COC Meeting 18th November 2004
Minutes
Present:
| Chairman: | Members: | Secretariat: |
| Professor P Blain CBE | Dr C Allen | Mr J Battershill (Scientific- DH) |
| Professor D Phillips (Item 6) |
Professor A Boobis OBE | Ms F Pollitt (Scientific- DH, pm only) |
| Dr P Carthew | Mr D Renshaw (Scientific-FSA) | |
| Professor P Farmer | Mr S Robjohns (Minutes - DH) | |
| Mrs Rosie Glazebrook | Mr K N Mistry (Administrative) | |
| Professor D Harrison |
||
| Ms D Howel | ||
| Dr S Kennedy | ||
| Professor D Phillips | ||
| Dr R Roberts | ||
| Professor D Phillips | ||
| Dr N Wallis |
| In Attendance: | |
| Dr S Bull | (DH Tox Unit, item 6) |
| Dr K Fletcher | (DH Tox Unit, item 6) |
| Ms A Grosskurth | (DH, item 4) |
| Mr K Okona-Mensah | (DH Tox Unit, item 5) |
| Terresa Quin | (HSE) |
| Annette Smith | (HSE) |
| Dr H Walton | (DH, item 5) |
| Assessors: | Observers: |
| Dr A Smith (HSE) | Dr D Binham (Imperial Tobacco ) |
| Mr R Shayer (PSD) | Dr J Collard (JT International) |
| Ms Jackie Maud (EA) | Dr E Massey (BAT) |
| Dr A McNeil (University College London) | |
| Mr K Scott (Gallagher) | |
| Mr J Thompson (BAT) |
| Contents | Paragraph(s) | |
| Item 1: | Apologies/announcements | 2 |
| Item 2: | Minutes of 24 June 2004 (CC/MIN/2004/2) | 5 |
| Item 3: | Matters arising not covered by later agenda items: |
|
| 3.1 3rd Draft working paper on prostate cancer (CC/04/27) |
6 | |
| 3.2 1st Draft working paper on Malachite Green/Leucomalachite green (CC/04/28) | ||
| 3.3 1st Draft working paper on Toxicogenomics (CC/04/29) |
||
| 3.4 HSE Priority programme: |
9 | |
| 3.4.1 HSE workshop on the epidemiology of occupational Cancer (CC/04/38) |
11 | |
| 3.4.2 Discussion of identification of priority chemicals (CC/04/39) |
14 | |
| 3.5 Genotoxic carcinogens and DNA repair at low doses - COM conclusions (CC/04/36) |
17 | |
| 3.6 Storage of ED01 nitrosamine data | 21 | |
| 3.7 COC guidance on risk assessment | 22 | |
| 3.8 Alcohol and breast cancer | 23 | |
|
||
| Item 4: | Re-assessment of toxicological testing of tobacco products (CC/04/30) |
24 |
| Item 5: | Childhood cancer: |
|
| 5.1 Childhood cancer - Overview paper (CC/04/31) | 30 | |
| 5.2 Childhood leukaemia and environmental exposures (CC/04/37) |
39 | |
| Item 6: | Horizon scanning paper (CC/04/32) | 45 |
| Item 7: | Papers for information: | 45 |
Published paper reporting NOEL for MeIQx |
||
| Item 8: | Any other business | 54 |
| Item 9: | Date of next meeting | 55 |
ITEM 1: APOLOGIES FOR ABSENCE/ANNOUNCEMENTS
2. Apologies for absence were received from Professor D Forman, Dr D Benford (FSA scientific secretary), Dr H Stemplewski (MHRA) and Alison Gowers (EA).
Announcements
3. The Chairman welcomed Dr D Renshaw (FSA) who was attending in place of Dr D Benford (FSA), Mr K Okona-Mensah (DH Tox unit), Dr K Fletcher (DH Tox unit), Dr S Bull (DH Tox Unit), Ms A Grosskurth (DH), Annette Smith (HSE), Terresa Quin (HSE) and Jackie Maud (EA) attending for Alison Gowers (EA).
4. Members were reminded of the need declare any relevant interests before discussion of items.
ITEM 2: MINUTES OF THE MEETING OF 24 JUNE 2004 (CC/MIN/2004/2)
5. The minutes were agreed subject to minor editorial changes.
ITEM 3: MATTERS ARISING NOT COVERED BY LATER AGENDA ITEMS
3.1 3rd Draft working paper on prostate cancer (CC/04/27)
6. The COC considered an overview paper on prostate cancer from the DH toxicology unit at the November 2003 meeting and a 2nd draft working paper was considered at the June 2004 meeting. Members were asked for any comments on a 3rd draft working paper that had been prepared following consultation with the COC epidemiologists.
7. The committee agreed the 3rd draft working paper with a number of minor amendments. The finalised statement would also be forwarded to the Advisory Committee on Pesticides for information.
3.2 1st Draft working paper on malachite green/leucomalachite green (CC/04/28)
8. The draft working paper on malachite green/leucomalachite green had been considered by the COM at its meeting on 7 October and a number of amendments were made. The COM had agreed that both malachite green and leucomalachite green should be regarded as in-vivo mutagens, but noted that the dataset was unusual and not entirely consistent. The COC agreed the draft working paper with a number of editorial changes.
3.3 1st Draft working paper on toxicogenomics (CC/04/29)
9. The committee was asked to comment on the COC relevant sections of a joint COT/COC/COM draft working paper on toxicogenomics. A further section reporting the presentation of from Dr David Lovell (held at a COT meeting on 7 September 2004) had been added after the COM meeting on the 7th October 2004.
10. Members agreed the draft working paper with a number of editorial changes. Members were informed that further consultation with COT members on the overall conclusions was required in order to finalise the statement.
3.4.1 HSE Workshop on the epidemiology of occupational cancer (CC/04/38)
11. Occupational carcinogens have been designated as one of the priorities in the HSE strategic programme to reduce risks posed by chemicals in the workplace. In June 2004, the COC was provided with a short introduction to the HSE plan for a programme of work on chemical carcinogens. Paper CC/04/38 provided more information on one of the first key activities, namely, a workshop of invited experts to look critically at the burden of cancer that could be attributed to occupational exposure in the UK. The COC was invited to comment on this activity. HSE informed members that the overall objective was to formulate a strategy which included recommendations for risk reduction by 2006. An initial data collection and assessment phase had been initiated which included the workshop and gathering views from independent advisory committees and stakeholders.
12. It was noted that the estimate of burden of cancer due to occupational cancer were based on the work published in 1981 by Doll and Peto that estimated the proportion of cancer mortality in the USA due to occupational causes to be around 4% (uncertainty range 2-8%) (Doll R, Peto R. (1981).J National Cancer Inst 66, 1191-1308). HSE planned to hold two workshops to review evidence on occupational cancer with the intention of reviewing the burden of cancer that can be attributed to occupation in Great Britain.
13. Members felt that this was a worthwhile and ambitious project. It was noted that the Doll Peto analysis had analysed cancer attributed to occupation in the USA. Members commented that industrial exposures to chemicals had changed rapidly over the past two decades and the estimate of cancer burden associated with chemicals in use could not be assessed on the available current cancer mortality data. The Committee asked to be kept informed on developments arising from the workshop.
3.4.2 Discussion of identification of priority chemicals for HSE sub programme on carcinogens (CC/04/39)
14. HSE had begun as part of the sub programme on carcinogens to collate available evidence on chemical carcinogens and information on occupational exposures.
15. Paper CC/04/39 provided the COC with a first opportunity to consider an initial draft list of priority carcinogens. Members noted the difficulty of using currently available data on carcinogens and exposures to select a priority list. Members had a number of suggestions for further consideration by HSE which included formaldehyde, a number of halogenated hydrocarbons, dioxins, PCBs, chromium III compounds and pesticides. The committee also queried inclusion of occupational carcinogens where exposures were well controlled and the number of potentially exposed individuals was low, eg wood dust. Members agreed the need to further consider diesel exhaust . One member noted the endogenous formation of ethylene oxide would need to be considered during the review process.
16. The Chairman thanked Members for their comments and asked any further comments should be forwarded to HSE or the secretariat. HSE thanked the Committee for an opportunity to present the paper and informed members that they would consider all the suggestions made in the light of the available evidence on carcinogenicity together with the outcome of the workshop to help formulate priorities.
3.5 Genotoxic carcinogens and DNA repair at low doses - COM conclusions (CC/04/36)
17. The COC had asked the COM to provide advice regarding an approach to evaluating the significance of DNA repair induction at low doses of genotoxic carcinogens in the context of the hormesis hypothesis. The COM recommended a literature search targeted on low dose effects of a few direct acting chemical mutagens on DNA adduct formation, mutation rates, and the significance of DNA repair mechanisms. The COM had also recommended that the search should concentrate on low molecular weight compounds such as ethylene oxide and ethyl or methyl methanesulphonate, for which there was a rich database. Members had agreed that bacteria would most likely demonstrate more sensitivity to low doses of mutagens than mammalian cells.
18. The DH Toxicology unit had prepared a paper (MUT/04/14), which evaluated low dose response data from mutagenicity studies where DNA repair of target cells had been modified. Overall, the COM had concluded that there was no convincing evidence for a 'J' shaped dose response relationship in any of the data considered. The COM agreed that the data considered in the paper did not warrant reconsideration of the COM's advice that it is prudent to assume that in-vivo mutagens do not have a threshold for mutagenicity, unless there is good evidence to the contrary.
19. The COC was asked whether any further consideration of DNA repair at low doses of mutagens should be undertaken and whether any further consideration of the concept of hormesis was warranted at the present time.
20. Members agreed with the COM conclusions and did not recommend further work at present, but considered that a watching brief should be kept on this topic. The COC felt that it was possible that DNA repair processes could be induced at low levels of exposure to mutagens, but that it would be very difficult to observe such effects experimentally in in-vitro mutagenicity assays. The committee concluded that for the purposes of carcinogen risk assessment it remained prudent to assume that there was no threshold for genotoxic carcinogens.
3.6 Storage of ED01 nitrosamine raw data and effects
21. Members were informed that the secretariat had arranged for the raw data (tissue samples and slides), arising from studies on low doses of nitrosomaines conducted by BIBRA in the early 1990s, to be stored at Qualogy for a period of 3 years.
3.7 COC Guidance on a Strategy for the Risk Assessment of Chemical Carcinogens
22. Members were informed that the COC Guidance on a Strategy for the Risk Assessment of Chemical Carcinogens had been published. The secretariat thanked all members for their contributions to the document.
3.8 Alcohol and Breast Cancer
23. Members queried when the COC statement on alcohol and breast would be published. The Committee was informed that the Imperial research group had not yet got the paper accepted for publication. Members agreed that the COC statement should be published immediately.
ITEM 4: RE-ASSESSMENT OF TOXICOLOGICAL TESTING FOR TOBACCO PRODUCTS (CC/04/30)
24. Dr Kennedy declared an interest and informed the committee that GSK marketed nicotine patches as aids to smoking cessation. She withdrew from the discussion. The Chairman welcomed observers from the tobacco industry who were asked to identify their sponsor organisations.
25. The Department of Health had asked for advice on the strategies which have been used to assess tobacco products and in particular Reduced Exposure Tobacco Products (PREPS). The advice is needed in the context of the request from the European Commission (EU). To submit, no later than 31 December 2004, a report on the application of Directive 2001/37/EC and in particular in respect of
Methods for more realistically assessing and regulating toxic exposure and harm.
Toxicological data to be required from manufacturers on ingredients and the manner in which they should be tested in order to allow public health authorities to assess their use.
26. The covering paper discussed generic aspects of toxicology testing to tobacco products. All three advisory committees (COT/COC/COM) are to be asked to comment on the paper. The COM had advised on mutagenicity testing (see appended draft minutes) and COT had provided advice on aspects of tobacco related disease other than carcinogenicity. Some preliminary comments on the value of the biomonitoring studies were obtained from COM members. The COC was specifically asked to comment on the approaches suggested and those which might be used to assess the risk of cancer associated with use of tobacco-based PREPs which were smoked. The Chairman noted that as a physician, he felt that the most appropriate advice was to stop smoking rather than use a tobacco-based PREP.
27. Members were aware that there were up to about 50 known chemical carcinogens present in tobacco smoke but the precise mechanisms of tobacco-smoke induce cancer (lung, oral cavity, pharynx, larynx, oesophagus (squamous-cell carcinoma), pancreas, urinary bladder and renal pelvis) were unknown. It was commented that it was not possible to predict the change in risk associated with modification of exposure to single chemical carcinogens (eg the tobacco specific carcinogen NNK) which had been investigated in some biomonitoring studies of tobacco smokers. Members queried the value of the animal model systems identified in the available papers (eg the A/J mouse and the Tg.AC transgenic mouse models) and commented that the predictive value of these models for single chemical carcinogens needed considerable investigation and validation and thus no conclusions could be drawn regarding the potential comparison of PREPS. One member noted that a recent published paper had established that whole body exposure of rats to mainstream smoke did result in the induction of bronchioloalveolar adenomas and carcinomas (Mauderly JL et al. Toxicological Science, 81, 280-292, 2004). This investigation had demonstrated the importance of appropriate exposure duration in animal models of tobacco-smoke induced carcinogenesis. The secretariat agreed to forward this paper to members for information at the next meeting. It was noted that the conclusions reached in respect of the current review would be based on the data in the submitted papers.
28. Members agreed it might be possible to develop a model to compare carcinogenic potency but this would have no value for comparing risks between products. The Committee concurred with the views reached by COM and COT. Members agreed with the conclusion reached by COT that attempting to design a risk reduction strategy for one toxicological effect associated with smoking tobacco did not have predictive value with regard to other toxicological effects caused by smoking. The Committee noted that the effect on risk of cancer of the addition of catalysts (such as palladium) to enhance burning qualities of tobacco could not be evaluated on the available data.
29. Overall, the committee agreed that that there was no adequate strategy for evaluating the carcinogenic risk associated with, or biomonitoring studies undertaken with, different tobacco-based PREPS. The Committee agreed to add a short summary of the discussion to the draft working paper. The Chairman invited comments from observers. One observer asked whether additional data could be submitted. The secretariat responded that additional studies could be forwarded to the secretariat but that the committee would only be asked to undertake further review work if there was a request from DH policy on tobacco for additional advice from the committees.
ITEM 5: CHILDHOOD CANCER
5.1 Overview paper (CC/04/31)
30. No interests were declared.
31. The Committee was informed that the preliminary discussion overview paper (CC/04/31) had been drafted as the result of a horizon scanning exercise for 2003 to evaluate the published literature on the possible increased incidence of childhood cancer in the UK and to address whether evidence from epidemiological studies suggests a possible chemical aetiology. Based on the available epidemiological data, four childhood tumours were identified as being relevant for further consideration: CNS tumours; acute lymphocytic leukaemia (ALL); germ cell tumours (GCT) and neuroblastomas (NBT). Members were also informed of the possible role of transplacental carcinogens, paternal exposure and the significance of animal models in the risk assessment of childhood cancer. Members were asked to consider whether the available evidence suggests that these tumours warrant further consideration with regard to a possible chemical aetiology, and to consider whether the subjects of transplacental carcinogens, paternal exposure and animal models should be reviewed further.
32. The Chairman asked members to examine each tumour in turn and to comment on the available evidence. Members were also reminded of a separate paper (CC/04/37) for later discussion, which summarises recent studies on the possible association between childhood leukaemia and chemical exposure arising from petrol stations, garages and road traffic.
33. Members considered that the review was well written. Members asked for clarification regarding the terminology used in describing CNS tumours. It was noted that this was important as a number of CNS tumours classified as benign had potentially serious consequences in patients if left untreated. Members also noted a few areas of concern that required some modification. It was agreed that although the data do suggest that there is an increasing trend in the incidence of CNS tumours in children, factors associated with data acquisition and histological typing were key limitations in diagnostic incidence trend analysis. The validity of comparing data collected 20 years ago with more recently collected data was also raised as a particular concern. Members proposed that independent experts on childhood CNS tumours be contacted for their views, to establish whether there was an increased incidence in CNS tumours in children. It was agreed that the Secretariat should contact a paediatric epidemiologist and also a paediatric neuropathologist to provide additional views on incidence and information on the diagnosis of CNS neuropathology over time. The Secretariat was provided with names of possible experts to contact.
34. Members considered the evidence suggesting an increase in the incidence of ALL in children. Members queried whether a fair comparison was being made with regard to the reported lower incidence trend in developing countries compared to developed countries. This was because the lower survival rate of children in developing countries from other childhood diseases could also account for the reduced numbers diagnosed, although it was noted that the IARC publication had included a correction for this factor. It was suggested that it would be valuable to obtain a definitive statement on whether childhood ALL was increasing in the UK. Members concurred with this view. Members suggested that the UK Childhood Cancer Study Group (UKCCSG) might be able to assist in providing advice on the incidence of ALL in children.
35. The Committee suggested that additional epidemiological advice was also required on the trends in the incidence of GCT and neuroblastomas. The Newcastle Children's Cancer Research Group was suggested as a possible source of additional advice
36. The overview paper presented a list of transplacental carcinogens in experimental animals and noted that, apart from the drug diethylstilboestrol (DES), there is currently no other established human transplacental carcinogen. The chair asked members to comment on the strength of evidence for those compounds implicated as possible transplacental carcinogens in humans. One member recalled the mechanism responsible for DES-induced carcinogenicity and described how DES causes a series of vaginal abnormalities: the presence of an abnormal epithelium in the vagina increases the risk of a carcinoma developing. It was pointed out that any risk assessment modelling of transplacental carcinogenesis needed to separate genotoxic compounds and non-genotoxic compounds.
37. The Committee noted the review of the potential for carcinogenesis via paternal exposure undertaken by the COM in 1997.
38. The Chair concluded by asking the secretariat to provide the further data on trends requested which would enable the committee to set priorities for additional review work.
5.2 Childhood leukaemia and environmental exposures (CC/04/37)
39. No interests were declared.
40. The Committee was informed that the additional preliminary discussion paper (CC/04/37) has been drafted at the request of the DH Air pollution unit to specifically address the evidence from selected published epidemiology studies for an association between residence near to petrol stations, garages, and road traffic exhaust fumes and the occurrence of childhood leukaemia (all types of leukaemia in individuals aged 0-14 years). In one of the studies, exposure to benzene was modelled and the investigation reported was based on the estimated exposure to benzene as a surrogate chemical for exposure to road traffic exhaust fumes. Members were also informed that some comments had been received from the oil companies' European organisation for environment, health and safety (CONCAWE, letter tabled).
41. The Committee considered that there were limitations with all three studies but most notable was the lack of direct benzene exposure measurements. Steffen C et al. Occupational and Environmental Medicine, vol 61, 773-778, 2004 had undertaken a hospital based case control study where an association between residence next to a petrol station or garage repair premises and acute leukaemia was documented (OR 4.0 (95% CI 1.5-10.3). The second study (Crosignani P et al Int J of Cancer, vol 108, 596-599, 2004) was a population based case-control which reported an association between childhood acute leukaemia and estimated benzene exposure (based on a diffusion model). The relative risk (RR) for heavily exposed children compared to those not exposed to road traffic emissions (>10 µg/m3 estimated annual average) was 3.91 (95% CI = 1.36-11.27) Members were unable to assess the adequacy of the model on the available information. The third study (Harrison RM et al, Occup Environ Med 56, 774-780) was a post-code analysis of childhood leukaemia cases compared to cancer cases with solid tumours. The Committee noted the wide confidence intervals for some of the reported findings in this paper and considered the information was too limited to draw conclusions.
42. Members noted that the results reported in the papers considered suggested an association with both ALL (Acute Lymphoblastic Leukaemia) and ANLL (Acute Non-Lymphoblastic Leukaemia) in children. Members recalled the epidemiological evidence suggested that benzene was associated predominantly with acute myeloid leukaemia in occupational exposure. The evidence for an association with several forms of leukaemia in children possibly represented a new finding. However it was agreed that no definite conclusions could be reached on the available information.
43. The Committee agreed that a full review of the epidemiology literature on environmental exposure and childhood leukaemia with residence near to petrol stations and garages and roads should be considered in the first instance. Members suggested that the review should examine all the available published literature including studies which reported on benzene exposure and should consider information on all types of leukaemia in children.
44. The Chairman thanked members for their comments and noted that the review requested by members should be considered concurrently with the additional work on the incidence of childhood leukaemia requested during the consideration of the general discussion paper on cancer in children. (CC/04/31). He noted that detailed consideration of the CONCAWE comments could also be undertaken during the review.
ITEM 6: HORIZON SCANNING. (CC/04/32)
45. The Horizon scanning paper has been produced by the DH Toxicology Unit in conjunction with the secretariat. There are 7 areas identified in the paper where advice from members would be welcomed. Specific questions are proposed for each section. In addition members can always suggest new areas.
46. Target organ mutagenesis and implications for carcinogen risk assessment. This topic was suggested by the recent consideration of malachite green and leucomalachite green. COM had agreed it would be useful to have a joint COC/COM symposium to provide guidance on how data from mutagenicity in target organs can be fed into the risk assessment process. Members agreed this was an important topic to follow-up in order to provide advice on the assessment of multi-site carcinogens.
47. Use of transgenic animal models in carcinogen risk assessment. Members will recall the conclusions reached with regard to the proposals from ILSI regarding use of hemizygous p53 and Tg.AC and other mouse models to replace the conventional mouse long-term bioassay. Members agreed there was a value in developing specific transgenic animal models for mechanistic studies but overall considered this topic should be given low priority for further COC consideration.
48. Risk assessment of non-genotoxic carcinogens. This subject was extensively reviewed during the preparation of the COC guidelines (published about 1 month ago). An update is provided of the research which was funded by DH on the investigation of gap junction function for inclusion in possible screens for non-genotoxic carcinogenesis. Members considered that further consideration of some worked examples of evaluation using the IPCS mode of action and the ILSI Human Relevancy Framework would be valuable for the Committee and to provide first hand experience to the secretariat. It was noted that further developmental work which aimed to amalgamate these two approaches was being considered in international fora.
49. Single exposure carcinogens. A short overview was provided regarding definitions of single and short duration exposures and the identification of single exposure carcinogens. An overview of one suggested approach to risk assessment using dose-rate scaling factors for amending the virtually safe dose estimate. Members agreed that this suggestion should be given high priority. One members asked whether there was any evidence that non-genotoxic carcinogens could induce tumours over a short duration of exposure.
50 Potential mechanisms of metal induced carcinogenesis. A very short overview of the literature had been provided. Members agreed that the research initiatives would be valuable with regard to elucidating the mechanisms of metal-induced carcinogenesis but considered overall that further work on this subject was not merited at this time.
51. Epidemiology. A short note on the recent referral of alcohol and oesophageal cancer and a proposal for further consideration of QRA approaches is provided. Members agreed to take forward the review of alcohol consumption and oesophageal cancer but asked the secretariat to undertake some initial work to define the key outcomes of the review. It was agreed that no work should be undertaken on QRA at this time.
52. Nanotechnology. COM considered it would be worthwhile undertaking a review of this subject. A similar short overview section had been provided with regard to carcinogenicity. Members agreed that this was a potentially important and interesting area of work. It was agreed that COC would be interested to see papers on this topic in the future.
ITEM 7: PAPERS FOR INFORMATION
53. The following were provided for information.
7.1 Published paper reporting a NOAEL for MeIQx in transgenic rats (CC/04/33).
7.2 Published paper on induction of preneoplastic rat liver lesions with an attenuated p53 response by low doses of diethylnitrosamine (CC/04/34).
7.3 Chemical risk factors identified for various cancers by Cancer Research UK (CC/04/35).
ITEM 8: ANY OTHER BUSINESS
54. There was no other business.
ITEM 9: DATE OF NEXT MEETING
55. 21 April 2005
ACTIONS
| ITEM | ACTION | WHO |
| 3.1 Draft working paper on prostate cancer | Finalise statement |
Secretariat |
| 3.2 Draft working paper on malachite green/leucomalachite green | Finalise statement | Secretariat/FSA |
| 3.3 Draft working paper on toxicogenomics | Finalise statement |
Secretariat |
| 3.4 HSE Priority Programme | Redraft priority list |
HSE |
| 4. Re-assessment of toxicological testing of tobacco products | Finalise statement | Secretariat |
| 5.1 Childhood cancer - overview paper | Contact epidemiologists | Secretariat/DH tox unit |
| 5.2 Childhood leukaemia and environmental exposure | Initialise review? | Secretariat/DH tox unit |
| 6. Horizon scanning | Joint COM/COC meeting on target organ mutagenesis, consider taking forward single exposure carcinogens, alcohol & oesophagus & nanotechnology | Secretariat/DH tox unit |