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IIIIRBEKT E. STOKlfl('IER, Ph.D. t h r e a u of Occupational Safety and Health, DIiEW This year marks the 25th anniversary of the and animal toxicity data of which it is difficult to appearance of the first list Threshold Limit Values find the equal. (TLVs).It would seem appropriate a t this quarter- century mark to evaluate not only what has been accomplished, but to define those problems that still remain, in an effort toovercome the problems The problem of data acquisition arid to improve the limits and make them more Thus we have the requisite group to handle the generally useful and effective. data and recommend limits, butwhy, in the face of several hundred new products placed on the Committee activities and related problems market annually, is the TLV Committee able to establish annually only two dozen or so limits for new substances? These relative figuresp o h t up The TLV Committee h a s two major activities: the greatest problem facing the Committee: The development ofTLVs a n d validation ofTLVs. Most, acqiiissltion of indrcstrial hygiene data of the ap- but not all, of the problems stem from these two propi-late type to develop TLVs on new substances. activities. Other problems arise from the misuse a n d mishandling of the TLVs by government agen- \f cies (military) or by the legal profession, by coinpany representatives (salesmen)and s o m e iridustrial hygienists who have not yet got the coniplrte The TLVs are industrfs values. But industry `Wneraliy does not near enoudJ oefstkaibnldi.sshai.nnda amounts of data that can be aTLVofa new substance. Rut us& r industry message. lias the sole responsibility to develoD data on ib p c n products: uovernm ent is not in a Dosition to dC W P uUcih facilities to handle the Droblem in Composition of TLV Committee fgtdi. nor should it, when re- icoloaic con- Because there has been s o m e question in the sultants are now available. minds of s o m e physicians on the conlpositicin and fitnessoftheTLVCommittee,it is important at the outset to identijl the professional standing and activities of i t s members. Of the 14-man committee: physicians, five (one representing Canada);industrial hygienists, toxicologists, eight could be counted here; industrial hygiene engineers, two;analytic chemists, three: pathologists, one. The record clearly shows this.'" 1 made a review of the situation in 1965 and found that in all Amencan chemical industry onlyseven companies have made significant contributions to basic data for TLVs of new substances. Of these seven, only two made major contributions; o n e company made what might be considered a significant but modest contribution, and four made only minor contributions. This is a pathetic situation when Most are individuals of national repute, several o n e realizes the dire need. There is n o question have international reputations, but probably more that inability t o obtain industrial hygiene data is important, many of the committee have a b x k - one of the greatest problems facing the committee ground of long experience in occupational hcnltli, today. and still more important, several are actively en- gaged daily in evaluating plant situations - and note also, membership is derived from the niost highly industrial states. To my mind the accwnulated background and experience of this cornniit- ' Read before the 28th Anriual AMA Congress on OccLlpa- tional Health, October 1, 1968,New York. Published in Arch. Etiu. /!earth 19277-281 (August 1969).Reprinted by pcrmission of the Americarl Pledical Association, tee provides a perspective in occupational health i 1969. i Thirty-fiveYears of TLVs TABLE I Distribution of Procedures Used to Develop or Validate ACGlH TLVs through 1968' Procedure No. Ob 7 o t a I Industrial (human)experience 157 38 Human volunteer experiments 45 11 Animal, inhala tion-chronic 83 20 Animal, inhalation-acute 82 Animal, oral-chronic 18 4.5 Animal, oral-acute 2 0.5 Analogy 101 24 ~~ * For 414 substances exclusive of "inert"particu1ates a n d vapors Types and kinds of data that industry can supply Perhaps a glanceatthe procedures used todate to develop TLVs will be helpful in seeing what kinds of data industry can supply to help solve the problem of data lack. In Table 1, I have determined the distribution of the procedures used for TLVs of 414 substances appearing in the 1968 list. It can be seen that industrialplant experience (medicalsurveillance, epidemiologic studies),led the listwith 38%.Here is a place that the industrial plant physician can be of real help in supplying data through good medical records, but only if combined with slrnuitaneouslg obtained enulroninental data. But note this type of plant data is most advantageous in validating a limit already set - rarely are the work conditions sufficiently stable to furnish data to initiate a limit (A few notable exceptions a r e butyl alcohol,acetone, and mercury.) Here the Industrial Hygiene Foundation's Repository of Anonymous Data can be of help; it is questionable whether any TLVs will result from the AMA registry. Humanvolunteer exposures (line2,Table I) are becoming increasingly popular of late. They are invaluable for arriving a t a n estimate of sensory (organoleptic) responses, irritants and narcosisproducing agents - substancesfor which animals just can't supply the answer. The procedure has lesser application for long-acting cumulative substances. For the fast actingsubstances, irritants et alia, exposures may be brief, a matter of a few hours. They should be repeated, however,with sufficient frequency to determine whether tolerance of sensitivity is a feature of the exposure. It has been the experience of the committee that TLVs of irritants e t alia,based o n single human exposures, all too commonly result in far too severe limits. The third listed procedure, chronic animal inhalation Lauldty, represents the crucial procedure about which this report is mainly developed. H e r e is the start in acquiring the basic data from which the TLV for new substances stems. This is the category from which the committee most needs data, and which is in the shortest supply. The data a r e in short supply because industries either do not develop long-term studies, o r if they do, more often than not do not see fit to release the data in the open literature. Various reasons a r e given for this: legal protection oftheir products, lack ofstaff time t o put data in publishable form. Whatever the reason, the data are not forthcoming. Validation of TLVs Since i t s inception, the TLV Committee h a s had the policy of reviewingannually the listed values: if new information coming to the attention of the committee indicated the need for change, such changes were proposed in a separate tentative listing. Here they remain for a period ofat least two years before being placed in the recommended list. Since 1963, deeper scrutiny h a s been made into t h e suitability of the limits. The list of substances that have been given o r are being given special and rather extensive scrutiny is shown in Table 11. Procedures used by the committee take three krms: A.The chairman and members of the appropriate subcommittee hold a meeting with i n d u s w s physicians and industrial hygienists and review their experience. This procedure is used where the data h a s not been assembled or published. This procedure has been used for the TLVs for the 4.chromate industry and the nitroglycols. Where the data o r reports have been published, these are reviewed by the chairman and the committee and the action taken is that mutually agreed upon by industry and American Conference ofQovernmental Industrial Hygienists by letter correspondence. This procedure has been used for beryllium, quartz, uranium, and vanadium pentoxide. Page 172 Ann. Am. Conl. Ind. //!/g., io/. 9 ( 1 9031 Stokinger: Current Problems of Setting Occupatiortal Exposure Standards TABLE I1 Substances Validated for TLV or Undergoing Validation Since 1963 Validated. In Process Beryllium Asbestos (all forms) Carbon monoxide Benzene Chromates & chromic acid Carbon disulfide Cristobali te Fibrous glass Ni troglycols Isocyanates Quartz Tetraethyl lead Uranium Tetramethyl lead ?Vanadium pentoxide? Petroleum distillates * By committee action. 3. Active cooperative projects with industry a n d toxicology a n d pathology section of the occupational health program (OHP) are entered intowhereby industry supplies the health records o r clinical data for review, o r active toxicologic research investigations a r e made by OHP in conjunction with clinical a n d environmental data obtained by industry. Such is being done cooperativelywith a large producer of isocyanates to determine means of detecting the hypersusceptible worker, a side bonus ofwhichwill be thevalidation ofthe TLVfor the isocyanates. A similar study is being cooperatively made of carbon disulfide. To give a clearer idea of how these validation procedures work, a most productive day's meeting was held with industrial physicians and hygienists ofthe chromate industry. The reason for selecting the chromate industry was that n o evidence of the suitability of the TLV for choromic acid o r chromates had ever been brought forth for the prevention of either nasal perforation o r bronchogenic carcinoma.All environmental levels had exceeded the recommended limit of 0.1 mg/cu mi when large excesses (29-fold)of lung cancer and nasal perforation were found in 1950, and the health experience had not been reviewed in these terms since the industry had improved i t s control measures to the recommended limit. In brief, the day's discussion revealed that the limit for chromic acid mist was satisfactory In preventing nasal perforation, a n d in addition contained a safety factor of three o r four; that the limit was probably satisfac- tory for the prevention of lung cancer, as n o new cases have appeared since the reduction in exposure occurred, but that the ten years in which the closer contrds were operative are probably too short a time to be certain its validity in this respect. In a similar meetingwith representatives of the dynamite explosives manufacturing industry, a question of a n improperly stated TLV for intermittent exposure to ethylene glycol dinitrate and nitroglycerin was resolved to the mutual satisfaction of each of the parties. Statements derived from the long experience of the medical directors of the companies that normally would never get to the attention of the committee were elicited in amicable discussions. -In regard to substances in the process ofvalida- tion, I can mention three asbestos, carbon disulfide, and isocyanates -that represent exten- sive, cooperative efforts by both industry a n d the PHS Occupational Health Program, and five substances that represent purely unsolicited effortsof industry to develop information on a valid TLV (benzene,fibrous glass, tetraethyl and tetramethyl lead and petroleum distillates). From these cooperative ventures and the increasing number of voluntary efforts of industry itself to validate s o m e of the more controversial limits, we see a n encouraging trend. More and more, industries are developingimpressive industrial medical departments. More and more, industries are either establishing their own toxicology laboratories or purchasing toxicologic studies from a rapidly expanding number of commercial toxicity testing laboratories. More than 50 of these are available, exclusive of university sources. Not more than a half-dozen are presently sufficientlywell equipped t o d o first rate long-term inhalation studies. Industrial associations, theAmerican Petroleum Institute, Lead Industries Association, American Welding Association, Automobile-Manufacturers' Association, among others, now have large research programs directed toward supplying data in support of safe limits of their sponsors' products. In addition,one can discern among i n d u s w s medical departments a keener interest in solving industrial hygiene and toxicology problems. Ann. Am. Conl. Ind. Hyg., Vol. 9(1984) Page 173 Thirty-five Years of TLVs These broadened activities of industry would s e e m to relieve considerably the problem of data lack mentioned earlier. But closer inspection of the type of data being developed indicates that present efforts a r e directed to the validation of limits already established; little progress has been made toward a freer access of the committee to information or, newly introduced industrial chemicals.This problem the committee still has with it. The problem of misinterpretation of TLVs Another vexing committee problem arises from the misinterpretation a n d misuse of the TLVs. Particularly culpable are the factory inspector and the legal profession. Their common fault lies in misinterpreting the TLVs a s fine lines between safea n d dangerous concentrations "either it is,o r it isn't" phenomenon. Such strict interpretation is not within the intent expressed in the preface to the TLVs, a n d places industry in undue jeopardy. Such misinterpretation fails to take into consideration that with few exceptions, the TLV is a timcweighted average value which permits excursions above the limit provided equivalent excursions below the limit occur. Thus, a single, or even several, concentrations monitored above the limit is not ipso facto evidence of injury.The reason this is so is that the TLV has a n inherent safety zone between the limiting value and the concentration capable of producing injury. Despite the fact that such principles have been clearly stated for many years in the annually issued TLV booklet, they have been commonly ignored. Recently, however, the development of short-term limits (Pennsylvania),ceilingvalues,and the concept of "peak' concentrations (USASI, 2-37 Committee)introduce into the picture the concept of variable permissiveness that is incompatible with the interpretation of a limit below which all values must fluctuate for the prevention of injury. Misapplication and misuse Misunderstanding on the relationship between TLVs and short-term exposures has on occasion come to the attention of the committee. I n attempting to arrive a t a short-term community exposure limit for beryllium, the Air Force suggested a limit of 750 pg-min/cu m for a single exposure. This was presumably derived froin t laber's Kule, C X t = K, using the Atomic E n e r p Conimission-recommended Implant limU 25pg/cu m for periods not to exceed 30 minutes. But the permissible CCvalue for community exposures is about 43 pg-min/cu m. Hence the 750 p g limit is considered dangerously excessive. In another instance, attempts by the Navy to obtain short-term exposure limits, the suggestion was made to multiply the TLV by 10 'lacross-theboard." This is not considered good practice because s o m e substances do not follow Haber's rule and high concentrations for brief periods are more toxic than equivalent exposures a t low concentrations, i.e., Ct is not always constant. Other misapplications Misuse of theTLVs as a measure of comparative toxicity - frequently used by industws salesmen to prove the virtues of their products over a competitor's gives the committee frequent headaches. U s e ofTLVs for comparative toxicity is permissible only when metabolism of the compared substances is similar. In most cases, however, either the metabolisms differ, o r they a r e unknown. In addition, the bases ofTLVs for different substances differ; not all TLVs are based on toxicity. A striking exarnple of t h e erroneousness of such a comparison is that of hydrogen cyanide (HCN),TLV 20 ppm, with sulfur dioxide (SO:!), TLV, 5 ppm. The TLVs indicate that SO:! is more toxic than HCN, which is ostensibly ridiculous! The reason is of course that the TLV for SOZis based not on health cffectsa s is HCN, but on irritation. -Future problems TLVs vs community air limits Perhaps o n e of the problems ofgreatest concern in the committee's future is how to reconcile to the satisfaction of chemical labor union leaders, unions workers, their wives and families, the often large discrepancies in the TLVs for those s u b stances in industry that are to appear (andare now appearing) a s community air limits. How to explain, for example, that when a community has a limit for lead in air of 5 pg/cu m (Pennsylvania) that is all right for their "boys" t o breathe 40 times this amount for theirworking lifetime in industrial plants? It is doubtful that the rational bases for the differences can be made sufficientlyconvincing to Page 174 Ann. Am. Cunf. Ind. tjyg.. Vul. 9119811 Stokinger: Current Problems of Setting Occupational Exposure Standards 4 be generally accepted - any more that the rationale for fluoridation has met with genetal acceptance. Legalization of industrial air standards Although it particularly difficult in these days of federal reorganizations t o be a prophet of "the s h a p e of things t o come," it might be worthwhile to try to foresee what problems will exist when the Occupational Health and Safety Act (or s o m e similar act) is m a d e into law. As the act is now written, the Department of Labor (USDL) will s e t standards for industrial air upon the counsel of an advisory committee. The present Occupational Health Program in the National Center for Urban and Industrial Health will establish the criteria on which the standards will be based. Because the standards will be "consensus'' standards, it is probable that neither t h e recommendations of the TLV Committee or those of the [JSASI, 2-37 Committee will be given "carte blanche" accep- tance. Being consensus standards, the dominant philosophy and voice of government may be less clear than in the past (the USASI Committee, dominated by industrial representatives, and whose findings are adopted now by USDL, presently attempts to attain a consensus from the scientific community). What the future problems will be, will be determined largely by how broad a cons e n s u s will be required, which in turn will determine the breadth of the advisory comrnlttee. Whether the presently constitued TLV a n d 2-37 Committees will continue to function in their present capacity s e e m s t o me problematic. The old problem of data acquisition, however, could be made easier if substantial government funds are made available to the Occupational Health Program to develop industrial hygiene data o n a broad basis. Reference 1. Stoklnger, H.E.: Industrial Contribution to Threshold Limit Values. Arch. Eiiu. Ileallh 10:609 (April 1965). Ann. Am. Conl. Ind. Hyg., Yof. 9 11985) Page 175 Thirty-five Yeni5 of TLVs animals but would be impossible t o detect, with our present techniques, in the human subject. Clinical observations The broader the base of the clinical investigation which is associatedwfth a finding of n o injury or n o significant injury a t a particular exposure level,the greater the reliability of the conclusion. To the critical investigator, however, the job is never complete, never without s o m e area in the study which could not have been strengthened or improved. The period of the study can extend into many years, and yet the end point can remain uncertain. -As other techniques a r e added to the evaluation program such a s studies of morbidity and absenteeism, reasons for dispensary visits, and analysis of cause of death - the problem of in- terpretation becomes increasingly complicated. An example may be cited in which two yo~irig women employees in the s a m e small department developed leukemia within a few months of each other. This occurrence was readily accepted as a chance finding because both girls had clerical positions with n o possible exposure t o an industrial toxin. Had this occurred following a common exposure, however brief o r minor, to a new chemical with a long a n d unfamiliar name, it is quite likely that medical testimony would have been developed, in a Workmen's Compensatioti hearing, attributing the disease to the exposure. T h e effect of the incident might well have extended beyond the cost of compensation a n d into the area of threshold limits by the publication of a case report. A fine discretion is required in recognizing the first o r isolated instances of injury to a new chemcial a n d yet avoiding the inclusion of cases solely on legal o r social motivation. In a study of the long-term effects of a solvent, records were kept of t h e causes for dispensary visits.Aslightly higher incidence ofgastrointestinal complaints was found in the exposed group, and since this had been reported previously bq others, it seemed significant However, the incidence of respiratory complaints was as much lower for the exposed individuals. In a n interpretation, it would have been equally proper to assume that the solvent vapors "protected"the individuals against respiratory disease, and that this beneficial efiect might offset the gastrointestinal difficulties. A s n?ight be suspected, when these relations were put to the test of statistical significance, both could have been d u e easily t o change alone. A final word is in order concerning the methods for developing data by which the environment is described - the conditions of exposure. As much variability can be, and is, encountered with this function as with the methods for laboratory experimentation and in-plant clinical examinations. The accuracy a n d reliability of the analytical techniques, the relation ofthe timeand site of sampling to the true exposure, the presence of other agents which might modify the single action of the toxin under study are s o m e of the many factors which must be critically examined in the light of their usefulness for correlation with a given s e t of experimental or clinical findings. It is obvious that there is n o single method or pattern of methods which can satisfy the varied requirements for establishing threshold limits. It is equallyobvious that even though rigid slandards were described which would satisfy a discrimi- nating jury of scientists, the available data for cstablishing threshold limits for all but a very few substarices would fail to satisfy s u c h limits. The real iisc for threshold limits, as a guide for industry i n tfie control of exposures and a s a measure for action by governmental agencies,demandsa con- tinuingimprovement in the quality and quantity of t h t riletliods by which truly valid criteria may be achieved. -- - < i* Prepared discussiont --I '-4 HERGERT E. STOKINGCR,Ph.D. Chief. Toxicologlcal Services, U S . Public Health Service Dr. Sterner has discussed the great dificulties attendant on developing adequate data for thres- + [>I. Stoltinger's discussion of the establishment of tliresholtl liniits appeared Immediately followirig Dr. Steiner's p::jwr on the same subject in Am. Itid. Ihjg. Assoc. Q. I 7:2H4-2RF (1956).l o keep the continuity of the subject it \%,;.IdSccidcd to break frorn tradition in tttlsvol~rrntarid b q i n this discussion in tfie same riianrier as tlie A I I M Q . Page 08 Stokinger: Prepared Discussion hold limits, the many imponderables in their interpretation, and their unsatisfactory and necessarily always incomplete nature. All these considerations should certainly be thoughtfully considered and strongly stressed, because errors in judgment cannot b e afforded. But lest these many considerations seem so formidable to many potential investigators as to prevent their needed contributions (which was far from Dr. Sterner's intention) or depress the more experienced contributors, it should be Immediately pointed out that there are a t least twopractical and very helpful means of overcoming certain deficiencies inherent in the basicdata. One is the safetyfactor, the other, the periodic re-evaluation of the threshold limit values. The safety factor has been built into most of the values in the threshold limits list" The factors 2,5,10or even greater have been applied to somevalues.There are,ofcourse, some notable exceptions, such as the present value for trichloroethylene, for which the threshold limit is the absolute ceiling, but generally such instances are rare. In general, the greater the uncertainty in the data's applicability to human industrial exposure, the larger the factor applied. This lowering of the limit value by a n arbitrary safety factor may a t times provoke s o m e controversy, because now the value becomes o n e of opinion, not fact Be that as it may, the safety factor incorporated in the air standards gives increased assurance of safety to many doubtful values. The re-examination of the listed values by the committee provides annually for readjustment of all values, whatever their sanctity, upon submission to the committee of new and experimentally supported findings. Repeated scrutiny and reappraisal of this sort can lead finally only to assignment of safe values o n which complete reliance can be placed. The committee welcomes all such information.B N e e d for more data In this connection another point implied in Dr. Sterner's discussion should be strengthened - namely, the need for more data substantiating the choice of safe exposure levels based on industrial experience. Much useful information is undoubtedly In the files of many plants. Indication of this was the fine evidence on six industrial substances derived from many years of plant experience that came to light last year ht these meetings from the presentation of Herbert J. Weber."' Others should have similar material that should be brought to the attention of the Threshold Limits Committee. Like Webet's material, all of it need not be novel or presented to show need for changing existing limits; equally valuable are data confirming existing limits. As never before, interest in the value of the control of industrial environments is being shared by management generally. Cheater numbers of industrial hygienists than ever before a r e being engaged by industry. Is it too much to hope that meetings such as these will orient the thinking of properly placed industrial hygienists t o secure much needed plant Information t o aid in the choice of safe limits of human exposure? The type of information needed may be listed as follows: 1.Air concentrations should b e determined for the substances under study through a complete cycle of plant operations and with reasonable regularity in order to obtain a true picture of the range and fluctuations of exposure. 2. The data should have good accuracy. -3. The observations should be carried out over a reasonable period of time a minimum of five years. 4. The air concentration data should be correlated with a good medical program. A pattern for such work is that of Dr. Sterner's 10-yearstudy of workers exposure to butyl alcohol.(') There is a real need for more data based o n industrial experience. The often-heard statement v h e incorporated safety factor in the threshold limit values, although added a t times because of uncertainly in the value as related to human exposure, often actually provides a n appreciable margin of safety. For this reason the correctness of the term "threshold ilmit' may be questioned, I t might more properly b e replaced with "air hygiene standard." BAtthe time this paper was written, the point of contact was Allan Coleman,Chairman Threshold Limits Committee, ACQIH. Connecticut State Department of Health, Hartford 1,Connecticuk Currently the address is: Committee o n Threshold LimitValues forChemiai Suhstances,c/o ACQlH, 6500 QienwayAve., Bldg. D-5,Cincinnati, OH 45211. Ann. Am. Conf. Ind. flyg.. Vol. 9 (1984) Page 89 Thirty-fiveYears of TLVs "the threshold limits a r e nothing but educated guesses" unquestionably reflects the wish a t least that more data be firmly based on industrial experience to substantiate the choice of limits. As a member oftheThreshold Limits Committee, I was concerned over the statementa n d took the trouble to revieweach substance in the threshold limit list for 1955as to t h e basis for choice of t h e level. The results a r e shown in Table 1. I t is possible that everyone would not arrive at precisely the same figures, but I believe that their magnitude would not be much altered. Although the table shows that the educated guesses account for a relatively small number, it does confirm the often expressed feeling of the need for more solidly based levels. Table I shows a number of other interesting facts: 1)that most of the values have s o m e sort of scientific basis; 2)that each level has been documented either by Warren A Cook,'3' or by the Committee onThreshold Limits;3) that thevalues based o n animal experiments account for the largest number, 42%; but 4 ) that values having s o m e industrial basis account for one-third of the total. -The values ascribed t o the "man"category arise from two sources that of Nelson et al,"' and those more recent publications of the Dow Chemical workers, Irish, Rowe, Spencer, Adams et al. The "educatedguess" A few words should be said in defense of the "educated guess." Areview ofthevalues described as guesses indicates in the instances in which sound information has later become available that the "guess"was remarkably good.Two prom- TABLE I Basis for Choice of Threshold Limit Values' Study Type No. of Listings Percent Total Listings 12231 Animal Industry Animal & industry Man "Educated guess" Animal & man Source uncertain 94 42 51 23 23 10 25 1 1 21 9 94 31 ' Based in part on Cook. W.A., Ind. Ned. 1 4 9 3 6 ( 1 9 4 s ) . and frtini doc umented material of Threshold Limits Committee. ACGItll053-1 O . i inent examples only suffice - hydrogen fluoride and irraniurn. A safe exposure level for hydrogen fluoride was s e t at 3 ppm o n the very limited evidence supplied by a study in animals by Ronzani in 1909.('' Last year a report?' culminating many years of study of fluoride exposure in the aluminum industry, involving thousands of air a n d urine analysis for fluoride a n d studies of roentgenographic changes in bone, showed without question that air levels double the accepted limit gave rise to perceptible changes in bone in only a few individuals, a n d onlyafter many years of exposure, thus validating the wisdom of this "educated guess." In the case of uranium, a n engineering benchmark had to be "guessed" a t early in t h e days of the Manhattan Project. After a review of the quite limited animal data o n uranium then avaible. Dr. StaffordWarren suggested that the "safe"exposure level for uranium be the same as that for lead,0.15 mg/cu.m. After $500,000 a n d many years had been spent in research, the safe levels of exposure to uranium compounds were found t o bracket this value very closely. Levels for cancerigens T h m still o n e group of substances for which s o m e method saxp l d be devised for estab- safe air standards - thehl.ustrial cancerigens. H o w shall we establish the limits for this ofsubstance? Thus far the question h a s been side- stepped uun&kl&As a result, with o n e excep- tion, nickel carbonyl, limits taking Into consideration potential cancerigenicity have not been assigned. Several industrial substances are known or suspected cancerigens; many more are suspect on the basis ofanimal experiments.As a suggested method of approach, the following is offered: to t h e level judged safe for other types of systemic injury add a safety factor for carcinogenicity. The magnitude of the safety factor is suggested to be from 100 to 500. This provides a t least a second power of 10,which, from the well-known dosageresponse hypothesis, provides a t least a fourfold longer interval before effectsmay be expected t o occur, o r conversely a t least a response with onefourth the intensity. This manner of approach h a s been used for nickel carbonyl. A tentatively safe lcvcl for systemic effects from repeated daily exposure h a s been s e t a t 0.1ppm; one-hundredth Page 90 Stokinger: Prepared Discussion this level, or 0.001ppm was s e t for nickel carbonyl o n the basis that nickel poisoning gives rise to a substantial increase in the incidence of lung cancer. It is realized that unfortunately the safe limits for all industrial cancerigens cannot be so readily resolved. This is especially true of dye intermediates, such as benzidine and naphthyl amines whose major route of entry is not commonly via the lungs butthrough the skin and gastrointestinal tract.These are laundry and protective equipment problems not solvable by air control. There a r e undoubtedly substances to which the suggested procedure may not strictly apply, but imperfect as it may be, the suggested method is felt to be a step in the right direction a n d serves better to curbexposuresto industrial carcinogens than considering the problem too difficult to cope with a t the present time. References 1. Weber, HJ.: Threshold Limits, A Panel Discussion. Am. h d . Hyg. ASSOC. Q.16:38 (1955). 2. Sterner. J.H., H.C.Crouch, H.F. Brockmyre, M. Cusack: ATen-Year Study of Butyl Alcohol Exposure. Am. Ind. Hyg. Assoc. Q. 1 0 5 3 (1949). 3. Cook, W.A.: Maximum AIlowabfe Concentrations of Industrial Atmospheric Contaminants. Ind. Ned. 14:936 (1945). 4. Nelson, K.W.,J.F.Ege, M. Ross et al: Sensory Response to Certain Industrial Solvents. J. h d . Hys. &Ton. 25282 (1943). 5. Ronzani, E.: Uber der Einflussder Blhatmungenvon reizenden Qasen der lndustrien auf die Schutzkraffe der Organismus gegenuber der infektiven Krankheiten. Arch./. Hyg. 70:217(1909). 6. Irwin, D.A.: Cllnlcal Findings Wblcb Can be Anticlpated After Long-Continued Exposure to Fluorldes Presented before Symposium on Fluorine. Kettering laboratories. Cincinnati, Ohio (May, 1954). Page I)1