Document 5Lenb6Q7ONrjq2wa8eMLbOznD

Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) Carcinogens in the Workplace David Schottenfeld and Joanna F. Haas CA Cancer J Clin 1979;29;144-168 This information is current as of February 22, 2007 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://caonline.amcancersoc.org To subscribe to the print issue of CA: A Cancer Journal for Clinicians, go to (US individuals only): http://caonline.amcancersoc.org/subscriptions/ CA: A Cancer Journal for Clinicians is published six times per year for the American Cancer Society by Lippincott Williams & Wilkins. A bimonthly publication, it has been published continuously since November 1950. CA is owned, published, and trademarked by the American Cancer Society, 1599 Clifton Road, NE, Atlanta, Georgia 30329. (American Cancer Society, Inc.) All rights reserved. Print ISSN: 0007-9235. Online ISSN: 1542-4863. Carcinogensinthe Workplace David Schottenfeld, M.D. Joanna F. Haas, M.D. Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) When international age-adjusted cancer incidence rates first became available in the early 1960's, patterns prevalent in the low risk countries of Africa and Asia were compared by Higginson2 with those pre vailing in the United States' white popula tion or in the western European countries. The total incidence of cancer in a hypo thetical population at minimal risk was calculated by summating the lowest age adjusted rate for each site from the most appropriate country. Ugandans, Nige rians, and the South African blacks, for example, were at lowest risk for cancers of the lung, stomach, large intestine, cor pus uteri and kidney. The Singapore regis try recorded the lowest rates for cancers of the pancreas, urinary bladder and breast. Conversely, the rate for primary hepato Dr. Schottenfeld is Attending Physician and Chief, Epidemiology and Preventive Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York. Dr. Haas is Assistant Attending Physician, Epidemiology and Preventive Medicine Service, Department of Medicine, Memorial Sloan-Ket tering Cancer Center, New York, New York. The authors wish to acknowledge the generous gift provided by the Jack Lazar Foundation to the William G. Cahan Research Fund of Me morial Hospital, which underwrote the special production costs incurred in preparing Table IV for publication. Reprinted with permission from Clinical Bul letin8:2,54-60,and 8:3, 107-119,1978.The articlweas originalltyitled:oeTWhoerkplaceas a Cause of Cancer,and appeared in two parts. cellular carcinoma was highest in Mozam bicans and in the South African blacks, whereas it was lowest in the United States white and black populations. Carcinoma of the nasopharynx was highest in Singa pore. Higginson estimated that the age adjusted cancer incidence in the hypothet ical population at minimal risk was one fifteenth of that in the males, and one ninth of that in the females of high risk countries. A preliminary analysis indi cated that the hypothetical cancer inci dence was one-third of that observed in the United States white population. From these geographical differences, it was pos tulated that 70-90 percent of human can cers are likely to be due to environmental factors and, by implication, preventable after extrinsic factors are identified. Studies of various migrant populations have measured shifts in cancer mortality and incidence as groups move from one part of the world to the other. If genetic factors were primarily responsible for the international differences in risk, then the prevailing rates among population groups that migrate should remain relatively fixed. However, the evidence to date in dicates that the risks of cancer in organs of the digestive (i.e., stomach and large intestine) and reproductive (i.e., breast, corpus uteri and ovary) systems were dis placed from the rates prevailing in the country of origin toward those experi enced by indigenous residents of the host country.3 144 CA-ACANCERJOURNAL FORCLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) In a monograph published in 1975, it was estimated that we already have the knowledge to prevent 30 to 40 percent of the common cancers in the United States@ Current oebestestimates of the percent age of all human cancers that may be at tributed to occupational exposure range between one and five percent.5 A more ex treme assessment of the causal fraction due to occupational exposure may pertain to uncommon types of cancer (e.g., angio sarcoma of the liver, mesothelioma of the pleura or peritoneum, scrotal cancer), or in the instance of squamous cell carcino mas of the lower urinary tract in men. Among men 20-74 years of age, approxi mately 20 percent of bladder cancers are related to occupational exposure.6 Industrial agents may not necessarily be confined to the workplace, but may spread by polluting ambient air or water in the general environment. Current esti mates from the Environmental Protection Agency (EPA) indicate that there are as many as 50,000 chemical substances, ex cluding pharmaceuticals and food addi tives, in common use. In the past 10 years, the production of synthetic organic chem icals in the United States has increased more than 2.5 times over that of previous years, although relatively few of the new compounds have been studied adequately for carcinogenic potential. Standards of Threshold Limit Values (TLV's) of expo sure have been promulgated for only a small number (less than 500) chemicals to which workers are exposed. Although new regulatory approaches are urgently re quired for occupational carcinogens, the present conservative posture of the federal agencies is to view human carcinogenicity of industrial chemicals as a relatively un common phenomenon.7 Historical Overview workers in certain arts and crafts sometimes derive from them grave inju ries, so that where they hoped for a sub sistence that would prolong their lives and feed their families, they are too often re paid with the most dangerous diseases... From De Morbis Artificum Diatriba, Bernardino Ramazzini, 1700 Up until the late Middle Ages, the impact of the occupational environment on the manual worker had not received careful attention by practitioners of medicine. Be cause expanding commercial enterprise during the 15th century increased the de mands for gold, silver, iron, copper and lead, the miners and metal workers were among the earliest occupational groups to be studied. The first publication concern ing an occupational disease was prepared in 1472 by Ulrich Ellenbog, a German phy sician from Augsburg. The pamphlet was entitled, On the Poisonous, Evil Vapors and Fumes of Metals, and described the irritating effects of the fumes of lead and mercury experienced by goldsmiths. In 1556, De Re Metallica was published by Georgius Agricola, who prepared a com prehensive treatise on the accidents and diseases prevalent among the miners and smelters of gold and silver. He attributed their chronic lung disease (oeminer'sasth ma)to the inhalation oTdust, and recom mended the use of facial masks and the need for adequate ventilation.6' With the publication in 1700 of the first edition of De Morbis .-4rtificum Dia triba (Discourse on the Diseases of Work ers), Bernardino Ramazzini founded oc cupational medicine. His book was a comprehensive survey of existing knowl edge of the nature of diseases believed to be caused by a particular craft or work setting. Physicians were instructed to go beyond traditional Hippocratic practice and inquire of the work activity of each patient. The patterns of disease or health within a given population were now to be viewed in the broad context of social class. The first clinical report of occupation al chemical (hydrocarbon) carcinogenesis has been attributed to Percivall Pott who described in a brief essay in 1775 cancer of the scrotum among chimney sweeps in England. The condition was acknowl edged in the trade as the oesowotart, be cause it was assumed to be due to chronic exposure to soot. As Pott wrote, oeThe disease in these people seems to derive its origin from a lodgment of soot in the rugae of the scrotum... Although this treatise, which appeared in Pott's book VOL 29, NO 3 MAY/JUNE1979 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) Chirurgical Observations, has been re garded as a seminal paper in preventive oncology, there was no explicit discussion of the compelling need for careful person al hygiene and laundering of work clothes. Domestic soots contain hydrocarbons and tars which arise from the incomplete combustion of carbonaceous materials such as wood, coal and oil. It is of interest that the incidence of scrotal or oesocoatn cerin England was reported to be signif icantly higher than in Scotland and Ger many. The geographic differences in risk were not registered precisely, but were of sufficient magnitude to require considera tion of the unique features of exposure and life style of the English sweeps. Such factors in England included earlier substi tution of coal for wood, employment of young children who would crawl through flues rather than pulling up the debris without working from within them, and marked differences in personal washing practices.'2'3 Henry Earle, a grandson of Percivall Pott, observed in 1823 that only a small proportion of the exposed individuals would manifest disease more than 20 years after their work experiences. He conjectured about oeconstitutionalpredis position... which renders the individual susceptible to the action of soot. Thus, the oesocoat ncer in chimney sweeps was serving to stimulate biologic concepts about external factors, predisposing host factors, tissue susceptibilities, and the la tency of chemical carcinogenesis. The expanding industrial revolution after 1850 created an increasing need of lubricating oils for machines. Volkmann, Bell and Butlin reported during the latter half of the 19th century that scrotal can cer occurred in tar, paraffin and shale oil workers. These derivatives of coal tar were also shown to be carcinogenic to the skin and vulva. Butlin also raised the troublesome prospect of inhaled and in gested domestic soots giving rise to inter nal cancers. In 1915, the Japanese work ers, Yamagiwa and Ichikawa, produced cancer on a rabbit's ear by painting it with tar. Later, similar results were produced in other animal species using soot, coal tar pitch, anthracene oil and creosote de rivatives of coal tar. Cook and Kennaway in the 1930's isolated benzo(a)pyrene, a potent, polycyclic hydrocarbon carcino gen, from coal tar.'4 EpidemiologicMethods For Determining Risks Among ExposedWorkers oepTrhoeper study of mankind is man. From Essay on Man, Alexander Pope, 1734 Evaluation of the risk of cancer in re sponse to suspect environmental agents rests in part on the evidence derived from observational, epidemiological studies. The initial suggestion of a relationship be tween an agent and a disease often ema nates from animal experiments or case re ports in patients with a common expo sure, or from both. Animal experimenta tion anticipated the subsequent confirma tion by epidemiologists of the hazards of occupational exposure to 4-aminobiphe nyl and other aromatic amines, vinyl chloride, bis(chloromethyl) ether and other alkylating alpha-haloethers, and mustard gas.'5-'8 Astute clinical observa tion initiated epidemiologic research con firming the high risk features of nickel re fining, woodworking in the furniture in dustry and other trades exposed to wood dust, manufacturing' of leather goods such as the shoe industry, and the mining of uranium and fluorspar.'92 Identifica tion of the risks of occupational exposure to the inorganic arsenicals has been pur sued by epidemiologists in the absence of satisfactory experimental models.'8 Epidemiology is concerned with iden tifying patterns of distribution of human diseases. Rates of incidence and mortality are reviewed in the context of time trends, geography, and personal characteristics. This descriptive profile of a disease serves to guide the pursuit of etiologic factors that are likely determinants of a specific pattern. The epidemiologic methods that are concerned with testing causal hypotheses can be classified either as case-control or cohort in type (Table I). The case-control (retrospective, case history) study is most 146 CA-ACANCERJOURNALFORCLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) suitable in studies of rare diseases, in of effect(s) likely to occur with frequency oefishingfor multiple factors of uncer greater than random chance if the ante tain significance, and for the initial ex cedent event or complex of events were of ploration of a specific etiologic hypothe causal significance.23 sis. The cohort (prospective, longitudi The methodological features of epide nal, follow-up) study is advantageous in miological studies of the workplace and that it provides a direct measure of the in cancer are reviewed in Table 111.23-35The cidence or risk of developing a disease in important parameters include the type individuals with a specific characteristic, and oestrengthof exposure, age at initial and is most suitable for testing a particu exposure, latency or the frequency distri lar hypothesis which has already been de bution of the interval from first exposure veloped from prior retrospective or cross to the initial diagnosis of disease, dura sectional studies, or both. For practical tion of exposure, intensity of exposure purposes, the various caveats about sam and its variability over the cumulating ple size in cohort studies guide the epide person-years at risk, and the spectrum of miologist to focus on hypotheses that in morbidity and mortality. In addition to volve a relatively common exposure (in the methodological issues summarized in more than two or three percent of individ Table III, there are other interpretive pit ualsat risk)a, relativecloymmon cancer falls in epidemiological research that may (incidence of 1/1,000/year), and for dis confound or obscure precise inferential cerning relative risks (risk ratios) in the reasoning.34 exposed individuals that are at least twice Confounding refers to the extraneous thatof thecontrolgroup. influence of factors, other than the mea The conduct of each epidemiologic sured occupational experience, on the as study requires some judgment about sociation with the risk of cancer. For ex whether or not an association is of causal ample, social class is closely linked with significance. The Surgeon General's Re occupational status, and may be more di port on Smoking and Health concluded rectly associated with the risk of develop an introductory discussion of judgment ing or dying from various types of cancer. and causal inference with the following: Social class factors may be linked with ~Thceausal significance of an associa personalhabits,aspectsof lifestylethat tion is a matter of judgment which goes includepatternsof nutritioannd non-oc beyond any statement of statistical proba cupational environmental factors, and ac bility. cess to and utilization of medical care ser The criteria most appropriate for eval uating an association are consistency, strength, temporal relationship, coher ence and specificity.2' The criterion of consistency is analogous to experimental vices. The observed increased risk of can cer may arise from mixed chemical and physical exposures or the interaction of occupational and non-occupational fac tors. replication, but may also rest on the dem The observations emanating from epi onstration that diverse investigative ap demiological studies may be suspect be proaches produce similar results. The cause of lack of accurate exposure data strength of an association may be ex and limited or incomplete follow-up from pressed in terms of relative risk (risk ra the onset of some remote exposure, even tio, odds ratio) and population attributa if it was of short duration. In the studies ble risk or etiologic fraction (Table 1122). that depend upon recall, the workers may Coherence embraces the criterion of bio be unaware of the identity of the substan logic plausibility, although it should not ces that they have handled. Routine rec discourage the consideration of unortho ords rarely satisfy the needs of epidemio dox, innovative hypotheses. The tempor logical research, but rather what may be al criterion requires that the presumed needed is the development of a standard cause must always precede the observed ized comprehensive occupational health effectw,hereasthecriterioonf specificityinformation system with prospective implies that there is a predictive pattern monitoring throughout a defined work VOL 29, NO 3 MAY/JUNE1979 147 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) CA-A CANCER JOURNAL FOR CLINICIANS 148 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) VOL 29, NO 3 MAYJUNE 1979 149 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) force.36 Job titles may not connote a spe the orientation is post hoc and not predic cific exposure, or the same title may en tive or applicable to new chemicals that compass a multitude of possibly toxic are in the process of being introduced into agents that are likely to produce a variety the workplace. of effects. Each individual worker may have moved through a number of differ ent jobs, even within the same manufac turing industry. The task is to attempt to group the various jobs into homogeneous Principles of Non-Human Testing for Chemical Carcinogen city: The Relevance of Animal and in Vitro categories of exposure.37-38 Studies for Predicting Human Risks Properly designed epidemiological studies may serve to identify the absence Current methods for estimating the risk of risk. The validity of any inference of human cancer from long term expo about minimal or no risk may be deter sure to low doses of chemical carcinogens mined by the adequacy of exposure and involve extrapolating from animal experi follow-up information. The ability to de ments conducted at doses high enough tect significant differences in risk will de and of sufficient duration to produce tu pend in part upon a statistically adequate mors in an appreciable fraction of the sample that will enable the determination animals tested. The process of extrapola of differences in risk if they do indeed tion or of using animals as surrogates for exist. However, a limitation of the epide people involves various assumptions and miologic method may be its insensitivity caveats: to measure, in retrospect, single or com a) chemicals that cause cancer in one plex low level chemical exposures that or more species of mammalian animal give rise to small increases in risk. In ad may be capable of causing cancer in hu dition, because of the long latency period, mans; 150 CA-A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) b) the dose-response curve assumed icalexaminationand optimalnumbers of for man may be analogous to that demon experimental and control animals. At strated in the most sensitive animal mod least two animal species, both sexes, and el; several dosage levels should be employed. c) although it is conceivable that at Although the choice of animal for routine certain dose levels even potent carcino testing should take into account the man gens will not produce tumors in humans, ner in which the chemical is metabolized a subthreshold dose or oesafelevel can in humans, more commonly the test ani not be determined with certainty by ani mals used, and in particular the mouse, mal assays; rat and hamster, are selected initially in d) higher dose levels of a chemical the absence of comprehensive knowledge carcinogen may increase the incidence of of pertinent aspects of human metabo commonly occurringor unusualcancers, lism. There may be significant differences or of thenumber of primarycancersper in the responses of various species to a animal, or shortenthe latencyperiod; given class of carcinogen. For example, and, an aromatic amine, such as 2-naphthyla e)targetorgan(s)fortumorsobserved mine, may give rise to tumors of the blad in experimental animals may not neces der (human, monkey, dog, hamster), or sarily predict the type(s) of tumor induced liver (mouse), while having no apparent in humans.39 effect on other species (rat, rabbit). The fact that aromatic amines induce tumors The prediction of the carcinogenic po inexcretoroyrganshas ledtotheconcept tential of chemicals in humans by animal that it is the N-hydroxylated metabolite, bioassay requiredcarefulselectionof and the species-specific capacity for meta suitable animal species, rigorous experi bolic activation, that are responsible for mental procedures, meticulous patholog the induction of cancer.4 VOL 29. NO 3 MAYJUNE 1979 151 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) Since the rate of occurrence of most cancers is related to the lifespan of a given species, bioassay systems have been con centrated on small rodents with an aver age lifespan of two or three years, and the longer lived animals such as the dog and monkey have been used for specialized studies. At present, chronic toxicity stud ies begin with weanling animals and are maintained at desired dose levels for a nat ural lifetime. The period of experimental observation should not be less than two years for rats and hamsters, or 18 months for mice. Where studies are concerned with the effects of exposure to the fetus, or during the perinatal period, then the protocol should be modified appropriate ly. The route and mode of administration of repeated exposures should reflect, whenever possible, the natural human ex perience. Artificial portals of administra tion require careful assessment of system ic levels of exposure, and whether or not tissue injury and degeneration are due to the prolonged presence of injected or im planted chemicals @41.42 The appropriateness of using very large or maximum tolerated doses in ro dents is a source of controversy and con fusion. The dose levels are selected on the basis of mortality and partial suppression of normal weight gain when compared with untreated controls. The justification for the routine use of a maximum toler ated dose is that it maximizes the sensitiv ity of the experimental system to detect the tumorigenic effects of oeweakcarcin ogens that would have been missed at lower dose levels within the relatively brief lifespan of rodents, and enables lim itation on the number of animals general ly recommended for testing. At the much lower dose levels which may correspond to common human exposures, several thousands of animals may be needed to estimate any increased carcinogenic risk. In determining in advance the re quired sample size, the investigator must consider the spontaneous incidence of or gan-specific cancers and mortality due to intercurrent (non-neoplastic) diseases that is to be expected in the unexposed control group. The sensitivity of the experiment or the magnitude of the difference in tu mor incidence between experimental and concurrent control groups (this may in clude a separate vehicle control group), and the degree of confidence required to detect such a difference, should be deter mined in advance. The higher the ex pected incidence of spontaneous cancers or the smaller the difference in cancer in cidence that is being sought, the larger the required sample size. Under a given set of experimental con ditions, has the agent been shown to be carcinogenic, and was there a oesafe dose, below which there was no indica tion of increased risk? As described by Cornfield ,@3the Environmental Protec tion Agency has defined the oenoobseryed effect levelas the oelev(eqluantity) of a substance administered to a group of ex perimental animals at which those effects observed or measured at high levels are absent, and at which no significant differ ence between the group of animals ex posed to the quantity and an unexposed group of control animals, maintained un der identical conditions, is produced. The basic problem in risk assessment for carcinogenic substances occurs when ex trapolation is attempted downward from the observed range of experimental ef fects to an assumed safe level through the application of mathematical assumptions which achieve linear low dose-response effects. Most mathematical models deny the assumption of a uniform threshold, or that there is a level of exposure below which there is no possible carcinogenic re sponse for the entire population at risk. The procedure for estimating human risk consists of extrapolation of experimental results achieved at high dose levels to much lower dose levels within the species tested, and then extrapolation of these es timated risks at low doses to risks in hu mans at comparable levels.@'47 Bioassay by in vivo animal studies of the many thousands of chemicals that are constantly entering the workplace and general environment would be an over whelming and costly task. Short term in vitro screening tests for mutagenicity and malignant transformation are being de veloped to facilitate the estimation of po 152 CA-ACANCERJOURNAL FORCLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) VOL 29, NO 3 MAY/JUNE 1979 153 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) tential human risk. In vitro methods un der controlled biologic conditions should afford the advantages of validity, reliabil ity, rapidity and economy. Selective test ing of suspect chemical agents should be guided by knowledge of structure and me tabolism, electrophilic reactivity of each compound and metabolites, genetic ef fects and extent of human exposure.48-52 There is a high degree of correlation qualitatively between mutagenic and car cinogenic activity as revealed in a wide variety of in vitro assay systems. A meth od that has attracted considerable interest uses several Salmonella typhimurium his tidine-dependent tester strains engineered by Ames and McCann@53.54 although other bacteria, fungi, plants, insects and mammalian cells are also being used. In the study by Ames and colleagues, 90 per cent of a selected battery of chemicals known to be carcinogenic in one or more animal species were detected as mutagens; almost all chemicals known to be carcino genic in humans were mutagenic in the Salmonella microbial-rat liver microsome system. About 13 percent of chemicals considered currently to be non-carcino genic showed some degree of mutagenici ty. The sensitivity of various bacterial strains to develop frameshift mutations or base-pair substitutions, which result in reverting the characteristic of histidine dependency, is enhanced through the ad dition of a mammalian liver microsome system, and selecting strains without lipo polysaccharide in the cell wall or without an effective system for repairing altered DNA. A positive in vitro test for mutage nicity would serve to identify chemical agents that require long term animal test ing and, if extensive human exposure has occurred, appropriate epidemiologic studies should be conducted @55.56 The close correlation between muta genic and carcinogenic properties implies that a primary mechanism in malignant transformation involves alteration of the genome. Meselson and Russell57 are even suggesting in their preliminary studies that there is a quantitative relationship between the carcinogenic action of a com pound in laboratory animals and its mu tagenic activity in the microbial system. However, the universality of the somatic mutation theory of the origin of cancer has been challenged in its application to higher (eukaryotic) organisms. Whether or not epigenetic mechanisms are of greater fundamental importance in the multistage process of human carcinogene sis does not necessarily detract from the utility of using non-mammalian systems for identifying chemical agents with potentially chronic toxicologic effects in hu mans.58 In addition, because of species differences in metabolism and detoxifica tion of various classes of chemical com pounds, in vitro assays for malignant transformation and mutagenic activity that use mammalian cells should be em ployed in conjunction with the microbial systems. 59,60 - Workplace Exposureto Known or Suspected Carcinogens Of the many commercially produced sub stances which have been reported to be tu morigenic in one or more in vivo test sys tems, only a limited number are of impor tance in clinical occupational medicine. These agents are listed in Table IV. Key animal studies of tumorigenicity are noted, particularly where these tests rath er than observations in human popula tions are the primary basis for concern over the agent's carcinogenic potential. For example, the carcinogenic potential for several of the aniline-derived agents was so dramatically demonstrated by ani mal studies that widespread human expo sure was averted. The extent of occupational exposure to the agents listed in Table IV varies widely. For some, such as asbestos and ionizing radiation, the work settings and job activities in which exposure may oc cur are extensive, diverse, and sometimes unexpected. For other agents, however, the potential for hazardous exposure is relatively circumscribed. The route of absorption of an agent is determined both by its physical properties and by the circumstances of exposure. In- halation of vapors and fumes is the most frequent route of exposure, while the skin is a potential route of absorption for both liquids and gaseous agents. Inadvertent 154 CA-ACANCERJOURNAL FORCLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) ingestionoccurswith agentsin a solid ronment. In parallel with these industrial phase, such as metallic dusts or salts of control measures, a prospective medical certaicnompounds. program of periodic general health exam The mean latency period, i.e., the ination and oetargetedclinical and labo average interval between onset of expo ratory medical surveillance (e.g., sputum sure and development of a neoplasm, and urine cytology, liver function tests, most often falls between 10 and 20 years, pulmonary function studies and reporting although the range may be considerably of pulmonary symptoms or skin lesions) wider. There is considerable variability in is an essential component of an occupa latency in individual cases, perhaps re tional health program. These procedures flecting intensity and duration of expo should serve to enhance the safety of the sure as well as ill-defined host biological working environment. Each preventive factors. Estimates of the relative risk of measure should be evaluated carefully as developing a neoplasm following expo to its potential effectiveness in diminish sure also vary. Patterns of exposure in ing subsequent incidence, morbidity and different groups of workers exposed to a mortality due to the various types of can common agent may differ greatly. The cer and precursor diseases. The rationale heterogeneity of exposure group, the du for control strategies emanates from the ration and completeness of follow-up best available epidemiologic information achieved, and the size of the exposed and extrapolation from animal re group vary from study to study. These search. 134,135 factors influence the magnitude and pre In the United States, control of carcin cision of estimates of relative risk and ac ogens in the workplace prior to the 1970's count for the sometimes broad range of involved using engineering controls and such estimates. personal protective devices to minimize For the most part, when cancer devel exposure, and substituting less toxic ma ops as a result of exposure to an occupa terials whenever possible. The Occupa tional carcinogen, it is predictably con tional Safety and Health Act of 1970 au fined to a limited number of target organs thorized the Occupational Safety and or tissues; in animal studies, the same or Health Administration (OSHA) within gans or tissues may not necessarily be af the United States Department of Labor to fected by the same agent (Table IV). Sev enforce maximum allowable concentra enteen agents among those listed have tions or Threshold Limit Values (TLV's) been included under the Federal Standard of exposure to carcinogens. A TLV refers for Carcinogens; this indicates that all to a time-weighted average level of air contact with the agent should be avoided borne concentration of a substance in the or reduced to the lowest possible level. working environment below which it is believed that nearly all workers may be Current Concepts of Prevention and Control of Occupational Cancers repeatedly exposed, day after day, with no adverse effects. The American Conference of Governmental Industrial Hygienists oeTChoengress declares. . . its purpose and has since established threshold limits for policy. .. to assure so far as possible every more than 400 suspect substances.'36 working man and woman in the Nation In addition, the recommendation of safe and healthy working conditions... standards to OSHA by means of scientific oecriteridaocuments is the responsibility The Occupational Safety and of the National Institute for Occupation Health Act of 1970 al Safety and Health (NIOSH), which is an agency of the Center for Disease Con A sound foundation for an occupational trol of the United States Public Health health program is based in part upon in Service. The official position of NIOSH stituting engineering and hygienic mea is that it is not currently possible to dem sures that control or limit contamination onstrate precise tolerance levels of @xpo by toxic substances in the working envi sure to chemical carcinogens, and, there VOL 29, NO 3 MAY/JUNE1979 155 @ U@ @C Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @ @ @ @ @ @ @ @@ @ @@@ @ @@ @ @ @@@ @ @@ @ @ @ 156 U C S S S C t& E E 0 U U) S. ~U 0 IU) C.) C, 0 -J 0 ~US. 0 CU 0z 4 S. -l 4 U zC @0 C.) 0 0, J) dC 00 U a-'@-- U) Ui p-S 0 C C- 0 U) -l 4 02 z 40 OC S E,-a I C_:@ cr'@ 4 V U 0 g'c U'@ !0C @-o aE 98 og 0 o (0@C' "o .0 0@ 0@ C 05 (01 C .J C'. C U (fl-0.-- U) (0 CD (0 "(0 U@ -@ .-0 a >.@ U U0 iiilU C' E C' C' EE V U @0 OCV 0N -0@. a@@00 1;; ii.21 U 0 0 (0 U C' E .2o U C'@ U@ U aC' V C o.@ >@E 1' C'@@ U C U V U C U C 0.@, .2.5 E @0C' U a " U 0) 0 0).- 0) E S U@>. a E E ~05 (0 CC@ 0 0 V U a 2C' <000 z0 0 0 V z0 U coa E C,) C 0 U C' V C' U .J@' UU VV VV C' C' 0 0 U) U) (0 ~C S "oeI) -JO) -JO) -JO) UU U C' a S 0 C' U 0) COC02 -J-J 15 U. C 0 C' U U .5 (0-0 UU _J _J U 0a 66 aa U a~0 EU 0) 0 5@ U@U C C' U 0) U0U .Jz " z.Ez 0a U 008 aa 0 .5 U 0 000 15' a U' 0 a U -@ 00 uio. aU U U V a (00 U U U@ 15 ..E a "0)01 CC E 01 U S 0 F, U (0(0 Cr1 a0 U it L0 (00 U 0a 0@ 2U @Cr C 2'! 0 0 00,, S U C C' S U C.) E S .C@ oa .EVC C' E@ a a .g0_U 0'-0@ 0 0 SS CC a0 C,)-. 0 @.0 0 0 U 0a C' U U Cr 0 aC' 0 0 0 CA-A CANCER JOURNAL FOR CLINICIANS @ u@@ .@ &U @. ~@ @.EC@ C@ Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @ @ C' @ a@ o -@ U o@9. og @ @o @ .C2@V @ @ U@ @ So CD o@ "- 0 U, .@a.U -22U>. EU)C' ,IU,_V at ~0 C'0 @C' 2 U C V .c E 8e.a. -@C@'.EOC0 ,C, 'OVVa ZV@ o o U~C."@u . C' @C' @C .D5C " UC C.-, Ua 0 0 0 0 @@~@@,V~E O'@'@ O'@ U,@ C R@ C'. 2- &@ O@ V@ C' 15 C "S X._. U. CCO'C @2 Q@C' ,@c @S ~CE C 8,, @2 IV@jC C'C' Ew 0C@ C3Q C' 0@ U) C' E C0 53 15 0 E> E g C 2 U) 0 "oe C' C'@ CV -" U "~2 E .92 U .@g 0 C'@ Fz @ @@ @c @ _JCI) @ @ @ @@ 1-U5> @.s _JCI) 1-515 CD .JC0O .@ C' ~a 2E .2 >0) ~ CO @~ .5@ 0) 0) ~- ~-~ ~ .9 @.s ~ 5 -(Cl) .Jc- u .9 C'@15 E .2 0 C' @.s 15 -(U) 2 C U @E 5 01 15 5 C' aE U ~a 2" @.c 2'.s _i U JO) @~ E U C 0 a 15 1U5 @151051a"0@C'@C'U 2C2V 15 E @o O@@-2@oe'a CC'C' CE'C2& 5V CE @ @ @ @ @ ooo @ aaa @ @ .a2' @ 0)5' U -@ C. 00 00 aa 15 U U @C)C . 0 01 U ! @ a @C 0 Ea C' C . >. 0 = @ @ @ @ Cr@ Ct 9 11 9@@9 ! UH .@ C o CO U) 5 ., @C' @E a8 2 C' C ~@ U C ., -@ C' ~@, 2 , S 2 a U >. C. . C' a .@ ,, Cl) .@ ,x U) C' ." .- UU C>@ C'@ C>.U C'@ SS o0 oo 15 .2@ oc@ 0@o@ -2 .2@.9 !@ Hil@ a >. , o@ 01 C , , C' oO.9 01d S C' V V .@ > 0.25 C' aU U o~E .1@5a S U@ @9 UC U C' C C C " > 2! WI r .2" .9 .9 I! H VOL 29, NO 3 MAY/JUNE1979 157 @ g@@ .. @ L@@a ~@ Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @ @ @ @@ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ ____ @ @ @ @ @ @ @ @ @ @ @ @ 158 23@ a@C'.! 2C'aE >.Ec@ C'2a@ 2C0''@E@ @ - @2C'C' Eo@ti O 0@C'U U 0W@ 00 2 C' C&@U US @2 C'@@ V aC' EC'01 O@"0CC ., C .5 DC Coe o,@ aUt?2 Va 201 C''. H ,@ C''-@ CC0@UO 0 0 01 .fl@1 >UV@@ @~8C@C ..0C' ~01 ~~s.YU15 @HI Q.,aa0 HCC'C' OU@732 @C..0I @@SOU .-CD'D Hilh <0oC'E2@ O ~@6@6 ~@E'@ W!@ ao@ C-@ 2@-. C0, @. U2 @a C'2C 0'.C'.@ s"C' 1@C'5C' 5U @VC0E@VC@ @F,&C&@0S < " <w C'U yr , 0 U 40C@ 25.! O)-J@ 15 " C U - U o .@0 CrW 0001@ 1@ 0 CO ~- CO'-CO U CO U ZC ft @.5 @O "SO) U .,.: .@zo DC o a -C C >. C UCa Z " -E 0E UgE L C') 15's @C' o,o a.! ~C,, 2C C'@ C@ U-@ C5@ 2.-U C C) ~a .s8@V @oe 2 0 0 2 ~ a @. 50 ~ @U ,@.? " 0 U 0)10) -- 0 ,@ 0 2,a C'Ep DUC2UCC ' aDCV E'-C o2C @C'U V - 5 .C 0 " C .5 - u C'0, C U U@ !S Z @U)JZ S @zS , 0 0000 a aaaa 0 000 a aaa ~ .50 U U@, S U .L.DC@.JDC>1@DC>'_'15 , 0 S S.JC 0 2 C 00U aa@ .5 U' C'EC' EUC' U>15 01'C' >5 @, CUa E@ @C a V-C01 .OC?C'a 0 S@ <@15 @152@t@"- ~@ 15@'@ @~- 0C'. @~5'C@2 (@@>@5@C' 0 ,c@ 0 U 0 C) ~.2 ,C ~@ .2 U'-''C C) C) CA-A CANCER JOURNAL FOR CLINICIANS @@ ,@ C@ @@C2 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @@ @ @ @ @ @ @ @ @ @ @ UU .? -J-J od @ aa @ U @ 0@ @@ @@ -. U CU C' U @>@C' UC'C @2a OC & -. 0a C' C-.. C ~U -@ OC'..C' U~5D0-5"C -. C U a 0C zS C'@ 8 DC C C U S C H C'U S@ 38 C01 C15 U DCC 5'. 52 JU) So a@ C' U@ C'C' @15 Ua U U 0a "C' U V V "aC'0 CC a>OC' CD CC' US a@ C') 0) >~C' %@ 5'. - C'2 0.. UC' CU 0@ UU a0 .? -J-J a a ~C' -S U' C'U 0% II215 =! oo aa So O@C U H 1' C' C EU -@ 5 C' C' a.-.. ii C.?" 0 U C' 0 C') CO DC C -J C' S 0 C' C' -i 0 ~C' Cr C' UU C' C' SS UU C) Iii 0 1 j,5DC @VU C @Cl) U, UU CO "o O 22 01 3 C.. 2 U 0= - 52 .~@ a,.: C C'0 0 = C' >. C'@ Eo 2'@ S. " -@ CU U2 C' 0.. S EC OC' @C' z15 IS Ua C'@ SU U% VS UC C'.- SC DC2 OC' -a 01 E@2 C' -C@@ 1-@" D0 C C 0 C0 ' C' EC@'.-o C -2@U SC'DC CUa @L2 OC' =a a C C' 2 U 0 VU S 8 C C' 5". 2 C' C0'@@C"@ -5 0. U 0... C, .5 0 0 C' C' U C' S U V ~O U C DC C U C 0a 0 0 E0 U C'U C' S U C C') C' 2's -JO) UU >> C'C' DCDC UU zz C 0 & C C U O@ C VC 01 5.5 EU DCc 2'. @2 OC' @JCl) 215 SE Va UU C'C' CS U DCU .? U ~.@ V@ U U DC 5 C' ..?JZU S C'' U'. 2 .53@ C' U C' S 60 aa U C U a 2U " -- " Cr@ g-@ U'. .5 C' @o0 DC.S 0 C' DC S DC 01 U C' S C 2 C' 0 -J 2 C' C .@ -C o.2 a " H -J Ca 0-@ a 0O,.C a CC OC'C' @CrI U'. U15 05 0'! . - ~@C'C U C C U C' S C a U 0a U C' U C' S C 2 0 C' DC V C) II ..UC .2 C' V 0 ~@ CJ@CC' c ;@ 215 S U C 0 5 iia15 cDC C U DC@ 5a " U C U -V U O)C - 0DC@ 2o 0 C' .2' S " U 2 0 0 VOL 29, NO 3 MAY/JUNE 1979 159 @5 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @ @ @ @ @ @ @ @ @ @ @ @ @ @@@ @ @ @ @ @ @ @ " E= .2 2 SUC CCDC C U V I ,p@.S01 f 2@C'@ C a V @oe- .-. C'@ / . 0) I -1 I2 3 C U)@o U)@V ~SC v/C-S C'aC'C' C a0 @U@152@ CC Za@CC @o 2(02 ~@01 t U-@ U@ 01" 15@ / C> / C'5 2@ 0'- 2 C' ~a ~C U Cr UlSO ~.0 Ua NC') UC VV C 8 I0 V C'@ (0 0, -a@ 0,C' C'C Z V C'@ ~ (0 ~0_ ~CC' C'C Z C 0U @0 U) W CC C." O) UU2'2 .-CDCCU'.@CIC CU , @V0 C2@ a " I S.2o> UtOC' 1 U@.SQ) @%a C' .2 01 15 @~a. V'- @0 I2 wo@-a.S@ , U s ~@ ~C DC@ CUC @C' .JZ ~ 0 a C U C' C U 2 o 10 CO 4 !,@ U 0, i8 0) 22 0 C')C'@.j 2 @ 2 C'? 5 C'@@a C'...,0@)s a o.S a@ CaE@ DC V- - 0@-U C' ft@ 91. 155.5 C 2S DC DC S -J C' -J 0,@, U UC)' C' S8 E .JO)0 SE'@ 2@@CC'C5'@aDC@@'. DC . IUC-S " U) @oeU _@ 2@~. .@ ~i 15~@ @01o " C @s oa S " U) Cr ~-@2 ~u'. DC C ~" C " .- 0a ""._ ,, ~. oCCC S" C'C' U .- ~C 0a EU ._Cfl U DCU ((C U @V C' o01S ~. 0, ((CU " C U 52 S 0, C a C V @. C C' C s'? ~a VC ~C' OC U'" C'VC <0 00 ..@ . @k 5.2' 1 ~H@ U C' .. 5 @I U .5 0 C' 0 ~. 5 " 0 0 0 " ~ 5 ii@ C'C' ZZ aa U 0@ @Cr I DC " 52! .JO)0 U C U C' C .. Vo S D0C ~@~@ @.S C'gC O) a U'@,_ (0 CD' C 01 2 CC C@CC'O 0 Cr 0 .t2 U CU - a a 0 @15 VU oa C., @2 <C 5 E H L@ @ .@ @ @ @ @ @ @ @@ @ @ @ DC C .J DC C -J C' S 0 0 C' U DC CC 0 0 -J @ > C 0 C' C' C C' UU O- 0 @ DC@ "C .oeU C' C ~C 15 U@ C.-I0 OC' 0,, C'@ CCV'U C EU 2 C@ -. C 2 E C S UV 0 @S15 C VUC@ @~ U .@ CDCD'.C VC C 2 &~ECO E OC' C' .@ C .2 o oeCO @I!I 2 15 UC'5 C ~CC UO U C15' g U U'2 V 9 o 2 Z DCC' U U CC C' 1C3 C01' U " 15 C' S o Ua aC' UU Cr C' C 0 C' US C' 0) C@ S 0 C' DC S 0) .@. C UU U > ~V CC' 0 C' C U 2' V C 0 U 0a U 0 0 a V C 0 0 D.C -C2 C U CU ~@0 " C' "C 9 UC' 5 U) U'@ oa _EQ U C 0 .2 U' Ca DC C' ~@ 2' C'@ o C'"@C C'i@ a a 2'U q o@2 ZUa5 C' U V 0 U DC C' C' S Ca' C DC'. C'U Z 0 UC C' a a15 C'U C' .9 U UC' S~E +a 0 a C' .DC C'C 0.J 0 - U 0 U S C' UUU U DC DC DC zUzUUz Ua U C V C' 0 C'C'C' C'C'C' CCC S_S_S U C 0 U Ca' 0U a- .5 U C'O@ C' 0 C' Cr U ~C C' S DC8 C'. -JO) OaC.'! V C 0 C' C', DC C'C' CrCr UU OV ao C'U DC - 15-p 01,9 C' OS DC - aDC O-@)-CJ0C@' ~. Va C C'13 S@ 25 UU CO S-C 0 C'O CU U -J UC' 01@ 22 U E2 6 a a15 a@ OC' 00 CU UE IIC' Cr 00 C0 2 .9 CU C) a1U'.C' oe2 I coC@-@ z 001 <150-'- CC' E .2 -a -g@ U VOL.29, NO 3 MAY/JUNE1979 161 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @ @@0 @. .@ Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) @ @ @ @ @ @ @ @ 162 U 0a S I S t& E C 0 U U) UI 0 Oo U) !~o U 1!@ C0, U0i S. @~C 0. UI 0Z@cC'".. 4 I@ 4-C _i.__ U ZC .1 ~@ U C U) UI 0 0C 5C Z 40 ~I i 0 C 0 C' V C' C a C@ UC') C DC OCO C V CD O@ V-.@ h ~CC C'C CO C C) Ca' C U SU) OaCO" >0) C' DC2 CC' CO CO ,U C'0 015 0.5 CCO DCC' 5-6 C'DC U 0" U = C) C C'. O)C)0 C'V SC 0C'C' @C'E C'0 ~C C rU U a@c E2 O U >0 CO U) 0 DC C' 0 -J 0 DCI 0 0 C' C U) _I 15 ~U C @Cr 5 0z VC 40 0 1U@ U 0 o4Et 2C 02 a 2 C) 0 U aC' C@ V C) aC' U C) S -J C 0 a0 C) 0 -C C) 0 E C, E 0 C) C) C) C) C) C,) C) .5 C) .C 0 5C 0 C) ~0 0 C) C C C) DO U) C) ~C C 0) C) -c C C 0 0 C) C ~0 C) C) C) C) C C) C) .5 2 C ~53 .2 C ~." 000 0 C) C) ~. F-'. 45a" CA-A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) fore, oeexposureto any known or sus increase in the incidence of benign and pected carcinogen must be reduced to the malignant tumors in the same tissue lowest level possible by whatever means would underscore the eviden@e for carci available. 13'!.38 nogenicity of the test substance. Other oTlgEoIaVvevLfbnefe)Voeri:raf4Tac4rc3c3'assoi-,,htt32td--bs1kyoenn4'2ie,e-.rfm9aas,d'yo0p0topie-roo01ch0fthsvmh09htCht1el7yehCufotyn76loetyfsrralhsirrouaclhmbaeteembhbNenymmmiewesrnitIwltnmsnliOaihioysnzceeansiia,SiaesccnicdzoHhaleoienlnspb-s,SeoeaObsncutRSiiazbtareHielssnvcegn-Atiade(ieanssa(onttn2rtgcdyhf-eooeehncnrssaiseethssocclfoaisionn(raniTcscrlTttsilaavsonuuob)iiodaexnvldeeionscilinadgsbtavarpAmfhoicsedleeeeocimeeinfntvrzoes)iewtesameeieaeinyncacndnentesbsstiecadansisawnecAbmutfftsfdscealosmiicoleeesllceotrl.nppj.v'd4'ewtt4tfefpan2iocto3loooeebhtsarr-iunralrrf'se4tdlecittoioFdpc4suhdsifunhutmeiotrotolbIaiheettfogvillchraxvendirgeeoicsezpeifsnsugnroeloFmsselesarrsohlooumnpuioneoommpurrtaagfdehaeatnitlipo,nn,irttadrtohselatdiieennossortrDktnhhartp.htwaenrhruevtctaheothgoeetechrweooedetarcifoiebtccasoehraeeantcDinksisaescradntcpcsneoarceiliclibnnantpaseCibiltpcsnonntoireuuneosroogevneoh,fosyeintn 2-acetylaminofluorene Since it is difficult to determine the 4-aminodiphenyl oesafelevel of human exposure to any 4-nitrobiphenyl suspect carcinogen with any degree of benzidine and its salts confidence, the concepts of oeacceptable p -propiolactone risk and oerisk-benefit analysis are vinylchloride emerging in counterpoint to the issue of a chloromethylmethylether(CMME) oerisk-freeworkplace. In essence, this bis-chiorometheytlher(BCME) has been the philosophy of the Environ ethyleneimine mental Protection Agency, which is N-nitrosodimethylamine charged with enforcing the Toxic Sub stances Control Act of 1976. ~T@he Sub In a 1972-1974 survey conducted by committee on Environmental Carcino NIOSH, it was estimated that approxi genesis of the National Cancer Advisory mately one percent of the total work force, Board summarized the judgmental nature or 880,000 employees, were exposed to of risk-benefit analysis as follows: one or more of the 17 regulated carcin oetIhnose cases in which a compound ogens.'39 This estimate of exposure for has been proved to be carcinogenic re the total work force appears too low mains the decision to what extent the pos when compared with that reported recent sible risks to man are counterbalanced by ly for asbestos workers; namely, the De the possible social, economic or medical partment of Health, Education and Wel benefits of that substance. Scientists must fare stated that 1.5 to 2.5 million current play a major role in these decisions by ly employed workers may be exposed to providing and interpreting the available asbestos.'4 As shown in controlled stud data. The final decision, however, must ies in humans and/or laboratory animals, be made by society at large through in a chemical carcinogen increases the risk formed governmental regulatory and leg of cancer in relation to the duration and islative groups.4' intensity of exposure. The National Can OSHA has recommended that envi cer Advisory Board Subcommittee on En ronmental chemical carcinogens should vironmental Carcinogenesis' report sug be categorized generically, based upon gested that the occurrence of only benign the epidemiological and experimental evi neoplasms in experimental animals signi dence for tumorigenicity and mutagenici fied that the agent should be considered ty.'46 The assessment of risk to a commu oepaotential human health hazard which nity of workers and to society in general @ requires further A parallel goes beyond the application of criteria for VOL 29, NO 3 MAY/JUNE 1979 163 predicting human carcinogenicity. For ex ample, a priority for more stringent regu lation should be assigned on the basis of tumorigenic potency and number of workers exposed, particularly if a seem ingly safe substitute material could be in troduced. The socioeconomic consequen ces of complying with regulatory action is a separate but essential feature of the pro cess of decision-making.'47-'48 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) References 1. Higginson, J.: Population studies in cancer. Acta Unio mt. Contra Canc. 16:1667-1670,1960. 2. Higginson, J.: Present trends in cancer epi demiology. In: Proceedings of the 8th Canadian Cancer Conference. Honey Harbor, Ontario, Canada, 1969, pp. 40-75. 3. Fraumeni, J.F., Jr.: Genetic and environ mental factors in human cancer. In: Proceedings of the 5th International Congress on Human Genetics. Mexico City, Mexico, 1976, pp. 339- 346. 4. Fraumeni, J.F., Jr. (ed.): Persons at High Risk of Cancer: An Approach to Cancer Etiol ogy and Control. Proceedings of a Conference, Key Biscayne, Florida. New York: Academic Press, Inc., 1975. 5. Wynder, E.L., and Gori, G.B.: Contribu tion of the environment to cancer incidence: An epidemiologic exercise. J. Natl. Cancer Inst. 58:825-832, 1977. 6. Cole, P.: A population-based study of blad der cancer. In: Doll, R. and Vodopija, I. (eds.) Host Environment Interactions in the Etiology of Cancer in Man. Lyon, France: IARC Scien tific Publications No. 7, 1973, pp. 83-87. 7. Identification, classification and regulation of toxic substances posing a potential occupa tional carcinogenic risk. Prepared by the Occu pational Safety and Health Administration. In: Federal Register, Vol. 42 (No. 192), October 4, 1977. 8. Sigerist, HE.: Historical background of in dustrial and occupational diseases. Bull. N.Y. Acad. Med. 12:597-609, 1936. 9. Rosen, G.: The diseases of workers. In: A History of Public Health. New York: MD Pub lications, Inc., 1958, pp. 93-96. 10. Hunter, D.: The Diseases of Occupations. London, England: The English Universities Press, Ltd., 1974, pp. 24-35. 11. Pott, P.: Chirurgical observations relative to the cataract, the polypus of the nose, the cancer of scrotum, the different kinds of rup tures and the mortification of the toes and feet. London, England: Hawes, Clarke, & Collins, 1775. In: National Cancer Institute Monograph No. 10, 1962, pp. 7-13. 12. Potter, M.: Percivall Pott's contribution to cancer research. In: National Cancer Institute Monograph No. 10, 1962, pp. 1-5. 13. Doll, R.: Seventh Annual Walter Hubert Lecture: Pott and the prospects for prevention. In: Proceedings of the B.A.C.R. 16th Annual General Meeting, (Part III), 1975, pp. 263-272. 14. Shimkin, MB., and Triolo, V.A.: History of chemical carcinogenesis: Some prospective remarks. Progr. Exp. Tumor Res. 11:1-20,1969. 15. Cole, P., and Goldman, MB.: Occupation. In: Fraumeni, J.F., Jr. (ed.) Persons at High Risk of Cancer: An Approach to Cancer Eti ology and Control. New York: Academic Press, Inc., 1975, pp. 167-184. 16. Waxweiler, R.J.; Stringer, W.; Wagoner, J.K., and Jones, J.: Neoplastic risk among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci. 271:40-48, 1976. 17. Nelson, N.: The chioroethers "occupa tional carcinogens: A summary of laboratory and epidemiology studies. Ann. N.Y. Acad. Sci. 271:81-90,1976. 18. Fraumeni, J.F., Jr.: Respiratory carcino genesis: An epidemiologic appraisal. J. NatI. Cancer Inst. 55:1039-1046,1975. 19. Acheson, E.D.: Nasal cancer in the furni ture and boot and shoe manufacturing indus tries. Prey. Med. 5:295-315, 1976. 20. Archer, V.E.; GiIlam, J.D., and Wagoner, J.K.: Respiratory disease mortality among ura nium miners. Ann. N.Y. Acad. Sci. 271:280293, 1976. 21. Smoking and Health: Report of the Ad visory Committee to the Surgeon General of the Public Health Service. Washington, D.C. U.S. Department of Health, Education, and Welfare. 1964, pp. 19-21. 22. Levin, M.L.: The occurrence of lung can cer in man. Acta Unio mt. Contra Canc. 9:531- 541, 1953. 23. Susser, M.: Judgment and casual inference: Criteria in epidemiologic studies. Am. J. Epi dem. 105:1-15,1977. 24. Selikoff, Ii.: Lung cancer and mesotheli oma during prospective surveillance of 1249as bestos insulation workers, 1963-1974. Ann. N.Y. Acad. Sci. 271:448-456, 1976. 25. Pasternack, B.S.; Shore, RE., and Albert, R.E.: Occupational exposure to chloromethyl ethers: A retrospective cohort mortality study (1948-1972). J. Occup. Med. 19:741-746, 1977. 26. Vigliani, E.C.: Leukemia associated with benzeneexposureA.nn. N.Y.Acad.Sci.271: 143-151, 1976. 164 CA-A CANCERJOURNAL FORCLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) 27. McMichael, A.J.; Andjelkovic, D.A., and ditives and Pesticides. Toxicol. AppI. Phar Tyroler, H.A.: Cancer mortality among rubber macol. 20:419-438, 1971. workers: An epidemiologic study. Ann. N.Y. 45. Mantel, N., and Schneiderman, M.A.: Es Acad. Sci. 271:125-137,1976. timating oesafelevels, a hazardous undertak 28. Polednak, A.P.; Stehney, A.F., and Row ing. Cancer Res. 35:1379-1386, 1975. land, R.E.: Mortality among women first em 46. Guess, H.A.,and Crump, K.S.: Can we use ployed before 1930 in the U.S. radium dial animal data to estimate oesafdeoses for chem painting industry. Am. J. Epidem. 107:179-195, ical carcinogens? In: Whittemore, A. (ed.) En 1978. vironmental Health: Quantitative Methods. 29. Pasternack, B.S., and Shore, R.E.: Statis Philadelphia: SIAM, 1977, pp. 13-30. tical methods for assessing risk following ex 47. Guess, H.A.; Crump, KS., and Peto, R.: posure to environmental carcinogens. In: Uncertainty estimates for low-dose-rate extra Whittemore, A. (ed.) Environmental Health: polations of animal carcinogenecity data. Can Quantitative Methods. Philadelphia: SIAM, cer Res. 37:3475-3483, 1977. 1977, pp. 49-69. 48. Legator, M.S.: The need to detect chemi 30. Nicholson, W.J.: Case Study I: Asbestos cally induced mutations in experimental ani The TLV approach. Ann. N.Y. Acad. Sci. 271: mals. In: Sutton, H.E., and Harris, M.I. (eds.) 152-16199,76. Mutagenic Effects of Environmental Contami 31. Milham, S., Jr.: Methods in occupational nants. Fogarty International Center Proceed mortality studies. J. Occup. Med. 17:581-585, ings No. 10. New York: Academic Press 1972, 1975. pp. 67-79. 32. Gaffey, W.R.: A critique of the standard 49. MaIling, H.V.: Monitoring of chemical ized mortality ratio. J. Occup. Med. 18:157-160, mutagens in our environment. In: Sutton, 1976. H.E., and Harris, M.I. (eds.) Mutagenic Ef 33. Wong, 0.: Further criticisms on epidemio fects of Environmental Contaminants. Fogarty logical methodology in occupational studies. International Center Proceedings, No. 10. New J. Occup. Med. 19:220-222, 1977. York: Academic Press 1972,pp. 27-39. 34. Enterline, P.E.: Pitfalls in epidemiological 50. Legator, M.S.: Mutagenesis and its envi research. An examination of the asbestos liter ronmental implications. J. Occup. Med. 16: ature. J. Occup. Med. 18:150-156, 1976. 672-675, 1974. 35. Goldsmith, JR.: Mortality and industrial 51. Drake, i.W. et al.: Environmental muta employment. II. Industries with high mortality genic hazards. Science 187:503-514, 1975. among young workers based on a social security 52. Claxton, L.D., and Barry, P.Z.: Chemical sample. i. Occup. Med. 19:249-254, 1977. mutagenesis: an emerging issue for public 36. Kerr, P.S.: Recording occupational health health. Am. J. Public Health 67:1037-1042, data for future analysis. J. Occup. Med. 20: 1977. 197-203, 1978. 53. Ames, B.N.: A bacterial system for detect 37. Gamble, I., and Spirtas, R.: Job classifi ing mutagens and carcinogens. In: Sutton, cation and utilization of complete work histo H.E., and Harris, M.I. (eds.) Mutagenic Ef ries in occupational epidemiology. J. Occup. fects of Environmental Contaminants. Fogarty Med. 18:399-404, 1976. International Center Proceedings, No. 10. New 38. Gamble, iF., Spirtas, R., and Easter, P.: York: Academic Press, 1972, pp. 57-66. Applications of a job classification system in 54. McCann, J., and Ames, B.N.: Detection of occupational epidemiology. Am. J. Public carcinogens as mutagens in the Salmonella! Health 66:768-772, 1976. microsome test: assay of 300 chemicals: Dis 39. Principles for Evaluating Chemicals in the cussion. Proc. NatI. Acad. Sci. 73:950-954, Environment. A Report of the Committee for 1976. the Working Conference on Principles of Pro 55. McCann, J., and Ames, B.N.: A simple tocols for Evaluating Chemicals in the Environ method for detecting environmental carcino ment. Washington, D.C.: National Academy gens as mutagens. Ann. N.Y. Acad. Sci. 271: of Sciences, 1975. 5-13, 1976. 40. Eckardt, R.E.: Extrapolating from animals 56. Ames, B.N.; McCann, J., and Sawyer, C.: to man: carcinogenesis. J. Occup. Med. 18:492- Letter: Mutagens and carcinogens. Science 494, 1976. 194:132-133, 1976. 41. Principles for the Testing and Evaluation 57. Meselson, M., and Russel, K.: Compari of Drugs for Carcinogenecity. World Health sons of carcinogenic and mutagenic potency. Organization, Technical Report Series, No. In: Hiatt, H.H.; Watson, J.D., and Winsten, 426, 1969. J.A. (eds.) Origins of Human Cancer. Book C: 42. Magee, P.N.: Tests for carcinogenic poten Human Risk Assessment. Cold Spring Harbor tial. In: Paget, G.E. (ed.) Methods in Toxi Conferences on Cell Proliferation: Cold Spring cology. Philadelphia: F. A. Davis Company, HarborLaborator1y9,77p,p.1473-1481. 1970, pp. 158-196. 58. Miller, E.C.: Some current perspectives on 43.CornfielJd.:Carcinogenriicsakssessment.chemical carcinogenesis in humans and experi Scienc1e98:693-6919,77. mental animals: presidential address. Cancer 44. Food and Drug Administration Advisory Res. 38:1479-1496, 1978. Committee on Protocols for Safety Evaluation: 59. Sivak, A.: Letter: The Ames assay. Science Panel on Carcinogenesis. Report on Cancer 193:272-274,1976. Testing in the Safety Evaluation of Food Ad 60. Harris, C.C.; Saffiotti, U., and Trump, VOL29,NO 3 MAY/JUN1E979 165 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) B.F.: Carcinogenesis studies in human cells and 77. Viola, P.L.; Bigotti, A., and Caputo, A.: tissues. Cancer Res. 38:474-475, 1978. Oncogenic response of rat skin, lungs and 61. Selikoff, I.i.; Churg, i., and Hammond, bones to vinyl chloride. Cancer Res. 31:516- E.C.: Asbestos exposure and neoplasia. JAMA 522, 1971. 188:22-26, 1964. 78. Van Duuren, B.L. et al.: Alpha-haloethers: 62.SelikofIf.,J.H;ammond, E.C.,andChurg, a new type of alkylating carcinogen. Arch. En J.: Asbestos exposure, smoking and neoplasia. viron. Health 16:472-476, 1968. JAMA 204:106-112,1968. 79. Laskin, S. et al.: Tumors of the respiratory 63. Asbestos. In: IARC Monographs on the tract induced by inhalation of bis (chlorometh Evaluation of the Carcinogenic Risk of Chem yl) ether. Arch. Environ. Health 23:135-136, icals to Man. Vol. 14, Lyon, France: IARC, 1971. 1977. 80. Figueroa, W.G.; Raszkowski, R., and 64.Lloyd,i.W.:Long-termortalitsytudyof Weiss, W.: Lung cancer in chloromethyl meth steelworkers V. respiratory cancer in coke plant yl ether workers. N. Engl. J. Med. 288:1096- workers. J. Occup. Med. 13:53-68, 1971. 1097, 1973. 65. Certain Polycyclic Aromatic Hydrocarbons 81. Sakabe, H.C.: Lung cancer due to exposure and Heterocyclic Compounds. In: IARC to bis (chloromethyl) ether. Ind. Health 11:145- Monographs on the Evaluation of the Carcino 148, 1973. genic Risk of Chemicals to Man. Vol. 3, 1973. 82. Walpole, A.L. et al.: Cytotoxic agents. IV. Lyon, France: IARC, 1973. The carcinogenic actions of some monofunc 66.Some AromaticAmines,Hydrazineand tionaelthyleneimidneerivativBers.J.Phar @ Related Substances, -nitroso Compounds macol.Chemo.9:306-32139,54. and MiscellaneouAslkylatinAggents.In: 83. Magee, P.N., and Barnes, J.M.: The pro IARC Monographson theEvaluatioonf the duction of malignant primary hepatic tumours CarcinogeniRciskofChemicaltsoMan. Vol. in the rat by feeding dimethylnitrosamine. Br. 4, 1974.Lyon, France: IARC. .1.Cancer10:114-12129, 56. 67.Key,MM. eta!.O:ccupationadliseaseas: 84. Some Inorganic Substances, Chlorinated guide to their recognition. NIOSH (DHEW), Hydrocarbons, Aromatic Amines, N-Nitroso 1977. Compounds, and Natural Products. In: IARC 68. Searle, CE.: Chemical carcinogens. Wash Monographs on the Evaluation of the Carcino ington, D.C.: American Chemical Society, genic Risk of Chemicals to Man, Vol. 1. Lyon, 1976. France: IARC, 1972. 69. Case, R.A.; Hosker, M.E.; McDonald, 85. Aksoy, M. et al.: Haematological effects D.B., and Pearson, J.T.: Tumors of the urina of chronic benzene poisoning in 217 workers. ry bladder in workmen engaged in the manu Br. J. Ind. Med. 28:296-302, 1971. facture and use of certain dyestuff intermedi 86. Aksoy, M. et al.: Acute leukemia due to ates in the British chemical industry. I. The role chronic exposure to benzene. Am. J. Med. 52: of aniline, benzidine, alpha-naphthylamine and 160-166, 1972. beta-naphthylamiBnre..J. IndustM.ed. 11: 87. Some Anti-Thyroid and Related Substan 75-104, 1954. ces, Nitrofurans and Industrial Chemicals. In: 70. Conzelman, G.M., Jr., and Moulton, J.E.: IARC Monographs on the Evaluation of the Dose-response relationships of the bladder Carcinogenic Risk of Chemicals to Man, Vol. tumorigen 2-nahthylamine: a study in beagle 7, 1974. Lyon, France: IARC. dogs. i. NatI. Cancer Inst. 49:193-205, 1972. 88. Falk, H.L., and Steiner, P.E.: The identifi 71. Melick, W.F. et al.: The first reported cases cation of aromatic polycyclic hydrocarbons in of human bladder tumors due to a new carcino carbon blacks. Cancer Res. 12:30-39, 1952. gen"xenylamine. i. Urol. 74:760-766, 1955. 89. Doll, R. et al.: Mortality of gasworkers 72. Melick, W.F.; Naryka, J.J., and Kelly, finarleporotfa prospectisvteudyB.r.i.Ind. RE.: Bladder cancer due to exposure to para Med. 29:394-406, 1972. aminobiphenyl: a 17-year follow-up. J. Urol. 90. Kipling, M.D., and Waldron, HA.: Poly 106:220-226, 1971. cyclic aromatic hydrocarbons in mineral oil, 73.Bonser,G.M.; Clayson,D.B.,and Jull, tar and pitch, excluding petroleum pitch. Prey. i.W.: The induction of tumours of the subcu Med. 5:262-278, 1976. taneous tissue, liver and intestine in the mouse 91. Weil, C.S.; Smyth, HF., Jr. and Nale, by certain dyestuffs and their intermediates. T.W.: Quest for a suspected industrial carcino Br. J. Cancer 10:653-667, 1956. gen. AMA Arch. Ind. Hyg. 5:535-547, 1952. 74. Walpole, AL., and Williams, M.H.: Aro 92. Allen, J.R.: Response of the nonhuman matic amines as carcinogens in industry. Br. primate to polychlorinated biphenyl exposure. Med. Bull. 14:141-145,1958. Fed. Proc. 34:1675-1679,1956. 75. Anthony, H.M. et al.: Tumors of the uri 93. Ito, N. et al.: Histopathological studies on nary bladder: An analysis of the occupations liver tumorigenesis induced in mice by technical of 1,030 patients in Leeds, England. J. NatI. polychiorinated biphenyls and its promoting Cancer Inst. 46:1111-1113, 1971. effect on liver tumors induced by benzene hexa 76. Chernozemski, I.N., and Warwick, G.P.: chloride. J. Natl. Cancer Inst. 51:1637-1646, Production of hepatomas in suckling mice after 1973. single application of propiolactone. J. Natl. 94. Kimbrough, RD., and Linder, RE.: In Cancer Inst. 45:709-717, 1970. duction of adenofibrosis and hepatomas of the 166 CA-A CANCERJOURNAt FORCLINICIANS Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) liver in BALB-cJ mice by polychlorinated bi and accessory sinuses in England and Wales. phenyls (Aroclor 1254.) J. Natl. Cancer Inst. Br. J. md. Med. 29:21-30, 1972. 53:547-552, 1974. 111.AchesonE,.D.;CowdellR,.H.,andJolles, 95. Kimbrough, R.D. et al.: Induction of liver B.: Nasal cancer in the Northamptonshire boot tumors in Sherman strain female rats by poly and shoe industry. Br. Med. J. 1:385-393, 1970. chlorinated biphenyl Aroclor 1260. J. Natl. 112. Lee, A.M., and Fraumeni, J.F.: Arsenic Cancer Inst. 55:1453-1459,1975. and respiratory cancer in man: An occupational 96. Lloyd, J.W.; Moore, R.M., Jr.; Woolf, study. J. Nail. Cancer Inst. 42:1045-1052, 1969. B.S., and Stein, H.P.: Polychlorinated biphen 113. Oh, M.G.; Holder, B.B., and Gordon, yls. J. Occup. Med. 18:109-113, 1976. H.L.: Respiratory cancer and occupational ex 97. Allen, J.R., and Norback, D.H.: Carcino posure to arsenicals. Arch. Envir. Health 29: genic potential of the polychlorinated biphen 250-255, 1974. yls. In: Hiatt, H.H.; Watson, J.D., and Wins 114.Axelson,0.; Dahlgren,E.; Jansson, ten, J.A. (eds.) Origins of Human Cancer. C.D., and Rehnlund, S.O.: Arsenic exposure Cold Spring Harbor Conferences on Cell Pro and mortality: A case-referent study from a liferation: Cold Spring Harbor Laboratory, Swedish copper smelter. Brit. J. Ind. Med. 35: 1977,pp. 173-186. 8-15, 1978. 98. Some Organochlorine Pesticides. In: IARC 115. Mancuso, T.F., and Hueper, W.C.: Oc Monographs on the Evaluation of Carcino cupational cancer and other health hazards in a genic Risk of Chemicals to Man, Vol. 5, 1974. chromate plant: A medical appraisal. I. Lung Lyon,FranceI:ARC. cancers in chromate workers. Ind. Med. Surg. 99.Case,R.A.,and PearsonJ,.T.:Tumorsof 20:358-363, 1951. the urinary bladder in workmen engaged in the 116. Davies, J.M.: Lung cancer mortality of manufacture and use of certain dyestuff inter workers making chrome pigments. Lancet I: mediates in the British chemical industry. Part 384, 1978. II. Further consideration of the role of aniline 117. Some Inorganic and Organometallic and of the manufacture of auramine magenta Compounds. In: IARC Monographs of the (fuchsine) as possible causative agents. Br. J. Evaluation of the Carcinogenic Risk of Chem Ind. Med. 11:213-216,1954. icals to Man, Vol. 2, Lyon, France: IARC, 100. Rehn, L.: Blasengeschwulste bei uchinar 1973. beiteren. Arch. KIm. Chir. 50:588-600, 1895. 118. Boyd, J.T. et al.: Cancer of the lung in 101. Zil'fan, V.N.; Fichidzhian, VS., and Po iron ore (haematite) miners. Br. J. Ind. Med. gosova, A.M.: Rezul'taty: Zuchenia khloro 27:97-105, 1970. prena na kantserogehnost, ~zhE.ksp. KIm. 119.Faulds,J.S.,and StewartM,.J.:Carci Med. 15:54-5179,75. noma of the lung in haematite miners. J. Pathol. 102.Infante,P.F.;Wagoner,J.K.,andYoun7g2,:353-36169,56. R.J.: Chloroprene: Observations of carcino 120. Lollinger, H. U.: Durch chronische Bleive genesis and mutagenesis. In: Hiatt, H.H.; giftung erzeugte Nierenadenome und carci Watson, J.D., and Winsten, J.A. (eds.) Origins nome beiRattenund ihreBeziehungeznuden of Human Cancer. Cold Spring Harbor Con entsprechenden Neubildungen des Menschen. ferences on Cell Proliferation: Cold Spring Virchows Arch. 323:694-710, 1953. Harbor Laboratory, 1977, pp. 205-217. 121. Van Esch, G.J.; Van Genderen, H., and 103. Lloyd, J.W.; Moore, R.M., Jr., and Bres Vink, H.H.: The induction of renal tumors by lin, P.: Background information on trichloro feeding of basic lead acetate to rats. Br. J. Can thylene. J. Occup. Med. 17:603-605, 1975. cer 16:289-297, 1962. 104. Eschenbrenner, A.B.: Studies on hepato 122. Doll, R.: Cancer of the lung and nose in mas. I. Size and spacing of multiple doses in nickel workers. Br. J. Ind. Med. 15:217-223, the induction of carbon tetrachloride hepa 1958. tomas. J. NatI. Cancer Inst. 4:385-388, 1944. 123. Sunderman, F.W., Jr.: Nickel carcino 105. Eschenbrenner, A.B., and Miller, E.: In genesis. Dis. Chest 54:527-534, 1968. duction of hepatomas in mice by repeated oral 124. Nelson, A.A.; Fitzhugh, 0.0., and Cal administration of chloroform with observa very, H.O.: Liver tumors following cirrhosis tions on sex differences. J. NatI. Cancer Inst. caused by selenium in rats. Cancer Res. 3:230- 5:251-255, 1945. 236,1943. 106. Report on bioassay of 1,2 dichloroethane 125. Ionizing Radiation: Levels and Effects. for possible carcinogenecity. In: Federal Regis A Reportof the UnitedNationsScientific ter, Vol. 43 (No. 187), 1978, p. 43564. Committee on the Effects of Atomic Radia 107. NIOSH. A recommended standard for tion, to the General Assembly. New York: acrylonitrile, 1977. United Nations, 1972. 108. Wada, S. et al.: Mustard gas as a cause of 126. The Effects on Populations of Exposure respiratory neoplasia in man. Lancet 1:1161 to Low Levels of Ionizing Radiation. Report 1163, 1968. of theAdvisoryCommitteeon theBiological 109. Heston, WE.: Carcinogenic action of the Effects of Ionizing Radiations. Washington, mustards. J. NatI. Cancer Inst. 11:415-423, D.C.:NationaAlcademyofScienceIs9,72. 1950. 127. Waterman, N.: Observations on the car 110. Acheson, E.D'.; Cowdell, R.H., and cinogenic effect of ultra-violet rays of different Rang,E.:Adenocarcinomoafthenasalcavity wavelengths on the skin of mice with some re VOL 29, NO 3 MAY/JUNE1979 167 Downloaded from caonline.amcancersoc.org by guest on February 22, 2007 (American Cancer Society, Inc.) marks on carcinogenesis. Geneesk. BI. 50:297- 347, 1963. 128. Cohn,S.H.;Skow,R.K.,andGong,J.K.: Radon inhalation studies in rats. Arch. Ind. Hyg. 7:508-515, 1953. 129. Cember, H.: Radiogenic lung cancer. Progr. Exp. Tumor Res. 4:251-303, 1964. 130. Dc Villiers, A.J., and Windish, J.P.: Lung cancer in a fluorospar mining community. I. Radiation, dust and mortality experience. Br. J. Ind. Med. 21:94-109, 1964. 131. Seltser, R.: Lung cancer and uranium mining: A critique. Arch. Environ. Health 10: 923-936, 1965. 132. Wagoner, J.K. et al.: Radiation as the cause of lung cancer among uranium miners. N. Engl. J. Med. 273:181-188, 1965. 133. Lundin, F.E., Jr. et at.: Mortality of ura nium miners in relation to radiation exposure, hard rock mining and cigarette smoking: 1950 through September, 1967. Health Phys. 16:571- 578, 1969. 134. Munn, A.: Extrapolation of experimental carcinogenecity to the reality of industrial ex posure. Ann. Occup. Hyg. 15:75-81, 1972. 135. Howe, H.F.: Organization and operation of an occupational health program. J. Occup. Med. 17:(Part 1) 360-400; (Part II) 433-445, 1975. 136. Rose, V.E.: Standards for the control of carcinogens in the workplace. J. Occup. Med. 18:81-84, 1976. 137.Fairchild, E.J., II: Guidelines fora NIOSH policy on occupational carcinogenesis. Ann. N.Y. Acad. Sci. 271:200-207, 1976. 138. Estimates of the Fraction of Cancer in the United States Related to Occupational Factors. Report prepared by the National Cancer Insti tute, the National Institute of Environmental Health Sciences and National Institute for Occupational Safety and Health, September 15, 1978. 139. Burnham, D.: U.S. study finds one in 4 workers exposed to hazards. The New York Times, October 3, 1977,p.22. 140. HEW News. National Institutes of Health, Office of Cancer Communications. August 8, 1978. 141. General criteria for assessing the evidence for carcinogenicity of chemical substances. Report of the Sub-committee on Environmental Carcinogenesis, National Cancer Advisory Board. J. NatI. Cancer Inst. 58:461-465, 1977. 142. Epstein, S.S.: Regulatory aspects of occu pational carcinogens: Contrasts with environ mental carcinogens. Lyon, France: IARC Sci. PubI. 13:389-402, 1976. 143. Lijinsky, W.: U.S. health will be jeopar dized if Delaney Clause is abandoned. Chem ical and Engineering News, June 27, 1977, pp.25-33. 144. Coulston, F.: Tolerance levels can be set for chemical carcinogens. Chemical and En gineering News, June 27, 1977, pp. 34-37. 145. Albert, R.E.; Train, R.E., and Anderson, E.: Rationale developed by the Environmental Protection Agency for the assessment of carci nogenic risks. J. Nail. Cancer Inst. 58:15371541, 1977. 146. OSHA announces proposed cancer policy. Amer. Ind. Hyg. Assoc. J. 38:24-29, 1977. 147. Pochin, E.E.: The acceptance of risk. Br. Med. Bull. 31:184-190, 1975. 148. Lee, W.R.: Some ethical problems of haz ardous substances in the working environment. Br. J. Ind. Med. 34:274-280, 1977. 168 CA-A CANCERJOURNAL FORCLINICIANS