COC meeting 22 March 2001
Minutes
1. Present
| Chairman: Professor P G Blain |
Members: Professor G Williams |
Secretariat: Ms F Pollitt (Scientific-DH) Mr J Battershill (Scientific- DH) Dr D Benford (Scientific-FSA) Mr S Robjohns (Minutes) Mr K N Mistry (Administrative) |
| Assessors: Mr A Browning (VMD) Mr T Holmes (PSD) Dr P Howden (HSE) |
||
| In Attendance: | ||
All Items
|
Item 5 Professor A Boobis (DH Tox Unit) Professor D Davie (DH Tox Unit) Dr K Leverton(DH Tox Unit) Dr S Cottrell (DH Tox Unit) |
Item 6 Mr G Kowalczyk (DH) Dr W Mathews (FSA) |
| Contents: | Paragraph(s) | |
| Item 1: | Apologies for absence/Announcements | 2 |
| Item 2: | Minutes of the meeting on 9 Nov 2000 (CC/MIN/2000/3) | 3 |
| Item 3: | Matters arising | 4 |
| Item 4: | Carcinogenicity of dioxins and dioxin like PCBs | 7 |
| Item 5: | Genetic Susceptibility to environmental carcinogens (CC/01/2) | 3 |
| Item 6: | 1,3-dichloropropanol/2,3-dichloropropanol (CC/01/6) | 35 |
| Item 7: | Annual report 2000 (CC/01/7) | 50 |
| Item 8: | Proposal for joint meeting of COT/COC/COM (CC/01/9) | 51 |
| Item 9: | Paper for information | 54 |
| Item 10: | Any other business | 55 |
| Item 11: | Date of next meeting | 56 |
ITEM 1: APOLOGIES FOR ABSENCE/ANNOUNCEMENTS
2. Apologies were received from Mrs K Cameron (DETR) and Dr H Stemplewski (MCA). Members were reminded of the need to make any relevant declarations of interest before the discussion of items.
Announcements
3. The committee welcomed Dr Diane Benford (FSA) attending as secretary to COT and as part of the joint COC/COM secretariat. The Committee was informed of the appointment of Dr D Harper (Head of Profession for DH scientists) as Branch Head for Environment and Health.
ITEM 2: MINUTES OF THE MEETING ON 9 NOVEMBER 2000 (CC/MIN/2000/3)
3. The minutes were agreed subject to a minor editorial change.
ITEM 3: MATTERS ARISING
Item 4 from 9/11/2000; 3-Mono-chloropropane-1,2-diol (3-MCPD)
4. Members were updated on the recent discussions of an EU Scientific Committee for Food (SCF) working group on 3-MCPD. The SCF accepted the COM opinion that 3-MCPD could be regarded as non-gentoxic in-vivo. The SCF working group considered the uncertainty factor of 1000-fold proposed by the COC in its statement in detail, but had not agreed a value. The Chairman told members that the secretariat would forward more information on the rationale used by the COC to the SCF working group.
Item 5 and 6 from 9/11/2000; developing a cancer strategy for the Environment and Health Branch
5. Members were reminded that, at the last two meetings, a proposed strategy for future work on environmental chemicals and cancer had been discussed. Three strands of work were identified which might be taken further. This included work on genetic susceptibility, ranking of environmental carcinogens and the development of statements on environmental carcinogens on an organ-specific basis. Genetic susceptibility was to be discussed further at this meeting. Members had expressed some reservations about the proposal to produce statements on the role of chemicals in the aetiology of organ-specific cancers and so it was decided not to develop this further at this stage. However it was noted that the committee believes that there is a need for more information for the public in this area.
6. The work on ranking would be taken forward at a future meeting in the context of a fresh look at the T25 and exploring the hazard ranking of carcinogenic air pollutants. DETR has asked for advice on the most important carcinogenic air pollutants.
ITEM 4: CARCINOGENICITY OF DIOXINS AND DIOXIN LIKE PCBs
7. The Chairman welcomed Dr A Smith (COT) to the meeting and informed members that Dr Smith had agreed to make a presentation to COC on studies on the mechanism(s) of toxicity of 2,3,7-8-tetrachlorodibenzo-p-dioxin (TCDD). The Chairman noted that the Committee had been asked by COT to revise the 1998 COC statement on dioxins and dioxin-like PCBs in the light of the draft review of the compounds published by EPA (http://www.epa.gov/ncea/pdfs/dioxin). He noted that the draft EPA review was under revision and thus asked members to comment on the general approach taken rather than the specific data and risk assessment reported in the EPA review. Members were told that the COT had also asked for the Committee's view as to whether a threshold approach could be used for risk assessment for carcinogenicity.
Presentation on mechanism(s)
8. Dr Smith referred members to Annex C of CC/2001/01, which was a summary prepared for the COT on the mechanism(s) of action of TCDD. The Committee agreed that there was good evidence that most of the toxicity of TCDD and other 2,3,7,8-substituted dioxin congeners (and dioxin-like PCBs) was a consequence of an initial binding to the Ah receptor (AHR). It was noted that although the term Ah receptor is in common usage, the binding protein was now more properly termed a 'ligand activated transcription factor' to distinguish it from cell surface receptors such as transferrin. Most of the evidence on TCDD induced gene transcription related to the CYP1A1 gene but it was now clear that the sequence of events from binding to AHR to transcription were very complex involving other transcription factors, chaperones such as HSP90 and regulatory proteins such as ARA9. Heterodimerisation of AHR with ARNT within the nucleus is apparently essential for TCDD activated AHR to induce DNA binding and transactivation in-vitro. Heterodimerisation can also occur with hypoxia inducible factor 1-a (HIF1a) and AHR repressor. There was also evidence that levels of these proteins may be regulated by cell type and activation and by stages of growth and differentiation. In addition there was some evidence to suggest that the phosphorylation status of AHR was important with regard to the mechanism of TCDD toxicity. Overall, the data were consistent with a complex multi-step process involving receptor binding and thus a threshold interpretation of TCDD induced carcinogenicity.
9. Members heard that although events leading up to gene transcription were quite well understood, there was very little information on how AHR induced gene-transcription manifested as overt toxicity. However there was good in-vivo evidence to support the view that AHR was involved in toxic effects of TCDD, including the fact that AHR null allele ("Knockout") mice strains are very resistant to TCDD toxicity. However there was evidence from such strains of mice that, at very high doses, TCDD could produce toxic effects via other mechanisms. Overall there was a considerable amount of research required before the mechanism(s) of TCDD induced toxicity could be fully explained.
10. Dr Smith commented that studies using human cells and tissues supported the view that TCDD mediated its toxic effects through binding to AHR, but noted that it was not possible to undertake appropriate in-vivo studies in humans to confirm this. Dr Smith showed data from gene array investigations, which provided evidence that suggested that caution needed to be exercised when interpreting dose-response data on the basis of single gene induction.
11. Members asked a number of questions regarding Dr Smith's presentation. It was agreed that mechanisms of TCDD toxicity other than binding to the AHR had not been excluded. Members agreed that there had to be a pragmatic use of the mechanism data in evaluating dose-response data for carcinogenicity. It was agreed that molecular analysis of tumours for mutational signatures could be helpful in interpreting the results of studies in experimental animals and epidemiology studies. Members considered that such studies could yield an insight into the promotion effects of TCDD.
Discussion of epidemiology and exposure monitoring data
12. Members commented that the epidemiology studies published since 1998 were predominantly updates of cohort investigations previously considered by the Committee. In general, these publications presented analysis of more data and had improved statistical power compared to previous studies. An attempt had been made in some studies to make allowance for confounding factors (e.g. smoking) by making internal comparisons but in no case was individual smoking data available. Overall the Committee agreed that the epidemiological data suggested consistent, albeit limited, evidence of carcinogenicity, i.e. a positive association had been observed in three large occupational cohorts between exposure to TCDD and an increase in relative risk for cancer mortality. A causal interpretation of these data was considered credible but confounding could not be ruled out. There was no single site or type of cancer that was consistently associated with exposure and the results were still too heterogeneous to draw specific conclusions with regard to lung cancer. It was noted that the approach taken to assess dose-response using back-extrapolation of TCDD or TEQ levels in blood to estimate body-burdens was generally the most appropriate approach that could be taken and in some instances the half life for TCDD used in such calculations had been adjusted for body fat and age. However members had reservations regarding the accuracy of ED01 estimations. The Chairman asked members to comment on each epidemiology paper separately before deriving conclusions on ED01 estimations and QRA.
Flesch-Janys D et al (1999) Organohalogen Compounds, 44, 379-382 (Hamburg Cohort)
13. This report presented the results of an investigation of breast cancer incidence in a cohort of female workers with high exposure to PCDD/Fs and to B-hexachlorohexane (HCH). It reported an increase in Standardised Incidence Ratio (SIR) for breast cancer in the cohort compared to background rates. The increase was significant in the groups with the highest estimates of PCDD/Fs and HCH exposures. Members agreed that there were limitations in the analysis of cancer incidence data in the women studied and in the exposure estimation. It was noted that reference incidence data was derived from a cancer registry in a different region of Germany and that exposure had been back extrapolated over 15-20 years in a sub group of women. The authors acknowledged the small size and low power of the study and were unable to adjust for the known risk factors for breast cancer. The Committee considered the study to be essentially hypothesis generating.
Flesch-Janys D et al (1998) Environmental Health Perspectives, 106 (Suppl 2), 655-662 (Hamburg Cohort)
14. Members agreed that the analysis of cancer mortality data had been adequately undertaken and that the conclusion of a significant increase in this cohort for both overall cancer mortality (40%) and for lung cancer mortality (50%) was sound. However the trend test for overall cancer mortality with estimated exposure was only significant for increasing TCDD dose and not for total TEQ, which was difficult to explain. No significant trend was seen for lung cancer. Members noted that the approach used by the authors to back-extrapolate exposure for 320 workers who had blood/adipose tissue samples and then use work histories to estimate exposure in all members of the cohort (n=1189) cases was acceptable but could have resulted in the inconsistency between TCDD and TEQ dose-response data. It was also noted that the use of blood data only when levels exceeded the 95% CI of German background concentrations may have biased the analyses.
Steenland K et al (1999). J. National Cancer Institute, 91, 779-786 (NIOSH Cohort)
15. Members agreed that the analysis of cancer mortality data in this update of the NIOSH study had been adequately undertaken but expressed reservations about the approach used to derive estimates of exposure which was based on assessment of workplace practices rather than estimation of body burden from back-extrapolation of blood or adipose tissue TCDD levels. Overall a significant but small excess in total cancer mortality of 13% was reported. No significant excess of lung cancer mortality was found. Analysis of dose response based on cumulative exposure score was statistically significant for total cancer mortality and for lung cancer, but after adjustment for of a 15-year lag period, was only significant for total cancer mortality. The reported elevation in total cancer mortality and lung cancer mortality for the subcohort with chloracne (which is an indication of high exposure) was just below statistical significance.
Hooiveld M et al (1998). American Journal of Epidemiology, 147, 891-901 (Dutch Cohort)
16. Members agreed that the analysis of cancer mortality and of exposure estimations had been adequately undertaken. Members agreed the excess of total cancer mortality in this cohort, which was exposed to phenoxy herbicides, chlorophenols and contaminants including TCDD, was 50%. There was no statistically significant increase in lung cancer mortality. In a subsequent analysis using estimated TCDD exposures, the data showed that excess cancer mortality occurred mainly in medium and high exposure individuals compared to low exposure individuals and thus contrasted with the evidence from the NIOSH study.
Lynge E (1998). Environmental Health Perspectives, 106, (Suppl 2) 683-688
17. Members agreed that the analysis of cancer incidence data had been adequately undertaken but expressed reservations regarding the adequacy of exposure estimations. It was not possible to assess exposure of the cohort to TCDD. Elevated SIRs for soft tissue sarcoma and non-Hodgkin's lymphoma were reported based on small numbers, but statistical significance was not achieved. No significant increases in SIR were documented for total cancers or lung cancer. Members agreed little weight could be attached to this study.
Viel JF et al (2000) American Journal of Epidemiology, 152, 13-19
18. This study reported clusters of soft-tissue sarcoma and non-Hodgkin's lymphoma in the vicinity of a municipal waste incinerator in the Doubs region of France. Members agreed that this ecological study of spatial clustering had been adequately undertaken but suffered from the known drawbacks associated with this type of design such as confounding by socioeconomic status, movement of subjects in and out of the study zone, and lack of information on exposures, in particular, past exposures. Members agreed that no definitive conclusions could be drawn from these data.
Estimation of ED01 and quantitative risk assessment
19. Members agreed that the approach taken by EPA to model dose-response from the epidemiology data needed to take into account the variable quality of the exposure estimations (i.e. extrapolation from a sub-cohort, or use of work history to estimate exposures in members of cohort for whom no biological monitoring data were available) and the uncertainties associated with back-extrapolating estimates of exposure. In addition, the available mechanistic data was not consistent with a linear dose-response. Members considered that the dose-response data from the NIOSH cohort was not adequate for dose-response modelling as blood/adipose tissue data on TCDD/TEQs were not available and thus inclusion of data from this study in the summary dose-response model limited the value of this particular analysis undertaken by EPA. It was noted that the ED01 value was highly dependent on the slope factor used and its confidence interval. Members agreed that the linear extrapolation for ED01 to estimate risks at background body-burdens was an assumption, which was not justified by the available data. Members also commented that the predicted kinetic profile of TCDD and other dioxins and dioxin-like PCBs following occupational exposure predominantly via the skin over several decades was likely to be considerably different to that of background exposure via the diet.
20. In conclusion members agreed that the review and risk characterisation of cancer undertaken by EPA as part of its review of dioxin and dioxin-like PCBs was a detailed and valuable scientific document, but the data and assumptions used to derive the ED01 estimations and the derivation of the slope factor and risk at background exposure levels were inadequate.
General Discussion
21. The Committee reconsidered its 1998 statement and agreed that TCDD was a multi-site carcinogen in several species of laboratory animals. Members confirmed that, in addition to the limitations on the dose-response modelling of epidemiological data which are discussed in the preceding sections of this statement, that it was also inappropriate to undertake quantitative risk assessment for cancer by modelling the dose-response for tumour data in animals fed diets containing TCDD in view of the assumptions needed for extrapolation from high doses used in such studies to background environmental exposures and in view of the uncertainties with respect to inter-species extrapolation. Members agreed it was still not possible to comment on the role of the AHR with regard to the mechanism of carcinogenicity in laboratory animals. Members agreed that the results of ongoing investigations of potential carcinogenicity of TCDD in AHR "knockout" mice could be of value in this respect. Members thought that molecular studies of tumours from animals exposed to TCDD might be helpful with regard to identification of tumour promotion effects of TCDD. Members confirmed that it was not possible to draw any conclusions regarding the significance of AHR mediated gene transcription in humans with regard to cancer. Members also considered that all the available epidemiology on dioxin and dioxin-like PCBs for cancer could be interpreted as suggesting that TCDD and other dioxins modulated the carcinogenic process induced by other risk factors to increase total cancers (i.e. the data are consistent with a tumour promoter effect).
22. In conclusion, Members considered that TCDD should be regarded as a probable human carcinogen on the basis of all the available data. The Committee agreed that, although a precise mechanism for carcinogenesis in laboratory animals or humans could not be elucidated from the available information, the data (ie negative genotoxicity in standard assays, and evidence from studies of mechanisms) suggested that a threshold approach to risk assessment was likely to be appropriate. In this respect members commented that the extrapolated body burdens in epidemiological studies of workers exposed to TCDD and other dioxins were 1-2-orders of magnitudes above the average background body burden.
ITEM 5: GENETIC SUSCEPTIBILLITY TO ENVIRONMENTAL CARCINOGENS (CC/01/2)
23. The Committee was reminded that it had discussed an overview paper on genetic susceptibility to environmental carcinogens produced by the DH Toxicology Unit at the July 2000 meeting. Members had suggested three main areas of work:
24. Criteria for the design of gene-environment epidemiology studies, a review of potential target genes for susceptibility to carcinogenesis, and a review of how gene-environment studies should be used in risk assessment process.
25. These three papers had now been drafted by the DH Toxicology Unit at Imperial College of Science Technology and Medicine, and were intended to form the basis of discussion. The overall objective was to publish a statement from COC on the design and interpretation of studies and the implication for risk assessment of gene-environment studies of chemical induced carcinogenicity. The statement was intended for use by Government Departments and Regulatory Agencies. The authors from the DH Toxicology Unit introduced their papers.
Criteria for the design of gene-environment epidemiology studies (CC/01/3)
26. Members noted that rapid development of technology would inevitably generate vast amounts of data on single nucleotide polymorphisms (SNPs) and possible association with cancer. The key issue in the design of studies that might be useful in risk assessment appeared to be establishing a valid rationale for gene selection. Members acknowledged that post-hoc analysis was likely to be the predominant approach used. The Committee agreed that ideally, a valid mechanistic argument was needed for each gene selected for study. Additionally it was agreed that there were often problems with selection bias and adjusting for confounding.
27. The Committee considered that good study design would include selection of case and controls (from the same population), identification of cancers, adequate exposure assessment, reporting of analyses, consideration of post-hoc analyses, and model calculations of study size given assumptions on penetrance, relative risk of disease and allele frequency. Members also highlighted the potential problem of random co-inheritance, where alleles of one gene (associated with increased risk) are inherited with specific alleles of adjacent genes (unrelated to risk) giving the false impression that these latter genes were also associated with increased risk. Therefore, in the absence of knowledge of which genes are co-inherited, it would be helpful to determine the mechanism of carcinogenesis of an environmental chemical.
28. The Committee agreed that the most efficient study design had not yet been established, and that the a priori hypothesis should be clearly stated, perhaps even lodged with a third party before the analysis. The Committee concluded that selection of the most efficient study design could possibly be determined from the range available by simulation, and agreed that further work was necessary to follow up this suggestion. The Committee agreed that it would be valuable to undertake further calculations of power and size of studies needed to determine an effect using all the study designs outlined in the paper. Members agreed that further work was required to determine the most appropriate statistical approach.
Selection of potential target genes for susceptibility to carcinogenesis (CC/01/4)
29. Members were aware that to date most studies of gene-environment interactions in cancer causation have focussed on enzymes of xenobiotic metabolism, and the relative risks identified so far have been low to negligible. Other potential gene targets commonly suggested include those that control so called 'caretaker pathways', such as DNA repair, cellular proliferation (e.g. cell cycle control, DNA replication) and immune surveillance. Few studies have addressed the importance of genetic variation in DNA repair pathways with respect to specific chemical susceptibility. Any genetic polymorphism that favoured a functional increase in the potential for malignant cells to escape immune detection was also likely to affect individual susceptibility to the development of cancer.
30. The extent to which such polymorphisms may interact with environmental chemicals has not been evaluated. The Committee agreed that it was difficult to know where to start in searching for gene variants with risks for environmentally induced cancers as this could plausibly involve many thousands of variants. However, members believed that benefits of improving and developing technology could result in this exercise being practical and useful in the future.
31. Members discussed the proposal that a hierarchy of genes could be established. Members agreed that although the proposal was worthy of consideration, it was not possible, with current knowledge, to attempt to do this. For example, genes controlling DNA repair are likely candidates but the precise role of these genes in cancer and the extent of gene redundancy was unknown. Members felt that a simpler approach using available knowledge for each specific cancer and including genes of both high and low penetrance was the most pragmatic approach that could be used at the present time. Members agreed with the conclusion reached in the paper CC/01/4 that it was not possible to prioritise gene targets for selection.
32. The Committee concluded that at present it is not possible to prioritise candidate targets because the number of biological pathways and genes involved within those pathways with a plausible mechanism for cancer is so large. Further work may involve developing a hierarchy of effects, which might help prioritise candidate gene selection. Candidate genes could include those encoding products involved directly in cancer development, those regulating the expression of these genes, and their transcription products, and those involved in a regulatory network.
The application of gene-environment studies to risk assessment (CC/01/5)
33. Members were aware that if data from gene-environment interaction studies are to be applied to risk assessment it is vital to establish strong evidence for causal association. The Committee considered the application of the Bradford-Hill criteria of, strength of association, consistency, specificity, temporality, biological gradient (dose-response) and biological plausibility with regard to gene-environment effects on cancer. Members agreed that other recognised criteria could also be applied to determine causality and suggested further work was required.
34. Members considered the calculated aetiologic fraction using data from bladder cancer and smoking, and lung cancer and smoking, as illustrative examples. It was agreed that these were useful for discussion and showed such calculations could be done. These particular examples could not be used to infer aetiologic fractions for other gene-environment interactions.
ITEM 6: 1,3-DICHLOROPROPANOL/2,3-DICHLOROPROPANOL (CC/01/6)
35. No interests were declared.
36. Following recent COC (and COM) consideration of 3-MCPD the committee was asked to assess the carcinogenicity of two additional chloropropanol co-contaminants, namely 1,3 DCP and 2,3 DCP. There are more data for the 1,3 isomer, including a carcinogenicity study, and this is the main focus of paper CC/01/06. The COC was asked to consider the recent COM advice (February 2001) and if necessary to update the COC 1991 opinion on 1,3 DCP. An opinion was also sought on 2,3 DCP. The advice will help inform future regulatory decisions on these contaminants that may be made by either the Drinking Water Inspectorate or by the Food Standards Agency.
37. Members considered CC/01/06 and a short addendum (CC/01/06 addendum) tabled at the meeting, which presented further analyses of tumour data from the FDA. The Committee was aware that toxicological data, including the genotoxicity and carcinogenicity of 1,3 DCP and 3-MCPD were to be reconsidered by JECFA in the summer of 2001.
38. It was noted that the discussion of this item had much in common with previous Committee discussions on 3-MCPD, as both 1,3 DCP and 2,3 DCP occur along with 3-MCPD in flocculants used in drinking water treatment. Additionally 1,3 DCP can occur along with 3-MCPD in certain foodstuffs. The Committee had previously examined 1,3 DCP in 1991 and concluded that it was "genotoxic and carcinogenic" and that it also "wished to see more detailed information from the relevant studies". The secretariat had obtained a summary report of the rat carcinogenicity study, from which additional information was presented in CC/01/06. In addition, there were new mutagencity data for both 1,3 DCP and 2,3 DCP. The COM had recently examined these data and concluded "that it would be prudent to regard 1,3 DCP and 2,3 DCP as potentially genotoxic in vivo"
39. Both substances were present as contaminants in polyamine flocculants and could theoretically arise in drinking water. In 1991, the maximum concentration of 1,3 DCP was estimated to be 16µg/l; current operational practices meant that maximum theoretical levels would be in the order of 2-3 µg/l; levels of 2,3 DCP were estimated to be approximately half those of 1,3 DCP levels. No actual monitoring of drinking water for these substances had been carried out. The only foodstuff for which 1,3 DCP concentration data were available was soy sauce; at the maximum concentration found (4.28mg/kg), an intake of 68µg could arise from a single serving.
40. For 1,3 DCP the limited toxicity data indicated a NOAEL from a 13week rat study of 1mg/kg/day. While 1,3 DCP was mutagenic in vitro there were no adequate in vivo data. The 104 week carcinogenicity study in the rat showed statistically significant increases in tumours (carcinomas and adenomas combined) at the highest dose (240mg/l in drinking water) in the liver and tongue of both sexes and additionally in the kidney of male rats. Much of these data had been seen previously by the COC in 1991. Additional information provided now showed that liver adenomas could arise at 26 weeks, liver carcinomas at 52 weeks, and other tumours noted at termination of the study, could arise at 78 weeks.
41. There were far fewer data for 2,3 DCP. In vitro mutagenicity studies were positive but there were no in vivo data and a carcinogenicity study had not been conducted. It was noted that while IARC had recently classified the brominated analogue, 2,3 dibromopropan-1-ol (2,3 DBP) as a category 2B carcinogen there was some evidence (presented in CC/01/06) of important metabolic differences between this compound and its chlorinated analogue 2,3 DCP.
42. The Committee was invited to consider the data provided and to comment on the draft conclusions presented in paragraphs 37 and 38 of paper CC/01/06.
43. The Chairman enquired why monitoring for these substances in drinking water had not been carried out. The Committee was informed that this was because a suitable analytical method had not been developed.
44. Members noted the COM evaluation of mutagenicity data for 1,3 DCP (tabulated in CC/01/06). This showed in vitro mutagenic activity in a range of test systems. However, the in vivo SMART assay in Drosophilla should not be considered to be significant to the evaluation of genotoxicity. As there were no adequate in vivo data the COM had considered that it would be prudent to regard 1,3 DCP as possessing genotoxic activity in vivo. Similarly, while there were far fewer in vitro data for 2,3 DCP, but in view of the absence of in vivo studies, it would also be prudent to regard this substance as also possessing potential genotoxic activity in vivo.
45. Members commented on the spectrum of tumours observed in the 104 week rat study with 1,3 DCP. The statistically significant increase in adenomas and carcinomas of the liver and adenomas and carcinomas of the tongue, reported in both sexes, was considered to be indicative of a clear carcinogenic effect of 1,3 DCP. Members commented that it was possible that the male kidney tumours could be associated with the high rate of chronic progressive nephropathy seen in the study and additionally, the thyroid follicular cell tumours could be associated with hyperplasia and elevated circulating TSH levels, a frequent toxic effect seen in male rats, however no specific mechanistic data were available.
46. Members agreed that topical application of the brominated derivative of 2,3 DCP (i.e. 2,3 dibromopropanol) resulted in tumours in a number of different organs but that no conclusions could be reached from these data regarding the carcinogencity of 2,3 DCP as it was not possible to extrapolate from dibromopropanol to dichloropropanol.
47. Members also enquired about potential levels of 1,3 DCP in foods other than soy sauce. The secretariat commented that surveys in other foods had not yet been reported. However there was an indication from other work that where 3-MCPD arose in foods, 1,3 DCP would also arise. 1,3 DCP could therefore be present in a wide range of foods, in particular those containing acid hydrolysed vegetable protein.
48. Members agreed with the proposed recommendations in paper CC/01/06, namely that levels of 1,3 DCP and 2,3 DCP should be kept as low as technologically feasible. Members agreed that regulatory authorities should review the likely exposures of 1,3 DCP and 2,3 DCP with the intention of achieving this recommendation. Members endorsed the proposal from COM for further mutagenicity studies on 1,3 DCP and 2,3 DCP.
49. A statement would be produced and circulated to Members for approval.
ITEM 7: ANNUAL REPORT 2000 (CC/01/7)
50. The Committee was informed that a draft Annual report had been produced and that the format was slightly different from last year, reflecting the need for statements to be available in full, both electronically and in hard copy. Members were requested to make any comments within two weeks.
ITEM 8: PROPOSAL FOR JOINT MEETING OF THE COT/COC/COM (CC/01/9)
51. The Committee was told that Members of the COT/COC/COM had identified a need for closer working between these three advisory committees during discussions of the report by Sir Robert May on the review of risk procedures used by Government advisory committees dealing with food safety. Toxicogenomics and proteomics have been highlighted as rapidly growing areas of toxicological science (which might be suitable topics for a joint meeting), and TOX/2001/09 presents short summaries of a number of recent publications on these subjects. As these technologies could be applied to toxicological risk assessment a number of questions were posed:
- What is the foreseeable role of toxicogenomics and proteomics in toxicological risk assessment?
- What advances are needed for the results of these technologies to be used by scientific advisory committees in their risk assessments?
- What criteria need to be considered for these technologies to be incorporated into regulatory toxicology studies?
- What advice should be given to Government Departments/Regulatory agencies at this time?
52. This paper had been submitted to COT and sent to COM. Members of the COC were asked to submit their view/suggestions to the secretariat.
53. It was noted that the toxicogenomics approach had been proposed for carcinogenicity screening of veterinary medicines. It would be important to cover the use of this technology for rapid screening at the joint meeting.
ITEM 9: PAPER FOR INFORMATION
54. A paper was provided for information. Verkassalo P K et al (2000). Circulating levels of sex hormones and their relation to risk factors for breast cancer: a cross sectional study in 1092 pre- and postmenopausal women (United Kingdom). Cancer causes and Control, 12, 47-59.
ITEM 10: ANY OTHER BUSINESS
55. The Committee was informed that the COC Website had been upgraded to include a "whats new section" where it is intended to publish a short resume of meetings shortly after each meeting.
ITEM 11: DATE OF NEXT MEETING
56. 28 June 2001
ACTIONS
ITEM |
ACTION |
WHO |
| 4. Carcinogenicity of dioxins and dioxin like PCBs | Draft statement for COC | Secretariat |
| 5. Genetic susceptibility to environmental carcinogens | Draft paper on criteria for causality for June meeting | Secretariat |
| 6. 1,3-dichloropropanol and 2,3-dichloropropanol | Draft statement to be circulated and agreed by Chairman's action | Secretariat |
| 8. Proposal for Joint meeting of the COT/COC/COM | Meeting to be arranged | Secretariat |