Document MGGdKqd30rB78wBKBrDJ2N8gL

PO Sox NO p--1 fata KECfcIVED imperial ' Welwyn Garden City Heritordelve AL71H0 OCT 27 197a - Tetoohone- WeTwyn Garden 23400 (STD Code 07073) Chemical Industries Telex 264251 U N. WHEFII^ Limited From J Stafford Division Msnager HealtifcECQEMfiBonnent Protection A To DEC 0 7 1978 See Circulation Below Copie* to Plastics Division r. N> WHEELER, JR. TO: SFX VINYL SUBCOMMITTEE ** t FROM: W D Davis/R N Wheeler November 28, 1978 Your ref. Our ref JS/AXB/D60-107 Tel ext J162 Date 17 October 1978 e PVC DOST i \ Tou say care to see the attached letter and N10SB report X have received froc Sr Dongle* of BOS. This report seaas reassuring but I would wtlcoae the opinion of our Kedical Coaalttea who hawe been considering how to design a good PVC duet Inhalation study. Eaa the need for such a study disappeared an a result of the NI06H work? Dr K N Johnson of B T Goodrich, when he saw us on 9 October, knew of thane results but was critical that the rodent species were sacrificed at 12 conths (nonkeys 22 nonthn). Dr Johnson thought that a well conducted full life study on PVC dust in halation should still be considered and the possibility of Transatlantic cooperation explored to derive both protocol and funding. Circulation =5 Dr W G T Adams Mr T V Koffitt Dr D P Duffield Dr L de Boer Dr G Pigott Dr J 0 Kaaeuller Dr B V Duck Mr J C Thooan Dr M Sharratt Mr H Bonnefoy Dr P Orasso Dr T Garlands Dr J T Carter Dr K N Johnson Dr D V Pleeter Dr T R Torkelson Dr G Paddle &XrlS N.Vhsaler (Jr)f Dr K S Villiaason JS (2) Dr I T H Purchase Sir C Lawrence Jones Dr T V Best Hr G J Sleddon Mr V Adana Dr R Davies ICI Melbourne Mr K H White, Duperial SAIC Chief Kedical Officer, AECI Mr 2 Sards Mr P H M Eharrock Krll Phillips Mr B N P Eutcbesson Hr H M Clayton ** l Mo 7 16019 *V9'ttv*C 0<Cf ImpfF.Al Chfwn<gl HOwtf. M.|l&hAW, London SW1P 3JF ucc 007042 ; \ $ fi '1 \ f 4 * \ \ * -.*4 t Health & Safety Executive Baynerds House 1 Chepstow Piece London W2 4TF Telephone 01 -229 34SC ext Dr J Stafford Division Manager Health & Environment Protection ICI Limited, Plastics Division P 0 Box No 6 Bessemer Road Welwyn Carden City AL7 1HD Your nlittnci Our reference l/MS/406/225/78 6 October 1978 Deer Dr PVC DUST Ibank you for sending me a copy of Waxweiler's report on PVC dust and the item from Tox-Tips. Both will be discussed at the next tri-partite medical meeting which should take place in late November. Dr Elliott Karris the head of the Division of Bio-Medical and 3ehavioural Science, NXOSH, was here on Tuesday 3 October and told me that the study by Dr Trent Lewis had been completed and no evidence of carcinogenicity or pneumoconiosis had been found in any of the animal species* I enclose copies of the reports given to me by Dr Harris. Yours sincerely D B Douglas Deputy Director of Medical Services cc: Dr R Cwer. Dr P:S Pairveather ucc 007043 fVC Chronic Inhalation Toxicology Study 4 Polyvinyl chlorida (PVC) la widely used In various for*a. Rigid FVC is used for tubing end fittings (Insulation materiel and drainage pipe), foils, films and sheeting (packaging, recording tapes), profiles (blinds, window frames), tiles, sound records, and fibers. Flexible PVC is used for cables, foils (decoration, roof covering), tubing, artificial leather, flooring, foaa rubber, paint, varnish (lacquer), and toys. . * Reports- of pulmonary dysfunction and pneumoconiosis in FVC workers and dust exposed animals point to the need for further studies on the i\ toxicological properties of the polymer. Also, cases of still-births, > miscarriages and malformations among workers engaged in the polymeriza tion of vinyl chloride have aroused great interest in the toxicological properties of PVC. Since FVC is a fine volatile dust, pathogenic ' effects of the lungs may be anticipated. B. F. Goodrich Company is a supplier of resins for vinyl dispersions using the trade name "Geon." The dispersions are fluid suspensions of special fine particle-size polyvinyl chloride resins in plasticizing liquids. When the system is heated to about 148 to 177*C (300 to 350*F), fusion (mutual solubilization of resin and plasticizer) takes place. 4 The dispersion turns into a homogeneous hot melt. When the melt is j cooled below 50 to 60*C (122 to 140*F), it becomes a tough vinyl product. The term "plastlsol" is used to describe a vinyl dispersion which contains no volatile thinners or diluents. Plastlsols often contain stabilizers, fillers, and pigments along with the essentials, dispersion resin and liquid plasticiser, but all ingredients have very low volatility under the processing and use conditions. Geon \21 is s high molecular weight resin. It has been the standard of the plastlsol industry for over 25 years and is an excellent resin for . .4 starting point formulations. Currently, it is being used in dip, slush and rotational molding, spread coating, foaa coating and molding, crown and jar meals, and caulks and sealants. In light of the relationship unequivocally established between occupational exposure to vinyl chloride monomer and liver angiosarcoma, and the concern expressed on potential risks to human health from exposure to polyvinyl chloride (PVC) dusts manufactured and used from polymerization of the vinyl chloride monomer, OBBS in FT'75 in its project plan on "Chronic Exploratory Toxicology Studies and Test of Validity of Industrial Air Standards" proposed an inhalation exposure study with PVC dust. Actual exposures to a representative material (S. F. Goodrich Company, Geon 121) began In February 1976 utilizing three species of animals -- monkey, guinea pig and rat*-- a^d-6-1/2 hours per day, 5 days per week exposure regimen, and at a 10 mg/m respirable PVC dust concentration. Exposure duration was for 22 months. The following table summarizes the above data. i ucc 007044 Anleal Species Monkey Guinea Pig Rat Selected Data from PVC Chronic Inhalation Exposure Study (Ceon 121) Ko. per Croup Exposed Control Duration of Exposure Calendar Exposure Exposure Days Days Hrs. Mean PVC Cone. mR/m* Mean Range of Cone. m*/o* 10 10 . 690 464 2816 10.8 4.65-9.25 40 40 379 245 1428 10.6 - 60 60 376 244 1424 10.6 - 4 CT Values (an/a*-Hrs.) Intended Actual 28,160 14,700 14,640 30,510 14,698 ^ 14,627 i ucc 007045 r ir Vw Partiele size analysis of collected exposure chamber samples Indicated thsc the generated PVC dust vss of geometric Been diameter of 0.53pm vAh more then 99Z of the ssapled particles below S.Oiim; 821 below 1.0pm. The manufacturer's specifications data states a particle size range for Ceon 121 of between 0.5 and l.Spa. Exposure System: Chambers used in the study were five feet square, stainless steel, and featured a dynamic airflow system of 40 cubic-feet per minute under a negative chamber pressure of approximately 0.2" HaO. The PVC aerosol was generated by means of a Wright Dust Feed Mechanism and the dust dispersed into the chamber at a rate sufficient to maintain the desired 10 mg/m* concentration. Gravimetric analyses were made four times per day on collected membrane filter samples for total dust con centrations, and once per day for respirable dust (lG-plate horizontal elutrlator sample). Biological response data evaluated from the exposed and control animals at time of serial aacrlfice/evaluation included: Blochemical/Cllnlcal Chemistry (Culnea Pig, Rat only): (SCOT, SGPT, alkaline phosphatase, gamma glutamyl transpeptidase, total protein and serum-protein electrophoresis). No significant differences were indi cated in rats for any parameter. Guinea pig data showed controls with higher SCOT, SGPT, and alkaline phosphatase. It was concluded that no extensive liver damage was detected by any of the liver clinical Indicator tests used. However, a sizable amount of liver damage must occur before these tests would indicate abnormalcy. One cannot conclude that there is no liver damage; but only that there is no extensive liver involvement. Pathology (All species): No significant alterations in liver tissue. The only contribution of the inhaled PVC dqst deposition and retention to pulmonary tissue morphology was aggregation df PVC-containing macro phages (refer to attached pathology reports and to report on Amorphous Silica exposed and control monkeys). Pulmonary Function (Monkey only): Fasted, exposed and control monkeys were tested for pulmonary function one day following their last exposure. Evaluations were accomplished through use of a variable pressure, wholebody plethysmograph. Tests evaluated were: Total lung capacity (TLC); vital capacity (VC); inspiratory capacity (IC); residual volume (RV) divided by total lung capacity (RV/TLC); forced expiratory volume in 0. 5 seconds (FeV 0.5); forced expiratory volume in 1.0 seconds (FeV 1.0); peak expiratory flow(PF); maximum mid expiratory flow (MMF); maximum expiratory flow volume curves (MEFV) at 50Z, 25X and 10Z of vital capacity; resistance; and compliance. A summary, of the extensive pulmonary function evaluations Indicated some signs of loss of lung recoil pressure, probably a result of the animals' aging process. In most eases differences were noted during the second and third testing periods (exposure months 6 and 16) and were indi cative of some small airway obstruction. At this time, however, these differences were not statistically significant. At the last evaluation (month 22) compared with baseline (pre-exposure) data there were no signi ficant differences for any parameter tested: Impairment of respiratory function does not appear to be indicated under the conditions of this study from exposure to respirable PVC dust. Attachments UCC 007046 IV i l.yj X.i. 1 JL7 WKi. CZNTKK nw HIM.AM" CONI Kill. NATIONAL INSYITUTK VIM Ot t HI A IKINAL SAHSIY ANU Mr.AI.lll -TO a : Chief, USB THROUGH: Chief, Pathology Section OATTi: Hay 5, 1977 PROM : Veterinary Pathologist, Pathology Section 1 1 : SUHJIiCT: Pathology Report on Rate Exposed to PVC *! '-='* Male rats were exposed by inhalation to polyvinyl chloride (PVC), respirable concentration 10 mg/m , for 6 hours/day for 5 days/veek for a period of 12 months. The animals ware sacrificed lsnedlntcly after 12 months of exposure to PVC. The following tissues on each animal were saved at necropsy for histopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The histopathology evaluation was performed on a total of 121 (exposed 57, control 64) mala rets. \ 1*1 Rats exposed to PVC 10 mr./re* for 6 hours/dey for 5 daye/veck -I by Inhalation. Path. Aces. Ko.: 76-1329, 76-1337, 76-1338, 76-1340 to -1393. Cross pathology: lungs: Multiple white foci of varying else either In one or more lobes of the lungs were seen In 76-1337, -1338, -1344, -1345, -1347. -1348, -1350, -1353, -1354, -1363, -1367, -1369, -1373, -1379, -1385, 1 end -1367. "Abscess" was seen in the lungs of each of 76-1346, -1351, -1352, -1363, and -1378. "Tumor" meaauring 1.5 x 2.0 cm and weighing 2.90 gm - was seen In 76-1375. Liver: Enlarged dark red liver was seen In 76-1337. Kidney: Small mineralized areas (stones) were seen In the kidneys of 76-1363 end 76-1366. Pituitary gland: Enlarged (10X) pituitary was occn in 76-1338. Histopatholony: Lungs: The lesions eoimonly associated with the chronic murine pneumonia (bronchiectasis, peribronchial, and perivascular accumulations of lymphocytes, .Coca] chronic active bronchitis and bronchiolitis. focal atelectasis) were seen in all -rats. Vascular (arterial) wall mineralization was seen .in all rats. Focal intense macrophage accumulations (solid sheets), sometimes displacing the normal structures, voio seen. Host of these macrophages had varying size globular to spherical structures in the cytoplasm (foam colls). ucc W 007047 * f < * < Chief, BSB These dense conglomerations of macrophages were occasionally associated with mild blue staining (mucin?) fluid material. The above-mentioned macrophages or macrophages surrounded by fluid when Accumulated at the periphery of the lung probably imparted the appearance of "white foci" grossly seen in the lungs. The intracellular, material in these macrophages was probably parti cles of the rvc. No birefringence was seen among these. Dr. Stettlcr and Mr. George Machay informed me that these, indeed, were PVC particles, based j on electron probe Analysis of some lungs from the rats exposed to PVC by inhalation as well as . by intravenous Injection. The macrophage accumu lations apart from physical displacement of the lung parenchyma do not seem to bestow any dele terious effects on these rats. No alterations (hyperplasia, etc.) of the alveolar or bronchial epithelium attributable to treatment were Been in these rats. Tracheobronchial lymph nodes (TBLN): Macrophage accumulations as seen in the lungs were seen in the medulla and cortex of all the TBLNs examined. Reactive hyper plasia of germinal centers was also seen. Liver: Mild fatty infiltration of hcpatocytcs was seen in 76-1338. Extra medullary hematopoiesis (mild) was seen In 76-1364 and 76-1371. Spleen: Macrophages containing yellow granular material in the cytoplasm and extramedullary hematopoiesis were seen in all the spleens examined. Heart: Mild focal myocarditis was seen in 76-1337, -1363, and -1377. Kidney: Multifocal mineralized areas of the tubules or the trensitional epithelium of the kidney pelvis were seen in 76-1348. -1353, -1356, -1363, and -1366. Focal tubular dilatation, focal tubular epithelial degeneration and regeneration and mild lymphocyte accumulations were seen in 76-1351, -1356, -1357, -1363, -1370, -1376, -1381, -1382 to -1384, -1387, -1388, -1390 to -1392. Pancreas: Mild hyperplasia of the islets of Langerhans was seen in 76-1355, -1361, -1363, -1364, -1367, -1368, -1370 to -1372, -1376, -1377, -1379 to -1381, -1335 to -1389, and -1391 to -1393. Adrenal: Moderate fatty infiltration of the epithelium of the cortex was seen in 76-1341 to -1344, -1348 to -1350, -1369, -1370, -1378, and -1381. An odrenal cortical adenoma was seen in each of 76-1365 and 76-1371. A phcochromocytoma was seen in 76-1358. 2 UCC 007048 Chief, BSB 3 Thyroid: Cyst(s) containing keratin was scon in 76-1337, -1338, -1341, -1342, -1345, -1346, -1353, -1355 to -1357, -1360, -1361, -1364, -1365, -1370, -1372, -1374, -1375, -1379 to -1382, -1388, -1391 to -1393. Testis: Vessel (artery) well mineralization was seen in 76-1358, -1378, -1385, and -1390. Mild hyperplasia of interstitial cells and atrophy of seminiferous tubules were seen in 76-1347, -1353, -1358, -1361, -1365, -1370, and -1378. Lymph node: Chronic lymph adenitis was seen in 76-1375. The lymph node was adjacent to a major artery suggesting it to be a mediastinal lymph node. Pituitary: A chromophobe adenoma was seen in .76-1338. All the other organs examined were unremarkable. 1.2 Untreated Hale' Rats Path. Accs. Wo.: 76-1394 to -1431, 76-1510 to -1520, 76-1523 to -1537, .76-1539 to -1548. Gross pathology: A cataract of the right eye wes seen in 76-1396. Consolidation of lung lobes was seen in 76-1395, -1400, -1416, -1527, -1530, -1537, -1540, -1546, end -1547. Brown dlscolorarion (76-1405) and an abseesa was seen in the lungs (76-1418). A multiloculeted mass 2.5 x 3.0 cm was seen attached to mesentery in 76-1427. Renal calculi were seen in 76-1518. Hlstopatholonv: Lungs: The morphological changes associated with the chronic murine pneumonia and pulmonary vascular wall minerali zation as seen in 1.1 were seen in all rats. Macro phage accumulations of far lesser degree in intensity were seen in all rats. These macrophages did not congregate in a solid sheet as seen in 1.1. The cyto plasm of most of these macrophages contained granular eosinophilic material. Ho alveolar or bronchial epithelial hyperplasia was seen in any rat. TBLH: Chronic reactive hyperplasia was a common finding in all rats. Liver: - A single cyst was seen in each of 76-1397 and 76-1399. Spleen: The changes seen were similar to those seen in 1.1 in all rats. w7 Heart: Mild focal myocarditis was seen in each of 76-1401, -1402, -1405, -1407, and -1415. Pancreas: Mild hyperplasia of endocrine elements was seen in 76-1395 to -1399, -1402, -1404 to -1410, -1414 to -1418, -1420, -1421. -1424 to -3426, -1426, -1429, -1510, -1511, -1514, -1515, -1518 to -1523, -153?., -1539 to -3542, and -1545. an UCC 007049 Chief, BSB 4 Kidney: Adrenal: thyroid: Testis: Eye: Mess: Tubular epithelial degeneration end regeneration, occasional tuhulnv dilatation and focal mild lympho cytic accumulation were aeon in 76-1394, -1396, -1397, -1399, -1401 to -1403, -1405, -1409, -1412, -1417 to -1419, -1421, -1422, -1425, -1431, -1515, -1524, -1527, -1534, -1546, and -1548. Focal mineralization of titular epithelium nnd/or the transitional epithelium of the renal pclvin was seen in 76-1518, -1527, and -1533. Adenoma of the adrenal cortex was noticed in 76-1400, -1518, -1523, and -1544.. Fhdochtomocytoma was seen in 76-1548, Moderate fatty infiltration of the cortex was seen in 76-1410 and 76-1544. Cyst(c) containing keratin von seen in 76-1395, -1397, -1399, -1402. -1403, -1406, -1410 to -1412, -1416, -1417, -1419, -1420, -1422, -1423, -1425 to -1427, -1429, -1510, -1512 to -1515, -1517, -1519 to -1527, -1529, -1530, -1532 to -1534, -1536, -1541, -1543 to -1548. Atrophy of seminiferous tubules and Leydig cell hyper plasia was seen in 76-1395, -1400, -1514, -1516, -3533, -1541, and -1548. Vessel (artery) wall calcification was seen in 76-1398 and 76-1533. Focal moderate mineralisation of seminiferous tibulcs was seen in 76-1418, -1510, and -1517. 76-1396*. Retinal atrophy - .unilateral. Adhesions between the retina and lens with dystrophic calcifi cation at some foci. The lens protein was well oriented with occasional basophilic bodies, probably nuclei from decidual lens colls. The calcific deposits coupled with the hyallnization of sclera imparted the opacity to the lens; cataract seen grossly. 76-1427: Granuloma of mesenteric fat. Comment: For comparison, this comment shall include rat and guinea pig data. Both the rats and the guinea pigs exposed to PVC by inhalation exhibited the presence of FVC parLleulatcs in the pulmonary macrophages, although the pattern of macrophage accumulation between the two species differed. Thc.ro was no influaimatory or any other deleterious effect seen in the lungs of.these animals that could be attributable to FVC inhalation. The incidence of perivascular lymphoid aggregations in the lungs Of guinea pigs was similar in both exposed and controls, The presence of bony spicules in the lungs of exposed nnd control guinea pigs was observed. The patho genesis of vhisc two comlilions is not known (Thompson, S. W., Hunt, R. D. ct al: dm. J. l'ntli. <40:507-517 (19fi2) ; Kaufman, A. F.: I.ab. Anim. Care 20:1002-1003 (1970)) and is worth exploring as NlOSH uses guinea pigs as UCC 007050 Chief, BSB 5 i one specie* of onlnols in biological experiments. The ncpbroealcinosis seen In the exposed and control guinea pigs nay be related to diet (J. C. Woodard: Am. J. Path. 65:253-268 (1971) and 65:269-278 (1971)). Corollary to the above observation was the finding oC invariable fatty infiltration of exocrine and endocrine elements of the pancreas in both the exposed and control guinea pigs and the hyperplasia of islets of Langerhans seen In both the rata and the guinea piga employed In this experiment. In addition, the vascular wall calcification in tho pul monary vesscla of rota la disturbing. All of these "incidental" finding strongly suggest that these animals had metabolic problems probably related to the animal diet. The changes aecn in the testes of rats were non-specific and probably not related to treatment. 2he Incidence of neoplasms in tho adrenals of rats is within tho normal range observed for Sprague-Oawlcy rats of this age. i H 1 1 > ucc 007051 MEMORANDUM TO Chief, ETB Through: Director, DBB5 __ . Chief, BSB Wti'Ak iMfcN VOF HEALTH. HDUCA'IION PUBLIC HEALTH SRRVKT. ,,___ __ ce*TM eo* duka** c-ontrih. national iHrtmrrr. me ocrurAiMmAt ANP> WHl-FAKI vn ,,, DATE: September 6, 1978 \ FROM \l M SUBJECT; Research Veterinary Medical Officer Pathology Report on Monkeys Exposed to FVC Ten male Cynomolgus (Donkeys were exposed to PVC at 10 mg/m* by I inhalation for 6 hours/day, 5 daye/veek for almost 22 month*. i Control male monkeys (10) vert maintained in an open animal room ( in their individual cages. The monkeys were killed within 48 hours after the final exposure. At the tine of autopsy, tissues from the lungs (all lobes with trachea), thyroid, heart, tracheobronchial lymph node* (TBLN), mesenteric lymph nodes (MLN), liver, spleen, kidney, urinary bladder, prostate, testia, stomach (pylorus), duodenum, pancress, adrenals, and akin from the abdomen were : :l saved for histopathology. Control Monkeys Path. Aeess. #77-2975, 77-2979, 77-2981, 77-2983 to 77-2986, 77-2991, 77-2993 and 77-2994. Cross and histopathology; See the pathology report on monkeys exposed to Silica-F, ,4 1.2 Monkeys Exposed to PVC | Path. Accss. #77-2974. 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2995, 77-2996, 77-2997 and 77-2999. Cross Pathology; Adhcsiona between the lobes of the lung and the thoracic wall were seen in 77-2980, 77-2995 and 77-2997. Multiple black areas were seen in the lungs of 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2996, 77-2997 and 77-2999, En larged and black MLKs were aeen in 77-2974 and 77-2976. Histopathology; Lung: Macrophages with anisotropic particles as in the -controls were similarly present in all these monkeys. Admixed with these macrophages were other macrophages with spherical material (PVC) of varying size In the cytoplasm. About 15Z of the total macrophage aggre gates (macules) in 77-2997, 77-2988 and 77-2980 contained black to brown anisotropic particles of the same degree of deposition .as in the controls. In the rest of the PVC exposed monkeys 20 to 22Z of t i i Ii ucc 007052 Chief, ETB I 2 the macule# had these black to brown particles. A total of 110 macrophage aggregates were seen at 25X magnification In most of the lungs. The diameter of many of these' aggregates varied from 100 to 200p while the largest, present In the alveolar region, measured 475p. The macro phage aggregatea were present In the alveolar walls, alveoli, partially obstructing the alveolar lumens. They were also present around tertiary bronchioles and In some alveolar ducts without causing observable obstruction. A few places showed submucosal accumulations with no polypoidal projections. With phase contrast Illumination these macrophage accumulations appear as blue aggregates. This tinctorial character Is distinct from the macrophage aggregates seen in amorphous silica (F, C and P) exposed monkeys. Focal hyperplasia of type II cells was present In 77-2989. Smooth muscle hyperplasia was seen around blood vessels and alveolar walls in 77-2996. Acute bronchopneumonia was seen in 77-2988. Plant material was present In a bronchus in 77-2999. Multiple gaint cells away from the plant material were seen in the 77-2999, Non-inflammatory arterlopathy as In the controls was present in all these monkeys. TBLN: As in the controls the medulla contained macrophages with anisotropic particles. In addition, other macro phages with cytoplasmic material (PVC - blue In color - see lung) were present. Together, these macrophages replaced most of the medulla of the TBLNs In all monkeys. Liver: Diffuse fatty infiltration of the hepatocytes was present in 77-2982 and 77-2996. Kidney; Multifocal calcification of cortical tubules was seen in 77-2995. MLN: See the controls. The other tissues examined were unremarkable. Comment; A slightly higher number of macrophage aggregates containing . black and brown birefringent particles were seen in PVC exposed than in the control monkeys. The pattern of distribution of the macrophage accumulations in the PVC exposed and the amorphous silica (F, C and P) exposed monkey lungs and the TBLNs was similar. The macules were smaller In size in PVC exposed than those seen in the amorphous silica (F, C and P) exposed monkeys. The monkey lung reaction suggests chat it may be a ucc 007053 Chief, ZTt 3 non-specific one, Inasmuch as these materials (PVC and amorphous silicas-F, C and P) show diverse chemical composition. The second paragraph under "Comment" in the pathology report on monkeys ex posed to amorphous ailica-F also applies here. The influence of ' the brown and black particles on the biologic effects of PVC are hard to define but should be carefully considered. The only contri bution of the inhaled PVC dust deposition and retention to pulmonary tissue morphology was numerous aggregations of PVC-contalning macrophages. Choudarl Komalnenl, Ph.D., DVH UCC 007054 1MEMORAND* UM ' DEPAUTMKNT Ol*' IIIALTM, HDUCATION. A NO Wr-LPAUI; HHII It' llliAl III MiKVICI- CIXTI R HIM IMJihAM! IIIHUUH NATIONAL INttlH'IT. MlkjOCClIrAIMINAI. XAFICIV AHII IIIAI 111 : chief. ESB THROUGH: Chief, Pathology Section DATU: May 10, 1977 irkOM : Veterinary Pathologist, Pathology Section ^SUBJECT: Pathology Report on Guinea Pigs to PVC Male guinea pigs were exposed by>inhalation to polyvinyl chloride (PVC), respirable concentration 10 mg/m , for 6 hours/day for 5 days/week for a period of 12 months. The animals were sacrificed Immediately after 12 months of'exposure to PVC, The following tissues on each animal were saved at necropsy for hlstopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The hlstopathology evaluation was performed on a total of 75 (exposed 36; control 39) male guinea pigs. 2.1 Guinea nigs exposed to PVC 10 me/m* for 6 houra/dav for 5 days/ week by Inhalation. Path. Ace a. Ho..- 76-1432 to 76-1*67. Cross pathology: Yellow specks were seen In the lungs of 76-1434, -1436, --1459, end -1464. Consolidation of lungs was observed in 76-1435, -1437, -1439, end -1449. Small areas of necrosis in the liver of 76-1443 were seen. Mesenteric fet necrosis was found in 76-1438 and 76-1441. Hlstopathology: Lungs: All guinea pigs exhibited moderate amount of eosinophilic serous exudate mixed with mild to moderate numbers of epithelial cells (decidual shewing varying stages of de generation) in the bronchial lumens. Another cornnon find ing among all guinea pigs was the presence of mulMple aggregates of lymphocytes. Mohl of these lymphoid aggre gates were oriented around or near small arteries or veins, thus giving an appearance of lymphoid follicles. The lnterstltium of all the lungs showed numerous macrophages. These macrophages contained spherical to globular hollow structures in the cytoplasm. These macrophages did not aggregate in the same fashion as those seen in rat lunge (1.1). Plant material with or without associated inflam mation was seen in bronchioles of 76-1432 and 76-1435. Bone formation (small spicules:) in alveolar area was seen in 76-1434, -1435, -1438, -1446, -1452, -1453, -1455, and -1456. Focal atelectasis was*seen in the lungR of all guinea pigs examined. ucc 007055 Chief, BSB 2 Liver: Mild fatty Infiltration of hepatoeycea vaa aecn In 76-1432, -1441, and -1467. The histology slides from 76-1443 did not show any hepatic necrosis. Search for liver tissue with necrotic areas from "wet tissue" was not fruitful. Heart: Focal mild myocarditis was seen In 76-1441, while 76-1449 showed focal mineralisation of myocardial e ! muscle bundles. - Spleen: Macrophages with yellow granular pigment In the cyto plasm were seen In all guinea pigs. Kidney: Multifocal mild mineralization of tubular epithelium was seen In 76-1432, -1437 to -1448, -1450 to -1460, -1462 to -1465, and -1467. Fenereae: Fatty Infiltration of the endocrine and exocrine ele ments was seen in 76-1439, -1442, -1444, -1447 to -1456, -1458 and -1461. Fatty infiltration of only exocrine elements and moderate hyperplasia of the endocrine ' elements were seen In all guinea pigs excluding the ones given above. Adrenal: Yellow granular pigment in the cytoplasm of the cortical epithelium was seen In all guinea pigs. Focal mild mineralization of the cortical epithelium was seen in 76-1435 and 76-1455. Urinary bladder: Mild focal hyperplasia of the transitional epithelium was seen In 76-1444. Mineralization of sur face epithelial cells was seen in 76-1452, -1453, and -1462 to -1465. 2*2 Untreated guinea pigs Path. Aces. Ho.: 76-1470 to 76-1508. i Cross pathology: Consolidation of lungs was seen in 76-1488, -1490, -1506. Small necrotic foci were seen in the livers of 76-1486, -1488, and -1491. A contracted kidney was seen in 76-1493. Necrotic fat (mass) was found attached to mesentery of 76-1475 (3.57 gm), -1477 (3 x 2 cm), -14B0 (4.5 x 2.5 cm), -1486 (1.0 x 2.0 cm). -1494 (1x2 cm), -1495, and -1496. Histopatholor.y: Lungs: The presence of eosinophilic fluid exudate with cellular debris and the lymphoid aggregation in all guinea pics was the same as seen in 2.1. The interstitium of all the lungs contained lesser number of macrophages than those seen In 2.1. The cytoplasm of these macrophages was granular nnd eosinophilic. Plant material with or without inflammatory infiltrates was seen in 76-1488 and -1490. Bone formation in the alveolar region was seen in -1474, -1475, -1476, -1478, -1490, -1493, -1499, -1501, and -1506. Focal consolidation of all lungs wav seen. ucc 007056 Chief, BSB 3 Liver: Fatty Infiltration (mild) of hepntoeytes was se n In 76-1472 and 76-1478. Moderate hyperplasia of bile duets vaa soon in 76-1474. A myclolIposarcona was seen in the liver of 76-1470. Spleen: Macrophages with yellow granular material in the cyto plasm were seen in all guinea pigs. Kidney: Multifocal mild to moderate mineralization of tubular epithelium was seen in 76-1470, -1471, -1473 to -1483, -1487 to -1508. Pancreas: Patty infiltration of exocrine and endocrine elements was seen in 76-1470 to -1475, -1478, -1480, -1482, -1486, -1488, -1490, -1492, -1494, -1495 to -1497, -1501, -1502, -1503, and -1507. The pancreas from the remaining guinea pigs showed fatty infiltration of exocrine elements and hyperplasia of endocrine elements. Adrenal: Yellow granular pigment in the cytoplasm of the epi thelium of the cortex of all guinea pigs was seen. Urinary bladder: Mineralization of the surface epithelium was seen in 76-1472, -1475, -1480, -1495, -1497, -1498, end -1504. Subacute cystitis was seen in 76-1470 end 76-1494. Mesenteric masses: 76-1473: Granuloma of mesenteric fat. Entrapped pancreatic exocrine elements were present. 76-1475: Cranuloma of mesenteric fat. 76-1477: Thrombosis of veins with degenerative fat. 76-1480: Thrombosis of veins and degenerating fat. 76-1486: Cranuloma of mesenteric fat; polarising yellow materiel seen. 76-1494: Degenerating fat. 76-1496: Cranuloma of mesenteric fet. Cement,; Por comparison, this comment shell include rat and guinea pig data. Both the rats and the guinea pigs exposed to PVC by Inhalation exhibited the presence of PVC particulates lu the pulmonary macrophages, although the pattern of macrophage accumulation between the two species differed. There was no inflammatory or any other deleterious effect seen in the lungs of these animals that could be attributable to PVC Inhalation. The incidence of perivascular lymphoid aggregations in the lungs of guinea pigs was similar in both exposed and controls. The presence of bony spi cules in Che lungs of exposed and control guinea pigs was observed. The pathogenesis of these two conditions is not known (Thompson, S. W., Hunt, R. D. et si: Am. J_. Path. 0:507-517 (1962); Kaufman, A. F.: Lab. Anlia. Care 20:1002-1003 (1970)) and is worth exploring ns NIOSH uses guinea pips as one species of animals in biological experiments. The ncphrocalcinosis seen in the exposed and control guinea pigs may be related to diet (J. C. Woodard: Am. J. Path. 65:253-268 (1971) and 65:269-278 (1971)). Corollary ucc 007057 Chief, USB 4 to the above observation was the finding of invariable fatty infiltration of exocrine and endocrine elements f the pancreas tin both the exposed and control gninca pigs and the hyperplasia of islets of Langcrltnns seen in both the rats and the guinea pigs employed in this experiment. In addition, the vascular wall calcification in the pulmonary vessels of rats la disturbing. All of these "Incidental" findings strongly suggest that these animals had metabolic problems probably related to the animal diet. The changes seen in the testes of rats were non-specific and probably not related to treatment. The Incidence of neoplasms in the sdrenals of rats is within the normal rangp observed for Sprague-Dawley rats of this age. UCC 007058 PLASTICS DIVISION- C NOTE ON A TELEPHONE CONVERSATION WITH DK M N JOHNSON OF BF GOODRICH, 20 OCTOBER 1978 PVC DUST - NIOSH STUDIES Dr Johnson 'phoned to say he had now had a talk with Dr Trent Lewis of NIOSH on the 3 mammal study. Dr Lewis emphasised that this was in no sense a carcinogenicity study. It was a study aimed at ascertaining about pulmonary function end fibrosis. Dr Lewis was happy with the outc me of the work in that nothing happened and therw was nothing to comment on the subject of pulmonary function and fibrosis. He thought the study was totally unsuited to gouge carcinogenecity. In Dr Lewis's view an unholation study of PVC dust on animals to demonstrot carcinogenicity is a very'difficult undertaking. He would be very unwilling to tockle it unless there was something equivocal in the epidemiology that needed to be resolved. Even then he would advocate expanding the epidemiology to get a more positive answer. If there is a positive answer from the epidemiology no amount of animal work would make any difference and again he stressed that dust inhalation tests for carcinogenicity on animals ara long, tedious, difficult and uncertain. J Stafford Division Manager Health & Environment Protection i JS/MJE/DSO-107 23 October 1978 Circulation Dr W G F Adorns Dr D P Duffield Dr C Pigott Dr B W Duck Dr M Shorrott Dr P Grosso Dr J T Carter Dr D W Plester Dr C Paddle Dr K S Williomson Dr I F H Purchase Sir C Lowrence-Jones Dr F W Best Mr G J Sleddon Mr W Adams Mr R Hords Mr P H M Shorrock Mr T L Phillips Mr B N P Hutchesson Mr H M Clayton Mr T W Moffitt Dr L de Boer Dr J G Kammuller Mr J C Thomas Mr M Bonnefoy Dr T Gorlonda Dr M N Johnson Dr T R Torkelson Mr R N Wheeler (Jr) JS (2) Dr R E Davies, ICI Australia Mr K H White, Duperial SAIC Chief Medical Officer, ACI UCC 007059