Information section--Fd Chem. Toxic. Vol. 30, No. 9 823

chronic ingestion (down to only about 4 pg/kg body weight/day if the 1-yr dog or 2-yr rat tests are used as a guide), but these have less relevance to the short-term problem of MITC contamination.

As wine contaminated with MITC was not of the "nature, substance or quality" demanded by the purchaser, its sale in the UK could have been re- garded as an offence under the Food Act 1984. However, the available published data do not suggest

that its withdrawal was essential on toxicological grounds. This of course assumes that the brief pub- lished summaries of industry tests are an accurate reflection of their findings. Only when industry stud- ies are published in full in peer-reviewed journals will the outside world be able to make a confident scien- tific appraisal of their implications.

[Christine Rostron--BIBRA]

C A R C I N O G E N S - - C L A S S I F I C A T I O N , R A N K I N G A N D H A N D L I N G

An erstwhile colleague once persuaded me to de- scribe the inability of free radicals to discriminate between intended and accidental targets as resulting in suitable chemical sites "whether brazenly flaunted on an industrial monomer or coyly secreted about a biologically important macromolecule" being approached "with equal relish" (cited in F.C.T. 1985, 23, 957). Whether my colleague obtained more pleasure from concocting the phraseology or from forever ascribing it to yours truly will probably never be revealed, but the point we were trying to make is an important one. Reactive chemicals are crucial to many industrial processes, humans make industrial processes work, and humans, composed of and con- taining a myriad of diverse molecules, are a potential target for reactive chemicals.

It is understandable then, that industry commits substantial resources to defining hazards and devising safe handling practices. Government has played its part in shaping a toxicologically acceptable working environment through regulatory measures such as the Health and Safety at Work Act, and the COSHH regulations.

One element in promoting safe handling practices is to ensure that appropriate advice on chemical hazards is available to those who need it. Before advice can be given, hazards need to be defined. Carcinogens have generally been classified by quali- tative schemes involving weight or strength of evidence, and the various schemes favoured by the EPA, NTP, IARC and ECETOC have been discussed in this journal (ibid 1989, 27, 147).

We later broadened the topic to encompass label- ling aspects (BIBRA Bulletin 1989, 28, 274); we felt that suppliers, in their individual endeavours to clas- sify and label carcinogens that did not appear on the Approved List, were not aided much by the rather vague wording of the EC categorization scheme. Tentatively then, we outlined our own proposals for classification criteria. While we hoped that the proposals would be favourably received and seen

*Safe handling of potentially carcinogenic aromatic amines and nitro compounds. Chemical Industries Association. 1992. ISBN 0-900-623-76-4.

generally as objective, a major aim of the article was to stimulate discussion and (rather over-optimisti- cally, as it turned out) elicit constructive suggestions from various quarters on how our proposed scheme could be improved. We emphasized that the scheme was designed to address carcinogenic potential per se, and was to be considered only a first step in the overall evaluative exercise.

In defining safe handling practices, classification of hazard may be a logical first step, but risk assessment features then need to be applied. In our discussion of the various qualitative schemes (loc. cit.) we noted the increasing recognition that, at least under the conditions of the standard experimental animal bioassay, carcinogenic potential was not a particu- larly uncommon characteristic of chemicals. With the safety evaluation studies turning up a larger number of animal carcinogens than had been anticipated, categories relating to carcinogenic potential for humans based on sufficient or limited evidence of animal carcinogenicity were becoming uncomfort- ably crowded, increasing the workload of the evalua- tors having to assess carcinogenic risk for humans and to prioritize risk management exercises. In common with other commentators, we suggested that one way forward might be to consider carcinogenic potency (in essence tumour yield per dose) in the various evaluative processes. The differences in mech- anism of tumour induction (genotoxic versus non- genotoxic) and the huge variations in potency estimations (e.g. some eight orders of magnitude separate saccharin from a nitrosamine on the cur- rently most favoured potency scale) provide some support for the introduction of ranking schemes within carcinogen classification categories.

A ranking scheme that takes into account both weight of evidence and potency factors for carcino- gens has recently been published by The Chemical Industries Association (CIA) in relation to poten- tially carcinogenic aromatic amines and nitro com- pounds*. This booklet was prepared by a Working Party consisting of representatives from Ciba-Geigy, ICI and Hickson & Welch Limited. (The scheme has been published in the primary literature as Crabtree et al., Mutation Research 1991, 264, 155.)

824 Information section--Fd Chem. Toxic. Vol. 30, No. 9

Essentially, the CIA scheme first classifies a chemi- cal in the fairly traditional qualitative way as a proven human, suspect human, proven animal or suspect animal carcinogen, as non-classifiable, or as a chemical for which there is "negative evidence" from good quality studies. The second, more innova- tive step is to obtain and apply, for the carcinogenic materials, a quantitative measure of potency, for which the Working Party favours the use of the TDs0*. Detailed guidance on selecting the most ap- propriate TDs0 value from the available studies is provided by the Working Party. Potency categories are defined, with cut-off ranges at < 1, 1-10, 10-100 or 100-1000 mg/kg body weight/day for suspect ani- mal carcinogens, <10, 10-100 or 100-1000mg/kg body weight/day for proven animal carcinogens, while suspect human carcinogens are divided into two groups, on the basis of whether the TDso in the animal study was less or more than 100 mg/kg body weight/day. The CIA scheme then provides a matrix that allows a carcinogenic chemical's weight of evi- dence and potency to determine its place in one of five carcinogenicity classifications.

The main objective of the Working Party was to arrive at safe handling guidelines, so the next stage in the exercise was to select one of four occupational hygiene control strategies: the 'Rolls Royce' Level 4 for proven human and A ranking carcinogens, Level 3 for B carcinogens, Level 2 for C and D carcinogens, down to the "basic" Level 1 for the non-carcinogens. Details of these strategies are given as an appendix to the report.

The Working Party efforts are commendably con- structive. On the ranking aspects, it was gratifying to see that a couple of worked examples are presented-- clear proof that the group has faith in its scheme. There is room for flexibility and toxicological exper- tise to influence decision making within the system; for instance, the worked examples demonstrate how discussions of dose-response, excessive mortality, historical control data and biological significance can have an impact on the qualitative assessment.

For hygiene controls the Working Party sensibly groups proven human and A ranked carcinogens together, as it does C and D ranked chemicals. Many of the differences between levels of control (which are described in detail) relate to equipment and employer practices rather than to worker practices, thus help- ing to minimize the risk that workers, by less than

*The TD~o is defined as the chronic dose rate (in mg/kg body weigh/day) that would halve the actuarially adjusted percentage of tumour-free animals at the end of the 'standard' lifespan for the species. An approximate definition is the chronic daily dose that induces tumours in half of the tested animals over their lifetime.

tGuidelines for the Evaluation of Chemicals for Carcino- genicity. Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment. Department of Health, Report on Health and Social Subjects, 42, 199t. Department of Health. HMSO, London.

proper working practices, could lower occupational health standards. The reader is reminded that the scheme only deals with carinogenic potential, and that other toxic effects of chemicals may dictate the final hygiene control strategy.

On the down side, I suspect that the "non-toxicol- ogists having some familiarity with toxicology", for whom the scheme is intended, may struggle with the discussions of which tumour types and incidence patterns are critical for qualitative classification. It is not clear how chemicals that produce tumours only at doses in excess of 1 g/kg body weight/day should be ranked. They should be considered suspect animal carcinogens according to the text on "weight of evidence", but the ranking matrix only appears to encompass chemicals producing TDs0 values of less than 1 g/kg body weight/day. Much play is being made at present of the hope that genotoxic and non-genotoxic carcinogens can be considered to pose very different risks at the likely low (i.e. subthreshold for epigenetic carcinogens) levels of human exposure, but the guidelines do not address this issue with any particular force, though they do give the available short-term genotoxicity data a role in influencing qualitative classification. While on the subject of genotoxicity and its relevance to carinogenicity classification, we might mention the recently ex- pressed CoC viewt that it is reasonable to regard an in vivo mutagen as a potential human carcinogen (even if carcinogenicity studies in laboratory animals have given negative results). Next time the CIA Working Party meets, the agenda may perhaps in- clude some discussion on where in the final occu- pational hygiene matrix these in vivo mutagens should feature.

I was unclear on how the CIA scheme might deal with two (theoretical) genotoxic chemicals, one proven, in the last few years, to be an animal carcinogen with a TDs0 of 105mg/kg body weight/day, and the other used for many years and proven to be an animal carcinogen, with a TDs0 of 95 mg/kg body weight/day. In this hypothetical in- stance, there is sufficient epidemiological information on the chemical that has been around for a long time, and perhaps not subject to modern standards of control during that period, to consider it to be a suspect human carcinogen. The newly developed chemical, on the other hand, will not have been or (we hope) ever will be given the opportunity to demonstrate any carcinogenic potential in humans. The proposed scheme would seem to rank the old carcinogens in carcinogenicity class A (and thus attract Level 4 hygiene control) and the new examples in class C (Level 2 hygiene control), respectively, a differentiation that appears difficult to justify. Of course, the sensible response to this "What i f . . . ? " scenario would be that all chemicals should be treated on their merits. I would certainly support this view, and merely indicate that the example highlights the need for administrative decision makers to recognize

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that decision schemes, while useful, are best used in conjunction with, rather than instead of, the expert judgement of the toxicologist.

This might be an appropriate point to mention some other recent expert views on carcinogen classifi- cation and ranking. UK Department of Health scien- tists have concluded that the use of the TDs0 as a ranking method is justified, and that analyses suggest that there is a good correlation between carcinogenic potency in animal studies and potency in humans as assessed from epidemiology studies (Woodward et aL, Carcinogenesis 1991, 12, 1061). It was felt that fine tuning of the TDs0 approach could be carried out along the lines suggested in a working paper of the International Commission for Protection against Environmental Mutagens and Carcinogens (Nesnow, Mutation Research 1990, 239, 83). In this way other aspects of the bioassay results, such as number of species of number of sites affected, have some quantitative influence. Moreover, Woodward et al. (loc. cit.) suggested that only chemicals likely to be human carcinogens should be included in any TDs0 ranking system if it is to be used for risk assessment, and that other chemicals that are non-genotoxic, or are unlikely to be carcinogenic in humans for pharmacokinetic reasons or operate by a mechanism known to be irrelevant to human risk assessment, should be omitted. For non-genotoxic carcinogens, Woodward et al. (loc. cit.) recommend the ADI route to be a more suitable route of risk assessment.

A more sophisticated qualitative classification scheme than those typified by the IARC scheme was proposed in 1990 by a group of experts drawn from a wide range of industrial companies (Ashby et al., Regulatory Toxicology and Pharmacology 1990, 12, 270). This group considered that an evaluation of the relevance of animal data to

human hazard was an important step to be carried out prior to classifying chemicals into one of eight categories. Expert judgement is needed to evaluate relevance, so this classification exercise cannot easily be reduced to a simple set of decision rules (Ashby et aL, loc. cit.).

Where does all this leave us? Although the CIA Working Party's remit was evidently focused on aromatic amine and nitro compounds, chemical classes of particular interest to their companies, it seems reasonable to suggest that the devised scheme would work equally well for the other chemical candidates. I like the idea of using a matrix that blends qualitative and quantitative aspects to rank carcinogens for the purpose of devising safe handling procedures. (Though of the available purely qualitat- ive classification systems, I find that of Ashby et aL the most attractive.) Carcinogens show different dose-response curves and the TDs0, being a single point value, gives no indication of the shape of the dose-response curve and therefore of the relative potency at lower doses, where human exposures would presumably be more likely. It would be inter- esting to see if a method using insights of both potency and slope could be devised--some sort of involvement of a TDs0/TDI5 ratio perhaps- -and how useful Nesnow's fine tuning of the TDs0 system might be. Whatever schemes are proposed, I would expect that the input of the expert toxicologist will be as vital as ever. With the present imprecision in our under- standing of the biology involved, I do not see the schemes ever being reduced to a simple set of decision rules that managers untrained in toxicology could use in isolation with confidence. Perhaps that is as it should be.

[Peter Watts--BIBRA]

F O O D E M U L S I F I E R S A N D S T A B I L I Z E R S

The CoT has reviewed the toxicology of all sub- stances currently permitted by the Emulsifiers and Stabilisers in Food Regulations, 1989, as amended, and has classified them as Group A (acceptable) or Group B (provisionally acceptable). The FAC has accordingly recommended that the substances should continue to be permitted, subject to the provision of further data within the time limits recommended by the CoT.

Items classified in Group A are lecithins; alginic acid and its sodium, potassium, ammonium and calcium salts; propylene glycol alginate; agar; locust bean (carob) and guar gums, subject to the existing limit of 15% in the food; tragacanth, acacia, xanthan and karaya gums; polyoxyethylene (20) sorbitan monolaurate, monooleate, monopalmitate, mono-

stearate and tristearate (Tweens 20, 80, 40, 60 and 65); pectin, amidated pectin and pectin extract; microcrystalline cellulose; methyl-, hydroxypropyl-, hydroxypropylmethyl- and ethylmethylcellulose; car- boxymethylcellulose, sodium salt; sodium, potassium and calcium salts, mono- and diglycerides, acetic acid esters of mono- and diglycerides, and polyglycerol esters, of fatty acids; sucrose esters of fatty acids and sucroglycerides, subject to a residue limit of I ppm for dimethylformamide; polyglycerol esters of polycon- densed fatty acids of castor oil; sodium and calcium stearoyl-2-1actylates; and stearyl tartrate.

Substances classified in Group B, with the data required in brackets in each case, are carrageenan (absorption and bioavailability of food-grade material, particularly by the immature gut, and