The Occupational Safety and health Act of 19"J emphasizes the need for standards to protect the healta -'tnd provide fcr the safety of workers occupationally exposed to an ever-'.acreasing runber cf potential hazards. The National Institute for Occupational Saiery and L'eaith (NIOSH) %-aluates all available research data and criteria and recommends standards for occupational xyosure. The Secretary of Labor v ili weigh thes- recommendations along with other considerations, such as feasibility and scans of implementation, in promulgating regulatory standards. NIOSH w ill periodically review the recommended standards to ensure continuing protection of workers and will make successive reports as cev research and epidemiologic studies are completed and as sampling and analytical methods are developed. A permanent Federal standard exists for worker exposure fo vinyl chloride.#
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ill.' r t -r .T T '. HIOSH recaaacnds that employee exposure to vin^rl halides in the workplace be controlled by adherence to the provisions for vinyl chloride in 29 CFR 1910.1017, the contents of which are provided as Appendix I of this document, with the exception that the respirator provisions la 29 CFR 1910-1017 (g)(l)(i-iv> and also 29 CFR 1910 (g) ( 6)Ui) shall be replaced with those given below. All provisions shall be adhered to for each of the vinyl halides as defined below. The recommended occupational exposure limits are Measurable by cechn.Tuas that are valid, ::roduc ib Le, .ind available to Indus tr* and ^overmaer.t agencies. Sufficient te-.hnolcgy exists to permit cccipliance vith the reconcended standard. Zaployers should 3>ake every effort to limit anployee exposure to the vinyl halides to concentrations that are as low as possible, with an eventual goal of zero exposure. Employee exposures shall be ' nc.pt at or below the limits prescribed In 29 CFR 1910.1017. The criteria and standard will be subject to review and revision as necessary.
These criteria and the recomended standard apply to workplace exposure of employees to the aonotaers vinyl chloride (CH2-CHC1), vinylidene chloride (CH2-CC12', vinyl bromide (CHI-CH3r) , vinyl fluoride (C2"CHF), and vinylidene fluoride (CH2-CF2), including any unreacfed monomer that may remain in pol/mers of these halides. As used in this document, "vinyls" and "vinyl nalides" refer only to these five compounds unless the terms are otherwise qualified.
The biologic effects of exposure to the vinyl halides say Include changes in behavior, cardiovascular abnormalities, degenerative changes In the liver and bones, and the induction of malignant neoplasms, especially angiosarcomas of the liver. A great deal of information is available concerning the effects of exposure of humans and animals :o vinyl chlorid'*, much of this is relatively new information having been developed sine- October 1974, when 29 CFR 1910.1017 was promulgated. Am pert of its effort to provide worker protection, NTOSH has extensively reviewed the newly completed studies as well as the older literature on v u y l chloride and has considered this information in its evaluation of the other vinyl halides. The data that are available from studies of carcinogenicity, mutagenicity, and metabolism, and predictions of biologic reactivity on the basis of physical and chemical properties of the vinyl halides suggest that the other vinyl halides have carcinogenic potentials similar to that of vinyl chloride. There Is strong evidence from animal studies of carcinogenicity on the pare of vinylidene chloride and vinyl bromide. Although there Is a lack of toxicity data on viayl fluoride and vinylidene fluoride, until some animal toxicity and/or metabolism data are available, there appears to be no reason to treat these two compounds differently from the other vinyl haldles in considerations of worker protection.

# INTRODUCTION
This report presents the criteria and the recommended standard based thereon that were prepared to meet the need for preventing impairment of health from occupational exposure to vinyl halides. The criteria document fulfills the responsibility of the Secretary of Health, Education, and Welfare under Section 20 (a)(3) of the Occupational Safety and Health Act of 1S70 to "develop criteria dealing with toxic materials and harmful physical agents and substances which will describe exposure levels...at which no employee will suffer impaired health or functional capacities or diminished life expectancy as a result of his work, experience."
After reviewing data and consulting with 'tl.ers, NIOSH formalized a system for the development of criteria on which standards can be established to protect the health and provide for the safety of employees exposed to hazardous chemical and physical agents.
The criteria and recommended standards should enable management and labor to develop better engineering controls resulting in more healthful work environments. Simply complying with the recomaended standard should not be the final oil.
These criteria for a recommended standard for vinyl halides are part of a continuing series of criteria developed by NI0S3.
The recommended standard applies to the handling, processing, manufacture, use, or storage of the vinyl 'halides. Ine standard was not designed for the population-at-large, and its application to situations other than occupational exposure is not warranted. The standard is Intended to: (1) protect against the development of shortand long-term systemic effects from exposure to vinyl halides; (2) protect against local effects on the skin and eyes; (3) minimize the risk of Induction of cancer;
(4) be measurable by techniques that are valid, reproducible, and available to industry and government agencies; and (5) be attainable with existing techrology. Th diagnosis of a rare liver cancer angiosarcoma, la employees involved in polymerization processes Involving exposure to vinyl chloride has generated research on related compounds, Including vlnylldene chloride and vinyl bromide.
The available data from studies with animals confirm the carcinogenic potential of vinyl chloride.
The available information on vinylidene chloride and vinyl bromide suggests that these compounds also are carcinogenic and may Induce the same type of characteristic tumor that is associated with exposure to vinyl chloride.
Although no reports of animal experiments have been located in which the effects of long-term exposure to vlnrl fluoride or vlnylldene fluoride were investigated, these compounds have b^en found to be mutagenic In bacteria, and they may have metabolic products and pathways similar to those of the other vinyl halides.
Examination of the chemical and physical properties of the vinyl halides Indicates that all of them or their metabolites may have similar macromolecular binding potentials. The limited data on vinyl fluoride and vinylidene fluoride suggest that they probably exert nearly the me tuaorigenic propensities as vinyl chloride, vinylidene chloride, and vinyl bromide.
To permit accurate assessment of the health hazards associated with the vinyl halides, additional research is necessary. This research should Include attempts to: (1) develop less toxic substitutes; (2) develop improved control technology; (3) develop respiratory protective devices, especially those with end-of-service-life indicators, for the inyl halides other than vinyl chloride; and (4) develop improved sampling and analytic?l methods and continuous monitoring equipment.

# III. BIOLOGIC EFFECTS OF EXPOSURE
Vinyl halides ere of growing Industrial Importance, especially In the plastics Industry. The vinyl halides, vinyl chloride, vlnylldene chloride, vinyl bromide, vinyl fluoride, and vinylidene fluoride, are easily polymerized or copolymerized with various compounds, such as acrylonitrlie, vinyl acetate, and styrene, to form pliable, lightweight plastics or thermoplastic resins. Whereas there are many reports of epidemiologic, carcinogenic, mutagenic, and metabolic studies of vinyl chloride, there are few reports of studies of the biologic effects of any of the other vinyl halides. Because of the paucity of information on these latter compounds, NIOSH has undertaken evaluations of the structure-activity relationships, based on chemical and physical properties, of the compounds and has used these relationships, along with data from the vinyl chloride literature, as a basis for extrapolation from actual to potential hazards for substances about which direct information is inadequate.

# Pertinent physical and chemical properties of these vinyl halides are presented in Table XVII-1, and a list of some of the synonyms for these compounds is presented in Table XVTI-2.
The vinyl halides undergo metabolic conversions, presumably initiated by enzymatic oxidation, to the corresponding oxlranes (epoxides) f1-A]. Subsequently, the oxlranes are presumed to either bind covalently to cellular macromolecules or be spontaneously rearranged to the aldehyde or acyl halide, hydrolyzed to the dlol, conjugated with glutathione, or reduced back to the parent compound. The major adverse biologic effects of the vinyl halides or their metabolites may include carcinogenesis, mutagenesis, teratogenesis, and damage to the liver.
Such effects may be associated with electrophlllc reactions (alkylation) with essential cellular components, whereas the rearrangements and other reactions (reduction, hydrolysis, conjugation) have often been considered to be detoxification mechanisms. It is realized that the rates of these possible reactions may vary rid that the risk of adverse effaces  would be' a function o f th- relative rates leading to, and corresponding half-lives of, each metabolic intermediate. Therefore, toxicity of a different order of magnitude may be elicited by each of these compounds. Indeed, not all of these effects have been associated with each of the vinyl halides.
The absorption and subsequent metabolism of vinyl chloride have been described as concentration-dependent; a saturable enzyme system, predominantly responsible for its metabolism at low concentrations, and a secondary oxidative system, predominant at higher concentrations, have been postulated .
The authors of these reports have further postulated that the oxlrane is formed predominantly at the higher concentrations, le, through the secondary oxiditive pathway. The halogenated acetaldehyde is common to both pathways, however.
Thus, even if the oxirane is not formed at low concentrations, the potential for macromolecular alkylation exists through the aldehyde and subsequent intermediates.
The covalent reactions of che vinyl halides and/or cheir metabolites with biologic materials may alter the chemical behavior and physical characteristics of the cellular constituents so as to prevent the altered molecules from functioning normally In physiologic processes.
The formation of stable reaction products may account, in part, for the subsequent harmful effects observed in biologic systems exposed to the vinyl halidis.
The alkylatlon of the biologic materials controlling cellular metabolism by the vinyl halides and/or their metabolites Is the most plausible basis for the Induction of genetic and neoplastic alterations in cell populations exposed to these chemicals. Because of the long latent period before adverse effects such as neoplasia become manifest, measurable effects may not be observable until many year3 after exposure at low concentrations.

# Ext .it of Exposure
NIOSH has estimated that approximately 2.5 million US workers may be occupationally exposed to vinyl halide monomers. A more precise estimate is difficult to make because of the lack of Information on exposure tn monomer released in manufacturing processes involving the polymers or copolymers. Some of occupations that involve exposure to the vinyl halides are listed In Table XVII-3.

# (a) Vinyl Chloride
Vinyl chloride has the chemical formula CH2-CHC1. At room temperature, it is a gas with a sweet, pleasant odor, and It has a boiling point of -13.9 C and a solubility in water of 0.11 g/100 ml at 24 C (Table XV1I-1). It is easily liquified and is stored and used industrially in the liquid form . Vinyl chloride was first prepared by Regnault in 1835 by reacting dlchloroethane with alcoholic potash . An effective industrial method for preparing vinyl chloride was established in 1913 by Griesheim-Elektron, using hydrochlorination of acetylene, with mercuric chloride as a catalyst, as described by Klatte and Rollett in 1911. It was not until World War II, however, that production of vinyl chloride for use in synthetic rubber was established on a large scale in the United States.
Vinyl chloride is currently produced commercially by the oxychloriration of ethylene, by the liquid or gaseous reaction of acetylene with hydrochloric acid, and by the pyrolysis of ethylene dichloride .
Production of vinyl chloride in 1975 in the United States amounted to about 4,063 million pounds , and the annual growth rate In the vinyl chloride Industry is expected to be about 6Z up to 1980 . It is still prepared commercially by reacting 1,1,2-trichloroethane with lime or caustic, most often aqueous calcium hydroxide, 3t 90 C . Other syntheses involve bromochloroethane, trichloroethyl acetate, tetrichloroethane, or catalytic cracking of trichioroethane .
The CS production of vinylidene chloride in 1974 was about 170 million pounds . It is primarily used in the production of plastics, including copolymerization with vinyl chloride or acrylonitrile to form various thermoplastic resins . In 1974 NIOSH estimated that 57,000 workers in the United States were potentially exposed to vinylidene chloride.

# (c) Vinyl Bromide
Vinyl bromide, CH2*CHBr, is a colorless gas at room temperature and has a boiling point of 15.85 C ai.d a solubility in water of 0.565 g/100 ml at 25 C (Table XVII-1). It was first prepared and described by Regnault, who obtained it by reacting dibromoethaae with alcoholic potash .
In 1872, Reboul reported the preparation if vinyl bromide after reacting acetylene with hydrogen bromide. The major commercial method for producing vinyl bromide is the reaction of ethylene dlbromlde with sodium hydroxide .

# Production of vinyl
bromide in the United States amounted to over 5 million pounds in 1976 . Currently, vinyl bromide is used primarily as a flame-retarding agent for acrylic fibers . In 1974 NIOSH estimated that 26,000 workers in the United States were potentially exposed to vinyl bromide. Although Che amount of vinyl fluoride used each year has not been reported, an average of 0.6 pound of acetylene is required to produce 1 pound of vinyl fluoride by the current method. F.ach year about 2 million pounds of acetylene are used in the United States for producing vinyl fluoride, which is used for making various copolymers that are used In end products such as insulation for electrical wires and in protective paints and coatings , indicating that some 3.3 million pounds of vinyl fluoride are produced annually. The number of workers potentially exposed to vinyl fluoride has not been estimated by NIOSH.

# (e) Vlnylidene Fluoride
Vlnylidene fluoride, CH2-CF2, is a colorless gas at room temperature with a faint, ethereal odor; it has a boiling point of -85.7 C and its solubility in water is 0.018 g/100 ml at 25 C (Table XVII-1). It was first prepared by Swarts by reacting 2,2-difluoro-l-bromoethane with sodium amylate . Vlnylidene fluoride is used in making polymers and copolymers t;hat are found in such end products as insulation for high-temperature wire, protective paints and coatings, and chemical tanks and tubing . In 1974 NIOSH estimated that 32,000 workers in the United States were potentially exposed to vinylidene fluoride.

# Historical Reports
The vinyl compounds assumed economic importance with the increased demand for synthetic rubber and the advent of the plastics industry. The first study  of the toxicity of vinyl chloride was conducted after its potential industrial Importance became apparent.
The authors concluded that the maximum concentration of vinyl chloride causing no acute effects on humans after exposure for 5 minutes was between 0.8 and 1.2Z . The authors also stated that "vinyl chloride causes clearcut intoxicating symptoms which can serve as adequate warning signs of its presence." While these conclusions were valid for the acute irritant and psychomotor effects caused by the 5-minute exposures to vinyl chloride, the possibility of adverse effects of vinyl chloride at concentrations lower than those necessary to produce these symptoms was not discussed. Suclu ec al  described clinical manifestations of vinyl chloride poisoning in 168 workers at two vinyl chloride manufacturing plants in Rumania.
Although workplace concentrations of vinyl chloride were given for each year from 1962 to 1972 (Table IIX-1), methods for these determinations were not reported.
The authors compared the workers' reports of symptoms indicative of effects on the nervous system in 1962 with those reported in 1966 .
For these 2 years, the percentages of workers (n-168) reporting dizziness were 47 and 10.2, drowsiness, 45 and 16.6, headache, 36.6 and 6.9, loss of memory, 13 and 8, euphoria, 11 and 1.2, and nervousness, 9 and 0.6. These data indicate that the central nervous system (CNS) effects observed were concentrationdependent . Th authors stated that the frequency of adverse effects had diminished between 1962 and 1972 because of the institution of exposure-control and therapeutic measures .
Tbese measures included reduction of workplace concentrations of vinyl chloride, flushing vinyl chloride from the reactors before cleaning, wearing gloves (unspecified type) during manual cleaning operations, reduction of the workshlft to 6 hours, semiannual medical examinations coupled with transfer to another workplace If poisoning was suspected, interdiction of smoking (presumably only at the workplace), administration of vitamin C, vitamin B complex, and iron for 10 days a month, and supplying ointments wiuj cortisone to prevent skin lesions. The authors stated that these measures "reduced all symptoms by tv -thirds."
The importance of this paper  lies in its characterization of the wide range of adverse effects observed in a worker population exposed to vinyl chloride; however, which exposures n d which workers were associated with particular effects is often unclear. The authors did not state in all cases whether or not the workers exmined in 1965 and In subsequent years were the same ones that were examined in 1962. The changes induced by the vitamin therapy and the changes caused by different engineering and administrative controls and work practices are &lso impossible to evaluate independently.
Veltman et al  studied the effects of exposure to vinyl chloride in 70 polyvinyl chloride workers who had been employed for from 6 months to 21.8 years (average 7.7 years) in cleaning autoclaves and centrifuges, in drying and sifting processes, and in wrapping polyvinyl chloride as a dry end product. Exposure concentrations were not reported. Arteries in the fingers were narrowed, and microscopic changes, notably fragmentation of elastic fibers, were found in the fingers of all workers with skin abnormalities and in 6 of 28 workers with apparently unchanged skin . Thrombocytopenia was associated with enlargement of the spleen, but it was also found in patients whose spleens were not enlarged. Only 6 of 29 patients with thrombocytopenia showed Improvement in their platelet cotints 1-1.5 ' years after having left their jobs; 20 had even lower platelet counts than those seen initially, and 3 showed no change. None of the most seriously affected workers showed improveaent in their platelet counts. All of the phalangeal lesions healed within 2 years after the workers left polyvinyl chloride production work, however.
The authors  stated that this study was significant because it showed that acroosteolysls was associated with employment in polyvinyl chloride production, it demonstrated that % vinyl chloride disease existed, and it Indicated that vinyl chloride disease might be detected by external signs (changes In fingers or skin) or blood tests (thrombocytopenia). The authors also stated that thrombocytopenia was the earliest manifestation of vinyl chloride toxicity and chat placelet counts should be required of vinyl chloride workers. However, only 8.62 had club-like changes of the fingertips and only 11.42 had skin changes. Although 812 of the workers had thrombocytopenia, which in some cases persisted or worsened after exposure tj vinyl chloride ended, the nonspecific nature of thrombocytopenia and the possibility that It might signal damage that Is already irreversible casts doubt on the usefulness of this clinical sign for the early detection and diagnosis of vinyl chloride disease. It is apparent that the vinyl chloride syndrome is complex, Involving change- in Che skin, bones, blood and blood vessels, liver, spleen, and possibly the nervous system.
Until the disease process is better understood, a decision on which changes are true constituents of a syndrome and which are Independent events, coincidentally discovered by the same examination, is impractical. Frequent dizziness in 26 of the 70 patients (37.12) In this study  supports the findings of Suciu et al  and suggests that the CNS may be affected by exposure to vinyl chloride, possibly indirectly by a vascular mechanism. Interference with CNS function might increase the risk of accidental injury to vinyl chloride workers.
Moulin and covorkers  observed four cases of scleroderma accompanying vinyl chloride-induced acroosteolysls in workers. Three of the four workers had scleroderma o.: the face, and each had shortening of the fingars, thickening of the skin of the fingers with adhesion to the deep layers, palmar erythema and hyperhydrosis, difficulty In extending eh- fingers completely, and thickened skin on the palmar surface of the wrist and forearm with hard projecting nodules that were most prominent over the flexor tendons. Raynaud's syndrore had been experienced by two workers, one of whoa whose feet, face, and hands had slightly edematous, scleroderma-llke lesions. One Individual's condition was studied in detail and followed for 4 years . The worker, aged 33 years, had for 4 years cleaned autoclaves used In vinyl chloride polymerization.
There wafi no suggestion of a predisposition toward the development of acroosteolysls in the medical history of either the Individual or his family. The worker had a history of consuming 2 liters of vine a day. Ha was hospitalized for malaise and was found to have slurred speech, paralysis of the right arm and right side of the face, and loss of skin sensations on the same side of the abdomen.
Results of neurologic, roentgenographlc, and electroencephalographic examinations showed mild deviations from normal.
While the worker was hospitalized, marked abnormalities of his fingers were noted. The last phalanx of each finger i t a u d shortened enlarged, with the nail clubbed and wider than It was long.
The patient had all the skin changes described previously as accompanying scleroderma. Microscopic examination of tvo nodules from his forearm showed a normal epidermis and a thickened, fibrous dermis vlth edema separating fragmented collagen fibers, but no signs of Inflammation. Elastic fibers vera few and segmented.
No significant abnormalities of the blood vessels were reported. Roentgenograms of both hands shoved osteolysis of the last phalanx of each finger of both hands, Che distal three-fourths of each phalanx having disappeared. A complete roentgenographic examination of Che skeleton shoved beginning sacroiliac arthritis, but nortial phalanges in the tees. Arteriography showed normal circulation chrough the arm, but decreased circulation in che wrist and hand caused by extreme hypertonia of Che blood vessels of the fingers.
Three years after assignment to other work, the individual shoved regression of .he scleroderma, the fibrous nodules, and the circulatory disturbances . The fingers remained hypothermic compared vlth the thumb, and painful paresthesia still affected the fingertips. Bone repair was seen in most of the phalanges.
Moulin and coworkers  concluded that Che incidence of acroosteolysls in vinyl chloridc polymerization workers could be considerably reduced by introduction of control measures to reduce exposure to vinyl chloride. They believed that the distal vasoconstriction they observed in these workers was not a true arteritis, although it was severe, and Chat the acroosteolysls and sclerodermatous changes in the skin were secondary complications of the peripheral vascular hypertonia. Because of the similarity of this disease to acrosclerotlc scleroderma, the authors suggested that dermatologists obtain an occupational nlstory from any patient: presenting the signs and symptoms described in their paper. , acroosteolysls  in workers exposed to vinyl chloride during its manufacture or polymerization. The information concerning signs and symptoms of vinyl chloride exposure in these reports is substantially the same as that in the reports previously discussed .

# Several other authors have reported CNS effects
Other studies have identified adverse liver effects on workers exposed to vinyl chloride. Marsteller et al  reported on 50 workers in a vinyl chloride polymerization plant, 45 cf whom underwent peritoneoscopy and 48 of whom had samples of liver taken for biopsy. All 50 underwent intravenous (lv) cholecystography and radiography of the upper gastrointestinal tract. Sclntography of the liver and spleen was oerformed for 48, using 197Hg. The llv*r was found by palpation to be enlarged in 31 cases and the spleen in 37 by sclntography.
The hepatic surface shoved conspicuously augmented vascularization and stellate, reticular, or nodular fibrosis and scarring of the capsule. The spleen was not well visualized ay peritoneoscopy except when lc was narlcdly enlarged; then the crenaca margin waa sharply indented and shoved capsular flbroala and subcapsular hemorrhage*. Early signs of portal hypertension were noted, including ascites and dilatation and tortuosity of gastric and peritoneal veins.
Muller et al  deacribed microscopic changes ibserved in liver speciaens taken for biopsy from 50 polyvinyl chloride production workers. Liver cells shoved focal hydropic svelling, single-cell necrosis, fjcal granular disintegration of the cytoplasm, hyperplasia with enlargement and polymorphism of cell nuclei, and often the presence of several nucleoli. Periportal and centrilobular fibroses were described, without accompanying cellular activity or involvement of the portal vessels, and about one-half of the specimens of liver contained fatty degeneration.
Changes in the cells lining the liver sinusoids were described as "most impressive,' and had begun to develop In the first few years of exposure. Proliferation of sinusal cells was the first change observed, and, after 6-10 years of exposure, sinusal cell nuclei had become markedly atypical.
Three cases of hemangioendothellal sarcoma of the liver vere discovered. The authors reported that the regions around the sarcomas gave the impression that there was a transformation of atypical sinusal cells to tumor cells and that the cytologic atyplas of sinusal cells might be of prospective importance.

# Thiess and Frentzel-Beyme
, acroosteolysis (16), and esophageal varices (13).
There vere five cases of "haemangioendothellosarcooa" in vorkers vho had been employed in vinyl chloride or polyvinyl chloride production areas for 11-17 years; four of the vorkers, aged 38-44 years, had died. Only 46Z of the vorkers exposed to vinyl chloride at one particular plant vere still vorklng in a polyvinyl chloride plant or were otherwise traceable; the rest vere lost to the statistical survey.
The authors noted that there vere many difficulties in retrospective surveys for occupational health hazards. They stated that: although mortality data vere accessary in identifying a new disease, morbidity data vere even more important, because death certificates vere not alvays accurate. They also stated that prospective investigations vere preferable to retrospective ones, although the latter approach had received priority due to considerations of the time required in relations to the yield of information.

# Physicians representing the government, universities, and the vinyl chloride and polyvinyl chloride industries in the Federal
Republic of Germany vere said to be cooperating in further epidemiologic studies. The authors pointed out that more data on vinyl chloride concentrations in Che workplace, periods of worker exposure, and control measures were needed before an association between exposure Co vinyl chloride and Che development of angiosarcoma and ocher disorders could be proven.
The authors stated that, with regard to the cause of death among employees at this plant, "a relatively large proportion of deaths occurring at ac early age, are due to unnatural causes of death I.e. accident at the work place or road accidents" . This may suggest that the worker exposed to vinyl chloride could himself become an occupational and social health hazard because of behavior-modifying effects of the material, and may therefore support the inferences drawn from the work of Veltman et al  and Suciu et al  discussed previously. Lange et al , in 1975, analyzed the medical ana work histories of 15 workers employed In the polyvinyl chloride processing industry In the Federal Republic of Germany for an average of 5 years (range 1.5-13 years). Seven of the workers (472) complained of sensations of pressure or pain in the upp^r abdomen, three (201) of frequent dizziness, tvo (132) of cold hands and feet, and one (72) of increasing weakness in his legs.
Medical investigations conducted on the workers consisted of a dermatologic examination and several laboratory t*sts. A BSP retention test was performed on 9 of the workers, a reticulocyte count on 10, roentgenograms of the chest, hands, and feet on 12, and a ilver-spleen scintigram, using 99 mTc-sulfur colloid on 11. Four of the workers also underwent laparoscopy and liver biopsy. Dermatologic examination revealed no clinical signs of scleroderma or Raynaud's syndrome . The results of the laboratory tests, however, showed slight to moderate thrombocytopenia (63,000-13S,000 cells/id.) in seven workers (472); increased BSP retention (5.2-15.12 at 45 minutes) in seven workers (472); reticulocytosls of 1.7-4. 42 In six workers (402); and leukopenia (3,250 cells/Ml) In one worker (72); more than one abnormality was found in some of the workers.
One of the workers examined by llver-spleen scintigram had slight splenomegaly and one of the workers who underwent laparoscopy and liver biopsy showed changes, although less distinct, "of the kind observed in PVCproductlon workers." The authors concluded that, despite the small sample size, thrombocytopenia, Increased BSP retention, reticulocytosls, splenomegaly, and leukopenia were characteristic of vinyl chloride disease. Lange et al  also presented case studies of tvo workers from the same polyvinyl chloride, plant who had died of malignant tumors. The fire:-;: case was that of a 38-year-old autoclave cleaner who was employed for 12 years in the plant. Physical examination in 1968 showed a large tumor in the upper abdomen la the area of the liver and spleen. Chest roentgenograms shoved destruction of the fourth rib, on the left side of the back. Laboratory findings included Increased erythrocyte sedimentation rate (22-67 mm/hour), considerable anemia, reticulocytosls of 62, a reduction of serum iron (25j*g/100 ml), an increased serum gamma-globulln (25 relative percent), an "Increased" alkaline phosphatase level (65 units/ml), and an Increased SGOT level (24 units/ml), r all indicative of livar damage. Th liver-spleen scintigram showed splenomegaly, hepatomegaly, and reduced storage in the liver reticuloendothelial system.
The patient then underwent a laparotomy, which revealed a generally enlarged liver with many palpable nodes on the surface. Microscopic examination of two of the liver biopsy specimens shoved hemangioendothelial sarcomas. After the laparotomy, the patienc was given cytostatic treatment, but his condition continued to deteriorat- and he died within a year after the initial diagnosis of the tumor.
The second case was that of a 39-year-old man who had worked for some portion of 11 years as an autoclave clearer in the plant and for 2 years in a machine-producing factory . He had felt pain in the lowtr right quadrant of his thorax for some months and had experienced a painful hardening in the upper right portion of his abdomen several weeks before his medical exam ination. Physical examination disclosed a tumor the size of an apple on the epigastric angle. Laboratory tests sh.^ed these values, which the authors considered abnormal: erythrocyte sedimentation rate (44-73 mm/hour), and the "lactic" dehydrogenase (296 units/ml), aud alkaline phosphatr.se (80 units/ml) activities in the scrum. Normal differentiated blood counts and platelet counts were found. Laparotomy, performed rwice on this worker, showed a fist sized whitish-yellow tumor on the lower part of the left Lobe of tne liver tnat extended to the posterior portion of the right lobe. Numerous other nodules were palpable in the liver.
A small degree of congestive spleen enlargement (not further defined) was also found. Microscopic examination of several biopsy specimens led to the diagnosis of hemangioendothelial sarcoma of the liver. Although postoperative radiotherapy was given, the patient died about a year after the initial diagnosis. , in 1974, reported that one of the authors, having noticed a diagnosis of angiosarcoma of the liver on a death certificate, recalled having performed a liver' biopsy 3 years earlier that led to the same diagnosis. An investigation shoved that both of these patients had worked in a. polyvinyl chloride plane la Kentucky,, and a search of plant and area hospital records showed autopsy reports of three other cases over a 10-year period; two additional cases were diagnosed by biopsy. A systematic program was therefore undertaken for detection of liver abnormalities in workers in a chemical plant producing polyvinyl chloride and synthetic rubber, using automated 12-or 18-factor blood analyses.

# Makk ct al

# Screening profiles
from the 12-or 18-factor analyses were obtained for 1,183 employees, of whom 75 (6.3Z) had either 2 liver-related abnormalities on the Initial screening or 1 such abnormality that persisted . Aa a result of further testing including exploratory laparotomy of these 75 workers, 2 unsuspected cases of angiosarcoma and 3 cases of portal fibrosis were discovered. A biopsy of the liver was performed on two other workers who requested it, but both samples proved to be normal. Abnormal test results were reported for serum alkaline phosphatase.in 35/72 ( The results of this study  have helped to provide a basis for Identifying clinical manifestations of vinyl chloride-induced liver damage. No single test was found to be pathognomonic or this disease, and both false positives and false negatives were common. Sometimes the clue to Che presence ot a n g ii3arcona of che liver was not the magnitude of elevation of an enzyme activity, eg, LDH, but the persistence at chac elevation. Curiously, Che p'.-centage of workers with abnormal 12-factor test results was lower in polyvinyl chloride production workers (21.52) than in either synthetic-rubber production workers (28.62) or all other workers (26.72). However, abnormal results serious enough to warrant comprehensive examinations were present in 9.82 of the polyvinyl chloride production workers, while only 6.92 of the synthetic-rubber workers and 4.92 of all other workers had such seriously abnormal results.
In a 1975 report, Creech and Makk  amplified C h i 5 early report of screening test results . Specimens of the liver for biopsy were obtained from 16 employees of that same plant, 3 of whom had normal results on clinical screening tests . The results of these three biopsies were normal, as were the results -from two other biopsies taken from employees with tainor abnormalities on the screening examinations. Two cases of angiosarcoma were detected, both with accompanying fibrosis. Periportal fibrosis was the most common biopsy diagnosis occurring in polyvinyl chloride workers and in two workers from other production areas.
Two polyvinyl chloride production workers also had enlarged spleens, splenic vein thrombosis, and esophageal varices.
Only one of seven workers with acroosteolysis had an abnormal battery of screening tests, and the test results returned to normal within 3 veeics after the employee stopped drinking alcoholic beverages. Results of tlie clinical tests were essentially the same as had been previously reported . The percentages of abnormal test results among 274 polyvinyl chloride production workers, compared with those of 411 other production workers, were: total bilirubin, 35. 6  Creech and Makk  concluded that no individual test was adequate to detect angiosarcoma or fibrosis, although the persistent 20-second "tumor blush" on angiography was useful for diagnosing angiosarcoma and venous U.rf pressure studies were useful for diagnosing fibrosis.
Blood tests did not predict the results on liver scans, and scans did not always detect fibrosis. The authors stated that a combination of blood tests, liver scans, venous pressure studies, angiography, and biopsies would be necessary for the diagnosis of fibrosis and angiosarcoma. This study, like the earlier one , concentrated on attempting to assemble a diagnostic test profile and did not report workplace vinyl chloride concentrations or attempt to correlate examination results with extent or duration of exposure.
In 1974, Creech et al  reported oa fcur cases of angiosarcoma of the liver diagnosed in employees in one chemical plant between 1967 and 1973, that have been previously discussed . The four workers, with a mean age of 44.5 years (36, 41, 43, and 58), had each worked at least 4 continuous years in the vinyl chloride polymerization section of the plant prior to the onset of the disease and had been exposed to vinyl chloride for an average of 18 years (14, 14, 17, and 27) . Extensive, nonalcoholic-type cirrhosis, in addition to the angiosarcoma, was found in all four workers. Gastrointestinal bleeding was found in two of the four; other effects observed in one or more wurkers Included portal hypertension, enlarged livers and spleens, weight loss, jaundice, an epigastric mass, and thrombocytopenia. Nons of the workers had a history of prolonged use of alcohol or exposure to hepatotoxins known to produce angiosarcoma, eg, uhorium dioxide or arsenic, either at work or elsewhere.
Falk et al , in conjunction with NIOSH, conducted an investigation at a vinyl chloride polymerization plant in Kentucky where seven cases of angiosarcoma of the liver had been discovered, including the four which had previously been reported by Makk et al . These seven cases were compared with four cases of portal fibrosis found in the same worker population. Factors in Che comparison were: age at diagnosis, initial symptoms, physical examination findings, liver function studies, biopsy or autopsy findings, and work performed and overall duration of employment.
The II - patient were whit males and were between the ages of 28 and 58. at the time of diagnosis.
The seven men with tumors had been employed at the plant for an average of 18.0 years; one had no complaints, but the authors reported fatigue, abdominal pain, chest pain, weight loss, black stools, bloody vomit, and weakness . The four men with nonmallgnant liver disease (portal fibrosis) had been employed an average of 20.6 years; one reported chest pain and weight loss, one reported having had black stools on two occasions, one had been noted to be jaundiced when hospitalized for hernia repair, and one had been hospitalized for gallstones.
The physical examinations of these 11 men  disclosed enlarged livers or spleens in 4 of the 7 with angiosarcoma and in 3 of the 4 wxth portal fibrosis.
In addition, one of the tumorous-patients had upper-rlght-quadrant tenderness. Two patients with angiosarcoma and 1 with portal fibrosis had no detectable abnormalities. Results of liver function studies on the men of the 'W two groups were similar.
In boch groups chere were elevations of the concentrations of total bilirubin and the activities of alkaline phosphatase, SGOT, and LDH in serum, but no consistent pattern matched to the clinical B A n i f e s tations emerged.
Of the seven workers with angiosarcoma, five had elevated SGOT activities, four had elevated activities of alkaline phosphatase or Increased concentrations of total bilirubin, three had heightened activities of LDH, and one had a decreased platelet count. Liver-spleen scans showed defects or other abnormalities in five. In the four workers with portal fibrosis, the concentration of total bilirubin and the activity of SGOT were each elevated in three, the activity of alkaline phosphatase was elevated in two, the activity of LDH was increased in one, and two had abnormal liverspleen scans.
Platelet counts were not reported for this group. Twelve samples of liver for biopsy were obtained by opening the abdomen and only three by puncturing the abdominal wall and the liver  '1th a Manghinl needle. In the seven men found to have angiosarcoma, liver biopsy findings included angiosarcoma In four, hepatitis in two, fibrosis in two, and cirrhosis in one. The biopsy sample from the four men without angiosarcoma revealed fibrosis of the liver; two of them had portal and subcapsular fibrosis, one had portal fibrosis, and one had chronic hepatitis with focal fibrosis. All five of the patlent3 who died of angiosarcoma had had biopsies, but angiosarcoma had been diagnosed In only two. Angiosarcoma had been diagnosed previously by biopsy in the two surviving patients, and fibrosis had been diagnosed previously by biopsy in the four without angiosarcoma. Falk et al  stated that the development of angiosarcoma was related to exposure to vinyl chloride and that it was more closely related to the type of work performed than to the overall duration of employment. They suggested that a higher risk was associated with longer duration of employment as a helper (reaction vessel cleaners) than with work in which the monomer was handled in a closed system or in which only polymerized material was handled. The data presented, however, do not completely support this suggestion since several workers without angiosarcoma had actually had longer duration of exposure as chemical helpers than those workers with angiosarcoma. Since conditions of exposure undoubtedly do not correlate exactly with job classifications, exposure concentrations and durations must be determined to permit assigning relative risk factors.

# Whelan et al .
Liver scans were performed on all of the 1,180 workers at the vinyl chloride polymerization plant , using radioisotopes of gold, iodine, or most often technetium. On 50 of the workers, hepatic venograms, hepatic and celiac angiograms, and pressures in the right atrium, the inferior vena cava, and both free and wedged hepatic vein positions were recorded. Specimens of liver for biopsy were obtained also. Vinyl chloride concentrations in the workplace were not reported.
Four employees had angiosarcoma of the liver; their average age was 43 years (range 37-49 years) and they had been employed in polymerization of vinyl chloride for 15 years (range 12-20 years) . Although several tuners were found In some livers, no tumors of the spleen were found although splenomegaly waa present In some cases. No outstanding pathologic condition was found In either the venous or the arterial systems of the liver, but the centers of the tumors appeared to be less vascular than normal liver tissue.
Because the wedged venous pressure measurements resulted In hepatic Infarction in three patients, these tests were discontinued as part of the routine screening procedure . The area of Infarction that resulted from measurement of wedged venous pressure caused one worker to appear erroneously to have angiosarcoma when he was examined angiographically. Spleen enlargement: occurred with and without portal hypertension; about 10Z of the 1,180 employees had enlarged spleens without any evidence of tumor.
Whelan et al  concluded that lsotopic liver scans were the most useful procedures for detecting angiosarcoma. They also concluded that a peripheral tumor stain, puddling of the contrast agent from ths midarterlal phase up to 34 seconds, and hypovascularlty of the central portions of the tumor were characteristic angiographic features of this tumor. Because hepatic Infarcts following measurements of wedged venous pressures may give a similar angiographic picture, the authors recommended that wedged venous pressure studies, when necessary, be done after angiography.
Popper and Thomas  studied surgical and autopsy samples from the livers of 11 vinyl chloride and polyvinyl chloride workers, in six of whom angiosarcoma of the liver had been diagnosed and five of whom had hepatic fibrosis. Two cases of primary hepatic carcinoma, one In a worker who had laminated polyvinyl chloride sheets for 17 year. and the other in the 8-yearold daughter of a vinyl chloride polymerization worker, were described also, but no information on the concentrations and durations of exposure of these two persons was supplied.
In addition to angiosarcoma of the liver, typical lesions found in the liver of the 11 patients Included subcapsular, portal, and perislnusoldal, fibrosis, Increased numbers of fibroblasts, formation of connective tissue epta, sinusoidal dilatation (without signs of passive congestion, such as compression of hepatocytes), Increased size and number of sinusoidal lining cells, and enlarged hepatocytes with hyperchromatic nuclei accompanied by bile stasis [39j.
These lesions were usually more prominent in the group with angiosarcoma than In that with hepatic fibrosis.

# Five patients
(two with angiosarcoma and three with precursor signs) had enlarged spleens with "grossly visible and conspicuously enlarged Malpighian follicles separated by a meaty-appearlng homogeneous red pulp" . The follicles had large germinal centers with phagocytic cells. The perlarterlolar lymphatic sheaths were markedly enlarged. Cells lining splenic sinusoids were enlarged but did not show phagocytosis; their elongated cuboldal shape made them resemble glandular cells. Perifollicular hemorrhages were noted, and in one case the presence of Gasma-Gandy bodies suggested old hemorrhages.
Popper and Thcmaa proposed Chat hepatic fibrosis and hepatic and splenic cellular proliferation were precursor stages in the development of angiosarcoma .
Their evidence was insufficient, however, to prove that these changes -ere irreversible or progressive. Portal fibrosis was not found to be predictive of the development of angiosarcoma, and the focal Intralobular fibrosis in these subjects was similar to that in many elderly patients, particularly diabetics.
Bepatic focal subcapsular fibrosis was characteristic of angiosarcoma, however, and could be seen by peritoneoscopy or during surgery. The authors noted that there were similarities between the development of portal fibrosis in workers exposed to vinyl chloride and diseases in European vineyard workers exposed to arsenical pesticides, patients in India with "Idiopathic portal hypertension" (Bantl's syndrome), and par.lents with psoriasis who were treated for prolonged periods with Fowler's solution (potassium arsenite).
This report is valuable for its comprehensive description of vinyl chloride-induced visceral lesions and its comparison of these with other fibrotic lesions.
Thomas et al  extended the previous microscopic studies  of the livers and spleens of workers engaged In vinyl chloride polymerization. Among the 15 cases of angiosarcoma of the liver that the/ studied, the tumor had metastasized to the duodenum in one case, to the lung in a second, and to the lung, heart, kidney, and lymph nodes in a third. Specimens from 20 patients were reviewed microscopically.
These authors  again postulated that their observations sight have illustrated a developmental continuum in which fibrosis precedes the development of angiosarcoma of the liver. They also noted that a specimen of liver obtained for biopsy from one patient 2 years after his last exposure to vinyl chloride showed that both hepatocytes and sinusoidal lining cells had returned to normal, but the fibrous scars persisted.
The case for development of angiosarcoma of the liver from a fibrotic precursor stage would be compelling, if Che specimens presented were . . obtained in a real-time sequence from an individual patient . The authors' arrangement of specimens from 20 different patients is plausible, however, because fibrotic changes are seen throughout anglosarcomatous livers and the same changes in the spleen accompany bcth fibrosis and angiosarcoma of the liver.
The disappearance of abnormal hepatocytes and sinusoidal lining cells from biopsy materials within 2 years after the worker was removed from exposure to vinyl chloride is additional evidence that this exposure caused the hepatic abnormalities.

# Zlmmermann and Eck  reported a case of angiosarcoma of the liver In a 38-year-old chemical laboratory assistant In Germany who was exposed to vinyl chloride at an unspecified concentration for 3 years and 5 months (1960-1963).
Be was axposed for 3-4 hours two or three times a week and wore no protective mask. The worker was hospitalized with marked- abdominal distress about a year before his death in 1974.
Tumors of the liver were suspected after l a p a r o s c o p y but could not b confirmed by microscopic examination of liver speclxnns at that time. An open-abdomen surgical sampling of the liver 6 months later produced evidence of occlusion of the portal vein, necrosis, and interstitial fibrosis. The changes were originally attributed :o tertiary syphilis, but serologic examinations were negative, and the patient's work history showed exposure to vinyl chloride. The patient lived for another 6 months and died from massive heniorrhage from esophageal varices. Post-mortem examination showed a metastasizing multilocular angiosarcoma or the liver with liver fibrosis.
The tumor had spread to the diaphragm, the pleura, and the lymph nodes around the pancreas. Hepatomegaly, with Icterus and fibrosis, and splenomegaly were also confirmed, and Che heart showed flaccid dilatation. Bronchitis was also indicated. . Liver structure was abnormal; lobular centers were often completely flbrotic, and branches of the portal vein were blocked by filamentary connective tissue and the diaphragm was bound to the liver by fibrous tissue. There were localized areas of recent necrosis. The spleen contained blood-forming centers for both red and white cell lines and had localized hemorrhages.

# Microscopic examination showed tumor cells bearing filaments and an abundance of connective tissue between atrophic liver-cell plates
The pancreas contained areas of fibrosis and of medlum-grade lipomatosis.
The testes shoved a reduction of spermiogenesls and slight fibrosis. Purulent n/ocarditis was found.
In the brain, there was localized atrophy of cerabellar Purkinje cells and necrosis of the frontoparietal cerebral cortex.  attributed the development of angiosarcoma in the patient, to his prior exposure to vinyl chloride, noting that primary angiosarcoma of the liver is extremely Infrequent. In addition to vinyl chloride, the patient had been exposed to methylene chloride, styrene, acrylonltrile, and other substances. This 'paper [4IJJ showed some of the problems encountered In determining whether angiosarcoma of the liver was Induced by vinyl chloride.

# Zlmmermann and Eck
The short duration of work involving exposure to vinyl chloride (less than 3.5 years), the long Interval (7 0 years) before the onset of symptoms, the mixed exposures, and the infrequent occurrence of this tumor made the diagnosis and determination of cause difficult. , in 1974, noted six microscopically confirmed cases of hepatic angiosarcoma of the liver in Connecticut, five of the cases having been diagnosed after 1966. Two of the patients had apparently been occupationally exposed to polyvinyl chloride. A 47-year-old man had worked for the previous 10 years as an accountant in a factory producing vinyl sheet3 and processing polyvinyl chloride resins and had frequently visited the plant's production areas.

# Christine et al
Another patient, a 61-year-old man, had spent 25 years in an electrical plant operating a machine that applied polyvinyl chloride-containing plastic to wires. Two other patients, a 73-year-old man with a history of chvonic intake of alcohol and an 83-year-old woman, had had no known occupational exposure to polyvinyl chloride, but both had lived 35 years or longer within 2 miles of the electric wire plant or within 0.5 mile of the vinyl products plant mentioned above.
The other two patients, a housewife and an alcoholic nan, had neither occupational nor probable residential exposure to vinyl chloride.
None of the six patients had a history of hepatitis or exposure to hepatotoxlc drugs, medications, or agents other than alcohol.
Many other reports are available in which cases of angiosarcoma in vinyl chloride workers are discussed . Several other papers contain reports of scintigraphic investigations , histopathologic studies , ind clinical aspects  of liver damage in workers exposed Co vinyl chloride. The infc-nr^nion contained in chese papers is substantially the same as that which has been presented in this section and these reports often discuss the same cases. Because of the prolonged latent period calculated from these data and che unavailability of complete information on exposure conditions or numbers of workers exposed in the worldwide production of vinyl chloride, any estimate of expected future cases of angiosarcoma in Che workforce would be unreliable.  in. 1975. They projected an incidence rate, using a linear dose-response model, of angiosarcoma as 0.0052/person/year of exposure in highly exposed workers (350 ppm or 896 mg/cu m, 7 hours/day, 5 days/week) from incidence rates in rats. Using data from epidemiologic studies of vinyl chloride workers and data on the exposure durations for the 14 US occupational cases of angiosarcoma that were known as of 1974, a projected Incidence rate for angiosarcoma of 0.0031/person/year was calculaced.

# NIOSH has compiled a listing as of

# An estimation, of risk was performed by Kuzmack. and McGaughy
The authors concluded from their calculations that 7.5% of all highly exposed vinyl chloride workers would be expected to develop angiosarcoma and that 15Z would develop primary cancers at some site during their lifetimes. They also estimated that, as of 1974, only 38Z of the predicted number of angiosarcoma caused by vinyl chloride had been diagnosed.
The authors  pointed out several possible sources of error in their estimates. These Involved uncertainties in the numerical estimates of the functions id conceptual inadequacies in the assumptions of the models. For example, the accuracy of the assumed exposure concentration of 350 ppm and the asauaed duration of 7 hours/day, j day:,/week, was uncertain. Also, biologic latency was not directly observable, ind the time of initiation of some unknown irreversible damage night not have been accurately represented by the duration of total exposure for the known cases. The predictions are based on the assumption that the set of stochastic variables, such as genetic conposltlors, previous medical histories, diets, etc, that might influence tumor formation Is homogeneous. If Is further assumed that the then current exposures will be continued with ac major change.
These two assumptions cannot be supported since homogeneity in worker populations from various geographic areas Is highly unlikely and 3ince exposures have been decreasing In recent years.
Two maps prepared by Falk  describe the geographic distribution of deaths f:.*om angiosarcoma of the liver in vinyl chloride polymerization workers (Figux. i XVII-1) and in people not engaged in work with vinyl chloride (Figure XVII-2). A comparlsou of these figures shows that there Is no reason to believe that some unknown geographic or demographic feature would account for the clustering of angiosarcomas of the liver in the vinyl chloride worker population.
Casterline et al [641, in 1977, reported a unique case of squamous-cell carcinoma of the buccal mucosa associated with chronic oral exposure to polyvinyl chloride.
The patient was a 22-year-old white male who had habitually chewed plastic insulation from wires and other plastic materials since he was 8 years old. He denied using any form of tobacco, alcoholic beverages, or illegal drugs. A pinhead-sized papule was found on the right anterior labial buccal sulcus a fte r an episode of aphthous stomatitis that lasted less than a week. In 3 month, the papule grew to about 1 centimeter in size a.id was excised by a dentist. Microscopic examination of the tissue resulted Ir. a diagnosis of Invasive squamous cell carcinoma.
A wider resection shoved that the tissua margins appeared free of tumor.
No recurrence.was noted in. the next 6 months.
The patient's oral hyglen appeared excellent, but his teeth were grooved as a result of his habit of stripping wire with them. He reported keeping plastic material in his mouth for 6-8 hours at a time. No abnormalities other than the buccal lesion were found, although a complete examination was made specifically to search for signs of vinyl chloride-induced functional aberrations.  believed that the development jf this cancer In an area of the mouth where the Individual frequently stored polyvinyl chloride materials was more than coincidental. They cited as further support for their belief the high incidence of cancers of the buccal cavity and pharynx found by Tabershaw and Gaffey  to be associated with exposure to vinyl chloride. Casterline and coworkers urged that electronics workers be informed of the hazard of repeatedly holding plastic-covered materials in the mouth, ir the authors' conclusion Is correct, a little-suspected but significant route of exposure to vinyl chloride may exist.

# Casterline et al
The possibility of coincidence, however, may be greater than the authors were willing to concede.

# (b) Vlnylldene Chloride
McBirney , In 1954, reported on a case of fatal poisoning In a worker exposed to the vapor from dlchlorethylene (Identified as vlnylldene chloride ) stabilized with 12 of a sodium .hydroxide solution. The worker was 35 years old and had worked 8 hours/day, 5 days/week, for a "short" time extracting oil from fish livers using this mixture.
The worker first complained that the odor and vapors from the extraction kettles made him nauseous . A day or two before he was suddenly taken ill, the worker had acted "strangely" and his covorkers at first had thought that he was drunk. He was hospitalized and died within 2 days.
At autopsy, the brain, heart, lui:gs, spleen, liver, and kidneys were observed to be congested. The cause of death wa.s listed as bronchopneumonia. , the possibility of a preexisting condition, and the possibility that the vapor described as dlchloroethylene may have been 1,2-dichloroethylene (a substance known to have been used in extracting fish oil ) does not allow any conclusions to be draws.

# Lack of exposure information in this report
Liver function tests and scans were performed on a group of 46 workers at a New Jersey plant in which the concentration of vlnylldene chloride in the air ranged from below the analytic limit o detection (O.QQ mg) to 1.45 ppm (about 5.6 mg/cu m) .
Previous company experience had established a typical range of 0-5 ppm (0-19.85 mg/cu m ) , with occasional peaks of 300 ppm (1,191 mg/cu m) associated with accidental spills or leaks and with removal of samples of product from the reactor. This plant used nearly 200 chemicals, including several known hepatotoxins, so that exposure to a single agent was net claimed. The cests Included measurements of SGGT, SGFT, and serum gammaglutamyl transpeptidase, LDH, and alkaline phosphatase activities, total bilirubin, and indocyanine green clearance.
None of the 46 employees was found to have total bilirubin counts outside of normal limits, but 39Z had abnormal LDH activity, 30Z had abnormal gamma-glutamyl transpeptidase activity, 28Z had abnormal SGOT activity, 21Z had abnormal SCPT activity, and 13Z had abnormal alkaline phosphatase activity. Fourteen men had abnormal liver scans, but only five showed what the author defined as "definite hepatomegaly." Six employees (13Z) had severe impairment of indocyanine green excretion (less than 10Z clearance), 25 (56%) had moderate impairment (10-17Z clearance), and 14 (30Z) were found to be normal (greater than 17Z clearance). Fifteen workers were retested for dye clearance; two had returned to normal, four had deteriorated, and the rest remained unchanged. On the basis of these tests, biopsy studies of the liver were recommended for 10 workers, but only 5 agreed to undergo this kind of study.
All five employees on whom biopsy studies of the liver were performed exhibited abnormal clearances of indocyanine green . Two had borderline or mild portal fibrosis on biopsy, one had mild nonspecific activation of hapatocytic nuclei and a borderline increase in fat, one had mild steatosis, and on had moderataly saver steatosis with stellate fibrosis that suggested an alcoholic llvar injury. Two of the five had enlarged livers. None of the microscopic changes was attributed by the pathologist to the effects of industrial toxins.
In a follovup study undertaken by NIOSH upon invitation by the company, 256 employees were surveyed for serum total bilirubin, and alkaline phosphatase, GOT, GPT, and gamma-glutamyl transpeptidase activity . Two criteria of abnormality were used. Criterion A was a deviation greater than two standard deviations from the normal population mean of the laboratory performing the analysis; criterion B was the occurrence of a value outside the normal range used by the laboratory performing the analysis. An abnormally high result by either criterion on any test was regarded as indicative of liver impairment. Duration of employment, work history, exposure conditions, use of alcoholic beverages, current symptoms, history of liver disease, and demograpt.lcs were also recorded.
Of these, the only significant variable (?<0.001) related to abnormality, according to the more stringent criterion B, was duration of exposure at the site: 5.11 years for "cases" and 3.64 years for "noncaaes." A total of 75 employees (29Z) at the plant were classified a3 abnormal by criterion B on the basis of enzyme activity teats .
On the Individual teats, NIOSH found 46 employees (19Z) with abnormal elevations of SGPT activity, 42 (16Z) with abnormal serum gamma-glutamyl transpeptidase activity, 31 (12Z) with abnormal SGOT activity, and 5 (22) with abnormally elevated serum alkaline phosphatase activity. Only one employee (0.4Z) had an elevated serum total bilirubin value.
Every area of the plant had at least one employee who was judged abnormal by one of the two criteria stated. The Incidence of abnormal alkaline phosphatase and bilirubin values in this study was lover than that reported previously  at a vinyl chloride plant.

# The
company had tested only a group of workers Involved in the p o ly m e r iz a t io n of vlnylldene chloride, who were exposed to this monomer at relatively high levels .
Whereas NIOSH had studied almost 88Z of the employees, nearly 5.6 times as many as the company had studied. The incidence of abnormal results on any test would be expected to be lower in NIOSH's study, therefore, as was the actual case.
The substances or the relative concentrations responsible for producing adverse effects where exposures are mixed cannot be identified conclusively. The case for the existence of actual liver damage from exposure to vlnylldene chloride rests on the company's correlation of microscopic and dye-clearance data with the liver enzyme studies.
In 1970, Henschler et al  and Broser et al  each reported on the same two cases of poisoning from occupational exposure to vlnylldene chloride copolymers that had occurred in Germany in 1965. In both cases the workers had been transporting an aqueous suspension of vlnylldene chloride copolymerized with another unspecified vinyl compound. The authors stated chat eh suspension contained about 0.42 of low molecular weight halogenated hydrocarbons, of which vlnylidene chloride comprised about one-half. Both workers developed symptoms of poisoning while manually cleaning the transport tank.
The first worker was 33 years old  . About 6 hours after he had worked in the tank for a "short," but indefinite time, he experienced fatigue, weakness, lack of appetite, and an "abnormal sense of taste." Nineteen hours after the initial exposure, he again entered the tank and remained for 45 minutes.
Five hours later, he experienced nausea, headache, dizziness, and eventually vomiting of blood. A "furry" feeling in the mouth and lips which he had noticed earlier now became more noticeable. He was admitted to a medical clinic 27-28 hours after his first exposure.
Conjunctivitis, inflammation of the epipharnyx, herpes labialls, pains in the epigastrium, perception disorders of the face, and deflection of the tongue to the right were observed.
Liver and kidney function tests were initially abnormal (low urine specific gravity, 3-6 leukocytes in the urine sediment, SGOT 20 mtJ, 82 BSP retention, 602 prothrombin time, and what was described as decreased water excretion of 570 ml); however, all findings except the sensory effects returned to normal after 3 weeks.
An extensive neurologic examination performed 3 months later revealed analgesia and hypoesthesia In the total trigeminal area, including the nose and oral mucosa  . In addition, hypoesthesia and hypalgesia in the region of both ear muscles and under the angle of the jaw and absence cf the corneal reflexes were noted.
Other findings were normal except for labile hypertension (blood pressure 170/90 mmHg). Followup examinations conducted 2 and 4 years later showed the same types of findings, and the worker complained of the same symptoms.
The second worker, 53 years old, was exposed in the same way, but for a shorter time than the first .
His initial symptoms were essentially the same as those of the other worker. On admission to the medical clinic, 5 days after exposure, herpes labialls, hypertonic fundus, high blood pressure (170/115 mmHg), mild diabetes mellitus, and polycythemia (5.34 million erythrocytes, hemoglobin 17.2 g, color index 32.4, hematocrit 482) were observed. Kidney and liver functions were not abnormal. Perception disorders in the face and in the fingertips of both hands, paresis of the muscles of the cheeks and tongue, and bilateral double vision were also noted. After 4 months, the subject complained of loss of the sense of taste, deficient saliva flow, and difficulties in opening his mouth, chewing, and eating .
Findings of a medical examination included hyposmia and hypogeusla and analgesia, thermoanesthesia, and hypoesthesia in the area of the trigeminal nerve, the skin of the face, the oral mucosa, the top of the bead, th- tragus, the ear muscles, beneath the angle of the jaw, base of the tongue, throat, and the external auditory, passages. Corneal, nasal, and vomiting reflexes were all absent. Followup examinations 2 and 4 years later revealed no Improvement.
The authors  attempted to find mono-and dlchloroacetylene in the aqueous mixture, because of the close resemblance between the signs and symptoms of intoxication vith vinyl derivatives and with acetylene dlchlorlde, but were unsuccessful; however, they postulated that the toxic effects observed In these workers could have been caused by mono-or dlchloroacetylene.
They suggested that caution be exercised where the potential existed for exposure to the Intermediate products of polyvinylidene chloride. , In a 1971 report, discussed similar effects on a 32-y<iar-old worker exposed to off-gas from an aqueous dispersion of a vinylidene chloride copolymer.

# Krieger et al
Several hour3 after receiving a jet of the gas in his face after opening a valve too soon and after manuaily cleaning a tank used to transport the copolymer, a job that lasted about 2 hour3, the worker developed pains in the upper lip, nose, and eyes, a frontal headache, and visual problems. Later he was bothered by a lack of sensation in his face and buccal mucous membraner, somnolence, anorexia, nausea, and difficulty in speaking and eating.
Fourth a days after the incident, an examining physician noted bilateral facial anesthesia, corneal anesthesia, and hypoesthesla. The worker had neuralgia involving the anterior two-thirds of his tongue, but no trigeminal motor involvement or facial motor disorders.
Krieger et al concluded that, because the clinical picture was similar to that described in previously published reports on the toxic effects of exposure to chlorinated acetylenes, these compounds probably were the toxic agents in Chls case.
Although none of these authors  suggested that vinylidene chloride itself was the cause of the "cranial polyneuritis" observed, each suggested that there is a potential hazard to workers exposed to intermediates or impurities of vinylidene chloride copolymerization processes.

# (c) Vinyl Bromide, Vinyl Fluoride, and Vinylidene Fluoride
No reports of toxic effects on humans from exposure to vinyl brer,aide, vinyl fluoride, or vinylidene fluoride have been located.

# (d) Summary
The human studies reported in this section do not permit comparisons of the modes of action of the various vinyl compounds. Only for vinyl chloride have reports of a full range of tests on a large population of workers been published. The adverse effects observed on humans exposed to vinyl chloride, eg, the serum enzyme aberrations, CNS effects, vascular abnormalities, and tumors, Indicate that such exposure is a serious hazard In the occupational environment.
The other vinyl halides are also suspect because of their chemical similarity to vinyl chlorldc. The paucity of human data for the other vinyls should not be construed as an indication that they are Innocuous; the potential hazar < from occupational exposure to these compounds was only recently postulated.
The hazards presented by thes? compounds nay vary only quantitatively rather Chan qualitatively, and the variations may be and are likely to be based on thalr relative bloreactlvlties.

# Epidemiologic Studies
Although more than 30 epidemiologic studies of populations subject to occupational and environmental e:cpo3ure to vinyl chloride have been published since 1971, only one epidemiclogic study of workers exposed to vinylidene chloride  has been located, and no epidemiologic reports on the other vinyl halides were found. In the first study , the experimental population consisted of 5,011 workers (96.4X male, 95.71 white, mean age 35.8 years).
The control population was the adult male population of Tecumseh, Michigan: 2,407 men over the age of 18. Criteria for selection of the control population were not presented, and analyses comparing vinyl chloride workers with controls were not given. In assessing health status, Dinman et al had each worker complete a., questionnaire designed to probe for signs or symptoms related to Raynaud's syndrome or peripheral vascular insufficiency and related hand Injuries. Roentgenograms of both hands of each worker were made and were reviewed Independently by tvo radiologists for signs of acroosteolysls.
Medical and occupational histories vere also obtained from each employee.
Twenty-five clear-cut cases of acroosteolysls were found in the worker population . These cases met the following diagnostic crltarla: defects along t&e shaft margin, sclerosis with recalcification, and shortening of the phalanges, or, marginal defects with residual fragments, transverse defects with or without distal fragmentation, and total resorption of the distal portion of the phalanx. Tventy-tvo of the 25 workers with abnormalities diagnosed by roentgenographic examination also indicated on the medical questionnaire that they had had symptoms characteristic of Raynaud's syndrome. The authors stated that in a few plants the concentrations cf airborne vinyl chloride had been measured inside the reactors during scraping operations, and that Che vinyl chloride concentrations had been generally below 100 ppm (256 mg/cu m) and usually about 50 ppm (128 mg/cu m) .
Air samples taken close Co the hards of Che scrapers had contained concentrations of ' .'inyl chloride ranging between 600 nd 1,000 ppm ; however, Che authors did not present details or identify Che plants where these measurements had been madt. .  concluded Chat work practices rather chan any one specific substance or combination of nacerials used In the manufacturing process were determinant of whecher or aot acroosteolysls would occ.ur.

# DInman and coworkers  ard Cook et al
They considered acroosteolysls to be a manifestation of a systemic intoxication rather than of local effects by a coxlc material, so that prevention of transpulmonarv, percutaneous, and gastrointestinal absorptions of materials scraped off the walls of the reactors was seen as the first line of defense of the health of the reactor cleaners, the group of employees in wLlch the greatest incidence of this disease was found. Bagger-packers also had a high incidence of acroosceolysls and were required to have protection against absoprtion of material from the polymerized produce from the reactors.
The authors  stated that, while gloves (unspecified type) were provided for reactor cleaners, the use of gloves was "Inconsistent" at those plants having workers with acroosteolysls.
They also stated that the procedure for airing out reactors before cleaning was frequently "short-cut" in. these planes.
They pointed oue that the complexity of the manufacturing processes, which involved -at least 227 different materials, including monomers, catalysts, ketones, and chlorinated hydrocarbon solvents, made conclusions about the hazard of any single ingrediert difficult.
They also proposed that "idiosyncratic sensitization or susceptibility" be considered as a possible determinant of the development of acroosteolysls. The authors also stated that there were several problems with the consistency of the diagnostic procedures, eg, the radiologists seldom agreed on a specific diagnosis, and with the accuracy of the survey techniques. The authors' investigation of differences in ehe planes' work pracclces did not provide an explanation as to why there were definitive cases of acroosteolysls in only 7 of ehe 32 plants . However, they did report that acroosteolysls was rare in plants using high-pressure water lances for cleaning the reactors and also In those that reduced the pressure within the reactor below the atmospheric pressure to the greatest extent and for the longest time before opening the reactor for cleaning.
The authors' suggestion that work practices and engineering controls might not be followed in those plants having cases of acroosteolysls was not documented. The fact Chat all cases of acroosCeolysis were diagnosed In workers vb-had been employed at sometime as reactor cleaners, although only 21Z of the total worker population had been employed in this category, Indicates that employees performing this task . were at greater risk of developing acroosteolysis. Since this task also has been found to have the potential for the highest exposure to vinyl chloride, it is reasonable Co assume that exposure to this substance contributes to the induction of acroosteolysis.
(2) Clinical Tests In 1972, Kramer and Mutchler [761 described a study in which environmental measurements were compared with clinical test results and meaical histories for 98 men who were occupationally exposed to vinyl chloride and to "small amounts" of vinylidene chloride in a polymerization facility.
Medical surveys and physical examinations had been conducted on 66 of these men during 1965 and 1-966, and the results were compared with results from a control group of 605 employees in other departments (not Identified) who were examined during the same period .
Ninety-five separate items were compared for the two groups by a test for differences between means assuming normal distributions.
The

# Six of 20 clinical variables
showed significant correlations (P<0.05) with the cumulative TWA concentration and the cumulative dose of vinyl chloride when allowance was made for the effects of age and obesity . Systolic blood pressure, diastolic blood pressure, BSP retention, icteric index, and serum beta-globulin concentration increased witn increasing TWA exposure concentration and total exposure dose (TWA concentration multiplied by cime on the job), while hemoglobin concentration decreased with increasing exposure. Although the authors did not present complete information on exposure concentrations, they stated that the mean TWA exposure concentration was 155 ppm (397 mg/cu m) in 1950 and 30 ppm (77 mg/cu m) in 1965. The authors noted that recent (not further defined) measurements of the workplace concentrations of vinyl chloride had shown them to average about 10 ppm (25.6 mg/cu m) with vinylidene chloride present in "trace" amounts, virtually always less than 5 ppm (19.8 mg/cu m ) . The authors also mentioned that data concerning exposures for each year since 1950 were available, but they did not present these data.  also calculated the expected clinical values for these tests as functions of career TWA exposure concentrations, using the regression coefficients from estimated exposures for the study population.

# Kramer and Mutchler
Because blood pressure and Che concentration of hemoglobin in the blood did not move outside the normal range of values aud the significance of change in the concentration of beta protein vas not known, Kramer and Mutchler considered that the only dependent variables significantly linked to possible injury induced by prolonged exposure co vinyl chloride with trace amounts of vinylidene chloride were BSP retention and the icteric index. These measures indicate some interference with the normal liver function.
The two persons with the greatest increases in BSP retention were reexamined in 1968, having been removed from further exposure in 1965. One individual, who had a M story of hepatitis before exposure to vlr.yl chloride, retained high value? or BSP retention and icteric index; the other individual had essentially normal laboratory findings.
In 1975, Wyatt et al  published an epidemiologic study of the results of selected blood screening tests and medical histories of workers in a chemical plant In Kentucky where polyvinyl chloride was made. Since angiosarcoma had been diagnosed in seven workers in the unit where polyvinyl chloride was manufactured (unit 62) in this plant, results from workers in this unit were compared with other workers in the chemical plant who had never worked In unit 62.
There were 413 employees with at least 1 month of experience in unit 62; they had means of 14 and 7 years of experience at the plant and In unit 62, respectively. They were compared with 469 employees who had never worked in unit 62 and who had a mean of 12 years of experience at the plant.
All employees in the study were male, and less than 10Z in each group were nonwhite. The average age was 40 in the unit-62 workers and 41 in the other group. Height and_welght were similar in the two groups.
Blood tests were performed for several months, beginning in January 1974 . Blood was drawn in the early morning after an overnight fast and the serum was analyzed for total protein, albumin, calcium, inorganic phosphate, creatinine, uric acid, total bilirubin, alkaline phosphatase, LDH, GOT, CPK, creatinine phosphate, and cholesterol. Normal values for each test were based on the experience of the clinical laboratory performing the tests. Intergroup differences were determined for the means of each teat, and significance was tested by calculation of chi-square. The effects of age were analyzed by regression analysis of the mean values of each test plotted by 5-year age groups.
The mean values of each test were not significantly different for the two populations . However, when the results of each test were classified as normal, above normal, or below normal, albumin, alkaline phosphatase, and GOT In the blood serum were found to differ significantly (P<0.05) with regard to percentages In each range. Multiple regression analyses showed significant differences (P<0.03) in the albumin and cholesterol tests for the two populations.
A comparison of the two populations by history of previous illness revealed significant differences (P<0.05) in the incidences of genitourinary disease, which was lower In the unit-62 workers, and "allergic" and "llver-spleen" illness, which were higher 'in the unlt-62 workers.  made no attempt tc assess such factors as length of employment, selective criteria for employment, age, or behavioral differences between the groups. They pointed out that many individuals in both groups had abnormal test results, but they stated that this oust be "interpreted cautiously," particularly in the absence of a true control group. This study provides no information on exposure to potential chemical hazards for either of the groups.

# Wyatt et al
Without this information, the observations of differences between the groups are of limited value.
In 1977, Waxweiler et al   The groups consisted of 134 rubber workers with "no" vinyl chloride exposure, 80 plastics workers vlth "light" vinyl chloride exposure, 126 chemical workers designated as vinyl chloride "exposed," and 71 former chemical workers who had had "past" vinyl chloride exposure. Information concerning exposure concentrations was not presented. Subjects were classified in one of the first three groups on the basis of their jobs at the time of the health survey. Basic blood screening tests and pulmonary function examinations were performed, and medical histories were obtained.
All test results were adjusted for age and the results of the pulmonary function tests and reports of respiratory symptoms were also adjusted for smoking. Alcohol consumption was analyzed, but no basis was found for adjustment o f the data.
Of the total study population, there were 21Z abnormal SGOT, 5% abnormal total bilirubin, 13Z abnormal alkaline phosphatase, and 4Z abnormal LDH .
The prevalence of these abnormalities was similar in all four groups, except that abnormal LDH values were present in 11.8Z of the former chemical workers.
The age-adjusted prevalence of hepatomegaly as diagnosed by palpation in current chemical workers (13.2Z) was almost twice that in rubber workers (7.1Z) and-plastics workers (7.32).
A similar gradient was noted when diagnosis was by percussion alone or by percussion and palpation together. One former and three current chemical workers had both abnormal values for two or more of the four liver function tests and hepatomegaly as diagnosed by both percussion and palpation. Liver scintlgraphs, after injection of 99 Tc sulfur colloid, were made for 123 workers exposed to vinyl chloride and were read by three specialists in nuclear medicine. In no case did all three specialists agree on whether any single film was abnormal; of the 29 films read as abnormal, only 4 were read as abnormal by 2 reviewers. No significant differences between the groups were reported for symptoms of Raynaud's syndrome . Twenty-two of 207 roentgenograms of the hand were read as abnormal for some state of acroosteolysis by one of two radiologists. Severe, persistent headaches were reported more frequently by the chem.cal (13.7Z) and plastics (12.7Z) workers than by rubber (8.6%) and former chemical (6.4Z) workers, and loss of consciousness on the job was more common in t h chemical (6.3Z), plastic (5.22), and former chemical (5.8Z) workers chan in the rubber (2.1Z) workers. Neurologic examinacion revealed "slightly" dim inished reflexes in Che chemical workers' group. The prevalence of angina pectoris, as measured by Che Rose Questionnaire for cardiovascular symptoms, was not noticeably different in the four groups. However, a much higher prevalence of systolic hypertension (>140 amHg) was noted in the former chemical workers.
A significantly higher (P90 nmHg) was seen in all three vinyl chloride-exposed groups compared with that in the group of rubber workers (39.4-41.0Z vs 24.3Z).
No differences between the four groups were found in tne prevalence of respiratory volume impairment (adjusted for smoking) or of respiratory flow impairment; volume impairment did n e t differ between smoking and nonsmoking workers, although pulmonary function c e s t 3 made before and after the workshift showed results related to smoking rather than to job w-itegory . Sputum cytologic and chest roentgenographic examinations revealed only "minor" intergroup differences. On the health questionnaire, the plastics workers and former chemical workeru reported prevalence? of chronic respiratory symptoms "substantially" higher than those In the rubber workers, while the current chemical workers reported prevalences only "slightly" higher than those in rubber workers.  concluded that the striking increase in LDH abnormalities in the former chemical workers (12Z vs 2-4Z for the other three groups) might have been a function of self-selection out of the chemical area because of symptoms of associated abnormalities. They also stated that the "most impressive" difference between the groups was the prevalence and degree of hepatomegaly, which showed a "weak" dose-response relationship with vinyl chloride exposure as estimated from job categories. Finally, the authors pointed out that, because of differences between plants in work practices, production techniques, composition of the workforce, the presence cr absence of various associated toxins, and other factors, general conclusions about the hazards of vinyl chloride exposure should not be drawn from the results of this single study.

# Waxweiler et al
The types of data most valuable In comparisons of epidemiologic reports, such as dally exposures and total accumulated doses, were not available to these authors .
Exposures considered "light" in this plant might have been classified differently in another plant.
The bias introduced by preselection for work and self-selection out of a hazardous environment is not quantifiable at present. The impact of these and other considerations, such as the latency of adverse effects on the estimation of the hazard of exposure to vinyl chloride remains to be determined.
Waxweiler and coworkers did, however, draw some tentative conclusions that merit further evaluation. The suggestion o^ a dose-response gradient for hepatomegaly, the significant increase in the Incidence of diastolic hypertension in the vinyl chlorideexposed workers, and the severe headaches and loss of consciousness indicate vinyl chlcrlde-induced health hazards that sho'uld be closely monitored.
3a la 1977, Fox and Collier  reported on the mortality of over 7,000 man exposed to vinyl chloride at some time between 1940 and 1974 at 8 polyvinyl chloride plants in Great Britain. TWA exposure concentrations were estimated by the companies (presumably on the basis of job description and area sampling data) and classified as high (>200 ppm or 512 mg/cu m ) , medium (25-200 ppm or 64-512 mg/cu m ) , or low  2 5 ppm or 64 mg/cu m ) , and as constant (most of the time) or intermittent (occasional).
The study Included a total population of 7,409 workers, 23Z of whom had 10 or more years of exposure to vinyl chloride .
The Standard Mortality Ratio (SMR), 100 times the ratio of the number of observed deaths in the population at risk and the number expected to occur from the same cause in a standard population of the same size on the basis of actual mortality figures, for this population was 75.4, using the sex-and age-standardized death rates for England and Wales for comparison. SMR's for all causes of death computed for eight factories revealed that at three of them there were significantly fewer deaths than expected, and that all had overall SMR's below 100. The SMR for cancer deaths was "marginally" higher than expected (101.4) in one plant. Four deaths from cancers of the liver were found, compared with 1.64 expected, for an SMR of 243.9. Two of these cancers were confirmed by microscopic examination as angiosarcoma, and two were confirmed as carcinomas rather than angiosarcoma. The two workers who died of angiosarcoma had had high constant exposures for 8 and 20 years. The two workers with carcinomas had had low, intermittent and medium, intermittent exposures for 6 and 18 years, respectively.
Three of the deaths from cancer of the liver occurred in one factory after 1966. One of these was an angiosarcoma. This was significantly in excess of the 0.13 deaths expected In this factory (P<0.01).
Analysis of mortality by year of entry into the industry showed that longer employment was associated with higher SMR's for cancer and circulatory disease .
Data on cancer of the liver suggested a dose-response relationship since both cases of angiosarcoma of the lives occurred is members of the highest exposure group. There was a general tendency for the age-adjusted SMR for all causes for those men alive 15 years after they began employment to increase with Increasing time on the job, from 100.6 (for men employed <- years or less) to 104.7 (5-9 years) and to 113.3 (10-14 years).
Approximately 75Z of the 7,409 workers had been employed for less than 10 years, and more than half of those ever employed were still employed at the time of the study . Since only about one-fourth of the workers had been exposed to vinyl chloride at high concentrations for a long time, and since most of them who had completed 20 years of service had done so only recently, Fox and Collier suggested that there had not been a sufficient followup period during which to evaluate the carcinogenic effect of vinyl chloride. They also pointed out the complicating factors cf the "healthy worker effect" and the "survivor effect" in analyzing these data. ' The healthy worker effect means (3) Mortality and Morbidity Studies that most people accepted fo? employment are healthy, and, as a result, the workplace population tends to be In better health than the general population. The survivor effect stipulates that people experiencing adverse effects at the workplace tend to leave their jobs of their own volition; therefore, the remaining work population is composed of a larger percentage of people who are more resistant to the adverse effects of the Industry than the population of all people hired. The authors concluded that vinyl chloride was probably a carcinogen causing cancer of the liver in exposed workers; they noted however, that the cases of angiosarcoma observed were associated with exposure at "very high" concentrations.
They added that no evidence was found that vinyl chloride caused cancers other than those of the liver, and that although the sy.R for cancers as a group was consistently higher than that for all deaths, cais was difficult to evaluate becauje of population selection factors. These authors' conclusions  axe necessarily biased by the choice of a general population as the control group, and this fact is pointed out by the authors in their discussion of preselection and survivor effects. Thus, the relation of observed effect's in the worker population to expected effects on the general population may give a less than objective analysis of the potential hazard.
In another report, Fox and Collier  examined the effects of selection for work and survival in the industry on mortality in Industrial cohorts. They used the previously described worker population and data for these comparisons ; however, they compared the employees working at the time of their deaths with those who had left the industry . For all causes of death, the SMS. for employees alive after 15 years is the industry was 74.0, while for former employees alive after 15 years, the SMR was 108.4. A comparison of SMR*3 for cancer of the lung between the two groups was particularly striking, 50 for current workers and 156 for former workers. Results of comparisons for other causes of death by 10-year age groups revealed similar differences in SMR's.

# Observed and expected deaths categorized by cause of death and length of employment demonstrated increasing SMR's with Increasing length of time on the job .
The SMR for all causes of death for all workers progressed from 37.4 (.for those employed for 0-4 years) to 62.9 (for those employed for 5-9 years) to 75.1 (for those employed for 10-14 years) and to 94.2 (for those employed for more than 15 years).
The authors  concluded that the results of the analyses showed clearly that death rates for employees in the polyvinyl chloride Industry depended on preselection for employment, their continuing employment in the industry, and length of the time during which the workers continued to work in the industry, asd the length of time during which the cohort was studied. They suggested that mathematical models taking these factors into consideration might be productive alternative methods for analyzing mortality studies. I Th studies  indicate the potential pitfalls of assessing an industrial hazard on th basis of comparisons with the general population. Th influences of presletion ard survival factors are demonstrated by the findings that SMR' are lower both for workers with less experience and for current workers than for former workers. If these factors actually affect the results of an epidemiologic analysis, the assessment of hazard may be lower than is correct.
In 1974, the results of a retrospective study on 8,334 men with at least 1 year of occupational exposure to vinyl caloride before December 31, 1972, were published by Tabershaw and Gaffey  and submitted as a report to th; Manufacturing Chemists Association by Tabershaw/Cooper Associates Inc . The study compared the mortality experience of the vinyl chloride workers with that of the general population and with that of other employee groups.
The vinyl chloride workers were separated into subgroups on the basis of intensity and duration of exposure and of combinations of these two factors. These subgroups were compared on the basis of the SMR's for various causes of death.
Thirty-five plants in the United States that either produced vinyl chloride or used it in the production of polyvinyl chloride gave information from their employment records .
Quantitative exposure data were not available for each job, but relative exposures were estimated by plant industrial hygiene and safety personnel.
Actual concentrations were not estimated. The authors calculated an exposure index (El) for each worker on the basis of an average monthly exposure score ranging from 1 (low' exposure) to 3 (high exposure).
The median birth year of the 7,128 workers traced successfully was 1931, '.he median duration of exposure was 80 months (6.7 years), the median El was 1.44, and the median year in which exposure bega-> vas 1962 . With the age-specific death rates as the standard of comparison, SMR's were calculated for approximately 30 causes of death.
No SMR for any cause of death was significantly greater than. 100 and SMR's for several causes of death were significantly below 100. For example, the SMR for "all causes'- was 75 (352 observed deaths vs 467 expected) and that for cardiovascular and renal diseases was 80.
When the workers with vinyl chloride were subdivided according to El (more or less than 1.5) and duration of exposure (above and below 5 years), no remarkable findings emerged from these tabulations .
No SMR's were significantly above 100, although several were significantly below 100. Several trends were apparent, however, from the cross tabulations. SMR's for all malignant neoplasms Increased with increasing El and duration, reaching an SMR of 141 for an employment duration of 5 or more years and an El of 1.5 or greater. Cardiovascular and renal diseases showed a similar trend, although the SMR's generally remained below 100 for all causes of death except hypertensive disease other than cardiac. There were slight, nonsignificant excesses of observed deaths from respiratory system, digestive organ and peritoneum, and "other" cancers that increased in relation to increased duration of employment and estimated exposure. Cancers of the buccal cavity *nH pharynx also appeared in excess but had their highest rate of occurrence in the low, short-exposure group.
The authors  stated that the lower than expected overall mortality of the vinyl chlorxde workers was not a surprising finding because of the 'healthy worker effect," even though vinyl chloride poses a significant risk of death from a particular cause, ie, angiosarcoma of the liver. Deaths from cancers of the digestive organs and peritoneum were further examined to study the role of angiosarcoma in overall mortality. Of the 19 deaths from cancers of the digestive organa and peritoneum, 7 were due to cancers of the liver, 2 of which were identified on the death certificates as angiosarcoma.
However, according to the authors, other investigators using the same study population Identified four other deaths from angiosarcoma; the death certificates stated the causes of death In three of these as cancer of the liver and in one as cirrhosis of the liver. Laennec's cirrhosis was given as an alternative? cause of death on one death certificate identifying cancer of the liver as the primary cause. If there had been no cases of angiosarcoma, the difference from the expected number of cancers of the digestive organs would have been insignificant.
The authors  concluded that the "consistent pattern of Increase" for particular causes of death with increasing exposure "appears" to relate mortality from cancer of the digestive syst:em or respiratory system, cancer of other unspecified sites, and lymphosarcoma to vinyl chloride exposure. They pointed out areas of possible bias In the studjr. The use of the US male population as a comparison group may have cauacd a slight overestimate of the SMR's, since the study population was from the eastern half of the United. States, where expected mortality is higher; also, 15% of the workers could not be traced and the assumption that their mortality distribution was similar to that of those traced may have been incorrect. The data obtained on workers who could not be^traced showed that; on. the average/ they were born 10 years earlier than the study group and had much shorter exposures and slightly higher El's.
The effect that these differences may have had on mortality is uncertain. Also, 1,500 workers whose exposures had occurred up to 35 years earlier were located too late to be evaluated In the study. Information about workers exposed for an extended period many years before might have more clearly elucidated the effects of occupational exposure and been especially valuable because of the apparently long latent period for vinyl chlorideinduced disorders.
Although the authors did not demonstrate a statistically significantly increased risk from exposure to vinyl chloride in this worker population, the observation that the SMR's for various cancers increased with increasing duration ofzemployment and increasing estimated exposure suggests that exposure to vinyl chloride Indeed contributes to increased cancer mortality risk-A followup study   None of Chese differences changed Che major conclusions of Che prior sCudy. One more deaCh from angiosarcoma of Che liver was discovered.
A final report , which included che data from the above studies , was prepared by Equitable Environmental Health Inc in 1978.
This report  increased the total worker group available for study to 10,173 from 37 plants. Although the successive additions to the study population resulted in changes In the SMR's, these changes were not significant or compound-related and did not cause any change from the conclusions reported in previous studies.  and 1975 . They e v a l u a t e d C h e morcallcy of che accive and pensioned workers ac two planes in Kencucky, one of which was the polymerization plane where C h e firsC cases of angiosarcoma were seen, che other of which produced the vinyl chloride used by the former. One hundred and sixty-one death records were analyzed for this study. Causes of death were taken from company abstracts of the death certificates, and the number of observed deaths from each cause, stratified into 5-year age-and time-specific groups, was compared with the number expected on the basis of age-, time-, and cause-specific proportional mortality ratios for US white males. While the comparison did introduce an obvious bias in the seacisclcal treatment of results, the authors  adequately pointed Chls out in their discussion.

# Mbnson et al published two nearly identical reports in 1974
The Crend in the raeios of observed to expected deaths from all cancers is a particular cause for concern since it indicated that the proportion of deachs caused by cancer was on che increase in this workforce. It must be remembered, however, that this was a study of workers at only two plants, and that che crend may noc have been relaCed to the vinyl chloride exposures alone. Ott et al  examined the mortality during 1942-1973 of 594 employees exposed to vinyl chloride between 1942 and I960 Several methods of sampling nd analysis of airborne vinyl chloride had been used since 1950. Samples showed vinyl chloride concentrations before 1959 to have been generally welt below" 500 ppm (1,280 mg/cu m ) , with occasional excursions to 4,000 ppm (10,240 mg/cu m). In 1959, the company established a guideline of 50 ppm, (128 mg/cu m) as an 8-hour TWA exposure limit, and subsequent exposures were "generally found" to be below this concentration. Occupational histories were obtained from plant records, and exposures in the two largest units, which accounted for 466 of the workers, were classified as low (200 ppm; >512 mg/cu m ) , and each worker was assigned to one of these exposure groups on the basis of the highest estimated concentration at which he had been exposed for longer chan 1 month. The 128 workers from the three smaller production units, for which industrial hygiene data were not adequate to characterize exposures, were classified as having unmeasured exposures, which company industrial hyglenists estimated were, primarily in the low to intermediate range. For purposes of analysis, each exposure group was subdivided according to exposure at that concentration for less than 1 year or for 1 year or more. Exposures of workers to vinyl chloride at lower concentrations than their assigned category were not considered; for example, worker exposure at concentrations between 25 and 200 ppm for 6 months, and less than 25 ppm for 10 years, would be classified as intermediate exposure for less than 1 year.
All but one of the employees were traced through 1973 . Causes of death were obtained from death certificates for all deceased workers except one who had been employed in a low-exposure job for less than 1 year. Expected numbers of deaths for each exposure classification were calculated from OS death data for white males by determining the number of person-years in each exposure group over 5-year periods by 10-year age groups.
The total number of deaths in the study population was 89, compared with 100.1 expected deaths [861. Malignancies accounted for 20 deaths vs 17;9 expected, and none of these were cancers of the liver. There were three deaths from cirrhosis of the liver (3.1 expected), all in workers exposed to vinyl chloride for less than 1 year. Seventy-two of the vinyl chloride workers had also been employed in an arsenicals production facility where workers previously had an increased cancer mortality risk, and these workers were therefore not Included in the population used for the vinyl chloride s tudy.
With arsenicals workers excluded, total deaths in the population of 522 vinyl chloride workers numbered 79, 91Z of the US death rate for white males, and the number of deaths due to malignancies was 13, compared with 16.0 expected deaths . When the mortality data were stratified according to exposure concentration, 9 of these deaths from cancer were found to have occurred in the 163 workers with high exposure,- compared with 5.1 expected, and 6 of these were in workers exposed at high concentrations for longer than L year (2.9 expected). Statistical comparison of the ratio of observed to expected deaths from cancer in the high-expoaure group with that of all other groups combined, assuming a Poisson distribution for small sample sizes, showed a significant difference (P<0.025).
When only deaths occurring 15 years or more after the employee's initial exposure to vinyl chloride were included, eight of nine deaths from malignancies were in the high-exposure group (PCO.Ol). A survey of case histories of the 13 vinyl chloride workers who died from cancer showed that 2 had also had substantial exposure to benzene, 1 had a family history of malignancies that included 4 deaths in his imnediate family, and at least 3 of the 5 who died from lung cancer were smokers.

# Ott et al [8 6
] concluded that, although the number of deaths was small, the distribution of malignant neoplasms with respect to exposure categories suggested a possible dose-response relationship.
No associations were noted for malignant effects in the lower-exposure categories where the estimated TWA exposure concentration ranged from 10 to 100 ppm.
In 1974, Nicholson et al  published a retrospective study of the mortality of a cohort of workers involved in the production of polyvinyl chloride at a plant In New York. From company and union records, 257 men were identified who had begun employment between 1946 and 1963 and who had worked for at least 5 years in the plant. The current health status of 255 workers was determined. More than half of the employees had worked primarily in polyvinyl chloride production, where reactor cleaning was routinely performed without respiratory protection, causing exposure to vinyl chloride. Approximately 25Z of the workers had been employed in maintenance, where exposures to vinyl chloride could be significant during repair work, and the remaining workers had been employed mainly in the shipping department and the laboratory. No records were kept of the vinyl chloride concentrations at which the workers were exposed. The only measurements made of environmental concentrations of vinyl chloride were those necessary to ensure that the explosive limit of 30,000 ppm (76.8 g/cu m) was not exceeded. The authors estimated that peak concentrations might often have exceeded 1,000 ppm (2,560 mg/cu m) and nay occasionally have reached 10,000 ppm (25.6 g/cu m ) . This estimate was based on the results of medical examinations conducted in March 1974 on a group of active and past workers, more than 50Z of whom reported symptoms of dizziness, headache, or euphoria, and 4Z of whom had lost consciousness on the job in comparison with the known development of these symptoms at high concentrations. The median age of the workers on the 10th anniversary of their employment was approximately 37 years, with 16Z under 30.
Of the 255 traceable workers, 82 had retired or were working elsewhere, 24 had died, and 149 were still employed at the same plant . Mortality among the workers was higher than expected based on death rates for New York State, excluding New York City, for deaths due to all causes and all cancers in groups exposed 10-15, 15-20, and 20-25 years, but not la the one exposed for 25 or more years. These increases were not statistically significant, however.
There were 10 deaths from all causes vs 6.1 expected in-the group exposed 10-15 years, 7 vs 6.6 in the group exposed 15-20 years, 7.0 vs 5.0 in the group exposed 20-25 years, and 0 vs 1.3 in eke group exposed 25 years or more. The observed vs expected numbers of deaths from all cancers in these groups were 3 vs 1.2 3 vs 1.4, 3 vs l.l, and 0 vs 0.3, respectively. There were chree deachs caused by angiosarcoma of Che liver and chree deaChs from other cancers (glioblascoma, reticulum cell sarcoma, and lymphosarcoma) that Che auChors suggesced might have been related Co exposure to vinyl chloride.
The authors  reported thaC Che three cases of angiosarcoma occurred in workers who had been exposed for the first time before 1951.
They suggested that, as the time from first exposure increased, additional cases of occupational cancer might occur in this group of workers.
The authors concluded that these data demonstrated the need to prevent exposure to vinyl chloride and to monitor, screen, and further study workers previously exposed to vinyl chloride.
In 1977, Chiazze et al  published a study of 4,341 deaths that occurred during 1964-1973 in a population of polyvinyl chloride production plant workers who had had exposure to vinyl chloride. A total of 55 plants of 17 companies supplied mortality data on employees who had died either while actively employed, after retiring from the company with retirement benefits, or after terminating employment but while still covered by a company-sponsored insurance program.
A frequency distribution based on hospital and area was calculated for subjects whose cause of death was listed as cancer or liver disease.
When one hospital or several hospitals in the same area appeared on several of these deaCh certificates, a Registered Records Administrator visited these hospitals and reviewed all of their pathology records to determine whether any cases of angiosarcoma of the liver had been diagnosed. Five cases of angiosarcoma were found in this manner, but none of these persons had ever been employed at any of the plants, in the study.
Over the 10-year study period, the size of many of the plants changed drastically  concluded that there "appeared" to be excesses in cancer mortality for both men and women in this study and that these excesses "appeared" to be concentrated in cancers of the digestive system. ^They listed several factors that made definitive Interpretation of the data "difficult. Th- use of PMR's, they pointed out, does not take into account the absolute risk of death in a population.
Also, the overall favorable mortality of working populations, which has been found in numerous Investigations, was not considered In this study. The authors did state, however, that their results "appeared to be consistent" w i t h p r e v i o u s l y p u b l i s h e d studies , and that these r esults s u g g e s t e d a nee d for c o n t i n u e d i n v e s t i g a t i o n . D e f i n i t i v e i n t e r p r e t a t i o n In each cancer mortality category, the calculated SMR. was higher for the 15-year group th a n for the 10-year group . The authors stated that this demonstrated Che importance of considering latency when looking for occupationally induced malignant neoplasms. They suggested that restricting the study to at least 10 years after initial worker exposure had minimized the "healthy worker effect," thereby eliminating the overall deficit of deaths In workers exposed to vinyl chloride often reported by other investigators. A similar pat-ern of latency had been reported previously by Nicholson et al . These results demonstrate an Increased risk of cancer for vinyl chloride workers and show the essentiality of taking latency into account.
In 1975, Duck ec al  reported on the mortality experience of workers exposed to vinyl chloride in a plant in Great Brltian. A total of 2,120 male workers who had beeu exposed to vinyl chloride at some time since 1948 was identified from company records.
Information from death certificates was compiled for these workers, and the mortality was compared with that of men in England and Wales. Workers who died at more than 74 years of age or before 1955 were excluded from consideration in both populations. SMR's were computed on the basis of cause of death, Job description, duration of exposure, and year of first exposure . No significant excess mortality was found for the workers in any of the comparison categories. No cases of angiosarcoma of the liver were Identified in either population within the study period ; however, the authors stated that one such death occurred ait^r the end of the study and before the paper was published.
The authors  pointed out that their comparisons did not allow for the selective effects of employment.
They also noted that their findings conflicted with those of Monson et al .
The significance of these observations is difficult to determine, since the authors did not supply exposure information in this report. It is possible that, because of .unique work practices and engineering and administrative controls, the aortality of workers from this plant may not be representative of workers from other plants or from the Industry as a whole. In none of the groups was the percentage of aberrations found in workers significantly different from that found in controls. The authors stated that the difference In mean age between the exposed and preemployment groups was not considered to be a "confounding" factor in their analyses, since the cytogenetic change most often associated with aging was chromosomal loss rather than chromosomal breakage. The authors concluded that adverse cytogenetic effects could be avoided in "controlled, minimal-exposure environments," but they did not suggest a quan-itative exposure limit. The frequency of breakage was significantly higher (P<0.05) in all three of the industry groups than in the CDC controls, but there were no significant differences between the Industry groups.
The majority (862) of the aberrations observed in each group were chromatid gaps. Chromatid breaks and isochromatid gaps and breaks were also observed.
The authors  also attempted to relate frequencies of breakage to duration of employment. No significant gradient was reported for the high and low exposure groups, but a signficant gradient (P<0.01) was observed for the industry controls (100-199 months, 0Z breaks, 2 subjects; 200-299 months, 1.3Z breaks, 2 subjects; 300-399 months, 6.7Z breaks, 13 subjects). The euthors stated that the interpretation of this gradient was "uncertain" because of the smell number of employees, and because the mean age Increased with employment duration (31.0, 44.5, and 51.8 years, respectively).
The authors  noted that their observations were not inconsistent with previous studies suggesting a twofold Increase in chromosome breakage frequency with occupational exposure co vinyl chloride; however, they concluded that the finding that the overall frequency of breakage did not differ significantly among high, low, and negligibly exposed industrial groups indicated that other agents in the chemical/rubber plant were capable of inducing the breaks, making it impossible to relate a particular agent to the abnormal effects observed. This difficulty does not diminish the concern warranted by the increased frequency of chromosome damage seen in chemical industry workers compared with that in workers outside the chemical industry. The difference was statistically significant (P<0.001); however, the frequency of abnormal cells was highest in the employees who had been exposed to vinyl chloride for the shortest pariod.

# Purchase et al  examined 100 lymphocyccs from each of 56 polyvinyl
chloride workers and 24 workers with no exposure co vinyl chloride. Workers who had been exposed to X-rays, prolonged drug treatment, or recent viral   infections were excluded from the study- Exposed workers had 6.32 of cells with breaks and gaps, 1.45Z of cells with unstable changes, and 0.382 of cells with stable changes, Nonsxposed workers had 3.632, 0.462, and 0.09Z of cells in these respective categories. The authors stated that all group differences were statistically significant (P<0.05).
A secondary analysis was conducted by Dresch and Norwood  os the data from a number of studies of human lymphocytic chromosomal aberrations . This analysis  made use of a binomial model, assuming a homogeneous group, and the Cochran model, a model t-rith provision for differences among clusters. The authors stated that the secondary analysis of each paper agreed with the authors' analysis, and that the cumulative data from all papers combined showed a statistically significant increase in the frequency of chromosomal aberrations with increasing exposure to vinyl chloride or polyvinyl chloride.
They pointed out, however, that the frequencies of aberrations were small, only a "fraction" of background, and that, In view of tb ; inconsistency between laboratories, the positive statistical evidence should be "treated with caution."
Reproduction Studies
Infante ,-r al , in 1976, reported on a study of pregnancy outcome in wives of workers exposed to vinyl chloride.
Interviews were conducted with 95 vinyl chloride polymerization workers and a control group of 158 rubber and polyvinyl chloride workers who were known to have had little or no exposure to vinyl chloride monomer. Paternal age, pregnancy outcome, and estimates of the date of conception for all pregnancies were obtained. Wives of the workers were not interviewed and maternal age and health status were not determined. The fetal death rates in the families of the exposed workers were agematched, for paternal age, with the control group, and the two groups were compared before and after exposure, ie, to vinyl chloride monomer for the exposed, group and to rubber and polyvinyl chloride fabrication emissions for controls .
Prior to exposure, there was no significant difference is fetal death rates between the offspring of vinyl chloride workers and those of the controls (6.1Z and 6.9Z). After exposure, however, this race was significantly higher (P<0.05) for offspring of vinyl chloride monomer workers (15.8Z vs 8.8Z). To determine the effect on the overall rate of fetal deaths of the data from women who chronically experienced abortions, workers' wives who had had more thas two abortions were excluded from the calculations. The results showed that prior to exposure the offspring of the controls had a higher fetal death rate than those of vinyl chloride workers (6.92 vs 3.1Z), but that after exposure of the fathers the rate for the offspring of the vinyl chloride workers was the higher (10.8Z vs 6.82).  postulated that germ-cell damage in the father was the leading possibility as the cause of fetal death.

# Infante et al
Unfortunately, this study relied on indirect knowledge of the key variable, fecal deaths, by interviewing only che fathers. Therefore, Che reliabilicy of this information muse be considered quescionable. No seasonal variation in the rate of CNS birth defects was noted.
The reproductive histories of mothers in both groups were similar in the number of previous pregnancies and the percentage of live births and of other children with congenital anomalies . However, a family history of birth defects was reported by 11 of the 41 families in the case group but by only 4 of the 41 families in the control group. A family history of CNS birth defects wa5 reported in 5 of the case families but in none of the control families.
Occupational histories showed that two fathers .... each group had been emp .oyed in the local polyvinyl chloride plant at the _ thel r infants were cenceived, and that none of the mothers had ever worked in the polyvinyl chloride plant.
In evaluating the distance from the polyvinyl chloride plant to both the place of work and the place of residence of the parents, Edmonds et al  found no significant differences between the birth defect and the control groups. However, multivariate analysis showed that, in families living within 3 miles of the plant, CNS birth defect cases were concentrated in the area northeast of the plant (?<0.02). The authors attempted to determine whether this clustering was related to atmospheric vinyl chloride concentrations, but concluded that existing data on plant emissions and meteorologic conditions were insufficient to reconstruct vinyl chloride concentrations at the time of conception. Edmonds and his associates concluded that there was no evidence Chat the high rate of CNS birth defects in Kanawha County for 1970-1974 was related to vinyl chloride exposure.

# (6) Summary
Although the results of the various vinyl chloride epidemiologic studies are sometimes contradictory, there is substantial evidence that workers in vinyl chloride plants may have an increased incidence of atypical liver function  that suggested an increased fetal mortality due to exposure of the fathers to vinyl chloride has also been published; however, the method of data acquisition for this study was of questionable validity.
Two reports  seem to indicate that birth defects and anomalies in offspring of parents living in the vicinities of vinyl chloride polymerization plants probably are not related to exposure to vinyl chloride.
Each of these studies has similar deficiencies, eg, the lack of exposure information for most cohorts, the relatively few workers for whom significant time has elapsed since first exposure, ie, >15 years, and the difficulties of assessing the "healthy worker" and "survivor" effects. Without this' information, it is impossible to quantitate the hazards from exposure to vinyl Comparison of the results of mortality experience of the total cohort, cohort with 15+ years of experience, and cohort with a total calculated dose exceeding 500 ppm-months (1,985 mg/cu m-monchs) showed no significant increase for any cause of death .
Comparison of the results of 17 clinical laboratory parameters showed no significant differences between the matched pairs of exposed and control workers.
Regressions . of the individual pair differences on estimated cumulative dose and duration of exposure showed no positive correlations at the 0.05 level.
The authors  concluded that there were no findings "statistically related or individually attributable to vinylidene chloride exposure" in the cohort studied.
The study included few workers, however, and they were all from a single plant. The authors recommended that additional epidemiologic studies be conducted to develop information on chronic exposure to vinylidene chloride. This study does not indicate that there is an occupational hazard from exposure to vinylidene chloride.

# (c) Vinyl Bromide, Vinyl Fluoride, and Vinylidene Fluoride
No epidemiologic studies on workers exposed to vicryl bromide, vinyl fluoride, or vinylidene fluoride have been located.

# Animal Toxicity
The results of experiments involving exposure of laboratory animals to vinyl halides show that some of these compounds can Induce the same toxic effects on rodents as on humans, Including the characteristic angiosarcoma of the liver. No lifetime animal experiments have been located that demonstrate a no-observable-adverse-effect concentration for any of the vinyl halides. Comparison of the results of mortality experience of the total cohort, cohort with 15+ years of experience, and cohort with a total calculated dose exceeding 500 ppm-months (1,985 mg/cu m-monchs) showed no significant increase for any cause of death .
Comparison of the results of 17 clinical laboratory parameters showed no significant differences between the matched pairs of exposed and control workers.
Regressions . of the individual pair differences on estimated cumulative dose and duration of exposure showed no positive correlations at the 0.05 level.
The authors  concluded that there were no findings "statistically related or individually attributable to vinylidene chloride exposure" in the cohort studied.
The study Included few workers, however, and they were all from a single plant. The authors recommended that additional epidemiologic studies be conducted to develop information on chronic exposure to vinylidene chloride. This study does not indicate that there is an occupational hazard from exposure to vinylidene chloride.

# (c) Vinyl Bromide, Vinyl Fluoride, and Vinjlidene Fluoride
No epidemiologic studies on workers exposed to vicryl bromide, vinyl fluoride, or vinylidene fluoride have been located.

# Animal Toxicity
The results of experiments involving exposure of laboratory animals to vinyl halides show that some of these compounds can induce the same toxic effects on rodents as on humans, including the characteristic angiosarcoma of the liver. No lifetime animal experiments have been located that demonstrate a no-observable-adverse-effect concentration for any of the vinyl halides. The recalculated LC100 values were 150,000 ppm for mici, 210.000 ppm for rats, and 280,000 ppm for guinea pigs and rabbits.
The authors reported that death was preceded by excitement, r.ontractioas and convulsions, and accelerated respirations. The excitement ph^se progressed to a state of "tranquility" characterized by Cheyne-Stoke i breathing and circulatory disturbances as Indicated by cyanosis and conjunctival congestion. This phase chen progressed into a state of deep narcosis chat was followed by respiratory failure and death.

# Abreu
and coworkers  surveyed the anesthetic effects of 18 halogenated hydrocarbons, including vinyl chloride, on mice. Although control procedures were not discussed, it is assumed that each animal served as its own control.

# The minimal certain anesthetic concentration (EC100 for anesthesia), highest tolerated concentration (LC0), 50Z anesthetic concentration (EC50 for anesthesia) and 50Z lethal concentration (LC50) on inhalation were estimated. To establish each point on each substance's effect-concentration

# Pulmonary resistance increased and pulmonary compliance and respiratory minute volume decreased with increasing vinyl chloride concentrations .
The only values of the exposed animtls that were significantly different (P<0.05) from those of controls were pulmonary resistance (15.35Z higher than controls) and respiratory minute volume (12.302 lower than controls) at vinyl chloride concentrations o 102. No significant changes in heart rate or aortic blood pressure were observed in these animals.
Oster et al , in 1947, investigated the anesthetic effects on dogs of vinyl chloride gas mixed with oxygen. Two dogs were "momentarily" exposed to vinyl chloride at a 502 concentration (500,000 ppm; 1,280 g/cu m) which was then decreased to 72 (70,000 ppm; 179.2 g/cu m) by volume.
During exposure, the dogs maintained good abdominal relaxation, but their legs became rigid and muscular movements became uncoordinated. A third dog, anesthetized with 252 vinyl chloride, had signs similar to those in the first two dogs. After exposure the dogs continuously "crowed" and salivated heavily.
Four additional dogs received a local anesthetic, monocaine hydrochloride, and their blood pressures were checked by cannulation of the femoral artery .
After control blood pressure measurements were obtained, the animals were anesthetized with 102 vinyl chloride (100,000 ppm; 256 g/cu m) in oxygen. During the vinyl chloride' exposure, the dogs had normal blood pressures, but they showed such cardiac irregularities as Intermittent tachycardia, ventricular extrasystoles, and vagal beats.. Similar irregularities were detected with a stethoscope in noncannulated dogs on the same exposure regimen.
Six other dog3 were anesthetized wi'h 102 vinyl chloride (100,000 ppm) in oxygen . Electrocardiographic (ECG) records (lead II) were obtained a^ exposures to vinyl chloride (not further defined) sufficient to produce light surgical anesthesia, surgical anesthesia, and threatened respiratory collapse. At exposures producing surgical anesthesia, several changes were noted In the cardiac rhythm, especially marked tachycardia followed by bradycardia.
In addition, two of the six dogs showed R-wave inversions, and one dog showed incipient ventricular fibrillation. All six dogs showed abnormalities in the ECG record, ranging from sinus arrhythmia and transitory extreme left axis deviation, to atrioventricular (A.-V) . blocks ventricular tachycardia,, ventricular multifocal extrasystoles, and inversion of the T-wave with elevated ST segments. As ttie concentration of vinyl chloride was increased toward that necessary for respiratory failure, the ECG abnormalities disappeared except for the greatly reduced R-wave amplitude.
The authors concluded that vinyl chloride caused muscular incoordination in the extremities and serious cardiac arrhythmias. They also concluded that vinyl chloride was not safe as an anesthetic and that its use in humans was not warranted.
In 1974, Belej et al  reported the changes in cardiac function of rhesus monkeys exposed to vinyl chloride at concentrations of 2.5, 5.0, and 10.02 (25,000, 50,000, and 100,000 ppm; 64, 128, and 256 g/cu m ) . Three animals were exposed at each concentration.
They were anesthetized with sodium phenobarbital, their tracheae were caanulated for artificial respiration, and their chests were opened by midstemal incisions to allow measurement of myocardial contractility, pulmonary arterial, aortic, and left atrial pressure. The vinyl chloride mixtures were administered for periods of 5 minutes alternating vlth lQ-ttinute exposures to room air. The number of test periods for each animal was not specified. Control procedures were not reported, but each animal probably served as Its own control.
The heart rate and aortic, left atrial, and pulmonary arterial pressures were not significantly different between any of the experimental and control groups .
The force of myocardial contraction in animals exposed to 10Z vinyl chloride was significantly different (P^es used were too high to allow a conclusion about whether inhalation of vinyl chloride may pose an acute threat to workers in times of fear-provoking stress or to those who may take medication containing epinephrine for asthma control or other reasons.

# Carr et al

# Clark and Tinston  exposed beagle dogs to vinyl chloride at various concentrations by mask, for 5 minutes.
During the final 10 seconds of exposure, a' 5-jxg/kg injection of adrenaline was administered iv. ECG's were recorded and analyzed for 3erious arrhythmias, such as multifocal ventricular ectopic beats or ventricular fibrillation. At each concentration., four to seven dogs were exposed. Vinyl chloride was calculated, by a moving average interpolation technique, to have induced cardiac sensitization in 50Z of the animals at a concentration of 5Z.
In 1970, Viola  reported on the effects on rats of exposure to vinyl chloride. Twenty-five male albino Wistar rats with an average weight of 150 g were exposed to vinyl chloride at a concentration of 3Z (30,000 ppm; 76.8 g/cu m) for 4 hours/day, 5 days/week, for 1 year.
Twenty-five similar rats served as controls.
Throughout the exposure period, the general physical appearance, behavior, and body weight of the animals were monitored.
After the exposures, some of the exposure survivors and some of the controls were killed at 20-day intervals, and gross and microscopic changes in the paws,-brain, liver, kidneys, and thyroid were noted. The number of rats surviving, Che number of examinations conducted, and the number of rats killed at each interval wexe not specified.
Exposure to vinyl chloride did not slgnlflcartly affect growth but was slightly soporific to the animals during the first 10 months of exposure .
During the 11th month, the exposed rats had lower body weights and showed less aggressiveness and less reaction to external stimuli chan the controls; they also suffered disturbances In equilibrium. No details about Che observations made were presented. Of che rats exposed to vinyl chloride, 13 died from cardiopulmonary complications and 2 died from hematoperltoneum. On microscopic examination, the authors observed chac most of che animals showed pathologic changes in the brain, liver, kidneys, and thyroid, and that six rats showed skeletal alteratious. He did not reporc whether these changes ware observed in the rats that died during exposure or in those that were killed after che exposure. The paws of che vinyl chloride-exposed racs had areas of hyperkeratosis, superficial chickening of the epidermis, and disappearance of che cucaneous "adnexa."
In addition, vacuolizaCion and degeneradon of che basal layer, a modest increase in the papillar layer, and edema of the epidermis were noted. The connective tissue of the skin showed fragmentation and decreased elastic reclculum and dissociation of collagen bundles. The small arcerlal vessels of che paws showed signs of endothelial fibrosis, and some vessels were completely occluded by proliferation of connective tissue.
Extensive metaplastis proliferadon of cartilage-like material was found around the small metatarsal bones .
The edges of the material were Irregular, with differential growth chac resulced in outward bending of Coes in areas of mature compact bone, che carcllaglnous elements were grouped around a cencral nucleus of the bone, giving che appearance of chondroid metaplasia. In small bones, this chondroid metaplasia was often extensive, and the bones appeared to be impregnated with a mucoid substance that obliterated the cement lines by altering the characteristic deposition of the bone tissue.

# Microscopic examination of the brains of rats exposed lc vinyl chloride
showed diffuse degenerative lesions of the gray and white matter . Flbrotic processes had often surrounded and Invaded the small nerve bundles of Che gray maCter. There was also evidence of neuronal phagokaryosis with satellltosls and deposition of neuroglial elements around the altered nerve cells of che whice matter. In the cerebellum, there were signs of atrophy of the granular layer and profound degenerative changes in some areas of the Purkinje cell layer.
"Animals exposed to vinyl chloride had enlarged livers . Some livers appeared yellowish with smooth surfaces and were slightly more britcle chan normal.
Microscopic examinacion revealed signs of diffuse interstitial hepatitis, functional degeneration or necrosis of the hepatic cells, and marked cytoplasmic and nuclear polymorphism. The Kupffer cells were often hypertrophic and showed evidence of abnormal proliferation. Numerous areas of partial necrosis and diffuse fatty degeneration often blocked the portal capillaries, centrllobular veins, and sinusoids.
Intense fibrosclerocic reactions were also noted in the areas of degenerative change in the livers of a few exposed rats.
In contrast, the kidneys of the exposed an imals were relatively unaltered except for signs of tubulonephrosis and occasional chronic interstitial nephritis . The author also noted colloid goiters and a marked increase in parafollicular cells in the thyroids of several animals. Examination of the controls showed no alterations in any of the organs.
The author  concluded that his investigation confirmed that rats were sensitive to vinyl chloride and that the lesions of bone and connective tissue were similar to those described in workers affected by acroosteolysis of the hands and to those in experimental "osteolathyrism." This report is valuable for its characterization of the systemic toxic effects resulting from chronic exposure to vinyl chloride.
An assessment of the hazard posed by exposure to vinyl chloride is not possible; however, because the information was not presented in sufficient detail to permit a statistical analysis. Observations on tumors produced in animals that were probably the same a& those in this paper were presented in a second paper by Viola et al  and are discussed in a subsequent section of this chapter.
In 1961, Torkelson et al  reported a three-part investigation on the effect of repeated exposure of rats, rabbits, dogj, and guinea pigs to vinyl chloride at 50, 100, 200, or 500 ppm (128, 256, 512, 1,280 mg/cu m).
In the first experiment, groups of 10 male and 10 female rats were placed in a 160-liter inhalation chamber containing vinyl chloride at a nominal concentration of 500 ppm for 7 hours/day, 5 days/week, for 4.5 months. The control group consisted of five male and five female rats.
Male rats exposed repeatedly at 500 ppm for 4.5 months showed at significantly higher (P<0.001) liver-to-body weight ratio than the controls .
Of the 20 exposed rats, 3 males and 1 female died during the exposure.
Microscopic examination showed an increased centrllobular granular degeneration of the liver and interstitial and tubular changes in the kidneys.
In the second experiment, the animals exposed to vinyl chloride at nominal concentrations of 100 or 200 ppm (152) for 7 hours/day, 5 days/week, for 6 months, included 20-24 male and 24 female rats, 10 male and 8 female guinea pigs, 3 male and 3 female rabbits, and 1 male and 1 female dog .
In addition, eight groups of five male r*ts each were exposed at nominal concentrations of 100 or 200 ppm (152) for 0.5, 1, 2, or 4 hours/day, 5 days/week, for 6 months. For each species and regimen, two control groups carefully matched on the basis of age, condition, and weight were used, one group of colony controls, and the other air-exposed in the chamber on a regimen similar to that of the experimental groups.
Of the 24 rats exposed at 100 ppm for 7 hours/day, 5 males and 1 female died . All racs exposed repeatedly for 7 hours/day shewed slight but significant; increases (?<0.05) in liver weight. Repeated exposure to vinyl chloride at. 200 ppm for 7 hours/day for 6 months resulted in the deaths of 3 of 12 rats . Of the five rata in each "short exposure" group, one, two, one, and one died after exposure for 0.5, 1, 2, and 4 hours/day, respectively. Organ weights were normal In all species, except that liver weights Increased in rats exposed repeatedly for 7 hours/day. At 8 weeks after exposure, male rats continued to have Increased liver weights, but the weights appeared to be returning to normal. Increases in liver weight of rats exposed for 2 or 4 hour3/day were not statistically significant.
All the rats exposed for 0.5 or 1.0 hour/day had normal organ weights compared with those of control rats. Microscopic examination showed liver changes characterized by centrilobular granular degeneration and necrosis with some foamy vacuolization in male rabbits and periportal cellular infiltration in female rabbits.
In the third experiment, 24 male and 24 female rats, 12 male and 12 female guinea pigs, 3 male and 3 female rabbits, and 1 male and 1 female dog were exposed to vinyl chloride at a concentration of 50 ppm for 7 hours/day, 5 days/week, for 6 months . Three additional groups of 10 male rats each were exposed for 1, 2, or 4 hours/day, 5 days/wesk, for 6 months. Matched groups of control animals were again used. Vinyl chloride concentrations in the chamber were determined by micro-Volhard titration. Repeated exposures to vinyl chloride at 50 ppm did not produce toxic signs in any of the animals. A decrease in the kidney weight was observed is the female rats, but it was not attributed to the exposure since it was not observed at higher concentrations.
Animals exposed repeatedly at 100, 200, or 500 ppm were found to have normal biochemical and hematologic values and urinalysis tests . Serum enzyme activities were normal is all dogs, rats, and rabbits. None of the organs examined had macroscopic tissue changes at. any exposure concentration. The authors concluded that repeated exposures f-r 7 hours/day at 100 ppm could cause increased liver weight.
Lester et al  conducted four experiments witn Sherman strain rats. In the first experiment, an unspecified number of rats were exposed in pairs to vinyl chloride at various concentrations for up to 2 hours In an exposure chamber. No control animals were described. In the rats exposed to vinyl chloride at a concentration of 5Z (50,000 ppm; 128 g/cu m ) , the righting reflex was lost; at 6Z (60,000 ppm; 153.6 g/cu m), however, it was said to be still present, but it was absent in rats exposed at 7Z (70,000 ppm; 179.2 g/cu m ) . The corneal reflex disappeared at a vinyl chloride concentration of 10Z (100,000 ppm; 256 g/cu m ) . Tne animals rapidly returned to normal after removal from the chamber. .One rat was killed after exposure to vinyl chloride at 10Z but showed no gross signs of adverse effects. Two rats exposed to vinyl chloride at 15Z were deeply anesthetized within 5 minutes. One rat had effusions of fluid from Che mouth and died cf asphyxia la 42 minutes; autopsy revealed edema and coogesclon of che lungs. The ocher rat remained under deep anesthesia for 2 hours bue recovered promptly when removed from Che exposure.
In Chelr second experiment with rats, Lescer et al  randomly assigned 18 male and 18 female rats co an experimental group and a control group. The experlmenCal animals were exposed Co vinyl chloride aC a concentration of 10Z (reduced co 8Z after 2 days) between 8:30 am and 4:30 pm. Two female raCs and an unspecified number of male rets in the experimental group died early in the experiment and were replaced, A total of three female rats died (days 2, 5,and 14) in the course of vinyl chloride exposure, and only two males survived all 15 day3 of exposure. In addition to mortality, exposure to vinyl chloride at a concentration of 3Z was associated with a failure to gain weight until day 9, followed by weight gain at a slower rate than the controls until the cessaClon of exposure, after which Che rates were equal. Neither grci'3 nor microscopic differences were noted becween experimencal and concrol livers and kidneys at necropsy. Some rats had parasitic liver cysts and focal necroclzlng pneumonia, buC kidneys were wlchln normal llmics of varlabillCy. Microscopic examination of the spleens of experimental rats showed a significantly higher incidence of severe abnormality than was found in controls, although some individual rats in the control group manifested equally severe splenic abnormalities.
Lester et al  performed anocher experimenc to ascertain whether vinyl chloride was a lung irritant. Three female and five male rats, matched with controls, were exposed as before for 8 hours daily for 19 consecutive days Co vinyl chloride at a concentration of 5Z in air. All animals were deprived of food and water while in the exposure chamber. Hemoglobin determinations were made during the exposure period.
On the 20th day, all animals were anesthetized with ether, and blood was drawn by cardiac puncture. The animals were killed by an overdose of ether, and necropsies were performed.
The terminal blood sample was tested for hemoglobin, prothrombin time, hematocrit, red cell, white cell, and differencial white cell counts, and unspecified serum transaminase activities.
Prochrombin time, hematocrit, and the serum transaminase activities were normal for both groups. The experimencal group had a statistically significant increase (PC0.05) in red blood cells and a decrease (P<0.01) in white blood cells. The differential white cell counts of control and experimental groups were not significantly different. The ratio of the weight of the liver to the body weight was significantly elevated (males, P<0.01; females, P<0.001) In the experimental group. The five male experimental animals had thinner coats than normal and scaly calls; all other rats were normal In appearance. One of the experimental males had fibrous pleural adhesions, but these appeared to be old and unrelated to che experimental exposure.
Microscopic examination of all organs and tissues failed to disclose abnormalities other than those in the liver in either group.
There were no differences in intracellular or total fat in the liver, but livers in the experimental group had widespread swelling and vacuolization of cells with compression of the sinusoids. This difference was significant (P<0.001).

# ' - f I
In ha last experiment of the aeries, rats were exposed to vinyl chloride ae a concentration of 2.0Z for 8 hours/day, 5 days/week, for 3 months . Sixty rats weighing about 75 g were separated randomly into two groups, each consisting of 15 males and 15 females. In the week before the rats were exposed to vinyl chloride, they were observed and weighed and blood was taken for hemoglobin determinations. All rats were weighed weekly, and hemoglobin determinations were made monthly. Four control and one experimental animal died in the course of the experiment. After 3 months, all animals were killed for necropsy after blood samples were drawn. The livers and spleens were veighed before being fixed in formalin. No significant differences were noced between the experimental and control body weights, hemoglobin levels, hematocrits, prothrombin times, or white cell monocyte and eosinophil counts. The livers of the experimental animals were significantly heavier (P<0.001) and the spleens significantly lighter (males, P<0.02; females, P<0.05) than in the control group. The experimental rats also had a statistically significant decrease (?<0.01) in white blood cell and neutrophil counts and an increase (?<0.01) in lymphocyte counts, when compared to the controls. Microscopically, the experimental group had fewer signs of kldnr.y damage but more extensive liver damage, as indicated by swelling of cells and compression of sinusoids, than controls. No microscopic differences between the spleens of the two groups were noted.

# In this
1963 paper, Lester and coworkers  concluded that the only suggestion of a specific toxic action of vinyl chloride was the increase in liver weight; the Increase was not only statistically significant, but also of substantial magaitude (30Z heavier than controls). The authors stated that they did not know the significance of the increase in liver weight after exposure to vinyl chloride, nor whether the liver returned -o normal after exposure ceased.
In addition, the authors pointed out the increasing neurologic deficits with increasing concentrations of vinyl chloride, finally terminating in death from respiratory insufficiency at concentrations of 15Z for a single exposure or of 10% for repeated exposures.

# (t>) Vinylldene Chloride
In 1963, Irish , stated that there were at that time essentially ac published data on vinylldene chloride toxicity and summarized dat. from unpublished reports of the Dow Chemical Company. He presented no detailed information on the animals exposed in these studies. Irish concluded that vinylldene chloride produced adverse effects at concentrations below those necessary to produce irritation and below the odor threshold of 500-1,000 ppm. Jaeger et al  estimated Che LC50's for fed and faseed rats exposed Co vinylidene chloride. One group of male Holeroan racs weighing 250-400 g was allowed continuous access Co food; anocher group was fasced for 18 hours before exposure.
Eight groups of fasted racs and six groups of fed rats, each group consisting of five or six animals, were exposed to vinylidene chloride ac various concencracions for 4 hours . The 4-hour LC50 ac 24 hours for the fasCed racs was 600 ppm (2,382 mg/cu m) and Che 24-hour minimum lethal concencracion was 200 ppm (794 mg/cu m ) . The estimated 4-hour LC50 at 24 hours for Che fed rats was 15,000 ppm (59.6 g/cu m), and the minimum lethal concentration for these animals was 10,000 ppm (39.7 g/cu m ) .
The authors  suggested that decreases in glutathione concentration in the livers of fasted rats was a possible explanation for the differences in lethality.
They pointed out that this could be of importance with regard to the occupational risk because of che known circadian pattern of glutathione concentrations in the liver. During the exposures, the animals were checked for any change in weight and activity.

# Siegel ec al
The rats were killed at the end of the exposures, and blood and organs were collected and tested. Macroscopic and microscopic examinations were performed on organs and fixed tissues. Rats exposed at 500 ppm developed nasal irritation (sneezing), did not gain weight normally, and suffered liver cell degeneration. Rats exposed at 200 ppm suffered only slight nasal irritation, and all organ.- were normal on necropsy. No further data were presented by the author.

# Slletchnik and Carlson ri21J published the results of a study to determine Che cardiac sensitizing effects of vinylidene chloride.
Adult male Charles Rivers rats weighing 250-400 g were lightly sedated with 25 mg of sodium pentobarbital/kg 4p, restrained, and then exposed to vinylidene chloride at 25,600 700 ppm (101.6 2.8 g/cu m) for periods of 10 minutes or longer. The rats were pretre; ted with 4 Mg of epinephrine/kg, and the m-fn-fmum amount of epinephrine naces^ary to produce cardiac arrhythmias or demonstrate a difference between pairs of animals was determined.
The exfect of pheno barbital was determined using weight-matched pairs of animals. One animal of each pair was administered phenobarbita1, 50 mg/kg ip, daily for 4 days and exposed to vinylidene chloride 24 hours after che last dose. The pair mate in each case received injections of saline and was similarly exposed to vinylidene chloride.
In rats exposed to air alone, epinephrine at 4 ^g/kg did not elicit any cardiac arrhythmias . The authors stated that vinylidene chloride alone caused sinus bradycardia and such arrhythmias as A-V-block, multiple continuous premature ventricular contractions, and ventricular fibrillation; they presented no further Information. Epinephrine at doses as low as 0.5 Mg/kg elicited cardiac arrhythmias in 29 animals exposed to vinylldene chloride.
Sensitivity to epinephrine Increased with increasing length of exposure to vinylldene chloride. The Increased sensitivity to epinephrine was reversible, since 5 minutes after removal from exposure the animals were again able to tolerate high doses of epinephrine without showing arrhythmias.
Premature ventricular contractions were seen in animals pretreated with phenobarbital, exposed to vinylldene chloride, and challenged with epinephrine . No arrhythmias were seen in the saline-traated animals challenged with the same amount of epinephrine.
Arrythmias were produced in the phenobarbital-created animals at a lower epinephrine dose and a shorter exposure to vlnylidene chloride.
The authors  concluded that the phenobarbital probably Induced vlnylidene chloride metabolizing hepatic enzymes and that a metabolite caused the cardlotoxlc effects. They further stated that, since the adrenal gland in humans may release up to 4 ;ig/kg/mlnute of adrenalin during stress, workers exposed to high concentrations of vinylldene chloride may be under a risk of these cardlotoxlc events. Immediately after each experiment, the animals were killed and necropsies were performed .

# Prendergast et al  conducted a series of
To estimate the effects of vinylldene chloride inhalation, the authors measured liver alkaline phosphatase, SGPT, serum urea nitrogen, and liver lipid content, and made hematologic determinations.
In the control populations, 7/304 rats, 2/314 guinea pigs, 2/48 rabbits, and 1/57 monkeys died prematurely.
Animals repeatedly exposed to vinylldene chloride at 395 mg/cu m (99.5 ppm) showed no microscopic tissue changes relatable to the exposure when compared with control tissues . Gross examination of tissues showed no changes la any animala except for one rat that had a gelatinous substance on Its kidney and bloody urine In the bladder.
The microscopic examination showed only nonspecific respiratory inflammation, which the authors considered not to be the result of vlnylldene chloride exposure. They did not give any reasons for this conclusion.
None of the repeatedly exposed animals died during the exposure, and only rabbits and monkeys lost weight.
Of the animals exposed continuously at 189 mg/cu m (47.6 ppm), seven guinea pigs died between days 4 and 9, and three monkeys died, one each on days 26, 60, and 64 .
Gross examination showed mottled livers in a majority of the experimental animals. Exposed rabbits, dogs, and monkeys lost weight, while rats and guinea pigs gained weight during the exposure. There were Increases in liver alkaline phosphatase and SGPT activity in rats and guinea pigs, but there were no significant changes in any other biochemical parameters. Two rats also showed Increases of 202 and 34.42 in liver lipid content.
Serum urea nitrogen concentrations in exposed rats were comparable with those of control rats. Three of the 15 guinea pig3 that were exposed at 101 mg/cu m '23.5 ppm) died between the 3^d and 6th exposure days, and 2 of the 3 monkeys exposed at 101 mg/cu m died, 1 on day 39 and the other on day 47.
White or bluish-gray spots and nodules were visible on the lungs of several guinea pigs and rats. Serum urea nitrogen concentrations of exposed guinea pigs were comparable with those of the control group. The appearance and demeanor of the rats ingesting vlnylldene chloride were not different from those of controls throughout-the atudy . Body weight gains and food and water consumption were similar for experimental and control animals. No compound-related abnormalities were m :ed In the results of hematologic studies, urinalyses, or serum chemistry analysas. No significant differences were noted in mean organ weights or organ *"o body weight ratios.

# Gross
and microscopic examinations revealed occasional statistical differences between exposed and control animals .
The differences considered compound-related were fatty changes or fatty degeneration of the liver in female rats in the 50, 100, and 200 ppm groups and in male rats ia the 200-ppm group. Although the incidence of these liver lesions in the males of the 100-ppm group was not significantly increased, it was higher than that in the controls. Centrllobular atrophy and periportal hypertrophy were also seen in the liver of the exposed animal. No target organ was found that showed a tumorlgenic effect which was considered compound-related, and the total tumor incidence in male and female rats In the various exposure groups was not considered different from that in the controls. Humiston et al  concluded chat the only compound-related deviations in these rats were the fatty changes or fatty degenerations of the liver. All other statistically significant deviations observed were considered to be within the normal variation encountered in lifetime studies with this strain of rat. They also concluded that these results did not indicate an "oncogenic effect for vlnylldene chloride ingested by rats." The data indicate that if a carcinogenic potential for rats exists for vinvlidene chloride, these cumulative doses muat be lower than that necessary to promote the expression of that potential. Jaeger et al  gave single doses of vlnylldene chloride dissolved in corn oil by stomach tube to lightly ether-anesthetized male Holtzman rats weighing 250-350 g. The rats were fasted for 4 hours before they received the vlnylldene chloride. Anesthetized control rats received corn oil only. Some of the experimental rats were given ip injections of sodium phenobarbital (30 mg/kg) to aid in measuring the time-response relationship for vlnylldene chloride.
This was indicated by the time between loss and recovery of the righting reflex. Three spontaneous rlghtlngs within a minute was considered evidence that the reflex had returned.
The liver glucose-6-phosphatase activity, serum alanine-alpha-ketoglutarate transaminase activity, liver triglyceride values, and the phenobarbital sleeping time were determined at different times after the animals received doses of vlnylldene chloride and were used as indices of liver damage. The rats were killed at intervals up to 24 hours after they were given the vlnylldene chloride or corn oil, and their blood was collected for preparation of serum. The livers were removed and used Co make hoaogenates for biochemical assays.
The phenobarbital sleeping time increased significantly (P<0.05) within 2-4 hours in rats given 400 mg/kg of vinylidene chloride, and Che naxlnrnm increase was observed aC 12-16 hours, alchough there were no statistical differences between the sleeping times at In the same study, Jenkins and associates  observed the effects of vinyiidene chloride on 9-co 11-week-old male and female rats given single oral doses of 400 mg/kg. They also studied the effects of vinylidene chloride on 21-to 24-week-old male and female rats given single oral doses of 200 mg/kg.
Liver and plasma enzyme activities were measured 20 hours after oral administration The older female rats showed a greater increase in liver glucose-6-phosphatase activity than the older male rats, and both groups of females had increased liver alkaline phosphatase activity in comparison with their respective male counterparts. From these observations, the authors concluded that female racs were more susceptible to the hepatotoxlc effects of vinylidene chloride than male rats. Leong and Torkelson  conducted two studies of the effects of inhaled vinyl bromide (99.72 pure) on various animal species, including rats, rabbits, and monkeys.
The impurities in the vinyl bromide included a polymerization inhibitor (paramethoxy phenol, 0.1Z), ethylene oxide (0.12Z), vinyl chloride (0.06Z), and traces of ethyl bromide, methylene chloride, acetylene, and various aldehydes. The first study involved exposing four groups of five male Wistar rats each to vinyl bromide at 10,000 ppm (43.8 g/cu m) in a 160-liter stainless steel chamber for 7 hours/day, 5 days/week, for either 3 days or, ', 2, or 4 weeks. Concentrations of vinyl bromide in the chamber were determined by infrared spectroscopy. Two control groups were exposed to room air. Immediately after the exposure, the surviving animals were killed, and macroscopic and microscopic examinations were performed on their organs and on fixed tissue specimens.
The rats exposed to vinyl bromide at 10,000 ppm became hypoactive during the 7-hour exposure period . They seemed drowsy after 1 hour of the first exposure and looked "sluggish" by he 13th exposure. The control animals remained active throughout the exposure period.
Exposed animals showed a significantly lower (P<0.05) weigh: gain than controls between the 15th and 20th days of exposure, and the differince was greater (?<0.01) after the 20th exposure. Gross examination of killed animals showed multifocal gray areas in the lungs, but the authors stated chat no "compound related" tissue changes were observed microscopically.
In Che second study, 2 groups of animals each consisting of 60 Charles River rats 6 New Zealand white rabbits, and 6 cynomologus monkeys, all equally divided according to sex, were exposed to vinyl bromide at 25C or 500 ppm (1,095 or 2,190 mg/cu m) for 6 hours/day, 5 days/week, for 6 months . A third group of 30 male and 30 female rats, 3 male and 3 female rabbits, and 4 female and 2 male monkeys was exposed to filtered room air. The experiments were conducted in the evening during the first 20 weeks of exposure and then were changed to dayClme. The auChor3 did noc state whether the concurrent control animals were also switched to a daytime schedule. Vinyl bromide concentrations In the chamber were monitored by gas chromatography. Gross and microscopic examinations were performed on organs and fixed tissue of exposed animals at the end of the experiment. The animals exposed for 6 months were observed for changes In activity, body weight, indications of respiratory distress, eye and nasal irritation, and skin condition.
Hematologic tests were performed on rats, rabbles, and monkeys in the control and 500-ppm groups prior to exposure and after 2, 10, and 24 weeks of exposure. All monkeys were examined for nonvolatile bromide in whole blood at the end of weeks 1, 2, 4, 3, 16, and 26.

# AC the end of Che 6 monChs of exposure*, all Che animals exposed Co vinyl bromide ac 250 or 500 ppm showed weight increases aC rates comparable with controls ,
Only rats had a decrease in mean weight when the exposure schedule was changed from evening to daytime during the 20th week of exposure. Microscopic examination of major organs of all groups and species showed no changes that resulted from exposure to vinyl bromide.
Analysis of blood showed elevated concentrations of bromide in all exposed animals, with monkeys chac had been exposed at 250 and 500 ppm having Che highesC levels.
No statistically significant changes were observed in the ocher measurements.
In the same report, Leong and Torkelson  summarized the results from unpublished data on the effects of vinyl bromide on rats.
An raspecified number of rats was exposed to vinyl bromide at nominal concentrations of 100.000 (437,600 mg/cu m), 50,000 (218,800 mg/cu m ) , or 25,000 ppm (109,400 ng/cu m) for 1.5 and 7 hours. Two weeks after exposure to vinyl bromide at 25.000 or 50,000 ppm, the rats that survived were killed and examined for microscopic tissue changes.
Exposure at 100,000 ppm caused deep anesthesia and death within 15 minutes . None of the rats exposed at 50,000 ppm for 1.5 hours died, but an unspecified number of deaths occurred during the 7-hour exposure. Within 25 minutes, the rats became unconscious.
Vinyl bromide at 25,000 ppm anesthetized the rats, but they recovered rapidly when removed from exposure. Microscopic examination of tissues showed slight to moderate liver and kidney damage in rats exposed aC 50,000 ppm. . Examination of tissues from rats exposed at 25,000 ppm showed no abnormalities.

# Leong and Torkelson  also gave male rats a 5OS solution of vinyl bromide in corn oil by oral intubation to determine the LD50.
They reported an LD50 of approximately 500 mg/kg but presented no supportive data. They also reported that vinyl bromide was irritating to the eyes but not to the skin of rabbits; data were not presented to support these findings.

# '(d) Vinyl Fluoride
In a book on the toxicity of anesthetics [1281, Clayton reported that a mixture of 800,000 ppm (1,504 g/cu m) of vinyl fluoride in oxygen was not lethal for rats exposed Co ic for 12.5 hours. He also stated chac unpublished daca. of Limperos (no furcher identification given) showed chat male and female rats exposed to vinyl fluoride at concentrations of 100,000 ppm (188 g/cu m) for 7 hours/day, 5 days/week, for 6 weeks gained weight normally, exhibited no behavioral changes, had no fatalities, and had no cissue changes as evaluaced by microscopic examlnaCion.
Claycon did not supply decails of Chese experiments.
In 1950, Lester and Greenberg  reported Che effeces of single exposures Co vinyl fluoride on adult white rats. Ra.Cs were exposed for 30 minuces aC concenCraCions ranging from 20 co 80% (200,000 to 800,000 ppm; 376 to 1,504 g/cu m) in an 11-liter glass chamber for 30 minutes. The rata were cesced for any abnormalities In Che poscural, righting, and corneal reflexes afcer Che exposure. AC Che 30Z (300,000 ppm; 564 g/cu m) concentration, Che racs exhibited "hindleg lnscabilicy" which Che auchors considered a sign of "slighc intoxication" . Ac 80Z, Che raCs experienced difficulcy in breaching buC recovered afCer a 1-mtnuce exposure to room air.
Postural and righting reflexes were lost between 50 and 60Z and beCween 60 and 70%, respeccively. Loss of Che poscural re fle x was also evidenc in racs exposed Co vinyl fluoride ac 80Z fo r 12.5 hours, buC these ra ts also regained Che reflex es soon a fte r breathing room air.
Results of an investigation on repeated exposures of rats to v-'-ryl fluoride were summarized in a technical report from E I du Pont de Nemours and Company . An unspecified number of rats were exposed to vinyl fluoride at a concentration of 100,000 ppm for 7 hours/day, 5 days/week, for a total of 30 exposures.
There were no differences in the rate of weight gain, in the results of necropsies, of microscopic examinations of fixed tissues, of organ weighcs, or of clinical observadons. It was concluded thac vinyl fluoride did noc conscitute "much of" an inhalation hazard.
However, the technical report did not present any daca for evaluation.

# (e) Vinylidene Fluoride
In a book on che toxicity of anesthetics . Clayton reported thac a mixture of 800,000 ppm (2,096 g/cu m) '>->f vinylidene fluoride in oxygen was not lethal to rats exposed to it for 19 hours.
No experimental details or data were offered Co support this statement.

# Lester and Greenberg
, in 1950, reported the effects of inhaled vinylidene fluoride on an unspecified number of adult white rats.
The rats were exposed to vinylidene fluoride at concentrations.ranging from 10Z Co 80Z (100,000 Co 800,000 ppm; 262 Co 2,096 g/cu m) in an 11-liter glass chamber for 30 minutes.
After the rats were removed from the chamber, their postural, righting, and corneal reflexes were tested.
The rats exposed to vinylidene fluoride at 10Z-80Z for 30 minutes lost none of the reflexes tested, but those exposed at concentrations of 40Z (400,000 ppm; 1,048 g/cu m) or higher showed slight intoxication, which was manifested at 80Z by the development of an unsteady gait without loss of the postural reflex . Rats exposed at 80Z for 19 hours showed no progressive signs of intoxication, and autopsies showed no evidence of pulmonary irritation.

# Carpenter et al [1181 reporced che effeccs of short-Cerm scacic iuhalacion exposures of Sherman albino raCs weighing between 100 and 150 g Co vinylidene fluoride.
The auchors reported that exposure to vinylidene fluoride at a concentration of 128,000 ppm (335.'+ g/cu m) for 4 hours was sufficient to kill two to four of the six test animals.

# From this observation, they concluded that vinylit'ene fluoride was slightly hazardous to rats.
No further iaforaation w*s presented.
Burgison et al  studied the myocardial sensitizing properties of viaylidene fluoride in eight dogs and tvo cats.
The animals vere first injected with epinephrine and then exposed by inhalation to vinylidene fluoride at 250,000-500,000 ppm (655-1,310 g/cu m) for 5-15 minute.-which time the epinephrine injection vas repeated.
ECG's, lead II, of h animal were recorded.
None of the animals developed myocardial sensitization to epinephrine.

# (f) Summary
The results of these studies show that each of the vinyl halides is capable of causing CNS effects.
Changes in liver function and structure were also observed in some experiments. The adverse effects noted after exposure were similar to Chose noted in worker populations exposed to Che vinyl halides.  152) in drinking water was also given to mice, rats, and rabbits exposed at 50 and 500 ppm, at 2,500 ppm (6,400 mg/cu m), and at 2,500 ppm, respeccively.

# TeraCogenicity and Effeccs on Reproduction
The auchors seated that ethanol altered the metabolism of vinyl chloride by blocking the primary and most rapid metabolic pathway. Ethanol with vinyl chloride at concentrations of 50 or 500 ppm decreased food consumption, weight gain, and liver weight In mice.
In animals exposed to vinyl chloride at 50 and 500 ppm with 15Z ethanol, weight gain and liver weight were lower than In those exposed to vinyl chloride alone.
In rats exposed at 500 ppm, there was a significant decrease (P<0.05) in maternal weight gain during days 6-21 of gestation. At 2.500 ppm, the liver weight of the rats was increased significantly (P<0.05) at day 21 of gestation. There was also a significant difference in food consumption but no difference between exposed and control animals in weight gain.
Rabbit3 showed a significantly decreased (P<0.05) food consumption ratt at 500 ppm, but no effects were noted at 2,500 ppm. Giving ethanol in addition to exposure to vinyl chloride at 2,500 ppm significantly increased the effects on rabbits and rats. Maternal mortality in mice exposed at 500 ppm was significantly increased (P<0.05) over concurrent control mortality. Also, there was an increase (?<0.05) in the incidence of resorptions, a decrease (P<0.05) In fetal body weight, and a reduction (P<0.05) in litter sl2 e.
No significant effects other than an Increase in crown-rump length (P. chloride at 500 ppm differed significantly (P<0.05) from concurrent control fetuses in incidences of unfused sternebrae, delays in ossification of the sternebrae, and delays in ossification of bones of the skull. The addition of 15Z ethanol to the drinking water of the dams significantly increased (P<0.05) the incidence of skeletal anomalies In the fetuses of these mice, including anomalies in the sternebrae, vertebrae, and skull at 50 and 500 ppm, and In the ribs as well at 500 ppm.
There was only one maternal death In rats exposed to vinyl chloride at 2.500 ppm (6,400 mg/cu o) . The only significant (P<0.05) fetal effects observed after exposure at 500 ppm (1,280 mg/cu m) were a reduction of the body weights, an increase in crown-rump length, and a significant increase (?<0.05) in the number of lumbar spur3 . Examination of the fetuses for soft tissue anomalies showed a significant increase (P< .05) in the incidence of dilated ureters at 2,500 ppm.
Skeletal anomalies at 2,500 ppm included significant decreases (?<0.05) in the incidence of unfused sternebrae and delayed skull ossifications.
One of the seven rabbits exposed to vinyl chloride at 2,500 ppm died during the 'xperiment . A significant decrease (P<0.05) was seen in the number of live fetuses/litter at 5C0 ppm, but not at 2,500 ppm. No other gross differences were observed.
The incidence of delayed ossification of the fifth sternebra was significantly increased (P<0.05) at 500 ppm. No other skeletal or soft tissue anomalies were seen in rabbits.

# John
et al  concluded that exposure to vinyl chloride at concentrations causing some maternal toxicity did not cause teratogenic effects on or embryonal or fetal toxicity in mice, rats, or rabbits. However, it is apparent that adverse effects did occur on the fetuses of the mice exposed at 500 ppm (1,280 mg/cu m) (sternebrae and skull anomalies) and in the ftusea of rats exposed at 2,500 ppm (6,400 mg/cu m) (dilated ureters).

# The authors'
determination that these effects did cot substantiate an embryotoxlc or fetotoxlc potential and were secondary to the maternal toxicity were not supported by clinical tests.
The authors regarded the changes as minor skeletal and soft tissue variations and concluded that the incidence of "major" skeletal or soft tissue malformations was not significantly greater in exposed animals than in the control groups.
In mice exposed at 500 ppm, there were significant increases in the incidence of resorptions and decreases in the fetal body weight and in litter size.
In rats exposed at 500 ppm, there was a significant decrease in the fetal body weight and an increase in crownrump length, and, in rabbits exposed at 500 ppm.
there was a significant decrease in the number of live fetuses/litter.
In both rats and rabbits, however, there was not a corresponding adverse effect at the 2,500-ppm exposure concentration.
Ethanol at 15% in the drinking water enhanced the effects of inhaled vinyl chloride, but the authors concludcd that maternal toxicity was more enhanced than was fetotoxicity. Twenty-five 3-month-old male albino Wistar rats were exposed to vinyl chloride at a concentration of 30,000 ppm (76.8 g/cu m) for 4 hours/day, 5 days/week, for 1 year; 25 similar rats served as controls. Rats were killed at unspecified intervals, and their tissues were examined microscopically.
These exposed animals wre apparently the same ones used in the study by Viola  that was discussed in Animal Toxicity.
Skin tumors, the most frequent types, were found in 65-70% of the animals after 10 months of exposure . These tumors developed in the paraauricular region, and most were epidermoid carcinomas. The authors also found two mucoepidermoid carcinomas and one papilloma of the skin.
In addition to the tumors, they found warty subauricular grcwtns and papillary epithelial proliferation with progressive increases in the thickness of the epidermis in a few rats.
In four rats, adenocarcinomas of the respiratory tract were found, and in one rat an epidermoid tumor was found. The authors also found osteochondromas in the metacarpal and metatarsal regions of all four limbs in five rats.
None of the control rats developed any of the types of tumors observed in the exposed animals.
In addition to the carcinomas, Viola et al      Adapted fromM altoni  K  The Sprague-Dawley rats exposed at 6,000 or 10,000 ppm (15.4 or 25.6 g/cu m) had been followed for only 59 weeks at the time of this report . Zymbal gland carcinoma was observed in some exposed animals, but no nephroblastoma or angiosarcoma of the liver was found. The preliminary results shown in Table III-6 suggest that exposure at 6,000 ppm for 100 hours during 25 weeks has a lower carcinogenic potential than exposure at 10,000 ppm on the same schedule or at 6,000 ppm for 100 hours during 5 weeks. These findings indicate that the severity cf exposure was :r.ore important than the total mass to which the rats were exposed 3nd suggest that metabolic and excretory processes may affect Lhe carcinogenic potential; however, more complete data are needed to substantiate thij inference.
The offspring of pregnant rats exposed to vinyl chloride at concentrations of 6,000 or 10,000 ppm (15.4 and 25.6 g/cu m) for 4 hours/day fror.i the 12th to the ISth day of gestation developed tumors . in 54 offspring from dams exposed at 10,000 ppm, the following tumors developed: 3 Zymbal gland carcinomas, 1 nephroblastoma, 1 subcutaneous angiosarcoma, 1 angiosarcoma of the leg, 1 Zymbal gland fibrosarcoma, and 1 ovarian leiomyosarcoma. In the 32 offspring from dams exposed at 6,00u ppm, 1 Zymbal gland carcinoma, 1 subcutaneous angiosarcoma, 1 intraabdominal' angiosarcoma, 1 Zymbal gland adenoma, 1 skin carcinoma, 1 subcutaneous fibrosarcoma, and 1 mammary carcinoma were observed following a 143-week observation period. Unfortunately, details of this experiment, including reproduction indices and signs of toxicity to the dams, were not reported. The author's suggestion that the results of this experiment indicate that vinyl chloride has a transplacental effect is reasonable, but it cannot be thoroughly evaluated without more detailed information chan was presented.
The experiments outlined by Maltoni and coworkers  were well designed. The presentation of data in these papers, however, was often confusing, and the information contained in the tables frequently disagreed with that presented in the text. It was often unclear whether they were presenting the number of animals with tumors or simply the number of tumors. Furthermore, preliminary data on tumors when the followup period was less than the probable latent period are of little value. Maltoni's observations and data do show that vinyl chloride induces various tumors in a variety of rodents, and that angiosarcoma of the liver is a characteristic lesion induced by vinyl chloride. The data also indicate chat chere are strain and species differences in the magnitude of the tumorigenic response elicited by exposure to vinyl chloride.
Lee et al in 1977  and in 1978  reported results of inhalation studies on 2-month-old albino CD-I mice and CD rats exposed to vinyl chloride (99.8% pure, Matheson Gas Products) at 50, 250, or 1,000 ppm (128, C40, or 2,560 mg/cu m). Groups of 36 females and 36 males of each species were exposed for 6 hours/day, 5 days/week, for 12 months. Two similar control groups were exposed to uncontaminated air. Throughout the exposure period, the animals were observed for changes in weight gain, food consumption, and mortality. Four animals of each species and sex exposed at each concentration were killed at the end of exposure months 1, 2, 3, and 9. Their organs were examined grossly and tissues were ixed and examined microscopically. Additional laboratory determinations, including hematologic and blood chemistry examinations, cytogenetic analyses of bone marrow cultures, pulmonary macrophage counts, DNA synthesis assays, and urinary analyses were performed at the interim examinations and at the termination of the experiment at 12 months. Roentgenograms of the limbs of those animals exposed for the longest periods were made also.
Of the mice exposed at 1,000 ppm (2,560 mg/cu tn), two males and one female died between the 3rd and 9th days of exposure . Between the 6th and 9th months, 13 male and 21 female nice died or wore removed from exposure because their health had deteriorated. By the end of the 9th month, all animals had been removed from exposure.
By the 6th month, the most evident effects on exposed mice were rough hair coat, lethargy, loss of appetite, and rapid weight loss . Additionally, abdominal distention and external tumor masses, such as mammary tumors in females, were noticeable between the 7th and 9th months, During the first 8 months of the experiment, exposed and nonexposed mice showed comparable weight gains; however, the exposed group showed a decline in weight by the 9th month. Also, by the 9th month of exposure, one female and most of the male mice had elevated pulmonary macrophage counts (from pulmonary washings) and had developed bronchioloalveolar adenomas.
Microscopic examination of hepatic and renal tissues from one female and two male mice that died after being exposed at 1,000 ppm for 3-9 cays revealed a number of lesions characterized by acute toxic hepatitis, focal to marked congestion, diffuse coagulation necrosis of hepatocytes in the centrilobular area, and tubular necrosis in the renal cortex . During the 8th and 9th months of exposure, mitotic figures were observed in mouse livers, but were not seen in livers of mice killed at other times.
Bronchioloalveolar adenomas were observed in 48 of the 72 mice exposed at 1,000 ppm, whereas only 1 of the 72 control mice developed this tumor . These tumors were first noted during the 2nd month of exposure to vinyl chloride and in the 9th month in the control. Mammary tumors. first observed in exposed female mice during the 6th and 7th months, included adenocarcinoma and carcinoma of squamous cells and of anaplastic ceils; metastasis wa3 prevalent to the lungs and pleurae. None of the control mice developed mammary tumors. Angiosarcoma of the liver was found in 31 exposed mice, being observed first during the 6th month of exposure. In addition, angiosarcoma was occasionally seen in the mammary glands, heart, gastrointestinal tract, pancreas, kidneys, epididymis, testis, mesenteric lymph nodes, and skeletal muscles. Angiosarcoma of the liver was more prevalent in females than in males. Two male and three female mice developed malignant lymphoma between the 6th and 9th months of exposure, whereas none were seen in controls.
All female mice exposed to vinyl chloride at 250 ppn (640 mg/cu m) died or had to be removed from exposure by the 9th month because of morbidity , Male mice were more resistant to the toxic actions of vinyl chloride than female mice, and some survived the 12-month exposures. No differences in body weight between> the-exposed and control mice were noted. One female mouse examined after the 9th month of exposure showed an increased pulmonary macrophage count. Bronchioloalveolar adenomas were first detected in exposed mice during the 2nd month; a total of 48, 22, and 12 mice exposed at 1,000, 250, or 50 ppm, respectively, developed this tumor. Only one control male mouse developed bronchioalveolar adenoma during the 9th month. Female mice also developed mammary tumors consisting of adenocarcinomas and squamous and anaplastic cell carcinomas, Of the mice exposed at 250 ppm, 23 (16 females) developed liver angiosarcomas, which were first evident after the 6th month of exposure. During the 9th month of exposure, malignant lymphomas developed in two female mice.
Between the 6th and 12th months of exposure to vinyl chloride at 50 ppm (128 mg/cu m), 6 male and 14 female mice either died or were removed from exposure because of deteriorating health . Throughout the exposure period, the body weights of exposed mice were comparable with those of control mice. Microscopic examination also showed mitotic figures in the liver during the 8th and 3th months of exposure. A significant increase in DNA synthesis, as measured by incorporation of 14C-thymidine, was detected in the livers of male mice exposed at 50 ppm for 11 months. There was no increase in the number of mitotic figures in the livers of these mice. During the 12th month of exposure, one of two surviving male mice had an elevated pulmonary macrophage count.
Bronchioloalveolar adenomas were seen in 12 mice exposed at 50 ppm (128 mg/cu m) . Three male mice developed angiosarcoma of the liver. Mammary tumors were observed in nine of the exposed mice, the first at 7 months. One female mouse developed a malignant lymphoma during the 6th month and another developed a hemangioma in the mediastinum. Control mice developed none of the tumors discussed.
From the effects observed in nice exposed to vinyl chloride at 1,000, 250, and 50 ppm (2,560, 640, and 128 mg/cu m), the authors  concluded that weight loss, mortality, and tumor incidence were dependent on the concentration of vinyl chloride and the duration of exposure. Vinyl chloride inhaled at 50-1,000 ppm for 6 hours/da^, 5 days/week, was found to be highly carcinogenic in mice. The duration of exposure before tumors were observed varied from 2 months for bronchioloalveolar adenomas to 6 months for mammary gland tumors and for angiosarcoma. The latter tumors occurred first in the liver and then in other organs. Angiosarcoma was more prevlent in female mice than in male mice exposed at 250 or 1,000 ppm. It was found mostly In the livers of mice exposed to vinyl chloride for -7-9 months. Mammary gland tumors were considered to be a complex type and were characterized by anaplastic and squamous cell metaplasia during the early stages of their development. Metastasis of anaplastic and squamous cell carcinomas to the lungs was common, \ronchloalveolar adenomas occurred in both male and female mice at a very young age and after a short period of exposure. More deaths and tumors were observed at 250 and 1,000 ppm than at 50 ppm. Other types of tumors observed in the exposed mice were hepatic cell carcinomas, renal adenomas, and k.eratoacanthomas of the skin.
In the second part of the experiment, Lee et al  exposed 72 adult male and female rats to vinyl chloride at concentrations of 50, 250, or 1,000 ppm (128, 640, or 2,560 mg/cu m) for up to 12 months, using the same exposure schedule previously reported. During the first 7 months of exposure, no remarkable adverse effects were seen in any rats. However, of the rats .exposed at 1,000 ppm, 8 male and 13 female rats either died or were removed from exposure during the 8th-12th months. None of the controls died during Che experiment. After the 4th week of exposure, female rats had gained less weight thar the controls. During the 9th month, the first cases of angiosarcoma of the liver were observed in four rats. By the end of the study, 22 rats had developed angiosarcoma of the liver, more females than males having the tumors. Of the 22 rats with angiosarcoma of the liver, 13 also developed angiosarcoma of the lungs. Additional angiosarcoma was found in the omentum of one rat, and two rats had hemangiomas in the adrenal glands.
Four maie and 10 female rats died or were removed from exposure during months 8-12 of exposure to vinyl chloride at 250 ppm (640 mg/cu m) . None of the control rats died during the exposure period. Body weight gain by exposed rats was comparable with that by the controls. Two rats developed angiosarcoma of the liver during the 9th month of exposure. By the end of the 12th month of exposure, 13 rats, 10 of them females, had developed angiosarcoma of the liver. Of the 10 female rats, 3 also had angiosarcoma of the lur.g3; angiosarcoma of the cmentum or mesentery was also found in two rats. None of the control rats had angiosarcoma.
During months 8-12 of exposure to vinyl chloride at 50 ppm (128 mg/cu m), two female rats died , Exposed and control rats had comparable body weight gain.
Subcutaneous angiosarcoma was found in two rats. No angiosarcoma of the liver, lungs, or other organs was observed in any of the rats exposed at 50 ppm, nor did any of the control rats develop angiosarcoma.
None of the laboratory tests performed on rats exposed to vinyl chloride at 1,000, 250, or 50 ppm showed any persistent changes . The authors indicated that female rats were more sensitive to the toxic action of vinyl chloride and that more females than males died between the 8th and 10th months of exposure. In general, rats were considered more resistant to both the carcinogenic and toxic actions of vinyl chloride than mice.
The experiments by Lee et al  indicate that vinyl chloride is carcinogenic in mice and rats, and that mice are more susceptible to its carcinogenic effects than rats. Since the experiments were conducted at various exposure concentrations, it can be concluded that the different responses probably were a function of species-specific factors and were not caused by structural differences between the species such as lung surface area. Since there are differences between species, there may be differences between strains within a species also. Such a situation would account for the apparent inconsistencies between the reports of various authors using different trains of the same species. This confounding factor must be considered in any attempt to extrapolate the results from animal experiments to human exposure situations.
Maltoni et al , in 1975, gave vinyl chloride by gastric intubation to 13-week-old Sprague-Dawley rats. Groups of 40 male and 40 female rats were given 50.00, 16.65, or 3.33 mg/kg of vinyl chloride dissolved in olive oil 5 times/week for 52 weeks. A fourth group of rats, 40 males and 40 females, was given olive oil without vinyl chloride as the control group. The number of tumors that developed in the rats of each group were recorded.
At 50 weeks, no tumors were apparent in the rats given the lowest dose (3.33 mg/kg), but one of the male rats given 16.65 mg/kg developed angiosarcoma of the liver, which was identified during the 49th 'eek of the experiment, and a female rat given 5C mg/kg had angiosarcoma in the thymus.
In an update of this study , Maltoni  in 1976 reported that after 34 weeks the rats receiving the 50.00-mg/kg dose had developed eight cases of angiosarcoma of the liver and four other tumors. At 16.65 mg,kg, angiosarcoma of the liver had developed in five rats, a Zymbal gland carcir.coa in one, and a nephroblastoma in one. No tumors were observed in animals given 3.33 mg/kg.
(b) Vinvlidene Chloride Lee et al in 1976  ana 1978  described the effects of inhaled vinylidene chloride (99Z pure, Aldrich Co.) o p 36 male and on 36 female 2xonth-old albino CD-I mice and 36 male and 36 female albino CD rats exposed at 55 ppm (218.4 mg/cu m) for 6 hours/day, 5 days/week, for 12 months. Vapor concentrations were monitored by gas-liquid chromatography during the exposures. Control animals were exposed to uncontaminated air. Organs and tissues from rats and mice were examined for microscopic changes at Che end of the 1st, 2nd, 3rd, 6th, 9th, and 12th months of exposure.
Two male mice died on the 13th day of exposure and were replaced in the study with healthy males . Microscopic examination showed a number of lesions in the two dead male mice. They were characterized by acute toxic hepatitis, focal to marked congestion, marked diffuse coagulation necrosis of 'nepatocytes, and narked tubular necrosis in the renal cortex. No additional deaths occurred, nor did any control animals die. Six mice were observed to have small nodules of bronchioalveolar adenoma by the 12th month of exposure; only one control male mouse developed a bronchioalveolar adenoma. The mice removed from exposure after the 9th month (two males) and 10th month (one female) had developed angiosarcoma in the liver. Neither mammary tumors nor malignant lymphomas were found.
Aftar exposures at 55 ppm (218.4 mg/cu m), fatty changes were seen ir the livers of rats . Two rats had also developed extrahepatic angiosarcoma (mesenteric lymph node, subcutaneous) by the end of the exposure period. None of the control rats developed liver tumors of any type.
In 1977, Maltoni et al  reported the research plan and preliminary results for a series of experiments with vinylidene chloride. Groups of 60-120 Sprague-Dawley rat3 were exposed by inhalation to vinylidene chloride at concentrations of 10, 25, 50, ICC, or 150 ppm (39-7, 99.3, 198.5, 397, or 595.5 mg/cu m) far 4 nours/day, 4-5 days/week, for 12 aonths. An increased incidence of mammary tumors was noted in the exposed animals; however, there was no apparent dose-related effect. One Zymbal gland carcinoma was found in an animal exposed at 100 ppm.
Swiss mice were, exposed to vinylidene chloride at 10 and 25 ppm (39.7 and 99.3 mg/cu m) on the same schedule . Exposure of these mice at concentrations of 50 ppm or higher produced an unacceptably high mortality in the study population within 4 days. Adenocarcinoma of the kidneys w?s observed in two groups exposed at 25 ppm with an incidence of 8" and 4". Ncne of these tumors were observed in arinals exposed at 10 ppm or in control animals.
Sprague-Dawley rats were given vinylidene chloride in olive oil by gavage at dose rates of 0.5, 5, 10, and 20 mg/kg/day, 4-5 days/week for 52 weeks . No increase in mammary tumors was observed; one rat developed a Zymbal gland carcinoma at the 10-mg/kg dose.
Although Lee et al  had reported that their -lice were exposed at 55 ppm of vinylidene chloride, Maltoni et al  found that exposure of his mice at concentrations of 50 ppm or more produced unacceptable mortalities within 4 days. Maltoni's mice exposed at 25 ppm of vinylidene chloride for 12 months did not develop angiosarcoma of the liver, whereas Lee et al stated that 3 of 72 mice exposed at 55 ppm for 12 months did develop this tumor. The discrepancies in the results of these studies may be caused by differences in the strains of animals used, and has been discussed previously. Maltoni et al  stated that neither inhalation exposures nor ingestion experiments with rats demonstrated a specific carcinogenic effect from vinylidene chloride such as had been demonstrated for vinyl chloride (Zymbal gland carcinoma and angiosarcoma of the liver). It should be remembered that these data are preliminary for rats, and that a longer followup period may reveal that these tumor types will be formed. The author also stated that mice were susceptible to a specific carcinogenic effect, adenocarcinoma of the kidney, and that this species difference probably resulted from a more "favorable metabolic condition for expressing the oncogenic potentiality." The authors pointed out that further research using different species was necessary to evaluate this hypothesis. A comparison of the frequencies of angiosarcomas at these exposure concentrations in this experiment  with the frequencies of angiosarcoma observed in rats exposed to vinyl chloride after a similar followup period  suggests that vinyl bromide may be more effective in inducing this tumor than vinyl chloride.
Further comparison with the vinyl chloride data indicates that after a longer observation period, angiosarcoma will be seen in those rats exposed to vinyl bromide at lower concentrations.

# (d) Vinyl Fluoride and Vinylidene Fluoride
No reports examining the carcinogenic potential of vinyl fluoride or vinylidene fluoride have been located.

# Each o the vtayl halides has been shown to be mutagenic in on or another test aystea.
The mutagenic activity of thcsa compounds increases with aacabolic activation by mammalian microsomal systems, showing that metabolites fcs wall as tha parent compounds have mutagenic potential.

# (a) Vinyl Chloride
Because the reported carcinogenic action of vinyl chloride in workers attracted considerable attention, several investigators became interested la evaluating its mutagenicity and chat of its known or presumed metabolites. Ames et al  showed that many known carcinogens activated by mammalian liver enzymes produced back mutations in auxotrcphs of the bacterium Salmonella tynhiaurium. Studies of the genetic activities of vinyl chloride and some of its metabolites have been performed in several bacterial species, yeasts, Neurospora, Drosophila, mammalian cell cultures, and alee. Strain TA1535 reverts to histidine independence by a base-pair surstitution, while in the other strains used, TA1536, TA1537, and TA1538, reversion results from addition or deletion of a base pair (frameshift mutation).
In addition to their Inability to synthesize histidine, these test strains Include a mutation that increases the permeability of the cell and anotner that decreases the repair of damaged DNA; these deletions enhance the sensitivity of the bacteria to certain mutagenic agents.
Because bacteria may not duplicate mammalian metabolic processes in activating potentially mutagenic substances, t';e substances under test were incubated with a 9,000 x gravity (G) microsomal extract frcm the livers of Sprague-Dawley rats .
For some experiments, a microsomal system was produced by mixing the microsomal supernatant with a dihydronicotinaaide adenine dinucleotide phosphate (NADPH) generating system.
In preliminary tests with strain TA1535, Rannug and coworkers  bubbled vinyl chloride gas through either water or a suspension containing the microsomal 3ystem, or they exposed the bacteria for 75 minutes to an atmosphere containing 112 (281.6 g/cu n) vinyl chloride. The vinyl chloride was analyzed by ga3 chromatography and mass spectroscopy and was reported to be of "very high" purity, containing only trace amounts of isopropanc*.
In a subsequent experiment, strain TA1535 was exposed to an atmosphere of 202 vinyl chloride with cha microsomal system or with the aicrosomal supernatant with t o MADPH-generating system, and to vinyl chloride alone, for intervals of 30, 60, or 90 minutes.
Controls were incubated with the aicrosomal system without vinyl chloride.
Finally, all four strains were exposed for 90 ainutes under Mutagenicity similar conditions.
To evaluate the lethality of the vinyl chloride preparation*, identically treated bacteria were cultured on a medium containing hiatidine, and the nuaber of surviving cells was determined.
To evaluate the cooperative mutagenicity of the vinyl chloride preparations, histidine-independent mutant colonies were counted on five plates of minimal media for each test, and the number of mutants/ 100 million surviving cells was compared to the spontaneous mutation rate using the Student's t-test. Exposure of strain TA1535 to vinyl chloride and the microsomal supernatant in the absence of the NADPH-geueratiag system also caused no significant change in the mutation rate.

# In the
In the final experiment, involving all four test strains, only TA1535 showed a mutagenic response to. vinyl chloride.
At the concentrations tesced, vinyl chloride with the microsomal 3ystesj did not affect bacterial survival on a complete medium, although vinyl chloride alone-reduced the survival rate slightly.
Rannug et al  concluded that vinyl chloride was mutagenic in Salmonella only after metabolic activation by m^tanalian microsomal enrymes. They suggested that the most plausible primary metabolite from vinyl chloride would be chloroethylene oxide, which could be formed in the NADPH-dependent oxidation by microsomal enzymes.
Since only strain TA1535 was affected, the mutagenically active metabolites of vinyl chloride appeared to be capable of Fractions of liver, kidney, and lung tissu were prepared from BD-IV rats and 0F-1 mice, sooe of which had been pretreated with sodium phenobarbital to increase hepatic microsomal enzyme activity . Microsomal supernatants were prepared by centrifuging homogenized tissue at 9,000 - C.
For sooe experiments, the microsomal supernatant was chan centrifuged at 100,000 x G to produce a purified aicrosoaal fraction and a supernatant containing aicrosomal protein.
The 9,000 x G microsomal supernatants froir four human liver biopsy specimens were also tested.
In the presence of a aicrosomal fraction derived from aice treated with sodium phenobarbital, with an NADPH-generating system, the autation rate in TA1530, the aost sensitive of the strains tested, increased ihe prevalence of mutations in the presence of the aicrosomal system was seven times as high as wirh vinyl chloride alone after 1.5 hours, but only twice as high after 48 hours; the difference in the autation rata induced by vinyl chloride alone and in the presence of a aicrosooal system reached a plateau after about 9 hours of exposure.
3artsch at al [146j attempted to characterize the enzymes involved in vinyl chloride mutagenicity by testing the activity of various mouse liver fractions on strain TA1530. In the absence of the NADPH-generating system, the 9,000 x G aicrosomal supernatant with 2Z vinyl chloride produced no increase above the autation rates produced by exposure to vinyl chloride alone for periods of up to 48 hours. Purified aicrosomes with an NADPH-generating system produced an increase in the vinyl chloride-induced mutation rate of about half of that obtained with the 9,000 x G microsomal system after 48 hours.
The 100,000 x G liver protein supernatant (cytosol) did not increase the mutagenic response compared to that induced by vinyl chloride alone. Addition of alcohol dehydrogenase and NAD+ to the microsomal systems did not affect the mutation rate, although alcohol dehydrogenase would be expected to convert any chloroethanol produced tc chloroacetaldehyde. This compound is known to be mutagenic to TA1530 .

# Comparison
-f tissues from various sources showed that rat liver aicrosomal supernatant was comparable to that from aouse liver in activating the autagenic response to vinyl chloride . Precreating the animals with phenobarbital increased the activity of the liver microsomal supernatant 15-402. _ _ Kidney and lung fractions from either pretreated or untreated animals increased the mutagenic activity of vinyl chloride only marginally over control values.
One of the four human liver specimens tested was nearly twice as active as those of rat or mouse liver, while the remaining three were somewhat less active than liver tissue from phenobarbital-treated rats and ole*.
Based oa data from pretreated animals, cha relative mutagenic activities of tissue fractions for strain TA1530 were: mouse liver 1002; rat liver, 802; mouse kidney, 202; rat kidney, 162; mouse and rat lung 72; and human liver, 170, 70, 64, and 4o2.
Bartsch et a.l  concluded that vinyl chloride was mutagenic to Salmonella in the absence of mammalian microsomal enzymes, probably through :he action of breakdown products produced either by bacterial enzymes or aonenzymatically. They pointed out that their findings strongly supported the enzymatic formation of mutagenic vinyl chloride metabolites-biuce the 9,000 x G microsomal extract gave a stronger response chan purified microsomes, the authors concluded chat soluble liver proteins (cytosol) played a role la che metabolic activation of vinyl chloride, cither by involvement in a cwo-scep activation mechanism or by prolonging che viability of che microsomal enzymes.
In a subsequent review paper, Bartsch  noted that the wide variation in human liver enzymatic activity, which wa- confirmed in mutagenicity testing of N-nltrosomorphollne, indicated that some individuals are genetically liable to a higher risk from exposure to carcinogens. Bartsch suggested that those estimating acceptable envlronaencal levels of suc.i substances should consider che possible risk for the most susceptible individuals.
In 1976, Garro et al  reported studies of che modification of che mucagenic activity of viayl chloride on Salmonella tvphiaurium TA1530 by suspensions of untreated and Aroclor 1254-pretreated rat or mouse hepatic microsomes In che presence of an XADPH-generating system ami by a system generating free radicals from riboflavin and N,M,N',>Ttetramethylethylenediamlne (TMED) under irradiation from fluorescent lamps. They described TMED as an accelerator of vinyl chloride phocopolymerizacion. Alchough incubation of vinyl chloride with native microsomal suspensions Increased its mutagenic activity by about 652, incubation of chis chemical with similar suspensions that had been heated to destroy their enzvmatic activlcy also increased, but at a somewhat reduced level, its. mutagenic activity. Mutagenesis In the presence of liver extracts was not XADPE dependent.
Incubation of vinyl chloride with the free-radical generating system apparently increased its mutagenic activity by nearly tenfold.
The authors took these findings to indicate "that the stimulatory effect of liver extracts on the mutagenic activity of vinyl chloride in the Salmonella auxotroph reversion test cannot be ascribed to enzymatic activation by a microsomal mixed function oxidase and...that the mutagenic effect of vinyl chloride may involve a free radical mechanism." Although Garro et al  found that riboflavin and che tertiary amine had an effect on the mutagenic activity of vinyl chloride for Salmonella typhimurium TA1530 only in the presence of light, they made no measurements that would confirm tha relationship of the presence of free radicals in thair photoactivated test system to increased mutagenic activity of vinyl chloride. Also, they did not rule out the possibility that the lighc itself altered the apparent mutagenic activity of vinyl chloride. These two uncertainties about  At a vinyl chlorld concentration of 48 millimolar for 60 minutes, tha mutation frequency at tha flv loci vas 62.43/10,000 surviving call, compared with a spontaneous mutation rata of 2.00/10,000. In scudies with Saccharomyces. treatment with 48 millimoles vinyl chloride for 300 clnutas in tha praaanca of purlfiad mlcrosomcs producad a gene conversion fraquancy of 8.47/100,000/locus in tha ad2 system and 4.36/iOO,000/locus in tha trp5 system; spontanaoua frequencies for these systems were 0.49/100,000/locus and 0.85/100,000/locus.
In the host-mediated assay, Loprieno et al  found that Schizosaccharomyces showed a autagenic response after incubation for 12 hours in the peritoneum of mice given vinyl chloride orally at 740 ag/'<g. The observed mutation frequency was 6.89 (t0.60)/10,000 cells compared with a concrol race of 1.33 (t0.19)/10,000 In yeast incubaced in racs not given vinyl chloride; regression analysis showed Che effecC Co be significant ac Che 1- level.
Comparing Che mutagenic effectiveness of che 16 millimoles of vinyl chloride used in vitro with that of 11.2 millimoles of vinyl chloride administered to the mice for in vivo studies, the authors concluded chat in vicro creacaenc was more effective. They attribuced chis co Che fact chat, in Che hosc-medlaced assay, Che presence of an acclve concentration of Che purported autagenic metabolite was minimal as a consequence of its short half-Ufe.
In a later study with Saccharomyces cert vislae, Shahin 

# Verburgt and Vogel
 stated that the data, which demonstrated an increasing frequency of lethal effects between concentrations of 0 ind 1 0 ,0 0 0 ppm, demonstrated that the mutagenic activity of vinyl chloride vas concentration dependent.
Since exposure at 30,000 and .50,000 ppm did not significantly Increase the mutation frequency above that seen at 1 0 ,0 0 0 ppm, they inferred that above a certain concantration (between 850 and 10,000 ppm) Drosophila was incapable of metabolically "activating" (for mutagenesis) further vinyl chloride, and that the enzymatic mechanism- were saturated.
Anderson et al  conducted a dominant lethality study with mice to determine whether vinyl chloride can induce genetic effects. Male CD-I mice were exposed in groups of 20 to vinyl chloride (purity not described) at concentrations of 3,000, 10,000, and 30,000 ppm (7.68, 25.6, and 76.8 g/cu m) 6 hours/day for 5 days.
A concentration of 30,000 ppm was the highest exposure level chosen because it had been shown in preliminary tests to be in tne "toxic range" and it was desired that the maximum tolerated dose or higher be included in the study protocol.
Control mice were exposed tc air alone. Two positive control groups of 15 and 25 mice were given 200 ng/kg of ethyl aethanesulphonate orally for 5 days or one ip dose of 200 ng/kg of cyclophosphamide on the 5th day.
After the exposure period, each of the surviving males, then 10-12 weeks old, was mated with two 8to 10-week-old females each week for 8 consecutive weeks. The females were killed 13 days after the asaumed date of mating, and their uteri were examined for live implantations, early fetal deaths, and late fetal deaths.
Of the male mice, only those exposed to vinyl chloride at 30,000 ppm showed significant mortality, with only 9 of 20 mice surviving 5-day exposures .
In females mated to vinyl chloride-exposed males, the frequency of pregnancy and the number of early and lat fetal deaths did not differ significantly from untreated control values. The number of implantations/pregnant female was not affected by vinyl chloride, except that it was significantly below the negative control value in females mated during the 4th week to mice that had been exposed at 30,000 ppm (10.00 vs 12.38, P<0.05); however, implantation frequency in this group was slightly above control values for 3 of the 8 week3 of mating. Both positive control groups were significantly higher than negative (air) controls in all the indicators of dominant lethality examined, attesting to the sensitivity of the system.
The authors  concluded that vinyl chloride at the stated exposure concentrations was not mutagenic in mice as measured by the dominant lethal test.
This suggests that the active mutagenic compound in the metabolism of vinyl chloride did not affect the germinal cells of these mice.

# Several investigators have attempted to obtain information on the mechanism of mutagenic and carcinogenic activity of vinyl chloride by testing Its known or suspected metabolites for their ability to cause mutations in microorganisms.
Malaveille et al  used Salmonella strain TA1530 to evaluate che mutagenic activity of three presumed metabolites, chloroacetaldehyde, chloroethanol, and chloroethylene oxide (chlorooxirane), and a known urinary metabolite, chloroacetic acid. The substances were tested, with and without a liver microsomal system from phenobarbitalpretreated mice, at concentrations of 40, 4.0, and 0.4 uaol/ml of medium; chloroethylene oxide was also tested at 0.04 pool/ml. Chloroacetaldehyde was highly toxic to bacteria at each teat concantration used, reducing survival to laaa chan 0.00&Z of control levels . Chloroacatic acid was toxic at concentration- of 4 and 40 aol/ml and waa tha only substance taatad that showed no autagenic activity. Chloroacetaldehyde caused a sixfold increase over the spontaneous rate at a concentration of 4
Mmol/ml in combination with the microsomal system; this substance also shoved direct mutagenic activity in the absence of mammalian nlcrosomes. At a concentration of 40 ^mol/ml, chloroethanol, which did not afiect bacterial survival, Increased the mutation frequency more chan 10 times in che presence of Che microsomal system and about 6 ciaes in its absence; at 4 mol/ml, chloroethanol approximately doubled the autation frequency of the bacteria, and its mutagenic activity was apparently unaffected by the aicroscnal system. Chloroethylene oxide was tested without aicrosomal activation only.. At a concentration of 0.4 aaol/ml. It reduced bacterial survival ta 11Z and produced a sixfold increase in the mutation frequency; at 0.04 (jaol/ml, it caused no increase over spontaneous mutation frequency. These findings indicate that chloroethylene oxide is a far more effective mutagen than chloroacetaldehyde, supporting the suggestion of Henschler and his colleagues  that the unstable oxirane was directly involved in vinyl chloride autagenesis.
McCann et al  compared the mutagenicity of vinyl chloride wlch that of its probable metabolites chloroacetaldehyde and chloroethanol, both with and without activation by a rat liver mlcrosGtaal system.
They used Salmonella strains TA1535 ana TA100, the latter being identical with TA1535 except that it contains a factor that interferes with DMA repair, thus Increasing its sensitivity to many mutagens.
Bacteria were exposed to 20Z vinyl chloride in air for 3-9 hours, while chloroacetaldehyde and chloroethanol were added directly to che media in concentrations of up to 30 /g/plate and 1-3 mg/plate, respectively.

# The mutagenic responses ox strains TA1535 and TA100 to vinyl chloride were similar, and McCann et al 
-bserved very little activation by a aicrosomal system from phenobarbital-pretreaced rats with exposure periods of up to 9 hours.
From the authors' graphs, the direct action of vinyl chloride on strain TA100 produced about 25 revertants/plate above spontaneous levels (which averaged 150 revertants/plate) with 3 hours of exposure and 200 at 9 hours; the corresponding levels with the microsomal system added were 65 and 225 revertants/plate above control levels. However, the authors added in a footnote that increasing the concentration of alcrosomes in the system had produced a tvofold increase over the direct activity of vinyl chloride in both TA100 and TA1535.
At the concentrations tested, chloroacetaldehyde, with no microsomal system, effectively reverted strain TA100 to histidine Independence but did not affect strain TA1535 . The mutagenic activity in strain TA100 increased with the concentration of chloroacetaldehyde, reaching 235 revertants/plate above the spontaneous rate at a concentration of 30 Mg/plate. Chloroethanol Increased the mutagenic reponse of strain TA100 to over twice th spontaneous levels and showed a trace of activity with strain TA1535. However, addition of the microsomal supernatant caused a small increase in the mutagenic response of strain TA1535 and a much greater increase in that of strain TA100; quantitative data were not given. The authors noted that an MADPH-generating system was not necessary for this activation. Comparing the mutagenic activity of the three substances in strain TA100 on an equimolar basis, the authors found that the number of revertants/ponol, with control levels subtracted, was 1.0 for vinyl chloride, 0.6 for chloroethanol, and 746 for chloroacetaldehyde.
Despite the high mutagenic activity of chloroacetaldehyde in strain TA100, McCann and coworkers  concluded that this subs, ance was probably not the active astaoolite involved in vinyl chloride mutagenicity. Vinyl chloride, with or without aicrosomes, was about equally active in the two bacterial strains tisted, while chloroacetaldehyde affected only strain TA100. By contrast, activation of chloroethanol by a microsomal system produced a relatively large Increase in the mutation rate of TA100, indicating that chloroacetaldehyde might be the mutagenically active metabolite of chloroethanol. The authors suggested that chloroethylene oxide might be the metabolic intermediate responsible for vinyl chloride mutagenicity. This conclusion is supported by the findings of Malaveiile et al  and of Sannug et al  chat chloroethylene oxide was several times more active than chloroacetaldehyde in the nonrepair-deficient strains TA1530 and TA1535.
In 1976, Rannug et al  compared the mutagenicity of chloroethlyene oxide, chloroacetaldehyde, 2-chloroethanol, and chloroacetic acid in Salmonella typhimurlum strain TA1535. The test substances were added to the bacteria before plating, in concentrations ranging from 0.1 to 1.5 millimolar; 2-cnioroethanol and chloroacetic acid were also studied at concentrations of up to 1 M. Ethylene oxide, described as a "well known mutagen," was used as a positive control. The authors also tested vinyl chloride at a concentration of 22 (51.2 g/cu m) in air for 3 hours, using the procedure described in their earlier study .
Chloroethylene oxide showed both a definite toxic effect and strong mutagenic activity . At a concentration of 0.75 millimolar, it produced 180 revertants/100 million surviving cells, 60 ciaes the spontaneous mutation rate. Chloroacetaldehyde also showed a mutagenic effect in this concentration range but was only about 52 as effective as chloroethylene oxide on a molar basis. 2-Chloroethanol and chloroacetic acid shoved no mutagenic effect up to 1.5 millimolar and were therefore retested at higher concentrations. 2-Chloroetnanol produced a weak mutagenic response only at 1 molar. Chloroacetic acid was highly toxic to bacteria at concentrations up to 0.5 molar, and no increase In mutagenic response could be detected. Ethylene oxide, the positive control substance, did not produce an increase in mutagenic response at concentrations below 5 millimolar, and ethylene oxide at 95.5 millimolar produced an Increase In the mutation rate equivalent to chat produced by chloroethylene oxide at a concentration of 0.15 millimolar.
la their experiments with 22 (51.2 g/cu a) vinyl chlorid*, Rannug t al  found that vinyl chlorida at this concentration in tha presence of a microsooal system produced 10.0 0.9 (SE) revertants/100 million calls, | significantly aora (P<0.001) than tha control rate of 3.8/100 million calls; naithar vinyl chloride alone nor the microsoaal system alone produced a significant increase.
Noting the difficulty of comparing vinyl chloride autagenlclty to that of the other compounds because of the difference in experimental conditions, the authors estimated that only if all the vinyl chloride was converted t-2-chlorcethanol would the concentration of this compound be great enough to account for the observed mutagenic activity of activated vinyl chloride.
Calculating that chloroethylene oxide was 10,000-15,000 times as mutagenic aa ethylene oxide, Rannug et al  concluded that this was in reasonable agreement with the ratio of the preliminary rate constants of the two compounds for reaction with the appropriate nucleophiles.
They considered this to be an indication that chloroethylene oxide acts in the same '/ay as ethylene oxide, as a monofunctional alkylating agent. The authors concluded on the basis of interpretations by Hussain and Osterman-Golkar  that chloroacetaldehyde was far more active as a mutagen than would be expected from its reactivity as an alkylating agent.

# In an addendum to the paper by Rannug et al , Hussain and Osterman-Golkar  analyzed the data of Rannug et al on a kinetic basis.
They noted that the higher-than-expected mutagenic activity of chloroethylene oxide, based on comparison of its rate constant for axK./lation with that of ethylene oxide, indicated "a certain role of the aldehyde groups." Chloroacetaldehyde, however, was several orders of magnitude more effective than expected, indicating "a reaction mechanism different from simple alkylation."
In 1977, Loprleno et al  tested vinyl chloride metabolites for mutagenic activity in yeasts.
Chloroethylene oxide, 2-chloroacetaldehyde, and ?-chloroethanol, added to the media in various concentrations, were tested in vitro; 2-chloroacetaldehyde was also tested in the host-mediated assay.
Test organisms and experimental procedures were the same as those used in their previous study .
Chloroethylene oxide showed the highest mutagenic activity in all systems examined . At a concentration of 0.1 millimole, the forward mutation frequency in pombe was 340 tlaes the control rate, and at 1 millimole the gene conversion rate in cerevlsiae was 40-50 times that in controls. 2-Chloroethanol in concentrations up to 50 millimoles showed no mutagenic activity in yeast cells, with or without microsomes.
2-Chloroacetaldehyde showed a weak mutagenic effect in vitro, increasing mutation rates 2-7 fold at concentrations up to 12.5 aillimoles.
When administered to male Swiss albino mice (25 g) in oral doses of 250 mg/kg, 2-chloroacetaldehyde produced no increase in the mutation rate of pombe incubated in the peritoneum for 3 -6 hours.
Elaore c al  evaluated vinyl chloride and it- metabolite- in a study designed to pervic accurate comparison- of their mutagenic activity and to provide additional insight as to the mechanists of thi- activity. Since previous investigators had not ascertained the purity of the metabolites used, Elaore and coworkers tested pure fora- of chloroethanol, chloroacetic acid, chloroethylene oxide, and chloroacetaldehyde.
The last compound can exist In coablnatlon- of four form*, depending on its preparation.
The authors therefore tested pure preparations of the monomer, licer hydrate, and trimer, plus the 50:50 mixture of monomer and monomer hydrate formed when the monomer is dissolved in water or physiologic systems.
They When the wild-type strain was treated with chloroacetaldehyde for 15 minutes before the DNA was extracted, there was a major depression of biologic activity in the transforming DNA, as evidenced by a decrease of 50" cr more in the number of transformants produced. This depression showed genetic-marker specificity, reducing transformation ac seme loci by over 90Z. The authors noced that DNA segments that have previously been shown to be associated with macromolecular structures such as the cell wall or cell aeabrana appeared to be selectively protected froa attack by chloroacetaldehyde.
The addition of a mammalian microsomal systea did not significantly alter the effect of chloroacetaldehyde on transformation efficiency. After exposure, the bacteria were cultured for up to 48 hours, and histidine-revertant colonies were counted on each plate.

# Huberaan et al
From one to four experiments were conducted at each concentration, each using a pool of four mouse livers; bacteria were plated in triplicate for each experiment.
The authors also compared the efficiency of liver, kidney, and lung microsomal systems from male OF-1 mice and female BD-VI rats in inducing mutagenic response to vinylidene chloride in strain TA100.
Both Salmonella strains showed a positive mutagenic response to vinylidene chloride in the presence of a mammalian microsomal system .
Ho mutagenic activity was observed in the absence of the NADPH-generating system.
In strain TA100, exposure to vinylidene chloride for 4 hours at 0.2Z produced an average of about 300 revertants/plate, compared with control levels of less chan 50. At 2Z vinylidene chloride, the number of revertants/plate In strain TA100 reached 500 23 (SE) above control levels, while at 20Z vinylidene chloride, the number was only 330 *29.
Strain TA1530 followed che saae pattern but was somewhat less sensitive.
The authors suggested that the reduction in mutagenic response at the highest exposure concentration might have resulted from inhibition of the microsomal enzymes responsible for the metabolic activation of vinylidene chloride. The authors  seated that the mutagenic activity of vinyl chloride, which caused a 563Z increase in mutations at Che arg+ locus, was "several times higher" than that of vinylidene chloride. It should be noted, however, that the measured concentration of vinyl chloride in the medium (10.6 m m millimoles) was over four cimes ehac of vinylidene chlorid. In addition, the difference in exposure technique required for the highly insoluble gaseous vinyl chloride necessitates that such comparisons be made with caution. Since Bartsch ec al  exposed bacteria to both vinyl chloride and vinylidene chloride in air, and thus determined the concentration in the medium under similar conditions, their comparisons of relative mutagenic activity are probably more accurate.
Furthermore, Henschler et al  pointed out in cheir discussion that vinylidene chloride is che most polar of the chlorinated ethylenes they tested, and its oxirane, which has not been successfully synthesized, would be expected to be Che least stable.
Thus, it should be expected to have a higher mutagenic activity than vinyl chloride. At 20Z vinyl bromide in che presence of a microsomal system, there was an average of 1,129 revertanCs/plate in scrain TA100 and 959/plate in TA1535; wichout Che activating system, the mutation rates were 620/plate for TA100 and 721/plate for TA1535.
Control rates of about 130/plate for TA100 and less than 20/plate for TA1535 were not significantly affecCed by che addicion of che microsomal system alone.
Although Simmon and Mangham did noc conduce simuleaneous scudies of vinyl chloride or measure che concencracion of vinyl bromide produced in che medium, chey postulated thac vinyl bromide was slighcly more mucagenic by chese procedures chan vinyl chloride. So data were offered in supporc of chis comparison.
The auChors' findings do support a conclusion thac vinyl bromide induces mucacions in Salmonella scrain TA100 and TA1535 wichouc microsomal accivadon, alchough microsomes enhance ics mucagenic accivicy. The mucagenic responses of both strains were concencracion-dependent in a nearly scraighcline relacionship, which showed a tendency to level out at the highest concentration tested (20Z). Since Simmon and Mangham did noc provide daca on baccerial survival, ic is not possible co determine whether this sacuration resulced from a coxic effecc of vinyl bromide at high concentracions.
In a 1976 review, Barcsch   Despite this apparent observation of extremely high mutation rates, the authors were unable to isolate any auxotrophic strains from the treated cultures .
They presented some evidence for the Induction of heritable changes in the fermentation patterns of certain carbohydrates, although it was not unequivocal.
While it is possible that qualitative changes in the mutation frequencies may have occurred, the failure to isolate auxotrophic strains from the treated cultures suggests that any such effects were minimal . Also, the selection method used by these authors does not allow the direct measurement of either the spontaneous or induced mutation rates or frequencies of a culture, although it may greatly enrich the ratio (frequency) of mutated cells to normal cells in the culture. Although strain TA-100 should also identify any potential mutagen capable of inducing base-pair substitution, the results were negative for this strain in these tests.
The most plausible explanation for this apparent discrepancy is that the presence of the resistance transfer factor on the TA-100 was in this case protective.
The results also indicate that some product of the metabolism of vinylidene fluoride is more mutagenic than the parent compound.
Watson also tested the ability of vinylidene fluoride to transform BAL3/3T3 cells. Cells vere exposed for various periods ranging from 0 to 48 hours, with and without tissue culture media. Only the cells exposed with culture media shoved an elevated number of transformations above background; however, these elevations were not significant. The major urinary excretion products of vinyl chloride have been characterized following both inhalation and oral exposures, and the compound has been shovn to be readily absorbed and videly distributed in body tissues and to be metabolized into several major and minor metabolites. Although strain TA-100 should also identify any potential mutagen capable of inducing base-pair substitution, the results were negative for this strain in these tests.

# Metabolism
The most plausible explanation for this apparent discrepancy is chac the presence of Che resistance transfer factor on the TA-100 was ia this case protective.
The resulcs also indicate thac some product of the metabolism of vinylidene fluoride is more mucagenic chan Che parent compound.
Watson also tesced the ability of vinylidene fluoride to transform BAL3/3T3 cells. Cells were exposed for various periods ranging from 0 to 48 hours, with and without tissue culture media. Only the cells exposed with culture media shoved an elevaced number of cransforaacions above background; however, chese elevations were not significant.

# Metabolism

# Metabolic pathways have not beea completely aad conviacingly delineated for any of the vinyl halides. That for vinyl chloride apparently is nearest to completion, but, even here, several key seeps in the initial reactions *re only postulated and have noc been conclusively proven by experimentation designed specifically Co elucidace intermediate metabolic products in vivo.
The proposed pathways for vinylidene chloride are sketchy at best, while the decerminations of pathways for vinyl bromide, vinyl fluoride, and vinylidene fluoride have oaly just begun.

# (a) Vinyl Chloride
Vinyl chloride metabolism has been studied extensively since che discovery of vinyl chlorideinduced angiosarcoma ia humans in early 197.
The aajor urinary excredon products of vinyl chloride have been characterized following both inhalation and oral exposures, aad the compound has been shown to be readily absorbed and widely distributed in body tissues and to be metabolized into several major and minor metabolites.
(1) Distribution and Elimination Hefner et al , In 1975, found that the metabolism of vinyl chloride during the first 15 hours after exposure of three male rats to 14C-(l,2-)vinyl chloride at 49 ppm (125.4 mg/cu a; a total estimated Intake of 0.49 mg/kg) for 65 minutes resulted in the formation of polar metabolites that were excreted predominantly in the urine (582 of the 14C activity). Lesser amounts of radioactivity were excreted in the feces (2.7Z) and in the expired air as carbon dioxide (9.8Z). At 75 hours after administration, 67.1Z of the radioactivity had been excreted in the urine, 3.8Z in the feces, and 14.0Z as expired carbon dioxide.
Trace amounts of radioactivity (0.02Z of that administered) were eliminated in expired air as unchanged vinyl chloride.
A small but significant amount of radioactivity (1.6Z) was retained in the liver for as long as 75 hours after exposure.
The skin retained 3.6% of the radioactivity, 0.2Z was found in the kidneys, and 7.6Z was found in the remaining carcass.
Hefner et al  also reported that the in vivo kinetics of uptake (metabolism) of inhaled vinyl chloride, determined for four male rats exposed together in a chamber at initial concentrations ranging from 50.5 to 1,167.0 ppm (129.3 to 2,987.5 mg/cu m) for 52.5-356.3 minutes, differed at different concentrations of vinyl chloride.
For concentrations of 50-105 ppm, the apparent first-order rate constane derived after seven separate exposures was 0.00804 :0.0034/minute, corresponding to a half-life of 86 minutes. After five separate exposures to vinyl chloride at concentrations ranging from 220 to 1,167 ppm, the first-order rate constant was determined to be 0.00265 0.00135/minute, a half-life of 261 minutes. Based on these results, Hefner et al concluded that there were differeut pathways for vinyl chloride metabolism and that at least one of them was readily saturated, so that the amounts of substrate degraded by the individual pathways were dependent on the concentration of vinyl chloride presented to the organism.
However, these variations in apparent first-order constants are equally consistent with the existance of a single saturable process and do not provide any conclusive experimental evidence for the existence of multiple biochemical pathways. For the liver, skin, carcass, muscle, lungs, and kidneys, ;xg equivalents of radioactivity per g of tissue were higher at 1,000 ppm than at 10 ppm. When the data were normalized for metabolized vinyl chloride, an apparent increase, although not a statistically significant one, was observed in the 14C activity of che liver and skin at 1,000 ppm.

# Watanabe et al  reported chat the largest amounts of radioactivity in rats exposed
In the rats exposed at 10 ppm, a greater percentage of the total recovered radioactivity was excreted in the urine and a smaller percentage in the expired air than in rats exposed at 1,000 ppm . The apparent first-order rate constants for pulmonary excretion at 10 and 1,000 ppm were 0.034 0.002 and 0.031 iO.01/hour, respectively, equivalent to half-lives of 20.4 and 22.4 minutes, respectively.

# The urinary excr' .on of radioactivity as a function of time for both concentrations of airborne vinyl chloride was nonlinear .
This could indicate that elimination was occurring from at least two compartments . From the initial linear portions of these data, apparent first-order rate constants were 0. Ninety-seven percent was excreted within 36 houra-After 36 hours, the excredon curves were qulce variable and represented less than 32 of che total urinary activity; hence, no estimates of rate constants were made. Hefner et al , in 1975, reported that when the whole body (excluding the head) of a male rhesus monkey was exposed to 14C-(1,2-)vinyl chloride at 7,000 ppm (17.9 g/cu m) for 2 hours, and a second monkey was similarly exposed at 800 ppm (2.1 g/cu a) for 2.5 hours, radioactivity could be detected only in the liver, bile, and kidneys. They also reported that very little gaseous vinyl chloride was absorbed percutaneously, 0.023 and 0.0312 of the total available radioactivity at 7,000 and 00 ppm, respectively. The authors stated that, nevertheless, about 100 times more vinyl chloride vas metabolized at the higher oral dose than at the lover one.

# Gehrlng et al  reported that metabolism of vinyl chloride by rats did not Increase proportionately as the concentrations

# At an lv dose of 250 Mg/kg, 99Z of the vinyl chloride vas excreted unchanged In expired air vlthln an hour after injection, Including 80Z within 2 minutes , The excretion profile of vinyl chloride after a single ip Injection at the low dose vas Intermediate betveen that occurring vlth oral or lv administration.
The authors suggested that some of che vinyl chloride in blood vas excreted unchanged through the lungs and some was absorbed into Che hepatic-portal system and metabolized by the liver.
From these data, the authors  concluded that the change in excretion pattern between high and low doses was due to a "saturable drug metabolism and to a highly efficient arterial-alveolar transfer of unchanged vinyl chloride from systemic blood that leaves a relatively low concentration of material available for biotransformatior. 1=. uctessive passes through the liver."
In another experiment by Green and Hathvay , three rats that received 3, 30, or 300 mg/kg/day of nonradioactlve vinyl chloride by oral intubation for 60 days were given single oral doses of 14C-(1,2-)vinyl chloride (O.b mg/kg, containing 2 aicrocuries) on days 1 and 60. For the first 24 hours after administration of Che radiolabeled vinyl chloride, urine and expired air were monitored fir radioactivity. The auchors concluded Chat chronic exposure for 60 days did not affect the excretion rate for a single oral dose of 14Cvlnyl chloride. The authors also concluded that vinyl chloride did not Induce its own metabolism and that excretion data for a single dose also applied to Che chronic situation. They concluded that the proportion of 14C eliminated by various routes was concentration dependent. Moreover, the dominant route of excretion at both concentrations was in the urine and the metabolites were predominantly nonvolatile or polar.
This finding supports Che earlier conclusions of Hefner et al  and Watanabe et al  that the elimination of vinyl chloride metabolites was dose dependent. The authors a'.so suggested that metabolism occurred at a reduced rate because body burden in terms of equivalents of radioactivity increased by only 27-fold as Che concentration of vinyl chloride was increased from 10 Co 1,000 ppm. They concluded thac chis also indicated that che primary mecabolic pathway for vinyl chloride was sacurable at high concencraclons, specifically ae 1,000 ppm. This work, in addition co the work of Hefner ec al , tends co support a hypothesis chac, ac concencraclons of vinyl chloride above 220 ppm, aleernaCe metabolic pathways *xist.
Hefner et al  reported that the urinary metabolites from rats exposed for 4, 5, or 7 w?eks to vinyl chloride at 5,000 ppm (12.8 g/cu m) were similar.
The polar metabolites in the urine appeared to be conjugated with glutathione or cysteine through covaler.t linkages to the sulfhydryl groups.

# Chromatographic analysis suggested the presence of S-(2-hydroxyethyl)cysteine. Two theoretically possible metabolites, S-(2-chloroethyl)cysteine and S-(2carboxymethyl)cysteine, were noc dececced, buc Hefner ec al posculaced chac S-(2-carboxymethyl)cysteine might not have been adequately resolved from the urine bi.ckgrouad.
When rats were exposed to vinyl chloride at 5,000 ppm for 9 weeks, chromatographic analysis of their urine showed the additional presence of monochloroacetic acid. Muller et al  exposed male rat3 continuously to vinyl chloride at 1,000 ppm fox 43 hours, and they found thiodiacetic acid as well as S"(carboxymechyl)cysteine in che urine.

# To identify the probable urinary mecabollces of vinyl chloride afcer ics administration by oral Intubation, Green and Hathway  gave each of four rats three doses of 50 mg of 14C-(l,2-)vlnyl chloride/kg at 3-hour intervals, for a total dose of about 10 microcuries of 14C. Major metabolites of vinyl chloride were Identified by mass spectral analysis as thiodiglycolic acid, -(2-chloroethyl)cysteine, and N-acetyl-S-(2-chloroethyl)cysteine.
Thiodif Some have stated that one pathway, suggested to be active at low levels of absorption, begins with a hydration reaction whose product is chloroethanol.
A proposed second pathway, suggested to be predominant at high absorption levels.
Involves the oxidation of vinyl chloride to chloroethyiene oxide by microsomal enzymes. These two pathways converge with the formation of chloroacetaldehyde as the second step in each.

# Investigators have also postulated that the metabolism of vinyl chloride Involves the formation of free radicals .
Reynolds et al , in 1976, proposed a scheme in which an epoxide (chloroethyiene oxide) was produced as a primary reactive metabolite of vinyl chloride.
This would involve the hepatic mixed-funcCion oxidase system , particularly the cytochrome P-450 component .
A wide variety of oxidative reactions, including epoxldatlon, can be mediated by these enzymes, located in the membranes oJ the endoplasmic reticulum of liver cells, with n \DPH serving as an electron donor. Rearrangement of the epoxide could then occur, producing a beta-chlorinated acetaldehyde, a dlol, or a glutathione conjugate as a secondary metabolite. These products could be formed by interaction of the epoxide with epoxide hydrase or with glutathione epoiJ.de transferase .
Vacanabe et al  reported that, at oral doses of 0.05 or 1 ag cf 14C-(1,2-)vinyl chloride/kg, 14C was consistently eliminated in the urine as nonvolatile, polar metabolites and in the expired air as carbon dioxide. At an oral dose of 100 mg/kg, however, the primary route of excretion was by expiration of unchanged viayl chloride. This indicated to the authors not only that metabolic pathways for vinyl chloride are dose dependent, but also that the process contains a saturable component. Comparing these results with their previous findings , the authors also concluded that the aetabolic fate of vinyl chloride is independent of the route of administration.

# In both oral and inhalation exposures to vinyl chloride, N-acetyl-S-(2hydroxyethyl)cystine was a major urinary metabolite .
One study  has indicated chat this compound could be formed from 5-formylmeChyl cyscelne and S-formylaechyl glutathione, which ac one time were considered either not co be formed or to be metabolized to S-carboxymechyl cysteine .

# Alchough Green and Hathvay  Identified (2-chloroechyl)cyscelne and M-acecyl-S-(2-chloroechyl;cysceine as urinary mecabolices of vinyl chloride in racs, Che formaclon of Chese produces may be an arclface  of Che
acthod of separation (methanol derivacizacion produces the chloro-coopound, whereas dlazoaechane derlvatlzatlon produces che hydroxy-compound) .
Froo daca presented by other authors , showing the formation of 14C-carbon dioxide after adminiseracion of 14C-vinyl chloride, Plugge and Safe  proposed two additional alternatives for its pulmonary metabolism. The first assumed chat the metabolism of vinyl chloride proceeded by che addicion and cransfer of a chloroacecyl group Co coenzyme A and by subsequenC metabolism in che Krebs cycle. The second scheme assumed formation of glycolate followed by oxidation Co glyoxylate, which entered the C-2 and C-l pools. By analogy with the metabolic pathway for chloroechylene oxide, the glycolate alternative seems to be the more feasible one . . Chloroacetate has been detecCed as a metabolite of chloroechanol , Mecabollsm of eicher chloroechanol or chloroacetace yields S-carboxymechyl cysteine, chlodlacecate (thlodlglycolate), and small amounts of glycolate .

# Chloroechanol has been reported to be transformed in vivo and in vitro via rat liver enzymes to S-carboxymechyl glutathione, which can also be derived froo the Cwo compounds, S-fonnylmethyl glutathione and chloroacetate
In another Investigation, thiodiacetate was detected as a product of the metabolism of S-carboxymethyl cysteine ; this conversion has been confirmed by Yllner .

# Bonse and
Henschler , in a 1976 review of the metabolism of chlorinated ethylenes, concluded that their oxidation via moaooxygenases to corresponding oxlranes (epoxides) conaltuted the Initial metabolic reaction. The authors suggesced chac eleccrophlllc reactions or alkylaeion of cellular components were essenclally responsible for che Coxlcity of che chlorinated ethylenes aud chac che ocher pachways were generally pare of a deCoxification mechanism. Afcer rearrangemenc, addicional mecabolic steps, including oxidacion of either aldehydic or alcoholic derivatives to carboxylic acids were suggested. The authors also suggested hydrolysis of acyl chlorides to acids as an alternate pathway.
Green and Hachway   concluded that chlorcacatic acid was not a part of tha major de^radative pathway for vinyl chlorida, but sinply a byproduct of chloroacetaldehyde matabolism, unless however, Cha glutathion- conjugation aechanism were Inhibited, whereupon the conversion of chloroacetaldehyr'e to cnloroacetlc acid would become an important detoxification alternative. They further supported this hypothesis bv administering lev e r a l vinyi c h l o r i d e aetabclites to rats and iticvl-.'.g that chlorcacetaldehvde -ind S-(carboxyaethy.)cystein, but not chloroacetic acid, were In the direct pathway for the formation of thiodiglycolic acid. These authors  also identified small quantities of H-acety1-S-vlnylcysteine as  urinary metabolite of vinyl chloride in rats, thus li-ndiag credanca to ti a hypothasizad pathway of an equilibrium between tha chloro-and t(< hydroxy-athyl glutathione derivatives, possibly through an aoi*ul;honlua ion Intermediate.
Plugge and Safe , in a 1977 review postulated that the metabolism of vinyl chlorida occurs both in vivo and in vitro via tha aixed-function oxidase system, primarily through the cytochrom- P--50 system, to an oxirane , In this case chloroethylana oxide.
The oxirane (epoxide) formed from vinyl chlorida would ba a strong alectrophilic molecule, and it may be unstable becsuse of tha presenca of its asymmetric chlorine.
This instability could result in intramolecular rearrangement of the chloroethylene oxide to chloroacacaldahyda. Tha authors considered that both chloroethylena oxide and chloroacataldahyda would bind either directly or enrymatlcally to glutathione, thereby forming S-formylmethyl glutathione. Via an NAIH-dependent aldehyde dehydrogenase, chlorocetaldehyde could also be oxidized to chloroacetate. This particular compound, if it was not. excreted, could bind with glutathione to form S-carboxymethy1 glutathione, which in turn could be hydrolyred to S-carboxymethy1 cysteine. S-carboxynetnyl cysteine could be either deaainated and decarboxylated to fora thiodiglycolace, N-acetylated, or excreted.
Van Duuren , in 1975, hypothesized that when rats were given large aaouncs of vinyl chloride, an epoxidatlon reaction would occur in which vinyl chloride was converted to chloroethylene oxide by the microsomal mixedfunction oxldaae system. Chloroethylene oxide would subsequently be reacted or would spontaneously rearrange to chloracetaldehyde .
Hafnar at al  conjectured that, with exposures balow 100 ppa of - Tinyl chloride, its metabolisa would occur by hydration to 2-chloroechanol followed by oxidation to 2-chloroacetaldehyde by cha vary rapid alcohol dehydrogenase pathway. Sloe- chloroacataldahyda reacts rapidly wlch the sulfhydryl of glutathione, only a traca amount of aonochloroacetlc acid would be formed. In 1977, Bolt et al  stated that vinyl chloride in the atmosphere of a closed system equilibrated with that in the tissues of rats within 15 minutes at varioua concentrations below 250 ppm (the concentration at which tha authors stated that saturation of the vinyl chloride-metabolizing enzymes is achieved) when metabolism of vinyl chloride was blocked by 6-nltro-l,2,3benzothiadiazole (an inhibitor of some cytochrome P-450-dependent oxidations). When rats not given the metabolic bio icing agent were tested, the concentration of vinyl chloride in the atmosphere declined exponentially with a half-life of about 1.1 hours.   In polychlorinaced biphenyl (Aroclor 1254) or phenobarbical-precreaced male racs, pyrazole and SKF-525A proCecCed againsc acuce hepacotoxicicy, while disulfiram (an inhibitor of aceCaldehyde dehydrogenase) and echanol pocenciaced che toxic effects of vinyl chloride.

# Bolt et al

# The auchors speculated chac che proceccion afforded by SKF-525A was due to mixed-function oxidase inhibicion, indicacing a disrupCion in che mecabolism of vinyl chloride co an acCive mecabolice. Protection by pyrazole was probably due parcially co inhibicion of mixedfunction oxidases and partially Co inhibicion of acecaidehyde dehydrogenase. The lack of coopedcive effeccs by echanol indicaCed Co the auchors chac che conversion of chloroechylene oxide co chloroeehanol was decreased, possibly because of Increased sponcaneous rearrangement of chloroechylene oxide co chloroacecaldehyde (bypassing che acecaidehyde dehydrogenase conversion seep) or because of caCalase conversion of chloroeehanol co a peroxide and subsequenc rearrangemenC co chloroacecaldehyde (again bypassing acecaidehyde dehydrogenase).
Hefner ec al  decermined the effeccs of vinyl chloride on liver sulfhydryl levels. Male racs were exposed for 7 hours/day co vinyl chloride ac concentrations of 15,000 ppm (38.4 g/cu m) for 5 days, 5,000 or 500 ppm (12.8 or 1.3 g/cu m) for 5 days/week for eicher 1, 3, or 7 weeks, or 50 ppm (128 mg/cu a) for either 1 hour, 7 hours, cr 5 days. No overt signs of toxicity were observed in rets exposed at any concentration. Significant reductions in nonprotein sulfhydryl levels were found in rats exposed to vinyl chloride at 50 ppm for 7 hours, at 500 and 5,000 ppa for 1 and 3 weeks, and 15,000 ppm for 1 week. Although the reduction in nonprotein sulfhydryl levels could not be definitively correlated with exposure concentration, the authors concluded that there was a tendency for such reduction to become leas obvious with repeated exposures. Four rats treated with ethanol before exposura to vinyl chloride at 1,070 ppm (2.7 g/cu m) for 105 minutes had significant decreases in hepatic nonprotein sulfhydryl levels (77.0 *12.8%) as compared with the controls (95,0 3.4%). The authors indicated that ethanol alone did not affect the liver nonprotein sulfhydryl levels. , in 1975, showed that male rats given drinking water containing 0.1% pentobarbital 7 days before either one or five consecutive 6hour exposures to airborne vinyl chloride at a concentration of 5% (128 g/cu m) exhibited a diffuse vacuolization of the cytop^sm of cells of the centrllobular liver parenchyma and focal areas of necrosis of midzonal parenchyma after the exposure. In the livers of pratreated rata exposed to vinyl chloride for 5 consecutive days, the authors found broad tracts of stroma depleted of parenchymal cells that corresponded in distribution and extent to the areas of necrosis found 24 hours after a single exposure. Since pentobarbital, an inducer of mixed-function oxidase activity, appeared to increase the liver toxicity of vinyl chloride, the authors concluded that the endoplasmic reticulum was the primary site for generation of toxic vinyl chloride metabolites. Moreover, Reynolds and colleagues suggested that these metabolites, possioly epoxides, were presumably responsible for the observed cellular injury as well as the potential for tumorigenesis.

# Reynolds et al

# Several reports  have detailed the in vivo and in vitro requirements for covalent binding of vinyl chloride (or its metabolites) with cellular macromolecular constituents, including DMA, RNA, and protein. In addition, these reports have identified some effects cf various chemical inducers or inhibitors of cellular metabolic processes on the metabolism of vinyl chloride.
In 1975, Bolt et al  reported that rat liver microsomes metabolized vinyl chloride to more polar metabolites during a 90-minute incubation and that these metabolites became covalently bound to the microsomal proteins. In addition, vinyl chloride metabolices became covalently bound to other 3ulfhydry1-containing proteins or to RNA when added to the incubation mixture. NADPH was reported eo be essential to the binding process, hence essential to this metabolic route for vinyl chloride. Similar results ^ere reported with microsomes from human liver, but the authors did not give experimental data. , using the same incubation procedure as that used by Bolt et al , confirmed the essentiality of NADPH in the covalent binding process.

# Kappus et al
In an additional paper, Kappus et al  reported that continued uptake of 14C-vinyl chloride by liver microsomes depended on NADPH. Without MADPH, uptake of 14C-(1,2-)vinyl chloride increased rapidly during the first 2 minutes and reached saturation after 5 minutes. With NADPH, the uptake of vinyl chloride continued beyond the incubation time of 60 minurs and a tenfold increase in the uptake of 14C-vinyl chloride by the 'iicrosomal preparation was noted. The authors also showed that vinyl chloride could he taken up by both protein and lipid components of microsomal meabranes; the single difference noted was that the time course differed from that for uptake by microsomes. Their data also suggested a greater ability on the part of liposomes to bind vinyl chloride reversibly. Prom these studies, the authors inferred that the NADPH-independent part of microsomal vinyl chloride uptake was at least partially due to the reversible binding of vinyl chloride to the lipids and proteins of the microsomal membranes.

# Kappus et al  also found that, of the total 14C-(1,2-)vinyl chloride taken up by the microsomes, about 1Z was bound irreversibly to the microsomal protein.
Moreover, Irreversible binding of the vinyl chloride metabolites to the microsomal proteins appeared to depend on the presence of NADPH, the incubation time, and the concentration of the metabolites.
In addition, the authors demonstrated that when atmospheric air was replaced by nitrogen in the presence of NADPH, vinyl chloride uptake was reduced. The amount of vinyl chloride metabolites irreversibly bound to protein also was lowered.  reported that vinyl chloride metabolites were also bound to added albumin, but not to concanavalin A, which contains no sulfhydryl groups.

# Kappus et al

# They found that the addition of glutathione or glutathione-containing cytosol to the incubation medium caused a 30Z depression in covalent binding to cellular proteins , thus Indirectly supporting the concept that free sulfhydryl groups must be present for binding to proteins to occur or for detoxification to occur. In further support of this concept, they reported that inhibition of the microsomal cytochrome P-450-dependent mixed-function oxidases by 4-(l-naphthyl)imidazole inhibited covalent binding by about 85Z.
Microsomal uptake of vinyl chloride was completely blocked by carbon monoxide, an inhibitor of cytochrome P-450 oxidation reactions . Irreversible binding of vinyl chloride metabolites to proteins was also blocked by carbon monoxide, whether NADPH was present or not. Boiling of the microsomes prior to incubation reduced vinyl chloride uptake in the presence of NADPH, and no irreversibly protein-bound vinyl chloride metabolites were detected. Addition of reduced glutathione to the microsomal incubation mixture with NADPH resulted in very little change in vinyl chloride uptake by the microsomes, but did result in a 25Z inhibition of irreversible protein binding.

# Microsomal uptake of vinyl chloride was not affected by trichloropropene oxide, an Inhibitor of epoxide hydras , However, irreversibly proteinbound vinyl chloride metabolites were increased twofold. No induction effect on vinyl chloride uptake could be
demonstrated in microsomes from phenobarbital-pretreated rats.
There also .were no changes in irreversible protein binding. Cytochrome P-450, however, was increased in the liver -m - microsomes from racs precreated with phenobarbiCal. Vinyl chloride uptake was similar in liver microsomal preparations containing added glutathione and cytosol obtained from control and pretreated rats. From the data presented, the authors suggested that the initial step in vinyl chloride metabolism involved an oxygenation reaction catalyzed by an enzyme system containing cytochrome P-450.
In addition, the arthors concluded that chloroethylene oxide was probably the initial reactive aecabolice.  presented additional evidence for involvement of the epoxide in the covalent binding reaction by using the xanthine oxidase model system, which generates hydrogen peroxide and an oxygen-radical.

# Kappus et al
They concluded chat demonstration of the binding of vinyl chloride metabolices Co albumin in Che presence of a complete xanthine oxidase syscem scrongly suggesced chac oxygen radicals, known Co be involved in epoxidacion by Che microsomal enzyme syscem, converc vinyl chloride Co a metabolite chac Chen binds covalencly to a protein, such as albumin. , in 1977, attempted to characterize the binding of vinyl chloride to hepatic macromolecules and nucleic acids by exposing male rats to 14C-(1,2-)vinyl chloride at nominal concentrations of 1, 10, 25, 50, 100, 250, 500, 1,000, or 5,000 ppm (range 2.96-12,800 mg/cu m) .

# Watanabe et al
The results suggested that increases in exposure concentration did not proportionately Increase the total amounts of radioactivity bound to hepatic macromolecules. The percentage of total 14C activity bound to hepatic macromolecules ranged between 20 and 222, except in rats pretreated with phenobarbital where it reached 392.

# Both the metabolized and bound vinyl chloride increased with increasing nominal concentration, but the ratio of bound to metabolized vinyl chloride declined with Increasing nominal concentration.
In rats exposed at nominal concentrations of 1, 10, 25, or 50 ppm (range 2.56-128 mg/cu m ) , Watanabe et al  found that the nonprotein sulfhydryl content of the liver was depleted, but not significantly so. However, at 100 ppm (256 mg/cu m) and above, a significant depletion (?<0.05) was noted. Since it seemed a reasonable assumption that Che major decoxificaclon of Che reacclve metabolites of vinyl chloride occurs by reaction with nonprotein sulfhydryl groups , Watanabe et al  considered it Important that at nominal concentraclons of 100 ppm and higher, h slgnflcanc dose-relaced deplecion of chac pool could be demonstraced. They also suggesced chat the carcinogenicicy of vinyl chloride was relaCed Co che decreased abilicy of exposed organisms Co decoxify che reacclve mecabolices of vinyl chloride.   reported shat five rats pretreated with phenobarbital (80 mg/kg/day) by ip injection 3 days before exposure to 14C-vinyl chloride at a nominal concentration of 100 ppm showed a markedly increased binding of 14C to hepatic oacromolecules when compared with nonpretreated animals, even chough there was no observable Increase in vinyl chloride metabolism. W3tanabe et al  concluded that their findings did not associate the carcinogenicity of vinyl chloride with a disproportionate increase in binding of Its electrophilic metabolites to hepatic macromolecules as the exposure concentration was increased. Because there was no demonstrable evidence to support preferential binding of the electrophilic metabolites to nucleic acids of the hepatocytes, they raised the possibility that the carcinogenic potential of vinyl chloride could not be associated with this commonly accepted mechanism for carcinogenesis. The authors suggested, however, that before alkylation of nucleic acids was excluded as the carcinogenic mechanism, more studies to determine the absence of such alkylation activity in the target tissue rather than the hepatocytes are required. They suggested that the hepatocyte itself, since it is susceptible to the toxicity of vinyl chloride, may function as a detoxifier. This would imply that tissues having  lesser ability to detoxify the reactive metabolites of vinyl chloride ma" themselves become the victims of toxicity.

# Gehrlng et al  stated that since "Toxicity, including carcinogenesis, is a dynamic process involving absorption of a chemical into the body, distuiDution to various tissues, reversible or irreversible reactions with cellular components, and ultimately clearance from the tissues and the body via metabolism and/or excretion," it follows that "the predictability of animal toxicological data for assessing the hazard of a chemical to man is enhanced if the fate of the chemical per se and/or its degradation products in animals is equated to the fate in man."
They stated that under ordinary conditions and ov r a selected range of doses, chemical kinetics fit a linear differential equation, the implication being that a knowir increase in dose will result in a linear Increase in tissue levels. They added, however, that many metabolic and excretory processes were easily overwhelmed and saturated, thus leading to a situation in which nonlinear Michaelis-Menten pharmacokinetics would prevail. The authors suggested that the results of Hefner et al , in which the rate of metabolism of vinyl chloride at low concentrations was rapid and the primary metabolic pathways were overwhelmed at high concentrations, supported this theoretical model.

# The data presented above suggest that alkylating metabolites of \-inyl chloride, such as chloroacetaldehyde ard chloroethylene oxide, are formed in vivo.
Both chloroacetaldehyde and chloroethylene oxide can conjugate with glutathione and cysteine and subsequently form the vinyl chloride metabolites that have been identified in urine, such as N~acetyl-S-(2-chloroethyl)cysteine , which may itself be a potent alkylating agent by virtue of its half mustard forming ability.
In terms of assessing the hazard of exposure to vinyl chloride, experimental data support the conclusion that the carcinognicity of vinyl chloride is a function of the metabolic formation of alkylating metabolites. The urinary metabolites identified so far indicate that the primary deactivation mechanism is conjugation with glutathione, a nonprotein, free-sulfhydryl containing compounds. Experimental data have indicated that as the nonprotein, free-sulfhydryl groups are depleted as a sequel of the absorption and metabolism of vinyl chloride reaction of the alkylating metabolites with tissue macromolecules, such as DNA or RNA, may be more likely to occur. As a result, toxicity of a different order of magnitude may be elicited at higher exposure concentrations.

# (b) Vinylidene Chloride
McKenna et al  showed that in rats exposed to airborne 14C ( The former compound represented about 45Z of the total urinary radioactivity, whereas the latter accounted for 25Z.
The authors concluded that the identification of these two compounds as urinary metabolites supported the hypothesis that glutathione conjugation was a major step in the biotransformation of vlnylidene chloride.

# Jaeger et al ,
in 1977, reported that fed and fasted male rats exposed to 14C-vinylidene chloride at 2,000 ppm (7.9 g/cu m) for 2 hours did not differ significantly in the rate of vlnylidene chloride uptake or of urinary excretion of 14C during che first 24 hours. Of the calculated dose, 36.7 and 36.5% were recovered within 24 hours in che urine of fed and fasted animals, respectively.
Thirty minutes after a 2-hour exposure, the kidneys of fasted rats concalned both the greater amount of total radioactivity and the larger amount of metabolites that were soluble in trichloroacetic acid (hence, not bound).
Fasted rats also had significantly greater amounts of total radioactivity in the spleen, heart, and serum than did fad rats. There was no significant difference between the 14C contents of the brain of fad and fasted rats. Th livers of fastad rats contained substantial amounts of radioactivity that was trichloroacetic acid-insoluble . This component represented either 14C that was tightly bound to microsomal or mitochondrial macromolecules or that had entered the metabolic pool.
The rates of disappearance of the trichloroacetic acid-insoluble 14C from the microsomal and mitochondrial fractions of the liver in fed and fasted rats were similar, although the amounts differed significantly; both had estimated half-lives of less than 3 hours.
Significantly sore radioactivity was found in the hepatic cytoplasmic fractions of fasted r 'ts than in those of fad rats. The authors suggested that on the basts of their data metabolism of vinylidene chloride was quite rapid, with trichloroacetic acid-soluble components being excreted by the kidney and trichloroacetic acid-insoluble components entering the metabolic pool.
They concluded that since a rapid turnover of bound 14C material occurred (half-life less than 3 hours), covalent binding to protein or tissue constituents must have been minimal. Jaeger et al  concluded that fasting had no effect on the rate or on the amount of in vivo metabolism, but that the in vivo metabolic pathway appeared to be significantly different la fasted rats than in fed rats.
They also reported that pretreatment with trichloropropane epoxide (an epoxide hydrase inhibitor) significantly Increased the toxicity of vinylidene chloride in rats, and on this basis, suggested the possible formation of an epoxide Intermediate as a result of the hepatic metabolism of vinylidene chloride. occurred in fasted rats at 150-200 ppm but only at or above 2,000 ppm in fed rats ;

# Several
this difference was also evident in an Isolated perfused rat liver system .
Diethylmaleate, a material that depletes glutathione, potentiated the hepatotoxic effects of vinylidene chloride on fed rats and on perfused livers from fed rats . Surgical or chemical thyroidectomy (resulting in increased liver glutathione) reduced the severity of hepatotoxic Injury in fasted rats exposed to vinylidene chloride at a concentration of 2 ,0 0 0 ppm for response of fed rats exposed to vinylidene chloride nor did it protect fasted rats fro the hepatotoxic effects of such exposure .
However, Reichert and Bashti  reported that SKF-525A in perfused rat liver preparations diminished the rate of metabolism of vinylidene chloride.
These data support the hypothesis that a major pathway for the detoxification of vinylidene chloride involves conjugation with glutathione and that blockage of its conjugation with glutathione greatly enhances its hepatotoxicity.

# Jaeger  noted that a significant elevation (P<0.05) of hepatic citric acid occurred after exposure of rats to vinylidene chloride at a concentration of 250 ppm.
He concluded that vinylidene chloride probably affected the mitochondria, leading to inhibition of the Krebs, cycle and subsequent mitochondrial damage.
Jaeger et ai , on the basis of prior work , hypothesized that chloroacetyl chloride, a metabolite of viaylidene chloride, was converted to monochloroacetic acid, which in turn was converted into chlorocitric acid, an inhibitor of the enzyme aconitase.
Inhibition of this enzyme would result in an accumulation of citric acid. This hypothesis was predicated oy analogy on the hypothesis of lethal synthesis, which suggests that fluoracetic acid is converted to fluorocitric acid, which inhibits aconitase .  reported that the lethality of vinylidene chloride in male and female mice exposed at various concentrations for 22-23 hours was reduced substantially by pretreatment with disulfiram. When exposures were increased to 22-23 hours/day for 2 days, prefreatment with disulfiram, dlethyldithiocarbamate, or thiram reduced the lethality of vinylidene chloride in male mice.

# Short et al
Pretreatment with methionine or cysteine also reduced the lethality of vinylidene chloride, but instead of protecting in terms of increasing the acut LC50 (as did the other three compounds), these compounds protected by delaying the onset of mortality after exposure.  also reported that disulfiram pretreatnent protected male mice from the hepatotoxic effects of exposure to vinylidene chloride at 60 ppm (238.2 mg/cu m) for 22-23 hours.

# Short et al
However, after two consecutive 22-to 23-hour exposures at 60 ppm, there was no protection frcm hepatotoxic!ty. Short et al  showed that covalently bound radioactivity could be detected in the macromolecule3 of the liver and kidneys of mice 4 and 24 hours after an ip injection of 3 mg of 14C-vinylidene chloride/kg. The kidneys contained more bound 14C/mg of protein than did the liver at 4 and 24 hours after administration of vinylidene chloride.
Pretreatment with'disulfiram greatly reduced the bcund 14C in both tissues at both time periods.

# Bonse and Henschler
 proposed in a 1976 review of polychlorinated aliphatic compound metabolism that an oxirane, a postulated metabolic intermediate of vinylidene chloride, spontaneously rearranged to chloroacetyl chloride and was then hydrolyzed to monochloroacetic acid. Since monochloroacetic acid is also a product of vinyl chloride metabolism, they speculated that its formation and fate in vinylidene chloride metabolism followed a similar scheme. The authors also noticed a cyclic excretion pattern for vinylidene fluoride in vhich ther- vas major excretion directly after exposure and again 5 days after exposure . The Authors proposed zhat either the fluoride ion, the parent compound, or the fluorine-containing metabolites were stored in some biologic compartment and then released with a turnover rate of about 5 days.

# Conolly
and Jaeger  reported that fasting had no effect on hepatoeoxicity in polychlorinated biphenyl-treated rats exposed to vinyl fluoride at 10,000 ppm (18.8 g/cu m) for 4 hours. Three consecutive daily doses of trichloropropane epoxide (an inhibitor of epoxide hydrase) before exposure to vinyl fiuoiicte produced Increased mortality in rats; however, fasting in addition to administration of trichloropropane epoxide did not exert a synergistic effect. This indicated to the authors chat glutathione may not be important in the detoxification of vinyl fluoride metabolites in polychlorinated biph.'.nyl-pre treated racs, but chat epoxida hydraie may be Involved in detoxifying fluoroethylene oxide.

# Structure-Activity Considerations

# Such an assessment of the carcinogenic potential of the vinyl halides requires an understanding of their mechanisms of action.
A review of the available metabolic data on vinyl chloride indicates that several reactive intermediates are produced (Figure XVXI-3). These intermediates are electrophiles, which have been shown to form covalent bonds with cellular macromolecules.
A similar metabolic route may be operative for che ocher vinyl halides, producing similar intermediates that also may bind covalently to cellular constituents.
The carcinogenic potential of each of the vinyl halides would therefore be the resultant potentials of these possible metabolites and of any unmetabolized compound.
One hypothesis for the mechanism by which vinyl chloride expresses its carcinogenic potential involves its metabolism, via the microsomal cytochrome P-450 mixed-function oxidase system, to the oxirane (epoxide), chloroethylene oxide .
One basis for predicting the carcinogenicity of Inadequately tasted vinyl compounds Is Che assumption that metabolic epoxldation Is Involved in Chelr metabolism as veil, and that the epoxide is the major reactive intermediate. The relative carcinogenic potential would then be Influenced by the relative ease with which the epoxides are formed from the corresponding halo-olefins and the relative reactivity of a particular epoxide toward cellular nucleophiles.
The propensities of vinyl halides to undergo chemical transformation to epoxides are dependent on the electronegativities of the substituents on the olefinic nucleus .
Increasing electronegativity result3 in rarefaction of the electron density of the double bond, and thereby in a decrease in the susceptibility of the olefin to apoxidation.
Thus, for the vinyl halides under consideration, the expected order of nou-enzymatic epoxldation would appear to be vinyl bromide > vinyl chloride > vinylidene chloride > vinyl fluoride > vinylidene fluoride.
Bonse and Henschler  supported this scheme of epoxldation by showing that the order of the rate of ozonization of a series of olefins was ethylene > vinyl chloride > trlchloroethylene > tetrachloroethylene.
Also, a study of the reaction rates of ozone, a strong oxidizing agent, vlth cnlorir.ated and conjugated olefins showed that the rate of ozone attack decreased strongly (1 ,0 00-fold from vinyl chloride to tetrachloroethylene) as the number of chlorine atoms in the olefin molecule increased .
Hanzlik et al  found that a series of para-substituted styrenes (vinyl benzenes) underwent metabolism via the cytochrome P-450 system of ratllver mlcrosomes at rates that were essentially substituent independent.
From the kinetic data of these authors, RL Schowen (written communication, August 1977) calculated a Hammett rho value (a measure of the sensitivity cf the reaction series to ring substitution) of around -0.  , Schowen concluded that these vinyl compounds would be expected to generate epoxide metabolites at similar rates.
Schowen also addressed the problem of estimating the reactivity of the epoxide intermediates that ere assumed to be formed.
He made two analyses, each dependent on an experimentally derived measure of reactivity for halide compounds.
One analysis used Swain-Scott substrate factors, S, which reflect electrophiliclty .
Based on S values determined for other halide alkylating agents, eg, S  1.00 for C1CH2C02-, 1.10 for BrCH2C02-, 1.33 for ICH2C02-, and Jor nonhalide agents, Schowen suggested that alkylating potentials of the vinyls relative to vinyl chloride would vary over a range of no more than 16.
In a second analysis using a leaving group parameter, L, from the Swaln-Lohmann equation 

# 053, reapacclvaly (saa Table XVII-I).
Their solubilities In blood alghe wall follow this same order alehough lipid solublliey and various eypes of aacroaolecular 5lading cannot ba Ignored. That Is '.o say, the relative aaouae absorbed Chrough Cha lungs aay ba about 20 times greater for vinyl broaida chan for vlnylidana fluorlda.

# Th expe^iaantal avldanca and cheoreeical considerations ara coapacibla wlch cha hypcehasis Chat eha five vinyl halides ara capable of undergoing biochaaical apoxidacion buc ehac cha cvo fluoro olefins aay ba soaewhaC lass suseapclbl Chan ch ochcr vinyl halidaa co this raacclon. Exerapolaelon of Ch estimates of Schowaa suggesCa ehac vinylidane chlorld, and vlayl broaida, aay have a similar or graacar carcinogenic poceneial chan vinyl chloride, but chat vinyl fluorlda and vlnylidana fluoride, although possibly carcinogenic,  '  - U a t on the basis of limited mutagenicity data, are likely to be less reactive (possibly up to 1,500 times less) than the other three.
The suggestion that the other vinyl halides resembl vinyl chloride in theit effects and mechanism of action is debatable on the basis that normal mammalian biochemical constituents such as steroids and unsaturated fatty acids contain the vinyl moiety and are not suspected of carcinogenicity.
It should be noted that variation either above or below a physiologically critical concentration range for many of these compounds may lead to toxic effects.
NIOSH is unable to suggest any systematic relationship between the toxic?ties of all compounds containing the vinyl group, although vinyl halides are treated here as a group because of the similarities in chemical and physical properties.
It may well be that it is the presence of the halide moiety which imparts a particular toxicity range to these agents by allowing them to be activated, epoxidated, or hydrated at sufficiently high rates, and, at the same time imparting to the metabolites a characteristic stab.'j.ity and inti^nsic activity that allows them to reach and interact with vital cellular constituents.
In the absence of additional toxicologic data on the vinyl halides under consideration, the relevance of th- theoretical considerations discussed above to estimation of the potential toxicity of these compounds might be tested by developing mathematical relationships between biologic activities and physicochemical parameters. These parameters could also consider any variations in steric interactions.
Sufficient consistent biologic data are not yet available, however, to permit the development of such equations.

# Correlation of Exposure and Effect
The vinyl halides have been shown to induce effects on the nervous, circulatory, respiratory, integumentary, skeletal, and digestive systems in humans and laboratory animals.
These effects are summarized in Tables III-2 to 111-10.
The modes of action of the vinyl halides art not clearly understood, and there is little published information on any of them other than vinyl chloride.

# It has been proposed that expression of the tumorigenic and mutagenic potential of vinyls depends on metabolic intermediates; this possibility is discussed in the section on Carcinogenicity. Mutagenicity. Teratogenicity, and Effects on Reproduction.

# Lethal concentrations of the vinyl halides have been determined.
For vinyl chloride, the LC50 for mice exposed for 10 minutes and observed for an unspecified period was 239,580 ppm .
In another study, the LC50's for 2hour exposures were calculated as 117,500 ppm for mice, 156,000 ppm for rats, and 238,000 ppm for guinea pigs and rabbits . The LClOO's were also determined In this experiment; they were 150,000 ppm for nice, 210,000 ppm for rats, and 280,000 ppm for guinea pigs and rabbles.
The duration of the observation period was not reported.
For vlnylldene chloride, t! - 4-hour LC50 In rats has been reported as 6,350 ppm with a 14-day observation period .
Other authors  reported that from two to four of six rats died within 14 days after one 4hour exposure at a concentration of 32,000 ppm.
A single 22-to 23-hour exposure of rats produced LC50 values of 98 ppm for males and 105 ppm for females . Two exposures for 22-23 hours gave LC50 values of 35 ppm for male rats, and the LT50 for exposure at 20 ppm was reported as 4 days. Thl3 experiment showed that mortality In rats exposed to vlnylldene chloride is in part a function of the total a'cumulated dose. The 24-hour LC50 valae in rats after one 4-hour exposure was determines as 15,000 ppm for fed animals and 600 ppm for animals fasted for 18 hours . The oral LD50 has tlso been calculated for adrenalectomized rats as 84 mg/kg for 24 hours and 81 mg/kg for 96 hours; In sham-operated controls, the LD50 was 1,550 mg/kg for 24 hours and 1,510 mg/kg for 96 hours . This Indicated that adrenal hormones provide some protection against the acute effects of vlnylldene chloride in rats.

# Exposure
to vinyl bromide at concentrations of 171,000 ppm has been tolerated by rats for 10 minutes .
In another experiment 1127], concentrations of 100,000 ppm were shown to be 1002 lethal in rats after 15 minutes, and some rats died (percentage unspecified) at concentrations of 50.000 ppm for 7 hours. An oral LD50 of 500 mg/kg (given in c o m oil) for vinyl bromide was also determined for rats .
Vinyl fluoride has been reported to be not lethal to rats exposed at a concentration of 802, with 202 oxygen, for 12.5 hours .
Vinyl fluoride at 100,000 ppm, 7 hours/day,   reported that four of seven rats pretreated with Aroclor 1254 and exposed to vinyl fluoride at concentrations of 102,000 ppm died after a 4-hour exposure.
Vlnylldene fluoride has been reported not to be lethal to rats exposed at a concentration of 802, with 202 oxygen, for 19 hours .
Another author , however, stated that a static exposure to vlnylldene fluoride at 128.000 ppm for 4 hours was sufficient to kill from two to four of six rats within 14 days, hot enough information was presented to evaluate whether or not the static exposure conditions, eg, decreased partial pressure of oxygen, were directly responsible for this difference in lethality.
These studies Indicate that vinyl chloride, vlnylldene chloride, and vinyl bromide present a low degree of acute toxic hazard in animals, and that, a- the duration of exposure increases, the concentration necessary to produce lethal effects decreases. One study  showed that 'xposure of male mice to vlnylldene chloride at concentrations as low as 20 ppm was lethal after dally exposures of 22-23 hours for 4 days. The information available suggests v chat Che acute toxicity of these compounds is dependent in pare on Che races of metabolism and excretion and the subsequent total accumulated dose.
The variability of the estimates of LC50 values, resulting in part from variability in the experimental protocols used, does not allow a ranking of the compounds according to acute toxicity, except that vinyl fluoride and vlnylldene fluoride are less toxic than the other vinyls and have not been found to have acute lethal actions on dynamic inhalation exposure in normal rats.

# Cardiovascular effects have been reported for vinyl chloride, vinylidene chloride, and vinylidene fluoride.
Twenty percent of 51 workers examined in 1965, who were exposed to vinyl chloride at a TWA concentration of 49 ppm, and 422 of 60 workers examined in 1969, exposed at a TWA concentrations of 43 ppm, showed elevated pulmonary arterial pressure . Durations of exposure for these workers were not presented.
In another report , workers who were currently exposed to vinyl chloride or who had been exposed In the past had a 39.  . Cardiac sensitization to epinephrine has also been demonstrated in dogs exposed to vinyl chloride at 50,000 ppm for 5 minutes .
Changes, such as tachycardia, sinus arrhythmia, and ventricular multifocal extrasystoles, have been observed in the ECG records of dogs exposed to vinyl chloride at 100,000 ppm without epinephrine stimulation . A significant decrease (P<0.05) of 28.52 in myocardial force of contraction has been observed in monkeys exposed to vinyl chloride at the same concentration for 5 minutes . Monkeys exposed at 50,00C ppm showed a decrease of 9.12 in myocardial force of contraction, and those exposed at 25,000 ppm showed a 2.32 decrease in force of contraction.
Decreases in aortic blood pressure followed a similar pattern in the monkeys.
This experiment indicates that the cardiovascular effects of vinyl chloride are dose dependent.
Vinylidene chloride, inhaled at concentrations of 25,000 ppm for 10 minutes, caused sinus bradycardia and such cardiac arrhythmias as AV-block and ventricular fibrillation in rats . Vinylidene chloride also>enhanced the cardiac sensitivity to epinephrine, and this sensitivity increased with increasing duration of vinylidene chloride exposure.

# No cardiac sensitization to epinephrine was noted in cats or dogs exposed
Co vinylidene fluoride at concentrations of 250,000-500,000 ppm for 5-15 minutes . This suggests that vinylidene fluoride does not have the same mode of action on the cardiovascular system as vinyl and vinylidene chlorides. Similar information is aot available for vinyl bromide or vinyl fluoride.

# CNS effects have been observed on animals after exposure to each of he vinyl halides.
In some instances, these effects might have been secondary to systemic effects caused by cardiovascular changes. The authors of the reports did not address this possibility. Vinyl chloride caused "certain anesthesia" in mice after a 10-minute exposure at 122,000 ppm, and 50% anesthesia after exposure a 10-minute exposure at 100,000 ppm .
Exposures at LC50's caused excitement, convulsions, and contractions in mice, rats, and rabbits . Exposure of dogs co vinyl chloride at 500,000 ppm momentarily, then at 70,000 ppm for an unspecified period, caused rigidity of the legs and uncoordinated muscular movements .
An experiment with human subjects showed that 5-minute exposures to vinyl chloride at 1 2 ,0 0 0 ppm caused dizziness in two, dizziness, nausea, lightheadedness, and dulling of vision and hearing at 16,000 ppm in five, and the same symptoms with more Intensity in all six, and a headache in one of them at 20,000 ppm . Among 168 workers exposed to vinyl chloride at a TWA concentration of 899 ppm for up to a few months, 47% complained of dizziness, 45% of somnolence, 36.6% of headache, 13% of loss of memory, 11% of euphoria, and 9% of nervousness . Of 168 workers exposed to vinyl chloride at a TWA concentration of 9d ppm (prior exposure information not available), 10.2% reported dizziness, 16.6% somnolence, 6.9% headache, 8 % loss of memory, 1.2% euphoria, and 0.6% nervousness. Frequent dizziness and weakness in the legs were also reported by other workers exposed to vinyl chloride , as was fatigut in 38.6% and headache in 12.9%  and in 13.7% of another group, of workers . These data Indicate that a decrease in the TWA concentration of vinyl chloride led to a decrease in the frequency of CNS symptoms, and that exposure at TWA concentrations as low as 38 ppm produced adverse effects.
Other findings that might be considered manifestations of CNS effect3 have included a "large proportion of accidents" occurring in a worker population  and an excess of suicides as the actual causes of death in another worker population (10 observed vs 5.3 expected) . Effects on brain cells have also been observed, ie, a localized atrophy of cerebellar Purkinje cells and necrosis of the frontoparietal cerebral cortex in one worker . Also, fibrotic processes surrounding and invading the small nerve bundles of the gray matter, neuronal phagokaryosis with satellitosis and deposition of neurologic elements around altered nerve cells of the white matter, and atrophy of the granular layer and degenerative changes in the Purkinje cell layer were observed in rats exposed at 30,000 ppm, 4 hours/day, 5 days/week,
for 1 year  .
Exposure to vinylidene chloride at about 4,000 ppm for a brief period caused "drunkenness" that progressed to unconsciousness in animals . Workers exposed to a vinylidene chloride copolymer while cleaning tanks developed pains in the lips, nose, and eyes, headache, somnolence, facial anesthesia, corneal anesthesia, hypoesthesii, difficulty in speaking and eating , and fatigue, weakness, nausea, and dizziness . Because of the composition of the copolymers to which these workers were exposed In aqueous suspension, it is not reasonable to assume that vinylidene chloride was the only causative agent of these CNS effects.
Vinyl bromide caused a ' 'certain anesthesia" at a concentration of 86,000 ppo for a 10-minute exposure in rats .
In another experiment, a 1.5-hour exposure at 25,000 ppm anesthetized all rats, and a 7-hour exposure at 10,000 ppa caused drowsiness in rats .

# Rats exposed for 30 minutes
to vinyl fluoride at 300,000 ppm showed instability of the hindlegs; at 500,000 ppm there was loss of postural reflexes, and at 600,000 ppo there was loss of the righting reflex .
Rats exposed to vinylidene fluoride for 30 minutes at 400,000 ppm showed slight Intoxication, and at 800,000 ppm showed an unsteady gait without loss of the postural reflexes .

# The available data indicate that vinyl chloride and vinylidene chloride can produce similar C N S ' manifestations
that may be secondary to the cardiovascular effects of these compounds. Arterial vessels of the paws also showed endothelial fibrosis. The same rats also ahowed akin papillomas and warty aubauricular growths .

# Human exposure information is not available concerning CNS
No reports were located of integumentary effects with exposure to vinylidene chloride, vinyl bromide, vinyl fluoride, or vinylidene fluoride. In one study , exposures to vinyl chloride were estimated at 50-100 ppm in air and 600-1,000 ppm close to tne workers' hands during reactor cleaning operations. No information was available in any of these reports on the duration of employment or exposure for the workers with acroosteolysir . It was noted that all workera with acrooateolyais had been mployed in reactor cleaning, whereas only 21Z of the entire vinyl chlorideexposed population had had experience as reactor cleaners . In rats exposed to vinyl chloride at 30,000 ppm for 4 hours/day, 5 days/week, for 1 ysar, observed effects included alteration in the characteristic bone deposition in the small bones with a mucoid Impregnation   The systemic effects that reportedly resulted from exposure to vinyl halides suggest that the vinyls or their metabolites Interfere with cellular processes primarily in the liver and the cardiovascular system.

# Skeletal changes have also been observed in humans and
Exposures to large quantities may also involve the skeletal, integumentary, and central nervous systems; however, these systems may also be affected secondarily by changes in the cardiovascular system, and the relative magnitudes of the effects resulting from primary action of the vinyl halides or their metabolites and from the suggested secondary ones are uncertain.

# Carcinogenicity. Mutagenicity, Teratogenicity, and Effects on Reproduction
The vinyl halides produce reactive metabolic intermediates, possibly including asymmetric oxlranes.
Several proposed intermediates in the metabolic pathways of the vinyl halides are capable of covalent binding with cellular macromolecules, and may therefore induce carcinogenesis and mutagenesis.
Although few experiments have been reported in which the carcinogenic or mutagenic potentials of the vinyl halides other than vinyl chloride arc evaluated, the vinyl halides considered In this document, as suggested earlier In this chapter, may be qualitatively If not quantitatively similar In their Induction potentials.
One report has suggested that exposure of male workers to vinyl chloride can Induce excess fetal deaths among their offspring .
However, as has been previously discussed, the methods of data collection used in this report are considered inappropriate.
The fetuses of mice, rats, and rabbits from dams exposed to vinyl chloride during pregnancy showed significant abnormalities, including increased crownrump length, in mice exposed at 50 ppm, and increased Incidence of resorptions, decreased fetal body weight, reduction in litter size, Increased numbers of unfused sternebrae, and delayed ossification of the bones of the skull In mice exposed at 500 ppm . Fetuses from rats exposed at 500 ppm showed a significant reductiou in the fetal body weights and a significant increase in the number of lumbar spurs and In crown-rump length. Fetuses from rats exposed at 2,500 ppm showed a significant increase in th<5 Incidence of dilated ureters and significant decreases in the incidence of unfused sternebrae and delayed 3kull ossifications.
The only other significant difference noted was an increase in the incidence of delayed ossification of the fifth sternebra in rabbits exposed at 500 ppm. The authors of this study regarded these effects as due to maternal toxicity and not to direct toxicity to embryos and fetuses.
However, the observation of characteristic cancers in progeny of dams exposed to vinyl chloride during their pregnancies  suggests that vinyl chloride or its metabolites cross the placental barrier and may have induced the abnormalities reported.
Pregnant rats exposed to vinylidene chloride at 80 ppm had significantly increased numbers of resorptions/implants and fetuses with significant increases in skeletal abnormalities such as delayed ossification of parietal bones, wavy ribs, and lumbar spurs .
Delayed ossification of skull bones and cervical vertebrae, along with wavy ribs, were also observed in fetuses of rats exposed at 160 ppm. No adverse effects were observed at 20 ppm.
In the rabbits exposed at 160 ppm, there was a significant increase in the number of resorptions/implants and a significantly decreased Incidence of delayed ossification of the fifth sternebra, and an increased incidence of a 13th pair of ribs.
No adverse effects were noted on the fetuses from dams exposed at 80 ppm.
In the fetuses of rats given access to drinking water containing vinylidene chloride at 200 ppm, the only significant difference from controls was an Increase in the fetal crown-rump length.
No reports have been located of studies in which the reproductive or teratogenic effects of vinyl bromide, vinyl fluoride, or vinylidene fluoride were investigated. Absorption and subsequent metabolism of vinyl chloride has been reported to be concentration dependent, with a saturable enzyme system responsible for metabolism at low concentrations and a secondary oxidative system predominant at higher concentrations .

# Covalent binding of the vinyl halides to cellular macromolecules such as
It has been postulated that the oxirane is formed only at the higher concentrations through the secondary oxidative pathway, but that halogenated acetalydehyde is common to both pathways.
Thus, even without the formation of the oxirane at low concentrations, the possibility of macromolecular alkylatlon exists through the action of the aldehyde intermediate. Accurate exposure information, to allow calculation of total accumulated dose, is not available for these workers.

# Kuzmack and McGaughy
, using data derived from epidemiologic studies, calculated that the incidence rates of angiosarcomi in workers exposed at concentrations of 350 ppm, 7 hours/day, for 5 days/week should be 0.0031/person/year of exposure.
Ad incidence rate of 0.0052/person/year of exposure was also calculated from the incidence rate in rats. Angiosarcoma of the liver was also observed in 1 of 59 rats exposed to vinyl chloride at 50 ppm, 4 hours/day, 5 days/week, for 52 weeks . The percentage of animals with angiosarccma of the liver increased from 2% at 50 ppm, to 71 at 250 ppm, 12% at 500 ppm, 22% at 2,500 ppm, 22% at 6,000 ppm, 15% at 10,000 ppm, and 30% at 30,000 ppm. Average latency increased with decreasing exposure concentration, from 53 weeks at 30,000 ppm to 135 weeks at 50 rpm. In another experiment , rats exposed at 50 ppm for 4 hours/day, 5 days/vi?ek, for 12 months showed no tumors over an unspecified observation period.
At 500 ppm., however, there was a significant increase (P<0.03) in the number of tumors seen, with 3% of the animals having angiosarcomas of the liver.
Increasing exposure concentrations to 2,000, 5,000, 10,000, and 20,000 ppm increased the frequency of all turners and of angiosarcoma of the liver to In addlclon, these racs did noc show Increased Incidences of ocher tumors compared wich Chose In concrols. A further experlmenc  showed an Increased Incidence of adenocarcinoma of Che ''Ldnay In Swiss mice exposed to vinylidene chloride aC 25 ppm for 4 hours/day, 4-5 days/week, for 12 months, but no increase in other tumors. The authors  stated that exposures at 50 ppm and higher were lethal to these animals.
Sprague-Dawley rats exposed on the same schedule at concentrations of from 10 to 150 ppm showed an increased incidence of mammary tumors; howevar, this increase was not dose dependent.
No cases of cancer in humans have been attributed to vinyl bromide exposure.
The preliminary results of one animal experiment The carcinogenicity data show that vinyl bromide at a concentration of 250 ppm induced angiosarcoma in 72 of Che animals after 1 year of exposure , and that vinyl chloride at a concentration of 250 ppm also induced angiosarcoma in 71 of Che animals, buC after 2 years of exposure . This indicates that, for this characteristic tumor, vinyl bromide has a stronger induction potential, since It is reasonable to assume that, within another year, more of Che vinyl bromide exposed animals would develop the tumors. A comparison of the induction potential of vinylidene chloride with that of vinyl chloride or vinyl bromide is more difficult.
One experiment with vinylidene chloride showed 42 angiosarcoma of the liver In CD-I mice exposed at a concentration of 55 ppm for 85,800 ppm-hcurs , another experiment showed no angiosarcoma in Swiss mice exposed to vinylidene chloride at 25 ppm for 23,000 ppm-hours , while an experiment with Swiss mice exposed Co vinyl chloride aC a concentration of 50 ppm for 30,000 ppm-hours showed a 22 Incidence of angiosarcoma of the liver .
These data are noC so easily compared as the data from the vinyl bromide and vinyl chloride experiments, but they do suggest that vinylidene chloride may be less active in Inducing angiosarcoma of the liver than vinyl chloride.
Because the behaviors of these compounds appear to fit the expecCed scructure-activity relationship, it is reasonable Purified microsomal fractions (100,000 x G) have been shown to be less active than the 9,000 x G fraction , while the supernatant cytosol produced no increase in mutagenic activity above that found for vinyl chloride alone.
Vinyl chloride has been shown to affect only loci at which mutation occurs by substitution . One dominant lethal study  with male mice exposed to vinyl chloride at 30,000 ppm for 6 hours/day for 5 days showed no mutations, which suggests that mammalian gametes may not be affected by exposure.
Vlnylldene chloride has been shown to be similarly mutagenic in bacterial systems .
Exposure of Salmonella for 2 hours, in media containing 0.33-33 millimoles of vlnylldene chloride and a mammalian microscmal system, resulted in 6-10 clmes the spontaneous number of ravertants .
Bartsch et al  reported that vlnylldene chloride was about three times as active as a mutagen as vinyl chloride on an equimolar basis.
In a study using E^ coli, Greim et al  concluded thac vinyl chloride was "several times" more mutagenically active than vlnylldene ' chloride; their data showed that vlnylldene chloride produced a onefold Increase over the spontaneous number of mutaclonj at a concentration of 2.5 mil.'.imolar, while vinyl chloride produced six Clmes the spontaneous number of mutations at the same locus at a concentration of 1 0 .6 mlllimolar. McCann et al  suggested that, although chloroacetaldehyde was the most active of the metabolites of vinyl chloride that they tested, i<: was probably not the major mutagenic metabolite of vinyl chloride, since chloroacataldahyde affected only tha repair-deficient Salmonella strain TA1C0. These authors suggested that chloroechylene oxide was the most likely mutagenic metabolite, although they did no; test its activity.

# Vinyl bromide aC concentrations of 202 in air was shown to be mutagenic in
However, the compound has been tested by other investigators on both repair-deficient  and nonrepair-deficient  strains, and it apocirj, like vinyl chloride, to be similarly active in each. These studies show that each of tha vinyl halides is mutagenic in various Case systems and that Cha putaclva metabolites are more strongly mutagenic chaa che parenc compounds.
The studies support the conclusions drawn from the limited carcinogenic data available and, further, raise a suspicion that the fluorides also may be carcinogens.
The failure of vinyl chloride to be mutagenic in tha mouse dominant-lethal test may indicate that ~he mutagenic factor may not ba distributed to mammallan gametes in sufficient concencradonj co produce slgnlficanc changes; however, further research is necessary Co determine fully cha pocenelal of ehese compounds for mammalian mutagenicity.  )0,000

# Tha available evidence c s e e m i n g the vinyl halides indicates that eeh

# S 3 N T T > O R lG E N IC E F F E C T S CM ANIM ALS FROM EX P O SU R E TO V 1 N Y L ID E N E F L U O R ID E 13Y ir^tA L A T lC N R e f -S p e c i e s C o n c e n t r a t i o n D u t a t i o n E f f e c t s e r e n c e (ppm
IV. ENVIRONMENTAL DATA Moat of the sampling and analytical procedures for airborne vinyls in occupational environments have been developed and tested for vinyl chloride. While these procedures may provide some guidance for choosing sampling and analytical conditions for the other vinyl halides, caution must be exercised in extrapolating or interpolating from vinyl chloride to vinylidene chloride, vinyl bromide, vinyl fluoride, and vinylidene fluoride.

# Certain physical and chemical properties of the latter compounds are quite different from those of vinyl chloride at ambient temperatures and pressures (see Table XVII-1).
The collection media used for sampling the various vinyls should be selected to permit reproducible air sampling, adequate collection efficiency, storage stability, retention, and minimum breakthrough of the specific compounds.

# Murdoch and Hammond
 used evacuated glass bottles to collect grab samples for the determination of vinyl chloride concentrations in polyvinyl chloride work areas.
After the samples were collected, the bottles were sealed with silicone rubber septa. Aliquots were later removed by syringe for analysis by gas chromatography.

# Williams et al 1236]
also reported using evacuated stainless-steel containers equipped with critical orifices for collecting grab or integrated samples of air that contained mixtures of vinyl chloride,.vinylidene chloride, and other compounds under laboratory conditions.
Identical results were obtained for samples collected in steel containers from a chamber and for samples taken directly from the chamber.
Stainless steel canisters and Tedlar bags have both been used for sampling for vinyl chloride. Losses of 0-10% vinyl chloride/day were reported for samples stored in Tedlar bags . The losses were attributed either to leakage from the bags or to reactions of vinyl chloride with other air contaminants, such as nitrogen dioxide and ozone.

# Sampling and Analytical Methods
Levine et al  compared the storage stability of vinyl chloride collected in Teflon and aluminized Scotchpak gas sampling bags.
The comparison showed the loss from Teflon bags to be about 20%/day, but it was not determined whether the loss resulted from the permeability of the Teflon, from chemical reaction, or from mechanical problems.
No detectable loss occurred during a 1-week period from aluminized Scotchpak bags that contained samples of vinyl chloride at concentrations of 0.1-1.1 ppm (0.256-2.8 mg/cu m ) .

# Ketterer
 found Teflon bags to be satisfactory for holding samples that would be analyzed for vinyl chloride soon after collection but did not repoct the time between sample collection and analysis. The relative standard deviations for seven samples of vinyl chloride at a concentration of 25 ppm (64 mg/cu tu) and for eight samples at a concentration of 52.2 ppm (133.6 og/cu m) were 2.24 ard 1.772, respectively, and the reported accuracy at both concentrations was 95Z. The author concluded that this degree of accuracy and reproducibility should be readily attainable in field use, since fluctuations in temperature and hunidity and the presence of other volatile organic materials had little effect. .
The major advantage of bag sampling is that it permits direct analysis of the sampled air, ie, without the adsorption and desorption steps required for collection on solid sorbents . Its disadvantages include the bulky equipment required for personal sampling and the relatively high detection limit, approximately 50 ppb (0.13 mg/cu m) tuat results from the sample not being concentrated. Another disadvantage of bag sampling is that the sample volume is limited.

# The most widely used sampling technique involves adsorption on solid sorbents such as Tenax-GC resin and activated charcoal. The major sampling problem in collecting vinyls on solid media is that vinyls have appreciable vapor pressures, which can result in sample migration or loss.
Tenax-GC resin was used by Ives  to concentrate grab samples of contaminated air. Average recoveries of 90Z for vinyl chloride at 6 ppb (0.015 mg/cu m) and 1002 at 60 ppb (0.15 mg/cu m) were reported when contaminated air in a 500-ml gas sampling tube was flushed with nitrogen through the Tenax-GC resin trap at a flowrate of 85 ml/minute for 35 minutes. The crap was cooled in dry ice. Ahlstrom et al  reported that Tenax-GC resin did not quantitatively adsorb vinyl chloride from the atmosphere, but they presented no data supporting thi3 conclusion.
Zado and Rasmuson  reported that the breakthrough volume for vinyl chloride on Tenax-GC resin was 170 ml at a flowrate of 30 ml/minute, but they did not specify the concentration sampled nor the dimensions of th*s resin bed. They stated that Tenax-GC resin had the next to the poorest breakthrough performance of 10 absorbents tested. Nelms et al  described a permeation sampling technique using a charcoal badge, 41 x 48 mm and 7 mm thick, pinned to the worker's clothing for has most oftan been analyzed by gas chromatography. This method has the advantages of being more specific and less expensive than infrared analysis. The authors noted that Its disadvantages Include the requirement of expensive equipment and the inability to make repeated injections of the sample.
They suggested using the less expensive Porapak N instead of Carbosleve B. However, the disadvantage of Porapak X Is its low breakthrough volume of 976 al, compared with greater than 2,000 ml for Carbosleve B, at a flowrate of 50 ml/mlnute. of charcoal.
After the charcoal was added, the flask was sealed and covered with dark paper, and the contents were stirred magnetically for 7 minutes. During this procedure, vinyl chloride is converted to 1,2-dibromo-lchloroethane, which has a much greater sensitivity to electron-capture detection than vinyl chloride.
For samples enriched by column chromatography and determined by gas chromatography using an electron-capture detector, the authors reported a recovery of at least 35%.

# Desorption of vinyl chloride with tetrahydrofuran was reported in an
Environmental Protection Agency (EPA) publication . Recovery was 88%, and there was le.. diffusion into the heaaspace than was evident with carbon disulfide d3orp:ion; however, the solvent volume and the desorption conditions were not reported.
Ethyl Corporation  reported that a carbon disulfide-pentane .xture was used to desorb vinyl bromide from about 14 g of Pittsburgh 20x50 activated carbon.
No data were located on the desorbing agent for vinyl fluoride and vinylldene fluoride samples.  XVII-8 shows the specificity and approximate detection limit of each of these detectors for vinyl chloride.

# Electron-capture detectors belong to the general class of direct-current ion chambers.
Nitrogen or argon is used as the carrier gas, and 3H or 63N1 is used as the radioactive source to excite the gas. As compounds are eluted from the gas chromatographic column, they become ionized by the excited carrier gas and produce an increased current flow across parallel electrodes. The current flow is proportional to the amount of compound present.
Electroncapture detection is more selective than flame-ionization detection, but it is less reliable and has a smaller dynamic range . A further disadvantage of electron-capture detection with respect to vinyl chloride analysis is that response to aromatic halides and polychlorinated hydrocarbons is relatively low . %}ffmann et al  have extended the electron-capture detection limit for vinyl chloride by brominating vinyl chloride to produce 1 ,2-dibromo-1-chloroethane. The detection limit for this compound was 15 pg/injection, and the response was linear between 50 and 300 pg . Mlcrocoulometrlc detection is highly sensitive and accurate for chloride ions . As chlorinated hydrocarbons are eluted from the gas chromatograph column, they are pyrolyzed to form hydrogen chloride gas. The hydrogen chloride causes silver chloride to precipitate, and to disturb the electrical balance at the positive silver electrode.
The couxometer regenerates silver ions until the electrical balance is restored, and the current generated to restore th balance is proportional to the number of chloride ions generated. Ernst and Van Lierop  used a Hall detector (microcoulometer) for the analysis of vinyl chloride; the vinyl chloride was pyrolyzed in a quartz tube in the presence of hydrogen and the hydrogen chloride formed was detected as a function of the increased conductivity of an aqueous reservoir. A detection limit of 0.07 ng, slightly better than the flame-ionization detection limit, has been reported , The major advantage of nicrocoulometry is its sensitivity to organohalides .
Its disadvantage is its electrical power requirements, which make the detector impractical for field use According to reports of t;ie NIOSH-acceptad method for the analysis of vinyl chloride , and the MCA uethod for vinylidene chloride , a sample of 0 .2 ng/injection of vinyl chloride and vinylidene chloride, respectively, can be detected by flame-ionization. However, the conditions under which the MCA method was tested were not specified.
For vinylidene chloride analysis, the NIOSH-proposed method  reports that a sample loading of 7 ig (about 35 ng/injection) had - desorption efficiency of greater than 802. Detector response is generally a function of the number of carbon atoms in a molecule of a compound, although a reduced response or no response may occur when the carbon atom is attached to atoms other than hydrogen, such as chlorine, oxygen, or sulfur several substances that are present in ambient air act as interferences, and thus the method is not specific for vinyl chloride. The EPA report  noted chat vinyl chloride is detectable at an absorption frequency of 941 or 917 1/an. The authors pointed out that these major problems could be circumvented by additional instrumentation, but they cautioned that the cost would be high.
Effective optical paths of 20 meters are required in order for infrared analyzers to achieve a detection limit of 1 ppm (2.56 mg/cu m ) .
Other methods that have been used to determine vinyl chloride concentrations Include colorimetry and polarography .
The sensitivities of the colorimetric methods are very much affected by such interferences as ethylene and methanol, and the sensitivity of the polarographic method is affected by any other volatile materials that may be present.

# Gronsberg
 used a photometric method to determine concentrations of vlnylldene chloride in air. Bis method is based on the reaction of vinylidene chloride with pyridine and on subsequent condensation of the reaction products with aniline or barbituric acid.
After the reaction, a polymethine dye complex is formed.
The method has a sensitivity of 2 tg/photometric cuvette volume and is capable of determining vlnylldene chloride in air at concentrations of 10 mg/cu m (2.5 ppm). . The author reported that vinyl chloride, acrylonltrile, dichloroethane, and hydrogen chloride had no effect on the analysis for vlnylldene chloride but noted that trichloroethylene and 1 ,1 ,2-trichloroethane produced analogous reactions.

# Color-specific detector tubes are available fcr the determination of vinyl chloride or vlnylldene chloride in the work environment.
Two types of color reactions, one using chromate and bromophenol blue, and the other using permanganate and o-tolidine, were used for analyzing for vinyl chloride . Their ranges of linearity were 0. Interferences by nitric oxide, carbon disulfide, and trlchloroethylene, however, are not removed by this scrubbing method.

# (4) Recommendations
The analytical methods described in detail in Appendices II-VI offer the necessary quantitative sensitivity and precision.
Their accuracy, technical requirements, and cost requirements are easily within the range of most analytical laboratories.  6)11. Continuous monitors should be Installed to monitor vinyl bromide, vinyl fluoride, or vlnylide.ie fluoride as soon as systems sensitive enough become available. The system Ideally should be highly sensitive and specific to the vinyl halides sampled and free of Interferences.

# Environmental Levels
In 1975, Barnhart et al  reported the results of NIOSH Industrial hygiene surveys of vinyl chloride monomer producers and polyvinyl chloride processers. Three vinyl chloride manufacturing plants and seven polyvinyl chloride processlr% plants were included in the study. Workplace air samples were collected on charcoal tubes and analyzed by gas chromatograph after desorption with carbon disulfide. The survey found concentrations in the range of 0.1-9.20 ppm (0.256-23.55 mg/cu m) in the monomer plants and 0.01-0.35 ppm (0.03-2.18 mg/cu m) in the polyvinyl chloride processing plants. The authors concluded from these data that polyvinyl chloride processors were rarely exposed to vinyl chloride at concentrations greater than 0.5 ppm (1.28 mg/cu m), which was the Federal action level at that time. Monomer production workers, on the other hand, had a greater risk of vinyl chloride exposure. Polyvinyl chloride producers were not included in this study.
Results of other vinyl chloride monitoring surveys have also been reported  and the data are presented in Tables IV-1 and IV-2.
Baretta et al  monitored the concentrations of vinyl chloride in a vinyl chloride polymerization plant, apparently before and during 1967, continuously with an infrared spectrometer. Five sampling probes were placed in the work area for each of four job classifications, and mean vinyl chloride concentrations were calculated weekly. Mean area concentrations for the coagulator operator, dryer operator, blender-packager, and polymer operator declined steadily during the 7 months of the study. The authors attributed the decline to undescrlbed "actions undertaken to reduce the atmospheric concentration" of vinyl chloride.
Weekly average vinyl chloride concentrations decreased from 205 to 40 ppm (524.8 to 102.4 mg/cu m) for coagulator operators and from 90 to 20 ppm (230 to 51 mg/cu m) for dryer operators. Blender-packagers and polymer operators were consistently exposed at concentrations below the target concentration of 50 ppm (128 mg/cu m) used in the plant at that time.
Kramer and Mutchler , in 1972, reported 8-hour TWA concentrations for vinyl chloride of from 0 to 300 ppm (0 to 768 mg/cu o) in a vinyl chloride polymerization plant. They stated that the mean TWA concentration was 155 ppm (396.8 mg/cu m) in 1950 and 30 ppm (76.8 mg/cu m) in 1965. Concentrations were estimated on the btsis of area sampling data.     Cook et al , in 1971, reported that concentrations of airborne vinyl chloride inside a reactor during scraping operations tended to be below 100 ppm (256 mg/cu m) and were usually about 50 ppm (128 mg/cu m). These estimates were developed from information supplied by a "small number" of unspecified plants, and the dates of the analyses were not reported.
In 1975, Ott et al   Ott et al , in 1976, also estimated TWA concentrations of vlnylldene chloride from data gathered by area monitoring In production and polymerization facilities from 1956 through 1965. Estimated concentrations ranged from 5 to 70 ppm (19.85-277.9 mg/cu m) with excursions to 1,900 ppm (7,543 mg/cu m). Dow Chemical USA (230] has provided NIOSH with vinylidene chloride monitoring data. These data are summarized in Table IV
Bales , in 1977, provided NIOSH with the results of two industrial hygiene surveys conducted at a vinyl fluoride polymerization and monomer production plant. Samples were collected in 7.7 -liter Teflon bags and were analyzed for vinyl fluoride by gas chromatography. TWA concentrations of vinyl fluoride ranged from 1 to 5 ppm (1.88 to 9.4 mg/cu a) for 11 samples collected from employees' breathing zones. Both personal and area samples collected in the monomer plant showed that concentrations of vinyl fluoride were less than 2 ppm (3.76 mg/cu m) for all but one (21 ppm or 39.5 mg/cu m) sample taken at the start of the operation.
Bales  also reported results from an industrial hygiene survey in a vinyl bromide monomer plant. The data are shown in Table IV

# Engineering Controls
Engineering controls should be used to eliminate the potential for exposure to vinyl halides in the workplace and to prevent fire and explosion. These goals can be achieved with properly constructed and maintained closedsyscem operations and appropriate safety precautions.
Closed-system operations provide the best means for eliminating employee exposures to vinyl halides. Closed-system operations are effective only when tl i integrity of the system is maintained by frequent inspection and by prompt repair of any leaks that are found. Closed-system operations should be performed under negative pressure.
Where closed systems cannot be adequately designed and effectively used, local exhaust ventilation systems should be provided to direct vapors and gases away from employe.es and to prevent the recirculation of contaminated exhaust air. Contaminated air should be directed to an incinerator equipped with scrubbers to remove any toxic combustion products. Exhaust ventilation systems for quality control laboratories or laboratory hoods where samples are prepared for analysis should be equipped with sorbers. Guidance for designing a local exhaust ventilation system can be found in Recommended Industrial Ventilation Guidelines , Industrial Ventilation-A Manual of Recommended Practice , or more recent revisions, and in Fundamentals Governing the Design and Operation of Local Exhaust Syst ms, ANSI Z9. 2-1971 . Ventilation systems of this type require regular inspection and maintenance for effective operation. These Inspections should include face-velocity measurements of the collecting hood or duct, inspection of the air mover and collector, and measurements of vinyl concentrations in workroom air. Continuous airflow indicators, such as oil or water manometers, are recommended and should be properly mounted on collection hoods, ductwork, or laboratory hoods and marked to indicate the appropriate airflow.  Adav-ed from Bales  Although ic may be unnecessary to ventilate monomer production equipment, since it is usually located outdoors, proper ventilation must be provided for Che building from which Che process is controlled . The control building should be maintained under positive pressure, and its air intake should be positioned so as to provide clean fresh air.
The procedures developed for vinyl chloride as discussed in the following paragraphs can also be used to control exposure to the ocher vinyl compounds.
Vinyl chloride monomer is manufactured in closed systems. The maintenance of the integrity of such systems is dependent on careful inspection of seals, especially at joints, valves, and pumps. Generally, where seals are closely inspected and maintained, escape of vinyl chloride can be prevented during monomer production. Several reports, however, have mentioned processes, periods, or areas of potential exposure . These include quality control sampling points , tank car loading , tank car gauging , storage and transfer systems , d istillatio n areas , and leaks from other equipment . These potential sources of exposure in monomer production should be avoided by the use of alternative methods of tank car gauging  (slip-tube gauging has been a source of exposure and should be controlled and monitored ), by the use of purge gas in loading and storage operations, prior to maintenance entry, and in quality-control sample collection , by the careful collection and purification of purge gas, by the use of closed-loop systems for tank car loading and quality control sampling , and by the use of properly maintained laboratory hoods for quality control laboratory procedures.
Most of the cases of angiosarcoma of the liver found in vinyl chloride workers have occurred among employees of vinyl chloride polymerization plants. Controls are needed to reduce worker exposure to vinyl chloride during the opening and cleaning of reaction vessels, at discharge points from relief valves and piping joints, while monomer is being stripped from the polymer, and while tank cars are being loaded or unloaded. A reduction in the frequency of manual cleaning of reactor vessels-is absolutely necessary. The crust on the vessel can contain up to 3-52 monomer, and 30-502 of this may be liberated during cleaning . Automatic high-pressure water, steam, or organic solvent vessel-cleaning systems can reduce the frequency of worker entry into reactor vesselsf . Organic solvents are also toxic to varying degrees, however, and theij use should therefore be carefully controlled. A proposed proprietary system for lining reactc essels is claimed to eliminate resin buildup on the reactor vessel surfaces 1286].
Because vinyl chloride polymerization reactions do not go to completion, polyvinyl chloride resins should be stripped of unreacted monomer. Stripping vessels, slurry tanks, centrifuges, and dryers must be enclosed and exhaustventilated .
If amount of residual monomers in polymers is reduced, the exposure of fabricating workers to vinyl chloride will be substantially reduced. The quantity of residual monomer that is released from a resin depends on the process temperature, the surface area of the resin, and the quantity of unreacted monomer in the resin . Manufacturers should control their process to reduce these factors to the greatest extent consistent with the demands of the process. Fabricators should know the residual monomer content of the polyvinyl chloride resins that they use. Methods are available, eg, aspiration and air stripping , for reducing the residual monomer content of resins early in the fabricating cycle, preferably during the compounding and dry-blending stages. Oberg  found vinyl chloride concentrations of 0.04-1.5 ppm during laboratory blending operations.
Unless adequate ventilation is provided, the escape of residual vinyl chloride from bagged or boxed resin can result in buildup of the vinyl chloride concentration in warehouses and storerooms . According to Oberg , vinyl chloride concentrations of 0.8-1.5 ppm have been found in storage areas. A manufacturer of vinylidene chloride reported that a latex containing 2,000 ppm of unreacted vinylidene chloride released 1,000 ppm of vinylidene chloride in 1 week of storage . High storage or processing temperatures aay also accelerate Che release of unreacted monomer. Oberg found ranges of vinyl chloride concentracions of 1.5-2.2 ppm aC 46-68 C and 60-120 ppm at 71-110 C.
In vinyl production areas, employers should in stall automatic, multipoint continuous monitoring systems with alarm devices sensitive to airborne vinyls at the recommended exposure lim its. Baker and Reiter  reported on a highly sensitive automatic monitoring system using a gas chromatograph equipped with a flame-ionization detector and an alarm device that activated when either the vinyl chloride concentration exceeded a preselected level, the check 3ample analysis was out of rar-ge, or the sample flow was insufficient. The system required 2 minutes for an analysis, and each analyzer could monitor up to 20 locations. Areas in which high vinyl concentrations are detected should immediately be monitored for gas leaks with a portable organic vapor analyzer. Also, entry into such areas should be limited to authorized personnel with proper protective clothing and equipment. As soon as a leak is located, properly equipped maintenance personnel familiar with emergency procedures should try to repair it.
Efforts should be made to minimize the extent to which vinyl vapors mix with air in confined or regulated areas and to prevent vapors from being exposed to any ignition source. A flexible hose ventilation unit and recovery system which can be moved to the source of the leakage should be available to control leaks which are not readily repaired.
Unloading vinyls from railroad tank cars Is especially hazardous while lines and hoses are being coupled and uncoupled. Vinyl chloride vapor and vapor from other vinyl halides also remain in tank cars after the liquid is removed. If compressors and pumps are used to remove the vapor, care should be taken fo avoid leaks from this equipment. It has been suggested that tank cars be emptied down to only the vinyl chloride vapor pressure, which eliminates the need to purge the car and reduces the use of pumps and compressors .
Storage and process areas where vinyl halides are stored as liquids shouJd be diked to prevent the uncontrolled spread of any spilled material. The diked areas should be designed with drainage systems to carry spilled material into holding ponds or other areas where the product can be recovered or disposed of in a safe manner.
The flaamability of some of thes- compounds mandates careful design and operation of a ll spark-or heat-producing equipment in vinyl halide work areas. Electric systems and motors must be spark-and explosion-proof. Sump pumps in diked areas must also be explosion-proof.
Achievement and maintenance of reduced concentrations of airborne vinyls In the workplace are dependent on the implementation of the engineering control recommendations. According to an unpublished report  submitted to NIOSH, Che available data suggest thac a combination of many control measures Is required to keep vinyl chloride concentrations at or below the current Federal occupational lim it of 1 ppm (2.56 mg/cu o ). Since the promulgation of the vinyl chloride standard in 1974, many different types of control techniques have been employed Id work areas, and employee vinyl chlorides to vinyl chloride have been greatly reduced. Table 17-5 shows the apparent reductions in vinyl chloride concentrations that have been achieved in typic.il vinyl chloride polymerization slants, especially during 1974-1975, when most of the controls were installed , r  In all workplaces where the vinyl halides are produced, handled, u se d o r stored, employers should supplement engineering and administrative controls with appropriate work practice programs. Work practice programs 3hould be oriented toward methods for handling vinyl halides, procedures for cleaning up spills and responding to emergencies, and use and care of personal protective clothing and equipment. In addition, a regular program of instruction should be established to ensure that all potentially exposed employees are familiar with the specific hazards of each vinyl halide and with appropriate procedures for handling them. Employers should inform employees of any adverse effects that could be caused by inhalation of decomposition products. If contractors are employed for maintenance and repair activities or cleaning of vinyl contaminated equipment, employers should ensure that the contractor personnel are also familiar with the hazards of the compounds and with precautions to be taken when performing their duties. Employers may use the Material Safety Data Sheet presented in Appendix XVI as a guide in providing employees with the necessary information.
The vinyl halides vary In their toxicities (Chapter III) and their chemical and physical properties (see Table XVII -1). Although this chapter and the literature cited in it deal mainly with vinyl chloride, all of the vinyl halides are similarly produced, handled, stored, and transported. Similar practices and engineering controls will usually be applicable, therefore, to all vinyl halides; those specific for each halide ate discussed separately. The control procedures outlined in Chapter IV for specific processes involving vinyl chloride are not a substitute for good general work practices.
Since the promulgation of the 1974 Federal occupational exposure limit of 1 ppm (2.56 mg/cu m) for vinyl chloride, many papers have been published on various ways to reduce workar exposure to this compound. Although some practices are applicable to work with vinyl chloride at any time, most controls and practices can be separated into those that apply to monomer production, those that apply during polymer production, and those that apply during polymer fabrication or processing.
Although closed loop systems may be used for quality-control sampling, the proximity of the employee to the sample cylinder connections greatly Increases the likelihood of exposure in the event of leaks . Therefore, caution should be used in collecting quality-control samples even where closed loops are used.
All work areas in which exposure to vinylidene chloride or vinyl bromide may occur should be posted with warnings that a potential human carcinogen is present. For potential exposure to vinyl chloride, the area should be posted to warn that a human carcinogen is present.
Entry into regulated areas, as defined in Appendix I (29 CFR 1919.1017 (e)), or confined or enclosed spaces should be carefully controlled by a permit system or the equivalent. A confined or enclosed space is usually thought of as any reactor, autoclave, tank, chamber, vat, pit, pipe, flue, duct, bunker, or undergrade room and only properly protected personnel trained in emergency procedures should be permitted to enter such areas . Unauthorized personnel and those not properly protected should not be permitted to enter regulated areas oi confined or enclosed spaces. Records of those who enter these spaces should be kept by means of a daily log, employment records, or the equivalent. Properly fitted protective clothing and equipment should be worn by anyone entering such areas, and suitable respiratory equipment should be worn if vinyl concentrations exceed the permissible exposure limits.
Whenever airborne vinyl halide concentrations exceed the recoranended environmental limits, respirators must be used in accordance with Table 1-1. The current Federal standard for vinyl chloride allows the use of a chemical cartridge respirator or a gas mask, front-or back-mounted canister, at concentrations of vinyl chloride not exceeding 10 ppm or 25 ppm, respectively. Service life requirements, 1 hour for a cartridge and 4 hours for a canister, are also listed (29 CFR 1910.1017 (g)). NI0SH, however, has also requited that end-of-servlce-life indicators be used with cartridge and canister airpurifying respirators. In December 1974, NI0SH and MSHA published the requirements for a canxster or cartridge respirator with end-of-service-life indicators for use in vinyl chloiride atmospheres . NIOSH has recently approved the 3M No. 8716 vinyl chloride cartridge respirator, which has an end-of-service-life indicator, for use in vinyl chloride at concentrations up to 10 ppm (DP Wilmes, written communication, February 1978). End-of-service-life indicators for canister gas masks for vinyl halides have yet to he developed. To prevent exposure through leakage, NIOSH recommends that each employee be provided ar- appropriate individuallyfitted respirator in good, clean condition, and that employees be drilled In the use of these respirators and In testing them for leakage, proper fit, and proper operation.
Since vinyl chloride, vinyl bromide, vinyl fluoride, and vinylidene fluoride are gases at ambient conditions and are liquids only under pressure, a hazard from splashes rarely exists under normal working conditions. These compounds can nevertheless cause eye and skin irritation, and contact with them should be avoided. Vinylidene chloride is a liquid at ambient conditions. Bccause the pressurized materials evaporate rapidly on release, excessive exposure to undiluted liquid vinyls could cause a "frostbite" type of "burn" . Warnings against skin irritation and burns from contact with liquid vinylidene chloride and vinyl chloride have been published . Phenolic inhibitors of polymerization, formerly used widely, have been implicated in the causation of burns by contact with surfaces from which he inhibiced vinyl monomer had evaporated, leaving a film of Che inhibicor . If a vinyl halide is splashed on the skin, the affected areas should immediately be washed v'ith soap and water. If eye exposure occurs, the affected eye should be rinsed with water for at least 15 mir.utes, and medical attention should be obtained as soon as possible , Eyewash fountains and emergency showers should be located near all vinyl exposure areas and should be readily accessible.
Employees who handle vinyl'1 or enter vinyl exposure areas should be provided with appropriate clothing. Protective clothing should be provided clean and dry for each use. To prevent contamination of otheir work areas, employees should not wear protective clothing outside exposure areas. In most vinyl operations, employees should use coveralls made of any nonsparking material . Employees should also wear safety goggles or glasses with side shields, hardhats, respiratory protective equipment, rubber gloves, and boots whenever they enter confined or regulated areas . One vinyl bromide manufacturer has recommended that neoprene gloves and boots be worn by employees opening process lines and repairing pumps and that a one-piece nylon suit, vinyl-coated on both sides, with attached neoprene boots and gloves be worn by employees entering a reactor vessel or tank . Employers should warn employees that heat stroke may result from the wearing of impervious clothing.
Vinyl-contaminated work clothing should be kept separate from street clothing and should not be removed from the work area. Employers should provide shower and change rooms with locker room facilities that allow for complete separation of work and street clothing. Employers should encourage all employees working in areas where exposure to vinyls might occur to shower before changing from work clothes into street clothes. Employers should be responsible for the laundering of contaminated or soiled clothing, and no employee should be allowed to take or wear home any work clothing. All work clothing should be adequately cleaned after each wearing. Employers should inform laundry personnel of the possible hazard from vinyl contaminants on work clothing. Although the vinyl halides 3re at most only slightly soluble in water, clothing contaminated with liquid vinyls should be allowed to dry befor being laundered. This should be done in a vacuum or other enclosed system provided with air ventilation devices in order to prevent vinyl halide release into the laundry or work area. Waste water should be handled in accordance with all applicable Federal, state, and local regulations.
The vinyl halides addressed in this document are flammable over wide ranges of concentrations in air, and contact with ignition source-should therefore be avoided. Vinyl chloride, vinylidene chloride, vinyl fluoride, and vinylidene fluoride have been reported to be explosive at concenCrations of 3.6-33.0, 7-16.0, 2.6-21.7, and 5.5-21.32 by volume in air, respectively . A producer of vinyl bromide reported that vinyl bromide at concentrations of 6.0-152 by volume in air may-ignite in the presence of highenergy ignition sources and suggested that vinyl bromide be handled as a moderately flammable material  .
Since the vinyl halides are so readily flammable, it is important to prohibit smoking, carrying of uncovered smoking materials such as matches and lighters, open flames, and use of materials that can cause sparks in areas where vinyls are present. Smoking If allowed at all on the plant site should be restricted to designated areas. Signs warning of a danger of fire or explosion should be posted in areas where vinyls are produced, handled, or stored, and transport, containers should have warning labels. Warning 3igns should also be prominently posted in areas where spills and leaks are likely to occur. rocess equipment, 3uch as tanks, pipelines, pumps, and compressors, should be grounded to prevent tne build up of static electricity . Firefighting and respiratory protective equipment should be readily available for use in case of emergency. Employers should inform firefighting personnel of the possible combustion products of the vinyl halides. Vinyl chloride combustion products include phosgene, hydrogen chloride, carbon monoxide, carbon dioxide, and water. Hydrogen chloride is also a major combustion product of vlnylidene chloride. Employers should therefore provide firefighters with protective equipment to prevent injury from inhalation or contact with the combustion products. Vandervort and Brooks  reported that the major thermal decomposition products of polyvinyl chloride films were di-2-ethylhexyl adipate and hydrogen chloride. The authors found no vinyl chloride emissions during hot-wire cutting of the film, but warned against inhalation of aerosol particles from di-2-ethylhexyl adipate and hydrogen chloride.
To ensure tne effectiveness of recommended work practices in protecting the employees' health, employers should require that a ll employees participate in an orientation program when they ara hired and in periodic Information seminars led by personnel qualified by experience or training. During orientation, employees should be informed of the hazards associated with handling of the vinyl halides and of the precautions that should be taken to prevent injury or illness. Employers should also inform employees that vinyl chloride is a known human carcinogen and that the other vinyls are potential human carcinogens. Employees should be made thoroughly familiar with emergency and evacuation procedures.
Periodic training of employees should include opportunities for employees to meet with management personnel to discuss or review safety procedures and new toxicologic findings. New Information an the vinyl halides should be posted in designated areas accessible to employees. It is essential to stress the Importance of the employees' cooperation with management in preventing adverse effects of exposure to vinyls, and employees should be encouraged to report all circumstances that might create the potential for such exposure. significantly pathologic, and they concluded that the accepted TLV for vinyl chloride of 500 ppm (1,300 mg/cu m) was adequate to protect workers. The 1966 documentation  concluded that, "although the available data are conflicting, the preponderance indicatej a compound of relatively low toxicity with which a threshold limit of 500 ppm is consistent."
In 1970, the ACGIH  announced its intentiou to reduce the TLV for vinyl chloride to 200 ppm. In 1972, the ACGIH  reduced the TLV for vinyl chloride to 200 ppm (770 mg/cu m , actually equivalent to 512 mg/cu m) as an 8-hour TWA concentration. Several studies supporting r.his action were cited in the 1971 Documentation of Threshold Limit Values for Substances in Workroom Air , including the 1961 study by Torkelson et al  and the 1963 study by Lester et al . The documentation alsc cited a study, conducted between 1950 and 1967 and presented in 1968 by Mutchler and Kramer , of exposure of chemical plant workers. Workers exposed to vinyl chloride (with about 5 ppm of vinylidene chloride) at a mean concentration of 160 ppm (410 mg/cu m) did not have significant changes in blood pressure, concentration of hemoglobin in the blood, or ECG's, and acroosteolysis was not found. Howevar, changes of possible physiologic significance were acted in serum beta-lipoprotein, Icteric index, and sulfobromophthalein retention. Based on analysis of these data, the authors suggested that some liver dysfunction might result from exposure to vinyl chloride (combined with 5 ppm of vinylidene chloride) at a TWA concentration of 300 ppm (768 mg/cu m) over a working lifetime. The 1971 documentation  concluded that a TWA environmental limit of 200 ppm (770 mg/cu m) for vinyl chloride (with a few ppm of vinylidene chloride) "seems appropriate to prevent adverse systemic effects from long-continued daily exposure."
In 1974, the ACGIH  published a notice that the TLV for vinyl chloride would be reassigned as a result of its newly discovered carcinogenic potential. No specific studies were citfid in support of this action. As of 1977, the TLV for vinyl chloride s till awaited reassignment pending the acquisition of more definitive data .
According to a 1968 joint report of the International Labour Office and the World Health Organization , permissible limits set by foreign countries for vinyl chloride In the working environment include 30 mg/cu m for Bulgaria and 1 mg/cu m for the United Arab Republic and the Syrian Arab Republic. The German Democratic Republic has a limit of 500 mg/cu m for vinyl chloride in the work environment .
Limits adopted in foreign countries since 1974 reflect the accumulating evidence of the carcinogenic potential of vinyl chloride. The United Kingdom has set 25 ppm (64 mg/cu m) a s a TWA limit, with a 50 ppm (128 mg/cu m) ceiling limit , until more definitive information is available. In 1976, the Federal Republic of Germany established Technical Guideline Concentrations for vinyl chloride of 10 ppm (26 mg/cu m) in .existing polymerization plants and 5 ppm (13 mg/cu m) elsewhere until such time as an MAC value could be assigned . Sweden established an 8-hour TWA limit of 1 ppm (2.5 mg/cu m) and a calling limit of 5 ppm (13 mg/cu a) for exposura to vinyl chlorida . The Swedish document notad that vinyl chlorida has carcinoganic properties and that It may be absorbed to a considerable extant through the skin.
The International Labour Office  recently published the following national occupational exposure limits for vinyl chloride: Yugloslavla, 75 ppm (300 mg/cu m , actually equivalent to 195 mg/cu m); Rumania, 100 mg/cu m as a TWA limit and 200 mg/cu m as a celling limit; Australia, 25 ppm (95 mg/cu m , actually equivalent to 64 mg/cu m); Hungary, 50 mg/cu m; Poland and USSR, 30 mg/cu m; Netherlands, 10 ppm (26 mg/cu m) as a ceiling limit; Finland, 10 ppm (26 mg/cu m); and Japan, 2.5 mg/cu m. In Italy, vinyl chloride is regarded as a human carcinogen, and an exposure limit of 5 ppm (13 mg/cu m) has been recommended. However, the exposure limit is intended as a guideline, as are those of Australia, Japan, and tne Netherlands, and is not legally blading. In Cvltzerland, vinyl chloride is regarded as a probable human carcinogen also, and a provisional exposure limit of 10 ppm (26.5 mg/cu m) has been established. Switzerland also requires that the best available technical and medical protective measures be applied to ensure maximum reduction o risk froiu exposure to vinyl chloride.
The 1971 US Federal standard for workplace exposure to vinyl chloride (29 CFR 1910.93) was a ceiling limit of 500 ppm (1,280 mg/cu m), based on the 1968 TLV . Cn January 22, 1974, NIOSH informed the Occupational Safety and Health Administration. (OSHA) that the BF Goodrich Chemical Company had reported the deaths of several or its employees from angiosarcoma of the liver, and that the deaths may have been occupationally related. A fact finding hearing began on February 15, 1974 (reported in the Federal Register 39:35890, October 4, 1974), after consultation with NIOSH and a joint inspection of the BF Goodrich plant by OSHA, NIOSH, and Kentucky Department oi Labor personnel. Preliminary reports of experiments conducted by Cesare Maltoni of the Instituto di Oncologia, Bologna, Italy, and other information disclosed at this hearing indicated that vinyl chloride could induce angiosarcoma in the liver of rats at exposure concentrations as low as 250 ppm (640 mg/cu m). OSHA concluded from the Information presented at the hearing and in posthearing comments that occupational exposure to vinyl chloride was probably the cause of angiosarcoma of the livers observed in workers in the industry. An Emergency Temporary Standard (ETS) was promulgated on April 5, 1974 (Federal Register 39:12342), as 29 CFR 1910.93(q). This standard reduced the permissible exposure level to 50 ppm (128 mg/cu m), as a ceiling limit, and established other requirements, Including monitoring and respiratory protection.
OSHA published a proposed permanent standard (Federal Register 39:16896, May 10, 1974) for the regulation of exposure to vinyl chloride. The proposed standard specified that employee exposure be limited to "no detectable level" as determined by a sampling and analytical method sensitive to 1 ppm with an accuracy of 1 ppm 4502. The proposal also called for monitoring employee exposures and Implementing engineering control and work practice programs when necessary. Hearings on this proposal were conducted from June 25 through June 28 and from July 8 through July 11, 1974. The carcinogenicity of vinyl chloride in three animal species was documented in the record of this proceeding by the studies of Maltoni and of Industrial Bio-Test Laboratories (Federal Register 39:35891, October 4, 1974). These studies demonstrated the induction of angiosarcoma of the liver in rats and mice exposed to vinyl chloride at concentrations as lov as 50 ppm (128 mg/cu m) and in hamsters exposed at higher concentrations. Evidence presented by these and other investigators also Indicated additional tumorlgenic and toxicologic properries of vinyl chloride. CSHA concluded from these findings of angiosarcoma of the liver in experimental animals and employees exposed ,:o vinyl chloride chat vinyl chloride "must be regarded as a human carcinogen, and the probable causal agenc of angiosarcoma of Che liver, and chat exposure of employees to vinyl chloride muse be controlled."
The current permanent standard for worker exposure to vinyl chloride was promulgated on October 4, 1974 (Federal Register 39:35896) and became effective Januarry 1, 1975. The standard (29 CFR 1910(29 CFR .1017, presented as Appendix I of this document, Includes an 8~uur TWA exposure limit of 1 ppm and a ceiling limit of 5 ppm, averaged over any period not exceeding 15 minutes. The standard specifies that no employee may be exposed to direct contact with liquid vinyl chloride.
The standard also establishes requirements for monitoring employee exposure, providing respiratory protection, and instituting medical surveillance programs. A TWA action level of 0.5 ppm (1.3 mg/cu m) also is specified in the standard. Where the results of monitoring show that no employee is exposed in excess of the action level, employers are exempted from certain provisions of the standard.
(b) Vinylidene Chloride In 1975, the ACGIH adopted a TLV of 10 ppm (40 mg/cu m) for vinylidene chloride . Several studies were cited in the 1971 Documentation of Threshold Limit Values for Substances in Workroom Air  in support of this limit. Increased mortality in rats, rabbits, guinea pigs, and monkeys exposed to vinylidene chloride at concentrations as low as 61 mg/cu m (15.4 ppm) for 90 days was reported by Prendergast et al , Gage  found that after vinylidene chloride inhalation 6 hours/day for 20 days at 500 ppm (1,985 mg/cu m) there was nasal irritation, retarded weight gain, and liver cell degeneration in rats. At 200 ppm (794 mg/cu m), there was only slight nasal irritation, and no liver cell abnormalities were observed. Irish  reported liver and kidney damage in rats, rabbits, guinea pigs, and dogs exposed to vinylidene chloride for 6 months at concentrations as low as 25 ppm (99 mg/cu m), and he suggested that concentrations In workplace- be maintained b-'low 25 ppm.
In 1976, the ACGIH  adopted a tentative Threshold Limit Value-Short Term Exposure Limit (TLV-STEL) of 20 ppm -(79 mg/cu m) for vinylidene chloride.
The TLV-STEL was described is the maximum concentration at which employees could be exposed continuously for up to 15 mirutes without suffering 1 i froa intolerable irritation, chronic or irreversible tissue changa, or narcosis sufficient to increase accident proneness, impair self-rescuc, or reduce work efficiency. It should be noted that the 1976 STEL's were not deterained on the basis of occupational or experimental data; rather, they were set eapirlcally. A provision limiting the number of 20-ppm excursions to no acre than four each day, with at least 60'minutes between exposure periods, was also Included.
According to the 1968 joint report of the International Labour Office and the World Health Organization , national permissible H alts for vinylidene chloride in the working environment include the following: Yugoslavia, 200 ppm (794 mg/cu m), listed as "dichloroethylene," and Bulgaria and Hungary, 50 mg/cu m, listed as "dlchloroethvlene." A 1977 publication of the International Labour Office  lists the following occupational exposure limits for vinylidene chloride in foreign countries: Rumania, 500 mg/cu a as a TWA limit and 700 mg/cu m as a celling limit; Poland and USSR, 50 ag/cu a as a celling limit; and Belgiom. Federal Republic of Germany, Netherlands, and Switzerland, 10 ppm (40 mg/cu m). Australia has established a provisional exposure limit of 10 ppm (40 mg/cu m) for vinylidene chloride. The exposure limits shown for Australia and the Netherlands are intended as guidelines and are not legally binding.
No US F---eral standard for workplace exposure to vinylidene chloride currently exists.
(c) Vinyl Bromide In 1971, the ACGIH  recommended a TLV for vinyl bromide of 250 ppm (1,095 mg/cu m). This TLV was adopted in 1972 .
Two studies were included in the 1971 Documentation of Threshold Limit Values for Substances in Workroom Air  as bases for this TLV. In an unpublished study cited by ACGIH, Torkelson determined an oral LD50 of 500 mg/kg in male rats. In acute inhalation studies, Torkelson observed no tissue changes in rats exposed to vinyl bromide at concentrations as high as 25,000 ppm (109,500 mg/cum). Leong and Torkelson  reported no significant pathologic changes in rats exposed for 20 days to vinyl bromide at 10,000 ppm (43,800 mg/cu m). In a chronic inhalation study, they found no significant changes in growth rate, hematology, organ-to-body weight ratio, or gross and microscopic tissue findings as a result of exposure to vinyl bromide at 250 or 500 ppm (1,095 or 2,190 mg/cu m). The ACGIH concluded that "a TLV of 250 ppm should protect against bromide intoxication and organic injury, and.. . excursions even to 500 ppm would be acceptable provided the timeweighted average does not exceed 250 ppm."
In 1976, in addition to the TWA exposure limit of 250 ppm (1,095 mg/cu m) for vinyl bromide, the ACGIH  adopted a tentative TLV-STEL of 250 ppm (1,100 mg/cu m). In 1977, the ACGIH  proposed a reduction of the TLV to 5 ppm (22 mg/cu m).
According to a 1977 publication of the International Labour Offica , axposura limits of 250 ppm (1,095 mg/cu m) for vinyl bromide hava baan sat by Australia, Balgiua, Finland, and tha Netherlands. Tha Australian and Dutch lialts ara intandad as guidalinas and ara not legally binding.
No US Federal standard for workplace exposure to vinyl bromide currently exists.

# (d) Vinyl Fluoride
The ACC1H has not adopted a TLV for vinyl fluoride. No US Federal standard for exposure to vinyl fluoride currently exists. No foreign standard3 have been located.

# (e) Vinylidene Fluoride
The ACGIH has not adopted a TLV for vinylidene fluoride. No US Federal standard for exposure to vinylidene fluoride currently exists. No foreign standards have been located.
Basis for the Recommended Standard (a) Permissible Exposure Limits Among the vinyl halides discussed in this document, only vinyl cr.lorlde is regarded as a known human carcinogen chat can induce a characteristic tumor, angiosarcoma of the liver . Animal studies have shown that vinyl chloride , vinyl bromide , and vinylidene chloride  are capable of inducing angiosarcoma of the liver and other tumors. In these experiments, erp<-rure to vinyl chloride at 50 ppm for 4 hours/day, 5 days/week, for 52 weeks induced angiosarcoma of the liver in 1/59 rats after 135 weeks ; vinyl, bromide at 250 ppm caused angiosarcoma of the liver in 2/30 rats after 52 weeks ; vinylidene chloride at 55 ppm for 6 hours/day, 5 days/week, for up to 12 months caused angiosarcoma of the liver in 3/72 mice . Exposure at higher concentrations induced a greater incidence of tumors and shortened the latency ior their development, indicating that there was a dose-response relationship for tumor Induction.
No reports in regard to the carcinogenicity of vinyl fluoride or vinylidene fluoride have been located. However, this lack of information cannot be construed as an indication that these compounds have no carcinogenic potential. Each of the vinyl halides may form reactive intermediates that can bind to cellular macromolecules 210]. Putative metabolic pathways and reactive Intermediates are shown in Figure XVII-3. The metabolic studies referenced with the figure, along with Information from reports on structureactivity relationships , indicate that both vinyl fluoride and vinylidene fluoride may have the capacity to fora intermediates capable of alkylating DNA, RNA, or proteins.
The hazard potential of these compounds In a biologic system Is difficult to determine, however, because of detoxication mechanisms (reduction, hydrolysis, and conjugation) that compete with alkylation, as well as repair, mechanisms.
Each of the vinyl halides has been found to be mutagenic in some test system. Vinyl chloride has been shown to have a direct mutagenic effect on Salmonella . Vinylidene chloride , vinyl bromide (VT Simoon and R Nangham, written communication, August 1977), and vinyl and vinylidene fluorides  have also been shown to be mutagenic in bacterial test systems. Since many mutagenic compounds are known to also be carcinogenic, these findings suggest that all the vinyl halides might be potential caicinogens.
No studies have demonstrated teratogenic or other affects on human reproduction from exposure to any of the vinyl halides. Structural abnormalities, including Increased numbers of unfused sternebrae, delayed ossification of skull bones, and an increase in the number of lumbar spurs in mice whose dams were exposed to vinyl chloride at 500 ppm during days 6-15 of gestation  and in ra^s exposed in utero to vinylidene chloride at 80 ppm during the same period , have been observed. Other reproductive effects included increased resorptions/implants, decreased numbers of live fetuses/litter, and increased fetal crown-rump length . The authors of these studies suggested that the abnormalities observed wer-seccndary to the maternal toxicity of the compounds.
Although tnese changes are not generally considered to be evidence of teratogenicity, they do indicate fetotoxic effects from maternal exposure to vinyl chloride.
Other adverse health effects attributed to exposure to vinyl halides include CNS 33,78,114,127,129], cardiovascular , respiratory , skin 32,111,112], and skeletal effects , as well as liver and spleen abnormalities 78,113].
The risk to the health of employees exposed to the vinyl halides is a combination of the risks of moplastic and other systemic effects from their inhalation or ingestion and of their subsequent metabolism to reactive intermediates.
The observation of neoplasms in humans and animals exposed to vinyl chloride and in animals exposed to vinylidene chloride and vinyl bromide, the similarities in the excreted metabolic products of the vinyl halides, and the calculations of relative reactivity of these compounds on the basis of their physical and chemical properties suggest that each of the five may have a neoplastic potential.
Concern for employee health requires that risk of carcinogenesis as a result of workplace exposure to these compounds be minimized. NIOSH believes that sufficient information does not exist to warrant changing the present Federal Standard for vinyl chloride as stated in 29 CFR 191029 CFR .1017.
Further,
NIOSH believes that the available information on vinylideie chloride and vinyl brooid indicates that they are at least as toxic as vinyl chloride. Although sufficient biologic information is not available concerning vinyl fluoride and vinylidene fluoride, chemical information suggests that these compounds may also exhibit toxicities similar to that of vinyl chloride, ie, until better animal toxicity and metabolism data are available, there appears to be no reason to treat the fluorides differently from the other vinyl halides.
Therefore, NIOSH recommends that workplace exposure to each of the five vinyl halides be controlled by adherence to the provisions of 29 CFR 191029 CFR .1017, and on the basis of animal carcinogenicity date:, NIOSH suggests that employers make every effort to limit employee exposures to the lowest feasible levels with an eventual goal of zero exposure. As pointed out in Chapter IV there has been a steady decline in workplace environmental concentrations of vinyl chloride since 1974. The lower limits of reliable detectability (see Appendices II-III) are 0.003 ppm for vinyl chloride and 0.5 ppm for vinylidene chloride. Workplace concentrations of vinyl bromide have been measured as low as 0.01 ppm . Vinyl fluoride and vinylidene fluoride in air samples have been measured at concentrations as low as 1 ppm and 2 ppm respectively (see Appendices V-VI).
Since the promulgation cf the vinyl chloride standard in 29 CF3 191029 CF3 .1017 in October, 1974, several advances in respirator technology have taken place.

# V I I. COMPATIBILITY WITH OTHLR STANDARDS
The Environmental Protection A^ancy (EPA), the Department of Transportation (DOT), the Food and Drug Adaialstratlon (FDA), and other Federal agencies have proposed or enacted standards regulating the use or release of several vinyl compounds. The standard recommended by NIOSH in this document for the vinyl halides 13 compatible with the standards promulgated and proposed by other Federal agencies. Standards proposed by other government agencies chat are direct'.y applicable to the standard proposed by NIOSH are reviewed below.
(a) Vinyl Chloride In 1976, CPA established a national emission standard for vinyl chloride (40 CFR 61.60-71) because vinyl chloride had been implicated in the development of angiosarcoma and other serious disorders in occupationally exposed persons and in experimentally exposed animals. Vinyl chloride emissions from ethylene dichlori^e and vinyl chloride production and purification processes were thereby limited to 10 ppm. For the oxychlorlnatlon process, vinyl chloride emissions were restricted to 0.2 g/kg of ethylene dichloride product. Vinyl chloride emissions from polymerization plants were limited to 10 ppm through the stripping stage and to 0.02 g/kg of polyvinyl chloride product when reactors were opened. Emissions of vinyl chloride were required to be controlled after stripping operations by reduction of residual monomer in the polymer to below 400 ppm (2,000 ppm for dispersion resins). Where control devices rather than stripping technology were used to limit emissions, dispersion resins were required to be controlled to 2 g/kg of polyvinyl chloride product and all other resins to 0.1 g/kg of polyvinyl chloride product. EPA assumed that adherence to these limits would reduce hazards to the health of the estimated i.6 million people who live within 5 miles of controlled plants so that '-he incidence of new primary cancers as a result of exposure to vinyl chloride in this group of people would not exceed 1/year of exposure (Federal Register 41:46560, October 21,1976). EPA stated that a complete ban on vinyl chloride emissions was not desirable because (1) vinyl chloride has beneficial uses for which substitutes are not available, (2) potential substitutes may have unknown health effects, (3) unemployment would result, and (4) control technology is available to greatly reduce vinyl chloride emissions.
On June 2, 1977, EPA proposed amendments to the national emission standard (Federal Register 42:28154-28159). Sources currently subject to a 10-ppm emission limit and new sources of this type would be required to limit emissions to 5 ppm. Emissions fron oxychlorlnatlon reactors la ethylene dichlorlde-vlnyl chloride plants would also be limited to 5 ppm. The amendments would direct that residual monomer .in the polymer after stripping be limited to 500 ppm in new dispersion resins and 100 ppm in all other new resins. Where control devices rather than stripping technology would be used co liole mission, aw dispersion resins would have to be controlled Co 0.5 */*g of polyvinyl chloride produce and all ochar new resins co 0.1 g/kg of polyvinyl chlorida produce. The proposed amendments also would prohibit any Increase in ealsslons due co che conseruccion of new sources wlchln 8 km - of exlsdng sources. EPA proposed chese amendments in an effort co conciaue tu approach the rero-em^ssions level for vinyl chloride with available technology because of Its determination that this is the only level absolutely procectivs of health-These H alts and proposed amendments are not directly comparable with those proposed by MlOS'i, since they do not specify breathing zone sampling. They do, however, reflect the same philosophy espoused by NIOSH; chit is, chat the final goal is zero exposure.
Aeroscl drug products containing vinyl chloride as an Ingredient or propellant are considered to be nsw drugs by FDA and are regulated s such (21 CFR 310.506). EPA (Federal Register 39:14753, April 26, 1974), FDA (21 C7R 700.14), and Che Consumer Product Safety Commission (16 CFR 1500.17(a)( 10)) have banned Che use of vinyl chloride as an lngredienc or propellanc in aerosol produces, including pesticides, cosmetics, and foods, intended for consumer use. These standards are more conservative than that proposed by NIOSH; however, they relate primarily to use of the product and only secondarily to occupational exposure.
FDA proposed rules for regulating the use of vinyl chloride polymers in contacC wich food on SepCember 3, 1975 (Federal Register 40:40529-37). FDA stated that the use of vinyl chloride polymers and copolymers should be prohibited where there was a reasonable expectation of migration of vinyl chloride monomer into food. FDA proposed a ban on the use of vinyl chloride polymers and copolymers in food-contact articles except where specifically permitted in the FDA regulations. Exceptions to this ban included coatings, gaskets, cap liners, flexible tubing, and plasticized films. Use of polyvinyl chloride in water pipe was also permitted on an Interim basis pending the outcome of studies to determine whether vinyl chloride could be extracted by water passing through such pipes. FDA has subsequently published regulations concerning the formulations and amounts of extractable monomer allowable in /inyl chloride copolymer components of paper and paperboard in contact with foods (21 CFR 176). Similar regulations for vinyl chloride copolymers used as basic components of single and repeated use food concacc surfaces have also been promulgated (21 CFR 177). These are compaclble, alchough noc directly comparable, wlch the provisions of the NIOSH standard specifying that no food 3hall be stored, dispensed, prepared, or consumed in vinyl halide exposure areas.
The Materials Transportacion Bureau of DOT has designaced vinyl chloride as a hazardous material for purposes of transportation in commerce and has escablished requirements pertaining Co les labeling, packaging, and eransporcation (49 CFR 172.101). Regulations for Che bulk cransport of vinyl chloride by water have been escablished by che US Coasc Guard . These regulations also sec an exposure llmic of 1 ppm (3 mg/cu a), averaged over any 8-hour period, or 5 ppm (13 mg/cu m), averaged - ft over any 8-hour period, or 5 ppm (13 ag/cu o), averaged jver any period noc exceeding 15 miautes, for personnel Involved in vinyl chloride transfer operations. Continuous nonltorlng oust be conducted during such operations, using a method with an accuracy of not less than t502 from 0.25 through 0.5 ppo, t35Z from 0.5 ppm through 1 ppm, and *252 over 1.0 ppm. The US Coast Guard  has also developed a cargo compatibility guide for bulk liquid chemicals indicating combinations of chemicals chat result In dangerous chemical reactions when accidentally mixed inside a cargo tank or pipe. Vinyl chloride Is listed as incompatible with nitric acid and caprolactao solution. Regulations for unmanned barges carrying certain dangerous bulk cargoes, including vinyl chloride, also nave been established by Che US Coast Guard (46 CFR 151). The Coasc Guard stai.iard for occupational exposure is less stringent than chat proposed by NIOSH.
(b) Vlnylldene Chloride FDA has published regulations concerning the formulations and amounts of extractable monomer allowable in vlnylldene chloride copolymer components of paper and paperboard that come into contact with foods (21 CFR 176). Similar regulations for vlnylldene chloride copolymers used as basic components of single and repeated use food contact surfaces have also been established (21 CFK 177).
The Materials Transposition Bureau of DOT has designated vlnylldene chloride as a hazardous material for purposes of cransportatlon in commerce and has established requirements pertaining to les labeling, packaging, and transportation (49 CFR 172.101). In its cargo compatibility guide for bulk liquid chemicals, the DS Coast Guard  has listed vinylidir.e chloride as incompatible with nitric acid and caprolactam solution. Regulations for unmanned barges carrying certain dar~erous bulk cargoes, including vlnylldene chloride, nave been established by the US Coast Guard (46 CFR 151).
NFPA  provides a compilation of information on the hazardous properties and firefighting aspects of vlnylldene chloride. This compound is very flammable and readily forms explosive mixtures in air. Polymerization may occur at elevated temperatures, possibly rupturing containers. A readily explosive peroxide may be formed during long-term storage. In the 1975 Manual of Hazardous Reactions , NFPA notes that vlnylldene c.iloride polymer is self-reactive and may explode under appropriate conditions. It also reports that mixtures of vlnylldene chloride and chlorosulfonic acid, nitric acid, or oleum (fuming sulfuric acid) in closed containers cause increased temperature and pressure. In firefighting operations, NFPA recommended that the gas flow be stopped and that dry chemical, foam, or carbon dioxide be used to extinguish flames. Water may be ineffective in putting out fires, but It should be used to cool containers, protect personnel la the area, flush spills away from flar.es, aad disperse vapors if appropriate. The provisions of the National Electrical Code  and those of the Sections of the National Fire Codes dealing with flammable and combustible liquids  and static electricity  should be complied with where applicable. (d) VInylidene Fluoride FDA has published regulations concerning the formulations and amount of extractable aononer allowable in polyvinylidene fluoride resin ccmponints of articles intended for repeated food-contact 'jse (21 CFR 177.2510).
(e) Vinyl Bromide No other standards were located for this compound.

# V I I I . RESEARCH SEEDS
The current information on biologic effects of exposure to the vinyl halides is incomplete. Vinyl chloride has been studied more extensively chan the ocher vinyl halides; however, ch? exact mechanism of its toxic action is not known. Further studies are needed Co obcain additional information.

# (a) Epidemiology
Since one scudy  has suggesced chac vinyl chloride causes increased fecal mortality in che wives of exposed workers, stjcies should be performed to invesr.igace tuis potential for each of che vinyl halides.
Epidemiologic studies should be conducted to compare cohorts from the same plart having various magnitudes of exposure. This can be done relatively easixy for Che vinyl halides since these compounds are generally produced and used in specific units of large chemical planes. The epidemiologic studies should include precautions to minimize the "healthy worker" and "survivor" effects usually apparent in any worker population.
(j) Toxic Effects Exposure to vinyl chloride has been shown to induce a wide variety of coxic effects including central nervous, respiratory, cardiovascular, digestive, skin, and skeletal system effects. Studies should be designed to determine which of these systems are affected directly by vinyl chloride or its metabolites and which effects if any are secondary to the primary systemic effects. Studies should also be conducted to determine che range of coxic effects of exposure to the other vinyl halides. These studies should be designed so that comparison of primary coxic effeccs can be made becweer. che compounds, ie, the same species, strains, and protocols should be used for each study.
Studies should be conducted to determine the long-term effects of inhaled and Ingested vinyl fluorides. Because of the Increasing latency of turner induction with decreasing exposure concentrations reported in studies of animals exposed to vinyl chloride , future experiments should not be terminated until the animals become moribund or die.
(c) Sampling and Analysis Experiments are needed to validate the lower range of the sampling ani analytical methods proposed for vinyl bromide, vinyl fluoride and vinylidene fluoride. Procedures and equipment should be improved to further minimize Interferences and standardize the measurement of these compounds.
Although continuous monitoring devices are conmerctally available for vinyl chloride and vinylidene chloride, such devices are needed for the other vinyl halides. Research should also be conducted to Increase che sensitivity and accuracy of che existing equipaent so that reliable, continuous records of exposure for all work areas can be obtained.
Research is also necessary to develop techniques for biologic nonicorlr.g. At present, because of che rapid aetabolism of che vinyl halides, blood ar.alyses have only indicated adverse effects rather chan determining exposures, and urinalysis has not been developed co che extent necessary to define exposures. Further studies of metabolism and excrecion may develop che information necessary co calculate che bodv burden from che excrecion produces, so chat an accurate assessment of che rotal accumulated dose :an be tia d e .
In addicion, resources should be expended co assess che currenc st re of concrol technology and the feasibility of implementing advances in this area. Thought should be given to the feasibility of using less toxic substitutes. Finally, respirators with end-of-service-life indicators should be developed for the vinyl halides for which they are not available. (2) No employee may be exposed to vinyl chloride at concentrations greater than 5 ppm averaged over any period not exceeding 15 minutes.
(3) No employee may be expor^d to vinyl chloride by direct contact with liquid vinyl chloride.
<rt) M onitoring. Cl) A program of Initial monitoring and measurement shall be undertaken In each establish ment to determine If there Is any em ployee exposed, without regard to the use of respirators, In excess of the action level.
(2) Where a determination conducted urider paragrapn (d)(1) of this section ihovvs any employee exposures, without regard to the use of respirators. In ex cess of the action level, a program for de termining exposures for each such em ployee shall be established. Such a pro gram:
 Shall be repeated a t least monthly where any employee Is exposed, without regard to the use of respirators. In ex cess of the permissible exposure limit.
(11) Shall be repeated not less then Tuarterly where any employee is exposed, without regard to the use of respirators. In excess of the action level.
(Ill) May be discontinued for any em ployee only when at least two consecu tive monitoring determinations, made not less than 5 working days apart, show ex posures for that employee a t or below the action level.
(3) Whenever there has been a pro duction, process or control change which may result In an Increase In the release of vinyl chloride, or the employer has any other reason to suspect that any em ployee may be exposed in excess of the action level, a determination of employee exposure under paragraph (d) (1) of this section shall be performed.
(4) The method of monitoring and measurement shall have an accuracy (with a confidence level of 95 percent) of not less than plus or minus 50 pcrcenfc from 0.25 through 0.5 ppm, plus or minus 35 pcrccnt from over 0.5 ppm through 1.0 ppm, nnd plus or minus 25 percent over 1.0 ppm-(Methods meeting these accuracy requirements are available In the "NIOSU Manual of Analytical Methods").
(5) Employees or their designated rep resentatives shall be afforded reasonable opportunity to observe the monitor ing and measuring requited by this paragraph ic) R egulated area. (1) A regulated area shall be established where:
(1) Vinyl chloride or polyvinyl chloride is manufactured, reacted, repackaged, stored, handled or used; and <U) Vinyl chloride concentrations are In excess of the permissible exposure limit.
(2) Access to regulated areas shall be limited to authorized persons. A dally roster shall be made of authorized p e r sons who enter.
(f) M ethods of com-pliance. Employee exposures to vinyl chloride shall be con trolled to at or below the permissible ex posure limit provided in paragraph (c) of this section by engineering, wori prac tice. and personal protective controls as follows:
(1) Feasible engineering and work practice controls shall immediately be used to reduce exposures to at or below the permissible exposure limit.
(2 Wherever feasible en?ineering a id work practice controls which cr.n be In stituted immediately are not sufficient to reduce exposures to at or below the per missible exposure limit, they shall none theless be used to reduce exposures to the lowest practicable level, and shall be supplemented by respiratory protection in accordance with paragraph (g) of this section. A program shall be established and implemented to reduce exposures to at or below the permissible exposure limit, or to the greatest extent lcasible, solely by means of engineering and work practice controls, as soon as feasible.
(3) W ritten plans for such a p e gram shall be developed and furnished upon request for examination and copying to authorized representatives of the Assis tan t Secretary and the Director. Such Plans shall be updated a t least every six months. (3) A respiratory protection program meetinc the requirements of ! 1910.134 shall established and maintained.
 Selection of respirators for vinyl chloi.le shall be os follows:
(5) (i) Entry Into unkoTvn concentra tions or concentrations greater than 36.0C0 ppm (lower explosive limit) may be made only for purposes of life rescue; and
(II) Entry Into concentrations of less than 36,000 ppm, but greater than 3,600 ppm may be made only for purposes of life rescue, firefighting, or securing equipment so as to prevent a greater hazard from release of vinyl chloride.
(6) Where air-purifying respirators are used:
(I) Air-purifying cannlsters or car tridges shall be replaced prior to the expiration of their service lire or the end of the shift in which they <Lve first used, whichever occurs first, and (II) A continuous monitoring and alarm system shall be provided where concentrations of vinyl chloride could reasonably excccd the allowable concen trations for the devices In use. Such sys tem shall be used to alert employees when vinyl chloride concentrations exreed the allowable concentrations for the devices In use.
(7) Apparatus prescribed for higher concentrations may be used for any lower concentration.
(h) Hazardous operations. (1) Em ployees engaged In hazardous operations. Including entry of vessels to clean poly vinyl chloride residue from vessel walls, shall be provided and required to wear and use;
(1) Respiratory protection in accord ance with paragraphs (c) and (g) of this section; and
(il) Protective garments to prevent skin contact with liquid vinyl chloride or with polyvinyl chloride residue from vessel walls. The protective garments shall be selected for the operation and Its possible exposure conditions.
(2) Protective garments shall be pro vided clean and dry for each use.
(1) Emergency situations. A written operational plan for emergency situa tions shall be developed for each facility storing, handling, or otherwise using vinyl chloride as a liquid or compressed gas. Appropriate portions of the plan shall be Implemented In the event of ai. emergency. The plan shall specifically provide that:
(1) Employees engaged in hazardous operations or correcting situations of ex isting hazardous releases shall be equipped as required in paragraph (h) of this section;
(2) Other employees not so equipped shall evacuate the area and not return until conditions are controlled by the methods required in paragraph (f) of this section and the emergency is abated.
(J) Training. Each employee engaged In vinyl chloride or polyvinyl chlor'de operations shall be provided training in a program relating to the hazards of vinyl chloride and precautions for its safe use.
(1) The program shall include:
(1) The nature of the health hazard from chronic exposure to vinyl chloride including specifically the carcinogenic hazard:
(li) The specific nature of operations which could result In exposure to vinyl chloride In c.xcess of the permissible limit and necessaiy protective steps;
(ili) The purpose for. proper use, and limitations of respiratory protective devices;
(Iv) The fire hazard and acute toxic ity of vinyl chloride, and the necessary protective steps;
(v) The purpose for and a description . of the monitoring program;
(vi) The purpose for, and a descrip tion of, the medical surveillance program;
(vii) Emergency procedures;
(viii) Specific Information to aid the employee In recognition of conditions which may result in the release of vinyl chloride; and
(lx) A review of this standard at the employee's first training and Indoctrina tion program, and annually thereafter.
(2) All materials relating to the pro gram shall be provided upon request to the Assistant Secretary and tl'? Director.
(k) M edical surveillance. A p.csram of medical surveillance shall be 'nstltuted for each employee exposed, with out regard to the use of respirators, to vinyl chloride In excess of the action level. The program shall provide each such employee with an opportunity for examinations and tests in accordance with this paragraph. All medical ex aminations and procedures shall be per formed by or under the supervision of a licensed physician, and shall be provided without cost to the employee.
(1) At the time of Initial assignment, or upon Institution of medical surveil lance;
(I) A general physical examination rhall be performed, with specific atten tion to detecting enlargement of liver, spleen or kidneys, or dysfunction In these organs, and for abnormalties in skin, connective tissues and the pulmonary system (See Appendix A).
(II) A medical history shall be taken. Including the following topics: (E) Gamma glustamyl transpeptidase.
(2) Examinations piovlded in accord ance with this paragraph shall be per formed at least:
(i) Every 6 months for each employee who has been employed in vinyl chlo ride or polyvinyl chloride manufacturing for 10 years or longer; and
(li) Annually for all other employees.
(3) Each employee exposed to an emergency shall be afforded appropriate medical surveillance.
(4) A statem ent of each employee'. ' ; suitability for continued exposure to vinyl chloride Including use of protec tive equipment and respirators, shall be obtained from the examining physician promptly after any examination. A copy of the physician's statement shall be pro vided each employee.
(5) If any employee's health would be materially impaired by continued ex posure. such employee shall be with drawn from possible contact with vinyl chloride.
(S) Laboratory analyses for all bio logical specimens included in medical examinations shall be performed In labo ratories licensed under 42 CFR Part 74.
(7) If the examining physician deter mines that alternative medical examina tions to those required by paragraph  of this section, if the employer obtains a statem ent from the examining physician setting forth the alternative examinations and the rationale for sub stitution. This statem ent shall be avail able upon request for examination and copying to authorized representatives of the Assistant Secretary and the Director.
(1) Higns and labels.  (m) Records. (1) All records main tained in accordance with this section shall include the name and social secu rity number of each employee where relevant.
(2) Records of required monitoring and measuring, medical records, and au thorized personnel rosters, shall be made and shall be available upon request for examination and copying to authorized representatives of the Assistant Secre tary and the Director.
(1) Monitoring and measuring records shall:
( (C) Be maintained for not less than 30 years.
(il) Authorized personnel rosters shall be maintained for not ess than 30 years.
(iii) Medical records shall be main tained for the duration of the employ ment of cach employee plus 20 years, or 30 years, whichever Is longer.
(3) In the event that the employer ceases to do business and there is no successor to receive and retain his rec ords for the prescribed period, these rec ords shall be transmitted by registered man to the Director, and each employee Individually notified in writing o ' this transfer.
(4) Employees or their designated representatives shall be provided access to examine and cop'' records of required monitoring and measuring.
(5) Former employees shall be pro vided access to examine and copy re quired monitoring and measuring records reflecting their o .?n exposures.
(6) Upon written request of any em ployee, a copy of the medical record of that employee shall be furnished to any physician designated by the ;mploy>"i.
(n) Reports. (1) Not later than 1 month after the establishment of a reg ulated area, the following information shall be reported to the OSHA Area Di rector. Any changes to such information shall be reported within 15 days.
(i) The address and location of each establishment which has one or m arl regulated are?s; and
(ii) The number of employees In each regulated area during normal operations. Including maintenance.
- 2) Emere<'ncl<*<!. and the facts ob tainable at that time, shall be reported within 24 hours to the OSHA Area Di rector. Upon request of the Area Direc tor, the employer shall submit additional Information In writin? relevant to the nature and extent of employee exposures and measures taken to prevent future emergencies of similar nature.
(3) W ithin 10 -working days following any monitoring and measuring which discloses that any emolovee has been exposed, without regard to the use of respirators, in excess of the permissible exposure limit, each such employee shall be notified in writing of the results of the exposure measurement and the steps being taken to reduce the exposure to within the permissible exposure limit.
(o) Effective dates. (1) Until April 1, 1975, the provisions currently set forth in 5 1910.93q of this Part shall apply.
(2) Effective April 1, 1975, the pro visions set forth in  1910.93q of this P art shall apply.
A r p r v t j i x A -S u p p l i m e n t a r t M c s ic a I.
I n f o r m a t i o n W hen required tests inder parnsrapli ( k ) ( l) of tills section chow abnorm alities, th e tests should be repeated as 6oon as p rac ticable. preferably w ithin 3 to 4 weeks. I i tests rem ain abnorm al, ">nslcJeratlon should be given to tvlthdraw al oi th e em ployee from co n tact w ith vinyl chlorldc, w hile a m ors com prehensive exam ination Is m ade.
A dditional tests which m ay be useful:
A.  January 29, 1976 . This method involves adsorption on activated carbon, desorption with carbon disulfide, and gas chromatography. The range for determination of vinyl cnloride using this method is 0.008-5.2 mg/cu m (0.003-2.03 ppm) in a 5-liter air sample. The precision (coefficient of variation-CV(T)) is approximately 0.08 at levels of 7 and 71 mg/cu m (2.73 and 27.7 ppm).

# Principle of the Method
A known volume of air is drawn through two sorbent tubes in series containing activated carbon (made from coconut sh ells), which adsorbs the vinyl chloride present in the air sample. The c o lle c te d vinyl chloride is then desorbed with carbon disulfide, and the resulting solutions are analyzed by gas chromatography with a flame-ionization detector. The areas under the resulting peaks are compared with areas obtained from the injection of standards.

# Range and Sensitivity
(a) The minimum detectable amount of vinyl chloride was found to be 0.2 ng/injection at a 1 x 1 attenuation of a gas chromatograph. This corresponds co an estimated concentration of 0.008 mg/cu m in a 5 -liter air sample analyzed by this method. However, the desorption efficiency from activated carbon of amounts of vinyl chloride as small as 40 ng (0.008 yg/liter x 5 liters) has not been determined. Therefore, the detection limit of the overall method may be somewhat higher than 0.008 mg/cu m.
(b) At a sampling flowrate of 50 ml/minute, the total volume to be sampled should not exceed 5 lite rs. Thu value is based on data indicating that more than 10 lite rs of air containing 2.6 g/liter (1 ppm) of vinyl chloride could be sampled on activated carbon before 52 breakthrough was observed. This would indicate that 5 lite rs of air containing no more than 5.2 mg/cu m may be sampled without significant breakthrough. If a particular atmosphere Is suspected of containing a high concentration of contaminants or a high humidity is suspected, the sampling volume should be reduced by 50%. A safety factor has been included in the 5-11ter volume, and the capacity of the first tube should be adequate within these limits except under the most extreme conditions.

# Interferences
(a) When Che amount of water in the air is so great that condensation actually occurs in the tube, organic vapors 'will not be trapped effectively. Experiments indicate that high humidity severely decreases the capacity of activated carbon for organic vapors.
(b) When two or more substances are known or suspected to be present in the air, this information, Including their suspected identitie.1, should be transmitted with the sample, since these compounds may interfere with the analysis for vinyl chloride.
(c) Any compound that has the same retention time as vinyl chloride under the operating conditions described in this method is an Interference. Hence, retention time data on a single column, or even on a number of columns, may not provide proof of chemical identity. Often, operating conditions can be modified to eliminate Interferences. Samples should be analysed by an independent method when overlapping gas-chromatographic peaks canno: be resolved.

# Precision and Accuracy
(a) A coeificient of variation of 0.0.76 was obtained from analysis of each of two sets of sorbent tubes, one set of 27 tubes exposed to vinyl chloride at a concentration of 7.2 mg/cu m in air and another set of 29 tubes exposed at a concentration of 71.3 mg/cu m. These values reflect total sampling and analytical error as well as desorption efficiency correction errors.
(b) Experiments were performed to obtain some indication of the accuracy of this method, although accuracy was difficult to evaluate. These experiments generally involved six sorbent tube samples exposed to a synthetic atmosphere. The calculated value was the concentration expected based on the measured amounts of vinyl chloride and air mixed to prepare the synthetic atmosphere. The calculated value was not the true value, since it was subject to experimental error. The value found from analysis of each sorbent tube, after correction for desorption efficiency, was also compared with that found by the direct injection of gas samples from the same synthetic atmosphere used in loading the tubes. The results of these experiments are shown in Table XI-1. It should be noted that average concentrations determined by analysis of sorbent tubes were within 62 of the average concentrations determined by analysis of gas samples. may lead to sane confusion as to whether sample loss has occurred. This migration effect can be considerably decreased by shipping and storing the tubes at -20 C or by using two separately capped tubes for the front and backup sections.
(c) The precision of the method is limited by the reproducibility of the pressure drop and, therefore, by the flowrates across the tubes. Because the pump is usually calibrated for one particular tube, differences in flowrates from tube to tube can cause sample volumes to vary.

# Apparatus
(a) Personal sampling pump: The pump should be a properly calibrated personal sampling pump for personal and area samples. The pump should also be capable of accurate performance at the recommended flowrates. It should be calibrated with a representative sorbent tube in the sampling line. A dry or wet test meter or a glass rotameter that w ill determine the flowrate to within 52 may be used for the calibration.
(b) Sorbent tubes: The glass tubes are flame sealed at both >nds. Each is 7 cm long, 6-mm outer diameter, 4-mm inner diameter, and contains two sections of 20/40-mesh activated carbon separated by a 3-nm portion of urethane foam. The activated carbon is prepared from coconut shells and is fired at 600 C prior to packing to remove adsorbed m aterials. The primary adsorbing section contains 100 mg of sorbent, the backup section 50 mg. A plug of silanized glass wool is placed in front of the adsorbing section. The pressure drop across the tube must be less than 2 inches of water at a flowrate z 0. (e) A mechanical or electronic integrator and a recorder or some method for determining peak area.
(f) Vials (2 ml) that can be sealed with caps containing Teflon-lined silicone rubber septa.
(g) Microliter syringes (10 fil and other convenient sizes for making standards).
(h) Gastight syringe (1 ml, with a gastight valve).
(1) Pipets (0.5-ml delivery pipets or 1.0-ml pipets graduated in 0.1-ml increments). (8) Cap the sorbent tubes with the supplied plastic caps immediately after sampling. Under no circumstances should rubber caps be used.
(9) Treat one tube in the same manner as a sample tube (break, seal, and transport), but do not sample any air through the tube. This tube is labeled as a blank.
(10) Pack capped tubes tightly to minimize tube breakage during transport to the laboratory. The use of two tubes in series during sampling eliminates the need for cooling during shipping. However, if only one tuba is used, and if the samples will spend a day or more in transit, then cool the tubes, eg, with dry ice, to minimize migration of the vinyl chloride to the backup section.
(11) Samples received at the laboratory are logged in and immediately storad in a freezer (around -20 C) until time for analysis. Samples may be stored in this manner for long periods of time witn no appreciable loss of vinyl chloride (2 months). Even.around -20 C, vinyl chloride will equilibrate between the two sections of activated carbon in one tube, ie, it will migrate to the backup section. This phenomenon is observable after 2 weeks and may be confused with sample loss after 1-2 months.
(b) Analysis of Samples (1) Cleaning of Equipment. All glassware used for the laboratory analysis should be washed with detergent and thoroughly rinsed with tapwater and distilled water.
(2) Preparation and Desorption of Samples. The two tubes used in the collection of a single sample are analyzed separately. If only one tube is used for sampling, then each section of activated carbon should be analyzed separately. Discard the glass wool from each tube. Transfer both sections of each tube to a small vial containing 1 ml of the precooled carbon disulfide. It is important to add the sorbent to carbon disulfide and not the carbon disulfide to the sorbent. Top vial with a septum cap. Discard the separating section in each tube. Tests indicate that desorption is complete in 30 minutes if the sample is agitated occasionally during this period. The samples should be analyzed within 60 minutes after addition to carbon disulfide.
(3) Gas-Chromatographic Conditions. The typical operating conditions for the gas chromatograph are: (4) Injection: The first step in the analysis is the injection of the sample into the gas chromatograph. To eliminate difficulties arising from blowback or d istillation within the syringe needle, use the solvent flush injection technqiue. Flush a 10-jil syringe with solvent several times to wet the barrel and plunger. Draw 2 jil of solvent into the syringe to increase the accuracy and reproducibility of the injected sample volume. Remove the needle from the solvent and pull the plunger back about 0.4 yl to separate the solvent flush from the sample with a pocket of air to be used as a marker. Then immerse the needle in the sample and withdraw a 5-jul aliquot to the 7.4-^1 mark (2 >1 of solvent + 0.4 1 of air + 5 jul of sample 7.4 jil). After the needle is removed from the sample and prior to injection, the plunger is pulled back a short distance to minimize evaporation of the sample from the tip of the needle.
Make duplicate injections of each sample and standard. No more than a 3Z difference in area from repeated injections is to be expected. Automatic sampling devices may also be used. A syringe equipped with a Chaney adapter may also be used in lieu of the solvent flush technique.
(5) Measurement of Area: Measure the area under the sample peak using an electronic integrator or some other suitable form of area measurement. Area measurements are compared with a standard curve prepared as discussed in Preparation of Standards. Preliminary results are read from a standard curve prepared as discussed below.
(c) Determination of Desorption Efficiency (1) Importance of Determination. The efficiency of desorption of a particular compound can vary from one laboratory to another and also from one batch of sorbenc to another. Thus, it is necessary to determine at least once the percentage of vinyl chloride that Is removed in the desorption process. Desorption efficiency should be determined on the same batch of sorbent tubes used in sampling. Results indicate that desorption efficiency varies with loading (total vinyl chloride on the tube), particularly at lower values, eg, 2.5 Mg.
(2) Procedure for Determining Desorption Efficiency. Sorbent tubes from the same batch as that used in obtaining samples are used in this determination. Inject a measured volume of vinyl chloride gas into a bag containing a measured volume of air. The concentration in the bag may be calculated if room temperature and pressure are known. The bag is made of Tediar (or other material that will retain the vinyl chloride and not absorb it) and should have a gas sampling valve and a septum injection port. Sample a measured volume from the bag through a sorbent tube using a calibrated sampling pump. Prepare at least five tubes in this manner. These tubes are desorbed and analyzed in the same nanner as the samples. Samples taken with a gastight syringe from the bag are also injected into the gas chromatograph. The concentration in the bag (standard) is compared with the concentration obtained from Che tube (sample).
The desorption efficiency equals the amount of vinyl chloride desorbed from the.charcoal divided by the product of the vinyl chloride concentration in the bag times the volume of synthetic atmosphere sampled, or; ___________ (amount of vinyl chloride desorbed from sorbent)___________ (vinyl chloride concentration in bag) x (volume of atmosphere sampled)

# Preparations of Standards
Caution: These laboratory operations involve carcinogens. Vinyl chloride has been identified as a human carcinogen and appropriate precautions must be taken in handling this compound.
A series of standards, varying in concentration over the range of interest, is prepared and analyzed under the same gas-chromatographic conditions and during the same time period as the unknown samples. Curves are established by plotting concentration in jug/al vs peak area or peak height. There are two methods of preparing standards, and they are comparable if highly purified vinyl chloride is used. If no internal standard is used in the method, standard solutions must be analyzed at the same time as the sample. This w ill minimize Che effect of day-to-day variations of the flameionization response.
(a) Gravimetric Method. Slowly bubble vinyl chloride into a weighed 10ml volumetric flask containing approximately 5 ml of toluene. After 3 minutes, weigh the flask again. A weight change of 100-300 mg will usually be observed. Dilute the solution to exactly 10 ml with carbon disulfide and use to prepare other standards by removing aliquots with syringes of various sizes. Subsequent dilution of these aliquots with carbon disulfide results in a series of standards that have linear values from the range of 0.2 ng/lnjection, the minimum detectable amount of vinyl chloride, to 1.5 Mg/injection. Standards are stored in a f:e e:er it -20 C and have been found to be stable at this cempenture for 3 davi. Ti^ht-fit t ing plastic tops on :he volumetric teem to retain the vinyl chloride better than ground-glass s toppers.

# Calculations
(a) The weight, in Mg, corresponding to the area under each peak is read frcm the standara curve for vinyl chloride. Mo liquid volume corrections are needed because S ch the standards and the samples are based on the number of Mg in 1.0 ml c carbon disulfide and the volume injected in both cases is identical.
(b) Corrections '>'- the blank are made for each sample: Mg  Mg(sample) -Mg(bian>0 A similar procedure is followed for the backup sections.
(c) Add ,the amounts present in the front and backup sections of the same sample tube to determine the total amount of vinyl chloride in the sample.
(d) The total amount is corrected for the desorption efficiency at the level of vinyl chloride measured:
Corrected amount (in Mg) - amount (in jig) desorption efficiency (e) The coueentration of vinyl chloride in air may be expressed in mg/cu m: mg/cu a  corrected weight (in Mg)______ volume of air sampled (in liters) (f) The concentration, may also be expressed in terms of ppa by volume:
ppm " ag/cu a x 24.5  November 21, 1977 . This method involves adsorption on charcoal, desorption with carbon disulfide, and gas chromatography. The range for determination of vinylidene chloride using this method is 2-12 mg/cu m (0.5-3.02 ppm) in 7 lite rs of air. The precision (pooled relative standard deviation) i3 approximately 5% for analysis of samples containing 12-85 MS of vinylidene chloride/sample.

# Synopsis
(a) A known volume of air is drawn through a charcoal tube to trap the vinylidene chloride present.
(b) The charcoal in the tube is transferred to a small vial where the vinylidene chloride is desorbed with carbon disulfide.
(c) An aliquot of the desorbed sample is injected into a gas chromatograph.
(d) The area or the height of the resulting peak is determined and compared with either the peak areas or heights obtained from injection of standards.
Working Range. Sensitivity, and Detection Limit (a) The method was tested with sample loading between 12 and 85 Mg of vinylidene chloride/charcoal tube. The samples were collected from atmospheres containing vinylidene chloride in the range of 7.6-10.0 mg/cu m and having a relative humidity of greater than 802.
(b) The slope of the calibration curve (response vs weight/sample) was 0.0322 area count/Mg when analysis was done by electronic integration. When analysis was done using peak height, the slope of the calibration curve was 4.75 x lO^^ajnpg/jjg.
(c) The lowest quantifiable limit for this method was determined to be 7 Mg of vinylidene chloride/sample. At this level the relative standard deviation of replicate samples was found to be less than 102 and the desorption efficiency was greater than 802. This limit could be lower if the charcoal used is shown to give better desorption characteristics at the lower level.

# Interferences
(a) When two or more substances are known or suspected to be present in the air, this information, including their suspected identities, should be transmitted with the sample, since these compounds may interfere with the analysis for vinylidene chloride.
(b) Any compound that has the same retention time as vinylidene chloride under the operating conditions described in this method is an interference. Therefore, retention time data on single or multiple columns cannot be considered proof of chemical identity.
(c) If the possibility of interference exists, separation conditions, eg, column packing, temperature, carrier flow, and detector, must be changed to circumvent the problem.

# Precision and Accuracy
(a) The pooled relative standard deviation of the analytical method was 4.87. for the analysis of 36 samples jver the range of 12-85 ^g vinylidene chloride/sample.
(b) The concentration of the sampled air was also determined using a gas phase infrared analyzer. The gas-chromatographic determinations averaged 57. lower when compared with the results of the infrared analyzer. No desorption efficiency corrections were used.
(c) The breakthrough volume and, therefore, the capacity ox charcoal for vinylidene chloride decreased with increasing relative humidity. At 872 relative humidity the breakthrough volume was 102 of the breakthrough volume at 102 relative humidity. The breakthrough volume was also found to be a function of concentration of vinylidene chloride. When high relative humidity air containing 144 mg/cu m of vinylidene chloride was sampled at 0.2 liter/minute the breakthrough volume was 3.7 lite rs . At a vinylidene chloride concentration of 10 mg/cu m and high relative humidity the breakthrough volume was 7.3 liters.
(d) Samples of vinylidene chloride on charcoal were found to be stable at 25 C for 7 days and for 21 days if stored at 5 C for the remainder of the period.

# Advantages and Disadvantages of Che Method
(a) The sampling device is small, portable, and involves no liquids. Many of the interferences can be eliminated by altering chromatographic conditions. The tubes are analyzed by means of a quick instrumental method.
(b) One disadvantage of the method is chat the amount of sample that can be taken is limited by the capacity of the charcoal tube. When the sample value obtained for the backup section of the charcoal tube exceeds 202 of that found on Che fronc section, Che possibility of sample loss exists. During sample storage the volatile compounds may migrate throughout the tube until equilibrium is reached (33% of the sample on the backup section). This can be minimized by storing the samples in a refrigerator until the analysis is performed.
(c) The precision of the method is limited by the reproducibility of the pressure drop across the tubes. Variation in pressure drop will affect the flovrate. The reported salnple volume will then be imprecise because the pump is usually calibrated for one tube only.
(d) The recommended gas-chromatographic packing will not separate vinyl chloride and carbon disulfide. Other gas-chromatographic packings that separate vinyl chloride and carbon disulfide do not separate vinylidene chloride and carbon disulfide. If analysis for each of these monomers is to be performed, it is necessary to use different columns to analyze the samples.

# Apparatus
(a) Personal sampling pump capable of accurate performance at 0.2 liter/minute and calibrated with a representative charcoal tube in the line.
(b) Charcoal tubes: Glass tubes with both ends flame-sealed, 7 cm long with a 6-mm outer diameter, and a -mm inner diameter, containing two sections of 20/40-mesh activated carbon separated by a 2-mm portion of urethane foam. The activated charcoal is prepared from coconut shells and is fired at 600 C prior to packing. The adsorbing section contains 100 mg of charcoal, the backup section 50 mg. A plug of silylated glass wool is placed in front of the adsorbing section. The pressure drop across the tube must be less than 1 inch of mercury at a flowrate of 0.2 liter/minute.
(c) Gas chromatograph equipped with a flame-ionization detector. Optional: electronic integrator.
(d) Silanized glass gas-chromatographic column (10 feet x 1/4-inch outer diameter) packed with Durapak OPN 100/120 mash. Any gas-chromatographic column capable of separating carbon disulfide and vinylidene chloride may be used.
(5) Measure and report the flovrate and time, or the sampling volume, as accurately as possible. The sample is taken at 0.2 liter/minute or less. The maximum volume sampled should not exceed 7.0 lite rs.
(6) Measure and record the temperature and pressure of the atmosphere being sampled. (7) Cap the charcoal tubes with the plastic cap3 supplied immediately after sampling. Under no circumstances should rubber caps be used.
For every 10 sa*3Dles taken, one charcoal tube shculd be handled in the same manner as the samples (break, seal, and transport), except that no air is sampled through this tube. This should be labeled as a blank.
(9) If samples are shipped to a laboratory, they should be packed tightly to minimize tube breakage during shipping.
(10) Six to twelve unopened charcoal tubes should also be shipped so desorption efficiency studies can be performed on the same type and lot of charcoal used for sampling.
(11) Samples received at the laboratory are logged in and immediately stored in a refrigerator.
(c) Analysis of Samples (1) Preparation of Samples. The charcoal tubes are removed from the refrigerator and permitted to equilibrate to room temperature to prevent water condensation on the cold charcoal. Each charcoal tube is scored with a file in front of the firs t section of charcoal and broken open. The glats wool is removed and discarded. The front section (larger) is transferred to a sm?l.". vial. The separating foam is removed from the tube and discarded. The backup section is also transferred to a small vial. The contents of each individual tube are desorbed before the next sample tube is opened.
(2) Desorption of Samples. After the two sections of a charcoal tube are transferred to small vials, 1.00 ml of carbon disulfide is pipetted into each of the two vials. A serum cap is then crimped into place immediately after the carbon disulfide has been added. (All work with carbon disulfide should be performed in a hood because of. the high toxicity of carbon disulfide). The capped samples are kept at room temperature with occasional agitation. Desorption is complete In 30 minutes. The samples should be analyzed the same day they are desorbed.
(3) Gas-Chromatographic Conditions: (A) 70 ml/minute helium carrier flow.
prepared by injecting an identical amount of cyclohexane stock solution into 1.0 ml of carbon disulfide. The samples and standards are analyzed as described in Analysis of Samples.
The desorption efficiency at each level is the ratio of the average amount found to the amount taken. A blank correction is not expected to be necessary. The desorption efficiency curve is constructed by plotting the amount of vinylidene chloride found in a sample vs the desorption efficiency.
Calibration and Standardization CAUTION: Vinylidene chloride has been tentatively identified as a carcinogen.
Precautions must be taken while handling this compound - to prevent contamination of personnel and the working area. It is convenient to express the concentration of standards in terms of M g / 1.0 ml of carbon disulfide or Mg/sample. The density of vinylidene chloride is used to convert the volume taken to the mass taken (1.218 mg/jil). A series of standards varying in concentration over the range of interest is prepared end analyzed under the same gas-chromatographic conditions and during the same t;ime period as the samples. It is best to alternate standard then sample, during the analysis. Curves are established by plotting the concentra:ion of the standards in Mg/1*0 ml of carbon disulfide vs peak area or p'eak hiight.

# Calculations
(a) The sample weight in Mg i3 read from the standard curve. (b) Blank corrections are not expected but, if the analysis shows a blank correction is needed, the correction is: WF -Ws -Wb where: WF - corrected amount (Mg) on the front section of the charcoal tube Ws - amount found on the 'front section of the charcoal tube Wb  amount (Mg) found on the front section of the blank charcoal tube A similar procedure is followed for the backup sections. The data presented in this proposed sampling and analytical method for vinyl bromide were adapted from NIOSH method No. P&CAM 127 for Organic Solvents in Air  and from information provided by Bales  and DW Yeager (written communication, February 1978). This proposed method, as outlined below, has not been tested by NIOSH but should allow routine analyses in the 1-ppm range.
Principle of the Method (a) A known volume .of air is drawn through a charcoal tube to trap the vinyl bromide present.
(b) The charcoal in the tube is transferred to a small, graduated test tube and desorbed with carbon disulfide.
(c) An aliquot of the desorbec sample is injected into a gas chromatograph.
(d) The area of the resulting peak is determined and compared with areas obtained from the injection of standards.

# Range and Sensitivity
No data are currently available. However, Bales  reported measurement of vinyl bromide concentrations down to 0.01 ppm using this general method.

# Interferences
(a) When the amount of water in the air is so great that condensation actually occurs in the tube, vinyl bromide w ill not be trapped. Preliminary experiments indicate that high humidity severely decreases the breakthrough volume.
(b) It must be emphasized that any compound which has the same retention time as vinyl bromide at the operating conditions described in this method is an interference. Hence, retention time data on a single column, or even on a number of columns, cannot be considered as proof of chemical identity. For this reason it is important that a sample of the solvent(s) be submitted at the same time so that identity(ies) can be established by other means.

# (c)
If the possibility of interference exists, separation conditions (column packing, temperatures, etc) must be changed to circumvent the problem.

# Precision and Accuracy
No data are currently available.
Advantages and Disadvantages of the Method (a) The sampling device is small, portable, and involves no liquids. Interferences are minimal, and most of those which do occur can be eliminated by altering chromatographic conditions. The charcoal tubes are analyzed by means of a quick, instrumental method.
(b) One disadvantage of the method is that the amount of sample which can be taken is limited by the number of mg that the tube will hold before overloading. When the sample value obtained for the backup section of the charcoal trap exceeds approximately 20% of that found on the front section, the possibility of sample loss exists.
During sample storage the more volatile compounds will migrate throughout the tube until equilibrium is reached.
(c) Furthermore, the precision of the method is limited by the reproducibility of the pressure drop across the two sections of the sampling tube. This drop w ill affect the flowrate and cause the volume to be imprecise, because the pump is usually calibrated for one tube only. This disadvantage could be eliminated by calibrating the pump with a representative charcoal tube.

# Apparatus
(a) An approved and calibrated personal sampling pump for personal samples. For an area sample any vacuum pump whose flow can be determined accurately at 1 liter/minute or less.
(b) Charcoal tubes: glass tube with both ends flame-sealed, 7 cm long with a 6-tnm outer diameter and a 4-mm inner diameter, containing two sections of 20/40-mesh activated charcoal separated by a 2-mm portion of urethane foam. The activated charcoal is prepared from coconut shells and is fired at 600 C prior to packing. The absorbing section contains 100 mg of charcoal, the backup section 50 mg. A 3-mm portion of urethane foam is placed between the outlet end of the tube and the backup section. A plug of silylated glass wool is placed in front of the absorbing section. The pressure drop across the tube must be less than 1 inch of mercury at a flowrate of 1 liter/minute. The data presented in this proposed sampling and analytical method for vinyl fluoride were adapted from NIOSH method No. P&CAM 127 for Organic Solvents in Air  and information provided by Bales  and DW Yeager (written communications, August 1977 and February 1978). The proposed method, as outlined below, has not been tested by NIOSH, but should allow routine analyses in the 1-ppm range.
Principle of the Method (a) A known volume of air is pumped into a Teflon bag. (b) An aliquot of the air sample in the bag is injected into a gas chromatograph.
(c) The area of the resulting peak is determined and compared with areas obtained from the injection of standards.

# Range and Sensitivity
The limit of detection has been reported as 1 ppm (1.88 mg/cu n) (DW Yeager, written communication, February 1978).

# Interferences
(a) It must be emphasized chat any compound which has the same retention time as vinyl fluoride at the operating conditions described in this method is an Interference. Hence, retention time data on a single column, or even on a number of columns, cannot be considered as proof of chemical identity. For this reason it is important that a sample of the bulk solvent(s' be submitted at the same time so that identity(ies) can be established by other means.
(b) If the possibility of interference exists, separation conditions (column packing, temperatures, etc) must be changed to circumvent the problem.  Calibration curves are prepared by plotting '  he concentration (mg of vinyl fluoride/2 ml) vs peak area.

# Calculations
(a) The weight, in mg, corresponding to each peak area is read from the standard curve for the particular compound. No volume corrections are needed, because the standard curve is based on mg/2 ml and the volume of sample injected is identical to the volume of the standards injected.
(b) The volume of air sampled (collected i.i bag) is converted to standard conditions of 25 C and 760 mmHg:
Vs " v x _L_ x 298 760 T+273
where: Vs -volume of air in lite rs at 25 C and 760 mmHg V  volume of air in liters as measured P  barometric pressure in'mmHg T - temperature of air in degress centigrade (c) The concentration of vinyl fluoride in the air sampled can be expressed in mg/cu m, which is numerically equal to yg/liter of air: mg/cu m - ftg /liter - total mg x 1,000 (qg/mg) Vs

# XV. APPENDIX VI

# SAMPLING AND ANALYTICAL METHOD FOR VINYLIDENE FLUORIDE IN AIR
The data presented in this proposed sampling and analytical method for vinylldene fluoride were adapted from NIOSH method No. P&CAM 127 for Organic Solvents in Air  and from information provided by the Pennwalt Corporation  and JL Sadenwasser (written communication, March 1978). This proposed method, as outlined below, has not been tested by NIOSH, but it should allow routine analyses in the 1-ppm range.
Principle of the Method (a) A known volume of air is drawn through two charcoal tubes in series to trap the vinylidene fluoride present.
(b) The charcoal in the tubes is transferred to a small, graduated test tube and desorbed with carbon disulfide.
(c) An aliquot of the desorbed sample is injected into a gas chromatograph.
(d) The area of the resulting peak is determined and compared with areas obtained from the injection of standard?

# Range and Sensitivity
No data are currently available. However, Sadenwasser (written communication, March 1978) reported measuring vinylidene fluoride concentrations down to about 2 ppm using this general method.

# Interferences
(a) When the amount of water in the air is so great that condensation actually occurs in the tube, vinylidene fluoride w ill not be trapped. Preliminary experiments indicate that high humidity severely decreases the breakthrough volume.
(b) It must be emphasized that any compound which has the same retention time as vinylidene fluoride at the operating conditions described in this method is an interference. Hence, retention time data on a single column, or even on a number of columns, cannot be considered as proof of chemical must be calibrated with representative charcoal tubes in the line. This will minimize errors associated with uncertainties in tha sample volume collected.
(b) Collection and Shipping of Samples (1) Immediately before sampling, the ends of the tube should be broken to provide an opening at least one-half the internal diameter of the tube (2 mm).
(2) Position the second charcoal tube next to the sampling pump in tandem with the firs t tube, to serve as a bickup. If one tube is used the smaller section of charcoal is used s a backup and should be positioned nearest the sampling pump.
(3) The charcoal tube should be vertical during sampling.
(4) Air being sampled should not be passed through any hose or tubing before entering the charcoal tube.
(5) The flowrate, time, and/or volume must be measured as accurately as possible. The sample should be taken at a flowrate of 0.5 liter/minute or less to attain Che total sample volume required. The sensitivity of the method is increased by using lover flowrates to increase the amount of sample collected (JL Sadenwasser, written communication, March 1978). (6) The temperature and pressure of the atmosphere being sampled should be measured and recorded. (7) The charcoal tubes should be carped with Che supplied plastic caps immediately after sampling. Under no circumstances should rubber caps be used.
(8) One tube should be handled in the same manner as a sample tube (break, seal, and transport), except that no air is sampled through this tube. This tube should be labeled as a blank.
(9) Capped tubes should be packed tightly before they are shipped to minimize tube breakage during shipping.
(10) Samples received at the laboratory are logged in and immediately stored in a refrigerator.
(c) Cleaning of Equipment. All glassware used for the laboratory analysis should be detergent washed and thoroughly rinsed with tap water and distilled water.
(d) Analysis of Samples (1) Preparation of Samples. The two tubes used in the collection of injection, the plunger is pulled back a short distance to minimize evaporation of the sample from the tip of the needle. Duplicate injections of each sample and standard should be made. No more than a 3% difference in area is to be expected. A larger 3ample injection may be used to increase the sensitivity of the uethpd (JL Sadenwasser, written communication, March 1978).
(5) Measurement of Area. The area of the sample peak is measured by an electronic integrator or some other suitable form of area measurement, and preliminary results are read from a standard curve prepared as discussed below.
(e) Determination of Desorption Efficiency (1) Importance of Determination. The desorption efficiency cf a particular compound can vary from one laboratory to another and also from one batch of charcoal to another. Thus, it is necessary to determine at least once the percentage of the specific compound that is removed in the desorption process for a given compound, provided the same batch of charcoal is used.
(2) Procedure for Determining Desorption Efficiency. Activated charcoal equivalent to the amount in the first section of the sampling tube (100 mg) is measured into a 5-cm, 4-mm inner diameter glass tube, flame-sealed at one end (similar to commercially available culture tubes). This charcoal nuic be from the same batch as that used in .obtaining the samples and can be obtained from unused charcoal tubes. The open end is capped with Parafiim. A known amount of the vinylidene fluoride is injected directly into the activated charcoal with a m icroliter syringe, and the tube is capped with more Parafiim.
At least five tubes are prepared in this manner and allowed to stand for at least overnight to assure complete absorption of the vinylidene fluoride onto the charcoal. These five tubes are referred to as the samples. A parallel blank tube should be treated in the same manner except that no sample is added to it. The sample and blank tubes are desorbed and analyzed in exactly the same manner as the sampling tube described in Analysis of Samples.
Two or three standards are prepared by injecting the same volume of vinylidene fluoride into 2 ml of carbon disulfide with the same syringe used in the preparation of the sample. These are analyzed with the samples.
The desorption efficiency equals the difference between the average peak area of the samples and the peak area of the blank divided by the average peak area of the standards, or:
Desorption Efficiency - Area sample -Area blank Area standard
It is convenient to express concentration of standards in terms of mg/2 ml of carbon disulfide because samples are desorbed in this amount of carbon disulfide. To minimize error due to the volatility of carbon disulfide, one can inject five times the volume of vinylidene fluoride into 10 ml of carbon disulfide. For example, to prepare 0.3 mg/2 ml of standard, one would inject 1.5 mg into exactly 10 ml of carbon disulfide in a glass-stoppered flask. The density of the specific compound is used to convert 1.5 mg into ql for easy measurement with a microliter syringe. A series of standards, varying in concentration over the range of interest, is prepared and analysed under the same gas-chromatographic conditions and during the sane time period as the unknown samples. Curves are established by plotting concentration in ng/2 ml vs peak area. NOTE: Since no internal standard is used in the method, standard solutions must be analyzed at the same time that the sample analysis is done. This will minimize the effect of known day-to-day variations and variations during the same day of the flame-ionization detector response.

# Calculations
(a) The weight, in mg, corresponding to each peak area is read from the standard curve. No volume corrections are needed, because the standard curve is based on mg/2 ml of carbon disulfide and the volume of sample injected is identical to the volume of the standards injected.
(b) Corrections for the blank must be made for each sample:
Correct mg = mg(s) -mg(b) where: mg(s) - mg found in front section of sample tube mg(b) - mg found in front section of blank tube A similar procedure is followed for the backup sections.
(c) The corrected amounts present in the front and backup sections of the same sample tube are added to determine the total measured amount in the sample.
(d) This total weight is divided by the determined desorption efficiency to obtain the total mg/sample. The following items of information which are applicable to a specific product or material shall be provided in the appropriate block of the Material Safety Data Sheet (MSDS).
The product designation Is inserted in the block in the upper left corner of r.he first page to facilitate filing and retrieval. Print in upper case letters as large as possible. It should be printed to read upright with the sheet turned sideways. The product designation is that name or code designation which appears on the label, or by which the product is sold or known by employees. The relative numerical hazard ratings and key statements are those determined by the rules in Chapter V, Part B, of the NIOSH publication, An Identification System for Occupationally Hazardous Materials. The company identification may be printed in the upper right corner if desired.
(a) Section I. Product Identification The manufacturer's name, address, and regular and emergency telephone mmbers (including area cods) are inserted in the appropriate blocks of Section I. The company listed should be a source of detailed backup informition on the hazards of the material(s) covered by the MSDS. The listing of suppliers or wholesale distributors is discouraged. The trade name should be the product designation or common name associated with the material. The synonyms are those commonly used for the product, especially formal chemical nomenclature. Every kr.jwn chemical designation or competitor's trade name need not be listed.
(b) Section II. Hazardous Ingredients The "materials" listed in Section II shall be those substances which are part of the hazardous product covered by the MSDS and individually meet any of the criteria defining a hazardous material.
Thus, one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, while a third component could be included both for its toxicity and its reactivity. Note that a MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known.
The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the "hole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets.
Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50skin-rabbit," "75 ppm LC man," or "permissible exposure from 29 CFR 1910.1000," or, if not available, from ocher sources of publications such as Che American Conference of Governmental Industrial Hygienists or the American National Standards Institute Inc. Flashpoint, shcck sensitivity, or similar descriptive data may be used to indicate flanmability, reactivity, or similar hazardous properties of the material.
(c) Section III. Physical Data The data in Section III should be for the total mixture and should include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor pressure, in conventional millimeters of mercury (ramHg); vapor density of gas or vapor (air  1); solubility in water, in parts/hundred parts of water by weight; specific gravity (water = 1); percent volatiles (indicated if by weight or volume) at 70 F (21.1 C); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor. These data are useful for the control of toxic substances. Boiling point, vapor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment. This information is also useful for design and deployment of adequate fire and sp ill containment equipment. The appearance and odor may facilitate identification of substances stored in improperly marked containers, or when spilled.
(d) Section IV. Fire and Explosion Data Section IV should contain complete fire and explosion data for the product, including flashpoint and autoignition temperature in degrees Fahrenheit (Celsius in parentheses); flammable lim its, in percent by volume in air; suitable extinguishing media or materials; special firefighting procedures; and unusual fire and explosion hazard information. If the product presents no fire hazard, insert "NO FIRE HAZARD" on the line labeled "Extinguishing Media."
(e) Section V. Health Hazard Information The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved.
Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be:
Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritatio n . Eye Contact-some pain and mild transient irritatio n ; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid.
Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic'procedures, and medical management of overexposed employees.
(f) Section VI. Reactivity Data The comments in Section VI relate to safe storage and handling of hazardous, unstable substances. It is particularly important to highlight instability or incompatibility to common substances or circumstances, such as water, direct sunlight, steel or copper piping, acids, alkalies, etc. "Hazardous Decomposition Products" shall include those products released under fire conditions. It must also include dangerous products produced by aging, such as peroxides in the case of some ethers. Where applicable, shelf life should also be indicated.
(g) Section VII. Spill or Leak Procedures Detailed procedures for cleanup and disposal should be , listed with emphasis on precautions to be taken to protect employees assigned to cleanup detail. Specific neutralizing chemicals or procedures should be described in detail. Disposal methods should be explicit including proper labeling of containers holding residues and ultimate disposal methods such as "sanitary landfill" or "incineration." Warnings such as "comply with local, state, and Federal antipollution ordinances" are proper but not sufficient. Specific procedures shall be identified.
(h) Section VIII. Special Protection Information Section VIII requires specific information. Statements such as "Yes," "No," or "If necessary" are not informative. Ventilation requirements should be specific as to type and preferred methods. Respirators shall be specified as to type and NIOSH or MSHA approval class, ie, "Supplied air," "Organic vapor canister," etc. Protective equipment must be specified as to type and materials of construction.
(i) Section IX. Special Precautions "Precautionary Statements" shall consist of the label statements selected for use on the container or placard. Additional information on any aspect of safety or health not covered in other sections should be inserted in Section IX. The lower block can contain references to published guides or in-house procedures for handling and storage. Department of Transportation markings and classifications and other freight, handling, or storage requirements and environmental controls can be noted.
(j) Signature a.id Filing Finally, the name and address of the responsible person who completed the MSDS and the date of completion are entered. This will facilitate correction of errors and identify a source of additional information.
The MSDS shall be filed in a location readily accessible to employees exposed to the hazardous substance. . trowa-i..

# XVII. TABLES AND FIGURES
The vinyl chloride concentration was later determined by gas chromatography.
The authors stated that temperature and humidity had no measurable effect on the determination of vinyl chloride. Of the compounds tested (including sulfur dioxide, nitrogen dioxide, and ozone) only ethylene chloride was reported to cause positive interference during analysis.

# Hill et al 1244] evaluated breakthrough volumes for vinyl chloride on 20
sorbents, 6 activated charcoals and 14 gas-chromatographic column packings, each contained in 1.5-cm sections of glass tubing with inner diameters of 4 mm.
Breakthrough volume was defined as the air volume sampled when 5% of the synthetic atmospheric concentration of vinyl chloride was detected in the tube effluent. Vinyl chloride was measured using a portable gas chromatograph with a flame ionization detector.
The results are shown In Table XVTI- High humidity or high concentrations of other organic contaminants could reduce the breakthrough volume, but this was not investigated . The authors suggested that maximum sample volumes of 5 liters at a flowrate of 50 ml/minute would not result in significant breakthrough.
These suggested values have been adopted for the NIOSH-accepted method .

# Cuddeback
-al  tested commercially available charcoal tubes from two manufacturers.
By examining the packings of the front sections of the tubes, they determined that MSA tubes averaged 99.7 mg of charcoal (62) for three samples in 16.5 mm (10.9%) tubes, and SKC tubes averaged 86.2 mg (3.1%) for six samples in 15.9 mm (7.8%) tubes. Breakthrough volumes, defined as those at which the effluent concentration of vinyl chloride was 10% of the inlet concentration, were measured using the front sections of the MSA tubes. As shown in Table XVII-6 , there was no consistent correlation between breakthrough volume and sampling rate.

# Several activated charcoals were evaluated
for vinyl chloride collection and breakthrough by Severs and Skory . They concluded that the Pittsburgh PCB had superior breakthrough characteristics for vinyl chloride sampling.
Breakthrough volumes for commercial tubes with different packings were also compared. Tubes packed with 600 mg of SKC (Lot 105) charcoal or 700 mg of Pittsburgh PCB carbon had a breakthrough of less than 2% for vinyl chloride at 25 ppm (64 mg/cu m) at a flowrate of 1 liter/minute for 30 minutes.
The same tubes packed with 150 mg of the SKC charcoal had breakthrough of 2% within 2 minutes for vinyl chloride at 1 ppm (2.56 mg/cu m) sampled at 1 liter/minute.
(2) Vinylidene Chloride Severs and Skory  used charcoal tubes for collecting vinylidene chloride in workplace samples.
No data on collection efficiency or storage stability were reported. Tubes packed with 600 mg of SKC charcoal had "good" retention capacity for vinylidene chloride.
At 31 ppm (123 mg/cu m) of vinylidene chloride, samples collected at a flowrate of 1 liter/minute had a breakthrough below 0.08% after 75 minutes.
Russell  reported that the breakthrough volume of vinylidene chloride on Carbosieve B was greater than 10 liters of air. The available methods for determination of'vinyls in the workplace include gas-chromatographic and infrared techniques, among others, but vinyl chloride f ! For solvent dsorption of vinyl chloride and other vinyls, carbon disulfide has generally been used. However, tetrahydrofluran and a brominehexane mixture have also been used.

# Hill et al
 reported using a 2-ml vial containing 0.5 or 1.0 ml of carbon disulfide for desorption of vinyl chloride fvom the front section of a charcoal tube (100 mg of charcoal). The 13-Mg samples were analyzed after desorption periods of 10-30 minutes at ambient temperature. The authors found that desorption efficiencies were generally in the 80-902 range.
Hill et al also determined that the addition of the charcoal to the carbon disulfide enabled more precise analyses at ambient temperatures than If the solvent were added to the ch.ircoal. They concluded that solvent temperature and volume had little effect on precision, although only one set of tests was performed at other than ambient temperature (0 C).
Studies of the stability of vinyl chloride samples by the same authors  demonstrated that vinyl chloride w as stable on charcoal for periods of over 2 weeks, but that migration from the front to the back section occurred when the tubes were stored at ambient temperatures.
Cooling to ^20 C retarded this effect. The authors suggested using two tubes in series as the front and backup sections to obviate the need for storage at low temperatures.  studied a desorption technique by which 1 g of PCB 12/30 charcoal was added slowly to 10 ml of carbon disulfide, the mixture was cooled in a dry ice/acetone slurry and agitated for 30 minutes.

# Severs and Skory
Samples were stored under refrigeration and held In a wet ice bath while they were analyzed.
An average recovery of 982 (93-1012) was reported. When the same procedure was applied to the desorption of vinylidene chloride, recovery ranged from 95 to 1002.
In neither case was sample loading specified.   indicated that guinea pigs exposed to vinyl chloride at 5,000 or 10,000 ppm (12,800 or 25,600 mg/cu m) for as long as 500 minutes "showed no symptoms." Cook  recommended an MAC of 1,000 ppm for prolonged exposure. Citing the lack of long-term animal experimentation data and of data on industrial exposure at known concentrations, Cook recommended medical observation of workers exposed to vinyl chloride at concentrations near the suggested limit.
In 1946, the American Conference of Governmental Industrial Hygienists (ACGIH)  recommended an MAC of 500 ppm (1,280 mg/cu m) for vinyl chloride. When the ACGIH changed its terminology in 1949 , this limit became the Threshold Limit .Value (TLV) for vinyl chloride. According to the 1962 Documentation of Threshold Limit Values , the ACGIH TLV was also based on the study by Patty et al . The 1962 documentation  noted that narcosis was the most important effect of exposure to vinyl chloride, and that the TLV of 500 ppm (approximately 1,300 mg/cu m) "appears to be sufficiently low to prevent significant narcosis."
In the Threshold Limit Values for 1963 , it was noted that a TLV in the form of a time-weighted average (TWA) concentration limit might not provide a sufficient safety factor for acutely acting substances. Consequently, a "C" or "ceiling" designation was appended to the value for vinyl chloride, indicating that the TLV, which remained at 500 ppm, was a limit that should not be exceeded.
Although the TLV had not changed, the 1966 Documentation of Threshold - Limit Values  cited several studies that presented conflicting data. Torkelson et al  found liver damage in rabbits exposed repeatedly for 7 hours to vinyl chloride at 200 ppm (512 mg/cu m) and slight increases in liver weights of rats exposed at 100 ppm. Other animals were unaffected at 100 ppm. The authors suggested that worker exposure be controlled so that results for practically all analytical measurements were less than 100 ppm (256 mg/cu m) and that the TWA concentration for all exposures be limited to 50 ppm (128 mg/cu m). Lester et al  found some increase in the relative weights of the liver apd spleen in rats exposed repeatedly to vinyl chloride at concentrations of 20,000 ppm (51,200 mg/cu m) for 92 days and 50,000 ppm (128,000-mg/cu m) for 19 days. They did not consider these changes (2) This section applies to the manu facture, reaction, packaging. repaci:aslng, storage, handling or use of vinyl chloride or polyvinyl chloride, but does not apply to the handling or use of fabri cated products made of polyvinyl chlo ride.
(3) This section applies to the trans portation of vinyl chloride or polyvinyl chloride except to the extent that the Department of Transportation maregulate the hazards covered by this sec tion.
(b) D e/in itio r.s. (1) "Action level" means a co.icentration of 'inyl chloride of 0.5 ppm averaged over an 8-hour work day.
(2) "Assistant Secretary" means the Assistant Secretary of Labor for Occupa tional Safety and Health, U.S. Depart ment of Labor, or his designee.
(3) "Authorized person" means any person specifically authorized by the em ployer whose duties requlr him to enter a regulated area or any person entering such an area as a designated representa tive of employees for the purpose oi ex ercising an opportunity to observe moni toring ar.d measuring procedures.
(4) "Director" means the Director. National Institute tor Occupational Safety and Health. U.S. Department oi Health. Education, and Welfare, or his designee.
(5) "Emergency" means any occur rence such as, but not limited to. equip ment failure, or operation of a relief de vice which is likely to. or does, result In massive release of vinyl chloride.
(6) "Fabricated product" means a product made wholly or partly from polyvinyl chloride, and which does not require further processing at tempera tures, and for times, sufficient to cause mass meltins of the polyvinyl chloride resulting in the release of vinyl chloride. 7) "H.-' .. ardous narration" mean-, any operation. pr'ii.ediire. or activity where a release of cither vinyl chloride liquid or cas mijht be expected as a consequence of the operation or because of an acci dent In the o^^r.Ttion, v/hich wculd result In an employee exposure in excess of the permissible exposure limit. Advantages and Disadvantages of the Method (a) The sampling device is small, portable, and involves no liquids. Interferences are minimal, and most of those that do occur can be eliminated by altering chromatographic conditions. The tubes are analyzed by a rapid instrumental method. The method can also be used for the simultaneous determination of two or more components suspected to be present in the same sample by changing gas-chromatographic conditions rrom isothermal to a temperature-programmed mode of operation.
(b) One disadvantage of the method is that the amount of sample that can be taken is limited by the amount of vinyl chloride that the cube w ill hold before i t becomes overloaded. When the value obtained for the backup section of the sorbent tube exceeds 20% of that found on the front section, there is a possibility of sample loss. During storage, volatile compounds such as vinyl chloride will migrate throughout the tube until equilibrium is reached. At this time, 332 of these compounds will be found in the backup section. This (j) Volumetric flasks (10 ml or convenient sizes for making solutions), preferably vich plastic stoppers.
(k) Gas bags, Tedlar or equivalent.

# Reagents

# Procedure (a) Collection and Shipping of Samples
(1) Immediately before sampling, break the ends of the two tubes to provide an opening of at least 2 mm, one-half the internal diameter of the tube.
(2) Position the second sorbent tube next tc the sampling pump in tandem with the first tube, to serve as a backup. If one tube is used, position the smaller section of tube nearest the sampling pump.
(3) Place the sorbent tubes in a vertical position with the larger section of sorbent pointing up during sampling to minimize channeling of the vinyl chloride through the sorbent.
(4) Do not allow air being sampled to pass through any hose or tubing before entering the sorbent tubes.
(5) Measure the flowrate and time, or the sampling volume, as accurately as possible. Take the sample at a flowrate of 50 ml/minute. The maximum volume to be sampled should not exceed 5 lite rs.
(6) Sample relatively large volumes (10-20 liters) of air through other sorbent tubes at the same time personal samples are taken. These bulk air samples w ill be used by the analyst to identify possible interferences before the personal samples are analyzed.

# K
(e) Vials (2 ml) that can be sealed with caps containing Teflon-lined silicone rubber septa.
(f) Microliter syringes, 10 m1 . and convenient sizes for making s tandards.
(g) Pipet, 1.0 ml.

# Reagents
All reagents used should be ACS Reagent Grade or better. (b) Collection and Shipping of Samples (1) Immediately before sampling, the ends of the tube are broken to provide an opening (2 mm) at least one-half the internal diameter of the tube.
(2) The tube is connected to the sampling pump via rubber tubing. The smaller section of charcoal is the backup and is positioned nearest the. sampling pump.
(3) .The charcoal tube should be vertical during sampling to prevent channeling through the tube.
(4) Air being sampled should not be passed through any hose or tubing before entering the charcoal tubes. (4) Injection. Inject a 5-jil aliquot into the i;as chromatograph. A syringe equipped with a Chaney adapter may be used in lieu of the solvent flush technique.
(5) Measurement of Area: Measure the area under the sample peak using an electronic integrator or another suitable form of area measurement. Area measurements are compared with a standard curve prepared as discussed in Preparation of Standards.
(6) Measurement of Peak Height. The product of peak height and attenuator setting is linear over the analytical range. The peak height is multiplied by the attenuator setting necessary to keep the peak on scale. Preliminary results are read from a standard curve prepared as discussed below.
(d) Determination of Desorption Efficiency (1) Importance of Determination. The desorpuion efficiency of a particular compound can vary between laboratories and batches of charcoal. Also, for a given batch of charcoal the desorption efficiency can vary with the weight of contaminant adsorbed. The charcoal used for the study of this method gave a desorption efficiency of 802 for a loading of 7 ^g of vinylidene chloride/LQ0 m3 bed of charcoal.
(2) Procedure for Determining Desorption Efficiency. The desorption efficiency should be determined at three levels with a minimum of three samples at each level. Vinylidene chloride can be dissolved in cyclohexane to giva stc~k solutions. The concentrations should be such that no more than 8 Ml of a stock solution will be injected onto the charcoal. Activated charcoal in an amount equivalent to that found in the larger section of the charcoal tube (100 mg) is placed in a small vial and capped. An aliquot of the stock solution is injected into the charcoal tube. Two of the levels should reflect the extremes of the analytical range while the third level is inbetween the high and low levels. Each vial is allowed to stand overnight to assure complete adsorption of vinylidene chloride onto the charcoal. Standards are (e) A mechanical or electronic integrator or a recorder and some method for determining peak area.
(f) Glass stoppered micro tubes. The 2.5-ml graduated microcentrifuge tubes are recommended.
(g) Hamilton syringes: 10 m1, and convenient sizes for making standards. (h-) Pipets: 0.5-ml delivery pipets or 1.0-ml type graduated in 0.1-ml increments.
(i) Volumetric flasks: 10 ml, or convenient sizes for making standard solutions. (1) Immediately before sampling, the ends of the charcoal tube should be broken to provide an opening at least one-half the internal diameter of the tube (2 mm).

# Reagents
(2) The smaller section of charcoal is used as a backup and should be positioned nearest the sampling pump. f (3) The charcoal cube should be vercical during sampling. (4) Air being sampled should noc be passed chrough any hose cr Cubing before eacering Che charcoal Cube.
(5) The flowrace, Cime, and/or volume musC be measured as accuracely as possible. The sample should be caken at a flowrace of 1 liter/minute or less Co aCCain Che Cotal sample volume required.
(6) The cemperacure and pressure of the atmosphere being sampled should be measured and recorded. (7) The charcoal tubes should be capped with the supplied plastic caps immediately after sampling. Under no circumstances should' rubber caps be used.
(8) One Cube should be handled in Che same manner as Che sample cube (break, seal, and Cransport), cxcept chat no air is sampled through this tube. This Cube should be labeled as a blank.
(9) Capped Cubes should be packed cighcly before they are shipped to minimize cube breakage during shipping.
(10) Samples received at the laboratory are logged in and immediacely scored in a refrigeracor.
(c) Cleaning of EquipmenC. All glassware used for Che laboratory analysis should be decergenc washed and choroughly rinsed wlch Cap wacer and discllled water.
(d) Analysis of Samples (1) Preparation of Samples. In preparation for analysis, each charcoal Cube is scored with a file in fronc of Che firsc secCion of charcoal and broken open. The glass wool is removed and discarded. The charcoal in Che firsC (larger) seccion is cransferred Co a small scoppered cesc Cube. The separaCing seccion of foam is removed and discarded; Che second seccion is Cransferred Co another CesC Cube. These cwo sections are analyzed separately.
(2) Desorpcion of Samples. Prior Co analysis, 0.5 ml of carbon disulfide is plpecced inco each cesc cube and Che glass sCopper is inserCed. (All work wich carbon disulfide should be performed in a hood because of ics high coxicicy.) Tescs indicace chat desorpcion is complece in 30 minuces if Che sample is agicaced occasionally during chis period. The use of graduated glass-scoppered, microcenCrifuge cubes is recommended so chac one can observe any change in volume during Che desorpcion process. Carbon disulfide is a very volacile solvenc, so volume changes can occur during che desorpcion process depending on Che surrounding cemperacure. The inicial volume occupied - I | J by the charcoal plus the 0.5 ml of carbon disulfide should be noted and corresponding voluat adjustments should be made whenever necessary just before gas chromatographic analysis.
(3) Gas-Chromatographic Conditions.
The typical operating 'conditions for the gas chromatograph are:
( Three microliters of solvent are drawn into the syringe to increase the acouracy and reproducibility of the injected sample volume. The needle is removed from *he solvent, and the plunger is pulled back about 0.2 to separate the solvent flush from the sample with a pocket of air to be used as a marker. The needle is then immersed in the sample, and a 5-;il aliquot is withdrawn, taking into consideration the volume of rhe needle, since the sample in the needle will be completely injected. After the needle is removed from the sample arid prior to injection, the plunger is pulled back a short distance to minimize evaporation of the sample from the tip of the needle. Duplicate Injections of each sample and standard should be made. No more than a 31 difference in area is to he expected.
(5) Measurement of Area. The area of the sample peak is measured by an electronic Integrator or some other suitable form of area measurement, and preliminary results are read from a standard curve prepared as discussed below.
(a) Determination of Desorption Efficiency (1) Importance of Dtermlnatlon. The desorption efficiency of a particular compound can vary from one laboratory to another and also from one batch of charcoal to another. Thus, it is necessary to determine at least once the percentage of t:he specific compound that is removed in the desorption process for a given compound, provided the same batch of charcoal is used.
(2) Procedure for Determining Desorption Efficiency. Activat charcoal equivalent to the amount In the first section of the sampling tube (100 ng) is measured lato a 5-cm, 4-mm inner diameter glass tube, flame-sealed at one end (similar to commercially available culcure tubes). This charcoal must be from the same batch as that used in obtaining the samples and can be obtained from unused charcoal cubes. The open end is capped with Parafilm. A known amount of the vinyl bromide is injected directly into che activated charcoal with a microliter syringe, and the tube is capped with more Parafilm.
At least five tubes are prepared in this manner and allowed to stand for at least overnight to assure complete absorption of the vinyl bromide onto the charcoal. These five tubes are referred to as the samples. A parallel blank tube should be treated in the same manner except that no sample is added to it. The sample and blank tubes are aesorbed and analyzed in exactly the same manner as the sampling tube described in Analysis of Samples.
Two or three standards are prepared by injecting the same volume of vinyl bromide into 0.5 ml of carbon disulfide with the same syringe used in the preparation of the sample. These are anal Samplingyzed rith the samples.
The desorption efficiency equals the difference between the average peak area of the samples and the peak area of the blank divided by the average peak area of the standards, or:
Desorption Efficiency - Area sample -Area blank Area standard

# Calibration and Standards
It is convenient to express concentration of standards in terms of mg/0.5 ml of carbon disulfide because samples are desorbed in this amount of carbon disulfide. To minimize error due to the volatility of carbon disulfide, one can inject 20 times the volume of vinyl bromide into 10 ml of carbon disulfide. For example, to prepare a 0.3 mg/0.5 ml of standard, one would inject 6.0 mg into exactly 10 ml of carbon disulfide in a glass-stoppered flask. The density of the specific compound is used to convert 6.0 mg into yl for easy measurement with a microliter syringe. A series of standards, varying in concentration over the range of interest, is prepared and analyzed under the same gas-chromatographic conditions and during the same time period as the unknown samples. Curves are established by plotting concentration in fg/0.5 ml vs peak area. NOTE: Since no Internal standard is used in the method, standard solutions must be analyzed at the same time that the sample analysis is done. This will minimize the effect of known day-to-day variations and variations during the same day cf the flame-ionization detector response.

# Calculations
(a) The weight, in mg, corresponding to each peak area is read froo the standard curve. No volume corrections are needed, because the standard curve is based on mg/0.5 ml of carbon disulfide and the volume of sample injected is identical to the volume of the standards Injected.
(b) Corrections for the blank must be made for each sample.
Correct mg -mg(s) -mg(b) where: mg(s) -mg found in front section of sample tube mg(b) - mg found in front section of blank tube A similar procedure is followed for the ba<_kup sections.
(c) The corrected amounts present in the front and backup sections of the same sample tube are added to determine the total measured amount in the sample.
(d) This total weight is divided by the determined desorption efficiency to obtain the total mg/sample. Advantages and Disadvantages of the Method (a) The sampling device is portable and Involves no liquids. Interferences are minimal, and most of those which do occur can be eliminated by altering chromatographic conditions. The samples are analyzed by means of a quick, instrumental method. No solvent desorption is necessary.
(b) One disadvantage of the method is that the amount of sample which can be taken is limited by the volume capacity of the bag. Full sample bags may interfere with the free movement of the worker.
(c) Furthermore, the precision of the method .s limited by the reproducibility of th*i sampling rate of the pump.

# Apparatus
(a) An approved and calibrated peristaltic sampling pump, diaphragm-pump, or vacuum pump, with filtered outlet to remove oil, for personal samples. For an area sample any vacuum pump whose flow can be determined accurately at 1 liter/minute or less. (a) Calibration of Personal Sampling Pumps. Each personal smapling pump must be calibrated with a representative bag In the line. This will minimize errors associated with uncertainties in the sample volume collected.
(b) Collection and Shipment of Samples (1) Tue flowrate, tine, and/or volume must be measured as accurately as possible. The sampling bags should be flushed before use. The sample should be taken at a flowrate of 1 liter/minute or less to attain the total sample volume required.
(2) The temperature and pressure of the atmosphere being sampled should be measured and recorded.
(3) Air samples are shipped to the laboratory for analysis in the Teflon bags. Appropriate precautions should be taken to prevent damage of the bags while in transit. (2) Injection Five m illiliters of air from the Teflon bag is withdrawn with a syringe. Two m illiliters are injected directly into the gas chromatograph.
(3) Measurement of Area. The area of the sample peak is measured by an electronic integrator or some other suitable form of area measurement, and preliminary results are read from a standard curve prepared as discussed below.
Procedure identity. For this reason it is important that a sample of the solvent(s) be submitted at the same time so that identity(ies) can be established by ~cher means.
(c) If the possibility of interference exists, separation conditions (column packing, temperatures, etc) must be changed to circuuvent the problem.
(d) If samples are not analyzed within 5 days, significant sample loss may occur. Although no specific data were provided, JL Sadenwasser (written communication, March 1978) stated that vinylidene fluoride was retained by the charcoal for at least 5 days with little loss.

# Precision and Accuracy
No data are currently available.
Advantages and Disadvantages of the. Method (a) The sampling device is small, portable, and involves no liquids. Interferences are minimal, and most of those that do occur can be eliminated by altering chromatographic conditions. The charcoal tubes are analyzed by means of a quick, instrumental method.
(b) One disadvantage of the method is that the amount of sample which can be taken is limited by the number of mg that the tubes w ill hold before overloading. When the sample value obtained for the backup section of the charcoal trap exceeds approximately 20% of that found on the front section, the possibility of sample loss exists. Sampling at 1 liter/minute caused a significant breakthrough after collection of 3 lite rs. Curing sample storage, volatile compounds such as vinylidene fluoride will migrate throughout the tube until equilibrium is reached.
(c) Furthermore, the precision of the method is limited by the reproducibility of the pressure drop across the two sections of the sampling tubes. This drop w ill affect the flowrate and cause the volume to be imprecise, because the pump is usually calibrated for one particular tube only. This disadvantage could be eliminated by calibrating the pump with representative charcoal tubes.

# Apparatus (a)
An approved and calibrated personal-sampling pump for personal samples. For an area sample any vacuum pump whose flow can be determined accurately at 0.5 liter/minute or less.
(b) Charcoal tubes: glass tube with both ends flame-sealed, 7 cm long with a 6-mm outer diameter and a 4-mm inner diameter, containing two sections of 20/40-mesh activated charcoal separated by a 2-mm portion of urethane foam. The activated charcoal is prepared from coconut shells and is fired at 600 C prior to packing. The absorbing section contains 100 mg of charcoal, the backup section 50 mg. A 3-mm portion of urethane foam is placed between the outlet end of the tube and the backup section. A plug of silylated glass wool is placed in front of the absorbing section. The pressure drop across the tube must be less than 1 inch of mercury at a flowrate of 1 liter/minute.
(c) Gas chromatograph equipped with a flame-ionization detPctoi.
(d) Column, stainless steel, 6-feet x 1/8-inch outer diameter, packed with Chromosorb 102, 80/100 mesh. Other columns capable of performing the required separations may be used.
(e) A mechanical or electronic integrator or a recorder and some method for determining pea*. area. - (f) Glass stoppered micro tubes. The 2.5-ml graduated microcentrifuge cubes are recommended.
(g) Hamilton syringes: 10 yl, and convenient sizes for making standards.
(h) Pipets: 0.5-ml delivery pipets or 1.0-ml type graduated in 0.1 j 1 increments.
(i) Volumetric flasks: 10 ml or convenient sizes for making standard solutions.

# Reagents
(a) Carbon disulfide, "spectroquality" or better. (b) Sample of the specific compound under study, preferably "chromatoquality" grade. In preparation for analysis, each charcoal tube is scored with a file in front of the first section of charcoal and broken open. The glass wool is removed and discarded. The charcoal in the first (larger) section is transferred to a small stoppered test tub. The separating section of foam is removed and discarded; the second section is transferred to another test tube. These two sections are analyzed separately.
(2) Desorption of Samples. Prior to analysis, 2 ml of carbon disulfide is pipetted into each test tube and the glass stopper is inserted. (All work with carbon disulfide should be performed in a hood because of its high toxicity.) Tests indicate that desorption is complete in 15 minutes if the sample is agitated occasionally during this period. The use of graduated glass-stoppered, :nicrocentrifuge tubes is recommended so that one ca:i observe any change in volume during the desorption process. Carbon disulfide is a very volatile solvent, so volume changes can occur during the desorption process depending on the surrounding temperature. The in itia l volume occupied by the charcoal plus the 2 ml of carbon disulfide should be noted and corresponding volume adjustments should be made whenever necessary just before gas-chromatographic analysis.
(3) Gas-Chromatographic Conditions. The typical operating conditions for the gas chromatograph are:
( Three microliters of solvent is drawn into the syringe to increase the accuracy and reproducibility of the injected sample volume. The needle is removed from the solvent, and the plunger is pulled back about 0.2 atl to separate the solvent flush from the sample with a pocket of air to be used as a marker. The needle is then immersed In the sample, and a 1-^1 aliquot is withdrawn, taking into consideration the volume of the needle, since the sample in the needle will be completely injected. After the needle is removed from the sample and prior to