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Minutes of the meeting
held at 10.30am on Monday 17 July in Room 125A, Skipton House, Department of Health, London SE1 6LH.
1. PRESENT
Chairman
Professor P G Blain |
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Members
Professor C Cooper
Professor D Harrison
Professor D Forman
Ms D Howel
Dr S Kennedy
Ms M Langley
Professor D Phillips
Dr R Roberts
Dr R Shuker
Professor A Renwick
Professor G Williams |
Assessors
Mr A Browning (VMD)
Mrs K Cameron (DETR)
Mr T Holmes (PSD)
Dr A Smith (HSE)
Dr H Stemplewki (MCA) |
Secretariat
Ms F Pollitt (Scientific)
Mr J Battershill (Scientific)
Mr S Robjohns (Minutes)
Mr K N Mistry (Administrative) |
In Attendance:
All Meeting
Dr J Greig (FSA)
Dr R J Fielder (DH)
Item 3
Dr H Walton (DH) |
Item 4
Professor K Chipman (University of Birmingham)
Dr A Mally (University of Birmingham item 4) |
Item 5
Professor A Boobis (DH Toxicology Unit item 5)
Mr R Pitts (Genetics commission)
Dr H Walton (DH) |
ITEM 1: APOLOGIES FOR ABSENCE
2. Apologies were received from Professor J Parry.
Announcements
3. New committee members were welcomed.
4. Members were informed that the secretariats for the COT, COM, and COC had been reorganised following the establishment
of the Food Standards Agency on 3 April 2000. The Committees would report to the Chief Medical Officer (Professor
Liam Donaldson) and also to the Chairman of the Board for the Food Standards Agency (Professor Sir John Krebs).
The terms of reference for the Committees would be altered in the near future to reflect this change. A joint DH/FSA
secretariat had been set up with FSA leading for the COT and DH leading for COC/COM.
5. Members were reminded of the need to declare interests before the discussion of each item. Members were informed
that the procedures for greater openness of Committee business were being followed.
ITEM 2: MINUTES OF
MEETING ON 23 MARCH 2000 (CC/MIN/2000/1)
6. The minutes were agreed subject to minor editorial
changes.
ITEM 3. A STRATEGY
FOR FUTURE WORK ON ENVIRONMENTAL CARCINOGENS
3.1 Work on cancer undertaken
by the Environment and Health Branch (CC/2000/8)
3.2 Strategy for identifying
and assessing the risk of environmental carcinogens (CC/2000/9)
7. The Environment and Health Branch of the Public Health Group, which provides the secretariat to the COC, is
responsible for advice on the health implications of chemicals and of radiation in the environment. The work currently
undertaken on cancer is summarised for information in CC/2000/8. The Branch has drawn up a strategy for future
work which could improve the Department's knowledge of the relationship between environmental chemicals and cancer,
which was outlined in CC/2000/9, and was seeking the committee's views on the proposed work programme and on any
areas of work which were missing from the draft strategy.
8. Members considered first a proposal that it develop authoritative statements about which of the human cancers
are associated with environmental chemicals. The committee considered that, where possible, the statements should
indicate the strength of any association and the confidence intervals. There would be a need to update the statements
as new information became available, as a major part of the strategy should be continuing work to identify new
environmental carcinogens.
9. The secretariat had proposed that the cancers to be considered in this way would be the most common cancers
- the committee suggested that cancers of the pancreas and cervix might be included in this group - and those cancers
which are increasing in incidence and where the increase cannot be accounted for by improvements in diagnosis or
registration. The committee advised that the second category should be those cancers where the incidence is changing,
since inclusion of cancers which are decreasing in incidence eg stomach cancer, would allow the hypothesis of a
relation between environmental chemicals and human cancer to be tested. Cancers likely to be associated with environmental
chemicals - leukaemias and liver cancer - should also be included. It would be valuable, in terms of public information,
to comment in the statements on what was known about other causes of the cancer under consideration.
10. Members then discussed a proposal to develop a ranking method for chemical carcinogens, with a view to producing
a priority list of environmental chemical carcinogens for regulatory or other action. It considered that this was
an attractive idea but could be difficult to realise given the limitations in the data available. Clear criteria
against which to rank a chemical would be needed in developing the method and it would be essential to keep in
mind the eventual use of any ranking list. Expert mathematical input may be needed in developing a model. The secretariat
was asked to prepare an overview paper with more detail on the proposed approach for discussion at the next meeting.
11. Detailed discussion of further work on the issue of genetic susceptibility to environmental chemicals was deferred
to Item 5. However, members commented that there was little information at present specifically on genetic susceptibility
to environmental chemicals and, therefore, although there was a pressing need to develop appropriate criteria to
evaluate such studies, it was considered that, work in this area might not contribute significantly to a strategy
on environmental chemicals at the present time.
12. Another important emerging area is the use of biomarkers to refine exposure assessments for carcinogens in
epidemiological studies. The committee was asked to comment on a proposal to carry out a review of the literature
in this area for comment and advice on the feasibility of further work. The committee agreed that a major difficulty
in assessing risk from low levels of chemicals was the exposure assessment, and that exposure assessments based
on biomarkers could potentially be helpful. However, in cancer studies there was the problem of the lag period
between exposure and effect, which made retrospective studies using biomarkers of little value unless suitable
stored samples were available. Prospective studies would be extremely expensive. The literature on biomarkers of
exposure was large and good reviews were already available but there were few studies in the literature on biomarkers
of risk. The committee concluded that there would probably be little value in pursuing this area in detail at present.
13. The final proposed area of work in the strategy addressed the potential risk of mixtures of environmental carcinogens.
Members considered that, although there was clear evidence of synergistic effects of some carcinogens at high levels
of exposure (eg tobacco smoke and asbestos or radon), there was no evidence of such effects in mixtures of chemical
carcinogens at the low levels found in the environment. This made it difficult to devise a research programme to
address this concern. Overall, in the context of a strategy on environmental carcinogens, this was not considered
a high priority area for further work.
14. The committee was also asked to comment on a proposal to estimate the size of the cancer risk from air pollutants
by considering the proportion of cases for the relevant cancer which are unexplained by other causes, and assuming
that not more than this proportion could be caused by an air pollutant known to be carcinogenic at this site. Members
considered that little value could be attached to such estimates in view of the limitations in deriving estimates
of population attributable risk and the multifactorial aetiology of most cancer.
ITEM 4: NON-GENOTOXIC
CARCINOGENS (IDENTIFICATION OF CHEMICALS FOR DH FUNDED RESEARCH CC/2000/10).
15. The development of rapid methods for the identification of chemicals that induce cancer by non-genotoxic mechanisms
that are relevant to humans will be beneficial for public health in allowing more compounds to be adequately assessed.
This would also reduce the need for long term studies using very large numbers of animals. For these reasons the
COC identified this as an important research area when considering research priorities in 1996. The COC reviewed
a paper prepared by the DH Toxicology Unit at the November 1999 meeting. Members noted that mutations are found
in many chemically induced cancers. Members agreed that the most important non-genotoxic mechanisms could be placed
into one of four groups, (i) persistent cytotoxicity accompanied by proliferative regeneration, (ii) chronic inflammation
accompanied by the production of reactive oxygen species, (iii) hormomimmetic activity and (iv) ligand binding
with xenobiotic induction receptors. Members considered that increased cellular proliferation was of particular
significance. Members also noted that no one test would be suitable for the detection of all non-genotoxic carcinogens.
16. CC/2000/10 outlined three approaches on the identification of non-genotoxic carcinogens that could be included
as test chemicals in the project. A number of chemicals have been identified as suitable for use in research to
evaluate the potential for developing a in-vivo test for non-genotoxic carcinogens.
The approaches were:
i) A systematic review of IARC groups I and 2A and E.U categories 1 and 2. This approach was intended to identify
non-genotoxic carcinogens, which are either known or probable human carcinogens. Less emphasis had been given to
identification of non-genotoxic carcinogens from IARC group 2B and E.U category 3 carcinogens as there was often
only limited evidence that such chemicals pose a hazard to humans.
ii) Non-genotoxic carcinogens which induce tumours via mechanisms which are believed to be relevant to humans.
iii) Non-genotoxic carcinogens suggested by regulatory authorities. These could include chemicals where there was
little or no toxicological information published in the scientific literature or chemicals where there were uncertainties
in the mechanism of carcinogenicity.
17. Professor Chipman made a presentation to COC on the outline of the proposed research project. The studies were
to involve daily administration of the test chemicals to rats over a period of 28 days using three dose levels
selected from the available information from carcinogenicty bioassays. Molecular markers indicative of disturbance
of cell cycle control, intercellular communication and inhibiton of apoptosis would be studied at two time points
(3d and 28d). The evaluation of mediators would involve the use of immuno-histochemical methods.
18. Members considered that analysis of regulation of the cell cycle and apoptosis would be important. The phosphorylation
of gene products (e.g. Rb, E2F) was critical for the regulation of the cell cycle and the members commented that
further consideration needed to be given to the phosphorylated status of the molecular markers. It was suggested
that the research team at Birmingham attempt to use antibodies for phosphorylated products and to look "downstream"
at products having increased expression. It was also suggested that NFKappaB as an inhibitor of apoptosis be assessed
as well as Bcl2.
19. The committee agreed that priority should be given to carcinogens that pose the greatest hazard to humans and
were also carcinogenic to the rat. For pragmatic reasons the work would only consider the oral route of exposure.
Members made a number of suggestions for research based on the information given in CC/2000/10 and stressed the
need for appropriate negative controls. Professor Chipman noted that inclusion of a further positive control (such
as phenobarbitone or a peroxisome proliferator) and d-limonene as a negative control in the female rat would be
valuable.
20. Members agreed that TCDD, oestrodiol, hexachlorobenzene and tetrachloroethylene should be considered as high
priority, and that cyclosporin should not be considered further as this chemical was not carcinogenic in standard
life-time bioassays on animals. It was suggested that chloroform, nitrobenzene, alachlor, methapyriline, pyrilamine
(a non-carcinogenic structual analogue of methapyriline), dichlrobenzene and paracetamol could be considered to
be of interest.
ITEM 5: GENETIC SUSCEPTIBILITY
TO ENVIRONMENTAL CARCINOGENS: DISCUSSION OF TOPICS FOR FURTHER REVIEW (CC/2000/7)
21. The committee was aware that potential genetic susceptibility to environmental chemicals had been the subject
of recent media attention. Members had seen the recent Friends of the Earth report 'Crisis in chemicals' cited
in ENDS Report 304 May 2000 (CC/2000/12) which had been submitted for information. There was a need to draw conclusions
on the available information on metabolic polymorphisms associated with specific cancers and to make statements
about the significance, if any, for public health regarding exposures to environmental chemicals. However this
was a difficult task, for example most available studies are too small to allow any definite conclusions to be
drawn. The list of nine polymorphisms reviewed by IARC in the recent scientific publication (CYP1A1, CYP1A2, CYP2D6,
CYP2E1, GSTM1, GSTM3, GSTT1, NAT1, NAT2) was suggested as a useful starting point. Members suggested that polymorphisms
for genes other than those involved in the metabolism of xenobiotics should be included (e.g. DNA repair). Members
noted that metabolic polymorphisms may provide some information on susceptibility but many other factors such as
exposure, diet, lifestyle are likely to be more important. Thus the implications of metabolic polymorphism studies
regarding susceptible and non-susceptible groups need to be reviewed in the context of all the available information
on a case-by-case basis.
22. The committee heard about the work of the Human Gene Commission and of the importance of ethical issues principally
concerning discrimination in the area of employment. The committee agreed that its remit was to advise on the scientific
aspects of gene-environment susceptibility to cancer. It was felt that the information to be reviewed by the committee
would most likely relate to small increases in relative risk that needed to be considered in relation to other
factors involved in the aetiology of cancer.
Members suggested three main areas for possible further work:
Criteria for the
design of gene-environment epidemiology studies
23. The committee considered that this should include the rationale for selection of polymorphisms in epidemiology
studies, such as metabolism, DNA replication/repair, and should include a discussion on the need for a mechanistic
link to cancer. Aspects of good study design would include selection of case/controls, identification of cancers,
exposure assessment, reporting of analyses, consideration of post-hoc analyses, and model calculations of study
size given assumptions on penetrance, and relative risk of disease.
A review of potential
target genes for susceptibility to carcinogenesis
24. This would not repeat the work of IARC regarding polymorphisms of metabolism. The paper could summarise the
available information for a wide range of potential target genes, including those with most evidence and possibly
identify those with little or no evidence for an association with cancer. The power and precision of previous studies
would need to be assessed. Members suggested that potential target genes other than those involved in the metabolism
of xenobiotics could be looked for, and that the results of such a review might be useful for the assessment of
future research priorities. Members agreed that this was a difficult task as the work could involve several hundreds
of genes of unknown function within the present level of understanding.
A review of how gene-environment
studies should be used in risk assessment process
25. The committee suggested the use of IARC proposals for criteria for assessing causality, could be used to determine
which gene-environment associations should be used in the risk assessment process. A discussion on the value, for
risk assessment, of identifying a susceptible population (i.e. what RRs have been found, what RRs would raise concern)
would be useful. Members also suggested that the practical value of evaluating the mode of interaction regarding
gene susceptibility to environmental carcinogens should be looked at, and asked what approaches could be developed
to take account of genetic susceptibility in the risk assessment of non-threshold genotoxic carcinogens.
26. Members agreed to review this subject when appropriate papers had been drafted.
ITEM 6: PAPERS FOR
INFORMATION
27. 6.1 Friends of the Earth (FOE) Report: Crisis in Chemicals (members only)
CC/2000/11
28. 6.2 ENDS Report
ITEM 7: ANY OTHER
BUSINESS
ITEM 8: DATE OF NEXT
MEETING: 9 NOVEMBER 2000
ACTIONS
| Item |
Action |
Who |
| 3.Strategy for
future work on Environmental carcinogens |
Review strategy and develop proposals and examples
of assessment |
Secretariat |
| 4.Non-genotoxic
carcinogens |
Consult members on proposals for chemicals and advise
Professor Chipman |
Secretariat |
| 5.Genetic susceptibility |
Outline proposals for further work - initiate appropriate
papers from DH Toxicology Unit |
Secretariat |
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