Document yxoEGL8yb6DKBNyoN4vB8ym3

To From INTEROFFICE MEMORANDUM R. Fleming R H. Schenck cc: J. T. Barr f\ Subject Date 8 Mav 1978 OSHA Carcinogens File No. M-q8-^-L Executive (UOCatloriT Organization, or Oourtmant) Law (Uocatlon, Organization, or Oapartmant) Attached is Appendix C containing NIOSH's responses to OSHAf s questions. RHSrrgs ATTACHMENT O^^Jl d-*^*-*-?*- i- -^i-^c^M.RciivEe MAY"-9 1073 (320) AP00049530 APPDmiX c The following ar$ responses to soma of those questions received roa OSEA. Responses to some questions have not been furnished in this appendix either because they have been discussed in the prepared statement or because of the complexity of the issues and the short amount of tine available to gather and evaluate the data, prepare an appropriate response and meet the April 4, 1978 due date for submissions to the OSEA Docket Office. heccwso WM 0 h ^ jjVW opt` AP00049531 Questions 1, 2 5 21 The proposal, ^recommends chat anima 1 studies be used to identify potential human carcinogens. This is quite appropriate. In fact, the purpose or the Proposal is to decrease human experimentation, i.a., decrease occupational exposures to carcinogens. Although there might not be 100% correlation between the effects of chemicals on animals and humans, that is not surprising nor should it discourage us from pursuing our goal, it should be noted that of Che chemicals and/or classes of chemicals that have been found to cause cancer in humans. Including; benzidine; 2naphthylamina; bischloroaathylether; chloromethyl methyl ether; 4aminodiphenyl; NjN-bisCS-chloroethylil'-naphthylaiaine; chrysotile; crocidolite; amosite; rarfwttiw compounds; chromium compounds; nickel compounds; arsenic compounds; beryllium compounds; benzene; auramine; diethylstilboestrol; and vinyl chloride, all except possibly benzene have been found to cause tumors in animals (Tomatis, 1976; Nevberne, 1975; Bayliss and Wagoner, 1977; Infante, et al., 1977; Oswald and Goertcler, 1971). Thousands of workers have developed cancer as a result of exposures to these agents. They have unwittingly provided scientists with the information needed to make the correlation between animal and human responses to carcinogens. Si t t3 'XZSL Another important consideration is the animal species and strain teat should be used in the test systems. The degree of correlation ber^ea species and humans as well as the relative cost in performing Che arud-^* 71irr* be considered before recocmendations can be made. O'oviousLy, tr.os* ii'***" which have been consistently positive when tested with known r.u=a_ Eg AP00049532 carcinogens are acceptable. Of the himan carcinogens mentioned above, alaoat 'ail have been shown to be positive in rats and several of then are positive in nice. Fortunately, these ace the mammalian species which are ' least costly to process, and, therefore, their use can be recommended with very few or no qualifications* Some scientists believe, however, that the mouse is too sensitive to carcinogens, and, therefore, the rat Is a better model. Implied in this opinion Is that mice will'"respond to lover doses of carcinogens chan will humans. Since quantitative data on carcinogen exposures to humans is almost non-existent, that comparison is Impossible to make. The fact that the mouse is slightly more sensitive to carcinogens than the rat is well-known (Tomatis, 1973), however, the modal should be designed to protect humans, not rats. Another, argument that has been frequently used to exclude mice is chat they have a high frequency of spontaneous tumors which might be .induced by hormones and/or viruses, and that tumor promotion, but not induction, is measured when chat model Is used. What Che proponents of that argument fail to recognize is that whatever variables are present in % mice might also be present in humans. Hunan tumors might also be induced by yet unrecognized viruses, and hormones certainly play a role in human carcinogenesis (Furth, 1975). It is not unreasonable to expect that the mechanisms of carcinogenesis operative in mice might be identical to chose in humans, for example, hum ana have no zymbal gland. It is certainly possible that many carcinogens in humans are in fact co-carcinogens. There is no method to determine this with any degree or certainty in humans. AP00049533 Onestion4 It .has been estimated that occupational cancer represan.cs about one to } five percent of the cancer cases reported annually in the United States. We don't know how valid Che estinates are of the total incidence of occupational cancer. We know that there are a significant nunber of occupational cancer cases e.g,, fron 2-caphchylanine, asbestos, arsenic, vinyl chloride and this alone justifies vigorous preventive action. Since numerous studies (vinyl chloride - 3(a)P, Hal coni and Lefeaiae, 1975; Bingham and Balk, 1969) etc., have proven that a dose-response relationship is evident in the area of carcinogenesis just as ia other areas of toxicology, it is readily apparent that positive results obtained at high doses indicate that lower rislcs are to be expected at lower doses. The specific linitatlotsia estimating the lower risk factors are inherent in the specific limitations of the data gathering system. Such factors as arrf-gaT nunbers, nunber of dose levels, confidence Units'and other factors oust be considered in properly evaluating the dose-response relationship. In addition to a socially acceptable value of risk., the establishment or an absolute value of risk, rather than a relative value of risk (Subccmaictee on Environmental Mutagenesis, 1977) is mandated by the OSKAct in regard ta occupational carcinogenesis. AP00049534 Question 5 a. The first direct connection between an occupational exposure and risk of a specific cancer was that of chimney sweeping and cancer or the scrotum pointed out by Poet in 1775. Es recognized this association becausa he saw several affected chimney sweeps but little or none of the disease in persona with other occupations. The disease was exceedingly rare in the general population, and the risk ratio for chimney sweeps was quite high. About IS80 Eirting and Eease shoved that "mountain disease'1 was a lung - neoplasm. This condition was recognised as an entity in the Middle Ages because ax its frequent occurrence among young miners despite the rarity in the general population. In 1895 the German surgeon, Rehn, published on the hazard of bladder cancer among dye workers. Rehn's association was based not on an exceedingly high risk ratio but rather on the absoLuta high frequency of the disease among exposed persons. During the past several decades instances of occupational carcinogens have continued to be recognized both on the basis of an extremely high risk ratio and a high incidence rate among exposed parsons. a The following tables show various agents which have been, identified as occupational carcinogens on the basis of epidemiologic studies and confirmed and suspected carcinogens by target organ. AP00049535 * TABLE l daisificalian of Occupational Carcinogen* A. Oi ganlc agents ' - '+ l. Aromatic hydrocarbon* Agents Coal soot Coal rat Other products of coal combustion Affected orgin(s) Lung, larynx, skin, scrotum, urinary bladder Incubation period (years) 9-23 Petroleum Petroleum coke Wax Creosote Anthracene PstiCfici Shale Mineral oils Benzene Nasal cavity, larynx, lung, skin, scrotum Bone marrow (leukemia) 12-30 d-14 kisk ratio 2-S . 2-4- 2-3 Occupation Cashouse wurkcrs.siokcrs, ftnd producers; asphalt, coal tar, and pitch wof'rxt. coke-oven workers; still cleaners; chimney sweeps Contact with lubrieacag. cooling, paraffin or '*xt un fuel oils, or cake; rub***" fillers; retormseasaaiw* weavers; diesel; -^3 M Explosives, or rubber workers: utert; CY* * Philip Cole and Marlene Goldman, Chapter 8-0 "Persons at High Risk o Cancer", edited by J. Frstraenic, Nseicrai Institute AP00049536 0 A. OipuicagtfMW (continued) 5. Aromatic hydrocarbons (continued) A,;CjUS Affected organs) Incubation period (years) ' Auirmunc Bcti/idiac aHUj|iluliylauiiuc -nsphthylamine Magana 4-aminodipbenyl 4-fiitrodiphenyl Urinary bladder 13-30 Risk ratio 2-90 4 Occupation Dycstoffs manufacturers and users; rubber workers (pressnen, fiHcnnwn, laborers); textile dyers; paint manufacturers 2. Alkylating agent* --' 1 Muitaid p* Larynx, lung trachea, bronchi 10-25 2-36 Mustard gas waiters 3. Others Isopropyl oil Nasal cavity to* 21 Producers Vinyl chloride liver (angiosarcoma), brain 20-30 200 (liver) Plastic workers 4 (brain) A. Organic agones (continued) - 3. Others (continued) Agents Affected orgin(s) Incubation period (years) Bh(chloromsLhyl) ether Grioromcthyl methyl ether Lung (oat cell circfnoma) S+ Fisk ratio 7-4S Occupation Chemical workers B. Inorganic agcntl l. Metal* Arsenic Skin,lung, liver 10* Chromium Nasal cavity and sinuses, lung, larynx 15-25 3-5 3--tO Miners; smelters; insecticide makers and sprayers; tanners; chemical workers; oil refiners; vintners Producers, ptocsssors, and users; acetylene and aniline workers; bleachers; glass, pottery and linoleum workers; bsttery makers AP00049537 * B, Inorganic agents (continued) 1. Metals (continued) - Agents Affected organ(s) Incubation period (years) Risk ratio * Occupation Iron oxide Lung, larynx Nickel Nasal sinuses, lung -- 3-30 2-5 Jreo ore (hematite) miners; metal grinders and polishers; silver finishers; Iron foundry workers \5-30 (lung) Nickel smelters, mixers. 100+ (nasal and roasters; electrolysis . sinuses) workers 7. Fibers - Asbestos Lung, pleural and peritoneal mesothelioma 4-50 3. Wood Leather Dusts Nasal cavity and sinuses Nasal cavity and sinuses, urinary bladder ,, 30-40 40-50 i.5-n M iners; millers; textile, insulation, and shipyard workers * - 50 (nasal sinuses) 2-S (bladder) Woodworkers Leather and shoe workers c physical agents I. Nomonisicg radiation Agents Ultraviolet rays Affected organ(s) Skin . Incubation period (years) varies with skin pigment and textute Risk ratio -- Occupation, Faxmers;sailors 2. lonliing radiation X-rays Radium Metotharium Skin, bone marrow (leukemia) Skin, lung, bore, bone marrow (leukemia) 10-25 10-15 3-9 3-10 Radiologists; medical personnel Radiologists; miners; radium dial painters; radium chemists 3. Other Hypoxia Bone ' - -- Caisson workers i AP00049538 I i s S Tab! 2 Confirmed and suspected occupational carcinogens* by target organ. 9 Trjwt Orinn/Tusu* Occupational Carcinggan Confirmed Surpccie Bone Beryllium Brain Vinyl Chloride Gastroenteric Tract Asbestos Hematopoietic Benzene Tissue (leukemia) Styrene Butadiene and other Rubber Manufacture Substances 9 Kidney Larynx Liver Coke Oven Emissions Asbestos, Chromium Vinyl Chloride Lead Aldria Carboa Tetrachloride 9 Chloroform DDT Dieldrm 9 Heptachlor PCB's Trichloroethylene Lung Arsenic Beryllium Asbestos Cadmium Bis (chloromethyi) ether Chloromethyl methyl ether Chloroprcns * Lead Chromates Coke Oven Emissions Mustard Gas Nickel Soots and tars Uranium Vinyl Chloride Lymphatic Tissue Arsenic Benzene Nasal Cavity Chromium, Isopropyl Oil, Nickel, Wood Dusts Pancreas Benzidine ?CB`s Pleural Cavity Prostate Asbestos Cadmium Scrotum Skin Soots and Tara Arsenic Chloroprccc 9 Coke Oven Emissions Cutting Oils Soots and Tars Urinary 4-Amir.obIphcnyl Au ramine 9 Bladder Benzidine B-Naphthylamine 4-NiirodiphenyI Magenta ^Occupational Diseases - A Guide to their Recognition - U.S. Depart:?,ent of 1 -t-V, C^nraf inn And Welfare - NIOSH... ............ AP00049539 a Table J Suspected carcinogens based upon structural similarity to vinyl chloride. Suspied Careiflajra . Structure Vinyl Chloride HjC*CH a Bronjopreno HjC = CHCHjBr Chloroprene H,C=*CHCH,a Eptbromchydria HjC -- CH--CHjBr ; V. Epichlorohydria Perbrctnoeihylene Pcrchloroethylenc Tiibromosthylene Trichloroethylene Styrene (Vinyl Benzene) Vinyl Bromide Vinylidene Bromide Yinylidcnt Chloride H,C\-0C/K-CH*a Bc,CC3ra 0,0=ca. BrjC=CH Br o3c=ch a H,C=C1 H ' H,C = CH Br K,C~CBr Br HjC^CCI a AP00049540 * No one study approach can provide ail or even nose of the needed * health Information* 'While epidemiologic studies in the occupational setting have the potential to determine affcct3 o long term lay level exposures, the difficulty in malting quantitative estimates of present exposures and the even greater problem in determining past exposures makes it hard to obtain accurate dose response data. On Che other hand, while more accurate dose response data can be derived from toxicological studies using experimental animals, one is always faced with the diffi culty of extrapolating results from experimental animals to humans and often with the additional problem of extrapolating from observed higher dose levels to lower dose levels. However, when the two study approaches are utilized in. a coordinated way, benefits of each approach can be maintained ard many of the individual methodological weaknesses can be overcome. The following table shows these strengths and weaknesses. AP00049541 Table 4* DISCIPLINARY APPROACHS TO IIEAI/ni EFFECTS OF.AIR POLLUTION PiwltllM ___ HrrTtk* ____ ____ yjn i--n Epidcmiotofy CeniaiunSltm Di**ed Croup* To*-{J*ST Animal* Biochemical cyitem* OJh N*tur*I exposure* ObxTxallo* in m* N txJrxpoUsi*** Yuf/ioraM* froupa fnftlud**! Long (crm. lawdexei effnu rraluxitd ._Suidy Hi**r ppl Ey t *b(us dt<rniiH dm Kapii dita.<^uMln'M Caos-effct anre deficits MKhiaisfflj cf mpiM Prtdiet >*U(ic of daw mponi# eur*m Administer Toiie ai*t<ruJ> Study ieul tod ebroaie effects Qutatiiyin* expeoore difficult M*ny cpiRiiet ilir-intil dM tespenae diu Af*6ettia **. auwlisrt Csa only dii* few health a^uBiTRitflU Leaf latest period* for a problem Ketlitde rauitlg f huoun dbfise? Esuipafifiss uumali to mu . Threshold / he**n inponit?' Artifietii tipwxrei * . ` ~ > * > t 1 I *Br. Carl Shy, ''Strengths and Vfealciesses of Epidsniological, Clinical 2nd Toxicological Study Approaches," Che.uist/Meteorclogist Workshop 1975, U,S. Energy Research and Development Administration i , j \ \ 1 i AP00049542 i. .The impact of epidemiologic studies in cancer research, such as the studies on cigarette smoking and lung cancer, prompted a recent Nobel Laureate to proclaim these studies as the major scientific finding of the 20th century. It is doubtful that the impact of snaking on lung cancer incidence would have been known if research had been limited solely to cellular and whole arrival studies. Although agents contained in cigarette smoke have been shown to Induce cancer in laboratory animals, the sum of the carcinogenic effects of the known agents does cot equal that of the cigarette smoke coodensata. Particular difficulty has been encountered in inhalation studies of cigarette smoke on laboratory animals because the animals, particularly smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in tobacco smoke. Another problem stems from the fact chat the upper respiratory tract of experimental animals, particularly the nose, is much different from analogous human structures resulting in a more efficient filtration of smoke in the upper respiratory tract of these animals. There i3 mounting epidemiologic evidence from a series of occupational health studies incriminating benzene as a possible leukemogenic agent. Thus far, no animal studies have been able to demonstrate this effect. Similarly, the carcinogenic activity of AP00049543 -k l I arsenic has been demonstrated through epidemiologic but not by j' tonlcolOgic studies. ' ;I If reliance were placed solely on cellular animal tests, Chen the importance of benzene and arsenic as and carcinogenic agents would presently be unrecognized. According to. Sir Austin Bradford Eill, more weight must be given to positive as opposed to negative studies. Negative epidemiologic studies^ particularly in cancer, cannot be construed as providing firm evidence of safety. This is because of the problems of latency and the small number of people often observed in epidemiologic carcinogenic studies which often preclude demonstration of statistically significant differences. d. If the appropriate steps are used in epideniologic research, then descriptive studies have the potential to identify unusual clusters and high risk individuals for subsequent study which should then limit the number of negative studies. AP00049544 Question 6 Iu has been customary to rely upon animal studies in the absence of human evidence for a carcinogenic assessment of chemicals. An enemination, of the literature'and of the experience in this method of approach reveals that animal data can be satisfactorily used aa a predictor of human response. The development of the vinyl chloride study, the coal car/coke oven emission studies and various other examples illustrate the predictive value of animal bioassay methods^... In addition, the correlation between species .with certain carcinogens such as benzo(a)pyrene, bischloramethylecher, aminadiphenyl, benzidine, vinyl chloride, etc., have been in excellent agreement, even though the * target tissue nay differ among the species tested. In the case of benzo(a)pyrene, nine species of animals have been tested and all found to respond to this widely tested ubiquitous carcinogen. (Survey of Compounds Which Esve Been Tested for Carcinogenic Activity - NCI) . If the responses of animals to known, human carcinogens are examined it becomes obvious that all human carcinogenic chemicals, with the possible exception of arsenic and benzene, are.also carcinogenic for animals. The inhalation and percutaneous routes of exposure are the obvious routes of choice in experimental carcinogenesis studies when considering occupational exposure to chemical carcinogens. These routes are also the AP00049545 choice whan considering experimental design of studies to investigateother caxifi 32SH&- Hovaver, it is veil known that clearance from both the upper airways and the deep lung involves the mucociliary escalator in which materials are cleansed from these areas and usually find their way into the alimentary tract, in lieu of expectoration. Therefore, the oral route of administration via either stomach intubation, for purposes of exact quantitation of dose, or through consumption of food or water containing contaminants, is a perfectly adequate route of administration to test the carcinogeacity of chemicals and complex mixtures found in the occupational environment Inhalation i3 usually the preferred route of a adminstsation in animal studies for judging the carcinogenicity of airborne substances. Because ox the expense of this type of study and neehodologic difficulties, other routes, especially per oral, are used. In the usual case, this route gives valid, extrapolatable information, but each case has to be considered individually. Similarly, ocher routes, e.g., topical application, give useful information. Injection site sarcomas by themselves, probably do not indicate carcinogenicity by other exposure routes. They may indicate specific hazards in the event of accidental implantation of the substances. The validity of using the maximum tolerated dose In rodent bioas'says has been discussed and debated for a tunaber of years. It is appropriate to mention that the National Cancer Institute as wall as other agencies such as NI0S3, FBA and EPA continue to consider this as an appropriate approach, in experimental bioassays. The reasons for this choice are obvious when considering economics and the probability of response. AP00049546 --------------------------- - -- --------------------------------------------------- Question 10 Present knengledge does not permit development af a consistent and rational basis for decisions on additive and synergistic effects. Complicating this problem is the question of promoting agents and co-carcinogens, widely and variously used terms without the same meanings to everyone. Additive effects should be assumed when two agents cause cancer at the same site, especially when the two agents also have chemical similaries, such as Ptf's or aromatic amines. Synergistic effects should be assumed only when there are data or principles suggesting in the specific case that potentiation is likely. Similarly, co--carcinogenicity and promotion should not be assumed except in a specific case where there are data or principles that apply. In clearcnt areas involving-personal.habits.sunh_as smoking, counseling of workers should be called for. Other areas of. personal habits, such as diet or lifestyle, should not be considered in this proposed standard, at least until the issues are clearer. AP00049547 Questions 15 & 3.6 Question^15 and 16 are closely related and will be answered together.- The I problem of additive and synergistic effects is extremely difficult to assess with, available scientific methodologies, either toxicology or epidemiology. To dace, the scientific community has not adequately dealt with this problem. Toxicology and epidemiology both provide valuable information about carcinogenic risk. The problems of additive Cor antagonistic) and synergistic effects do_ not make dose-response data in test animals" irrelevant-.- Epidemiology and toxicology have both strengths and weaknesses. However, by combining two methodologies, in this case toxicology and epidemiology, it is often, possible to overcome some of the weaknesses of each individual methodology, yet retaining their strengths. From this point of view, corroborating data on carcinogenic risk from both epidemiology and toxicology provides the most defensible data as to carcinogenic risk. Host toxicology studies assess effaces of single exposures. It is virtually impossible to artificially generate an exact replica of the complex workplace environment in any toxicologic experiment. One of the greatest strengths of the epidemiology approach is to observe the effects of this complex enviroraeat directly in man. However, unless the possible synergistic or additive effect is specifically tasted either epidemiologically or toxicologically, it is impossible to assess the imoortance of such interactions. In the final analysis, though, health nay still be protected even if precise information on interactions is not available. This is because a given compound in a complex mixture nay often serve as an index, which when controlled, will also result in decreased exposure to all compounds in the complex mixture. The situation with coke oven emissions is an excellent example in this.regard. s 5 * AP00049548 / Question 19 Latency refers^ to the long period of cancer induction. Because of Che > i uncertainties in identifying the specific time or event in the genesis or the cancer and the uncertainties in/identifying the cancer itself, the cert !; f latency is not precise. It usually! is taken to be chat interval becveen the first known exposure to thJJ cancer-causing substance and the first '// evidence of the consequent cancer, which is often at autopsy. / Whether the cancer process is initiated by the first exposure is not known; it is generally thought that the process is initiated by the- effect of repeated exposures, but there are rational bases for suggesting that any one of these repeated exposures may have been the initiating event. It is conceivable that both ideas are correct, for example, it night be that the * cancer is initiated by one exposure and is enhanced sufficiently by subsequent exposures to progress to enough overt cases to constitute a statistically significant excess (whether in an epidemiologic survey or an experimental animal investigation) . However, this .speculation should not obscure the point that latency is an imprecise term referring to the many years required for the development of most cancers to the point they are observed and is defined more precisely in specific investigations or surveys for Che purpose of chat study. AP00049549 Question. 28 According a report from the DSEW Subcommittee on Environmental Mutagenesis (1977) , mutagenesis (short-term, or in vitro) testing, in addition to providing valuable information on the risk to future generations, can provide valuable information regarding other toxicological manifestations. Examples are cited stating that there is an "apparent relationship between carcinogenicity and mutagenicity" (McCann, et al.t 1975; McCann and Anas, 1976). However, the predictive value or short-term mutagenicity-tests for ^carcinogenicity is currently under investigation, involving numerous. efforts to assess the use of short-term mutagenicity tests; The Subcommittee Report goes on further to stats that the utility of mutagenicity test procedures for screening of chemicals for scmatic effect, for example, carcinogenicity is not predicated on the assumption that the effect is due to mutations in scmatic cells; but "the empirical demonstration of a high correlation, between mutagenicity and the effect of concern (carcinogenesis) is a sufficient basis tor establishing a role for mutagenicity testing as a predictive tool regardless of the mechanism involved." There is widespread belief among investigators in the cancer araa that DMA damage is involved in the induction of cancer. This is the basis for the supposition that carcinogens might be detected by the consequences of DMA damage in simple systems (Bridges, 1976). AP00049550 Shore Cara or in vitro tests that have had same testing for validation purposes included thos-p referenced by Bridges (L976) . Many other validation tests are ongoing (DeSerres, 1977; Dimka1, 1978). Reports are available commenting on the state or the art status of in vitro testing for carcinogenesis (Casta, 1977; Kouri and Schechman, 1977; Conservation Foundation, 1977) . For scientific purposes, justification of the use of short-term tests for the purpose of screening thousands of chemicals for their suspected carcinogenic activity and for the purpose of prioritizing these chemicals for long-term, animal bioassay, appears to be adequate. However, the original intent for utilization of these tests was only for these two objectives and not for use as a confirmations! test for long-term animal bioassay. * It is inappropriate at this cine to atcea.pt to substitute a short-term, test for a long-term animal bioassay for at least two reasons: (1) Validation procedures are not complete and correlations between Che test systems have not been, adequately performed; and (2) The outcome or the short-term tests as compared to the long-term bioassay are not biological equivalents. In one case the end point is mutagenesis, in the other case, carcinogenesis. However, one (mutagenesis) may often cause the other (carcinogenesis). AP00049551 It has also been observed, that a carcinogen, does not always produce tusors in the same organs in all species. The mouse liver responds aora readily o than most other tissues with most of the carcinogens that have been tested. Yet it is Still predictive for cancer at other sites in other species, including aaa (Toaatis, 1973; Nevbeme, 1975) . Another consideration in evaluating a predictive model for human carcinogens is the route of administration. Although the route of administration might not be important in determining whether or cot an agent is carcinogenic for research purposes, it is important, from a preventive health standpoint. To properly evaluate carcinogenicity, Che suspect agents should be administered to animals by the same routes a3 humans are exposed, namely, via the lungs, gastrointestinal tract, deroally and in some cases intramuscularly, intradernally and subcutaneously. The latter conditions would apply, for example, to those agents such as metal fragnsQts that might become embedded in skin or muscles. In industrial exposures to particulates, oral exposures are frequently as important as pulmonary exposures in as much as the particulates that are trapped in the upper respiratory tract are usually swallowed. Although in the above discussions chemicals have been given primary consideration 33 carcinogens, some consideration should also be ..given to physical agents, e.g., ultraviolet and infrared irradiation and heat. To exclude physical agents from consideration in the regulatory process is unwarranted. To exclude any agent on the basis of its proposed mechanism of action, is also unwarranted, since the mechanism is not being regulaced, but instead the agent. It is, therefore, recommended that paragraph (1) in section 1990.111 be deleted from the Proposal. AP00049552 * Question 31 In. the attempts co develop models for predicting human carcinogens prolonged debates have centered around the type of lesion in animals that' must be induced before a chemical can be called a carcinogen. Particular attention has been given Co the nous* hepatoma (Butler and Newbeme, 1975) . Some scientists believe that most mouse hepatomas are not cancers because they do not metastasize, and imply that the mouse hepatoma is, therefore, not predictive. This argument is illogical. In the first place, not all hepatocellular' carcinoaas-metastasize in any species studied, yet they are frequently responsible for tbe death of the hosts. Of 33 mica that died subsequent to chronic exposures to 4-dimethylaminoazobenzene, 71X died as a result o hepatocellular carcinoma (vita ascites and/or anemia) yec pulmonary metastases were infrequently observed (Gallatly, L975) . Hetastasas are observed in humans in only approximately one-half of patients with hepatocellular carcinomas (Robbins, 1975). In. the second place, even the spontaneous hepatocellular carcinomas in nice seldom metastasize. In fact, very few of any of the spontaneous neoplasms in mice or rats ever metastasize. In this way, rodents are more resistant chan humans and possibly are not sensitive enough to the induction of cancer as we know it in humans. The reasons for that might also be explained on various factors that modify the ability of tumors to metastasize (Tidier, 1975). Thirdly, for predictive purposes there is no reason why the rodent tumors''need metastasize. There need only be a correlation between cancer la man and a neoplasm in animals, and this has already been demonstrated many times. AP00049553 yc ^ February 20 f 1979 *2*' \<S 7,1 From* T.' R. Hlllhouse (PAG) Vi-* To t AIHC Legal Committee Members Subject! PROPOSED ORGANIZATION AND RESPONSIBILITIES OF THE AIHC LEGAL COMMITTEE 3 Attached, please find an outline of the proposed Organization and Responsibilities of the AIHC Legal Committee. This document was pulled together at the request of Chairman Ferguson by a Committee consisting of Messrs, Hlllhouse (PAG), Campanella (General Electric), Hanavan (DuPont), Sielaty (NACA), and Ms. White (Union Carbide), This document will be discussed at the AIHC Legal Committee meeting on March 8 in New York City, If you are unable to attend that meeting and have any comments on this document, please contact the undersigned (513-5^2-^517) TRHtsl Attachment T R, Hlllhouse AP00049554 WORKING GR* i*S RECOMMENDATIONS REGARDING COMPOSITION AND FUNCTIONS OF THE AIHC LEGAL COMMITTEE BACKGROUND At the November 28, 1978 AIHC Legal Committee meeting, the Chairman, Mr, Ferguson1 (Olin), appointed a Working Group, consisting of Messrs. Hillhouse (P&G), Chairman? Campanella (General Electric); Hanavan (DuPont); Sielaty (NACa); and Ms. White (Union Carbide), to look into the Steering Committee's request for a recommendation regarding the future functions of the Legal Committee, The Working Group met twice, and its original recommendation was discussed at length during the December 20 Legal Committee meeting. Based on these discussions, the Working Group recommends as follows; RECOMMENDATIONS 1. The specific recommendations which follow are based on the Working Group's under standing of AIHG's current organization and anticipated short-term organization. No position was taken on the future structure/organization of the AIHC itself. It should be recognised., howeve: , that the recommendations made below may require revision, depending upon the direction which the Steering Committee ultimately takes with respect to AlHC's future directions, 2. The success of future Legal Committee activity is dependent on the commitment of AIHC membership to actively participate/contribute to Committee affairs. Generally, it is believed that membership on the Legal Committee should be open to all AIHC members. Nevertheless, it is the experience of most of us that active participa tion in Association affairs falls on a relatively small group of people who are able and. willing to devote the needed time and talents to the affairs of the Association. Recognizing, this, it is the position of the Subcommittee that those members who do not actively participate in attending Legal Committee meetings, and who do not ac tively participate in its functions, should not formally serve as members of the Legal Committee; rather, they should be made associate members Of the Committee in the sense that they would receive information with respect to the proceedings of the Committee. 3. Organization and Responsibilities A. Organization (i) The Legal Committee should be under the leadership of a Chairperson and Vice-Chairperson appointed by the Steering Committee. (ii) A Steering Committee of the Legal Committee should be established, composed of the Chairperson, Vice-Chairperson, and Chairpersons of any Legal Subcommittees or Task Forces. (iii) The Legal Committee shall, from time to time, establish such stand ing Subcommittees as shall be deemed necessary (such as litigation, regulatory, legislative, etc.) to deal effectively with the matters falling within the areas of responsibility of AIHC, and to deal with other specific matters of indefinite duration. Ad hoc Committees and Task Forces may be established, as required, to deal with matters of more limited duration. AP00049555 B, Responsibilities (i) The ultimate responsibility for the legal affairs of the Association should reside in the Legal Committee. (ii) AIHC should have a General Counsel, appointed by the Steering Com mittee vrith the advice and consent of the Legal Committee, to advise on routine legal questions relating to the Association's activities, attend Committee meetings, and counsel to the extent appropriate on matters being considered at such meetings, (ill) The Legal Committee should xepcTt and recommend action to the AIHC Steering Committee on all legal (including litigation), legislative, and regulatory matters referred to or considered by the Legal Com mittee, (iv) The Legal Committee should be responsible for the selection, on an ad hoe basis, of outside counsel to handle specific litigation and regulatory proceedings, as directed by the Steering Committee. TRHisl 2/20/79 AP00049556