FdChem. Toxw Vol 30, No 7, pp 663~65, 1992 0278-6915/92 $500+0.00 Pnnted m Great Britain Pergamon Press Lid

Information Section

E V A L U A T I N G C H E M I C A L C A R C I N O G E N I C I T Y : T H E U P D A T E D U K V I E W

Ten years have elapsed since the UK Committee on Carcmogenicity published its original set of guide- lines on carcinogenicity testing. These guidelines were very brief (30 pp) and dealt almost exclusively with the design of animal carcinogenicity studies. In two short paragraphs on short-term tests (STTs), the Committee concluded that STTs and carcinogenlcity bioassays both had value, but that the former could not be considered substitutes for the latter. The recent publication of an updated version of these guidelines provides an ideal opportunity to assess how the views of the premier UK committee on these matters have changed over the last decade

On the technical side the picture has altered very little. Many opinions on protocol modifications have been offered by eminent toxicologists since the original guidelines were published, but the latest report does not discuss protocol in any depth, instead referring the aspiring experimentalist back to the earlier version and other fairly old supranational pronouncements for detailed guidance on this score. The opportunity has been taken, however, to cover some of the wider issues involved in the evaluation of carcinogenic potential, and a very thought-provoking document, some three times longer than the original, is the result.

These wider issues are addressed in sections on epIdemmlogy, the relevance of STTs, mechanisms of tumour induction and risk assessment. An enthusi- asm is shown for the subdivision of animal car- cinogens into genotoxic and non-genotoxic agents. The Committee nevertheless admits to the difficulty of defining very clearly a non-genotoxic carcinogen. The favoured definition--a chemical that induces tumours but which shows no activity in a series of well conducted, fully validated genotoxicity tests-- seems quite helpful when given on page 2 of the report but seems slightly less so when, at the bottom of a table of examples (presumably the best examples) of non-genotoxic carcinogens on page 6, one finds a "note" that "Some of the compounds listed here show limited, weak or equivocal evidence of genotoxic activity in various short-term tests". The position is perhaps more fairly stated on page 21 where it is said to be "convenient" to divide carcino- gens into genotoxic and non-genotoxic categories, but it is conceded that "the distinction between these categories is sometimes imprecise".

Confident demarcation between genotoxic and non-genotoxic carcinogens is very important to the Committee from the perspective of risk assessment.

The induction of tumours by some non-genotoxic carcinogens as a secondary event following a threshold toxicological effect logically means that there will be no carcinogenic threat at dose levels below this toxic threshold. Whilst the CoC sub- scribes to this general view, it seems appreciably more cautious about these sort of things than many pundits in the world at large. As well as an absence of activity in genotoxlclty tests, qualification for a threshold approach also requires, in the Committee's opinion, that "the mechanism of action has been established". If such a mechanism has not been established--as in the case for most, if not all, carcinogens--then it is believed the prudent approach of assuming no threshold for the carcinogenic effect should apply.

For genotoxic carcinogens, the CoC discusses briefly the basis and limitations of various models, much favoured in the US, for quantitative risk assessment. The Committee concludes that "the present mathematical models are not validated, are often based on incomplete or inappropriate data, are derived more from mathematical assumptions than from a knowledge of biological mechanism a n d . . , demonstrate a dlsturbingly wide variation in risk estimates depending on the model adopted". The models are said to give "an impression of precision which cannot be justified from the approxi- mations and assumptions upon which they are based" and thus the CoC has decided to stick with what it describes as "qualitative risk assessment", the comparison of "hazards in terms relative to other situations" A few examples would have been helpful at this stage!

On the question of STTs, the report contains the interesting proposition that it is probably unnecess- ary to subject m vzvo mutagens to carcinogenicity testing, better simply to assume the worst and regard such compounds as having (genotoxic) carcinogenic potential. In v ivo mutagens for these purposes include compounds able to induce chromosomal damage in somatic cells. Even if investment is made in carcino- genicity testing and an (unexpected) negative result found, the Committee implies that the negative find- ings are just as likely to be ascribed to the lack of sensitivity of the test system as to the lack of cancer potential of the test material!

The very popular two-stage animal cancer studies are mentioned only briefly. The Committee points out that their main use is in the experimental context rather than in safety evaluation, and implies that such studies are unlikely to have any direct

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regulatory influence The hint is given that decision makers would be better advised spending their money on tissue culture approaches to analyse tumour pro- motion. Practical and interpretative difficulties mean that, generally speaking, a thumbs down is also given to in utero exposure in cancer studies, a procedure once much in vogue Enthusiasm is shown, however, for the idea of two Identical but distinct control groups to allow better insights into the innate vari- ability of spontaneous lesions. Journal editors are also offered some advice that if taken, may well change their way of hfe. The Committee is keen that sufficient detail is included in final published reports to allow referees to satisfy themselves about "key elements" of the study Some (14 or so) of these key elements are itemized, and it seems not unfair to say that very few papers that are satisfying the current peer review process would pass on all these counts.

It was mentioned earlier that m t, ivo mutagens, in the opinion of the CoC, warrant a low priority for carcinogeniclty testing since, for risk assessment purposes, they are already deemed to be potential carcinogens. Having said this, the Committee still believes STTs have some role to play in determining cancer testing priorities, in particular an m vitro mutagen that cannot be appropriately tested for mutageniclty in vtvo would push itself up the carcino- genicity testing schedules. On the other side of the coin, however, negative STT results do not auto- matically preclude the need for cancer testing,

Using the spectre of dloxin, an STT non-genotoxin that is carcinogenic in laboratory animals at daily doses of/~g/kg body weight, the CoC warns against the increasing temptation of automatically assuming that low level human exposures to non-genotoxins should be regarded, for practical purposes, as carrying no carcinogenic risk. Negative mutagenicity

results, therefore, cannot be construed as proof that a compound is non-carcinogenic, and the Committee concludes that there is no acceptable alternative to long-term carclnogenicity studies in rodents where human exposure "is likely to be extensive (in terms of amount and/or duration)", not a particularly helpful form of words since the extensive duration criterion would encompass every detectable component in the normal human diet!

New to the guidelines is a discussion of the value of epidemiology in evaluating putative human car- cinogens The advantages of the epidemlological approach are that data are derived directly from human populations and the problems of extrapo- lating observations from laboratory animals are avoided. Epidemlology lacks the control over the observational setting and the precision of measure- ment basic to experimental science; nevertheless, the Committee is supportive of its benefits in the study of human risk from carcinogens provided that appropriate scientific rigour is observed.

In summary, the CoC has provided a useful insight into Its thoughts on general issues, mech- anisms of tumour induction, epidemiology, STTs, study design, interpretation and risk assessment. The report acknowledges that not all the issues are clear-cut, and the Committee's approach to making the necessary decisions is outlined in fairly general terms. It would have been helpful to illustrate the various evaluative policy positions with carefully chosen case histories. [Guidehnes for the Evaluation of Chemicals for Carcinogenlcity. Committee on CarclnogenicIty of Chemicals in Food, Consumer Products and the Environment. Department of Health. Report on Health and Social Subjects 42. HMSO, London pp. 80, 1991, £7.30.]

James Hopkins--BIBRA

A B S T R A C T S F R O M

Bmssel sprouts

An effect on blood coagulation (increased prothrom- bin time) occurred in rats fed for 4wk on a diet containing 2.5% Brussels sprouts (approximately 2.5g/kg body weight/day). Lower concentrations were not tested. At higher dietary levels effects on the thyroid and changes in the kidney and hver were observed. The investigators concluded that "2.5% Brussels sprouts dry matter in the diet was not without effect" and that "a more detailed study might reveal effects at lower feeding levels" (De Groot et al., Food and Chemical Toxzcology 1991, 29, 829).

Fish oils

Analysis of the composition of fat tissue from 136 UK men who died of heart disease and that of 95 controls dying of other causes indicated that

T H E L I T E R A T U R E

"the cases had consumed a greater amount of hydro- genated marine oils manufactured from certain highly unsaturated raw oil", in particular of the menhaden type. This "did not rise from medical advice favouring margarine .. but rather a fortu- itous selection of margarine brand". The investigator, who is based at the Polytechnic of Wales, suggests that the hydrogenation results in a product which prevents the utilization of 'good' polyunsaturated fatty acids (Thomas, Journal o f Epidemiology and Community Health 1992, 46, 78).

Cooked beef

The frequency of micronucleI ( a form of chromoso- mal damage) in the bone marrow cells increased in mice fed for 21 days on a diet supplemented with well-done 'pan-fried' beef, rare charcoal-barbecued