UNITED STATES – CONTINUED SUSPENSION OF OBLIGATIONS IN THE EC – HORMONES DISPUTE
Document: Report of the Panel Addendum
Date: 31 March 2008
Document codes: WT/DS320/R/Add.7; WT/DS320/R.
Complainant: EU
Respondent: U.S.
Third parties: Australia, Brazil, Canada, China, Taiwan, India, Mexico, New Zealand, Norway
Dispute stage: Appellate Body
Agreements cited: Art. I, II  GATT 1994Art. 3.7, 22, 23.1, 23.2, 21.5  Dispute Settlement Understanding (DSU)

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

Report of the Panel

Addendum

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

 – Annex A: Add.1
 – Annex B: Add.2
 – Annex C: Add.3
 – Annex D: Add.4
 – Annex E: Add.5
 – Annex F: Add.6

ANNEX G

TRANSCRIPT OF THE PANEL'S JOINT MEETING
WITH SCIENTIFIC EXPERTS 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 delegation will introduce himself or herself.
4. Good morning. My name is Thomas Jürgensen – 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 officials, 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.

12. Annie Sasco from the University of Bordeaux, cancer epidemiologist.
13. Manfred Metzler, Professor of Food Chemistry, University of Karlsruhe, Germany.
14. Niels Skakkebaek, Medical Professor, Growth and Reproduction, Copenhagen University.
15. Henrik Leffers, Microbiologist, Growth 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 French 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,

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 the 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.

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 provided 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 slowly. 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 statements should be shared with the interpreters so as to
facilitate their task and ensure 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

international organization representatives to make some concluding remarks, if they so wish, before
moving on to next area. In addition to the four predetermined 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 facts. 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 meeting 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. Each 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 information 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

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 residues 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 important 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 should 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.

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.

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 trained 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 control 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 prepared 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 speciality is to do refined steroid analysis in very
small samples from children, from premature 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 already 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.

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 age 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 children. I thank you for your attention.
Chairman

73. Thank you. I now request Dr. Miyagishima, the Codex representative, to take the floor.

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 continued 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.

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 veterinary 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

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 any 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 carcinogenic. 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.

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 course changes specific meanings and significance. 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 substance 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?

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 mechanism, there is this concept that has 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 observation 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 mode 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

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 whether 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.

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

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 prostate 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 you 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 provided 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 combination 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

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 extracted 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 CO 2, for example, which is radioactive if it is the
carbon of the CO 2 that is marked – it is not because this CO 2 is reincorporated in a protein synthesis
that it will necessarily pose a safety problem for the consumer. In other 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.

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, and 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.

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 absorption, 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

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 males, 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 the 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

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, takes 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.

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. There 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

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 per day, and how they are converted. Dr. Boobis.

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 much mass in grams per one litre of liquid. They are
scaled to units of 10 according to the Système international, 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 absolute 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 per 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.

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 – depending on the sensitivity of the receptor – it is

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 directions, 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 coming 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, because 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 xenobiotic, it can be xenobiotic in one species and not in another one,
and also in certain conditions.

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-receptor 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 genotoxicity, 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.

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.

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 (17β).
Chairman

213. Dr. Boobis
Dr. Boobis

214. Oestradiol-17β 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 clarified some of our questions. Thank you.

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

liver, 50 grams kidney, 50 grams fat, 1½ litres of mi lk, 100 grams of eggs and 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

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 the 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 consider other factors in setting the final 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

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 finally, 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 recommended 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?

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 transmitted 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 other 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 Codex 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.

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 considerations; 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 evaluated 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 rather 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.

exposures, to simplify the two questions. As I mentioned 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 then 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

whatsoever. There will be risk at any dose no matter 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 give 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

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 enables 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

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 enabled the Committee to set an ADI for 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 consideration 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 substance 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

State, in each country, according to the nutrition habits 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, national 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

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 whether 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 they 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.

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.

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?

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 protocol – that work has been going on for a number of years within the

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 and 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 attempted 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 Alimentarius. 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 Canadian 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.

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 available, 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

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 health 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 invited by JECFA to the Committee meetings?

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 other'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.

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 still 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 cancer in endocrine sensitive tissues.

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 birth-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 available, 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 the 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 was 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 Research 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.

Dr. Boisseau

331. Thank you, Mr. Chairman. There are two hypothetical 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 added and to take this additional uncertainty into account. Thank you.

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 the 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 this 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.

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 the 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

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.

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 ask: 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 questions – 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

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 information 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 scientific 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.

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 the 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, perhaps, 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

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 evidence? 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 practically 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 questions, 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

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 assessment. The nature of the
evidence available on science in general 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 repeat 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

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, what 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

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 description, but there are also written comments to the
deterministic versus probabilistic, 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

what is called quantitative risk assessment, extrapolating 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, and 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 been 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

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

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.

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 threshold? 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

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 ...

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 adverse 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 are 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

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 IARC 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

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-response 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 ...

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 step 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 quantitative 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 itself 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 just 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 produce a quantitative risk assessment.

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 assessment, 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.

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 identification 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 characterization 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.

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 quantitative 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 years 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 consideration before drawing any final conclusions.

Chairman

464. EC.
European Communities

465. Sorry, I did it on purpose not to ask specifically 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, which 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 formalized. 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

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 check 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

we have not got into this yet, when JECFA ev aluated the specific compound in question – and what
my answer was was a general 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 this 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-assessment 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.

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 remaining questions on area 2. As you may recall,
before we adjourned the meeting yesterday 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 representative, 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 evidence telling us about that endpoint. Thank you.
Chairman

488. Thank you. Any others – Dr. Boisseau.

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 approach requires a de novo evaluation 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

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-17β – 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 genotoxicity person with us at that meeting 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

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 organizations 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 have 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.

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 substance 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?

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 Director 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 the basic text of the Food and Agricultural Organization of the United
Nations, and as Dr. Tritscher explained, the same rules 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

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 where 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-17β, 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

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-evaluation 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 the 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 2006. 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.

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 pose their questions. Starting with EC.

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 forms 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

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 more 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 particular with respect to quality of the study. There

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 submitted are scrutinized in detail, checked for accuracy and
then summarized and described in detail. 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-17β, is much higher.

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-sensitive 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-17β, 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.

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 discussion 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 evidence that is on the record.

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, levels 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 been validated adequately, but secondly 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 higher 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 measured by the most sensitive assays?
Chairman

575. Dr. Sippell.

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 myself, trained as an auditor, and when I go to a lab
and they have qualitative methods (of 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 laboratory 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).

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 greater 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 another. 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).

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 body, the natural hormones
are indistinguishable from the native hormones and would 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 particularly 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 don't have the time to ask our questions.

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 the 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.

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 about 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 hormone 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 question 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

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 ask. 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 assessments. 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 about normal exposure conditions. 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

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 question 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

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 residues linked to the treatment. Even
if there is no treatment, there is in any case a basic level 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

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?

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 consensus 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.

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 data date from the 1970s and 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 question, 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 depletion studies that were provided by the Food and
Drug Administration of the United States. Now these 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.

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

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 editing 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

think, the hormones were evaluated in the mid-1980s and 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 fundamentally 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.

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 components 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 today'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 melengestrol acetate because we don't have the means,
we don't allow it and why should we do that, it is not our task.

Chairman

676. Yes. I would like to remind the delegations that 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 level 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

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 and 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-17β. 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

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 pragmatism 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 takes 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 been 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 and 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 1980s 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

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 monograph 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 mentioned 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 ...?

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

response, they are a genotoxicity response, and so I would say that I have yet to be convinced that
oestradiol 17β 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 significance 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.

European Communities

717. Thank you. This is, I think, an important clarification. 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 think 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 examples, 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 effect 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 JECFA 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, because 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 European Union level, since everybody works in the same way. So we

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 whatsoever, 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.

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 should 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, the 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

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.

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 clarifications 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

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 testimony 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.

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.

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 slide, 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 problem and avoid any delays, we are not going to show
the slide in this instance to please and satisfy 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 context, 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 their questions. OK. US, you have the floor.

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 scientists to say whether as risk 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.

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 difficult 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

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 scientific 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 those 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.

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 growth 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 practice, 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 are 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

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 cancer 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 add 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 increased, associated with the use of these types of
chemicals in products.

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 perspectives 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.

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 for 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.

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.

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, but 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.

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 received 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

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 same 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.

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 evidence 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 anything 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 relevance of that, and the other thing of course is that I

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 list 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 consumed 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 turns them into early puberty.

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

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 that 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.

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, and not a European inspector, but there are.

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 with 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 exhausted its list of questions.
Canada

888. We just have one more question on detection methods of residues 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 recovery is low, so if you 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 drive 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.

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 constraints I don't expect that we will get the data we
need to answer these questions 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 any 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

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 consistent 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 experts, 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.

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 throughout 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

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

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 have 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.

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-hormonally 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?

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 remember 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?

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 point 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.

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 assessment? 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-17β. 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.

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 were 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 significantly 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.

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 environmental dose. So this is nothing 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, which 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

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 correctly, 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

bullet-point list of gaps you have identified, a nd in your reply to question 61 you speak of an
assessment for melengestrol acetate 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.

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-17β?
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

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 actually 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.

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 like 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 tumours 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.

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-sensitive 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.

Dr. Cogliano

1023. Thank you. I think the comment that a lot of th is is a question of interpretation, 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.

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 within 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?

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 mentioned 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 hormonal cause is assumed to result from pre-existing
mutations, and then those pre-existing mutations, those 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.

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, beginning to stimulate and inhibit an entirely different
set of genes and an entirely different set of responses. 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 use 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.

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 explanations. 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

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.

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 suggested, 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

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 known 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

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 colleagues 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-day 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.

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 paradoxical 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 adults, but something very special!
They are our future!

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) E2 levels in
prepubertal girls than in boys readily explains fundamental
features of human biology 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 women 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) E2 levels in
prepubertal girls than in boys readily explains fundamental
features of human biology for the first time:
(2)
• Higher weight for height/BMI in girls than in boys at start of
normal puberty

CPP Girls during/after GnRHa Treatment:
Weight Development (BMI – SDS) until Final Height
BMI SDS
-2
0
2
4
6
8
Start
 of Rx
End
 of Rx
Diagnosi
s
Final hei
ght
BMI SDS
-4
0
4
8
12
BMI SDS (diagnosis)
-4 0 4 8
BMI SDS (final ht)-4
0
4
8
r=0.422, p<0.01
DxStartEnd FH
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) E2 levels in
prepubertal girls than in boys readily explains fundamental
features of human biology 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

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

Attachment 2

Slides shown by Dr. Tritscher

International
Food Safety Standards
Risk AssessmentRisk Assessment
WHOWHO
&&
FAOFAO
Risk ManagementRisk Management
CACCAC
&&
Member StatesMember States
Risk CommunicationRisk Communication
JECFAJECFA
JMPRJMPR
JEMRAJEMRA
CCFACCCFAC
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
EvaluationEvaluation
Exposure Exposure
AssessmentAssessment
Key NOAEL
Uncertainty
factors
Safety standardSafety standard
e.g. ADI=NOAEL/Ufs
Chemical
analysis
Food
consumption
X
ExposureExposure
Safety assurance:Safety assurance:
ExposureExposure < ADIADI
ExposureExposure > ADIADI

Management
Decision

Marker residue
JECFA Residue Evaluation
Total residue
Ratio marker/total residue
Metabolism &
Distribution studies
Field trials &
GPVD
Depletion curve &
Confidence interval1. estimate
ADI
Intake < ADI
2. estimate accept MRL;
option to adjust MRL
adjust MRL or
MRL not recommend
F
MRL
1. estimate
ADI
2. estimate
Intake assessment
Model food basket
Median Residue
Intake > ADI