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Fourth Annual Report on Carcinogens Summary 1985 NTP 85-002 U.S DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service AP00054861 Contents fMCUttv Summary Page 1 . Mroductlon 5 Hb*t*nc68 or groups of substances, and technological or v, IMnufscturlng processes that are known to be carcinogenic: 4-Aminobiphenyl AndQestc mixtures containing phenacetin * .Arsenic and certain arsenic compounds , , Asbestos Azathioprine Benzene Benzidine N,N-bis(2-chloroethyl)-2-naphthylamine (chiornaphazine) Bis(chloromethyl)ether and technical grade chloromethyl methyl ether 1,4-Butanediol dimethylsulfonate (myleran) Certain combined chemotherapy for lymphomas Chlorambucil Chromium and certain chromium compounds Coke oven emissions Conjugated estrogens Cyclophosphamide Diethylstiibestrol Hematite underground mining Isopropyl alcohol manufacturing (strong-acid process) Manufacture of auramine Melphalan Methoxsaien with ultra-violet A therapy (PUVA) Mustard gas 2-Naphthylamine Nickel refining Rubber industry (certain occupations) Soots, tars, and mineral oils Thorium dioxide Vinyl chloride 20 24 26 29 31 34 37 44 46 47 52 54 58 50 61 64 05 201 202 203 125 126 13G 137 138 204 205 189 199 AP00054862 -'-Agents in italics are new lo this Report. iii AP00054863 may ue m waieuouses. borne ) nibtreated children's sleepwear, manufac tured prior Jo 1978 and stored in more susceptible to cancer induction by. urelhane than were adult mice.536 warehouses, may reappear illegally in the marketplace. Consumers who PROPERTIES suspect they may be purchasing pre-1978 TRIS-trealed sleepwear are advised to contact the manulacturer or call the CPSC Hotline at (800)&38-2772. CPA regulates TRIS under the Resource Urethane, also called ethyl carbamate, is colorless, odorless, and wafer solubles Urethane is available in the United' Slates in crystal form or as a fused did. Conservation and Recovery Act, the Comprehensive environmental Re USE sponse Compensation and Liability Act, and under Section 8(a) oi the Toxic Substances Control Act, which requires Urethane mainly is used as a chemical' intermediate in the preparation of amino resins, ft also is an intermediate in the/ that SPA be notified of intent to resume manufacture or importation. production of pharmaceuticals, insec-'tic'ides, and fungicides, and is used in biochemical research and in human' URETHANE CARCINOGENICITY and veterinary medicine. Formerly, urelhane was an active ingredient in/ drugs prescribed for the treatment neoplastic diseases; it also was a hyp1, There is sufficient evidence of the car cinogenicity of urethane in experimen tal animals.535 Urelhane was car cinogens in mice, rats, and hamsters following inhalation, oral administration (in drinking water or by stomach tube), and subcutaneous or intraperitoneal in jection, producing lymph system nolle, a component of a sclerosing sofuv tion for varicose veins, and a topical* bactericide. In 1970, approval ot new' drug applications for products contain ing urethane as an active ingredient was withdrawn after researchers found that urethane was ineffective. Urethane also: has been used as an inactive Compaq cancers, liver cancers, melanomas, and vascular, lung, and other tumors. It was an initiator of skin carcinogenesis in mice when given either orally or topic ally. Urethane also enhanced the leuke- mogenic effect of x-irradiation in mice. )t was carcinogenic in single dose ex nent or solubiii2er in liquid preparations for infections, but FDA withdrew the new drug application approval for all drug products containing urelhane as an in*, active ingredient537 Additionally,, urethane can occur as a contaminant in., two anticonvulsant drugs (trimethadiooa periments and following prenatal ex posure. Neonatal and infant mice were and paramethadione), with an afiowstofa limit of 1 ppm; these anticonvulsant' drugs may be used only to treat epftep-/ S3Sstnternational Agency lor Research on Cancer. (ARC Monographs on frte Evaluation of the Car cinogenic Risk of Oicmtc.aN to Humans Supple prneenunlit*A A)? ){> I, ,>n F r,v,, n (APC l HO? Ap sy that is refractory to other available. ^International Agency lor Research on Cancer,. (ARC Monographs on the Evaluation of (fie Car cinogenic Risk of Chemicals to Man. Vol. 7. 323 pp Lyon. France 1ARC. 1974, pp I1M40. i'1/o Ri'tjisltif. n i FH 9.r>?3, 4, Ftibruary 27. 198 Otugs. IMO USllll'BlB WcSb uvuutuJiv. iv^ i on the volume of urethane now used in the United States, but it is believed (o be small. waste and will determine the appro prialeness uf additional regulatory o other control actions. The use c PRODUCTION urethane in drugs is piohibited; o< February 27, 1976, FDA withdrew af The 1979 TSCA Inventory identifies five companies producing C.105,000 million pounds ot urelhane, with some site limitations.530 Several companies now produce urethane solely for research. prova) lor all drugs containing urelharv as either an active or inactive iiigt edien FDA has prohibited the use ol dietly pyrocarbonate as an additive to huma food, U.S, companies have produced urethane commercially since 1945. EXPOSURE Reports of possible human exposure to urethane are not available, in 1974, the National Occupational Ha2ard Survey made no estimate on the potential worker exposure to urethane. Urethane is volatile at room temperature, and ex posure can possibly occur through in halation and skin absorption during manufacture and processing. Urethane also may possibly be ingested by humans. Investigators have found urethane in diethylpyrocarbonatetreated beverages, and in wine, beer, orange juice, and some soft drinks. Urelhane also has been found to occur in foods not treated with diethyl procar bonate but made by a fermentation pro cess, including ale, beer, bread, wine, soy sauce, yogurt, and olives. VINYL CHLORIDE CARCINOGENICITY There is sufficient evidence that vin chloride is a human carcinogen.*39 I target organs are the liver (angiosf comas), brain, lung and hemo- and tyr phopoietic systems Although eviden' of a carcinogenic effect of vinyl chlori* in humans has come from groups c cupattonally exposed to high doses vinyl chloride, there is no evidence tf there is an exposure level below whi no increased risk of cancel would i cur in humans.5,10 There is sulficient evidence lor 1 carcinogenicity of this compound in perimental animals.540 Vinyl chfor was tested in mice, rats, and hamst by inhalation exposure and in rats oral, subcutaneous, and inlraperitor administration. Inhalation exposure/ REGULATIONS duced tumors at different sites in three species, including angiosarcor EPA regulates urethane under the Resource Conservation and Recovery Act and the Comprehensive Environ mental Response Compensation and Liability Act. EPA also has designated ''''international Agency lor Research on Csi IA8C Monographs on Ihe FvaluaUoir ol ll>e cinogenk; Risk ot Chemicals to Hoi nans. So men! 4. 292 pp. Lyon, France IAHC, *9; 200-202. `^Internaltonal Agency lor Research on Cl "Toxic Substances Control Act, Chemical Substance Inventory, 1979; public record IARC Monographs on Ihe I-valuation ol tin cinogenic Hisk ol Chemicals lollumans. Vi 5l3pp. Lyon. Frarx:e IAHC, >979. pp 371 199 AP00054864 ol the liver, following gastric intubation of a solution in olive oil, vinyl chloride was carcinogenic in rats. Vinyl chloride was carcinogenic in rats following prenatal exposure. A dose response has been demonstrated.5*0-54' PROPERTIES Vinyl chloride is a colorless gas that is slightly soluble in water. USE Vinyl chloride is used mainly in the pro duction of plastics. It also is used to syn thesize other chemicals, and it was formerly a component of aerosol pro pellants. Vinyl chloride-vinyl acetate copolymers are used extensively to pro duce vinyl asbestos floor tiles. PRODUCTION Annual production of vinyl chloride in the United States is about 7 billion pounds. The 1979 TSCA Inventory identifies 17 companies producing 6.9 billion pounds of vinyl chloride, with some site limitations; theCBI Aggregate is more than 1 billion pounds.542 Earlier, domeslic production of the homopolymer of vinyl chloride was reported as 5 billion pounds; imports amounted to 55 million pounds. Estimated domestic production of the acetate copolymer of vinyl chloride is 279 million pounds. 441 Inter national Agency lot Research on Career. EXPOSURE Potential human exposure to vinyl chloride occurs mainly through inhala tion and. less frequently, through skin absorption. More than 3.5 million workers posstbfy are exposed lo (he chemical. Others potentially exposed in clude 4.6 million people who live within 5 miles of industrial sites al which en vironmental emissions occur. Air emis sions measured near several production facilities contained 3.1 to 12.5 ppb ol vinyl chloride. Very low exposure may occur if unreacted vinyl chloride remain ing in packaging materials made from polyvinyl chloride leaches into food and beverages (0.05 to 25 ng/kg) or medical products. Also, cigarette smoke is reported to contain 5 ng to 16 ng/cigarelte of vinyl chloride.543 REGULATIONS CPSC, EPA, and FDA each banned the use of vinyl chloride as an aerosol pro pellant, eliminating exposure of 1 million to 5 million people annually. Under the Clean Wafer Act, foPA published a water quality criteria document for the protec tion of human health, addressing vinyl chloride. The Clean Air Act, National Emission Standards for Hazardous Air Pollutanls, addresses vinyl chloride emissions from production and manufacturing facilities. The Resource Conservation and Recovery Act sub jects the chemicals waste products, offspecification batches, and spill residues to handling and report/recordkeeping requirements; it also designates vinyl chloride as a hazardous constituent of wqqrp qnd si;bi^'iCln wastes known fn ing requirements under the Compie-hensive Environmental Response Com; pensation and Liability Act. f FDA eliminated the use of vinyl chloride in drug products and has alerted food manufacturers to the need for monitoring packaging materials that 'may contain it. FDA's Center for Food ' Salety and Applied Nutrition presently ' is reevaluating its position on the September 3, 1975, proposal and i withdraw it in October 'BM, OS adopted a standard of 1 Hun (or \ chloride, as an 8-hour ir/no wHyl average, with a 5-ppm ceiling for 15-minute period; OSHA requ medical surveillance, iMming workers, use ol protective clothing respirators, warning signs, proc labeling, and periodic monitoring Occupational Exposures Associated Wi A Technological Process HEMATITE UNDERGROUND MINING CARCINOGENICITY There is sufficient evidence lor the car cinogenicity in humans of underground hematite mining (with exposure to -fadon).544 Underground hematite * miners have a high incidence of lung ? cancer, whereas surface hematite - miners do not. It is not known whether o this excess risk may be due to hematile; to radon (a known lung carcinogen); to ' Inhalation of ferric oxide or silica; or to Q combination of these or other factors. Some studies of metal workers exposed lo ferric oxide dusts have si town at creased incidence of lung cancer, w other studies have not1'"145'15 ihe Ituence of faclotsin the workplace, o than ferric oxide, cannot eliminated 545 No carcinogenic effects were served in mice, hamsters, or yui pigs given ferric oxcle mlratrac ally.545 PROPERTIES Hematile is iron ore. and ferric: oxicj its major constituent. Most iron nte < contains between 10 and 20 pore silica. Iron and feme oxide am soli in acids, but not in water fn dnnif salty air, iron oxidizes lo imrir. nxn 'international Agency lor Research un Cancel U c c u p a u o iic ti- E p id e m io lo g y ' r e r p ^ s Inc Q cj CO - >, 00 Q| Sg--JE "3 X u s 1 3xo: 3 < *. *0 Ca U -2 --0 "3 Oj t^o -=J -a rs QcOd SI ^i OO X! oM o c4 a P Q c3 opN ftS AP00054865 AP0005486 ,al mortality Lll-lio IU1 ,,i. v.l..-- ^scs, usually by 10 lo 20%. Therefore, even if there is no absolute excess aihong a group of deceased persons, for rnetliodologic reasons an excess of ' 'Mght be expected. Note that in the realm of rate ratios, this is a very weak n. I'lVIRs tend to be more intcrpretable for uncommon causes of death than for -'aiises. If the rate of some uncommon disease such as lung cancer is increased the SMR and the SPMR will each reflect this increase. However, if a illness such as circulatory disease is increased by 200%, the SMR will still s increase, while the SPMR will be increased considerably less. Also, whereas ,r two or more causes are essentially independent of each other, SPMRs for [Ofc causes are interdependent, since the sum of the expected numbers must sum of the observed numbers, c of these limitations to SPMR analyses, they are most useful and provide ion that usually differs little from that obtained in an SMR analysis. It is i instructive to do SPMR and SMR analyses on the same data, so as to cval.cpretation of the results of these two methods of analysis. pie -- Rubber Workers ler again the data in Table 6.1. In assessing whether a specific cause of death esj, one might look only at causes for which the SMR is greater than 100. If -'rion is used, only leukemia and cancers of the stomach, large intestine, and are in excess among the entire group of rubber workers. However, it might be hat because of the HWE (or because of some other bias), SMRs greater than causes'* SMR should be considered to be in excess. Intuitively, one assesses cess by dividing each cause-specific SMR by the all-causes SMR to obtain a ted" SMR (CSMR).16 csults of such a division are illustrated in Table 6.J7. In Column I are the same is in Table 6.1 (note that the SMRs differ slightly because the analyses were out at different times). In Column II are the CSMRs. CSMRs less than 100 i only for diseases other than cancer or cardiovascular disease. In Column HI SPMRs from a proportional mortality analysis. By definition the all-cause and the SPMR arc 1.00. n be seen that the CSMR and the SPMR for the several causes illustrated are Part of the similarity no doubt is due to the relatively weak associations beJiscase and working in the rubber industry. However, under any of the three Is used to compute expected numbers, one would wish to investigate further rom bladder cancer and the lymphatic and hematopoietic cancers, e is one tendency in Table 6.17 that may be of interest. For diseases of old s, e.g., bladder cancer and stroke, the CSMR is higher than the SPMR. For s of young persons, e.g., brain cancer and external causes of death, the SPMR er than the CSMR. Whether this tendency is a general property of the CSMR e SPMR is unknown. If it is a general property, it no doubt results from the le weights differ between a SMR computation and SPMR computation, i.e., ,-years vs. numbers of deaths. unple -- Vinyl Chloride Workers 974, three cases of angiosarcoma of the liver among vinyl chloride workers were Division "Laid Off" Chemical Aerospace Tires Industrial products Services Rubber reclaim Processing Total Alf caMi Ever Usual _ 74 (161) 74 (711) 79 (1968) 76 (1600) 33 (2238) 75 (313) 79 (833) 8l (319) 74 (68) 81(282) 81 (1345) 81(796) 84(1638) 72 (93) 87 (538) -- 82(5079) AH CMctti Ever -- 85 (32) 92(155) 92(J97> 84 (309) 90 1405) 94 (68) 98 (177) 69 l-M* 80 (t^ 89(3^ 94U\n^ 9*1 - 94 1^ * Data differ slightly from those presented in Tabie 6.1 Table 6.17 NUMBER OF DEATHS OBSERVED AMONQ RUBBER WORKERS AND RATIOS OF OBSERVED TO EXPECTED ACCORDING TO THREE METHODS Cause of death Observed deaths Obscrved/expccled' l II m All causes All cancer Digestive Bladder Brain Lymphatic and hematopoietic CNS vascular Circulatory External All other causes 4982980 364 48 20 106 493 2445 278 786 0.82 0.94 0.98 1.22 0.80 1.13 l .00 2.17 1.22 1.52 1.00 1.42 l i.t> 1-2) l-Av Mix 0.91 0.83 0.62 0.65 1.13 1.03 0.77 0.74 1.0' 1.04 0,7* Excludes 97 deaihs of unknown cause. * 1 Expected numbers based on 5-yeai age-time specific mortality rates for U.S. white males ISMR/iQO). II Expected ratios in I have been divided by 0.82 (ail causes SMK/1Q0) and by 0.98 to correct for 97 deaths of unknown cause (CSMR/IOO). III Expected numbers based on 5-year age-time specific pioportionai mortality ratios for U.S. white males (SPMR/J00). reported.2` ILater In the same year, the results of two cpidemio(v^ ported. In one, a standardized proportional mortality analysis w^'1' causes of dpath among 161 deceased persons, most of whom h^ ^ plant as the (hree with angiosarcoma.11 In the second, a stand*v^ AP00054867 Table 6.18 OBSERVED AND EXPECTED DEATHS AMONG VINYL CHLORIDE WORKERS IN A PROPORTIONAL MORTALITY STUDY' Cause of dead) Observed Expected SPMR All causes All cancer Digestive Liver and biliary Lung Brain Other CNS vascular Circulatory External All other causes 161 J61.0 100 41 27.9 150 13 8.3 160 8 0.7 1100 I] 7.9 160 5 1.2 420 10 10.5 95 8 9.S 80 66 68.6 96 22 24.5 90 24 30.5 79 Expected numbers based on proportional mortality ra tios (or United Stales white males. * SPMR m Standardized proportional mortality ratio 100 * observed/expected. s was conducted on the mortality among 8384 men who had worked with vinyl c, including those at the same plani as above.11 Among these 8384 workers were o had died, including most of the 16i included in the above report, tble 6.18 are presented the results of the SPMR study. A 50% excess of cancer *n, which was due entirely to cancers of the liver, the lung, and the brain. In >.19 are presented the results of the SMR study. As compared to the general tion, there was essentially no excess of cancer. However, the CSMR was (102/ 00 or 136. There were large excesses of cancers of the liver and of the brain, piratory cancer, while the SMR was close to 100, the CSMR was 140. rite two studies reported similar results, even though one was smaller and based on a SPMR analysis. In this study an analysis according to age and year of >f persons with cancer was also done (Tabic 6.20). As can be seen, while there lend with age at death, there is a steady increase in the SPMR with year of T his suggests that many more persons will die from cancer because of exposure 1 chloride. judgment as to whether the excesses of specific causes of death are likely lo be is based on reason rather than any statistical significance. There can be little that vinyl chloride (or sonic closely related compound) is responsible for the ireoma. This disease was extremely rare before it was discovered among vinyl c workers. The rate ratio among vinyi chloride workers must be in the 1000s. lease occurred mainly in the men who worked for many years (10+ ) cleaning otors; these men accumulated a high dosage of exposure to vinyl chloride. While ireoma association is at the top of the highly likely to be causal group. This i: in epidemiology (or any science) is ever absolutely certain, the vinyl-chlorideircoma association is at the top of the highly likely to be casual group. This after the first three eases of angiosarcoma were identified. ' rrs nrrt f n I'nnrrri of l hr hr a in and of l hr* Inn v a rn i i sn l in In nrrl n 1 in n of the Table 6.19 OBSERVED AND EXPECTED DEATHS AMONG VINYL CHLORIDE WORKERS IN A MORTALITY STUDY* Came of death Ohsei ved Expected SMR All causes All cancer Digestive Liver Respiratory Brain Other CNS vascular Circulatory External All other causes 352 467.1 75 79 77 2 102 19 21.7 88 7 1.7 412 25 2.3.9 r 05 , 7 2.3 2 BO 10 9.3 1(18 13 24.5 57 142 178.8 52 91.7 79 57 66 95.1 69 Expected numbers based on morlalii y i ates for United States white males. Table 6.20 OBSERVED AND EXPECTED DEATHS FROM ALL CANCERS AMONG VINYL CHLORIDE WORKERS IN A PROPORTIONAL MORTALITY STUDY ACCORDING TO ACE AND YEAR OF DEATH Characteristic Category Obsei ved Expected Sl'MK Age of death <50 50--59 >60 II 7.6 140 17 8.1 210 13 12.2 1 Id Year of death <1965 12 1 1.4 no 3565--69 10 7.3 140 >1970 19 9.2 210 lung cancer. Exposure must be reduced because of its highly likely role ii angiosarcoma. If some lung and brain cancer are also prevented, so much tl IV. CASE-CONTROL STUDIES WITHIN A COHORT On occasion, personnel records may be available for a cohort of employet but it may be too expensive to review all of the records to determine the wo of each person. Some sample of the records is selecled to be reviewed. Since interest in such review is to determine association between work and diseasi is given to reviewing the work histories of persons with one or more diseases o Por purposes of comparison, the work histories of "controls" arc also dctcrir A. Procedure AP00054868 orta! L'pidtru/olotty `eficii Medical Association, Standard Nomenclature of Diseases and Operations, 5ih cU., TUor^p- '< T., and Hayden, A. C., Eds., McCraw-Hiil. New York, 1961. 'n*. !>., Shapiro, S>.. and MieUinen, O. Case-con fro) surveillance of serious illnesses attributable ar)it>uJjNc>ry drug ate, m Epidemiototkaf Evaluation of Drugs, Colurobo. F., Shapiro, S,, Slone, ^dTognoni.G-, Eds., Elsevier, Amsterdam, J977, 59. ,nt, D.t Shapiro, S., Rosenberg, L., Kaufman, D. W., Hartr, S. C. Rossi. A. C., Stolley, P. D., d O. S.t Relation of cigarette smoking <o myocardia) infarction in young women, N. >*l. J. Med.,298. I27J, 1978. Chapter 9 CURRENT PROBLEMS IN OCCUPATIONAL EPIDEMlOLO<j> I. INTRODUCTION The purpose of occupational epidemiology is lo provide information an ) health (hat can be used to prevent human illness. As time goes by data accumui* the relationship between occupational exposures and human diseases. Sonic v,sj data can be interpreted unequivocally and can provide a firm basis for a cbv% behavior. Other data arc subject lo more than one interpretation or may be civ** as to veracity. As indicated throughout these pages, data by themselves pro*\ indication as to whether or not they reflect true processes in human population In this chapter a variety of problems related to occupational exposures anj- ^ ered. These problems are illustrated by referring to recent literature in epidemiology. Tht intent is to provide an overview of general problems rather * provide a detailed review of specific issues. Excellent reviews of the knovvn ^ pected effects of exposure to substances used in industry can be lound in th-. Documents published by the National Institute for Occupational Safety ar*4 j (NIOSH) and in the reports of the International Agency foi Research u* ^ (IARC).1-1 For each of the studies reviewed in this chapter, the collection, analysis, precation of the data are presented and the meaning of the results is discus^yj of the studies arc models on how to conduct research; some of the studies. problems in methodology that should be avoided. All of the studies illustrate ^ ities encountered in conducting research in occupational epidemiology amj ^ preting the results of that research. II. OCCUPATION AND REPRODUCTIVE EFFECTS Exposure to substances used in industry may lead to effects on the system in men or in women or may lead to an effect on the unborn fetus. ^ have been published on the general relationship between occupation and reproduction. Untii recently few pregnant women have been exposed to iiKU^ vironments. Any effects on male workers are difficult to detect. Any effects o\> * have not been studied to any extent. A. Vinyl Chloride and Fetal Deaths In October 1974, interviews were conducted with male workers expose ^ chloride monomer (VCM), polyvinyl-chloride (PVC) or rubber.3 Question* N ' about the interviewee's health as well as about the outcomes of pregnancy .. T ers' wives. The fetal death rate subsequent to exposure for VCM was the families of exposed men than among the families of controls (Table 9, i^ This study is difficult to classify. It is not a retrospective cohou stvjq^. workers were not followed either in retrospect or in prospect for the ck\-^ ' fetal deaths. It is not a case-control study, because subject selection wax |U>J presence or absence of fetal deaihs. It is best thought of as a cross-sevi|n 1 where exposure is presence or absence of a history of VCM exposure * .. - f 1,,/t r^l^l A .. l't AP00054869 Table 9.1 FETAL DEATH RATES AMONG FAMILIES OF MEN EXPOSED TO VINYL CHLORIDE MONOMER AND AMONG FAMILIES OF CONTROLS Feltl death rale* Prior to exposure Subsequent to exposure Group Crude Standardized Crude Standardized Exposed 10.1 6.1 16.5 15.8 Controls 6.9 6.9 8.8 8.8 * Numhci of feiat deaths per I DO pregnancies. o increased feial death, but if controls with fetal deaths terminated at a higher ban exposed workers with fetal deaths. This can be thought of as selection bias. `'Ction bias also was possible because not all workers eligible for the study were iewed. The data in Table 9.1 could have resulted if exposed workers with a hisT Tetal deaths selectively agreed to participate in the study. ause the interviews were not conducted blindly, observation bias was possible, 'ala in Table 9.1 could result if workers with exposure to VCM over-reported, or trols under-reported, the occurrence of fetal deaths. information on smoking of mothers is presented. Smoking is known to be assoI with an increased fetal death rate.'1 The data in Table 9.1 could have resulted confounding by smoking if the wives of VCM workers smoked more than the of controls. - primary procedure used in the analysis was direct standardization of rates, bethe age distribution differed between exposed and control groups. Because the urd used was the age-distribution of the controls, the crude and standardized for controls in Table 9.1 were identical. For the exposed, there was a substantial tion in the standardized rate prior to exposure. This occurred because the exposed > was older than the control group, and because the rate of fetal deaths increased lge (Table 9.2).* i his example the standardization behaved well, since the age-standardized rates II as the age-spectfic rates showed essentially no differences in fetal death rates en the exposed and the control groups. However, the potential difficulties of standardization with respect to small numbers can be seen. If there had been controls in the <20 category, and if there had been two or three fetal deaths u. the seven exposed persons in the <20 category, that stratum would have con ed heavily to a high standardized rate among the exposed group. In such a situit is best to limit the analysis to overlapping age-strata in which there aresuffinumbers, e.g., ages 20 to 29. In any standardization procedure attention must en to the elements being standardized meaning of this single study is unclear. Some of the criticisms raised above must wed as far-fetched. The likelihood of selection bias seems remote. The possibility servation bias is more real, inasmuch as the interviews were conducted shortly the carcinogenic properties of vinyl chloride were announced. If anything, the Table y.2 FETAL DEATH RATES PRIOR TO EXPOSURE AMONG FaMILII OF MEN EXPOSED TO VINYL CHLORIDE MONOMER AND AMONG CONTROLS ACCORDING TO AGE OF FATHER Age of father Number of pregnancies Group Exposed Control <20 7 31 20--24 44 80 25--29 56 3R 30--34 27 6 >35 14 a Petal deatli rate* Exposed Control 0.0 6.5 4.5 5.0 12.5 10.5 IK. 5 16-7 71 0a * Number uf feial deaths per 100 pregnancies if wives of exposed men smoked more, the association between smoking deaths is weaker than the association seen in this study. As suggested by the above paragraph, the meaning of the results of this matter of opinion, not of science. Different persons will raise differem cri different defenses. Certainly the results of (his one study are not definitive. With respect to future public health policy, it is not a major concern whe chloride exposure to men tends to increased fetal deaths among their offsp association between VCM and angiosarcoma is many limes stronger and VCM exposure must be reduced. Such reduction would be expected to min adverse effects of VCM on the reproductive system. However, it is of public health concern that VCM might affect pregnat directly. In order to address this concern, studies must be made of prcgnai exposed to VCM and of their children. B. Paternal Occupation and Childhood Cancer !. Children in Quebec "In reviewing, for other purposes, a small sample of birth and death certi Quebec children, the impression emerged of a large number of fathers in petr occupations when the cause of death was cancer."* To quantify this impre occupation of the father was obtained from the birth certificate of 386 child (he age of 5 who died from cancer. For comparison put poses, two matcher per case were selected -- the preceding and succeeding child in the buth t registry. As seen in Table 9.3, approximately (wice as many cases had fa( potential exposure to petrol and other hydrocarbons. The odds ratio is (71 (75 x 315) = 2.1. The 95% confidence interval of the odds ratio is 1.5 to 3.0. Selection bias is an unlikely explanation since paternal occupation was i tained until after cases were defined. Observation bias could have led to the: The authors admit to a prior notion that petro-relaled occupations were i childhood cancer. In classifying a father's occupation, it is possible that oo difficult to classify were coded as petrol-related for cases but not for centre ever, the authors state that occupation was coded by a person who was blin case-control status. Thus, for this reason, observation bias was not possible. Confounding by some factor related to occupation and childhood umrer ways be an explanation. However, no data on potential confound in* fuel Methodology foe Ranking the Degree of Hazard Associated with Exoosuce to Carcinogens and Other Toxic Chemicals (U.S.) Environmental Protection Agency Washington/ DC Feb 85 PB85-I6790G i ClSaw tfsfejei fcdiRSiiiw &*nnc* ?W lJJ ><. wl'V\T i iirar n in it st'eaa AP00054870 peeS-167906 EPA/600/0-35/040 February 1935 METHODOLOGY FOR RANKING THE OEGREE OF HAZARD ASSOCIATED WITH EXPOSURE TO CARCINOGEN'S ANT) OTHER TOXIC CHEMICALS by Elizabeth L. Anderson3, Margaret Chub, Michael Doursonc, and Christopher DeRosa0 director. Office of Health and Environmental Assessment U.S. Environmental Protection Agency Washington, DC 20460 ^Toxicologist, Carcinogen Assessment Group Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Office of Health and Environmental Assessment Office Cincinnati, OH 45268 OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT OFFICE Of RESEARCH AND DEVELOPMENT U.S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460 (fm)tA(i r NATIONAL TECHNICAL INFORMATION SERVICE tu.0(rj[(Rr or cohmocE vxmcriao. i*. mu AP00054871 METHODOLOGY FOR RANKING THE DEGREE OF HAZARD ASSOCIATED WITH EXPOSURE TO CARCINOGENS ANO OTHER TOXIC CHEMICALS* Elizabeth L. Andersonb, Margaret Chuc, Michael Dourson^, and Christopher OeRosae aTh1s paper is adapted from two documents prepared by the Office of Health and Environmental Assessment. Office of Research and Development, U. S. Environ mental Protection Agency: Technical. Suooort Document and Summary Table for the Ranking of Hazardous Chemicals 8asea on Carcinogenicity (Car'cinogen Assess ment~iJtoup^_External Review OraftT GHEA-C-GT3'7"">JuTy ' 1983"); and Methodology and Guidelines far Reportable Quantity Determinations Based on Chronic Toxicity Oata~(^xterrra~i RevTew Draft, Environmental Criteria and Assessment Office,'ECAO-CIN-R2.45, August 1983). ^Director, Office of Health and Environmental Assessment, RD-639, U.S. Environ mental Protection Agency, *01 H St., S.W., Washington, D.C., 20450. cToxicologistCarcinogen Assessment Group, Office of Health and Environmental Assessment. ^Toxicologist, Environmental Criteria and Assessment Office - Cincinnati, Office of Health and Environmental Assessment. Geologist, Environmental Criteria and Assessment Office - Cincinnati, Office of Health and Environmental Assessment. I AP00054872 T = CHMCAL ntPORT OATA J - F.PA/600/D-S 5/040 - j ,3 =1 tZ. >, r s ACC' 35IC'* *.C j - ' . * _ = -s; i.il.T.i S ae3t'T OATS Methodolocy for Ranking the Oegree of Hazard Associated "phruqrv 1085 With Exposure to Carcinogens and Other Toxic Chemicals S. NO coce -j Elizabeth L. Anderson, Margaret Chu, Michael Dourson, and. Christcoher DeRosa J si . ic iOCOEJS Office of Health & Environmental Assessment/ORD U.S. Environmental Protection Agency 401 M Street, S.W. Washinoton, D.C. 20460 12. iVUNSQBiv.C JCtNCY \ iJ6 ANC AcaP5S Office of Health & Environmental Assessment/ORO U.S. Environmental Protection Agency 401 M Street, S.W. Washington. D.C. 20460 15. Sl^lEVNTASV NOTES S. AN i 2 A f 1A S P cj ** '*0 lO. JBOOSAM 6 l. M 6 N T Si Q n coNTr.ACT.cflANT no. n/a 13.TTEOf R{OBT ANOPERlODSOVEnES 11, SPONSORING AGENCY COOS EPA/600/21 To A hazard-index is an overall indicator or the potential harrrfoT a nazaroous substance to humans and the environment. This paper describes the use of a carcino genicity index and a systemic (chronic) toxicity index in setting reportable quanti ties under Section 101(14) of the Comprehensive Environmental Response, Compensation, aM Liability Act (CERClA) of 1930. The three types of evidence used to evaluate a substance's carcinogenic hazard are 1) epidemiological, 2) experimental and 3) supportive evidence from short-term tests, metabolism and pharmacokinetics and structure-activity correlations. Hazard ous substances suspected of carcinogenic potential are ranked by the level of this evidence and the potency factor. The potency factor is 1/ED^g, where ED^q ''s the estimated dose associated with a lifetime cancer risk of 10&. The toxicity index for substances with systemic (chronic) toxicity potential is based on the minimum effective dose levels for chronic exposures via environmental media and the type of effect. About 200 potential carcinogens and 200 chemicals associated with other diseases have been evaluated and assigned a hazard ranking.. oescsiffons <r'WOBOS ANC DOCUMENT ANALYSIS h. 1DGNT1F fSflS/OPEN 6.M06D TEW MS c. cosat: i ititi Cruup - . V. 9_AT'.lcNT Release unlimited; distribute through NTIS , 1223-1 13-7}) 13 Sfe CU " V CL ASS i put Report/ Unciassified 20 SECURITY CLASS . PutP'tzet t Unclassified n no offiCi 55 AP00054873 CONTENTS I, Introduction.................................................................................................. [[. Toxicity Index of Potentially Carcinogenic Substances. ..... The Weight-of-Evidenee Approach to Evaluating the Evidence for Carci noganici ty.................................... .................................................... Summarizing the Weight-of-Evidence for Carcinogenicity Using the International Agency for Research on Cancer ([ARC) Criteria.................................................................................................. Potency Factor Estimates ............................ Potency Factor Grouping ........................................................................ . Cancer Hazard Ranking Sased on Combined Qualitative and Quantitative Assessments ..................................................................... .. III. Toxicity Index for Substances with Systemic (Chronic) Toxicity Potential. .................................................................... The Minimum Effective Dose (MED) ......... ......................... Rating Potentially Hazardous Chemicals According to the Severity of Disease......................................................................................... Toxicity Hazard Ranking Based on the MED and the Severity of Disease.................... [V. References................................................ Appendix: International Agency for Research on Cancer Classification System for the Evaluation of the Carcinogenic Risk of Chemicals to Humans............................................................................. I 3 3 5 5 5 7 8 8 8 8 45 47 ill AP00054874 LIST OF TABLES Taole I. Sumnary cf Ha2a. ` ,'anking for Potential Carcinogens................ Table II. Severity of Oisease Rating Values for HOAELs, LOAELs, and FELs Used to Derive Reportable Quantities Based On Chronic Toxicity ................ . ..................... Table III. Summary of Hazard Ranking Based On Chronic Toxicity. .... 12 29 LIST OF FIGURES Figure 1. Rating Values for Doses Used to Derive Reportable Quantities Based On Chronic Toxicity................................................. 27 fv AP00054875 I. ItfTaOOUCTIGM Inadvertent exposures of populations to hazardous chemicals make it neces sary for public health officials to have immediate knowledge of the severity of potential effects; and the doses that cause the effects observed. A hazard index has been developed in response to the neeo to establish a rating scheme to characterize hazardous chemicals according to the severity of disease and tne associated hazards, and to prescribe quantities of hazardous chemicats which, when spilled, must be reported to the U.S. Environmental Protection Agency. About 200 potential carcinogens and 200 chemicals associated with other diseases have been evaluated. The hazard index for potential carcinogens couples the weight of evidence indicating potential carcinogenicity with the potency of the chemical to rate the relative cancer hazard. Similarly, the hazard index for chemicals that may cause other diseases couples rating factors for the severity of disease with the dose which causes the onset of disease to rate the relative hazards of these chemicals. These hazard indexes and the data for the chemicals thus far evaluated may have more general applications in assessing chemical risks to the public in response to accidental exposures. Toxicity indexes, such as lethal dose for 505 cf animals (LDsq) and noobserved-effect-level (NOEL) can be used in the setting of permissible levels of harmful substances in the environment or for setting priorities of concern of harm to human health or the environment. Hazard index can be defined as the overall indicator of potential harm of a hazardous substance to humans and the environment. Hazard Indexes can be estimated by talcing into consideration all parameters related to the fate, effects, and dose-response character!sties of the hazardous substances. Thus the chemical structure; physicochemical properties; mechanisms of action; chemical, biological and environmental transformation and 1 AP00054876 transport; and toxicity indexes arc important parameters for estimating hazard indexes of chemicals in the environment. Soma of the above parameters can be estimated from experimental data, while others may nave to be estimated using statistical techniques. The extent and the form of hazard indexes deperds on the purposes for which they are used. This paper describes the use of a systemic (chronic) toxicity index and a carcinogenicity index in setting reportable quantities (RQ) under Section 101(14-) of the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA or " Superf und") of 1980- Section 103 of CERCLA requires immediate notification from any person in charge of a vessel or an offshore or onshore facility who releases an amount of a hazardous substance equal to or greater than its RQ. Under CERCLA Section 102(b), the RQ of any hazardous substance designated in Section 101(14) is one pound unless a different RQ has been established pursuant to Section 311(b)(4) of the Federal Water Pollution Control Act. These are statutory RQs for the CERCLA Section 101(14) hazardous substance unless and until the Administrator of EPA promulgates regulations establishing different quantities to be reported when released. CERCLA also permits EPA to establish a single RQ for each hazardous substance, regardless of the environ mental medium into which the substance is released. The Emergency Response Division of the Office of Emergency and Remedial Response proposed to use "Selected Criteria Processing'1 (SCP) to adjust the statutory RQs. SCP includes 1gnitability, reactivity, carcinogenicity, aquatic toxicity, acute mammal 1 an toxicity (oral, dermal, inhalation) and chronic toxi city as the six primary criteria for adjusting RQs. The RQ for each hazardous substance is the lowest numerical value of all applicable RQs derived from the primary criteria. The RQ is then readjusted using biodegradability, hydrolysis, and photolysis as secondary criteria. 2 AP00054877 n. TOXIC ITY INDEX of potentially carcinogenic substances Hazardous substances suspected of carcinogenic potential are ranked usinr as toxicity index the level of evidence in support of their carcinogenicity and the Strength (potency factor) they exhibit In Inducing carcinogenic responses. Three types of evidence are used to evaluate a substance's carcinogenic hazard potential. They are: (1) epidemiologic evidence; (2) experimental evidence derived from long-term animal bioassays; (3) supportive or suggestive evidence from short-term tests, metabolism and pharmacoklnetics, and structure-activity correlations. THE WEIGHT-OF-EVIUENCE APPROACH TO EVALUATING THE EVIDENCE FOR CARCINOGENICITY The weight-of-evidence is defined as the strength of evidence indicating potential carcinogenicity, not relative carcinogenic activity or potency of Che agent- Tf]us, an overall decision as to whether an agent may pose a carcinogenic hazard to humans is based on a careful evaluation of all relevant scientific data, including the design and conduct Of the study and the nature and type of resoonses. In the most complete form, a weight-of-evidence determination should be made from a consideration of the-strengths and weaknesses of each piece of evidence, including epidemiological investigations, long-term animal studies, and supporting information. Primary Sources of Information Epidemiology Studies-- Human information provides direct evidence of the association of increases in tumor incidence or mortality in humans with exposure to chemicals. Welldesigned and conducted analytical epidemiology studies, especially case-control and cohort investigations, are of prime importance; descriptive studies and case 3 AP00054878 reports provide ancillary i ^formation. [moortanc elements in interpreting the lively causality of epidemiological observations include the magnitude .;r" Lhe risk estimates (strength of cne asso ciations); the likelihood of their being due to chance (statistical significance); "he rigor of the study design to avoid various kinds of bias, including those related to selection, confounding, classificatlon, and measurement; the doseresponse relationships; the temporal relationships between exposure and disease; the specificity of the associations; their biological plausibility; and the reproducibility of the findings. Long-Term Animal Studies -- Confidence in the results of animal experiments is gained when carcinogenic effects have been confirmed in repeated experiments, in different animal strains or species, or in different dose groups or sexes within a given study. Other measures Include demonstration of a highly significant increase In tumors, the presence of tumors at multiple anatomical sites, the histological types of tumors present, and the shortening of tumor latency in treated groups as compared with controls. Dose-response relationships also support a conclusion of carci nogenicity. In reaching an overall evaluation of the experimental animal evidence, each long-term study is reviewed with regard to the following factors: a) tumor incidence b} tumor development c) preneoplastlc lesions d) target-o-gan toxicity e) other relevant biological and chemical information. 4 AP00054879 Supporti uq [n format-ion Short-Term Testing-Apprpprla-te in vivo and in vitro short-term :ests provide ancillary cmpi - rica! and potentially mechanistic information bearing on the carcinogenicity of an agent. Biological Test Results-Many toxicological, physiological, and biochemical observations, such as comparative metabolism and pharmacokinetic studies and certain mechanistic in vestigations, can contribute to a determination of cardnogenicity. Structure-Activity Relationships-- 4 General information bearing on the biological reactivity of compounds che mically related to the agent under investigation is useful in the evaluation of the carcinogenicity of the agent, a SUMMARIZING THE WEIGHT-OF-EVIDENCE FOR CARCINOGENICITY USING THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) CRITERIA After the data have been evaluated, the weight-of-evidence for carcinoge- nicity is classified according to the IARC criteria (see Appendix). In this approach the strength of the evidence for human and animal studies is evaluated' separately, and all relevant factors are combined into an overall qualitative evaluation of the Mketihood that the'agent is a human carcinogen. POTENCY FACTOR ESTIMATES After the decision has been made that a compound has the potential for causing cancer tr humans, a potency factor F, defined as I/EO^q, is estimated. ED]_q is the estimated dose associated with a lifetime cancer risk of 10%. The '1 1 j i I | ri I \ t j ! 1 j j j \ \ ! j AP00054880 potency factor F is used together with the qualitative weight-of-evidenca for carcinogenic! ty in the ranking of the carcinogenic hazard potential of the chemicals. The potency factor F is used in place of the potency factor q^r, which the Carcinogen Assessment Group (CAG) normally uses in the estimation of upper bounds of risk, because the objective here is to rank chemicals for their poten tial to cause carcinogenic harm and not to estimate risk associated with a par ticular level of exposure. Furthermore, using the potency factor F has the advantage of avoiding the many assumptions that are required for calculating and/or using q^ This is possible because the dose associated with a lifetime cancer risk of 10% is usually within or close to the experimentally observable range. Other advantages of the potency factor F are: a. It is relatively insensitive to the choice of the dose-response extrapo lation model. b. The point estimation of ED^o, which has some optimal statistical pro perties, can be used to calculate F. Therefore, it is not necessary to use a statistical upper-bound estimate. POTENCY FACTOR GROUPING The potency factor estimates are indicators of relative magnitude (potency) to cause carcinogenic harm. These numerical values are useful tools for setting toxicity indexes. When the relative potency factors are estimated by the procedure outlined above, they are aggregated into four groups. Thos* chemicals with the highest potency factor are placed in group l, intermediate potency factor chemicals are t q* is the upper confidence limit for the linear coefficient in the multistage model. 5 AP00054881 placed in group 2, low potency factor chemicals are placed in group 3, and the lowest potency factor chemicals are placed in group 4. The method used for grouping 192 chemicals for the RQ project is to place chemicals with potency factors (F) above IDO into group 1; chemicals with potency factors from 10-100 into group 2; chemicals with potency factors from 1-10 into group 3; and chemi cals with potency factors below l into group 4. The major disadvantage of this method is that the grouping of chemicals with borderline potencies between groups is arbitrary. While toxicologic Information could be used to aid in placement, the process would still be somewhat subjective. Another method of grouping is analysis for clustering in addition to potency numerical value cut off poi nts. CANCER HAZARD RANKING BASED CN COMBINED QUALITATIVE ANO QUANTITATIVE ASSESSMENTS The culmination of the hazard ranking process described in this study is accomplished by combining the qualitative weight-of-evidence for carcinogenicity with the potency_group placement to arrive at a final carcinoyanicity index for each chemical. Substances are ranked as posing a high, medium, or law cancer hazard according to the following scheme: Carcinogenicity Indexing for Reportable Quantities under CERCLA Potency Group IARC Group 1 F>100 2 F * 10-100 3 F * 1-10 4 F<L 1 HIGH HIGH MEDIUM LOW 2A HIGH MEDIUM MEDIUM LOW 2B HIGH MEDIUM LOW LOW 3 Cannot Be Ranked in General* 7 AP00054882 The hazard rankings for about 200 suspected carcinogens are cresented in Table I {page 12). III. TOXICITY INDEX FOR SUBSTANCES WITH SYSTEMIC (CHRONIC) TOXICITY POTENTIAL The toxicity indexes on chronic toxicity reflect two primary attributes of each chemical: 1. The minimum effective dose (MED) levels for chronic exposures (mg/day for a 70-kg man) via alternative environmental media (air, water, etc.). 2. Type of effect (liver necrosis, teratogenicity, etc.). THE MINIMUM EFFECTIVE DOSE (MED) The dose rating for a given chemical is based upon the MED transformed to values ranging from 1-10 using the graph in Figure 1 (page 27). Substances having an effect at a low dose (i.e.* those that are more highly toxic) will be given a high rating on this graph, while those requiring a high dose (less toxic) will be g;ven a low rating. The rating values range from 1 to 10. RATING POTENTIALLY HAZARDOUS CHEMICALS ACCORDING TO THE SEVERITY OF DISEASE The effect rating for an individual chemical will range from 1 to 10 depen ding on severity (Table II, page 23), with 10 being the most severe. These values must be assigned on a chemical-by-chemical basis. TOXICITY HAZARD RANKING BASED ON THE MED AND THE SEVERITY OF DISEASE A final Composite Score (CS) which is the chronic toxicity index is deter- * The group 3 category includes chemicals for which the evidence from animal studies is limited or Inadequate, and for which there is no human evidence. For those studies with reliable dose-related data, a potency estimate is determined and a hazard ranking is oerformed. 3 AP00054883 mined by multiply!ng the dose rating by the effect rating. The possible range of C3s is thus 1 to ICO. Using this scheme, only those compounds inducing what are judged to be the most severe effects at low levels of exposure would fall into the high toxicity Index category. The following step-by-step text gives additional details for this proce dure: 1. Identify subchronic or chronic no observed adverse effect levels (NOAELs), lowest observed adverse effect levels (LOAELs) or frank effect .levels (FELs) based on animal or human data from the avail able literature. Note the dose/exposure and the effect. 2. .Convert all NOAELs, LOAELs and Pels to units of mg/kg/day. Inhala tion, dietary or drinking water exposure data will be converted to units of tng/kg/day doses based on the methods outlined previously (U.S. EPA, 1980). 3. If the NOAEl, LOAEL or FEU is based on subchronic exposure, a corresponding chronic value will be estimated by dividing the subchronic value by 10 or less. 4. The MEDs based on animal data will be converted to human MEDs using the cubed root of the body weight ratio approximation, and the subsequent value will be multiplied by 70 kg to put the MED in units of mg/day for a 70 kg man.** **This is based on the assumption that metabolic rate Is a function of body weight to the two-thirds power. Thus, the human dose, assuming a body weight of 70 kg, i s equal to: animal dose x / 70 *<g \V3 l "animal weighty This equation can be rearranged so that the human dose in mg/day equals: 70 kg 9 i AP00054884 5. Assign a dose rating value (R'/d) to the dose associated with the MED as described in Figure i. 6. Assign an effect rating value (RVe) to the effect associated with the MED as described in Table II. 7. Cal culate tne CS as: CS * RVd x RVe 8. If more than one MED can be used to calculate a CS for a route of exposure (oral or inhalation), the MED for the route of exposure which will be used in setting the RQ will be selected by the following criteria: If adequate chronic data are available, disregard MEDs based on subchronic data. If more than one MED remains, select the MED which is based on the `'best" data. I If considerations of data quality do not lead to the selection of a single MED, the MED resulting In the highest CS for a given route will be used. 9. Having selected a single MED and derived a CS for each route of exposure, the MED used to determine the RQ will be the MED from the route of exposure with the highest CS. 10. The reportable quantities (RQs) are tnen assigned based on the following relationship to CS: Composite Score (or chronic toxicity index) 81-100 41-80 21-40 6-20 1-5 RQ (lbs) 1 10 100 1000 5000 10 AP00054885 The composite scores for about 200 potentially hazardous chemicals are presented in Table III (page 29). 11 94 AP00054886 AP00054887 TABLE I SUJUIAKY OF KAMIUj KAhkiNU rort roit.uikl c/ULltiJCuHj Chemical Nui Accnaphthane tCMIlphtllJ'ltll* cel yl ajiioftuorone Acrylonitrile Uliloiln B| AidrSn 9-Amlnobl phenyl lallrol* Incnlia blchroeite laonlui chrtxaete Intliracene Incnlo and Compound* Iretnlo Mold Araento dlsulfl d* nuilo trichloride Client cal (CAS) (83-32-9) (20B-96-8) (53-96-J) II07-IJ-I) (1162-65-8) O09-00-Z) (92-67-*) (61-82-5) (7789-09-5) (7780-98-9) (120-12-7) (70-)B-2) (77/8)9-9) 11303-32-8) (7701-3*-*) llrjrec of Frlilnicc lltnana Aulaia 1 3 I iiA(lei|iial e I rudcqu.ite 1 nadoqui.l e Iliailcqoalo I nadequat Sufficient Limited Sufficient Limited Sufficient lnaOeqintla Limited Sum ct ent Surricicut 1 surrici i-nt 1 nerlaquale I fi.1-kfiu.tl if I nedequa le 1nadequate Inadequate 1 nadi|uate Suf flclent (nadequale LlmtteJ 1 nailoqualo Limited Inadequate Limited I iittdoqiiAl# Grouping Oased on IAHC CrtteiU 3 3 ?U 2A 2k 20 1 20 1* *S 3 1 2A1* 2A<1 2A1* lotcncf Factor poLcncr 11 a i^ I Eatlm-ite Croup II on h 1 nfl NA HA 32.00 0.06 10,000.00 6 } .00 87-00 9-20 s 6 tu I )o,ao d <i a NA t> HA b 2 Nrd|in A Lww 1 III tli 2 Hc-11 in 2 III fii< i l.uu NA HeJ1 m NA Had1 in lA b N* II1 ftl* IIA lllA< NA High NA lllglt Note: The data herein without additional analysis should not be used for risk assessment purposes. 12 m TAULE I. SUIIMAUr UF M/iiA in f hi ui i. j \%i , . .. Chcalul Aracnlo pentoalUe Irssnlg trloitda Irstnlu trljuiridi Ill<09t0> Aurfcatna liitcrlnc Izirldlna Otnxnt fitmldlni and Its sail* Benu(t]t>rr(n Bfliitol b Jf 1 uoranthena BeutofgM )parjiaa 6<nt[k]riuok'wilhnt Banzjrl Ctilortda Bcncf a Janthracene Cheatcal ins) (OOJ-28-2) (1327-53-3) ( I30J-33-9) <lJ]2-2t-> (2165-27-2) (115-02-6) (151-56-*) Ih-M-Zl (92-A7-5) (50-32-8) (205-95-2) (l9l-2*-2> (207-08-9) (loo-M-T) (56-55-3) OuRrcn of Eil dunce ihwanj All l O.l ] 3 United ] nodo<]ii.il e Sufficient l nadoqiiol u l_l*t ted Inadequate Sufficient Surflclcnt Inadequate Sufficient Inadequate Sufficient Inadequate) UileJ Sufficient Halted surricint. Inadequate sum ci mi 3uffI clent Inadequate Sufficient Inadequate Inadequalo Inadequate Inadaquel l!*tted lllted l nAdeqoat a Sufficient Grouping Dascd on miC Criteria 2AJ 1 2*J I 20 23 2D 1 1 2B 21 3 3r 3r 2D Potency factor Esllento Potency ||a?.nril Ci <i*11 IM nkiug d IjO.OO <J P 1.20 J10.00 0.26 1.90 500.00 150.00l HA N HA 21,00 HA l-'A1* > ' * f.i HA ingh Pp 3 l.OV HA 0 1 High 1 l.cu 3 Hodl ta 1 High l High HA b HA c HA 0 2 He,l [ in Note: The data herein without additional analysis should not be used for risk assessment purposes. 13 AP00054888 TAULE l. SH/1MAKY Of hAi'AHu i< -'Jti 1 N ' . Wj f ^v i " 111. 11! v* .1 1 Chuatc*l Hut CtnjJo Jucrtdlno OerjiUUn auU Ccnpoindf 6U(2-chloroet liyl Jclhcr tlslcliloroatillirl Jollier Cacodyl to aol a 'C*U*Uu Md Cudpoianl.1 Ctdalia acoltla Cadalis Lroalda Csjum dijoria* ifiWlua fulfil* CatcUs ar*CAlo Calclui arstnlla CficiiM cilTCttCtO CirUn lelriihlorldf CIJ or**UioJ 1 ClK.|C4l (CIS) (225-5I-*) U*4D-tl-7) (II1--4-N) (v^-Qe-n (75-60-5) (77lQ-i3-9) (5*3-90-8) (7769-^2-6) (IOIOb-6U~2) (IOI24-)6-<l) uiia-tt-i) (527*0-16-6) (11765-IV-O) (56-27-5) (30S-07-7) Decree of Lvldcnco llmjiij AlllBJlf ItiaduquaLe LIbUciI luudoi|uala iuffic|cut llllll4|Ulll( Halted lulled Halted I.UIted Halted Hailed LUUad Sufficient Inudoquale Suf fjcleol I. la l `.u<4 Suf f 1 cl ciil Sufficient sumeum Inadequate Sufficient Sufficient Sufficient Sufficient Sufflclenl luudoqgjle Inaduquate Sufft cleal Sufficient Suf O cienl Groii|i|ng flaoej on UliC Cri 1 erl * y 2k* 211 1 3 2lf 2/ 2lf 2lf 2Af 2iu 2*d l 2a l Potency factor fallaula puleucy ll**.vvd Croup hunhlng ' isqa.ou */^CiO J 13.OU I9OQ.00 IU 60.UQ* k ll k k 4 a & 39.00 1 tieJl in 2 HulII ia 2 Meill in 1 mtgi IU u 2 tied 1 in Ml HoJUa IU Hod 1 UJ HI Ho J1 M> III HtJI in HI Ills!) IU IllrtH IU HeJ1iu 2 Hedl isi ill a Note: The data herein without additional analysis should not be used for risk assessment purposes. 14 0 AP00054889 l .TMilE SUMtlAKY Uj' ijA/AjiD Note: The data herein w ith o u t a d d itio n a l analysis should not be used for r is k assessment purposes. AP00054890 TAULE 1. SulUiAKV itr :n\ "i- ! : 'll i 1 ?* i . i ; < ; j.\n:r <. (r'mtiivu- M > Chualcal Hm* CyclcpfiaapJiajalde Paunoeyclu POD DUE POT Ptetlale 2, 1 -01 m 1 ik 191 u n 1, 2, T. fl-U 1 rene Dibe>ii[ h ,h pnliirticena 1,2 -D 1 Iruao- 3 - cl* 1 oro pro pane SikityinitrosuIrM 1, l*-0 1 clt loro tuna 1 dine 1,2-DlclitoroctUne. 1,1-Dlcliloroclli>|cne Plcihlorojdienji are In* Clu-elcal (CIS) iso- ia-o) UuSju.dl-j) (72-51-B) (72-55-9) 150-29-3) (230)16-1) (95-00-7) I l0|> 55-9) (53-70-3) (96-12 6) (921-16-1) (91-91-1> (101-06-2) U5-35-1) .(696-26-6) Degree of ErlUcnce iluaene Atileald Sufficient Sufficient inadequate Sufficient Inadequate Sufficlenl lnadequoLe Sufftclenl Inadequate Sufficient Inadequate Sufficient inadequate Sufftoienl | liadoijvljl* SufficJ.i.l Inadequate Sufficient inadequate inadequate Sufficient Sufficient Inadequate Sufficient Inadequate Sufficient Inadequate LUlled inadequate Inadequate Grouping Daaod on UKC Criteria i 2D 2U 2U 2U ?U ?u 2U an 2U 20 ?H 21) 3r 3 Potency factor tatleate Pol onejr Itaxard Croup Ranking IB. 00 0. 10 3.00 5.60 2.tO 3.00 ILiuo. no 170.00 31.oo 7.10 0.2) 1.60 JU 2 iilfiii N* 0 1 Leu 3 Lou 3 Low J Low 3 l.uW u o 1 High 1 ><igii 2 M om 11 n 3 Leu 1 Low 3 Low N* b Hote: Tlte data herein without additional analysis should not be used for risk assessment purposes. 16 rs AP00054891 TAUL C 1. su/imr-r ur r;A.*Ar-*.t p.v.tj ..r ' i iii ; * Cheat cal N>w 01 ttr In DiiUkjrbctn PloUwiiulnltroiulni Ulolliyl train# 1,2-DfalhvlhyJrasln# Dlalhylnilruaaalu* 0 lathy letII UMrok 01hydro##rrol 3, )'-0 laollkoi; toiiridln* Plaothjrl ulf*t Utaalli)rlu|(K>*ix)bnz(>a T 112-0 lavtliyt Uniz[# 1 nllirbccna UlaattijrlcBrbojioyt chlurldf 1, l-OJatl)|rth]>dr#zlna 1,2>DI#ilhplijdrzln Chualcal (CIS) (tu-ST-1) ( I161-5J-5) <1116-59-7) (692-12-2) (I6IS-0O-I) (65-10-5) (66-53-1) (91-50-6) (U9~90.ll) (77-78-1) 460-11-1) (57-V7-6) UlMI-l) (67-19-9) (5*0-73-8) Uearce of Kvlilenco lltami Anleal a Inadequate Sufficient J naj(!q<nl Sufficient lindoi|uil Sufficient Inadequate 1 i(adequate Inadequate Sufficient Inadequate Sufficlent Sufficient Sufficient Inadequate Sufficient > Inadequate Sufficient Inadequate Sum cl out Inadequate Sufficient Inadequate Sufficient Inadequate Sufflclent Inadequate Sufficient Inadequate Sufficient Cruujilns Uaeed on UNO Crl terla Polency Kect or Calleat e potency lluiar J (.roup Hunk l (Ig 2a 1)0.00 1 IMtjli 2b 8.50 ) Lou 20 17.00 2 Nodhaa 3 111 HI t 2U A HA 0 20 1000.00 1 mail 1 7900.00 1 iii&Ji 211 1.10 3 Lev 20 0.01 1 Low aQ 2U HI 20 2D0.00 1 hi /i 2U 200,0(10.00 I men 20 510.00 1 nieJi 2fi IJ.OO 2 Medl m 20 6/0.00 1 uieii Note: The data herein without; additional analysis should not be used for risk assessment purposes. 1? i AP00054892 AP00054893 81 sosodjnd quowssassp Joj posn aq 30U pvnoqs icuopippv ujajatj 8)8p am :3on C'| Ml tt'* VI h c [f'(l 00 <} *> ir-M l 00'[l * II \ OO'OM W'l qi -o 0 t irM 1 hrv| YH t Y?l V 09*11 YH JOT) YH q YH YH YH YN YH c OU'C a m ir-'H YH YH OV fv? Pit nii'H p.irl^n A.-niain.f U11C3 JD13BJ XCMlSJO,) nz YZ nz nz nz nz nz 1 nz i. QZ t nz fl.irnf.iD OHYt uo racni Hu)iInnJ3 Via [ofJJnS sqcnbapntl i P1 in VUtoUJnS t^rnbapru| >Lrtn|lJnsr ovnbe|<u[ nuataujns Ytnbapii| lnbo|>| VUl.->UJns Ybapcu| ICI'llUfiDd ( l<inbppeu| Y'jainuJi'S 1nbapeu( ^nbopr*ij icnbepeu) rY1H a irnbojitu | a)vnlinpr<i| Itnbspcuj Vioiou jns a VrnbnpBU j vonbapru] B^Pl'BpC<iI Y',!*)fU)h5 ov>bpru | cirvY turn'll i>3apj*3 ju oa.tflnij (8-lZ-^U 6-901) (O-0W9) (8-68-901) U-Y9-t29) U-99-ZZD (b'6["ZZi) (|-l6-t2l) f6-6(-09) (Z-OZ-qng) (8-51-619) (Z-YI-Ut) U.-10-Z09) (6-51-Z9) (9Y3) 9Jtvo|in*uitiia n*o tifaixtna VpiBOjqtp KtXt|ia 1<MY3 Uf Jpil|J|l|^|rl3 u |n ccj| |u |<do U1I.tpXn|4uaM|(I-Z'l tKitMlXiuxMlO-N'K orYofq-v'i uen^nioJimia-v'C um |loJi |u| o*9`2 uunjovoji |ii|a-5'Z iefiuJi|u;a-^,2 *iflo ioyojy t10-*z iilVT-rn.il fit M<|ia*Mf bvth tV3|vo SH3DOMOIIV3 IVUNSlOd UOJ 'JUliHNV!! (1UV7VH JU AIIVHKIIS 'I 3in\U "i TMi ( i r sui\n,\i(Y or iia / ahu kahking fun P O riM iA i caiicinugims * Wu 5U a o2--s o a a a l. a i_ a COCO -- -- 3 > -t O iX/II VaO CO S_ Q tXO/1) ^433 CO 3o CO 1/3 </3 0s033 3 X> AP00054894 3 *cs3 I ! "5*! 1X-1 uo o 35 *5 S M l\ ss 4 ffl yu s i. l a a --o 3l i itij <v i3 ? v 3 o4 aL. O 34 ~4 3 n C 5 C oA c ^ - 3 3ZT S4# a z c/1 4i/1I a c CJ VvolI VVIi cn &. OL. -cc3a/jl 4) -3 cO CM 13 2 c/i VI Vi >v a /ct3z 11"333 O * c u%SJ_ 13 a9 41 <SJ a AP00054895 TAUIF I. SUhJl/tKY iji IIA f.rwt.' i ..a i ,K -lie.;.'...,, x . .I.i . . : ( ' ' i Clteelcal Kug U-Helliy|-U`-uUro-Mnitro^ugiu'it Jlna HI iMfOlu C Huolard ga* 1-Haj.Ml.yleelne 2-UiipiltiylMlfli Michel end Cuapound* Nickel 4Ejicxtiua Sulfltl Hickel urlnnjri Nickel olilorldo 4 Nickel cyanide Nickel ItydroilUa Ulchel nitrate Nickel ulouiriJ -Kick*! auirala tHiroawetuylurtUuna Cltrtal cal (CIS) (70-25-7) (50-07-7) 15U5-60-?) <si-s9-aj (74X0-02-0) 41503?-16-0) 0)463-39-3) (7718-51-9) (SSI-19-7) ( 12051-46-7) ( 13418-06-7) (120 JS-72-2) (77M-0M) IM5-S3-2) Degree uT Ctlriunco tlm.iiu inla^ia liu Juqiiji e Suf i i ci cnl l uetloqutl o Sufftclcnl Snffl cl ent United tnadoqi ale l lial led Suf f 1 cl ent SuffJ clent United SUriclenl United United Hailed Sufficient LUI ted Lie It ad till led Mai ted United Llaltod United LUlUd Lie Ue<J Sufficient Untied |.lei led Kudaqnita Sufficient Croiijilf'S I*-1 ltd on lAkC Criteria i'll 20 1 V 1 z.1* 24h ?Ah 21* 2Ah 2A*1 2Ah 24h 2Ah 2D potency Factor Esl lo potency Urunp ll^uni KnnJc1 Mg 50 .uo HA 5.20 I.IU1 1 l 1 1 1 1 i.ol 1 2X00.00 2 HA HA IIA 3 3 HA HI HA HA HA HA NA HciJI c 0 c He<J Ivm* Ked t lb hod| ia HocJ | LB HcOlia Hoi 1 IB HodlVM H cell IB Hod k ia H eJ l IB lllfif. (tote; The data herein without additional analysis should not be used for risk assessment purposes. 21 AP00054896 AP00054897 zz 'sasod-jnd tiuouissssse joj pasn aq }ou pinoqs sjs^ipup iPuojilPpe ^notniM ti|sjnq pqpp aqx :a*oM * irH *' ir>n ' lp(*H '1PH <rBiH if*|M ' lra H i^in Ml q fVJ nr^T n[ M 11I l Z N VM Vl< z 1 <1 vri h ( ti t i CQ-^,1 ro*U j 9 P [* u00` K 00*0011 ru ZQ'O 09* \ (VO OD`n62 OVOil SuiVirH itnn.M) SK|15S p.r?r|| Xr>to >o,J joiarj /aua^nj 0? n? s' B1 r'2 rV2 02 \ S ( m .,E 02 02 omt *> paci-ft Ji pfirug )i>t>bopU[ inajoijjnff O'lCiiliepvui a 1 ci'lopou I 9 1 f*li [ 0 j ni|l>.i|i*u 1 poi-ii poiiuri o Vl'bopmi 1 fun jFnbaprof lUSIBtJJTlS 1ti1>n|>ru l 'tt'MolJjr'S ^nnt>p<n>I e >i'li>pFj | inn |ofJ flij e tenbapeu( r-'Uf>n 1 VIlllOpPU t a trnbopru| isnliappuf irr.bspro | C | *|W rurutu naiinp)*^ JO 03J<1.T(1 <|-U'02H> (9-oo-figai (6-OV8AU) (2-05 l?l0l) <C-9C-9t(l tt-29-phl) (9-90-OrJ (9-tO-9> (2-b W9> <-e9*29> (e*9W.6) <2-$V0(6) (S3) lF3|r.n|3 *ujluojidruj ooifhc trrtfo.1,1 lFBMJIjr'tl *1 1 tCB loj aiicntoi tUSCJ* WI|CCp|Oj c|<ubi)4|i painri|^a4|0j pj>cnH oujif( iMnjeiouoiu uoaf|1iiut|4 Uf )aua<|j BUsluaqoJi |iiojoi t|at MP1" l0|-0-04b|H-5 uipj leJj/.iloeojim-K u|p | Jfrj tHotrtJi f n-N MK Tat3H3 (p.>nuiiuot) SNinoiipmn >n /mi'.'/vh .) ahvwwis *i ainvi TABLE I. (SUM/lAKf tlF IlfUAKU lu^MhG r ui< t'O i 1Al *.j\K ihu Note: The data herein without additional ana AP00054898 TABLE 1. SUHHAUY OF HAZARD RNiKI HU FOR POTENTIAL CARCI MK.EHS (Continued) Chcalcal IImi 0-Tolul(llo n4 Ui f.ydruciilurJdt Tou(4in li l,2.Trli;hlorMLI\(M Trlcfilwoaltiytana 7,1,6-Trichtoroplienol Trl a (2, J-dl troAOpropyl ) f>hOaplkt Trypan blua Urtcll Hualard Untluin Vfuyl dtlorld* Ciieatcat (CS> 0)9-91-7) (6J6-21-5) 76001-35-2) (79-00-5) (79-01-6) (66-06*2) U26-72-7) (72-57-1) (66-T*M) (51-79-6) (75-OM) Decree o/ trl Utitce (lUIAA) Anlaals Inadeipikla sufficient Ll-UcJ Sum ct coi Inadequate 5uf fl clent Inadequate l. Jailed X iwidaqUHt a l. Jailed Inadequate Sufficient Inadequate Su f71ctcut ] nadequate Sufficient Inadequate 3uf f 1 olcol Inadequate Sufficient bufflot tut Sufficient Grouping lUscd on 16KC Criteria 21) 2k 26 r r 20 20 20 20 20 \ Potency faotur tal laat Patency H u urd Oroup Hank 1 an 27.00 0.22 2 Hudlia H Low 9-70 0-30 o. a . o.ua 9.80 i Lou ) L uw H l.Ohl 1 Low 3 1. w 0.0| 0.6t 0. It 1 Lou tn o l.Ott H Low Note: The data herein without additional analysis should not be used for risk assessment purposes. 24 AP00054899 TAULC I. SUMMARY Of HAZARD RANKING FOR POTENTIAL CARCINOGENS (Continued) Clitalcil Uua< Cheatcel (CA3) Degree or Evidence llusao* Anlaets Grouping UaseJ on 1ANC Criteria Potency Kautcr Csllnala felcmsy HuaiJ Group Hanking *Ct> available are Inadequate for calculation of potency factor using current aelltodolugy. An appropriate Method of eallBtllng a potency factor for these types of data la currently molar dovulojocnl l>y CAd. b Ot..r toslclly endpoints aiut U used as ti)li for burl ranking. Q Carcinogen lit surd ranking will be possible when eellaoJuiogy to calculate a reasonable potenoy 'factor la developed or now date becoos availehlt. Grouping and potency factor estlaat* la based on weight of evidence for arsenle and ersonlo oupounda In Ilia drinking uatar of (means (assmod to bo predominant 1 y tlia trjoatde). *0rduplng la baaed on watgftl of evidence for tarylllu* aulfata. ^(licupliif la baaed on weight of evidence Tor oadstu* eoapouuds as a claaa. ^Grouping la baaod on weight of evidence for chroeat* production and anlaal data which indicates that hevavalcnt nhroctliia la oarolnognnlc. potency estlaat# la bused on opidcaeology data for total cliroalua exposure of chroaate workers.. Grouping Is based on weight of evldunce for nickel coapeunds as a class. ?)>a ^Calculated. using Mia potonay factur aatlaata far bemu(a {pyrene as reference. Votonoy ullaita la based on data frva lorylllia aulfata rvpoaure In rats, y Potency estimate Is based On eptdcaculogy dete'for cadatin saoltors. Picas* note that potency csllanto based on anlaal data would bo at least IUQ llacs higher, please refer to (MIEA ducuaeut IdJouduw to the Health iascasaont Uccuaenl for Cadsliai, lyflj* fur details, ^Potenoy oatlaele is baaed on dole for nlokel aubaulfldo. "fbtenoy estlaat* Is based on data for kroalor 12&Q. echo I cel grade clil oreaolliyl aelliy I ether la centa*lusted with bls(oh) area ethyl lather, and the hazard ranking is Lite refora based on Mia avldcnce fur bla(cli|oroaeVltyl )otber. _ Q Inappropriate to group or rank for envlrcnaental considerations because available evidence la taxed on subcutaneous and lnlraxiuscular Injectlun asparlaenta. A rA potency factor estlsala for asbestos la Inappropriate hare becuuss Ilia carcinogenic potential of asleston Is related to specific fiber stupes, alias, and alauspharlo concentrations. Air concentrat Ions ace usu.-illy neaaured either as nutter of fibers or visi, lluuiwor, no direct rtlglltnillp aklsla between air ft bor/td (>5 Microns) concentrat I Otis (by the phase contrast II ght Microscope Method ) and asss concentratI nn i iv ji j/ w * I del era I ned by electron Microscopy). The relationship dupands on the type uf environment asoplcd, the type of asbestos In tbe^ air, and II.a size uf ll.a fibers. Vuttnty factor MlUale Is based on data for heptachlof since haptachlor epoxide Is e Metabolite of licptachlor. rTha Group } category Includes cheeloals for which Hie evidence fro* anlael studies la Halted or Inadequate and there la no li>sa*n evldaiica. Tliesa are group 3 chrulcala with Halted anlaal evidence, for tiaiss with good dose-related data, a potency estimate Is JuUtaliKd and e hazard ranking Is pcrfoiacd. CtajaJuids with group I potency factor estimates (>100) are given *tdlu* hazard ranking. Ccapounds In potency group ?,} or V ar* given low* lusard rankings. MA Mol applIcabla 25 AP00054900 IV. REFERENCE 3 Andersen, E.L., and the Carcinogen Assessment Group of tne U.S. Environmental Protection Agency. 1983. Quantitative approaches in use to assess cancar risk. Risk Analysis 3(4): 277-295. Dourson, M.L., and J.F. Stara. 1983. Regulatory history and experimental support of uncertainty (safety) factors. Reg. Toxicol. Pharmacol. (In press). Hansch, C., and A.J. Leo. 1931. Pomona College Medicinal Chemistry Project. Seaver Chemistry Laboratory, Claremont, CA. International Commission on Radiologic Protection (ECRP). 1977. Radinucllde release into the environment!: Assessment of doses to man. ICRP Publication 29. Elmsford, NY: Pergamon Press, p. 76. Kushner, L.M., R.C. Wards, and V. Fong. 1983. The potential use of the ADI in Superfund implementation. Mitre Corporation, McLean, VA. p. 68. McNamara, B,P 1976. Concepts in health evaluation of commercial and industrial chemicals. In: New concepts In safety evaluation: Advances in modern toxicology 1(1):61-115. National Institute for Occupational Safety and Health (NIOSH). 1992. Registry of toxic effects of chemical substances. U.S. Department of Health, Education, and Welfare, Cincinnati, OH. 45 4k AP00054901 Stara, J.F., 0. Kello, and P.R. Dur'<in. 1980. Human health hazards associated with chemical contamination of aquatic environment. Environ. Health Perspect. 34:145-133. Stars, J.F., M.L. Dourson, arj C.T. OeRosa. 1981. Water quality criteria: methodology and app1icatiqns. In: Conference Proceedings: Environmental risk assessment: How new regulations will affect the utility industry. Electric Power Research Institute, Palo Alto, CA. U.S. EPA. 1976 (May 25). Interim procedures and guidelines for health ri sic and economic impact assessments of suspected carcinogens. Federal Register 41:21402. U.S. EPA. 1980 (Nov 25). Guidelines and methodology for the preparation of health effects assessment chapters of the ambient water quality criteria docu ments. Federal Register 45:79347. U.S. EPA. 1980. Guidelines and methodology used in the preparation of health effects assessment chapters of the consent decree water quality criteria. Federal Register 45:79313-79379. Weil, C.S., and D.D. McCollister. 1963. Safety evaluation of chemicals. Relationship between short-and long-term feeding studies in designing an effective toxicity test. Agric. Food Chem. 11:436-491. 46 AP00054902 &S ^;y.V>t!sysy$i^ rr:% y? <-.,y;,7?.V^.. '-v^ r:-??7</A': M-:- HUMAN HEALTH AND THE ENVIRONMENT AP00054903 AP00054904 AP00054905 AP00054906 AP00054908 Copyright (c) 1964 by REINHOLD PUBLISHING CORPORATION AU rights reserved Library of Congress Catalog Card Number: 64-22237 Printed in the United States of America AP00054909 AP00054910 viii Contents Basic Types of Poiyethylenes Ethylene Copolymers High Pressure Poiyethylenes Low Pressure Polyethylene New Processes Commercial Volume and Price Range Properties of Commercial Poiyethylenes Commercial Poiyethylenes References Polymer Chemistry High-Pressure Polyethylene References Low Pressure Polyethylene References Polymerization Processes High-Pressure Polyethylene Process References Polymerization Processes--LinearPolyethylene References Blending and Compounding Blending Compounding Extrusion References The Structure of Polyethylene Molecular Weight and MolecularWeight Distribution Chain Branching Unsaturation Crystallinity Copolymer Structure References Properties of Polyethylene The Structure of Polyethylene as Determined by Infrared Spectroscopy References Transitions References Electrical Properties and Usesof Polyethylene References Optical Properties of Polyethylene References 70 jq 7^ 70 70 73 75 77 80 81 81 91 92 99 100 100 118 118 122 123 123 125 127 135 136 136 138 138 139 140 141 141 141 146 146 149 150 153 153 157 AP00054911 AP00054912