high-level c onsumer, mean-level consumer – on the exposure 
assessment,  individual points on the dose-respon se curve, whereas probabilistic takes distribution 
into account – like I explained earlier, you have variab ility in responses, and to take this into account 
is a much more complex way of doing risk assessments.  I am not aware that even on the national level really probabilistic risk assessments are perform ed.  This is highly complex and is not routinely 
done.  Increasingly probabilistic exposure assessment s are done, meaning where one takes into 
account the variation of levels of different chem icals in food and the variation of consumption 
patterns, variation in portions of what people eat .  That is increasingly taken into account; whereas 
when it is just a point estimate, what is the mean level of occurrence, what is the mean portion size.  
Taking also probabilistic approaches into account on th e toxicological side, if you would think about 
the graphs that I had, so that, going down the left  arm of the graph, taking also distributions into 
account is highly complex and definitely not done r outinely,  and – other than, let's say, in the 
scientific experimental field – I am not aware that this is done in the regulatory field.  Again, on the 
international basis, in the context of JECFA we ar e basically bound to use deterministic approaches, 
because we basically have to cover scenarios for the whole world.  However, again, having said this, 
the increase in the efforts now, at least on the exposur e assessment, we try to take distributions into 
account.  And I do not understand the second question, what is the hazard-based approach.  Any risk 
assessment starts with the hazard, it is the hazard- based approach, so apologies, I do not understand 
the question. 
Chairman
 
 
384. As I understand it, that terminology was used by one of the experts or parties in their replies 
or submissions, which I cannot identify for the moment.  Dr. Boobis. 
Dr. Boobis  
 385. Well, I suspect, what Dr. Tritscher has just  explained is exactly what I understand by 
deterministic versus prob abilistic, but I have a suspicion that something different is meant here.  
Obviously we are trying to get to a different place , so that deterministic is where we use point 
estimates, conservative assumptions, but the underlyi ng assumption, based on analysis of the data, is 
that there is a point at which one can reach a safe level of exposure, an acceptable level of exposure, 
and so that is the basis for arriving at an ADI based  on point estimates.   One could do it in different 
ways, probabilistic, which is much more complex.  But I think that what this is to be contrasted with 
is the idea that there isn't a safe level of exposur e and what one could use under such circumstances is  WT/DS320/R/Add.7 
 Page G-63 
 
 
  what is called quantitative risk assessment, extrapola ting down levels of  exposure, where one gets to a 
level where there is still a risk, but the risk, in the vi ew of the risk manager, is considered acceptable.  
Now that is not an approach that  JECFA has used before for veterinary drug residues.  A hazard-based 
approach, I would imagine, is a qualitative risk asse ssment, if you like, where one stops once one has 
identified a hazard that is deemed unacceptable.  So, for example, the compound is shown to be 
direct-acting genotoxicant; this is considered unacceptable at any level of exposure, permitting 
exposure would not be appropriate, a nd then one stops the risk assessment at that point.  So it does not 
need to take account of exposure, because any level of  exposure is deemed to be of concern.  There 
are some who argue that certain other endpoints, such  as certain types of neurotoxicity, would fall into 
that category as well.  There are intermediate positions , which is that even if there is such a hazard, 
one could think about what is the margin of exposure,  or what is the exposure with respect to the so-
called threshold of toxicological concern.  These are newer strategies which have been designed to 
deal with endpoints which may not have a discerni ble threshold, but where some exposure may be 
unavoidable, for example a contaminant, and so we have to determine whether we need to prioritize 
resources to bring exposure down to lower than that.  The issue of veterinary drug residues, which are 
compounds that are added intentionally to animals, is a wider discussion and I won't even enter into 
that here because it is outside of the thrust of the question.   
Chairman  
 386. I think I did understand the issues but could you repeat once again, but in a much briefer way, 
the difference between deterministic  and probabilistic approaches.   
Dr. Boobis
 
 387. I am not sure that that is helpful here, Mr. Ch airman.  The deterministic approach is to use 
single estimates of, for example, the toxicological no observable adverse effect level, the exposure 
level etc.  One uses conservative assu mptions for those values.  The pr obabilistic approach is to take 
distributions of those values and try to get closer to the real world situation.  We are not all exposed to 
the highest level of residues our entire lifetime and with the sensitivity of the most sensitive animal, 
and the most sensitive endpoint.  So we can use dist ributions of those values, multiply them together, 
and say the probability of an individual lying on the curve is X, very low, medium, high, whatever.  And then that requires the risk manager to take a decision as to a percentile of the population they 
wish to protect, because you never reach a 100 per cent on a distribution curve.   
Chairman
 
 388. Thank you.  If there are no other follow-up qu estions, let me put the next question.  If a 
substance is genotoxic, can a threshold be estab lished?  If there are any substances for which no 
threshold can be established, how does this aff ect the conduct of a risk assessment for such a 
substance, and what happens to the four steps?  Dr. Boobis. 
Dr. Boobis
 
 389. There are substances for which there are thr esholds for genotoxicity; it depends on how it 
causes the genotoxicity.  For example, it may be acti ng indirectly through the apparatus that allows 
cells to divide, the so-called spindle apparatus, wh ich is actually a protein which allows the DNA to 
segregate during cell division.  And it has been s hown that inhibition of that process has a clear 
threshold, and there are some pesticides which have b een regulated accordingly.  It is deemed that it is 
possible to adopt a deterministic approach for su ch compounds, with an allowable daily intake 
because there is a threshold.  Most thresholds ar e demonstrated experimentally, mechanistically and 
in vivo .  Whether there is a threshold can be establis hed on the basis of scientific evaluation of the 
underlying mechanisms but not just on the observable data.  I think it would be fair to say that the WT/DS320/R/Add.7 
Page G-64  
 
  conduct of the risk assessment would depend upon the purposes of the risk assessment.  If it was a 
contaminant, there would still be the need to pro ceed to determine where is the level of exposure 
relative to the level of concern.  If it was a veterina ry drug residue, then one might consider that it 
would not be acceptable to allow a non-thresholded co mpound to be present in the diet.  But it is very 
much at the discretion and direction, I would say,  of the risk manager as to how one would proceed. 
Chairman
 
 390. When it comes to the question of establishing a threshold, what is the difference between a 
genotoxic substance and a substance with genotoxic potential?  When a substance is genotoxic, by 
definition, and is there any possibility of  not being able to set a threshold? 
Dr. Boobis
 
 391. Yes, absolutely.  If it was shown to be a di rect-acting genotoxicant which caused mutation, 
and there was an indication that that also occurred in vivo,  then it's very likely one would conclude 
that it was not possible to identify a threshold.  There are one or two rare examples of compounds 
which are direct-acting genotoxicants, which because of  metabolic reasons there is considered to be 
an in vivo  threshold, but they are very very rare.  As I said before, and as others have said on this side 
of the table, it very much depends on examinat ion of the underlying data and the scientific 
interpretation of that data as to where one gets to  in considering the significance of genotoxicity, and 
whether or not one can establish a threshold for that compound.  There are no absolutes in this.   
Chairman
 
 
392. Dr. Guttenplan. 
Dr. Guttenplan  
 393. Most genotoxic compounds that we know of now are of the type that directly damage DNA 
and cause mutations, and they don't exhibit a threshol d.  In terms of risk assessment then, the critical 
factor would be exposure.  If exposure is near zero , then whether there is a threshold or not, it does 
not make a difference, you are not exposed, there is  no risk.  But determining the exposure is then 
critical in the case of a compound that exhibits no threshold.  Now many of these genotoxic compounds, from what we can determine in animal s, do not have, and this was discussed before, a 
linear dose-response curve.  So determining risk  from a compound without a threshold, where you 
don't know the dose response at the low levels, requires a fairly high level of extrapolation, and there 
is going to be a larger uncertainty, and that is one reason for the uncertainty factors.   
Chairman
 
 394. Thank you.  Any additional questions from the Panel.   
Ms Orozco
 
 395. I would please ask Mr. Guttenplan to repeat what  he has just said, because I am trying to 
think through, and I am not sure that I did understand. 
Dr. Guttenplan
 
 
396. Well, let me see if I can recapitulate.  Yes, the type of genotoxic agent that damages DNA and 
causes mutations, as opposed to the spindle-active compound that has a threshold, is not going to have 
a threshold.  And then its risk is largely going  to be determined by how effective it is as a  WT/DS320/R/Add.7 
 Page G-65 
 
 
  genotoxicant and the exposure level.  If you are not exposed, or the exposure is very low, then the risk 
may be insignificant.  However – yes. 
Ms Orozco  
 397. Sorry to interrupt, but if I allow you to end, then  I will ask you to start again.  Exactly this is 
the point where I lost you.  If the premise is th at a genotoxic substance can create damage to DNA, 
why do you say that at low exposures that changes? 
Dr. Guttenplan
 
 398. I didn't say it changes.  I said that there ma y be no appreciable risk.  We have naturally 
occurring substances within our bodies that cause DNA damage, they are always there.  Oestrogens 
may be in that class of compounds.  We live wi th this.  You cannot do anything about that 
background.  That small amount that comes from a genotoxic agent if the exposure is very low may 
be insignificant in comparison to the natural background.   
Chairman
 
 
399. Thank you.  If there are no other additional follow-up ... Dr. Cogliano. 
Dr. Cogliano  
 400. Can I try the same thing with an example we had two years ago at IARC, with formaldehyde, 
and that's again another substance that is carcinogeni c to humans.  It is genotoxic and there was a lot 
of discussion about what is the shape of the do se-response curve as you get down to lower doses.  
And when you have no threshold basically it means your dose-response curve goes down in some shape, but it does not go hit the x axis and be flat.  A threshold means your low dose is a flat 0, and 
then it goes up after some threshold dose.  No threshold means that as soon as you leave zero you are going to have some risk.  Now, so what Dr. Guttenplan said, at very low doses, you also have very 
low risk.  Now the question is, we don't really know, there is uncertainty about the shape of the dose-
response curve at the lowest doses, and this is wh at came out in the modelling that was discussed at 
the IARC meeting on formaldehyde.  Possibly you c ould have a dose-response curve that goes linear 
all the way down to zero.  Possibly you could have a dose-response curve that is very steep at high 
doses and then at low doses it still goes down in a stra ight line, or you could have something that is 
curved all the way down but it is still slightly above  zero for any finite dose.  The point is, we don't 
have studies that are powerful enough to tell us what is happening at the lowest of the low doses.  So 
there is some uncertainty.  But when you have no threshold, it means you are not looking for a dose 
where you are absolutely safe, what you are looking for is a dose where you have some low level of 
risk.  And you do your best to try to describe that dose-response curve as low as you can, but at some 
point you still have uncertainty and you cannot with any degree of confidence say what is the shape in 
this very very low range.  Does that help any? 
Ms Orozco
 
 401. Up to your last sentence there I got it.  You were saying – and thank you for the effort too, to 
explain this important element – if there is a thresh old, it means that a dose that is lower than your 
threshold does not pose any apparent risk? 
Dr. Cogliano
 
 402. That's right.  The risk curve is flat up to a thr eshold dose, and then it begins to rise, so below 
that dose, yes, your risk is zero.   WT/DS320/R/Add.7 
Page G-66  
 
  Ms Orozco
 
 403. So why is it important to know what happens below that dose? 
Dr. Cogliano
 
 
404. That's if you have a threshold, it's not im portant to know; but if you cannot establish a 
threshold, you may have some leve l of risk, and we were really talking about cases where we cannot 
establish a threshold and there is uncertainty a bout whether the dose-response curve is going down 
with some undefined shape, and how low is that risk at the lowest of doses. 
Ms Orozco  
 
405. And when is it that you cannot establish a th reshold?  Is it because of the mechanism? 
Dr. Cogliano  
 406. Yes, the mechanism gives us clues as to whethe r something has a threshold.  I think it has 
been stated by a couple of people that a direct-acting mutagen is not likely to have a threshold.   
Chairman
 
 407. I think my follow-up question is also related to  the question which has been responded to just 
now.  Would you clarify the difference between linear and non-linear situations, which are referred to 
by the parties?  When would it not be feasible to set this threshold below which there is no 
appreciable risk?   
Dr. Cogliano
 
 408. Linear simply means the dose-response curve go es down at low doses at a straight line.  Its 
not a straight line all the way up to past 100 per cent risk, its going to level off.  But at low doses, 
linear means the risk is proportional to dose, and at  any level of dose higher than zero there will be a 
risk higher than zero.  Non-linear means the curve has some other shape and that's what is really 
problematic, because at those low doses, we don't have  enough animals or our epidemiological studies 
are not big enough to observe what happens at one picogram of exposure.  With a typical animal study with 50 animals, the lowest you can observe is a 2 pe r cent risk.  With an epidemiological study that's 
got 10,000 people, the lowest you can observe is  the one in 10,000 risk, but you still don't know if 
there is some lower level of risk at lower exposure levels.  So the problem is that when you have a 
non-linear dose-response curve, you really don't know the exact shape at low doses, and that's where 
we get into what Dr. Boobis had said; we take con servative assumptions and try to predict what is the 
worst it can be, because we really can't precisely specify  what the risk is there, so we say, well, the 
highest it could be is this, and then a risk manager ha s to decide if that is an acceptable level of risk, 
given all of the other factors that a risk manager thinks about. 
Chairman
 
 409. Even in the linear situation could there be  a situation where the threshold cannot be 
established? 
Dr. Cogliano
 
 
410. In the linear situation we do not have a threshol d.  Threshold means it's flat at zero and then 
starts to go up, like a hockey stick perhaps, it's flat  against the ice and then it goes up to the person's  WT/DS320/R/Add.7 
 Page G-67 
 
 
  hand.  Linear means it is just a straight line from the origin of the graph and there is a risk at the 
lowest of doses.  Now that risk can be very very ve ry small, and if exposure is very very very small 
the risk is very very very small, but the risk is not  zero.  I think that is the distinction between linear 
and a threshold kind of response. 
Chairman  
 
411. It may be linear, but it never hits the bottom, zero.  After all it has to be flat at some point. 
Dr. Cogliano  
 412. I don't think there is consensus that it has to be flat at some point.  I think that is one of the 
scientific arguments a lot of risk assessors have, ab out whether everything has a threshold or not.  I 
think there is a consensus that there can be low leve ls where risks are very very low, and some people 
will say the risks are zero. 
Chairman
 
 
413. Dr. Guttenplan? 
Dr. Guttenplan  
 414. Yes, the problem is in the second question.  That question says: when would it not be feasible 
to set a threshold below which there is no appreciab le risk?  And that is the question; what do you 
consider appreciable?  One in a million, one in a thousand? 
Chairman
 
 415. Well, actually, that is the Pane l's next question (laughter).  Le t us go directly on to that 
question:  what is appreciable risk, no appreciable risk, no apparent risk, zero risk, no additive risks, 
no adverse effects – what are the differences between all these terms? 
Dr. Guttenplan
 
 416. Lets see all the terms and then (laughing).  As far as what is an appreciable risk, I think that is 
up to the risk management to decide, what they c onsider appreciable and acceptable.  If there are 
many compounds with additive risk, and if you ha ve several compounds, each has a risk, and each 
risk is independent, then they are additive. 
Chairman
 
 417. But if the appreciable risk is a concept relate d to risk management rather than the risk 
assessment, then it could vary depending on the level of protection chosen by each country. 
Dr. Guttenplan
 
 
418. Exactly, yes. 
Chairman  
 419. Then there would be no objective criteria at  all.  It could vary from zero to ...  WT/DS320/R/Add.7 
Page G-68  
 
  Dr. Guttenplan
 
 420. In performing a risk assessment you can come up with a number, but which number in terms 
of risk a country wants to use is up to their own individuals, is up to their own risk managers.   
Chairman
 
 
421. Dr. Boobis. 
Dr. Boobis  
 422. I think part of the confusion is the innate sel f-preservation of scientists who don't want to 
commit themselves to absolutes.  Most of those terms there genera lly have similar meanings, no 
appreciable risk, no apparent risk, zero risk, no adve rse effects, maybe not the one no additive risk, we 
can talk about that later.  And I will just try to e xplain why it is we use this term quite frequently, no 
appreciable risk.  First of all, it is true, the level of  protection is set by the risk manager, in that by 
usage and by adoption there is an implicit if not exp licit level of protection for a thresholded residue, 
and that is how we set the ADIs as has been e xplained, based on default assumptions on the safety 
factors that are in common use.  This provides, de f acto, a certain level of protection.  That level of 
protection, to this date, has been accepted by th e risk manager as being appropriate, because they 
accept the risk assessments, and the assumptions that ar e in those risk assessments are clearly laid out, 
if we are using a safety factor default of 100 in th e absence of other information.  We don't call it zero 
risk usually, we call it no appreciable risk, and I am talking here only about compounds which have a 
threshold.  And the reason we call it no appreciable ri sk is because of the two extrapolation factors we 
talked about, one to extrapolate from experimental  animals to humans, and one to allow for human 
variability.   
423. And we are really talking about two different th resholds.  The first threshold is the threshold 
in a dose-response curve, and really we have been ta lking about that largely today, that is when we 
talk about thresholds, that somewhere on the dose -response curve we reach a low dose and there is no 
response below that dose.  But the second threshold is a population threshold, that within a population 
there is a variability in sensitivity, and that second threshold is the one that makes toxicologists and 
risk assessors reluctant to say zer o risk, because we cannot say with  absolute certainty, within a 
population of 6 billion human beings at the presen t, that there is not somebody somewhere under a 
given set of particular circumstances that might not be ultra-sensitive, so we hedge our bets if you like 
and say no appreciable risk.  We are protecting a very very large percentile if not the entire 
population.  I would stress, however, this does not mean to say we are not protecting certain sections of the population such as the young or the elderly, because they are definable groups and the risk assessment takes account, to  the extent it can, of such subgrou ps within the population.  We can 
discuss how we do that, I assume later today or to morrow, but I am talking about a rare sensitive 
individual, not the population. 
Chairman
 
 424. OK.  We also have related questions on the terms such as additive risk, additional risk, 
aggregate risk and cumulative risk.  So would you explain further the differences.   
Dr. Boobis
 
 
425. Additive risk.  Could we maybe have those term s – OK.  Aggregate risk and cumulative risk 
have come to mean something by definitions that were devised by the US.  They defined what is 
meant by aggregate and cumulative risk, it is not an  intuitive meaning, it is not a meaning that would 
automatically be understood from the words themselves, so I must stress that.  So what we mean by  WT/DS320/R/Add.7 
 Page G-69 
 
 
  aggregate risk is, simply by convention, a lot of  people use the term in that way, the same for 
cumulative risk, so that is just to clarify that.  Aggregate risk in the sense that it has been defined 
under the Food Quality Protection Act, where this ca me from, is the risk from all sources of exposure 
to the same substance.  We were talking earlier about, if we think of just oestradiol, all the different 
possible sources of exposure to oestradiol; if we were doing an aggregate risk assessment, we would 
add up all those sources together.  A cumulative ri sk is thinking about substances which might act on 
the same target, so, in the case of hormones, all possible oestrogenic substances acting on the 
oestrogen receptor, we would have to think about ex posure to all of those compounds by all different 
routes, and find some way of combining them.  You would not just add up the amounts, because a phyto-oestrogen is going to be a lot less potent than oestradiol;  diethylstilbestrol is more potent than 
oestradiol, so you have to normalize them for poten cy, which is a technical issue in respect of 
conducting a cumulative risk assessment .  Additive risk is additional risk or risks over and above the 
background level of risks that already exists.   
Chairman
 
 
426. So all these terms are not necessarily limited to the problems arising from the long latency 
period.   
Dr. Boobis  
 427. No, they don't relate to it at all. 
Chairman
 
 
428. OK, thank you. 
Ms Orozco  
 429. Just one question.  Aggregate risks – that was for Dr. Boobis. 
Chairman
 
 430. OK, we will continue to the next question and th en come back to this  question again.  Our 
next question is:  what are the components of  a qualitative risk assessment compared with a 
quantitative risk assessment?  Could you please clarify whether in your view the four steps of risk 
assessment as defined by Codex and JECFA are not applicable for qualitative risk assessment?  
Maybe this question could be addressed particularly to Dr. Cogliano.  The EC indicated that it has 
carried out a qualitative dose-response assessment.  We would appreciate it if the experts could 
provide their views about this argument, and probab ly the EC may also want to respond to this 
particular part of the question. 
Dr. Cogliano
 
 
431. I would say qualitative risk assessment could be  described as what IA RC does when we come 
up with a determination that an agent is carcinogenic to humans or probably not carcinogenic to humans.  It's simply the statement that a hazard does exist, without trying to further characterize that 
hazard as to dose level or duration of exposure of  susceptible populations.  This qualitative risk 
assessment can be a more quantita tive risk assessment that could include developing dose-response 
relationships, establishing levels wh ere you don't see adverse health effects, measuring exposure and 
comparing the exposure to the dose-response curve.  So I would say, any time you are starting to get into dose-response curves and into exposure leve ls, you are getting into the quantitative risk WT/DS320/R/Add.7 
Page G-70  
 
  assessment; the qualitative risk asse ssment is just the establishmen t of whether a hazard exists, 
whether something causes cancer.   
Chairman
 
 432. You have a question?   
Mr. Ehlers
 
 433. Well actually, and I thank you for that answer, it goes on to the last part of our question.  It 
would seem then that to say that a qualitative risk assessment, if it is qualitative, then a dose response 
is a contradiction, because a dose response requires quantitative, and that is why this part of the 
question was put in.  Can you carry out a qualita tive dose-response assessment if the dose is 
quantitative by nature?  That is what we are trying to get at. 
Dr. Cogliano
 
 434. When IARC does its qualitative evaluations that en d up in simply a statement that an agent is 
carcinogenic or possibly carcinogenic, or probably not carcinogenic, it does look at dose-response 
relationships because, for example in an epidemiological  study or an animal study, if high levels of 
exposure give you higher levels of risk, that increas es your confidence that you do have a carcinogen.  
If you had a dose-response curve that went up and dow n, you are not sure what you have.  And so we 
do look at dose-response relationships.  What distinguishes qualitative from quantitative risk 
assessment is how the conclusion is expressed.  IARC expresses the conclusion by saying this agent is 
carcinogenic to humans or this agent is probably carci nogenic to humans, but we don't get into if it's a 
dose-response relationship that's linear, that there' s a safe dose; that's part of the quantitative risk 
assessment later.  So I think I would refine my first answer by saying that the difference between qualitative and quantitative is how you  express your conclusions, and if your conclusions have any 
element of a safe dose, dose-respon se curve, susceptible populations, then I think you have gotten into 
a more quantitative assessment. 
Chairman
 
 435. So the same requirements and steps and compone nts should be applied to the qualitative risk 
assessment even though their conclusion may be made in the form of a qualitative decision rather than 
quantifying? 
Dr. Cogliano
 
 436. I would express it this way.  The qualitative risk assessment is the first of the four steps, it's 
the hazard identification phase.  When IARC says th is agent is carcinogenic to humans, we have 
identified a hazard.  If IARC says this agent is probably not carcinogenic to humans, we have made a 
hazard statement that this agent probably is not a hazard, at least for cancer.   
Chairman
 
 437. Do you mean that when it comes to a qualitativ e assessment, stopping at the first step of the 
four steps could satisfy the requirements of risk assessment?  I will give the floor to Dr. Boobis and 
then ...  WT/DS320/R/Add.7 
 Page G-71 
 
 
  Dr. Cogliano  
 438. I think there are cases where calling something a carcinogenic hazard has led an agency to 
make a decision just on the qualitative element alone.  But I think many agencies still prefer to see a quantitative risk assessment that th ey will then carry out, based on the exposures in their country, to 
determine what to do.  The reason IARC does the qualitative assessment only is that we really don't 
have the resources or the expertise to identify all the types of exposures in every country, and there does seem to be a need for an authoritative statem ent about what is carcinogenic and what we don't 
feel right now is carcinogenic.  But then the next st ep is for national agencies or local agencies to look 
at their local exposure situation and compare it with a dose-response relationship or safe dose and 
make a determination about whether some action should or should not be taken. 
Chairman
 
 439. If we follow your views, then there would be no need to get into the exposure assessment by 
way of doing qualitative or quan titative dose-response assessment. 
Dr. Cogliano
 
 440. In some cases no.  I would say for example cigarette smoking;  I am not aware of any dose-
response assessment that says your risk per cigarette you smoke is X.  I think the totality of the evidence about smoking, that it causes, I think, 16 di fferent types of cancer in the most recent IARC 
monograph, and just the consistency of positive results  everywhere, I think is enough to have caused 
action to be taken.  But smoking obviously is a ve ry extreme case about having a lot data and a case 
where qualitative assessment is in itsel f sufficient to take an action. 
Chairman
 
 441. Thank you.  Dr. Boobis and Dr. Tritscher. 
Dr. Boobis
 
 442. Well, I think that it does depend upon why the ri sk assessment is being conducted and what 
the risk manager requested, and in the case of a ve terinary drug residue, one is seeking to determine 
whether residues at the level that occur in the diet are considered to be without appreciable harm or 
risk.  And if a mechanistic consideration led to the conclusion that the hazard was such that the dose 
response was going to be linear, there is no threshold as we discussed just before, then it might be that 
one would stop the risk assessment at that point.  But that would be an unusual circumstance, and in most circumstances one would want to understand the relationship between the hazard and the level of 
exposure that was occurring.  For that reason one  would progress at least to a semi-quantitative 
evaluation of the exposure and risk, rather than ju st stopping at a simple identification of hazard. 
Chairman
 
 443. Dr. Guttenplan. 
Dr. Guttenplan
 
 444. Yes. The comment was made, if you have a do se-response curve for an animal, you have a 
quantitative dose, why isn't that a quantitative ri sk assessment.  Usually when you are testing a 
carcinogen in animals, you will test  in both sexes at several doses a nd often in several species, and 
you will get different dose responses in each one of those.  So just having a number for a particular animal species is not enough to pr oduce a quantitative risk assessment.   WT/DS320/R/Add.7 
Page G-72  
 
  Chairman
 
 445. We have ten minutes before 6 o'clock so I think the Panel has – OK sure. 
Ms Orozco
 
 
446. Sorry, I go back to something that was being mentioned, the aggregate risk.  If you talk about 
evaluating aggregate risk, what that does is to modi fy the scope of the risk assessment, if I understand 
you well? 
Dr. Boobis  
 
447. It does indeed, because one of the big questions that has to be asked is how widely do you 
cast the net for all exposures?  Do you include ther apeutic application of the same drug used in 
deliberate administration to patients?  Whose respons ibility is it to take account of all the different 
sources of exposure?  And these are very difficu lt questions, and on the international scene are 
particularly problematical because the totality of exposure will vary with the circumstances of the 
region, and that is one of the reasons that it has been very difficult up till now to conduct aggregate 
risk assessments globally.  And I would add we are still struggling with this, we have not answered 
these questions yet, we have not reached solutions yet.   
Chairman  
 448. EC. 
European Communities
 
 449. Gentlemen, I would not intervene, since yo u say the EC, that we have carried out a 
quantitative dose-response assessment.  And I would re quest the scientists tonight that they have a 
look at our risk assessment and we can take up the subject tomorrow.  We said we have carried out a 
dose response, in particular for the children, and I would request the scientists to have a look at our 
1999 first risk assessment.  We have done this for a ll the hormones, the six hormones.  It is on page 
36, 37 and 38 for oestradiol and there are corres ponding pages for the other hormones, and then we 
can take up this issue tomorrow.  I am not posing  a question now, but I would request, because it is 
not true that we have carried out only a qualita tive dose-response assessment.  We explain we have 
examined the ADIs and the rest proposed by JECFA and those levels demanded by the US.  We have 
tried to go through this dose-response quantitative assessme nt, in particular for children.  As far as the 
genotoxicity of these substances, it is true we ha ve made a qualitative dose-response assessment.  But 
it is not true we did not try to do a quantitative risk assessment, and I give these pages for oestradiol 
but there are comparable pages for each of these si x hormones.  They are in our 1999 first risk 
assessment.  They are in the documentation of all th e experts.  So please have a look tonight to see.  
We did not stop at the hazard identification, that's not true. 
Chairman
 
 450. Well, we are here not to make a decision, we are just getting advice from the scientific 
experts.  I was expecting to see the representative of  JECFA, Dr. Tritscher raised her flag on this 
question.  We are wondering whether JECFA has done qualitative or quantitative assessments for 
these hormones at issue, and I am wondering whet her JECFA agrees that the hazard identification 
alone equals a qualitative risk assessment.  WT/DS320/R/Add.7 
 Page G-73 
 
 
  Dr. Tritscher  
 451. Thank you.  I had actually taken down my flag because I thought that we had clarified or had 
moved on, but it really addresses the last point here  on the slide and we may have contributed in our 
response a little bit to the confusion in this contex t.  So it is in the context of dose-response 
assessments, and dose-response assessment is an integral  part of each risk assessment.  Now this can 
be done qualitatively or quantitatively, and I tried to explain what we mean with that.  In a qualitative 
sense, a dose-response assessment is simply determination of a no effect  level.  One looks at all the 
measured effects, identifies the dose where one sees an adverse effect, goes one step lower, the next 
dose lower is the no effect level.  The outcome is a number, in that sense it is quantitative, that may be 
the confusion, but it is not doing a complete quan titative mathematical dose-response analysis, taking 
all the points of the dose-response curves into account.   This is what we meant with the quantitative 
dose-response assessment.  But even a derivation of a no-effect level and derivation of an ADI 
considers dose-response assessment, but not in a ma thematical quantitative modelling way.  Sorry if 
that raised any confusion in that context.  Regarding the six hormones, JECFA did identify the no-
effect levels and derived an ADI, so in the termi nology, the way I introduced it, which may be a little 
bit misleading, this would be a qualitative dose-response assessment. 
Chairman
 
 452. Am I right to understand your comment as saying that even in the qualitative assessment you 
have gone through all these four steps of risk assessment? 
Dr. Tritscher
 
 453. Yes;  that is the short answer.  Hazard identif ication is not a risk assessment, a risk assessment 
comprises the four steps, and one can simplify it, the hazard identification and hazard characterization 
steps are often done together, or can  be done together.  This is the toxicological assessment, again, the 
left arm; the right arm is the exposure assessment.  The integration of the outcome of these two 
assessments is the actual risk characteriza tion step and yes, JECFA has done this. 
Chairman
 
 454. Thank you.  Dr. Boisseau. 
Dr. Boisseau
 
 
455. Please excuse me, Mr. Chairman, but I had raised my flag following the Panel's question on 
cumulative risk.  In Dr. Boobis' example, the cumula tive use of the same substance as an additive and 
as a veterinary drug theoretically poses a complex ri sk assessment problem.  In practice, there may be 
no problem.  I think we need to be fairly pragma tic, because whereas a growth promoter may be used 
repeatedly or even continuously, the same substa nce used for therapeutic purposes may only be used 
on a one-off basis.  The evaluation of the safety of residues is something which, according to the 
ADI definition, is done on a long-term basis.  In other words, supplementary ingestion of residues in 
connection with the one-off therapeutic administrati on of veterinary drugs is relatively less important 
in terms of exposing consumers to the residues of th at substance.  Furthermore, we must not forget 
that therapeutic application is not oblivious of pu blic health.  There is what is known as the waiting 
time.  Consequently, the possible supplementary ingestion of a given substance administered 
therapeutically can often be considered negligible.  Thank you. 
Chairman  
 456. Thank you.  Dr. Miyagishima. WT/DS320/R/Add.7 
Page G-74  
 
  Dr. Miyagishima
 
 457. Thank you, Mr. Chairman.  The Codex Commission as such does not conduct any risk 
assessment, but it has expressed its position on risk  assessment, and this is found in the Codex 
Working Principles for Risk Analysis for Applica tion in the Framework of  Codex Alimentarius.  
Paragraph 20 of this document states that risk ass essment should be based on all available scientific 
data.  Risk assessment should use available quantitativ e information to the greatest extent possible.  
Risk assessment may also take into account qualitative  information.  Therefore I think that one could 
interpret this phrase as the desire of the C odex Commission that risk assessors use as much 
quantitative information as possible, whether it is in the framework of what can be seen as a 
qualitative risk assessment or quantita tive risk assessment.  Thank you. 
Chairman
 
 458. May I give the floor to Dr. Guttenplan before I give the floor to EC. 
Dr. Guttenplan 
 
 
459. The term cumulative risk assessment has come up, and one way that could be interpreted is 
the accrual of damage or mutations; if one is talk ing about a genotoxic substance over time.  One can 
estimate, for instance, for certain number of year s smoked you will increase your risk of lung cancer 
by a certain amount, or for a certain number of y ears of taking oestrogen replacement therapy you will 
increase the risk of breast cancer by a certain amount .  So this is an example of a cumulative risk 
assessment.  The longer you are exposed the greater your risk. 
Chairman  
 460. EC has the floor.   
European Communities
 
 
461. Chairman, just a quick clarification and a question to JECFA.  When you identify a substance 
as being directly genotoxic, do you go  on in your risk assessment or you stop at hazard identification?  
Thank you. 
Chairman  
 
462. Dr. Tritscher. 
Dr. Tritscher  
 463. It depends, it is very difficult, again, to an swer very generally on these questions, it depends 
very much on the mechanism, again, as was explaine d in detail further.  With respect to oestradiol, 
since this was the example used in this context, and I have to correct  a statement that was made earlier 
by the EC, JECFA stated in the report of the fift y-second meeting that the Co mmittee, JECFA in that 
case, concluded that oestradiol has genotoxic potential  – it is worded that way on purpose, because of 
the scientific uncertainty that was alluded to earlie r by the experts, and I am not in a position to 
comment on the content there.  And in that case, the risk assessment was taken further in the sense 
that all other information is being looked at, in  particular with compounds that have a genotoxic 
potential.  One has to, of course, as a next step l ook if there are cancer bioassays, does the chemical 
cause cancer in animal studies, in the long-term studies or not.  So it is the totality of the information 
that has to be taken into considerati on before drawing any final conclusions.  WT/DS320/R/Add.7 
 Page G-75 
 
 
  Chairman  
 464. EC. 
European Communities
 
 
465. Sorry, I did it on purpose not to ask specifica lly about oestradiol, because the views of JECFA 
are known as genotoxic potential on this one.  If  you without uncertainty identify a substance as 
being directly genotoxic, do you then go on? 
Dr. Tritscher  
 
466. Yes, again, the answer is exactly  the same.  One has to take the totality of the information into 
account.   
European Communities  
 467. Gentlemen, the question is if you follow the four  steps if the substance – we are not talking 
now for this question for oestradiol – in general, if  you come to the conclusion, and we are not talking 
about uncertainty, if you come to the definite conc lusion that a substance is genotoxic, would you still 
go on doing the four steps? 
Dr. Tritscher
 
 468. I would say yes.  It depends on what level of detail you go into.  But now I have to, apologies 
for the time, but I have to explain a little bit longer, because its very different if we are talking about 
compounds that are added to foods for a specific purpose, or if we talk about unintentional and potentially unavoidable contaminants, that is a very  different story.  But traditionally in the food 
safety assessment area for compounds that have been added intentionally to food, veterinary drug 
residues, pesticides, what have you, if there is in in vitro , in vivo  studies a clear-cut conclusion that the 
compounds are genotoxic, and traditionally no formal risk assessment was performed in a sense, not 
quantitating it and so forth, but the recommendation,  and I guess that is what you want to hear now, 
that's what you are alluding to, is invoking the so -called ALARA principle, meaning that exposure to 
compounds that are unwanted in food should be reduced  to as low as reasonably achievable.  Again, 
one has to differentiate between unintentional compounds and intentional compounds, to say very 
briefly, and it is up to the risk management to ma ke decisions on the regulatory level what to do to 
reduce exposure.  For example, with compounds that are added, like veterinary drugs, one can make 
different legislative ruling than for example for contaminants.   
469. Now going back to the contaminants, JECFA as well as EFSA, the European Food Safety 
Authority, and then together in a joint EFSA/WHO effo rt, is trying to go a step further to get away 
from this ALARA principle, to give more advice to the risk managers for contaminants in food that 
have genotoxic and carcinogenic properties, whic h includes compounds where you cannot necessarily 
make the link;  there are genotoxic properties, carc inogenic properties, not necessarily linking that the 
carcinogenic mechanism, the carcinogenicity has to be  provoked by genotoxic mechanisms.  In order 
to give better directions to the risk managers as to which compounds are really of public health 
concern – so where to put your efforts, for manage ment measures, for public health protection, the 
concept of the margin of exposure has been now forma lized.  I want to say it is not a new concept, but 
formalizing it, which compares certain effect levels for model studies with the estimated human 
exposure, and the larger the difference between tho se two, the lower the public health concern.  By 
formalizing this approach, this allows compar ison between different compounds, and gives some 
indication which are of more concern to health th an other compounds.  But having said this, I have to WT/DS320/R/Add.7 
Page G-76  
 
  emphasize again this is a concept that JECFA applie d or developed a formalized approach now, and it 
is applied only to contaminants.  Thank you. 
Chairman
 
 470. Even if in seven minutes it's already 6 o'clock, I th ink this is a rather important issue, so I will 
continue until we complete discussion on this partic ular issue this evening.  I am wondering whether 
interpreters are available until that time.   
Interpreter
 
 471. Could you tell me how long you might expect to  last, how much longer you would like us to 
be here?  I will have to check.  I think that is alright but I will ch eck with my superior.  Thank you. 
Chairman
 
 472. May I request each one of the experts to be as brief as possible in his or her response to this 
question.  Dr. Boobis. 
Dr. Boobis
 
 473. Briefly, just from an independent scientific pers pective, regardless of whether I participate in 
JECFA or not, if I was talking about a veterina ry drug which was generating a residue and were 
evaluating that compound and it was shown to be  a DNA reactive mutagen which was expressed 
in vivo,  I would consider it unnecessary to proceed with the risk assessment, with a proviso that for 
any reason the risk manager did not ask for some scen ario evaluation.  For example, it might be that 
there was a particular essentiality for that compound and the risk manager might say well, what is the 
margin of safety, along the lines Dr . Tritscher has just outlined, it w ould be possible to conduct a risk 
assessment on that basis. 
Chairman
 
 
474. Thank you.  I saw many flags raised a few minutes ago.  EC. 
European Communities  
 475. Gentlemen, we are grateful for the interventi on of Dr. Boobis, because on the basis of what 
we have been hearing from the representative of JECFA, then an exposur e assessment in that 
situation, that means where you had a genotoxic s ubstance, defined and uncontested, you only need to 
count how many people will die definitely, and the qu estion is why you are supposed to do it, because 
this is the question, why you are going to go alon g with the risk assessment  if you know that the 
substance is genotoxic?  And by the way, I would like to ask, how are you going to do it since you 
don't know if there is no threshold there?  So I a ppreciate the intervention, because it clarified the 
situation.   
Chairman
 
 476. Thank you.  Dr. Boobis. 
Dr. Boobis
 
 
477. I regret that I have been misrepresented, Chai rman.  I have chosen my words with extreme 
care – I would like to repeat, I said a DNA reactive muta gen.  I would also like to point out, although  WT/DS320/R/Add.7 
 Page G-77 
 
 
  we have not got into this yet, when JECFA ev aluated the specific compound in question – and what 
my answer was was a genera l answer – the specifics are that they did not conclude that that compound 
was a DNA reactive mutagen, which is the reason wh y JECFA was able to proceed with this risk 
assessment, it felt it was appropriate to do so.  These ar e different scenarios.  As I stressed before, and 
I do again, it depends entirely upon the conclusions that  an evaluation of the data lead to as to how 
you proceed.   
Chairman  
 478. Thank you.  Dr. Boisseau, and I will conclude  
Dr. Boisseau
  
 
479. Yes, thank you Mr. Chairman.  I simply want to mention, since we are speaking of general 
principles, that it is obvious that if a product has been shown to be mutagenic following a series of tests, it will be mutagenic for the target animal.  Bu t we are not talking about a target animal, we are 
talking about the consumer, so that the risk remains for the consumer to the extent that the mutagenic 
product is present as a residue.  Imagine a parent subs tance that is definitively mutagenic but that is 
completely metabolized:  I have in mind carbodox, fo r example.  The substan ce, which is toxic as 
such, may not ultimately generate toxic residues in the foodstuff.  So the evaluation must always be 
comprehensive, and indeed, stopping an evaluati on as soon as a hazard has been detected, without 
trying to evaluate the possible risk for public health, is a procedural shortcut that could lead to an 
erroneous assessment of the risks without necessar ily providing a comprehensive and reasoned view 
of the case as a whole.   
Chairman
 
 480. Thank you.  We do have some more questions th at, I am sure, will be asked by the parties, 
because some them have already made comments in  relation to conflicting evidence on the table and 
so on.  So I would rather stop our discussions th is afternoon here and see you tomorrow morning at 10 
o'clock in this room.  But before I adjourn th e meeting – excuse me, there was a request from my 
colleague in the Panel to go on.  Instead of ge tting into the question and answer session again, on the 
remaining questions, I just want to put the questions  verbally so that you can consider these questions 
for the discussion tomorrow morning in responding to the questions posed by the parties. 
481. Our question was on the weight of evidence appr oach, which was, to my knowledge, used by 
Dr. Boobis, and the remaining two questions ar e:  please comment on the EC statement in its 
comments on question 19, where it states that it has a standing request to review the hormones at 
issue.  The last question is about Codex and JE CFA.  In response to question 3, Codex makes 
reference to ongoing work regarding risk analys is principles applied by the Codex Committee on 
Residues of Veterinary Drugs in Food and risk-assessm ent policy for the setting of MRLs in food.  Do 
you expect major changes to Codex/JECFA work in this area once these documents are adopted? 
These are the remaining questions for your consideration at tomorrow morning's session. 
482. Thank you for your cooperation, and I particularly appreciate the patience and cooperation of 
the interpreters for staying with us until this time and I hope you will have a good evening and see 
you tomorrow morning at 10 o'clock sharp in this room. WT/DS320/R/Add.7 
Page G-78  
 
  28 September 2006, morning 
 
Chairman
 
 483. Good morning.  I hope you all had a good sleep last  night and, for those who have travelled a 
long way from another continent, recovered from the jetlag, I hope.   
484. This morning we are going to continue the rema ining questions on area 2.  As you may recall, 
before we adjourned the meeting y esterday afternoon, the Panel read out three questions, the question, 
Nos. 18 and 23 and 24, which you might have noticed on the screen, but we believe that 24 has already been answered by JECFA repr esentative, so I hope we can start with the experts' replies to the 
Panel's questions 18 and 24.  
485. For your reference I will read out the questions once again:  could you please explain what the 
weight of evidence approach is?  And the other one is:  please comment on the EC statement in its comments on question 19 where it states that it has a standing request to review the hormones at issue.  These are two remaining questions of the Panel on whic h we expect the replies from the experts at the 
beginning of this morning's session.  And then, as I mentioned in my opening statement yesterday 
morning, the Panel will invite parties to pose their own questions to the experts on the area 2 items.  
And on area 3, the Panel has the intention to let the parties go first with their own questions and then 
the Panel will follow up the questions already posed by the parties.  And I would like to remind the 
delegations that we have a time-limit to finish our  business until the end of this session.  And also I 
would like the delegations to know that one of th e JECFA representatives, Dr. Tritscher, has a prior 
engagement this afternoon, so she has to leave af ter the lunch break.  So we have to finish our 
discussions on the remaining questions under area 2 a nd, if possible, all the questions under area 3, 
that is scientific evidence, and there are many JECF A-related issues even under area 3.  So I hope we 
can conclude our discussions on area 2 and area 3 this morning so that we can move into the 
remaining areas, that is EC's risk assessment and others .  So, all in all, time is very constrained, so I 
hope the parties will be very strict in selecting the questions of their own, so that they can economize 
the time given during the remaining meeting today.  Be fore Dr. Tritscher leaves this afternoon, parties 
are requested to pose questions on JECFA-related issu es this morning, even if that falls into the 
category under area 3, that is scientific evidence.  I am not sure whether I was quite clear to the 
delegations. 
486. OK, with that understanding may I ask the expe rts to respond to the Panel's questions on 
Nos. 18 and 23.  Dr. Boobis. 
Dr. Boobis
 
 487. Mr. Chairman, I would like to address the issue of weight of evidence.  The weight of 
evidence is the evaluation of the available inform ation about a particular toxicological endpoint,  
taking into account factors such as the adequacy a nd number of available studi es and the consistency 
of results across studies.  It is not an issue of seek ing to weight one person's opinion against another.  
It is a specific situation where one is faced with a large body of information on a particular endpoint, 
and we can talk about, for example, genotoxicity.  Where there are multiple tests of genotoxicity, and 
the results of those tests are not entirely consis tent, a weight of evidence approach requires an 
examination of the quality of each study individua lly – because sometimes the studies will not all be 
done to the same standards – and the consistenc y across those studies, and then eventually an 
evaluation of what is the totality of the evid ence telling us about that endpoint.  Thank you. 
Chairman
 
 488. Thank you.  Any others – Dr. Boisseau.  WT/DS320/R/Add.7 
 Page G-79 
 
 
  Dr. Boisseau  
 489. Thank you, Mr. Chairman.  I would like to support what has just been said by Dr. Boobis 
concerning the genotoxicity and mutagenicity test s.  In fact, these tests currently pose a double 
problem, I think.  Over the past twenty years, th e number of such tests has increased considerably, 
with the inevitable result that since we are using a greater number of tests to study a substance, the 
chances of our ending up with a positive result obviously increase accordingly.  The second problem is that these tests, which have flourished over the past few years, have not always been validated 
according to internationally accepted criteria – so th at whereas fifteen years ago when a committee of 
experts considered the results of a serie s of what was usually four tests, two in vitro  and two in vivo , 
where there were one or two positive tests it was not  too difficult to declare the substance genotoxic 
or mutagenic, today we always have one or two pos itive tests and two or three dubious tests out of a 
total of fifteen;  and when the tests used ha ve not necessarily all been validated, it is easy to 
understand that the willingness of a committee of experts to declare the substance genotoxic or mutagenic is not very strong.  Thank you Mr. Chairman. 
Chairman
 
 490. If there are no other additional comments, then shall I move into the next – OK, then I will 
open the floor for EC. 
European Communities
 
 
491. Thank you.  Without wishing to prolong the de bate, I would like to ask  the scientists which 
have responded and also the other scientists which have not taken the floor:  the United States 2002 
National Carcinogenesis Reports have classified oest rogen and oestradiol as capable of causing direct 
and indirect damage, cancer.  This is part of th e file we have submitted to the Panel and you must 
have it.  Is it clear?  The question then is: in your  conception of the weight of the evidence approach, 
where would you place this United States National Carci nogenesis Report?  Why is it not part of the 
weight of the evidence? 
Chairman  
 492. Dr. Boobis. 
Dr. Boobis
 
 
493. The report on carcinogenicity of the United Stat es is the consequence and evaluation of the 
data, it is a conclusion.  The weight of evidence a pproach requires a de novo ev aluation of the data, so 
you don't use somebody else's conclusion in a weight of evidence approach.  You may ask the question why does one reach a different conclusion, that  is a perfectly justifiable question, but it is not 
appropriate to take other people' s conclusions in a weight of evidence evaluation of the data. 
Chairman
 
 494. US and then EC. 
United States
 
 
495. Thank you, Mr. Chairman.  I would like to follow up on Dr. Boobis's comments and on the 
EC citation to the 2002 US report on carcinogens, and act ually this is a question to Dr. Boobis with a 
short lead in.  The EC has cited this re port as evidence that steroidal oestrogens per se  are known to 
be human carcinogens, and as you might be aware if you have looked at this report, the conclusions WT/DS320/R/Add.7 
Page G-80  
 
  rely heavily on an evaluation conducted by IA RC in 1999 entitled Post-Menopausal Oestrogen 
Therapy.  Dr. Boobis, if you are familiar with the US report on carcinogens and these IARC monographs, can you comment on the relevance of these reports to the specific risk alleged by the EC, 
which is that posed by oestradiol 17 β residues in beef and beef products? 
Chairman
 
 
496. Dr. Boobis. 
Dr. Boobis  
 497. I am certainly familiar with the IARC evaluation and familiar to some extent with the RC.   
As I understand it, the conclusion was that oestradiol-17 β was a likely human carcinogen; but neither 
of those reports, as I understand it, said that genotoxic ity was the mode of action.  And, based both on 
the evidence of other bodies and also on its own prim ary evaluation of the epidemiology – because at 
that meeting there were distinguished interna tional epidemiologists present who did their own 
evaluation of the world's literature on the possibilit y of a risk of cancer from exposure of humans to 
oestradiol-17 β – JECFA accepted at that time that was a risk.  But, and it is a very big but, the 
conclusion was that this was not associated with genotoxicity.  And critical to the JECFA evaluation 
was the relative level of exposure, and the conclu sions of JECFA were based on an evaluation of the 
exposure that was likely to occur from the use of  the hormones in beef-producing animals.   
Chairman
 
 
498. Thank you.  EC. 
European Communities  
 499. Thank you, Chair.  A simple question, going back to the weight of evidence and the 
explanation given by Professor Boobis. I would just like to know whether you mean to say that the 
weight of evidence approach involves interpretati on of data of the kind you have explained in your 
reply to question 52.  Thank you. 
Chairman
 
 500. Dr. Boobis.  Is Dr. Boobis ready to respond? 
Dr. Boobis
 
 
501. In fact, the IPCS report to which I refer did u se a weight of evidence strategy.  I was using 
weight of evidence in a narrower sense in my earlie r response in that we were very much focussed – 
and this is common practice when one is deali ng with multiple studies on the same endpoints, or 
related endpoints, one has to have some process to determine what is the consensus picture of that 
data set.  This is not a question of what people th ink and minority opinions, it is a question of looking 
at the data, and we had an expert ge notoxicity person with us at that me eting to help us to evaluate the 
quality of the studies and the likelihood of outcome.  Now when one looks at genotoxicity testing, some tests are more prone to artifactual results than  others.  So an Ames test, the bacterial test for 
mutagenicity, is generally a very reliable indicator of DNA damage, because there are few ways in which one can generate an artifact if the test is done to a reasonable standard.  If one looks at some 
other tests, toxicity and other methods of interferi ng with a cell can influence the endpoint, so it is 
very important that one looks under the conditions of  the protocol of the study as to the reliance that 
one is placing on the endpoint of that study.  When one looks at 100 studies of genotoxicity, for most compounds one can find the odd positive, even for a ge nuinely negative substance.  And so that is  WT/DS320/R/Add.7 
 Page G-81 
 
 
  what I mean by the weight of evidence.  If you have 99 negative studies all done well, one study done 
badly which gives a positive, what is the weight of  evidence?  The compound is negative.  I am not 
arguing this is the case with oestradiol-17 β, is was not quite as clear-cut, but using a weight of 
evidence approach, the co mmittee was able to reach a conclusi on as to what the genotoxicity was 
telling us, and that was the case for many other organi zations that have looked at the body of evidence 
available for this compound's genotoxicity.  There is an element of interpretation of the quality of the 
study, I accept, but that is why you ha ve experts on the evaluation committee. 
Chairman  
 502. EC. 
European Communities
 
 503. So Dr. Boobis and also the other scientists, do you accept that different groups of scientists 
can view the same set of data and reach different conclusions to that question? 
Chairman
 
 
504. Dr. Boobis. 
Dr. Boobis  
 505. The simple answer is yes, one can always get different interpretations with the same dataset, 
but some datasets are more likely to give a consiste nt answer than others for most people, if that 
makes sense.  So the example I gave earlier of 99 good studies giving a negative, or let's put it the 
other way around, 99 good studies giving a positive and one bad study giving a negative, one would 
hope that the vast majority of people looking at that  dataset would reach the same conclusion.  It is 
just possible that somebody would say that the negative study is the one we should put the weight on. 
Chairman
 
 
506. Let me give the floor to Dr. Guttenplan and Dr. Boisseau first. 
Dr. Guttenplan  
 507. Yes, I guess I want to answer some of the questi ons.  I think it is proba bly fair to say that 
most of the agencies that look at or have looked at these compounds or other compounds use a 
weight-of-evidence approach.  I think that is true  of the National Toxicology Program Report on 
Carcinogens, it is certainly true of the IARC monogr aphs.  It means that you get a lot of experts 
together and they look at the positive and the negativ e studies, they consider multiple interpretations, 
they try to weigh which studies should contribute most to the evaluation and come up with a reasonable judgement.  Also, as Dr. Boobis said, it is possible for different groups of experts to come 
to different opinions.  That is why we invite grou ps of experts, so that we are not too dependent on 
any one person's opinion.  And in most cases when  the IARC monographs programme looks at data, 
they do have a consensus, although there are cases wh ere the dataset is sufficiently mixed that there is 
a close vote.  So there are some cases where the overall signal about whether something is 
carcinogenic is an issue.  I don't think that is th e case with steroidal oestrogens, I think many bodies 
have said that steroidal oestrogens are carcinogenic.  I think that the next le vel down of questions is: 
How is it carcinogenic?  Is it carcinogenic through a hormonal mechanism, through a genotoxic 
mechanism, only one of them, possibly a mixture of both?  And I think that there is some uncertainty and there is some difference of opinion among the expe rts.  So in that case it is possible for different 
groups of people to reach different evaluations.   WT/DS320/R/Add.7 
Page G-82  
 
  Chairman
 
 508. Thank you.  Dr. Boisseau. 
Dr. Boisseau
 
 
509. Thank you, Mr. Chairman.  I would go along with wh at was just said.  The fact is that expert 
committees are currently issuing different opinions in  the area of genotoxicity, perhaps because they 
are focusing more on the results.  I am convinced that if we brought together competent and independent experts and if they began by objectiv ely evaluating the validity of the methods, there 
would be far fewer problems with the results that th ose methods produce.  I do not think that we place 
enough emphasis on the validity of the methods.  Sec ondly, to favour consensus, it is important to 
know what these short-term mutagenicity or toxici ty tests can produce and what they cannot produce 
in order to avoid erroneous in terpretations depending on the results obtained.  Clearly these 
techniques are used with large quantities of the substan ce that have nothing to do with residue content.  
This is particularly true of in vitro  methods:  they are conducted in conditions which do not reflect the 
fate of a substance in an orga nism, determined by pharmacokinetics and the metabolism – they are 
merely screening tests, and nothing more.  They  cannot, under any circumstances, lead to a 
determination of dose effects, and at best, they can only provide information on the mechanisms of 
action.  Thus, if the experts focus on the validity  of the methods, on what these methods can produce 
and what they cannot produce, I am convinced th at there would be much more consensus on the 
interpretation of the results of the methods.  Thank you. 
Chairman
 
 510. I have a procedural question.  What if there are conflicting views, half and half, or almost half 
and half, among the experts participating in the JECFA Committee?  What is the decision-making 
process in that case?  Do they still make conclusions on the issues that do not provide any sufficient 
scientific evidence, or avoid making decisions and refe r it to the next committee or to a later stage?  
Dr. Boobis. 
Dr. Boobis
 
 511. First of all, Chairman, this is a hypothetical question, because it has not occurred.  I want to 
make that clear.  The JECFA Committee – at least as far back as 1997 – have been able to reach an 
agreed position on all the questions before them.  In  the event that there wa s a disagreement, there 
would be two possible options – one  would be not to proceed furthe r and seek further evidence, and 
the other would be, as has been indicated already by the secretariat, if the majority was of one view and a minority was of another view, to issue a so- called minority opinion or minority report as well, 
which reflects a contrary view on the interpretati on of the data.  As I said earlier, this has not 
happened, there was unanimity.  Generally what happe ns is that there is a discussion, there may be 
varying interpretations of a dataset , the experts get together over th e period of a meeting and explore 
the various possibilities, bringing new information,  or new insights and reach a common position, and 
that has worked generally very successfully in th e evaluation of the compounds over the last 10 years 
I have been involved in JECFA.  Thank you. 
Chairman
 
 
512. Are all these decisions made by consensus, or sometimes by voting?  WT/DS320/R/Add.7 
 Page G-83 
 
 
  Dr. Boobis  
 513. At JECFA the decisions have always been made by consensus, to my knowledge no vote has 
been necessary. 
Chairman
 
 
514. Dr. Tritscher. 
Dr. Tritscher  
 515. Thank you.  I have to explain a little bit what I did not do in the beginning, what the role of 
JECFA is within the WHO Constitution.  JECFA is  an Expert Committee, and expert committees are 
the highest level scientific expert groups that exis t within the WHO Constitution, and there are very 
strict rules for scientific groups.  And as I said, an expert committee is the highest-level committee 
with very stringent rules with respect also to the sel ection of the experts and so forth.  With regard to 
decision-making, it is the basic documents of the WHO which lay out the rules for expert committees, 
which are convened to develop a recommendation to the Di rector General for his or her decision.  It is 
made very clear that scientific decisions are not subject to vote, that is very clear.  And as Professor Boobis said, your question is indeed a hypothetical one  because the whole purpose of an international 
expert committee is to reach a conclusion.  If theo retically there would be a situation where you have 
a 50/50, 60/40 or very close decision, and then it is in the discretion of the Chairman on how to 
proceed.  If it appears that no consensus opinion will be reached, then that subject would not be 
concluded on.  If there is a minority, then there are also  very clear rules, and there is the option that if 
it is not possible to reach consensus, a minority opinion can be expressed, and has to be expressed, if 
there is no consensus.  And again, this minority opi nion is published in the report, with the names of 
the experts having this minority opinion and a clear description of their rationale and their opinions.  
Thank you. 
Chairman
 
 516. Dr. Wennberg. 
Dr. Wennberg
 
 517. Thank you, Mr. Chairman.  Yes, as I was explaining yesterday, the existence of scientific 
committees is also laid down in th e basic text of the Food and Agricultural Organization of the United 
Nations, and as Dr. Tritscher explained, the same rule s apply to the experts which participate in expert 
committees called by FAO to help the internationa l scientific committees to elaborate on scientific 
issues.  And may I also say that as far as the experti se is concerned, there is a transparent procedure in 
how these experts are called upon, are selected, are put on rosters which are agreed by the 
Director-General of FAO and by the member count ries from where these experts are coming, and the 
experts have to sign a declaration of interests for every meeting in which they participate, and these 
declarations of interests are filed by the Organization.  Thank you. 
Chairman
 
 518. Thank you.  EC. 
European Communities
 
 519. Chairman, can I make a short statement instead of a question, or it is both.  A clarification for 
Dr. Boobis.  In the United States 2002 carcinogenesis re port, is it not true that they examined and WT/DS320/R/Add.7 
Page G-84  
 
  declared oestradiol as a direct and indirect genotoxic substance?  They have also said, and I can read, 
veterinary use of oestradiol estrogens to promot e growth and treat illness of animals can increase 
oestrogens in tissues of food-producing animals to above  their normal levels.  This is in the report.  
They didn't make just a general finding, they have linked it to the residues from meat of animals treated with hormones for growth promotion, it is written in the text.  And later on we come to the 
more precise question of the growth response.  Thank you. 
Chairman
 
 520. US. 
United States
 
 
521. Thank you, Mr. Chairman.  I think you know that the issue that the EC has raised is one that 
we can discuss on Monday of next week when we discuss these issues.  But I would note that the 
statement made by the EC is nowhere linked, in that report, to the carcinogenic effect that the EC seems to be alluding to.  So just as a point of cl arification, and perhaps any of the experts who have 
read the report would like to speak to that issue. 
Chairman
 
 522. OK.  Question 23 regarding the EC statement that it has a standing request to review the 
hormones at issue has not been answered by the experts or the JECFA representatives.  
Dr. Miyagishima.   
Dr. Miyagishima
 
 523. Thank you, Mr. Chairman.  Yesterday I e xplained briefly how the Codex Committee on 
Residues of Veterinary Drugs in Foods operates, but please let me reiterate what I explained yesterday 
a little bit, and answer the question posed.  CCRVDF  uses the so-called priority list as a means of 
communication with JECFA.  Prior to each meeting of CCRVDF, the Codex Secretariat circulates or 
distributes a circular letter to all Codex members a nd observers, and this circular letter invites any 
nominations of compounds for evaluation or re-eva luation.  The comments or proposals received in 
reply to the circular letter are usually considered by  an ad hoc working group that meets the day prior 
to the beginning of the CCRVDF session.  The discussion and conclusions of the ad hoc working 
group are presented to the plenary session of CCRVDF wh ere the final decision takes place as to what 
compounds should be included in the priority list and then communicated to JECFA.   
524. Now, with regard to the five substances fo r which the Codex established MRLs, that is, 
oestradiol-17 β, progesterone, testosterone, trenbolone acetat e and zeranol, the only reference found in 
the reports of CCRVDF is the intervention made  by the European Commission – which was an 
observer at that time, participating in CCRVDF – on behalf of the European Community, at the 
eleventh session in 1998.  The European Community  requested that the re-evaluation of these five 
substances that was being scheduled in 1999 be de ferred to a later session of JECFA, in view of 
substantial studies that were being prepared by the European Union at that point of time.  Since 1999, 
CCRVDF has met five times, as I explained, at the interval of approximately 18 months.  In the reports of CCRVDF, there is no record of proposal s, either from the European Community or from 
member States of the European Co mmunity, to include these five substa nces in the priority list for re-
evaluation by JECFA.  With regard to melengestro l acetate, it was included in the priority list for 
recalculation of MRLs and TMDI by the fifteenth  session of CCRVDF that met in 2005.  However, 
the request did not come from the European Co mmunity, but came from an industry observer present 
at the meeting.  These are the records found in the reports of CCRVDF, and given the fact that Codex rules or internal procedures allow for any memb er to go on record for any decisions taken by  WT/DS320/R/Add.7 
 Page G-85 
 
 
  CCRVDF contrary to its wish, it is unlikely, read ing from the reports of CCRVDF, that a request was 
made from the European Community for re-evaluati on or evaluation of these substances.  Thank you. 
Chairman  
 525. Thank you.  Madam Orozco.   
Ms Orozco
 
 526. Thank you, Mr. Chairman.  I have two follow-up questions, one to the EC, as to what they 
means by a standing request to review the hormones at issue, because that has b een stated in some of 
your documents.  I would like clarification as to what  the actions are, or how this request has been 
submitted.  And second, I have a follow-up question to the Codex representative as to what was the 
answer, and the reasons for the answer to that in tervention by EC requesting postponement of the re-
evaluation.  Thank you. 
European Communities
 
 
527. Mr. Chairman, I can be very brief on this.  We  have sent to the Panel Exhibit No. 63, where 
we have attached the exchange of letters we had with the JECFA and Codex secretariat.  In the last 
letter, the reply of the joint secretariat, it is stat ed that we had been requesting JECFA to postpone the 
re-evaluation of 1999, which nobody has requested.  It was coming from the s ecretariat themselves, 
which is a very rare procedure to apply.  And we have requested them to postpone because the new 
data was coming.  And they have replied to this letter that once the new data becomes available we 
will review them, and they conclude we will be happy to place again these substances on the agenda 
of a future meeting of JECFA.  And the issue was left there.  We never said after the re-evaluation 
don't do it, it was there on the table since we were communicating on this question since 1999.  It is true we didn't put it on a priority list subsequently, but the understanding was, at least this is how I 
understood it, that when the new data become availabl e, they will review that.  And the truth is, when 
they presented the 1999 evaluation to the Codex Committee, they said we did not ask you to re-
evaluate, and they didn't consider that.  So I think it would be reasonable, in the light of these letters 
which we have exchanged, and th e promise that they will be happy to place again these substances on 
the agenda, they would have done it.  That is all, it's no more than that.  Thank you. 
Chairman
 
 
528. Thank you.  Dr. Miyagishima. 
Dr. Miyagishima  
 529. Thank you, Mr. Chairman.  Just to complement my previous intervention by saying that the 
latest session of CCRVDF actually met earlier this year, and there was a circular letter, Codex circular 
letter 2005/43, was circulated in September 2005 to invite nominations for compounds for evaluation, 
with a deadline of 28 February 20 06.  No replies were received from any member or observer.  Thank 
you. 
European Communities
 
 530. Excuse me.  I have the question for Codex and for JECFA as to what was the answer to the 
intervention made by the EC observer referring to the deferral of the re-evaluation.   WT/DS320/R/Add.7 
Page G-86  
 
  Dr. Miyagishima
 
 531. The request from the European Commission ma de at the eleventh session of CCRVDF was 
duly recorded in the report of that particular sessi on and as such it was brought to the attention of the 
JECFA secretariat, and that was the action taken by the Codex side.   
Chairman
 
 532. Thank you.  Dr. Wennberg. 
Dr. Wennberg
 
 
533. Thank you, Mr. Chairman.  The JECFA secretariat and the exchange of the letters that was 
talked about – the reason why JECFA put the substa nces on the agenda of JECFA was that there was 
new important epidemiological data that had beco me available since these  substances had been 
evaluated in 1987.  The JECFA secretariat may place any substance on the agenda for re-evaluation, 
even though no outside request has been received.  It is not permissible that the JECFA secretariat 
should postpone a re-evaluation of a substance wh en new important information has come to the 
attention of the secretariat – let's make that clear.  The second point I would like to make is that the 
procedure to put substances on the agenda of JE CFA, through the CCRVDF, is open to all members 
of Codex and even observers, as we have heard.  So it's not because there is a letter responding to this 
request for postponing a re-evaluation that the secret ariat would issue a call for data for re-evaluation 
of the substances when there is no explicit request from a member of Codex to do so.  The procedures 
have been very well explained by Dr. Miyagish ima and they are followed by everybody.  The 
secretariat never received any information on the stud ies, the studies themselves, or the study report 
from the EC.  Thank you. 
Chairman  
 
534. Thank you.  Dr. Tritscher. 
Dr. Tritscher  
 535. Just to add to what my colleague already said,  it's really that there are three main routes or 
main ways for a compound to get on the agenda of JECFA; through the priorities working group in 
CCRVDF, but also requests from FAO and WHO member States can be brought forward directly to 
the JECFA secretariat with the request for evaluati on or re-evaluation, with justification, data 
availability and this kind of information.  And the third is that the JECFA secretariat can re-schedule 
the re-evaluation of a compound if they are made aw are that there is significant new data available.  
What that requires usually is that these data are r eally made available, not just saying that there are 
new data, here it is, but there has to be a very clear lis t of what type of data, to allow, with the help of 
experts often, to judge if this is justified, if th e data are significant enough to justify a re-evaluation.  
And it is not correct that this is an extremely ra re procedure.  Sorry, there is one other way for 
compounds to be nominated for evaluation; it is actually through specific FAO and WHO programmes themselves.  It is commonly the case that, for example for the WHO drinking water 
guideline programmes, compounds are requested for evaluation through JECFA or through JMPR for pesticides.  And although the main route for nom ination of compounds for evaluation is through the 
Codex Committee, it is not correct to say on the othe r side that it is extremely rare; it really happens 
frequently.  Thank you. 
Chairman
 
 536. We now invite the delegations to po se their questions.  Starting with EC.  WT/DS320/R/Add.7 
 Page G-87 
 
 
  European Communities  
 537. Thank you, Chairman.  So we move now to another area.   
Chairman
 
 
538. Another area, you mean area 3, or are we still in  the risk assessment techniques?  Have you 
exhausted all your questions on item 2?  Do th e US and Canada have any questions on risk 
assessment techniques?  Canada. 
Canada  
 
539. Thank you, Mr. Chair.  Our questions are just cl arifications on some of the answers that have 
been provided.  First for Dr. Cogliano.  You said yesterday that IARC conducts qualitative risk 
assessments in that it stops after identifying a hazard.   You also said that it's qualitative because of the 
way it expresses its conclusion as possibly carcinogenic or a known carcinogen.  My question is, then, can you use the qualitative conclusions of a JE CFA monograph to evaluate the potential for 
occurrence of the hazard that is identified for given exposure scenarios?  Perhaps – you are going to 
answer that one first then. 
Chairman
 
 540. Thank you.  Dr. Cogliano. 
Dr. Cogliano
 
 
541. It is true, the IARC monographs do stop with a statement that something is carcinogenic or 
probably not carcinogenic to humans.  That can be enough, depending on the structure in which you make a decision.  The monographs on different fo rms of tobacco were enough for WHO to conduct its 
framework convention on tobacco control.  It does not give you dose-response information about what 
is happening at lower doses; it will simply tell you what are the substances for which carcinogenicity 
should be considered, and then different decision-ma king authorities will have to decide whether that 
evidence is sufficient for them to  make a decision, or whether they do need to conduct further 
analysis.   
Chairman
 
 
542. Thank you.  Canada. 
Canada  
 543. On its own, then, the conclusion is not useful for evaluating occurrence in a specific exposure 
scenario though, is that what I understand?  It might  lead other authorities to determine in specific 
circumstances whether there is a risk that  that particular hazard would occur.   
Dr. Cogliano
 
 544. Yes.  Other authorities would need to determine whether there is a risk.  Now occurrence is a 
different matter.  Occurrence simply means is th ere some exposure to the chemical through some 
particular pathway.  The IARC monographs do atte mpt to identify the different types of exposures 
people encounter, whether it is o ccupational exposure, whether some thing is found in food, whether 
something is widespread in the environment; so  the monographs identify occurrence, but not the WT/DS320/R/Add.7 
Page G-88  
 
  specific levels of exposure in a particular populati on.  There are a lot of terms, like occurrence, 
exposure, risk and I'm trying to be precise here.  
Chairman
 
 545. Thank you.  Is that all Canada? 
Canada
 
 546. I have just two more questions.  Dr. B oobis, you explained the difference between 
deterministic approaches and probab ilistic approaches to risk assessments.  I wonder if you could 
comment further on – I think in fact you did comment  on – which approach is more often used, but if 
you could further comment on which is the mo re conservative of the approaches.   
Chairman
 
 547. Dr. Boobis. 
Dr. Boobis
 
 
548. In terms of the toxicological side, the h azard side, of risk assessment, the probabilistic 
approach has only very rarely been used.  We almost always use a deterministic approach.  In terms of 
the exposure side, the majority of risk assessments  have also used deterministic approaches, although 
increasingly people are using probabili stic approaches.  Where data ha ve been obtained, it is quite 
clear that almost always the deterministic appr oach is more conservative than the probabilistic 
approach, and sometimes by orders of magnitude.   
Chairman  
 549. Thank you.  Canada. 
Canada
 
 
550. A final question then, Mr. Chairman, and this  would go to the representatives of the JECFA 
secretariat, or I guess any other expert that is familiar with the operation.  In light of the suggestion by 
the EC in its comments that JECFA takes for gran ted all the unpublished data  from industry, I wonder 
if you could describe the steps that JECFA take s to verify the quality and sufficiency of the 
preparatory data it receives from industry.  Thank you. 
Dr. Tritscher  
 551. Thank you.  I don't understand what is meant with  taking for granted, maybe that has to be 
explained later if I am not addressing what is act ually meant with that.  When compounds are put on 
the agenda, the JECFA secretariat publishes a call for data on the internet that goes out publicly to 
everybody.  With compounds that are commercia lly produced and sold, very often important 
toxicological information is proprietary information a nd is not publicly available.  This information is 
submitted by the company to the JECFA secretariat,  and JECFA requests the complete study reports, 
so not the summaries or the conclusions or what have you, but the complete detailed individual 
reports with all the details, individual numbers,  individual data, completely the whole set of 
information.  And in addition, all the experts perfo rm literature searches using standard techniques in 
order to, in addition to the non-publicly submitted info rmation, to take into account everything that is 
publicly available in the public domain as relevant sci entific information.  The data that are submitted 
are scrutinized in detail by the JECFA experts, in pa rticular with respect to quality of the study.  There  WT/DS320/R/Add.7 
 Page G-89 
 
 
  are criteria with respect to good laboratory practice that are very well defined.  Modern newer studies 
have a statement to that effect, a legal statemen t, quality assurance statements, statements regarding 
good laboratory practice in their study reports.  All those studies before these methods were implemented very often do not have such official quality-assurance statements and so forth.  And then 
it is the responsibility of the experts to scrutinize in detail the study reports, if current good laboratory 
practice techniques have been followed.  That means characterization of the test material, appropriate 
analytical methodology and any kind of really basic information that is available.  If this is not available, if it is concluded that a study w as not conducted according to what would be called good 
laboratory practice; it does not necessarily discred it the study as such.  Sometimes these studies can 
still contain important information, in particular if you talk, as was explained earlier, in the context of 
the weight of evidence approach.  Sometimes such studies still give important information, but one 
would not base an evaluation on such studies.  It is in the overall context of evaluating the whole database.  And again, all the data that are submitte d are scrutinized in detail,  checked for accuracy and 
then summarized and described in deta il.  I hope this addresses the question. 
Chairman
 
 
552. Canada. 
Canada  
 553. That concludes our questions on item 2.  Thank you. 
Chairman
 
 
554. Thank you very much.  May I now invite the EC to pose questions on item 3, scientific 
evidence.  Please go ahead. 
European Communities  
 
555. Thank you, Chairman.  I would like to come back  to the issue of the most sensitive segment 
of the population, in particular prepubertal children,  and I would like to ask Dr. Sippell, for example, 
whether the values which we have seen yester day on the screen from JECFA are the values for 
prepubertal girls and boys which are their actual production rate, daily prod uction rate, or whether 
they are based on the detection limits of the assays used for the calculation. 
Chairman  
 
556. Dr. Sippell. 
Dr. Sippell  
 557. As far as I could see the official production ra tes, and it is difficult to calculate exact 
production rates in prepubertal children because firs t you have to have a tr ue level of endogenous 
production, blood levels, so that you  can calculate the production rate.  They have been based on the, 
so to speak, traditional levels measured by radi o immuno assays, and usually by radio immuno assays 
without prior extraction.  We all know that the sensi tivity of such procedures is not enough compared 
with more modern techniques, so to speak, th e extractive procedures involving radio immuno assays, 
but even more modern molecular base techniqu es like recombinant cell bioassays, of oestrogen, 
oestradiol or oestrogen activity.  And these, as I have pointed out in my answers to the Panel, are 
significantly below the levels previously thought, and by that the production rate now is significant 
lower.  And this of course implies that any risk from exogenous sources, for example beef treated with 
hormones, treated with oestradiol-17 β, is much higher.   WT/DS320/R/Add.7 
Page G-90  
 
  Chairman
 
 558. Thank you.  EC. 
European Communities
 
 
559. You have also made reference yesterday to the latest method in the USA to calculate the daily 
production rates, and you made a reference to the ass ay of the group of Klein which became relevant 
after the evaluation made by JECFA, so does this in  your view put in doubt the validity of the values 
given in JECFA, and I am precise as to the potentia l risk for prepubertal children from eating meat 
treated with hormones for growth promotion.  It's an important point to clarify in my view.  Thank 
you. 
Chairman  
 560. Dr. Sippell. 
Dr. Sippell
 
 
561. Yes, that's indeed the case.  This ultra-sensitiv e assay has been recently confirmed, its validity 
has been confirmed by another lab, you know the Klein methodology.  The main author is George Chrousos, by the way, who was for many many years director of the children's section at the National 
Institutes of Health, and this new supersensitive assay has been confirmed by another laboratory 
which also is very well-known and considered to be very thorough and applying good laboratory 
practices, of course; that is the lab of Professor Charles Sultan in Montpellier, and coming to quite 
similar levels and, as I said yesterday in my introduction, many basic biological features can only be explained by the validity of these supersensitive oest radiol assays.  There is no other explanation 
among scientists, among paediatric endocrinologists, th an very very low levels, significantly higher 
levels of secretion in prepubertal girls, significantl y higher than in prepubertal boys.  Therefore there 
is no doubt, as I told yesterday already, there is no doubt among the scientists, also in the United 
States and Canada, that this is really the case, and th is supersensitive assay is not being put into doubt 
really by the experts I have been speaking to.  Th erefore, there really is concern that the exogenous 
load from, for instance, oestradiol-17 β, might be significant. 
Chairman
 
 
562. I will give the floor to the US and then back to EC. 
United States  
 563. Thank you, Mr. Chairman.  Just as a point of clarification, to the best of our knowledge the 
Klein assay has not been used subsequent to its 1994 publication for regulatory purposes.  But beside 
that point, I think there are two important questions here, one of which I would like to pose to the 
experts generally, which is:  what does it mean wh en an assay is validated?  And I think the follow-up 
to that is an appropriate question for Dr. Boobis, which is:  given the considerable debate in these 
proceedings regarding blood levels of oestradiol in prepubertal children, and given the EC's heavy 
reliance on the Klein assay which purportedly shows lower circulating levels  of oestrogen, I was 
wondering if in Dr. Boobis's opinion the Klein assay indeed establishes that circulating oestrogen 
levels in prepubertal children are lower than prev ious reported, and whether that assay has indeed 
been validated by the evid ence that is on the record?  So a two- part question, one to all the experts – 
what does it mean to validate an assay? and then secondly – h as the Klein assay indeed been 
validated? – to Dr. Boobis.  WT/DS320/R/Add.7 
 Page G-91 
 
 
  Chairman  
 564. Is any expert prepared to answer the first part of the question?  Dr. Guttenplan, please. 
Dr. Guttenplan
 
 
565. If an assay has been confirmed independently in  a number of laboratories, I would consider 
that validated.   
Chairman  
 566. Dr. Boobis. 
Dr. Boobis
 
 567. I am not an expert on residues, and there are people here who can speak on this better than 
me, but as I understand it, in residue analysis th e process required for assay validation to measure and 
analyse biological samples for regulatory purposes is fairly well defined and consists of a number of 
steps, such as ruggedness, precision, sensitivity, reproducibility, transferability, availability of 
standards, etc. etc.  There is a procedure which the chemical societies have agreed internationally, that 
before an assay can be described as validated, as oppo sed to fit for purpose, these are different things, 
that for validation it has to undergo this procedure which has been recognized as a systematic analysis 
of the different performance characteristics of the assay. 
Chairman
 
 
568. Dr. De Brabander, please. 
Dr. De Brabander  
 569. Yes, I agree with what Dr. Boobis said, it completely described what validation is of a 
analytical method.  Of course I don't have experien ces with assays for very low amounts of oestrogen 
in blood, we don't work in blood, but it is co mpletely described.  The most essential thing is 
specificity – that you are really measuring what come s up, and in that respect yesterday we talked 
about qualitative and quantitative methods in risk assessment, we have the same nomenclature in 
analytical chemistry, qualitative and quantitative methods, and both are always mixed.  Every 
quantification needs a qualification; you must be sure  of what you are counting; the specificity of the 
method is extremely important.  And also, if you have a qualitative method, you get always a signal 
and you get some kind of quantification, but it is onl y qualitative and again, you will have to fit the 
rules for quantification, a calibration curve etc. etc.   I can put at your disposition a number of papers 
on validation, but I don't think we will start a discu ssion on validation as it is strictly described.   
Chairman
 
 
570. Thank you very much.  Any other experts?  US. 
United States  
 571. And then, just as a follow-up, if in Dr. Boobi s's opinion the Klein assay has indeed been 
validated by any of the evid ence that is on the record. WT/DS320/R/Add.7 
Page G-92  
 
  Dr. Boobis
 
 572. Not to my knowledge.  I would just comment on my concerns about the Klein assay.  There is 
a review published in the Journal of Paediatric Endoc rinology and Metabolism in July of this year by 
the Klein laboratory, or with Klein as an author  I should say, and it states in the review summary: 
prepubertal boys have oestradiol levels of 0.4 plus or minus 1.1 picograms per ml – which is 
somewhat higher than the level that was reported in the 1994 paper, which was 0.08 picograms per 
ml, that is significantly different.  Now the Klein assay uses a recombinant assay in yeast with the 
human oestrogen receptor and therefore it is not specific to oestradiol-17 β; if it is, there is something 
strange about the biology, because one would not  imagine that that receptor could discriminate 
between different oestrogens with absolute cer tainty, because otherwise the whole concept of 
oestrogenicity would not work.  There are extrac tion procedures in the assay which might help select 
out certain compounds or others.  Having looked at the characteristics of the assay, I find it 
extraordinarily difficult to understand why that assay  would be so specific, or so sensitive, to 
oestradiol as opposed to other oestrogen agonists.  There are other assays based on the recombinant 
oestrogen receptor; one of them utilizes a mammalian  cell, not a yeast cell, and it is by Dr. Paris's 
laboratory.  They have reported, using this assay, leve ls of oestradiol, of I think a couple of picograms 
per ml, yes, 1.44 picograms per ml.  So we can s ee now that using these recombinant assays there is a 
variation from below 0.1 to 0.4, to 1.4, so that my view, having looked at these data is that, first of all, 
the recombinant assay has not yet b een validated adequately, but sec ondly there is evidence, when one 
looks at these data, to suggest that the circulating le vels of oestradiol in male children are lower than 
previously thought, I would accept that, but I would not think they are as low as in the original 
publication by Klein et al,  because there have been numerous publi cations since then using a variety 
of assays which suggest that the levels are certainly hi gher than those very low levels first reported.   
Chairman
 
 
573. Can I give the EC and then Dr. ... 
European Communities  
 574. Gentlemen, I think we have a different inte rpretation of the data, and we will review 
references made by Dr. Boobis and will reply to that on Monday and Tuesday, but we understand that 
all the latest assays, and the one mentioned by Dr. Sippell later on, from the professors in Montpellier, 
they confirm that the level of oestrogen is much much lower, many more times lower than the ones 
reported in the JECFA report.  There is no doubt, and even Dr. Boobis in his reply says in the first sentence of his replies that there is no doubt toda y that the levels are much lower.  This minor 
difference to which he has made reference, they ar e not statistically different important differences, 
they are minor differences which sometimes you ob serve in the assays, and if you normalize the 
assays, you will see the values you expressed in the different assays, you will see there is no doubt 
about it, that it is significantly lower.  But I have to move on from that debate and come back again to 
Dr. Sippell, and other scientists may come in, for example.  In the risk assessments which the European Communities has performed and which you ha ve in your files – and I refer to our 1999 and 
again to 2002 assessments – do you think that the European Communities has attempted to evaluate 
the risk for the prepubertal children from exposure to these hormones, taking into account these latest 
values which have been measure d by the most sensitive assays? 
Chairman
 
 575. Dr. Sippell.  WT/DS320/R/Add.7 
 Page G-93 
 
 
  Dr. Sippell  
 576. I think that the risk is, and I have read sever al papers on that and also from my clinical 
experience, that as I pointed out yesterday, the le vels probably are still lower than what has been 
measured by a radio immuno assay, and that the reco mbinant assays, they might differ, but they are 
with a lot of indirect evidence much  closer to the truth than the tr aditional assays that we are all using 
nowadays in a routine lab.  And if you calculate, then the exposure certainly is much higher if you have the low levels with the recombinant assays as a basis, and therefore I think some people have 
calculated that as little as 10 grams of meat ingested per day for a prepubertal boy might be or will be 
above his own production rate, and this is something one should consider.   
Chairman
 
 577. Excuse me, I don't think the US questions have b een fully answered, so may I invite experts 
other than Dr. Boobis to add their comments on the fi rst part of the US question and then move into 
the second part of the question.  Is there any expe rt who is willing to add comments on the first part, 
on validated or not. 
Dr. De Brabander
 
 578. Well, as I said, there are rules for validation and normally if a lab performs well it is 
controlled by some organization.  I don't know, I tell just for Belgium, you have the Belgian 
accreditation system, and labs who work in accredita tion regularly have inspection from auditors.  I 
have experience with that because I am an auditor my self, trained as an auditor, and when I go to a lab 
and they have qualitative methods (o f course you don't test every method every time) I ask samples to 
be analysed.  For example if it is urine and they ha ve a method for testing urine, I ask them to prepare 
some samples of urine and I ask the components an d then I take out amounts of the components and 
put them into the urine and then say do the test and show me the results.  And then you can say that 
your method is validated.  Of course, there are rules on paper – but in practice you can see if it works.  
And if it does not work, you can get the feedback to the lab – that's not in order, you should do that; that being the validation.  It is not that you just ha ve paperwork, there is control, and if you have a lab 
that works on GLP or accreditation, you have labora tory control on the results.  In addition, maybe 
what was said, that a method is good when it is done in two labs, we use that also, performing analysis 
in two labs, and you see that for us chemists is it normal that if you get, for example, one ppb in one 
lab and two ppb in another lab, that's nearly the sam e.  They are using slightly different procedures 
and it is within the variation of the method.  And there is also evidence fo r that; there is a curve 
published by Horwitz, from the United States, w ho says that the uncertainty goes up when the 
concentration goes down.
3  The lower the concentration, the more difficult.  Of course, you can 
understand that it is really impossibl e to have exactly the same figure.  So the figure may vary a little 
bit within ranges, giving the same results. 
Chairman  
 579. One follow-up question.  In order for this scientif ic data by one laboratory to be validated, do 
we need a kind of endorsement by another laborat ory or a number of laboratories on the same data? 
Dr. De Brabander
 
 
580. No, it is not necessary, you have different systems, like I said, you have an accreditation 
organism who control that your lab is accredited.  Within the accreditation you are also obliged to do 
                                                      
3 W. Horwitz, L.R. Kamps, K.W. Boyer, J.A.O.A.C. 63  (1980) 1344-1354.  (Reference provided 
subsequently). WT/DS320/R/Add.7 
Page G-94  
 
  ring tests.  There are organisms who will prepare samples with certain amounts of components, the 
laboratories that are accredited need to analyse t hose samples and produce results.  If your results are 
outside of a certain z-score
4, as they call it, outside the normal range, you are alerted, and if you come, 
during an accreditation audit, you can ask: can you give me the results of your ring test, how have you 
done for that component, how have you performed for that component, you can control that.  And 
that's not another laboratory, that's an organization who controls it.  I hope that answers your question. 
Chairman  
 581. Dr. Boisseau. 
Dr. Boisseau
 
 
582. Thank you, Mr. Chairman.  Yes, I would like to confirm what Dr. De Brabander just said.  
However, we are talking about two different things  here.  We need to draw a proper distinction 
between the accreditation of a laboratory and the valid ation of a method.  Dr. De Brabander has just 
spoken of an accreditation, and I have nothing to ad d to what he said.  But, the question that was 
asked concerned the validation of a method.  Dr. Boobis had reminded us of all the internationally 
recognized criteria for validating a method, and as Dr. De Brabander said, it is well known that the 
lower the target in terms of concentration, the gr eater the uncertainty and the lower the reproducibility 
and the reliability of the method – this is well known.   There are two ways of validating a method:  
there is intra-laboratory validation, which takes place within one and the same laboratory, i.e. it is the 
same laboratory that repeats a certain number of  dosages at different periods with different 
technicians, and if the results fall within an accepted range, the validation takes place within the 
laboratory.  But more importantly, there is inter-l aboratory validation, in which a certain number of 
laboratories are selected within th e framework of what is known as a circular test, and the method is 
tested for precision, reproducibility, reliability, and what is also known as strength to see if it is 
exportable from one laboratory to anot her.  Thank you Mr. Chairman.  
Chairman  
 583. Thank you. Ambassador Ehlers has a follow-up question. 
Mr. Ehlers
 
 584. Thank you very much.  The question has basically three elements.  The first one is: do these 
hormones accumulate in the body or does the body elim inate them in total or in part?  If so, do the 
adverse effects depend on this accumula tion or not?  And thirdly, if they do, then if you start with a 
lower endogenous level, would you not say that the risk also diminishes?  Thank you. 
Chairman
 
 
585. Dr. Boobis. 
Dr. Boobis  
 586. The hormones don't accumulate to any appreciable  extent in the body because of the natural 
production of similar or the same hormones, and these hormones would not be able to function if they 
accumulated in the body.  So we have evolved mech anisms to allow the turnover of the hormones.  
                                                     
 
4 In statistics, a standard score (also called z-score or normal score) is a dimensionless quantity derived 
by subtracting the population mean from an individual (raw) score and then dividing the difference by the 
population standard deviation.  (Explanation provided subsequently).  WT/DS320/R/Add.7 
 Page G-95 
 
 
  All hormones have to have a turnover so that we  can switch on and switch off the signalling pathway 
as necessary to off-regulate or down-re gulate the target receptor system, and that would be true of the 
xenobiotic exposure to the hormones as well, because  once they are in the b ody, the natural hormones 
are indistinguishable from the native hormones and w ould be eliminated by the same processes.   
Chairman  
 
587. Dr. Sippell. 
Dr. Sippell  
 588. Again, the special situation in children before  puberty – there is evidence that for instance 
secretion of sex steroids is pulsatile on a very very lo w level and that the sensitivity of the organism is 
such that these extremely low levels are being pi cked up and being recorded in the centres, in the 
hypothalamus, so in the brain, and also in the pitu itary for regulation, also for imprinting.  And we 
know that prepubertal boys or prepubertal girls, in case of oestradiol, are par ticularly sensitive to very 
very low exogenous levels of oest rogens.  We have, for instance, the natural example of Turner 
syndrome girls who lack ovaries and thereby ova rian function and thereby have no endogenous 
oestrogens.  And we know that with as little as 25 nanograms per kilogram body weight per day we 
can promote growth in these poorly-growing girls.  So I think if you make the point that levels are very low, then at the same time sensitivity is of course adjusted to these low levels, which has to be 
taken into account also for exogenous exposure.   
Chairman
 
 
589. Yes please … 
Mr. Ehlers  
 590. Yes, thank you, I followed that explanation and th ere is part of my question that has not been 
answered yet, maybe somebody can do it.  That is  – since the body eliminates, then there is no 
accumulation, or if it is only temporary until the bo dy has done its work, the adverse effects then do 
not depend on that.  But you were trying to say that  the fact of starting at a lower level does not 
diminish the risk but it keeps it at the same rate. 
Chairman
 
 
591. May I give the floor to Madam Orozco to follow-up on the question.   
Ms Orozco  
 592. Would there be any comments to the follow-up qu estion of my colleague before I change the 
subject?  Because I would ... 
Chairman
 
 593. I will give the floor to the US first and then the EC. EC. 
European Communities
 
 594. When we started the meeting, if we think of a fa ir distribution of time, I think they have been 
asking quite a lot of questions and we do n't have the time to ask our questions.  WT/DS320/R/Add.7 
Page G-96  
 
  United States
 
 595. I think this is a very quick question if the Pane l will indulge.  Yes, it is related to Dr. Sippell's 
response.  Very quickly for the members of the expe rt panel who have had experience in JECFA, that 
is Dr. Boobis, Dr. Tritscher, Dr. Boisseau, Dr. Wennberg, I am wondering, does JECFA in its 
evaluations take into account populations such as prepubertal children or sensitive populations, and 
how do they do that? 
Dr. Tritscher
 
 596. It's a basic principle of every risk assessment to  take – it's a general remark – to take into 
account sensitive subpopulations, it's a basic principle.  Because that is the part of the population that 
you want to protect with what you are doing, and th is is based on the availability of data, what is 
taken into account.  But it is definitely it's the goal of the risk assessment to identify who would be the 
most susceptible, the most sensitive part of the popula tion, and that is the part of the population that 
the risk assessment is targeted to. 
Ms Orozco
 
 597. Just a quick follow-up question:  how was it done in the 1990 evaluation? 
Dr. Tritscher
 
 598. I cannot respond to that question.  I am  not entitled to respond to that, sorry. 
Chairman
 
 599. Dr. Boobis. 
Dr. Boobis
 
 
600. The Committee had available to it studies conducted in developing animals, where one of the 
assumptions is, based on research and scientific inform ation, that the basic physiology of the test 
species that were used has a simila rity to that in humans, and based  on an evaluation of effects in 
those sensitive life stages, together with the othe r available information, the Committee concluded 
that it had been possible to evaluate th e risks to all susceptible populations.   
Ms Orozco  
 
601. One more question, Dr. Boobis.  How was the endpoint chosen in the 1990 evaluation? 
Dr. Boobis  
 602. One of the hallmarks of a toxicological evaluation is that we don't focus on a specific 
endpoint because of the concern that we would miss so mething.  So we use, as much as possible, to 
start with a so-called holistic approach, so we l ook at the totality of effects, evaluating multiple 
endpoints for the possibility of a compound-related e ffect.  So in this case we looked at reproductive 
outcomes, we looked at the developmental effects and we looked at a range of other effects that were 
the normal hallmarks of reproduction and development in an animal.  WT/DS320/R/Add.7 
 Page G-97 
 
 
  Ms Orozco  
 603. Just one more question.  The ADI that has been established – is that protection enough if you 
would take into account the new data ab out sensitivity of prepubertal children? 
Dr. Boobis
 
 
604. I have done a calculation, which was in my responses to the questions, based on what I 
consider a consensus concentration that was somewh at higher than the lowest concentration, but was 
still significantly lower than that originally repor ted, and I calculated that the ADI would still be 
protective.  I should add that what has not been ment ioned so far is that we should not just take the 
external exposure and assume this translates into an  internal dose or concentration.  There are two 
factors which go against this.  One is the pre-syst emic metabolism we mentioned earlier – I think it 
was assumed this was 100 per cent in the EC evaluati on, sorry, zero per cent, it was all absorbed.  
Whilst I accept that it is likely lower than in an a dult, it will be very unlikely to reach zero per cent, 
particularly after the first week of life, and there will not be exposure to the hormones in meat in the 
first week of life as I understand it.  And the second is  that the hormone is not circulating completely 
free, a very appreciable amount is bound to sex horm one binding globulin and other proteins and there 
is good evidence that only the non-bound form is able  to cross cell membranes and interact with the 
oestrogen receptor, and so that will reduce the circul ating concentration as well.  So that one has to 
consider those aspects in the evaluation. 
Chairman  
 
605. OK. Canada wanted to ask a related questi on quickly and then we move back to EC. 
Canada  
 606. Yesterday there was some discussion about th e extent to which the human population is 
exposed to exogenous sources of hormones in their diet, and Dr. Boobis yesterday indicated that there 
was a significant amount of exposure to oestrogens or to phyto-oestrogens or oestrogens in plant 
material, and my question then to the experts is:  in  establishing the ADI, is the extent of exposure to 
exogenous hormones taken into consideration, particular ly in the diet of a prepubertal person, and is 
there any evidence that in the normal food, a diet with a normal food consumption, that prepubertal 
boys are at risk from exposure to exogenous hormones? 
Chairman
 
 607. Thank you.  Dr. Sippell. 
Dr. Sippell
 
 
608. I can be very brief.  I believe that nobody has ever investigated this probably, also due to the 
fact that this is extremely difficult, also  ethically, as I pointed out yesterday.   
Chairman  
 609. OK.  One more. 
Canada
 
 
610. Dr. Sippell, in 2001, I believe, you co-authored  an article that was looking into precocious 
puberty and you indicated, I believe, in your conclusi on that there was no evidence in the literature WT/DS320/R/Add.7 
Page G-98  
 
  that exogenous exposure to oestr ogens led to pseudo puberty, whic h is to be distinguished from 
central puberty.  But I wonder if you could elaborate on that conclusion that there was no evidence in the literature to suggest that exogenous exposure to oestrogens  cause precocious puberty?   
Dr. Sippell
 
 
611. Yes.  This was, as you just said, more than six years back – I think that meeting was in 1999 –
and this was a review article, so we combined a little bit of our own research with the opinions 
published in the periodic review literature.  And at that  time we came to that conclusion.  Since then 
the acceptance of the significance of the super sensitive oestradiol assay s within paediatric 
endocrinology increased tremendously because, as I said before, it for the first time gave an 
explanation for basic physiological peculiarities wh ich we did not understand before, and therefore 
there has been really a change of our understandi ng since then, and therefore my opinion now is quite 
different from that opinion in the one review article you cited.   
Chairman  
 
612. I will give the floor to the EC. 
European Communities  
 613. Chairman, I said that I had two related questions to as k.  First, it is not disputed that oestradiol 
produces a number of metabolized and other substan ces when administered to animals, and quite a 
substantial part of this is in the form of this so-called fatty esters, or lipoidal esters, which are thought 
to be eight times more potent than oestrogen it self, and we know that from the review of JECFA 
papers that the potential risk from these esters have  not been taken into account in order to measure 
the effects on the humans when they are administered  This goes back to Dr. Boobis, to what he said.  
He explained how they have taken into account the prepubertal children.  Here we are not talking 
about developing animals, that's not the point, th e point here we are talking about is developing 
human beings, boys and girls, and we cannot extr apolate from developing animals, which we know 
nothing about their organism, and draw a conc lusion about human beings which nowadays it is 
internationally agreed, and Dr. Boobis has also said, th at is at a much lower level of production.  By 
the way, we have gone through the JECFA report and we didn't see any reference to developing 
animals.  They have done the classical type of tests which are on animals, as they do it, and so all this 
is really questionable, and if there is any different view, then all the scientists can take the floor.  The 
most important metabolite, which accumulates in the fat of meat, the fatty esters, which are more 
important, they are not taken into account.  You cannot extrapolate for young animals, here we are talking about human beings, and this has not been  done.  And Dr. Sippell has confirmed, and if you 
would like to intervene, if you wish to explain why this is significant, and I posed the question in the 
beginning, we have provided the evidence, it is our 1999 and 2000 risk assessment s.  We have tried to 
estimate what would be the effects on prepubertal  boys and girls, taking into account these recent 
findings from the residues in meat treated with hormones, under normal exposure conditions.  And 
here we are talking about normal exposure conditi ons, we are not talking about other kinds of 
exposure which make up from misuse and abuse, we w ill come back to that later on, that is not the 
question.  Here we are talking abou t normal exposure cond itions.  Thank you. 
Ms Orozco
 
 
614. I would like to ask, because I think it is a very important issue that is being touched right now 
and it was asked before, and I would like to hear  answers from as many experts as we have, as to 
whether the EC evaluated the risk to prepubert al children from the exposure of eating meat from 
treated animals.  I think that is a very important question for the parties and for the Panel on which to 
hear views from the experts, please.  And I am ta lking about the risk assessment, that is the three  WT/DS320/R/Add.7 
 Page G-99 
 
 
  Opinions that have been submitted by the EC and the supporting studies, I think that is the limit of 
their assessment for the purposes of this exercise. 
Chairman  
 615. Dr.  Boobis. 
Dr. Boobis
 
 616. The EC estimated the possible exposure of pr epubertal children to food-derived hormones 
making a number of assumptions which we could debate  here; they were certainly conservative, let's 
put it that way.  For example, that everything that they were exposed to would be absorbed into the 
circulation – that is a conservative assumption, you could not get more than that but you could 
certainly get less than that.  But what was not done w as to consider what would the actual risk be, this 
was an exposure evaluation, I could not find in the documentation what the adverse effect that they 
were comparing that exposure to would be.  So cer tainly they have done an evaluation of potential 
exposure, with certain assumptions, but I could not  see how that was a complete risk assessment in 
those populations.  Just to add, if they wish to refer to page 70 of technical document 43 of JECFA, 
you will find reference to the reproductive toxicity studies that were available for evaluation.   
Chairman
 
 617. Turning to the JECFA recommendations, how would you comment on Dr. Sippell's response 
indicating that scientific material referred to  by the EC requires the revision of the Codex 
recommendation with respect to oestradiol.  In the replies of Dr. Sippell to the Panel's question 42 
there was a statement that scientific material referr ed to by the EC requires the revision of the Codex 
recommendations with respect to oestradiol.  This a comment by Dr. Sippell.  Are any other experts 
willing to add their own comments on this statement?  If none, EC. 
European Communities
 
 
618. Chairman, I think we can provisionally make a little connection to this issue by making 
reference to the dose response, which is also impor tant to understand, because children indeed are a 
very sensitive segment of the population, this is not disputed, and it is not disputed that they have 
much more lower level of endogen ous production.  And it has been said yesterday, for example, that 
here we are not talking about zero risk because the risk is non-appreciable, but the concept non-
appreciable does not mean zero risk.  There is some risk and we have heard that it is not possible to 
calculate it exactly because the shap e of the curve is not clearly defined, we don't know how it is 
defined.  We have evidence and the scientists whic h are around me can take the floor if they wish to 
explain in more detail.  The ques tion is the following:  we know and we have observed – the scientists 
and experts and the studies which we have submitted to the Panel and in our risk assessment – with 
the exposure already to the background levels, endogenously produced, we observe a biological 
action, several biological actions on the organism of young children.  Some of them may lead even to cancer, this is not also disputed.  So the questi on is:  since we know this already and we have 
evidence, a few molecules, one or two or three, in the experiments already initiate the cells to grow 
and proliferate and divide, the question is how does this enter into the risk  assessment of JECFA in 
this particular case of residues in meat from animal s treated with hormones for growth promotion?  
This is a very specific question.  Because we have tried to take this into account in our risk assessment 
and came to the conclusion which is now in our docum entation.  The point I make is I don't want to 
fudge the issue, this is taken into account on page 70 .  It is very precise, knowing that a very small, 
limited number of molecules, one or two, have a biological action on the organs of young boys and 
children.  Why was this not taken into account when JECFA has evaluated these hormones? And is WT/DS320/R/Add.7 
Page G-100  
 
  this an important element to take into account in th e light of the new evidence which is now available, 
for example, by JECFA? 
Chairman
 
 619. Dr. Boobis first and then US. 
Dr. Boobis
 
 620. Chairman, I must seek clarification.  I am not  clear yet whether the question relates to the 
DNA reactivity of oestradiol or to the hormonal effe cts of oestradiol.  So far, what Dr. Sippell was 
talking about, as I understand it, was the hormonal effects.  The genotoxicity argument is an 
additional argument and I was not clear in my own mind as to what was being asked by the EC. 
Chairman
 
 621. Would you like to clarify first? 
European Communities
 
 
622. Chairman, the debate about the genotoxicity data  is separate indeed, in our statement, what 
we are discussing here is about the hormonal effe cts, the effects through the hormone receptors' 
mediation.  
Chairman  
 
623. Thank you.  Dr. Boisseau. 
Dr. Boisseau   
 624. Thank you, Mr. Chairman.  When it comes to the hormonal effect on pre-pubertal children 
exposed to hormone residues, and I am speaking of natural hormones, I think we need to recall the 
context of these discussions and to separate oestra diol, for example, from a xenobiotic, because when 
we say that an adult or young person is exposed to residues, we need to know what residues we are 
talking about.  Since there is an  endogenous production in the animal s consumed for which we need 
to make allowances, what we are talking about is the additional resi dues linked to the treatment.  Even 
if there is no treatment, there is in any case a basic leve l of residues that are natural.  So what I want to 
know is, in view of these well-known variations in re sidues that are naturally present in meat, what is 
the risk already identified in connection with these  residues alone and what is the additional risk 
linked to the supplementary residues resulting from th e treatment.  Oestradiol must not be treated as a 
xenobiotic on an all or nothing basis.  The problem of oestradiol is that whether or not there has been treatment, we are still exposed to residues, and we must not forgot those residues. 
Chairman
 
 
625. US. 
Mr. Ehlers  
 626. Thank you.  That is similar to what I was going to ask, not only about beef but about other 
sources, eggs or vegetables or others that also have  hormones that come into our – or to children's, for 
that matter – diet.  Do we have to stop their consum ption of all of those also?  Because if the effect is 
very great by just a few molecules,  then it is not only the beef that is treated with these hormones, but  WT/DS320/R/Add.7 
 Page G-101 
 
 
  all other sources should also be stopped.  Do we have  to set an age limit for consumption of any beef, 
any eggs, any broccoli or whatever other source of these hormones exists in nature? 
Chairman  
 627. Any experts?  Dr. Guttenplan, please. 
Dr. Guttenplan
 
 628. Not a direct answer but a clarification.  When th e term "a few molecules" is used, that really 
is a simplification.  It is not a few molecules, it 's a small number of molecules per unit of whatever 
unit, usually its weight that you are talking about.  So it isn't that if you have one or two molecules 
you are going to have a biological effect, it's basically a low concentration, I think this is what the EC 
is referring to, and not a few molecules. 
Chairman
 
 629. But still the question remains to be answered .  No expert?  Dr. De Brabander please. 
Dr. De Brabander
 
 630. I cannot comment on risk assessment because I am  not a specialist in risk assessment, I would 
just comment on the broccoli Mr. Ehlers mentioned.   You know that for young children all kinds of 
these things should not be given because they contai n some natural thyreostats which are not good for 
young children – for thyroid function, yes.  Some food should be forbidden for young children, 
including broccoli.   
European Communities
 
 631. Chairman, here the point is that there is no valid reason to overburden the human body, in 
particular of young children, with other sources,  exogenous sources of these substances if it is not 
necessary.  Normally we do it with children when  it is for medical treatment, when there is a 
necessity; here there is no necessity to do it.  But I would like to ask Dr. Guttenplan, and his 
qualification was very useful, this small quantity of  molecules that you said, would they be present 
taking into account the ADI which has been fixed and the MRLs, if that quantity has just been fixed 
by JECFA, would that be sufficient to agree that a small number of molecules can indeed initiate or 
promote cancer?  Would that be sufficient in the small quantity which has been defined as an ADI or 
an MRL? 
Dr. Guttenplan
 
 632. You are asking whether the ADI that is curren tly accepted is sufficient to protect against 
cancer.  Is that the question? 
European Communities
 
 633. Yes, we have turned the question another way.  My question was: if we agree that a small 
number of molecules, not one, two or three as you said but nevertheless a small set of molecules, can indeed initiate biological action, cells brought into  separation and division, would the quantity which 
is included in the ADI from the residues in meat  treated with hormones, would that quantity of 
molecules that can come from the ab sorption of these residues be sufficien t to give rise to this kind of 
biological action when eaten? WT/DS320/R/Add.7 
Page G-102  
 
  Dr. Guttenplan
 
 634. If you are talking about cancer, I don't believe th ere is a risk from consumption below the 
ADI for cancer.  Those low levels might have a greater effect on developmental abnormalities in children though – I think Dr. Sippell has commented on that already.   
European Communities
 
 635. So you would agree that there would be other developmental effects on children, but probably 
you don't know if that will be leading eventually to cancer? 
Dr. Guttenplan
 
 
636. I don't think that the levels that produce devel opmental effects in children, that might produce 
developmental effects in children, would be sufficient to induce cancer later in life.   
Chairman  
 
637. Dr. Boisseau would like to add? 
Dr. Boisseau  
 638. Thank you, Mr. Chairman.  Very quickly, th e statement by the European Communities that 
there is no reason to overburden an intake of residue s clearly has to do with risk management.  Here, 
we are talking about risk assessment, and I think it is important to separate the two concepts.  When 
we say that a few molecules could possibly genera te tumours, excuse me for saying so, but we are 
talking of induced hormonal cancers.  I think that th ere is currently a consensu s that cancer associated 
with hormonal activity can give rise to a threshold,  so we must stop speaking of a few molecules, 
since in the case at issue, we ar e not talking about induction, we are talking about genotoxicity, in 
other words promotion.  And I think that there is a consensus on the fact that there is a threshold 
effect:  this has been confirmed in writing by many committees.  Thank you. 
Chairman
 
 639. The focus of our discussion at this point of time is scientific evidence in terms of risk 
assessment in general.  Dr. Wennberg would like to ... 
Dr. Wennberg
 
 
640. Just to recapitulate what I was saying yesterda y about the additional residues that could be 
calculated from the residue depletion studies, where there were animals which were treated and animals that were not treated, the concentrations of  the three natural hormones were analysed – what 
the excess amount of hormone would be in the beef  – and compared to the ADI.  The figures which 
are in the JECFA report and also in our report to th e Panel say that the total oestrogen highest excess 
would be in the range of less than 4 per cent of th e ADI, so that is a very small amount of the ADI.  
For the progesterone, the additional residues from th e treatment would be 0.003 per cent of the ADI 
for progesterone, and for testosterone it would represent around 0.2 per cent of the ADI for 
testosterone.  So we are talking about, in these st udies, where there were control animals and treated 
animals, where there was variability in the natura l hormonal discharge from these animals, that it is 
quite a small amount which could be considered additive to the natural background levels.    WT/DS320/R/Add.7 
 Page G-103 
 
 
  Chairman  
 641. Thank you.  Yes. 
European Communities
 
 
642. I would like to ask the representative of JECFA, do you know the date of these studies?  Since 
when do they date?  Because we know that these da ta date from the 1970s a nd 1980s.  Could you give 
us the date of the studies to which you refer?  We have been asking for this data, to see them.  
Dr. Wennberg  
 
643. These studies are available publicly reviewed by the committee with individual animals so 
you could have studied them all by yourself in  FAO Food and Nutrition Paper 41/12.  These are 
studies which were provided to the committee by the Food and Drug Administration of the 
United States and were the studies that were used  for the authorizations for particular products 
containing these substances.  If you consider that these studies were not sufficient for the 
authorization of these hormones in the United Stat es, I think you should ask the questions to the 
United States.  Thank you. 
Ms Orozco  
 644. Excuse me, I have a follow-up question, please.  Wh at is the date of the residues data JEFCA 
used in the re-evaluation report of 1999?  Or  maybe, because we don't need a list of all the 
information used, but maybe to cut short the questi on, did you have new residues data for the 1999 re-
evaluation?  Did you use any residues data that was not used before? 
Dr. Wennberg
 
 645. Yes, as I was saying, for the 1999 evaluation th e data that was reviewed, that was not 
reviewed before, was the complete set of residue de pletion studies that were provided by the Food and 
Drug Administration of the United States.  Now th ese had not been evaluated before by JECFA. 
European Communities
 
 646. Chairman, on this point, because this is important .  I refer, and it should be in the records of 
the Panel, to Canada's Exhibits 17, which is th e residues analysis monograph prepared for the 1999 
evaluation by JECFA.  It is on the record.  Canada 's Exhibit 17 and I refer to pages 88 and 89, where 
the studies upon which the evaluation was based are cited.  And I don't see any of these studies cited 
here that it is more recent than 1989, they all date to 1979, 1982, and quite a number of them are 
undated and unpublished, so presumably they date  from the 1970s and 1980s.  I don't see any studies 
of the date which the representative of JECFA and Codex cite now.  It is on the record. 
Mr. Ehlers
 
 647. Thank you very much.  I would like to add another point to this.  First of all, of course, what 
is at stake here is not the JECFA studies themselves but  rather the EC risk assessment, that is what we 
have to study.  But perhaps the question more lik ely should be whether since the 1999 study to now 
new information has come to light that would ques tion, undermine or require that a re-evaluation be 
made now in the light of new information that has a ppeared since that re-evaluation of 1999.  So this 
would be my question to everybody.  Has new information come to light, new studies, that would indicate that the basis for the 1999 re-evaluation has changed so much that a new evaluation is needed 
now?  Thank you. WT/DS320/R/Add.7 
Page G-104  
 
  Chairman
 
 648. Thank you.  In addition to that I am posing th is question to JECFA: whether or not the new 
data available in the 1999 assessmen t were publicly available since that  time?  In order to know what 
was the reason why the EC has not received all these data materials since that time. 
Dr. Wennberg
 
 649. Thank you, Mr. Chairman, but I think that we are in the wrong, reverse sort of situation here.  
It is not for JECFA to submit data to the EC, it's for the EC to submit data to JECFA if they want 
JECFA to evaluate anything.  So the data which are the basis for these perc entages that I was quoting 
before are available in the report of JECFA, so they are available to everybody and not only to 
JECFA.  That is the point of JECFA, to publish the evaluations. 
Chairman
 
 650. Does this include the new data that is not those produced in the 1960s and 1970s? 
Dr. Wennberg
 
 651. Well, as I now look at the reference list, many of these studies are from the 1980s and some 
are from late 1970s, some are not dated, but it's not true to say that they are all from the 1960s and 1970s.  But may I also say that even if they were older, if the methodology that was used, and if the 
methods had been validated properly, there is no reason to discredit any studies because they were 
done a long time ago. 
Chairman
 
 652. But my question was that JECFA said that new data were also reviewed and that all those data 
were publicly made available.  I am wondering wh ether those new data were also publicly made 
available.  If that is the case, then there is no reas on why the EC is continuing to claim that it has not 
received any new data other than  that from the 1960s and 1970s. 
Dr. Wennberg
 
 653. The data that was evaluated by JECFA in 19 99 as concerned the residues part are the data 
which had not been previously evaluated by JE CFA.  JECFA does not produce studies themselves, 
JECFA receives data from various sources, as we have explained before, from companies, from 
governments, from other institutions perhaps, and so what JECFA received and evaluated in 1999 was 
the complete residue dossier for these particular pr oducts, which are mentioned by name here in the 
report, from the Food and Drug Administration in the Un ited States to JECFA.  That was new data.  It 
does not mean that all this data was produced in 199 9, it means that the data was made available to 
JECFA for this evaluation, and there are studies fr om 1986, I read here in the reference list, 1979, 
1982, 1983, 1989 and so on and so forth.  I don't think I have to go further on this issue. 
Chairman
 
 654. Dr. Tritscher. 
Dr. Tritscher
 
 
655. I would like to add just some general comments.   As we have explained in our response to 
question No. 13, I refer to page 12 in our respon se, all documents from JECFA are published and are  WT/DS320/R/Add.7 
 Page G-105 
 
 
  publicly available in the public domain, all JECFA assess ments, and I think that is one of the features 
of JECFA, to write very detailed monographs with  very detailed descriptions of the database and 
complete references.  In general, all these documen tations are available within a timeframe from 8 to 
12 months after the meeting, as printed versions.  Due to this lengthy editin g and printing process, we 
make draft monographs available to interested partie s, to member states, based on requests, earlier if 
so done.  With respect to data that are looked at again, JECFA does not create data as such, it reviews 
data.  The call for data is always published approx imately one year ahead, so the planning for each 
JECFA meeting starts approximately one year ahead.  There is a public call for data out, where it is detailed very clearly what kind of substances are ev aluated, for what purpose and what type of data 
the Committee would want to have.  An d just posting things on the Inte rnet is a very passive way, so 
there are additional means of distributing this call for data, in particular through the Codex 
distribution lists.  Member States, parties here, they are all represented at the respective Codex committee meetings, and they do receive via this me ans also the call for data.  We cannot actively go 
out and retrieve, so it is the responsibility of the me mber States to provide available information, and 
that is then submitted to the secretariat, to the relevant expert and reviewed.  Thank you. 
Mr. Ehlers
 
 656. Yes, I would just like to make sure, since nobody answered specifically what I asked, I take it 
then that the answer is there is no new scientific information that would fundamentally change what 
was already analysed in the 1999 review.   
Chairman
 
 
657. EC. 
European Communities  
 658. Mr. Chairman, I don't think one can draw this c onclusion.  I think the scientists should speak, 
each and every one of them, on this question, be cause it is very important. There should be no 
conclusions by default, I would guess. 
Mr. Ehlers
 
 659. That is why I put in those terms to see if I could actually.. . 
European Communities
 
 
660. Could you put the question in a negative way so that we could also see the reaction of the 
experts, there might be another way of putting the question, please. 
Chairman  
 
661. Dr. Cogliano and the US and Canada. 
Dr. Cogliano  
 662. The way the conclusion was just summarized by the Panel would not be my conclusion.  We 
were not asked as experts to review all the scientific  data that has become available since 1999, so I 
cannot make a conclusion.  I certainly cannot make a conclusion that the data are sufficient for a new 
evaluation, or that the data are not sufficient for a new evaluation.  That is not what the experts were 
asked to look at.  I would say that it is normal that as new scientific data becomes available all 
different kinds of international bodies do take new looks  at the data every few years.  We have seen, I WT/DS320/R/Add.7 
Page G-106  
 
  think, the hormones were evaluated in the mid-1980s a nd then in 1999, so there seems to be that every 
10 years or so there might be an accumulation of new data that warrants a new evaluation.  But we 
were not specifically asked to look at the data and I don't think that any of us can really comment, or 
at least I cannot comment on the adequacy of the new data.   
Ms Orozco
 
 
663. But most likely you have received all the inform ation that has been submitted by the parties 
and drawn on the information that everyone has receiv ed from what has been submitted to the Panel.  
Is it your opinion that there is new information or is it your opinion from the review of all of that 
information that there is nothing new that merits a new assessment? 
Dr. Cogliano  
 664. Speaking from the monograph meeting on hormones last year, these are again birth-control 
pills and hormone therapies at higher levels, there did seem to be some emerging data on genotoxicity 
for these hormones at those levels of doses.  There seems to be lower levels of hormones in 
prepubertal boys than had been believed 10 or more  years ago, there seems to be data about what 
might be happening at extremely low concentrations that contribute to uncertainty of the dose-response curves.  Now whether those would fundamen tally alter the ADI or change any conclusions, I 
think that is why you convene an expert group to evalua te all of that, and I don't think, I wouldn't feel 
comfortable making a snap judgement, that it is or is not sufficient to conduct a new evaluation.  There do seem to be some new data but that's typical of all science.  Scientists take the current state of 
knowledge and ask the next question, and at some point the answers may change, but I don't know if 
we are at that point at this time.   
Chairman
 
 665. OK.  US. 
United States
 
 666. Thank you, Mr. Chairman.  I think I glean from the Panel's question that the Panel was asking 
about residue studies in animals and whether new da ta had been put on the record regarding that 
aspect of the EC's risk assessment.  I would like to ask the experts who have reviewed the data, has the EC put forward scientific evidence that supports the conclusion that previous residue data looked 
at by JECFA, for example, is no longer adequate or  sufficient to assess the risk of the three hormones? 
Chairman
 
 667. I will give the floor to the experts first and then EC. 
Dr. Boobis
 
 
668. To my knowledge I have not seen any new in formation on residues data on the hormones 
following their use according to good veterinary prac tice.  There have been some new data on their 
use according to abuse scenarios and we  need to discuss the relevance of  that later I assume.  But in 
terms of the standard residue package which form s the basis for a risk assessment, as far as I know 
there are no new data, and there are no reasons to beli eve that the data that JECFA evaluated were not 
appropriate for that purpose.  WT/DS320/R/Add.7 
 Page G-107 
 
 
  Chairman  
 669. Thank you.  Dr. De Brabander. 
Dr. De Brabander
 
 
670. Yes, Mr. Chairman, I think we all agree that there are no new data, and I just speak for the 
analytical part, the concentrations of the compone nts etc. are produced in the years 1980, 1986 maybe, 
and it is a fact that analytical methodology in the years from 1986 on until now increased considerably, and it is not only the limit of detec tion which is decreased but also the separation power 
of components.  You are able now to separate much more components from each other than in those 
days, and there are some examples, and I don't wish  to go into analytical details, but you separate 
components in what we call a chromatogram, a ser ies of peaks, and one peak can stand for one 
component but can stand also for two or three components, and if the analytical methodology improves, we see that suddenly a peak that was th ought to be one component can split into two or 
three, and you can have three other components with different properties.  I cannot, and it was not our 
job, and it is not possible just on paper, say the analytical data are not valid from that time, but you 
cannot be sure that they are valid because they are produced with methods which are not modern.  It is 
not because they were validated in that time that they are still valid, because validation is a continuous 
process each time, that's why we as laboratories have  to perform a new ring tests each year.  We don't 
like that, we have to do it to keep up our perform ance, otherwise you say we perform one ring tests, 
OK, we are good for 50 years.  That is not the case,  we have to do it consta ntly, improve our methods 
and constantly improve  our performance.   
Chairman
 
 671. US.  Is it directly related? 
United States
 
 
672. Dr. Boisseau has spoken of the issue of "old" da ta and whether "old" data is by nature bad 
data in his responses to the Panel's question.  I though that would be a good follow-up to 
Dr. De Brabander's response.   
Chairman  
 
673. EC. 
European Communities  
 674. Thank you Chairman.  So Dr. De Brabander, if I have understood well, you are saying that 
these data which are old, from the 1970s and 1980s, because we have new, more powerful and more 
accurate analytical methods, their validity is in  doubt because they are old and they have been 
measured with measurement methods which are by toda y's standards not credible, are not accurate.  Is 
that the conclusion? 
Dr. De Brabander
 
 675. That is my conclusion.  I cannot say that the data are bad, I don't say that, I just say you don't 
know that they are good, and you have to check th em with modern analytical methods, but nobody 
performs that; we will not do experiments with me lengestrol acetate because we don't have the means, 
we don't allow it and why should we do that, it is not our task. WT/DS320/R/Add.7 
Page G-108  
 
  Chairman
 
 676. Yes.  I would like to remind the delegations th at we have 30 minutes before lunch break, but I 
have not given the opportunity to the other delega tions so far to put their own questions.  I am 
wondering whether the EC has exhausted, or almost exhausted, their list of questions under area 3? 
European Communities
 
 677. We have not exhausted the ques tions Chairman, but I can consider that the delegations ask 
one of their questions and then we can take the floor, if you agree. 
Chairman
 
 
678. If you have – I see, OK.  Dr. Boisseau first. 
Dr. Boisseau   
 679. Thank you, Mr. Chairman.  I wish to speak very  briefly on the validity of the results obtained 
with methods that were used 20 years ago.  What the Commission said is true as regards the results 
that are at the level of the limits of detection of  the methods previously used.  But once the results 
obtained are clearly over the limits of detection, what counts is the precision of the method and its 
reproducibility.  The fact that the method used to provi de these results is old is irrelevant to the extent 
that they have been validated.  Indeed, we need only concern ourselv es with the uncertainty that we 
may have regarding the very low values at the le vel of the limits of detection.  Thank you. 
Chairman
 
 680. Dr. De Brabander, please. 
Dr. De Brabander
 
 
681. On an analytical point, I would agree with what Dr. Boisseau says on veterinary drugs and 
xenobiotic agents, but not for hormones which are al so naturally present and in the company of a lot 
of very similar components.  You force me to go into a technical question, but a lot of molecules have the same molecular mass, it means that they weigh the same, but they have different structures and 
they are not easy to separate.  So I know for a certain component like AED (androstenedione)  and 
beta-boldenone we have to do a special procedure,  separate them first in a liquid chromatogram and 
afterwards in a gas chromatogram, to separate  the two components from each other, because you 
cannot otherwise distinguish them.  That was tec hnically not possible in the 1980s, so again I do not 
say that the data are not correct, I cannot say that because I have not examined them.  You have got to be sure that you are correct, and it's not just the limit  of detection, it is also the specificity, meaning 
the separation power of components has increased considerable since that year.  
Chairman
 
 682. Dr. Wennberg. 
Dr. Wennberg
 
 683. I think that maybe this is the final comment on this issue with the analytical methods.  These 
methods which were used are also described in the report.  The methods that were used were 
radioimmunoassay methods, which are very specific fo r the compounds in question at the time that  WT/DS320/R/Add.7 
 Page G-109 
 
 
  they were used.  I don't want to go into the technical  details here, but I think it is for the parties to 
argue whether these data are acceptable or not.  For JECFA in 1999 they were evaluated and accepted.   
Chairman  
 684. I see all the experts are waving their flags, starting with Dr. Boobis. 
Dr. Boobis
 
 685. I just want to make a point about specificity an d that is the problem that Dr. De Brabander has 
just alluded to, which would in fact result in mo re conservative assumptions.  That is, if you have 
cross-reactivity of your antibody detection system with  something else, if that is not more potent than 
oestradiol or the analyte and it is hardly likely that it would be, then you over-estimate the residue 
present, so you are over-estimating your exposure.  So while it is true that modern, very sophisticated 
analytical methods might allow you more precise estimates, my prediction is that the specific analyte would go down, not up.   
Chairman
 
 
686. Thank you.  Dr. De Brabander, please. 
Dr. De Brabander  
 687. Yes, it is a possibility that concentrations go down,  but there is also a possibility that they go 
up by other means.  I had a colleague, I won't ment ion his name, neither the country, which has very 
very bad experience with radioimmunoassays.  They did a radioimmunoassay and they say that 
animals are positive.  They questioned the analysis , they did a separation and it was something else 
which caused a response on the radioimmunoassay.  Radioimmunoassays are indeed – selectively but 
you can have cross reactions, you can have systems where the concentrations go down.  Then I gave 
the explanation of modern methods, even in mode rn methods you have (in mass spectrometry, for 
instance) a phenomenon which is called ionization suppression.  It means that when the component 
goes into the machine, it is not ionized and you d on't see it and you underestimate the concentration.  
If you do a better  separation, that ionization suppr ession is gone and you see the component and its 
real concentration.  You have both: concentrati ons going down, concentrations going up, for modern 
methods corresponding with older methods.  But again I would say I would not comment that the data 
are not valid, I don't know, and we don't know if they are valid. 
Chairman
 
 688. Thank you.  Dr. Sippell. 
Dr. Sippell
 
 
689. I can only agree with what was just said, and this  applies particularly for the first period after 
birth.  For neonates, for infants and for young children a standard  commercially-available 
radioimmunoassay is not able to pick up the real concentrations, because there are numerous other 
cross-reacting steroids, for instance, that will really  obscure the real concen tration, for instance for 
oestradiol-17 β.  And therefore you have to do an extraction, you have to subject the extracts to a 
separation method, liquid column chromatography or  HPLC, and then you have to quantitate, you can 
do that by either radioimmunoassay or by a gas chromatography and I think at the moment the new 
development is tandem mass chromatography, wh ere you can have these separation procedures 
repeatedly and then, as Dr. De Brabander said, you separate many peaks and can quantitate them WT/DS320/R/Add.7 
Page G-110  
 
  accordingly.  And I think the analytical met hodology is consistently improving right now and 
therefore one should really look to the new data.   
Chairman
 
 690. Dr. Boobis. 
Dr. Boobis
 
 691. Mr. Chairman, the point has already been made that science moves on, probably in few areas 
more than analytical chemistry, where the advan ces in mass spectrometric techniques have been truly 
remarkable.  But I would like to put in a point of pr agmatism here.  It is not possible to re-evaluate the 
residues data of veterinary drugs and pesticides every year, or every two years.  The EU itself has a 
periodic review programme of pesticides which ta kes 10 years before a compound is rescheduled, and 
it probably takes longer because of the need to generate  the data, so we have to live with the methods 
that are available.  They have been validated, th e immunoassays that were used at that time were 
validated for their purpose, which is not to say that  there are not newer, better methods, but they were 
validated at the time, they were adequately fit for purpose.  I would make the point that a method that 
is used to measure low levels of oestrogens in in fants is a different question from a method that is 
being used to measure resides in food.  The analytical challenges are quite different and the methods 
that were developed in the 1980s for the residues were fit for that purpose, and that is what they were 
used for.  If you ask the question about the circulating concentrations, that is a different issue.  So in 
terms of the residues the methods were suitable.  We reviewed the data in 1999.  It would be 
unrealistic to expect a complete new residues data package to be generated over a period of a few 
years because analytical methods had advanced.  At an appropriate period of time in the future new 
data may be generated and it woul d not be unreasonable at that time to look again at the exposure 
data.   
Chairman
 
 
692. Thank you – OK. 
European Communities  
 693. But there are part of the file which the Eur opean Communities submitted to the Panel, and it 
is provided to you, Exhibits number 7 up to 43, among those Exhibits a number of papers precisely 
provide new data about the residues in meat fro m animals treated with these hormones for growth 
promotion.  But not only that, these new data have b een generated with the latest methods of detection 
and measurement,  the most recent ones to which Dr. De Brabander has made reference.  So then the 
question is why these new data which are available an d produced with the latest methods available are 
not sufficient to lead JECFA to do a new evaluation?  This is the first question.  And why would the 
European Communities, who has performed such a risk assessment on the basis of those data, be 
considered not to be part of the latest data availa ble that have to be taken into account, as were the old 
data of the 1970s and 1 980s which were submitted to Codex?  Thank you. 
Chairman
 
 694. Can I give the floor to Canada first and then to Dr. Wennberg? 
Canada
 
 695. Thank you, Mr. Chair.  I have a question for the experts who have been involved in JECFA 
and it is a question of clarification between the ty pe of data you use in a residue monograph and the  WT/DS320/R/Add.7 
 Page G-111 
 
 
  type of data you use in a toxicological monograph, and whether or not advancements in analytical 
techniques that relate to the type of data you w ould use in a residue monogra ph would have an impact 
on the data used in the toxicological monograph, which is the monograph from which the ADI is recommended.  So a distinction between the two types of dataset, the dataset you would use for a toxicological monograph and the data set you woul d use for the residue monograph, and whether or 
not advancements in the analytical techniques,  the types of studies you would do for residue 
monographs would have an impact on the type of  studies that are looked at in the toxicological 
monograph from which the ADI is derived.   
Chairman
 
 
696. OK.  Dr. Tritscher. 
Dr. Tritscher  
 697. Thank you.  Going back to the graph I put up yesterday, the toxicological evaluation and the 
residue evaluation and then the exposure assessment are two different parts of the risk-assessment 
procedure, and there are different datasets underlyi ng these procedures.  In the case of veterinary 
drugs, for the residue studies there are metabolism studies, residue-depletion studies and so forth in the food-producing animal, so it is a different speci es, we are talking about cows, pigs, for whatever 
purpose the specific veterinary drug is registered.  For the toxicological studies you have a completely different dataset and you look at normal test animal species, rodents in most cases, and in the case of the specific hormones we are talking about there were  a lot of human data that were looked at in a 
toxicological study.  There is some overlap, in  particular with respect to metabolism studies for 
comparative purposes.  If the metabolism is comparable in the test animal species, in the rodents, to 
what happens in the field, in the real applica tion of the veterinary drugs of the food-producing 
animals.  I think I will leave it with that. 
Chairman
 
 
698. Would you be quick please. 
Dr. Wennberg  
 699. First, I would like to respond to what the EC said about their data.  As far as I can consider 
from the JECFA secretariat point of view, as I menti oned before, there was never any request from the 
EC to have these data evaluated.  Secondly, it w as up to the scientific experts which were appointed 
by the Panel to review the exhibits which were submitted by the different parties, so that does not 
have anything to do with JEFCA per se .  And the final point I would like to make is that for the 
residue data that was evaluated in 1999, can I remi nd everybody that what was analysed was both the 
endogenous and the exogenous substances together, together with the metabolites that results from the 
elimination of the substances from the body of the animals, and there was no difference between what 
the natural production was as compared to what was ad ministered.  So there were quite high levels 
normally, so the point about low levels and more s ophisticated techniques in this sense does not make 
any difference to the evaluation, because the levels  were high in both cases and they were slightly 
higher in some instances when hormones were given,  but the background level was quite high in both 
the control animal and the test animals.  Thank you. 
Chairman
 
 700. Dr. Miyagishima, would you like to ...? WT/DS320/R/Add.7 
Page G-112  
 
  Dr. Miyagishima
 
 701. Thank you, Mr. Chairman.  I just wanted to make sure that the Panel is clear about the 
different roles of Codex and JECFA.  As far as Co dex is concerned, it has a built-in mechanism that 
would allow it to put in question the adopted MRLs, and in that case the procedure is through the 
inclusion of the compound in the priority list for re -evaluation.  And the initiative should be taken by 
a member, and it is not for the Codex secretariat or other parties to take the initiative.  Thank you. 
Chairman
 
 702. So having heard what the JECFA and Codex re presentatives mentioned, I think it is quite 
clear that it is for the members and not the secret ariat themselves to request the new data to be 
evaluated by JECFA, Codex, right?  That is quite clear.  Canada please. 
Canada
 
 703. Yes, that's fine, our question was adequately answered.  Thank you. 
Chairman
 
 704. So we have only 15 minutes to go before lunch break, but as I believe that a large portion of 
the EC questions have already been addressed, I will give the same opportunity to the US and Canada 
during the remaining time of the morning session and the afternoon session, and then come back to 
the remaining questions from the EC, if necessary, a nd others too.  OK.  I will give the floor to the 
US. 
United States
 
 705. Thank you, Mr. Chairman.  A question to the experts who have spoken on the issue of 
genotoxicity of oestradiol-17 β.  I wonder, does the scientific ev idence relied on by the European 
Communities in its Opinions support the conclusion that oestradiol-17 β is genotoxic in vivo  at levels 
below those associated with a hormonal response?   
Chairman
 
 706. The floor is open for comments from the experts.  Dr. Boobis. 
Dr. Boobis
 
 
707. I find it difficult to be persuaded that the evid ence indicates such, because we have to be clear 
that the question of the genotoxicity of oestradiol-17 β has been tackled in a number of different ways.  
Firstly, it used a variety of endpoints, a variety of test systems in vitro  and a variety of endpoints 
in vivo , but more particularly it has used precursor s of the presumed genotoxic metabolite.  Quite 
frequently what has been administered is not oest radiol, it's one of the metabolites or the quinone 
product to an in vivo  situation or even in vitro  situation, and it is those metabolites that have generally 
given some indication of a positive result.  Now it is my view that the genotoxicity of oestradiol 
in vitro  functions other than by a DNA reactive mechanism of the parent or metabolite, that it may be 
through redox cycling, generating reactive oxyge n species or per-oxidative products, and that as a 
consequence one can overcome in-built protective mech anisms of detoxication and repair by adding a 
high level, relative to the parent, a high concentration of the metabolite.  So what happens is that you 
bypass a de facto threshold by giving that metabo lite.  And that is in my view what happens in vivo  
when these metabolites give a positive.  These positives are not of, as I understand it, a mutational  WT/DS320/R/Add.7 
 Page G-113 
 
 
  response, they are a genotoxicity response, and so I would say that I have yet to be convinced that 
oestradiol 17 β at low concentrations is capable of producing a genotoxic response in vivo . 
Chairman  
 708. Thank you.  Dr. Guttenplan, please. 
Dr. Guttenplan
 
 709. There is recent evidence where they have detected the DNA adducts, that means damaged 
DNA products that have been produced from the reacti on of oestradiol with DNA in the urine.  As far 
as I know this data is only submitted for publication.   However, the levels are extremely low and I 
question whether such low levels have any signifi cance with respect to cancer-inducing properties.   
United States
 
 710. Thank you, Mr. Chairman.  As a follow-up, I think, to Dr. Guttenplan's comment, to the 
experts who have opined on this issue in writing, does the scientific evidence relied on by the EC in 
its opinions support the conclusion that oestradiol-17 β is carcinogenic at levels found in residues in 
meat from cattle treated with the hormone for growth promotion purposes? 
Dr. Boobis
 
 711. I can be very brief, Chairman.  I would say no, that I am not persuaded by the evidence 
presented that the levels present of oestradiol-17 β in cattle treated for growth promotion have the 
capacity to produce cancer in those so exposed. 
Chairman
 
 712. Thank you.  Dr. Guttenplan, please. 
Dr. Guttenplan
 
 
713. We were asked to comment on potential, and the potential is there, but I think I agree with 
Dr. Boobis that in actual practice or in actual situations the risk is minimal. 
Chairman  
 714. Thank you.  EC. 
European Communities
 
 715. Chairman, can I have a follow-up to a specific poi nt, just to clarify.  So is it correct to 
understand then that we cannot say that there is no risk, but the risk is small, minimal as you say, but the risk is not zero? 
Dr. Guttenplan
 
 716. The risk is not zero.  We really cannot calculat e such low levels, but it might be less than one 
in a billion.  But we were asked to calculate on potential, and I have a problem with that word 
potential in my responses.  So it is almost like sayi ng is it possible, yes almost anything is possible, 
but in a real situation – is it likely to occur at a significant level? – no.   WT/DS320/R/Add.7 
Page G-114  
 
  European Communities
 
 717. Thank you.  This is, I think, an important clarif ication.  Here we are talking about the residues 
from meat treated with hormones for growth promotion,  and the reply was that the risk is not zero, it 
is small and it cannot be evaluated.  So we are not talking about zero – I thi nk it is important to clarify 
for the Panel and then come back with the question.   In the previous panel which has examined the 
substances in 1998 there was another expert in th e place where you now sit by the name of George 
Lucier, and he made an evaluation at that time that  there would be a risk of one in one million from 
residues in meat, but then the subsequent Panel a nd Appellate Body reports said that his conclusion 
does not come from concrete exampl es, from concrete experiments he himself has conducted.  So this 
statement which has been made is very important.  The conclusion that the risk is not zero comes from 
residues in meat treated with growth hormones; it is small but we cannot calculate it.  Could you 
please confirm this. 
Dr. Guttenplan
 
 
718. Yes, that's right.  It is small, we cannot calcula te what it is.  I might also say that every time 
we cook meat we produce new carcinogens, so ever y time we consume meat we are increasing the 
possibility that we will get cancer from the meat, but the likelihood is very small.   
Chairman  
 719. Let me give the floor to Dr. Boisseau and Dr . Boobis and then back to the United States. 
Dr. Boisseau
 
 720. Thank you, Mr. Chairman.  Concerning this carcinogenic potential associated with the 
hormonal properties of oestradiol, we come back to  a general problem.  When  we carry out long-term 
carcinogenicity tests on animals, in order to be ab le to see anything, we have to use heavy doses 
which have nothing to do with the residue content in foodstuffs;  if we used quantities more or less 
similar to the residue content, we would see nothing at all.  In other words, as with the short-term 
mutagenicity and genotoxicity tests, we use high co ntents, and where there is a carcinogenic effect, 
we establish a relationship between the dose and the eff ect in the chosen experimental area.  Once this 
has been done, and if indeed there is a dose/eff ect relationship, the problem becomes complicated, 
because we have to extrapolate from this experime ntal area to small doses in order to figure out 
whether there is a threshold and to determine the poten tial effect associated with a small dose.  And at 
that point, we simply do not know what to do.  Consequently, the JECFA like other committees, uses 
the principle of the safety factor.  It is true that this  is rather a simplistic system, and the truth is that it 
is open to criticism, because depending on the slope of the effect/dose ratio, the same safety factor will provide different levels of protection.  Bu t, as Sir Winston Churchill once said about democracy, 
it may not be an ideal system of government, but the other systems are worse. 
721. Indeed, the mathematical extrapolation models wi ll give you very different results based on 
the same data, depending on the model chosen and the criteria taken into account.  So in the end, the 
pragmatic system that is used is worth what it is wo rth:  it may not be perfect, but it is just as good as 
many others.  Accordingly, when we say, as I have ju st heard, that when we have an effect/dose ratio 
following a carcinogenicity study and we cannot say that  the risk is zero at low doses, the fact is that 
we simply don't know, we cannot say that it exists, nor can we say that it does not exist.  So in order 
to protect itself and to protect public health, the JECF A opted for a safety factor of 1,000, in general, a 
figure which I think does provide guarantees – but we cannot make any claims, we cannot provide proof, nor can we cause alarm among populations, becau se in these cases we are not dealing only with 
hormones, there is all the rest, all the work that has been done by the JECFA for other substances, the 
work that has been done at the Eu ropean Union level, since everybody works in the same way.  So we  WT/DS320/R/Add.7 
 Page G-115 
 
 
  have to be careful about casting doubt on a genera l working method in the case of hormones, because 
there is no reason to stop at hormones.  We would have to cast doubt on everything that has been done 
over the past twenty years.  Thank you. 
Chairman  
 
722. Dr. Boobis. 
Dr. Boobis  
 723. Thank you, Mr. Chairman.  I wanted to make rather  similar points and I will be brief.  First is 
that my view is that the risk of cancer from the le vels of oestradiol in its use according to GVP as a 
growth promoter is such that it is not appreciable .  This is the definition of ADI, so I believe the 
threshold approach and safety-factor approach, wh ich is widely used for compounds which are not 
direct-acting genotoxicants, is appropriate for this compound.  And as Dr. Boisseau has pointed out, when we say not appreciable, it is because no risk as sessor worth his salt is going to say zero risk, an 
absolute guarantee of safety.  This underpins a ll risk assessment.  If the policy makers, the risk 
managers, would seek an assurance of zero risk, then they should provide the methods to generate that 
assurance.  These are not known yet and it is not clear to me how you would ever conduct a risk assessment and guarantee that, without ensuring zero e xposure, and of course that would cease all use 
of all compounds where there is any risk whatsoev er, and they all have some risk.  Thank you. 
Chairman
 
 
724. Thank you.  Let me give the floor to Canada be cause I have seen the flag being raised since 
long time ago. 
Canada  
 725. Mr. Chairman, if indeed the EC has a specific follow-up question rather than a running 
monologue and argument with the experts we can wa it for their question and then we will pose our 
own question. 
European Communities
 
 726. Thank you, Mr. Chairman.  It is not going to be a monologue but it's a precise question.  
Dr. Boobis, thank you for clarifying that non-appreciable does not mean zero, it is a small risk.  But 
supposing it is one in one million, supposing that will come from residues in meat treated with 
hormones for growth promotion in accordance with good veterinary practice.  Is this what you said? 
Dr. Boobis
 
 727. I would rather that words were not put in my m outh, Chairman.  I tried to give my answers as 
precisely as possible, I hope they were clear.  What I said was that there was a very low risk, I did not 
say it was one in a million, it could be much less than that. 
European Communities
 
 728. But it is not zero. WT/DS320/R/Add.7 
Page G-116  
 
  Dr. Boobis
 
 729. I am talking about a potential, not necessarily a real risk, I am saying we cannot give an 
absolute assurance of the absence of risk.  If that was possible I would be very enthusiastic that a risk 
manager would provide the methodology where that could be done for any compound whatsoever.  It 
is the underlying principle of all risk assessment, within the EU and within JECFA and within all 
other organizations that conduct risk assessment of ch emicals.  I will not go into the details of risk-
assessment methodology here, but one of the questi ons was did they use state of the art risk-
assessment approaches at JECFA, an d the answer is yes we did, and those approaches are still 
generally accepted worldwide as the most appropriate  way of evaluating the risks of compounds to 
which humans are exposed.   
Chairman
 
 730. Thank you.  The floor is for Canada now. 
Canada
 
 
731. Thank you, Mr. Chair.  Recalling the discussion of yesterday about the components of the risk 
assessment, and in particular the circumstance s in which a dose-respon se assessment should be 
conducted.  As a result of the absence of evidence th at several experts have just indicated about the 
genotoxicity of oestradiol, is it your opinion that  a dose-response assessment s hould be conducted in a 
risk assessment of oestradiol in this case.? 
Chairman  
 732. Dr. Boobis and then Dr. Boisseau. 
Dr. Boobis
 
 
733. Based on the weight of evidence evaluation of the genotoxicity of oestradiol – and I just 
wanted to clarify a point, I don't think that anybody on this side of the table has denied that oestradiol 
is an in vitro  genotoxicant, there is no good evidence that it is mutagen, but it is certainly a 
genotoxicant in vitro  – but based on the weight of evidence, th e view certainly of JECFA was that that 
was due to a mechanism likely to have a thres hold and therefore it would be appropriate and 
necessary to conduct a dose-response analysis of the in vivo  responses, because any underlying 
mechanism would have a threshold in  the view of the experts present. 
Chairman  
 734. Thank you.  Dr. Boisseau. 
Dr. Boisseau
 
 
735. Thank you, Mr. Chairman.  Let me just say a few words on the zero risk concept mentioned 
by the Communities.  I merely wish to recall that, at least as concerns substances that are authorized 
and deliberately included as additives or as veterinary drugs, i.e. administered to animals, this zero 
risk concept was abandoned at least 20 years ago.  It is valid today only for prohibited products for 
which, indeed, the most sensitive analytical method must  be used to ensure that there is no fraud.  So 
if I understood properly, as regards oestridiol and the carcinogenic risk associated with a hormonal 
effect, it is thought that extrapolation to low doses do es not enable us to eliminate the least risk;  but 
in that case, I repeat what I already said this morni ng, we must not lose sight of the characteristics of 
oestradiol, to name but one hormone, which is not a xenobiotic but for which part of the residue is a  WT/DS320/R/Add.7 
 Page G-117 
 
 
  natural result of the physiology of animals.  So th at if we infer that zero risk for the most minute 
quantities or oestradiol residues does not exist, then  once again, what are we speaking of?  Should we 
prohibit the consumption of bovine meat on the gr ounds that without treatment it will make a 
contribution in terms of oestradiol that could, if  I follow this reasoning, generate a risk, however 
minute, but in any case not zero?  Once again, even if  we forget about the administration of oestradiol, 
the risk, however small, already exists in normal meat .  We must bear this is mind, and this involves a 
quantitative evaluation of the risk, since even where oestradiol is not administered to animals we 
would – and I say this in the conditional tense – be exposed to that risk. 
Chairman  
 
736. I will give the floor to Dr. Tritscher and Dr. Boobis. 
Dr. Tritscher  
 737. Thank you.  I would like to make some genera l remarks and clarifications regarding dose-
response assessments.  The point to differentiate he re is what we discussed already yesterday, I am 
sorry if I repeat something, but the differen ce between a qualitative and a quantitative dose-response 
assessment.  A quantitative dose-re sponse assessment requires extrapolation to the low dose range 
outside of the observed experimental studies.  And this extrapolation down to low exposure levels 
requires a number of assumptions that go into a mathematical modelling to describe the shape of the dose-response curve in the low exposure range.  And if this is possible or not with a reasonable level, 
an acceptable level of uncertainty and acceptable leve l of assumptions that go in, totally depends on 
the data that are available.  It is not depende nt on the compound, it is exclusively dependent on the 
quality and appropriateness of the data as a first instance.   In this context I would like to point out that 
there is a lot of discussion regarding dose-res ponse assessment and low-dose extrapolation in 
particular.  And the International Programme on Chem ical Safety has held an international expert 
consultation on dose-response assessmen t in general, and the experts define a six-step procedure for 
dose-response assessment where the fi rst, maybe the first three, I don't have the exact layout now in 
my head, but the first three are in line, they en d with the NOAEL and the ADI, because this is a dose-
response assessment where no extrapolation to the low dose range outside the observable range is 
done.  But then, depending on the quality of the da ta, the reliability of the data, you can do low-dose 
extrapolation.  However, any low-dose extrapolatio n is mathematical modelling, it's the best-guess 
estimate.  But this would allow a quantitative estimate of a risk, again, a quantitative estimate of a risk 
at a certain exposure level.  But to achieve th at quantitative dose-response assessment, you have to 
have the appropriate data, and I do  not believe that in the case of the hormones the appropriate data 
are there.   
Chairman
 
 
738. Thank you.  Dr. Boobis. 
Dr. Boobis  
 739. I just wanted to emphasize this generality of the acceptability of the concept of no zero risk.  
This is the EMEA's definition of an ADI for est ablishing maximum residue levels of veterinary 
medicinal products in foodstuffs of animal origin al, exactly congruous to the issue we are talking 
about.  The ADI is the estimate of the residue, e xpressed in terms of micrograms or milligrams per 
kilogram of body weight, that could be ingested daily over a lifetime without any appreciable health risk.  So the EMEA, an organ of the European Unio n, has apparently not been able to come up any 
more than we have at JECFA or anybody else h as, with a methodology that can guarantee the absence 
of any risk.   WT/DS320/R/Add.7 
Page G-118  
 
  Chairman
 
 740. Quickly, very quickly. 
European Communities
 
 
741. Well, for the benefit of Dr. Boobis I should cl arify the EMEA is just a sub-organ of the 
European Commission and it evaluates the substances for therapeutic treatment only, not for growth 
promotion.  So this statement has no relevance wh atsoever for the residues of meat treated with 
hormones for growth promotion.  This is the role of EFSA.  But Chairman if you allow … 
Dr. Boobis  
 
742. Does that mean that we can have zero risk in other circumstances, and could I ask the EC to 
provide a reference to where the methodology is so that I can apply it in my work? 
Chairman  
 
743. Excuse me, it is already five minutes past 1 o' clock and the interpreters won't be available 
from now on, so if you all agree, then, shall we resume our discussion in the afternoon with more 
questions by the US?  The meeting will start at 3 pm here in this room. 
28 September 2006, afternoon  
 
Canada  
 
744. Chairman, I have a point of order to make, and th e point of order arose as a result of the brief 
display of what appeared to be a new piece of evidence on the projector.  As I think I mentioned yesterday, we have seen this exercise as the Panel' s chance to explore the issues to the extent possible 
with the experts.  We have already exchanged thro ugh letters and through cl arifications with you how 
we thought we might proceed, particularly in respect of the kind of argumentation and evidence that 
might be put before you, and you have already prov ided that answer and you have reiterated that 
answer yesterday morning.  Over the last two days I think we have exercised considerable restraint in 
raising procedural objections whenever we have ha d statements more in the nature of arguments 
rather than questions; but I think it really is importa nt to keep on track.  What was on the screen we 
have not seen before, to that extent it is new ev idence, and if the EC proposes to put forward new 
evidence, then we want a ruling from you that that provision of new evidence is simply not permitted.  
You have already provided that, you have already str essed that yesterday, and at this point I think it 
should go beyond a reminder, and it should be a ruling from the Chair.  Thank you Sir. 
Chairman
 
 
745. Thank you.   
European Communities  
 746. I would like to make a point.  This point can be made orally, it can be made better by means 
of a diagram, and it is in response to comments made by scientists this morning, it is not new evidence.  If the Canadian delegation thinks that this will be considered as new evidence they have 
not seen, we can make the point orally.  We thought th at this way it was easier to understand the point 
which we would like to make.  And it is in response to  what has been said by scientists, so we are not 
submitting new evidence; it is the natural development of the dialogue in this room that we would like  WT/DS320/R/Add.7 
 Page G-119 
 
 
  to make this point.  As I said, we can make it or ally, we can make it through diagrams so everybody 
understands what one of our scientists said.  That's all. 
Chairman  
 747. Thank you.  US has the floor first and then Canada. 
United States
 
 748. I would just make a quick point, Mr. Chairman , and then I am happy to move on with our 
questions as well.  It is hard to say that a piece of  evidence is responding to a question when there is a 
prepared power point slide, and I think, whether the ev idence is oral or via some visual aid, I have to 
support the discussion of Canada on this issue. 
Chairman
 
 749. Canada. 
Canada
 
 
750. Thank you, Mr. Chairman.  I wish to underline that a point presented by scientific experts on 
the European Commission delegation is either expert t estimony or it is new evidence to the extent that 
it is there to challenge what the scientific expert s of the Panel have put forward.  If the EC has a 
question to ask on the basis of what is on the record it may do so, but if it is a new point, then it is either extra testimony by the EC's delegation, or ne w evidence, and that is not permitted.  Thank you, 
Sir. 
Chairman
 
 751. OK.  EC. 
European Communities
 
 
752. Maybe a point of clarification to the Canadi an delegation.  The Canadian delegation was 
referring to a paper quoted by Professor Sippell this morning, of 2001.  I am not aware of this being 
on the record.  Maybe Canada wants to comment on this. 
Chairman  
 
753. US. 
United States  
 754. The paper by Dr. Sippell was actually cited in the US comments on the experts' comments, so 
it is on the record. 
Chairman
 
 755. Yes, you have the floor. WT/DS320/R/Add.7 
Page G-120  
 
  European Communities
 
 756. Professor Boobis this morning has made a reference to a new paper by Klein, which we didn't 
know, and we have now found the data.  Are we not allowed to make a comment on that?  I don't 
understand what is the purpose of this meeting if  we cannot comment upon something which has just 
been referred to. 
Chairman
 
 757. Before I answer that question, would you r espond to the point made by the Canadian 
delegation just before, whether it is  a testimony of the experts of the EC delegation or new evidence? 
European Communities
 
 758. Chairman, it is neither of the two.  It is just a question through a means of presentation, or 
made orally; it is neither new evidence nor extra testimony. 
Chairman
 
 
759. So, with that understanding, would Canada and the US delegation agree to the EC delegation 
moving on with their oral presentation on whatever issues they have, with or without the videotape screen? 
Canada
 
 
760. Two points, Mr. Chairman.  I understand first of a ll that as a matter of procedure I think the 
US is going to go next in questioning.  It's impos sible in advance of hearing the question to say 
whether we agree with the question as either expe rt testimony or a quote, unquote point.  I don't know 
what that means.  But very simply, if a point is be ing raised from outside of the record to question or 
to impugn what the experts have said, and we have not had notice of it, then we cannot respond to the 
point that is being raised by EC.  That is the whole point of the procedural rules that are in place.  So 
all I can say is that for your benefit, and to allow the process to go forward, we  can agree to hear the 
question.  We will reserve however our right to raise a point of procedure and then at that point to ask 
you to disallow the question.  If that would help the process to go forward we will go along with that.   
Chairman  
 
761. To my understanding, whether to take a cert ain argument or presentation of the views or 
materials as evidence is up to the Panel.  I don't know  whether we as a Panel have to make a ruling on 
that procedural point at this particular point in time, but whether to accept it as evidence or argument 
or whatever will be decided by the Panel.  So in order to prevent this process from being suspended or 
interrupted I hope the EC delegation will be very clear  on this point so that US and Canada can agree 
on proceeding from here on.  Would you further clarif y on the point made by the Canadian delegation 
once again. 
European Communities  
 762. Chair, to be deadly honest with you, I have not fully understood the point.  Is the Canadian 
delegation saying that the EC cannot make its own experts or part of the delegation intervene to 
provide a scientific view on issues that have been discussed here?  Thank you.  WT/DS320/R/Add.7 
 Page G-121 
 
 
  Chairman  
 763. I don't think that is the point.  Canada has the floor. 
Canada
 
 
764. I agree with you Mr. Chairman, that is not the point. 
Chairman  
 765. EC. 
European Communities
 
 
766. Would the Canadian delegate care to restate his point please.   
Canada  
 767. Mr. Chairman, it's very simple.  We see some thing on the display we have not seen before; 
the other experts here have not seen it before; we ca nnot respond to that.  Now whatever it is, a point, 
piece of evidence, argument, expert testimony by one of the experts, we have not seen it before; we cannot respond to it.  I don't know if the experts have  seen it before.  Something is being brought into 
this process from outside of the record and that is the simple point that we are making.  If the experts 
on the EC delegation hear something that the Panel's experts are saying and they disagree; if there is 
something that they have said that does not fit w ithin the record, then they impugn that, but they 
cannot bring in something that they have not seen before, that is simply not in accordance with the 
rules. 
European Communities
 
 768. Before you rule, can I provide a way out.  We  don't insist, we don't want to delay these 
proceedings any more, so we will not show this slid e, but we would appreciate if we had the time later 
on for one minute to make the point orally, like we  have been making comments orally the whole day 
yesterday and today, and we have not seen the comments nor heard Canada's comments and the arguments they were going to make orally either, we don't know what they are going to say now.  We are in the same situation.  So just to avoid the pr oblem and avoid any delays, we are not going to show 
the slide in this instance to please and satis fy the Canadian delegation.  Thank you. 
Chairman
 
 769. I think that is a quite positive response from th e EC delegation, and I would like to remind all 
the delegations that the purpose of this meeting, as I mentioned in my opening statement yesterday, is 
to get the advice of the experts which the Panel has invited, for the Panel to get their understanding of 
the scientific and technical issues at hand.  In that c ontext, I think we are here to pose any questions or 
comments to the experts to get their understanding a nd advice, not in the form of a presentation of 
materials on evidence or whatever you may call it, so I hope delegations in putting questions do not 
get into the kind of exercise of presenting new evid ence or new materials or new data.  With that 
understanding, can the US and Canadian delegations  agree that the EC delegation may have the 
chance to make their point a little bit later during our discussion this afternoon.  And I will give the 
floor to the US delegation, as I mentioned this morning, because we have been stopped during our 
discussions when the US delegation was posing th eir questions.  OK.  US, you have the floor. WT/DS320/R/Add.7 
Page G-122  
 
  United States
 
 770. Thank you, Mr. Chairman.  Continuing on with the questions, I would like to shift gears and 
discuss the five other hormones at issue in these pro ceedings.  To the experts with experience in risk 
assessment, who spoke on this issue in their answ ers:  does the scientific evidence relied on by the 
European Communities in its opinions support the conclusion that it is not possible to complete a risk 
assessment for those hormones? 
Chairman
 
 771. The floor is open for comments or responses from the experts.  EC. 
European Communities
 
 772. Thank you, Chairman.  It's a question of order, I think.  This is a risk management question, I 
think.  This question, as it is posed, requires the scien tists to say whether as ri sk managers we can do a 
risk assessment.  I don't have any objections that the US poses this question, but he needs to pose it as 
a question addressed to risk scientists during the ri sk assessment, not to the risk managers.  Thank 
you. 
Chairman
 
 773. Before giving the floor to the US, let me ask the experts whether they have any views or 
comments on this point.  The question was posed to the experts first.  Dr. Boobis.  
Dr. Boobis
 
 774. I cannot speak for the EC, and I think what has ju st been said is quite correct.  I can speak for 
JECFA in which I participated, and in our view we had enough information to complete a risk 
assessment.  I don't know if that is helpful, but that  was the situation when we looked at the available 
data on those five other hormones. 
Chairman
 
 775. Thank you.  Dr. Cogliano.   
Dr. Cogliano
 
 
776. I think the way I would look at questions like th is is that it is possible to complete risk 
assessments up to a certain point.  IARC could do assessments of those, but IARC's risk assessment 
stops with the hazard identification and a stat ement about whether or not these hormones are 
carcinogenic.  JECFA's assessment then continues to develop an ADI, which involves looking at the 
animal studies, selecting the dose where they thin k there are no observed adverse health effects, 
considering everything they can and dividing by safet y factors.  That's another more detailed risk 
assessment than IARC does.  A further level of de tail in risk assessment would be to do a dose-
response curve down to lower doses and try to predic t what would happen at very low levels, what 
would be increased risk, if there is any.  And I thi nk most people here have been very reluctant to say 
that you can extrapolate the dose-response cures and get any kind of precise level.  So I think when 
we sometimes say can you complete a risk assessme nt, I think you cannot just say a risk assessment, 
but a particular type of risk assessment.  I think you can complete a risk assessment that's an ADI 
style of risk assessment, you cannot complete a risk  assessment that's a fu ll dose-response curve and 
try to get a prediction of risk at very low exposure levels.  WT/DS320/R/Add.7 
 Page G-123 
 
 
  Chairman  
 777. OK.  US. 
United States
 
 
778. Then perhaps a good way to follow up would be  to ask: does the scientific evidence relied on 
by the EC in its Opinions support the conclusion th at any of these five hor mones is carcinogenic at 
levels found in residues in meat from cattle tr eated with the hormones for growth promotion 
purposes? 
Chairman  
 
779. Dr. Boobis. 
Dr. Boobis  
 780. My view would be that, given the information th at was available, it would have been possible 
to conclude that there was no evidence that at the levels present in meat these compounds would 
represent a risk of cancer in individuals so exposed.   
Chairman
 
 781. Thank you.  Any other comments?  EC. 
European Communities
 
 
782. Chairman, I would not like to ask a question now, but would I have the chance to cover this 
point later on, if you allow me, so that I give the chance to the Canadian delegation to continue? 
Chairman  
 
783. If it is a one-time question then I would give th e floor to the EC delegation now, but if you 
have to continue on then I will come back later.   
European Communities  
 784. Well, I think we would like to ask Dr. Boobis a nd eventually the other scientists to clarify 
what kind of risk we are talking about.  Is it the same as we were talking before, no appreciable risk, 
or no risk at all?  I don't want necessarily to come  to generate all this discussion again, but we argue 
that here we are not talking about a theoretical risk , we are not talking about zero risk, we are talking 
about a risk which has not been measured, which is diffi cult to quantify.  This is the point and this is, I 
think, useful to clarify because there are different legal regimes that we apply for oestradiol and the 
other five hormones.  Thank you. 
Chairman
 
 785. Dr. Boobis. 
Dr. Boobis
 
 786. In the case of the five hormones and oestradiol, the risk we are talking about is based on a 
view that there is a threshold for any carcinogenic response and therefore it is possible to apply the WT/DS320/R/Add.7 
Page G-124  
 
  safety-factor approach widely used in the determ ination of an ADI, and whatever the ADI definition 
is by whoever wishes to set it, these compounds fall  into that category.  I will not use the words no 
appreciable risk because it has been  persistently misrepresented.  
Chairman
 
 
787. Thank you.  US. 
United States  
 788. Thank you, Mr. Chairman.  I only have a c ouple more questions.  To the experts who 
evaluated the EC's risk assessment, does the scientif ic evidence, including epidemiological studies put 
forward by the EC in its opinion, support the conclu sion that other human health risks, such as effects 
on the immune system, are posed by consumption of residues of these five hormones in meat from cattle treated for growth promotion purposes?   
Chairman
 
 
789. Before I give the floor to any experts I saw Dr. Guttenplan raising his flag before.  I give the 
floor to Dr. Guttenplan. 
Dr. Guttenplan  
 790. With respect to the five additional hormones, if we said that there is no appreciable risk from 
oestradiol, then the five other hormones have a much less than appreciable risk, because I see no 
evidence in whole animal studies that any of tho se compounds have genotoxic or carcinogenic effects. 
Chairman
 
 791. I will give the floor to Dr. Boobis first. 
Dr. Boobis
 
 
792. Chairman, if there is a follow-up to that, I was going to answer the next question.   
Chairman  
 793. Is Dr. Boisseau going to answer the question now  or is it related to the question put forward 
by the US. 
Dr. Boisseau
 
 794. Thank you, Mr. Chairman.  I simply wanted to  associate myself with what was just said 
following the question by the Communities, so that there is no need to repeat what Dr. Boobis said 
concerning the conditions for establishing an ADI thr eshold.  However, there is an additional safety 
factor which Dr. Wennberg spoke of this morning, I th ink, namely that the exposure of a consumer to 
residues is considerably less than  the dose that would be acceptable in terms of the ADI.  In other 
words, we must not forget that asi de from the safety factor that has been determined and that is used 
to determine an ADI, there is another safety factor, since the dose, the TMDI, th e dose that is in fact 
ingested, is far lower – somewhere around 4 per cen t for oestradiol – than the dose that would be 
tolerated in terms of the ADI.  We must not forget this other safety factor which minimizes the risk, if 
indeed there is such a risk.    WT/DS320/R/Add.7 
 Page G-125 
 
 
  Chairman  
 795. I am wondering whether there is any other expert  who is ready to respond to the US question, 
not the EC one.  US. 
United States
 
 
796. I would simply reiterate, Mr. Chairman, my other question, Dr. Boisseau and Dr. Guttenplan 
spoke eloquently to the issue of level of risk.  But as to whether the EC has actually produced any 
scientific evidence that supports a conclusion that any of these five hormones are going to pose other 
health risks when used for grow th promotion purposes in cattle.   
Chairman  
 797. Thank you.  Dr. Boobis. 
Dr. Boobis
 
 
798. I have seen no evidence that from the levels pr esent in meat following the use of the five 
hormones according to good veterinary practi ce, that there is a risk to human health. 
Chairman  
 799. Thank you.  Any other expert wishes to respond?  EC. 
European Communities
 
 
800. Chairman, I think now is probably the point we would like to make with the diagram, we can 
make it orally on this precise question, so inst ead of making it later on, probably you will give us a 
minute or two to make this question; it relates to this precise point. 
Chairman  
 
801. Can I ask the EC delegation to do that in the fo rm of posing questions rather than giving a 
presentation? 
European Communities  
 802. My name is Frederik Vom Saal and I am a professor of biology at the University of Missouri.  
I appreciate the opportunity to address the Panel and the experts, and the first issue relates to what was 
just said, and I would like to ask Dr. Sippell who work s with the system a question.  We see in animal 
studies that very small differences – and when I say small in terms of free oestradiol levels 0.05 parts per trillion, that is 0.05 pictograms per ml of oestra diol – are related to differences in prostate size in 
animals, and it suggests that very small background di fferences in oestrogen ar e related to differences 
between individuals, and we know th at individuals have different le vels of oestrogen and different 
response to them, and when we give extra oestroge n to these animals, the amount of response of the 
animal is greater in the animal with the greatest amount of background level of oestrogen, and that 
shows that there is in fact no threshold, because the endogenous amount of hor mone is already above 
the threshold and the added amount of hormone in  again a phenomenally small amount, below a part 
per trillion, is detectible against this very sm all background amount.  So I would ask Dr. Sippell 
whether he really believes that when you are eating meat that has oestrogens in it, is the background 
level against which it is operating to be considered  zero the way it is in a typical risk assessment in 
calculating an acceptable daily intake, or is the en dogenous amount already above threshold and any WT/DS320/R/Add.7 
Page G-126  
 
  amount added to that is just going to add to the ri sk and the types of effects caused by the endogenous 
hormone?  Is this a question that you can answer? 
Chairman
 
 803. Dr. Sippell. 
Dr. Sippell
 
 804. It is, of course, difficult to answer such a qu estion as a clinician, but from the experience we 
have with the low levels, I mentioned this several  times before, with the extremely low levels that 
have been measured by these new recombinant assays, it is conceivable really that this extra burden of 
oestradiol poses a risk to very small children and par ticularly prepubertal boys, and this is in line with 
the very very high sensitivity of prepubertal child ren to oestrogens induced for other purposes.  I 
mean, lets say, I mentioned the example of Turner  girls, whom you treat with really minute amounts 
of oestradiol. 
Ms Orozco
 
 
805. I would like to take advantage of your knowle dge to pose a question.  If such minute amounts 
of additional oestrogens create an appreciable or more than appreciable risk in your view, why we 
don't we seem to see effects in prepubertal children or at a later stage in their lives from eating eggs, 
meat and milk? 
Dr. Sippell  
 
806. That's actually an excellent question.  One of the important parts of the answer to that is to ask 
whether there have been changes in human health trends over the past 50 years associated with the 
beginning of the use of the very large number of di fferent types of estrogenic chemicals that children 
are now exposed to that they weren't before World War II when most of these chemicals began to be 
used.  And if you look at human health events such as breast cance r and related diseases (for instance, 
gonadal cancer, genital malformation). 
Ms Orozco  
 807. So that we talk about the same things, I am not talking about chemicals and residues of 
chemicals, but I am talking about the hormonal comp onent that it is naturally present in food derived 
from animals.  
Dr. Sippell
 
 808. I guess my response to that would be that they are part of a mix of additional chemicals that 
humans are exposed to now that were not being used  40 years ago, and it is not really possible, for 
somebody in epidemiology for instance, to state the added risk, the increase in  the incidence in breast 
cancer, in prostate cancer, in obesity  – all of the types of things that are related to oestrogen are only 
associated with one particular source, but each of these sources of oestrogen increase the risk.  Each 
of them independently and they ad d together, and everything you do to reduce one of those sources of 
risk reduces the overall risk.  So the answer to your  question is the evidence from human health trends 
that practically every oestrogen-related disease has in creased, associated with the use of these types of 
chemicals in products.    WT/DS320/R/Add.7 
 Page G-127 
 
 
  Chairman  
 809. I will give the floor to Dr. Boobis and Dr. Sippell and Dr. Boisseau to respond. 
Dr. Boobis
 
 
810. Mr. Chairman, just in the interest of clarity I would like to make a brief point, which is that 
the issue of the effects of endocrine disrupting chem icals found in our environment is one of the most 
complex and controversial issues in biology today.   There is absolutely no clear consensus among 
scientists; very reputable scientists have different pe rspectives because the heterogeneity of the data is 
extreme.  There have been a number of internati onal respected reviews which have reported that they 
could find no direct evidence of harmful effects.   I recognize that the absence of evidence is not 
evidence of absence, which is why I choose my words carefully, but I just wanted to say that we are 
opening up a very major issue which, as an expert  on this group, I have not had the opportunity, nor 
was I asked, to explore in response to the questio ns addressed.  I would also add that it does not 
appear to me that the EC used  such a consideration in their risk assessment; I can find nowhere 
reference to some of these papers which were published prior to the EC risk assessment.   
Chairman  
 811. Thank you.  Dr. Sippell. 
Dr. Sippell
 
 
812. In view of the fact that we just lack epidem iological studies in children eating normal meat to 
be compared with those eating hormone-treated meat, we can at the moment rely only on indirect evidence.  And if we talk to our American paedia tric endocrinology colleagues, they always report us, 
and this has been published, that the mean age of st art of puberty in girls is lower in the United States 
– particularly in the not so well-off children, pa rticularly those from black background and Hispanic 
background – than in Europe.  Everybody here in the room knows that the problem of childhood 
obesity is the highest in the United States on earth, and it is increasing in Europe now, but luckily at a 
lower rate, and there are some other not so obvious indirect pieces of evidence.   
Chairman
 
 813. Thank you.  Dr. Boisseau. 
Dr. Boisseau
  
 814. Thank you, Mr. Chairman.  Just a question for the scientist who spoke for the Communities.  
He said that there was a trend revealed by an epidem iological study.  In his view, is there an actual 
correlation between this trend and the use of gr owth hormones in the country of which he was 
speaking, given that over the past 20 years, although consumption of meat has been steadily 
increasing, people have been living longer and longer?  Is the epid emiological study to which he 
refers discriminating enough to be able to estab lish a correlation between the observed effect and the 
cause?   
Chairman
 
 
815. EC. WT/DS320/R/Add.7 
Page G-128  
 
  European Communities
 
 816. That's an interesting question.  Of cour se in many epidemiological studies establishing 
carcinogenic effects is very difficult.  But one of the important issues is that associated with the use of 
these chemicals.  There have been very recent trends , such as what was just pointed out by Dr. Sippell 
– a change in the incidence of puberty which is clea rly oestrogen driven, and changes in obesity that 
have been related to oestrogen.  And so associated with the use of these chemicals in beef we do have 
public-health data that suggest an increase in inci dences of abnormalities, and again I agree with 
Dr. Boobis, the absence of evidence cannot be taken as evidence for the absence of harm, and we have 
to be careful when studies have not been done to assume that that means that there is no effect.  
[change of speaker.] Chairman, for the benefit of Dr . Boobis, can I refer him to our risk assessment of 
1999, it is on page 20 of our risk assessment, unde r sections 2.3.2.3, where precisely Professor Vom 
Saal is cited for his research in the risk assessment,  his name appears in the risk assessment, and there 
is precisely the title of this section is called "The  Issue of Dose", and we go through this argument in 
our risk assessment, so it is not true that we have  not included that in our risk assessment, and it goes 
on for two pages.  It is on page 20.  Thank you. 
Chairman
 
 817. Dr. Boisseau would like to have the floor. 
Dr. Boisseau
  
 
818. Thank you, Mr. Chairman.  Just a quick word on what Dr. Sippell said concerning the clear 
trend towards obesity among children in the United Stat es.  He also pointed out that the situation was 
getting worse in Europe, in the countries where growth hormones are prohibited and are not used.  This brings me back to my question concerning the capacity for discrimination of epidemiological 
studies, since under two different systems – an Am erican system where growth hormones are used 
and a European system where they are not used – we note that when it comes to obesity in children 
there may be a delayed effect in Europe, but the trend is similar.  
Chairman
 
 819. Dr. Sippell. 
Dr. Sippell
 
 
820. But the obesity trend in Europe is at a much  much lower rate, so the data from the (US) 
Centre for Disease Control – I think most of you are familiar with that map of the United States, 
where year by year the colour is getting darker in almost every state of the United States, in virtually 
every state.  If you compare this with Europe, the rate of progression is much higher (in the USA).   
Chairman  
 821. Before we further proceed, as I mentioned, given the time constraint I may not be able to give 
you a coffee break during this afternoon's session, but fo r your information, the snack bar will be open 
for services for us from 5 to 5.30 so please feel fre e to get coffees during our conversations.  OK.  
And for your information, three of our experts have  to leave this evening by 7 o'clock so I hope we 
can conclude our discussions by 6, but not beyond 7 o'cl ock at all.  With that I will give the floor to 
EC.  WT/DS320/R/Add.7 
 Page G-129 
 
 
  European Communities  
 822. Chairman, we have promised to the Panel that we  will do our best to finish indeed by the time 
you have alluded to, but there may be questions we really would like to ask, and you appreciate that 
this is an important occasion to clarify these issues.  If we don't manage by then, what are we going to 
do? 
Chairman
 
 823. So that I hope all the delegations will cooperate  with the Panel and experts so that we can 
complete the discussions before some of the experts leave.  Without your full cooperation we cannot 
finish our business. 
United States
 
 824. Shall I continue with questions, Mr. Chairman? 
Chairman
 
 
825. Please, US, go ahead. 
United States  
 826. I only have one more question, actually, to keep things short, and it was interesting that there 
was a long debate on oestradiol when the questi on I asked was about the five provisionally banned 
hormones, and they are not involved in this debate  whatsoever.  To the experts who have opined on 
this issue, do any of the scientific materials presente d by the EC in its opinions support the conclusion 
that bovine ears containing hormone implants enter the human food supply in the United States?  If 
so, what is this evidence? 
Chairman
 
 
827. Can I ask any of the experts to respond.  There seems to be none 
European Communities  
 828. Is it part of any of our areas of expertise to be able to trace what happens to bovine ears in the 
United States.  I mean it is not in my area of expertise.   
United States
 
 829. Perhaps I can clarify it, Mr. Chairman.  The EC in its 1999 opinion has a section under its 
misuse section that claims there is a risk from impl ants in bovine ears being processed into the human 
food supply, and I am wondering if the experts are aware of any evidence put forward in that Opinion 
that supports that hypothetical situation? 
Chairman
 
 830. No experts ready to respond.  Dr. Boobis.   WT/DS320/R/Add.7 
Page G-130  
 
  Dr. Boobis
 
 831. I could find no direct evidence for such an o ccurrence.  I found studies which explored the 
implications should it occur, but I could find no direct study of such an occurrence.  I am not an expert and I could not say how this would be done, bu t in reading the literature provided, the materials 
provided, I could not find a specific study in whic h that had been investigated with the results 
presented. 
Chairman
 
 832. Thank you.  EC. 
European Communities
 
 833. Chairman, probably the scientists have not unde rstood, and if you allow me I would like to 
come in on this point because I think that it is an important point.  We have submitted a number of Exhibits to the Panel and they are also mentioned in our risk assessment.  The point is  whether there 
are estimations or not how sure are we today that good veterinary practice is always respected in the 
United States, and in the evidence we have pr ovided there are instances where good veterinary 
practice has not been observed.  We have done sp ecific inspections in the United States by our 
veterinarians; they came up with a written report which has been submitted to the United States and 
Canada, they are aware of this report, that identif ies clear instances of the use and misuse, and I can 
refer to Exhibits 50, 52, 65, 67, 68.   
Chairman
 
 834. Is that question posed to the experts or to the US  delegation?  I am afraid that the experts may 
not be in a position to respond to that question.  Canada. 
Canada
 
 
835. I don't want to cut off the US questions, if the US has any more questions or any follow-ups.  
We have a number of questions, with your permission. 
Chairman  
 836. OK.  Please go ahead, Canada has the floor. 
Canada
 
 837. I think we are going to start with a follow-up on this point. [change of speaker]  Yes, 
Dr. Boisseau in his answer to one of the definiti ons under the terms and definitions section indicated 
in describing these hormones that the hormones are impl anted in the ear and that the ear is discarded, 
and the comment of the European Communities on this  was that he should have said the ear should be 
discarded.  But I wonder if Dr. Boisseau could give  some explanation as to the operating procedures, 
if you will, in a slaughterhouse that are typically ad opted so as to prevent or minimize the extent to 
which contaminants enter the food chain.  And here perhaps not just a referenc e simply to the ear but 
to other types of contaminants like faeces,  hair, hide, and those sorts of things. 
Chairman
 
 
838. Thank you.  Dr. Boisseau.  WT/DS320/R/Add.7 
 Page G-131 
 
 
  Dr. Boisseau   
 839. Thank you, Mr Chairman.  I apologize, but si nce I am neither a veterinary doctor nor an 
inspector, I am unable to answer that question.  I am terribly sorry. 
Chairman
 
 
840. Canada. 
Canada  
 841. OK.  We have a couple of other questions on a separate issue.  [change of speaker] Thank 
you, Mr. Chair, I have to take us back a little bit in the discussions, my apologies for reverting to an 
earlier question that came up only indirectly in so me of the answers from the experts; it might be 
important to get some more information on this.  In the comments from the experts they referred to 
homeostatic control or what might be also referred to as balancing systems.  Perhaps a few experts could comment on the function of those balancing sy stems and further describe the implications of 
these systems for low doses of oestradiol receive d from meat from treated animals.  Thank you. 
Chairman
 
 842. Thank you.  Any comment?  Dr. Boobis, please. 
Dr. Boobis
 
 
843. Well, as indicated earlier, the endocrine system of which the estrogenic system is part plays a 
critical role in a number of physiological functions  and Dr. Sippell has described some of these very 
clearly.  We have also heard that we are subject to natural oestrogens in our diet and we have been for 
a long time.  We have also heard that oestradiol levels can vary or fluctuate, and because of the 
criticality of the signalling system, it is important th at the body is able to balance the levels of 
oestradiol against that required to produce the res ponses necessary.  And so in general terms there is a 
system of checks and balances where the turnover of the hormone – any excess hormone tends to be 
balanced out to some extent.  That is part of the role of the binding hormones, sex hormone binding 
globulin SHBG, it binds a large percentage of the free oestradiol in the circulation normally.  And so 
the homeostasis is a way of preventing extraneous sources from completely unbalancing a tightly regulated system.  That is just a general descripti on, I am not saying that that is always the case under 
all circumstances at all life stages, but that is a general description of the homeostatic regulation of 
these systems.   
Chairman
 
 844. Thank you. Dr. Sippell. 
Dr. Sippell
 
 845. I only agree, but there are instances and reports, of course case reports, not epidemiological 
studies, that for instance children who are exposed to oestrogen-containing ointments, for example, 
which are being wrongly prescribed, and I have observed personally such cases, young girls get breast development and get a growth spurt and have changes in their behaviour and after this effect has been 
detected and the cause of that effect has been stopped, then, because the body and the hypothalamus 
of course react to the withdrawal of this exogenous source very sensibly, then this young girl enters 
into central precocious puberty, which then creates another problem.  So precocious pseudo puberty 
caused by oestrogens from outside, if this is being stopped then the body reacts with central WT/DS320/R/Add.7 
Page G-132  
 
  precocious puberty, and this to our understanding might be the underlying mechanism why chronic 
low-dose oestrogen exposure to prepubertal children mi ght result in an early onset of puberty.  And, 
just to give you another example, several other ob servations have been made with DDT exposure in 
young children that have been adopted (from the Thir d World) to European countries, and in them 
also a high incidence of precocious-central puberty has been observed, after withdrawal of this 
exogenous oestrogenic compound. 
Chairman
 
 846. Dr. Boobis and then to Dr. Guttenplan. 
Dr. Boobis
 
 
847. I just wanted to make a comment, Chairman, about the observational studies suggesting 
changes in, for example, the instance of precocious puberty and how that might be associated with the 
levels of hormones in meat.  But as any epidemiologi st would be happy to explain, there is a serious 
danger in trying to compare disease trends in tw o different countries because of the substantial 
differences that can exist.  It is always possible to  point to one factor and say it might be responsible, 
and of course it might be, we cannot say, but that is  one of the reasons that in a risk assessment we 
tend to base our conclusions on evidence and not on speculation.  And in the case, for example, of 
US versus Europe, we can all point to very ma ny differences, any number of which can explain 
differences in disease trends, and it's impossible to say th at it is due to levels of the hormone, and in 
fact it is less likely to be due to that than to so me other clearly discernable differences between those 
populations.  And on the homeostatic question, I would ju st add this is very much a question of dose.  
Toxicity or adverse effect is sometimes descri bed as the breaking of homeostasis, you exceed the 
level within which the body is able to compensat e by homeostatic regulation and then you begin to 
generate adverse effects.   
Chairman  
 
848. Dr. Sippell. 
Dr. Sippell  
 849. Very briefly.  If I understand the literature co rrectly all these homeostatic experiments have 
been derived from adult individuals, and not from pr epubertal or very young children, and I wonder 
whether these mechanisms are the sa me in the young child as they are in the adult.  And you just said, 
those case reports have been put together by speculati on, this is really not the case, the levels have 
been measured in these individuals, in these patients,  because they are patients and we are allowed to 
measure at least in them. 
Chairman
 
 
850. With the understanding of Dr. Guttenplan, may I give the floor to Dr. Boobis to respond first. 
Dr. Boobis  
 851. I certainly did not suggest that the case reports were speculation.  I am talking about the 
differences in trends between the US and Europe, and that the linkage is the growth hormones in 
meat.  That is speculation because we have no eviden ce for that.  It might be biologically plausible 
speculation to some, but it is speculation; there is no direct evidence for that.    WT/DS320/R/Add.7 
 Page G-133 
 
 
  Chairman  
 852. Thank you.  Dr. Guttenplan please. 
Dr. Guttenplan
 
 
853. I actually was going to respond to the homeostatic question, but just to comment on 
Dr. Boobis's last comment.  Maybe it is not speculation, but  often, the term that's used is it's consistent 
with.  So yes, the trends, the time trends in diffe rent countries are consistent with the effect of 
oestrogens, but they are consistent with a lot of othe r trends too.  So I would not say it's speculation, 
but on the other hand there is certainly no direct ev idence that one particular component is responsible 
for a time trend in oestrogenic or prepubertal effects.  With respect to the homeostatic control, at least 
in experimental animals it's very easy to exceed that.  There have been many studies published on 
animals where oestrogens were administered by all different routes, and you get oestrogenic effects.  
So homeostatic mechanisms act, but they are not 100 per cent effective. 
Chairman  
 
854. EC. 
European Communities  
 855. Chairman, on this point, I think it was a very useful clarification by Dr. Guttenplan.  So do I 
understand correctly then, when you say it is consistent  with, that means it is one possible explanation 
why we observe it.  We cannot say this is the only one, but it can be one of the explanations why.  
That is your statement? 
Dr. Guttenplan
 
 856. That is correct. 
European Communities
 
 857. Thank you. 
Chairman
 
 858. Thank you.  I am sorry, sometimes I don't notice the flag of the Canadian delegation.  I give 
the floor to Canada now. 
Canada
 
 859. Thank you.  We don't usually tend to be as noisy as some of our friends.  I just wanted to ask 
a point of clarification.  First of all I should say that in the Canadian diplomatic service Brussels is 
usually known as a 10 kilogram posting;  that is to say that in the first year on average everyone who 
gets posted there adds about 10 kilos.   I am not sure that this is an ything to do with levels of hormones 
in Belgian beef, but it may have something to do wi th the levels of butter.  The question I had was 
with respect to Dr. Sippell's instances and reports ; I understand that he me ntioned something about 
children who are exposed to oestrogen-containing oint ments, and I'm far from being an expert in this 
area or indeed even remotely close to being a scien tist, but I gather that ointments are a different 
means of getting a particular drug into your system than eating something, considering that there is, 
well, the intestinal tract that about 9 meters long a nd things happen to it in a different way than when 
you put an ointment on.  So I wonder about the relevan ce of that, and the other thing of course is that I WT/DS320/R/Add.7 
Page G-134  
 
  go back to what Dr. Boobis mentioned and Ms Or ozco, that these oestrogens or oestrogen-like 
compounds can be found in many green plants.  I mean  is there any observation, any instance of a boy 
turning into a girl as a result of eating too much bro ccoli?  You know, that is the kind of information 
that perhaps we are lacking.  But my specific ques tion was to Dr. Sippell in respect of the ointment.  
Is there not a difference between ointments and taking something orally? 
Dr. Sippell
 
 860. May I answer to that very briefly.  Oestradiol-17 β is a highly lipophilic substance which 
means that it is being absorbed al most 100 per cent by an infant's sk in, more than by the intestinal 
tract.  And this is long known to paediatricians an d to endocrinologists, and as a matter of fact for 
instance testosterone replacement in adult men now  is being done by topical gels and creams and 
ointments. 
Canada
 
 861. Thank you, Dr. Sippell, you have made exactly  the point I wanted to make.  Thank you. 
Chairman
 
 862. Thank you.  Does this exhaust the lis t of questions from Canada?   
Canada
 
 863. In light of the discussion about consistent with  and relationships between a consumption of 
hormone residues in meat from treated animals and the early-on set of puberty, if I recall correctly 
there was some mention of the fact  that the incidence of early puberty in females of African-American 
descent was higher than in other sub-populations, a nd my question is:  is there any evidence to 
suggest that this sub-population consumes more hor mone-treated meat than other sub-populations?  
And if the evidence was that they didn't consume more, that they c onsumed on average the same, then 
would that not be evidence that the exposure to horm one-treated beef is consistent with a conclusion 
that it has no impact whatsoever on the early onset of puberty, becau se the early onset of puberty is 
occurring for other reasons? 
Chairman
 
 864. Dr. Sippell. 
Dr. Sippell
 
 865. Unfortunately there are no epidemiological data to prove or to discard this very question, but 
there is indirect evidence.  Ther e has just been a new study in Germany where they compared the 
eating habits of children in different levels of the population, high-income, middle-income, low-
income families, and they found out that children from low-income families consumed considerably 
more junk food, so-to-speak, and also higher amounts than an average-income-family child or a high-income-family child.  For inst ance because they don't even have a common meal at home.   
Unfortunately we don't have such scientifically-sound da ta, but this might very well relate it with the 
increasing obesity.  And we also know that fat tissues  really aromatize, so convert androgens from the 
adrenals to oestrogens.  So those (fat) kids ha ve an additional source of oestrogens entering (from 
increased adrenal androgens) that turn s them into early puberty.    WT/DS320/R/Add.7 
 Page G-135 
 
 
  Chairman  
 866. Dr. Guttenplan. 
Dr. Guttenplan
 
 
867. Just as I mentioned the term consistent with, I would say studies or at least the statistics 
among the black and Hispanic community are inconsis tent with the hypothesis that oestrogen in beef 
is responsible for prepubertal and other oestrogenic effects, because I would guess, and I am not sure 
about this, that consumption of beef by lower soci oeconomic status individuals is lower, because beef 
is expensive.  If you look at what is ordered at McDonalds, it is French fries and Coca Cola.   
Chairman  
 868. Thank you.  Our discussion is going too far be yond the issues of our constitution here, the 
focus of our discussions is whether or not the sci entific evidence is sufficient in terms of risk 
assessment of hormone-treated beef consumption.  So I think in order to focus our discussion on the 
subject at hand, I hope the delegations and partie s and experts may not go beyond this range of 
discussions here. 
Ms Orozco
 
 869. Mr. Chairman, in order to bring back the discussi on to the problem that we need to solve, I 
would like to come back to a question that was raised, I think, by the United States some moments 
ago, and I would like to ask the experts if th ey can please one by one express opinions, because the 
time is running and you will go away and we will have to decide, and we need your best judgements.  
With respect to the five hormon es, progesterone, testosterone, tre nbolone, zeranol and melengestrol 
acetate, was the existing evidence, the existing scientific information sufficient to complete the risk 
assessment?  We started to answer that question, and I would like to go back to  that question, and in 
those cases where you think the information was not enough, if you can identif y what in your view 
would be missing, or if the information would be enough to complete the risk assessment.  I think 
Dr. Cogliano was answering and was explaining that it depends on what type of risk assessment.  The 
type of risk assessment that we have in mind is th e completion of four steps that are common to risk 
assessments nowadays.  So I would really appreciat e if we can go back and try to address those two 
points of that question.   
Chairman
 
 870. The floor is open.  Dr. Cogliano. 
Dr. Cogliano
 
 
871. I would say that if you are going to do a JECF A-style ADI, the data are sufficient to do all 
four steps of the risk assessment.  If you wanted to do a low-dose prediction of risk at levels you 
might find in hormone-treated meat, the data are not sufficient because you cannot estimate that dose-
response curve with any kind of certainty.  I th ink I would like to get away from the idea "is 
something sufficient to show a risk from a partic ular kind of low-dose exposure", because I think in 
many cases, in industrial chemical s for example, we get data from occupational studies or from high-
dose experimental studies, we conclude that a risk is possible at lower doses and we take action 
without asking the question – do we have evidence th at eating fish from the Hudson river is going to 
increase your burden of something?  People don't of ten do studies at very low levels; we know what 
we know about hormones often from high-dose studies in animals, or from large studies in human populations, generally of people who have taken higher doses.  I think that I see a disconnect in the WT/DS320/R/Add.7 
Page G-136  
 
  way the scientists like to talk about something a nd the way the lawyers can phrase questions, because 
I can answer that, no, the data do not demonstrate th at there is a risk from consuming hormone-treated 
meat.  I can also say, yes, the data are consistent with the possible risk, and I think it is the way these 
questions are phrased.  I go back to your question about: are the data sufficient to do a risk assessment?  If I were to assume a threshold exists, the data are sufficient to do the kind of – take a 
no-effect level and divide it by 100 or 1,000.  If I were not to assume a threshold, the data are not 
sufficient for me to describe the low-dose risk and to  predict whether it is one in a billion or one in 5 
trillion; what the risk is from eating hormone-t reated meat, because I cannot estimate that dose-
response curve.  That's more the way I would thin k about it: in the language of science rather than 
phrasing a question to elicit a yes answer or a no answer.   
Chairman
 
 872. Dr. Boobis. 
Dr. Boobis
 
 
873. In my opinion there are sufficient data on all of these hormones to perform a risk assessment 
and the data support it.  In deterministic risk assessment, which means there is no requirement to 
extrapolate to very low levels of exposure, we  can establish an ADI and compare this with the 
estimated human exposure, and when this was done, the exposure, as you heard from the JECFA 
secretariat, is only a tiny fraction of that ADI, and so the risk assessment was possible. 
Chairman  
 
874. Thank you.  Dr. De Brabander. 
Dr. De Brabander  
 875. Yes, Mr. Chairman, I was a little bit, more than a little bit, surprised about the question put by 
the United States about the implants in the ear.  If im plants in the ear should enter the food chain, that 
should not be very well, I think.  But it was linked to good veterinary practice and the application of 
good veterinary practice, and there was put in eviden ce, and I cite EC-12 here, that meat which was 
imported from a hormone-free programme  in the United States and analysed in European labs still 
contains hormones, first, and secondly contains hor mones which were not allowed for the type of 
animal.  Those are facts.  So I would ask – I am not in a position to ask questions to you, I think, 
Mr. Chairman – you could ask, if there are such findings in an hormone-free programme, what should 
be the findings in a not hormone-free programme?  And that is the question.  All we heard from JECFA is all the data we are talking about, I w on't go into risk assessment because I am not a 
specialists in it, but it always said it has to be acco rding to good veterinary practice, and here clearly 
shown from data, from evidence, that even in an  hormone-free programme good veterinary practice is 
not followed.  So can we be sure that good vete rinary practice is followed in a not hormone-free 
programme?  And as I answered, there are more produc ts that can be used for growth-promotion than 
just hormones, and it can add an effect above the hormones.  And if there is no monitoring for them, 
how can you be sure that they are not being used  and that good veterinary practice is used?   
Chairman
 
 
876. On this point?  Thank you.  WT/DS320/R/Add.7 
 Page G-137 
 
 
  European Communities  
 877. Well, I would like to ask, because it is part of the evidence. Dr. De Brabander, if hormones, 
for example in the United States – we know they ar e sold over the counter.  Really, is that good 
veterinary practice in your view?  
Dr. De Brabander
 
 878. In my view not.  Normally in Europe we have a very strict regulation and that is one of our 
problems in the laboratories, that it practically causes a lot of paperwork for us to have just a standard for analyzing samples.  If we would have all th e standards, 20 milligrams, 10 milligrams of them, 
which would not be enough to anabolize a fly or mou se or something alike and it can just be used for 
analytical purposes.  We have to fill in piles of  papers and in other places they are sold freely. 
Chairman
 
 879. Thank you.  Do you want the floor now? 
United States
 
 880. I don't want to get in the way of Madam Orozco's question -- this is sort of a distraction from 
that.  The United States looks forward to speaking of these issues probably on Monday, when we get into the evidence that has been provided here t oday.  I would make two comments though, one of 
which was the United States question whether implan ts in ears had found their way into the food 
chain.  This is a conclusion, a scenario that the EC's 1999 opinion postulates.  There simply is no 
evidence of that.  There is nothing there in the Op inion that demonstrates this conclusion.  Now if 
occasional situations where the US hormone-free progr amme had incidences of meat that was outside 
of normal ranges, the United States, we feel, and as we are ready to discuss on Monday, has a very 
robust system, and finding problems, addressing problems, and taking care of them within a 
regulatory structure, I think, is the utmost attemp t to achieve good veterinary practice, rather than 
evidence against achieving good veterinary practice.  And again I look forward to going into that in 
great detail.  I would note that on the other hand th e EC, which has chosen to ban these materials, has 
a well-documented black market for their use per the Stephany paper that the United States has 
presented.  So, when we talk about failure of good vete rinary practice, I think this is a fairly complex 
discussion that maybe these most recent comments oversimplified a little bit.   
Chairman
 
 881. I will give the floor to Canada. 
Canada
 
 
882. Yes, I would like to ask a follow-up question to Dr. De Brabander's comments, and that is: are 
you familiar with the Canadian Food Inspection Ag ency National Chemical Residue Monitoring 
Programme, and have you had an opportunity to review  the results of that Programme for, let's say, 
the last five years? 
Dr. De Brabander  
 
883. No, I'm not, that is simple.  I am a chemist, I am  working in a lab, involved in routine control, 
I'm not inspector, a veterinary inspector, a nd not a European inspector, but there are. WT/DS320/R/Add.7 
Page G-138  
 
  Canada
 
 884. So you don't have any expertise to share with th is Panel as to the control mechanisms in place 
in Canada to minimize or to prevent misuse and abuse of these hormones. 
United States
 
 
885. We will just follow-up, Mr. Chairman, and ask  the same question of the US system of 
controls. 
Dr. De Brabander  
 
886. I think the question is beyond our role as an expe rt.  As an expert we have been asked to 
examine the papers, and my role is not going inspec ting in the United States, neither in Canada.  But 
evidence is here.  I was involved in problems with the import of American pork meat.  I was asked by 
the USDA to perform some analysis and some studies on that phenomenon, from which there was 
evidence from urine that also pork should be treated w ith hormones.  That I have practical experiences 
in. 
Chairman  
 887. I think Canada has been interrupted so ma ny times while you were posing questions; I am 
wondering whether Canada has e xhausted its list of questions. 
Canada
 
 
888. We just have one more  question on detection methods of r esidues and perhaps we can ask this 
question.  I think this question follows on one of the Panel's question and it was answered by both 
Dr. De Brabander and Dr. Boisseau.  And the questi on is that if you have a Codex MRL, a maximum 
residue limit that has been adopted by Codex, and you have a detection method that is of a sufficient 
limit of quantification so as to be able to detect  residues at that MRL, so for instance an MRL of 
10 micrograms per kilogram, and your detection method  has a limit of quantification, about, say, half 
that, 5 micrograms per kilogram, the fact that y ou have developed more sophisticated analytical 
methods that now have a lower li mit of quantification, lets say a limit of quantification now of 
1 microgram per kilogram, does that mean that the other type of detection method, assuming that it was fit for purpose, that that other detection method is no longer fit for purpose?  That's my question. 
Dr. De Brabander
 
 889. That goes into very technical details of anal ysis, technical terms like recovery.  What is 
recovery?  Recovery is if you take a piece of meat  and you mix it with methanol for example and you 
add hormones to it, how much do you recover.  And that is very dependent upon your analytical 
technique, and in most cases when you do that your r ecovery is low, so if y ou have an MRL of 10 and 
your recovery is less than 50 per cent, you cannot detect a residue at all.  It's that simple.  
Furthermore, you should be certain that you det ect the component in the right form.  Certain 
components may be bound, maybe in another form than  you detected.  You must be sure that you free 
them, so it is a question which you can hold a conference on, I think, and maybe I should take a comparison with cars.  If you drive at 100 kilometres an hour and you drive it with a car which just is 
able to get that maximum speed limit you are not co mfortable, but if you drive a Ferrari or another 
racing car who can get up to 220 kilometres, then you dr ive safely at 100.  It's a little bit the same with 
the analytical technique, if you have an analytical technique that is capable of 1 ppd or 0.5 ppd comfortably, then you can more easily and more co rrectly measure your MRL.  I hope I was clear in 
that for you.  WT/DS320/R/Add.7 
 Page G-139 
 
 
  Chairman  
 890. Dr. Sippell. 
Dr. Sippell
 
 
891. And this is just the follow-up to answer your qu estion regarding the situation in children.  We 
just don't have yet everywhere where it would be necessary the methodology, the analytical tools to 
measure as sensitively as we should do it, and therefore I think that the data available are insufficient.  
And I also already said before that due to ethical c onstraints I don't expect that we will get the data we 
need to answer these questi ons in the near future. 
Chairman  
 892. Dr. Boisseau. 
Dr. Boisseau
 
 
893. Thank you, Mr. Chairman.  I would like to re vert to the question concerning the methods of 
analysis.  I have already answered, but since the qu estion has re-emerged, I'll answer once again.  We 
have to decide what we are talking about.  The initial hypothesis was that  there was an adequate 
method to control the established maximum residue limit, i.e. that this method must have been 
validated.  This means, in particular, that the limit of quantification is compatible with the ADI value.  
I am not speaking of the limit of detection, which is  lower, but rather of the limit of quantification.  
Moreover, this method needs to meet a certain numb er of criteria defined by the ISO standards such 
as reliability, reproducibility, precision, linearity in a gi ven range of concentration etc.  Assuming this 
method of analysis has been validated, it must also be practicable.  Since any analysis has a cost, it is 
not necessarily a good idea to choose an ultra-sophisticat ed method, since what counts is to be able to 
ensure that the controls are economically reasonable.  So if a method meets all of the criteria, there is 
no point in using a more recent and more sophisticat ed method.  If other laboratories choose to use 
such methods, that is fine with me, but if a cont rol laboratory is operational and produces good results 
for the control of that MRL with a method that may be ten years old but that works, I see no reason why it should be changed.  The point of the MRL is th at it offers the possibility of stopping this rush 
towards ever-better performance of me thods of analysis, since analysts, like scientists, appear to have 
an infinite capacity to improve, to do more, to be more precise, to be more sensitive, and in general, 
this means higher and higher costs.  Where there is no  need, there is no point in investing in that area. 
Dr. Boobis
 
 894. I wanted to come back to this question of the sufficiency of information and the correct 
comments from one of my colleagues that it is highl y unlikely we will be able to get information in 
children of the sort that would be suitable for a risk  assessment because of ethical reasons.  And this is 
for oestrogenic or hormonally-active substances.  I just want to reflect on the implications of that, because it implies we cannot proceed with a risk  assessment without information that cannot be 
achieved or acquired, and that if we add to that the argument that there is no bottom end to the dose-
response curve for oestrogen, and we look at the range of compounds and the range of potencies of 
hormonally active substances – this is a very diver se and wide-range of materials – does that imply 
that it is impossible to conduct a risk assessment on an y of those materials?  I do not believe that is the 
case.  I believe that with a fundamental understandi ng of biology and appropriate model systems we 
can make intelligent deductions about the likely risk to  the population.  That is not to say that there 
may not be some gaps in scientific knowledge and th at there may be severe gaps, but the implication 
that we can never proceed without information in the target population of children means that we are 
going to be completely blocked from dealing w ith these compounds, and these compounds, as I said a WT/DS320/R/Add.7 
Page G-140  
 
  minute ago, are an extraordinarily wide range of co mpounds, because we have this idea that there is 
no zero risk for an endocrine-active material. 
Chairman
 
 895. Thank you.  Dr. Miyagishima first. 
Dr. Miyagishima
 
 896. Thank you, Mr. Chairman.  I would like to clar ify that the terms of reference of Codex on 
residues of veterinary drugs in foods currently include consideration of methods of sampling and 
analysis for the determination of veterinary drug residues in foods.  And there is a document called  
Compendium of Methods of Analysis Identified as Suitable to Support Codex MRLs.  This is not a 
document which is located in the Codex Alimentarius in  a strict sense, but this is a list of methods that 
are considered to be useful for governments to ch eck that residues in food samples are in compliance 
with the Codex MRLs.  Currently in this comp endium there are no methods mentioned for the 
determination of oestradiol, progesterone  or testosterone.  This is consis tent with the fact that there are 
no numerical MRLs in place within the Codex Alimentarius.  However, this compendium 
recommends method of analysis for trenbolone acet ate and zeranol, for which there exist Codex 
MRLs, and for melengestrol acetate, for which the dr aft MRL is currently at step 7 of the Codex 
elaboration procedure. 
Chairman
 
 
897. Thank you. Dr. De Brabander. 
Dr. De Brabander  
 898. Just a small clarification, Mr. Chairman, on wh at Dr. Boisseau said about the MRL.  He said 
that the MRL was installed to stop the race for lowe r concentrations.  Am I correct?  And I thought 
hearing from the JECFA that the MRL was really based on toxicological evidence, it had nothing to 
do with an analytical technique.  I was not aware that they want to stop chemists of doing our work better and better. 
Chairman
 
 899. Thank you.  No comments from the expert s, then I will give the floor to EC. 
European Communities
 
 900. Chairman, I would like to take the floor and ask Dr. Boobis – because in his reply to 
question 64, precisely as he has said, and it is very im portant in my view to understand, that the level 
obtained in a residual risk has never been quantified, but  is considered to be acceptable to society.  So 
– if I say something wrong, please, Dr. Boobis, correct me – that means he is making a value 
judgement for himself.  He accepts that the residua l risk has never been quantified, but he then goes 
on, every scientist, not a risk manager, every scientist  to suggest that this is acceptable to society.  
And my simple question is: do you think it is a proper position to take of the scientists who are 
supposed to do a risk assessment in  the strict sense?  For example this is mentioned in the Codex 
Manual of Procedure.  If I have misinterpreted what you wish to say please clarify it.  Thank you. 
Dr. Boobis
 
 901. I will clarify.  You completely misrepresent  what I said and misunderstood my meaning.  WT/DS320/R/Add.7 
 Page G-141 
 
 
  European Communities  
 902. Could you explain then what is the meaning of what you said?   
Dr. Boobis
 
 
903. Because the risk assessments of JECFA are adopted  by Codex, it is implicit that they as risk 
managers have accepted and established the level of risk that is acceptable for society.  This is nothing 
that JECFA says; it uses a procedure which is accepta ble throughout the world,  is used by the EU 
itself to establish ADIs.  Implicit in that procedure is  therefore the recognition of the level of risk that 
is represented by that process.  It is not my j udgement, it is the judgement of risk managers, I am 
simply interpreting what the risk manager's conclusi ons must be to allow us to do the risk assessment 
according to the principles that have been accepted th roughout the world.  And I stress again, I am not 
making a value judgement here. 
Chairman  
 
904. Thank you.  Dr. Boisseau. 
Dr. Boisseau  
 905. Because the question that has been  asked is really quite important in terms of principles, I 
would like to back up what Dr. Boobis has just said.  The experts in the JECFA, in particular – but the 
same applies to the CVMP – do not define a socia lly acceptable level of risk.  They have a working 
method which uses – within the frame work of a deterministic approach – a certain number of safety 
factors.  I note, moreover, that although I made this  suggestion yesterday, there was no mention of the 
chain of safety factors used throughout the procedure up to the determination of the MRLs.  There is a 
whole series of factors, and it is a shame not to bear  them in mind, because this would perhaps give us 
a better idea of the protection provided by the met hod used by the different scientific committees.  
Once again, the scientist in charge of risk assessme nt does not determine beforehand what a socially 
acceptable risk is, and it is not his job to do so.  He makes recommendations on the basis of a methodology which, although not written out, is know n to all and used everywhere.  At the Codex 
level, the CCRVDF (the risk mana gement body), fully aware of the method, was perfectly capable of 
accepting or not accepting the ADIs or the MRLs.  We need to distinguish, when it comes to risk 
management, between those who make the proposal s and those who end up deciding.  The risk 
managers are those who decide – they are not th e ones who propose.  The same is true in other 
agencies, such as the AFSSA (French Agency for Food Safety), where I worked.  As the Agency 
responsible for assessing all risks connected with f ood, it often made proposals with respect to 
management, but it was ultimately the Ministry that  decided, and never was the AFSSA criticized for 
the proposals it may have made in the area of risk management.   
Chairman
 
 906. Well, before I give the floor to the delegations , I would like to remind all the delegations that 
discussions should not escalate to the point of ma king any offensive remarks in the posing of 
questions.  And I believe that the pa rties have exhausted their list of qu estions by now.  If that is the 
case, then I will give the floor to my colleagues in the Panel so that we can also pose questions on 
area 3, and with that understanding I am wonderi ng whether – the US still wants the floor?  OK.  
Canada has the floor. 
Canada
 
 907. Thank you.  We just have a couple of more qu estions for Dr. De Brabander, and this is in 
relation to your comments that in your opinion  there are economic incentives to illegally use WT/DS320/R/Add.7 
Page G-142  
 
  hormones, and I would just like to ask you a few questions on this.  At one point in your advice you 
indicated that hormones can negatively affect be haviour, and my question to you is if you add 
increasing amounts of hormones to cows, does that increasingly affect their behaviour?  And I believe you have mentioned at one point that it makes the cattle more aggressive.  So does increasing the 
amount of hormone increase the level of aggressivity? 
Dr. De Brabander
 
 908. I think that is a little bit more than I said, what you take out of my words.  I said that 
hormones may influence behaviour, and there are expe riments, not with cattle but with rats, where 
hormones were added which made them more aggressive.  That's right, that's known, that's facts, just 
facts.  I don't know of experiments of a dose-res ponse curve of aggressivity against hormones, and 
certainly not in cattle.  Such experiments we woul d not do in Europe, not in Belgium, because of 
ethical reasons.  For each animal experiment we have to do we also have to fill in a couple of papers, 
a number of papers.  Luckily at our school we ha ve our own ethical committee, a committee which is 
controlled, which assesses what experiments must be  done, what can be done.  I cannot answer your 
question because it is too far gone, the only thing I said is they really will influence behaviour and that 
is known in test animals.   
Canada
 
 909. Thank you.  My question was: if you add more, do you expect to see some sort of a 
relationship between the effect of behaviour and th e amount of hormones, so that if you add more 
hormones, if you multiply the dose, if you ad d considerably more hormone than what is 
recommended, whether this is likely to have an adverse effect on the level of aggression in the 
animal? 
Dr. De Brabander
 
 
910. That is too a complex question to answer here on the floor, I think.  I think it is a subject for a 
research programme, and certainly there are people w ho would like to carry out that programme, but 
we cannot answer that.  I have just said they have an influence on behaviour, that's qualitatively, 
quantitatively that's not to answer at this moment. 
Canada  
 
911. OK.  Thank you.  I just have another question for Dr. De Brabander.  Do you know whether 
or not the administration of hormones or the overdosing of hormones has an effect on the carcass grade quality – and by that I mean the quality grade of the meat, grade A, US grade A, US double grade A, triple grade A?  I take it that the grade is  related to the amount of marbling, to the amount of 
fat distribution, in the carcass.  Does administer ing more hormones than is recommended have an 
impact on that grade? 
Dr. De Brabander
 
 912. Yes.  That is also difficult to answer having studied these papers.  What I have said is not the 
addition of more hormones, what I said was ther e are other components, and I mentioned here 
zilpaterol, a beta agonist of the third generati on which is legal in Mexico, and I mentioned an 
experiment with zilpaterol  I was looking at literatu re for zilpaterol because we have to monitor it and 
bring it into line with other beta agonists monito ring programmes.  We found out that experiments 
with zilpaterol were done, and to my surprise the blank animals were not blank animals, but were 
animals treated with the regular US hormones and they  had an extra profit.  So if you ask: are there  WT/DS320/R/Add.7 
 Page G-143 
 
 
  incentives to use other growth promoters, yes ther e are, and the same incentives that's the same 
everywhere in the world: money. 
Chairman  
 913. I think it is our turn, but before I give the floor  to my colleague, the floor is for the EC.  A 
quick question. 
European Communities
 
 914. Chairman, I would like to say that we have a couple of questions more to ask on this area.  I 
don't know if now is the moment or later. 
Chairman
 
 915. Yes, please go ahead. 
European Communities
 
 
916. Thank you.  That question relates to the discussion ... (end of tape) ... concerning the 
genotoxicity and whether the evidence which we ha ve, which is reported in our risk assessment and 
subsequent papers which we ha ve submitted, of genotoxicity in vivo  – because Dr. Boobis has made a 
statement just before the break saying that in his opi nion the evidence is not convincing, I think that is 
more or less what he has used.  So I would like on this precise point, because he made a reference to 
some papers, to give the floor, with your permission,  to one of our scientists to make a short statement 
and then probably ask a question on this precise point – it's Dr. Metzler.  Thank you.  
Chairman  
 917. There is a question to be posed to Dr. Boobis?  OK go ahead. 
European Communities 
 
 
918. Thank you, Mr. Chairman.  It has been stated  that there is not sufficient evidence for the 
mutagenicity of oestradiol and its metabolites in vivo .  Before I go into this question, let me just 
reiterate that we all agree, I think, that, first, the DNA-directed mutagenicity of oestradiol is not due to 
the oestradiol molecule itself but to one or sever al of its metabolites which need to be formed.  
Secondly, these reactive metabolites, which bind to DNA, causing DNA adducts, are weak mutagens, 
as has been shown in in vitro  studies.  Despite this fact, to my knowledge there are three studies 
demonstrating in vivo  mutagenicity of these metabolites and also of oestradiol, one study in mice and 
two studies in rats.  As Dr. Boobis has correctly stated, in most of the studies the metabolite under suspicion for causing mutagenicity has been tested, but in one of the studies in rats, also in addition to 
this metabolite, E
2, oestradiol itself has been administered to the rat and led to an increased mutation 
frequency in the mammary gland.  So there are three in vivo  studies on the mutagenicity of oestradiol 
and its metabolites.  And let me just add one little piece of in vivo  evidence; there is a paper that has 
demonstrated that the very adducts of reactive oest radiol metabolite that have been shown mutagenic 
in cell culture studies in vitro  is present in the human target tissue, the human breast.  These adducts 
have been demonstrated to be there, and this de monstrates, in my view, that even in normal women 
these adducts are formed, and in my view obviou sly any additional oestradiol would increase the 
frequency of these in vivo  adducts.  Thank you. WT/DS320/R/Add.7 
Page G-144  
 
  Chairman
 
 919. Dr. Boisseau – US first. 
United States
 
 
920. Thank you, Mr. Chairman.  I would just make one point.  If the experts are going to respond 
to this, I would hope that they would discuss the leve ls of hormone that were used in the studies that 
were just were referred to.  I think we may find th at the levels used in these studies are exponentially 
higher or greatly higher than those that are relevant  to the subject matter at hand, which is hormone 
residues in meat, but I leave that to the experts if they are indeed going to respond to this statement.  
Not to the EC's expert but to … 
Chairman  
 921. Right, thank you, that is clear.  I will give the floor to Dr. Boisseau  first and then to 
Dr. Boobis. 
Dr. Boisseau
 
 922. Thank you, Mr. Chairman.  When we revert to this series of short-term tests to suggest, or 
conclude, that oestradiol is associated with genot oxicity, potential genotoxicity or mutagenicity, this 
means that we credit oestradiol with the capacity to induce tumours through a channel other than the 
hormonal effect.  Since the short-term tests are screening tests, these hypotheses, which are perfectly 
valid with respect to the results of the short-term  tests, need to be confirmed through studies on 
animals, experimental carcinogenicity  studies.  So this leads me to a question for Dr. Boobis, who is a 
specialist in this area:  have the experimental carcinogenicity tests – 18 months on mice and two years 
on rats – been able to identify the appearance or increase of tumours in non-hormonally-dependent 
tissues which are predictive of the same tumours in human beings?  In other words, did any tumours 
appear or develop in non-hormona lly dependent organs in animals whose physiological and metabolic 
characteristics were such that what was taking pl ace in animals was predictive of what could take 
place in human beings?  Thank you Mr. Chairman. 
Chairman
 
 923. Thank you.  Dr. Boobis. 
Dr. Boobis
 
 924. I was just concerned to identify the three studi es mentioned by the EC, so that I can look at 
them.  You mentioned three studies that were positive in vivo , I would like to know what they were.  
Thank you. 
European Communities
 
 925. May I answer that question?  They were cited in  EC Exhibit 125, so they have been provided. 
Dr. Boobis
 
 926. Authors of those papers, to help me find them?  WT/DS320/R/Add.7 
 Page G-145 
 
 
  European Communities  
 927. The first author is Cavalieri, and I think Professor Guttenplan is also on the author list.  I am 
sorry, there are a number of authors and I cannot re member all of them but there are seven or ...  
Chairman
 
 
928. Dr. Boobis, do you need some time?  Dr. Boobis, I think the secretariat may provide you with 
the relevant materials.  OK.  So  in the meantime, can I give the floor to the EC to respond to the 
question put forward by Dr. Boisseau?  Dr. Boisseau please. 
Dr. Boisseau   
 
929. Excuse me, Mr. Chairman.  I had directed my question to Dr. Boobis, and not to the 
Communities. 
Chairman  
 
930. Thank you.   
Dr. Boobis  
 931. Chairman, what I have in front of me at the moment is EC 125, an unpublished review.  Is 
that correct? 
European Communities 
 
 
932. The draft you have is the prepublication availa ble for the internet and it has been published 
and it has appeared in the meantime, in August 2006. 
Chairman  
 
933. Thank you. 
European Communities  
 934. It's a review and it contains also original data on later pages. 
Chairman
 
 
935. Please go ahead, Dr. Boobis. 
Dr. Boobis  
 936. I have not had time to evaluate these date.  This is a recent review, I hear that it came out less 
than six weeks ago, I have not been in my office for much of that time, I have not had time to read this 
paper.  If possible I will look at it and maybe be able to have a comment in the next half hour. 
Chairman
 
 937. Thank you very much.  I would appreciate it if you could do so.  Does the EC want the floor? WT/DS320/R/Add.7 
Page G-146  
 
  European Communities
 
 938. I think we are satisfied with the reply and we w ould appreciate it if there is a reply later on.  
Thank you. 
Dr. Boisseau
  
 
939. Thank you, Mr. Chairman.  Without wishing to ha rass Dr. Boobis, could I ask him please to 
answer the question that I directed to him – or pe rhaps he did not hear it;  he may have been looking 
at the documents that he had just received from the Communities. 
Chairman  
 
940. Before I give the floor – Canada has the floor. 
Canada  
 941. My apologies for interrupting the flow of discussion s.  It is simply a point of clarification.  
My colleagues tell me that the document as published may well be slightly different or different in 
certain key aspects, however way one looks at it, fro m the documents as a draft that has been put in 
evidence.  So I just want to confirm whether in fa ct those who are familiar with the published version 
can guarantee to us, talking about appreciable risk, if  they can guarantee to us  that the document as 
published is in fact the one that we have in our possession, or alternatively what the differences are.  
We would like to know if in fact the reference made is to the published article or to the draft article.  
You will forgive the confusion here, but I think a better precision is probably useful, and we don't 
want Dr. Boobis to review a document that in fact  may not be the document to which reference is 
being made. 
Chairman
 
 
942. I think regarding that question we can benefit from the response or comments by 
Dr. Guttenplan, because he was one of the co-authors.   We can ask Dr. Guttenplan to clarify on that 
point later maybe.  Is the US poi nt also related to this one? 
United States  
 943. Simply to say that I was going to try to assist Dr. Boobis in his search.  I think a relevant 
section to look at is section 5.2.1 in that study.  There are a couple of paragraphs there that might shed 
some light on the methodology and how it actually relat es to this dispute.  That assumes I am looking 
at the unpublished version that – oh I am looking at a published version, I am not sure which version 
the EC's Exhibit is. 
Chairman
 
 
944. EC has the floor. 
European Communities  
 945. Chairman, if you see with our comments on the co mments of the parties which we have sent 
on 12 July, it is all these papers cited by Dr. Bo isseau, Dr. Metzler, they are cited there in our 
comments to question 13.  So this has already been sen t to the Panel, and the other papers as well, at 
least on 12 July when we submitted these papers.  Y ou will see them clearly cited, all the three papers 
have been mentioned.  Thank you.  WT/DS320/R/Add.7 
 Page G-147 
 
 
  Chairman  
 946. Thank you for that clarification.  I am afraid that Dr. Guttenplan was out of the meeting room 
for around ten minutes, so I am wondering whether he has followed the discussions so far? 
Dr. Guttenplan
 
 
947. No, I haven't. 
Chairman  
 948. Maybe the EC can briefly explain what he mentioned again. 
European Communities 
 
 949. Well I can answer that question, I think, if I understood correctly.  What has been submitted 
in May or June or in July was the pre-publication,  and the pre-publication means it is not a draft, but 
it's the final paper that appears on the internet, because the Journal where it is published usually 
appears two or three months later.  So it is identi cal and it has appeared in the Journal now in August 
and I would be happy give you the reference, which is volume 1766, pages 63 to 78, Biochem. 
Biophys. Acta., as is already on the pre-publication. 
Chairman
 
 950. So, until we reach the time when Dr. Boobis is r eady to respond to that particular point, shall 
we move on to the next item on EC's risk assessmen t?  If we have wound up the discussions on area 3, 
I will give the floor to the EC first to put  questions on section 4.  EC has the floor. 
European Communities
 
 951. Chairman.  With your permission, while Dr. Guttenplan was away, I think a member of the 
Panel, Madam Orozco, has posed the question on the sufficiency of the evidence, and I think 
practically all the scientists have replied, I thought , except Dr. Guttenplan, if I am not mistaken.  So 
could you please make sure that we have the views of  all the experts on this issue, and probably, if I 
may suggest, that Madam Orozco repeats the question again if possible.  Thank you. 
Ms Orozco
 
 
952. Yes, Mr. Chairman and the experts who are assisting the Panel, I posed a question and I 
would appreciate answers as complete as possible, b ecause we have a situation where the European 
Communities has stated that in their view they  did not have sufficient evidence, sufficient 
information, to be able to carry out a full risk assessment on the five hormones other than 
oestradiol-17 β.  I have posed the question and I have asked your views as to whether or not the 
information that is available is sufficient to carry out the four-step risk assessment that we are talking 
about.   
Dr. Guttenplan  
 953. These are the five hormones in addition to oestradiol?  I don't know about a full risk 
assessment, but I think there is enough data to carry  out a risk assessment as Dr. Cogliano refers to. WT/DS320/R/Add.7 
Page G-148  
 
  Ms Orozco
 
 954. Because the terms are not always used in the same  sense, what we are talking about is the four 
steps of a risk assessment, or a risk assessment that for some good reason does not have them, but in 
principle we are talking about a risk assessment that  would have a hazard identification, that would 
have a hazard characterization, that would have an  exposure assessment and that would have a risk 
characterization step.  Whether or not the informatio n that is available would be enough.  If not, what 
is it in your view that is missing to be able to carry out a full risk assessment?   
Dr. Guttenplan
 
 
955. I think there is sufficient information out there. 
Chairman  
 956. Thank you.  Dr. Boisseau. 
Dr. Boisseau
  
 
957. I am going to answer along the same lines as Dr. Guttenplan, in that the method usually 
applied by the JECFA is considered satisfactory becau se it is a deterministic method.  Now, if we are 
talking about a probabilistic method with effect–dose extrapolation to low doses, the data may not be 
sufficient.  Consequently, my reply to Mrs Oro zco's question is that my answer depends on the 
method applied by the JECFA. 
Chairman  
 958. Thank you.  Dr. Boobis. 
Dr. Boobis
 
 
959. I have a comment on one of the studies that we re referred to recently.  Would you be prepared 
to listen to that now?  A comment on one of the ge notoxicity studies that were referred to a moment 
ago.  This is an in vivo  study of oestradiol.  I note that it was a high dose – it was toxic – and that the 
mutational spectrum, which is a very important measure of the underlying  mechanism whereby the 
interaction with DNA was occurring, was not significan tly different from the control animals, and that 
the 4-hydroxy-oestradiol, which was the presumed me tabolite, as Dr. Metzler has just pointed out – a 
possibility that the parent is not itself responsible  but a metabolite – had a quite different mutational 
spectrum.  So my view would be that this study is not sufficient at the present time to override the 
conclusions that we had come to earlier, that low doses of oestradiol do no cause a mutagenic response in vivo .   
Chairman
 
 
960. Thank you.  Dr. Guttenplan please. 
Dr. Guttenplan  
 961. The mutational spectrum for 4-hydroxy-oestradiol was different in the control.  WT/DS320/R/Add.7 
 Page G-149 
 
 
  Dr. Boobis  
 962. I stipulated that the mutational spectrum for 4-hydroxy-oestradiol was different from the 
control, but that of oestradiol was not, and if th e hypothesis was that the effect of oestradiol in 
producing that response is through  the 4-hydroxy metabolite, the anticipation would be that there 
would not be a very big difference in the mutational spectrum; there was. 
Dr. Guttenplan
 
 963. Well, we don't know how much of the oestradi ol gets converted to the 4-hydroxyoestradiol, 
and it has been detected in vivo,  or at least the conjugates have, in breast tissue from human women, 
and we know that that gives a different mutational spectrum than the control. 
Chairman
 
 964. Thank you. 
Dr. Boobis
 
 
965. Could I just respond, please?  But the problem I am having, Chairman, is that the compound 
we are concerned about is oestradiol.  I can find no difference in the mutational spectrum, which is a 
signature of the response to the DNA, from the contro l.  So it may be exaggerating something that is 
going on naturally, and I would repeat that the dose of  oestradiol used in these studies was so toxic 
that not all the animals actually survived.   
Dr. Guttenplan  
 966. Yes, this is a common problem with any toxicological study, you have to increase the dose in 
order to see something that is significant in the an imals, you don't have enough animals to do the 
experiment if you were to use an e nvironmental dose.  So this is noth ing different than what is done in 
usual toxicological studies.   
Dr. Boobis
 
 967. There have been guidelines established for dose setting in studies in which mutational 
responses have been observed in vivo.  I do not believe that any of those guidelines recommend going 
up to doses which are lethal.  There is supposed to be some slight evidence of toxicity at the top dose, 
but by no means lethality, so this would be a heroic study.   
Dr. Guttenplan
 
 968. 4-Hydroxyoestradiol was not toxic though, just oestradiol alone, and often this is what you 
do, you test the presumed active metabolite.  And th is is often done, this is classical studies in 
metabolism of benzpyrene, as you are familiar, whic h were eventually done with the end product. 
Chairman
 
 969. One last chance for Dr. Boobis. 
Dr. Boobis
 
 
970. I agree entirely with what was just said.  In the case against benzpyrene, however, the parent 
compound and the metabolite produced the same muta tional spectrum, therefore confirming the likely WT/DS320/R/Add.7 
Page G-150  
 
  involvement of the metabolite in the response.  Here, when we see a different mutational spectrum, 
the interpretation for me is: something else is going on; and it certainly does not confirm, it by no means confirms, the involvement of that metabolite.  It may be that there was too low a level, but 
these data cannot be used to confirm that meta bolite's involvement in response to the parent 
compound.  That's all I was saying. 
Chairman
 
 971. Well, we have spent more than two hours alre ady and we still have the most important issue 
of our consideration this afternoon, so I think it is better for us to move on to the next section on the 
EC's risk assessment, and then I will give the floor to  the EC first to ask questions to the experts.  You 
have the floor, EC. 
European Communities
 
 972. One question I would like to ask the experts, and in particular probably Dr. Guttenplan or 
Dr. Boisseau, is that, as we know these substances,  the implants contain several of these hormones 
that, as we were told, they practically never are administered as a single substance, and Dr. Boisseau 
in his reply has confirmed that.  The toxicological evaluation was made on an individual substance.  Now how important do you think it is to know the possible synergistic effects, given that the actual 
administration of these implants involves more  than one of these hormones?  Thank you. 
Chairman
 
 
973. Thank you.  Dr. Guttenplan. 
Dr. Guttenplan  
 974. I think that the biological effects of oestradiol so overwhelm the other effects that I would not 
be concerned with any synergistic effects.   
Chairman
 
 975. Is any other expert prepared to respond?  If none, the EC has the floor. 
European Communities
 
 976. Chairman, it is not entirely clear how the current  section differs from the previous one.  In 
your instructions, your indications, you said section (c) and part of section (d), so I would like to 
discuss a specific aspect of the EC  risk assessment which was discussed  under the previous section.  If 
you allow me to ask a question to Dr. Guttenplan. 
Chairman
 
 
977. Sure.  There is no clear-cut dividing line be tween these two areas.  You can put whatever 
questions you feel are necessary. 
European Communities  
 978. Thank you.  It is just that, if I understood co rrectly, Dr. Guttenplan, you said that the scientific 
evidence on the five hormones was sufficient to conduc t a risk assessment.  In your reply to questions 
61 and 62 you actually state differently, so could you explain the differences?  There is a whole  WT/DS320/R/Add.7 
 Page G-151 
 
 
  bullet-point list of gaps you have identified, a nd in your reply to question 61 you speak of an 
assessment for melengestrol acet ate which seems sound for example.  Could you explain? 
Dr. Guttenplan  
 979. That means that the risk assessment was alright.   
European Communities
 
 980. Would you care to elaborate on the gaps  you have identified and question 62? 
Dr. Guttenplan
 
 
981. Yes, on subsequent reading I could not find anyt hing to indicate adverse effects, and I now 
think that risk assessment is alright. 
European Communities  
 982. Can I reformulate the question?  Because I think probably we have an issue of understanding 
each other.  Can I ask, Dr. Guttenplan, whether your reply to question 61 is correct as you see it 
today? 
Dr. Guttenplan
 
 983. Well, I said the ability varies between compounds, but that does not mean you can't make a 
risk assessment, it just means the accuracy  of the risk assessment is different. 
European Communities
 
 984. You also say, for example, that it does not appear that accurate ADIs can be established at this 
point. 
Dr. Guttenplan
 
 
985. Well accurate means – if it's not accurate, there is just a larger range, but you can still do a 
risk assessment. 
Chairman  
 986. I will give the floor to the US. 
United States
 
 987. Thank you, Mr. Chairman.  Dr. Guttenplan actually  spoke to our question, which was whether 
these particular items he had identified in this question actually prevented the conduct of a risk 
assessment, which is entirely separate from whether there are certain small gaps, whether you can 
actually conduct a proper risk assessment. 
Chairman
 
 988. EC, please, go ahead. WT/DS320/R/Add.7 
Page G-152  
 
  European Communities
 
 989. Chairman, we have asked previously a ques tion about the fact that the hormones are 
administered in combinations containing more of these hormones, and only Dr. Guttenplan has replied.  Probably Dr. Boisseau would like to give  a reply.  Would it be necessary to have an 
assessment that takes into account  the real administration of these hormones and not the individual 
compounds in question? 
Chairman
 
 990. Dr. Boisseau, please. 
Dr. Boisseau
  
 991. The same type of study was conducted for tre nbolone, which, if I recall, is administered 
jointly with oestradiol, and no particular potentiati on effects emerged.  These studies of combinations 
of hormones were not conducted for all hormones.  The JECFA considered th at since the receptors 
were not the same and the biological properties were not the same, the prospects of a hormonal 
potentiation effect through the action of another horm one was unlikely.  So if I am not mistaken, 
toxicological studies were made only for trenbolone.  That is all I can say. 
Chairman
 
 992. Thank you.  I would like to thank Dr. Wennberg  and Dr. Miyagishima for their contributions 
and presence in this meeting.  I would like to let th e delegations know that they are leaving.  Thank 
you.  The floor is for the EC again. 
European Communities
 
 993. Chairman, I would not ask a question now; we  will wait for the other part before we 
intervene.   
Chairman
 
 994. OK, good news.  US has the floor. 
United States
 
 
995. Thank you, Mr. Chairman.  A question for all of the experts who have looked at the EC's risk 
assessment and have comprehension of the four st eps of risk assessment; hazard identification, hazard 
characterization, exposure assessment  and risk characterization.  In light of these components, have 
you identified any deficiencies in the EC's opinion relating to oestradiol-17 β? 
Chairman  
 
996. Thank you.  Any volunteers?  Dr. Boobis. 
Dr. Boobis  
 997. Well, in looking at the four stages of risk ass essment, as we have heard earlier, for various 
reasons the EC evaluation tended to focus more on the hazard identification side.  There was some 
hazards characterization but it was not complete d and, as far as I could gather, there was no  WT/DS320/R/Add.7 
 Page G-153 
 
 
  independent exposure assessments undertaken.  And so , from the perspective of the four stages, it 
would certainly not be regarded as a complete risk assessment.   
Chairman  
 998. Dr. Boisseau? 
Dr. Boisseau
  
 999. I concur with Dr. Boobis. 
Chairman
 
 
1000.  Thank you. EC? 
European Communities  
 1001.  Can we follow up on this?  Dr. Boobis, is your reply based on the assumption that there 
would be a threshold, so that your reply would act ually not apply in the case of direct genotoxicity? 
Dr. Boobis
 
 1002.  That is partially correct, but I would have an ticipated some exploration of the type of 
genotoxicity and whether it did have a threshold, an d that does not seem to have been carried out very 
rigorously and there was not what I call the weight of  evidence, a sort of balancing of the quality of 
the studies and the endpoints that they were responding to. 
Chairman
 
 1003.  Dr. Boisseau. 
Dr. Boisseau
  
 
1004.  Thank you, Mr. Chairman.  We always seem to come back to the problem of thresholds.  
Once again, short-term tests that can show a ge notoxic or mutagenic potential are not intended for 
determining thresholds.  If we re ally want to know whether this potential is real, it needs to be 
confirmed by long-term carcinogenicity tests.  So I come back to my question to Dr. Boobis:  in the long-term tests on mice and rats, was it possible to identify tumours in non-hormonally dependent 
organs that could confirm a mutagenic potential obser ved in short-term tests, and if so are such 
tumours in non-hormonally dependent animal orga ns predictive of what could happen in human 
beings? 
Chairman
 
 1005.  Thank you.  Dr. Boobis. 
Dr. Boobis
 
 1006.  Apologies, Chairman, I did not catch that question to respond to earlier.  From my 
knowledge, the studies in rodents have not shown an y target tissues for carcinogenicity which are not 
hormonally dependent and that these tissues are targets one would have anticipated for an 
oestrogenically active substance.  That is the factual evidence.   WT/DS320/R/Add.7 
Page G-154  
 
  Chairman
 
 1007.  Do these answer the question by the US? 
United States
 
 
1008.  Yes, Mr. Chairman, thank you.   
Chairman  
 1009.  No further questions from the US?  What about Canada? 
Canada
 
 
1010.  No further questions from Canada. 
Chairman  
 1011.  Thank you.  I give the floor to the EC. 
European Communities
 
 1012.  Thank you, Chair.  On this last reply of Dr. Boobis we would like to intervene, and I would 
like to give the floor to Dr. Alain Paris who would lik e to respond to this please.  [Change of speaker.]  
Out of courtesy towards Dr. Boisseau, I am going to sp eak in French.  I am surprised at the division 
that has appeared, with regard to the action of oestrogens and their effects, between what passes 
through the oestrogen receptors and what passes via genotoxicity phenomena.  To revert to the 
genotoxicity phenomenon, this is essentially a rando m process;  and I wonder about the deterministic 
approach, as mentioned earlier, which would appear  to be more efficient than the probabilistic 
approach, in that the deterministic  approach, in my opinion, is incapable of taking account of all of 
these random phenomena.  
Chairman
 
 1013.  Thank you.  Dr. Boisseau. 
Dr. Boisseau
 
 1014.  Thank you, Mr. Chairman.  I am no specialist in these areas, but reverting to what you said, 
and I agree with you, a phenomenon based on genot oxicity or mutogenicity is random, which means 
that this genotoxic potential, if it exists, should,  in a carcinogenicity study, provoke tumours which 
should concern a certain number of tissues in a random manner and not only those which are hormonally dependent.  Hence my question earlier on, which was answered.  For the moment, the 
only tissues affected by the development of tumour s are hormonally dependent.  This does not support 
the idea of a non-hormonal genotoxic-type mechanism.  Finally, the statistical evaluation of the effect 
of small doses is another problem. 
Chairman
 
 1015.  Thank you.  Dr. Guttenplan please.  WT/DS320/R/Add.7 
 Page G-155 
 
 
  Dr. Guttenplan  
 1016.  The genotoxic effects, at least the mutagenic effects, are also dependent on cell proliferation, 
and sometimes they are extremely dependent on cell proliferation, so that hormonally-sensitive tissues 
in the event of a random distribution of a genotoxic effect are going to show the first genotoxic 
effects.  So it is not surprising that you see effects in animals in hormonal-sens itive tissues.  Of course 
one could make the same arguments for a non-horm onal mechanism, too.  On the other hand, one 
could make the same argument on a hormonal mode l as a genotoxic model, but even the hormonal 
model is dependent on mutagenic effects; it is ju st spontaneously occurring and not as a result of the 
oestrogen.   
Chairman
 
 1017.  Dr. Boobis, would you like to ...?  EC has the floor. 
European Communities
 
 
1018.  If you allow us to come in on this again, Alai n Paris. [change of speaker.]  Probably, the 
tumours that are detected, with regard to the admini stration of oestrogens, are revealed in a terminal 
stimulation process, and here we are combining initiation and promotion phenomena, knowing that 
promotion is extremely dependent on the oestrogen receptor.  But this comes on top of the very premature initiation phenomenon which takes place vi a the activation, the bioactivation of the 
oestradiol molecule or its principal metabolites that  will be found as residues, particularly oestradiol 
alpha.  
Chairman
 
 1019.  Thank you.  Dr. Boobis ...  The United States have the floor. 
United States
 
 
1020.  I don't mean to interrupt Dr. Boobis, I was just going to note that I failed to discern a question 
in the statement that was just made and refer back  to Canada's statement from earlier in the meeting 
regarding submission of evidence, and whether we ar e asking questions of the panel of experts that 
the Panel has comprised or whether the parties ar e providing evidence through their own experts at 
this point.  Thank you. 
Dr. Boobis  
 1021.  I was going to make a somewhat similar comment.  We are getting into the realms of 
interpretation of data.  My view is that the da ta are interpretable as a non-mutagenic genotoxicity 
in vivo,  if there is any response, with a threshold.  Othe rs have chosen to interpret the data differently.  
I was asked here for my opinion, my scientific opinion , based on the totality of the evidence.  That is 
my opinion.  So when we get into a discussion a bout the relevance of initiation and promotion in 
endocrine tumours, it critically depends upon the interpretation of the e ffects seen of these 
compounds.  As I have just said, my view is that they do not support an in vivo  initiation mechanism. 
Chairman
 
 
1022.  Thank you.  Dr. Cogliano. WT/DS320/R/Add.7 
Page G-156  
 
  Dr. Cogliano
 
 1023.  Thank you.  I think the comment that a lot of th is is a question of inte rpretation, as Dr. Boobis 
has just said, is actually the hear t of the scientific disagreement that we see here.  I actually am not 
competent to tell whether there is or is not a thres hold, but I can tell from my long experience in risk 
assessment that that is the fundamental scientific argument that is going on here.  And so to be as 
helpful as I can to the Panel, the JECFA assessme nt felt that a threshold could be assumed even 
though there is some evidence of genotoxicity, because they felt that a hormonal mechanism was 
likely what was going on.  Therefore they assumed th ere was a threshold and they computed the ADI 
and they went forward with an assessment.  And it seems to me from reading the papers submitted by 
the European Commission as well as the arguments we have heard the last two days, they are 
unwilling to assume that there is a threshold.  So metimes I think the argument has been that because 
there may be some genotoxicity they are unwilling to  assume a threshold, and sometimes I think they 
are unwilling to assume a threshold because there may be  some other effects of these chemicals at low 
doses, but because they are unwilling to assume a thr eshold they say they cannot do a risk assessment 
because they cannot really predict a dose-response curve.  Now I think those are the scientific 
arguments on both sides.  I think that the way we phrase questions sometimes leads you to an answer 
of yes or an answer of no, but I think that is r eally the fundamental scientific issue that marks the 
difference between the JECFA asse ssment and the EC assessment; the willingness to conclude that 
there is a threshold for these compounds.   
Ms Orozco
 
 
1024.  Dr. Cogliano, I don't want to sound legalistic, but is  that disagreement arb itrary?  I am sorry, 
but we have to find ways to assess what has been  done and sometimes there is a fair amount of 
information whereby professionals can disagree, scientists can disagree; other times the amount of information, the quality of the information, might not  allow those variations.  So what would be your 
assessment? 
Dr. Cogliano
 
 1025.  I don't want you to put the word arbitrary in my mouth because I know that means something 
to lawyers and I don't fully understand what it means, but I would say it is a long-standing area of disagreement among scientists for many years about wh ether there are thresholds for carcinogens by 
different mechanisms.  And the reason it is a contro versy, I think, is the assumptions that scientists 
bring to risk assessment.  There really are no data, we have heard that you cannot scientifically firmly 
establish that there is a threshold, but there are a lot of clues that a lot of scientists conclude that there 
is a threshold.  But I think it really is an area of legitimate scientific disagreement that has gone on for 
many years.  I don't wish to characterize that as arbitrary, I think it is more a matter of professional 
scientific judgement. 
Ms Orozco
 
 1026.  … of course, legitimacy or reasonableness ... 
Dr. Cogliano
 
 
1027.  I don't think that there is a set of studies that  can be done that will convince everybody one 
way or the other of a threshold or lack of a threshold.  WT/DS320/R/Add.7 
 Page G-157 
 
 
  Chairman  
 1028.  I think this is also related to the so-calle d long-term latency peri od and cumulative effects 
arising from the cumulative exposure to the hormones at issue.  I don't know whether or not the DNA 
repair mechanism is effective enough to deal with these kinds of long-term adverse effects.  This is 
one thing I would like to hear from the experts.  Dr. Boobis. 
Dr. Boobis
 
 1029.  Well, of course experimentally when we are l ooking at the carcinogenic potential in animal 
models we dose the animals for what we call the life time, I mean it is not actually the full lifetime but 
it is a very substantial portion of a lifetime, two y ears in rats and 18 months in mice, and during that 
time any latency should be reveal ed.  It takes into account accumulation of damage, DNA repair and 
any other components that might lead to a progression of effects, and indeed cancer is a multi-step process.  It is well established now that you need sev eral different overlapping stages before you get a 
malignant tumour and therefore these are encompassed w ithin the scope of an experimental model.  In 
the epidemiology studies one would have to look ove r a period of several decades to be able to 
account for such latency if the endpoint of concern was cancer.  
Chairman
 
 1030.  What if DNA damage is done because of reasons we are not aware of due to the scientific 
uncertainty in the contemporary world and the adverse effects appear 30 or 40 years later; are current 
risk assessment techniques or mechanisms safe e nough to deal with these kinds of problems?  
Dr. Boobis. 
Dr. Boobis
 
 1031.  The paradigm we have, and there is some evidence  to justify the case that this is a reasonable 
assumption, is that the effects observed scale to the life time of the organism, and so that is one of the 
reasons we use shorter-lived organisms in our toxico logical testing.  We use rats and mice which live 
for a couple of years; otherwise we would have to test for a lifetime in a longer-lived species which 
might be 40 or 50 years.  So we are working on the principle that effects that are not evident within 
the lifetime of a rodent would not be evident, all other things being equal, within the lifetime of a 
human being.  And there is actually very good evidence that that is the case.  For a number of 
carcinogens that IARC have evaluated it takes approxi mately a quarter of a lifetime after an initial 
exposure for those tumours to become apparent, and that  is true in rodents, it's true in dogs and it's 
true in humans.  So I thing that the paradigm is reasonable that if there is going to be an effect 
manifest over a lifetime, it will be revealed in tho se experimental systems and therefore be predictive 
of lifetime effects in humans by and large.  
Chairman
 
 1032.  Thank you.  Dr. Boisseau and Dr. Guttenplan. 
Dr. Boisseau
  
 1033.  Thank you, Mr. Chairman.  I would like to go back to what Dr. Boobis has just said.  If the 
protocol he has described permits us, where the experimental test s yield positive results, to predict an 
obvious effect on human beings after a reasonable peri od of time, why is it, if we are pleading for an 
absence of thresholds for this kind of oestroge n-related cancer, that the human epidemiological 
studies that have developed exponentially over the last  twenty years have not been able to make any 
headway in highlighting this type of cancer? WT/DS320/R/Add.7 
Page G-158  
 
  Chairman
 
 1034.  Thank you.  Dr. Guttenplan, please. 
Dr. Guttenplan
 
 
1035.  Actually, two points.  You mention DNA repair in long-term tests.  When DNA is damaged, 
DNA repair usually occurs relatively rapidly within  hours and days.  If the cell divides before repair 
occurs, you have a mutation.  At least – I should not say that.  If it divides and if the damage is of such a type that division does not produce an accurate reproduction of the original DNA molecule, then a 
mutation can result.  Mutation is permanent, it cannot go away, and so once that has happened, there 
is some increased level of risk.  But, as I menti oned before, most mutations are innocuous, most genes 
in which mutations occur are not going to result in , say, cancer or another adverse biological effect.  
So DNA repair takes care of most damage, but on ce the damage has occurred and has not been 
repaired before the cell divides it is permanent damage .  As far as the threshold of oestrogens, and this 
I sort of throw out to the experts, if one assumes th at there is a hormonal cause of cancer as a result of 
oestrogens as opposed to a genotoxic cause, the hor monal cause is assumed to result from pre-existing 
mutations, and then those pre-existing mutations, th ose cells containing the pre-existing mutations, are 
caused to turnover and divide because of the oestro gen stimulation.  Unless there is a threshold for 
oestrogen stimulation, there should not be a thres hold then for the hormonal effects of oestrogen, 
because the genotoxic effects, the effects of oestroge n, are indirectly genotoxic effects, they are 
promoting genotoxic effects.  Now I don't know if th ere is a threshold for oestrogen receptors, I just 
throw that out as a piece of information.   
Chairman
 
 1036.  Thank you.  Dr. Boobis. 
Dr. Boobis
 
 
1037.  There is, and we have measured it.  Endocr ine-sensitive cells have a threshold for the 
mitogenic effects of oestradiol, it is absolutely cl ear, and we are not the only people, there have been 
many such studies to demonstrate that.  I am talk ing about the mitogenic effects, I mean there are 
other effects that have been mentioned here and I am not qualified to discuss them in detail, but in 
terms of the mitogenic effect on, for example, the mammary gland, which is one of the targets we are 
considerably concerned about, there is a clear thr eshold for cell division.  And that makes a lot of 
sense, you would not want circulating oestrogen to be  stimulating cell division at whatever level it 
was, it has to be part of this homeostatic regul atory mechanism that allows the body to signal cell 
division when necessary by up-regulating the level of oestrogens.   
Chairman  
 
1038.  Thank you.  EC. 
European Communities  
 1039.  Chairman, we do appreciate the questions you have  posed, they have been very appropriate in 
our view, and we have a number of scientists from our side – since we don't have other questions, we 
can make a statement in the form of a question,  because they would like to  intervene.  These are 
important issues.  There will be no new evidence, ju st comments on what has been said to clarify our 
debate.  WT/DS320/R/Add.7 
 Page G-159 
 
 
  Chairman  
 1040.  Comments once again in the form of questions? 
European Communities
 
 
1041.  Yes. – Dr. Boobis, in the comments you have ma de, you refer to receptor-mediated events as 
thresholded and then be able to use them to create an acceptable daily intake.  It is very clear that in 
the very low dose range oestrogen binds to oestr ogen receptors, and then as the number of receptors 
are occupied, the receptors are inhibited as the do se of oestrogen goes up, until that response goes 
away, that is called the biphasic dose-response cu rve that has been known for 50 years.  Then 
oestradiol begins to bind to androgen receptors, be ginning to stimulate and i nhibit an entirely different 
set of genes and an entirely different set of respon ses.  If you begin your dose-response curve at a very 
high dose, what you will do is come to the bottom of a very bizarre set of events , that is the binding of 
oestrogen to androgen receptors.  You will then u se that as your NOAEL and calculate an ADI from it 
and completely miss the whole bottom part of the dose-response curve that is qualitatively different 
and completely unpredicted by what happens at the top part, and aside from the fact that you have an 
endogenous level of oestrogen that the oestroge n is operating against which argues against the 
threshold issue, could you explain how you can cal culate an accurate ADI off of a hormone that 
operates through multiple mechanisms across a very wi de dose-response curve that is never examined 
in a risk assessment study? 
Chairman  
 
1042.  Dr. Boobis. 
Dr. Boobis  
 1043.  Mr. Chairman, do you wish me to answer this? 
Chairman
 
 1044.  It's up to you.   
Dr. Boobis
 
 1045.  I'll have a go.  There are three components, one is the question of a threshold.  I am sure 
Professor Vom Saal is familiar with the recent stud ies using transcriptomic experiments, looking at 
the totality of a gene expression profile in hormona lly sensitive tissue, and there has been a clear 
threshold for every single gene transcript in those studies demonstrated.  It is difficult therefore to 
understand how one can argue against a threshold.  In our own studies using proteomic approaches, 
looking at the proteins that change within the cell,  we have come to an identical conclusion.  There 
are concentrations or doses of oestradiol-17 β below which nothing changes – nothing.  In answer to 
the second part of the question, how did we find a dose, a NOAEL where we could proceed to set an 
ADI.  I said earlier it is based on a more holistic evaluation of the data.  We are not concerned primarily with an intermediate response, we are concerned with adverse responses.  What is the 
outcome for the organism, is there an adverse effe ct on reproduction, development, carcinogenicity?  
Based on such considerations on the totality of the available data we were content that we could 
identify a no-observable, and I stress this is by de finition a no-observable adverse, and again I stress 
adverse, effect level.  And this is the paradigm as adopted by all risk assessment bodies throughout the 
world.  Thank you. WT/DS320/R/Add.7 
Page G-160  
 
  Chairman
 
 1046.  Thank you.  Yes, EC. 
European Communities 
 
 
1047.  Would I be able to ask a question back from that?  The point here is that at the very very high 
end of the dose-response curve you are looking at adverse effects mediated through an entirely different system than the system that oestradiol  operates through in a dose range a thousand times or 
so below the dose range that you are actually testing in your risk assessment, and I do agree that you are seeing adverse effects and that they will go away, the problem is that you then are not aware that 
there is a whole other set of adverse effects that can occur down below that, and I totally agree that 
there are different thresholds for turning on genes,  and the endogenous level of oestradiol is high 
enough to exceed every single one of them.  And that as you are adding extra oestradiol, you are altering the whole profile of genes that are expresse d, and there was a PNAS paper by Toshi Shioda 
last year that showed that in exquisite detail. 
Chairman
 
 1048.  Dr. Boobis. 
Dr. Boobis
 
 1049.  The studies I mentioned were against the backgr ound of normal oestrogen levels.  There were 
several papers published in the last three years showing that against that background there is no 
change from the control level in any transcript.  As far as this ultra-low, U-shaped dose response 
curve is concerned, I would simply say that, as I mentioned earlier, this is one of those areas where 
there is considerable scientific controversy and I rea lly don't think we can resolve it here; it is a major 
issue of controversial information.  I could point to papers which show other results.  
Professor Vom Saal can point to many papers supporting his argument, quite correct.  But as I say, 
currently, I think, it is fair to say within the scientific community it is an unresolved question. 
Chairman
 
 1050.  Thank you.  We have no confusion about th at.  Well, I don't know whether we have to 
continue this discussion on this particular point that this hour; we have 15 minutes to go before 
six o'clock.  One question for EC. 
European Communities
 
 1051.  Chairman, if you allow me, I will give the floor to  one of our scientists who would like also to 
make one more point, this is Madam Annie Sasco, who is the expert on epidemiology. 
European Communities
 
 1052.  OK.  So I will be brief.  I just want to make a point because it has been asked why did 
epidemiology fail to find any effect;  and I am  not sure epidemiology failed completely.  
Epidemiology, which is a study of the occurrence of disease and risk factors in populations, can be 
done at two levels.  Levels of populations – and this was already discussed this morning when you 
looked at rates of disease potentially linked with ho rmonal factors in different countries.  And this 
evidence is consistent with the hypothesis that  these products may increase the risk of hormonal-
dependent cancer, but there may be alternative explan ations.  And it's very complex, because cancer is 
a multi-factorial disease, so even beyond hormones ther e are also factors, other risk factors, which  WT/DS320/R/Add.7 
 Page G-161 
 
 
  intervene and play a role.  It has long latency, we have to study for example diet 30 years ago to find 
the effect today, and therefore these population comp arisons are just putting in some information that 
are not definitive.  And the same can be said about time trends, and we have seen in most countries of 
the world we are still seeing increases in hormonal-de pendent cancers, but the countries at the top of 
the scale are countries where these products have been used.   
1053.  The difficulty with these population statistics leads to the second type of epidemiological 
studies, where comparison is being done at the leve l of individuals; so we want to try to find out 
whether the people who have been exposed to th ese products are the ones getting cancer today.  But 
when we look at an exposure like the one we are discussing, it is exceedingly difficult to do it, 
because all countries have been exposed, France as a whole country at the same time was exposed 
when this product was used, in the US almost ever yone is exposed, so it's very difficult within a 
country to find differences and exposures between in dividuals, and I guess that is one of the reasons 
why it has not been attempted, because it will be a difficult exercise.  But I think it could be 
attempted, at least in countries like the US, if  we could identify population groups who only eat 
hormone-free meat and compare them with the ones eating hormone-treated meat.  So I think we 
should not say that epidemiology will never be able  to do it, it would be very difficult to do it, but 
maybe it could be attempted, and only now, because we needed to have 20 years, 30 years of exposure 
before we can see an impact.  But I think for the whole topic, if we look at the effects on puberty, then 
in a way, from an epidemiology point of view it w ill be easier to see it, because we have to wait less 
years and maybe also because the difference is greater.   
Chairman  
 
1054.  Thank you.  Canada. 
Canada  
 1055.  Thank you, Mr. Chairman.  I am very sorry to make this point so late in the day.  Was that an 
argument, was that a statement, was that an expert  testimony, was there a question in there somewhere 
for the experts?  We are here at this point to h ear from the experts, not from the EC delegation.  We 
have heard enough, 19 volumes of evidence I unders tand, could you please clarify the role, even at 
this late hour, so that the time is not taken up by monologues.   
Chairman
 
 
1056.  I have no intention to further continue this discussion, so in the way of exchanging the views 
from the experts, the Panel has invited in experts in each delegation.  So just leave this matter to the 
Panel with confidence and trust, and then I would like to give the floor to the US. 
United States  
 
1057.  Thank you, Mr. Chairman.  That was an interes ting statement.  I would note that the Panel 
expressly asked this question to the experts in questi on 26; it asked, which is relevant for this dispute, 
what the EC did in its purported risk assessment regarding epidemiological studies.  And I think that Dr. Boisseau, Dr. Boobis, Dr. Coligano and Dr. Guttenplan  all spoke to this issue.  I won't put words 
in their mouths; if they would like to reiterate thei r answers to that question, they are welcome, but 
otherwise I would just note that this question has been asked and answered in the written responses.  WT/DS320/R/Add.7 
Page G-162  
 
  Chairman
 
 1058.  So if delegations have no further questions or comments to be put to the experts, I have the 
intention of giving the floor to each and every expert  to make concluding remarks if they so wish 
before we conclude our meeting this afternoon.  The floor is yours, distinguished experts.  Dr. Boobis. 
Dr. Boobis
 
 1059.  Thank you Mr. Chairman.  I have no specific comments.  I hope that I have answered the 
questions put to me as clearly and succinctly as possi ble.  I do believe that the information I provided 
in my written responses amplifies a number of those questions and hopefully will be a source of 
information as well to the Panel in their delib erations next week, and I thank you for your 
consideration and attention. 
Chairman
 
 1060.  Thank you.  Dr. Guttenplan first. 
Dr. Guttenplan
 
 1061.  Although I have mentioned genotoxic effects of oe strogens, I would like to point out that in 
an adult woman, typical levels of oestrogen are 180 to 2,000 picomols per litre, and this is going to 
occur over their lifetime with the exception of me nopausal state and pre-pubescence state.  They are 
only about 2 in girls.  So the potential genotoxic da mage that is done in an adult would overwhelm 
that that could be done in a child.  However, in boy s the levels are even lower, and there I think we 
have to worry about developmental effects, and ther e has been less said on that – Dr. Sippell has been 
the major proponent of that – and I still think that th ese could be investigated epidemiologically or in 
some type of study.  We might, as Dr. Boobis suggest ed, need a surrogate, perhaps saliva or urine, but 
I think it is perhaps the most important issue to a ddress is the sensitivity of children.  I should also 
mention hormone-sensitive cancers in post-menopausal women, it could be another concern.  Post-
menopausal women have levels of oestrogen that ar e similar to those of pre-pubescent girls, and if 
those levels are significantly elevated and you have a hormonal-sensitive cancer, you might be increasing the risk. 
Chairman
 
 
1062.  Thank you.  Dr. Sippell. 
Dr. Sippell  
 1063.  I just would like to add that after these two da ys and hearing all the other experts' further 
comments to their written answers, I think that as mu ch as children are concerned, we know really by 
no means enough and the data are really insufficient to tell or to be confid ent that this additional 
exposure from hormone-treated meat poses no risk.  I am very much concerned. 
Chairman
 
 1064.  Thank you.  Dr. Boisseau. 
Dr. Boisseau
  
 
1065.  Thank you, Mr. Chairman.  Over these past two days, I have done my best to provide as many 
clarifications as possible, responding to questions on  the methodology used in the different expert  WT/DS320/R/Add.7 
 Page G-163 
 
 
  groups, in particular the JECFA which I know well.  I insisted on the fact th at the evaluation is a 
collective evaluation, conducted by competent and i ndependent experts.  This method, even if it has 
not been formalized or officially adopted, was know n to everyone, and used practically throughout the 
world in the same way for all of the substances that  were evaluated.  I think that the hormones of 
which we have spoken were given special attention, a nd the data used were sufficient to enable us to 
come up with a risk assessment.  Having said this , an assessment can always be updated to take 
account of scientific progress.  Thank you Mr. Chairman. 
Chairman  
 1066.  Thank you.  Dr. Coligano. 
Dr. Coligano
 
 1067.  Thank you very much.  I found these last two days  extremely interesting and stimulating.  I 
think that there are times I'm glad that I am in science  and not in law, but I am sure that the rest of you 
are probably glad that you are in law and not in sci ence.  And I think what we are seeing here is the 
messiness of science as the data begin to accumulate but are not really sufficiently definitive to 
convince the entire scientific community, the way they are perhaps for something like tobacco 
smoking.  And actually I think that the last comment that the leader of the US delegation made about question 26; our responses are emblematic of wh ere these are.  Question 26 was what are the 
differences between breast cancer and prostate cancer between the US and Europe; are they due to this factor?  My own response was that it's one pl ausible cause but that there are many factors for 
breast cancer and the epidemiological studies cannot at this point sort out the difference between other 
dietary factors, physical activity, ethnic differences  between the different countries, to be able to 
attribute causality to any particular cause with any reasonable confidence.  So we are at this stage 
where we have suggestions but we cannot really r esolve them, and I think that is what you see the 
scientists trying to struggle with.  And when science  is in this phase you will find scientists on both 
sides of issues, as we just heard about ten minutes ago.   The idea of low dose effects of this is one of 
the major scientific controversies, and you do see scie ntists point to many studies on both sides of the 
issue, and it's not like going to be resolved any time soon.  But I hope you have gotten a sense of the 
range of scientific thought, I thin k you actually can see that among the experts in the written answers 
and in these discussions.  And I hope we have been he lpful and I wish you luck in going on to making 
a decision on this important issue.   
Chairman
 
 1068.  Thank you.  Dr. De Brabander. 
Dr. De Brabander
 
 
1069.  A small final remark, Mr. Chairman.  There is a lot said about risk assessment and I realize 
that indeed I was unable to help you very much on that item because I am an analytical chemist and 
control chemist, but as I expressed in my answers, I think there is more than  human health only, and 
then the following of good veterinary practice only,  there is also the influence of hormones on the 
behaviour of animals and animal welfare, there is also a concern about the environment.  And I think 
in the future, concern with the environment will be  more and more important, wherever it is in the 
world, and these are items I want to state in my final statement.  Thank you. 
Chairman  
 1070.  Thank you all very much for your contribution and active engagement in the discussion on the 
issues at hand.  I am particularly grateful for yo ur patience, sitting with us for two full consecutive WT/DS320/R/Add.7 
Page G-164  
 
  days, even without having one minute coffee break.  It was really difficult for us physically also.  I 
myself, and I think the same is true of my colleagu es in the Panel, we have learned a lot from our two-
day meeting, even though I must confess that I di d not fully digest your comments and replies on the 
technical issues; but I was very much impressed by  the depth of the expertise and breadth of the 
knowledge you have brought to the area of your expertise, and I think it will greatly contribute to the 
Panel's work in the future.  In the opening statem ent yesterday afternoon I stated that the Secretariat 
will provide a summary of the information and a tr anscript of the meeting for today and tomorrow.  
The Secretariat will do their best to make a tran script of the two-days meeting, but given the 
complexity of the issues and the difficulty to dig est the terminology used during the meetings, they 
cannot be quite sure about whether they can make a complete transcript of the meeting.  So at this 
point of time, the only thing I can say to you is that they will do their best to prepare that, but not with 
a 100 per cent guarantee.  I don't know whether my co lleagues in the Panel have additional comments 
before we conclude our meeting.  Then I will conclude this two-da y expert meeting now and the Panel 
will be meeting with the parties next week, starting on Monday, 2 October at 10 am.  The meeting will be held in the same room as today.  The meet ing of the Panel with the experts is concluded.  
Thank you very much for all your contributions.  Any point?  Canada. 
Canada
 
 1071.  Thank you, Mr. Chairman.  Just a very simple question.  Would the parties be provided with 
the transcript when it is provided?   
Chairman
 
 
1072.  I have been advised by the Secretariat that if the transcript is prepared, then it will be sent to 
the parties and experts for their comments.  WT/DS320/R/Add.7 
 Page G-165 
 
 
  Attachment 1  
 
Slides shown by Dr. Sippell 
 
WTO Panel on Hormones
Geneva, 27th & 28th September 2006
Paediatric Aspects
Wolfgang G. Sippell, MD, PhD
Professor of Paediatrics
Head, Division of Paediatric Endocrinology & Diabetology
Dept. of Paediatrics, Christian-Albrechts-Universität zu Kiel
University Children‘s Hospital 
Kiel, Germany
 
 
WTO Panel on Hormones
Geneva, 27th & 28th September 2006
•Although this dispute has already been going on for more 
than a decade, to my knowledge no paediatrician, let alone 
a paediatric endocrinologist, has been involved as a 
member on one of the expert committees.
•This is incomprehensible and pa radoxical in view of the fact 
that prepubertal children are indisputably the most sensitive and vulnerable members of the population (smallest body 
size, longest life expectancy).
•I see my mission here as advocate of and spokesperson for 
children and their specific needs:
Children are not just small adul ts, but something very special! 
They are our future!
 WT/DS320/R/Add.7 
Page G-166  
 
  WTO Panel on Hormones
Geneva, 27th & 28th September 2006
Factors supporting the validity of the supersensitive RCBA for 
Estradiol (E2) developed at the N.I.H., U.S.A.  (Klein et al. 1994)
The novel finding of significantly higher ( ∼8x) E2levels in 
prepubertal girls than in boys readily explains fundamental 
features of human biol ogy for the first time:
(1)
•Earlier onset of puberty in girls than in boys (mean 1 year)
•Faster bone maturation in girls than in boys
•Lower adult height in wome n than in men (mean 13 cm)
 
 
WTO Panel on Hormones
Geneva, 27th & 28th September 2006
Factors supporting the validity of the supersensitive RCBA for 
Estradiol (E2) developed at the N.I.H., U.S.A.  (Klein et al. 1994)
The novel finding of significantly higher ( ∼8x) E2levels in 
prepubertal girls than in boys readily explains fundamental 
features of human biol ogy for the first time:
(2)
•Higher weight for height/BMI in girls than in boys at start of 
normal puberty
  WT/DS320/R/Add.7 
 Page G-167 
 
 
  CPP Girls during/after GnRHa Treatment:
Weight Development (BMI – SDS) until Final Height
BMI SDS
-202468
Start of Rx
End of Rx
Diagnosis
Final heightBMI SDS
-404812
BMI SDS (diagnosis)-4 0 4 8BMI SDS (final ht)-4048
r=0.422, p<0.01DxStart EndFH
Heger/Partsch/Sippell, JCEM 1999
WTO Panel on Hormones
Geneva, 27th & 28th September 2006
Chronic estrogen excess increases BMI in children
(N = 52)
 
 
WTO Panel on Hormones
Geneva, 27th & 28th September 2006
Factors supporting the validity of the supersensitive RCBA for 
Estradiol (E2) developed at the N.I.H., U.S.A.  (Klein et al. 1994)
The novel finding of significantly higher ( ∼8x) E2levels in 
prepubertal girls than in boys readily explains fundamental 
features of human biol ogy for the first time:
(2)
•Higher weight for height/BMI in girls than in boys at start of 
normal puberty
•Incidence of Central Precocious Puberty (CPP) about 10x 
higher in girls than in boys
•Incidence of Constitutional Delay of Puberty much more 
common in boys than in girls
 WT/DS320/R/Add.7 
Page G-168  
 
  WTO Panel on Hormones
Geneva, 27th & 28th September 2006
•For ethical reasons studies to  investigate whether eating 
hormone-treated beef elevates estrogen levels in 
(prepubertal) children cannot  be performed (physical/ 
psychological injury in healthy children).
•Epidemiological studies comparing adverse effects in 
matched populations of (healthy) children eating beef from 
hormone-treated and untreated animals would also be 
unethical.
→“Protect children from unnecessary clinical trials!”
- Declaration of Helsinki
- Good Clinical Practice Guidelines- EU Parliament Ruling (“Better Medicines for Children”)Ethical considerations WT/DS320/R/Add.7 
 Page G-169 
 
 
  Attachment 2  
 
Slides shown by Dr. Tritscher 
 
International 
Food Safety Standards
Risk AssessmentRisk Assessment
WHOWHO
&&
FAOFAORisk ManagementRisk Management
CACCAC
&&
Member StatesMember States
Risk CommunicationRisk CommunicationJECFAJECFA
JMPRJMPR
JEMRAJEMRACCFACCCFAC
CCPRCCPR
CCRVDFCCRVDF
CCFHCCFH• International food safety standards (Codex standards) are 
developed following the risk analysis paradigm
• They are based on independent international scientific risk 
assessments 
• Codex Standards are an integral legal part in international food 
trade (WTO-SPS agreement)
 
 
ToxicologicalToxicological
EvaluationEvaluationExposure Exposure 
AssessmentAssessment
Key NOAEL
Uncertainty
factors
Safety standardSafety standard
e.g. ADI=NOAEL/Ufs
Chemical 
analysisFood 
consumption
X
ExposureExposure
Safety assurance:Safety assurance:
ExposureExposure < ADIADI
ExposureExposure >ADIADI;:Management
Decision
 WT/DS320/R/Add.7 
Page G-170  
 
  Marker residueJECFA Residue Evaluation
Total residueRatio marker/total residue
Metabolism &
Distribution studies
Field trials & GPVDDepletion curve & Confidence interval
1. estimate
ADI
Intake < ADI
2. estimateaccept MRL;
option to adjust MRLadjust MRL or
MRL not recommendF
MRL
1. estimate
ADI
2. estimateIntake assessment
Model food basketMedian Residue
Intake > ADI
 
 
 
 
__________