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Risk Assessment for Carcinogens: A Cornparison of Approaches of the ACGIH and the EPA Michael C.R. Alavanja,A Charles Brown,8 Robert Spirtas,1-D and Manuel Gomez" AEpiderniology and Biostatistics Program, Division of Cancer Etiology, National Cancer Institute, Executive Plaza North ® uilding, Room 543, Bethesda, Maryland 20892; BBiostatistical Methodology and Cancer Control Epidemiology Section, Division of Cancer Prevention and Control, National Cancer Institute, Executive Plaza North Building, Room 344, Bethesda, Maryland 20892; cNational Institute of Child Health and Human DeveH)pment, Executive Plaza North Building, Room f07, Bethesda, Maryland 20892; °Mernber of the Americzu1 Conference of Governmental Industrial Hygienists' Chemical Substances Threshold Lin'it Values Committee The rel ative carcinogenic potency of 16 chemicals evaluated by both the U.S. Environmental Protection Agency (EPA) and the Chemdcal Substances Threshold Limit Values (CS-TLV) Com- mittee of the American Conference of Governmental Industrial Hygienista, (ACGIH) were compared. The estimated cancer risk resulting from occupational exposure to the threshold limit values (TLVs) were also computed using dose-response curves devel- oped as a part of EPA quantitative risk assessments. Subst:untial agreement between the EPA and the CS-TLV Com- mittee was found when the relative potency of these carcinogens was compared. Use of EPA's risk model to estimate lifetime cancer risk from occupationall exposure at the TLV levels often resulted in high cancer risk estimates. The approaches used to assess cancer risk by both groups is described and a suggestion is made i~oir incorporaring existing quantitative risk assessments into the IjLV evaluation procedure. AlStla* M.C.R.; BroMfft, C.; Spirtas, R.; hmez, lbl.: Risit Ameststent for Carctrogem A foffoarison of Approa%es of 4he ACG}9 and tbe F.PII. Appi. Occup. Erwrwt. Ftyg. 5:510-51 7; 1990. Introducrtiion The Chemical Substances Threshold Limit Values (CS- TLV) Committee of the American Conference of Govern- mental Industrial Hygienists (ACGIH) has been reviewing its policie.s and procedures regarding carcinogens. Spirtas et al. (1985) described the current process the CS-TLV Committee uses to make the qualitative decision to des- ignate a chemical as a workplace carcinogen and the quan- titative decision to recommend levels of exposure for the guidance of industrial hygienists.0) Threshold limit values (TLVs) (for carcinogens as well as other toxic agents) are time-weighted averages (TWAs) for a normal 8-hour work- day, 40-hour workweek. The TLV is set for inhalation ex- posure, with special notifications for agents where ab- sorption from skin exposure is important. The TLV is assumed to be protective for "nearly all workers" assuming the workers to be healthy adults <') TLVs are guidelines for good work practices to be used only by professional industrial hygienists. For substances which cause chronic diseases such as cancer, however, there may not be a sharp cutoff point (threshold) between effect and no effect; it is, therefore, important that professional judgment be used in monitoring and protecting workers exposed to such substances. When deciding on guidelines for carcinogens, the CS- TLV Committee gives greatest weight: to epidemiologic studies having data onn quantitative exposure levels.<' ) Such substances receive an Al categorir.aion and are calied "Confirmed Human Cardnogens:'IVext in importance, and more typically available, are mamn>alnn toxicologic stud- ies having whole-bocty bioasstys. Such %Aam= are given an A2 designation and are called "Suspected Human Car- cinogens:" In reviewing the key experimental toxicology studies, the Committee considers route of entry (greatest weight given to inhalation studies), dose-response gra- dient, potency, mechanism of action, <2ncer site, time-to- tumor, length of exposure, and underiyi.ng incidence rate for the type of cancer and species under study. Replication of results is important, especialty if eomparable in different species. Other types of studies are useful in confirming Thiti article representti the views of the authors aad not tfiose of the Americui Ccxiference of Governmental InKlustrial Hygienists or its Chetn- ical tiutwances Threshold Limit Values Committee, or those of ttie U.S. De}rartment of Health and Human Services, the Natiotnl ir>stitutes of Health, and the National Carxer Institute 510 APPL OCCUP. pYYHiONI. NY& 50 • AU6lSSi 1le0

that a substance is a carcinogen but are no* usually helpfu! in setting a TLV. A safety factor is often applied to estabiisE; a TLV for carcinogens, by taking the lowest level known to induct cancer (or the no-effect level) and then dividing that hv in arbitrarv factor, such as 10 or 100. The CS-TLV C;ommittee. realizing the imprecision of setting TLV,, for carcinogtn.ti. recommends that. for all carcinogens having a TlY. "worker exposure by all routes should he carefully controlled to levels as low as reasonably achievable (A1ARA) below the TLV:"') In the earlv 1970s, the U.S. Environmental Frotection Agency (EPA) developed an approach that wa5 different from that of the CS-TLV Committee. Early decisions by the EPA conveyed the idea that the only acceptable degree of regulation of carcinogens would be a total ban on expo- sures.(3.") However, the impracticality of achieving zero risk on a broad scale for a large number of economically important chemicals became increasingly apparent to many, including die U.S. Congress. As a result, the EPA in 1976 became the first federal agency to adopt formal guidelines embracing a two-step process of risk assessment. The first step is a determination of whether a particular substance constitutes a cancer risk, i.e., hazard identification. The second step includes a quantitative risk assessment (QRA) as a key component of determining the degree of regu- latory action needed to protect the publict5~ - As part of the QRA process, the EPA computes dose- response curves, makes low-dose extrapolations, and es- timates the size and degree of exposure of the exposed populations in order to estimate the number of excess cancers exp~cted in the total U.S. population. The rationale and procedures for the EPA approach are used to guide regulatory actions which are meant to protect each mem- ber of the general public over a lifetime against exposure via inhalation or ingestion.(6) Regulatory action is taken only after the results of the QRA are integrated with en- gineering data and with social, economic, and political concerns.C> Confusion-has arisen from the different approaches used by the CS-TI V Committee and the EPA in estimating risk Although tihe TLVs continue to be used widely by profes- sional industrial hygienists around the world to evaluate the safety of workplace exposures, the QRA approach is viewed by some as riore objective. Recently, criticism of TLVs has focused attention on the objectivity and scientific standards of the CS-TLV Committee.ts> Several examples were given of chemical substances for which unpublished data (primarily from the files of industrial companies) were important in setting the recommended TLV. Since, in many instances, the TLV is the only number available to industrial hygienists, it is important that the CS-TLV Committee's pol- icies and procedures regarding carcinogens be reviewed to assess the results of the current TLV approach. We be- lieve a quani:itative comparison of the EPA and the TLV approaches may provide some important information re- garding thi.; assessment. Reflecting on some of these issues, Andersent9> pre- sented a critical review of quantitative risk assessment in occupational health in the 1988 Herbert E. Stokinger Lec- ture, concluding that, "Quantitative Risk ASSessment is not just coming to the occupational environment. It is here now and is an issue to be reckoned with by everyone of us in the industrial hygiene profession"") in his review, Andersen suggetits that QRA during the past 13 years has been "damned" hv its misapplication. Overly conservative quantitative approaches to predicting risk would lead to risk estimates that "greatly restrict commercial operations, decrease our ability to compete in world markets, and lead to large expenditures to change work practices with no concomitant increase in health protection:' He went on to suggest that the problems faced by the use of overly con- servative techniques can be overcome in part by the use of recent cancer models that have greater biological rel- evance, e.g., the physiologically based pharmacokinetics models (PB-PK)t10> and the Moolgavkar, Venzon, Knudson (MVK) models.t t t> Although the theoretical appeal of these cancer models is clear, the bulk of the QRAs developed and published since 1976 have come from regulatory agen- cies which have not used these new techniques. We cannot compare current TLVs to the results of risk assessments using the MVK or PB-PK approaches; however, comparing established TLVs for carcinogens with the results of the EPA QRAs may help determine whether, and under what circumstances, the CS-TLV Committee may consider using QRAs as part of its decision-making process. This article presents a comparison between the ACGIH TLVs and the EPA QRAs for the 16 chemical carcinogens that have been evaluated by both groups. These QRAs were chosen for comparison since they are the largest available collection of risk as.5essment5 developed by a standard methodologic approach. f ARedods 8etd Reaults The comparison reported herz is derived from the ACGIH 1988-1989 list of'II.Vst12) and an EPA list of carcinogens taken from the Integrated Risk Information System.t13)'Itie ACGIH list contains over 700 agents of which 55 are clas- sified by the Committee as carcinogens in the adopted list plus 3 in the Notice of Intended Chznges List. These 55 substances are listed along with their TLVs, where available, in Table I. The EPA list, in Table II, oontains 54 agents, including a substantial number of pesticides and nitrosa- mines for which a unit risk factor fbr inhalation exposure is available. The EPA's unit risk factor is a conservatively estimated risk to humans from constant lifetime exposure of breathing contaminated air at a level of 1 µggm3. This risk estimate is derived from the availabL- results of animal bioassays, biochemical studies, and epidemiologic studies. To assure safety, conservative assumpaons are used to sup- plement missing or unknown information (e.g-, using re- sults from the most sensitive animal species and the lin- earized multistage dose-response model and extrapolaring using the upper 95 percent confidence limit of the ex- perimental evidence). The ACGIH TLVs are compared with the EPA QRAs APPL OCCUP. ENb7RON. 1fYG. 50 • AUGUST 1990 511

TABLE L_CPtemicaf Substances Classified as Carciragens by I4C6M1 witth Tfieir Respective TtVs (1988-1989 Adopted YaNye.s) Substance TLV I Subsfanca TLV Acrylamide-Skin" 0.03 rnqhrr' Ethylene dibromide-Skin - Acrylonitrile--Skin^ 4.5 mg/m3 Ethytene oxide" 1.8 mglm3 4-Aminodiphynyl-Skin e Formaldehyde" 1.5 mg m' Antimony triouide production Hexachforobutadiene-Skin" 0.21 mghrrj Arsenic trioxice production Hexamethyl phosphoramide-Skin - Asbestos Hydrazine-Skin 0.13 mg/m' Amosite 0.5 fiber/cc 4,4'-Methylene bis(2-chloroaniline)-Skin 0.22 mg/m3 Chrysotile 2 fibers/cc Methylene chloride (Dichloromethane)" 175 mg/rn3 CrocidoliCe 0.2 fiber/cc 4,4'-Methylene dianiline 0.81 nxyrrt3 Other fonns 2 fiberslcc Methyf hydrdzine---Skin 0.35 nxynr3 Benzene' 32 mg/m3 Methyl iodide-Skin 12 mg/n~ Benzidine-Sk:n B P-Naphthylarnine B Benzo(a)pyrene - Nicked sulfide roasting, furne & dust 1 mWm', as Ni BeryfliurM 0.002 mgm3 4-Nitrodiphenyt ® 1,3-Butadierk'A 22 rig(mrl 2-Nitropropane 35 mg(m3 Carbon tetrachloride-Skin" 31 mg/rn3 N-Nitrosodimethybmine--Skin Chloroform" 49 mcym3 N-Pherryl ~pt~r}2mir~e bis-(ChtoronMethyf)eW 0.005 mghrr3 Ptery4trydrazine-Skin 22 mgrm' Chlomiethyf r*fryf ethes - PrOpane sJlforle - Chromates of Is3d, as Cr 0.05 rtxyrtrj P-PrombcWt 1.5 mg+m' Chromite ore pnxessin0 (chromate) 0.05 m{ynP, as Cr Propylene imine-51dn 4.7 mgW Chromium (Y), certain water insoluble compouro 0.05 nxym;, as Cr o-Totidine-Sfdn - Chrysene - o-Toluidine--Skin 9 MgVm' Coal tar pitch velaCGfes 02 rrKym3, as bentene p-Toluidins---Skin 9 RWTP solubles Vinyl bromide 22 rnPP 3,3'-Dichforotenadine--Skin Ynyf dtrotide 13 mom' Dimethyl carlkunlyl chloride Vrryi *Wmerie 6WAe-_%n 57 mg/rn3 1,1-Dirnethyftdrazine--Skin 12 mg/rr-P Zinc dvoirraft 0.01mgim3,asCr Dimethyf sulfale--Skin 0.5 mg(nr3 _ Ploticce o( kftXW OWN)es ('Oor 1985-1999) Cadmium and canpocmds" 0.1 mgirna Etlry1 wY& 20 mglm3 Xytidine (nroW isorr~rs}- Skin 25 mglrts' "(3t~emiqls corKainEd on both Ux TLV and EPA rardnogen IisL BSubstance desigried by CS-TLV Cartmittee as a confimred txman caraaogen wftait a nV. Wa4ds oTosed bfia arbslarxe should be `popey equiav~d n vfrYaMy d;ma;* ap oPOMue •~ in two ways: 1) do the ACGIH and EPA place these chemicals in the same order of toxicity? and 2) what level of risk do tf, e EPA unit risk factors imply from exposure to the ACGIH's TLVs? The EPA dose-response assessment commonly begins with the multistage model, P(d) = I -- exp(qid + q2d2 + . .. + qkdk), puts an upjD<!r 95 percent confidence limit on the linear term of the dase-response (qIs) based on a sratistical eeal- uacion of anitnal bioassay data (with consideration of spe- cies, route of administration, duration of exposure and followup, and other experimental design criteria deemed most relevantt to human risk assessment), and then uses the linearized multistage model (only the linear term is included) to estimate the risk of lifetime exposure to low doses. Bera,uLq.e the linearized multistage model used by the EPA for its unit risk Pactor is equivalent to the single hit model, our estimate of lifetime risk of developing can- cer from occupational exposure is based on the model, Prob (d) = 1 - exp(-ad), where Prob(d) is the lifetime probability of developing cancer from exposure to a daily level of d µg/m3 during a working lifetime of a 40-hour workweek/168-hour week, a 50-week/workyear, a 40-year career, and an average life span of 74 years. The slope of this dose-response curve (a) directly indicates cancer risk, thus a larger slope im- plies a larger risk at the same dose. The slope is derived from the EPA unit risk factor and is adjusted as follows to reflect different exposure situations. To adjust for different exposure durations, we use the simple assumption ti= the dose-response slope for oc- cupational exposure is (40/168) x(50/52) x(40/ 74) = 0.124 of the complete lifetime exposure slope. The EPA assumes a normal respit:gion rate of 20 cubic meters in a 24-hour period white sm assume a r2te of 10 cubic meters in an 8-l~our avurking day. Ttyerefcxe, to adjust for different breathing rates for working and nonworking per- sons, we assume the occupational exposure slope is (10/8)/(20r24) = 1.5 times the EPAA slope. Figure 1 displays the comparison of the ACGIH and EPA arrangements of the 16 common agents in decreasing or- der of risk (increasing TLV level and decreasing unit risk order). The spearman rank eorrelation coefficient for these two orderings is r = 0.78 implying substantial, yet im- perfect, agreement. The major disagreements are the or- derings of hexachlorobutadiene,l,3-butadiene, vinyl chlo- ride, formaldehyde, 'and chloroform. The ACGIH has hexachlorobutadiene with a greater carcinogenic risk than 1,3-butadiene, and vinyl chloride with a greater risk than 512 APPL OCCt1P. &VNROAb M'6. SfN • AUBUSi i!!0

chloroform, while the EPA reverses this order. In addition, ti>rmaldehycie is substantially higher on the ordering by ACGIII than by EPA. In establishing TLVs for vinyl chloride and chloroform, the C5-TLV Committee probably weig'.ited heavily the positive epidemiologic evidence for vimyl chlo- ride, in deciding to establish a relatively more protective value for vinyl chloride than for chloroform. The TLV for formaldehyde is based primarily on prevention of eye, nc>se. and tl• roat irritation. These acute effects have been ohserved in humans at levels below the lowest effect seen for carcinogenicity in rodents. The discrepancy for 1,3- buradiene rin be explained, in part, by the CS-TLV Com- mittee minimizing the relevance of an animal bioassay which induced angiosarcomas of the heart, a rare tumor in humans. ' Table III gives the TLVs and adjusted unit risk for these agents along with the EPA's estimate of daily occupational exposure h---,els corresponding to lifetime cancer risks of one in a million and one in a thousand. This table also gives an eitimate of the lifetime risk from occupational exposure to a daily level at the TLV. Eight of these 16 estimated lifi>time cancer risks from occupational expo- sure to the TI1,V lie between 1 and 10 percent with the two highest estimates being chloroform at 19 percent and 1,3- hutadiene at 158 percent while the two lowest estimates are he.Y:.tchlorobutadiene at 0.1 percent and beryllium at 0.09 percent. On the average, the TLVs for these 16 agents are over 25 tiree,, greater than the EPA estimated daily expo- sure level ~is;;ocia¢ed with a risk of 1/1000. Table III also Tl. v Order Beryllium B is(chloromethyl )ether Cadmium Acrylamide Chromium VI Hexachlorobutadiene Nickel Refinery Dust Ethylene Oxide Acrylonitrile Vinyl Chloride 1,3 Butadiene Benzene Carbon Tetrachloride Chloroform V Formaldehyde Benzene Vut--yI Chloride I Methylene Chloride et y erte on e, RM 1. Ordering of chemicals by estimated risk by the Chemical Sub- stances TLV Committee and the U.S. Environrttertal Proiecfion Agency. TABLE ll. C#ttmicals Catdnwgens for Which QuaciftOM RiSIcs Fare Been 0 Group for httalabon 6tpo:are by U.S al1's CsrraaoyAn AnewrorE Compour>ds Unii Risit Factors' CUMMEXIS Uait Risit FsdoPS` _ Acetaldehyde 22x10-6 12-Dipt>erryttt}rdrarirte 4.5 x 10-t Acrylamide 1.3x10-3 Epid>lorohydrin 12 x 10-6 Acrylonitrile 6.8 x 1U-5 Ethylene oxide 1.8 x 10-2 Aldrin 4.9x10-3 Fomlaldefrytie 1.1 x iU-' Arsenic 4.3 x 10-3 Heptactda 1.3x10-3 Asbestos 2-3 x 10-1 H"chlor Ma" 26x10-3 Azobenzene 3.1 x 1o--5 Nexadtlorobutadiene 22 x 10-5 Benzene 8.3 x 10-6 Headtbrocyclohmrte 21 x tUs Betuidene 6.7 x 10-z Whnical Wade 2.0 x 10-r Beryllium 2.4 x 10-3 alpha ison>et 1.8 x 1(F3 1,3-Butadierte 28 x 10-4 befa isomw 5.3x1Q-' Cadmium 1.8 x 10-3 Hexisch1otod+bqizoftxirt 1.3 x 104 Carbon tetrachloride 1.5 x 10-5 tiytbatirtPhtyd~aatte srtffale 4.9 x 10-3 Chlordate 3.7x10-5 Nidtei ref'urery dusi 24x10-4 bis(2-cttloroeih!(I)~tter 3.3x10-' Nir,lei sulwtfide 4.8x10-4 Chloroform 2.3 x 10-5 NiVoso-dim~e 1.4x10-2 bis(chlorometh}l)Eltter 62x10-2 Di-bt4yiamirte 1.6x10-' Chromium VI 12 x 1D-z Dewftsam4* 43x10-z DDT 9.7 x 10-s N-rtitrosopysrolidMe 6.1 x 10-4 1,2-Dibromoettlan, 22 x 10-t 2-Tehactdaoetttane 1,1,1 7.4 x 10; Dibutylnitrosamir>E, 1.6 x 10-3 , 22-Tetrathloroefhane 1 1 5.8x10-s 1,2-Dichloroeft>itrH: 26 x 10-s , , Toxaphene 32x1o-4 1,1-Dithloroett>ulene (Vinylidene chloride) 5.0x10-5 1,1,2-Tricttloroettlarte 1.6 x 10-5 DichlorometharNS (Methylene chloride) 4.1 x 10-6 Tridtioroethyfene 13 x 104 Dieldrin 4.6 x 10-3 2,4,6-Trichloropt>enoi 5.7x10-6 Diethylnibosamine 4.3 x 10-2 Vinyl chloride 7.1 x 1Q-i Dimethylnitrosarnine 1.4 x 1U-2 `Eslimafed risk !o hunws from consW lifetime evwe ol txeatMrg cordamirgted air at a IeveM ot i µryrnd. EPA Order Bis(chloromethyl)ether Chromium VI Beryllium Cadmium Acrylamide 1,3 Butadiene Nickel Refinery Dust Ethylene Oxide Acrylotritrile Chloroform Hexachlorobutadiene Carbon Tetrachloride APPL OCCUP. ENVIRON. HYG. 50 • AUGUST 19911 513

TABLE 111. Estimated Lifetime Cancef R6sh from Ocmpafionaf ExpoSVre to the TLV IARC TLV Adjusted Daify Expsure (µg/m') Assaciated with Risk of Estirrtated Life6me Carrcer Risk from Substance Class µg/V Unit Risk' 1/10' 1/101 ExQostrre to TLV Acry)arnide 28 30 2.4 x 10-' 4.2 x 10-; 4.2 0.0072 Acrylonitrile 2A 4500 1.3 x 10-5 7.7 x 10-z 7.7 x 10' 0.057 Benzene 1 30000 1.5 x 10-6 6.7 x 10-' 6.7 x 102 0.044 Beryllium 2A 2 4.5 x 10-' 2.2 x 10-' 2.2 0.0009 1,3-Butadiene 28 22000 5.2 x 10-5 1.9 x 10-2 1.9 x 10' 0.68 Cadmium 2A 10 3.3 x 10-' 3.0 x 10-3 3.0 0.0033 Carbon tetrachloride 2B 30000 2.8 x 10-6 3.6 x 10-' 3.6 x 102 0.081 Chloroform 213 50000 4.3 x 10-b 2.3x10-' 23x102 0.19 bis(Chlorometltyl)e~ 1 5 1.2 x 10-2 8.3 x 10-5 8.3 x 10-z 0.058 Chromium (VI) 1 50 2.2 x 10-3 4.5 x 10-* 4.5 x 10-' 0.10 Dichloromethane 2B 175000 7.6 x 10-' 1.3 1.3 x 103 0.12 (M4etiiylene chloride) Ethylane oxide 2A 2000 2.0 x 10-5 5.0x10-z 5.0x10' 0.039 Famnalde?* 2A 1500 2.4 x 10-6 4.2 x 10-' 4.2 x 102 0.0036 Hexachlorobuhadierre 3 240 4.1 x 10-6 2.4 x 10-' 2.4 x 102 0.00098 fdickel refinery dusf 1 1000 4.5 x 10-5 22x10-2 22x10' 0.044 Vinyl chloride 1 10000 1.3 x 10-6 7.7 x 10-' 7.7 x 102 0.013 'From Table If adoed fa ocapatiatal aqwstxe. Estirnaled risic b hanm kan epOSUe b a time-aeigtled ayeape d 1 µphrr' br a noma! 8-hau wakday. 40-1m workweelc 4anar career (see ie4. contains the Iinternational Agency for Research on Cancer's (IARC) classification of each of these chemicals.(1`') This classification scheme evaluates the likelihood that these chemicals are human carcinogens but makes no attempt to quantify their potential risk or to set "safe" exposure levels. Hexachlorobutadiene is classified by IARC in cate- gory 3, "the agent is not classifiable as to its carcinogenicity to humans:'t14> Seven other chemicals: acrylamide (2B), acrylonitrile (2A), beryllium (2A),1,3-butadiene (2B), cad- mium (2A), carbon tetrachloride (2B), chloroform (2B), methylene chloride (dichloromethane) (2B), ethylene ox- ide (2A), and formaldehyde (2A) are in IARC category 2, "the agent is probably (2A) or possibly (2B) carcinogenic to humans." The remaining five chemicals, benzene, bis(chloromethyl) ether, chromium VI, nickel refinery dust (nickel comlxiund5), and vinyl chloride are in IARC cate- gory i "human carcinogens." Using vinyl ~chloride as an example, Figure 2 illustrates the typical relationship found between the dose-response curve resulting from a QRA of the type performed by the EPA, the empirical data on wh;.:i the modeling is per- formed, and the TLV established by the ACGII 1. The slope of the dase-response curve shown here (i.e., 0.0013) is derived from ihe EPA unit risk factor for vinyl chloride adjusted to reflect the exposure situation of the occupa- tional environment. Discussion In this set of 16 chemicals, both the EPA and the ACGIH approaches r,tnk them in approximately the same order of carcinogenic risl:. However, the EPA is far more con- servative, refle(aing the agency's objective to piotect all members of the community, not just healthy adults. The authors could ;not definitively comment on the relative accuracy of the two approaches because our theoreticall understanding of the dose-response relationship for oc- cupational carcinogens is still elementary, and we are, therefore, limited in our ability to discriminate between the accuracy of the'ILV and QRA approaches. One is further hampered by the fact that the empirical data available to assess the carcinogenicity of specific chemicals are usually the result of animal experiments at high doses, together with a battery of short-term tests which are sometimes augmented by epidemiology studies that usually have scanty exposure information. The available occupational cohort studies have not followed workers for their entire lifetime and, thus, do not give complete inforntation on agents which cause cancer many years after exposure. Conse- quently, no one at the present time can speak with scientific certainty about "safe" levels of exposure to carcinogens. Although decisions on the perrnissible exposure to car- cinogens are fraught with difficulty, we believe that rec- ommending maximum levels of occupational exposure should be guided by three principles: 1. Scientifically, one should seek the most appropriate data and methnds for predicting the effect of human exposure to carcinogens based on our latest theo- retical understaaditt¢; of the prooess of carcinogenesis. 2. As a public health issue, one should admit the im- precision of our knowledge and compensate for our uncertainty by building into the system a margin of safety. 3. As public policy, one should explicitly document the methodology. The increasing motivation to use QRA as a tool to es- tablish occupational health standards dates from the 1980 decision by the Supreme Court to overturn the Occupa- tional Safety and Health Administratfon's (OSHA) newly proposed benzene standard.0 5) The court maintained that 514 APPt- oCCUP. eW1NaVt PlYS. 3/t! • A06tJSt 1990

OSHA ha,d failed to show a significant reductior in risk going frc;m 10 to I ppm. Although OSHA did not propose a fi>rmal policy in response to the decision, the agenn, has generalhy accepted the view that quantitation of risk is required for the regulation of carcinogens, and it has in- Q-()rporated QRAs into its standard setting activitysince that time. A~iiitLst th.e controversy associated with modeling a pro- cess th: is incompletely undersaxxi scientifically and the judicial political climate which favors the use of a quan- titative procedure to help regulate carcinogens in the gen- eral environment and workplace, the EPA and other reg- ulatony agencies have opted for the use of a conservative approach in the development of risk assessment proce- dures. For example, the QRAs are usually based on t;,e most sensitive species and use of the most conservative dose-response curve, while low weight is given to neg- ative epidem iological data.~ 5) Although this procedure has been criticized by some industry representatives(16) and some academic scientists,07t it would be difficult to per- form numerous risk calculations involving all plausible options for the many judgments that must be made in the development of a QRA. For most chemicals, this would result in such a wide range of risk estimates that the anal- vsis would not be u.seful to the regulatory agency or to others formulating public policy. The CS-TLV Committee, on the other hand, provides recommendations for the use -3 -2 10 10 . rn9/m3 -1 10 10 0 of industrial hygienists rather than setting governmental standards, and the Committee bases its recommendation on the professional judgement of its members. Both the TLVs and QRAs are subject to external reviews before adoption. With this perspective in mind, the authors compared the chemical carcinogens which were quantitatively evaluated by the two procedures. The first qualitative comparison is that only 16 chemicals appear on both the CS-TLV Com- mittee list and the EPA list. However, this apparent dis- agreement is not too surprising because of the substantially different mission of these two organizations and the ap- proaches they take when classifying the hazardous "po- tency" of chemicals. TLVs are quantitative guidelines for recommended exposures in the workplace, hut there is no explicit estimate of the health risk associated with these leveLs. On the other hand, the EPA unit risk factor explicitly relates dose to cancer risk by means of a mathematical, linearized, multistage model of rarcinogenesis, but few have been translated into pc rmissible exposure levels. Op- erating as an independent organization, the IARC reviews all relevant scientific information in order to assess the evidence that an agent could alter the incidence of cancer in humans but makes no attempt to extrapolate beyond the range of the available data. Likewise, no recommen- dation is given for safe exposure levels for regulation or legislation.t t4/ 1 10 10 2 3 10 concentration (tog scate)• 10 It 10 5 FGURE 2. Comparison of TLV, EPA unit risk dose-response, and animal bioassay re.sufts for vinyl cttlotide exposure. APPL OCCUP. ENV78ON. NYG. 3/81 • AUGUST 1990 515

The principal reason for this wide disparity between the EPA and the CS-TLV Committee may be explained primarily bv the underlying philosophical principles governing the two organizations rather than the technical differences be- tween the two methods. The CS-TLV Committee is gov- erned hy the principle that "Threshold limit values refer te~ airh<;rne concentrations of substances and represent cUnditiUns under which it is believed that nearly all work- ers ma%- he repeatedh• exposed day after day without ad- verse effect. Because of wide variation in individual sus- ceptibiliiv, however, a small percentage of workers may experience discomfort from some substances at concen- trations at or below the threshold limit; a smaller per- centage miy be affected more seriously by aggravation of a pre-exi.sting condition or by development of an occu- pational il;lness"11z> Use of the TLV for other purposes, such as community air standards, is specifically discour- aged by the Committee. Thus, the CS-TLV Committee rec- ommendations imply that there is a small degree of risk of occupat.ional illness to some workers who are more susceptible than others. The Clean Air Act, which in part governs EPA's approach to performing QRAs, is more philosophically conservative. The Act states that Primary Air Standards must protect the public heal¢h with an adequate margin of safety based on a review of air quality criteria which reflects the latest state of scientific knowledge about the pollutant. The require- ment for an "adequate margin of safety" is intended both to address inconclusive scientific and technical information and to provide a reasonable degree of protection against hazards that: research has not ,vet identified Recognizing that imposing zero emission for some substances would impose too heavy an economic burden on society, EPA has addressed tlle problem by proposing that the Best Avail- able Technology (BAT) be used to control carcinogens. If BAT controls leave an unreasonable residual risk, further controls will be considered ! 17) When making a quantitative comparison between the ACGIH and the EPA approaches, substantial agreement is found when classifying the relative potencies of these car- cinogens, but substantial disparity in the actual levels pro- posed or rec.omtnended Estimating lifetime cancer risks from occupational exposure at the ACGIH's 'ILV levels by using the EM's QRA model sometimes resulted in extraor- dinarily high risk estimates, 68 percent from exposure to 1,3-butadiene and 19 percent from exposure to chloro- form, which may reflect either limitations in the QRA mod- eling approach or the TLV safety factor approach. A safety /actor approach, such as that used by the CS- TLV Committee, is theoretically no more or less conserv- ative than a QRA approach which is linear at low doses and assumes no threshold. In practice, however, use of a safety factor of 5-10 or even 100-1000 is markedly less conservative than the QRA approach which determines an exposure level associated with a very small risk level such as 1/1oc'. This p:)int is illustrated for vinyl chloride in Figure 2 which compares the EPA unit risk factor for the upper confidence limit on the estimated human dose-response with the TLV and the results of animal bioas.tiays. With no attempt made to acknowledge the inconsistency produced by these differing methcxis, confusion and skepticism have resulted. Although there are strengths and weaknesses as- sociated with the approach of each group, it would seem that the CS-TL%' Committee could make a major contri- bution to fostering control of carcinogens in the workplace bk• reviewing any available EPA QRA, or comparable mod- eling data when it updates or establishes a new TLV for a conlirmed or suspected human carcinogen. When possi- ble, the CS-TLV Committee should also consider the results of studies that use more refined modeLs for QRA Being les,s constrained by the judicial-political climate than the regulatory agencies, the CS-TLV Cotnmittee should be bet- ter able to promptly adopt the most scientifically defensible extrapolation procedures available when a particular chemical is being studied in terms of recommended oc- cupational exposure values. Although many scientists remain skeptical about the pos- sibility of extrapolating the effects of carcinogens to low doses, a systematic evaluation of the results of these esti- mates in future editions of the TLV Documentation volume would help alleviate the confusion that now exists. Referenees 1. Spirtas, R.; Steinberg, M.; Wands, RC.; Weisburger, EK: Identification and Clmsification of Carcinogens Procedures of the Chemical Sub- uancesThreshold timit Value Committee, ACGQ-I. Am.J. PubLc Health 76(10):1232-1235 (1985). 2. American Conference of Governmental ItAtstrial Hygienists: Thresh- ' old Limit Values for Chemical Substances Biotogical Exposure Indices for 1989-1990. ACGIH, Cmcinnui, OH (1989). 3. U.S. Environmental Protection Agesx.y: Respondans brief in support of propevied findings, catcfusions and order at 63-64, in re-. Stevens tndtn•try, Inc (Consotidued DJT Hearings), Agril 5, 1972. 4. U.S. Environmental Pnoteaiat Agency: Respondents motion to de- termine wltether or not the negistratiotis of mhrx should be canceled cx amenafed; Attachment A, September 5, 1975. 5. U.S. Environmental Protection Agesxp: lnoerim Procedures and Guidelines for lealth Risk and Economic lmpoct Asewtents of Sas- pected Cardnogem Fed- Reg. 41:21402-21405 (1976). 6. Office of Science and Tecimoiogy: Policy on: Qtanial Carcittogenr A Review ofthe Scieneeand itsAssociMedPrindpals. Fed. Reg 50:10372- 10442(Febrtnty 19B5k 7. xatkx>at Research Courtcit: Risk Aneswmt in the Federal Govertr metu: iNaaagirg the Process. NatiotW t.ratlemy Ptess, Rashington DC (1983). 8. Cauletrnn, B.L; Zietn, G.E.: Corpotate lulhxtaoe on Threshold limit Vafte-s. Am. J. Ind. Med. 13:531-559 (1968)- 9. Andersen, M.E: Qu7¢vtiu&ve Risk AssewweM mtd Occvpational Car- cino~ Appl. ind Hyg. 3(l0}267-272 (1964 10. Comlie4d, J_ Carcinogenic Risc Assessz~ Science 19&693--b49 (1977). 11. M<x>Jgavkar, S.FL; Knudson, Jr., AG.: lAtxuion and Cancer: A Model for Hurmn Cucinoget>ests. J. Natl. Cx-scer Itffit. 66:1037-1052 (1961). 12_ American Conference of C'iowertutient IndssttW f•iygicnist: 74trestroid Limit Values and Biological Exposure Indices for 1967-1988. ACGIH, Cincinnati, OH (1967). 13. U S. Environmental Protection Agetxy: Integnted Risk Infam=ion System. EPN600V8-86/0321 Office of Health and Envim.urterual As- s~xr~t Us Environrnerual Protet.~tion Agency, Washagton, DC (1987). 14. tnternaticxtal Agency for Research on Csneer: Overall Evsluxions of Careinogenicity, Suppi. F. An Updatiag of IARC!<4onographs Volumes 1 to 42. JARC, Lyon, France (Mardi 1987). 516 APPL OCCUP. EiWIROM NYG. 50 . AUGUST 1990

Ii. Supreme Qturt of the United States: Industrial Union Depanment, AFl: CIO v. American Petroleum Institute. et al., argued October 10. 19'9. dee:ided July 2. 1980. No. .'8-911. Washington, DC (1980). IG. Anierican Industrial Health Council: Q mment on: A Rep ut < f the GueraKenq- Regulatory Liaix>n Group Entitled ':ticientific Ba.u~ for Ielentif}•inK Potential Carcinogens and Estimating their Ri,k." AIHC. "iar.uLle. ( btay S. 19-9 ). 17. Purchase, LF.: Inter•,pecies Compari.xxts of Carcinogenicity. Br. J. Cancer 41:454-46K (19ki0). 18. l'.S. EmOronmerttal Protection Agency: Policy and Procedures for IdentiF<ing, and A,sessinR and Regulating Airtx)rne Substances Pc .tiinR a Risk of Cancer. Pr<tpu ecl Rule Fed. Reg. a4:5£3(i42 (19t30). Received 8 28r89: review decision 12/t/89; revision 2/8190; accepted 3/9/90 APPL OCCUP. ENVIRON. HYG. 5/8) • AUGUST 1990 517