Information Section--Fd Chem. Toxic. Vol. 32. No. 2 193

Conclusion

What is our view of the current status of ethylene's carcinogenicity? Certainly we would not disagree that the CI1T study provides no convincing evidence of laboratory carcinogenicity in animals. Moreover, there is only scant support for a carcinogenic action in humans from the NIOSH epidemiological study. While the ethylene molecule per se may not have sig- nificant carcinogenic potential, we do believe that the data on metabolic conversion to a genotoxic carcino- gen provide a fairly good basis for suggesting that an expert, detailed reconsideration of the possible car- cinogenic risks of inhaling ethylene would be timely. The rat study and the available cancer ¢pidemioiogy do not fully negate the concerns raised. On the basis of this argument, we believe a re-evaluation of the need for a specific industrial limit should be given a high priority, as should the funding of additional metabolic and epidemiological studies in humans.

In recent years the efforts of the toxicological profession have led to the increased sophistication of the regulatory process. There is now a far greater likelihood that the evaluation of a chemical cancer hazard (and risk) will be based on the totality of the available biological information rather than on tu- rnout data alone. Much scientific investigation has been authorized with the sensible objective of ensur- ing that there is no automatic assumption on the part of the regulators that a finding of cancers at high doses in a rodent study necessarily has a direct relevance to lower exposures and to the human perspective. That is why the ethylene story is an interesting test of the credibility of the new era. In this case there may be the opposite danger, that is a too literal interpretation of the rodent cancer study may lead to an underestimation of the low-dose rodent and human risks.

[James Hopkins--BIBRA]

References

Bolt H. M. and Filser J. G.(1987) Archires of Toxicology 60, 73.

CIIT (1980) Ethylene. Chronic 24-month Final Report. Chemical Industry Institute of Toxicology.

EH40/93. Occupational Exposure Limits 1993. Health and Safety Executive. HMSO, London.

Ehrenberg L. et al. (1977) Mutation Research 45, 175.

Filscr J. G. and Bolt H. M. (1983) Mutation Research 120, 57.

Garman R. H. et al. (1986) Food and Chemical Toxicology 24, 145.

Gibson G. G. et al. (1987) Ethel Browning's Toxicity and Metablolism of Industrial Solrents. 2nd Ed. Vol. l: Hydrocarbons. Chapter 4. I. Ethene. Edited by R. Snyder. Elsevier, Amsterdam.

Guidelines for the Evaluation of Chemicals for Carcinogenicity (1991) Report on Health and Social Subjects No. 42. Committee on Carcinogen- icity of Chemicals in Food, Consumer Products and the Environment. Department of Health. HMSO, London.

Harem T. E., Jr et al. (1984) Fundamental and Applied Toxicology 4, 473.

IARC (1987) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Orerall Eraluations o f Carcinogenicity: An Updating of IARC Monographs. Volumes i to 42. Suppl. 7. International Agency for Research on Cancer, Lyon.

Lcflingwell S. S. et al. (1983) Neurocpidemiology 2, 179.

Lynch D. W. et al. (1984) Toxicology and Applied Pharma- cology 76, 69.

Maples K. R. and Dahl A. R. (1993) Inhalation 7bxicalogy 5, 43.

NTP (1987) Toxicology and carcinogenesis studies of ethylene oxide in B6C3FI mice (inhalation studies). NTP TR 326. NIH Publication 88-2582.

Segerb/ick D. (1983) Chemico-Biological Interactions 45, 139.

T6rnqvist M. et al. (1988) Journal of Applied Toxicology 8, 159.

T6rnqvist M. A. et al. 0989) Scandinm,ian Journal o f Work Environment and ttealth 15, 436.

T H E R O L E O F C A N C E R M E C H A N I S M IN I A R C C A R C I N O G E N C L A S S I F I C A T I O N

Whenever a group of toxicologists regularly gathers together, sooner or later their thoughts will turn to carcinogen classification. As well as the inherent in- tellectual satisfaction of tackling this complex subject, the major incentive to devise a robust classification scheme must be to widen the understanding amongst their colleagues within the company and the legis- lature that chemical carcinogenicity is not a rare property and that, since not all carcinogens are alike, they may not warrant the same degree of industrial and regulatory attention. Up until quite recently a possible further stimulus to the periodic pronounce- ments in this sphere (1) has been a certain amount of disgruntlement within industry over the efforts of the International Agency for Research on Cancer, the 'market leader" in carcinogen hazard evaluation.

It was the perceived reluctance of IARC to fully embrace mechanistic precepts in cancer evaluation, when mechanism appeared to be a critical aspect, that probably prompted some of industry's grumbles. Is there any basis to the accusation that IARC is a reluctam player of a mechanistic tune?

The first thing to note about IARC's carcinogen assessment programme is its longevity: the first set of monographs originated at a Lyon meeting of invited experts in December 1971 (2). Whereas in those earliest days the conclusions on a compound's carcinogenicity were expressed in free text, the late 1970s saw the introduction of the standardized terms that are still used today (3). The aim of each IARC exercise then (as now) was the evaluation of human cancer hazard, the potential to cause cancer, and

194 Information SectionwFd Chem. Toxic. Vol. 32, No. 2

not cancer risk, the probability that this potential is realized for a particular section of the population in a defined set of circumstances. This clarification needs to be continually made, if only to combat the false impression given by the current running title of the monograph series--"IARC Monographs on the Evaluation of Carcinogenic Risks to Humans".

An IARC assessment is conducted in a number of stages. The first step involves a determination of the strength of evidence of an agent's carcinogenicity separately in humans and laboratory animals, which each working group, using IARC guidelines, describes using a small number of standard phrases ("sufficient", "limited" or "inadequate evidence of carcinogenicity °', and "evidence suggesting lack of carcinogenicity"*). In laboratory animals, for example, "sufficient evidence of carcinogenicity'" is considered a worthy conclusion for a compound that produces an increase in malignant turnouts in two or more species of animals or in two or more independent studies in one species.

In 1979, IARC first saw the need to derive an over- all classification of carcinogenic hazard to humans for each agent (4). This resulted in a re-evaluation of the monographs of the 20 working groups that had participated in the programme up to that point. Compounds providing sufficient evidence of carcino- genicity in humans were assigned to Group i. Group 2 was used when there was evidence of carcinogenic activity but not of the quality to qualify for the top ranking. This Group was divided into 2A, for when "the evidence of human carcinogenicity is almost sufficient", and 2B, generally for compounds produc- ing sufficient evidence of carcinogenicity activity in animals. At that time, compounds in both Groups 2A and 2B were described as "probably carcinogenic for humans". The remaining category, Group 3, was for compounds on which there were inadequate experimental data to justify classification.

Some IARC acknowledgement o f t h e possible influence of mechanism in carcinogen assessment came in 1982 with the decision to include a geno- toxicity evaluation in the overall scheme of things (5). For a short period (1983-87), the working groups were required to deliver three separate verdicts, two covering, respectively, the strength of evidence of carcinogenicity in humans and in laboratory animals, and the third being a standard statement describing the evidence of activity in short-term tests for genotoxicity (6). "Sufficient evidence" of genotoxic activity was provided by at least three positive assay results (which had to include two of the three major endpoints, DNA damage, mutation and chromosomal effects), one of which had to involve mammalian cells (either in vitro or in vivo ).

Another examination of IARC evaluative prac- tices, as well as a review of all previous working

*In the earlier years "negative... or no evidence of carcino- genicity" were the preferred phrases.

group verdicts, took place in March 1987, a mam- moth task since by this time a total of 42 working groups had pronounced on over 600 agents or processes (7). It was at this meeting that the basic structure of the classification system that is still in operation was first promulgated. A new group was introduced (Group 4), and Group 2B was renamed (see Scheme). The potential importance of geno- toxicity status was confirmed by the recommendation that it could on occasion directly influence the overall classification. The standardized description of short- term test results was no longer considered useful, but it was accepted that clear evidence of activity across a broad spectrum of assays could allow the transfer of a compound from Group 3 to Group 2B or from Group 2B to Group 2A and this "other relevant data" clause was invoked in over 25 classification decisions, including those of styrene (to get to 2B) and the oxides of styrene and propylene (to get to 2A).

Group !

Group 2A

Group 2B

Group 3

Group 4

IARC Classification Scheme

(Arising from ad hoc Working Group of March 1987)

The agent is carcinogenic to humans Sufficient evidence of carcinogenicity in humans

The agent is probably carcimJgenic to humans Limited evidence of carcinogcnicity in humans and sufficient evidcnce of carcinogenicity in experimental animals Exceptionally, limited evidence of carcinogcnicity in humans only, or sufficicnt evidence of carcinogenicity in experimental animals is strengthened by supporting evidence from other relevant data

The agent is possibly carcinogenic to humans Generally, limited evidence of carcinogenicity in humans in the absence of sufficient evidence in cxpcrimcntal animals May also be used for inadequate or no data on human carcinogcnicity but sufficient evidence of carcinogenicity in experimental animals In some instances also applicable to limited evidence of carcinogcnicity in animals together with supporting evidence from other relevant data

The agent is not classifiable as to its carcinogenicity to humans Used when no other category is applicable

The agent is probably not carcinogenic to humans Evidence suggesting lack of carcinogenicity in humans together with evidence suggesting lack of carcinogenicity in experimental animals In some circumstances, inadequate or no evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data.

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Although the working groups that have met since January 1987 have maintained the practice of using genotoxicity findings to occasionally justify transfer from Group 2B to 2A and from 3 to 2B, other mechanistic arguments have also been invoked when the assembled experts saw the need. This need was seen very rarely, in fact on a handful of occasions only. Perhaps the most interesting of these is the decision (in October 1990) on atrazine. Despite a carcinogenicity profile of "inadequate evi- dence" in humans and "limited evidence" in laboratory animals - -which normally would not have warranted anything other than Group 3 classification (not classifiable)--atrazine was assigned to Group 2B. It was noted that "the increased risks for tumours that are known to be associated with hor- monal factors, which were oberved in studies [with atrazine] of both animals and human beings, are consistent with the known effects of atrazine on the hypothalamic- pituitary-gonadal axis" (8). In October 1989 chloramphenicol was assigned to Group 2A even though there was only "limited evidence" of its carcinogenicity in humans and "in- adequate evidence" in animals. The additional support for the 2A decision was said to be chloram- phenicors ability to induce aplastic anaemia in patients, in the knowledge that the condition is known to be related to the occurrence of leukaemia (9). On a more mundane note, limited evidence of carcinogenicity in animals for marine diesel oil was considered suitable for a Group 2B classification (rather than Group 3) because a number of other petroleum fractions containing structurally similar components had given clearer indications of their carcinogenicity ("sufficient evidence") in laboratory animals (10). A similar structural analogy case has been used to supplement a few genotoxicity-based promotions.

Observing the need of some working groups for a wider range of observations to arrive at what they felt was the most appropriate carcinogen classifiction, the IARC Secretariat in June 1991 invited some of the great and the good to Lyon to consider the general place of mechanism in the identification of cancer hazard (1 I). A working group of 39 experts, drawn from all the major disciplines involved in the study of carcinogenesis, produced a consensus statement to assist future working groups in their evaluation of specific chemical agents.

The consensus statement noted that consideration of mechanism would be assisted if the available data were considered within four broad, possibly inter- connected, categories ("descriptive dimensions"!). As well as the previously identified genotoxicity criteria, the three other descriptive dimensions concerned effects on the expression of relevant genes (functional changes at the intracellular level), on cell behaviour (for example morphological or behavioural changes in the cells of tissues), and "'the time and dose relationships of carcinogenic effects". This last

category covered insights into whether a compound was operating at an early or late stage in the carcino- genic process or whether it was involved in initiation. promotion or progression.

The strength of evidence that any carcinogenic effect was due to a particular mechanism would need to be assessed and described as either "weak", "moderate" or "strong". Each working group would then consider whether the proposed mechanism was likely to be operative in humans. Operational guide- lines were said ideally to be needed for the consistent use (from working group to working group) of these adjectival qualifiers. It was accepted (with some regret) that this ideal could not as yet be realized (hence presumably their absence from subsequent IARC Monographs). Amongst the general issues that would assist in the evaluation of the strength of evidence for a mechanism of action was the need to check the endpoint in several different species, the need to check whether the time sequence between exposure, endpoint and cancer was compatible with a cause-effect relationship, and the need to seek tenable alternatives to a cause-effect between exposure and endpoint.

The general principle was thus confirmed, mechan- istic conclusions could quite possibly have an impact on final carcinogen classification. Even Group !, which up until then had been restricted to compounds or processes producing sufficient evidence of carcino- genicity in humans, was said also to be appropriate for agents for which evidence in humans is less than sufficient, but on which "there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts on a relevant mechanism of carcinogenesis". On the other side of the coin, a Group 3 verdict (not classifiable) would now be considered suitable for a compound that has produced sufficient evidence of carcinogenic- ity in animals if there is also "strong evidence that the mechanism ofcarcinogenicity in animals does not operate in humans".

It can be seen, therefore, that IARC has allowed mechanism an influence in its classification scheme for some years, although admittedly this has been mostly a genotoxicity influence. IARC cannot be accused of tardiness in accepting the premise that, all other things being equal, a clearly genotoxic carcinogen is of greater concern to humans than is a non-genotoxic carcinogen. Even in wider mechanistic territory it is unlikely that many working groups up until now would have felt their interpretative freedoms greatly limited by IARC guidelines. On first (and perhaps second) sight IARC guidance, with its multiplicity and multi-layered sets of definitions, conjures up images of a bureaucratic, restrictive world. In actual use, however, there are probably enough nooks and crannies within the system to have allowed the final verdict on hazard to have usually reflected fairly the totality of evidence, mechanistic information included.

FCT }2,-~--H

196 Information Section--Fd Chem. Toxic. Vol. 32, No. 2

A look at the working groups' overall record in recent years shows that when there was a need to give weight to a mechanistic finding to arrive at a classi- fication higher than that indicated by a literal inter- pretation of the tumour data, then the nettle appears to have been grasped. The newest set of guidelines on mechanism are, in the main, only attempting to en- courage a little more consistency in what is happening already. Where new ground has been broken is that future assessors will be allowed, when the evidence is strong enough, to use mechanistic insights to down- grade the classification on a clearly positive animal carcinogen. In the past this is where some working group frustration may have been experienced. For example, the last Working Group that looked at saccharin, in 1987 (7), may have been convinced that findings in the rat--sodium saccharin produces bladder tumours in male rats--were of no relevance to humans. The Working Group nevertheless may have felt reluctant to break with the guideline sugges- tion that the most suitable classification for agents that produce sufficient evidence of carcinogenicity in animals (with inadequate evidence in humans) was Group 2B. Under the newer guidelines, of course, strong evidence that the mechanism is of no relevance to man would ease saccharin into Group 3. We will have to wait for saccharin's next appearance on an IARC agenda to see if it has yet achieved this state of grace as regards mechanism.

Having the scope to use mechanism to downgrade from Group 2B to 3 may not mean that it will be used very often. IARC pronouncements will probably retain their strong health bias. Working group membership is typically dominated (numeri- cally) by academics and scientists from regulatory agencies and they are unlikely to display any great evangelical fervour over a particular hypoth- esized mechanism that suggests a classification downgrading. An impressive body of empirical data will be required before a compound-induced animal cancer is ignored for human hazard classification purposes.

While on the subject of working group line-up, it is as well to emphasize that IARC's own scientists are not in fact responsible for the individual compound evaluations. Their role is to co-ordinate and act as the scientific secretariat to the various groups of experts they invite to Lyon to undertake the actual assess- ments. Whilst the early draft of the monograph is usually prepared by IARC staff, each working group has to assure itself that the coverage of the published literature is comprehensive and derive its own overall evaluations of cancer hazard. To achieve some sort of inter-group consistency in assessment, the working groups need to be provided with general guidance on what is expected of them, but the IARC staffare keen to emphasize that these guidelines are not rigid rules and are not applied as such. A particular working group may exhibit the views (and any prejudices) of its most vociferous members; pre-meeting predictions

on classification outcomes are therefore something of a gamble.

One feature of the new IARC era that may cause some difficulty in the future is the widening of the definition of Group 1. There is now the possibility (not as yet used) that, on the basis of animal data and mechanistic relevance to humans, compounds that have not been judged human carcinogens will finish in a group entitled "The agent is carcinogenic in humans"--a possible offence, in my view, under the Trade Descriptions Act. When the first compound with less than "sufficient evidence of carcinogenicity in humans" gets into Group I there will surely be a need to modify the Group's title. The obvious modi- fication that comes to mind is the strategic addition of the term "probably" but this would immediately run into problems because "probably carcinogenic in humans" is already in use for Group 2A. Perhaps IARC would welcome suggestions on a new name. What about "The agent is, or almost certainly is, carcinogenic to humans"? On balance. I think it would be preferable to keep Group I epidemio- logically pure.

Having made the point that the IARC guidelines have so far demonstrated a flexibility to cope with most mechanistic contingencies, there is a Working Group meeting scheduled for February 1994 that might uncover a chemical class that falls outside the current carcinogen assessment framework. The potential pathfinding chemicals on the agenda include ethylene and propylcne. Hazard evaluations by IARC may be taking a further step wherein the presence of mutagenic metabolites at any concen- tration are considered as a basis for carcinogen classification. If this step is taken IARC should require clear evidence that these metabolites are produced in sufficient quantities to cause a genotoxic response. When last subject to IARC attention, in 1979 (12), there were no adequate human or animal carcinogenicity data on either ethylene or propylene, and both were therefore assigned to Group 3. Since that time good quality animal carcinogenicity studies have been reported and it is ironic in the light of the results--no convincing evidence of activity--that these olefins should be back for another IARC evaluaton. The main area of current scientific interest is not the cancer data per se but the compounds' metabolism and pharmacokinetics. The interpretative problem arises because there is now a fair body of information (more on ethylene than propylene) to suggest that rodents convert a small proportion of the olefin they systemically absorb to the correspond- ing genotoxic, carcinogenic oxide (as summarized in 13-15). Both ethylene oxide and propylene oxide are IARC Group 2A compounds. On this basis it is not unreasonable to suggest that any species that possesses a propensity to generate these oxides may be potentially exposed to mutagenic metabolites when exposed to either ethylene or propylene. Whether or not this potential is expressed is a more

Information Section--Fd Chem. Toxic. Vol. 32. No. 2 197

complex issue, dependent on relative rates of metab- olism, detoxification and repair within the body. From our current understanding of the metabol- ism and pharmacokinetics of the olefins and their oxides in rodents, the expected number of tumours in any ethylene and propylene long-term study is going to be low, and indeed no statistically significant increases were seen in any of the ethylene or propylene bioassays. Since bioassays may be insufficiently sensitive to detect low levels of carcino- genic activity, it is important to look for underlying genetic effects that could ultimately lead to a low level of cancer. Such data need to be considered in the carcinogen classification of substances such as ethylene and propylene that might otherwise be deemed carcinogenic based solely on the formation of metabolites.

Whilst all these metabolic complexities will no doubt be discussed in detail at the Working Group meeting, the most likely conclusion of the experts would be that further information on metabolism and adduct formation is still needed for any confident assessment of human cancer hazard. Ethylene and propylene will probably, therefore, be left in Group 3. Nevertheless, if and when better information becomes available on the possible genotoxic consequences of exposure to these olcfins, then a suitable IARC classification could be determined by factoring in these data. This might be where some guideline modification would become necessary. Even the most imaginative interpretation of the present guidelincs could not get a chemical that itself gave no exper- imental evidence of carcinogenic activity in labor- atory animals into anything other than Group 3 or 4.

Although mechanistic research can affect the classification decisions generated by the IARC, it is likely that other areas of scientific investigation will rarely play any part in these hazard assessment processes. Remember that these are evaluations of hazard and not risk and as such it would be very hard to conceive of many instances when classical epi- demiologicai investigations (which assess risk) could do very much to rescue the reputation of a compound that has provided clear evidence of its carcinogenic potential in laboratory animals. Even the perfect negative cohort study, finding no evidence of carcino- genicity in an infinitely large number of exposed workers who had been followed for their whole life- span, can only provide information on the cancer risk at the particular range of exposures that have been experienced. If these exposures are low this 'perfect' negative study will make little contribution to an assessment of cancer hazard and indeed will provide little reassurance that a potent laboratory animal carcinogen is not a real carcinogenic hazard to humans (if given the chance). I need not stress that most epidemiologicai studies suffer in many (most) aspects in comparison with a perfect protocol. By contrast, the epidemiologist who reports a study that provides positive evidence of activity will have every

chance of making an immediate and important classification impact-- in this sense there is a health bias built into the system--and few would argue against that.

While on the subject of hazard and risk it is as well to mention some of the dangers of extrapolating one too readily to the other. It is tempting, for example, to assume that similar degrees of exposure to two compounds within the same IARC classification group would pose roughly similar cancer risks. It is probably even more tempting to believe, that all other things being equal--exposure included, that com- pounds in, say, IARC Group 2A are going to pose a greater human cancer risk than compounds in Group 2B. The motto should be--yield not to temptation: neither assumption is necessarily correct. The cause of this apparent affront to common sense is the schemes' lack of interest in cancer potency. Let me illustrate this point with a couple of examples. The analgesic phenacetin, which is in Group 2A, pro- duced increased turnout yields in rodents as a result of oral daily doses in the region of 300-900 mg/kg body weight given for long periods (16), whereas 1,2-dimethylhydrazine, in Group 2B, given orally to rats at doses below 25 mg/kg weight for short periods produced turnouts of the intestine (17). If I was told I had to add one or other of these materials to my evening meal for life to provide a dose of, say, 5 mg/kg body weight/day i know which one I would choose--give me a pain-flee existence every time! On a similar theme, dioxin, which is able to induce liver tumours in female rats at a dose of 0.1 ~lg/kg body weight/day (18), currently resides in the same category, Group 2B, as 1,4-dioxane, which is also a liver carcinogen in rats but only at dose levels in excess of 500 mg/kg body weight/day (19). With this laboratory experience few would argue that similar human exposures to dioxin and 1,4-dioxane arc likely to pose similar cancer risks.

If, because of this blindness to cancer potency, there is potentially a wide range of carcinogens (requiring a wide range of risk management strategies) within any one of the three positive IARC groups, there is, if anything, a still wider spectrum of biological character in the well populated Group 3 - - " n o t classifiable" (which includes over 60% of all agents evaluated). Understandably IARC has set a fairly high general qualification for Group 2B since it would not do to describe a compound as "possibly carcinogenic to humans" too readily. The other end of the Group 3 spectrum is of course defined by a failure to qualify for a place in Group 4 - - "p robab ly not carcinogenic to humans". The difficulty in achiev- ing Group 4 status is demonstrated by the fact that only one compound, caprolactam, in the history of the IARC programme has been thought to merit such a classification. Within Group 3, therefore, are com- pounds that have given indications of carcinogenieity but only in a single animal study, compounds that have been tested hardly at all, compounds that have

198 Information Section--Fd Chem. Toxic. Vol. 32, No. 2

been subject to a high quality cancer study and have given negative results and, presumably, at some future time, compounds that have given clear evid- ence of their carcinogenicity in laboratory animals but that operate by a mechanism that appears to be irrelevant to humans. To overlook all these complex- ities and treat an IARC classification decision as the end of a carcinogen assessment process, rather than just the start of it, is at best naive and at worst negligent. Any legislative action that is essentially based on the downloading of complete IARC classi- fication classes onto the statute book is worthy of a similar description.

1 mentioned in the introduction that one of the possible advantages of a classification scheme is to demonstrate that cancer potential is not a rare prop- erty of chemicals. The IARC endeavours certainly have achieved this; over 30% of all agents subject to working group scrutiny have been described as poss- ibly carcinogenic to humans or worse. I also implied that an ideal scheme should positively encourage a case by case approach to regulation. It is more debatable whether the IARC scheme, with its very small number of classification groups and a lack of interest in cancer potency, has been quite as success- ful in this regard. On mechanism, though, the IARC track record in fairly good.

[James Hopkins--BIBRA]

References

(I) Watts P. (1993) The classification of carcinogens. Chapter 5. In The Laboratory Environment. Edited by R. Purchase. Royal Society of Chemistry. In Press.

(2) IARC (1972) IARC Monographs on the Evaluation o f Carcinogenic Risk o f Chemicals to Man. Vol. L Some Inorganic Substances, Chlorinated Hydrocarbons, Aromatic Amines, N-Nitroso CompoundL and Natural Products.

(3) IARC (1978) IARC Monographs on the Evaluation o f the Carcinogeniv Risk o f Chemicals to Humans. VoL 17. Some N-Nitroso Compoundv.

(4) IARC (1979) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. (Suppl. I). Chemicals and Industrial Processes Associ-

ated with Cancer in Humans. IARC Monographs Vols 1 to 20.

(5) IARC (1982) IARC Monographs on the Evaluation o f the Carcinogenic Risk of Chemicals to Humans. (Suppl. 4). Chemicals, Industrial Processes and Industries Associated with Cancer in Humans. IARC Monographs Vols 1 to 29.

(6) IARC (1987) IARC Monographs on the Evaluation o f the Carcinogenic Risk of Chemicals to Humans. VoL 42. Silica and Some Silicates.

(7) IARC (1987) IARC Monographs on the Evaluation of the Carcinogenic Risks of Chemicals to Humans. (Suppl. 7). Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Vols I--42.

(8) IARC (1991) IARC Monographs on the Evaluation o f the Carcinogenic Risks to Humans. Vol. 53. Occupa- tional Exposures in Insecticide Application, and Some Pesticides.

(9) IARC (1990) IARC Monographs on the Evaluation o f the Carcinogenic Risks to Humans. Vol. 50. Pharma- ceutical Drugs.

(10) IARC (1989) IARC Monographs on the Evaluation o f the Carcinogenic Risks to Humans. Vol. 45. Occupa- tional Exposures in Petroleum Refining; Crude Oil and Major Petroleum Fuels.

(I I) IARC (1992) IARC Scientific Publications No. 116. Mechanisms of Carcinogenesis in Risk Identification. Edited by H. Vainio, P. N. Magee, D. B. McGregor and A. J. McMichael.

(12) IARC (1979) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chcmivals to Humans. Vol. 19. Some Monomers, Plastics aml Synthetic Elastomers, and Avrolein.

(13) Hopkins J. (1993) BIBRA Bulh, tin 32, 245. (14) BIBRA (1993) Toxicity Profile: Ethylene. BIBRA

Toxicology International. (15) BIBRA (1993) Toxicity Profile: Propylene. BIBRA

Toxicology International. (16) IARC (1980) IARC Monographs on the Evaluation

o f the Carcinogenic" Ri,~ks of Chemicals to Humans. Vol. 24. Some Pharmaceutical Drugs.

(17) IARC (1974) IARC Monographs on the Evaluation o f the Carcinogenic Risk o f Chemivals to Man. Vol. 4. Some Aromatic" Amine,,, Hydrazine and Related Substances, N-Nitroso Compound.* and Miscellaneous Alkylating Agents.

(18) Kociba R. J. et al. (1978) ToxicohJgy and Applied Pharmacology 46, 279.

(19) IARC (1976) IARC Monographs on the Evaluation o f the Carcinogenic Risk of Chemicals to Humans. Vol. I /. Cadmium, Nickel Some Epoxides, Miscellaneous Industrial Chemicals and General Considerations on Volatile Anaesthet&s.

C O M M I T T E E S ON T O X I C I T Y , M U T A G E N I C I T Y A N D C A R C I N O G E N I C I T Y

The UK Committees on Toxicity, Mutagenicity and Careinogenicity (COT, CoM and CoC) have pub- lished their second joint annual report.

During 1992 the CoT gave advice on aspartame, BHA, comfrey, dimethyldicarbonate and guidelines for microbial enzymes, as already announced ( M A F F letter ADF 1055; M A F F Food Safe ty Directorate News Release FSD 44/92. 30 July 1992; M A F F letter ADF 975, I I May 1993; M A F F Food Safe ty Direc- torate News Release FSD 10/93, 2 March 1993; M A F F l e t t e r ADF 1211/883D, 23 March 1993). The Committee also considered MAFF analytical data suggesting mean daily iodine intakes of 190ttg for

adults and 204 vg for infants aged 6--12 months, both well above the reference nutrient intakes rec- ommended by COMA of 140/~g and 60 pg, respect- ively (cited in F.C.T. 1991, 30, 792). However, in the former case the excess gave little cause for concern, and some reassurance over the infant intake was derived from a 1962 study in which no toxic effects were apparent in 14 children given 1000 t*g daily for 4 months.

Direct food additives considered during the year were the intense sweetener alitame and the antioxi- dant propyl gallate. The CoM noted that alitame had given negative results in bone marrow micronucleus