Occupational Cancer Prevention and Control, Resúmenes de Cambio Social

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O C C U P A T I O N A L S A F E T Y

A N D H E A L T H

SERIES

No. 3 3

OCCUPATIONAL CANCER -

PREVENTION A N D CONTROL

I N T E R N A T I O N A L L A B O U R OFFICE - GENEVA

ISBN 92-2-101827-X

First published 1977

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Pa.qe

APPENDIX 2 - ILO international instruments 29

Convention No. 139 concerning prevention and control of occupational hazards caused by carcino- genic substances and agents 29

Recoanendation No. 147 concerning prevention and control of occupational hazards caused by carcino- genic substances and agents -....<.. 32

FOREWORD

The question of the prevention of occupational cancer and the protection of workers against this risk has been under active con- sideration by the ILO during the past decade, in particular follow- ing the adoption of a resolution on this subject by the 1967 session of the International. Labour Conference. It bécane a priority subject when the ILO Governing Body decided to convene a meeting of experts to examine possible ILO action with a view to submitting to the International Labour Conference proposals for international standards on this question. The Conference discussed at two successive sessions, in 1973 and 1971», the principles for the organisation of technical and medical prevention, and finally adopted two international instruments, a Convention (No. 139) and a Recommendation (No. 147) concerning the prevention and control of occupational hazards caused by carcinogenic substances and agents. The Convention states the most essential principles: replacement of carcinogenic substances by less dangerous ones; establishment of a list of carcinogens to be prohibited, or made subject to authorisation or to control; recording of data concerning exposure and exposed workers; medical surveillance; information and education. In the Recommendation, these principles are expanded and member States are invited, when implementing the provisions of the instruments, to take into account guides and other technical publications prepared by the ILO. The intention of the Conference was therefore to lay down general principles for implementation at the national level of the specific and detailed measures required and for the development of adequate control programmes.

Recognising the difficulties of action in this field, the 1975 session of the International Labour Conference also adopted two resolutions related to the problems of occupational cancer. The first refers to the adverse social and economic consequences, both for the workers and for the industry which may follow the implementation of strict preventive and protective measures prescribed by national legislation, and methods of meeting the hardships involved; the second asks for the establishment of an appropriate consultation mechanism to be used by the ILO in order to provide up-to-date information on the results of research and on the most effective methods of preventing occupational cancer. One important task specified in this connection is to provide guidance for the implementation of the principles set forth in the ILO Convention and Recommendation (see Appendix 2).

This publication represents a first step in this direction. It was originally drawn up with the valuable help of a group of consultants 1 and reviewed by the ILO Panel of Consultants on

1 Participated in this consultation (10-12 November 1975): Dr. E. Bolinder, Chief, dedicai Department, Swedish Trade Onion Con- federation, Stockholm (Sweden); Dr. B. Holmberg, Associate Professor of Toxicology, National Board of Occupational Safety and Health, Stockholm (Sweden); Dr. A. Munn, Division Medical Officer, Imperial Chemical Industries Ltd., Manchester (united Kingdom); Dr. V.E. Rose, Department of Health, Education and Welfare, Houston (USA); Dr. G. Smagghe, Chef des Services de médecine et de toxicologie, Société de produits chimiques Dgine-Kuhlmánn, Paris (France); Prof. R. Truhaut, Directeur du centre de recherches toxicologiques, Faculté des sciences pharmaceutiques et biologiques, Paris (France).

1. PROBLEMS RELATING TO THE ESTABLISHMENT

OF OCCtJPATl5NAL~STÏNDÏRDS~POR_CARCÏNOGENS

For the purpose of this document, occupational carcinogens are chemical substances, physical agents or work processes which nay cause cancer in man due to conditions of exposure in the workplace. Occupationally induced tumours are no different in type and nature from those arising from non-occupational factors. Indeed, they may cause a significant increase of a particular type of cancer in the exposed working population.

These considerations extend to the so-called "benign" tumours. Many benign spontaneous human neoplasms and induced animal neoplasms may become frankly malignant, so that for the purpose of prevention, no differentiation is made between "tumourigens" and "carcinogens".

1.1 Animal experimentation

Current approaches to the control of occupational cancer now rely heavily on animal experimentation usually involving the rat or mouse. More and more the approach fron the regulatory point of view is to consider experimental carcinogens as potential human carcinogens when a significant human exposure exists. In following this line of reasoning, however, the magnitude of the potential problem becomes considerable. For example, the National Institute for Occupational Safety and Health (NIOSH) of the United States has identified some 1,300 substances which have produced some tumourogenic or carcinogenic effect in animals. 1 However, a number of these cases need further confirmation because they are inferred from published studies for which there are insufficient data with regard to the design of the research or the criteria for evaluation.

The actual extent of occupational exposure to many of these chemicals may be minimal. Nevertheless, there can be no doubt that some, if not many, of these substances are capable of* producing cancer in humans. In addition, the number of chemicals to which workers are exposed and which lack adeguate evaluation is unknown.

In evaluating experimental animal data, it must be recognised that this is not a perfect tool. There are substances, such as the inorganic compounds of arsenic, which are highly suspected of producing an increased incidence of cancer in workers, but for which animal experimentation has to date been unsuccessful. 2 Just as "false negative" results exist, so do "false positives". There is some evidence to indicate that while certain substances, such as o- toluidine and diethyleneglycol, are carcinogenic in test animals, their hazard potential in the workplace is not significant.

Another factor of concern involves the evaluation of trace impurities especially as more sophisticated analytical techniques

» National Institute for Occupational Safety and Health (1975) SusEêçtgd_çarçinogensi A_subfile of the__NI0SH Toxic Substances LÏit7~NIOSH7~ROckvïïïë~7iâryïând77~P~3'»2T 2 International Agency for Research on Cancer (1973) I£RÇ. Monographs on the Evaluation of Carcinogenic Risk of Chemicals to fias" I?

become available. Serious concerns exist as to whether the basic chemical or the impurity is the aetiological agent. The best example of this probably involves 1- and 2-naphthylanines. Here the 2-isomer is without doubt a carcinogen. Some researchers have attributed the increased incidence of bladder cancer among workers involved in the manufacture of 1-naphthylamine to the 2-impurities. However, lacking definitive data, certain countries which regulate carcinogens have chosen to include 1-naphthylamine as a carcinogenic substance.

another area of current controversy involves the concept of dose-effect relationship and the existence of a "no effect" dose level. The problem of "no effect" levels of «xposure to carcinogens has been much debated over many years. Our knowledge about dose- effect relationships and cancer is mainly based on animal experimental work. The dose-frequency curve obtained with, for instance, methylcholanthrene after a single subcutaneous injection has the S shape known fron classical toxicology. 1 The shape of the curve implies the existence of a zero-effect level of the carcinogen. In a probit diagram the S shape curve can be transformed to a linean curve.* It should be remembered, however, that an increase in the number of experimental animals per dose group increases the probability of obtaining an animal with a tumour at a low dose level. The zero-effect dose seems thus to be a phenomenon closely related to the number of animals, the species and the route and type of administration, which cannot be extrapolated to other population sizes, nor to other species, absorption routes or exposure- times.

The fractioning of a single dose of a potent carcinogen into small doses administered over a long period seems to increase the response.2 Thus, twelve subcutaneous injections of 0.042 mg each of benzo(a)pyrene in mice induce tumours in 70 per cent of the animals. The same total dose (0.5 mg) administered at one single injection induces tumours in about 20 per cent of the animals. If any generalisation can be made from one experiment with one substance, then it would appear to be more dangerous to be exposed to small amounts of a carcinogen repeatedly and for a long time than to have one single peak exposure.

Dose-latency studies seem to indicate that low single doses induce tumours with long latent periods, while high singlé doses induce tumours with short latent periods.» It should therefore be theoretically possible to derive a dose for a given animal species, number of animals, route and type of administration, which does not induce a tumour within the life expectancy of that particular species. However, even if this were possible for one substance and one test species, it is not possible to extrapolate such a zero- effect dose level to any other species.

1 Bryan, H.R. and Shimkin, S.B. (1943) Journal_of_the_National Cancer .Institute. 3, 503. - - -

2 Payne, W.U. and Heuper, U.C. (1960) American Industrial Hygiene association Journal. 21, 3S0. ~

least 2,995 test animals in each dose group. Such a comparison is based upon the assumption that human populations and test animal populations respond identically, an assumption which may well be false.

!afeiÊi **'_** fiSfber_of_anina1s_in_toxiçit£ experiments

Probability of toxic Animals in experiments* effects in man Probability Probability («) 0.95 0.

Source: Zbinden G. (1973) Progress in Toxicology. 1, Springer, New ïork.

«Number of animals to be included in an experiment in order to find at least one subject with the toxic effect (assuming identical incidence of toxic effect in animals and man). (Calculated by T. Harthaler, Biostatistics Centre, University of Zurich.)

It is clear from the above points that the study of the response to low doses of carcinogens is extreoely difficult. Extrapolation from high dose levels down to low dose levels might be regarded as a possibility. Such an extrapolation can be done from a linear dose-response curve in a probit diagram. Our' knowledge about the shape of dose-response curves at low dose levels is, however, limited. & study on chemical carcinogenesis referred to above, indicates that the dose latency curve has a flatter slope at low dose levels than at high levels, though a linear curve at all dose levels studied is suggested for tobacco carcinogenesis and for radiation-induced cancer in human populations. A simple extrapolation of a linear part of a dose curve obtained by epidemiological studies may thus be hazardous even when a safety factor is introduced.

The conclusion is, in summary, that experimental studies on chemical carcinogenesis, although providing very useful information, are insufficient for establishing a risk estimate for human exposure in the work environment. The best way to establish a true risk estimate for human exposure is by means of an integrated evaluation

of epidemiological studies and proper animal experiments. In the absence of an adequate dose-response curve for a human population as obtained by epidemiological studies, animal data should essentially be used to establish carcinogenicity as such, and possibly for comparing the risk potential from one substance to another. Experimental animal testing remains indeed necessary in the case of new substances for which epidemiological studies are obviously not applicable. From a practical point of view, exposure to an experimental carcinogen should be kept as close to zero as possible in the occupational environment, irrespective of dose level in the test system, animal species, tumour site, type or frequency.

1.3 Epidemiological studies

The most effective contribution to the establishment of a reliable risk estimate for human exposure in the working environment is by means of epidemiological studies. &n epidemiological study is a statistical means of comparing the frequency of a particular effect in one group of people with that of another group or with the population as a whole. Ideally, it should be possible in such a study to measure the level of exposure and the incidence of effects so as to establish a dose-response relationship. This is however, seldom possible in studying the incidence of occupational cancer because of the small populations at various risk levels and of inadequate or even complete absence of relevant analytical data on the contaminants. when these data are available, then valid information is obtained. Some recent studies have confirmed the validity of this method for assessing the relationship between the incidence of certain types of cancer and an occupational exposure. This was the case, for example, for pleural mesothelioma in asbestos workers and for hemoangioma of the liver in vinyl chloride workers.

Many uncontrolled factors can contribute to making an epidemiological study on occupational cancer less informative or even to making it non-valid. Thus, the size of exposed populations may be small or the exposure time shorter than the time period necessary for tumour induction;, information on past exposure levels may be semi-quantitative or even absent, the technological process may have changed quantitatively or qualitatively during the actual induction period, etc., all factors negatively influencing the risk assessment. In some occupations a multiplicity of chemical products is used making it impossible to correlate exposure to a given agent with an increased risk of cancer.

The problems of establishing a dòse-response relationship at low dose levels are of the sane magnitude in human populations as in test animal populations. This means, among other things, that for practical purposes the concept of a safe level of exposure for human populations is closely connected to the size of the exposed population and any increase in population size may increase the probability of observing a cancer due to occupational exposure. Moreover, epidemiological studies are naturally based upon comparisons with control populations which are themselves changing. The cancer incidence in the population of industrial societies is increasing even over a relatively short-time perspective. For certain cancer sites, for instance lung cancer, the incidence in some countries has increased considerably over a ten-year period. Any risk estimate obtained in an occupationally-exposed population is thus based on a comparison with a population having a con- tinuously increasing "background noise", and it might be argued that

tests, the present approach is therefore to carry out tests in animal systems on chemicals which (a) are found to be active by screening tests for mutagenicity; and (b) are structurally related to known experimental or human carcinogens. Other important factors to be considered when establishing priorities are the physical, chemical and biochemical properties, especially as they relate to potential routes of exposure; the quantity of material produced or the anticipated potential: the number of workers exposed and the level of exposure; the ultimate community involvement, whether for instance exposure is limited to industrial settings or a wider contamination is possible. These problems have been actively studied in recent years.»

fts a consequence it has been felt necessary to develop practical guidelines for the conduct of these experimental studies. it the international level such guidelines have been developed by the International Agency for Research on Cancer (IARC) and, in essence, these require: exposure to dose levels lending to measurable effects; appropriate length of testing; presentation of a satisfactory protocol involving appropriate exposure routes; use of an adequate control group; interpretation of results in relationship to a control group.

In addition to experimental studies and animal testing, epi- demiological studies should be performed in order to establish a risk estimate for chemicals in use.

The final evaluation, especially as regards the establishment of preventive regulatory measures, should consider the carcinogenic hazard to working populations. Consequently, several factors should be taken into consideration, among which are: evaluation, both qualitative and quantitative, of experimental data; critical evaluation of epidemiological data when available; consideration of physical, chemical and bio-chemical factors; the nature of the technology where exposures may result; and other possible influencing factors, such as synergistic/antagonistic potential, the potential for personal factors such as diet and smoking to have a contributory effect and the possibility of mutagenic and/or teratogenic effects to be manifested, especially where exposure of females of childbearing age is possible.

» See also:

world Health Organisation (1971) Principles for the testing and evaluation of drugs for carcinogenicity. Technical Report Series No. «82, WHO, Geneva.

World Health Organisation (1971) Evaluation and testing of drugs for mutagenicity: principles and problems. Technical Eeport Series No. U82, WHO, Geneva.

World Health Organisation (1974) Assessment of the carcinogenicity and mutagenicity of chemicals. Technical Report Series No. 546, WHO, Geneva.

2. CLASSIFICATION OF CARCINOGENS FQR THE

£2iIös|_ö?_LECllLÄ2I9ä

In the field of occupational carcinogenesis, as in other scientific fields, very little is known in comparison with what is not known. The resources available to cope with the entire spectrum of occupational safety and health problems are finite, and occupational carcinogenesis is just one part of this spectrum. Hence the need to classify carcinogens by some rationale, in order that governmental authorities, employers and employees can put the problem into a proper perspective.

While every classification system is arbitrary, it is accepted that some form of classification is useful. For practical purposes a list of carcinogens can, for instance, be structured according to one or more of the following criteria:

(a) human carcinogens/animal carcinogens;

(b) highly/moderately/low potent carcinogens;

(c) prohibited/permitted carcinogens according either to "necessity" (cost-benefit assessment), or technological feasibility, or to potential hazard, i.e., degree of risk, as regards occupational exposures.

A listing according to principle (ay would for instance include 2-naphthylamine, bis-chloromethyl ether, benzene and vinyl chloride as human carcinogens. The most satisfactory criterion for listing a substance as a human carcinogen is an increased cancer risk (adjusted for age, sex and other compounding factors) in occupationally exposed groups (at best with different dose levels) compared to control groups. This is derived from epidemiological studies which are unfortunately only available in a minority of cases for the establishment of the carcinogenic activity of chemicals.

Further, the number of factors already mentioned which can influence negatively a correct risk assessment, and the multiplicity of exposure to chemicals inside and outside the work site, may invalidate the conclusions of such inquiries or call for caution in their interpretation. There is thus a tendency to underestimate the true number of human carcinogens. This means that a listing of human carcinogens apart from experimental carcinogens, in so far as the listing implies separate levels of restriction of the occupational exposure, does not necessarily reflect the true risk situation. A rather widely accepted pragmatic approach from the regulatory point of view is to consider experimental carcinogens as potential human carcinogens when a significant human exposure exists. This point is illustrated by the findings concerning, for instance, vinyl chloride, bis-chloromethyl ether, diethylstil- boestrol, which, having shown carcinogenic action in animal experimentation, were subsequently found to be carcinogenic also for man.

A listing of carcinogens according to potency is the second possibility. This, however, is not accepted by a number of scientific workers, because of the difficulty of defining criteria of potency. Generally speaking, potency may be defined as being the amount of carcinogen required for the production of a given

Due to the paucity of epidemiological data, uncertainties in extrapolating animal data to human exposures, and the conceptual difficulty in formulating acceptable degrees of risk, it would appear particularly difficult to recommend "safe" levels of exposure for carcinogenic substances at this time. There is, however, from a practical point of view* a clear need to provide guidance for cases in which the production or use of carcinogenic substances cannot be dispensed with, in particular where they also present other types of risks, such as intoxication, explosion, etc. One way to cope with this need at the present time is to prescribe for certain carcinogens the "technical reference concentrations" referred to above, whose role is to give guidance in the implementation of technical preventive measures designed to reduce to a minimum the exposure to these substance's. This has been done in certain national lists, where provisional limit values have been assigned to less dangerous carcinogens.

3. PREVENTIVE MEASURES

3.1 Ggneral_ErincÍEles

Safety and health measures should be applied to ensure that work involving the use of one or more carcinogens does not endanger the health of workers or of persons living in the neighbourhood of the plant, by giving due consideration to all the various possible modes of contamination and to the circumstances under which this contamination might occur. Carcinogens may enter the body by: inhalation (vapours, mists, dusts), skin absorption (splashes, soiled work clothes) or ingestion (eating with soiled hands, smoking, etc.). The nature and scope of these measures may therefore vary depending on the situation; they «ay also vary depending on the evolution of scientific or technical knowledge.

The material set out in this section is intended to be used as a guide to enable each case to be studied individually and at the same time enable consideration to be given to the different points listed herein.

Each carcinogen encountered in a plant should be the subject of a document which indicates the practical measures to be taken in relation to the agent's characteristics and to the type of occu- pational exposure.

Where appropriate, workers or their representatives should be involved in the development of specific procedures and should have the reasons for these procedures explained to them.

The installations (areas, buildings) or workplaces for which special measures should be drawn up and applied should be designated. If necessary, "controlled areas" or "supervised zones" should be marked out.

These measures should be related to the health hazard as it may arise through inhalation, skin absorption, or ingestion, for:

(a) workers involved directly in the process in question or doing jobs close by; production workers and maintenance workers; direct employees and indirect employees (external contractors);

(b) persons living in the neighbourhood who may be exposed to: airborne effluents (gases, dusts, mists); liquid effluents; and solid wastes.

All aspects of the industrial process should be covered, including:

sources of hazard (raw materials, intermediates, by-products, finished products, impurities);

all stages of manufacture, packaging, transport and use;

production;

laboratory operations;

normal operating conditions;

Technological study

The installation is then designed on the basis of the specific data provided by the above special study in such a way that the eguipnent gives rise to no external contaoination. The over-all and detailed phases of the technological study should deal in particular with:

the plant location (prenises with permanent ventilation equipment or open-air installations) ;

the design of the plant itself, its equipment, the choice of materials, etc., making allowance for any subsequent maintenance or repair work which might entail a substantial hazard (for example, foresee the likelihood of the workers being involved in such operations having to wear complete airtight "divers" suits with maybe bulky, self-contained respirators), special gaseous, liquid or solid effluent circuits sealed off from the environment, and the special processing of effluents to ensure purification prior to waste disposal, and the development of decontamination procedures for spillage;

safety and rescue procedures to minimise the risk of contamination and to deal with possible breakdowns or failures;

suitable washing facilities (washbasins with a regular soap supply, disposable drying materials or hot-air dryers) and immediate decontamination facilities (emergency showers).

Operating instructions

Procedures should be established in relation to the potential hazards. They should be. expressed clearly in language readily understandable so as to exclude all improvisation. They should be designed in such a way tha.t, during potentially hazardous operational phases, the workers are not burdened by time limits. Possible incidents should be foreseen and simple precautionary measures indicated; if necessary, provision should be made for interruption of the process which can then be recommenced after a break.

Emergency exits and emergency protective equipment should be clearly marked and their location pointed out to each worker individually.

Foreseeable repair procedures should be drawn up, specifying the individual operations involved and the responsibility of each department in the total process.

These procedures should include the technical data and also specify personal protective measures such, as special clothing, respiratory protection, and the rules for any possible personal decontamination that might prove necessary.

Depending on the severity of the potential hazard, maintenance and repairs should be carried out under the effective control of a supervisor or line manager with a special knowledge of the hazard and the necessary safety measures.

As far as possible, maintenance and repair work should always be entrusted tò the same workers who will, consequently, acquire intimate knowledge of the plant and the work itself, become well aware of the hazards and the safety measures and, moreover, be subject to specific medical supervision.

3.3 Personal protective measures

Working_çlothes

Working clothes specially suited to the potential hazard should be given to workers engaged in operations involving potential exposure to carcinogenic substances. The type of clothing will depend on the nature of the product, its physical properties, its consistency, etc. Workers may receive complete sets of clothing including underclothes and footwear or may, for example, receive only overalls. The intervals at which this clothing is changed will depend on the foregoing properties.

An adequate stock of clean replacement clothing should be available to ensure correct laundering and immediate replacement in the event of soiling. The intervals at which this clothing is washed will depend on the severity of the potential hazard and the properties of the product. Special provision should be made for collecting and laundering contaminated clothing. If necessary the clothing may undergo special pre-treatment and then be washed separately from the rest of the working clothes in the plant. Before evacuation into the general sewage system, the effluents from this treatment may be required to undergo a purification process to remove the product in question.

Changing rooms

The changing rooms for these employees should be separate from the general changing rooms and their design related to the potential hazard. In general, they should be divided into three consecutive sections: town-clothing changing rooms, showers, work-clothing changing rooms, so that, at the end of the shift, there is no contact between the working clothes, which are all left in the work changing room in special containers where necessary, and the town- clothing; employees put on their town-clothes only after compulsory showers. Each employee should systematically be provided with suitable washing materials with clean towels daily.

These premises should be lined with materials which can be cleaned completely each day. The changing room cabinets should be designed so that nothing but clothes can be stored in them. Working clothes that have been worn should not be taken into the town- clothing changing room or into the showers. Only clean working clothes can be taken through the town-clothes changing rooms.

Workers should be informed of the best personal procedures for avoiding possible contamination, for example: precautions to be taken to avoid soiling the inside of gloves, contamination of tools, removal of clothing after any unusual contaminating operation, etc.

It should be forbidden to bring food and drink into the work area. Mess rooms for personnel working in the areas in question