Document mqmOEgjrJvaOGKx4w5ZpZQE5Q

of Regulations on Occupational Carcinogenstn,Several Industrialized Countries F. Camevale, md, R. Montesano, mo, PhD, C. Partensky, bsc, and L. Tomatis, md Regulations controlling the manufacture and use of carcinogens in the industrial setting of various countries are examined. In addition, the occupational exposure limits (OEL) of chemicals known or suspected to be carcinogenic in humans are listed, and criteria for the establishment of OELs are discussed. It is also stressed that control measures should not be confined to a few developed countries, and it is hoped that attracting attention to their unevenness will contribute to the implementation of a more efficient primary prevention of cancer. Key words: legislation, occupational carcinogens, OEL (occupational exposure limits) INTRODUCTION The occurrence of cancer in workers as a result of exposure to carcinogenic substances through their occupation is a major health problem in many countries. It has been estimated that the percentage of cancers attributable to occupation in the United States of America (USA) is 4%, with a range of 2-8% over the whole population [Doll and Peto, 1981]; higher percentages have been calculated by others for cancers at specific target organs [Cole et al. 1972; Pastorino et al. 1984]. These estimates imply that one of every five cancer cases among occupationally exposed populations is attributable to exposure in the workplace [Saracci, 1985: Tomatis. 1987] and indicate that in countries like France and Italy some 6.000-8.000 cancer deaths occur every year as a result of occupational exposure. The implementation of primary prevention, by identifying carcinogenic agents and subsequently banning them or reducing exposure by regulatory measures, is relatively recent. A survey of regulatory measures for controlling exposure to occupational carcinogens in several industrialized countries carried out 10 years ago [Montesano and Tomatis. 1977] resulted in the following conclusions: I) legislation prohibiting the manufacture of chemicals shown to be carcinogenic to humans or known to represent a possible cancer hazard to humans existed in only a limited number of the Servizio di Prevenzione Igiene e Sicurezza nei Luoghi di Lavoro. Florence. Italy (F.C.). International Agency for Research on Cancer. Lyon. France (R.M.. C.P., L.T.). Address reprint requests to R. Montesano, M.D.. Ph.D.. International Agency for Research on Cancer. 150 cours Albert Thomas. 69372 Lyon Cedex 08. France. Accepted for publication May 21, 1987. 1987 Alan R. Liss, Inc. If r !fll HWBUI0002036 454 Carnevale ct al 14 countries considered and did not cover the same chemicals in each country: 2) in only a few of the countries was both the importation and the manufacture of certain chemical carcinogens prohibited; 3) the fact that most countries recognized a limited right to compensation but did not provide adequate legislation for prohibiting or even limiting exposure to carcinogens indicated that these important means of primary' prevention were not yet widely accepted; 4) there is no reason for the great disparity in legislation in different countries, since the carcinogenicity of chemicals does not stop or change at national borders; 5) legislation in certain countries that prohibits the manufacture and use but permits the importation of carcinogens allows, and surrepti tiously stimulates, their manufacture in countries with less stringent regulations: and 6) the criteria used to label chemicals as possibly hazardous to humans on the basis only of experimental evidence of carcinogenicity were arbitrary and over-exclusive. During the last decadei. regulatory agencies in a few countries have become more receptive to accepting evidence of carcinogenicity in humans and/or in animals for determining measures to control exposure to occupational carcinogens. The present paper analyzes the evolution that has occurred in this context during that time, taking into account the progress that has been made in understanding the carcinogenic process. The countries considered are all industrialized, as it was easier to obtain reliable information for these than for less developed countries, where, often, specific legis lation on occupational cancer risks does not exist. Exclusion of a country from this survey does not imply that legislation or regulations controlling exposure to carcino gens do not exist. The analysis is based on two types of information: regulations and legislation prohibiting or controlling the manufacture, use, or importation of carcin ogens, and information on how data on carcinogenicity are used to establish permis sible occupational levels.' SOURCES OF INFORMATION Laws and regulatory standards were obtained from health and labor offices in the various countries. The term "regulation" is used in a broad sense in this paper and includes specific laws. The World Health Organization and the International Labour Office were valuable sources of information. Assistance provided by several colleagues is also acknowledged. A summary of the regulations and legislations for each country considered and the relevant source of information are provided in the footnotes to Tables I and II. In each country, control concerning occupational exposure to toxic substances is covered by a number of laws or regulatory standards and implemented by different bodies. We have attempted to confine our analysis to legislation and regulations in which the carcinogenic activity of chemicals has been the basis for specific regula tions; such information is not always clearly given in the original documents, which might result in some apparent inconsistencies in the tabulations of the data. In this document the terms "occupational exposure limit" (OEL) or "permissible exposure limit" (PEL) are used; these are derived from government authorities devoted to controlling exposure to occupational carcinogens. The term TLV (threshold limit value) applies only to values recommended by the ACGEH (USA); these are recom mendations made by a non-governmental organization for use as guidelines in the occupational setting. HWBUI0002037 Regulations on Occupational Carcinogens 4S5 LEGISLATION OR REGULATORY STANDARDS PROHIBITING OR CONTROLLING THE MANUFACTURE, USE OR IMPORTATION OF CARCINOGENS The classical studies of Rehn, published in 1895, and by Case et al. in 1954, showing a high risk of bladder cancer among workers exposed to benzidine, 2naphthylamine, and other aromatic amines, resulted in the cessation of production of 2-naphthylamine in the 1940s, of 4-aminobiphenyl in 1953, and of benzidine in 1971 in the Federal Republic of Germany (FRG) [Ehrlicher, 1971]; and of 2-naphthyllamine in 1949 and of benzidine in 1962 in the United Kingdom (UK) [Parkes, 1976]. Production of 2-naphthylamine persisted in the USA until 1970 and in Japan until 1972. and benzidine is still manufactured in other parts of the world [Parkes, 1976]. A law prohibiting the manufacture of chemical carcinogens was formally introduced in the UK in 1967; it specifically concerned four carcinogens: 2-naphthylamine. benzidine, 4-aminobiphenyl, and 4-nitrobiphenyl. This measure was taken more than 50 years after the incrimination by the International Labour Office [1921] of certain "amino-compounds", in particular benzidine and 2-naphthylamine, as being respon sible for the occurrence of tumors of the bladder among workers in dye factories. By 1977, only four countries had regulated production of these four compounds, although the prohibition was also extended to certain other carcinogens in some countries [Montesano and Tomatis, 1977]. Prohibition of some uses of asbestos, arsenic, benzene, 2-naphthylamine, 4-aminobiphenyl, and 4-nitrobiphenyl was introduced in the FRG in 1975. - At present (see Table I), more countries control occupational exposure to chemical carcinogens by prohibiting their manufacture or use; the number of prohib ited carcinogens has increased, particularly in the FRG, Sweden, and Finland, where legislation was introduced in 1975, 1981, and 1983, respectively. In the countries considered in Table I. the four aromatic amines mentioned above are the carcinogens that are most frequently regulated. Prohibition of the processing or fabrication of crocidolite or substances containing crocidolite exists only in the FRG, Sweden, and the Netherlands; in the UK prohibition refers also to amosite. In most of the other countries considered, the prohibition refers solely to the application of asbestos by means of spraying. In the case of benzene, the prohibition applies to solvents containing it at concentrations of more than 0.2% (France), more than ]% (FRG). more than 5% (Japan), or, in some types of exposure, to more than 2% (Italy). In the USA. recent epidemiological evidence [Rinsky et al. 1987] shows that a significant risk of leukemia exists following an exposure to 1 ppm of benzene, a level promul gated by the OSHA in 1978 and subsequently invalidated by the Supreme Court [Ashford. 1987], The Commission of the European Communities has issued proposals and direc tives prohibiting the production and use of 2-naphthylamine. 4-aminobiphenyl. 4nitrobiphenyl, benzidine, and the spraying of materials containing asbestos. In some countries (e.g.. Belgium, FRG. Italy. USA), there is no regulation specifically prohibiting the manufacture and use of carcinogens, but the exposure of workers is controlled by reducing exposure to the lowest achievable levels. The impact of such measures depends upon the availability of valid methods to reduce exposure to zero level and of appropriate structures, which may vary from country to country, to ascertain their proper application. It is realized that controlling workers' 456 Carnevale et al TABLE I. List of Occupational Carcinogens and Countries in Which Specific Legislation or Regulatory Standards Prohibit or Control Their Manufacture and Use Carcinogen NeihcrBclgiurC' Finland11 France1' FRG'1 Ireland0 Italy1 Japan1* lands1' Sweden1 UK1' USA1 USSR1, F.Clm 2-Acetylaminofluorene ortho- Aminoazotoluenc 4-Aminobiphenyl Asbestos (croeidolite) Benzene Benzidine Benzidine-based dyes Bis(chloromethyl)ether Chloromethyl ntethyl ether 1,2-Dibromo-3-chloropropane 3,3 '-Dichlorobenzidine 4-Diinelhylaininoaz.obenzene Hexamethylphosphoramide 20-Methylcholanthrene Mustard gas 1-Naphthylamine 2-Naphthylamine 4-Nitrobiphenyl N-Nitroso-N-mcthylurea N-Nitrosodiincthylanrine Propane sultone (3-Propiolaetone 2,3,7,8-Tetraehioro dibenzo-para-dioxin ortho-Toluidine Tris(2,3-dibromopropyl) phosphate Yellow fatly dye___________ +" + + 4n 4 . n 4n 4 4 4 4n 4n 4" 4" 4 4n 4 4 4n 4 4n 4 4 4 4 4 4" 4 4 4n 4 4 4-n 4n 4 44 4 4n 4 4 4 +r 4 f +4 4 f f 4n 4 r{ 4 4 4i 4f 4 +4 4 4 4 44 4 4- 4 4 4- 4 4 4 4 4 4 "Belgium: The Royal Decree, dated 25 October 1967, prohibits a concentration of benzene higher than 0.25% by volume in hydrocarbon spirits or solvents used for cleaning or degreasing purposes or in photoengraving, adhesives, and paints. For all other uses, the benzene concentration may not exceed 1% (this provision dt>es not apply to engine fuels, petrochemicals, or products for laboratory use). Royal Decree amending Article -W ol the General Labour Protection Regulations. Ministry of Employment and Labour and Ministry of Public Health, Brussels. Dated October 25, 1%7 Enforcement date November I, 1%9 Moniteur Beige, Brussels, November 1. I%7 HWBUI0002039 Regulations on Occupational Carcinogens ''Finland: Decree of the Mmixliy ol Social Allans and Health. December 21. 1983 'France. I Voice No. 78 394 ol Man'll 30 I07X prohibits I he use of asbestos nr products containing more than I g ol asbestos pc r l(K) g tor the spraying ol buildings iJ. (XI.. Match 23. I*)7K. p 1279). Decree No. 86-269 of f-'ebniary 13. 1986 (J. Off., February 27. 1986, p 3111) prohibits the use ol solvents or diluents containing hen/cnc al more Ilian 0.2% by volume, except in closed systems. An order ol June I, 1078 suspended the niamifacture. importation, and marketing ol clothing and textiles treated with the flame retardant tris(2.3-dibroniopropyl)phosphate (TRIS) (.1. Off.. June 24. [979. p 1312). 111 K(i: Verordmmg iiher gclalirliche Slolfe ((iefabrsioffverordnung -GefStoffV) vmn August 26, 1986 (BGB1. I S. 1470), C'arl Hcymanns Verlag KG. Ktiln, Berlin, Bonn, Miinchen (1986). 'Ireland. UK: In 1907. specific legislation on carcinogenic chemicals in industries was introduced in the UK (The Carcinogenic Substances Regulations. S.I. No. 879, 1907, London, bet Majesty's Stationery Office); similar regulations were introduced in Ireland in 1972 (sec Factories, Carcinogenic Substances, Processes Regulation, S.I. No. 242, 1972, Dublin). These regulations, which apply to policies subject to the Factories Act 1901, prohibit the manufacture or use of certain carcinogens, namely, 2-naphlhylaminc, benzidine, 4-aminobiphenyl, 4-nitrobiphcnyl, and then salts, and of any substances containing these compounds. Products containing not more than 1% are, however, excluded from this prohibition, provided the prohibited substance is present solely as a by-product of a chemical reaction. However, benzidine may be manufactured cither as its monohydrochlondc or dihydrochloride or a mixture of both these salts, if this is done in a totally closed system. These salts of ben/idinc may only be used outside a closed system, as in the form of a slurry with water, consisting of not less than one part writer to two parts hcn/idinc salt. Special exemption from this part of the regulations may be granted by the Chief Inspector of Factories for (he production ot a prohibited substance that will he used only for the purpose of medical and scientific research. flic same regulations control the employment of persons in factories manufacturing or using 1-naphthylaminc, ortho-toluidine. ortho-dianisidine. 3..V dichlorobcn/idine. and their salts, as well as auraminc and magenta. In the case of the latter two substances, the regulations apply only to their manufacture. This control consists of avoidance hy all practicable means of any exposure of the worker and of periodical medical examinations, including cvtological examination of the urine for abnormal cells every 6 months, during employment in factories subject to the regulations. A register of these employees is kept with particulars of their employment. When they are examined medically and upon termination of employment, the workers are given cautionary cards that recommend continuation of such screening tests and indicate where they may be undertaken. In Ireland, the regulations also require a register of persons employed in the manufacture of the ''controlled" substance. This register records the periods ol employment m connection with the above-mentioned substances, as well as the monthly medical examinations, and (his must be kept available for inspection lot at least 20 years from the date of the medical examination. A separate regulation prohibits the importation into the UK of so-called prohibited carcinogens (The Carcinogenic Substances Regulations (Prohibition of Importation!. S.I. No Ib73. 1907. London. Her Majesty's Stationery Office). _ flic "Mule Spinning (Health) Special Regulations 1933" specifics that for lubrication of mule spindlers, no oil other than "white oil" or oil entirely of animal or vegetable origin or mixed should be used. Asbestos (Prohibitions) Regulations (Health and Safety Commission Newsletter No. 43, p 3, August 1983) prohibit: 1) the importation of crocidolitc and aniositc fibre, 2) supplying these minerals and products containing them as an article or substance for use at work, 3) the use of those minerals and products containing them in the manufacture and repair of any other product, 4) asbestos spraying, and 3) installation of new asbestos insulation. (continued) 457 HWBUI0002040 HWBUI0002041 HWBUI0002042 Carnevale et al TABLE IS. Occupational Exposure Limits in Various Countries of Industrial Chemicals Shown to Be Carcinogenic in Humans and/or Experimental Animals____________________________ Chemical, process or industry3 Evidence of carcinogenicityb OSHA USA1 (ACG1H) Acrylonitrile ortho-Ami noazotoluene 4-Aminobiphenyl ortho-Anisidine Arsenic and arsenic compounds Arsenic and soluble compounds as As Arsenic and inorganic compounds Arsenic trioxide production Arsenic trioxide and arsenic pentoxide. arsenous acid, arsenic acid, and their .salts Arsine Asbestos Amositc Chrysotile Crocidolite Other forms Fine dust containing asbestos Auramine (technical grade) Manufacture of auramine Benzene Benzidine 2A 2B 1 2B 1 1 2B 1 1 1 4,5* _* (0,5) (0.2) 0.1 (-*) 0.2 0.2 fiber/cm3 (0.5 fiber/cm3*) (2 fibers/cm3*) (0.2 fiber/cm3) (2 fibers/cm3) 30* --* Occupational exposure limit FRG1* 7* _* _* 0.5 Sweden1' 4.5* p\ 0.2* 0.2* 0,05* --* 0.2 1 fiber/cm3* 1 ftber/cm3*) 0.5 ftber/cm3* 0.05 0.5 fiber/cm'* pA 0.5 fibcr/cm3* 2* _ * pit 16* 16* pA European France' communities^ 4.5* 0.007* P 0.2' 0.2 1 fiber/em1* I liber/cm'* 0.5 fibcr/cm** 0.5 lihcr/cm1* * .* 15* (l.tK)X* 16.25* P HWBUI0002043 HWBUI0002044 HWBUI0002045 HWBUI0002046 Carnevaie et al TABLE II. Occupational Exposure Limits in Various Countries of Industrial Chemicals Shown to Be Carcinogenic in Humans and/or Experimental Animals (Continued)_________ Chemical, process or industry11 Ethylene dibromidc Ethylene oxide Evidence of carcinogenicityb OSHA 2A 150 2A 1.8 USAC (ACGIH) (_*) (2*) Ethylene thiourea Ethyl methanesulphonute Formaldehyde (gas) Furniture and cabinent making Wood dust (beech. oak) Soft wood Hexachlorobenzene Hexamethylphosphoramide Hydra/inc Indeno| 1.2,3-cd|pyrenc Lead and lead compounds (inorganic) Lead dusts and fumes (as Pb) Total dust Respirable dust Lead arsenate as Pbj (AsOjji Lead chromate as C'r Lead compounds (orgunolead) Tetraethyllead as Ph I'etramethyllead as Ph 2B 2B 2A 1 2B 2B 2B 2B 2B 3 4.5 1 5 _* 1.3 0.05 (1.5*) (0.1*) (0.15) (0.15) (0.05*) (0.1) (0.15) Occupational exposure limit FRGU _* 5* 1.2 Sweden1' P y* New installation 5* pH P" 1 --0 _* 0.13* --* 4+ pa 0.1* 0.1 ,,* _* 0.075 0.075 0.1 0.05 0.02* 0.05 0.05 France1 ... * 10 European communities8 .+ 3" 0.1* 0.15 0.15 HWBUI0002047 HWBUI0002048 TABLE II. Occupational Exposure Limits in Various Countries of Industrial Chemicals Shown to Be Carcinogenic in Humans and/or Experimental Animals (Continued) Chemical, process or industry11 carcinogenietty11 N-Pheny 1-2-naphthyl- amine 3 Polychlorinated biphenyls 2A Chiorobiphenyl 42% Chlorine 54% Chlorine 1,3-Propane sultone 2B fJ-Propiolactone 2B Rubber industry 1 Soots 1 2,3,7,8-Tetrachlorodiben/.o- para-dioxin (TCDD) 2B Thioacetamide 2B 4,4'-Thiodianiline 2B Thiourea 2B ortho-Toluidine 2B Urethane 2B Vinyl chloride 1 OSHA ~ _* _* - 2 USAC (ACGIH) (-*) 1 0.5 (1.5*) (9*) (10*) Occupational exposure limit FRGd Sweden1' France1 European communities8 _ P" 0.01* 1 0.5 _* _* P" P" _* _* __ * --* Existing installations 8* Others 5* 3 .... * pH pH P" 2.5* y* Existing installations 7.5* New 2.5* 7 ppm/8 h *Tllc chemicals listed tire those considered in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vols. I 42; the evaluation of carcinogenicity to humans is given (Group 1, Group 2A, Group 2B). A few chemicals (analogues of carcinogens, parent compounds of carcinogenic metabolites, and compounds present in carcinogenic mixtures) are also listed, although they belong to Group 3, agents not classifiable as to their carcinogenicity. Occupational exposure limits are given in mg/m3 unless otherwise specified. indicates that evidence of carcinogenicity was taken into account in establishing the occupational exposure limit. -indicates that an occupational exposure limit has not been established. P indicates that the chemical is prohibited (see also Table I). ''International Agency for Research on Cancer (1987): [ARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Supplement 7. Overall Evaluations of Carcinogenicity; An Update of [ARC Monographs, Volumes 1-42, Lyon. ! o p p HWBUI0002049 Regulations on Occupational Carcinogens 467 ' L. 7; cc O2 o E TJ u c a &< 'i 5ili* I-2'-5 rr* o a > T. Q- 5) -- -30 g s I S' E jr > c ec:a ot- 1 S' a5 >> CJ .r: x T3 -- su = O "" 2 a -3 -5.1 Ij s <2 g 5 s|i X? X TuJ ^t c H .5 JM ^ u i Iu SO cl > 00 4P5 '--3EL. XcuOtc-' c0 2-- Xn x z1 1- 5a. 9 02 8 ;> xt/j 5 = *5 I1; * -a * RS , < -5 : c- c 2P 0 c z > 5 03 O c oc s * S.S o2 * ?, t) x -a 73 E U3 S cj 2 o . tr o. C. .* 2 E <l s w * . .23 Eo SO IS CcD U.. '% . o 4i =s OQ.-tHo o U rt tr 5 00 <0 Eo H- o OW CT3u a 7? c s -5 2 1 "O T3 C/3 (QA o 1'P ,5LJ. /OyL 5A tA ; 32fc S ,< 6 z c s 'c is ; ^5 ca u nun , -O = c _g y s ^ II > to O e eu 3* 'S r; *S 3gU 2 s-2 S& 8 u a 2O: io2 'i ->a >O c= '. Z>L>. Os<- ZS cn| yEt. 2JC Wo o < 'via: 3 -- --' Z- O 12 o ceg u <> _w_ Cl r*. sa 3 CO cc E ' 2 2U O' -- C/3 ^ 8 o .g I ! S O r?. 0 vd o3 g E Ml UJ < 1o J. ' . 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O ' S' o- > SZ SSzz - --J ^ - 2^1 e" ?! g 2< U E C ni L. r~ g e* u 3o^ 2 2 ; C oc CC y r Tf3> -- c-. L--C --o o CJ S <rC J * - L is a -- 5 I 3 > '0 ^ H O a. r- O uj a 5 < S C a E" v: 1" - f-; !" fri -o <zCa m tmHWBUI0002050 468 Camevale et al exposure to carcinogens results from measures originating from various authorities within a given country. Thus, in Table I, for USA, the OSHA regulatory standards for carcinogens are given, noting that prohibition of the manufacture of an occupa tional carcinogen could result from a decision of the EPA or the FDA. Similar situations exist in other countries. Of the countries listed in Table I, only two--Japan and the UK--have legislation prohibiting the importation of carcinogens (2-naphthylamine, 4-aminobiphenyl. 4-nitrobiphenyl. and benzidine) in addition to the prohibi tion of production and use within the country. In the UK, regulations prohibiting the import of crocidolite and amosite fibre also exist. In countries where such regulations did not exist, the import of carcinogenic substances can reach consideration propor tions. For instance, it was found that within a period of three months in Italy the import of asbestos was of approximately 13.5 million kg, that of benzene 19 million kg, and that of vinyl chloride 13 million kg [see Guariniello, 1985]. REGULATORY MEASURES TO CONTROL EXPOSURE TO INDUSTRIAL CARCINOGENS FOR WHICH THERE IS EVIDENCE OF CARCINOGENICITY TO HUMANS Table II lists the chemicals and types of occupational exposures that have been evaluated within the [ARC Monographs program (International Agency for Research on Cancer, 1987a) for carcinogenicity to humans and/or experimental animals. It includes chemicals or types of exposures for which the degree of evidence of carcinogenicity was classified in Group 1 (the agent is carcinogenic to humans)'. Group 2A (the agent is probably carcinogenic to humans)', or Group 2B (the agent is possibly carcinogenic to humtms). For each chemical, the occupational exposure limit is given, and there is an indication as to whether evidence for the carcinogenicity of the chemical was taken into account in establishing the occupational exposure level. It should be noted that the countries listed in Table II follow different criteria for determining the occupational exposure levels for chemical carcinogens. Both the American Conference of Governmental Industrial Hygienists (ACGIH) (USA) and the Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (FRG) separate chemical carcinogens for industrial use into two groups, on the basis of evidence of their carcinogenicity in humans or in experimental animals. In neither of these countries is the use and manufacture of chemicals proven to be carcinogenic in humans prohibited, although it is recom mended that technical improvements be made so that workers are not exposed. In Sweden, the use and manufacture of at least some proven carcinogens is prohibited (see also Table I). In the ACGIH list, this recommendation is confined to the four aromatic amines mentioned above; in the FRG and Sweden, many more industrial carcinogens are listed, but OELs are not established for them. For others, an OEL or a TRK (Technische Richtkonzentration [technical guiding concentration]) is provided, based on evidence of carcinogenicity. In the FRG, TRKs are established ad hoc. It must be emphasized that the scientific basis for carcinogenesis does not permit the determination of a level below which no cancer risk exists. Thus, the establishment of TRKs is rather arbitrary, based on both technical feasibility to avoid exposure and on socio-economic considerations. The TLVs recommended by the ACGIH (USA) imply instead that the degree of carcinogenic potency of a chemical can be determined and thus that a "safe" threshold value can be determined (see footnotes to Table 13). Regulations on Occupational Carcinogens 469 Discrepancies among the various countries considered are also evident concern ing the regulation of carcinogenic aromatic amines (4-aminobiphenyl, 4-nitrobiphenyl, benzidine, and 2-naphthylamine). The use and manufacture of these carcinogens are prohibited in many countries (see Table I), or special protective and surveillance measures are required (e.g., FRG, USA [ACGIH]). In France, an OEL (although low) is given for three of these carcinogens; in Italy, a directive exists for exposures to aromatic amines, which does not, however, include'any prohibition or exposure limit value. The use of crocidolite is banned in FRG, Sweden, and The Netherlands, but not in the other countries considered. These are some of the most apparent inconsistencies in the regulations for exposure to industrial chemicals that were shown to be carcinogenic to humans many decades ago. Even greater differences exist in the weight given to data on carcinogen icity obtained only in experimental animals. DISCUSSION The survey of measures taken by certain industrialized countries to reduce exposure of workers to carcinogens indicates that some improvements have taken place during the last two decades and that greater consideration is given to experimen tal carcinogenicity data, at least in some countries. Data on carcinogenicity in experimental animals are taken into account in the classification but not in the setting of exposure limit values, particularly in the FRG [Henschler, 1987]. In Sweden, the number of carcinogens regulated on the basis of such data is greater, and the permissible level of exposure is, in general, lower than in other countries. In the USA and the UK, carcinogenicity data in animals play a minor role in the establishment of exposure limit values, which are still mainly based on the a posteriori evidence provided by the epidemiological data. Even in situations where both experimental and epidemiological carcinogenicity data have been conclusive, as for aromatic amines, the time lag for implementing control measures has been long. For example, for four carcinogenic aromatic amines that were prohibited in 1967 in the UK, control measures were introduced in other European countries either only in the last few years or not at all. In some countries, the use or manufacture of these aromatic amines is not prohibited, but technical devices are to be introduced to exclude or reduce exposure to low! levels. This approach implies that such techniques are available and that the proper organizational structure exists to ascertain that human exposure does not occur: however, the implementation of such measures and the surveillance of exposures are left to private initiative. As a second example, the use and manufacture of crocidolite are prohibited in the FRG. Sweden, the Netherlands, and the U.K.. but not in other countries. These two examples of different attitudes towards well-established human car cinogens indicate that in some countries factors other than those related to public health (namely economic) are still of considerable importance in regulating human exposure to industrial carcinogens. In addition, evidence of carcinogenicity to animals does not appear to be taken into consideration in establishing regulatory measures for some chemicals. Past experience [Tomatis et al, 1982: Wilbourn et al. 1986] indicates that properly conducted and evaluated carcinogenicity experiments in animals are useful in predicting human cancer risk. It is valid to refer to the much-quoted example of' 4-aminobiphenyl that was not introduced in industry in the UK because it was 470 Carnevale et al shown to be carcinogenic in animals [Walpole et al, 1954]. Long-term carcinogenicity tests in animals have been and are still under criticism, but it is worthwhile to note that the results of properly conducted and evaluated carcinogenicity tests provide a valuable basis for assessing the carcinogenic risk of a chemical to humans [Interna tional Agency for Research on Cancer. 1987b]. For many chemicals there are no data in humans, and the only carcinogenicity data available are those in experimental animals. This is the case for some 200 chemicals that were evaluated by [ARC as having sufficient evidence of carcinogenicity [International Agency for Research on Cancer. 1987a], and occupational exposure exists for some 50-60% of these chemicals. The carcinogenesis process is known to be composed of various stages (initia tion, promotion, progression), and there is some epidemiological and experimental evidence that different carcinogens act at one of these stages predominantly. A classification of carcinogen^ according to their mechanism of action cannot, on the basis of today's knowledge, be exhaustive or definite, but examples derived from experimental and epidemiological observations can be used to illustrate possible differences among carcinogens. Direct alkylating agents, such as N-nitroso-N-ethylurea (which has a half-life of a few minutes), induce tumors in vivo in experimental animals after a single dose on the order of a few milligrams per kilogram body weight, while carbon tetrachloride induces tumors of the liver only after high dose levels given over an extended period of time. Exposure to polycyclic aromatic hydrocarbons may result in the occurrence of tumors at various sites, but, at particularly low levels they can lead to increased susceptibility to cancer development after subsequent exposure to a promoting agent. One such example is prenatal exposure to 7,12-dimethylbenz[a]anthracene followed by exposure to 12-O-tetradecanoylphorbol 13-acetate later in life [Yamasaki et al, 1987], Epidemiological studies indicate that asbestos acts at an early stage in the development of mesothelioma and at a late stage for lung cancer; similar considera tions apply for tumors resulting from exposure to nickel, namely, lung cancer at a late stage and nasal cavity cancer at an early stage [Peto et al, 1982; Peto, 1984], The same observations have been made for the induction in mice of liver and bladder cancer by 2-acetylaminofluorene [Day and Brown, 1980], Classification of carcinogens into two categories according to whether or not they can induce DNA damage has also been discussed [Williams, 1983]. It was suggested that carcinogens that do not show this activity should be labelled "epige- TABLE III. Benzidine-Based Dyes Imported to the USA (in pounds) [Samuels (1981)] Country of origin 1974 Year 1976 1979 India Egypt Poland Rumania France Canada 16,193 None 3,910 None 250 None 23,149 None 32,684 79,365 17,750 440 47,733 86,641 21,714 11,023 220,018 2,205 Total 20,353 153,388 389,334a aThe total quantity reported for 1979, including imports from the Benelux countries, was 469.917 pounds. HWBUI0002053 Regulations on Occupational Carcinogens 471 netic" carcinogens or "promoters." and that regulatory measures for controlling exposure to them should be less stringent than for carcinogens that are "genotoxic" [Weisburger and Williams. 1981], Although classification of carcinogens according to their mechanism of action could be an important contribution to cancer prevention, present understanding of the mechanisms of carcinogenesis does not justify it. Since the same carcinogen can act as an "initiator" in one tissue and as a "promoter" in another, agents cannot be classified simply as "initiators," "promoters," or "com plete carcinogens" [see International Agency for Research on Cancer, 1983, for further discussion]. Moreover, it cannot be excluded that the late stage of carcinogen esis. which is usually called promotion and which often overlaps with the phase of progression (stage of clinical appearance of the tumors), is also due to a mutational event, or at least that a mutational event is involved. This inability to classify carcinogens according to their mechanism of action at the present state of our understanding of the mechanisms of carcinogenesis leaves open the debate about whether different types of regulations are warranted for chemicals that have been shown to be carcinogenic at levels of exposure that vary by several orders of magnitude. One unwanted side effect of the adoption of more regulations on the production and use of chemical carcinogens in developed countries has been the transfer of dangerous industrial processes to developing countries, where regulations controlling worker exposure are either nonexistent or much less stringent [Navarro, 1984], The extent of this practice is only partially documented [Castelman, 1979, 1983], Table III, showing the rates of importation of benzidine-based dyes to the USA following the introduction in 1974 of strict regulations controlling benzidine manufacture [Sam uels, 1981], provides indirect evidence of the size of the phenomenon: it is also of interest that imports increased by approximately 20 times between 1974 and 1979, and, furthermore, that imports came not only from developing countries but also from some developed countries. International organizations, by their very nature, can be instrumental in ensuring that information on the carcinogenic risk of chemicals is widely disseminated and that effective regulatory measures to control exposure to carcinogens do not remain confined to a few countries. A resolution concerning exchange of information about banned chemicals was issued by the United Nations in 1979 [United Nations. 1982]. Several useful and reliable sources of information are available, including the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans [International agency for Research on Cancer. 1987a]; the Environmental Health Criteria, issued by the International Programme for Chemical Safety [1976-1987]: the International Register of Potentially Toxic Chemicals [1985]: and the International Labour Office [1983], It is hoped that this paper, by attracting attention to the uneveness of the measures that could, all over the world, prevent occupational cancer, will contribute to implementation of a more efficient primary prevention of cancer. acknowledgments The authors would like to acknowledge the collaboration and valuable comments of the following persons from different countries in collecting and preparing the material discussed in this paper: T. Fletcher. S.S. Fluss, M. Gilbert. D. Habashi, D. Henschler, M. Ikeda. B. Pannett. J.L. Pasquier, M. Reynier. R. Saracci. L. Simon- 472 Carnevale et al oto, A. Tossavainen, H. Vainio, M.T. van der Venne, P. Westerholm. and J. Wilbourn. The editirig by Mrs. E. Heseltine is greatly appreciated, and the secretarial assistance of Mrs. E. Perez has been invaluable. REFERENCES Ashford NA (1987): New scientific evidence and public health imperatives. N Engl J Med 316:10841085. Case RAM. Hosker ME. McDonald DB. Pearson JT (1954): Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. 1. The role of aniline, benzidine, alpha-naphthylamine and beta-naphthylamine. Br i Ind Med 11:75-101. Castelman B1 i 1979): The export of hazardous factories to developing nations, lnt J Health Serv 9:569606. Castelman BI (1983): The double stanbard in industrial hazards. Int J Health Serv 13:5-14. Cole P. Hoover SR. Friedell GL (1972): Occupation and cancer of the lower urinary tract. Cancer 29:1250-1260. Day NE. 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U wa DW g 8 r1 h3 Q a w frl O' > _U/ ao oa h < K w k<4 wa a w Q Q5 W ES foe CoO C4 O HWBUI0002057 TABLE A-l CHEMICALS FOR WHICH THERE IS SOTP1CIEHT EVIDENCE OF CARCINOGENICITY IN EXPERIMENTAL ANIMALS Acrylonitrile* Actinomycins Aflatoxins* ortho-Aminozotoluene 4-Aminobiphenyl* 2-Amino-5-(5-nitro-2-furyl>- 1,3,4-thiadiazole Amitrole* Aramite Asbestos* Azaserine Benz [a] anthracene Benzidine* Benzo [ b] fluoranthene Benzo [a] pyrene Benzyl violet 4B Beryllium* Beryllium oxide Beryllium phosphate Beryllium sulphate Bis(chloromethyl)ether* B-Butyrolaetone Cadmium* Cadmium chloride Cadmium oxide Cadmium sulphate Cadmium sulphide Calcium chromate Carbon tetrachloride* Chlorambucil* Chlordecone (Kepone) Chloroform Chromium* Citrus red No. 2 Cycasin C yclophospham ide * Daunomycin NjN'-Diaeetylbenzidine 4,4,-Diaminodiphenyl ether 2,4-Diaminotolvene Diabenz [athl acridine Diabenz [ a,j] acridine Diabenz fa,h] anthracene 7H-Dibenzo lc,g] carbazole Table A-l continued on next page * As evaluated by IARC, 1979. ** Chemicals with data on cancer in humans. 104 TABLE A-l (continued) CHEMICALS FOR WHICH THERE IS SUFFICIENT EVIDENCE OF CARCINOGENICITY IN EXPERIMENTAL ANIMALS Dibenzo [a,e] pyrene Dibenzo la,h] pyrene Dibenzo [a,il pyrene l,2-Dibromo-3-chloropropane 3,3'-Dichlorobenzidine* S^'-Dichloro-A^'-diaminodiphenyl ether 1,2 Dichloroethane Diepoxybutane 1,2-Diethylhydrazine Diethylstibestrol* Diethyl sulphate Dihydrosafrole 3,3'-Dimethoxybenzidine (ortho-Dianisidine) para-Dimethylaminoazobenzene trans-2 [(Dimethylamino)methylimino] - 5_[2-(5-nitro-2-furyl)vrnyl] -1,3,4oxadiazole 3,3'-Di methylbenzidine (ortho-Tolidine) Dimethylcarbamoyl chloride* 1,1-Di methylhydrazine 1,2-Dimethylhydrazine Dimethyl sulphate* 1,4-Dioxane Ethinyloestradiol Ethylene dibromide Ethylenethiourea Ethyl methanesolphonate 2-(2-Formylhydrazino)-4. (5-nitro-2-furyl) thiazole Glycidaldehyde Hexachlorobenzene Hexamethylphosphoramide Hydrazine Indenotl,2?3-cd3 pyrene Iron dextran* Isosafrole Table A-l continued on next page * As evaluated by IARC, 1979. * * Chemicals with data on cancer in humans. 105 HWBUI0002058 TABLE A-l (continued) CHEMICALS FOR WHICH THERE IS SUFFICIENT EVIDENCE OP CARCINOGENICITY IN EXPERIMENTAL ANIMALS Lesiocarpino Lead acetate Lead phosphate Lead sabaeetate M elphtilnn* M erphalan M estranol 2-Mcthyluziridine M ethylazoxyrnethnnol acetate 4,4'-\l ethylene bis(2-chloroaniline) bis(2-methylaniline) and its Methyl iodide methunesulphonate N-Methyl-N'-mtro-N-nitrosoguanidine Methylthiouracil M irex M itomycin r Monocrotaline 5-{Morpholinornethyl)-3- ((5-nitrofurfurylidine)-amino] -2 oxazolidinone 2-Naphthylamine* Nickel* Nickel subsulphide Niridazole 5-Nitroacenaphthlene 1- [ (5-Nitrofurfurylidene)amino] 2-midazolidinone N- [ 4-(5-Nitro-2~furyl)- 2-thiazolyl l acetamide] Nitrogen mustard and its hydrochloride 4,4'-M ethylene Nitrogen mustard N-oxide hydrochloride Methyl N-Nitrosodi-n-butylamine N-Nitrosodiethanolamine N-Nitrosodiethylamine N-Nitrosodimethylamine N-Nitrosodi-n-propylamine N-Nitroso-N-ethylurea N-Nitrosomethylethylamine N-Nitroso-N-methylurea N-Nitroso-N-methylurethane Table A-l continued on next page * As evaluated by IARC, 1979. ** Chemicals with data on cancer in humans. 106 TABLE A-l (continued) CHEMICALS FOR WHICH THERE IS SUFFICIENT EVIDENCE OF CARCINOGENICITY IN EXPERIMENTAL ANIMALS N-Nitrosomethylvinylamine N-Nitrosomorpholine N-Nitrosonornicotine N-Nitrosopiperidine N-Nitrosopyrrolidine N-Nitrososareosine Oestradiol-17B Oestrone Oil orange SS Polychlorinated biphenyls* Ponceau MX Ponceau 3R 1,3-Propane sultone B-Propiolactone Propylthiouracil Safrole Soots, tars and oils* Sterigmatoeystin Streptozotocin Testosterone Thioacetamide Thiourea Toxaphene Tris(aziridinyl)hosphine sulphide (thiotepa)* Tris(2,3-dibromopropyl)phosphate Trypan blue (commercial grade) Uracil mustard Urethane Vinylchloride* * As evaluated by IARC, 1979. ** Chemicals with data on cancer in humans. 107 HWBUI0002059 TABLE A-2 s CHEMICALS WITH VERY STRONG EVIDENCE FOR CARCINOGENICITY IN TWO ANIMAL SPECIES 3-A m ino-9-et hyIcarbazole hydrochloride ortho-Anisidine hydrochloride C hlordecone Chldoroform 4-Ohloro-ortho-phenylenediamine para-Cresidine Cupferron 2.4-Dtaminoanisole sulfate 2.4-Diaminotoluene Dibromochloropropane 1.2-Dichloroethtme 1.2-Dichloroethane 1.4-njoxane Hydruzobenzene 4,4'-Methylene-bis (N,N-riirnethyl)benzenamine Michlor's ketone 1.5- Naphthalenediamine 5-Nitroacenaphthene Nitrilotriacetie acid, trisodium salt Nitrilotriacetie acid Phenzopyridine hydrochloride Phenoxybenzamine hydrochloride Procarbazine Reserpine Selenium sulfide Sulfallate 4,4l-Thiodianiline Thio-TEPA ortho-Toluidine hydrochloride 2.4.5- Trimethylaniline Tris(2,3-dibromopropyl)- phosphate TABLE A-3 CHEMICALS WITH VERY STROHG EVIDENCE FOR CARCINOGENICITY IK ONE SPECIES AND SUFFICIENT EVIDENCE IN A SECOND SPECIES 2-Aminoanthraquinone l-Amino-2-methyl-anthraquinone 5-Nitro-ortho-anisidine Nitrofen para-N itrosodiphenylam ine Phenestrin 2,4,6-TrichIorophenoi Trimethylprosphate * National Cancer Institute (NCI) data as evaluated by R.A. Griesemer and C. Cueto, Jr., 1980. 108 * National Cancer Institute (NCI) data as evaluated by R.A. Griesemer and C. Cueto, Jr., 1980. 109 HWBUI0002060 TABLE A-4 CHEMICALS WITH VERY STRONG EVIDENCE FOR CARCINOGENICITY IN ONE SPECIES ANI) HO EVIDENCE IN A SECOND SPECIES Aoronycine 4- .\ mino-2-nitrophenol Aniline hydrochloride Azobenzenc Chlordane Chlorobenzilate 3- (Ohloromethyl)pyridine hydrochloride 5- Chloro-ortho-tolujdine 4- C hloro-ortho-toluidine hydrochloride Chlorothalonil C innnmylii-anthranilate rnetn-Cresidine Dapsonc para, para'-DDE N,N'-Dimethoxyhenzidine4,4'-di isocyanate Direct dye, blue fi Direct dye, black 38 Direct dye, brown 95 Heptuchlor Hexachloroethane Lasiocarpine 2-Methyl-l-nitroanthraquinone 6-Njtrobenzi midazole N-Nitrosodiphenylamine 5-Nitro-ortho-toluidine Oestradiol mustard Pivalolactone para-Quinone dioxime 1,1,2,2-Tetrachloroethane Tetrachloroethylene Toxaphene Triehloroethyelene Triflurulin TABLE A-5 CHEMICALS WITH SUFFICIENT EVIDENCE FOR CARCtNOGENldTY IN TWO SPECIES 4-Chloro-meta-phenylenediamine ICRF-159 Isophosphamide Nithinzide * National Cancer Institute (NCI) data as evaluated by R.A. Griesemer and C. Cueto, Jr., 1980. 110 HWBUI0002061