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PLAINTIFF'S EXHIBIT A/C Pipe Producers Association Board of Directors tternational Affairs Committee 7^ ------------- - (j. F. Welch, Vice-President Internal Correspondence August 17,1984 DATE SUBJECT U.S. National Institute of Environmental Health Sciences (NIEHS) - Asbestos Feeding Studies REF: (1) JFW correspondence, U.S. Environmental Protection Agency (EPA) Advance Notice of Proposed Rulemaking on National Drinking Water Regulations (2) JFW correspondence, same title, April 30, 1983 ACTION REQUIRED: Review for information Reference (1) mentions the reported finding of "nodules" in rats fed chrysolite in the National Toxicology Program (NTP) animal studies. NTP Draft Technical Report on the Toxicology and Carcinogenesis Studies of Chrysctile Asbestos in F344/N Rats Enclosed are excerpts from the report. To summarize, oral administration of "short range" chrysotile did not cause any overt toxicity and neoplastic or nonneoplastic disease. These results are consistent with NTP studies feeding amosite and croeidolite asbestos to rats and hamsters. In male rats fed "intermediate range" (IR) chrysotile, however, benign neoplasms called adenomatous polyps were observed in the large intestine. The incidence of these neoplasms was not statistically significant when compared to the control group (not fed asbestos) in this study. When the incidence is compared with all male control groups in NTP's oral asbestos studies, it is considered highly significant. Thus, the report concludes that there is some evidence of carcinogenicity in male rats fed intermediate range chrysotile. In the section entitled "Discussions and Conclusions," NTP interprets the significance of these findings. Five important observations are made: (1) adenomatous polyps are benign neoplasms, (2) no malignant neoplasms were observed in this study (or any of the other oral asbestos studies), (3) the polyps did not progress to carcinomas even though, (4) this was a lifetime study that allowed progression to malignancy. Finally, no gastrointestinal tumors were observed in female rats in the same experiment. Discussions with NTP Staff On July 27, 1984, NTP's Board of Scientific Counselors peer reviewed the draft technical reports of the chrysotile feeding studies. According to Dr. E. E. McConnell, Project Officer, the Board determined that the polyps were "absolutely related to exposure to intermediate range chrysotile." Unfortunately, the Board did not address the question of why neoplasms were induced by IR chrysotile but not induced by amosite and croeidolite of comparable fiber dimensions in the same test animals. McConnell went on to say, "It's real. The neoplasms are definitely treatment-related. These results probably would not have been detected in a study involving a smaller number of animals (e.g. Smith, et al) and indicate that ingested asbestos certainly is not a rip-roaring carcinogen." He said that the Donham animal study, in which an asbestos dosing level of 10% resulted in a "trend toward increased colon lesions," suggested that neoplastic CAP CO JEN 0011599 response might occur but did not do so with statistical significance. The larger number of animals in this NTP study permitted this "trend" to develop fully, in his judgement. Public Health Significance When questioned about the point, McConnell stated that the current findings "meant very little with regards to human health." He said (not a direct quote), "From a public health standpoint, we obviously know that inhaled asbestos is carcinogenic. Ingested asbestos is probably not much of a public health threat,-especially since many of the fibers in water are much shorter than IR chrysotile. The dosing levels in these studies were 160,000 to 16 billion times greater than the projected level of possible human exposure. I'm not going to lose any sleep worrying about drinking water coming out of A/C pipe." After the peer review meeting, McConnell discussed the Board's conclusions with NTP Director Dr. David Rail. Rail concurs with McConnell's views, including the public health implications. Staff Analysis It would have been highly desirable for all the NTP studies to show no evidence of carcinogenicity with all fiber types, size ranges, and animal species and sexes. The current findings demonstrating "some evidence of carcinogenicity" blemish what previously was a strong, consistent body of animal toxicology studies showing no carcinogenic effects from ingested asbestos. It is not known whether EPA will share NTP's views about the public health implications of these findings. If anything, they complicate the question of whether asbestos in drinking water should be regulated and may well slow down the Agency's decision-making process. For example, the Office of Drinking Water may reraise the issue with the EPA Science Advisory Board. The matter definitely will be discussed at the next meeting of the National Drinking Water Advisory Council. CAP CO JEN 0011600 Staff plans to issue an A/C Advisory on this NTP study and McConnell's comments so that undue significance is not imparted to the findings. If you have any questions, please do not hesitate to call. JFW/bwm Enclosure cc: A. H. Kahn, Esq. Timothy S. Hardy, Esq. AIA AIA/NA CA1C W. E. Smith, M.D. B. T. Com mins, Ph.D. copies to: Board of Directors International Affairs Committee L. Ambler L. Cejudo J. M. Couture B. Layton L. Taylor a R. Dorner A. Junes G. Zaviezo M. A. Elola A. Lluch R. Hobbs R. Jalan H. Hudson S. Al-Tarkait M. Delcourt B. Dubois E. van der Rest E. Costa J. Schmaus F. Mansour P. Hart A. Saoulis V. Pattabhi C. Barton C. Saeng-Xuto B. Giboin J. Bryant 0172081301 Chrono CAPCO JEN 0011601 Board Draft, 7/84 NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF CHRYSOTILE ASBESTOS (CAS NO. 12001-29-5) IN F344/N RATS (FEED STUDIES) E. E. McConnell, D.V.M. (Chemical Manager) ft NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park North Carolina 27709 NOTICE This is not a final report. Until this DRAFT is' reviewed and approved by the Technical Reports Review Subcommittee of the NTP 3oarc of Scientific Counselors, this DRAFT does r.ot represent the official position of the National Toxicology Program. NTP TR 295 NIH Publication No. 84-2551 NTP-83-173 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health NTP TR 295 Chrysot e Asbestos CAP CO JEN 0011602 7/84 NOTE TO THE READER The=e studies are designed and conduct to characterize and evaluate the toxicologic potential, clud'in* carcinogenic activity, of selected chemicals in laboratory animals (usuallv two species, fats a mice) ^Chemicals selected for testing; in the XTP Carcinogenesis Program are chosen primarily on t bases of human exposure, level of production, and chemical structure. Selection per se is not an ir.dicaof a chemical's carcinogenic potential. Negative results, in which the test animals do not have a greaincidence ofcancer than control animals, do not necessarily mean that a test chemical is not a carcmog' inasmuch as the experiments are conducted under a limited set of conditions. Positive resu demonstrate that a test chemical is carcinogenic for animals under the conditions of the test and indict that- exposure to the chemical has the potential for hazard to humans. The determination of the risk humans from chemicals found to be carcinogenic in animals requires a wider analysis which exter beyond the purview of this study. Five categories of interpretative conclusions were adopted in June 1983 for use in the Technical Repo series to specifically emphasize consistency and the concept of actual evidence of carcinogenicity. F each definitive study result (male rats, female rats, male mice, female mice), one of the following quin will be selected to describe the findings. These categories refer to the strength .of the experimental e dence and not to either potency or mechanism. Clear Evidence of Carcinogenicity is demonstrated by studies that are intemreted as showin: chemicallv related increased incidence of malignant'neoplasms, studies that exhibit a si stantiallv'increased incidence of benign neoplasms, or studies that exhibit an increased incider of a combination of malignant and benign neoplasms where each increases with dose. Some Evidence of Carcinogenicity is demonstrated by studies that are interoreted as showin chemically related increased incidence of benign neoplasms, studies that exhibit marginal creases in neoplasms of several organs/tissues, or studies that exhibit a slight increase in i common malignant or benign neoplasms. ' Equivocal Evidence of Carcinogenicity is demonstrated by studies that are interpreted showing a chemically related marginal increase of neoplasms. No Evidence of Carcinogenicity is demonstrated by studies that are interpreted as showing chemically related increases in malignant or benign neoplasms. Inadequate Study of Carcinogenicity demonstrates that because of major oualitative or qui titative limitations, the studies cannot be interpreted as valid for showing either the presence absence of a carcinogenic effect. Additionally, the following concepts (as patterned from the International Agency for Research on Cani Monographs) have been adopted by the NTP to give further clarification of these issues: The term chemical carcinogenesis generally means the induction by chemicals of neoolasms : usuallv observed, the earlier induction by chemicals of neoplasms that are commonly observed, the induction by chemicals of more neoplasms than are generally found. Different meehar.is: may be involved in these situations. Etvmologically, the term carcinogenesis means induction cancer, that is, of malignant neoplasms: however, the commonly accepted meaning is the ir.ducti of various types of neoolasms or of a combination of malignant and benign neoplasms. In the Te< nical Reports, the words tumor and neoplasm are used interchangeably. This studv was conducted under contract to the National Institute of Environmental Health Scienc National Toxicology Program. The study described in this Technical Report has been conducted unc XTP health and safety requirements and/or guidelines for toxicity studies'. Individual toxicology testi contractors are. required to demonstrate corporate health and safetv programs in comoliance with X` chemical health arid safety requirements arid to meet or exceed alf applicable Federal, state, and io' health and safety regulations. Although every effort is made to prepare the Technical Resorts as accurately as possible, mistakes m occur. "Readers are requested to identify any mistakes so that corrective action may oe taken. Furth anyone who is aware of related ongoing or oubiished studies not mentioned in this resort is encouraged make this information known to the NTP. Comments and ouestior.s about the National Tqxicoie Program Technical Resorts on Toxicoiogv and Carcinogenesis Studies should be directed to Dr J E. Hi National Toxicology Program. P 0. Box f'2233, Research Triangle Park, XC 2770S 919-541-STSO-. These NTP Technical Reports are available for sale from the National Technical Information S-.-rvi C 5. Department of Commerce. -5255 Port Royal Road. Springfield. VA 22131 03-4$7-465,l- Sir., cosies of this Technical Resort are available'without charge' -and while supplies last: from, the N Public Information Office. National Toxicoiogv Program.. P.'O Box 12233, Researcn Triar.g.e Par.-t. 27709 CAP CO JEN 0011603 Board Draft, 7/84 CONTENTS PAGE ABSTRACT ............................................. ............................................................................................................. CONTRIBUTORS........................................................................... .. ..................................................................... 11 13 I. INTRODUCTION.............................................................................................................................. 15 II. MATERIALS AND METHODS...........................................................................'......................... 23 PROCUREMENT AND CHARACTERIZATION OF TESTMATERIALS... PREPARATION OF FORMULATED DIETS AND DOSEMIXTURES.... LIFETIME STUDIES OF SHORT-RANGE OR INTERMEDIATERANGE CHRYSOTILE ASBESTOS................................................................... .. . . STUDY DESIGN.................................................................................................. SOURCE AND SPECIFICATIONS OF TEST ANIMALS................. ANIMAL MAINTENANCE................................................................................. SAFETY PRECAUTIONS................................................................................. CLINICAL EXAMINATIONS AND PATHOLOGY.................................. STATISTICAL METHODS. .. ...................................................................... 24 27 29 29 29 31 33 33 36 III. RESULTS........................................................................................................................................... t LIFETIME STUDIES OF SHORT-RANGE OR INTERMEDIATERANGE CHRYSOTILE AS3ESTOS......................... '....................t........................ ESTABLISHMENT OF TEST GROUPS.................................................... BODY WEIGHTS AND FEED CONSUMPTION....................................... PATHOGEN BURDEN......................................................................................... CLINICAL SIGNS....................................... '.........................................'. . . SURVIVAL...................................................................... \................................... PATHOLOGY AND STATISTICAL ANALYSES OF RESULTS........................................................................................ 41 42 42 43 49 50 53 59 IV. DISCUSSION AND CONCLUSIONS....................................................................................... 78 V. REFERENCES................................................................................................................................... 94 NTP TR 295 Chrysotiie Asbestos CAP CO JEN 0011604 TABLE B2. SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS IN THE LIFETIME FEED STUDY OF INTERMEDIATE-RANGE (IR) CHRYSOTILE ASBESTOS (Continued) < CONTROL IR + IR + (UNTR) DMH IR DMH PW IR ENDOCRINE SYSTEM (Continued) #PANCREATIC ISLETS - ISLET-CELL ADENOMA ISLET-CELL CARCINOMA (87) 2 (2%) 4 (5%) (124) 1 (17a) l (1%) (249) 6 (2%) 7 (3%) (175) 1 (1%) l (1%) (99) 4 (4%) 3 (3%) REPRODUCTIVE SYSTEM MAMMARY GLAND (88) CARCINOMA, NOS t (1%) ~ ' ADENOMA.NOS 6 (7%) -- ADENOCARCINOMA, NOS 5 (6%) -FIBROADENOMA 49 (56%) CHONDROMA VULVA (88) FIBROSARCOMA, INVASIVE CLITORAL GLAND (88) CARCINOMA, NOS SQUAMOUS CELL CARCINOMA l (1%) VAGINA (88) FIBROMA FIBROSARCOMA ENDOMETRIAL STROMAL POLYP ENDO METRIAL STROMAL SARCOMA ENDOMETRIAL STROMAL SARCOMA, INVASIVE #UTERUS (87)` PAPILLARY ADENOCARCINOMA PAPILLARY CYSTADENOMA. NOS LEIOMYOMA 2 (2%) ENDOMETRIAL STROMAL POLYP 13 (15%) ENDOMETRIAL STROMAL SARCOMA 1 (1%) *CERVIX UTERI (87) FIBROMA LEIOMYOSARCOMA ENDOMETRIAL STROMAL POLYP l (1%) ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL STROMAL SARCOMA. INVASIVE UTERUS/ENDOMETRIUM (87) CARCINOMA. NOS PAPILLARY CARCINOMA ADENOMA. NOS PAPILLARY ADENOMA *OVARY (87) PAPILLARY ADENOCARCINOMA THECOMA 1 (1%) GRANULOSA-CELL TUMOR l (1%) (125) 2 (2%) 36 (29%) . (125) (125) 5 (4%) U25) 1 (1%) . (125) 7 (6%) 2 (2%) (125) (125) (125) (250) 3 (1%) . 21 (8%) 9 (4%) 128 (51%) (175) 5 (3%) 1 (1%) 41 (23%) (250) 1 (0%) (250) 16 (6%) 2 (1%) (250) (175) (175) 4 (27a) (175) 1 (0%) 2 (1%) (249) , l (1%) (175) 1 (0%) 22 (9%) 2 (1%) (249) 1 (0%) 3 (1%) (249) 1 (0%) l (0%) (249) l (0%) 4 (2%) 15 (9%) 2 (1%) (175) 1 (IYa) 1 (17a) l (17a) (175) 1 (17a) 4 (27o> 1 (I7a> (174) 1 (17a) (100) 1 (1%) . 11 (11%) 4 (47a) 58 (58%) . I (1%) (100) (100) 4 (4%) (100) l (1%) (99) 1 (!%) . 1 (17a) 10 (10%) 1 (17a) (99) l (1%) l (1%) (99) (99) 2 (27a) CAP CO JEN 0011605 BLE B2. SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS IN THE LIFETIME FEED STUDY OF INTERMEDIATE-RANGE (IR) CHRYSOTILE ASBESTOS (Continued) ._ ... CONTROL (UNTR) DMH RVOUS SYSTEM CEREBRUM ASTROCYTOMA BRAIN CARCINOMA. NOS, INVASIVE GRANULAR-CELL TUMOR, NOS GLIOMA. NOS ASTROCYTOMA iPINALCORD OLIGODENDROGLIOMA (87) 1 (1%) (87) 4 (5%) 1 (1%) (88) (125) (125) I (196) (125) IR (250) (250) 13 (596) 5 (296) (250) l (095) IR + DMH (175) (175) l (196) 1 (196) (175) IR + PW IR (100) (100) 1 (196) 1 (196) 1 (196) 1 (196) (100) * ICIAL SENSE ORGANS :ye FIBROMA :yeud SQUAMOUS CELL CARCINOMA JAR, SQUAMOUS CELL CARCINOMA IYMBAL GLAND SQUAMOUS CELL PAPILLOMA SQUAMOUS CELL CARCINOMA ADENOMA. NOS SARCOMA. NOS. INVASIVE (88) (88) 1 (1%) (88) (88) 1 (1%) JSCULOSKELETAL SYSTEM MAXILLA SQUAMOUS CELL CARCINOMA FEMUR OSTEOSARCOMA SKELETAL MUSCLE RHABDOMYOSARCOMA ABDOMINAL MUSCLE MIXED TUMOR, INVASIVE (88) (88) . I (1961 (88) (88) (125) (125) (125) (125) . 1 (1%) 14 (1196) (250) l (096) (250) (250) (250) 7 (396) (125) (125) (125) (125) (250) 1 (096) (250) (250) (250) (175) (175) . (100) (100) (175) 1 (196) (175) 2 (196) 26 (1596) 1 (196) (100) (100) 2 (296) 1 (196) (175) (175) (175) (175) 1 (196) (100) (100) (100) 1 (196) (100) CAP CO JEN 0011606 TABLE B2. SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS IN* THE LIFETIME TEED STUDY OF INTERMEDIATE-RANGE (IR) CHRYSOTILE ASBESTOS (Continued) ; CONTROL IR + IR + (UNTR) DMH IR DMH PW IR BODY CAVITIES MEDIASTINUM -- MUCINOUS CYSTADENOCARCINOMA. METASTATIC ABDOMINAL CAVITY . LEIOMYOSARCOMA ABDOMINAL WALL . MIXED TUMOR. INVASIVE MESENTERY ------SQUAMOUS CELL CARCINOMA, * ' ` "INVASIVE * MIXED TUMOR. INVASIVE (88) (125) (88) l <l?o) (88) (88) ' (125) (125) (125) (250) (250) (250) (250) (175) l (1%) (175) (175) l (1%) (175) 1 (17c.) (100) (100) (100) (100) 1 (17c.) ALL OTHER SYSTEMS -MULTIPLE ORGANS (88) ADENOCARCINOMA. NOS. \TFTA STATIC ALVEOLAR/BRONCHIOLAR CARCINOMA. METASTATIC PAPILLARY ADENOCARCINOMA. METASTATIC CORTICAL CARCINOMA. METASTATIC C-CELLCARCINOMA. METASTATIC l (17c) MUCINOUS CYSTADENO- CARCINOMA. METASTATIC SIGNET RING CARCINOMA. METASTATIC SARCOMA. NOS MIXED TUMOR. METASTATIC CARCINOSARCOMA. METASTATIC OSTEOSARCOMA. METASTATIC 1 (1%) THORACOLUMBAR REGION OSTEOSARCOMA l PERINEUM FIBROSARCOMA LOWER LEG OSTEOSARCOMA 1 FOOT FIBROMA ADIPOSE TISSUE MUCINOUS CYSTAD ENOCA. METASTATIC MIXED TUMOR, INVASIVE BROAD LIGAMENT LEIOMYOMA (125) 1 (1%) 6 (555.) 1 (155.) 1 (15E.) 1 (155.) 1 (1%) (250) 1 (0%) 1 (0%) 2 (1%) l 1 1. (175) 10 (6%) 4 (2%) I 3 (100) # NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED CAPCO JEN 0011607 TABLE B2. SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS IN THE LIFETIME FEED STUDY OF INTERMEDIATE-RANGE (IR> CHRYSOTILE ASBESTOS (Continued) ; CONTROL IR + IR 4- (UNTR) DMH IR DMH PW IR BODY CAVITIES MEDIASTINUM - MUCINOUS CYSTADENOCARCINOMA. METASTATIC ABDOMINAL CAVITY . LEIOMYOSARCOMA ABDOMINAL WALL . MIXED TUMOR, INVASIVE MESENTERY SQUAMOUS CELL CARCINOMA, ' TNVASIVE ' - MIXE D TUMOR. INVASIVE (88) (88) 1 (1%) (88) (88) ` (125) (125) (125) (125) (250) (250) (250) (250) (175) l (1%) (175) (175) l (1%) (175) 1 (1%) (100) (100) (100) (100) 1 (1%) ALL OTHER SYSTEMS -MULTIPLE ORGANS (88) ADENOCARCINOMA. NOS. NTFTA'JT A TIP ALVEOLAR/BRONCHIOLAR CARCINOMA. METASTATIC PAPILLARY ADENOCARCINOMA. METASTATIC CORTICAL CARCINOMA. METASTATIC C-CELL CARCINOMA. METASTATIC I (1%) MUCINOUS CYSTADENO. CARCINOMA. METASTATIC SIGNET RING CARCINOMA, METASTATIC SARCOMA. NOS MIXED TUMOR. METASTATIC CARCINOSARCOMA. METASTATIC OSTEOSARCOMA. METASTATIC 1 (1%) THORACOLUMBAR REGION OSTEOSARCOMA l PERINEUM FIBROSARCOMA LOWER LEG OSTEOSARCOMA l FOOT FIBROMA ADIPOSE TISSUE MUCINOUS CYSTADENOCA. METASTATIC MIXED TUMOR. INVASIVE BROAD LIGAMENT LEIOMYOMA (125) 1 (1%) 6 (5%) 1 (1%) I (1%) 1 (1%) 1 11%) (250) l (0%) I (0%) 2 (1%) l I 1 (175) 10 (6%) 4 12%) l 3 (100) # NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED CAP CO JEN OOI1608